CA2088195A1 - Cholecystokinin antagonists, their preparation and therapeutic use - Google Patents

Abstract

Novel cholecystokinin antagonists useful as agents in the treatment of obesity, hypersecretion of gastric acid in the gut, gastrin-dependent tumors, or as antipsychotics are disclosed. Further, the compounds are antianxiety agents and antiulcer agents. They are agents useful for preventing the response to the withdrawal from chronic treatment with use of nicotine, diazepam, alcohol, cocaine, coffee, or opioids. The compounds of the invention are also useful in treating and/or preventing panic. Also disclosed are pharmaceutical compositions and methods of treatment using the antagonists as well as processes for preparing them and novel intermediates useful in their preparation. An additional feature of the invention is the use of the subject compounds in diagnostic compositions.

Description

W092/0404s PCT/I'S91/06180 2~3~.3~

NOVEL C~OLECYSTOKININ ANTAGONISTS, THEIR PREPARATION AND TH~RAP~UTIC USE

CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part c' United States Serial Number 07/576,628, 'iled August 31, 1990.

BACKGROUND OF T~E INVENTION

Agents acting at central cholecystokinin (CCK) receptors may induce satiety (Schick, Yaksh, and Gc, Reaulatorv PePtides 14:277-291, 1986). They are also expected to act as analgesics (Hill, Hughes, and Pittaway, Neuro~harmacoloav 26:289-300, 1987), and as anticonvulsants (MacVicar, Kerrin, and Davison, Brain Research 406:130-135, 1987).
Reduced levels of CCK-peptides have been found in the brains of schizophrenic patients compared with controls (Roberts, Ferrier, Lee, Crow, Johnstone, Owens, Bacarese-Hamilton, McGregor, O'Shaughnessey, Polak, and Bloom, Brain Research 288:199-211, 1983).
It has been proposed that changes in the activity o' CCK neurones projecting to the nucleus accumbens may play a role in schizophrenic processes by influencing dopaminergic function (Totterdell and Smith, Neuroscience 19:181-192, 1986). This is consistent with numerous reports that CCK peptides modulate dopaminergic function in the basal ganglia and particularly the nucleus accumbens (Weiss, Tanzer, and Ettenberg, Pharmacolocv, Biochemistrv and Behaviour 30:309-317, 1988; Schneider, Allpert, and Iversen, Pe~tides 4:749-753, 1983). It may therefore be ezpected that agents modifying CCK recepto_ activity W092/04045 PCT/US91/061&0 - ~Q~9~ -2-may have therapeutic value in conditions associated with disturbed function of central dopaminergic function such as schizophrenia and Parkinson's disease.
CCK and gastrin peptides share a common cz-boxy terminal pentapeptide sequence and CC~ peptides can bind to the gastrin receptor of the stomach mucosa znd elicit acid secretion in many species including humzn (~onturek, Gastrointestinal ~ormones, Ch. 23, p~ 529-_ _ .
564, 1980, ed. G. B. J. Glass, Raven Press, NY).
Antagonists of the CCK-B receptor would also be expected to be antagonists at the stomach gzstrin receptor and this would also be of value for conditions involving excessive acid secretion.
CCK and gastrin peptides have trophic effects on the pancreas and various tissues of the gastro-intestinal tract (Johnson, ibid., pp 507-527), actions which are associated with increased DNA and RNA
synthesis. Moreover, gastrin secreting cells are associated with certain gastrointestinal tumors as in the Zollinger-Ellison syndrome (Stadil, ibid., pp 729-739), and some colorectal tumors may also be gastrin/CCK dependent (Singh, Walker, Townsend, and Thompson, Cancer Research 46:1612, 1986; Smith, J. P., Gastroenterolo~v 95:1541, 1988). Antagonists of CCK/gastrin receptors could therefore be of therapeutic value as antitumor agents.
The CCK peptides are widely distributed in various organs of the body including the gastrointestinal tract, endocrine glands, and the nerves of the peripheral and central nervous systems.
Various biologically active forms have been identified including a 33-amino acid hormone and various carboxyl-termi~us fragme~ts of this peptide (e.g., the W092/04045 PCT/~'S91/06180 _3_ 2 ~ 8 ~1 9 j octape?tide CCK26-33 and the tetrapep~ide CCK30-33) (G. J. Dockray, Br. Med. Bull. 38(3):253-258, 1982).
The various CCX peptides are thoughl to be involved in the control of smooth muscle contractility, exocrine and endocrine gland secretio.., sensory nerve transmission, and numerous brain func'ions. Administration of the native peptides cause gall bladder contraction, amylase secretion, e~.citz=ion of central neurons, inhib .ion o' feedins, anticonvulsive actions and other behavioral effects.
(Cholecvstokinin: Isolation Structure and Functior.s, G. B. ~. Glass, Ed., Raven Press, New York, 1980, P? 169-221; J. E. Morley, Life Sciences 27:355-368, 1980; Cholecvstokinin in the Nervous Svstem, J. de 3elleroche and G. J. Dockray, Ed., Ellis Horwood, Chichester, England, 1984, pp 110-127.) The high concentrations of CCK peptides in many brain areas also indicate major brain functions for these peptides (G. J. Dockray, Br. Med. Bull.
38(3):253-258, 1982). The most abundant form of brain CCX found is CCK26-33, although small quantities of CCK30-33 exist (Rehfeld and Gotterman, J. Neurochem.
32:1339-1341, 1979). The role of central nervous system CCK is not known with certainty, but it has been implicated in the control of feeding (Della-Fera and Baile, Science 206:471-473, 1979).
Currently available appetite suppressant drugs either act peripherally, by increasing energy expenditure (such as thyroxine), or in some other manner (such as the biguanides), or act by exerting a central effect on appetite or satiety.
Centrally acting appetite suppressants either potentiate central catecholamine pathways and tend to be stimulants (for example, amphetamine), or influence 3; sero~onergic pathways (for example, fenfluramine).

W092/04045 PCT/USg1/06180 ~ 4-Other forms of drug therapy :- lude bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety.
CCK is known to be present in some cor~ical interneurones which also contzin gamma-aminobutyric acid (GABA) (H. Demeulemeester et al, J. Neuros-ience - 8:988-1000, 1988). Agents that modify GABA ac~ion may have utility as anxiolytic or hypnotic agents (S. C. Harvey, The Pharmacoloc_cal Basis of Thera~eutics (7th ed.) 1985, ~p 339-371, MacMillan).
Thus, agents which modify CCK action may have parallel anxiolytic or hypnotic activities. The roie of CC~
anxiety is disclosed in TI~S 11:271-273, 1990.

SUM~ARY OF THE INVENTION

The invention relates to novel compounds of the formula ~,--C--(CH2)5 (x)q--(cHR3) --(cHR~5--(y)t--(cR2o~i2)u--(cHRl3)v--Ar I
) n A~r2 and the pharmaceutically acceptable salts thereof wherein Rl, R2, R3, R4, R5, R6, Ri2 Ri3 R20 A X Y
E, Ar~, Ar2, n, m, p, q, r, s, t, u, and v are as defined hereinbelow.
In commonly owned copending applications 07l576,308, 07/576,296, 07/576,315, 07/576,024, and 07/576,297 filed on August 31, 1990, by Horwell, et 2û3~19~

al, the disclosures of which are incorporated herein by reference, CCK antagonists are disclosed.
In the continuation-in-part applications of the above applications also commonly owned and copending and filed on even date herewith by Horwell, et al, the disclosures of which are incorporated herein by reference, CCK antagonists are disclosed.
In like manner, the present invention relates to a pharmaceutical composition containing an effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for appetite suppression.
~5 The compounds are also useful as anxiolytics, antipsychotics, especially for treating schizophrenic behavior, as agents in treating disorders of the extrapyramidal motor system, as agents for blocking the trophic and growth stimulating actions of CCK and gastrin, and as agents for treating gastrointestinal motility.
Compounds of the invention are also useful as analgesics, and they potentiate the effect of morphine. They can be used as an adjunct to morphine and other opioids in the treatment of severe pain such as cancer pain, and reduce the dosage of morphine required in the treatment of pain where morphine is contraindicated.
An additional use for compounds of the invention is that a suitable radiolabeled isotope gives an agent suitable for treatment of gastrin dependent tumors such as those found in colonic cancers. I-125 radiolabeled compounds of the invention can also be used as diagnostic agents by localization of gastrin and CCK-B receptors in both peripheral and central tissue.
The invention further relates to a method o appetite suppression in mammals which comprises administering an amount effective to suppress appeti-e of the composition described above to a mammal in neec of such treatment.
The invention also relates to a pharmaceu-ical composition for reducing gastric acid secretion containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing gastric acid secretion.
The invention also relates to a method for reducing gastric acid secretion in mammals which comprises administering an amount effective for gastric acid secretion reduction of the composition described above to a mammal in need of such treatment.
The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing anxiety.
The invention also relates to a method for reducing anxiety in mammals which comprises administering an amount effective for anxiety reduction of the composition desc-ibed above to a mammal in need of such treatment.
The invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating gast_ointestinal ulcers.
The invention further relates to a method for trezting gastrointestinal ulcers in mammals which W092/04045 PCT/US91/~6180 20~819~

comprises administering an amount effective for gastrointestinal ulcer treatment of the composition as described above to a mammal -r. need of such treatmen..
The invention also relates to a pha-maceutical com?osition containing an effec~ive amount of a compound of formula T in co~b nation with a pharma-ceutically acceptable car-ie_ in unit dosage form effective for treating psychosis, i.e., schizophrenia.
The invention furthe- re;ates to a method fo-treating psychosis in mammals which compr sesadministering an amount effec~ive for tre2tins psychoses of a composition as described above to a mammal in need of such treatment.
The invention also relates to pharmaceutical com?ositions effective for st mulating or blocking CCK
o- gastrin receptors, for alte-ing the activity of brain neurons, for schizophrenia, for treating disorders of the extrapyramidal motor system, for blocking the trophic and grow_h stimulating actions of CCK and gastrin, and for treating gastrointestinal motility.
The invention also relates to a pharmaceutical composition for preventing the withdrawzl response produced by chronic treatment for abuse of drugs or alcohol The invention further reiates to a method for treating the withdrawal respor.se produced by withdrawal from chronic treat~.ent or withdrawal from abuse of drugs or alcohol. Such drugs include benzodiazepines, especially d-azepam, cocaine, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an effec=ive withdrawal treating amount of a compound of the ir.vention.
The invention also relates to a pharmaceutical composition containing an effe~tive amount of a W092/0404~ ~95 PCT/US91/061 compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating and/or preventing panic.
The invention also relates to a method for treating and/o_ preventing panic in mammals which com?rises administering an amount effec_ive fo- p2nic treatment and/or prev~ntion of the composi'ion described above to a mammal in need of such treatmer._.
The invention fu_ther relates to the use o' the compounds of formula I to prepare pha-maceutical and diagnostic compositions for the treatment and diagnosis of the conditions described above.
The invention further provides processes for the preparation of compounds of formula I.
The invention further provides novel intermediates useful in the preparation of compounds of formula I and also provides processes for the preparation of the intermediates.

DETAILED DESCRIPTION

The compounds of the present invention are represented by the formula R--A--~--(CH2),~ C--(CH2)p (X)q--(CHR3)--(CHR4)s--(y)--(cR2sR;2)u--(cHR;3)v_AzlI
( CRsR~ ) n or a pharmaceutically acceptable salt thereof wherein:
Ri is a cyclo or polycycloalkyl hydrocarbon or mono-or polyheterocycle moiety (wherein the hetero atom(s) can be N, O, and/or S o' 'rom 3 to WO92/04045 PCT/US91/0618~

208819~
_g_ 12 carbon atoms with from 0 to 4 substituents each independently selected from a straight or branched alkyl of from 1 to 6 carbon atoms, halogen, CN, OR*, SR*, CO2R*, CF3, NR5R~, or (CX2)roR5 wherein R*, R5, and R6 are each independently hyd-ogen or a straight o- branched alkyl of from 1 to about 6 carbon atoms;
m, n, p, q, r, s, t, u, and v are each independently an intege~ of from 0 to 6 with the proviso tha-q, _, and s are not all 1 when m, p, t, u, anc v are all 0 except when X is not CONR9 or A-E is nct (CH2)rCONX-, -SO2NH-, -S(O)NY.-, -NHCONH, -(CX2)n-OCO-NH-SCONX-, -O(CX2)rCO- or -HC=CHCON:.-wherein n is as above, A is a bond, O, S, NR*, --(CH2) nCO~Z, S2 Z~
--SO--Z, --S--Z, -NHCO-Z, o ll tCH2)n OC Z, --SCO--Z, --O--(CH2)r,CO~Z~
-HC=CHCO-Z, wherein Z is a bond, oxygen, sulphur, or -NR*-wherein R* is as defined above;
E is a bond, an amino acid residue, -~CHR3)r~, -(CHR3) r~ ~CHR4)S-, -CONH-, . 9 3 -NHCO-, --OCO--, --COO--, -CH2N(R3)-, -CH2O-, --CH2 S--, --C=C--, S
-C-NR-, --S 02NR3--, --NR3So2 -, -NHCONH-N-~/
~s~
N-~/
~S~
N-N
~. "
1, N-O
~ ' , N-N

N , wherein r and s are independently as definec above;
R2 and R20 are e~ch independently hydrogen, a straight or branched alkyl of from 1 to 6 carbon atoms, -XC=CH2, -C3CH, -(CH2)~CH=CH2, -(CH2)rC3CH, --(CH2)rAr~ CH2)nAr2, -(C.i2)nOR*, --~CH2)_0Ar, WO 92/04045 PCr/US91/06180 20~819~
-tCH2)nCO2R*, -(CH2)r,NR5R6 wherein n, R*, R5, and R6 are as defined above, and Ar1 and A- are as defined below;
X and Y are each independently:
-CONH-, -CON~9, -NHCO-, --OCO--, --COO--, -CH7N(R3)-, --CH20--~
--CH2 S--, --OCH2--, 1 5 --c=c--, s -C-NR3, S

-NR3-C-r --So2NR3--, --NR3So2--, -NHCONH-, -C:~OR*)CH2-, --COCH2 -, --CH2CO--, --NR3CH2 -, N--~,~
~ ~
Q , N _ Q~

W092/04045 PCT/USg1/06180 ~ ~g~9~ -12-N-N
N
N
N-O
~

N-N
~ N ~ R

wherein Q is 0, S, or NR9;
R3 and R~ are each independently the same as R' o--(CH2)r,-B-D wherein n' is an integer of from O to 3i B is a bond, -OCO(CH2) n ' -O(CH2) n~' -NHCO(CH2) n ' -CONH(CH2) n~ ' -NHCOCH=CH-, -COO(CH2)n ' -CO(CH2)n ' --S~)(CH2)r.
-S(CH2)n~~
-SO2(CH2) n ' -13- 2Q8819~
NHCO-C-C-NHCO-C-C- , CONH-C=C-, or H H
l l CONH-C-C-, R7R~
wherein R7 and R8 are each independently selected from hydrogen and R2 or together form a ring (CH2)~ wherein m is an intege-of from 1 to 5, D is -COOR*, CE120R, --CHR20R*, --CH2SR*, -CHR2SR*, --CoNR5R6 ~
-CN, -OH, -H, and acid replacements such as tetrazole;

Q,~

HC~ R~ ~N~ R;~ is OH, NH2, CH3, or Cl llo J~ , ~ ~PO3H2 1, 2, ~ oxadiazole N-N HS~N F\ ~R R is CN, '`~2-~ ~
~N~ N~ ~ HN~fN N~ N
u. ' H ' ' H
~r N--N PhSO2NHCO-% HO ~ O
C~N 9~ CF3CONHCO-%, ~
H ~ ~ CF3502NHC0-%, `o ~ CH3 H2NS02-% ~

H` H

2 0 ~ S ( ) b--~ N ,~ 5 ( ) b~ S ~ ) b~N

--5(0) ~ S(O)b~R.

wherein b is an integer of from 0 to 2, wherein R*, R2, R5, and R6 are as defined above R9 is H, or a straight or branched alkyl of from one to SiY. carbon atoms, ~(CH2)nCO2R*! (CH2)nOAr', (CH2)_Ar', (CH2)nNR5R5, wherein r. R*, R5, and R6 are as de~ined above or taken from R3 and Ar' is taken from A- ac defined below;

W092/04045 PCT/US91/061~

-1~088~5 ~12 and R13 are each independently hydrogen or taken together form a double bond, or are -(CH2) r~~~3 as defined abovei and Ar and Ar2 are each independently a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or carbo- or heteroaromatic moiety; and Prefe-red Arl is substituted phenyl, fused a-yl, heterocycle, fused he.erocycle, or perhydroaryl.
Preferred Arl is 2 or 3-thienyl, 2 or 3-furanyl, 2, 3 or 4-pyridinyl or an unsubs~ituted o~ substituted benzene ring ~ E ' ~\
F

wherein El and F are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoY.y, trifluoromethyl, nitro, hydroxy, NH2, OCF3, NHCOCH2CH2OH~ or CH2CH2C2H
Preferred cycloalkyl or polycycloalkyl substituents have from SiY. to ten carbon atoms.
Preferred compounds of the instar.t invention are those wherein cycloalkyl is a substituted or unsubst~tuted x--~ J

and wherein polycycloalkyl is selected from W092/04045 PCT/US91/0618~

~Q~9 -16-~;_X ~X ~ and wherein W, X, Y, and Z are each independen'ly hydrogen, a straight or branched alkyl of from one to siY carbon atoms, CF3, NR5R6, -(CH2)rCO2R , o- CN, F, Cl, 3-, OR , SR , wherein R is hydrogen or a st-aigh_ or branched alkyl of from one to SiY. carbon atoms and R5 and R~ are as defined above and n is ar. integer of from i to 3.
Preferred mono- or polyhe~erocyclic moieties wherein the heteroatom can be W, O, and/or mono- and polycyclic hydrocarbons include compounds wherein WO 92/04045 PCltl~'591/0618~

Rl is Cu3 ~ I~hCn~)2U, Ue~

~r~ ~ or C~, W092/04045 PCT/US91/~6180 Other preferred compounds o' the instant invention are those wherein R is 2-adamantyl or 1-(S)-2-endobornyl;
A is -NHCO-, -OCO-, -SO2-, -S(=O)- o- -CH2CG-R2 is -CH3, -CH2CO2CH3 or -CH2C--CH;
R- is -(CH2)n-B-D or H; and R4 is -(CH7)n,-B-D or H.
~.ore p;eferred compounds of ths insta-..... r.ver.- on are those wherein R- is 2-adamantyl or 1-(S)-2-endosornyl, o A is -O-C-, R2 is -CH3i R3 is H, -CH2OH, -CH2OCOCH2CH2CO2H, --CH20COCH=CHC02H, --CH2C02F.--,--CH,SCH,C02H--, -CH2SCH2CH2CO2H-, -CH2N:~COCH2CH2CO2~., or -CH2NHCOCH=CHCO2H and R4 is H, -NHCOCH2CH2CO2H ([D] configuration) or -NHCOCH=CHCO2H ([D] configuration).
The D and the L configurations are possible at the chiral centers and are included in the scope Oc the invention:
1. Preferred is when R2 is -CH,~D] configurationi 2. Preferred is when R3 is -CH2OCOCH2CH2CO2H or -CH2NHCOCH2CH2CO2H with the [D] configuration at the ~rp -carbon atom and the [L] configuration at the Phe-x-carbon atom; and 3. Preferred is when R4 is -NHCOCH~CH~CO2H[D]
configuration or NHCOCH=CHCO2H[D~ conf:~uration with the [D] configuration at the Trp ~-carbon atom.
Most preferred compounds of the instant invention are:
Carbamic acid, [2-[~1-(hydroxymethyl)-2-phenylethyl]amino]-1-(lH-indol-3-ylmethyl)ethyl]-, tricyclo[3.3.1.13~7]dec-2-yl este-, [S-(R*,S*)]-, W092/04045 PCT/~S91/06180 2~88~9~
--lg--Carbamic acid, ~2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-l-(lH-indol-3-ylmethyl)ethyl-, tricyclo[3.3.1.13~7]dec-2-yl ester, [S-(R*,R*)j-, Tricyclo[3.3.1.13 7]dec-2-yl[l-[[[l-hydroxy-methyl)-2-phenylethyl]carbonyl~amino]-2-(lY. indol-3-yl)ethyl]carbamate, Ca-bamic acid, [2-[(2-hy_~oxy-2-?henylelhyl)-amino]-l-(lY.-indol-3-ylmethyl)-1-methyle'hy~]-, tricyclo[3.3.1.13 7]dec-2-yl este_ (hydroxy center is RS, othe_ center is R), Carbamic acid, [2-[[1-(hydroxymethyl)-2-phenyl-ethyl]amino]-l-(lY.-indol-3-ylmethyl)-1-methylethyl]-, tricyclo[3.3.1.13~7]dec-2-yl ester, [R-(R*,S*)]-, 4-methylbenzenesulfonate (1:1) (salt), Benzenepropanol,~-[[2-(lY.-indol-3-yl)-2-t[t-icyclo[3.3.1.13~7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-, acetate (ester), [R-(R*,S*)]-, 4-methylbenzenesulfonate (1:1) (salt), Carbamic acid, [[2-~acetyl[l-(hydroxymethyl)-2-phenylethyl]amino]-1-(lH-indol-3-ylmethyl)-1-methyl]-ethyl]-, tricyclo[3.3.;.13~7]dec-2-yl ester, [R-(R*,S*)]-, 5,13-Dioxo-2,8-diazatetradec-10-enoic acid, 3-(lY.-indol-3-ylmethyl)-3-methyl-4,9,12-trioxo-7-phenyl-, tricyclo[3.3.1.13~7]dec-2-yl ester, [S-(R*,S*)]-, 5,13-Dioxs-2,8-diazatetradecanoic acid, 3-(1~-indol-3-ylmethyl)-3-methyl-4,9,12-trioxo-7-phenyl-, tricyclo[3.3.1.13~7]dec-2-yl ester, [R-(R*,R*)~-, Carbamic acid, [l-(lH-indol-3-ylmethyl)-1-methyl-2-[(1-oxo-4-phenylbutyl)amino~ethyl]-, tricyclo]3.3.1.13~7]dec-2-yl ester (R)-, Carbamic acid, [2-(benzoylamino)-1-(lY.-indol-3-ylmethyl)-l-methylethyl]-, tricyclo[3.3.1.13~7]dec-2-yl ester, (R)-, W092/04045 PCT/US91/061gO

~3~3~ -20-Carbamic acid, [l-(lH-indol-3-ylmethyl)-i-methyl-2-[(1-oxo-3-phenylpropyl)amino]ethyl]-, tricyclo[3.3.1.13~7]dec-2-yl ester, (R)-, Carbamic acid, [l-(l~-indol-3-ylmethyl)- -me~hyl-2-[(2-phenylacetyl)amino]ethylj-, tzicyclo-[3.3.1.13~7]dec-2-yl ester, (R)-, Carbamic acid, [2-[[3-[[1-(hyd-oi:vme~hyl)-2-phenylethyl]amino]-3-oY.opropy']amino]-'-(':-~-indo'-3-ylmethyl)-l-methyl-2-oxoethyl]-, [R,(R*,S*)j-, Carbamic acid, [l-(l~.-indol-3-ylmethyl)-2-~[3-[[l-(hydroxymethyl)-2-phenylethyl]amino]-3-oxo?ropyl]amino]-l-methyl-2-oxoethyl]-, tricyclo-[3.3.1.13~7]dec-2-yl ester, [S-(R*,R*)j-, D-Phenylalaninamide, a-methyl-N-[(tricyclo[3.3.1.13 7]dec-2-yloxy)carbonyl]-D-tryptophyl-~-alanyl-, L-Phenylalaninamide, a-methyl-N-[(tricyclo[3.3.1.13~7]dec-2-yloxy)carbonyl]-D-tryptophyl-~-alanyl-, L-Phenylalaninamide, a-methyl-N-[(t-icyclo[3.3.1.13~7]dec-2-yloxy)carbonyl]-L-tryptophyl-~-alanyl-, D-Phenylalaninamide, a-methyl-N-[tricyclo[3.3.1.13~7]dec-2-yloxy)carbonyl]-L-tryptophyl-~-alanyl-, 12-Oxo-2,5,9-triazatridecanoic acid, 3-(lr.-indol-3-ylmethyl)-3-methyl-4,8,11-trioxo-l0-(phenylmethyl)-, t.icyclo[3.3.1.13~7]dec-2-yl ester, [R,(R*,R*)]-, L-Phenylalanine, N-[N-[a-methyl-N-[(tricyclo[3.3.1.13 7]dec-2-yloxy)carbonyl]-D-tryptophyl]-~-alanyl]-, phenylmethyl ester, Propanoic acid, 2-[[3-[[3-(1~.-indol-3-yl)-2-methyl-l-oxo-2-[[(tricyclo[3.3.1.13~ 7 ] dec-2-yloxy)carbonyl]amino]propyl]amino]-l-oxopropyl]-amino]-3-phenyl-, phenylmethyl ester, [S-(~.*,R*)]-, W092/04~5 PCT/US91/06180 2 ~ 9 ~

D-Phenylalanine, N-[N-[a-methyl-N-[~t_icyclo[3.3.1.13 7]dec-2-yloxy)carbonyl]-D-tryptophyl]-~-alanyl]-, L-Phenylalanine, N-[N-[a-methvl-N-[(tricyclo[3.3.1.13 7]dec-2-yloxy)carbonyl]-D-tryptophyl]-~-alanyl]-, L-Phenylalanine, N-[N-[~-methyl-N-[(tricyclo[3.3.1.13 7]dec-2-yloxy)ca-bonyl]-L-tryptophyl~-~-alanyl]-, Benzenepropanoic acid, ~-~3-[[3-[(lH-indo -3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.13~7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxopropyl]-amino]-, [S-(R*,S*)]-, Glycine, N-[2-methyl-N-[(tricyclo[3.3.1.13~ ]dec-2-yloxy)carbonyl]-D-tryptophyl]-, phenylmethyl ester, Carbamic acid, [3-(lH-indol-3-ylmethyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidinyl]-, tricyclo[3.3.1.13~7~dec-2-yl ester, (+)-, Carbamic acid, [1-(lH-imidazol-4-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]-, ljl-dimethylethyl ester, (+)-, Carbamic acid, [3-(lH-indol-3-yl)-1-methyl-1-[[(2-phenylethyl)amino]carbonyl]propyl]-, tricyclo[3.3.1 13~7]dec-2-yl ester, (+)-, Carbamic acid, [1-[[[1-hydroxymethyl)-2-phenylethyl]amino]carbonyl~-3-(1~-indol-3-yl)-1-methylpropyl]-, tricyclo[3.3.1.13~7]dec-2-yl ester (hydroxymethyl center is S, other center is RS), 12-Oxa-2,5,~-triazatetradec-10-enoic acid, 3-[2-(lH-indol-3-yl)ethyl]-3-methyl-4,5,12-trioxo-7-phenyl-, tricyclo[3.3.1.13~7]dec-2-yl ester [TRP center is R/S mi~ture, other center is R], L-Phenylalaninamide, N-[[(l,1-dimethylethoxy)-carbonyl]-a-methyl]-L-tryptophyl]-L-methionyl-~-a-aspartyl-, ~lycine, N-[2-methyl-N-[(tricyclo[3.3.1.13~7~dec-2-ylc y)carbonyl]-D-Iryptophyl]-L-phenvlalanyl-, Carbamic acid, [l-[[[l-(hydroY.yme_hyl)-2-phenylethyl]amino]ca-bonyl]-2-~lH-indol-3-yl)p-opvl]-, tricyclo[3.3.1.13~ 7 ] dec-2-yl ester (hyd-o~ymethyl center S, other centers RS), 2,4-Heptadienoic acid, 6-[[3-(1~.-in~ol-3-yl)-2-ms~hyl-l-oxo-2-[[(t-icyclo[3.3. .1-~ 7] dec-2-ylo~y)-carbonyl~amino]propyl]amino]-7-pheny -, [R,R*,S*-(E,E)]]-, and Glycine, N-[2-methyl-N-[(t-icyclo[3.3.1.13~7]dec-2-yloxy)carbonyl]-D-tryptophyl]-, phenyimethyl ester.
Table I, below, illustrates represen~ative compounds of the invention. The numbe-s on the left-hand column in Table I correspond to the compound numbers given above. All of the compounds shown in Table I have their stereochemical configurations shown.
In addition to the compounds shown in Table I, the compounds of the present invention include compounds of formula I wherein the indole moiety is a 2-indolyl.
The compounds of the invention include solvates and hydrates and pharmaceutically acceptable salts c.
the compounds of formula I.

WO 92/04045 -23- Pcr/usgl/06l80 ~ ~ 208819~5 't.: ~ ~ =
V~ _ ~ =

, _ , ~, ~ o o o Y ~ =

~- .~ Z Z Z
Z Z Z
,~ o ~ o ., ,. .. ..
~y S .r .. ,. .. ..
''o: o .
X Z Z ~Z
. ,,, o ~y Z Z Z
O -O O
'I'L J~

~ Z '' ~ ~

wo 92/04045 -24- PCI /USgl /06180 ~¢
~ ,.
~3 , I ~

il ~ I

Z Z
~ ¦ O O G O
~ ~ Z Z Z Z
~ ~ O O O
¢ .~ O Z Z
~ ~, ~ ,. ..
~ = O o O
I tr ~ ~ ,.
I X Z = Z ~:
I ~4 I e o o o o ~ Z Z Z
¢ S S Z z I X o ~ ~ ~
! ~ Z I

WO 92/04045 -26- PCr/US91/06180 C ,.1 .o~; = = S
:~ =
_ _ ~ _ , 4 ~ O O
1~1 ~
~ O ~ - _ ~ 2 , O o _, ,, . Z Z o . O o ~ _ ,~ . .~
~ z z r~

~ ,, X - ~SSo o o, _ _ o o ~: ~
O OO O

2 2 z , s S 2 s rr~ f~ s~ rt~

K O

WO 92tO4045 25 PCr/US91/06180 ¢ ~ ~b ~ ~ 2 l~ 8 8 1 9 '' C ,, ~ ~ .
= S
~1~
~ "
o~ o~ ~ ~
, ,, ,~ , o 1, , , o o 1 `~
Z
~ , = o ~ = = Z Z
.. ,, ,, o o ~ ,, ,, _ , n ~ ,~ ~ O
_( ¢ ~ O, D. = Z
1~ ~ O
rl~ 3: - = Z

O' r~
X ~ O ~ o O O _~ ~

O O O O

Z Z Z
~ O O O
"~; ~

LC Z _~ N 0. e WO 92/04045 -27- PCI'/US91/06180 ~ ~ 2 0 8 8 1 9 ~

,oc~
~:

4 r S C C

__~ _ _ rl~ _ S
r~ _ r~ r~ z o ~1 ~ _ = O O
r ,~
~c '~: _ _ _ ' ,~

~ :: S
I C
X _ z O O
~ O O O O
..~ ~
~ O O O O

~ ~ ~ 5 Z
~ Z Z o O
,-~ rt~

K o ~ r ~D

5 -28- P~/USg1/06180 9?~e C ~ ,. ~ ,.
~o~ V~ S
lv~ U~

! e l ~ ~ C

i = = = =

O o o O o V ~
~ _ = O o L r .~
e ~ ~. :c ~.

Ir~ =
D' r~
I X _ Z S :~:
o o o o ~ ~ ~ V
l ~ O O O O
~; ~ ~ Z Z
~Z = Z Z

¦ ~ Z ¦ ~~ r ~

WO 92/04045 29 PCI/~591/06180 2 ~ 8 g 1 9 ~

~ = _ = =

s r I
O
~" ! = = = =
o o o Z
., j - ~ ~
- o V
w n ,, ,, _~ O
.~ ~ _ ~ ~ Z

~,~

I r X o O o o D. O O O O
I '~c o O o o o I ~ Z Z Z Z
_ z O o wo 92/04045 30 Pcr/usgl/o6l8o "¢

1: ~ N N N
.o~ =
~: = _ _ =
rU r ~ ~ U

O O O

! z z z o ~ ~ ~
.
,. o o o ,. Z Z Z o ~ n O O O O
lil r~ _~ r~

~4 ~ r~ ~I r~
~ C

D' ~
X O o O Z

D~ ~ O O O
U ~ ~
O O O O
~ ::~ z Z

1~ s o zo oo x o ~" ~ O

WO 92/04045 -31 PCr/US91/06180 .~ ,.~b 2 0 8 ~ ~ 9 ~ I

C ~ ~ o o o o ~, Z Z Z
= Z
., ,. o o .
~ o ~ ~ o ,. n O O O O
~ ~ _l -l ~ ::

~ C T C

j C' i _ _ _ _ I X 1, o o O O
~ I

~ ¦ ~ =

- Z o O

I X Z I ~ ~

W092/04045 ~ PCT/US91/061 ~Q~ ~

Other examples of compounds of the invention include:
T_icyclo[3.3.1.1-~7]dec-2-ylcarbamic acid, 2-[[2-hydroxy-l-(hydroxymethyl)-2-phenylethyl]amino~-1-(lH-3-ylmethyl)-1-methyl-2-oxoethyl este-, N-[2-Hydroxy-l-(hydroxymethyl)-2-?henylethyl]-a-me~hyl-a-(2-oxo-2-tricyclo~3.3.1.13~7]aec-2-ylethoxy)-lH-indole-3-propanamide, N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-a-(2-hyd-oxy-2-tricyclo[3.3.1.1~~7]dec-2-ylethoxy)-a-methyl-lH-indole-3-propanamide, [(Tricyclo[3.3.1.13 7]dec-2-ylamino)carbonyl]-sulfamic acid, 2-[[2-(hydroxy-1-(hydroxymethyl)-2-phenyle~hyl]amino]-l-(lH-indol-3-ylmethyl)-1-methyl-2-oxoethyl ester, [(Tricyclo[3.3.1.13~7]dec-2-ylamino)sulfonyl]-carbamic acid, 2-[[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]amino]-l-(lH-indol-3-ylmethyl)-1-methyl-2-oxoethyl ester, [[2-[[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]amino]-l-(lH-indol-3-ylmethyl)-1-methyl-2-oxoethoxy~sulfonyl]carbamic acid, tricyclo[3.3.1.13~7]-dec-2-yl ester, N-[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]-methyl-[[2-oxo-2-(tricyclo[3.3.1.13!7]aec-2-ylamino)-ethyl]amino]-lH-indole-3-propanamide, N-[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]-a-methyl-a-[[(tricyclo[3.3.1.13~7]dec-2-ylamino)acetyl]-amino]-lH-indole-3-propanamide, N-[2-Hydroxy-l-(hydroxyme,hyl)-2-phenylethyl]-a-methyl-a-[(2-oxo-2-tricyclo[3.3.1.13~7]dec-2-ylethyl)amino]-lH-indole-3-propanamide, N-[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]-a-l(2-hydroxy-2-tricyclo[3.3.1.13~7]dec-2-yle ~yl)amino]-a-methyl-lH-indole-3-propanamide, W092/04045 PCT/USgl/061~

_33- 20881 95 N-[2-Hydroxy-l-(hydroy~ymethyl)-2-phenylethyli-a methyl-a-[[[[~tricyclo[3.3.1.13'7]dec-2-ylamino)-carbonyl]amino]sulfonyl]amino]-lH-indole-3-propanamide, N-[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]-a-methyl-a-[[[[(tricyclo[3.3.1.13'7]dec-2-ylamino]-sulfonyl]amino]carbonyl]amino]-lH-indole-3-propanamide, [[[2-[[2-Hydroxy-l-(hydroxymethyl)-2-phenyl-ethyl]amino]-1-(lH-indol-3-ylmethyl)-1-methyl-2-oxoethyl]amino]sulfonyl]carbamic acid, tricyclo[3.3.1.13~7]dec-2-yl ester, [[[2-[[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]amino]-l-(lH-indol-3-ylmethyl]-1-methyl-2-oxoethyl]amino]carbonyl]sulfamic acid, tricyclo[3.3.1.13~7]dec-2-yl ester, N-[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]-a-methyl-a-[[(tricyclo[3.3.1.13~7]dec-2-ylamino)-sulfonyl]amino~-lH-indole-3-propanamide, N-[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]-2-(lH-indol-3-ylmethyl)-2-methyl-N'-(tricyclo-[3.3.1.13~7]dec-2-ylmethyl)propanediamide, N-[2-Hydroxy-l-(hydroxy,methyl)-2-phenylethyl]-2-(lH-indol-3-ylmethyl)-2-methyl]N'-tricyclo[3.3.1.13~/]-dec-2-ylpropanediamide, N-[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]-a-[[imino(tricyclo[3.3.1.13~7]dec-2-ylamino)methyl]-amino]-a-methyl-lH-indole-3-propanamide, a-[[(Cyanoimino)(tricyclo[3.3.1.13~7]dec-2-ylamino)methyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)-2-phenylethyl]-a-methyl-lH-indole-3-propanamide, N-[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]-a-methyl-a-[[(nitroimino)(tricyclo[3.3.1.13'7]dec-2-ylamino)methyl]amino]-lH-indole-3-propanamide, W092/04045 PCT/~S91/06180 [2-[[2-~ydroxy~ hydroxymethyl)-2-phenylethyl]amino]-l-(l~.-indol-3-ylmethyl)-l-methyl-2-oxoethyl]phosphoramidic acid, phenyl _-icyclo[3.3.l I3' 7 ] dec-2-yl este-, ~-[2-[[2-Hydroxy-l-(hydroxymethyl)-2-phenylethyl]amino]-l-(lH-indol-3-ylme-hyl)-:-methyl-~-oxoethylj-N-tricyclo[3.3.l.l-~ 7 ] dec-2-ylphosphorodiamidic acid phenyl ester, T-icyclo[3.3.l.l- 7 ]dec-2-yl?nosphoramidic acid, 2-[[2-hydroxy-l-(hydroxymethyl)-2-phenylethyl]amino]-l-(l~-indol-3-ylmethyl)-l-methyl-2-oxoethvl phenyl ester, and Phosphoric acid, 2-[[2-hydroxy-l-(hydro~y-methyl)-2-phenylethyl]amino]-l-(l~-indol-3-ylmethyl)-l-methyl-2-oxoethyl phenyl tricyclo[3.3.l. 13' 7 ] dec-2-y:
ester.
The compounds of the present invention can have multiple chiral centers including those designated in the above formula I by the symbol t, depending on their structures. ~or example, when R3 taken with R4 and Rl2 taken with Rl3 form double bonds to their carbon atoms, they are no longer chiral. In addition, centers of asymmetry may exist on the other substituents. In particular, the compounds of the present invention may exist as diastereomers, mixtures of diastereomers, or as the mixed or the individual opticzl enantiomers. The presen_ invention contemplates all such forms of the compounds. The mixtures of diastereomers are typically obtained as a result of the reactions describec more fully below.
Individuai diastereomers may be separated from mixtures of the diastereomers by conventional techniques such as column chromatography or repetitive recrystallizations. Individual enantiomers may be ~5 separ2ted by convention method we:l known in the art W092/04045 PcT/~S91/06180 _35- 2 0 ~ 81 g~
such as conversion to a salt with an o?tically ac~ive compound, followed by separation by ch-omatography or recrystallization and reconversion to the nonsalt form.
The compounds of the present invenlion can be formed by coupling individual substitutec ~-amino acids by methods well known in the art. (See, fo-exampie, standard synthetic methods discussed in ~he multi-volume treatise "The ~ep.ides, Analysis, Synthesis, Biology," by Gross and Meienho-^er, Academi~
~ress, New York.) The individual subs-ituted alpha amino acid starting materials are generaliy known o-, if not known, may be synthesized and, ~^ desired, resolved by methods within the skill G_ the art.
(Synthesis of racemic ~DL]-x-methyl tryptophan methyl ester - see Brana, M. F., et al, J. Heterocvclic Chem., 1980, 17:829.) A key intermediate in the preparation of compounds of formula I is a compound of formula ~ ~ TI
ROCONH M COOH

wherein R is selected from R1, 9-_luorenylmethyl, ~z and other suitable N-blocking groups. These are useful as intermediates in the preparation of compounds of formula I. The compounds wherein R is 1-adamanty', 2-adamantyl, 4-protoadamantyl, exo-bornyl, endo-bornyl, exo-norbornyl, endo-norbornyl, 2-methylcyclohexyl, 2-chlorocycloheY.yl, o- camphoryl are novel and are preferred.

