WO1995029159A1 - SUBSTITUTED SULFONAMIDES AS SELECTIVE β3 AGONISTS FOR THE TREATMENT OF DIABETES AND OBESITY - Google Patents

SUBSTITUTED SULFONAMIDES AS SELECTIVE β3 AGONISTS FOR THE TREATMENT OF DIABETES AND OBESITY Download PDF

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Publication number
WO1995029159A1
WO1995029159A1 PCT/US1995/004956 US9504956W WO9529159A1 WO 1995029159 A1 WO1995029159 A1 WO 1995029159A1 US 9504956 W US9504956 W US 9504956W WO 9529159 A1 WO9529159 A1 WO 9529159A1
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WIPO (PCT)
Prior art keywords
ethyl
hydroxy
amino
phenyl
pyridinyl
Prior art date
Application number
PCT/US1995/004956
Other languages
French (fr)
Inventor
Michael H. Fisher
Elisabeth M. Naylor
Dong Ok
Ann E. Weber
Thomas Shih
Hyun Ok
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Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/404,566 external-priority patent/US5541197A/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to SK1361-96A priority Critical patent/SK136196A3/en
Priority to NZ284718A priority patent/NZ284718A/en
Priority to JP52779795A priority patent/JP3149186B2/en
Priority to KR1019960705994A priority patent/KR970702252A/en
Priority to AU23937/95A priority patent/AU687558B2/en
Priority to EP95917116A priority patent/EP0757674A1/en
Priority to MXPA/A/1996/005192A priority patent/MXPA96005192A/en
Publication of WO1995029159A1 publication Critical patent/WO1995029159A1/en
Priority to FI964314A priority patent/FI964314A0/en
Priority to NO964548A priority patent/NO964548L/en

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • ⁇ -Adrenoceptors have been subclassified as ⁇ i and ⁇ 2 since 1967. Increased heart rate is the primary consequence of ⁇ i -receptor stimulation, while brohchodilation and smooth muscle relaxation typically result from ⁇ 2 stimulation.
  • Adipocyte lipolysis was initially thought to be solely a ⁇ i -mediated process. However, more recent results indicate that the receptor-mediating lipolysis is atypical in nature. These atypical receptors, later called ⁇ 3-adrenoceptors, are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis (breakdown of fat) and energy expenditure.
  • a major drawback in treatment of chronic diseases with ⁇ 3 agonists is the potential for stimulation of other ⁇ -receptors and subsequent side effects.
  • the most likely of these include muscle tremor ( ⁇ 2) and increased heart rate ( ⁇ l).
  • ⁇ 2 muscle tremor
  • ⁇ l increased heart rate
  • these phenylethanolamine derivatives do possess some ⁇ 3 selectivity, side effects of this type have been observed in human volunteers. It is reasonable to expect that these side effects resulted from partial ⁇ l and/or ⁇ 2 agonism.
  • the instant invention is concerned with substituted sulfonamides which are useful as antiobesity and antidiabetic compounds.
  • a still further object is to describe processes for the preparation of such compounds.
  • Another object is to describe methods and compositions which use the compounds as the active ingredient thereof. Further objects will become apparent from reading the following description. DESCRIPTION OF THE INVENTION
  • the present invention provides compounds having the formula I:
  • A is (1) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
  • R2 and R3 are independently
  • X is (1) -CH2-
  • R6 i is (1) hydrogen or
  • R7 i is Z-(Rla) n ;
  • R a is (l) Rl, with the proviso that when A is phenyl, R ⁇ a is not
  • phenyl optionally substituted with up to 4 groups independently selected from R , NR R8 ? OR8, SR8 and halogen, or
  • Z is (1) phenyl
  • R8 is (1) hydrogen
  • R9 is (l) R8 or
  • RlO is (1) Cl-ClO alkyl, or
  • A is a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
  • A is phenyl or benzene fused to a C3-C8 cycloalkyl ring.
  • R2 and R3 are hydrogen or methyl;
  • X is -CH2-;
  • n is 0 to 3;
  • m is 1;
  • r is 0 to 2;
  • R4, R5 and R6 are hydrogen.
  • A is phenyl or a 6-membered heterocyclic ring with 1 or 2 heteroatoms selected from nitrogen and sulfur;
  • Rl is hydroxy, halogen, cyano, trifluoromethyl, NR8R8,
  • NR8SO2R 9 NR8COR9, NR8CO2R8, C1-C6 alkyl optionally substituted by hydroxy; and r is 0 or 2.
  • (8) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, halogen, R8, NR8R8, OR , and SR 8 ;
  • Z is (1) phenyl
  • X is -CH2-
  • R8 and R9 are as defined under formula I.
  • n 0 or 1 ;
  • R 1 is NR R8;
  • R2 and R3 are independently
  • Rl a is (1) halogen
  • a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, SR8, OR8, and NR8R8 ; when B and the benzene ring form a fused ring system, Rla is attached to either ring; R8 is (1) hydrogen,
  • Cl-ClO alkyl having 1 to 4 substituents selected from hydroxy, halogen, Cl-ClO alkyl, C3-C8 cycloalkyl, and Z optionally substituted by from 1 to 4 of halogen, Cl-ClO alkyl or Cl-ClO alkoxy;
  • R9 is (l) R8 or
  • RlO is (1) Cl-ClO alkyl, or
  • Rl is (1) hydroxy
  • (6) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to three groups independently selected from oxo, halogen, R8, NR8R8, OR8 and SR8;
  • Z is (1) phenyl
  • X is -CH2-
  • R2 and R3 are independently hydrogen or methyl.
  • antiobesity and antidiabetic compounds of the present invention include the following:
  • the compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in structural Formula I. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule, in particular, R2 and R3. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention.
  • the asymmetric center represented by the asterisk in Formula I it has been found that the compound in which the hydroxy substituent is above the plane of the structure, as seen in Formula Ic, is more active and thus more preferred over the compound in which the hydroxy substituent is below the plane of the structure.
  • n, m, r, A, Rl, R 2 , R3, R4, R5 ? R6, R7 an d x are as defined above under formula I.
  • alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration.
  • exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
  • alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration.
  • exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • halogen is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
  • Examples of 5 and 6-membered heterocycles and fused heterocycles of A, Z and Rla include pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, thiazolyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, tetrahydroquinolinyl, furopyridine and thienopyridine.
  • a and Z are phenyl, naphthyl, benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or heterocycles with from 1 to 4 heteroatoms independently selected from one of oxygen or sulfur, and/or 1 to 4 nitrogen atoms.
  • A is phenyl, pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, and thiazolyl.
  • Z are phenyl, naphthyl, quinolinyl, thienyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazolyl, tetrahydrobenzothiazolyl and tetrahydroquinolinyl.
  • Z When Z is attached to -NS ⁇ 2(CH2)r ⁇ , it is preferably phenyl, naphthyl or a benzene ring fused to a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
  • Z is part of the definition of R8, it is preferably phenyl, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrog * en, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring.
  • Rla The preferred heterocycles of Rla are thienyl, thiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, and pyrazolyl.
  • NR8R8 may represent NH2, NHCH3, N(CH3)CH2CH3, and the like.
  • THF tetrahydrofuran The compounds (I) of the present invention can be prepared from epoxide intermediates such as those of formula II and amine intermediates such as those of formula III. The preparation of these intermediates is described in the following schemes.
  • n, m, r, A, Rl, R 2 , R 3 , R 4 , R 5 , R6, R7 and X are as defined above.
  • the enantiomerically enriched (R) and (S) epoxides II are readily available by asymmetric reduction of haloketones 2 using chiral reducing agents such as (-) or (+)-DIP-Cl, (R) or (S)- Alpine borane or (/?) or (-S')-tetrahydro-l-methyl-3,3- diphenyl-l /,3 -pyrrolo[l,2-c][l,3,2]oxazaborole-borane ((R) or (5)- OAB-BH 3 ).
  • chiral reducing agents such as (-) or (+)-DIP-Cl, (R) or (S)- Alpine borane or (/?) or (-S')-tetrahydro-l-methyl-3,3- diphenyl-l /,3 -pyrrolo[l,2-c][l,3,2]oxazaborole-borane ((R) or (5)- OAB-
  • Methylketone 4 may be converted to the corresponding haloketone using a variety of reagents known to those in the art and summarized in Larock Comprehensive Organic Transformations; VCH: New York, 1989, 369-372. Conveniently, methylketone 4 is treated with chlorine or -V-chlorosuccinimide in acetic acid with an additional acid source such as hydrogen chloride or aluminum chloride.
  • an additional acid source such as hydrogen chloride or aluminum chloride.
  • X Br
  • bromine, dibromobarbituric acid or NBS with hydrogen bromide or aluminum bromide may be used.
  • the chloro or bromoketones 2 may be commercially available.
  • methylketones 4 are commercially available or readily prepared by methods described in the literature and known to those skilled in the art. Rl substituents on the acid chlorides 1 or methylketones 4 may need to be protected during the subsequent procedures. A description of such protecting groups may be found in: Protective Groups in Organic Synthesis. 2nd Ed., T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, 1991.
  • Compounds III can be conveniently prepared by a variety of methods familiar to those skilled in the art.
  • a convenient route for their preparation when R6 is hydrogen is illustrated in Scheme 3.
  • Compound 5 is selectively protected as a suitable carbamate derivative 6 with, for example, di- rf-butyl dicarbonate or carbobenzyloxy chloride.
  • This compound is then treated with a sulfonyl halide, preferably the sulfonyl chloride 7-. and a base such as pyridine in an anhydrous solvent such as dichloromethane or chloroform for 0.5 to 24 hours at temperatures of -20 to 50°C, preferably 0°C, to provide the sulfonamide 8.
  • the protecting group is then removed with, for example, trifluoracetic acid in the case of Boc or catalytic hydrogenation in the case of Cbz, to give the desired amine 9.
  • the sulfonyl chlorides 7, many of which are commercially available, can also be readily prepared by a number of methods familiar to those skilled in the art.
  • One suitable method involves the addition of an organolithium reagent or a Grignard reagent to sulfuryl chloride following the procedure of S. N. Bhattacharya, et. al., J. Chem. Soc. (C), 1265-1267 (1969).
  • Another convenient method involves the treatment of a thiol with sulfuryl chloride and a metal nitrate according to the procedure of Y. J. Park, et. al., Chemistry Letters, 1483-1486 (1992).
  • Sulfonic acids are also conveniently converted to the corresponding sulfonyl chloride by treatment with PCI5, PCI3 or SOC12 (J. March, Advanced Organic Chemistry. 4th Ed., John Wiley and Sons, New York: 1992, pi 297 and references sited therein).
  • Aromatic and heteroaromatic compounds may be chlorosulfonylated directly by treatment with Vilsmeier's reagent or chorosulfonic acid (Organic Synthesis, I, 8).
  • the diamines 5 are commercially available or readily prepared by methods described in the literature or known to those skilled in the art.
  • Compound 5 where R2 or R3 is methyl can be prepared from the corresponding amino acid following the method of J. D. Bloom, et. al., J. Med.
  • Diamines 5 or sulfonamide amines ° . where X is -CH2O- and m is 1 are also readily prepared by methods described in the literature or known to those skilled in the art.
  • the sodium salt of 4-nitrophenol 16 is alkylated with 1- bromo-2-chloroethane, conveninetly in refluxing 2-butanone with a base such as potassium carbonate to give chloro derivative 17.
  • the chloride is converted to the corresponding amine by treatment with lithium azide followed by reduction with, for example, triphenylphosphine in aqueous tetrahydrofuran.
  • diamine 5 where X is -CH2O- and m is 1 is available from intermediate 19 by treatment with trifluoroacetic acid.
  • This diamine may then be modified as illustrated in Scheme 3.
  • Diamines 5 and sulfonamide amines 9 where X is -CH2CH2- and m is 1 are also readily prepared by methods described in the literature or known to those skilled in the art. For example, as shown in Scheme 7, bromo derivative 21 is treated with sodium cyanide to provide nitrile 22. The nitro group is selectively reduced by treatment with hydrogen and catalytic palladium to provide amine 23. Amine 23 is acylated with sulfonyl chloride 7 to give the corresponding sulfonamide 24. Reduction of compound 24 with cobalt chloride and sodium borohydride provides the desired amine 25.
  • diamine 5 where X is -CH2CH2- and m is 1 is available from intermediate 23 .
  • This diamine may then be modified as illustrated in Scheme 3.
  • the product is purified from unwanted side products by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still, et. aL, J- Org. Chem. 43, 2923 (1978), medium pressure liquid chromatography, or HPLC.
  • Compounds which are purified by HPLC may be isolated as the corresponding salt. Purification of intermediates is achieved in the same manner.
  • the coupling product I from the reaction described in Scheme 8 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • An alternate method for the synthesis of compound I is illustrated in Scheme 9.
  • Epoxide II is coupled to amine 5 as described above for coupling intermediates II and III (Scheme 8) to give aniline derivative 27.
  • the secondary amine is selectively protected, for example, as a carbamate by treatment with di-terf-butyldicarbonate to provide carbamate 29.
  • nitro amine 26 is used in the coupling reaction to provide 28.
  • the nitro group is reduced, for example, by catalytic hydrogenation with palladium catalyst or raney nickel, to provide intermediate 29.
  • other group may be reduced concomitantly.
  • R is halogen in intermediate 28, it may be converted to hydrogen in intermediate 29.
  • compound I from the reaction sequence illustrated in Scheme 9 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7, as described above.
  • manipulation of substituents on any of the intermediates in the reaction sequence illustrated in Scheme 9 may occur.
  • One such example is illustrated in Scheme 10.
  • Compound 30, which is prepared as outlined in Scheme 9 from the corresponding epoxide, is subjected to reduction using tin(II) chloride to provide compound 21.
  • substituents on compound I which may be reduced to the corresponding amine by methods commonly known to those skilled in the art include nitro groups, nitriles, and azides.
  • the compounds (I) of the present invention can also be prepared from amine intermediates such as those of formula III and haloketone intermediates such as those of formula 2, as shown in Scheme 11.
  • Amine III is alkylated with haloketone derivative 2, conveniently by treatment of a mixture of III and 2 with base such as potassium carbonate or triethylamine in a polar solvent such as acetonitrile, acetone or dimethylformamide.
  • base such as potassium carbonate or triethylamine
  • a polar solvent such as acetonitrile, acetone or dimethylformamide.
  • the resultant aminoketone 32 is reduced with, for example, sodium borohydride in methanol to give the desired aminoalcohol I.
  • the product I from the reaction described in Scheme 11 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7.
  • These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
  • compound I may be synthesized directly from intermediate 27 without protection of the secondary amine.
  • aniline derivative 27 is treated with sulfonyl chloride 7 and a base such as pyridine in a solvent such as dichloromethane at a temperature of -30 to 50 °C, typically 0 °C, to provide compound I.
  • the product I from the reaction described in Scheme 13 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7, as described above.
  • R 3 are hydrogen can also be prepared from acid intermediates of formula 36 and aminoalcohols of formula 37, as shown in Scheme 14.
  • Acid 36 is available from the corresponding ester 35, typically a methyl or ethyl ester, by treatment with sulfonyl chloride 7 and a base such as pyridine, followed by hydrolysis of the ester with aqueous acid or base.
