WO2003068738A1 - Pyrrole derivatives as ligands of melanocortin receptors - Google Patents
Pyrrole derivatives as ligands of melanocortin receptors Download PDFInfo
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- WO2003068738A1 WO2003068738A1 PCT/US2003/004455 US0304455W WO03068738A1 WO 2003068738 A1 WO2003068738 A1 WO 2003068738A1 US 0304455 W US0304455 W US 0304455W WO 03068738 A1 WO03068738 A1 WO 03068738A1
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- 0 CCCCCC*CCCCCCC(*)(*[n]1c(*)c(*)c(C)c1*)C(C)(C(C)(*)CC(*)=C)*=C Chemical compound CCCCCC*CCCCCCC(*)(*[n]1c(*)c(*)c(C)c1*)C(C)(C(C)(*)CC(*)=C)*=C 0.000 description 5
- IQHDVTCYMGYMBK-UHFFFAOYSA-N CS(c1ccc(C2N(CC3CCNCC3)C(c3cccc(Oc4ccccc4)c3)=CC2)cc1)(P)=O Chemical compound CS(c1ccc(C2N(CC3CCNCC3)C(c3cccc(Oc4ccccc4)c3)=CC2)cc1)(P)=O IQHDVTCYMGYMBK-UHFFFAOYSA-N 0.000 description 1
- ZBSNZXYMOLJCTC-UHFFFAOYSA-N C[Os](c(cc1)ccc1-c1ccc(-c2cc(Oc3ccccc3)ccc2)[n]1CCCC=O)(=C)=O Chemical compound C[Os](c(cc1)ccc1-c1ccc(-c2cc(Oc3ccccc3)ccc2)[n]1CCCC=O)(=C)=O ZBSNZXYMOLJCTC-UHFFFAOYSA-N 0.000 description 1
- HBEPUKGCKLXVLQ-UHFFFAOYSA-N NCC(CC1)CCN1C#N Chemical compound NCC(CC1)CCN1C#N HBEPUKGCKLXVLQ-UHFFFAOYSA-N 0.000 description 1
- USIUVYZYUHIAEV-UHFFFAOYSA-N c(cc1)ccc1Oc1ccccc1 Chemical compound c(cc1)ccc1Oc1ccccc1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 1
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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- C07D401/14—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 three or more hetero rings
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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- C07D405/06—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 carbon chain containing only aliphatic carbon atoms
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- C07D417/04—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 directly linked by a ring-member-to-ring-member bond
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Definitions
- This invention is generally directed to ligands of a melanocortin receptor, specifically pyrrole-based ligands, and to compositions and methods for using such ligands to alter activity of a melanocortin receptor.
- MC receptors are members of the family of G-protein coupled receptors. To date, five distinct MC receptors ⁇ i.e., MC1-R, MC2-R, MC3-R,
- MC4-R and MC5-R have been identified in a variety of tissues and these receptors have been shown to mediate a number of physiological processes.
- Ligands including peptides and small molecules, have been shown to act as agonists or antagonists at these receptors.
- MC receptors The role of specific MC receptors in physiological processes has been the object of intense study since their discovery and cloning. These receptors are expressed in a variety of tissues including melanocytes, adrenal cortex, brain, gut, placenta, skeletal muscle, lung, spleen, thymus, bone marrow, pituitary, gonads and adipose tissue. A putative role of MC receptors has been shown in melanocytes, stimulatory actions on learning, attention and memory, motor effects, modification of sexual behavior, facilitation of nerve regeneration, anti-inflammatory and antipyretic effects, and the regulation of food intake and body weight.
- the pro-opiomelanocortin (POMC) gene product is processed to produce a number of biologically active peptides that are expressed in the pituitary, and two locations in the brain: the arcuate nucleus of the hypothalamus and the solitary tract nucleus of the brain stem. These peptides elicit a range of biological activities.
- MC4-R melanocortin receptors that respond to POMC peptides (reviewed in Rec. Prog. Hor. Res. 51, 287-318, 1996). Each receptor in this family is pharmacologically distinct in its particular response to the POMC peptides ⁇ -MSH, ⁇ -MSH and ACTH and to two peptide antagonists.
- MC4-R has the highest affinity for ⁇ -MSH.
- MC4-R differs from the other MC receptors in that it binds both natural melanocortin antagonists, agouti (Nature 371, 799-802, 1994) and ⁇ g ⁇ wtz-related protein (AgRP) ⁇ Biochem.
- MCl-R is expressed primarily in melanocytes, while MC2-R is expressed in adrenocortical cells.
- MC3-R is expressed in brain, placenta and gut, and MC4-R is expressed primarily in the brain where its mRNA can be detected in nuclei that bind ⁇ -MSH.