W092/04W5 PCT/USg1/061~

~ 9 -36-The disclosure of U.S. 4,757,151 is hereby incorporated by reference. It describes the 5-fluorenylmethyl blocking group.
Compounds of formula II are prepared by reac'inc RO~ I I -wherein R is as defined above, with phosgene or a phosgene substitute to produce a corres?onding compound of formula ROCOCl IV

and then reacting a compound of formula IV with -methyltryptophan to produce the desired compound of formula II above.
Alternatively, a compound of formula IV can be reacted with an ~-methyltryptophan methyl ester to produce H

~ V
Me which can be converted to a compound of formula II by known means such as hydrolysis w_th aqueous lithium hydroxide.
The schemes below illustrate procedures for preparing intermediates useful in producing final products of formula I.

_37_ 2 08 8l 9 ~
Scheme I below illustrates pre?arative steps in the process of making compounds of the instant invention. Treatment of 2-adamantvioxyca-bonyl-tryptophan 1 wi~h N-methylmorpholine 'ollowed by isobutylchloroformate gave an inte mediary mixed anhydride, this when mixed wi_h N,O-dimethylhyc-o-acylamine hyd-ochlo-ide gave the hvdroxamate 2 which yielded the aldehyde 3 on reduc.ion with L,AlH~.
Reductive amination of 3 with S-phenylalaninol and NaCNBX3 gave the amino methylene 4 (_xample l).
Example 2 (compound 5) was preparec in Zh exactly analogous manner. The intermediate mixed anhyc.-ide aescribed above was treated with Me,SiN, to make the acid azide which then reacted with P-ni~robenzyl alcohol in the presence of DABCO to give the bis urethane 6. Hydrogenation using Pearlman's catalyst to the monourethane, and treatment of the amine with the HOBT ester of 2-(acetoxymethyl)-3-phenylpropionic acid gave the compound 7, Example 3 after saponification of the ester with LiOH in aqueous THF.
Example 4, compound l0 was prepared in three steps from 1 Here the mixed anhydride o 1 was treated with diazomethane to sive the diazoketone 8. Reaction with nCl to the chloro ketone followed by reaction with sodium diethylbenzyl malonate gave a diester which, upon saponification, deca-boxylated to the acid 10, Example 4.

WO 92/04045 PCJ/US91/061~

SC~FME 1 ~31 ~3 2-AdOCOE~ Co.X 2-AdO-OHN C5NO~e ~,~

~ \i~, \
p. ~ p. \~ :.

2-AdOCOE~ COCNN- 2-AdOCo~; NXCOOCH ~ N_ 2-AdOCOh~; CP.o Iv Iv 1-~i P. P.

~ ~ OH ~
2-AdOCOHN COCX.Cl 2-AdOCOHN NHCo ~ Ph 2-AdOCOHN 8 ~ Ph 7 EXan~ 3 4 EX~
~ EY.~ 2 ~ S
l ~
,~3 2-AdOC08N COCH2CXCN2Ph COOH
~51 EY.alnP10 4 RE" i) isobutylchloroformate, N-methyl mor?holine, CX30NH(Ch3)-HCl; ii) LiAlH4; i -) S-phenylalaninol, NaCN3n3;
iv) i~obutylchloroformate, N-methylmor?holine, Me3SiN3 the-.
40C then Dara-N02-C6H4CH20P., DA3CO;
2,4-diazabicyclo[2.2.2]octane ~DA3CO); v) Pd~0:)2 H2, the-.
RS-H02CCCP(CH2Ph)CH20Ac; then LiOH, TH~;
vi) isobutylchloroformate, N-methylmor?noline~ CP2N2;
vii) PCl-dioY.ane; viii) NaI, NaO.~, ther.
~odiodiethylbenzylmalorate, ther. NaOH., _her. P_l, then hea:.

W092/04045 PCT/US~1/06180 2~881~

Scheme 2 Example 5, compound 12 was prepared by reduction of the amide in 11 using Li3H4 and ~e3SiCl.
Similarly, Example 6, compound 14 was prepared ~rom 13. 14 was treated with acetylchloride to give Exampie 7, in the presence of base. The major produc~
W2S compound 15a, which was hydrolyzed ~o Example 8, com?ound 16, on treatment with lithium hydroY.ide. The thiazoline 17, Ex.am?le 9, was prepared by heating '3 with Lawesson's reagent.

W O 92t04045 PCT/US91/06180 2-AdOCOH!i CONH ~Ph 2~! '^ _xa-?_e g 21 2 O.' 2-AdOCO.'.`;'lM--CONH~p 2-AdO-O:-,:;~ !è - 2N~?

_ _xa.-?ie S

H
,~ 1 _ ,~
2-AdOCOHN CNH~ph 2-Ad5coH~ Me C~2NH~p,~
OH OH
1~ Exam?le 6 H ~

2-AdOCO.U~ ~ ~ ~ Ph 2-AdOCOHN ~C:-.2j ~
oR2 ' 7 Example 16 . - - 2 I _xar-?le 7 .~ ', 2 = Ac _xa..pie 8 ~ = Ac, 22 =, 2 - Ac, 22, A_ ~EY i) LiBH4, ~e3SiCl; ii) CH3COCl (E~a~ple 7); o_ C~3COCl, Et3N
tnen LiO~ ~E~.a~ple 8); ii_) Lawes~or.'s Reager._.

-41- 2 ~8 81 g ~
Scheme 3 shows the synthesis of examples of ester isosteres. Monomethylfumarate was condensed with R-phenylglycinol via its HOBT ester to give 18.
Further condensation of this with R- or S
2-Adoc-a-MeTrpOH in the presence of N,N'-carbonvldiimidazole gave Examples 10 (com?ound lC) and 11 (compound 20), respectively. In an exactly analogous way Example 12 (compound 22) was made except using monomethyl succinate.

Wo 92/04045 PCr/US91/06180 9~ -42-SCHE~E 3 NH~O~C02Ve ~C2--~CO2Me _, , _ L^ ~ D ~, ~X
r ?;:J-C ~C021Ve 2-AdocoN~:~rcoc ~?h 1 Example 10 - R-con'l_~:-ation 20 Example 1 ' S-config:ration NHCO~C02Me ~CO2Me i, ii ~!o~i~Ph 2~
!
~ . , R ~ NH'`O ~^02Me 2-AdOCONH1~COC
Me --R`?h 22 Exa~?_e 12 KEY i) HOBT, DCCI; ii) R-phenylalanin_l; iii) P- or S-2-Adoc-MeTrp-OH (Compound 23).

_43_ 2 08 81 9 Scheme 4 Reduction of 23a to the primary alcohol 24 with LiAlH~ followed by treatment with phenyl acetic acid and N,N'-ca,bonyldiimidazole gave the este- isostere 25, Example 13. Oxidation of 24 to the aldehyde 26 provided a very versatile intermediate. This aldehyde 26 was .reated ~ith Wittig reagents .o give 27 (Exampie 14) and 29. Compound 29 was modi-^ied 'u-ther to 30, Fxample 16 by hydrolysis of the es~er and subsequent condensation with ar.iline. Treatment of aldehyde 26 with the Grignard reagen- 3-phenyipropyl magnesium bromide afforded the seconda-y alcohol 28 (Example 15).

W O 92/04045 PCr/US9l/06l80 2-Adc~oH; Me CO2~t 2-AdOCOHI; M
1'~ ~
H

2-AdOCOH~' CHO 2-AdO-C:'~ O''OCH2?^.

i Exampi~ i3 H i,~ H

2-AdOCOHt;~ 2-AdOCOH~ph Me Me 77 Example 14 2~ Exampie 15 K~ i) LiAlH~; ii) PhCH2C02H: carbonyldiimidazole;
_ii) Tetrap-opylammonium per~uthe~ate; iv) PhCH2CH2PiPh3--, ~a~.; v) PhCH2C~2CH2MgB~

W092/0404~ PCT/US91/~6180 208819~

Scheme 5 shows the synthetic routes to some examples of homologated a-me~hyltryptophans, and their reverse amide isosteres. The miY.ed anhyc-ide of 23b prepared by using isobutylchloroformate and N-methylmorpholine was treated with diazomethane to sive the diazoketone 3~, this as a solution in benzyl alcohol was treated with silver benzoate and Et,N to yield the homolosated benzyl ester 32. Hydrosena~ior.
afforded the acid 33 which was condensed in the usuzl way via the pentafluorophenyl ester with S-phenyl alaninol to give 34 (Example 18).
The amide of 23b, 35 was prepared bv bubbling ammonia gas through a solution of the pentafluorophenyl ester. This amide was reduced to the amine 36 with Me,SiCl/LiBH4 in THE. This amine was subsequently reacted with phenyl acyl chlorides to give Examples 19-22 inclusive.

WO 92/04045 -46- PCr/US~1/06180 7,,~

Z o ~
a r, ~

- ~ 4 V ~ ~ X

- ~ 4 2: ~
` .
o W092/04045 PCT/US91/06t80 -47_ 2~&~ ~9 ~
Scheme 6 illustrates the synthesis of a-methyltryptophyl-~-alanine derivatives. The 2-adamantyl oxycarbonyl a-methylt_yptophan 23b (R
isomer) or 38 (S isomer) is condensed wi_h 5-alanine ester in the usu21 manner. This este- can then be hyd-olyzed using standard methods (e.s., aaueous EiO:., etc) to afford the czrboxylic acid 41 o- 42. Ei'he_ o' these two isomers may be condensed w _h an ap?-opriate amine to give Examples 23 and 2~ (usinc S-phenyl alaninol), Examples 25-28 incl sive (using ~
and S phenyl alaninamide) and Examples 29-3' inclusive (using phenylalanine ester. EY.amples 29-3i and compound 52 may then be hydrolyzed using known methods to afford the products Examples 32-35 inclusive.

WO 92/04045 PCr/US91/n6180 ~ ' ~ i Me 2ROCO:-`: _OX~~CO2Me ;~ S^~ 2 ^ ~'^ R ~ C S
~ ::
,~h3 ~ :1: ,~
RJ_C.-:`; CONH~COt;'r: `'.e C0 ~ Ext;
S S 2 S / ¦ v ~ 7 2S

H :

ROCOHh~NH3 CONH ~.h ROCOHX~ CONH ~. h ~ ExN ~'~ ExN
R R 25 4q R R 2~

7 5 S 2 7 ~ ~ S S 3 1 ~ C02'r:
ROCOHt'~---OXH~CONH ~?:^
~ ExtNC
5~ R R 32 ;~ R S 33 - cc S S 3S
~ S R 35 K~ Reaaents: i) PFP, DCC, B-Alar.ine ~e este , EtOAc;
) LiOP., aq dior.ar.; iii) DC-, (S)-(-)-2-amino-3-phenvl-'-propanol EtOAc; iv) PFP, DCC, (R)-phenylalaninamide, EtOAc, v) PFP, DCC, (S)-pnenylalanine Denzy' ester, EtOAc or PF?, DCC, (R)-pne3ylaianine methyi este-, ~tOA-; vi~ H2, Pd/C, ~tOY

W092/04045 PCT/~S91/06180 208~19 a Scheme 7 describes synthetic steps ~owards derivatives of ~-methyl tryptophyl glycine. As an illustration, 2-Adoc-~-methyltryptophan 23b may be easily condensed with glycine benzyl este- via the pentafluorophenyl ester of 23b. Hydrogenation o' this este- using 10% palladium on ca_bon in a.. ethanol solu~ion affords the carboxylic acid 58 in high yield.
Trea~ment of this acid with N,N'dicycloheY.yl-carbodiimide and pentafluorophenol gives the active este- which undergoes reaction with phenylalaninol readily to give the product compound 59, Example 37.

W O 92/04045 PCT/~rS91/06180 ~9~ -50- i ~ ~ Me ~ ~
2AdOCHN ~ co2~ 2AdOCHN CONP.~-~C5~C~ h 23b 57 Ex~,ple 3-lii Me ~` ~ ~OH iii Me ~ ~
2AdOCHN ~ CONH--CONH ~ Ph 2AdOCHN B CONH~--`CO2H

~2 Example 37 ~

~E~ Reaaen~s: i) PF2, DCC, alycine benzyl este- hydrochlGride, E:3~, EtOAc; ii) H2 Pd/C, EtO~.; iii) PF~, DC_, ~-pnenylalaninol, EtOAc.

-Sl- 2 0 8 8 19 ~
Scheme 8 describes synthetic steps towards derivatives of a-methyltryptophyl-y-aminobutyric acids. As an illustration, the carboxylic acid 235 may be condensed with y-aminobutyric acid methyl ester to give 60, hydrolysis of this with LiOH affords zcid 61. The product 62, Example 39 is produced when 6' is condensed with phenylalaninol via an active pentz'luo-ophenyl ester.

W O 92/04045 PCT/USgl/~618 Me~ ~ Me~ ~
2AdocHN B C2~2AdOCHN C~NH~-~^~CO~MC

~ > O
lii H H

Me ~ ~ ~OH iii Me ~ ~
2AdOCHNCONH "^~`~^`CONH ~ Ph2AdOCHN CONH~'~-~^~CO2H

~ Example 39 hl KEV Rea~ents: i) PFP, DCC, gamma-aminob~_yric ac-d methyieste-hydrochloride, E~3N, EtOAc; :i) LiOH, ac ;,4-dioxar.;
iii) PFP, DCC, s-phenylalanincl, E-OA^.

W092/0404~ PCT/~S91/06180 _53_ 20881~
Scheme 9 outlines the -~ynthesis o' a-substituted try?tophanylphenethylamides and their intramolecula-cyclizations to compound 68, xample 40. The isonitrile 63 (prepared by the method desc-ibed in Svnthesis 465, 1990) in ethanol at -5C was treatec with ethanolic HCl to sive the amine 64. This underwent coupling with 2-adamantylchloroformate to the urethane 65. Hydrogenation of 65 using 10%
palladium on charcoal at 45 psi yielded .he mono acid mono este- 66 which was condensed in the usual way ~o 2-phenethylamine giving 67. The produc~ was forme~ by treatment of 67 with LiOH which abstracts the amide NP
proton and cyclizes onto the ester grou?, liberatins methoxide.

SC~E~E 9 '-OOCH2Ph COOCH2Ph ~_,COOCH3 , ~,;~COOCrs-Boc 6~ 6~

COOCH2Ph COOY.
; ii ~ ZH;

CONHCH2CH2Ph vl ,~

0~_ ~ Exa~::~le 40 Y.Z`' P.eaaer~ i) EtOH HCl, 67%; ~ ada~r,a3-yi-O''OCl, Et3N, E~OAc, 58%; iii) Pd/Y.2, E~OY., 3~; iv) Y.2NC:-s2C~12Pr., PFP, ~~'~, DMAP, EtOAc, 73%; v) I,iOH ~0 . 01~.), 0_, TYF/~12~, 79% .

_55_ 2 ~8 8~ 9~' Schems l0 outlines the synthetic steps towards ~-subs.ituted tryptophan derivatives. Isopropylamine, when added to ace~aldehyde and treated with KOH, gives 69 which reacts with indole in glacial acetic acid over 5 days to produce 70. The isopropylamino ethylidene 70 then reacts with 71 in 'he p-esence of NaOMe in hot toluene, yielding 72. Saponi ication an_ decarboxylation a'fords 74 as a miY.tu-e o~ separable diastereoisomers.
The amide 74 is dissolved in 4N s~lphu-ic acid a~
reflux, then cooled to ambien~ tempera_ure, and treated with 0.4N barium hydroxide un'il a pH of 8 is obtained, yielding the free amine 75 which reacts wi~h 2-adamantyl chloroformate 76, yielding the urethane 77. This is then condensed with phenyl alaninol in the normal manner to give the product 78, Example 89.

WO 92/04045 Pcr/usgl/06l80 ~3~ SCHEME lo H.C Ci;;
- >--NHN3C--CHO f;3C--CH=.i--<CX;

~, A^o:' CH; ~C5~3z C:.3 '' .CO.Bz_, CO Bz ¢~ C.~, ~0 0~1 , ~ ~ ~3~d~Ph C~13 0 ~J;~, Ph W092/04045 PCT/US91/~61~

~57~ 208819~
GENERAL PROCESS FOR REACTION SCXEMES

Scheme 15a:
Cyano acetic esters or subs_itu-ed derivatives _ are alkylated with gramine and a base, e.g., NaOX in toluene, to compounds 2 in analosy to known methods.
Compounds 2 are hydrogenated catalytically with ~aney nickel alloy to the amino estsrs 3, which are reactecd with chloro- or fluoroformates to the carbami_ acid esters 4. The esters 4 are hyd-olyzed to the acids o, which are converted to ac~ivated esters, e.g., wi_h pentafluorophenol and dicycloheY.ylca-bodiimids to the pentafluorophenyl esters. The activated esters are reacted with an appropriate amine to an amide of formula 6. Further conversions at the amide part o~
the molecules are done in analogy to known methods.

Com~ounds of aeneral formula 15a R -o-co-NH-cH2-i-co-NH-(cHR3)c- CH~ -Ar Ia ~3 , where R' = l-adamantyl, 2-adamantyl, (lS)-2-endo-bornyl R2 = H or Me ~ , c = 0 or l H

R3 z H, -CH2OH, -CHzO-CO-(C:2)zCO2H

R~ = H, -NH-CO2-t-Bu, --NH--CO--CH~--CH~--C02Bz, --NH--CO--CH2--CH2--CO~H
-NH-CO--CH=CH-C02Me, --NH-CO-CH=CH-C02H
t t are prepared according to Svnthetic Scheme 15a:

Wo 92/04045 PCr/US91/~6180 203819~

SYNTHETIC SC~EME 15a R12 gramine R2 NC -CH-CO2Et NC -C - CO2Et analog to ¦ Raney-Ni J. Org. Chem.
1953, 18, 1440, 1447 Rl-O-CO-Cl H2N - CH2- C - CO2EtR - O - CO -NH - CH2- C -CO2E-~3 ~
3 H ~ Y.

LiOH Rl _ O - CO-NH - CH2 - C -CO2H

~ H

Ri - O -CO -NH - CH2 - C -CO-NH-(CHR3)c-CHR~-C6n-~3 H

Scheme 15b:
Compounds of general formula Ia, where R2, R3, and P~4 are H are also prepared according to Svnthetic Scheme 15b. Cyano acetic esters 7 are reacted wi~h approp-iate amines to the cyano acetamides ~ which are condensed with indole-3-czrboxaldehyde and catalytic amounts o piperidine to compounds 9 in analogy to known methods, and thereafte- hyd-ogenate_ catalytically wi~h Raney nickel alloy to the 3-indolylmethyl substituted ~-aminopropionamides lC.
Reaction with chloro- or fluoroformates yields the carbamic acid ester derivatives 11.

Wo 92/04045 PCr/US91/06180 208819~

SYNTHETIC SCHEME 15b NC-CH2-Co2Et C6H -CH7(CH2)~-NH7 NC-CH2-CO-NH-(Cn2)--analog ;o JACS 72, 25a2 ( indole-3-carboxaldehyde H2 ~ NC - C-CO -NH -(cH2)c-cH~-c6Hs analog tO 11 Raney-N-J. Org. Chem. CH
lq~, 2~, 1165 H2N-CH2- CIH - CO -NH - (CH2)C-CH2-C6Hc u lQ ~ -Cl R -O-CO -NH-CH2- Cn - CO - NH -(CH2) -CH2-r6:--~3 '11 ' W092/04045 PCT/~'Sgl/~6180 Scheme 15c:
Compounds of general formula Ia, where R2 = H or -CH ~
'~ -and R3 and R~ are H
are also prepared according to Sv-.lhe'-- S^heme '5c.
Cyano acetamides 8 are alkylated with c-amine and c base, e.g., NaOH in toluene, to compounds '2 and 13, which are hydrogenated catalytically with Raney nicke alloy to the mono- or bis-(3-indolylmethyl) substituted ~-aminopropionamides '0 and 16. Reac_ion with chloro- or fluoroformates yields the carbamic acid ester de-ivatives 11 and 17.

W O 92/04045 PC~r/US91/061X0 2~8~19~

SYNTHETIC SCHE~E 15c Nc-cH2-co-NH-(~H2~c-cH2-c6Hs H
~ gra~ine CIH2 NC - CH-CO -NH -(cH2)c-cH2-c6H; + NC -C - CO -NH -(C:-.2)C-C:i~-C~:H-¦ Raney-Ni ¦ Raney-Ni H2N - CH - CO -NH -(CH2)C-CH2-C6H5 ~

H lQ H2N--C--CO--NH--~CH2)C--CH2--C6H5 ¦ R -O-CO-Cl ~

R -O-CO -NH-CH2- CH - CO -NH - (CH2)c-cH2-c6Hs j R -G-CO-Cl Rl-O-CO -Nh-CH2- C - CO -NH -(CH2) -CH2-Co'i H '~

Scheme l6:
Compounds of the general formula Ib, R---CO--NH--CH2--C--CO--NH--(CHR3) --Cr.R~--Ar Ib ~3 where R;, R2, R3, R~, and c are as defined above a-e prepared according to Svnthetic Scheme l5.
Aminoesters 3 are reacteà with carboxyl_c acid chlorides to give the amides 18. The ester groups of compounds 18 are hydrolyzed with lithium hydroxide to the carboxylic acids 19, which are converted to activated esters, e.g., with pentafluorophenol and dicyclohexylcarbodiimide to the pentafluorophenyl esters. The activated esters are reacted with an appropriate amine to an amide of formula 20. Further conversions at R3 and R4 are done in analogy to known methods.

WO 92/OqO45 PCr/US91/06180 20881~

R2 ~2 ~2~--C~2--'~--C02E~ Rl-CO-Cl Rl--CO--Nr.--CH2--¢--''02Et 3 ~ H

LiOH
Rl--CO--NH--CH2--C--CO2H

1 9 ~

Rl--CO--NH--CH2--¢--CO--NH--(CHR3) c--CHR4--A-W092/04045 PCT/~'Sgl/061 Scheme 17 Compounds o' general formula Ic, R---O--CO--NH--C--CO--NH--(CHR3) --CHR;--P.

CH2 Ic H
are prepared to Svnthetic Scheme 17.
1-(3'-indolyl)-butan-3-one is converted with potassium cvanide and ammonium carbonate in a Bucr.erer synthesis to the hydantoin 21, which is hydrolyzea with aqueous sodium hydroxide to the amino acid 22, which is consequently esterified with methanol a~d hydrogen chloride to 23. Compound 23 is reacted with chloro-or fluoroformates to the carbamic acid esters 24. The ester groups of compounds 24 are hydrolyzed with lithium hydroxide to the carboxylic acids 25.
Acids 25 are converted to activated esters, e.g., with pentafluorophenol and dicyclohexylcarbodiimide to the pentafluoro phenyl esters. The activated esters are reacted with an appropriate'amine to an amide of formula 26. Further conversions at R3 or R4 are done in analogy to known methods.

WO 92/04045 PCr/US91/06180 208819~

SYNTHETIC SCHE2~: 17 CH2--C:i2--C~--ch3 Ci2--ci2 Me R (N:-i4) 2CC3 ~XN- NaO:-.
e:-a;Aec-on Le::. ~ a~, 2577 Me Me I .
:i21`i--C--C2r H2N--C--C02Me MeOH" H' I R -O-CO-C:
(CH2) 2 _ (cH2) 2 2~ ~ 21 ~3 H H

Me Me R;--O--CO--NH--C--CO2Me LiOH R~--O--CO--NH--C--CO2H
(cH2) Z (cH2) 2 H H

Me h --O--CO--NH--c--CO--NH--(C:~R31c--CHR4--.6:iS
(cH2) 2 2~ ~ ' ' .

W092/04~5 PCT/US91/0618 9~ -68-Scheme l8 Compounds of general fo_mula Id, p2 R --C--CO--NH--(CH2) 2--C--CO--NH--(C~ --CH~ CCH~
CH2 , ,, ?~3 where R-, R-, R4, and c are as de-ined above and R2 =
Me are prepared according to Svn hetic S-heme 18.
Diethyl methylmalonate 27 is alkylated with gramine and a base, e.g., NaOH in toluene, to compound 28 by known methods. The diester 28 is hydrolyzed with potassium hydroxide to the mono acid 29. The ester group of 29 is selectively reduced with borane methyl sulfide complex to compound 30, which is esterified with methanol and sulfuric acid to the methyl ester 31. The hydroxy compound 31 is reacted with p-toluene-sulfonyl chloride and pyridine to the tosylate 32. Nucleophilic substitution with potassium cyanide gives the cyanoester 33, which is hydrogenated catalytically with Raney nickel alloy to the amino ester 34. The amino ester 34 is reacted with chloro-or fluoroformates to the carbamic acid esters 35. The ester groups of compounds 35 are hydrolyzed with lithium hydroxide to the carboxyli- acids 36, which are converted to activated esters, e.s., with pentafluo-ophenol and dicyclohexylcarbodiimide to the penta'luorophenyl esters. The a^tivated esters are reacted with an appropriate amine to an amide of formuia 37. Further conversions at R3 and R4 are done in analogy to known methods.

WO 92/04045 PCl/US91/06180 2~8819~

SYNTHETIC SCHE~; 18 Me Me E:C2C--CH--CO2-- gramine E:C2C--C--CO2E_ KO:-, analog to J. Org. Chem 0795~, ~, 144S, 1447 CH2 2~ ~o .:
Me Me 3H3 ' Me25 ¦CH30U, R, E:v2C--'--CC2- HO--C.'i2--C--C02H
ci2 C'2 H H

Me Me TsCi I KCN
HO-CH2--C--C02Me ~ Ts--O--CH2--C--C02Me :~y-idine Me Me NC-CH2--C--C02tMe H2 H2N--CH2--CH2--C--C02Me Rl-O-CO-Cl CH2 C:i2 -' ~13 3~ ~

Me Me R; ---CO--N ---(C-2) 2--C--C02Me LiOH R;--O--CO--Nr.--(_H2) 2--C--C02H
CH2 Cn2 _ ~ ~ ~

R;--O--CO--NH--(CH2~ 2--C--CO--NH--(CHR3)c--CHR~--C$7s CH~

u H N

M~ 2 M;~
,~ OCONH COCHN2 ~g~OCONH~ C02H

~3 H N
M~ ~ 4 M~o~
~ OCONH CH2CO2C . ,~ ''.

H

h ~ n Reaaents: 1) N-Methylmorpholine, iBuoCOCl; 2) CH2N2;
3) AgOCOPh, HOCH2Ph, AgOCH2Ph, 4) H2Pd/C; 5) DPP, DCCi, Phenylglycine Methylester; 6) CiOP.

W092/04045 PCT/USg1/06180 M ~ ~ y ~

M
OCONH CONH

Rezaents: 1) DCCi, DMF; 2) Phenylglycine, DMF

W092/04045 PCT/US~1/06180 Me ~ - 3-ind Me ~ - 3-ind ~ ~ ~ _rPh 2-Ad-OCON COOH 2-AdOCON CONH
H H

1) LiBH4, 2) pTsO~
Me3SiCl Me ~ 3-ind 2-AdOCON C:i2NH-r H . Tosylate / (30% baQed on rec. SM) AcCl / ¦EtO2C ~ COC

~ ~Et3N

Me ~ 3- nd Me ~ 3-1nd 2-AdOCON CH2N 2-AdOCON Cn2N
H I H I COOEt 192 1~_ (81%) jLiOH

Me ~ 3-ind 2-AdOCON C~2N-r CO~,COOH

l9d (81%) W092/04045 PCT/US9l/Q618Q

_73- 2 ~ 8 81 9 1 ) pentafluoro?heno' 3-ind /3_.n~
~ 2) (S)-Pne-oi 2-AdOCON ~ COOH ' 2-AdOCON ~ C:' P:
H H O J
,.
(71%) 1) t-3uMe2SiCl (75%) 2) Lawesson's (21~) 2eagent ~

/3-ind 2-AdOCON ~l ~
~.~i Pn W092/04045 PCT/USg1/0618 (See Examples 97-102) ..
O Na O

C ~, Cd~Cr; _ ~o'`-7C:

Gramine me~hi~dide CH;
~7~`t CH CH

¦ OH /H20 ~CH;

,0[~ ~, N~12 ~OH
OH ~f ~ NH ~

¦ MCeOH/H20 H2N~o~O H

DC~, ~;

""'0~

WO 92/04045 PCI~/US91/06~80 208819~

SYNTHETIC SCHEME 23 (cont) ~NH2 4 h~ CC ~ ~z o:~ i H20 [~ ~NH

lQ

2 "", :, o~~ l~CC

[~NN----h20/~.Cl ¦ ¦_ ~'` tO, ~\OH
OH

WO 92/04045 PCJ/~'S91/06180 S YNTHE T I C S CHE~; 2 3 ( c ont ) N 2 "~S

[~ ~ooH -- 1~ S

~ o 1) HC' (5) ¦ CH2C12 o 2 ) K2Co3 CH3 ~ ~ OCCl CH3 NH ~ ~ NH

H
~ a,b HCl/H~O ~

a, b WO 92/04045 PCT/US~1/061g~
2~3881~3 SYNTHETIC SCEIEME 23 (co~t) [~0~ ~N~

~Cl(g)~ 19 ~/CH2C12 1 ~3 NH~C02CH3 O

~,OCCl N ~ N

NEt3 ~ N~2 ~N~ [~

W092t04~5 PCT/US91/06180 The biological activity of compounds of the present invention was evaluated employing an initial screening test which rapidly and accurately measured the binding Oc the tested compound to known CCK
receptor sites. Specific CCK receptors have been shown to exist in the central ne-vous system. (See Hays et al, Neuro~e~tides 1:53-62, 1980; and Satuer et al, Science 208:1155-1156, 1980).
In this screening test, the cerebral cortices taken from male CFL~ mice weighing between 30-40 g we e dissected on ice, weighe~, and homogenized in 10 volumes of 50 mM Tris-HCl buffer (pH 7.4 at 0-4C).
The resulting suspension was centrifuged~ the supe~nate was discarded, and the pellet was washed by resuspension in Tris-HCl buffer followed by recentrifugation. The final pellet was resuspe~ded _n 20 volumes of 10 nM Hepes buffer (pH 7.2 at 23C) containing 130 mM NaCl, 4.7 nM KCl, 5 nM MgC12, 1 nM
EDTA, 5 mg/mL bovine albumin, and bacitracin (0.25 mg/mL).
In saturation studies, cerebral cortical membranes were incubated at 23C for 120 minutes in a final volume of 500 ~L of Hepes incubation buffer (pH 7.2) together with 0.2-20 nM tritiated-pentagastrin (Amersham International, England).
In the displacement experiments, membranes were incubated with a single concentration (2 nM) of ligand, together with increasing concentrations (10- -to 10-1~M) of competitive test compound. In each case, the nonspecific binding was defined as that persisting in the presence of the unlabeled octapep~ide CCK26_,, -o Following incubation, radioactivity bound to mem~ranes was separated from that free in solution by rapid filtration through Whatman GF/B filters and W092/04045 PCT/USg~/06180 _79_ 208819~
washed three times with 4 mL o f ice cold T-is-HC1 buffer. Filters from samples incubated with tritiated-pentagast~in were placed in polyethylene vials with 4 mL of scintillation cocktail, and th-radioactivity was estimated by liquid scintillationspe^=rometry (e''iciency 47-52%).
The specific binding to CCK receptor sites was def-ned as the total bound t-itiated-pentagastr_r.
minus the amount of tritiated-pentagastrin bound in the ?resence of 10-~ octapeptide, CCK~6~
Saturation curves for specific tritiated-pentagastrin binding to mouse cortical membranes were analyzed by the methods of Scatchard (Ann. New Vork Acad. Sci. 51:660-672, 1949, and Hill (J. Phvsiol.
40:,V-VIII, 1910), to provide estimates fo- the maximum number of binding sites (Bmay) and the equilibrium dissociation constant (Ka)~
In displacement experiments, inhibition curves were analyzed by either logit-log plots or the iterative curve fitting computer program ALLFIT
~DeLean, Munson and Redbard, 1978) to provide estimates of the IC50 and nH (apparent Hill coefficient) values). (IC50 values were defined as the concentration of test compound required to produce 2; 50% inhibition of specific binding.) The inhibition constant (Ki) o~ the test compcund was then calculated according to the Chen~-Prusoff equation:
K IC!jC
1 1 [L]/Xa where [L] is the concentration of radiolabel and Ka is the equilibrium dissociation constant.

W092/04~5 PCT/US91/06180 S~9 The K. values for several representative compounds of the present invention are present in Table III.
The utility of the compounds of the present invention as appetite suppressants is tested according to the procedure described hereinbelow.
In the Palatable Diet Feeding assay, adult male Hooded Lister rats weighing between 200-400 g are housed individually and trained to eat a palatable die~. This diet consists of Nestlés sweetened condensed milk, powdered rat food and rat water whicn when blended together set to a firm consistency. Each rat is presented with 20-30 g of the palatable diet for 30 minutes per day during the light phase of the light-dark cycle over a training period of five days.
The intake of palatable diet is measured by weighing the food container before and after the 30-minute access period (limits of accuracy 0.1 g). Care is taken to collect and correct for any spillage of the diet. Rats are given free access to pellet food and water except during the 30-minute test period.
After the training period, dose-response curves are constructed for CCK8 and several representative compounds of the present invention (n = 8-10 rats per dose level). MP~50 values ('95% confidence limits) are obtained for the anorectic effects of these compounds and are shown in Table III.
In therapeutic use as appetite suppression agents, the compounds of the instant invention are administered to the patient at dosage levels of from about 200 to about 2800 mg per day.
Table III below s:,ws the binding data for 2088~95 TABLE III
Binding Data on Cerebral Cortexes Taken From Male CFLP Mice Binding to Central CCK
Example Number Receptors Ki (nM) 3 Isomer 1 1230 3 Isomer 2 780 21 >100 >10~

NT = Not tested W092/04~5 PCT/US9l/06180 ~ale Hooded Lister rats (175-250 g) are housed individually and are caused to fast ove-night (free access to water). They are anesthetizsd wi~h u e~hare (1.5 g/kg IP) and the trachea cannulated to aid spon-aneous respiration. The stomach is per'use~
conlinuously using a modification of the originai methoc o' Ghosh & Sch_ld in "Con,inuous reco-dins o' acid secretion in the rat", Brit. J. P:-,a~mac. 13:54-61, 1956 as described by Parsons ir. "Quantita;ive studies of drug-induced gastric acid secretion".
(Ph.D. Thesis, University of London, 1969). The cavi-y of the stomach is perfused at a rate of 3 mL/min with 5.4% w/v glucose solution through both the esophageal and body cannula. The fluid is propelled by a roller pump (Gilson, ~iripuls 2), through heating coils to bring its temperature to 37 ~ 1C. The perfusion fluid is collected by the fundic collecting funnel and passed to a pH electrode connected to a Jenway pH meter (PHM6). An output is taken from the pH meter to a ~ikadenki chart recorde-for the on-line recording of the pH of the gastric per'usate.
Pentagastrin is stored as a frozen aliquot and diluted to the required concentrations with sterile 0.9% w/v NaCl. Novel compounds are dissolved in sterile 0.9~ w/v NaC1 on the d~y of the experiment.
Drugs are administered IV through a cannulated jugula-vein as a bolus in a dose volume of 1 mL/kg washed i-.
with 0.15 mL 0.9% w/v NaCl. Basal pH is allowed to stabilize before administration of compounds is begur Typically 30 minutes elapses between surgery and the '_rst compound administration.
The compounds of the instant invention are also useful as antiulcer agents as c scussed hereinbelow.

Aspirin-induced gastric damage is zssessed in groups of 10 rats each.
Ali animals are made to fast for 2 hours before and du~ing the expe~iment. Drug or vehicle is giver.