  • Acid 36 is coupled to amine 37, which is known in the literature or readily prepared by methods known to those skilled in the art, using a coupling agent such as benzotriazolyl-N-oxy- tris(dimethylamino)phosphonium hexafluorophosphate or l-(3- dimethylaminopropyl)-3-ethylcarbodiimide methiodide to provide the amide 38- This is treated with a reducing agent, typically borane, to provide the desired compound I.
  • a coupling agent such as benzotriazolyl-N-oxy- tris(dimethylamino)phosphonium hexafluorophosphate or l-(3- dimethylaminopropyl)-3-ethylcarbodiimide methiodide
  • Compounds of the general Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
  • a suitable solvent for example methanol or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.
  • the instant compounds can be isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids.
  • acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic and the like.
  • certain compounds containing an acidic function such as a carboxy or tetrazole, can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
  • the compounds of the present invention have valuable pharmacological properties.
  • the present invention also provides a compound of the general Formula I or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.
  • the present invention provides a compound of the general Formula I or a pharmaceutically acceptable ester thereof: or a pharmaceutically acceptable salt thereof for use in the treatment of obesity in human or non-human animals.
  • the present invention further provides a compound of the general Formula I, or a pharmaceutically acceptable ester thereof; or pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia (diabetes) in human or non-human animals.
  • the disease diabetes mellitus is characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia.
  • Research on the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Treatments have included parenteral administration of exogenous insulin, oral administration of drugs and dietary therapies.
  • Type I diabetes or insulin-dependent diabetes
  • Type II diabetes or insulin-independent diabetes
  • Most of the Type II diabetics are also obese.
  • the compounds of the present invention lower triglyceride levels and cholesterol levels and raise high density lipoprotein levels and are therefore of use in combatting medical conditions wherein such lowering (and raising) is thought to be beneficial.
  • they may be used in the treatment of hyper- triglyceridaemia, hypercholesterolaemia and conditions of low HDL (high density lipoprotein) levels in addition to the treatment of atherosclerotic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions.
  • the present invention provides a method of lowering triglyceride and/or cholesterol levels and/or increasing high density lipoprotein levels which comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the formula (I) or pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating atherosclerosis which comprises administering, to an animal in need thereof; a therapeutically effective amount of a compound of the formula (I) or pharmaceutically acceptable salt thereof.
  • the compositions are formulated and administered in the same general manner as detailed below for treating diabetes and obesity.
  • They may also contain other active ingredients known for use in the treatment of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lovastatin, simvastatin and pravastatin; inhibitors of cholesterol absorption for example beta-sitosterol and (acyl Co A: cholesterol acyltransf erase) inhibitors for example melinamide; anion exchange resins for example cholestyramine, colestipol or a dialkylaminoalkyl derivatives of a cross-linKed dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics.
  • fibrates such as clofibrate, bezafibrate and gemfibrozil
  • inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lova
  • the compounds of the instant invention also have the effect of reducing intestinal motility and thus find utility as aiding in the treatment of various gastrointestinal disorders such as irritable bowel syndrome. It has been proposed that the motility of non-sphincteric smooth muscle contraction is mediated by activity at ⁇ 3 adrenoreceptors. The availability of a ⁇ 3 specific agonist, with little activity at ⁇ l and ⁇ 2 receptors will assist in the pharmacologic control of intestinal motility without concurrent cardiovascular effects.
  • the instant compounds are administered generally as described below with dosages similar to those used for the treatment of diabetes and obesity.
  • the compounds which act as agonists at B3 adrenoreceptors may be useful in the treatment of gastrointestinal disorders, especially peptic ulcerations, esophagitis, gastritis and duodenitis, (including that induced by H. pylori), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis) and gastrointestinal ulcerations.
  • ⁇ 3 receptors have been indicated to have an effect on the inhibition of the release of neuropeptides in certain sensory fibers in the lung.
  • sensory nerves may play an important role in the neurogenic inflammation of airways, including cough
  • the instant specific ⁇ 3 agonists may be useful in the treatment of neurogenetic inflammation , such as asthma, with minimal effects on the cardio- pulmonary system.
  • ⁇ 3 adrenoreceptors are also able to produce selective antidepressant effects by stimulating the ⁇ 3 receptors in the brain and thus an additional contemplated utility of the compounds of this invention are as antidepressant agents.
  • the active compounds of the present invention may be orally administered as a pharmaceutical composition, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • these active compounds may be incorporated with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like.
  • Such compositions and preparations should contain at least 0.1 percent of active compound.
  • the percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams.
  • the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention are administered at a daily dosage of from 1 milligram to about 1000 milligrams per kilogram of animal body weight, preferably given in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 10 milligrams to about 10,000 milligrams, preferably from about 10 milligrams to about 500 milligrams.
  • the total daily dose will generally be from about 70 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy- propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form mus be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Hexylamine 12.15 ml (9.2 mmol) was added dropwise to a solution of 10 ml (9.2 mmol) of phenyl isocyanate in THF (150 ml) at 0°C, and stirring was continued for 1 h. The solvent was removed in vacuo, and the resultant hexyl phenyl urea was used without further purification.

Abstract

Substituted sulfonamides having formula (I), are selective β3 adrenergic receptor agonists with very little β1 and β2 adrenergic receptor activity and as such the compounds are capable of increasing lipolysis and energy expenditure in cells. The compounds thus have potent activity in the treatment of Type II diabetes and obesity. The compounds can also be used to lower triglyceride levels and cholesterol levels or raise high density lipoprotein levels or to decrease gut motility. In addition, the compounds can be used to reduce neurogenic inflammation or as antidepressant agents. The compounds are prepared by coupling an aminoalkylphenyl-sulfonamide with an appropriately substituted epoxide. Compositions and methods for the use of the compounds in the treatment of diabetes and obesity and for lowering triglyceride levels and cholesterol levels or raising high density lipoprotein levels or for increasing gut motility are also disclosed.

Description

TITLE OF THE INVENTION
SUBSTITUTED SULFONAMIDES AS SELECTIVE β3 AGONISTS
FOR THE TREATMENT OF DIABETES AND OBESITY
CROSS REFERENCE
This is a continuation-in-part of co-pending application U.S.S.N. 08/233,166 filed April 26, 1994, which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION β-Adrenoceptors have been subclassified as βi and β2 since 1967. Increased heart rate is the primary consequence of βi -receptor stimulation, while brohchodilation and smooth muscle relaxation typically result from β2 stimulation. Adipocyte lipolysis was initially thought to be solely a βi -mediated process. However, more recent results indicate that the receptor-mediating lipolysis is atypical in nature. These atypical receptors, later called β3-adrenoceptors, are found on the cell surface of both white and brown adipocytes where their stimulation promotes both lipolysis (breakdown of fat) and energy expenditure.
Early developments in this area produced compounds with greater agonist activity for the stimulation of lipolysis (β3 activity) than for stimulation of atrial rate (βi) and tracheal relaxation (β2). These early developments disclosed in Ains worth et al., U.S. Patents 4,478,849 and 4,396,627, were derivatives of phenylethanolamines.
Such selectivity for β3-adrenoceptors could make compounds of this type potentially useful as antiobesity agents. In addition, these compounds have been reported to show antihyperglycemic effects in animal models of non-insulin-dependent diabetes mellitus.
A major drawback in treatment of chronic diseases with β3 agonists is the potential for stimulation of other β-receptors and subsequent side effects. The most likely of these include muscle tremor (β2) and increased heart rate (βl). Although these phenylethanolamine derivatives do possess some β3 selectivity, side effects of this type have been observed in human volunteers. It is reasonable to expect that these side effects resulted from partial βl and/or β2 agonism.
More recent developments in this area are disclosed in Ains worth et al., U.S. Patent 5,153,210, Caulkett et aL, U.S. Patent 4,999,377, Alig et aL, U.S. Patent 5,017,619, Lecount et aL, European Patent 427480 and Bloom et aL, European Patent 455006.
Even though these more recent developments purport to describe compounds with greater β3 selectivity over the βl and β2 activities, this selectivity was determined using rodents, in particular, rats as the test animal. Because even the most highly selective compounds, as determined by these assays, still show signs of side effects due to residual βl and β2 agonist activity when the compounds are tested in humans, it has become apparent that the, rodent is not a good model for predicting human β3 selectivity.
Recently, assays have been developed which more accurately predict the effects that can be expected in humans. These assays utilize cloned human β3 receptors which have been expressed in Chinese hamster ovary cells. See Emorine et al, Science. 1989, 245:1118-1121; and Liggett, Mol. Pharmacol.. 1992, 42:634-637. The agonist and antagonist effects of the various compounds on the cultivated cells provide an indication of the antiobesity and antidiabetic effects of the compounds in humans.
SUMMARY OF THE INVENTION
The instant invention is concerned with substituted sulfonamides which are useful as antiobesity and antidiabetic compounds. Thus, it is an object of this invention to describe such compounds. It is a further object to describe the specific preferred stereoisomers of the substituted sulfonamides. A still further object is to describe processes for the preparation of such compounds. Another object is to describe methods and compositions which use the compounds as the active ingredient thereof. Further objects will become apparent from reading the following description. DESCRIPTION OF THE INVENTION
The present invention provides compounds having the formula I:
Figure imgf000005_0001
where n is 0 to 5; m is 0 or 1 ; r is 0 to 3;
A is (1) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(2) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(4) phenyl, or
(5) a benzene ring fused to a C3-C8 cycloalkyl ring; Rl is (1) hydroxy,
(2) oxo,
(3) halogen,
(4) cyano,
(5) NR8R8, (6) SR8,
(7) trifluoromethyl,
(8) Cl-ClO alkyl,
(9) OR8,
Figure imgf000006_0001
(l l) OCOR9,
(12) NR8COR9,
Figure imgf000006_0002
(16) Cl-ClO alkyl substituted by hydroxy, halogen, cyano, NR8R8, SR8, trifluoromethyl, OR8, C3-C8 cycloalkyl, phenyl, NR8COR9, COR9, S02R9, OCOR9, NR8S02R9 or
Figure imgf000006_0003
R2 and R3 are independently
(1) hydrogen,
(2) Cl-ClO alkyl or
(3) Cl-ClO alkyl with 1 to 4 substituents selected from hydroxy, Cl-ClO alkoxy, and halogen;
X is (1) -CH2-,
(2) -CH2-CH2- ,
(3) -CH=CH- or
(4) -CH20-; R4 and R5 are independently
(l)hydrogen,
(2) Cl-ClO alkyl,
(3) halogen,
(4) NHR8,
(5) OR8,
(6) SO2R9 or
Figure imgf000006_0004
R6 i is (1) hydrogen or
(2) Cl-ClO alkyl;
R7 i is Z-(Rla)n; R a is (l) Rl, with the proviso that when A is phenyl, R^a is not
Cl-ClO alkyl,
(2) C3-C8 cycloalkyl,
(3) phenyl optionally substituted with up to 4 groups independently selected from R , NR R8? OR8, SR8 and halogen, or
(4) 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, NR8R8, OR8, SR8, and halogen;
Z is (1) phenyl,
(2) naphthyl,
(3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(4) a benzene ring fused to a C3-C8 cycloalkyl ring,
(5) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(6) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or
(7) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring;
R8 is (1) hydrogen,
(2) Cl-Clθ alkyl,
(3) C3-C8 cycloalkyl,
(4) Z optionally having 1 to 4 substituents selected from halogen, nitro, oxo, NRIORIO, Cl-ClO alkyl, Cl-ClO alkoxy, Cl-ClO alkylthio, and Cl-ClO alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, Cθ2- Cl-ClO alkyl, SO2-C1-C10 alkyl, C3-C8 cycloalkyl, Cl- ClO alkoxy, and Z optionally substituted by from 1 to 3 of halogen, Cl-ClO alkyl or Cl-ClO alkoxy, or (5) Cl-ClO alkyl having 1 to 4 substituents selected from hydroxy, halogen, C02H, CO2-C1-C10 alkyl, SO2-C1-C10 alkyl, C3-C8 cycloalkyl, Cl-ClO alkoxy, Cl-ClO alkyl, and Z optionally substituted by from 1 to 4 of halogen, Cl-ClO alkyl or Cl-ClO alkoxy;
R9 is (l) R8 or
(2) NR8R8;
RlO is (1) Cl-ClO alkyl, or
(2) two RIO groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with Cl-ClO alkyl; or a pharmaceutically acceptable salt thereof
In one embodiment of the instant invention A is a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
In another embodiment of the instant invention A is phenyl or benzene fused to a C3-C8 cycloalkyl ring.
Preferred compounds of the instant invention are realized when in the above structural formula I: R2 and R3 are hydrogen or methyl; X is -CH2-; n is 0 to 3; m is 1; r is 0 to 2; and
R4, R5 and R6 are hydrogen.
Other preferred compounds of the instant invention are realized when in the above structural formula I: A is phenyl or a 6-membered heterocyclic ring with 1 or 2 heteroatoms selected from nitrogen and sulfur; Rl is hydroxy, halogen, cyano, trifluoromethyl, NR8R8,
NR8SO2R9, NR8COR9, NR8CO2R8, C1-C6 alkyl optionally substituted by hydroxy; and r is 0 or 2.
More preferred compounds are represented by the formula la:
NH-S02-Z-(R1a)n
Figure imgf000009_0001
la
wherein n is 0 to 3; m is 1 Rl is (1) halogen or
(2) NR8R8;
R2, R3 are independently hydrogen or methyl; Rla is (1) halogen,
(2) Cl-ClO alkyl, (3) NR8R8,
Figure imgf000009_0002
(6) COR9,
(7) OCOR9, or
(8) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, halogen, R8, NR8R8, OR , and SR8;
Z is (1) phenyl,
(2) naphthyl, (3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(4) benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, or
(5) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring;
X is -CH2-; and
R8 and R9 are as defined under formula I.
Even more preferred compounds are those represented by formula Id:
Figure imgf000010_0001
Id
n is 0 or 1 ;
R1 is NR R8;
R2 and R3 are independently
(1) hydrogen, or (2) methyl;
B is (1) hydrogen,
(2) benzene fused to the benzene ring to form naphthyl, or
(3) a 5 or 6-membered heterocycle with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atom fused to the benzene ring;
Rla is (1) halogen,
(2) Cl-ClO alkyl,
(3) NR8R8,
(4) NR8COR9,
(5) NR8CO2R8, (6) COR9, or
(7) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, SR8, OR8, and NR8R8; when B and the benzene ring form a fused ring system, Rla is attached to either ring; R8 is (1) hydrogen,
(2) Cl-Clθ alkyl,
(3) Z optionally having 1 to 4 substituents selected from nitro, oxo, and NRIORIO, or
(5) Cl-ClO alkyl having 1 to 4 substituents selected from hydroxy, halogen, Cl-ClO alkyl, C3-C8 cycloalkyl, and Z optionally substituted by from 1 to 4 of halogen, Cl-ClO alkyl or Cl-ClO alkoxy; R9 is (l) R8 or
(2) NR8R8; RlO is (1) Cl-ClO alkyl, or
(2) two RlO groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with Cl-ClO alkyl; and Z is (1) phenyl,
(2) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(3) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or
(4) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring.