10 minutes before an or21 dose o' 1 mL c' a 45-mg/mL
suspension of aspirin in 0.5% ca-boxyme-hylcellulose (CMC).
The animals are sac-ificed 5 hou_s af~e- aspi-_n administration and the stomachs removed and opened fo-examina_ion.
Gastric damage is scored as follows:
Score 1 Small hemorrhage 2 Large hemo-rhage 3 Small ulce-4 Large ulcer Perforated ulcer The specific dosages may, however, be varied depending upon the patient, the severity of the condition being treated, and the activity of the compound employed. Determination of optimum dosages is within the skill of the art.
The compounds of the instant inven-ion are also useful as anxiolytic agents as described and discussed below. Anxiolytic activity is assessed in the light/dark exploration test in the mouss (3. J. Jones, et al, Brit. J. Pharmac. 93:985-993, 1988).
The apparatus used is an open-topped box, 45 cm long, 27 cm wide, and 27 cm high, divided into a small (2/5) area and a large (3/5) area by a partition that extended 20 cm above the walls. There is a 7.5 x 7.5 cm opening in the par'ition a~ floor level.
The small compartment is paintec black and the large compartment white. The floor of each compartment is marked into 9 cm squares. The white compartment is W092/04045 PCT/USg1/06180 illuminated by a 100-watt tungsten bulb 17 cm above the box and the black compartment by a similarly placed 60-watt red bulb. The laboratory is illuminated with red light.
All tests are performed between 13 hundred hours, 0 minutes and 18 hundred hours, 0 minutes. Each mouse is tested by placing it in the center of the white area and allowing it to explore the novel environmen fo- ive minutes. Its behavior is recorded on videotape and the behavioral analysis is performed subsequently from the recording. Five parameters are measured: the latency to entry into the dark compart-ment, the time spent in each area, the number of transitions between compartments, the number of lines crossed in each compartment, and the number of rears in each compartment.
In this test an increase in the time spent in the light area is a sensitive measure of, that is directly related to, the anxiolytic effects of several standard anxiolytic drugs. Drugs were dissolved in water or saline and administered either subcutaneously, intraperitoneally, or by mouth (PO) via a stomach needle.
The compounds of the instant invention are useful as antipsychotic agents and can be tested for their ability to reduce the effects of intra-accumbens amphetamine in the rat as described hereinafter.
Male Sprague Dawley (CD) Bradford strain rats are used. The rats are housed in groups of five at a temperature of 21 ~ 2C on a 12 hour light-dark cycle of lights-on between 07 hours 00 minutes and 20 hours 00 minutes. Rats are fed CRM diet (La~sure) and allowed water ad libitum.
Rats are anesthetized with chloral hydrate 3S (400 mg/kg SC) and placed in a Kopf stereotaxic frame.

208819~

Chronically indwelling guide cannulae (constructed o stainless steel tubing 0 65 mm diameter held bilaterally in Parspex holders) are implanted usins standard stereotaxic techniques to terminate 3.5 mm above the center of the nucleus accumber.s ~Ant. 9.4, Vert. 0.0, Lat. 1.6) o- 5.0 mm above the central nucleus of the amygdala (Ant. 5.8, ver~. -1.8, Lat. ~4.5) (atlas of De Groot, 1959). ~he guides z-e kept patent during a 14-day recovery pe-iod using stainless steel stylets, 0.3 mm diamete-, which extended 0.5 mm beyond the guide tips.
Rats a-e manually restrained and the stylets removed. Intracerebral injection cannulae, 0.3 mm diameter, are inserted and drugs delivered in a volume of 0.5 ~L over 5 seconds (a further 55 seconds was allowed for deposition) from ~amilton syringes attached via polythene tubing to the injection units.
Animals Are used on a single occasion only.
Behavioral experiments are conducted between 07 hours 30 minutes and 21 hours 30 minutes in a quiet room maintained at 22 i 2C. Rats are taken from the holding room and allowed 1 hour to adapt to the new environment. Locomotor activity is assessed in individual screened Perspex cages (25 x 15 x 15 cm (high) (banked in groups of 30) each fitted with one photocell unit along the longer axis 3.5 cm from the side; this position has been found to minimize spurious activity counts due to, for example, preenins and head movements when the animal is stationary.
Interruptions of the light beam are recorded every 5 minutes. At this time animals are also observed for the presence of any nonspecific change in locomotor activity, e.g., sedation, prostration, stereotyped movements, that could interfere with the recording o' locomotor activity.

~9~ -86-The abilities of the compou-ls of the invention ~o inhibit the hyperactivity causea by the injection o - amphetamine into the nucleus accumbens o' the rat are measured.
An increase in locomotor activity followed the bilaterai injection of amphetamine (20 ~g) into the nucleus accumbens; peak hyperactivity (50 to 60 COU3=S
5 minutes~l) occurs 20 to 40 minutes af,er injectior This tes_ is known to be predic~ive o~ antipsychotic activity (Costall, Domeney & Naylor & Tyers, Bri_. J. ~harmac. 92:881-894).
The compounds of the instant invent on prevent and treat the withdrawal response produced when chronic treatment by a drug is stopped or when alcohol abuse is stopped. These compounds are the-efore useful as therapeutic agents in the treatmen of chronic drug o_ alcohol abuse as discussed and described below.
The effect of the compounds of the instant invention is illustrated, for example, in the mouse "light/dark box" test wherein five animals are given nicotine, in a range of 0.1 to 100 mg/ks i.p. b.d. for 14 days. After a 24-hour withdrawal period, compound (20) is given at 1.0 mg/kg i.p. b.d. The increased time spent in the light area is a sensitive measure of the effect of compoun~ (20) as an agent to treat withdrawal effects from nicotine.
For preparing pharmaceutical compositions from the compounds of this invention, ine-t, pharmaceutically acceptable carriers can be either solid or liquid.
Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances which may also act as diluents, 'lavoring agents, solubilizers, lubricants, suspending agents, binders, W092/04~5 PCT/US91/06180 -87- 2~88195 or tablet disintegrating agents; it c2n also be an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active com?onent is mixed with tne carrier having the necessary _ind_ng prope-_ies in suitable proportions an~ compacted in the shape and size desired.
For preparing suppository prepara_ions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and tne active ingredient is dispersed therein by, fo~ example, stirring. The molten homogeneous mix~ure is then poured into convenient sized molds and allowed to cool and solidify.
The powders and tablets preferably contain 5% to about 70% of the active component. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl celluloQe, a low-melting wax, cocoa butter, and the like.
Preferred pharmaceutically acceptable salts are the N-methyl glucamine salt and sodium.
~ harmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydrochloride, hvdroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, q.~ ' ' phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannata, tartrate, teoclate, triethiodide, benza_hine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, anc zinc.
The term "preparation" is intended to include the formulation of the active component with encapsula_ing material as a carrier providing a capsule in which the ac~ive component (with or without other carriers) is su-rounded by a carrier which is thus in association wi'h it. Similarly, cachets are included.
Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid form preparations include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring asents, stabilizers, and thickening agents as desired.
Aqueous suspensions for oral use can be made by dispersing the finely divided ac_ive component in water together with a viscous material such as natural synthet-c gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
Preferably the pharmaceutical preparation is in unit dosage form. In such form, the preparation is W092/04045 PCT/USgl/061~
2~8~

divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged prepara.ion, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be z capsule, cachet, o- tablet itself, or i' can be the appropriate number of any o' these packaged forms.

E~PLES

Tricvclo~3.3.1.13~7ldec-2-vl(R)- r 1- ( lH-indol-3-vl-methvl)-2-(methoxvmethylamino)-2-oxoethvllcarbamate (2) To a solution of acid (1) (859 mg, 2.25 mmol) in dichloromethane ~8 mL) was added N-methylmorpholine (495 ~L, 4.50 mmol). The mixture was cooled to -15C
(CO2/benzyl alcohol) and isobutylchloroformate (292 ~L, 2.25 mmol) was added. The mixture was stirred at -15C for 15 minutes followed by the addition of N,O-dimethylhydroxylamine hydrochloride (219 mg, 2.25 mmol). The reaction mixture was stirred at -15C for 1 hour, then warmed to room temperature and stirred for a further 15 hours. The mixture was filtered and the filtrate washed sequentially with sodium hydrogen carbonate, water, 10% citric acid and brine, dried (MgSO4) and evaporated to dryness. The crude material was purlfied by column chromatography to give hvdroxamate (2) (694 mg, 73%) as a white foam;
m.p. 72-80C. (Found: C, 67.4; H, 7.35; N, 9.8%.
C24H~1N3O4 requires C, 67.7; H, 7.3; N, 9.9%); [a]20 =
-9.4 (C = 0.3, CHC13); (S-ISOMER) [a]2o = +8.9 (C =
0.3, CHC13)); ~maY (film); 1 695 (CO urethane), l 657 (CO amide) 741 cm~1 (disubstituted Ph~; H (CHCl3), ~

W092t04045 , PCT/US91/06180 0~

1.30-2.01 tl4H, m, adamantyl), 2 99-3.24 (SH, m, indole CH2 + NCH3), 3.58 (3Y., s, OCH3), 4 7 (lX, s, adamantyl 2-H), 5 00 (lH, br d, CH (N~.R)CON-), 5.36 (lH br d, urethane NH), 6.92-7.17 (3H, m, indol~
2,5,6-H), 7.27 (lH, d, J 8 Hz, indole 7-H), 7.53 (1:~, d, J 8 Hz, indole 4-H), 7 99 (lH, s, indoie NH) Tricvclo~3 3 1.13~ ldec-2-vl(R)-~l-Cormvl-2-(l:-.- ndol-3-vl)e'hvl carbamate (3) Lithium aluminum hydride (45 mg, 1 2 mmol) was added portionwise over a period of 30 minutes to a solution of the hydroxamate (2) (197 mg, 0 460 mmol) in TH- (3 mL) at 0C The mixture was st-rred for z further 30 minutes, then ether (30 mL) w~ added followed by an ice cold solution of 10% citric acid (40 mL) The mixture was stirred vigorously for 30 minutes, then the layers were separated and the aqueous layer extracted with ether (5 x 10 mL). ~he ether extracts were combined and sequentially washed with saturated sodium hydrcgen carbonate (25 mL), water (25 mL), 10% citric acid (25 mL), and brine (25 mL), dried (Na2SO9) and concentrated in vacuo to give aldehvde (3) (140 mg, 83%) as a white foam;
(film) 1 725 sh (aldehyde C=O) and 1 693 cm~
(urethane C=O); H (300 M Hz; CDC13), ~1 47-2 13 (14H, m, adamantyl), 3.26 (2H, d of d, J 15 and 7 Hz,-indCH2), 4.58 (lH, br d, CH(NH~)CHO), 4.84 (lH, s, adamantyl 2-H), 6.98-7.26 (3H, m), 7.35 (lH, d, J
8 Hz, indole 7-H), 7.60 (lH, br d, J 8 Hz, indole 4-H), 8.24 (lH, br s, indole NH), 9.64 (lH, s, CHO).

W092/04~5 PCT/US91/06180 208~19~

--91-- ,, Tricvclo r 3.3.1.13~71dec-2-YlrS-(R)l- r 2-~tl-(hvdro~v-methvl)-2-phenvlethvllaminol-1-(lH-indol-3-vlme'hvl)ethvllcarbamate (4), EY.am~le 1 Sodium cyanoborohydride (37 mg, 0.59 mmol) was added portionwise over a period of 15 minutes to a solution of aldehyde (3) (136 ms, 0.370 mmol) and (S)-2-amino-3-phenyl propanol (61 mg, 0.40 mmol) i?.
methanol-acetic acid (99:1) (5 mL). The mix;u_e was stirred for 2 hours at room temperature then chilled (ice bath). Saturated sodium hydrogen carbonate (30 mL) was added with stirring, followed by ethyl acetate (45 mL). The organic layer was separated, washed with brine (5 mL), dried (Na2SO~) and evaporated to dryness. The crude product was purified by column chromatography (SiO2:dichloromethane-methanol (95:5) as eluant] to give amino alcohol (4) (60 mg, 32%) as a beige foam; m.p. 59-61C. (Found:
C, 73.7; H, 7.8; N, 8.3%. C3lH39N3O3 0.2 H2O requires C, 73.7; H, 7.9; N, 8.3%); ~maX (film) 3 325 (OH), 1 690 (CO urethane), 1 496 (N-H), 1 266 (OH), 1 048 (C-O), 740 and 701 cm 1 (monosubstituted Ph); H (CDC13) 1.31-2.04 (16H, m, adamantyl + NH + OH), 2.44-3.01 (7H, m, indCH2, -CH2NH-, CH2Ph, NH-CH(CH2OH)CH2Ph), 3.21 (lH, dd, J 11 and 6 Hz, CH of CH2OH), 3.47 (lH, dd, J 11 and 4 Hz, CH of CH2OH)! 3.97 (lH, m, -CH2CH(NHCO2R)CH2NH-), 4.66 (lY., br d, urethane NH), 4.73 (lH, s, adamantyl 2-H), 6.87 (lH, d, J 2 Hz, indole 2-H), 6.96-7.24 (7H, m, indole 5,6-H + Ph), 7.29 (lH, d, J 8Hz, indole 7-H), 7.55 (lH, d, J 7 Hz, indole 4-H), 7.97 (lH, brs, indole NH).

W092/0404~ PCT/US91/061~
9~

EXAMoeLE 2 Tricvclo r 3.3.1.13 7ldec-2-vl rs- (s) l-2- r rl- (hvdroxv-methvl)~2-~henvlethvllaminol-1-(lH-indo;-3-vlmethvl)-ethvllcarbamate (5) Exam~le 2 Compound 5 (253 mg, 23%) was synthesized using the same procedure as that described above _or compound (4). White foam, m.p. 62-63C. (Found: C, 73.3; X, 7.8i N, 8.3%. C~,H39N30, 0.4 H2O requires C, 73.2; H, 7.9; N, 8.3~). Umay (film) 3 331 (OH), 1 692 (CO urethane), 1 513 (N-H), 1360 (O-H), 1048 (C-O), 739 and 701 cm~l (monoslbstituted Ph); :i (CDC13), 1.47-2.10 (16H, m, adamantyl + NH + OH), 2.54-3.04 (7H, m, CH2 indole, CH2NH, CH2Ph + CH2CH(CH2OH)CH2Ph), 3.30 (lH, dd, J 11 and 6 Hz, CH of CH2OH), 3.59 (lH, dd, J 11 and 4 Xz, CH of CH2OH), 4.06 (lH, m, -CH2CH(NHCO2R)CH2NH-), 4.81 (2H, br s, adamantyl 2-H +
urethane NH), 6.86 (lH, brs, indole 2-H), 7.06-7.32 (7H, m, indole 5,6-H ~ Ph), 7.35 (lH, d, J 8 Hz, indole 7-H), 7.59 (lH, d, J 8 Hz, indole 4-H), 8.03 (lH, br s, indole NH).

_ricvclo r 3.3.1.13~ 7 ldec-2-vl- r 2-(lH-indol-3-vl)l-r r r ( 4-nitro~henvl)methoxvlcarbonvllam nolethvll-carbamate (6) To a solution of acid (1) (3.62 g, 9.74 mmol) in anhydrous THF (36 mL) at -10C was added N-methylmorpholine (1.15 mL, 10.4 mmol) and n-isobutyl chloroformate (1.35 mL, 10.4 mmol). This mixture was stirred for 20 minutes at -10C then filtered.
Trimethylsilyl azide [Aldrich] (i.89 m~, 14.2 mmol) was added to the filtrate and the resulting solution stirred at -10C for 1 hour. The solvent was then removed in vacuo at 25C and the residue partitioned between ethyl acetate (100 mL) and sa'urated sodium W092/04045 PCT/~'S91/061~
208819~

hydrogen carbonate (100 mL). The layers were separated and the organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo at 25C The residue was taken up in toluene (100 mL) and treatec at 40C until rearrangement to the isocyanate was complete. (IR: Umav N~ 2139, ~ma~ NCO 2249 cm~ ).
p-Nitrobenzylalcohol (2.20 g, 14.3 mmol) and DABCO
(149 mg, 1.33 mmol) were added and the mixture lef_ at 40C for 15 hours. The solvent was removed in vacuo and the crude product purified by column chromatography [SiO2:ether-hexane (4:1) as eluant] ,o give (6) (2.12 g, 42%) as a yellow solid which was recrystallized from ether/hexane, m.p. 148-149C. Y.
NMR (300 m Hz), ~1.39-2.03 (m 14H, adamantyl), 3.07 (brs, 12H, CH2 ind + H2O/HOD), 4.64 (s, lH, adamantyl 2-H), 5.14 (s, 2H, CH2Ph), 5.37 (m, lH, CH
(NHCO2)-NHCO2), 6.90-7.29 (m, 4H, indole H-2, H-5, H-6, and NH), 7.34 (d, J 8 Hz, 2H, H-subst. Ph), 7.46-7.62 (m, 3H, ind H-4, ind H-7, NH), 8.16 (d, J
8 Hz, 2H, 4-subst. Ph), 10.61 (s, lH, ind NH); IR
(film): 2908 + 2855 (adamantyl), 1703 (br, CO
urethane), 1520 (NO2), 1347 (NO2).
Anal. C29H32N4O6 requires C, 65.40; H, 6.06i N, 10.52.
Found: C, 65.25i H, 6.03i N, 10.50.

Tricvclo r 3.3.1.13~ldec-2-vl r 1 - r r r l-hvdroxvmethvl)-2-~henvlethvllcarbonvllaminol-2-(lH-indol-3-vl)ethvll-ca-bamate Com~ound (7), Exam~le 3 The urethane (6) (190 mg, 0.357 mmol) in ethyl acetate (36 mL) was hydrogenated over palladium hydroxide on carbon (Pearlman's catalyst) at 45 psi and 30C for 1 hour. The mixtu-e was filtered through celite to remove the catalyst into a flask containing W092/04045 ~ PCT/~S91/061~
~,9 the HOBT ester of 2-(acetoxymethyl)-3-phenylpropionic acid [the latter was generated via the reaction of 2-(acetoxymethyl)-3-phenylpropionic acid (8- ms, 0.36 mmol) in ethyl acetate (5 mL) with l-hydroxybenzotriazole (57.5 mg, 0.426 mmol) and DC-(85.9 ms, 0.416 mmol) at 0C for 30 minutes]. The resul~ing mixture was stir-ed a~ room tem?e-ature 'o-18 hours. The solution was concentrated in ~acuo, chilled (ice-bath), filtered, and evapo-ated to dryness. the residue was taken up in THF:MeOH:H2O
(3:2:1) (6 mL), lithium hydroxide monohydrate (2B ms, 0.67 mmol) added, and the mixture stirred at room temperature for 18 hours. The reaction mixtu e was ~oured into 2N HCl (50 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phase was washed with saturated NaCl, dried (MgSO4), Ciltered, and evaporated to dryness. The crude product was purified by column chromatography [SiO2: dichloromethane-methanol (95:5) as eluant~ to given an approximately 50:50 mixture of diastereomeric alcohols (7) (16 mg total, 8%) as yellow oils. Isomer I: TLC Rf = 0.24 (CH2C12-MeOH (95.5)); lH NMR (300 M Hz): ~1.43-2.04 (br m, 17H, adamantyl + H2O~, 2.42 (m, lH, NHCO, CH), 2.67-3.22 (br m, 5H, CH2 ind + CH2Ph + OH), 3.67 (m, 2H, CH2OH), 4.78 (s, lH, adamantyl H=2), 5.40 (brs, lH), 5.58 (brs, lH), 6.26 (brs, lH, amide NH), 6.82 (s, lH, ind H-2), 7.02-7.37 (m, 9H, ~h + ind H-5, ind H-6, ind H-7, + CHC13), 7.44 (d, J 8 Hz, ind H-4), 8.16 (s, lH, ind NH); IR (~ilm): 3540-3140 (br, OH), 2910 + 2855 (adamantyl), 1695 (urethane Co), 1660 (amide CO); Isomer II: TLC Rc = 0.19 [CH2Cl2-MeOH
(95:5); H NMR (300 M Hz): ~1.47-2.08 (m, 17H, adamantyl + H2O), 2.42 (m, lH, NHCO-CH), 2.61-2.97 (m, 3H, CH2 + OH), 3.19 (d, J 7 Hz, CH2), 4.68 (brs, 2H, 3; CH2OH), 4.75 (s, lH, adamantyl H-2), 5.18 (brs, lH), W092/04045 PCT/US9l/0618~
2088~95 _95_ 5.49 (brs, 1~), 6.30 (brs, lH, amide NH), 6.96 (s, lH, ind ~-2), 7.02-7.30 (m, gH, Ph + ind ~-5, ind ~-6 +
CHC13), 7.37 (d, J 8 Hz, lH, ind H-7), 7.57 (d, J
8 Hz, lH, ind H-4), 8.12 (s, lH, ind NH); IR ('ilm):
3520-3160 (br, OH), 2907 + 2855 (adamantyl), 1696 (urethane CO), 1660 (amide CO).

2-Adamantvloxvcarbonvltrvpto~handiazoketone (8) Pre~aration of diazomethane. CAUTION!
DIAZOMETHANE IS HIGHLY TOXIC AND EXPLOSIVE (NO GROUND
GLASS JOINTS). HANDLE WITH CARE IN A FU~E HOOD.
n-MET~YLNITROSUREA IS HIGHLY TOXIC AND CARCINOGENIC.
HANDLE IN A FUME HOOD USING A FULL FACE MASK AND
GLOVES.
A solution of 40% potassium hydroxide (4.5 mL, 32 mmol) was added dropwise to a suspension of N-methylnitrosurea (1.5 g, 15 mmol) in ether (25 mL), cooled in an ice-salt bath. After all the solid had dissolved (additional base is added if necessary), the ethereal solution of diazomethane was dried over solid potassium hydroxide. This drying process was repeated twice more and the diazomethane u~ed immediately.
To a solution of 2-adamantyloxycarbonyltryptophan (1) (1.77 g, 4.61 mmol) in THF (25 mL) at 0C was added N-methylmorpholine (557 ~L, 5.07 mmol) and isobutylchloroformate (6g8 ~L, 5.07 mmol). The miY.ture was stirred for 20 minutes at 0C, then filtered. To the filtrate was added a solution of diazomethane (10 mmoL) in ether (produced from N-methylnitrosurea (1.0 g, 10 mmol)). The resulting solution was stirred for 15 minutes at 0C, then for 15 hours at room temperature. The solvent was removed in vacuo and the residue taken up in ethyl acetate ~100 mL). This solution was washed with water W092/04045 PCT/~S91/06180 ~3 -g 6-(2 x 10 mL), 5% citric acid (2 x 10 mL), lN NaHCO
(10 mL), and brine ~10 mL). It was dried (MgS04) and the solvent removed in vacuo. The crude product was purified by column chromatosraphy [SiO2:hexane-ethyl acetate (5:4) as eluant] to give diazoketone (8) (1.35 g, 72%) as a yellow foam, m.p. 72-75C. v (CDC13 film) 2 109 (N2); 1 697 (CO) and 740 cm~
(disubstituted Ph); ~. (d6-acetone), ~1.39-2.02 (i4r, m, adamantyl), 3.13 (lH, dd, J 15 and 8 Y.z, CH o' C:i2 indole), 3.29 (lH, dd, J 15 and 5 Hz, CH of CH2indole), ~.51 (lH, m, CH2CH(NHR)CO), 4.69 (1:-, S, adamantyl 2-H); 5.90 (lH, brs, CHN2); 6.~1 (lH, s, Nr.
CO); 7.01 (lH, t, J 7 Hz, indole 5 or 6-H), 7.09 (lH, t, J, 7 Hz, indole 7-H), 7.61 (lH, d, J 9 Hz, indole 4-~.), 10.05 (lH, brs, indole NH).

2-Adamantvloxvcarbonvltrv~tophanvl Chloromethvl Xetone (9) Hydrochloric acid (11.1 mL of a 0.30 M solution in dioxane) was added dropwise with stirring to a solution of diazoketone (8) (1.35 g, 3.32 mmol) in THF
(100 mL) at 0C. The reaction was monitored by infrared for the disappearance of the N2 peak (2 109 cm~~) in the starting material. When all the diazoketone had gone (ca 60 minutes) the reaction mixture was quenched with saturated sodium hydrogen carbonate (20 mL). The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and saturated sodium hydrogen carbonate (1090 mL). The layers were separated and the aqueous extracted further with ethyl acetate (2 x 100 mL). The combined ethyl acetate fraction was washed with brine (50 mL), dried (MgSO4), and the solvent removed in vacuo. The crude product was rec-ystallized from ethyl acetate-hexane to give W092/0404~ PCT/USg1/061~
208819~

chloroketone (9) (1.29 g, 94%), m.p. 138-140C.
(Found: C, 66.6; H, 6.7; Cl, 8.3; N, 6.9~.
C2,~27ClN2O3 requires C, 66,6; H, 6.6; Cl, 8.5; N, 6.75%). ~maY (CDCl, film), 1 740 (CO a chloroketone), 1 698 (CO urethane), and 736 cm~l (disubstituted Ph);
H (CDC13) ~1.45-2.06 (14H, m, adamantyl), 3.27 (2P., m, CH2ind), 3.96 (lH, d, J 16 Hz, C:i o' CH2Cl), 4.1i (1:., d, ~ 16 ~2, CH of C:i2Cl), 4.83 (2H, m, CH2CHCO and adaman~yl 2-H), 5.35 (1~, d, J 7 Hz, NH), 7.00 (lH, d, J 2 Hz, indole 2-H), 7.14 (lH, t, 6 Hz, indole 5 or 6-X), ,.22 (lH, t, J 6 Hz, indole 5 or 6-H), 7.37 (lH, d, J 8 Hz, indole 7-H), 7.61 (lH, d J 8 Hz, indole 4-H), 8.20 (lH, s, indole NH).

a-r4-(lH-indole-3-vl)-2-oxo-3- r ~ (tricvclo~3~3~ 3 dec-2-vloxv)carbonvllaminolbutvllbenzene ~ro~anoic acid Com~ound (10) Exam~le 4 Sodium iodide (Aldrich) ~51 mg, 0.34 mmol) was added to a solution of chloroketone (126) (112 mg, O.27 mmol) in anhydrous DML (5 mL) at room temperature. This mixture was stirred at room temperature for 15 minutes, then an aliquot (800 ~L, 0.30 mmol) of an anion solution [generated by the reaction of sodium hydride (60% dispersion in oil) (88 mg, 2.2 mmol) in anhydrous DME (5 mL) with diethylbenzylmalonate (950 ~L, 4.0 mmol) at room temperature] was added. The resulting solution was stir_ed at room temperature for 2 hours. The solvent was removed in vacuo, the residue taken up in dichloromethane (50 mL), washed with brine, dried (MgSO~), and evaporated under reduced pressure. The crude material was purified by column chromatography [SiO2:hexane-ethyl acetate (2:1) as eluant] to yield ketodiester (100 mg, 59%); m.p. 49-54C. (Found: C, 70.8; H, 7.2; N, 4.4%. C37H44N2O? requires C, 70.7; H, W092/0404~ PCT/US91/06180 9~

7.05; N, 4.5%). U~a~ (CH2Cl2 film) 1 728 cm 1 ~CO)i Y
(CDC13 ~1.42-2.08 ~14H, m, adamantyl), 2.98 ~lH, d, J
19 Y.z), 3.18 (lH, dd, J 15 and 6 Y.z, CH2ind), 3.24 (lH, d~, J 15, and 6 Hz), CH2ind), 3.34 (2H, s, CH2), 4.18 (4H, m, 2 x CH2), 4.62 ~lH, m, CH2C:~(CO)NH), 4.7g (lH, s, adamantyl 2-H), 5.30 (lH, d, ~ 8 Hz, NH), 6.84 (2X, d, ~ 7 Hz, Ph 2,6-H), 6.92 (lH, d, J 2 P.z, indoie 2-H), 7.07-7.25 (5H, m, indole 5, 6-~ h 3,4,5-P.), 7.34 (1~., d, J 8 Hz, ind 7-H), 7.62 (lr., d, J 8 ~z, indole 4-H), 8.07 (lH, s, indole NH).

A solution of the keto diester (1.19 g, 1.89 mmol) in ethanol ~5 mL), and 6N NaOH ~946 ~L, 5.67 mmol) was stirred at room temperature for 1 hou_. The solvent was removed in vacuo and the residue diluted with H2O
~10 mL). This aqueous solution was acidified to pH 2 with concentrated HCl, then extracted with ethyl acetate (3 x 50 mL). The organic extract was washed with saturated sodium chloride solution, dried ~MgSO4) and concentrated in vacuo. The residue was taken up in dioxane ~30 mL) and refluxed for 18 hours. The solvent was removed in vacuo and the crude material purified by column chromatography [SiO2:
toiuene-acetic acid ~9:1) as eluant] to give ke~oacid ~10) ~783 mg, 78%) as a yellow foam, m.p. 66-80C. lH
N~R ~300 m Hz): yl.38-2.22 ~m, 16H, adamantyl + H2O), 2.55-3.25 ~vbr m, 12H, CH2ind, CH2Eh CO, CH2CH +
Y.2C/HoD), 4.26 ~m, lH, NHCHCO), 4.57 ~s, lH, adamantyl 2-H), 6.95-7.37 (m, 10H, Ph + ind 2-H, ind 5-r., ind 6Y, ind 7-H + NH), 7.49 (d, J 8 Hz, lH, ind 4-H), 10.58 ~s, lY., ind NH). IR ~film): 3460-3200 ~br, OH), 2920 + 2856 ~adamantyl) 1707 ~br, ester ketone CO, acid CO, urethane CO). Anal. C32H3~N205 requires C, 72.70; H, 6.86; N, 5.30%. Found C, 73.18; H, 6.98;
N, 5.05%.

2~88~9~

Tricvclo~3.3.1.13 7ldec-2-vl r 1- [ (2-hvdroxv-2-phenvl-ethvl)aminol-3-(lH-indol-3-vl~-2-methvl~rop-2-vll-carbamate (12) This com?ound was prepared by a route simila~ to tha' used to make compound (14) (Example 6) except that compound (11) was used. Recovered 0.42 g (43%);
m.p. 78-80C; IR (neat) 2910, 1694 (C = O urethane) cm~~ ; NMR (CDC13) ~ 8.1 (lH, br s, indoie N~), 7.6 (lH, d, J 8 ~.z, indole H-4), 7.4-7.1 (8n, m, Ph +
indole H-5, ~-6, ~-7), 7.0 (lH, m, indole H-2), 5.0-4.6 (3H, m, adamantane H-2 + urethane N:i + CHOH), 3.5-2.6 (6H, m, 3 x CH2), 2.1-1.5 (15H, m, adamantane +
OH) 1.4 (3~, s, CH3); [a]D + 18 (CHCl3, 22C, c =
0.2); FABMS (m+/e)502 (m++H); anal C3,H39N303. 0.5 H2Oi requires C 72.91%, H 7.90%, N 8.23%; found: C 72.56~, H 7.84%, N 7.95%.

EXAMP~E 6 Tricvclo[3.3.1.13~71dec-2-vl~R-(R* S*)l-l-~l-(hvdroxv-methvl~-2-~henvlethvl1aminol-3-(lH-indol-3-vl)-2-methvl~ro~-2-vlcarbamate (14) To a solution of lithium borohydride (4 mL, 2M
solution, 8 mmol) in dry tetrahydrofuran under nitrogen was added a solution o' chlorotrimethylsilane (1.75 g, 16.0 mmol) in dry tetrahydrofuran (5 mL). A
white ppt of lithium chloride was observed. After 2 minutes a solution of Compound (13), (1 g, 2 mmol) in tetrahydrofuran (15 mL) was added slowly (over 3 to 4 minute period) and the reaction was stirred for 20 hours at ambient temperature. The reaction was treated cautiously with methanol (5 mL) and the volatiles were removed in vacuo (40C). The residue was purified by flash chromatography on normal phase silica gel using hexane/ethyl acetate eluant (a W092/04045 PCT/~rSg1/~6180 9~

gradient elution technique was employed, ranging -om 80% hexane:20% ethyl acetate to 100% ethyl acetate).
Recovered 0.60 g starting material and 0.26 g (27%) desired product (14) as a white foam; IR (neat) 290G, S 1694 (C = O urethane)cm~l ; NMR (CDCl3) ~ 8.1 (1~, b-s, indole N~), 7.6 (lX, d, J 8 Hz, indole H-4), 7.4-7.1 (8:~, m, Ph + indole ~-5, H-6, Y.-7), 6.9 (1~, d, 2 ~.z, indole ~.-2), 4.9 (lH, s, urethane N~), 4.8 (1~, s, adamantane H-2), 3.6-3.3 (2~, m, CH2-OH), 3._ (2:-, m, CH2-indole), 3.0-2.6 (5H, m, 2 x CH2 + 1 x CH), 2.1-1.5 (15~, m, adamantane + OH), 1.25 (3H, s, CU.3).
A mono-4-toluenesulphonate salt was prepared by dissoiving (14) (0.2 g, 0.4 mmol) and 4-toluenesulphonic acid monohydrate (0.074 g, 0.40 mmol) in acetone (10 mL) and subsequent removal o solvent in vacuo to give a white solid;
m.p. 110-113C. IR (neat) 2915, 1790 (C=O
urethane) cm l; [a]D + 20 (CHC13, 23C, c=l) ~ FAB MS
(m+/e) 516 (m+ + H); anal: C32H4lN3O3-C7H8SO3 0~5H20 Requires: C, 67.22; ~, 7.23; N, 6.03; S, 4.60.
Found: C, 67.23; H, 7.26; N, 5.84; S, 4.36.

rR-(R*,S*)l-~-rr2-(1~-indol-3-vlmethvl)-2-r[tricvc'o-r 3.3.1.13~7ldec-2-vloxycarbonvllaminol~ro~vllaminol-benzene~ro~anol acetate (15) To a solution of (14) (0.05 g, 0.10 mmol) in dichloromethane (10 mL) at ambient temperature was added acetyl chloride (0.10 mL, 1.4 mmol) and the reactants were stirred for 1 hour, the volatiles were removed in vacuo (40C) and the residue pu-ified by iash chromatography usinc % hexane : 20% ethyl acetate as eluant. Recove 1 0.024 5, (44%) of (38) as an amorphous white solid. IR (neat) 2910, 1739 (C
= O ester), 1700 (C = O urethane)cm ; NMR (CDC13) ~

W092/04045 PCT/US91/061~

-101- 208819~
8.2 (lH, s, indole NH), 7.6 ~lH, d, J 8 Hz, indole ~-4), 7.4-7.0 (8H, m, Ph ~ indole H-5, H-6, H-7), 6.9 (lX, d, J 2 Hz, indole ~-2), 5.1 (lH, s, urethane NX), 4.8 (1~, s, adamantane H-2), 3.9 (2:-., d, J 4 Hz, CH2OCO), 3.1 (2H, m, CH2-indole), 3.G-2.5 (4H, m, C:i2Ph + C~2N), 2.1-1.4 (17;~, m, CH3CO + adaman_ane), 1.3 (3~., s, CH3).
A mono-4-toluenesulphonate salt was p_epared by dissolving (15) (0.02 g, 0.04 mmol) and 4-toluenesulphonic acid monohydrate (0.007 g, 0.04 mmol) in acetone (5 mL) and subseauent removal o-solven_ in vacuo to give a white solid, m.p. 98-101C;
[~13 + 32 (CHCl3, 24C, C = 0.5); FAB MS (m /e) 558.5 (m + H)i anal: C34H43N304 C7H8S03 H20 requires C
65.84~, H 7.14%, N 5.62%, S 4.29%. Found: C 65.48%, H
7.08%, N 5.53%, S 4.31%.

EXAMPL~ 8 rR-(R*~s*)l-B - racetvlr2-(lH-indol-3-vlmethvl)-2-rrtricvclor3.3.1.13~71dec-2-vloxvcarbonyllaminol-pro~yllaminolbenzene ProPanol acetate (15a) To a solution of (14) (0.05 g, 0.10 mmol) in dichloromethane (10 mL) at ambient temperature was added triethylamine (l mL, 7 mmol) followed by acetyl chloride (0.1 mL, 1.4 mmol) and the reactants stirred for 1 hour. The volatiles were remove~ in vacuo and the residue purified by flash chromatography using hexane:ethyl acetate as elua~t. Recovered 0.043 g, (74%) of (88a) as an amorphous solid; IR (neat) 2920, 1740 ~C = O ester), 1709 (C = O urethane), 1632 (C = O
amide) cm~l.

W092/04~45 PCT/USg1/06180 ~:b"9~
9~ -102-Tricvclo~3.3.1.13~7ldec-2-vlrR-(R*,S*)l-racetvl r 1 -(hvdroi:vmethvl)-2-phenvlethvllaminol-2-(lH-indol-3-vlmethvl)~ro~-2-vlcarbamate (16) To a solution of ~15a) (0.03 g, 0.05 mmol) in tet-ahydrofuran (5 mL) was added a solu,ion o' lithium hydroxide (0.1 g, 2.4 mmol) in water (5 mL) and the reactants stirred for 15 min. The reac'ion was 'hen acidified with hydrochloric acid (2N aq) and the produc~s extracted with ethyl acetate (50 mL). The extract was d_ied (magnesium sulphate) and eva?orated in vacuo (40C). The residue was purified by fiash chromatography using hexane:ethyl acetate eluan_.
Recovered 0.024 g (86%) of (89) as a white sclidi m.p.
109-112C, [a]D + 31 (22C, CHCl3, c = 0.5); IR
(neat) 2900, 1694 (C = O urethane), 1621 (C = O
amide)cm~l ; NMR (CDCl3) ~ 8.1 (lH, s, indole NH), 7.5 (lH, d, J 8 Hz, indole H-4), 7.4-7.0 (8H, m, Ph +
indole H-5, H-6, H-7), 6.9 (lH, s, indole H-2), 5.3 (lH, br, urethane NH), 4.8 (lH, br, adamantane X-2), 4.4 (lH, s, OH), 3.9 ~lH, d, J 12 Hz, one of CH2OH), 3.8-3.7 (2H, m, one of CH2OH + one of CH2N), 3.5 (lH, m, CH), 3.4 (lH, d, J 14 Hz, one of CH2 indole), 3.3 (lY., d, J 13 Hz, one of CH2N), 3.1 (2H, d, J 8 Hz, CH2Ph), 2.8 (lH, d, J 14 Hz, one of CH2-indole), 2.0 (3H, s, CH3CO), 1.9-1.4 (14H, m, adamantane), 1.1.
(3H, s, CH3); anal C34H4,N304- 0.5 H2O; requires C
72.06% H 7.82% N 7.41%; found C 72.20% H 7.73% N
7.30%; FAB MS (m/e) 558 (m + H).

EXA~2LE 9 Tricvclo r 3.3.1.13~71dec-2-vl (R)-~l-(lH-indol-3-vlmethvl)-2-methvl-2-~(2-~henvlethvl)aminol-2-th~oxoethvllcarbamate To a solution of (29) (0.1 g, 0.2 mmol) in toluene (10 m~) was added Lawesson's reager.t (0.10 g, W092/0404~ PCT/US91/06180 208819~

0.25 mmol) and the reaction was heated to reflux for 1 hour. The reaction was allowed to cool to ambient temperature and was purified by flash chromatography (dichloromethane/ether eluant). Recovered 0.065 g (63%) of 30) as a white foam, m.p. ~1-85C; IR (neat) 2916, 1703 (C=O methane), 1520 (C=S) cm~l; NMR (CDC13) ~8.1 (lX, br, indole NX), 7.8 (lH, br, this amide N~), 7.6 (lH, d, J 8 Hz, indole ~-4),7.5-6.9 (9H, m, indole ~-5, P-6, H-7, H-2, + phenyl), 5.3 (lH, br, urethane NX), 4.7 (lH, brs, adamantane ~-2), 3.8 (2H, m, CH2-N), 3.6 (lH, d, J 14 Hz, one of CH2-indole), 3.4 (lH, d, J 14 Hz, one of CH2-indole), 2.6 (2X, m, CH2-Ph), 2.0-1.6 (14H, m, adamantane), 1.5 (3H, s, CH3); R~ (30% ethyl acetate/hexane) 0.3.

Methvl (R)-4- r ( 2-hvdroxv-1-phenvlethvl)aminol-4-oY.o-2-butenoate (18) To a solution of monomethyl fumarate (3.0 g, 23 mmol) ïn ethyl acetate (40 mL) was added l-hydroxy~enzotriazole hydrate (3.0 g, 22 mmol), followed by N,N'-dicyclohexylcarbodiimide (4.5 g, 22 mmol) and the reaction stirred at ambient temperature for 1 hour. The solid was filtered of' and discarded. To the filtrate was added (R)-a-phenylglycinol (3.0 g, 22 mmol) and stirring continued for 20 minutes. The volatiles were removed in vacuo (40C) and the residue purified by flash chromatography on normal phase silica gel using hexane:ethyl acetate (l:l) as eluant. Recovered 2.5 g (46%) of (1~) as a white solid, m.p. 75-77Ci IR
(neat) 3250 (OH), 1729 (C = O ester), 1666 (C = O
amide), 1640 (C = C)cm 1 ; NMR (CDC13) ~ 7.3-7.4 (5X, m, Ph), 7.0 (1~, d, J 15 Hz, trans alkene), 6.8 (lH, d, J 15 Hz, trans alkene), 6.6 ~lH, br d, NX), 5.2 WO 92t04045 PCI~/US91106180 ~' H, m, CH), 3.9 ~2H, t, J 3 ~z, CH2), 3 8 (3H, s, CH3), 2.3 (lH, t, J 5 Hz, OH); [~]D ~53 (CHC13, 24C, c = l); anal C13Hl~N04; requires C 62.64~ H 6.07% N
5.62%; found C 62.72% H 5.92% N 5.48%.

Tricvcloi3.3.1.13~71dec-2-vl 3- r (lH-indo'-3-vl)methvl~-3-methv -4 9-dioxo-7-phenvl-5,13-diox2-2,8-diaze-tet_adec-10-enoate (19) To a solution of N,N'-carbonyldiimidazole (0.15 5, 0.90 mmol) in dichloromethane (40 mL) was added (23b) (0.25 ~, 0.63 mmol). After 20 minutes stirring at ambient temperature (18) (0.2 5, 0.8 mmol) was added and the reaction was heated to reflux for 10 hours.
On cooling to ambient temperature the volatiles were removed in vacuo (40C) and the residue was purified by flash chromatography (hexane/ethyl acetate eluant).
~ecovered 0.28 g ~71%) of (19) as a white solid, m.p.
96-99C. IR ~neat) 2910, 1730 (C=O ester), 1695 ~C=O
urethane), 1670 (C=O amide + C=C) cm~i: NMR (CDC1 8.3 (lH, br, indole, NH), 7.5 (lH, d, J 8 Hz, indole H-4), 7.4 (lH, d, J 8 Hz, indole H-5), 7.3-6.9 (lOH, m, indole H-6, H-7, H-2 + phenyl + amide NH + one o' al~ene CH), 5.3 (lH, br, one of CH2-0), 5.1 (lH, s, urethane NH), 5.0 (lH, br, CH), 4.8 (l:d, brs, adamantane H-2), 4.1 (lH, dd, J 11 Hz, 4 Hz, one of CH2-0), 3.8 (3H, s, CH3), 3.5 (1:-, d, J 14 Hz, one of CH2-indole), 3.3 (lH, d, J 14 Hz, one o' CH2-indole), 2.1-1.4 (18H, m, adamantane + C:-.3): ~]D + 25 (CHC13, 24C, C = 0.2): FAB MS (m~/e) 6281 (m~ + H): Anal;
C36H~N,07 requires C 68.88%; H, 5.58%; N, 6.69%; found C, 68.56%; H, 6.83%; N, 6.57%.

W092/04045 PCT/US91/061~
2~88l9s EXAMPL~ 11 Tricvclor3.3.1.13 71dec-2- Yl 3-~(lH-indol-3-vl)methvl1-3-methvl-4,9-dioxo-7-~henvldioxa-2,8-diazatetradec-10-enoate (20) Prepared by a route similar to that used to make compound (19). Recovered 0.30 g (76~) o' (20) zs z white solid, m.p. 104-105C; IR (neat) 292~, 1728 (C=O
ester), i720 (C=O) urethane), 1700 (C=C), 1670 (C=O
amide) cm~ ; NMR (CDC13i ~ 8.3 (1:-., b_, indole NX), 7.5 (lH, d, J 8 Hz, indole H-4), 7.4 (lH, d, J 8 Hz, indole H-5), 7.3-7.1 (7H, m, indole H-6, H-7 +
phenyl), 7.1-6.7 (4H, m, indole H-2 + amide NH +
alkenes), 5.3 (2H, br, urethane NH + one o- CH2-O), 4.8 (lH, br, adamantane H-2), 4.7 (lH, m, CH), 4.1 (lH, dd, J 11 Hz, 4 Hz, one of CH2-O), 3.8 ~3H, s, ester, CH3), 3.4 (lH, d, J 14 Hz, one of CH2-indole), 3.2 (lH, d, J 14 Hz, one of CH2-indole), 2.1-1.5 (17H, m, adamantane + CH3): [a]D-36O (CHCl3, 22C, C=l).
FAB MS (m+/e) 628 (m+ + H): Anal; C36H4lN3O7 requires C, 68.88%i H, 6.58%; N, 6.69%i found: C, 68.86%; H, 6.57%; N, 6.77%.

Methvi (R)-4-~(2-hvdroxY-l-~henvlethvl)zminol-4-oxobutanoate (21) Prepared by a route similar ~o that used to make compound (18) (see Example 10). Reco~ered 3.6 g, (65%) of (21); m.p. 59-61Ci IR (neat) 3250 (OH), 1737 (C = O ester), 1651 (C = O amide)cm~- ; NMR (CDC13) 7.2-7.4 (5H, m, Ph), 6.4 (lH, br d, NH), 5.1 (lH, m, CH), 3.7 (3H, s, CH3), 2.8-2.5 (6H, m, 3 Y. CH2), 1.7 (lH, br, OH); [a]D -53 (CHC13, 22C, c = l); anal C.3H17NO4; requires C 62.14% H 6.82% N 5.57%; found C
62.21% H 7.13% N 5.73%.

W092/04~5 PCT/USg1/06180 ~9~
~oo~
~V -106-Tricyclo~3.3.1.13 71dec-2-vl 3- r (lH-ind~1-3-vl)methvll-3-methvl-4,9-dioxo-7-Phenvl-5,13-dioxo-2,8-diazatetra-decanoate (22) To a solution of 1,3-dicyclohexylcarbodiimide (0.3 g, 1.5 mmol) and 4-dimethylaminopyridine (0.05 g, 0.40 mmol) i~ dichloromethane (40 m~) was added (23) (0.50 g, 1.3 mmol. After sti-ring for 20 minutes a.
ambient temperature (21) (0.30 g, 12 mmol) was added and the reaction was heated to reflux for 2 hou-s.
The volatiles were removed in vacuo (40C and the residue purified by flash chromatography (hexane/ethyl acetate eluant). Recovered 0.41 g (52%) as a white solid, m.p. 69-71C. IR (neat 2920, 1739 (C=O es~er), 1700 (C=O urethane), 1660 (C=O amide): NMR ~ (CDCl 8.3 (lH, br, indole NH), 7.5 (lH, d, J 8 Hz, indole H-4), 7.4-6.9 (lOH, m, indole H-5, H-6, H-7, H-2 +
amide NH + phenyl), 5.3 (lH, m, CH), 5.2 ~lH, brs, urethane NH), 4. 8 (2H, br, adamantane H-2 + one of CH2-O), 4.1 ~lH, m, one of CH2-O), 3.7 (3H, s, ester CH3), 3.4 ~2H, M, CH2-indole), 2.7-2.5 ~4H, m, 2xCH2), 2.1-1.5 (17H, m, adamantane + CH3): [a]D-18 (CHC13, 22C, C=l). FA3 MS (m+/e), 630.0 (m + H); Anal:
C36N~N,o? 0.5H2O requires C, 67.69; H, 6.94; N, 6.58;
found C, 67.36; H, 6.99; N, 6.51.
NOTE: some small peaks at ~4.4-4.2 in the NMR
spectrum may indicate the presence cf a small amount of another isomer.

ExAMoeLE 13 ricvclo[3.3.1.13~7ldec-2-vl (R)- r 2-hvdroxv-1-(lH-indol-3-vlmethvl)-1-methvlethvllcarbamate (24) To a solution of (23) R=Me) (1.0 g, 2.4 mmol) in d-y TH~ (20 mL) at 0C und_r a nitrogen atmosphere was added a solution of lithium aluminum hydride in ether (3 m~ of a lM solution, 3 mmol) and the reaction was -107- 2 Q8 81 9 ~
stirred for 20 minutes. Ethyl acetate (20 mL) was added cautiously and the resulting solution was washec with acid (2N HCl, 2x100 mL), dried over magnesium sulfate, and evaporated to dryness. Recovered 0.~5 g (91%) of (24) as a white solid, m.p. 72-74C; IR (nea~
2918, 1693 (C=O urethane) cm~ ; NMR (C~Cl3) ~ 8.1 (lF., br, indole NH), 7.6 (lH, d, J 8 Y.z, indole r.-4), 7.~5 (lH, d, J 8 Hz, indole H-5), 7.2-7.0 (3:-., m, indole H-6, r:-7, H-2), 4.85 (lH, b- s, urethane NH), 4.8 (1:-., br, adamantane H-2), 4.0 (lY, br, OH), 3.8 (2H, m, CH2-O), 3.25 (lH, d, J 14 Hz, one of CH2-indole), 3.0 (lH, c, J 14 Hz, one cc CH2-indole), 2.1-1.5 (14~, m, adamantane), 1.2 (3H, s, CH3); [~]D + 42 (CHC13, 22'C, C=l); FAB MS (m/e) 383 (m+ + H); Anal:
C23H30N2O3 0.5H2O requires C, 70.56%; H, 7.98%; N, 7.15%; found: C, 7.35%; H, 7.83%; N, 6.94%.

3-(lH-indole-3-vl)-2-methvl-2-rr(tricvclor3.3.1.13 71-dec-2-yloxv)carbonvllaminol~ro~vl (R)-benzeneacetate (25) To a solution of N,N'-carbonyldiimidazole (0.40 g, 2.5 mmol) in dichloromethane (20 mL) was added phenylacetic acid (0.30 g, 2.2 mmol). After 10 minutes stirring at ambient temperature alcohol (24) (0.3 g, 0.8 mmol) was added and stirring was continued for 40 hours. The volatiles were removed ln vacuo and the residue was purified by flash chromatography (hexane/5~ ethyl acetate eluant).
Recovered 0.30 g (77%) of (25) as a white foam, m.p. 57-60C; IR (neat) 2917, 1722 (C=O ester), 1700 (C=O urethane) cm l; NMR (CDCl3) ~ 8.05 (lH, br, indcle NH), 7.5 (la, d, J 8 Hz, indole H-4), 7.4-7.2 (6H, m, indole H-5 + phenyl), 7.16 (lH, ', J 7 Hz, indole H-6), 7.07 (lH, t, J 7 Hz, indole H-7), 6.9 (lH, d, J
2 Hz, indole H-2), 4.8 (lH, br, adamantane H-2), 4.6 W092/04045 ~ PCT/US91/06180 C~' ~~' .' (lH, br, urethane NH), 4 3 (lH, d, J 11 Hz, one of CH2-O), 4.2 (lH, d, J llH, one of CH2-O), 3.7 (2X, s, CH2-Ph, 3.2 (lH, d, J 14 Hz, one of CH2-indole), 3.0 (lH, d, ~ 14 Hz, one of CH2-indole), 2.1-1.4 (14P., m, adamantane), 1.2 (3H, s, CH3); [a]D+13 (CHC13, 22C, C=O.S); FAB MS 501 (m+ + H). Anal: C3,H36N2O~
requires C, 74.37%; H, 7.25%; N, 5.60%; found: C, 74.20~; H, 7.32%; N, 5.52%.

Tricvclo r 3.3.1.13~ 7 ldec-2-vl (R)-~l-formvl-2-(lP-indol-3-vlmethvl)-1-methvlethvllcarbamate (26) To a solution of (24) (0.03 g, 0.08 mmol) in dichloromethans (40 mL) at ambient temperature under argon was added N-methylmorpholine-N-oxide (0.1 g, 0.9 mmol), molecular sieves (4A activated powder, 0.5 g), and tetra-n-propylammonium perruthenate (0.01 g, 0.03 mmol). After stirring for 30 minutes the volatiles were removed in vacuo (40C). The residue was taken up in ethyl acetate and purified by flash chromatography (hexane/5% ethyl acetate eluant).
Recovered 0.2 ~ (67%) of (24) as a white solid, m.p.
178-179C; IR (neat) 2900, 1732 (C=O aldehyde), 1692 (C=O urethane) cm l; NMR (CDC13), ~ 9.6 (lH, s, CHO), 8.1 (lH, br s, indole NH), 7.6-6.9 (5H, m, indole), 5.2 (lH, br, urethane NH), 4.8 (lH, s, adamantane H-2), 3.3 (2H, br, CH2-indole), 2.1-1.3 (17H, mj adamantane + CH3); [~]D + 22D (CHC13, 22C, C=l); FAB
MS (m+/e) 381 (m+ + H). Anal: C23H2~N2O3 requires C, 72.61%; H, 7.42%; N, 7.36%; found: C, 72.31%; H, 7.46~; N, 7.31%.

W092/04~5 PCT/US91/06180 3. ~

ExAMoeLE 14 Tricvclor3.3.1~~ 71 dec-2-vl rR-(z)l-r~ H-indol-8 methvl)-l-methvl-5-phenvl-2-~entenvllcarbamate (27) A mixture of triphenylphosphine (0.35 g, 1.3 mmol) and 1-bromo-3-phenylpropane (0.27 g, 1.3 mmol) was heated to 110C, at which point the molten reac~ants solidified. On cooling to ambient temperature and trituration with hexane a white solid was recovered (0.4 g, 65%). This was added to a suspension oS
sodium hydride (50 mg of 50% in oil dispersion, 1 mmol) in toluene (40 mL) and the reaction was refluxed for 20 minutes. Aldehyae (0.2 g, 0.5 mmol) was added and heating continued 1 hour. The volatiles were removed in vacuo and the residue purified by flash chromatography (hexane/10% ethyl acetate eluant). Recovered 0.20 g (79%) of (27) as a white solid, m.p. 49-52C; IR (neat) 2904, 1696 (C=O
urethane), 1683 (C=C) cm l; NMR (CDC13): ~ 8.3 (lH, s, indole NH), 7.6 (lH, d, J 8 Hz, indole H-4), 7.3-7.0 (8H, m, indole H-5, H-6, H-7 + phenyl), 6.g (lH, s, indole H-2), 5.6 91H, d, J 12hz, CH by a-centre)~ 5.4 (lH, dt, J 5, 12 Hz, CH-CH2), 4.8 (2H, m, urethane NH
+ adamantane H-2), 3.3 (lH,~ d, J 14 Hz), one of CH2-indole), 3.1 (lH, d, J 14 Hz, one of CH2-indole), 2.6-2.4 (4H, m, 2xCH2), 2.1-1.4 (14H, m, adamantane), 1.4 (3H, s, CH3).

Tricvclo r 3.3.1.13~71dec-2-vl~2-hvdroxv-1-(lH-indol 3-ylmethvl)-1-methvl-5-~henvl~entvllcarbamate (28) To a stirred mixture of magnesium metal (0.5 g, 21 mmol) and dry ether (20 mL) at 0C under a nitrogen atmosphere was added l-bromo-3-phenylpropane (0.20 mL, 0 26 g, 1.3 mmol) and one crystal of iodine. After 20 minutes the reaction mixture became colorless, so W092/04045 PCT/US91/061~
9~

the solution was removed by syringe and added to a solution of (26) (0.30 g, 0.8 mmol) in dry ether zt 0C under a nitrogen atmosphere. After 20 minutes the reaction was allowed to warm to ambient temperature and was ouenched in dilute hydrochlo-ic acid (2N, 50 mL). The products were eY.tracted with ethyl aceta~e (50 mL), dried ove- magnesium sulfate, and evaporated in ~acuo. The residue was pu-ified by flash chromatography (hexane:ethyl acetate eluant);
recovered 0.31 g (79%) o' (28) as an oil which appears to be a 1:1 mixture of the possible diastereomers.
Further chromatography gave a single diastereoisomer:
IR (neat) 2908, 1690 (C=O urethane): NMR (CDCl3) ~ 8.1 (lH, br, indole NH), 7.6 (lH, d, J 8 Hz, indole H-4), 7.4-6.9 (9H, n, indole H-5, H-6, H-7, H-2 ' phenyl), 4.8 (lH, br, adamantane H-2), 4.7 (lH, br s, urethane NH), 3.6 (lH, m, CH-OH), 3.5 (lH, d, J 14 Hz, one o' CH2-indole), 3.1 ~lH, d, J 14 Hz, one of CH2-indole), 2.7 (2H, m, CH2-Ph), 2.1-1.3 ll9H, m, adamantane 1 2xCH2 + OH), 1.1 ~3H, s, CH3).

EXAMoeLE 16 Tricvclor3.3.1.13~71dec-2-vlR-(R*,S*~ 4,5-dihvd-o-4-(~henvlmethvl)-2-thiazolvll-2-(lH-indol-3-vl)-1-methvlethvllcarbamate (17) ~o a solution of (13) (0.1 g, 0.2 mmol) in toluene (10 r~) was added Lawesson's reagent (0.10 g, 0.25 mmol) and the reaction was heated to refluY. for 1 hour. The reaction mixture was allowed to cool to ambient temperature and was purlfied by flash chromatography (dichloromethane/ether eluant).
O~tained 0.07 g (70%) of the producti IR (neat) 2910, 1697 (C=O urethane), 1620 (C=N) cm i: NMR (CDC13 ~ 8.1 (lH, br, indole NX), 7.7 (lH, d, J 8 Hz, indole H-4), 7.4-6.9 (9H, m, indole H-5, H-6, H-7, H-2 + phenyl), W092/04~ PCT/US91/061~
2~88195 --111-- , 5.8 (lH, br, urethane NH), 4.9 (lH, br, adamantane H-2), 4.6 (1~, m, CH), 3.7 (lH, m, one of CH2-S), 2 g (lH, m, one of CH2-S), 2.8 (lH, br, one of CH2-Ph), 2.2 (lH, br, one of CH2-Ph), 2.1-1.4 (14H, m, adamantane), 1.3 (3H, s, CH3); FAB MS (m /e) 529 (m _ ~
H), 47%), 398 (m+-(indole-CH2), 44%), 130 (indole-CH2), 100%): R (30% ethyl acetate/hexane), 0.85.

Phenvlmethvl (R)-~-methvl-~-[~ icvclo r 3.3.1.13~ lde^-2-vloY.v)c3~bonvllaminol-lH-indole-3-bu~anoate Steo 1 A solution of N-methyl morpholine (253 mg, 2.50 mmol) and 2-Adoc-oMe-R-TrpOH (23b) (990 mg, 2.50 mmol) in anhydrous THF (20 mL) was cooled to 0C
and treated with a solution of i-butylchloro~ormate (360 mg, 2.S mmol) in anhydrous THF (10 m~) dropwise over 10 mm. This was stirred at 0'~ for a further 20 minutes and filtered. A solution of diazomethane (6 mmol) in Et2O was added to the filtrate and left at 0C for 4 hours, then allowed to warm slowly to -~om temperature over 12 hours. Excess diazomethane was quenched with acetic acid and the solvents removed in vacuo. The residue was chromatographed using 25%
EtOAc in n-hexane to give the diazoketone (300 mg, 29%); IR (film) 3400-3200, 2913, 2854, 2106, 1693, and 1353 cm~l; NMR (CDCl3) ~ 1.49 (3H, s), 1.50-1 60 (2H, m,), 1.70-2.05 (12H, m), 3.30-3.40 (2H, br s 4.86 (lH, br s), 5.20-5.40 (lH, br s), 5.56 (lH, s), 6.95 (lH, d, J 2 Hz), 7.08 (lH, t, ~ 7 Hz), 7.16 (lH, t, J
7 Hz), 7.33 91H, d, J 8 Hz), 7.55 (lH, d, J 8 Hz), 8.50 (1~, s).

~, ~' C~

Ste~ 2 A solution of the diazoketone (Schem~ 5, No. 31) (1.04 g, 2.50 mmol) in benzyl alcohol (10 mL) was treated with a solution of silve- benzoa~e (4 mL, 17 mmol) in triethylamine (5 mL) portionwise, and left to stir for 1 hour. EtOAc (30 mL) was .hen adaed and this solution treated with activated cha-coal and 'iltered through a filter and the solven= was remove in vacuo and the residue ch-omatogra~hed usins 30~
-EtOAc in n-Hexane as eluant to give the benzyl ester (44.0 ms, 35~); IR (film) 3500-3200, 2907, 2855, 1720 and 1698 cm~l; NMR (CDC13) ~ 1.37 (3H, s), 1.50-1.55 (2X, m), 1.65-1.85 (8H, m), 1.90-2.0; (4h, m), 2.67 (lH, d, v 14.5 Hz, 2.97 (lH, d, J 14.5 Hz), 3.22 91H, d, J 14 Hz), 3.29 (lH, d, J 14 Hz), 4.68 (lH, s), 4.82 (lH, s), 5.09 (2H, s), 6.95 (lH, d, v 2 Hz), 7.06 (lH, dt, J 7.5 and 1 Hz), 7.15 (lH, dt, J 7.5 and 1 Hz), 7.25-7.35 (6H, m), 7.57 (lH, d, J 8 Hz), 8.28 (lH, s).

W092/04045 PCT/US91/061 sn 2Q~8lg~

Tricvclo[3.3.1.13~ 71 dec-2-vl ~R-(R*,S*)l~3-[~1-(hvdroxvmethvl)-2-~henvlethvllaminol-1-(lH-indol-3-ylmethvll-l-methvl-3-oxo~roDvllcarbamic acid n~ , "" _ ~ N~1 ¦
'' " `1 `~' ~
~1 ' ~J' ,~
Ste~ 1 A solution of benzyl este- (Example 17, Scheme 5 No. 32) (440 mg, 0.88 mmol) in absolute EtOH (100 m~) was treated with Pd/C (50 mg, Ca 10% w/w) and put under an atmosphere of hydrogen at 50 psi and 30C
with agitation for 16 hours. The reaction mixture was filtered through a filter aid and the filtrate evaporated to dryness in vacuo. The residue was chromatographed over reverse phase silica using 25~
H2O in MeOH as eluant to give the acid (180 mg 50%), m.p. 91-99C (MeOH/H2O); ~]D + 20.0 ~C=l, MeOH); IR
(film) 3500-3300, 2912, 2856, 1704 cm~l; NMR (CDCl3) 1.41 (3H, s), 1.53 (lH, s), 1.57 (lH, s), 1.70-1.85 (9H, m), 1.95-2.10 (4H, m), 2.69 (lH, d, J 14.5 Hz), 3.05 (lH, d, J 14.5 Hz), 3.21 (l:i, d, J 14.5 Hz), 3.32 (lH, d, J 14.5 Hz), 4.86 (lH, s), 5.10-5.30 (lH, br s), 7.04 (lH, d, J 2hz), 7.07-7.20 (2H, m), 7.3S (lH, d, J 8 Hz), 7.60 (lH, d, J 8 Hz), 8.16 (lH, s).

W092/04045 PCT/US91/061~
9~

Ste~ 2 A solution of the carboxylic acid (Step 1, Scheme 5, No. 33) (160 mg, 0.39 mmol) and pentafluorophenol (72 mg, 0.39 mmol) in EtOAc (20 ~_~
was cooled to 0C and treated with a solution of N,N'-dicyclohexylca~bodiimide (80 m-, 0.39 mmol) i?.
EtOAc (S mL) and lef~ stirring at 0C _o- 18 hours.
After this time it was filte;ed anc S-?henyl zla?.ir.o}
added (121 mg, 0.8 mmol), and the mi~.ture left a- -oom temperature for 24 hours. The so}ven. was then removed in vacuo and the residue ch-omatographeA usins 30% EtOAc in n-Hexane as eluant to give the produc~ 2S
a white solid (140 mg, 66%)i IR ('ilm) 3500-3200, 2909, 2855, 1694, 1651, and 1570 cm l; NMR (CDCl3) ~ 1.27 (3H, s), 1.51 (lH, s), 1.55 (lH, s), 1.70-2.05 (12H, m), 2.46 (lH, d, J 13.5 Hz), 2.75-2.81 (2H, m), 2.87 (lH, d, J 13.5 Hz), 2.90-3.05 (lH, br), 3.08 (lH, d, J 14 Hz), 3.28 (lH, d, J 14 Hz), 3.50 (lH, dd, J 11 and 5 Hz), 3.61 (lH, dd, J 11 and 3.5 Hz), 4.10-4.20 (lH, m), 4.81 (lH, s), 5.14 (lH, s), 6.26 (lH, d, J
8 Hz), 6.99 (lH, d, J 2 Hz), 7.08 (lH, t, J 7 Hz), 7.10-7.30 (6H, m), 7.33 (lH, d, J 8 Hz), 7.58 (lH, d, J 8 Hz), 8.32 (lH, s).

W092/04045 PCT/USgl/061gO
208~19~

Carbamic acid, rl-(lH-indol-3-vlmsthvl~-1-methvl-2-~(l-oxo-4-phenvlbutvl)aminolethvll-, t-icvclo-r3.3.1.13~71dec-2-vl este- (R~-`;

This was prepared in the same manner as described in Example 21. Scheme 5 No. 37d, m.p. 70-75C (foam);
[a]D-9~2 (C=l, MeOH); IR (film) 3400-3100, 2908, 2853, 694, 164S, and 1526 cm 1; NMR (CDC13) ~ 1.24 (3H, s), 1.50-2.10 (16B, m), 2.20 (2H, t, J 7 Hz), 2.64 (2H, t, J 7 Hz), 2.98 (lH, d, J 14.S Hz), 3.2S (lH, d, J
14.S Hz), 3.55 (lH, dd, J 14 and 6 Hz), 3.70 (lH, dd, J 14 and 6 Hz), 4.81 (lH, s), 4.94 (lH, s), 6.50-6.60 (lH, br s), 7.00 (lH, d, J 2 Hz), 7.05-7.30 (7H, m), 7.35 (lH, d, J 8 Hz), 7.57 (lH, d, J 8 Hz), 8.17 (lY., lS s); Anal. C33H41N3O3, C, H, N.

~ , .
~ 116-q ~ EXAMPLE 20 Carbamic acid, r2-(benzovlamino)-1-(lH-indcl-3-ylmethvl)-l-methylethyll-, tri~vclor3.3.1.13~71dec-2-v' ester (R)-~' ~]"'`"l~Nn ~
~

This was prepared in the same manner as described in Example 21. Scheme 5 No. 37a, m.p. 220.0-220.1C
(MeOH); [a]D + 24C (C=0.25, MeOH); IR (film) 3500-3200-2907, 2855, 1695, 1646, and 1533 cm~ i NMR
(CDCl3) ~ 1.30 (3H, s), 1.50-1.60 (2H, m), 1.70-2.10 ~12H, m), 3.07 (lH, d, J 14.5 Hz), 3.31 (lH, d, J
14.5 Hz), 3.76 (lH, dd, J 14 and 6 Hz), 3.89 (lH, dd, J 14 and 6 Hz), 4.84 (lH, s), 5.03 (lH, s), 7.01 (lH, d, 2 Hz), 7.05-7.20 (2H, m), 7.35-7.50 (4H, m), 7.60 (lH, d, J 8H, 7.77 (2H, d, J 7 Hz), 7.60-7.90 (lH, br), 8.39 (lH, s); FAB MS m/e 485.3 (34), 355.3 (63), 290.3 (29), 177.2 (37), 154.1 (100); Anal. C30H~5N,0 C, H, N.

W092/0404~ PCT/US91/0618~
2 0 ~

EXAMoeLE 21 Carbamic acid, ~l-(lH-indol-3-vlmethvl)-1-methvl-2-~tl-oxo-3-~henvl~ro~vl)aminolethvl-, tricvclo-~3.3.1.13~71dec-2-vl este-, (R)-D
nO 11 ~D"~IJ~N~ " ,~

~, ~/ Nn Ste~ 1 Carbamic acid, r2-amino-1-(lH-indol-3-vlmethvl)-1-methvl-2-oxoethvl~-, tricvclo~3.3.1.13~71dec-2-vl ester, (R)- AdOC-a-Me)DTrp-NH2 (See Scheme 5, No. 35 2-Adoc-a-Me-R-Trp NH2) D

,' ~ / ~ / j/~

[~/

2-Adoc-a-Me-R-TrpOH (23b) (9.5 g, 24 mmol) as a solution in EtOAc (150 mL) was treated with pentaSluorophenol (4.4 g, 24 mmol) and cooled to 0C.
A solution of N,N'-dicyclohexylcarbodiimide (5.lS g, 25 mmol) in EtOAc (20 mL) was added dropwise and the '5 resultant mixture allowed to stir 6 hours, then left a Surther 12 hours at 4C. This was then filtered and the Siltrate evaporated to d_yness in vacuo. The W092/04045 PCT/US91/~6180 ~ .
q~

residue was redissolved in THF (100 mL) and ammonia gas bubbled through at 0C for 1 hour. ~he solven, was removed in vacuo and the residue ch_omatographed ove- reverse phase silica using 30% H2O in MeOH as eluant to give the amide ~35, Scheme 5) (9.2 g, 97%) as whi~e crystals, m.p. 136-149C (MeOr.); [a]D + 42.1 (C=l), MeOH); IR (film) 3351, 2906, 28_5, 1675, anc 1588 c~.~-; NMR (CDC13) ~ 1.50-1.60 (2H, m), 1.5e (3:-, s), 1.70-2.05 (12H, m), 3.33 (lH, d, J 4.5 Hz), 3.51 (1~., c, J 14.5 Hz), 4.86 (lH, s), 5.2~ (lH, s), 5.40-_.55 (lH, br), 6.20-6.35 (lh, br), ,.04 (1:;, d, J
2 Hz), 7.08-7.21 (2H, m), 7.36 (lH, d, J- 8 Hz), 7.63 (lX, c, J 8 Hz), 8.24 (lH, s); MS (FAB) m/e 396 (100) Anal. C23H29N3O3; C, H, N-Ste~ 2 (See Scheme 5, No. 36) T-imethylsilylchloride (4.34 g, 40 mmol) was added dropwice to a solution of LiBH4 ~11 mL of a 2M
solution, 22 mmol) in THF under an atmosphere of nitrogen. A solution of 2-AdocoMe-R-TrpNH2 (Scheme 5, N35) 'rom the previous step (3.95 g, 10.0 mmol) in anhydrous THF (20 mL) was added dropwise over 20 mm and the reaction mixture stirred 10 minutes at room temperature, then at gentle reflux for 3 hours. This was then cooled to 0C and MeOH (16.5 mL) added with caution. All solvents were then removed in vacuo and the residue chromatographed over raverse phase silica using 30% H2O in MeOH as eluant to give 1.25 g (32%) of sta-ting amide and 1.29 g (34%) of the product amine, m.p. 138-144C (MeOH); [a]D + 51.6 (C=l, MeOH); IR (film) 2912, 2854 and 1690 cm~l; NMR (CDC13) ~ 1.32 (3H, s), 1.40-1.55 (2H, m), 1.65-2.05 (12H, m), 3.04 (lH, d, ~ 14 Hz), 3.20-3.30 (2H, m), 3.40-3.50 (lH, m), 4.78 (lH, s), 5.10-5.30 (lH, br s), 7.00-7.20 (3H, m), 7.34 (lH, d, J 8 Hz), 7.52 (lH, d, J 8 Hz), W092/0404~ PCT/~S91/0618~
2~8819~

8.56 (l.i, s), 8.67 (2H, br s); FAB MS m/e 382.3 (100).

Step 3 (See Scheme 5, No. 37c) A solution of 3-phenylpropionic acid (75 mg, 0.5 mmol) in EtOAc (5 mL) was treated ~ith pentafluorophenol (92 ms, 0.5 mmol) and cooled to 0C.
A solution of N,N'-dicyclohexylcarbodiimide (103 mg, 0.5 mmol) in EtOAc (2 mL) was added and the mixture left 12 hours at 4C. This mixture was then filtered and solid amine (from Step 2, Scheme 5 N36) (198 mg, 0.5 mmol) added, and left at room tempe-ature for 24 hours. The reaction mixture was washed with lM
citric acid solution (2 x 10 mL), NaHCO3 (2 x 10 mL of a lM solution), and H2O (2 x 10 mL) and the organic phase dried over MgSO4. The solvent was then removed in vacu~ and the residue chromatographed o~er silica gel using 2% MeOH in CH2C12 eluant to give the product (230 mg, 90%) as white crystals, m.p. 171-175C
(MeOH); [a]D-12.3 (C=0.56, MeOH); IR (RBr) 3400-3100, 2906, 2854, 1694,~1649, an 1528 cm~1; NMR
(CDC13) ~ 1.13 ~3H, s), 1.50-2.10 (14H, m), 2.50 ~2H, t, J 7 Hz), 2.90 (lH, d, J 14 and 6 Hz), 3.65 ~lH, dd, J 14 and 6 Hz), 4.81 (lH, s)" 4.88 (lH, s), 6.40-6.60 (lH, br), 6.96 (lH, d, J 3 Hz), 7.05-7.30 (7H, m), 7.35 (lP., d, J 8 Hz), 7.53 (lH, d, J 8 Hz), 8.15 (lH, s); FAB MS m/e 514.4 (8), 383.3 (32), 205.2 (32), 170.2 (47), 135.2 (100); Anal. C32H39N3O3; C, H, N.

W092/04045 PCT/US~1/061~

~9~

Carbamic acid, rl-(lH-indol-3-vlmethvl)-1-methvl-2-[(2-~henvlacetvl)aminolethvll- tricvclor3 3.l.l-~71-dec-2-vl ester, (R)- 0 ~,o~ , Nn~ p~

This was prepared in the same manner as described in Example 21 (see Scheme 5, No. 37b), m.p.
176.5-180C ~MeOH); [a]D-l. 6 ~C=O 56, MeOH); IR
(Cilm) 3400-3100, 2911, 2854, 1694, 1656, and 1520 cm~
; NMR (CDC13) ~ 1.16 (3H, s), 1.50-2.10 (14H, m), 2.90 (1~, d, J 14 Hz), 3.16 (lH, d, J 14 Hz), 3.50 (lH, dd, J 14 and 6 Hz), 3.57 (2H, s), 3.65 (lH, dd, J
14 and 6 Hz), 4.73 ~lH, s), 4.80 ~lH, s), 6.30-6.40 ~lH, brs), 6.94 ~lH, d, J 2 Hz), 7.07 (lH, t, J 8 Hz), 7.16 (lH, t, J 8 Hz), 7.25-7.40 (6H, m), 7.48 ~lH, d, J 8 Hz), 8.11 (lH, s); FAB MS m/e 500.5 ~100), 369.3 ~87); Anal. C31H37N3O3; C, H, N-EXAMP~E 23 Carbamic acid, r2-[r3-rrl-(hvdroxvmethvl)-2-phenvl-ethvllaminol-3-oxoPro~vllaminol-i-(lH-indol-3-vlmethvl)-1-methvl-2-oxoethvll- tricvclo-r3.3.1.13~71dec-2-vl ester rR-(R*,S*)l-The acid as prepared in Example 30, Step 2 (1.17 g, 2.80 mmol) and pentafluc-ophenol (461 ms, 2.5 mmol) as a solution in EtOAc (50 mL) was treated with dicyclohexyl carbodiimide (542 mg, 2.60 mmol) and left at 0C for 18 hours. his was Ciltered and the Ciltrate treated with s-phenylalaninol (454 mg, 2~88l~

3.00 mmol) and the reaction miY.ture left stirring 18 hours at room temperature. This was then concentrated in vacuo and the residue chromatographed over reverse phase silica using 75% MeOY. in H2O as eluant to gi~e the product as a white, noncrystalline solid (l.i7 5, 78%); m.p. 94-98C; [a]D2o + 14.7 (c=l), MeOH); IR (film) 3306, 2904, 2854, 1693, and 1651 cm~ ; NMR (DMSO-d6) ~ 1.29 (3H, s), 1.60-2.00 (14H, m), 2.05-2.25 (2H, m), 2.62 ~lX, dd, J 14 and 8 Hz), 2.83 (lH, dd, J 14 and 6 Hz), 3.10-3.40 (5H, m), 3.85-3.95 (lH, m), 4.70-4.80 (2H, m), 6.70 (lr., b s), 6.90-7.35 (9H, m), 7.44 (lH, d, J 8 Hz), 7.70 (lr., d, J 8 Y.z), 7.75 (lH, br s), 10.85 (lH, s); FAB MS m/e 601 (m+l), 100); Anal. C35H44N405 0.25H20; C, H, N.

ExAMæLE 24 Carbamic acid rl-(lH-indol-3-vlmethvl)-2- r r3-rrl-hvdroxvmethvl)-2-Phenvlethvllaminol-3-oxoProPvll-aminol-l-methvl-2-oxoethvll- tricvclor~.3.1.13~ 7 ldec-2-vlester, [S-(R*,R*)l-O O
~0~ h This was prepared in the same manner as described in Exam?le 23 (see Scheme 6, No. 44), m.p. 95-97C
(MeOH/H2O); [a]D2-31.3 (c=l), MeOH); IR (film) 3314, 2910, 2856, 1696, and 1651 cm~ ; NMR (CDCl3) ~ 1.53 (5H, s), 1.70-2.05 (12H, m), 2.10-2.30 (2H, M), 2.79 (2H, d, J 7 Hz), 3.25 (lH, d, J 14.5 Hz), 3.35 (lH, d, J 14.5 Hz), 3.30-3.55 (3H, m), 3.65-3.70 (lH, m), WO92/OqO45 PCT/US~I/061~
9~

4.10-4.20 (1~, m), 4 79 (lH, s), 5.26 (lX, s), 6.20-6.35 (1~, br s), 6.69 (lH, t, J Hz), 6.97 (1~, d, J
2 Hz), 7.06-7.29 (7H, m), 7.34 (1~, d, J 8 Hz), 7.57 (lH, d, J 8 Hz), 8.49 (1~, s); FAB MS m/e 601 (100)i Anal. C35H44N405 0.25H20i C, H, N. MS FAB m/e 614 (m+1) and 217 (100); Anal. C,cH4,NcO~ 0.5H2Oi C, H, N.