Other more preferred compounds are represented by formula lb:
Figure imgf000012_0001
lb
wherein n is 0 to 3; m is 1
Rl is (1) hydroxy,
(2) cyano,
(3) NR8R8 or
(4) halogen; Rla is (1) halogen,
(2) NR8R8,
Figure imgf000012_0002
(5) OCOR9, or
(6) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to three groups independently selected from oxo, halogen, R8, NR8R8, OR8 and SR8;
Z is (1) phenyl,
(2) naphthyl or
(3) benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen;
X is -CH2-; and
R2 and R3 are independently hydrogen or methyl.
Representative antiobesity and antidiabetic compounds of the present invention include the following:
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]- 4-(hexylaminocarbonylamino)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-
4-iodobenzenesulfonamide
N- [4- [2- [ [2-hydroxy-2- (6-aminopyridin-3 -y l)ethy 1] amino] ethy 1 jpheny 1] - benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]ρhenyl]-
2-naphthalenesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-
3-quinolinesulfonamide
N- [4- [2- [ [2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl] -
5-benzisoxazolesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-
4-[(hexylmethylaminocarbonyl)amino]benzenesulfonamide
N- [4- [2- [ [2-hydroxy-2-(6-aminopyridin-3-yl)ethy 1] amino] ethy l]phenyl] -
4-[(dimethylaminocarbonyl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-
4-(3-hexyl-2-imidazolidon- 1 -yl)benzenesulfonamide
N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyl]- phenyl]-4-(hexylaminocarbonylamino)benzenesulfonamide
N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyl]- phenyl]-4-iodobenzenesulfonamide
N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyl]- phenyljbenzenesulfonamide
N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyl]- phenyl]-2-naphthalenesulfonamide
N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyll- phenyl]-3-quinolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-
(hexylaminocarbonylamino)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4- isopropylbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-2- naphthalenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-3- quinolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-
[(hexylmethylaminocarbonyl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-4-(3- hexyl-2-imidazolidinon- 1 -yl)benzenesulfonamide
N- [4- [2- [ [2-hy droxy-2-(3 -py ridinyl)ethy 1] amino] ethy l]pheny 1] -4- iodobenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3- cyclopentylpropyl)-[l,2,4]-oxadiazol-3-yl]benzensulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(l- oxoheptyl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-4-[(l- oxo-4-phenylbutyl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-
[(propoxycarbonyl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[[(fur-
2-ylmethyl)amino]carbonyl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[[(2- phenylethyl)amino]carbonyl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[[(2- indol-3-ylethyl)amino]carbonyl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-
[[(octylamino)carbonyl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-
[(hexylamino)carbonyl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-
[(octylamino)carbonyl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[(N- methyl-N-octylamino)carbonyl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(l- oxononyl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- methylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- octylthiazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- ethyl-5-methylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- octy 1-2-imidazolidinon- 1 -yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-
(4,4,4-trifluorobutyl)-2-imidazolidinon-l-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3- ρhenylpropyl)-2-imidazolidinon- 1 -yljbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-
(4,4,5,5,5-pentafluoropentyl)-2-imidazolidinon- 1 - yljbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2- cyclohexylethyl)-2-imidazolidinon- 1 -yljbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl]phenyl]-4-[3-[3-
(4-chlorophenyl)propylJ-2-imidazolidinon-l-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJamino]ethyl]phenyl]-4-(3- pentyl-2-imidazolidinon- 1 -yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJaminoJethyl]phenylJ-4-[3-(3- cyclopentylpropyl)-2-imidazolidinon- 1 -yljbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJaminoJethyl]phenyl]-4-[3-(2- cyclopentylethyl)-2-imidazolidinon- 1 -yljbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl]phenyl]-4-[3-(3- cyclohexylpropyl)-2-imidazolidinon- 1 -yljbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethylJphenyl]-4-[3-(2,2- dimethylhexyl)-2-imidazolidinon- 1 -yljbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethylJρhenyl]-4-(3- hexyl-2-imidazolon- 1 -yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl]phenyl]-4-[3-
(4,4,4-trifluorobutyl)-2-imidazolon- 1 -yljbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethyl]ρhenyl]-4-(3- octyl-2-imidazolon- 1 -yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJaminoJethyl]phenyl]-4-[3-(3- cyclopentylpropyl)-2-imidazolon- 1 -yljbenzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJamino]ethylJphenylJ-4-(2- octyl-3-oxo-[l,2,4]-triazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethylJρhenyl]-4-(4- hexyl-5-tetrazolon-l-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethylJphenyl]-4-(4- octyl-5-tetrazolon- 1 -yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]aminoJethylJphenyl]-4-[(3- cyclopentylpropyl)-5-tetrazolon- 1 -yljbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJamino]ethyl]phenylJ-4-(2- pentyloxazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethylJaminoJethyl]phenylJ-4-(2- octyloxazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2- cyclopentylethyl)oxazol-5-ylJbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(4- ethyl-5-methylthiazol-2-yl)amino]benzenesulfonamide
N- [4- [2- [ [2-hydroxy-2- (3-pyridiny l)ethyl] amino] ethyl]phenyl] -4-
[(4,5,6,7-tetrahydrobenzothiazol-2-yl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- hexylimidazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(l- methyl-2-octylimidazol-5-yl)benzenesulfonamide
N- [4- [2- [[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4- [ 1 - methyl-2-(2-cyclopentylethyl)imidazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[l- methyl-2-[2-(4-fluorophenyl)ethyl]imidazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- pentyl-[l,2,4]-oxadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2- cyclopentylethyl)-[l,2,4]-oxadiazol-3-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- heptyl-[l,2,4]-oxadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-4-(5- octyl-[ 1 ,2,4]-oxadiazol-3-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- hexylthio-[l,2,4]-triazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[4-(4- propylpiperidin- 1 -yl)- 1 , 1 -dioxo-[ 1 ,2,5]-thiadiazol-3- yl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[4-
(hexylmethylamino)-l,l-dioxo-[l,2,5]-thiadiazol-3- y 1] amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[4-(N- heptyl, N-methylamino)- 1 , l-dioxo-[ 1 ,2,5]-thiadiazol-3- yl] amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(l- octyl-2,4-imidazolidinedion-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]anono]ethyl]phenyl]-4-[3-(3- nitrophenyl)-5-pyrazolon- 1 -yljbenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(l- hydroxy-l-hexylheptyl)-5-methyl-[l,2,3]-triazol-2-yl]benzenesulfon- amide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(l- hydroxyheptyl)-5-methyl-[l,2,3]-triazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]-2-methylpropyl]- phenyl]-4-(3-hexyl-2-imidazolidinon- 1 -yl)benzenesulfonamide
N- [4- [2- [ [2-hydroxy-2-(3-pyridinyl)ethyl] amino] -2-methylpropyl] -■ phenyl]-4-iodobenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]-2-methylpropyl]- phenyl]-4-[[(hexylamino)carbonyl]amino]benzenesulfonamide
N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-4-iodobenzene- sulfonamide
N- [4- [2- [(2-hydroxy-2-pheny lethy l)amino] ethyl]phenyl] -2-naphthalene- sulfonamide
N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-3-quinoline- sulfonamide
N-[4-[2-[[2-hydroxy-2-(3-chlorophenyl)ethyl]amino]ethyl]phenyl]-3- isopropylbenzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-chlorophenyl)ethyl]amino]ethyl]phenyl]-2- naphthalenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-chlorophenyl)ethyl]amino]ethyl]ρhenyl]-3- quinolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]ethyl]- phenyl]-4-(hexylaminocarbonylamino)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]ethyl]- pheny 1] - 1 - [(octylamino)carbony 1] -5 -indolinesulf onamide
N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]ethyl]- phenyl]-4-(3-hexyl-2-imidazolidinon- 1 -yl)benzenesulfonamide
N- [4- [2- [ [2-hydroxy-2-(4-amino-3 ,5-dichlorophenyl)ethyl] amino] ethyl] - phenyl]-4-(3-octyl-2-imidazolidinon- 1 -yl)benzenesulfonamide
N- [4- [2- [[2-hy droxy-2-(4-hy droxyphenyl)ethyl] amino] ethyl]pheny 1] - benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]ethyl]phenyl]-4- iodobenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-4-
(hexylaminocarbonylamino)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-3- quinolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- hexyl- [ 1 ,2,4]-oxadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- heptyl-5-methyl-[l,2,3]-triazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- hexyl-2,4-imidazolidinedion- 1 -yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- octyl-2,4-imidazolidinedion- 1 -yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3- cyclopentylpropyl)-2,4-imidazolidinedion-l-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- pentyl- [ 1 ,2,4]-oxadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- hexyl-[ 1 ,2,4]-oxadiazol-5-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- heptyl-[ 1 ,2,4]-oxadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- octyl-[ 1 ,2,4]-oxadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2- cyclopentylethyl)-[ 1 ,2,4]-oxadiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3- cyclopentylpropyl)-[ 1 ,2,4]-oxadiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- pentyl- [ 1 ,2,4]-thiadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- hexyl-[ 1 ,2,4]-thiadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- heptyl-[l,2,4]-thiadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-4-(3- octyl-[ 1 ,2,4]-thiadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2- cyclopentylethyl)-[ 1 ,2,4]-thiadiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3- cyclopentylpropyl)-[ 1 ,2,4]-thiadiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- pentyl-[ 1 ,2,4]-thiadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- hexyl- [ 1 ,2,4]-thiadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- heptyl-[ 1 ,2,4]-thiadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- octyl-[ 1 ,2,4]-thiadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]a ino]ethyl]phenyl]-4-[5-(2- cyclopentylethyl)-[l,2,4]-thiadiazol-3-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3- cyclopentylpropyl)-[ 1 ,2,4]-thiadiazol-3-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- pentyl-3-oxo-[l,2,4]-triazol-2-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- hexyl-3-oxo-[l,2,4]-triazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- heptyl-3-oxo-[l,2,4]-triazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- octyl-3-oxo-[l,2,4]-triazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(2- cyclopentylethyl)-3-oxo-[l,2,4]-triazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3- cyclopentylpropyl)-3-oxo-[l,2,4]-triazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- pentyloxazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- hexyloxazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- heptyloxazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- octyloxazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2- cyclopentylethyl)oxazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3- cyclopentylpropyl)oxazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- pentyloxazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- hexyloxazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- heptyloxazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-4-(4- octyloxazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(2- cyclopentylethyl)oxazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3- cyclopentylpropyl)oxazol-2-yl]benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- hexyloxazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- heptyloxazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3- cyclopentylpropyl)oxazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(4- cyclohexylbutyl)oxazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-[2-
(4-fluorophenyl)ethyl]oxazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- pentyloxazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- hexyloxazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- heptyloxazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- octyloxazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-4-[2-(2- cyclopentylethyl)oxazol-4-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3- cyclopentylpropyl)oxazol-4-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- pentylthiazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- hexylthiazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- heptylthiazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- octylthiazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2- cyclopentylethyl)thiazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-4-[5-(3- cyclopentylpropyl)thiazol-2-yl]benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- pentylthiazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- hexylthiazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- heptylthiazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- octylthiazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(2- cyclopentylethyl)thiazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3- cyclopentylpropyl)thiazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- pentylthiazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- hexylthiazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- heptylthiazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- octylthiazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2- cyclopentylethyl)thiazol-4-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3- cyclopentylpropyl)thiazol-4-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- pentylthiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- hexylthiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- heptylthiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-4-(2- octylthiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2- cyclopentylethyl)thiazol-5-yl]benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3- cyclopentylpropyl)thiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- methylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- pentylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- hexylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- heptylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- octylthiazol-2-yl)-5-indolinesulfonamide
N- [4- [2- [ [2-hydroxy-2-(3-pyridinyl)ethyl] amino]ethyl]phenyl]- 1 - [5-(2- cy clopentylethyl)thiazol-2-yl] -5-indolinesulf onamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[5-(3- cyclopentylpropyl)thiazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- pentylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- hexylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- heptylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[4-(2- cyclopentylethyl)thiazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[4-(3- cyclopentylpropyl)thiazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- methyloxazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- pentyloxazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- hexyloxazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- heptyloxazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- octyloxazol-2-yl)-5-indolinesulfonamide
N- [4- [2- [ [2-hydroxy-2-(3-pyridinyl)ethyl] amino]ethyl]phenyl]- 1 - [5-(2- cyclopentylethyl)oxazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[5-(3- cyclopentylpropyl)oxazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- methyloxazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- pentyloxazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- hexyloxazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- heptyloxazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- octyloxazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[4-(2- cyclopentylethyl)oxazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[4-(3- cyclopentylpropyl)oxazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(3- methyl-[l,2,4]-oxadiazol-5-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(3- pentyl-[ 1 ,2,4]-oxadiazol-5-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(3- hexyl-[ 1 ,2,4]-oxadiazol-5-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(3- heptyl-[ 1 ,2,4]-oxadiazol-5-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-l-(3- octyl-[ 1 ,2,4]-oxadiazol-5-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[3-(2- cyclopentylethyl)- [ 1 ,2,4]-oxadiazol-5-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[3-(3- cyclopentylpropyl)-[l,2,4]-oxadiazol-5-yl]-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- methyl-[l,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- pentyl-[l,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- hexyl-[l,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- heptyl-[l,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(5- octyl-[l,2,4]-oxadiazol-5-yl)-3-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[5-(2- cyclopentylethyl)-[l,2,4]-oxadiazol-3-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-[5-(3- cyclopentylpropyl)-[l,2,4]-oxadiazol-3-yl]-5-indolinesulfonamide
The compounds of the instant invention all have at least one asymmetric center as noted by the asterisk in structural Formula I. Additional asymmetric centers may be present on the molecule depending upon the nature of the various substituents on the molecule, in particular, R2 and R3. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof, be included within the ambit of the instant invention. In the case of the asymmetric center represented by the asterisk in Formula I, it has been found that the compound in which the hydroxy substituent is above the plane of the structure, as seen in Formula Ic, is more active and thus more preferred over the compound in which the hydroxy substituent is below the plane of the structure.
The following stereospecific structure represents the preferred stereoisomers of the instant invention:
Figure imgf000026_0001
Ic
where n, m, r, A, Rl, R2, R3, R4, R5? R6, R7 and x are as defined above under formula I.
Throughout the instant application, the following terms have the indicated meanings:
The alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The alkoxy groups specified above are intended to include those alkoxy groups of the designated length in either a straight or branched configuration. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term "halogen" is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
Examples of 5 and 6-membered heterocycles and fused heterocycles of A, Z and Rla include pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, thiazolyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, tetrahydroquinolinyl, furopyridine and thienopyridine.
The preferred values of A and Z are phenyl, naphthyl, benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or heterocycles with from 1 to 4 heteroatoms independently selected from one of oxygen or sulfur, and/or 1 to 4 nitrogen atoms.
The more preferred values of A are phenyl, pyridyl, quinolinyl, pyrimidinyl, pyrrolyl, thienyl, imidazolyl, and thiazolyl.