D-Phenvlalanamide, a-methvl-N-~(t_icvclo~3.3.1.13 dec-2-vloxv)carbonvl1-D-'rvGto~hvl-~-alanvl-~, D~, ~ ~ 2 D ~

This was prepared using a method similar to Example 26. The acid from Example 30, Step 2 (117 mg, 0.25 mmol) and pentafluorophenol (46 mg, 0.25 mmol) as a solution in EtOAc (10 mL) was treated with dicyclohexylcarbodiimide (52 mg, 25 mmol) and left stir-ing at room temperature for 2 hours before being filtered. S-Phenylalaninamide (50 mg, 0.3 mmol) was then added and the mixture left s'irring at rGom temperature for 72 hours. The reaction mixture was then washed with lM HCl (10 mL), :i2O (10 mL), lM NaOH
(10 mL), ànd H2O (10 mL). The organic phase was dried over MgSO~ and concentrated in vacuo. The residue was chromatographed over reverse phase silica gel using 75% MeOH in H2O as eluant to give the product as a white noncrystalline solid (130 m5, 85%); m.p.

208819~

113-118C; [a]D20 + 27.5 (C=0.5, MeOH); IR (film~
3311, 3055, 2908, 1700, and 1659 cm~-; NMR (CDC13) 1.49 (2X, s), 1.52 (3H, s), 1.60-2.05 ~12X, m), 2.19 (2H, t, J 6 Hz), 3.01 (lH, dd, J 7.5 and 14 Hz), 3.08 (lX, dd, v 7.5 and 14 Hz), 3.27 (lH, d, J 14.5 Hz), 3.42 (lH, d, ~ 14.5 Hz), 3.35-3.50 (2H, m), 4.59 (lH, dd, J lS and 7 Hz), 4.80 (lH, s), 5.29 (lH, s), 5.47 (1~., s), 6.20 (lH, s), 6.50 (lH, d, ~ 7 Xz), 6.76 (lH, t, J 5 Hz), 6.96 (lH, d, J 2 Hz), 7.05-7.35 (7X, m), 7.34 (lH, d, J 8 Hz), 7.57 (lH, d, J 8 Hz), 8.36 (lX, s) .

EXAMæLE 26 L-Phenvlalaninamide, a-methvl-N- r (tricvclo~3.3.1.13~7l-dec-2-vlo~v)carbonvll-D-trvPto~hvl-~-alanvl-~J' D ~_ i l~J

15 m.p. 112-118C (MeOH/H2O); [a]D20 + 16.3 (c=l, MeOH);
IR (Cilm) 3309, 2907, 2855, 1690, 1652 cm ~; NMR
(CDC13) ~ 1.50-2.05 (17H, m), 2.10-2.20 (2H, m), 2.98 (lY., dd, ~ 14 and 8 Hz), 3.09 (lH, dd, J 14 and 7 Xz), 3.24 (lH, d, J 14.5 Hz), 3.35 (lH, d, J 14.5 Hz), 3.25-3.55 (2X, m), 4.58 (lH, dd, J 15 and 7.5 Hz), 4.78 (lH, s), 5.28 (lH, s), 5.48 (lH, s), 6.27 (lH, br s), 6.54 (lY., br s), 6.75 (lH, m), 6.99 (lH, d, J
2 Hz), 7.05-7.30 (7H, m), 7.34 (lX, d, J 8 Hz), 7.58 ~,,9~

(lH, d, J 8 Hz), 8.41 (lH, s); F~B MS m/e 614.3 ~100)i Anal. C35H43NsOso 75H2oi C~ H~ N-L-Phenvlalaninamide, ~-methyl-N- r (tricvclo~3.3.1.'~~ l-- dec-2-vloxv)carbonvll-L-trv~to~hvl-~-alanvl-m.p. 114-119C (MeOH/H2O); [a]D2-15.2 (c=0.5, MeOH);
IR (film) 3323, 2909, 2855, 1700-1640 cm~~; NMR (CDC13) 8 1.50 (2H, s), 1.54 (3H, s), 1165-2.00 (12H, m), 2.10-2.20 (2H, br s), 2.95 (lH, dd, J 14 and 8 Hz), 3.10 (lH, dd, J 14 and 6 Hz), 3.23 (lH, d, J 14 Xz), 3.32 (lH, d, J 14H), 3.20-3.30 (1:., m), 3.40-3.50 (lX, m), 4.55 (0.5H, 0, J 8 Hz), 4.60 (0.5H, d, J 8 Hz), 4.78 (lH, s), 5.35 (lH, s), 5.68 (lH, s), 6.41 (lH, s), 6.65-6.85 (lH, m), 6.82 (lH, _, J 6 Hz), 6.97 (lH, d, J 2 Hz), 7.05-7.30 (7H, m), 7.33 (lH, d, J 8 Hz), 7.57 (lH, d, J 8 Hz), 8.55 (lH, s); FA~ ~S m/e 614.3 (50-7), 236.1 (100); Anal. C35H43N 05 0.5H20; C, H, N.

W092/04045 PCT/USg1/06180 208~

D-Phenvlalanlnamide ~-methvl-N-~tricvclo[3 3.1.1 dec-2-vlo~v~carbonvll-L-trv~to~hvl-~-alanvl-O D
, , 0 , ~ " ~2 Il, ~J

m.p. li3-118C (MeOH/H20)i [~]~2_30~ (c=0.5, MeOH) ('ilm) 3313, 2909, 2856, 1694-1652 br. cm -; NMR
(CDCl3) ~ 1.45 (3H, s), 1.50 (2H, s), 1.65-2.00 (12H, m), 2.14 (2H, s), 2.90 (lH, dd, J 14 and 8 Hz), 3.06 (lH, d, J 14 and 5.5 Hz), 3.2-3.4 ~4H, m), 4.56 (0.5H, d, J 7.5 Hz), 4.60 (0.5H, d, J 7.5 Hz), 4.80 (lH, s), 5.54 (lH, s), 6.14 (lH, s), 6.70 (lH, s), 6.87 (lH, s), 7.00-7.30 (lOH, m), 7.51 (lH, d, J 8 Hz), 8.87 (lY., s); F~ MS 636.4 (100), 614.4 (61); Anal.
C,5H4,N505 0.5H20i C, H, N.

Wo 92/04045 ~ PCI/US91/06180 12-Oxa-2,5,9-triazatridecanoic acid 3-(lH-indol-~-vlmethvl)-3-methvl-4,8,11-t~ioxo-10-(Pheny,methvl~-, tricvclo~3.3.1.13~7ldec-2-vl ester, ~R-(R* R*)l- ~See Scheme 6, No. 49) O

I~ J

In a manner similar to Example 30, the following was pre?ared, m.p. 86-90C (foam); [a]D2o + 17.4 (c=0.5, MeOH); IR (film) 1738, 1698, and 1656 cm~l;
NMR (CDC13) 8 1.55 (3H, s), 1.50-1.60 (2H, br s), 1.65-2.05 (12H, m), 2.10-2.35 (2H, m), 2.99 (lH, dd, J
14 and 8 Hz), 3.11 (lH, dd, J 14 and 5 Hz), 3.20-3.30 (lH, m), 3.31 (2H, s), 3.55-3.65 (lH, m), 3.68 (3H, s), 4.73 (lH, dd, J 13 and 8 Hz), 4.80 (lH, s), 5.33 (lH, s), 6.40-6.60 (lH, br s), 6.90 (lP., br s), 6.98 (lH, d, J 2 Hz), 7.05-7.35 (8H, m), 7.59 (lH, d, J
8 P.z), 8.45 (lH, s); MS FAB m/e 629.2 (lOOj; Anal.
C36H44N406 0.25H20; C, H, N.

W092/04~5 PCT/US91/06180 L-Phenylalanine,N-rN--ra--methvl--N-r(tricvclo~3,3.1,1~?1, dec-2-vloxv)carbonvll-d-t~vDtoDhyll-~-alanvll-~henvlmethvl ester Step 1 (See Scheme 6, No. 39) A solution of 2-Adamantyloxyca-bonyl-~-methyl-~-tryptopha~ (8.0 g, 20 mmol) in E.OAc (100 mL) was treated with pentafluorophenol (3.68 5, 20.0 mmol) and cooled to 0C. Dicyclohexylcarbodiimide (4.33 g, 21.0 mmol) was then added and the mixture left to stir fo_ 18 hours at 0C. After this time the mixture was filtered and ~-alanine methyl ester (2.47 g, 240 mmol) added and the mixture left stirring a further 18 hours at room temperature, filtered, and the filtrate washed with lM HCl (3 x 30 mL), H2O (2 x 30 mL), saturated NaHCO3 solution (3 x 30 mL) H2O (2 x 30 mL). The organic phase was dried over MgSO4 and concentrated in - vacuo and the product crystallized from ether to give the ester (7.8 g, 81%); IR ~film) 3700-3200, 3000-2800), 2723, 1695, and 1659 cm_l.

Step 2 (See Scheme 6, No. 41) ~-Alanine,N-~a-methvl-N- r (t-icvclor3.3.1.13~ 71 dec-2-vloxv~carbonvll-D-trvptophvll The ester from Step 1 (5.20 g, 10.8 mmol) as a solution in 1.4 dioxane (300 m~) was treated with a solution of LiOH-H2O (454 mg, 10.8 mmol) in H2O
(100 mL) dropwise at room temperature and left stir~ing 18 hours. lM HCl (10.8 mL) was added and the mizture distilled to dryness in vacuo and the residue chromatographed over reverse phase silica gel using 70% MeOH in H2O; as eluant to give the product (3.23 g, 51%) along with starting ester (1 g); m.p.
98-103C ~MeOH/H2O); []D20 + 29 (c=l, MeOH); IR

W092/04045 PCT/USgl/06~80 ~(film) 3351, 2911, 2855, 1706, and 1658 cm~ ; NMR
(CDC13) ~ 1.50-2.00 (17H, m), 2.39 (2H, br s), 3.25 (lP., d, J 15 Hz), 3.40-3.50 (3H, m), 4.80 (lH, s), 5.42 (lH, br s), 6.75 (lH, t, J 6 Hz), 6.99 (lH, d, v 2 Hz), 7.05-7.20 (2H, m), 7.33 (lH, d, J 8 Y.z), 7.57 (ln, d, J 8 Hz), 8.37 (lH, s); FAB MS m/e 468 (m+l) and 2i7 (100); Anal. C2~H,,N3O~-0.25H2O; C, H, N.

Ste~ 3 A solution of the acid from Step 2 (467 mg, 1.00 mmol) and pentafluorophenol (184 mg, 1.00 mmol) in EtOAc (50 mL) was treated with dicyclohexyl-carbodiimide (206 mg, 1.00 mmol) at 0C and left 18 hours. This was then filtered and S-phenyl alanine benzyl ester (306 mg, 1.20 mmol) added and left stirring 18 hours at room temperature. This was then washed with lM HCl (2 x 20 mL), H2O (20 mL), saturated NaHCO, solution (2 x 20 mL), and H2O (20 mL) The organic phase was dried over MgSO4 and concentrated in vacuo and the residue chromatographed over reverse phase silica gel using 75% to 85% MeOH in H2O as eluants to give the product (500 ms, 71%); m.p.
75-82C (MeOH/H2O); [a~32 ~ 28.1 (c=0.45, MeOH); IR
(film) 3324, 2908, 2855, 1737, 1698, and 1657 cm- ;
NMR (CDCl3) ~ 1.50 (3H, s), 1.50-1.55 (2H, m), 1.70-2.00 (12H, m), 2.10-2.30 (2H, m), 3.06 (lH, dd, v 14 and 7 Hz), 3.14 (lH, dd, J 14 and 6 Hz), 3.29 (lX, d, v 15 Hz), 3.25-3.60 (3H, m), 4.75-4.85 (2H, m), 5.08 (lH, d, J 12 Hz), 5.15 (lH, d, J 12 Hz), 5.29 (lP., br s), 6.20-6.30 (lY., br m), 6.81 (lH, br m), 6.95 (lH, d, J 2 Hz), 7.00-7.35 (13H, m), 7.57 (lH, d, J 8 Hz), 8.20 (lY, s); Anal. C~2H48N4O6; C, H, N.

WO 92/04045 PCI/I~S91/06180 208~1g~

In a manner similar to Example 30 the follo~7in~
was preDared, m.p. 77-~2C (foam); [a]~25-19.2 (c=0.5, MeO~.); IR ( ilm) 3305, 2906-2857, 1735, 1696, and 1658 cm~-i N~R (CDCl3) ~ 1.51 (3X, s), 1.50-1.60 (2:, m), 1.70-2.10 (12H, m), 2.10-2.30 (2:H, m), 3.01 (1:, dd, ~ 19 and 8 Y.z), 3.12 (lH, dd, J 14 and 5 Hz), 3.20-3.30 (lH, m), 3.31 (1:-, s), 3.55-3.65 (lH, m), 4.75-4.85 (2X, m), 5.07 (lH, d, J 12 Hz), 5.15 (1:., c, J 12 P.z), 5.28 (lH, b- s), 6.30-6.50 (1:., br s), 6.80-6.90 (lH, br), 6.97 (lH, d, J 2 Hz), 7.05-7.35;
MS FP~ m/e 705.2 (71) and 327.2 (100); Pnal.
C~2-48N~O6; C~ H, N-EXAMoe~E 32 D-Phenvlalanine, N- rN- r ~-methvl-N- r (t_icvclo-r 3.3.1.13~7ldec-2-vloxv)carbonvll-D-trvDtoDhvll-~-alanvll-D D
, r ~ / ~I ~ i~J~ ~' ~ ~ CD2~4 This was prepared in a manner similar to that described in Example 33, m.p. 119-129C (MeOH/H2O);
[]~20 + 5.8 (c=0.5, MeOH);IR (~ilm) 2907, 2855, 1700, 1651 cm~l; NMR (CDCl3 + CD30D) ~ 1.53 (5H, s), 1.70-2.05 (12H, m), 2.10-2.30 (2H, br s), 2.95-3.05 ~ ., m), 3.15-3.60 (5H, m), 4.65 (lH, s), 7.00-7.40 W092/04045 PCT/US91/0618() 9~
~Q~ -130-(9H, m), 7.57 (lH, d, J 8 Hz); FAB MS m/e 615 2 (58), 216.9 (100); Anal- C35~42N4O6-0-5H2O; C~ ~ N-EXAMoe~E 33 S-Phenvlalanine, N-~N-[a-methvl-N-~(tricvclo-s r 3.3.1.1-~7ldec-2-vloY.v)carbonvll-R-Irvs'o~hvll-~-alanvll A solution of the benzyl ester (450 mg, 0.64 mmol) in absolute EtOH (100 mL) was treated with 10% Pd/C
(45 mg, 10% w/w) and put under an atmosphere of hydrogen at 50 psi for 2 hours with agitation. The mi~ture was then filtered through a 'ilter aid and concentrated in vacuo and the residue chromatographed ove_ reverse phase silica gel using 70% MeOH in H2O as eluant to yield the product as a white, noncrystalline solid (300 mg, 76%); m.p. 114-119C; [a]D2o + 37.8 (c=l), MeOH); IR (film) 3331, 2911, 2856, 1700, and 1656 cm~l; NMR (CDCl3) ~ 1.41 (3H, s), 1.45-1.55 (2H, m), 1.70-2.00 (12H, m), 2.10-2.20 (2H, m), 3.01 (lH, dd, J, 14 and 8 Hz), 3.15-3.50 (5H, m), 4.00-5.00 (lH, v.br), 4.66 (lH, dd, J 13 and 7 Hz), 4.82 (lH, s), 5.46 (lX, br s), 6.50-6.70 (lH, br s), 6.87 (2H, br s), 7.00-7.30 (8H, m), 7.52 (lH, d, J 8 Hz), 8.44 s); ~nal. C~5H42N4O6; C, H, N-W092/0404~ PCT/US91/06180 208~19~

L-Phenvlalanine, N-rN-~a-methvl-N-~(t-icvclo-~3.3.1.13~ 71 dec-2-vloxv)carbonvll-L-trv~to~hvll-~-alanvll-3~ ~ ~2 This was prepared in a manner similar to that described in Example 33, m.p., 115-120C (MeOH/H2O);
[a]D2-7.2O (c=0.5, MeOH); IR (film) 3391, 2906, 2854, 1700, and 1646(s) cm~l; NMR (CDCl3 + CD30D) ~ 1 51 ~3H, s), 1.54 (lH, s), 1.57 ~lH, s), 1.70-2.05 (12H, m), 2.15-2.30 (2H, m), 2.99 (lH, dd, J 14 and 8 Hz), 3.15-3.55 (5H, m), 4.66 (lH, dd, J 8 and 5 Hz), 4.79 (lH, s, 7.0Q-7.40 (9H, m), 7.56 (lH, d, J 8 Hz); FAB
~S m/e 615 (100); Anal. C35N~2N4O6; C, ~, N.

wo 92/04045 PCI/US91/06180 ~ ` -132-Q ~

Benzene~ro~anoic acid a-[r3-[r3-r(lH-indol-3-vl)-2-methvl-l-oxo-2-~(tricvclor3. 3 .1.13~7ldec-2-vloxv)-carbonyllaminol~ropvllaminol-l-oxoPropvllamin rS-(R*,S*)l-~ ~ `G ~ ~

m.?./ 116-124C (MeOH/H2O); [a]D20 - 350 (c=0.5, MeOH);
IR (film) 3500-3200, 2912, 2856, 1700, and 1654 cm ~;
NMR (CDC13) ~ 1.42 (3H, s), 1.47 (1, s), 1.51 (lH, s), 1.65-2.20 (14H, m), 2.90-3.00 (lH, m), 3.10-3.50 (5H, m), 3.50-4.50 (br, CO2H and H2O), 4.61 (lH, s), 4.82 (lH, s), 5.45 (lH, s), 6.50-6.80 (lH, br s), 6.85-7.30 (llH, m), 7.52 (lH, d, J 8 Hz), 8.58 (lH, s); FAB MS
m/e 615.2 (100; Anal. C35H42N406-0.4H20; C, H, N.

W 0 92/04045 PC~rtUS91/06180 -133- 2088~95 EX~PLE 36 Glvcine, N-r2-methvl-N-~(tricvclor3.3.1.13~71dec-2-vloxv)ca-bonyl-D-trv~to~hvll-, ~henvlmethvl ester ll J

A solution of 2-Adoc~-Me-R-TrpOH (Scheme 7, N23b) (3.0 g, 7. 6 mmol) in EtOAc (40 mL) was treated with pentafluorophenol (1.39 g, 7.6 mmol), and cooled to 0C. A solution of N,N'-dicyclohexylcarbodiimide (1.56 g, 7. 6 mmol) in EtOAc (10 mL) was then added dropwise and stirred 12 hours at 4C and filtered.
Glycine benzyl ester hydrochloride (1.8 g, 9.0 mmol) was added followed by the dropwise addition of triethylamine (0.9 g, 9.0 mmol) in EtOAc (10 mL).
This was allowed to stir 18 hours at room temperature.
The reaction miY.ture was then washed with lM citric acid solution (2 x 50 mL), lM NaHCO3 solution ~2 Y. S0 mL) and H2O (2 x 50 mL). The organic phase was dried over MgSO4 and evaporated to dryness ln vacuo. The residue was chromatographed over reverse phase silica using 25% H2O in MeOH as eluant to give the product as a white foam (2.83 g, 68%) along with 0.9 g starting active ester, m.p. 76-82~C (foam);
[a]~2G + 36 (c=1, MeOH); IR (film) 3500-3200, 2908, 285;, 1745, 1702, and 1665 cm l; NMR (CDCl3) ~ 1.45-1.60 (4H, m), 1.69-2.00 (13H, m), 3.30 (lH, d, 2_ J 14.5 Hz), 3.50 (lH, d, J 14.5 Hz), 3.95-4.10 (2H, W092/04045 PCT/US91~061~J

m), 4.84 (lH, s), 5.13 (2H, s), 5.21 (1:-, s), 6.7g ~lH, s), 7.01 (lH, d, J 2 Hz), 7.08 (lH, t, ~ 7 Hz), 7.15 (l.H, t, J 7 Hz), 7.30-7.40 (6H, m), 7.57 (lH, d, J 8 Hz), 8.26 (lH, s); FAB MS 544.4 (1:), 414.3 (11), 348.2 (36), 135.2 (100); Anal.; C32H37N3O5; C, H, N.

W092t04~5 PCT/US91/06180 208819~

Carbamic acid, ~2- r r2- r [ 1- (hvdroxvmethvl~-2-phenvlethyllaminol-2-oxoethvllaminol-1-(lH-indol-3-vlmethvl)-l-methvl-2-oxoethvll-, tricvclo~3.3.1.1~71-dec-2-vl ester, [R-(R*,S*~l- AdOC-(a-Me)DTr~-Glv-NH((S)-l-(hvdroxvmethvl)-2-~henvlethv') l~

Ste~ 1. Glvcine~ N-r3-tl~-indol-3-vl)-2-methvl-1-oxo-2- r r (tricvclor3.3.1.13~71dec-2-vloxv)carbonvllaminol-ro~vl-, (R)- Adoc-(a-Me)DTrp-Glv D~ ~ ~ ~ \Co~H

A solution of the benzyl ester (Example 36, Scheme 7, No. 57) (2.5 g, 4.6 mmol), in absolute ~tO~.
(100 mL) was treated with 10% Pd/C (250 mg, 10% w/w) and put under an atmosphere of hydrogen at psi and 20C fos 5 hours with agitation. The reaction mixture was filtered through a filter aid and th~ filtrate W092/04045 ~ PCT/US91/n618~

o~ ,, concentrated in vacuo The residue was then chromatographed over silica gel using 0.5% AcOH, 5 MeOH in CH2Cl2 as eluant to give the product (1.87-3 g, 90%) as a white solid; m.p. 112-117C
(MeOH/H2O); [a]D2c +40o (c=l, MeOH); I~ (film) 3500-3200, 2910, 2856, 1702, 1660, and 735 cm~ ; N~
(CDCl3) ~ 1.26 (lH, s), 1.51 (lH, s), 1.58 (3H, s), 1.70-2.00 (12H, m), 3.00-4.0Q (lH, br), 3.28 (lH, d, 14.5 Hz), 3.45 (lH, d, J 14.5 Hz), 3.94 (2H, d, J
5 Hz), 4.85 (lH, s), 5.35-5.50 (lH, br s), 6.85 (lH, b_ t), 7.04 (lH, d, J 2 Hz), 7.05-7.18 (2H, m), 7.32 (lH, d, J 8 Hz), 7.56 (lH, d, J 8 Hz), 8.39 (lH, s);
Anal. C25R~N,O5; C, H, N-Ste~ 2 A solution of the acid (Scheme 7, No. 59, Step 1) (226 mg, 0.5 mmol) and pentafluorophenol ~92 mg, 0.5 mmol) in EtOAc (20 mL) was cooled to 0C and treated with a solution of N,N'-dicyclohexyl-carbodiimide (108 mg, 0.525 mmol), in EtOAc (5 mL).
This was leCt 12 hour at 0C, filtered and the _iltrate treated with S-phenylalaninol (91 mg, 0.6 mmol). This reaction mixture was stlrred at room temperature for 18 hours, evaporated to dryness vacuo and the residue chromatographed using 30%
n-hexane in EtOAc as eluant to give the product (202 mg, 66%); IR ~film) 350G-3200, 2911, 2855, 1695, and 1658 cm~-; NMR (CD3OD) ~ 1.44 (3H, s), 1.52-1.62 (2H, m), 1.70-2.10 (14H, m), 2.78 (lH, dd, J 13.5 and 8 Hz), 2.93 (lH, dd, J 13.5 and 6 Hz), 3.24 (lH, d, J
14.5 Hz), 3.41 !lH, d, J 14.5 Hz), 3.53 (2H, d, J 5.5 Hz), 3.57 (lH, d, J 17 Hz), 3.71 (lH, d, J 17 Hz), 4.05-4.15 (lH, m), 4.88 (lH, s), 6.98 (lH, dt, J 7.5 and 1 Hz), 7.00-7.25 (7H, m), 7.32 (lH, d, J 8 Hz), 7.50 (lH, d, J 8 Hz).

W092/04~5 PCT/US91/06180 -137- 2 0~ 81 9 5 ~ XAMæLE 39 Carbamic acid, r 2-[ r 4- r r 1-(hvdroxvmethvl)-2-phenvlethvllaminol-4-oxobutv'laminol-1-(lH-indol-3-vlmethvl)-l-msthvl-2-oxoethvll-, tricvclo[3.3.1.1~~
dec-2-vl ester, ~R-(R*,S*)l-~,~

Ste~ 1. Butanoic acid, 4-rr3-(lH-indol-3-vl)-2-methvl-l-oxo-2- r r (tricYclo r 3.3.1.13~71dec-2-vloxv)-carbonvllaminolpropvllaminol-, (R)-D
~," ~ CD2t~
)~\

A solution of the methyl ester (Example 38, Scheme 8, No. 60) (2.6 g, 5.2 mmol) in 1,4-dioxan (500 mL) was treated dropwise with a solution of LiOH
(104 mL of a 0.05M solution, 5.20 mmol) over 24 hours with vigorous stirring. This mixture was stirred at room temperature for 24 hours and quenched with lM HCl (5.2 mL). The solvent was removed in vacuo and the residue chromatographed using 0.5% AcOH, 5% MeOH in W092~04~5 PCT/US91/06l80 ~ -138-C~
H2Cl2 to give 80 mg of starting ester along with 1.32 g of product, 55% yield, 77% conversion, m p.
92-96C (CH2Cl2); [a]D20 + 29.3 (c=, MeOH); I~ (film) 3600-3200, 2909, 2856, 1702, and 1651 cm~ ; MMR (CDC13) ~ 1.50-1.55 (2H, mn), 1.61 (3H, s), 1.62-2.00 (14H, m), 2.10-2.25 (2H, m), 3.20-3.40 (2H, m), 3.24 (1., d, J 14.5 Hz), 3.45 (1~, d, J 14.5 Hz), 4.8~ (lP., s), 5.47 (lH, s), 6.58-6.65 (l~., b- m), 7.03 (lP., d, v 2 Hz), 7.09 (lH, t, J 7 Hz), 7.17 (lH, t, J 7 Hz), 7.35 (lH, d, J 8 Hz), 7.57 (l~, d, J 8 Hz), 8.59 (lH, s); Anal. C27H,5N3O5-0.2~20; C, H, N.

Ste~ 2 A solution of the acid (Step 1, Scheme 8, No. 61) (240 mg, 0.5 mmol), and penta'luorophenol (92 mg, 0.8 mmol) in EtOAc (20 mL) was cooled to 0C and treated with a solution of N,N'-dicyclohexyl-carbodiimide (108 mg, 0.55 mmol) in EtOAc (5 mL).
This mixture was left at 0C for 12 hours, filtered, and the filtrate treated with S-phenylalaninol. This reaction mixture was left stirring at room temperature for 24 hours, the solvent removed n vacuo, and the residue chromatographed using 10~ MeO~. in CH2CL2 as eluant to give the product as a white solid (153 mg, 50%); IR (~ilm) 3500-3200, 207, 2850, 1692, and 1642 cm~~; NMR (CD30D) ~ 1.43 (3:-, s), 1.50-1.70 (4~, m), 1.75-1.95 (8H, m), 2.00-2.15 6H, m), 2.7s (lH, dd, J 14 and 8 Hz), 2.91 (lH, dd, J 14 and 6 Hz), 2.95-3.35 (3H, m), 3.45-3.50 (3:., m), 4.07-4.17 (lH, m), 4.81 (~H + HOD), 6.93-7.09 (3H, m), 7.10-7.30 (5H, m), 7.31 (lH, d, J 8 Hz), 7.53 (lH, d, J 8 Hz).

WO 92/04045 PCJtUS9ltO6180 2~8819a ~ XAMPL~ 40 Tricvclo~3.3.1.73~7ldec-2-vl-(+)- r 3-(lH-indol-3-vl-methvl)-2,5-dioY.o-1-(2-~henvlethvl~-3-~vrrclidinvl~-carbamat~ (68) Ste~ 1. Methvl-(_)-~-amino-~- r (~h~nvlmethoxv)-carbonvll-lY.-indole-3-butanoate (64) l-Methyl-(=)-~-cyano-l-[l,l-dimethylethoxy)-carbonyl]-lH-indole-3-butanoate (63) (0.241 g, 0.50 mmol) was dissolved in ethanol (5 mL). The solution cooled to -5C in an acetone-ice bath and ethanolic HCl was added dropwise. H2O (0.1 mL) was added and the reaction was warmed to room tempera~ure.
The solution was left to stir for 24 hours, and the solvent evaporated off in vacuo. The oil was dissolved in ethyl acetate (50 mL) and washed with 10%
Na2CO3 (50 mL) solution. The organic layer was dried (MgSO4), filtered, and evaporated to dryness. The product was isolated by flash chromatography (ethyl acetate:hexane, 1:1) to yield the wanted product.
(0.120 g, 67%) as a yellow oil, VmaX (cm~l, thin film) 3350 (NH); 3425 (NH br); 1741 (CO ester), H (300 M Hz, CDC13), ~ 2.12 (2H, brs, NH2); 3.17 (lH, d, J 18 Hz, CH2CO2CH3); 3.28 (lH, d, J 18 Hz, CH2CO2CX3); 3.37 (lX, d, J 15 Hz, indole-CH2); 3.43 (3H, s, OCH3); 3.53 (lH, d, J 15 Hz, indole-CH2); 4.82 (lH, d, J 12 Hz, CH2Ph);
4.92 (lH, d, J 12 Hz, CH2~h); 6.73 (la, d, J 2 Hz, 2-H); 6.95-7.21 (8H, m, 5-H + 6-H + 7-H + Harom); 7.47 (lH, s, 4-H); 8.42 (lH, s, NH).

CO~ ' ~tep 2. Methvl~ (phenvlmetho~v)carbonvll-~-~(tricvclo-[3.3.1.13~1dec-2-vlo~v)carbonvll-aminol-lH-indole-3-butanoate (6;) Methyl-(')-B-amino-~-[(phenylmethoxy)carbonyl~-lH-indole-3-butanoate (64) (120 mg, 0.33 mmol) was dissolved in dry THF (10 mL) under argon.
Triethylamine (55 ~L, 0.40 mmol) was injected. The solution was cooled to 0C in an ice- alt batn and 2-adamantyl chloride (77 mg, 0.36 mmol) dissolved in THF (5 mL) was injected. The solution was stirred fo-12 hours at room temperature before triethylamine hydrochloride was filtered of Dichloromethane (50 mL) was added and the solution was washed with water (2 Y. 25 mL). The organic payer was dried (MgSO4), filtered, and evaporated to dryness. The product was isolated by flash chromatography (ether:
hexane, 1:1), to furnish the title compound (105 mg, 58%), m.p. 61.5-62.5C. ~maY: (cm~~, thin film) 3412 (NH), 1738 (CO), H (300M Hz, CDC13), 1.49-2.09 (14H, m, adamantyl-H); 3.12 (lH, d, J 15 Hz, CHH2CO2CH3);
3.30 (lH, d, J 15 Hz, CH2CO2CH3); 3.38 (s, 3H, OCH3) 3.72 (lH, d, J 15 Hz, indole-CH2); 3.80 (lH, d, J
'5 Hz, indole-CH2); 4.83 (lH, brs, CH); 4.98 (lH, d, 112 Hz, PhCH2); 5.11 (lH, d, J 12 Hz, PhCH2); 6.88 (lH, s, NH); 6.79 (lH, s, 2-H); 7.03 (lH, t, J 7 Hz, 6-H); 7.14 (lX, t, J 7 Hz, 5-H); 7.17-7.34 (6H, m, 7-H, Harom)~ 7.48 (lH, d, J-8 Hz, 4-H), 8.30 (lH, s, NH). m/z (FAB) 545 (M+l); 501; 130. Found: C, 70.6%; H, 6.8%; N, 5.0%; C32H3~N2O5 requires C, 70.6%
H, 6.7%; N, 5.1%).

W092/04045 PCT/USg1/061~
~08819~

Ste~ 3. Methvl-(+)-~-carbox~-~- r ~ (tricvclo-~3.3.1.13~71dec-2-vlo~v)carbonvllaminol-lH-indole-3-butanoate (66) In a 250-mL glass vial, methyl-(~ -[(pheny}-methoxy)carbonyl]-~-[[~t~icyclo[3.3.1.1~ 7~dec-2-yloxy)carbonyl[aminoj-lH-ind~le-3-butanoate (65) (105 ms, 0.19 mmol). Palladium on cha-coal (lC~, C~
20 mg) and ethanol (75 mL) was added. The vess~l was sealed in a ~a_r Hydrogenation Apparatus and cna-ged with H2 gas (45 psi). Shakins was initiated a~ter pressurization and continued ~or 12 hours. Upon completion, palladium on charcoal (10%) was filtered of and the filtrate evaporated to dryness. The product was isolated by flash chromatography (methanol: water, 2:1) to yield a white powder (77 mg, 88%j, m.p. 108-9C. ~maY (cm -, thin ~ilm) 3413 (NH);
1733 (CO). ~ H (300M Hz, CDCl3), 1.47-2.07 (14H, m, adamantyl-H); 3.14 (lH, d, J 16 Hz, CH2CO2CH3); 3.26 (lH, d, J 16 Hz, CH2CO2CH3); 3.64 (3H, s, OCH3); 3.76 (lH, d, J 15 Hz, indole-CH2)i 3.84 (lH, d, J 15 Hz, indole-CH2); 4.83 (lH, brs, CH); 5.75 (lH, brs, OY.);
5.96 (lH, s, NH); 6.98-7.04 (2H, m, 2-H + 6-H); 7.10 (lH, t, J 7 Hz, 5-H); 7.28 (lH, d, J 8 Hz, 7-H); 7.61 (lH, d, J 8 Hz, 4-H); 8.34 (lH, s, NH). ~ c (75.5M Hz, CDCl~) 27.0, 27.2 31.3, 31.7, 32.1, 36.4, 37.4, 39.7, 51.8, 62.4, 78.0, 108.9, 111.1, 118.7, 119.4, ;21.7, 124.1, 128.2, 135.7, 154.8, 171.3, 176.2. m/z (FAB) 455 (M+l), 411, 217, 135, 130. Found: C, 65.7~; :., %; N~ 6-0%- C25H30N26 requireS C, 66.1%; H, 6.65~;
N, 6.2%.

W092/04045 ~ PCT/US91/061~0 Step 4. Methvl~ -[[~2-phenvlethvl)aminolcarbonvl-(tricyclo~3.3.1.13~ 71 dec-2-vloxv)ca-bonvllaminol-lH-indole-3-butanoate (67) Methyl~ -[[(tricyclo[3.3.1.13 7~dec-2-yloxy)-carbonyl[amino]-lH-indole-3-butanoate (66) (200 mg, 0.44 mmol) was dissolved followed by dicyclohexylcarbodiamide (100 mg, 0.48 mmol). The solution was left stirring fo- 2 hours before phenylethylamine (60 mg, 0.50 mmol) was injected to the solutio~. The raixture was left st--ring overnight. The solution was evaporated down to dryness, ethyl acetate added, and dicyclohexylurea filte-ed of^ The filtrate was evaporated down to dryness and the product was isolated by flash chromatography (hexane:ethyl acetate, 3:1) to give a white solid (180 mg, 73%), m.p. 78.0-79.5C. vma~ (cm~
1, thin film), 3333 (NH), 1730 (CO), 1659 (CO amide), H (300M Hz, CDCl3), ~ 1.51-2.04 (14H, m, adamantyl-H);
2.61 (2H, m, CH2NH); 2.94 (lH, d, J 16 Hz, CH2CO2CH3);
3.21 (lH, d, J 16 Hz, CH2CO2CH3); 3.37 (lH, d, J 7 Hz, CH2Ph); 3.41 (lH, d, J 7 Hz, CH2Ph); 3.46 (lH, d, J
15 Hz, indole-CH2); 3.57 (lH, d, J 15 Hz, indole-CH2);
3.62 (3X, s, OCH3); 4.78 (lH, brs, CH); 5.88 (lH, b-s, NH urethane); 6.58 (lH, brs, NH amide); 6.92 (lH, d, 2 Hz, 2-H); 7.03-7.26 (7H, m, 5-H + 6-H + P~2rom); 7.33 (lH, d, J 8 Xz, 7-H); 7.56 (lH, d, J 8 Xz, 4-H). mz/
(FAB). 558 (M+l), 362, 331, 231, 135, 130, 105.
(Found: C, 69.0; H, 6.8; N, 7.2. C~3H~gN7O5-0.75H2O
requires C, 69.4; H, 7.1; N, 7.4).

W092/04~5 PCT/~591/06180 ~08819~

Stçp 5. ~ricvclor3.3.1.1~ 71dec-2-vl-(~ 3-(lX-indol-3-vl-methvl)-2,5-dioxo-1-(2-PhenYlethvl)-3-~vrrolidinvll-carbamate (68) The ester (67) above (110 mg, 0.20 mmol) was dissolved in 20 mL ~HF and cooled to 0C. Lithium hydroxide (21 mL, 0.01 M) was added dropwise to the solution over a 3-hour period. The solution was kep-stirring for a fuzther 1 hour and then allowed tO wa~m to room temperature. Hydrochloric acid (2.1 mL, 0.1 M) was added and the solution extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried with MgSO4, filtered, and evaporated to dryness, to afford (105 g, 98%) of crude product.
The product was isolated by flash chromatography (methanol:water, 4:1) as a white powder (84 mg, 78.5%). ~maY (cm 1, thin film). 3347 (NH), 2912 (CH) 1781 (CO), 1701 (CO). H (300M Hz, CDC13) ~ 1.55-1.97 (14H, m, adamantyl-H); 2.38 (2H, m, NHCH2); 3.00 (lH, d, J 18 Hz, CH2CON); 3.05 (lH, d, J 15 Hz, indole-CH2); 3.47 (2H, t, J 8 Hz, CH2Ph); 4.80 (lH, s, CH); 5.49 (lH, s, NH); 7.04-7.35 (8H, m, 5-H + 6-H +
7H + Ha~om; 7.56 (lH, d, J 8 Hz, 4-H); 8.68 (lH, s, NH). C (75.5M Hz, CDCl3), 26.9, 27.1, 31.7, 32.3, 36.3, 37.3, 39.8, 40.2, 59.95, 76.4, 107.3, 111.4, 118.6, 120.2, 122.7, 123.7, 126.4, 127.4, 128.7, 136.0, 138.0, 154.9, 174.1, 176.1. m/z (C.I.) S28 (M+l). 527, 526, 374, 331, 130. Found: C, 72.6%; H, 6.7%i N, 7.9%; C32H~eN3040.25H20 requires C, 72.5~; Y., 6.7%; N, 7.9%).

pS2 = Me, Qee Scheme 15a) A suspension of powdered sodium hydroxide (2 g, 50 mmol) and ethyl 2-cyanopropionate (20 g, 157 mmol) in 150 m~ toluene was heated undez nitrogen atmosphere W092/04045 PCT/US~1/061 to 100C and gramine (30.1 g, 172 mmol) added in portions. A.ter 30 minutes the temperature was raised to 130C (oil bath) and the mi~.ture gen'ly re1uxed for 16 hours. Then 100 mL water and 200 mL ethyl acetate were added, the miY.ture neutral zed with acetic acid, the organic laye- separatec, washed ~it..
water (100 mL), dried (sodium sulfate) and evaporate_.
The residue was pu-ified by ch-omatos-a?hy over silicz gel using toluene/ethyl acetate (1:1, v/v, Rf 0.4).
2a was isolated as a light brown viscous oil (34.5 ~, 86~). MS (70eV): m/z 256 (M;, 8%), 130 (100%).