The more preferred values of Z are phenyl, naphthyl, quinolinyl, thienyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl, dihydrobenzofuranyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazolyl, tetrahydrobenzothiazolyl and tetrahydroquinolinyl. When Z is attached to -NSθ2(CH2)r~, it is preferably phenyl, naphthyl or a benzene ring fused to a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. When Z is part of the definition of R8, it is preferably phenyl, a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrog*en, a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or a 5 or 6- membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring.
The preferred heterocycles of Rla are thienyl, thiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl, pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, and pyrazolyl.
Certain of the above defined terms may occur more than once in the above formula and upon such occurrence each term shall be defined independently of the other; thus for example, NR8R8 may represent NH2, NHCH3, N(CH3)CH2CH3, and the like.
The following abbreviations are used throughout the specification:
Boc : tert-butyloxycarbonyl
Cbz : carbobenzyloxy
DIP-C1 : diisopinocampheylchloroborane
DMF : dimethylformamide DMSO dimethylsulfoxide HPLC high pressure liquid chromatography Me methyl MPLC medium pressure liquid chromatography
Ms methanesulfonyl (mesyl)
NBS N-bromosuccinimide
NCS N-chlorosuccinimide nHex n-hexyl
TBAF tetrabutylammonium fluoride
TBS (TBDMS) t-butyldimethylsilyl
TFA trifluoroacetic acid
THF tetrahydrofuran The compounds (I) of the present invention can be prepared from epoxide intermediates such as those of formula II and amine intermediates such as those of formula III. The preparation of these intermediates is described in the following schemes.
Figure imgf000028_0001
π m where n, m, r, A, Rl, R2, R3, R4, R5, R6, R7 and X are as defined above.
Compounds II are known in the literature or may be conveniently prepared by a variety of methods familiar to those skilled in the art. One common route is illustrated in Scheme 1. Acid chloride 1, which may be commercially available or readily prepared from the corresponding acid by treatment with, for example, thionyl chloride or oxalyl chloride, is treated with diazomethane in a solvent such as diethyl ether. The resultant diazoketone is then treated with hydrogen chloride to give chloroketone 2 (X = Cl). The haloketone 2 is then reduced with a reducing agent such as sodium borohydride. The resultant alcohol 3 is treated with base such as potassium carbonate in refluxing acetone to provide the desired epoxide II. The enantiomerically enriched (R) and (S) epoxides II are readily available by asymmetric reduction of haloketones 2 using chiral reducing agents such as (-) or (+)-DIP-Cl, (R) or (S)- Alpine borane or (/?) or (-S')-tetrahydro-l-methyl-3,3- diphenyl-l /,3 -pyrrolo[l,2-c][l,3,2]oxazaborole-borane ((R) or (5)- OAB-BH3).
SCHEME 1
Figure imgf000029_0001
Figure imgf000029_0002
An alternate route to the desired haloketones 2 is illustrated in Scheme 2. Methylketone 4 may be converted to the corresponding haloketone using a variety of reagents known to those in the art and summarized in Larock Comprehensive Organic Transformations; VCH: New York, 1989, 369-372. Conveniently, methylketone 4 is treated with chlorine or -V-chlorosuccinimide in acetic acid with an additional acid source such as hydrogen chloride or aluminum chloride. For the synthesis of 2 (X = Br), bromine, dibromobarbituric acid or NBS with hydrogen bromide or aluminum bromide may be used. In some cases, the chloro or bromoketones 2 may be commercially available.
SCHEME 2
Figure imgf000030_0001
Many of the methylketones 4 are commercially available or readily prepared by methods described in the literature and known to those skilled in the art. Rl substituents on the acid chlorides 1 or methylketones 4 may need to be protected during the subsequent procedures. A description of such protecting groups may be found in: Protective Groups in Organic Synthesis. 2nd Ed., T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, 1991.
Compounds III can be conveniently prepared by a variety of methods familiar to those skilled in the art. A convenient route for their preparation when R6 is hydrogen is illustrated in Scheme 3. Compound 5 is selectively protected as a suitable carbamate derivative 6 with, for example, di- rf-butyl dicarbonate or carbobenzyloxy chloride. This compound is then treated with a sulfonyl halide, preferably the sulfonyl chloride 7-. and a base such as pyridine in an anhydrous solvent such as dichloromethane or chloroform for 0.5 to 24 hours at temperatures of -20 to 50°C, preferably 0°C, to provide the sulfonamide 8. The protecting group is then removed with, for example, trifluoracetic acid in the case of Boc or catalytic hydrogenation in the case of Cbz, to give the desired amine 9.
SCHEME 3.
Figure imgf000031_0001
Compounds III where R6 is not hydrogen may be conveniently prepared as illustrated in Scheme 4. Sulfonamide 8^ prepared as described above, is alkylated v/ith an appropriate alkylating agent LO in the presence of base to provid sulfonamide LL Removal of the protecting group as above gives the desired compound 9a. SCHEME 4
Figure imgf000032_0001
9a
The sulfonyl chlorides 7, many of which are commercially available, can also be readily prepared by a number of methods familiar to those skilled in the art. One suitable method involves the addition of an organolithium reagent or a Grignard reagent to sulfuryl chloride following the procedure of S. N. Bhattacharya, et. al., J. Chem. Soc. (C), 1265-1267 (1969). Another convenient method involves the treatment of a thiol with sulfuryl chloride and a metal nitrate according to the procedure of Y. J. Park, et. al., Chemistry Letters, 1483-1486 (1992). Sulfonic acids are also conveniently converted to the corresponding sulfonyl chloride by treatment with PCI5, PCI3 or SOC12 (J. March, Advanced Organic Chemistry. 4th Ed., John Wiley and Sons, New York: 1992, pi 297 and references sited therein). Aromatic and heteroaromatic compounds may be chlorosulfonylated directly by treatment with Vilsmeier's reagent or chorosulfonic acid (Organic Synthesis, I, 8). The diamines 5 are commercially available or readily prepared by methods described in the literature or known to those skilled in the art. Compound 5 where R2 or R3 is methyl can be prepared from the corresponding amino acid following the method of J. D. Bloom, et. al., J. Med. Chem., 35, 3081-3084 (1992). As illustrated in Scheme 5 for R3 = methyl, the appropriate (R) amino acid 12 is esterified, conveniently by treatment with methanolic hydrochloric acid, and then treated with di-terf-butyl dicarbonate to give compound 13. The ester group is reduced with a hydride source such as lithium borohydride and the resultant alcohol is converted to a leaving group such as a mesylate. Removal of the Boc protecting groups gives diamine L4- This compound is subjected to catalytic hydrogenation in the presence of base such as sodium acetate to give the desired α-methyl amine 15. The other enantiomer is available through an analogous sequence starting with the corresponding (S) amino acid.
SCHEME 5
Figure imgf000034_0001
Diamines 5 or sulfonamide amines °. where X is -CH2O- and m is 1 are also readily prepared by methods described in the literature or known to those skilled in the art. For example, as shown in Scheme 6, the sodium salt of 4-nitrophenol 16 is alkylated with 1- bromo-2-chloroethane, conveninetly in refluxing 2-butanone with a base such as potassium carbonate to give chloro derivative 17. The chloride is converted to the corresponding amine by treatment with lithium azide followed by reduction with, for example, triphenylphosphine in aqueous tetrahydrofuran. Protection of the resultant amine, conveniently as its t-butyl carbamate by treatment with di-tert-butyldicarbonate. gives derivative lj8. The nitro group is then reduced, for example, by catalytic hydrogenation to provide amine 19. Acylation of intermediate 19 with sulfonyl chloride 7, followed by deprotection with acid such as trifluoroacetic acid gives the desired intermediate 20.
SCHEME 6
Figure imgf000035_0001
16
Figure imgf000035_0002
1. R7(CH2)rS02CI (Z), pyridine, CH2CI2
BocNH'
NH2 2. TFA/CH2CI2 (1 :3)
19
Figure imgf000035_0003
20
Alternatively, diamine 5 where X is -CH2O- and m is 1 is available from intermediate 19 by treatment with trifluoroacetic acid. This diamine may then be modified as illustrated in Scheme 3. Diamines 5 and sulfonamide amines 9 where X is -CH2CH2- and m is 1 are also readily prepared by methods described in the literature or known to those skilled in the art. For example, as shown in Scheme 7, bromo derivative 21 is treated with sodium cyanide to provide nitrile 22. The nitro group is selectively reduced by treatment with hydrogen and catalytic palladium to provide amine 23. Amine 23 is acylated with sulfonyl chloride 7 to give the corresponding sulfonamide 24. Reduction of compound 24 with cobalt chloride and sodium borohydride provides the desired amine 25.
SCHEME 7
Figure imgf000036_0001
H , Pd/C N R7(CH2)rS02Cl (7)
MeOH
Figure imgf000036_0002
NH2 pyridine, CH2C12
23
Figure imgf000036_0003
Figure imgf000036_0004
Alternatively, diamine 5 where X is -CH2CH2- and m is 1 is available from intermediate 23. by reduction of the nitrile group with, for example, cobalt chloride and sodium borohydride. This diamine may then be modified as illustrated in Scheme 3.
Intermediates II and III are coupled by heating them neat or as a solution in a polar solvent such as methanol, acetonitrile, tetrahydrofuran, dimethylsulfoxide or TV-methyl pyrrolidinone for 1 to 24 hours at temperatures of 30 to 150°C to provide compounds I as shown in Scheme 8. The reaction is conveniently conducted in refluxing methanol. Alternatively, a salt of amine III, such as the trifluoroacetate or hydrochloride salt, may be used. In these cases, a base such as sodium bicarbonate or diethylisopropylamine is added to the reaction mixture. The product is purified from unwanted side products by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still, et. aL, J- Org. Chem. 43, 2923 (1978), medium pressure liquid chromatography, or HPLC. Compounds which are purified by HPLC may be isolated as the corresponding salt. Purification of intermediates is achieved in the same manner.
SCHEME 8
Figure imgf000038_0001
III
Figure imgf000038_0002
I
In some cases, the coupling product I from the reaction described in Scheme 8 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. An alternate method for the synthesis of compound I is illustrated in Scheme 9. Epoxide II is coupled to amine 5 as described above for coupling intermediates II and III (Scheme 8) to give aniline derivative 27. The secondary amine is selectively protected, for example, as a carbamate by treatment with di-terf-butyldicarbonate to provide carbamate 29. Alternatively, nitro amine 26 is used in the coupling reaction to provide 28. Following protection as described above, the nitro group is reduced, for example, by catalytic hydrogenation with palladium catalyst or raney nickel, to provide intermediate 29. In some cases, other group may be reduced concomitantly. For example, if R is halogen in intermediate 28, it may be converted to hydrogen in intermediate 29. Treatment with a sulfonyl chloride in the presence of a base such as pyridine followed by removal of the protecting group with, in the case of a terf-butylcarbamate, acid such as trifluoroacetic acid or methanolic hydrogen chloride, provides the sulfonamide I.
SCHEME 9
Figure imgf000039_0001
n
(R1) '
Figure imgf000039_0002
Figure imgf000039_0003
0 1 ) R7(CH2)r-S02CI, base I
2) TFA or HCI/MeOH
In some cases, compound I from the reaction sequence illustrated in Scheme 9 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7, as described above. In addition, manipulation of substituents on any of the intermediates in the reaction sequence illustrated in Scheme 9 may occur. One such example is illustrated in Scheme 10. Compound 30, which is prepared as outlined in Scheme 9 from the corresponding epoxide, is subjected to reduction using tin(II) chloride to provide compound 21. Other examples of substituents on compound I which may be reduced to the corresponding amine by methods commonly known to those skilled in the art include nitro groups, nitriles, and azides.
SCHEME 10
Figure imgf000040_0001
SnCI2 aq. HCI-MeOH
Figure imgf000040_0002
31
The compounds (I) of the present invention can also be prepared from amine intermediates such as those of formula III and haloketone intermediates such as those of formula 2, as shown in Scheme 11. Amine III is alkylated with haloketone derivative 2, conveniently by treatment of a mixture of III and 2 with base such as potassium carbonate or triethylamine in a polar solvent such as acetonitrile, acetone or dimethylformamide. The resultant aminoketone 32 is reduced with, for example, sodium borohydride in methanol to give the desired aminoalcohol I.
SCHEME 11
Figure imgf000041_0001
III
Figure imgf000041_0002
[H]
I
In some cases, the product I from the reaction described in Scheme 11 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art.
An alternate synthesis of key intermediate 29 is shown is Scheme 12. The alcohol of intermediate 3 is protected, for example, as its t-butyldimethylsilyl ether to give TBS derivative 33- This compound is then treated with amine 5 and a base such as diisopropylethylamine in a solvent, typically polar aprotic such as acetonitrile, at temperatures of 25 to 150 °C for 1 to 72 hours. Typically, an iodide source such as sodium iodide is added to facilitate the reaction. The protecting group is then removed, in the case of silyl ether, by treatment of the resultant amine 34 with a fluoride source such as tetrabutylammonium fluoride. Protection of the secondary amine as before gives key intermediate 29.
SCHEME 12
Figure imgf000042_0001
Figure imgf000042_0002
In some cases, compound I may be synthesized directly from intermediate 27 without protection of the secondary amine. For example, when R2 and R3 are both methyl, aniline derivative 27 is treated with sulfonyl chloride 7 and a base such as pyridine in a solvent such as dichloromethane at a temperature of -30 to 50 °C, typically 0 °C, to provide compound I.
In some cases, the product I from the reaction described in Scheme 13 may be further modified, for example, by the removal of protecting groups or the manipulation of substituents on, in particular, Rl and R7, as described above.
SCHEME 13
Figure imgf000043_0001
R7(CH2)r-S02CI (Z)
base
The compounds (I) of the present invention where R2 and
R3 are hydrogen can also be prepared from acid intermediates of formula 36 and aminoalcohols of formula 37, as shown in Scheme 14. Acid 36 is available from the corresponding ester 35, typically a methyl or ethyl ester, by treatment with sulfonyl chloride 7 and a base such as pyridine, followed by hydrolysis of the ester with aqueous acid or base. Acid 36 is coupled to amine 37, which is known in the literature or readily prepared by methods known to those skilled in the art, using a coupling agent such as benzotriazolyl-N-oxy- tris(dimethylamino)phosphonium hexafluorophosphate or l-(3- dimethylaminopropyl)-3-ethylcarbodiimide methiodide to provide the amide 38- This is treated with a reducing agent, typically borane, to provide the desired compound I. SCHEME 14
1> CIS02(CH2)r-R7 (Z), base
Figure imgf000044_0001
2) aqueous acid or base
35 R = Me or Et, etc.
Figure imgf000044_0002
36
Figure imgf000044_0003
Figure imgf000044_0004
[H]
Compounds of the general Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
Alternatively, any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.
The instant compounds can be isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic and the like. In addition, certain compounds containing an acidic function such as a carboxy or tetrazole, can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
As previously indicated, the compounds of the present invention have valuable pharmacological properties.
The present invention also provides a compound of the general Formula I or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.
In one aspect, the present invention provides a compound of the general Formula I or a pharmaceutically acceptable ester thereof: or a pharmaceutically acceptable salt thereof for use in the treatment of obesity in human or non-human animals.
The present invention further provides a compound of the general Formula I, or a pharmaceutically acceptable ester thereof; or pharmaceutically acceptable salt thereof, for use in the treatment of hyperglycemia (diabetes) in human or non-human animals.