EXA~PLE 42 2 = Me, see Scheme 15a) Compound 2a (5 g, 19.5 mmol) in 250 mL dioY.ane, saturated with ammonia, was hydrogenated (100 bar, 80C) with Raney nickel alloy ~0.95 g) in an autoclave for 1 hour. After filtration and evaporation the residue was purified by chromatography over silica gel using dichloromethane/methanol (95:5, v/v, Rf 0.1).
3a was isolated as a colorless viscous oil (4.76 g, 94%). MS (70eV): m/z 260 (Ml, 17), 130 (100), 117 (48).

(R- = 2-adamantvl, R2 = Me, see Scheme 15a) To a stirred solution of 2-adamantylchloroformate (4.45 g, 20.7 mmol) in dry THF (50 mL) under N2 atmosphere was added a solution of 3a (4.76 g, 18.3 mmol) i~ dry THF (100 mL) followed by a solution o' triethylamine (3.7 g, 36.6 mmol) in dry THF (50 m_) d-opwise. After 15 minutes the reaction mixture was filtered, the solvent removed and the residue column chromatogra?hed on silica gel using CH2Cl2/MeOH (98:2) W092/04045 PCT/US91/~6180 20~81~

as eluents to yield 4a as a colorless amorphous solid (7.8 g, 97~). MS (70eV): m/z 438 (Mi, 20), 130 (lOG).

(R- = 2-adamantvl, R2 = Me, see Scheme l~a) To a solution of 4a (3.~ g, 8.9 mmol) in cioxane/H20 2:1 (60 mL) was added an excess Oc LiOY.
(0.325 g, 13.5 mmol) and sti__ed at room temperature for 72 hours. After removin~ the solven. in vacuo the residue was suspended in wate- (50 mL), neutralized with acetic acid, extracted with CH2Cl2 and the organic layer separated and dried (sodium sulfate).
Afte- filtration and evaporation the residue was chromatographed using CH2Cl2/MeOH 95:5 (v/v, Rc 0.
as eluents to yield the acid 5a as a colorless, amorphous solid (2.5 g. 69%). MS (70eV): m/z 410 (~+, 4), 130(100).

(R1 = 2-adamantvl, R2 = Me, R3 = -CH20H, c = 1, R4 = H, see Scheme 15a~
Carbamic acid, r3-rrl-(hvdroxvmethvl~-2-pher.vlethvllaminol-2-(lH- indol-3-vlmethvl)-2-methvl-3-oxo~ro~vll-, tricvclor3.3.1.13~7l dec-2-vl ester r~-(~*,RS)l-To a solution of 5a (1 5, 2.44 mmol) in dry ethyl acetate (40 mL) was added pentafluoropAenol (0.45 g, 2.44 mmol) and stirred for 10 minutes. The reaction miY.ture was cooled to 0C and 2 solution of dicyclohexylcarbodiimide (0.505 Sl 2.44 mmol) in ethyl acetate (10 mL) was added d-opwise. This solution w2S
sti-red for one hour at 0C ther. at room temperature for four hours before leaving it at ~C overnight.
The miY.ture was filtered an~ the precipitate washed ~itr. cold ethyl acetate (lO mL) and a solution of (S)-(-)-phenylalaninol ~0.405 g, 2.68 mmol) in ethyl acetate (25 mL) was added dropwise to the combined fil-rates. The mix~ure was left to s'ir for 4 days at roo~. temperature. The reaction mix~ure was diluted wit~ ethyl acetate (100 mL), washed with wate-(100 m~), d-ied (sodium sul'ate) and eva?o_atec. mhe residue was chromatographed on silica gel usins CH~Cl2/MeOH (98:2) as eluan~s tO yie_d 6a as a colo-less amorphous solid (0.780 g, 59~, mixtu-e o' lQ two diastereomers), m.p. 85-95C. CI-MS (70eV, N;-.3):
m/- _44 (MH , lO0), 392 (76).

In an analogous manner Examples 46-57 are prepared:
(C~ = conciguration at the chiral C-atom of the substituted 2-phenylethylamide residue, R2 center is always RS) EX~LE 46 (Rl = (lS)-2-bornvl, R2 = Me, R3 = R4 = H, c = 1) Carbamic acid, r 2-(lH-indol-3-vlmethvl)-2-methvl-3-ox.o-3- r (2-ohenvlethvl)aminoloroPvl-, 1,7,7-t~lmethvlbicvclor2.2.11 hePt-2-vl ester (Bicvclo svstem is lS-endo, chain ce'nter is RS) m.p. 60-70C, MS (70eV): m/z 515 (M ,5), 130 (100) (R- = l-adamantvl, R2 = Me, R3 = R4 = H, c = l) Carbamic acid, ~2-(1~.-indol-3-vlmethvl)-2-methvl-3-oxo-3- r (2-ohenvlethvl)aminoloroovl-, tricvclo-r 3.3.1.13~7ldec-1-vl ester, (+)-m.p. 75-85C, M.S (70eV): m/z 513(M+,100), 305(91) W092/0404~ PCT/US91/06180 208gl9~

(R^ = 2-adamantvl, R2 = Me, R3 = R4 = H, c = 1) Carbamic acid, [2-(lH-indol-3-ylmethvl)-2-methvl-3-oxo-3- r ( 2- ~henvlethvl)aminolDro~vll-, tricvclo r 3.3.1.13~7ldec-2-vl este-, ( )-m.p. 75-85C, MS (70eV): m/z 5i3 (M ,25), 305 (88), 134 (100) EXAMæLE 49 (Rl = (lS)-2-bornvl, R2 = Me, R3 = CH~OP., R4 = ., c = 1, C* = S) Carbamic acid, ~3-[~1-(hvdroxvmethvl)-2-phenvlethvllaminol-2-(lP.-indol-3-vlmethvl)-2-me'hv'-3-oxopro~vll-1,7,7-trimethvlbicvclo ~2.2.1lhe~t-2-vl ester (Bicvclo svstem is lS-endo, hvdroY.vmethvl center is S, othe_ center is RS) m.p. 75-85C, MS (70eV): m/z 545 ~M~,7), 130 (22), 95 (77), 44 (100) EXAM~LE 5O
(R- = 2-adamantyl, R2 = Me, R3 = H, R4 = NHCOCH2CH2CO2Bz, c = 1, C = R) 14-Ox2-2,6,9-triazapentadeCanoic acid, 4-(1~-indol-3-vlmethvl-4-methvl-5,10,13-trioxo-8,15-diPhenvl-, tricvclo~3.3.1.13~71-dec-2-vl ester, ~R-(R*,R*)l-m.p. 80-90C, CI-MS (CH4): m/z 611 (21), 459 (21), 135 (100) ~ ' EXAM~LE 51 (Ri = 2-adamantyl, R2 = Me, R3 = H, R- = NHCOCH = CHCO2Me, c = 1, C = R) 14-Oxa-2,6,9-triaza~entadec-11-enoic acid, !4-(lH-indol-3-vl-methyl)-4-methvl-5,10,13-trioxo-8-~henvl-, t-icvc1O~3.3.1.13~'1 dec-2-vl este-, r~- r~*, R*-(E~l-m.p. 105-120C, CI-MS (CH~): m/z 641 (M.- , 1), 151 ('8), '35 (100) EXAMæLE 52 (R = 2-adamantvl, R2 = Me, R3 = H, R4 = NHCO2-t-Bu, c = 1, C = R) 11-Oxa-2,6,9-triazatridecanoic acid, 4-(lH-indol-3-vlmethvl)-4,12,12-trimethvi-l,S,10-trioxo-8-Dhenvl-, tricvclor3.3.1.13~71 dec-2-vl ester, ~R-(R*,R*)l-m.p. 100-110C, CI-MS (CH4): m/z 629 (Mr., 8), 135 (100) (Rl = 2-adamantvl, R2 = Me, R3 = H, R4 = NHCOCH2CH2CO2H, c = l, C = R) Butanoic acid, 4-~r2-~2-(lH-indol-3-vlmethvl)-2-methvl-1-oxo-3-[r(tricvclor3.3.1.1~~7ldec-2-vloxv)carbonvllaminol-~ro~vllaminol-l-~henvlethvllaminol-4-oxo-, rR-(R*,R*)l-m.p. 110-125C, CI-MS (CH4): m/z 628 (M-,21), 164 (100) W092/04~5 PCT/US91/06180 ~08819a (Rl = 2-adamantvl, R2 = Me, R3 = H, R4 = NHCOCH = CP-CO?Y., c = 1, C~ = R) 2-3utenoic acid, 4-[2-rr2-(lH-indol-3-vlmethvl)-2-methvl-1-oxo-3-r r (tricvclo r 3.3.1.13~ 7 ldec-2-vloxv)czrbonvllaminol-~ro~vllaminol-'-~henvlethvll-4-oxc- (T~ center RS; othe- center R: double bond ~) m.p. 210-220C, CI-~S (CH4): m/z 626 (M-,7), 474 (100), 164 (88) EXAMoeLE 55 (R- = 2-adamantvl, R' = Me, R~ = H, c = 0) Carbamic acid, r2-(lY.-indol-3-vlmethvl)-2-methvl-3-oxo-3- r (phenvl methvl)aminolPropvll-, tricvclo r 3.3.1.13~ 7 1 dec-2-vl ester, (~)-m.p. 80-90C, MS (70eV): m/z 499 ~.+,25), 291 (47), 130 (100) (Rl = (lS)-2-bornvl, R2 = Me, R3 = CH2OCOCH2CH2CO2H, R4 = Y., c = 1, C = S) Butanedioic acid, mono 2-rr2-(lH-indol-3-vlmethvl)-2-methvl-l-oxo-3-rr(1,7,7-t-imethvlbicvclor2.2.1lhe~t-2-vloxv)carbonvll-aminolProPvllaminol-3-~henvl~roPvl este- (Bicvclo svstem is lS-endo, Phenvlmethvl center is S, other center is RS) m.p. 115-130, CI-MS (C~4): m/z 646 (MH+, 34), 528 (78), 101 (100) W092/04045 ~ PCTt~591/061~0 C~9~
q_ (Rl = 2-adamantvl, R2 = Me, R- = CH2OCOCH2CH2CO~H, R4 = ~, c = 1, C = S) Butanedioic acid, r2- ~ r2- (lH-indol-3-vlmethvl)-2-S methvl-l-oxo-3-~(t-icvclo~3.3.1.13~7ldec-2-vlo~v)carbonvllaminol~ro~vll-aminol-3 ~henvl~ro~vl este_ (T~ center RS; other center S) m.p. Q5-95C, CI-MS (C4:il0): m/z 643 (M , 16), 642 (19), 235 (100) The cor.version of compound 5a ~R- = 2-adamantyl, R = Me) to the compounds 6f, 6g, 6h, 6i, 6k, and the conversion of compounds 6a and 6e to the compounds 6m and 6n has been done in analogy to already described procedures. Compounds of general formula Ia, where R2, R3 and R4 are ~. are also prepared according to synthetic scheme 15b:

lc = 1, see Scheme 15b) A solution of N-(~-phenylethyl)cyanoacetamide (8a, lô.ô g, 0.1 mol), indole-3-carboxaldehyde (14.5 g, 0.1 mol) and piperidine (5 drops) in ethanol (100 mL) was refluxed for 16 hours. After cooling to room temperature the precipitate was filtered off, washed with ethanol (2 x 20 mL) and ariec to give 9a as-yellow crystals (29 g, 92~). MS ,70eV): m/z 315 (~',14), 195 (100).

(c = 1, see Scheme 15b) Compound 9a (3.15 g, 10 mmol) in 50 mL dioxane, saturated with ammonia, was hydrogenated (100 bar, 80C) with Raney nickel alloy (0.5 g) in an autoclave or ;7 hours. After filtration and evaporation the W092/04045 PCT/US91/0618~
2~88~95 residue was chromatographed on silica gel using C~2C12/MeOH 9:1 (~/v) as eluents. lOa was obtained as colorless crystals from ethyl acetate ~1.16 g, 36%).
MS (70eV): m/z 321 (M+, 46), 170 (93); 130 (100).

EXAMoeLE 60 (R1 = 2-adamantvl, c = 1, see Scheme 15b) Carbamic acid, r2-(lH-indol-3-vlmethvl)-3-oxo-3-l(2-~henvlethvl)aminolpro~vll-, tricvclo~3.3.1.13~71dec-2-vl ester (')-The conversion of lOa to lla was done according to the conversion of 3a to 4a. After ch_omatographic separation using CH2Cl2/MeOH 9~:2 as eluents lla was isolated as a colorless amorphous solid (87%), m.p.
115-140C. MS (70eV): m/z 499 (M+, 3), 291 (100).

(c = 1, see Scheme 15c) A suspension of powdered sodium hydroxide (0.5 g, 12.5 mmol) and N-(~-phenylethyl)cyanoacetamide (8a, 8 g, 42.5 mmol) in 50 mL toluene was heated under nitrogen atmosphere to 100C and gramine (7.4 g, 42.5 mmol) added in portions. Ater 30 minutes the temperature was raised to 130C (oil bath) and the mixture gently refluxed for 2 hours. Then 50 mL water and 200 mL ethyl acetate were added, the mixture neutralized with acetic acid, the organic layer separated, washed with water (100 mL), dried (sodium sulfate) and evaporated. The residue was separated by chromatography on silica gel using C~2C12/EtOAc 9:1 (v/v) as eluents.
1. fraction: compound 13a as colorless crystals (4.5 g, 47%) MS (70eV): m/z 446 (Mi, 4), 130 (100).
2. fraction: compound 12a, colorless crystals from WO92/04045 ~ PCT/US~ 6180 ethanol (3.05 g, 23%). MS (70eV): m/z 317 (M , 18), 130 (100).

~R1 = 2-adamantvl, c = 1) Carbamic acid, r2,2-bis(lX-indol-3-vlmethvl)-3-oYo-~-~(2-~henvleth~l!aminol~ro~vll-, tricvclof3.3.1._~ 7 ~ -dec-?-vl este-The conversion of 13a (c = 1) to 17a (R1 = 2-adamantyl, c = 1) was completed in analogy to the conversion of 2a to 4a. Afte_ purification by chromatography on silica gel using CH2Cl2/MeOH 98:2 17a was isolated as a colorless amorphous solid (yield 50% from 13a), m.p. 105-110C. CI-MS (NH3): m/z 629 (MX', 100%).

ExAMæLE 64 1 = 1-adamantvl, R2 = Me, see Scheme 16) To a stirred solution of 3a (3 g, 11.5 mmol) in anhydrous THF (100 mL) at room temperature was added adamantane-1-carbonyl chloride (2.28 g, 11.5 mmol), followed by a solution of triethylamine (3.2 mL, 23 mmol) in THF (20 mL) dropwise. The reaction was complete after 30 minutes as assayed by thin layer chromatography. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified by chromatography over silica gel using CH2Cl2/MeOH 98:2 as eluents. 18a was isolated as a colorless amorphous solid (3.25 g, 67%). MS (70eV):
m/z 422 (M+, 35), 293 (34), 130 (100).

(R~ adamantvl, R2 = Me, see Scheme 16) To a solution of 18a (3.25 g, 7.7 mmol) in 1.4-dioxane/H2O (2:1, 90 mL) was added an excess o' LiO~

W092/04045 PCT/~rSg1/0618~
2~881~

(0.37 g, 15.4 mmol) and the solution stirred a~ room temperature for 48 hours. After removing the sol~ent in vacuo the residue was dissolved in water (150 m~), acid~fied with citric acid (10% in ~-ater) and extracted with dichloromethane (2 Y. 100 mL). The organic layer was dried (Na7SO4) and evaporated. l9a was isolated as a colo_less, amor~hous solid (3 g, =100%). TLC (silica gel): ~f 0.2 (C:i2Cl7/MeOY. 9~:5).

(Rl = l-adamantyl, R2 = Me, R3 = -CH70~., c = 1, see Scheme 16) lH-Indole-3-proPanamine, N-~l-(hvdro~vmethvl)-2-phenvlethvll-x- msthvl-x- r r (tricvclo r 3.3.1.13~ 7 ldec-2-vlcarbonvl)aminolmethvll- (indole center is RS, cther center is S) The conversion of l9a to 20a was done in analogy to the conversion of 5a to 6a. After purification by chromatography on silica gel using CH2Cl2/MeOH 98:2 20a was isolated as a colorless amorphous solid (52%), m.p. 85-95C. MS (70eV): m/z 527 (M ,30), 335 (100).

~here is obtained in an analogous manner:

(R- = l-adamantvl, R2 = Me, R3 = H, c = 1, R4 = H) lH-Indole-3-ProPanamide, ~-methvl-N-(2-~henvlethvl)-x-r r (tricvclo~3.3.1.13~71dec-2-vlcarbonvl)aminolmelhvll, ( ) A colorless amorphous solic, m.~. 80-90C. MS
(70eV): m/z 497 (Mi,9), 305 (43), 184 (56), 135 (64), 130 (100).

W092/04~ PCT/U~9l/06180 EXA~PLE 68 (See Scheme 17) In an autoclave 1-(3~-indolyl)-bu.an-3-one (12.32 g, 65.9 mmol), potassium cyanide (4.7 g, 72.3 mmol), zmmonium carbonate (6.9 g, 71.8 mmol) and ammonium hydroxide (25~, 13 mL) in wate- (25 mL) and methanol (75 mL) were heated to 60C 'o- 16 hou_s wi_h stirring. The solutio~ was diluted w_-h water (100 mL), the methanol evaporated and the residual mixture acidi'ied (2n HCl). The precipitated hydantoin 21 was filtered of', washed with water anc dried. Yield: 15.2 g ~90%) colorless crystals. MS
(70eV): m/z 257 (~+, 22), 144 (96), 130 (100).

EXAMoeLE 69 (See Scheme 17) In an autoclave 21 (10 g, 38.9 mmol) in 5% aqueous sodium hydroxide (125 mL) was heated to 150C for 16 hours. After cooling to room temperature, the solution was neutralized with hydrochloric acid (37%) and if necessary filtered immediately to remove traces of hydantoin 21. The solution was stirred at room temperature for 2 hours and the precipitated amino acid 22 filtered off, washed with water (20 mL) and dried. 22 was isolated as pale beige crystals (8.52 g, 94%). MS (70eV): m/z 232 (M , 26), 144 (100), 130 (92).

(See Scheme 17) A solution of 22 (5 g, 21.5 mmol) in dry methanol (375 ~) was warmed to 40C and satu-ated with hydrogen chloride (1 hour). Afte- stirring at 40-45C
for 5 hours and at room temperature for another 15 hours the solvent was evaporz_ed. Water (100 mL) W092/04045 PCT/USg1/061~
2 0 8 819 ~

was added, the mixture neutralized with aqueous sodium carbonate and eztracted with ethyl acetate (2 x 100 mL). The organic layer was washed with diluted sodium bicarbonate solution (50 mL) then with water (50 mL) and dried (Na2SO4). A~ter removing the solvent the residue was chromatog-aphed on silica ge' usins C~2Cl2/MeOX 98:2 (v/v) as eluents. 23 was isolated as beige crystals (4.0 g, 75~). MS (70eV):
m/z 246 (M~, 25), 144 (71), 130 (100).

EX~MPLE 71 l = 2-adamantv', see Scheme 17) The reaction of aminoeste_ 23 with 2-adamantyl-chloroformate was done according to the conversion o~
3a to 4a. 24a was isolated in 86% yield as a colorless amorphous powder. MS (70eV): m/z 424 (M+, 42), 281 (41), 144 (100), 135 (78).

= 2-adamantvl, see Scheme 17) The hydrolysis of 24a with lithium hydroxide was done according to the hydrolysis of 4a to 5a. 25a was isolated without chromatography as a pale beige amorphous powder in quantitative yield, pure enough to be used in the next step (-cee Example 73) without further purification. MS (70eV): m/z 410 (M+, 5), 130 (100).

(R1 = 2-adamantvl, R3 = R4 = H, c = 1, see Scheme 17) Carbamic acid, r 3-(1~.-indol-3-vl)-1-methvl-1-[[(2-Phenvlethvl)aminolcarbonvllPro~vll-, tricvclo-r 3 . 3, 1 . 13' 71 dec-2-yl ester, (+)-The conversion of 25a with 2-phenylethylamine to 26a was done according to the conversion of 5a to 6a.

W092/04045 PCT/US91/0618~
~ i . -, c~oo After chromatographic separation on silica gel using CH2Cl2/MeOH 98:2 (v/v~ 26a (Rf 0 2) was isolated _r.
69% yield as a colorless amorphous powder, m.p 75-85oC. MS (70ev): m/z 513 (M , 1), 370 (67), 130 (100).

}n analogous manner zre prepa-ed:
(C = configura_ion at the chiral C-atom of the substituted 2-phenyle'hylamiae residue, other cente-is always RS) (Rl = 2-adamantvl, R3 = CH20H, R4 = H, c = 1, C = S) Carbamic acid, r 1- r r r 1- (hvdroxvmethyl)-2-~henvlethvll-aminolcarbonvll-3-(lP.-indol-3-vl)-1-methvlPro~vll-, tricvclo r 3.3.1.13~7ldec-2-vl ester (hvdroxvmethyl center is S, other center is RS) m.p. ô0-90C, CI-MS (C4Hlo): m/z 544 (MH+, 2), 392 (100) (Rl = (lS)-2-bornvl, R3 = R4 = H, c = 1 Carbamic acid, f3-(lP.-indolr3-vl)-1-methvl-1-~r(2-phenvlethvl)-aminolcarbonvll~-oPvll-, 1,7,7-trimethvl-bicvclof2.2.11he~t-2-vl ester, flR-~ la, 2~(S), 4all-m.p. 70-80C, CI-MS (CH4): m/z 516 (MHi, 2), 362 (100) (Rl = 2-adamantvl, R3 = H, R4 = NHCOCH = CHCO2Me, c = 1, Cr = R) ~3-Oxa-2,5,8-triazatetradec-10-enoic acid, 3-f2-(lH-indol-3-vl) ethvll-3-me'hvl-4,5,12-trioxo-7-Phenvl-, tricvclo-f3.3.1.13~71dec-2-vl ester (TRP center is R/S
mixture, other center is R, double bond E) m p. 117-123C, CI-MS(C4H10): m/z 640(~l-,19), 4P7(100) (Rl = 2-adamantyl, R3 z H, R4 = NHCOCH2CH2CO2Bz, c = 1, C = R) 13-Oxz-2,5,8-triazatetradecanoic acid, 3- r2- (l~.-indol-3-vl)ethvll-3-methvl-4,9,12-trioxo-7,14-di~henvl-, tricvclo-r3.3.1.13~71dec-2-vl ester (TRP center is R/S
mixture, other center is R) m.p. 85-95C, CI-MS (C~Hlo): m/z 627 (20), 475(100), 251(44) (Rl = (lS)-2-bornvl, R3 = CH2OH, R4 = H, c = 1, C = S) Carbamic acid, r2-r r rl-(hvdrOY.vmethvl)-2-~henvlethvllaminol-carbonvll-3-(lH-indol-3-vl)-1-methvl~ro~vll-, 1,7,7-trimethvlbicvclo-r2.2.1lhe~t-2-vl ester (Bicvclo svstem is lS-endo, hvdroxvmethvl center is S, other center is RS) m.p. 75-85C, CI-MS (CH4): m/z 546 (MHI, 82), 153 (100 ) (Rl = 2-adamantvl, R3 = H, R4 = NHCOCH2CH2CO2H, c = 1, C = R)) 3utanoic acid, 4-rr2-rr4-(lH-indol-3-vl)-2-methvl-1-oxo-2- r r(tricvclor3.3.1.13~7ldec-2-vloxv)carbonvll-aminolbutvllaminol-l-~henvlethvllaminol-4-oxo- (indole center is RS, other center is R) m.p. 115-125C, CI-MS ~C4Hlo): m/z 629 (M~ , 191 (28), 135 ~100) W092/040~5 PCT/US91/0618 (R1 = 2-adamantvl, R3 = H, ~4 = - NHCOCH = CHCO2H
c = 1 C* = R) 2-Butenoic acid 4-r2-~r2~r2-(1~.-indol-3-vl)ethvll-2-methvl-1-oxo-3-r[(tricvclo r 3.3.1.13~7ldec-2-vloxv)-ca-bonvllaminolpro~vllaminol-l-~henvle~hvll-~-oxo-(indole center is RS other cente- is ~, double bond E) m.p. 190-200C, CI-MS (NH3): m/z 626 (M-, 24), 201 (60), 151 (100) The conversion of 26d to 26h and .he conversion of 26e to 26g were done in analogy to already described procedures.

(See Scheme 18) The method is as described for 2a (compare lit.
J. Ora. Chem. 18:1440, 1447, 1953). Alkylation of diethyl methylmalonate with gramine provided compound 28 after chromatographic separation on silica gel using CH2Cl2tMeOH 98:2 (vtv) as eluents as a light red brown syrup (yield 90%). MS (70eV): m/z 303 (M+, 11), 130 (100).

(See Scheme 18) To a solution of the diester 28 (31 g, 0.102 mol) in dry ethanol (80 mL) was added a solution of potassium hydroxide (6.5 g, 0.116 mol) in ethanol (65 mL) dropwise at room temperature (1 hour) and stirred for another 16 hours. The reaction mixture is filtered and the filtrate evaporated. The residue is cuspended in water (700 mL), neutralized with hydrochloric acid and extracted with ether (3 x W092/04~5 PCT/US91/061~
20g81~ , 250 m~). The ether solution was dried (Na2SO4), evaporated and the residue purified by chromatography on silica gel using CH2C12/MeOH 95:5 (v/v) as eluer.ts ~he monoacid 29 (Rf 0.1) was isolated as a light redbrown syrup (18 g, 64%). MS (70eV): m/z 275 (~~, 9), 130 (100).

EXAM~LE 83 tSee Scheme 18) mO a solu_ion cc compound 29 (37 g, 0.134 mol) in dry tetrahydrofuran (500 m1) at 0C under nitrogen was added dropwise a 2 M solution of borane-methyl su__ide complez in tetrahydrofuran (100 mL, 0.2 mol) (45 m n.) and stirred for 3 hours at 0C. Then water (100 mL) was added dropwise, the mixture diluted with more wate_ (400 mL) and ethyl acetate (800 mL). The organic layer was separated, washed with water (3 Y.
150 mL), dried (Na2SO4) and evaporated. The residue was suspended in CH2Cl2 (100 mL), the precipitated 29 filtered off and washed with CH2Cl2 (30 mL). 29 was isolated as colorless, sometimes slightly red crystals (26.74 g, ô5%), pure enough to be used in the neY.t step. TLC (silica gel): Rf 0.15 (toluene/tetrahydrofuran 1:1).

(See Scheme 18) To a solution of 30 (26.6 g, 0.114 mol) in dry methanol (1.5 l) were added 4 ~ sulruric acid (95-97%) and the solution stirred a- room temperature Cor 2 days. The solution was neutralized with sodium bicarDonate solution, partially evaporated to remove the methanol, diluted with wate- (500 mL) and eztracted with ethyl acetate (2 z 500 mL). The organic layer was washed with wate- (250 mL), dried W092/04045 PCT/US91/~6180 Na2SO4) and evaporated. The residue was chroma.ographed on silica gel using toluene/ethyl acetate 3:1 (v/v) as eluents. 31 was isolated as a colorless, viscous syrup (25.7 g, 91x). MS (70eV):
m/z 247 (M+, 8), 130 (100).

(See Scheme 18) To a solution of 31 (5.0 g, 20.2 mmol) and pyridine (3.2 g, 40.4 mmol) in d-y dichloromethane (lO0 mL) at 0C was added p-toluene sulphonyl chloride (5.0 5, 26.3 mmol) in small por'ions. The solution was zllowed to stand for 4 days in the refrigerator ~' 0-5C. The solution was washed with sodium bicarbonate solution (2 x 50 mL), d-ied (Na2SO4) and evaporated. The residue was chromatographed on silica gel using toluene/ethyl acetate 95:5 (~/v) as eluents.
Compound 32 (Rf 0.3) was isolated as a viscous oil, which was recrystallized from diisopropyl ether to yield colorless crystals (6.94 g, 85%). MS (70eV):
m/z 401 (M+, ô), 130 (100).

(See Scheme 18) Compound 32 (3.5 g, 8.13 mmol) and potassium cyanide (0.850 g, 13.1 mmol) in dry dimethylformamide (60 mL) were stirred at 110C for 16 hours. The solution was evaporated in vacuo and the residue dissolved in ethyl acetate (200 mL) and water (200 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel using toluene/ethyl acetate 9:1 ~v/v) as eluents. Compound 33 was isolated (Rf 0.4 in toiuene/ethyl acetate 4:1) as a W092/04045 PCT/~S91/06180 20~819~

colorless syrup (1 5, 45%). MS (70eV): m/z 256 (M-, 8) 130 (100).

ExAMoeLE 87 (R- = 2-adamantvl, R- = R4 = H, c = , see schems 18~ -Carbamic acid, r3-(lH-indo'-3-vlmethvl)-3-methvl-4-oxo-4-r(2-Dhenvlethvl)amino]bu.vll-, ~~-cvclo-r3.3.1.13~'ldec-2-vl ester, ( )-The conversion of compound 33 .o compounds _7 has been done in anaiogy to the conversion of com?ounds 2 to compounds 6 (see synthetic scheme 15a). 37a has been isolated after chromatographic separation on silica gel usins CH,Cl2/MeOH 98:2 (~/v) as eluents 25 a colorless amorphous solid in 52% yield, m.p. 7G-80C. MS (70eV): m/z 527 (M+, 2), 130 (100).

EXAMæLE 88 Rl = 2-adamantvl, R3 = -CH~OH, R4 = H, c = 1, see Scheme 18) Carbamic acid, r4-rrl-(hvdroxvmethvl)-2-phenvlethvll-aminol-3-(lH-indol-3-vlmethvl)-3-melhv1-4-oxobutvll-, t-icvclo-r3.3.1.13~7ldec-2-vl ester In an analogous manner to the synthesis of 37a, compound 37b has been isolated after chromatos-aphic separation on silica gel using CH2Cl2/MeOH 98:2 (v/v) as eluents as a colorless amorphous solid in 52%
yield, m.p. 70-80C. MS (70eV): m/z 527 lM+, 2), 130 ~100). 37b is a mixture of two diastereomers (S-configuration at the chiral center derived from (S)-(-)-phenylalaninol).

~XAMoeLE 89 Ethvlidene-isoDroDvlamine (69) Isopropylamine (85 mL, 1.0 mol) was added gradually over a Deriod of 1 hour to acetaldehyde W092/040 ~ PCT/US91/n618~
0~ ' (56 mL, 1.0 mol) cooled in an ice bath. Afte- the addition was complete, the mixture was s~irred ~Gr an additional 20 minutes. Potassium hydroxide flakes were added until the solution separated into two 12yers. The organic phase was separated and stored over crushed potassium hydroxide at 0C. The dried material was distilled under vacuum at _oom temperature to yield the title compound (1) (5i.4 g, 60~), b.p. 25-30C/lO mm; ~ H (300 M Hz; CDCl3); 1.09 (6H, d, ~ 6.3 Hz, 2CH3), 1.88 (3H, à, ~ 4.8 Hz, CH,CH).

3-(Iso~-o~vl-aminoethvlidene)-indole t70) A solution of indole (25.0 g, 0.213 mol) in glacial acetic acid (150 mL) was cooled in an ice bath and ethylidene-isopropylamine (69) (17.3 g, 0.203 mol) in toluene (50 mL) added dropwise, with stirring over a period of 1 hour. Tha resulting mixture was kept at 0C for 5 days. After this period the mixture was poured onto an ice-ether mixture. The ether layer was separated and extracted with lN potassium hydrogen sulphate (2 x 100 mL). The combined aqueous phase was washed with ether (2 x 50 mL), then made basic with lON sodium hydroxide (keeping the temperature below 25C). The alkaline solution was extracted with ether (4 x 250 mL). The organic phase was dried (MgSO4) and evaporated to dryness to give the title compound (2) (24.6 g, 60%), m.p. 107-112C (lit.,1 108-114C); ~2r (film) 3 479 cm~1 (indole NH); ~ ;- (300 M Hz, CDC13), 1.01 (3P., d, J 6 Hz, CH3), 1.09 (3H, d, J 6 Hz, CH3), 1.52 (1.52 (3H, d, J 6.6 Hz, CH3), 2.88 (lH, septet, 6 Y.z, CH(CH3), 4.27 (lH, q, J 6.6 Hz, indCH)CH3), 7.08- 25 (4H, m), 7.35 (lH, s, J 8 Hz, NH), 7.71 (lH, d, J 8 Hz, indole 4-H), 8.21 (lY., brs, indole NH).

W092/04~5 PCT/US91/06180 2Q8819a Dibenzvlacetamidomalonate (71) Diethylacetamidomalbonate (9.1 g, 42 mmol) [Aldrich] in benzyl alcohol (26 mL, 0.25 mmol) was heated in an oil bath at 200C. A slow stream of nitrogen was bubbled through the solution and the ethanol distilled out. Afte- 4 hours the reactior.
mixture was cooled to room temperature and the e~.cess benzyl alcohol removed in vacuo with the oil bath temperature being slowly raised to 185-190C, at which point distillation became very slow. Thé solution was cooled to room temperature and the resulting precipitate recrystallized from iso?ropanol to yield the~title compound (71) (12.2 g, 85%); m.p. 111-112C
(lit.,; 110-113C); UmaX (film) 1752, 1734 (ester C =
O), 1651 (amide C = O), 740 and 694 cm~l (mono substituted pH); ~ H (300 M Hz, CDC13), 2.05 (3H, s, CH3CO), 5.17 (2H, s, CH2Ph), 5.18 (2H, s, CH2Ph), 5.29 (lH, d, J 7 Hz, CHC02CH2Ph)2), 6.53 (lX, brd, J 6 Hz, NH), 7.27 (lOH, m, 2Ph), ~ c (75.5 M Hz, CDC13), 22.5, 56.5, 68, 128.5, 134.5, 166, 170.

Dibenzvl (3-indolvlethvlidene)acetamidomalonate (72) The amine (70) (5.41 g, 26.7 mmol), diester ,1) (9.12 g, 26.7 mmol) and sodium methoxide (38 mg, 0.70 mmol) were heated in toluene (30 mL) at 85-95C
(bath temperature) while a slow stream of nitrogen was bubbled through the solution. The reaction mixture was kept at this temperature fo~ 5 hours, then cooled to -40C (freezer). The crude product was filtered and recrystallized from isopropanol to yield the title compound (72) (8.22 g, 64%), m.p. 162-163C (Pr OH) (lit.,l 161-163C); ~ma~ 1737 (ester C a 0) ~ 1672 (amide C = O), 743 and 697 cm~ (monosubstituted Ph);
8 H (300 M Hz, CDC13), 1.57 (3X, d, J 7 Hz, CH3), 1.97 (3X, s, CH~CO), 4.32 (lH, q, J 7 Hz, CH CH3)), 4.72 W092/04~5 PCT/US9l/061~

(lH, d, J 12 Hz, one of CH2Ph), 4.89 (lH, d, J 12 Hz, one of CH2OH), 5.08 (lH, d, J 12 Hz, one of CH2Ph), 5.20 (lH, d, J 12 Hz, one of Ch2Ph), 6.56 (lH, s, NH), 6.86 (lH, d, J 2 Hz, indole 2-H), 7.02-7.33 (13H, m, indole + 2Ph), 7.54 (lH, J 8 Hz, indole 4-H), 8.15 (lH, br s, indole NH), ~ C (75.5 M Hz, CDCl3), 18, 23, 37, 68, 70, 111.5, 115, 119.5, 122, 122.5, 127, 128, 134.5, 136, 167, 168, 169.5.

(~-Indolvlethvlidene)acetamidomalonic acid (73) The diester (72) (930 mg, 1.92 mmol), palladium hvdroxide on carbon (Pearlman's catalyst) (125 mg) and 95% ethanol (110 mL) were placed in a Parr hydrogenation vessel and subjected to a hydrogen pressure of 45 psi at 25C for 3 hours (until the uptake o' hydrogen ceased). The reaction mixture was filtered through Celite to remove the catalyst, then evaporated to dryness to give the title compound (73) (576 mg, 99%) which was used without further purification. ~ H (300 M Hz; D2O), 1.55 (3H, d, J
7 Hz, CH3), 1.99 (3H, s, CH3CO), 4.09 (lH, brd, J
7 Hz, CH,(CH3), 7.12-7.24 (3H, m), 7.49 (lH, d, J
8 Hz, indole 7-H), 7.71 (lH, d, J 8 Hz, indole 4-Y).

2-Acetamido-3-t3-indolvl)butanoic acid (74) The malonic acid (73) (5.48 g, 18.0 mmol) was refluxed in pyridine/water (1:1) (20 mL) until no diacid remained (S.O2:EtOH-EtOAc (1:1) + 1% AcOH; r' 0.26). The reaction mixture was cooled, diluted with water (50 mL), and acidified with 10% sulphuric acid (50 mL). The resulting solution was left at 0C
overnight to crystallize. The brown solid was filtered off and dried to yield 2-acetamido-3-(3-indolyl)butanoic acid isomer A (74A) (1.30 g, 28%); ~ H (300 M Hz; d6-DMSO), 1.32 (3H, J 9 Hz, CH3), W092/ 04045 2 ~ ~ 8 ~ ~ ~ PcT/usg1/06l8n 1.84 (3H, s, CHH3CO), 3.46-3.55 (lH, m, indCH(CH-,)-), 4.58-4.67 (lH, m, CH(COOH)NHAc), 6.93-7.19 (3H, m), 7.34 (lH, d, _ 8 Hz, amide NH), 7.54 (lH, ~ 8 Hz, indole 7-H), 8.04 (lH, d, J 9 Hz, indole-4Y), 10.81 (lH brs, indole NH), ca 12.4 (vbrs, C~2H). The 'ilt-ate was extracted with ethvl acetate (4 x 100 mL). The ethyl acetats ext-2cts were combined and washed with water (2 x 50 mL) then extrac~ed with 10% sodium hydrogen carbon2te (2 x 100 mL). The sodium hydrogen ca-bonate ex~ract was acidified with 4N sulphuric acid then extracte~
with ethyl acetate (2 x 75 mL). The ethyl acetate solution was washed with water (2 x 25 mL) then evaporated to dryness to give a beige foam, 2-acetamido-3-(3-indolyl)butano c acid isomer B (74B) (2.17 g, 46%); ~ H (300 M Hz, d~-DMSO), 1.32 (3H, d, 7 Hz, CH3), 1.84 (3H, s, CH3CO), 3.50 (lH, M, ind CH(CH3)-), 4.66 (lH, m, CH(COOH)NHAc), 6.93-719 (3H, m), 7.34 (lX, d, J 8 Hz, amide NH), 7.63 (lH, d, J
8 Hz, indole 7-H), 7.84 (lH, d, J 9 Hz, indole 4-H), 10.83 (lH, s, indole NH), ca 12.5 (vbrs, CO2H).

Deacetvlation of acids (74A~ and (74B) The acids (74A) and (74B) we-e deacetylated separately by the same procedure. Nitxogen was bubbled throush a mixture of ac d (74B) (3.96 g, 15.2 mmol) in 4N sulphuric acid (25 mL) for 30 minutes, then the mixture was refluxed until all the solid dissolved. The solution was cooled to room temperature and neutralized to pH 8 with 0.4N barium hydroxide. The barium salts we-e precipitated with solid carbon dioxide, the mixtu-e heated to boilins point and filtered hot. The so vent was removed in vacuo and the crude product pur fied by reverse phase column chromatography [methanol-wate- (1:6) as eluantj W092/04045 PCT/USgl/0618 ~ -166-to give 2-amino-3-(3-indolyl)butanoic acid (7S) (2.34 g, 71%) in a ratio of 1:3 (75A:75B), m.p. 198-212C (lit.l, 218-225C dec); isomer A ~ H
(300 M Hz, D2O), 1.33 (3X, d, J 7 Hz, CH3), 3.66-3.75 (2H, m, indCH(CH3)- + CH(Co2H)NH2), 7.2G-7.34 (2.-., m), 7.57 (lH, d, J 8 Hz, indole 7-H), 7.87 (lH, d, J 8 :-z, indole 4-H), isomer B, ~ H (300 M Hz, D2O), 1.37 (3:-., d, J 7 r.z, CH3), 3.30-3.42 (2Y., m, ind C_(C:i2)- ~
-CH(CO2H)NH2), 7.09-7.24 (3:-, m), 7.48 (lX, d, J 8 Hz, indole 7-H), 7.73 91H, d, J 8 Hz, in~ole 4-H).

2-Adamantvlchloroformate A solution of 2-adamantanol (10.1 g, 66.5 mmol) ir.
dichloromethane (200 mL) was cooled in an ice bath.
Bis(trichloromethyl)carbonate (triphosgene) (7.55 g, 25.4 mmol) was added followed by dropwise addition c' pyridine ~6.2 mL, 77 mmol) at such a rate that the temperature remained below 20C. After a further 10 minutes the mixture was warmed to room temperature and stirred for a further 2.5 hours. The dichloromethane was removed in vacuo without heating and the residue slurried with ethyl acetate (50 mL).
The pyridinium hydrochloride was filtered off and the iltrate evaporated to dryness without heating to yield 2-adamantylchloroformate (76) (13.7 g, 96%); ~ H
(300 M Hz, CDC13, 1.48-2.32 (14H, m, adamantyl), 5.01 (lH, t, J 3 Hz, adamantyl 2-H); (lit.,2 ~ H (CC14) 1.3-2.4 (14H, m), 4.95 (lH, s).

2-(2-Adamantvloxvcarbonvl)amino-3-(3-indolvl)butanoic acid (77) Percent amino acid (75) (449 mg, 2.29 mmol) in lN
sodium hydroxide (2.29 mL) was added to sodium hydrogen carbonate (211 mg, 2.5 mmol). This mixture was cooled to 0C (ice bath), dioxan. (2.29 mL) was W092/04045 PCT/US91/0618~

2~8819~

added, followed by dropwise addition with stirring of a solu'ion of the chloroformate (76) (742 mg, 34.46 mmol) in dioxan (2.29 mL). Wnen all the amino acid had gone (TLC SiO2:4% methanol in dichloromethane), the dioxan was removed n vacuo and the residue partitioned between 10~ cit-ic acid and ethyl acetate. The aqueous phase W2S extracted further with ethyl acetate. The o-ganic extra-ts were combined, dried (MgSO4), and evaporated to dryness.
The crude acid was purified by column chromatography on normal silica ~hexane:ethyl acetate (3:20 + 0.5%
acetic acid as eluant] to give 2-(2-adamantvloxv-carbonvl)amino-3-(3-indolvl) butanoic acid (77) (570 mg, 63%); ~ H (300 M Hz, d6-D~.SO), 1.34 (3H, d, J
8Jz. CH3), 1.68-2.00 (14H, m, adamantyl), 3.40-3.53 (lH, m, indCH(CH3)), 4.36 (lY., brt, CH(CO2H)), 4.59 (lH, s, adamantyl 2-H), 6.73 (lH, d, J 9 Hz, urethane NH), 6.96 (lH, t, J 7 Hz, indole 5-H), 7.06m (lH, t, J
7 Hz, indole 6-H), 7.17 (lH, brs, indole 2-H), 7.33 ~lH, d, J 8 Hz, indole 7-H), 7.60 (lH, d, J 8 Hz, indole 4-H), 10.83 (lH, s, indole NH)m, ca 12.6 (vbrs, C02H) -2-Adamantvloxvcarbonvl-D,L-~-methvl-D,L-trv~to~han-L-~henvlalaninol (78) The carboxylic acid (77) (288 mg, 0.726 mmol), N,N'-dicyclohexyl-carbodiimide (DCCI) (173 mg, 0.838 mmol) and l-hydroxybenzotriazole (HOBT) gl21 mg, 0.895 ~.mol) in ethyl acetate (5 mL) were stirred for 1 hour at 0C. Dimethylaminopyridine (DM~) (23 mg, 0.19 mmol) and phenylalaninol (163 mg, 1.08 mmc ) were added, and the mixture stirred for a further 2 hours at 0C then for 48 hours at room temperature. The mixture was filtered and the filtrate washed with 5%
citric acid (2 z 10 mL), saturated sodium hydrogen wo 92/04045 PCr/US91/06180 208~ 168-carbonate ~10 mL), 5~ citric acid aga_n (10 mL), and brine (10 mL), dried (MgSO4), and eva?orated to d-yness. The crude product was purified by column chromatography on no-mal silica [ethyl acetate:hex.ane (1:1) as eluant] to yield 2-adamantvlo~vcarbonvl-~ L-~-methvl-D L-trv~.o~han-L-~henYl212n~nol (78) (45 ms, 12%); m.p. 99-101C (Found: C, 71.7; H, 7.65; N, 7.4.
C32H39N3O~ 0.5H2O re~uires C, 71.35i X, 7.5i N, 7.8~);
~aY (film) 3360 (OF.), 1 695 (ure~hane C = O), 1658 (amide C = O), 746 2nd 702 cm~l (monosubstituted ~h);
~H (300 M Hz, CDCl3), 1.42 (3H, d, J 7 r.z~ CH3), 1.45-2.10 (14H, m, adamantyl), 2.20 (lH, brs, OH), 2.43-2.69 (2H, m, Cr2Ph), 2.84 (lH, brs, ind CH(C:d3-), 3.39 (2H, br, m, CH2OH), 3.86 (lH, brs, CH(CH2Ph)CH20H), 4.49 (lH, m, CH(NMR)(CONH-), 4.79 (lH, s, adamantyl 2-H), 5.49 (lH, brs, urethane NH), 6.87 (lH, brs, amide NH), 6.95-7.38 (9H, m, indole +
Ph), 7.69 (lH, d, J 7 Hz, indole 4-H), 8.26 (lH, s, indole NH); m/z (FAB) 530 (M+ + 1), 257, 232, 217, 181, 144, 126 (100~); 109.

N-rD-3-(1~-indol-3-vlmethvl)-3-me'hvl-N- r (tricvclo r 3.3.1.13 ' 7 1 dec-2-vloxv)carbonvll-~-alanvll-L-2-phenvl~lvcine, AdOC-((D)-3-(lH-indol-3-vlmethvl)bAla-(L)-2-~henvl)Glv Ste~ 1. Synthesis of 2AdocoMeRT~p CHN2 (diazoketone).
A solution of N-methylmorpholine (253 mg, 2.50 mmol) and 2ADOCoMe-_-TrpOH (990 mg, 2.50 mmol) ir.
anhydrous THF (20 mL) at 0C was treated dropwise with a solution o iso-butyl chloroformate (340 mg, 2.50 mmol) in anhydrous THF (10 m~) and left stirring for 20 minutes). The reaction mixture was then filtered and a solution of diazomethane (6 mmol) in W092/0404~ PCT/US91/06180 208~19~

ether was added to the filtrate. This was ther.
allowed to warm to room temperature and left 12 hours Excess diazomethane was quenched wi~h AcOH (1 mL~ and the mixture evaporated to dryness ir. vacuo. The residue was then separated by silica gel chromatography using n-hexane:EtOAC (4:1 then 3:1) as eluants to give the diazoketone (Scheme 19, No. 2) as yellow crystals. M.?. 182.2-182.7C (MeOH);
[a]D20 = +64 (c = 0.5, MeOH); IR (film) 3400-3200, 2913, 2854, 2106, 1693 and 1352 cm i NM~ (CDC13)~ '.49 (3H, s), 1.50-1.60 (2H, m), 1.70-2.05 (12H, m), 3.30-3.40 (2H, br s), 4.86 (lH, s), 5.20-5.40 (lH, b~ s), 5.56 (lH, s), 6.95 (lH, d, J 2 Hz), 7.08 (lH, t, J
7 Hz), 7.16 (lH, t, J 7 Hz), 7.33 (lH, d, J 8 Hz), 7.55 (lH, d, J 8 Hz), 8.50 (lH, s); MS 71e (FAB) 421.3 (11), 393.2 (54), 351.2 (9), 307.2 (22) and 259.1 (100) i AnalysiS for C24H28N43 Calc.: C, 68.55; H, 6.71i N, 13.32%
Found: C, 68.51i H, 6.73; N, 13.26%

Phenvlmethvl (R)-~-methvl-~- r r (tricvclo r 3.3.1.13~7ldec-2-vloxv)carbonvllaminol-lH-indole-3-butanoic acid Ste~ 2. Synthesis of the above compound (Scheme 19, No. 3) A solution of the diazoketone (as prepared in Step 1) (4-20 g, 10.0 mmol) in benzyl alcohol (30 mL) was treated with a solution of silver benzoate (6 mL
of a solution containing 1 g silver benzoate in 10 mL
Et3N) at room temperature. This was stirred for 4 hours, treated with activated charcoal and flltered through gypsum. The benzyl alcohol was removed ln vacuo and the residue separated by silica gel chromatography using CH2Cl2 as eluan~ to give the W092/04045 PCT/USg1/06180 benzyl ester (Scheme I, No. 2) as a glass ~3.3 g, 66%); m.p. 47-52C; [~20 = +17.6 ~c = 1, MeOP); IR
(film) 3500-3200, 2908, 2855, 1750-1680 cm~l; NMR
(CDCl3)~ 1.39 (3H, s), 1.51 (lH, s), 1.54 (1~., s), 1.70-2.05 (12H, m), 2.68 (lH, o, J 14.3 ~z), 2.97 (lP., d, J 14.3 Hz), 5.10 (3~, s), 6.99 (l:Y, d, J 2.3 ~.z), 7.08 (lH, t, J 7 P.z), 7.16 (1~., b, ~ 7 ~.z), 7.30-7.35 (6~, m), 7.58 (lH, d, J 7.8 Hz), 8.05 ~l:i, s); MS M~
(FAB) 501.3 (28), 370.3 (24), 326.3 (29), 306.2 ~32) and 135.2 (100);
AnalysiS for C31~36N2C4 Calc.: C, 74.37; H, 7.25; N, 5.60%
Found: C, 74.44; H, 7.20; N, 5.75%

(R)-~-methvl-~- r ~ (tricvclo r 3.3.1.13~7ldec-2-vloxv)carbonvllaminol-1~-indoie-3-butanoic acid AdOC-(a-Me)DTrD

Step 3. Synthesis of the above compound (Scheme 19 ~o. 4) A solution of the benzyl ester (as prepared in Step 2) 1.O g, 2 mmol) in absolute ethanol (100 mL) was treated with 10% palladium on carbon (100 mg, 10%
w/w) and the resulting suspension subjected to an atmosphere of hydrogen at 50 psi for 4 hours with agitation at temperature of 30C. This reaction mixture was then filtered through gypsum and the solvent removed ln vacuo. The residue was column chromatographed over reverse phase silica using MeOH:H2O ~3:1) as eluant and the solid product recrystallized from chloroform to give the acid as a white solid (700 mg, 85%), m.p. 198-201C (CHCl3)i [a]20 = +20 (c z 1, MeOH); IR (film) 3500-3300, 2912, 2856, 1704 and 734 cm ;; NMR (CDCl3)~ 1.41 (3~, s), '.53 (lH, s), 1.57 (lP., s), '.70-1.85 (9~, m), W092/04~5 PCT/USg1/06180 1.95-2.10 ~4H, m), 2.69 (lH, d, J 14.~ Hz), 3.05 (1~, d, J 14.3 Hz), 3.21 (lH, d, J 14.3 Hz), 3.32 ~lX, d, 14.4 Hz), 4.86 (lH, s), 5.10-5.30 ~lH, br s), 7.04 (lH, d, J 2.2 Hz), 7.07-7.20 (2H, m), 7.;35 (lY., d, 8 Hz), 7.60 (lH, d, J 7.7 Hz), 8.16 (ln, s); ~S ~/e (FAB) 411.5 (9) and 217.2 (100);
Analysis for C2~H30N4O~
Calc.: 70.22; H, 7.37; N, 6.82%
Found: 70.03; H, 7.38; N, 6.78%

Methvl N-rD-3-(lH-indol-3-vlmethvl)-3-me~hvl-~-~(tricvclo~3.3.1.13~ 7 1 dec-2-vloxv)ca_bonvll-~-alanvl~-L-2-~henvlalvcine Ste~ 4. Synthesis of the above compound (Scheme 19 No. 5) A stirred solution of the acid (as prepared in Step 3) (500 mg, 1.20 mmol) and pentafluorophenol (224 mg, 1.2C mmol) in EtOAC (50 mL) at 0C was treated with N, N'-dicyclohexylcarbodiimide (263 mg, 1.30 mmol). This mixture was stirred 18 hours at 0C, filtered and S-phenyl glycine methyl/ester (303 mg, 1.50 mmol) added to the filtrate. This reaction mixture was left at room temperature for 48 hours, washed with lM citric acid solution (2 x 20 mL), saturated NaHCO3 solution (2 x 20 mL) and H2O
(2 x 20 m). The dried (MgSO4) organic phase was evaporated to dryness in vacuo and the residue separated by reverse phase sllica gel chromatography using MeCH:H2O ~ :1) as eluant to give the ester (Scheme 1 No. 5) as a noncrystalline solid (600 mg, 90%). M.p. 72-82C; [a]D22 = +55.36 (c = 1, MeOH); IR
(film) 3500-3200, 2916, 2856, 1743, 1694, 1657 and 1504 cm~l; NMR (CDCl3) ~ 1.35 (3n, s), 1.40-1.55 (2H, m), 1.70-2.05 (12H, m), 2.54 (1:-, d, J 13.3 Hz), 3.04-W092/04045 PCT/USgl/061~
"~\

3.15 (2H, m), 3.31 (lH, d, J 14.2 Hz), 3.71 (3H, s), 4.71 (lH, s), 5.09 (lH, s), 5.48 (lH, d, J 6.6 Hz), 6.85 (lH, d, J 6.1 Hz), 7.04 (lP., d, ~ 2 Hz), 7.0~
(lH, g, J 7 Hz), 7.17 (lH, g, J 7 Hz), 7.30-7.40 (6H, m), 7.59 (lH, d, J 7.6 Hz), 8.14 (lH, s); MS M/e (FAB), 558.3 (12), 383 (11), i98.1 (34), 170.1 (27) and 135.1 (100);
Analvsis for C,,H39N~O~:
Calc.: C, 7i.07, H, 7.05; N, 7.53%
Founc: C, 71.31i H, 7.30; N, /.28~

Glvcine, N-~D-3-(lH-indol-3-vimethvl)-3-methvl-N-~(tricvclo~3.3.1.13~'ldec-2-vloxv)carbonvll-~-alanvl~-L-2-~henvl-AdOC-((D)-3-(lH-indol-3-vlmethvl)bAla-(~L~-2-~henvl)Gly ....
,r\ /~ Ph h~
I~:J
Step 5. Synthesis of Example 90, Scheme 19, No. 6 A sti_red solution of the ester (as prepared in Step 4) (399 mg, 0.70 mmol) in TH~ (20 mL) was treated with a solution of ClOH (30 mg, mmol) in H2O (5 mL) at room temperature. After 2 hours the mixture was made acidic to pH paper by adding lM HCl solution.
.he solvent was then removed under vacuum and the -esidue separated by reverse phase silica gel chromatography using MeOH:H2O (3:1) as eluant to give the product (Example 90) as a noncrystalline solid 2_ (200 mg, 53%); m.p. 120-125Ci [a~ 20 = +49.2 W092/04~5 PCT/USgl/061~

20~8~9~

(c = 0.5, MeOH); IR (film) 34S0-3250, 2916, 2856, 1750-1600, 1510 and 1256 cm i; NMR (CDCl3) ~ 1.34 (3H, s), 1.50-1.55 (2H, m!, 1.60-200 (12H, m), 2.5Q (lH, d, J 12.7 Hz), 3.00-3.25 (3H, m), 2.50-4.00 (lH, br~, 4.60-4.75 (lH, br s), 4.90-5.20 (lH, br s), 5.54 (1:., ~
d, J 6.5 Hz), 7.00-7.60 (10:H, m), 7.58 (1:~, d, J
7.9 Hz), 8.14 (lH, s);
Analysis for C32H37N3~ 3 H2O:
Calc.: C, 70.00; H, 6.90i N, 7.65%
Found: C, 69.97i H, 6.85; N, 7.64%

rR-(R*,S)l-a- r [ 3-(lH-indol-3-vl)-2-methvl-l-oxo-2-r r (tricvclo r3 . 3.1.13~7ldec-2-vloxv)carbonvllaminol ~ro~vllaminolbenzene3cetic acid, ~R-(R*,S*)l-AdOC-(~-Me)DTr~-L-~henvlqlvcine (See Scheme 20) Step l. Synthesis of oxazolone (R)(4-(lH-indol-3-ylmethyl)-4-methyl-2-(tricyclo[3.3.1.13~7]dec-2-yloxy)-5(4H)-oxazolone) ~No. 2, Scheme 20) A solution of AdOC~Me-R-TrpOH (1.0 g, 2.5 mmol) and N,N'dicyclohexylcarbodiimide (0.52 g, 2.5 mmol) in anhydrous DMF (5 m~) was stirred for 1 hour at room temperature. This mixture was then filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on silica gel using hexane:EtOAC
(6:1) as eluant to give the oxazoline (2, Scheme 20) as white crystalline needles (850 mg, 90%).
M.p. 150.5-150.9C (hexane); [a~ 20 = +g.oo (c = 1, MeOH); IR (film), 2910, 2857, 1823, 1681 and 1399 cm~l; NMR (CDCl3) ~ 1.10-1.20 (lH, m), 1.30 (15H, m), 2.04 (lH, s), 3.20 (lH, d, J 14.5 Hz), 3.25 (lH, J
14.5 Hz), 4.72 (lH, t, J 3.5 Hz), 6.'9 (lH, d, J
2.4 Hz), 7.07 (lH, dt, J 7.1 Hz), 7.14 (lH, dt, J 7.5 and 1 Hz), 7.29 (lH, d, J 7.3 Hz), 7.64 (lH, d, J

7.6 Hz), 8.02 (lH, s); MS M/e ~CI) 379.2 (52), 178.3 (47), 163.3 (61), 135.2 (74) and 130.2 (100);
Analysis for C23H26N23 Calc.: C, 72.99; H, 6.92; N. 7.40~
Found: C, 72.88; H, 6,96; N, 7.37%

Ste~ 2 A suspension of S-phenylglycine (42 mg, 0.28 mmol), NaHCO3 (23 mg, 0.28 mmol) and the oxazolone (Scheme 20, No. 2) (100 mg, 0.26 mmol) in DMF:H~O (1:1) (10 mL) was stirred a_ ~oom temperalure fo- 18 hours. The solvent was then removed in vacuo and the residue suspended between EtOAC (20 mL) and l.M
citric acid solution (20 mL). The aqueous phase was partitioned and extracted with EtOAC (2 x 20 mL) and the combined organic phases washed with H2O
(3 x 10 mL), dried over MgSO4 and the solvent removed in vacuo. The residue was then subject to silica gel chromatography using 3% MeOH in CH2Cl2 then 5% MeOH, 0.5% H2OH in CH2C12 to give the product ~Example 91) as a noncrystalline solid (106 mg, 77%). M.p. 138-143C;
[a]~24 = +82 (c = 1, MeOH); IR (film) 3500-3200, 2913, 2855, 1696, 1666 and 1499 cm i; NMR (CDC13) ~ 1.40-1.50 (2H, m), 1.56 (3H, s), 160-1.95 (12H, m), 3.26 (lH, d, J 14.6 Hz), 3.40 (lH, d, J 14.6 Hz), 4.73 (lH, s), 5.68 (lh, d, J 6.8 Hz), 5.40-5.80 (lH, br), 6.90 (lH, s), 7.00-7.15 (2H, m), 7.20-7.30 (6H, s), 7.35 (lH, d, J 6.8 Hz), 7.53 (lH, d, J 7.5 Hz), 8.~1 (lH, s); MS
M/~ (FAB) 530.5 (13), 217.2 (38)i Analysis for C3 H3eN30eO2H20:
Calc.: C, 69.83i H, 6.69i N, 7.88%
Found: C, 69.85; H, 6.66; N, 7.74%

W092/04045 PCT/USg1/06180 Tricyclo[3.3.1. 13' 71 dec-2-vl(r)-~2-~2-~henvlethvl)-aminol-1-(lH-indol-3-vl)-i-methvlethvllcarbamate (See Scheme 21) To a solution of lithium borohydride (4 mL, 2M
solution, 8 mmol) in dry THF under a nitrogen atmosphere was added a solution of chlorotrimethylsilane (1.75 g, 16.0 mmol) in d-v TH~
(5 mL). A white precipitate ~of lithium chloride) was observed. After 2 minutes a solution of (18) ( 5, 2 mmol) in THE (15 mL) was added slowly (over 3-4 minute period) and the reaction miYture was stirred for 20 hou-s at ambient temperature. The reaction was treated cautiously with MeOH (5 mL) and the volatiles were removed in va^uo at 40C. The residue was purified by silica gel chromatography using hexane:ethyl acetate (80:20) as eluant to give (19) (0.14 g, 14%) as a colorless oil, and recovered (18) (0.52 g; yield of (19) based on recovered starting material 30%). The amine (19) (0.14 g, O.28 mmol) was taken dissolved up in MeOH (5 mL) and treated with 4-toluenesulfonic acid hydrate (0.054 g, 0.28 mmol). The solution was evaporated to leave a white solid. [a]D = +22 (c = 0.25, MeOH) IR (film) 2928 and 1708 (c = urethane). NMR (DMSO-d6) ~ 1.2 (3~, s, CH3), 1.4-2.1 (14H, m, adamantyl), 2.3 (3H, s, CH,Ph), 2.9-3.7 (8H, m, 4 x CH2), 4.7 (lH, br s, adamantyl H-2), 6.9-7.6 (15H, m, aromatics), 8.3 (lH, b_, one of NH2~), 8.5 (lH, brr one of NH2+), 11.0 (lH, s, indole NH); MS M/e (FAB) 486 (m+ + H) (100), 136 (52);
Analysis for C3~H3sN32 C7Hôso3 o-75H2o Calc.: C, 67.98; H, 7.28; N, ~ ^6 Found: C, 67.96; H, 7.31; N, 6~3. M.p. 90-93C

W092/04~s PCT/US91/06180 20~95 -176-Ethvl~R-(R*,S*)1-4-[~2-~henvlethvll-~3-(lH-indol-3-vl)-2-methvl-2-~ r (tricvclor3.3.1.1-~7ldec-2-vloxv)carbonvllaminol~roPvllaminol-4-oY.o-butanoate (19b Scheme 21).
Prepared by a similar method to compound (19a).
Recovered a white solid 0.102 g (81%)i [a]D2- = +25 (c = 0.5, CHC13)i IR (film) 2905, 2853, 1732, î711, 1634 cm -; NMR (CDCl3) ~ 1.2 (6r., m), 1.3-2.1 (14H, m), 2.6 (4H, b_ s), 2.9 (2H, m), 3.0 (lX, d, J 14 Hz), 3.3-3.8 (4H, m), 4.0-4.2 (3Y., m), 4.8 (lY., b- s), 5.
(lH, br), 6.9-7.6 (lOH, m), 8.1 (lH, br s); MS M/~
(FAB) 614 (36) (M+ + H), 483 (100), 419 (24);
Analysis for C37H47N305 Calc.: C, 72.40; H, 7.72; N, 6.85%
Found: C, 72.11; H, 7.87i N, 6.16%. M.p. 67-70C

Tricvclor3.3.1.13~71dec-2-vlrR-(R*,S*)1-~2-racetvlr2-~henvlethvllaminol-l-(lH-indol-3-ylmethvl)-1-methvlethvllcarbamate (19a in Scheme 21) To a solution of (19) (0.1 g, 0.2 mmol) in dichloromethane (20 mL) at 0C was added acetyl chloride (0.3 mL, 4 mmol), followed by triethylamine (4 drops). Stirring was continued at 0C for 20 minutes, then the reaction mixture was dissolved in ethyl acetate (50 mL), washed (HCl ac, H20, NaHC03 2g ag), dried (MgSO4) and evaporated to cryness. The residue was purified by column chromatography using hexane-ethyl acetate eluent to give an off-white solid (0.092 g, 85%). [a] 2_ = +24 ~c = 0.25, CHCL3), IR
('ilm) 2909, 2855, 1709, 1610 cm~l; NMR (CDCl3) ~ 1-3 (3H, s), 1.4-2.1 (17H, m), 2.8 (2H, m), 3.1 (lH, d, J
14 Hz), 3.3-3.7 (4H, m), 4.0 (lH, d, J 14 Hz), 4.8 (lH, s), 5.5 ~lH, br s), 6.9-7.7 (lOr., m), 8.1 (lH, b-s); MS M/e (FAB), 528 (45) (M+ + H), 397 (100), 333 (27).

W092/04045 PCT/US91/061~
9 ~
-1~7-4-[[3-(lH-indol-3-Y1)-2-methVl-2-[[(tricvclo[3.3.1.13'7~-dec-2-yloxy)carbonvl~amino]ProDvl~(2-DhenvlethYl)amino~-4-oxobutanoic acid (19d, Scheme 21).
To a stirred solution of (19b) (0.04 g, 0.06 mmol) S in THF (5 mL) was added methanol (5 mL), water (; mLj and lithium hydroxide monohydrate (O.1 g, 2.4 mmo').
The reaction mixture was stirred for 40 minutes a ambient temperature, then acidified (2NHCl as, 50 mL) and the products extracted into ethyl acetate (50 mL).
The organic phase was dried with magnesium sulphate and evaporated in vacuo (40C). The oily residue was purified by column chromatography using dichloromethane/
methanol (9:1) as eluent. Recovered 0.031 g (81~) of a white solid; IR (film) 340 (br), 2912, 2852, 1714, 1700, 1635 cm 1; NMR (MeOH-d4) ~ 1.1-2.2 (17H, m, CH3 + adamantane), 2.6-3.2 (6H, m, 3 x CH2), 3.4-4.1 (6H, m, 3 x CH2), 4.8 (lH, br, adamantane H-2), 7.0-7.6 (lOH, m, aromatics); [a~D 14C ~MeOH, C - 0.2, 22C);
FAB MS 586 (51) m~ + H), 455 (100), 391 (24)~
Analysis of C35H43N305 0.25 H20 Calc.: C, 71.22, ~, 7.43; N, 7~12 Found: C, 71.24; H, 7.46i N, 6.87~, m.~. 99-96C

~X~MoeLE 93 Tricvclo~3.3.1.13~71dec-2-Yl ~R-tR~,S*)1-~2-t~l-(hvdroxvmethvl)-2-~henvlethvllaminol-l-~lH-indol-3-vlmethvl)-2-oxoethvllcarbamate The carboxylic acid 56 ~380 mg, 1.0 mmol) and N,N'-dicyclohexylcarbodiimide (230 mg, l.l mmol) and pentafluo~ophenol (200 mg, 1.1 mmol) were ~u9pended in EtOAC (25 mL) and ~tirred for 2 hours then treated with (S)-2-amino-3-phenyl-1-propa~ol (150 mg, 1 . O mmol~ and ~tirrcd at 40C for 18 hour~. The mixture was filtored and the filtrate waQ wa~hed with at aqueouJ citric acid followed by Jat aq NaXCO~ _ W092/04~5 PCT/US91/~6180 ~ ' Q ~9 -178-ollowed by H2O. The organic layer was dried ~MgSO4), filtered, concentrated in vacuo and purified by reverse-phase silica gel chromatography (LiChroprep~
~-18) using MeOH:H2O (4:1) as eluant to give ths product 6 (0.36 g, 71~); [~]~2C = 20.4 (c = 0.25, CH2Cl2); NMR (CDC13) ~ 1.8 (14H, m), 2.60 (2:., d)i 3.~0 (4P., m), 4.05 (lH, m), 4.42 (lP., q, ~), 4.78 (lH, m), 5.45 (lH, b- s), 6.15 (lR, b- s), 7.30 (8E, m), 7.37 (lH, d, J), 7.67 (lH, d), 8.25 (lH, b- s).
~ydroxyamide (6) (See Scheme 22) (517 mg, 1.00 mmol), im dazole (146 mg, 2.15 mmol), and tertiarybutyldimethylsilyl chloride (354 mg, 2.35 mmol) in DME (6 mL) were stirred 2~ room temperature for 18 hours. The reaction was quenched with H2O (40 mL). The emulsion was ex,racted with ether (80 mL). The ether was washed with brine, dried (MGSO4), filtered and concentrated in vacuo. The crude material was purified by column chromatography [SiO2:hexane-ethyl acetate (2:1) as eluant] to give the silyl protected amide (474 mg, 75%) as a white foam. lH NMR (CDCl3) ~ 8.12 (lH, s, indNH), 7.76 (lH, d, J 7 Hz, ind H-4), 7.40 (lX, d, J 8 Hz, ind H-7), 7.34-7.06 (8H, m, Ph+ind H-2, H-5, H-6), 6.98 (lP., s), 5.91 (6H, br s, NH?), 5.44 (0.4H, br s, NH?), 4.90 (1~, s, adamantyl H-2), 4.53 (lH, m, NHCH(CH2ind)CO), 4.14 (lH, m, NHCH(CH2OSi)CH2Ph), 3,39 (2H, m, CH2ind), 3.22 (2H, br, m, CH2Ph), 2.12-1.54 ~14H, br, m, adamantyl), 0.88 (2, 9H, tBu), 0.02 (6H, s, 2 x CH3)i lR (film) vmax 2927 + 2856 (adamantyl), 1703 (CO
urethane), 1663 cm~l (CO amide).
Silyl protected amide (418 mg, 0.664 mmol) and Lawesson's reagent [Aldrich] (268 mg, 0.663 mmol) were refluxed in toluene (10 mL) for 30 minutes. The solution was cooled to room temperaturs and poured onto a column of silica gel. The column was eluted -179- 20881~
with CH2Cl2 to remove the toluene and a high rf (0.74 Lawesson's reagent by-product. Elution was then continued with a hexane-ethyl acetate gradient (0-30%) to give thiazolene (9) (73 mg, 21%) as a white foam.
M.p. 56-63C. 1~ NMR (CDC13) ~ 8.16 (lH, s, ind N~.), 7.63 (lH, d, J 8 Hz, ind H-4), 7.38-6.96 (9H, m, ind H-7, H-6, H-5, H-2 + Ph), 5.44 (lH, br, d, J 7 Hz, u-ethane NH), 4.8~ (lH, br s, ind CH2C:~), 4.82 (lH, s, adamantyl H-2), 4.62 (lH, m, NCHCH2Ph), 3.44-2.~3 (5H, m, ind CH2 + PhCH2 + CH of CH2S), 2.6~ (lH, dd, J , 14 Xz, CH of CH2S), 2.09-1.43 (14H, m, adamantyl); _R
(film! vmax 2909 + 2854 (adamantyl), 1698 (CO
urethane), 1621 cm~- (C = N); MS (M/e;
AnalysiS for C31H3sN3S2:
Calc.: C, 72.48; H, 6.87i N, 8.18; S, 6.24%
Found: C, 72.32; H, 7.09; N, 7.75; S, 6.09%

(l-PhenvlcvcloPentvl)methvl r 1 s - r lR*(R*),2R*ll and r 1 s-r lR*(S*), R*ll-~2-~2-hvdroxy-1-(hvdroxvmethvl)-2-phenvlethvllaminol-1-(lH-indol-3-vlmethvl)-1-methvl-2-oxoethvllcarbamate (l-Phenvlcvclo~enlvl)methvl carbonochloroidate Step A. To a stirred solution of l-phenyl cyclopentylmethanol (0.53 g, 3.0 mmol) in methylene chloride (15 mL) was added bis (trichloromethyl) carbonate (0.33 g, 1.1 mmol) followed by pyridine (0.24 g, 3.3 mmol) in methylene chloride at 0C. The reaction mixture was warmed to room temperature and stirred for an hour. The reaction mixture was concentrated and diluted with etnyl acetate (25 mL).
The pyridinium hyarochloride precipitate was filtered off and filtrate was concentrated to give semisolid (0 65 g, 90%), ;H NMR (200 MHz, CDCl~) ~ 7.50-7.10 W092/04~5 PCT/~S9l/n6180 6;;;~
v -180-(5H, m), 4.30 (2H, s), 2.10-1.90 (4H, m), 1.90-1.7;
(4H, m)-a-Methvl-N-[~(l-~henvlcvclopentvl)methvllcarbonvll-D;
trvPtoPhan methvl ester SteP B. To a stirred solu~ion o. i-phenyl 1-cyclopentyl methylchloroformate (0.6S g, 2.75 mmol) n dry TX~ (10 mL) was added a solu~ion of ~-methyl-D~-tryptophan methyl ester (0.60 g, 2.5 mmol) followed by triethylzmine (0.5 g, 5.0 mmol) in dry T.~F. The reaction mixture was s~irred for 30 minutes and then filtered, concentrated and chromatographed to give an oil (0.9 g, 90%). lH NMR (200 M~.z, CDC13) ~ 8.0 (lH, br s), 7.50 (lH, d, J 7 Hz), 7.40-7.0 (8H, m), 6.6 (lH, br s), 5.35 (lH, br s), 4.15 (2H, s), 3.65 (3H, s), 3.6-3.0 (2H, m), 2.10-1.85 (4H, m), 1.85-1.60 (4r., m), 1.55 (3H, s).
a-Methvl-N- r ~ (l-phenvlcvclopentvl)methvllcarbonvll-DL-trvPto~han Ste~ C. To a stirred solution of intermediate B
(0.87 g, 2 mmol) in aqueous 1,4-Dioxane (1:2) (6 mL) was added LiOH (0.13 g, 3 mmol) znd s' rred at room temperature overnight. The reac_ion mix ure is concentrated, diluted with water (50 mL), acidified with dilute HCl, extracted with ethyl acetate and chromatographed to give a white foam (0.8 g, 95%).
H NMR (200 MHz, CDCl3), 8.05 (1:-., br s), 7.55 (lH, d, J 7 Hz), 7.45-7.00 (9H, m), 5.25 (lH, br s), 4.20-3.90 (2H, s), 3.35-3.05 (2H, m), 2.00-1.85 (4X, m), 1.85-1.65 (4H, m), 1.50 (3H, br s).

W092/04045 PCT/US~1/061B~
2088~

(l-Phenvlcyclopentvl)methvl~lS- r lR*(R~),2R*ll and rlS-rlR*(S*),2R*ll-r2-[r2-hvdroxv-1-(hvdro~vmethvl)-2-phenvlethvllaminol-l-(lH-indol-3-vlmet~vl)-1-me~hvl-2-oxoethvllcarbamate Ste~ D. A solution of intermediate C (0.42 g, 1.0 mmol) in ethyl acetate (10 mL) was treated wlth dicyclohexylcarbodiimide (0.23 5, 1.1 ~mol) and l-hydroxybenzotriazole hydrate (O.i7 S~ 1.1 mmol).
After stir_ing for an hour at room tem?erature, it was filtered. To this filtrate, 2-amino-1-phenyl-1,3-propanediol (0.18 g, 1.05 mmol) in l:i mixture of methylene chloride and ethyl acetate was added and stirred overnight. The reaction mixture was filtered, concentrated and chromatographed to yield (0.25 g, 44%) of the title compound as a white foam.
m.F. 78-83C.