The disease diabetes mellitus is characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia. Research on the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Treatments have included parenteral administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are now recognized. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type II diabetes, or insulin-independent diabetes, often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese.
In addition the compounds of the present invention lower triglyceride levels and cholesterol levels and raise high density lipoprotein levels and are therefore of use in combatting medical conditions wherein such lowering (and raising) is thought to be beneficial. Thus they may be used in the treatment of hyper- triglyceridaemia, hypercholesterolaemia and conditions of low HDL (high density lipoprotein) levels in addition to the treatment of atherosclerotic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions.
Accordingly, in another aspect the present invention provides a method of lowering triglyceride and/or cholesterol levels and/or increasing high density lipoprotein levels which comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the formula (I) or pharmaceutically acceptable salt thereof. In a further aspect the present invention provides a method of treating atherosclerosis which comprises administering, to an animal in need thereof; a therapeutically effective amount of a compound of the formula (I) or pharmaceutically acceptable salt thereof. The compositions are formulated and administered in the same general manner as detailed below for treating diabetes and obesity. They may also contain other active ingredients known for use in the treatment of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lovastatin, simvastatin and pravastatin; inhibitors of cholesterol absorption for example beta-sitosterol and (acyl Co A: cholesterol acyltransf erase) inhibitors for example melinamide; anion exchange resins for example cholestyramine, colestipol or a dialkylaminoalkyl derivatives of a cross-linKed dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics.
The compounds of the instant invention also have the effect of reducing intestinal motility and thus find utility as aiding in the treatment of various gastrointestinal disorders such as irritable bowel syndrome. It has been proposed that the motility of non-sphincteric smooth muscle contraction is mediated by activity at β3 adrenoreceptors. The availability of a β3 specific agonist, with little activity at βl and β2 receptors will assist in the pharmacologic control of intestinal motility without concurrent cardiovascular effects. The instant compounds are administered generally as described below with dosages similar to those used for the treatment of diabetes and obesity.
It has also been found unexpectedly that the compounds which act as agonists at B3 adrenoreceptors may be useful in the treatment of gastrointestinal disorders, especially peptic ulcerations, esophagitis, gastritis and duodenitis, (including that induced by H. pylori), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis) and gastrointestinal ulcerations.
In addition, β3 receptors have been indicated to have an effect on the inhibition of the release of neuropeptides in certain sensory fibers in the lung. As sensory nerves may play an important role in the neurogenic inflammation of airways, including cough, the instant specific β3 agonists may be useful in the treatment of neurogenetic inflammation , such as asthma, with minimal effects on the cardio- pulmonary system. β3 adrenoreceptors are also able to produce selective antidepressant effects by stimulating the β3 receptors in the brain and thus an additional contemplated utility of the compounds of this invention are as antidepressant agents. The active compounds of the present invention may be orally administered as a pharmaceutical composition, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, which includes sublingual administration, these active compounds may be incorporated with excipients and used in the form of tablets, pills, capsules, ampules, sachets, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated.
When treating diabetes mellitus and/or hyperglycemia generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
When treating obesity, in conjunction with diabetes and/or hyperglycemia, or alone, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from 1 milligram to about 1000 milligrams per kilogram of animal body weight, preferably given in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 10 milligrams to about 10,000 milligrams, preferably from about 10 milligrams to about 500 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 70 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy- propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form mus be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The following examples are provided so that the invention might be more fully understood. They should not be construed as limiting the invention in any way.
EXAMPLE 1
Figure imgf000050_0001
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(tetrazolo[l,5-a]pyrid-6- yPethylamine
A solution of 1.62 g (10 mmol) of (R)-2-(tetrazolo[l,5- ajpyrid-6-yl)oxirane (See Fisher and Wyvratt, European Patent Application 0 318 092 A2 for the synthesis of this compound.) and 4.1 g (30 mmol) of 2-(4-aminophenyl)ethylamine in 30 mL of methanol was heated at reflux for 5h. The reaction mixture was concentrated and the residue chromatographed on silica gel (2% methanol/98% methylene chloride) to give 1.69 g (56%) of the title compound: JH NMR (400 MHz, CD3OD) δ 9.01 (d, IH, J =1.3 Hz), 8.02 (d,l H, J = 9.2 Hz), 7.82 (dd, IH, J = 1.3, 9.2 Hz), 6.94 (d, 2H, J = 6.3 Hz), 6.63 (d, 2H, J = 6.3 Hz), 4.91 (m, IH), 2.82 (m, 4H), 2.67 (t, 2 H, J = 7.1Hz). EXAMPLE 2
Figure imgf000051_0001
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(tetrazolo[l,5-a]pyrid-6- yPethylcarbamic acid 1.1-dimethylethyl ester
A solution of 1.69 g (56.7 mmol) of the amine from Example 1 and 1.23 g (56.7 mmol) of di-tert-butyl dicarbonate in 10 mL of tetrahydrofuran (THF) at 0° C was stirred for 2 h. The reaction mixture was concentrated and the residue chromatographed on silica gel (4% methanol/96% methylene chloride) to afford 2.2 g (97%) of the title compound: H NMR (400 MHz, CD3OD) δ 8.96 (s, IH), 8.05 (m, 2H), 7.85 (m, 2H), 6.93 (dd, 2H, J = 7.7, 8.3 Hz), 6.66 (d, 2H, J = 8.3 Hz), 4.99 (m, IH), 3.49 (m, 4H), 2.70 (t, 2H, J =6.5 Hz), 1.26 (s, 9H).
EXAMPLE 3
Figure imgf000051_0002
4-(Ηexylaminocarbonylamino)benzenesulfonyl chloride
Hexylamine, 12.15 ml (9.2 mmol), was added dropwise to a solution of 10 ml (9.2 mmol) of phenyl isocyanate in THF (150 ml) at 0°C, and stirring was continued for 1 h. The solvent was removed in vacuo, and the resultant hexyl phenyl urea was used without further purification.
A 6-g (2.7 mmol) portion was added over 20 min to chlorosulfonic acid at 0°C, followed by heating at 60°C for 2h. After cooling, the mixture was added to ice/water (100ml) and the aqueous phase extracted with EtOAc (3x100 ml). The combined organic phase was washed with brine (50 ml), dried with MgSθ4, concentrated, and purified by flash chromatography (silica gel, 75% hexane/ 25% ethyl acetate) to give 6 g (70%) of the title compound: IH NMR (CDCI3) δ 7.85 (d, 2H, J = 9.6 Hz), 7.54 (d, 2H, J = 9.6 Hz), 6.79 (br.s, IH), 4.71(br. s, IH), 3.23 (t, 2H, J = 8 Hz), 1.54-1.44 (m, 2H), 1.33-1.20 (m, 6H), 0.91-0.79 (m, 3H).
Figure imgf000052_0001
(R)-N-[4-[2-[N-(l,l-dimethylethoxycarbonyl)-N-[2-hydroxy-2-(tetra- zolo[l,5-a]pyrid-6-yl)]ethyl]amino]ethyl]phenyl]-4-(hexylam ylaminolbenzenesulfonamide
To a stirred solution of 0.200 g (0.502 mmol) of the Boc- compound from Example 2 in 3 mL of methylene chloride was added 80 mg (1.00 mmol) of pyridine followed by 0.16 g (0.75 mmol) of the sulfonyl chloride from Example 3. After being stirred for 5h, the reaction mixture was concentrated and the residue chromatographed on silica gel (10% methanol/90% methylene chloride) to afford 0.303 g (88%) of the title compound: IH NMR (400 Hz, CD3OD) δ 8.95 (s, IH), 8.0-8.08 (m, IH), 7.75-7.87 (m, IH), 7.40-7.62 (m, 4H), 7.00 (m, 4H), 4.95 (m, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 2.75 (m, 2H), 1.52 (t, 2H, J = 6.0 Hz), 1.33 (m, 8H), 1.21 (s, 9H), 0.90 (t, 3H, J = 6.0 Hz). EXAMPLE 5
Figure imgf000053_0001
(R)-N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]- phenyll-4-(hexylaminocarbonylamino)benzenesulfonamide
A mixture of 0.302 g (0.44 mmol) of the tetrazine from Example 4, 0.20 g (0.88mol) of tin(II) chloride dihydrate and 0.3 ml of concentrated aqueous hydrochloric acid in 2 mL of methanol was heated at reflux for 5 h. The reaction mixture was concentrated and the residue purified by reverse-phase MPLC (C8, 47%methanol/53 0.1% trifluoroacetic acid buffer) to give 0.32 g (78%) of the title compound as its bistrifluoroacetate salt: H NMR (400 MHz, CD3OD) δ 7.96 (dd, IH, J = 2.0, 9.2 Hz), 7.86 (d, IH, J = 2.0 Hz), 7.59 (d, 2H, J = 8.8 Hz), 7.43 (d, 2H, J = 8.8 Hz), 7.14 (d, 2H, J = 8.4 Hz), 7.07 (d, 2H, J = 8.4 Hz), 7.03 (d, IH, J = 9.2 Hz), 4.92 (m, 1H), 3.23 (m, 2H), 3.15 (m, 2H), 2.93 (m, 2H, 4.0 Hz), 1.49 (t, 2H, J = 6.0Hz), 1.32 (m, 8H), 0.91 (t, 3H, J = 6.0 Hz); CI MS /z 555(M+1).
Following the procedures outlined for Examples 1-5, the compounds listed in Table 1 were prepared.
Figure imgf000054_0001
Figure imgf000054_0002
EXAMPLE 14
Figure imgf000055_0001
3-(2-Chloroacetyl pyridine hydrochloride
To a solution of 12 g (11 mL, 100 mmol) of 3- acetylpyridine in 100 mL of ethyl ether was added 100 mL of 1 M ethereal hydrogen chloride. The resultant precipitate was filtered and 15.0 g (95.2 mmol) was collected and placed in a 500-mL round bottom flask equipped with a magnetic stir bar. To this was added 95 mL of 1 M hydrogen chloride in acetic acid. After the mixture was stirred until all the solid had dissolved, 12.7 g (95.2 mmol) of N-chlorosuccinimide (NCS) was added in one portion. The solution turned yellow and the NCS gradually dissolved. After 4 h, a white precipitate had formed. The mixture was allowed to stir for 2.5 days. It was then filtered. The solid collected was washed with 10 mL of acetic acid and 200 mL of ethyl ether to give 15.2 g (83%) of the title compound as a white solid: IH NMR (200 MHz, d6-DMSO) δ 9.22 (t, IH, J = 1 Hz), 8.29 (dd, IH, J = 1.6, 5.1 Hz), 8.55 (td, IH, J = 2, 8.1 Hz), 7.82 (ddd, IH, J = 0.8, 5.1, 8.1 Hz), 5.27 (s, 2H).
EXAMPLE 15
Figure imgf000055_0002
(R - -Chloromethyl-3-pyridinemethanol
To a stirred solution of 3.67 g (11.5 mmol) of (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] in 11 mL of THF at -25 °C was added a slurry of 1.00 g (5.21 mmol) of the product from Example 14 in 5 mL of THF via a cannula. Following the addition of 0.80 mL (5.79 mmol) of triethylamine, the reaction mixture was stirred at -25 °C for 4 days. To the mixture was added 10 mL of water which was then allowed to warm to room temperature. To the mixture was added 20 mL of ethyl acetate and the organic phase separated. The aqueous phase was neutralized with saturated NaHCθ3 solution then extracted six times with ethyl acetate. The combined organic phase was concentrated in vacuo to afford a yellow oil. Flash chromatography (silica gel, 75 - 100% ethyl acetate-hexanes) afforded 561 mg (68%) of the title compound as a pale yellow oil: iH NMR (400 MHz, CD3OD) δ 8.58 (d, IH, J = 1.8 Hz), 8.46 (dd, IH, J = 4.9, 1.5 Hz), 7.90 (d, IH, J = 7.9 Hz), 7.44 (dd, IH, J = 7.9, 4.9 Hz), 4.93 (m, IH), 3.75 (m, 2H).
EXAMPLE 16
Figure imgf000056_0001
(R -(Pyrid-3-yl)oxirane
To a solution of 557 mg (3.55 mmol) of the product from Example 15 in 16 mL of acetone was added 1.80 g of potassium carbononate. The mixture was heated at reflux for 20 h then cooled to room temperature. The mixture was filtered and the filtrate evaporated in vacuo. Flash chromatography (silica gel, 2% methanol-methylene chloride) afforded 262 mg (61%) of the title compound as a pale yellow oil: iH NMR (200 MHz, CDCI3) δ 8.54 (m, 2H), 7.52 (m, IH), 7.24 (m, IH), 3.86 (dd, IH, J = 4.0, 2.5 Hz), 3.17 (dd, IH, J = 5.4, 4.0 Hz), 2.80 (dd, IH, J = 5.4, 2.5 Hz). EXAMPLE 17
Figure imgf000057_0001
(R -N-r2-r4-(Aminophenyl 1ethyll-2-hydroxy-2-(pyrid-3-yl ethylamine
To a stirred solution of 377 mg (2.44 mmol) of ' 4-aminophenethylamine in 10 mL of methanol was added a solution of 300 mg (2.48 mmol) of the product from Example 16 in 15 mL of methanol. The mixture was heated at reflux for 16 h then cooled to room temperature. The methanol was removed in vacuo and the residue chromatographed (silica gel, 6 - 8% methanol, 1% ammonia-methylene chloride) to afford 101 mg (16%) of the title compound together with 279 mg of a mixture that was rechromatographed (5% methanol, 1% ammonia-methylene chloride) to give a further 54 mg (9%) of the title compound as an off-white solid: iH NMR (500 MHz, CD3OD) δ 8.52 (d, IH, J = 1.8 Hz), 8.43 (dd, IH, J = 4.8, 1.4 Hz), 7.81 (m, IH), 7.40 (m, IH), 6.95 (d, 2H, J = 8.3 Hz), 6.67 (d, 2H, J = 8.3 Hz), 4.81 (m, IH), 2.90-2.65 (m, 6H).
Figure imgf000057_0002
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(pyrid-3- yl)ethylcarbamic acid 1.1-dimethylethyl ester
A solution of 386 mg (1.77 mmol) of di-tert-butyl dicarbonate in 3.5 mL of THF was added, via a cannula, to a stirred slurry of 456 mg (1.77 mmol) of the product from Example 17 in 3.6 mL of THF cooled to 0 °C. The yellow solution was stirred at 0 °C for 3 h, then the THF was removed in vacuo. Flash chromatography (silica gel, 10% methanol, 1% ammonia-methylene chloride) afforded 549 mg (87%) of the title compound as an off white solid: iH NMR (500 MHz, CD3OD, mixture of rotomers) δ 8.45 (m, 2H), 7.83 (d, 0.6H, J = 7.4 Hz), 7.78 (d, 0.4H, J = 6.9 Hz), 7.41 (m, IH), 6.94 (d, 0.8H, J = 8.0 Hz), 6.89 (d, 1.2H, J = 7.8 Hz), 6.66 (d, 2H, J = 7.3 Hz), 4.89 (m, IH), 3.42-3.21 (m, 4H), 2.67 (m, 2H), 1.39 (s, 5.4H), 1.36 (s, 3.6H).
An alternative synthesis of the aniline derivative in Example 18 is illustrated in Examples 19-23:
EXAMPLE 19
Figure imgf000058_0001
2-Chloro-5-(2-bromoacetyl pyridine hydrochloride
A solution of 784 mg of 2-chloro-5-acetylpyridine in 10 mL of THF was added via canula to a solution of 1.44 g of dibromobarbituric acid (DBBA) in 10 mL of THF. The resultant solution was heated at 50-55 °C for 12 h, and then an additional 0.72 g DBBA was added. After stirring at 50-55 °C for 2.5 more hours, 0.36 g DBBA was added. The mixture was allowed to stir for 2 h at which point NMR analysis of an aliquot indicated 87% conversion. The reaction mixture was cooled, diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15% ethyl acetate/hexane) provided 0.86 g (73%) of the title compound as a white solid: Η NMR (400 MHz, CDCI3) δ 8.96 (d, IH, J = 2.6 Hz), 8.21 (dd, IH, J = 2.5, 8.3 Hz), 7.46 (d, IH, J = 8.4 Hz), 4.37 (s, 2H). The NMR also indicated the presence of the corresponding 2-bromo derivative. The ~4: 1 mixture was carried on through the synthesis.
Figure imgf000059_0001
(R)-α-Bromomethyl-3-(6-chloropyridine methanol
To a solution of 602 mg (1.88 mmol) of (-)-DIP-Cl in 0.5 mL of THF at -25 °C was added via canula 200 mg of ketone from Example 19 in 1.5 mL of THF at -25 °C. The reaction mixture was allowed to stir at -25 °C for 17 h. It was then quenched by the addition of water and extracted with ether. The ether phase was diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15 and 25% ethyl acetate/hexane) gave 170 mg (84%) of the title compound: IH NMR (400 MHz, CDC13) δ 8.38 (d, IH), 7.70 (dd, IH), 7.32 (d, IH), 4.97 (m, IH), 3.61 (dd, IH), 3.50 (dd, IH), 2.85 (d, IH).
EXAMPLE 21
Figure imgf000059_0002
(R -(2-chloropyrid-5-v oxirane
To a solution of 100 mg of bromoalcohol from Example 20 in 2 mL of 1:1 THF: water was added 1 mL of 5 N aqueous sodium hydroxide solution. The mixture was allowed to stir for 10 min. It was then extracted with three portions of dichloromethane. The combined organic phases were washed with two portions of water and brine, dried over magnesium sulfate, and concentrated to give 98 mg (93%) of the title compound which was used without further purification: *H NMR (400 MHz, CDC13) δ 8.34 (d, IH), 7.48 (dd, IH), 7.29 (d, IH), 3.86 (dd, IH), 3.18 (dd, IH), 2.78 (dd, IH).
EXAMPLE 22
Figure imgf000060_0001
(R)-N-[2-[4-(Nitrophenyl)]ethyl]-2-hydroxy-2-(2-chloropyrid-5- yPethylcarbamic acid 1.1-dimethylethyl ester
Following the procedure outlined in Examples 17 and 18, the title compound was prepared from the epoxide from Example 21 and 4-nitrophenylethylamine: IH NMR (400 MHz, CDCI3) δ 8.32 (d, IH, J = 1.3 Hz), 8.13 (d, 2H, J = 8.6 Hz), 7.66 (br m, IH), 7.30 (d, 2H, J = 8.1 Hz), 7.27 (br m, IH), 4.94 (br m), 3.38 (br m, 4H), 2.84 (br m, 2H), 1.40 (s, 9H).
EXAMPLE 23
Figure imgf000060_0002
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(pyrid-3- yl)ethylcarbamic acid 1.1 -dimethylethyl ester
To a solution of 80 mg (0.19 mmol) of the nitro compound from Example 22 in 2 mL of ethanol was added 0.114 mL (0.57 mmol) of 5 N aqueous sodium hydroxide solution and 20 mg of raney nickel. The reaction mixture was shaken at room temperature under 45 psi hydrogen for 16 h. The mixture was neutralized with saturated aqueous sodium phosphate monobasic and extracted with three portions of ethyl acetate. The combined organic phases were washed with water and brine, dried (magnesium sulfate), and concentrated to give 40 mg (59%) of the title compound which was identical to the sample prepared in Example 18.
EXAMPLE 24
nHex.
Figure imgf000061_0001
4-(3-Hexyl-2-imidazolon- 1 -yDphenylsulphonyl chloride
Hexyl iodide (50mmol, 7.38ml) was added to a mixture of 2-amino acetaldehyde dimethyl acetal (lOOmmol, 11ml) and potassium carbonate (50mmol, 6.9g) in DMF (10ml) at 0°C. Stirring was continued for 16h before diluting with ethyl acetate (200ml), and filtering the solution through a plug of celite. Concentration in vacuo was follwed by column chromatography (eluant ethyl acetate) to give N- hexyl 2-amino acetaldehyde dimethyl acetal (7.39g, 78%) as a colourless oil. To the amine (38.6mmol, 7.3g) in methylene chloride
(100ml) at 0°C was added 4-(chlorosulphonyl) phenyl isocyanate (38.6mmol, 8.4g). The reaction mixture was stirred for 20mins until a clear solution had formed, and 1: 1 water: trifluoroacetic acid (100ml total) was added. Vigorous stirring was continued for 16h., the layers separated, the organic layer was diluted with ethyl acetate (500ml) and washed with saturated sodium bicarbonate solution (4x50ml), brine (50ml), dried with anhydrous magnesium sulphate, and concentrated in vacuo. Column chromatrography (eluant 3 hexane/ 1 ethyl acetate) yielded the title compound as pale yellow crystals (8.8g, 67%). EXAMPLE 25
Figure imgf000062_0001
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4- (hexylaminocarbonylamino benzenesulfonamide
To a solution of 302 mg (0.845 mmol) of the product from Example 18 and 137 mL (1.69 mmol) of pyridine in 10 mL of methylene chloride was added 296 mg (0.928 mmol) of 4-(hexylaminocarbonylamino)benzenesulfonyl chloride from Example 3. The reaction was stirred for 12 h then the solvent removed in vacuo. Flash chromatography (silica gel, 6% methanol, 0.5% ammonia- methylene chloride) afforded 468 mg (87%) of the BOC-protected title compound.
A solution of 468 mg (0.731 mmol) of BOC-protected title compound in 5 mL of methylene chloride and 5 mL of trifluoroacetic acid was stirred for 30 min then the volatile components removed in vacuo. The residue was azeotroped twice with 10% methanol/toluene, twice with methanol, then dried in vacuo to give 521 mg (93%) of the title compound as its trifluroracetate salt: iH NMR (400 MHz, CD3OD) δ 8.88 (s, IH), 8.79 (d, IH, J = 5.5 Hz), 8.53 (d, IH, J = 8.2 Hz), 7.99 (m, IH), 7.59 (dd, 2H, J = 6.9, 1.9 Hz), 7.43 (dd, 2H, J = 6.9, 1.9 Hz), 7.15 (dd, 2H, J = 8.6, 2.1 Hz ), 7.08 (dd, 2H, J = 8.6, 2.1 Hz), 5.23 (m, IH), 3.40-3.10 (m, 6H), 2.94 (m, 2H), 1.49 (m, 2H), 1.32 (m, 6H), 0.90 (m, 2H). EXAMPLE 26
CbzN
Figure imgf000063_0001
(N)- [4- [2- [(phenylmethoxycarbonyl)amino]ethyl]phenyl]-4- cyanobenzensulfonamide
Following the procedure outlined in Example 4, the title compound was prepared from 2-(4-aminophenyl)ethylcarbamic acid phenylmethyl ester (see Fisher, et. al., Eur. Pat. Appl. 0 611 003 Al, 1994) and 4-cyanobenzenesulfonyl chloride: lH NMR (400 MHz, CD3OD) δ IH NMR (400 MHz, CDCI3) δ 7.81 (d, 2H, J=8.7Hz), 7.69 (d, 2H, J=8.7Hz), 7.32 (m, 5H), 7.06 (d, 2H, J=8.4Hz), 6.96 (d, 2H, J=8.4Hz), 6.75 (s, IH), 5.06 (s, 2H), 4.71 (t, br, IH), 3.38 (q, 2H, J=6.9Hz), 2.74 (t, 2H, J=7.0Hz).
EXAMPLE 27
Figure imgf000063_0002
(N)- [4- [2- [(phenylmethoxy carbonyl)amino] ethy l]phenyl]-4- aminooximidomethvDbenzensulfonamide
A mixture of the nitrile from Example 26 (2.7 lg, 6.23mmol), absolute ethanol (65ml), finely divided K2CO3 (5.17g, 37.4mmol), and hydroxylamine hydrochloride (2.17g, 31.2mmol) was refluxed for 6 h. The ethanol was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate and washed with water 3 times. The organic phase was concentrated in vacuo to 2.87g (98%) of the title compound as a white powder which was of sufficient purity to be used in subsequent steps: !H NMR (400 MHz, CD3OD) δ 7.71 (s, 4H), 7.31 (m, 5H), 7.04 (d, 2H, J=8.4Hz), 6.99 (d, 2H, J=8.4Hz), 5.02 (s, 2H), 3.25 (t, 2H, J=6.8Hz), 2.67 (t, 2H, J=6.7Hz).
EXAMPLE 28
Figure imgf000064_0001
(N)-[4-[2-[(phenylmethoxycarbonyl)amino]ethyl]phenyl]-4-[5-(3- cyclopentylpropylVri.2.41-oxadiazol-3-vHbenzensulfonamide To a solution of compound from Example 27 (0.468g, l.OOmmol) in dry pyridine (5.0ml) was added 4-cyclopentylbutyryl chloride (0.175g, l.OOmmol). The mixture was refluxed for 3.5 h. The pyridine was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (35% ethyl acetate in hexanes) to give 0.152g (26%) of the title compound: iH NMR (400 MHz, CDCL3) δ 8.12 (d, 2H, J=8.7Hz), 7.81 (d, 2H, J=8.7Hz), 7.31 (m, 5H), 7.03 (d, 2H, J=8.1Hz), 6.97 (d, 2H, J=8.4Hz), 6.67 (s, IH), 5.05 (s, 2H), 4.70 (t, br, IH), 3.37 (q, 2H, J=6.5Hz), 2.91 (t, 2H, J=7.6Hz), 2.72 (t, 2H, J=7.0), 1.90-1.70 (m, 5H), 1.65-1.30 (m, 6H), 1.06 (m, 2H). EXAMPLE 29
Figure imgf000065_0001
N-[4-(2-aminoethyl)phenyl]-4-[5-(3-cyclopentylpropyl)-[ 1,2,4]- oxadiazol-3-yl1benzensulfonamide
A mixture of Cbz amine from Example 28 (0.145g, 0.246mmol), palladium hydroxide on carbon (0.02g), and glacial acetic acid (5.0ml) was hydrogenated for 2 h. The acetic acid was removed under reduced pressure. The residue was purified by silica gel chromatography (1 : 9 of 10% ammonium hydroxide in methanol : methylene chloride) to give 0.058g (52%) of the title compound: iH NMR (400 MHz, CD3OD) δ 8.11 (d, 2H, J=8.6Hz), 7.87 (d, 2H, J=8.5Hz), 7.06 (d, 2H, J=8.6Hz), 7.02 (d, 2H, J=8.7Hz), 2.97 (t, 2H, J=7.5Hz), 2.84 (t, 2H, J=6.9Hz), 2.67 (t, 2H, J=7.5Hz), 1.90-1.75 (m, 5H), 1.70-1.40 (m, 6H), 1.12 (m, 2H).
EXAMPLE 30
Figure imgf000066_0001
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4- r5-(3-cyclopentylpropylH1.2.41-oxadiazol-3-yl1benzensulfonamide
To a solution of amine from Example 29 (0.053g, 0.117mmol) in dry methanol (30.0ml) was added 3-pyridine epoxide from Example 16 (0.021g, 0.175mmol). The resulting solution was refluxed overnight. After concentration, the residue was purified by silica gel chromatography (13% methanol in methylene chloride) to give O.Olg (15%) of the title compound: iH NMR (400 MHz, CD3OD) δ 8.52 (d, IH, J=1.9Hz), 8.42 (dd, IH, J=1.5, 4.8Hz), 8.13 (d, 2H, J=8.6Hz), 7.85 (m, 3H), 7.40 (dd, IH, J=4.8, 7.8Hz), 7.10 (d, IH, J=8.6Hz), 7.03 (d, 2H, J=8.6Hz), 4.81 (dd, IH, J=4.9, 8.1Hz), 2.96 (t, 2H, J=7.5Hz), 2.93-2.70 (m, 6H), 1.90-1.72 (m, 5H), 1.68-2.48 (m, 4H), 1.42 (m, 2H), 1.11 (m, 2H). EX AMPLE 31
Figure imgf000067_0001
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4- [4-(l-hydroxy-l-hexylheptyl)-5-methyl-[l,2,3]-triazol-2- yl]benzenesulfonamide and (R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3- yl ethyllaminolethyllphenyll-4-r4-('l-('R.S)-hvdroxyheptyl)-5-methyl- f 1.2.31-triazol-2-yllbenzenesulfonamide
To a solution of 180 mg of (R)-N-[4-[2-[[2-Hydroxy-2- (pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(4-methoxycarbonyl-5- methyl-[l,2,3]-triazol-2-yl)benzenesulfonamide (prepared according to the procedures outlined in examples 14-19) in 2 mL of distilled THF under argon at 0°C was added, dropwise, 2 mL of a 2.0M solution of n-hexylmagnesium bromide in ether. After 5 min, the reaction was quenched with cautious addition of 5 mL of aqueous ammonium chloride followed by ethyl acetate extraction of the aqueous layer. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude products. Preparative layer chromatography (PLC) on 2X0.5 mm thick silica gel plates eluted in 9:1 (v/v) dichloromethane:methanol gave two bands A (20 mg) and B (60mg). IH NMR (500 MHz, CD3OD) of A: δ 8.51 (d, IH, J=2 Hz), 8.41 (dd, IH, J=1.5, 5 Hz), 8.01 (dd, 2H, J=2.5, 6.5Hz), 7.81 (m, IH), 7.78 (dd, 2H, J=2.0, 9.0 Hz), 7.37 (m, IH), 7.07;7.02 (ABq, 4H, Jab= 8.5 Hz), 4.86 (s, CD3OH), 4.79 (dd, IH, J= 7.5, 8 Hz), 2.9-2.7 (m, 6H), 2.44 (s, 3H), 1.85 (m, 4H), 1.40-1.15 (m, 16H), 0.83 (t, 6H, J=7 Hz) indicating the dihexyl tertiary alcohol adduct, mass spec, expected 677 found 677. *H NMR (500 MHz, CD3OD) of B: 8.51 (d, IH, J=2 Hz), 8.41 (dd, IH, J=1.5, 5 Hz), 8.03 (d, 2H, J=9 Hz), 7.78 (d, 2H, J=9 Hz), 7.37 (dd, IH, J= 4.8, 7.7 Hz), 7.07;7.02 (ABq, 4H, Jab=8 Hz), 4.86 (s, CD3OH), 4.80 (m, 2H), 2.9-2.7 (m, 6H), 2.38 (s, 3H), 1.87 (m, 2H), 1.44 (m, IH), 1.4-1.2 (m, 7H), 0.87 (t, 3H, J=7 Hz) indicating the mono-hexyl adduct. Mass spec expected 591 (for the hexyl ketone) found 593 (hexyl alcohol, intermediate ketone reduced by Grignard reagent in situ).