(4-Nitrophenvl)methvl r 4S- r 4a 5a(R*)ll and r 4S-~4a,5a(S*)ll-r2-[(2,2-dimethvl-4-phenvl-1,3-dioxan-5-vl)aminol-1-(lH-indol-3-vlmethvl-1-methYl-2-oxoethYll-carbamate a-Methvl-N- r r ( 4-nitro~henyl)metho~vlcarbonvll-~L-trv~to~han methvl ester Step A. The method was as descr bed in Step B, Example 94, except p-nitro benzyl chloroformate was used. The title compound was obtained as a semisolid (2.5 g, 49%) iHNMR (250 MHz, CDCl3) ~ 8.20 (2H, d, J
8.5 Hz), 8.10 (lH, br s), 7. 60-o.80 (7H, m), 5. 64 (lH, br s), 5.2-5.0 !2H, m), 3.71 (3H, s), 3.55 (lH, d, J
14 Hz), 3.35 (lH, d, J 14 Hz), 1.72 (3H, s).

W092/04045 PCT/USgl/0618 ~3 a-Methvl-N-r[(4-nitrophenvl)methoxvlcarbonvl1-~L-trvptoDhan Step B. The method *as as described in Step C, Example 94, except the product of Step A was used.
The title compound was obtained as a 'oam (1.8 g, 75%). lHNMR (250 MHz, CDC13) ~ 8.15-7.35 (3:~., m), 7.60-6.9 (7H, m), 5.53 (lH, br s), 5.2~ (2X, s), 3.60-3.20 (2~, m), 1.73 (3H, br s).

(4-Nitro~henvl)methvl r4S-r4,5a(R~)ll and r4S-~4a,5a(S*)ll-r2-~(2,2-dimethvl-4-Dhenvl-1,3-dioxar.-5-vl)aminol-l-(lH-indol-3-vlmethvl-1-methvl-2-oxoethvllcarbamate SteP C. The method was as described in Step D, Example 94, except the product of Step B and 5-amino-2,2-dimethyl-4-phenyl-1,3-dioxan instead of the product of Step C and 2-amino-1-phenyl-1,3-propanediol, respectively. The title compound was obtained as a foam (2.3 g, 85%). m.p. 92-102C.

EXAMP~E 96 r4S-f4a,5a(R*)ll and r4S-~4a,5a(S*)ll-N-(2,2-dimethvl-4-phenvl-1,3-dioxan-5-vl)-a-methvl-a-~rrr(l-phenvl-cvcloPentvl)methvllaminolcarbonvll-l~-indole-3-~ro~anamide r4S-r4a,5a(R*)ll and r4s-r4a~5a(s*)ll-a-amino-N-(2~2-dimethvl-4-~henvl-1,3-dioxan-5-vl)-a-methvl-1~-indole-3-ProPanamide Ste~ A. A solution of the title compound of Example 95 (1.65 g, 2.8 mmol) in absolute ethanol was treated with catalytic amount o' 10% palladium on carbon and stirred overnight under a positive pressure of hydrogen. The reaction mixture was then filtered over celite and washed with ethanol. The filtrate wzs W092/0404~ PCT/US91/06180 ~88~5 -1~3-concentrated and passed through small plug of silic2 gel to give a white foam (1.1 g, 100%). m.p. 182-185C.

r4S-r4a,5a~R*)ll and ~4S-r4a,5a(S*) l1-~-(2,2-dime hvl-4-~henvl-1,3-dioxan-5-vl)-a-methvl-a- r ~ ~ r (1 -~her.vl-cvcloDentvl)methvllaminolcarbonvll-lH-indole-3-~ro~anamide Ste~ B. To a stirred solution of the produc~ Oc Step A (0.49 g, 1.2 mmol) in dry T~F (15 mL), was added l-phenyl cyclopentylmethylisocyanate (0.26 g, 1.3 mmol) in dry THF (5 mL) at room temperature. The reaction mixture was concentrated, chromatographed and crystallized to give the title compound (0.21 g, 30%) m.p. 125-28C.

r lS- r lR*(R*),2R*ll and rls- r lR*(S*),2R*ll-N-r2-hvdroxv-l-(hvdroxvmethvl)-2-phenvl ethvll-2-(lH-indol-3-vlmethvl)-2-methvl-Nl tricvclor3.3.1.13~71dec-2-vlPropanediamide N,N,N-Trimethvl-l~:-indole-3-methanaminium iodide Gramine methiodide (2) (JACS 66 200 (1944)) Gramine (1) (43.5 g, 0.29 mmol) (see Synthetic Scneme 23 for Compounds 1-23) was dissolved in absolute ethanol (200 mL) and methyl iodide (17 mL, 0.27 mmol) was added dropwise over 0.5 hour. A mild exotherm occurred with the formation of a white precipitate. The reaction mixture was stirred overnight at room temper^^ure and then cooled to 0C
for 2 hours. The white soiid was collected by filtration, washed four times with ethanol (50 mL), three times with diethyl ether (50 mL), and dried in vacuo. The product was obtained as a white solid.

W092/~ ~5 PCT/~S91/0618 70.4 g (83%). IR (KBr) 3306, 1483, 1346, 810, 760 cm -Diethvl(lH-indol-3-vlmethvl)methvl~ro~anedioate (3 Sodium hydride (4.0 g, 0.1 mmol) was added in portions over 10 minutes to a mixture o~ diethylmethyl malonate (17.4 g, 0.1 mmol) in DMF (200 mL) at room temperature. The reaction mixtu_e was s_irred 5-minutes and gramine methiodide (33.5 g, 0.11 mmol) was added and the whole mixture warmed to 50C for 0.5 hour and was then stirred overnight at room temperature. Water (200 mL) was carefully added to quench the reaction. The entire mixture was diluted with diethyl ether ~500 mL) and wate- (300 mL). The layers were separated and the organic layer was washed with water (3 x 200 mL). The combined aaueous layers were extracted with diethyl ether (1 x 500 mL), the ether layer washed with water, the organic extracts combined, dried (MgSO4), iltered and concentrated.
The residue was filtered through silica gel (70-230 mesh) using hexane/ethyl acetate, 1/1, as eluant. The product containing fractions were combined, concentrated, and~filtered through silica gel (70-230) using 8/2 hexane/EtOAC as eluant. The - product was obtained as a red ~iscous oil. 13.1 g (43%). IR (film) 3397, 2983, 1731, 1376, 1254, 1108 cm~1.

Ethvl hvdroaen(lH-indol-3-vlmethvl)-methvl~ro~ane-dioate (4) To a solution of diester (4.85 g, 0.016 mmol) in 95~ ethanol (50 mL) at room temperature was added lN
aqueous sodium hydroxide solution (16 mL) and enough water until the solution just became cloudy. Water was added as the reaction proceeded. A~ter 2 hours W092/04045 PCT/US91/061~

-18;- 2~8~9~
the reaction mixture was concentrated on the rotary evaporator to remove ethanol, diluted with water, washed with ethyl acetate, made acidic with 10% citric acid solution, brine was added, and the entire mixture extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4), filtered and concentrated to a b_own oil. The brown oil was chromatogzaphed on silica gel (70-230 mesh) using ethyl acetate as eluan~
and the~ rechromatographed on silica gel (70-230 mesh) using hexane/ethyl acetate, 1/1, as eluant. The produc_ 4 was obtained as an orange/tar. oil. 2.92 g (66%) ~R (film) 3402, 2982, 1718, 1458, 1098, 742 c~.~.

Ethvl(-)-a-methvl-a-r(tricvclor3~3~ 7l dec-2-vlamino)carbonvll-lH-indole-3-Pro~anoate (5 A mixture of acid (1.41 g, 0.005 mmol), adamantanamine hydrochloride ~0.95 g, 0.005 mmol) 1-hydroxybenzotriazole H2O (0.68 g, 0.005 mmol), and CH2Cl2 (50 mL) was cooled to 0C and triethylamine (0.8 mL, 0.0057 mmol) was added and the mixture stirred 5 minutes. Then dicyclohexylcarbodiimide (1.04 g, 0.005 mmol) was added all at once. The reaction mixture was stirred 3 days at room temperature, concentrated to dryness, the residue taken up in ethyl acetate, washed with 10% citric acid, sodium carbonate and sodium chloride solutions.
The organic layer was dried (MgSO4), filtered, and concentrated to an orange oil. Addition of 1/1, hexane/ethyl acetate caused the oil to solidify. The solid was collected by iltration. 2.05 g (98%). IR
(KB-) 3418, 3327, 2907, 1713, 1630, 1540, 1457, 1113 cm~1, W092/04~5 PCT/US91/0618 (+~-a-methyl-~-r(tricvclor3.3.1.13~71dec-2-vlamino)carbonvll-lH-indole-3-Pro~anoic acid (6) The ester (1.04 g, 2.5 mmol) was dissolved in ethanol (10 mL) and lN sodium hydroxide solution (3.5 mL) was added and just enough water to make the solution cloudy. The reaction mixture was brieCly warmed to 50C to get solution. The reaction m-x~ure was allowed to sit 14 days at room temperature. The reaction mixture was concentrated to remove ethanol, diluted with water, washed the aqueous solution with ethyl acetate, made the aqueous layer acidic with 10 citric acid solution, extracted with ethyl acetate, washed the ethyl acetate solution with brine, aried (MgSO4), filtered, and concentrated 'o an off-white 'oam. The foam was filtered through silica gel (70-230 mesh) using ethyl acetate as eluant. The product was obtained as an off-whit solid. 0.87 g (90~). IR (KBr) 3411, 2908, 1716, 1617, 1540, 740 cm~l.

r4S-r4a,5a(R*)ll and r4Sr4a,5a(S*)llN-(2,2-dimethvl-4-~henvl-1 3-dioxan-5-vl)-2-(lH-indol-3-vlmethvl)-2-methvl--N~-(tricvclor3.3.1.13~71dec-2-vl)propanediamide (7) Dicyclohexylcarbodiimide (0.3G g, 1.46 mmol) was added to a mixture of (4S,5S)-(+)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane (0.^;1 g, 1.44 mmol), acid (0.53 g, 1.39 mmol), and l-hydroxybenzotriazole (0.22 g, 1.63 mmol) in a mixture 10/1, CH2C12/DMF, (30 mL) at 0C. The reaction mixture was allowed to sit 1 hour at 0C and then 3 days at room temperature.
The reaction mixture was concentrated to dryness, the residue taken up in ethyl acetate, the ethyl acetate colution washed with saturated sodium chloride solution, dried (MgSO4), filtered and concentrated to W092/04045 PCT/USgl/06180 an orange oil. The oil was purified by filtration through silica gel (70-230 me~h) using heY.ane/ethyl acetate, 7/3, as eluant. The product was obtained as a white solid. 0.247 g (31%). IR (KBr) 3341, 2310, 1665, 1508, 1201, 742 cm~l. -rlS-rlR*(R*),2R*ll and rlS-rlR*(S*),2~*1l-N-r2-hvdroxv-l-(hvd-oxvmethvl)-2-~henvl ethvll-2-(lY.-indol-3-vlmethvl)-2-methvl-Nltricvclor3.3.1. 13'71 dec-2-yl~ro~anediamide (8) A mixture of the acetonide (0.16 g, 0.28 mmol), methanol (10 mL), and lN HCl (1 mL) was allowed to sit at room temperature for 4 hours. The reaction mix_ure was concentrated to dryness without heating. Ethyl acetate was added, the ethyl acetate dried (MgSO4), filtered, concentrated, and the residue chromatographed on silica gel (70-230 mesh) using ethyl acetate as eluant. The product was obtained as a white foam. 0.0727 g (49%).

[lS-rlR*(R*),2R*ll and rlS-rlR*(S*),2R*ll-N-r2-hvdroYv-l-(hvdroY.vmethvl)-2-~henvlethvll-2-(1~-indol-3-vlmethvl)-2-methvl-N'-(tricvclo r 3.3.1. 13' 7 ldec-l-vlmethvl)~ro~anediamide Ethvl a-methvl-a-rr(tricvclor3.3.1.13 ' 7 ldec-l-vimethvl~aminolcarbonvll-lH-indole-3-~ro~anoate (9) Compound 9 was prepared from Compound 4 according to the procedure for Compound 5. The product was obtained as an off-white solid. 3.49 g (58~). IR
~KBr) 3402, 3337, 2913, 2904, 1718, 1652, 1116 cm~'.

W092/04045 PCT/US91/061~

~9~ -188-)a-methyl-~-[[(tricvclor3.3.1.13~71dec-l-vlmethvl)-aminolcarbonvll-lH-indole-3-Dropanoic acid (10) Compound 10 was prepared from Com?ound 9 accord-ng to the procedure for Compound 6. The product was obtained as a white solid. 1.95 g (71%) IR (KBr) 3440, 2912, 1713, 1652, 1621, 1189, 746 cm~;.

r4S-r4a,5a(R*)ll and r4S-r4a 5a(S*)ll-N-(2 2-dime_hvl-4-phenvl-1 3-dioxan-5-vl)-2-(1~-indol-3-vlmethvl~-2-methvl-N'-(tricvclo[3.3.1. 13 ' 7 ldec-l-vlmethvl-proDanediamide (11) Compound 11 was prepared from Compound 10 according to the procedure for Compound 7. The product was obtained as a white foam. 0.83 g, (72%).
IR (RBr) 3418, 2904, 1666, 1558, 1106 cm 1.

rlS-rlR*(R*) 2R*ll and rlS-rlR*(S*),2R*ll-N-r2-hvdroxv-l-(hydroxvmethyl)-2-phenvlethvll-2-(lP.-indol-3-ylmethyl)-2-methvl-N'-(tricvclo[3.3 . 1 . 13'71 dec-l-vlmethvllpropanediamide (12) Compound 12 was prepared from Compound 11 according to the procedure for Compound 8. The product was obtained as a white foam. 0.2633 g (91%).
IR (XBr) 3341, 1652, 1588, 1544, 1477, 699 cm~i.

W092/04045 P~T/~S91/061~

~8819~

rlS-rlR*(R*),2R*ll and rlS-rlR*(S*~,2R*l la-r r r r2,6-bis(l-methvlethvl~henvl1aminolcarbonvllaminol-N-r2-hvdroyv-l-(hvdroxvmethvl~-2-~henvletr~vll-a-meth~L
indole-3-~ro~anamide r 4 s - ~4,Sa(R*)ll and r4s-~4a~5a(s*)~ l-dimeth ethvlr2- r (2 2-dimethvl-4-~henvl-' 3-_ioxar.-5-vl)-amin~l-l-(lU-indol-3-vlmethvl)-l-met~.vi-2-oY~oe~hvl 7 -ca-bamate (19) Compound 14 was prepared according to the procedure of Compound 7. The produc_ was obtained as a white foam. 4.70 g (98%). IR (KB-) 3413, 1707, 1663, 1507, 1501, 1458, 1168, 743 cm~'.

r4S-r4a,5a(R*)ll and r4S-r4a,5a(S*)ll-a-amino-N-(2 2-dimethvl-4-~henvl-1 3-dioxan-5-vl)-a-methvl-1~-indole-3-~ro~anamide (15) Anhydrous hydrogen chloride gas was bubbled through a solution of t-butyloxy carbonyl amine 14 (3.4 g, 6.7 mmol) in dichloromethane (80 mL) for 5 minutes. The reaction mixture was allowed to sit at room temperature for 1 hour and was then poured into saturated aoueous sodium bicarbonate solution. Sodium chloride solution was added and the aqueous solutior.
as eY.tracted two times with ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered and concentrated. The residue was filtered through silica gel (70-230 mesh) using ethyl acetate as eluant to give the product as an off-white solid.
2.18 g (80%). IR (KBr) 3356, 3244, 1646, 1514, 744 cm~-.

..
s' ''~

4S-~4a,5a~R*)ll or r4S-~4a,5a(S*~ -!rrr2,6-~id~'-methvlethvl)phenvllaminolcarbonvllaminol-N-(2,2-dimethvl-4-Dhenvl-1,3-dioxan-5-vl)-~-methvl-lH-indole-3-DroDanamide (16a) r4S-r4a,5a(R*)ll or r4S-r4a,5a(S~)ll -a- r r ~ r2,6-bis(l-methvlethvl)phenvllaminolcarbonvllaminol-N-(2 2-dimethvl-4-Dhenvl-1 3-dioxar.-5-vl)-~-me~hvl-1~.-indole-3-~ro~anamide (16b) A mixture of amine 15 (0.40 g, 1 mmol) and 2,6-diisopropylphenyl isocyanate (0.23 g, 1.1 mmol) in ethyl acetate (30 mL) was heated briefly to achieve solution. The reaction mixture was allowed to sit 2 days at room temperature. The reaction mixture was concentrated to a viscous oil, which was chromatographed on silica gel (70-230 mesh) using ethyl acetate as eluant. The less polar diastereomer, 16a, was obtained as a white solid. 0.2876 g. The more polar diastereomer, 16b, was obtained as a white solid. 0.2369 g. Total yield (87%). IR (Kbr) 3431, 2964, 1675, 1500, 1239, 741 cm~1.

rlS-rlR*(R*),2R*ll and rlS-rlR*(S*),2R*lla-rrrr2,6-bis(l-methvlethvl)phenvllaminolcarbonvllaminol-N-r2-hvdroxv-1-(hvdroxvmethvl)-2-phenvlethvll-a-methvl-lH-indole-3-DroDanamide (17a) 2S Compound 17a was prepared from 16a according to the procedure for Compound 8. The product was obtained as a white foam. 0.0893 g (48%). IR ~KBrj 3400, 3343, 1733, 1663, 1513, 742 c~-1.

W092/04~5 PCT/US91tO6180 20~819~

~X~oeLE 100 ~lS-rlR*(R*),2R*1l or [lS-rlR*(S),2R*lla-rr[[2,6-bis(l-methvlethvl)phenvllaminolcarbonvllaminol-N-~2-hvdroxv-1-(hvdroxymethvl)-2-phenvlethvl1-a-methvl-1~-indole-3-pro~anamide (17b) Compound 17b was prepared from 16b according to the procedure for Compound 8. The produ-t was ob~ained as a white foam. 0.096 g (66%). IR (KBr) 3420, 3299, 1734, 1716, 1662, 1507, 1058 cm~1.

~XAMPLE 101 N- r (1, l-dimethvlethoxv)carbonvll-L-Phenvlalanvl-a-methvl-N-tricvclor3.3.1.13 71dec-2-vl-DL-trv~to~hanamide r9S-r4a,5a(R*) 11 and ~4S-r4a 5a(S*)ll-r2-r(2 2-dimethvl-4-~henvl-1,3-dioxan-5-vl)aminol-1-(lH-indol-3-vlmethvl)-1-methvl-2-oxoethvllcarbamate (18) The amine 15 tO.4 g, 1 mmol) and 2,6-diisopropylphenyl chloroformate (0.51 g, 2 mmol) were taken up in tetrahydrofuran (50 mL) and triethylamine (0.34 mL, 2.4 mmol) was added. The reaction mixture was stirred 5 days at room temperature and then concentrated to dryness. The residue was filtered through silica gel (70-230 mesh) using hexane/ethyl acetate, 1/1, as eluant. The product was obtained as a foam/solid. 0.395 g (66%).
IR (~Br) 3326, 1654, 1636, 1520, 1257, 742 cm~1.

N-rNr(l,l-dimethvlethoxv)carbonYl1-L-~henvlalanvl1-a-methvl-DL-trvptophan methvl ester (19) Compound 19 was prepared from BOC-L-phenylaianine and RS--Me tryptophan methyl ester according to the procedure for ~xample 7. 4.74 g (99%). IP~ (KBr) 3408, 3353, 1734, 1696, 1617, 15G7, 1457, 1165 cm~1.

W092/04~5 PCT~US~1/0618~

2~88~9~ -192-a-methvl-N-L-phenvlalanvl-DL, methvlester, monohvdrochloride (20) Anhydrous hydrogen chloride gas was bubbled through a solution of 19 (l.S0 g, 3.1 mmol) in dichloromethane (50 mL) for 2 minutes at room temperature. The reaction mixture was allowed to s t overnight at room temperature. The solvent was -emoved in vacuo. Ether was added ,wice and concentrated. The residue was ta~en U? in methanol and ~hen concentrated. E'her was added and then removed on the rotary evaporator yielding the product as a tan foam. 1.32 g (100%). IR XBr) 3403, 3396, 3343, 3231, 1734, 1684, 1677, 1498, 1216, 743 cm~l.

N- rN- r (l l-dimethvlethoxv)carbonvll-L-~henvlalanvll-a-me'hvl-DL-trvPto~hvl (21) Compound 21 was prepared from 19 according to the procedure for Compound 6. The product was obtained as a white foam. 2.34 g (96%). IR (XBr) 3375, 1716, 1708, 1702, 1498, 1457, 1368, 1164, 743 cm~l.

N-r(l,l-dimethvlethoxv)carbon~ll-L-~henvlalanvl-~-methvl-N-tricvclor3.3.1.13~71dec-2-vl-DL-trv~toDhanamide (22) Compound 22 was prepared from 21 and 2-adamantamine according to the procedure for Compound 7. The product was obtained as a white solid. 0.585 g (38%). IR (KBr) 3411, 3333, 1696, 1672, 1653, 1519, 1165 cm~l.

N-rN-r(tricvclor3.3.1.13'71dec-2-vloxv)carbonvll-L-phenvlalanvll-DL-trvptoPhan~ methvlester (23) Compound 20 (1.25 g, 3.0 mmol) was added to 2-adamantyl chloroformate (0.70 g, 3.3 mmol) in THE

W092/04~5 PCT/US91/0618~

20~81~5 (80 mL), then triethyl amine (0.9 mL, 6 5 mmol) was added and the reaction mix'ure cooled to 0C. After 0.5 hour the reaction mixture was concen'rated to dryness, the residue was dissolved in ethyl acetate.
The ethyl acetate solution was washed with 10%,zueous citric acid and saturated sodium chloride solutions, cried ~MgSO4), filtered and concentratec. The -esidue was filtered through silica gel (70-230 mesh) using hexane/ethyl acetate as el~ant. The p_oduct was obtained as a white foam. 1.12 g (67%). I~ (KBr) 3342, 2912, 1672, 1663, 1507, 1361, 1254, 1101 cm~l.

Tricvclo r 3.3.1.13~7ldec-2-vl(~ 2-~(3,4-dihvdro-2 benzoovran-3-vl)aminol-1-(lH-indol-3-vlmethvl)-1-methvl-2-oxoethvllcarbamate A solution of 2-adamantyl oxycarbonyl amethyl, ~L
tryptophane (0.79 g , 0.002 mmol) in ethyl acetate (60 mL) was treated with dicyclohexylcarbodiimide (0.495 g, 0.002 mmol) and l-hydroxybenzotriazole hydrate (0.3 g, 0.0023 mmol). After stirring for 2 hours at room temperature the precipitated d cyclohyexyl urea was remo,ved by filtration. To the clear filtrate was added 3,4-dihydro-2,4-1-benzopyran-3-amine (0.37 g, 0.002 mmol). The reaction mixture was stirred at room temperature overnight. The ethyl acetate solution was washed with 5% citric acid, 5%
Nd.~CO3 and brine. The organic phase was dried over MgSO4 and concentrated in vacuo to yield a white foam.
The product was chromatographed over silica using 50%
ethyl acetate, 50% hexane as eluant to give the title compound (0.66 g, 61%).
Analysis for C32H37N3O4 ~H20 MW 536.679;
Calc.: C, 71.61; H, 7.13; ~, 7.82;
Found: C, 71.67; H, 6.93; N, 7.75.

W092/04~5 PCT/US91/06180 ~,~t~ 154-Tricvclor3.3.1.13~71dec-2-vl(i~-rl-(lH-indol-3-vlmethvl)-l-methYl-2-oxo-2-!t(1,2,3,4-tetrahvdro-1-na~hthalenvl)methvllaminolcarbamate In a process analogous to Example 103 by substituting 1,2,3,4-tetrahydro-1-naphthalene-methenamine (0.32 g, 0.002 mmol) for 3,4-dihyd~o-2,4-l-benzo?yran-3-amine one obtains the . tle compound (0.76 g, 69%).
AnalySis for C34H4~N3O3 ~H2O MW 548.734:
Calc.: C, 74.42; H, 7.71; N, 7.65;
Found: C, 74.27; Y., 7.57; N, 7.36.

T-icvclor3.3.l.13~71dec-2-vl(+)-rl-(lH-indol-3-vlmethvl)-1-methvl-2-oxo-2-~(9H-xanthen-9-vlmethvl)-aminolethvllcarbamate A solution of 2-adamantyl oxycarbonyl-a-methyl DL
tryptophane (0.79 g, 0.002 mmol) in methylene chloride (60 mL~ was treated with hydroxybenzothiazole hydrate (0.3 g, 0.0022 mmol), 1-~2-dimethylamino propyl)-3 ethyl carbodiimide HCl (0.38 g, 0.002 mmol) and triethyl amine (0.202 g, 0.002 mmol). After stirring at room temperature for 2 hours a solution of 3H-xanthane-9-methenamine (0.495 g, 0.002 mmol) in methylene chloride (10 mL) was added. The reaction mixture was stirred at room temperature overnight.
The clear solution was concentrated in vacuo. The result-ng oil was taken up in ethyl acetate. The ethyl acetate solution was washed with 1 NHCl, saturated NdHCO3 and brine. The oryanic phase was dried over MgSO4 and concentrate in ~racuo to give a white foam. the product was chromatographed over silica using 50% ethyl acetate; 50% hexane as eluan' to give the title compound (0.72 g, 59%).

-195- 208~195 Anaiysis for C37H39N3O~ H2O MW 607.761:
Calc.: C, 73.13; H, 6.79; N, 6.91;
Found: C, 73.53i H., 6.80i N, 6.61.

Claims (22)

1. A compound of formula I

or a pharmaceutically acceptable salt thereof wherein:
R1 is a cyclo or polycycloalkyl hydrocarbon or mono- or polyheterocyclic moiety wherein the hetero atom(s) can be N, O, and/or S, of from 3 to 12 carbon atoms with from 0 to 4 substituents each independently selected from a straight or branched alkyl of from 1 to 6 carbon atoms, halogen, CN, OR*, SR*, CO2R*, CF3, NR5R6, or (CH2)nOR5 wherein R*, R5, and R6 are each independently hydrogen or a straight or branched alkyl of from 1 to about 6 carbon atoms;
m, n, p, q, r, s, t, u, and v are each independently an integer of from 0 to 6 with the proviso that q, r, and s are not all 1 when m, p, t, u, and v are all 0 except when X is not CONR9 or A-E is not (CH2)nCONH-, -SO2NH-, -S(O)NH-, -NHCONH, -(CH2)n-OCO-NH-, -SCONH-, -O(CH2)nCO- or -HC=CHCONH- wherein n is as above, A is a bond, O, S, NR*, -(CH2)nCO-Z, -SO2-Z, -SO-Z, -S-Z, -NHCO-Z, , -SCO-Z, -O-(CH2)nCO-Z, -HC=CHCO-Z, wherein Z is a bond, oxygen, sulphur, or -NR*- wherein R* is as defined above;
E is a bond, an amino acid residue, -(CHR3)r-, -(CHR3)r-(CHR4)s-, -CONH-, -NHCO-, -OCO-, -COO-, -CH2N(R3)-, -CH2O-, -CH2S-, -C=C-, , -SO2NR3-, -NR3SO2-, -NHCONH-, , , , , wherein r and s are independently as defined above and R3 and R4 are as defined above;
R2 and R20 are each independently hydrogen, a straight or branched alkyl of from 1 to 6 carbon atoms, -HC=CH2, - C?CH, -(CH2)nCH=CH2, -(CH2)nC?CH, -(CH2)nAr1, -(CH2)nAr2, -(CH2)nOR*, -(CH2)nOAr, -(CH2)nCO2R*, -(CH2)nNR5R6 wherein n, R*, R5, and R6 are as defined above, and Ar1 and Ar2 are as defined below;
X and Y are each independently:
-CONH-, -CONR9, -NHCO-, -OCO-, -COO-, -CH2N(R3)-, -CH2O-, -CH2S-, -OCH2-, -SCH2-, -C=C-, , , -SO2NR3-, -NR3SO2-, -NHCONH-, -CH(OR*)CH2-, -COCH2-, -CH2CO-, -NR3CH2-, , , , , or ;

wherein Q is O, S, or NR9;

R3 and R4 are each independently the same as R2 or -(CH2)n,-B-D wherein n' is an integer of from 0 to 3;
B is a bond, -OCO(CH2)n-, -O(CH2)n-, -NHCO(CH2)n-, -CONH(CH2)n-, -NHCOCH=CH-, -COO(CH2)n-, -CO(CH2)n-, -SO(CH2)n-, -S(CH2)n-, -SO2(CH2)n-, , , , or , wherein R7 and R8 are each independently selected from hydrogen and R2 or together form a ring (CH2)m wherein m is an integer of from 1 to 5, D is -COOR*, -CH2OR*, -CHR2OR*, -CH2SR*, -CHR2SR*, -CONR5R6, -CN, -NR5R6, -OH, -H, and acid replacements such as tetrazole;

R10 is OH, NH2, CH3, or Cl , HO3S-?
?-PO3H2 1,2,4 oxadiazole , , , , R11 is CN, CO2H, or CF3 , PhSO2NHCO-?, , , CF3CONHCO-?, CF3SO2NHCO-?, H2NSO2-?, , , , , , , wherein b is an integer of from 0 to 2, wherein R*, R2, R5, and R6 are as defined above;
R9 is H, or a straight or branched alkyl of from one to six carbon atoms, -(CH2)nCO2R*, (CH2)nOAr', (CH2)nAr', (CH2)nNR5R6, wherein n, R*, R5, and R6 are as defined above or taken from R3 and Ar is taken from Ar1 as defined below;
R12 and R13 are each independently hydrogen or taken together form a double bond, or are -(CH2)n-B-D as defined above; and Ar1 and Ar2 are each independently a mono- or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or carbo- or heteroaromatic moiety.

2. A compound according to Claim 1 wherein Ar1 is phenyl, substituted phenyl, fused aryl, heterocycle, fused heterocycle, or perhydroaryl.

3. A compound according to Claim 1 wherein Ar1 is 2- or 3-thienyl, 2- or 3-furanyl, 2-, 3-, or 4-pyridinyl, wherein E' and F are each independently hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl, nitro, hydroxy, NH2, OCF3, and R3 as defined above.

4. A compound according to Claim 1 wherein the polycycloalkyl is selected from the group consisting of , , , and wherein W, X, Y, and Z are each independently hydrogen, a straight or branched alkyl of from one to six carbon atoms, CF3, NR5R6, -(CH2)nCO2R*, CN, F, C1, Br, OR*, SR*, wherein R*, R5, and R6 are as defined in Claim 1 and w is an integer of from 1 to 3.

5. A compound according to Claim 1 named:
Carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)ethyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester, [S-(R*,S*)]-, Carbamic acid, [2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)ethyl-, tricyclo[3.3.1.13,7]dec-2-yl ester, [S-(R*,R*)]-, Tricyclo[3.3.1.13,7]dec-2-yl[1-[[[1-hydroxy-methyl)-2-phenylethyl]carbonyl]amino]-2-(1H-indol-3-yl)ethyl]carbamate, Carbamic acid, [2-[(2-hydroxy-2-phenylethyl)-amino]-1-(1H-indol-3-ylmethyl)-1-methylethyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester (hydroxy center is RS, other center is R), Carbamic acid, [2-[[1-(hydroxymethyl)-2-phenyl-ethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methylethyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester, [R-(R*,S*)]-, 4-methylbenzenesulfonate (1:1) (salt), Benzenepropanol,.beta.-[[2-(1H-indol-3-yl)-2-[[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-, acetate (ester), [R-(R*,S*)]-, 4-methylbenzenesulfonate (1:1) (salt), Carbamic acid, [[2-[acetyl[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl]ethyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester, [R-(R*,S*)]-, 5,13-Dioxa-2,8-diazatetradec-10-enoic acid, 3-(1H-indol-3-ylmethyl)-3-methyl-4,9,12-trioxo-7-phenyl-, tricyclo[3.3.1.13,7]dec-2-yl ester, [S-(R*,S*)]-, 5,13-Dioxa-2,8-diazatetradecanoic acid, 3-(1H-indol-3-ylmethyl)-3-methyl-4,9,12-trioxo-7-phenyl-, tricyclo[3.3.1.13,7]dec-2-yl ester, [R-(R*,R*)]-, Carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(1-oxo-4-phenylbutyl)amino]ethyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester (R)-, Carbamic acid, [2-(benzoylamino)-1-(1H-indol-3-ylmethyl)-1-methylethyl]-, tricyclo[3.3.1.13,7]-dec-2-yl ester, (R)-, Carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(1-oxo-3-phenylpropyl)amino]ethyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester, (R)-, Carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-[(2-phenylacetyl)amino]ethyl]-, tricyclo-[3.3.1.13,7]dec-2-yl ester, (R)-, Carbamic acid, [2-[[3-[[1-(hydroxymethyl)-2-phenylethyl]amino]-3-oxopropyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-, [R,(R*,S*)]-, Carbamic acid, [1-(1H-indol-3-ylmethyl)-2-[[3-[[1-(hydroxymethyl)-2-phenylethyl]amino]-3-oxopropyl]amino]-1-methyl-2-oxoethyl]-, tricyclo-[3.3.1.13,7]dec-2-yl ester, [S-(R*,R*)]-, D-Phenylalaninamide, .alpha.-methyl-N-[(tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl]-D-tryptophyl-.beta.-alanyl-, L-Phenylalaninamide, .alpha.-methyl-N-[(tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl]-D-tryptophyl-.beta.-alanyl-, L-Phenylalaninamide, .alpha.-methyl-N-[(tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl]-L-tryptophyl-.beta.-alanyl-, D-Phenylalaninamide, .alpha.-methyl-N-[tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl]-L-tryptophyl-.beta.-alanyl-, 12-Oxa-2,5,9-triazatridecanoic acid, 3-(1H-indol-3-ylmethyl)-3-methyl-4,8,11-trioxo-10-(phenylmethyl)-, tricyclo[3.3.1.13,7]dec-2-yl ester, [R,(R*,R*)]-, L-Phenylalanine, N-[N-[.alpha.-methyl-N-[(tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-.beta.-alanyl]-, phenylmethyl ester, Propanoic acid, 2-[[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxopropyl]-amino]-3-phenyl-, phenylmethyl ester, [S-(R*,R*)]-, D-Phenylalanine, N-[N-[.alpha.-methyl-N-[(tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-.beta.-alanyl]-, L-Phenylalanine, N-[N-[.alpha.-methyl-N-[(tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl]-D-tryptophyl-.beta.-alanyl]-, L-Phenylalanine, N-[N-[.alpha.-methyl-N-[(tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl]-L-tryptophyl]-.beta.-alanyl]-, Benzenepropanoic acid, .alpha.-[[3-[[3-[(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]amino]propyl]amino-1-oxopropyl]-amino]-, [S-(R*,S*)]-, Glycine, N-[2-methyl-N-[(tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-, phenylmethyl ester, Carbamic acid, [3-(1H-indol-3-ylmethyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidinyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester, (?)-, Carbamic acid, [1-(1H-imidazol-4-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]-, 1,1-dimethylethyl ester, (?)-, Carbamic acid, [3-(1H-indol-3-yl)-1-methyl-1-[[(2-phenylethyl)amino]carbonyl]propyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester, (?)-, Carbamic acid, [1-[[[1-hydroxymethyl)-2-phenylethyl]amino]carbonyl]-3-(1H-indol-3-yl)-1-methylpropyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester (hydroxymethyl center is S, other center is RS), 13-Oxa-2,5,.beta.-triazatetradec-10-enoic acid, 3-[2-(1H-indol-3-yl)ethyl]-3-methyl-4,5,12-trioxo-7-phenyl-, tricyclo[3.3.1.13,7]dec-2-yl ester [TRP
center is R/S mixture, other center is R], L-Phenylalaninamide, N-[[(1,1-dimethyl-ethoxy)-carbonyl]-.alpha.-methyl]-L-tryptophyl]-L-methionyl-L-.alpha.-aspartyl-, Glycine, N-[2-methyl-N-[(tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl-, Carbamic acid, [1-[[[1-(hydroxymethyl)-2-phenylethyl]amino]carbonyl]-2-(1H-indol-3-yl)-propyl]-, tricyclo[3.3.1.13,7]dec-2-yl ester (hydroxymethyl center S, other centers RS), 2,4-Heptadienoic acid, 6-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-7-phenyl-, [R,R*,S*-(E,E)]]-, Glycine, N-[2-methyl-N-[(tricyclo-[3.3.1.13,7]dec-2-yloxy)carbonyl)-D-tryptophyl]-, phenylmethyl ester, Tricyclo[3.3.1.13,7]dec-2-yl-R-(R*,S*)]-[1-[4,5-dihydro-4-(phenylmethyl)-2-thiazolyl]-2-(1H-indol-3-yl)-1-methylethyl]carbamate.

6. A pharmaceutical composition comprising an amount of a compound according to Claim 1, effective to suppress the appetite in a mammal, and a pharmaceutically acceptable carrier.

7. A method of suppressing appetite in a mammal, comprising administering an effective appetite suppressing amount of a compound according to Claim 1.

8. A pharmaceutical composition comprising an amount of a compound according to Claim 1, effective to reduce gastric acid secretion in a mammal, and a pharmaceutically acceptable carrier.

9. A method of reducing gastric acid secretion in a mammal, comprising administering an effective gastric acid secretion reducing amount of a compound according to Claim 1.

10. A pharmaceutical composition comprising an amount of a compound according to Claim 1, effective to reduce anxiety in a mammal, and a pharmaceutically acceptable carrier.

11. A method of reducing anxiety in a mammal, comprising administering an effective anxiety reducing amount of a compound according to Claim 1.

12. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective to treat gastrointestinal ulcers in a mammal, and a pharmaceutically acceptable carrier.

13. A method for treating gastrointestinal ulcers in a mammal comprising administering an effective gastrointestinal ulcer treating amount of a compound according to Claim 1.

14. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective to treat psychotic behavior in a mammal, and a pharmaceutically acceptable carrier.

15. A method of treating psychosis in a mammal, comprising administering an effective psychosis treating amount of a compound according to Claim 1.

16. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective to block the reaction caused by withdrawal from drug or alcohol use in a mammal, and a pharmaceutically acceptable carrier.

17. A method of blocking drug or alcohol withdrawal reaction in a mammal comprising administering an effective withdrawal reaction blocking amount of a compound according to Claim 1.

18. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective to potentiate the effects of morphine and other opioids in treating pain.

19. A method of treating pain in a mammal, comprising administering an effective amount of a compound according to Claim 1.

20. A pharmaceutical composition comprising an amount of a compound according to Claim 1 effective to treat and/or prevent panic.

21. A method of treating and/or preventing panic in a mammal, comprising administering an effective amount of a compound according to Claim 1.

22. Method of use of a radioactive iodo compound of formula I to prepare a pharmaceutical or diagnostic composition for the treatment or diagnosis of gastrin-dependent tumors.