Following the procedures outlined for Examples 14-31, the compounds listed in Table 2 were prepared.
TABLE 2
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
58 4-(3-pentyl-2- 3.82 (m, 2 H), 3.53 (m, 2H), 2.94 imidazolidinon- 1 - (m, 2H), 1.57 (quintet, 2H, J=7.4 yl)phenyl, Hz), 1.39-1.28 (m, 4H), 0.916, (tr, bistrifluoroacetate salt 3H, J=7.1 Hz).
J 59 4-[3-(3- 3.81 (m, 2H), 3.51 (m, 2H), 3.23 (t, cyclopentylpropyl)-2- J = 7.3 Hz, 2H), 1.78 (m, 3H), 1.57 imidazolidinon- 1 - (m, 6H), 1.33 (m, 2H), 1.17 (m, yl]phenyl 2H)
10 60 4-[3-(2- 3.83 (m. 2H), 3.53 (m, 2H), 2.94 cyclopentylethyl)-2- (m, 2H), 1.81 (m, 4H), 1.65-1.53 imidazolidinon- 1 - (m, 5H), 1.16 (m, 2H). yl]phenyl, bistrifluoroacetate salt
15 61 4-[3-(3- 3.83 (m, 2H), 3.51 (m, 2H), 3.22 (t, cyclohexylpropyl)-2- J = 7.3 Hz, 2H), 1.71 (m, 5H), 1.56 imidazolidinon- 1 - (m, 2H), 1.20 (m, 6H), 0.88 (m, yl]phenyl 2H)
62 4-[3-(2,2- 3.82 (m, 2H), 3.60 (m, 2H), 3.03 (s,
20 dimethylhexyl)-2- 2H), 1.28 (m, 6H), 0.93 (m, 3H), imidazolidinon- 1 - 0.91 (s, 6H) yljphenyl
63 4-(3-hexyl-2- 6.93 (d, IH, 4Hz), 6.70 (d, IH, imidazolon- 1 -yl)phenyl 4Hz), 4.79 (m,lH), 3.64 (t, 2H,
25 8Hz), 1.71-1.64 (m, 2H), 1.35-1.28 (m, 6H), 0.91-0.86 (m, 3H).
64 4-[3-(4,4,4- 6.97 (d, IH, 3Hz), 6.73 (d, IH, trifluorobutyl)-2- 3Hz), 3.73 (t, 2H, 7Hz), 2.23-2.19 imidazolon- 1 -yl]phenyl (m, 2H), 1.98-1.92 (m, 2H).
30 65 4-(3-octyl-2- 6.93 (d, IH, 4Hz), 6.69 (d, IH, imidazolon- 1 -yl)phenyl 4Hz), 3.64 (t, 2H, 7Hz), 1.70-1.63 (m, 2H), 1.33-1.23 (m, 10H), 0.90- 0.85 (m, 3H).
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Starting with commercially available (R)-styrene epoxide and following the procedures outlined for Examples 17,18 and 25, the compounds listed in Table 3 were prepared.
TABLE 3
Figure imgf000076_0001
Figure imgf000076_0002
5 EXAMPLE 93
0
Figure imgf000076_0003
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]-2- methylpropyllphenyl1-4-(3-hexyl-2-imidazolidinon- 1 - yPbenzenesulfonamide
A solution of pyridine epoxiάe (160mg,1.32 mmol) from example 16 and 4-amino-a,a-dimethylphenethylamine (1.2g, 7.3 mmol), prepared according to J. Biol. Chem. 1981, 256. 11944-50, in methanol (8 ml) was warmed at reflux for 16 hours. After cooling, the reaction mixture was concentrated and purified by flash chromatography (silica gel, 95:5 CH2CI2: 10% NH4OH/CH3OH) to give 23 mg (0.080 mmol) of product as an oil.
The above product (18 mg, 0.063 mmol) was dissolved in CH2CI2 (1 mL) and pyridine (0.05 mL). The resulting solution was cooled to 0°C and treated with 4-(3-hexyl-2-imidazolidinon-l- yl)benzenesulfonyl chloride (22 mg, 0.063 mmol). The mixture was allowed to stir at 0°C for 20 hours and was then purified by flash chromatography (silica gel, 95:5 CH2CI2: 10% NH4OH/CH3OH) to give the desired product (21 mg, 0.035mmol) as an oil: IHNMR (CD3OD) δ 8.53 (s, IH), 8.44 (d,lH, J=5.0), 7.83 (d, 1H, J=7.9), 7.63 (m, 4H), 7.40 (dd, IH, J=5.0, 7.9), 6.98 (m, 4H), 4.72 (dd, IH, J=4.0, 8.4), 3.80 (m, 2H), 3.49 (m, 2H), 3.22 (t, 2H, J=7.2), 2.78 (m, 2H), 2.62 (m, 2H), 1.55 (m, 2H), 1.31 (m, 6H), 1.01 (s, 3H), 0.99 (s, 3H), 0.89 (m, 3H).
Following the procedure outlined above, the compounds in Table 4 were prepared.
TABLE 4
Figure imgf000077_0001
Example | R Selected lH NMR (CD3OD) Data
Figure imgf000078_0001
EXAMPLE 96
Figure imgf000078_0002
(R)-4-amino-α-(bromomethyl)-3,5-dichlorobenzenemethanol, dimethyl-
1, 1-dimethylethylsilyl ether
A solution of t-butyldimethylsilyl chloride (1.67 g, 11.1 mmol) in DMF (15 mL) was added slowly to a stirred solution of (R)-4- amino-α-(bromomethyl)-3,5-dichlorobenzenemethanol (2.1 g, 7.4 mmol, see Judkins, et. al, European Patent Application 0 460 924) and imidazole (0.75 g, 11.1 mmol) in DMF (6 mL) with an ice-water bath cooling. After being stirred at RT for 3h, the reaction mixture was poured into water (300 mL) and the product was extracted with ether. The organic phase was washed with saturated aqueous sodium bicarbonate solution, brine, dried(MgS04) and evaporated to dryness. The crude product was purified on silica (95/5 hexane/ethyl acetate) to give the title compound (2.73 g, 93 %): iH NMR (400 MHz, CDCI3) δ 7.14 (s, 2H), 4.67 (dd, IH, J=2.1, 6.4 Hz), 3.33 (m, 2H), 0.87 (s, 9H), 0.89(s, 6H) - 11 -
EXAMPLE 97
Figure imgf000079_0001
(R)-N-[2-[4-(Aminophenyl)]ethyl]-2-[(dimethyl-l,l- dimethy lethy lsily l)oxy ] -2-(4-amino-3.5-dichlorophenyl ethylamine O-TBDMS bromo compound from Example 96 (2.73g, 6.86 mmol) was dissolved in CH3CN (50 mL) and 4-amino- phenethylamine (1.86 g, 13.72 mmol) was added, followed by the addition of N,N'-diisopropylethylamine (3.58 mL, 20.6 mmol) and sodium iodide (1.03 g, 6.86 mmol). After being heated at reflux for 48 h, the reaction mixture was concentrated and the residue chromatographed on silica (50/50 ethyl acetate/hexane) to provide the title compound (2.3 g, 75 %): iH NMR (400 MHz, CDCI3) δ 7.08 (s, 2H), 6.94 (AA', 2H, J=8.4 Hz), 6.60 (BB*, 2H, J=8.4 Hz), 4.63 (m, IH), 4.37 (s, 2H), 3.53 (br s, 2H), 2.87-2.60 (m, 6H), 0.80 (s, 9H), -0.03 (s, 6H)
EXAMPLE 98
Figure imgf000079_0002
(R)-N-[2-[4-(Aminophenyl)]ethyl]-2-hydroxy-2-(4-amino-3,5- dichlorophenyPethylamine
To a stirred solution of silyl compound from Example 97 (2.2 g, 4.8 mmol) in THF (20 mL) at RT was added tetrabutylammonium fluoride (10 mL of 1.0 M solution in THF) in one portion. After being stirred at RT for 2h, the reaction mixture was concentrated and chromatographed on silica (10/90 CH3OH/CH2CI2) to give the title compound (1.59 g, 97 %): H NMR (400 MHz, CD3OD) δ 7.15 (s, 2H), 6.92 (AA', 2H, J=8.3 Hz), 6.60 (BB*, 2H, 8.3 Hz), 4.58 (m,lH), 2.83-2.65 (m, 6H)
EXAMPLE 99
Figure imgf000080_0001
(E)-N-[4-[2-[[2-Hydroxy-2-(4-amino-3,5- dichlorophenyl emyl1amino1ethyll-phenyl1-4-
(hexylaminocarbonylamino)benzehesulfonamide
Following the procedure outlined in Example 18 and 25, the title compound was prepared from the aniline derivative from Example 98: NMR (400 MHz, CD3OD) 7.57 (AA', 2H, J=2.7 Hz), 7.42 (BB', 2H, J=2.7 Hz), 7.16 (s, 2H), 7.04 (AA', 2H, J=2.0 Hz), 7.00 (BB', 2H, J=2.0 Hz), 4.58 (t, IH, j=7.1 Hz), 3.14 (t, IH, J=7.0 Hz), 2.80 (m, 2H), 2.73 (m, 4H), 1.49 (m, 2H), 1.32 (m, 6H), 0.90 (t, 3H, J=6.7 Hz). ESI MS m/z 622 (M).
Following the procedure outlined in Examples 96-99, the compounds in Table 5 were prepared. TABLE 5
Figure imgf000081_0001
Figure imgf000081_0002
EXAMPLE 103
Figure imgf000081_0003
(R)-N-[4-[2-[[2-Hydroxy-2-(4- hydroxyphenyl ethyl]aminolethyllphenyl1-benzenesulfonamide
A solution of 5 g of 4-aminophenethyl alcohol in 50 mL of DMF was silylated with 5.5 g of t-butyldimethylsilyl chloride (TBDMS- Cl) and 2.5 g of imidazole overnight at room temperature. Extraction of the product following an aqueous ammonium chloride workup afforded 6.6 g of the O-TBDMS ether. This aniline derivative was then coupled to benzenesulfonyl chloride in pyridine-dichloromethane to give the sulfonamide in greater than 80% yield after chromatographic purification. The TBDMS group of the sulfonamide was removed with methanolic HCl at room temperature for 30 min. The crude alcohol was oxidized to the corresponding carboxylic acid with Jones reagent in acetone (RT 30 min, ethyl acetate extraction).
To a solution of 180 mg of (R)-octopamine and 300 mg of the resultant 4-N-benzenesulfonamidophenylacetic acid in 7 mL of DMF was added 0.5 mL of triethylamine and 490 mg of benzotriazolyl-N- oxy-tris(dimethylamino)phosphonium hexafluorophosphate. The reaction mixture was stirred at RT 2h, flash chromatography over silica gel eluting with 95:5 chloroform-methanol gave 322 mg of purified amide.
A solution of 220 mg of this amide in 13 mL of 1.0 M borane-THF was refluxed under argon for 2h followed by the addition of 3 mL of N,N-dimethylaminoethanol and further reflux for another hour. The solvent and excess volatiles were removed in vacuo and the residual solid was taken up in acetone and purified by PLC on silica gel (9:1 ethyl acetate:methanol) to yield 61 mg of the title compound: H NMR (500 MHz, CD3OD) δ 7.73 (dt, 2H, J=2.1^ 8.2Hz), 7.53 (tt, IH, J=l .4, 7.6Hz), 7.44 (t, 2H, J=8 Hz), 7.18 (d, 2H, J=8.4 Hz), 7.05 (ABq, 4H, Jab=8.5 Hz), 6.76 (d, 2H, J=8.4Hz), 4.75 (dd, IH, J=7.5, 7.6 Hz), 3.05-2.90 (m, 4H), 2.81 (t, 2H, J=7.6 Hz). Mass spec calcd. 412.5 found 413.2. EXAMPLE 104
Figure imgf000083_0001
(R)-N-[4-[2-[[2-Hydroxy-2-(4- hydroxyphenyDethyl]aminolethyllphenyl1-4-iodobenzenesulfonamide
Following the procedure outlined in Example 103, the title compound was prepared: *H NMR (500 MHz, CD3OD) δ 7.77 (d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz), 7.15 (d, 2H, J=8.5 Hz), 7.02 (ABq, 4H, Jab=8.7 Hz), 6.75 (d, 2H, J=8.5 Hz), 4.67 (dd, IH, J=4.4, 6.6 Hz), 2.90-2.66 (m, 6H). Mass spec calcd. 538.4 found 538.9.
EXAMPLE 105
Figure imgf000083_0002
3-(2-bromoacetyl benzonitrile
To a solution of 1.02 g (7.04 mmol) of 3-acetylbenzonitrile in 70 mL of ethyl ether was added 1.02 g (3.52 mmol, 0.5 equiv) of dibromobarbituric acid. The mixture was allowed to stir at room temperature overnight. The resultant white slurry was filtered and the filtrate was concentrated. Purification by flash chromotography (silica gel, 20% ethyl acetate/hexane) gave 1.28 g (81%) of the title compound as a white solid: IH NMR (400 MHz, CDCI3) δ .8.26 (t, IH, J = 1.4 Hz), 8.20 (td, IH, J = 1.5, 8.0 Hz), 7.87 (dd, IH, J = 1.3, 7.8 Hz), 7.64 (t, IH, J = 7.9 Hz), 4.40 (s, 2H).
EXAMPLE 106
Figure imgf000084_0001
(R - -Bromomethyl-3-cvanophenylmethanol
To a suspension of 181 mg (0.623 mmol) of (R)- tetrahydro- 1 -methyl-3 ,3-diphenyl- 1 H,3H- pyrrolo[l,2c][l,3,2]oxazaborole-borane (R-OAB catalyst) in 6 mL of THF at 0 °C was added dropwise 6.24 mL (6.24 mmol) of a 1 M solution of borane in THF. The resultant clear solution was allowed to stir for 5 min, and then a solution of 1.27 g (5.67 mmol) of bromoketone from Example 105 in 6 mL of THF was added slowly over 1 h. After the reaction was allowed to stir for 30 min more, it was quenched by the dropwise addition of 6 mL of methanol and concentrated. Purification by flash chromatography (silica gel, 20-25% ethyl acetate/hexane) provided 944 mg (74%) of the title compound as a clear oil which crystallized: IH NMR (400 MHz, CDCI3) δ 7.70 (d, IH, J = 1.5 Hz), 7.62-7.60 (m, 2H), 7.48 (t, IH, J = 7.7 Hz), 4.95 (dd, IH, J = 3.4, 8.4 Hz), 3.63 (dd, IH, J = 3.4 Hz), 3.49 (dd, IH, J = 8.4 Hz).
EXAMPLE 107
Figure imgf000084_0002
(R)-(3-cyanophenyl)oxirane To a solution of 937 mg (4.14 mmol) of bromohydrin from Example 106 in 8 mL of methanol was added 601 mg (4.35 mmol, 1.05 equiv) of potassium carbonate. The reaction mixture was allowed to stir at room temperature for 7 h. It was then diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, 20% ethyl acetate/hexane) provided 573 mg (95%) of the title compound: *H NMR (400 MHz, CDC13) δ .7.59-7.55 (m, 2H), 7.49 (dd, IH, J = 1.6, 7.9 Hz), 7.44 (t, IH, J = 7.7 Hz), 3.87 (dd, IH, J = 2.5, 4.0 Hz), 3.17 (dd, IH, J = 4.1, 5.5 Hz), 2.74 (dd, IH, J = 2.5, 5.4 Hz).
EXAMPLE 108
Figure imgf000085_0001
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(3- cyanophenyl)ethylcarbamic acid 1.1-dimethylethyl ester
Following the procedures outlined in Examples 17 and 18, the title compound was prepared from the epoxide from Example 107: IH NMR (400 MHz, CDCI3) δ 7.58-7.52 (br m, 3H), 7.41 (t, IH, J = 7.5 Hz), 6.89 (br d, 2H, J = 7.6 Hz), 6.65 (br d, 2H, J = 7.8 Hz), 4.82 (br dd, IH, J = 2.7, 7.9 Hz), 3.42-3.05 (br m, 4H), 2.75-2.55 (br m, 2H). EX AMPLE 109
Figure imgf000086_0001
(R)-N-[4-[2-[[2-Hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-4-
(hexylaminocarbonylamino benzenesulfonamide
Following the procedure outlined in Example 25, the title compound was prepared from the Boc aniline derivative from Example 108: IH NMR (400 MHz, CD3OD) δ 7.70 (s, IH), 7.63-7.57 (m, 4H), 7.48 (t, IH, J = 7.7 Hz), 7.43 (d, 2H, J = 8.9 Hz), 7.06 (d, 2H, J = 8.5 Hz), 6.99 (d, 2H, J = 8.5 Hz), 4.77 (dd, IH, J = 3.9, 8.5 Hz), 3.15 (t, 2H, J = 7.0 Hz), 2.86-2.69 (m, 6H), 1.49 (br m, 2H), 1.31 (br m, 6H), 0.90 (br t, 3H).
EXAMPLE 110
Figure imgf000086_0002
(R)-N-[4-[2-[[2-Hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-3- quinolinesulfonamide
Following the procedure outlined in Example 25, the title compound was prepared from the Boc aniline derivative from Example 108 and 3-quinolinesulfonyl chloride: *H NMR (400 MHz, CD3OD) δ 9.02 (d, IH, J = 2.3 Hz), 8.68 (d, IH, J = 1.9 Hz), 8.06 (d, IH, J = 8.3 Hz), 8.02 (d, IH, J = 7.9 Hz), 7.90 (ddd, IH, J = 1.4, 7.0, 8.4 Hz), 7.72- 7.69 (m, 2H), 7.62-7.58 (m, 2H), 7.47 (t, IH, J = 7.7 Hz), 7.07 (d, 2H, J = 8.7 Hz), 7.03 (d, 2H, J = 8.7 Hz), 4.76 (dd, IH, J = 4.0, 8.5 Hz), 2.85- 2.68 (m, 6H).
Following the procedures outlined for Examples 14-31, the compounds listed in Table 6 were prepared.
TABLE 6
Figure imgf000087_0001
Figure imgf000087_0002
Figure imgf000088_0001

Claims

WHAT IS CLAIMED IS:
1. A compound having the formula I:
Figure imgf000089_0001
where n is 0 to 5; m is 0 or 1 ; r is 0 to 3;
A is (1) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(2) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(4) phenyl, or
(5) a benzene ring fused to a C3-C8 cycloalkyl ring; Rl is (1) hydroxy,
(2) oxo,
(3) halogen,
(4) cyano,
(5) NR8R8,
(6) SR8,
(7) trifluoromethyl, (8) Cl-ClO alkyl,
(9) OR8,
Figure imgf000090_0001
(l l) OCOR9, (12) NR8COR9,
Figure imgf000090_0002
(16) Cl-ClO alkyl substituted by hydroxy, halogen, cyano, NR8R8, SR8, trifluoromethyl, OR8, C3-C8 cycloalkyl, phenyl, NR8COR9, COR9, S02R9, OCOR9, NR8S02R or
Figure imgf000090_0003
R2 and R3 are independently
(1) hydrogen, (2) Cl-ClO alkyl or
(3) Cl-ClO alkyl with 1 to 4 substituents selected from hydroxy, Cl-ClO alkoxy, and halogen; X is (1) -CH2-,
(2) -CH2-CH2- ,
(3) -CH=CH- or
(4) -CH20-; R4 and R5 are independently
(l)hydrogen,
(2) Cl-ClO alkyl,
(3) halogen,
(4) NHR8,
(5) OR8,
(6) SO2R9 or
Figure imgf000090_0004
R6 is (1) hydrogen or
(2) Cl-ClO alkyl; R7 is Z-(Rla)n;
Rla is (1) Rl, with the proviso that when A is phenyl, Rla is not
Cl-ClO alkyl, (2) C3-C8 cycloalkyl,
(3) phenyl optionally substituted with up to 4 groups independently selected from R8, NR R8, OR8, SR8 and halogen, or
(4) 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, NR8R8, OR8, SR8, and halogen;
Z is (1) phenyl,
(2) naphthyl,
(3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(4) a benzene ring fused to a C3-C8 cycloalkyl ring,
(5) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(6) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or
(7) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring;
R8 is (1) hydrogen,
(2) Cl-Cio alkyl,
(3) C3-C8 cycloalkyl,
(4) Z optionally having 1 to 4 substituents selected from halogen, nitro, oxo, NRIORIO, Cl-Cio alkyl, Cl-ClO alkoxy, Cl-ClO alkylthio, and Cl-Cio alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, CO2- Cl-ClO alkyl, SO2-C1-C10 alkyl, C3-C8 cycloalkyl, Cl- ClO alkoxy, and Z optionally substituted by from 1 to 3 of halogen, Cl-ClO alkyl or Cl-ClO alkoxy, or (5) Cl-ClO alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, CO2-C1-C10 alkyl, SO2-C1-C10 alkyl, C3-C8 cycloalkyl, Cl-Cio alkoxy, Cl-ClO alkyl, and Z optionally substituted by from 1 to 4 of halogen, Cl-ClO alkyl or Cl-ClO alkoxy;
R9 is (1) R8 or
(2) NR8R8;
RlO is (1) Cl-ClO alkyl, or
(2) two RIO groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with Cl-Cio alkyl; or a pharmaceutically acceptable salt thereof
2. A compound of Claim 1 where n is 0 to 3; m is l; r is 0 to 2;
A is phenyl or a 5- or 6-membered heterocyclic ring with from
1 to 4 nitrogen atoms;
X is -CH2-;
Rl is (1) hydroxy,
(2) halogen,
(3) cyano,
(4) trifluoromethyl,
Figure imgf000092_0001
(9) Cl-ClO alkyl optionally substituted by hydroxy;
R2, R3 are independently
(1) hydrogen or
(2) methyl;
R4, R5 and R6 are each hydrogen;
R7 is Z-(Rla)n; and R8, R , Z and Rla are as defined in Claim 1, and when Rl is part of the definition of Rla has the meaning defined in Claim 1.
3. A compound of Claim 1 having the formula la:
OH H R2 (R )n~ : jrCHCH2Nγ(χ)riτ- rNH"s°2~z-(Rla)n
N 0 la
whereir n is 0 to 3; 5 m is 1
Rl is (1) halogen or
(2) NR8R8.
R2, R3 are independently hydrogen or methyl;
Rla is (1) halogen, ° (2) Cl-Clθ alkyl,
(3) NR8R8,
(4) NR8COR9,
(5) NR8C02R8,
(6) COR9, 5 (7) OCOR9, or
(8) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, halogen, R8, NR8R8, OR8, and SR8; 0 Z is (1) phenyl,
(2) naphthyl,
(3) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (4) benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, or
(5) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring;
X is -CH2-; and
R8 and R9 are as defined in Claim 1.
4. A compound of Claim 3 wherein R2 and R^ are each hydrogen.
A compound of Claim 1 having the formula lb:
Figure imgf000094_0001
lb
wherein n is 0 to 3; m is Rl is 1) hydroxy,
2) cyano,
3) NR8R8 or
4) halogen;
Rla i is 1) halogen,
2) NR8R8,
Figure imgf000094_0002
5) OCOR9, or (6) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to three groups independently selected from oxo, halogen, R8, NR R8, OR8 and SR8; Z is (1) phenyl,
(2) naphthyl or
(3) benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; X is -CH2-; and
R2 and R^ are independently hydrogen or methyl.
6. A compound of Claim 1 having the formula Id
Figure imgf000095_0001
Id
n is 0 or 1;
Rl is NR8R8;
R2 and R- are independently (1) hydrogen, or
(2) methyl; B is (1) hydrogen,
(2) benzene fused to the benzene ring to form naphthyl, or
(3) a 5 or 6-membered heterocycle with 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atom fused to the benzene ring; R a is (1) halogen,
(2) Cl-Cio alkyl,
(3) NR8R8,
(4) NR8COR9, (5) NR8C02R8,
(6) COR9, or
(7) a 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, SR8, OR8, and NR R8; when B and the benzene ring form a fused ring system, Rla is attached to either ring; R8 is (1) hydrogen,
(2) Cl-ClO alkyl,
(3) Z optionally having 1 to 4 substituents selected from nitro, oxo, and NRIORIO, or
(5) Cl-ClO alkyl having 1 to 4 substituents selected from hydroxy, halogen, Cl-ClO alkyl, C3-C8 cycloalkyl, and Z optionally substituted by from 1 to 4 of halogen, Cl-ClO alkyl or Cl-ClO alkoxy;
R9 is (1) R8 or
(2) NR8R8;
RlO is (1) Cl-ClO alkyl, or
(2) two RlO groups together with the N to which they are attached formed a 5 or 6-membered ring optionally substituted with Cl-ClO alkyl; and
Z is (1) phenyl,
(2) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
(3) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or
(4) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C3-C8 cycloalkyl ring.
7. A compound of Claim 1 selected from the group consisting of: N- [4- [2- [(2-hy droxy-2-phenylethyl)amino] ethyl]phenyl] -4- iodobenzenesulf onamide ;
N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-2- naphthalenesulfonamide; and N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-3- quinolinesulfonamide.
N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]- ethyl]-phenyl]-4-(hexylaminocarbonylamino)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]- ethyl]-phenyl]-l-[(octylamino)carbonylamino]-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]- ethyl]-phenyl]-4-(3-hexyl-2-imidazolidon-l-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]- ethyl]-phenyl]-4-(3-octyl-2-imidazolidon-l-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]-ethyl]phenyl]- benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]-ethyl]phenyl]-4- iodobenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-4- (hexylaminocarbonylamino)benzenesulfonamide, and N-[4-[2-[[2-hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-3- quinolinesulfonamide
8. A compound of Claim 1 selected from the group consisting of:
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-
4-(hexylaminocarbonylamino)benzenesulfonamide;
N- [4- [2- [ [2-hydroxy-2-(6-aminopyridin-3-yl)ethyl] amino]ethy l]phenyl] -
4-iodobenzenesulfonamide; N- [4- [2- [ [2-hydroxy-2- (6-aminopyridin-3-yl)ethyl] amino] ethy l]pheny 1] - benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-
2-naphthalenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-
3-quinolinesulfonamide; N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-
5-benzisoxazolesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminoρyridin-3-yl)ethyl]amino]ethyl]phenyl]-
4- [(hexylmethylaminocarbonyl)amino]benzenesulf onamide ;
N-[4-[2-[[2-hydroxy-2-(6-aminoρyridin-3-yl)ethyl]amino]ethyl]phenyl]-
4-[(dimethylaminocarbonyl)amino]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-
4-(3-hexyl-2-imidazolidon- 1 -yl)benzenesulf onamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-4-
(hexylaminocarbonylamino)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4- isopropylbenzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-2- naphthalenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-3- quinolinesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]ρhenyl]-4-
[(hexylmethylaminocarbonyl)amino]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- hexyl-2-imidazolidon- 1 -yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4- iodobenzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3- cy clopentylpropyl)-2-imidazolidon- 1 -yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- octy 1-2-imidazolidinon- 1 -yl)benzenesulf onamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- hexyl-2-imidazolon- 1 -yl)benzenesulf onamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-(3- octyl-2-imidazolon- 1 -yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3- cyclopentylpropyl)-2-imidazolon- 1 -yl]benzenesulf onamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-l-(4- octylthiazol-2-yl)-5-indolinesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- pentyl-[l,2,4]-oxadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- hexyl-[ 1 ,2,4]-oxadiazol-3-yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- heptyl-[l,2,4]-oxadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5- octyl-[ 1 ,2,4]-oxadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2- 0 cyclopentylethyl)-[l,2,4]-oxadiazol-3-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3- cyclopentylpropyl)-[l,2,4]-oxadiazol-3-yl]benzensulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- pentyloxazol-5-yl)benzenesulfonamide 5 N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- hexyloxazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- heptyloxazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2- ° octyloxazol-5-yl)benzenesulf onamide
N-[4-[2-[[2-hydroxy-2-(3-ρyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2- cyclopentylethyl)oxazol-5-yl]benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3- cyclopentylpropyl)oxazol-5-yl]benzenesulfonamide 5 N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- hexyl-5-tetrazolon- 1 -yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4- octyl-5-tetrazolon- 1 -yl)benzenesulfonamide N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(3- ° cyclopentylpropyl)-5-tetrazolon- 1 -yl]benzenesulfonamide
9. A compound of Claim 1 with the structural formula Ic:
Figure imgf000100_0001
Ic
where n, m, r, A, Rl, R2, R3, R4, R5, R6, R7 and X are as defined in Claim 1.
10 A method for the treatment of diabetes which comprises administering to a diabetic patient an effective amount of a compound of Claim 1.
11. A method for the treatment of obesity which comprises administering to an obese patient an effective amount of a compound of Claim 1.
12. A method for lowering triglyceride levels and cholesterol levels or raising high density lipoprotein levels which comprises administering to a patient needing lower triglyceride and cholesterol levels or higher high density lipoprotein levels an effective amount of a compound of Claim 1.
13. A method for decreasing gut motility which comprises administering to a patient in need of decreased gut motility, an effective amount of a compound of Claim 1.
14. A method for reducing neurogenic inflammation of airways which comprises administering to a patient in need of reduced neurogenic inflammation, an effective amount of a compound of Claim 1.
15. A method for reducing depression which comprises administering to a depressed patient an effective amount of a compound of Claim 1.
16. A method for treating gastrointestinal disorders which comprises administering to a patient with gastrointestinal disorders an effective amount of a compound of Claim 1.
17. A composition for the treatment of diabetes or obesity or for lowering triglyceride or cholesterol levels or increasing high density lipoprotein levels or for decreasing gut motility or for reducing neurogenic inflammation or for treating depression or for treating gastrointestinal disorders which comprises an inert carrier and an effective amount of a compound of Claim 1.
PCT/US1995/004956 1994-04-26 1995-04-21 SUBSTITUTED SULFONAMIDES AS SELECTIVE β3 AGONISTS FOR THE TREATMENT OF DIABETES AND OBESITY WO1995029159A1 (en)

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