- MC4-R is notably absent from adrenal cortex, melanocyte and placental tissues. Both MC3-R and MC4-R are expressed in arcuate and paraventricular neurons.
- MC5-R is expressed in brain, adipose tissues, muscle and exocrine glands.
- ⁇ -Melanocyte stimulating hormone is a tridecapeptide whose principal action ⁇ i.e., the activation of a set of G-protein coupled melanocortin receptors), results in a range of physiological responses including pigmentation, sebum production and feeding behavior.
- Cyclized peptide derivatives of ⁇ -MSH are potent modulators of these receptors.
- peptides exhibiting MCR-4 antagonist activity increase food intake and body weight.
- agouti- related peptide AgRP
- AgRP agouti- related peptide
- MC4-R antagonists of the MC4-R would selectively enhance the feeding response.
- MC4-R antagonists have a unique clinical potential because such compounds would stimulate appetite as well as decrease metabolic rate.
- chronic MC4-R blockade causes an increase in lean body mass as well as fat mass, and the increase in lean body mass is independent of the increase in fat mass.
- Orally active forms of a small molecule MC4-R antagonist would provide a novel therapeutic strategy for indications in which cachexia is a symptom.
- the MC receptors are also key mediators of steroid production in response to stress (MC2-R), regulation of weight homeostasis (MC4-R), and regulation of hair and skin pigmentation (MCl-R). They may have additional applications in controlling both insulin regulation (MC4-R) and regulation of exocrine gland function (MC5-R) ⁇ Cell 91, 789-798, 1997); the latter having potential applications in the treatment of disorders such as acne, dry eye syndrome and blepharitis. Melanocortin peptides have also been reported to have anti-inflammatory activity, although the receptor(s) involved in mediating these effects have not yet been determined.
- Endocrine disorders such as Gushing 's disease and congenital adrenal hyperplasia, which are characterized by elevated levels of ACTH, could be effectively treated with ACTH receptor (MC2-R) antagonists.
- M2-R ACTH receptor
- Some evidence suggests that depression, which is characterized by elevated levels of glucocorticoids, may also be responsive to these same compounds.
- elevated glucocorticoids can be an etiological factor in obesity.
- Synthetic melanocortin receptor agonists have been shown to initiate erections in men (J. Urol. 160, 389-393, 1998).
- An appropriate MC receptor agonist could be an effective treatment for certain sexual disorders.
- MCl-R provides an ideal target for developing drugs that alter skin pigmentation.
- MCl-R expression is localized to melanocytes where it regulates eumelanin pigment synthesis, hi fact, two small clinical trials indicate that broad-spectrum melanocortin agonists induce pigmentation with limited side effects.
- the desired compound would have a short half-life and be topically applied.
- Applications include skin cancer prevention, UV-free tanning, inhibition of tanning and treatment of pigmentation disorders, such as tyrosinase-positive albinism.
- U.S. Patent No. 6,054,556 is directed to a family of cyclic heptapeptides which act as antagonists for MCI, MC3, MC4 and MC5 receptors;
- U.S. Patent No. 6,127,381 is directed to isoquinoline compounds which act upon MC receptors for controlling cytokine-regulated physiologic processes and pathologies;
- published PCT Application No. WO 00/74679 is directed to substituted piperidine compounds which act as selective agonists of MC4-R.
- this invention is directed to compounds which function as melanocortin (MC) receptor ligands.
- ligand means a molecule that binds or forms a complex with one or more of the MC receptors.
- This invention is also directed to compositions containing one or more MC receptor ligands in combination with one or more pharmaceutically acceptable carriers, as well as to methods for treating conditions or disorders associated with MC receptors.
- this invention is directed to MC receptor ligands that may be characterized as "substituted pyrroles” and having the following structure (I):
- the MC receptor ligands of this invention have utility over a broad range of therapeutic applications, and may be used to treat disorders or illnesses, including (but not limited to) eating disorders, cachexia, obesity, inflammation, pain, skin disorders, skin and hair coloration, sexual disfunction, dry eye, acne and/or Cushing's disease.
- a representative method of treating such a disorder or illness includes administering an effective amount of a ligand of this invention, preferably in the form of a pharmaceutical composition, to an animal (also referred to herein as a "patient", including a human) in need thereof.
- the ligand may be an antagonist or agonist or may stimulate a specific melanocortin receptor while functionally blocking a different melanocortin receptor.
- pharmaceutical compositions are disclosed containing one or more ligands of this invention in combination with a pharmaceutically acceptable carrier.
- the present invention is generally directed to compounds having the following structure (I):
- A is a direct bond or -N(R 8 )-; n is 3, 4, 5 or 6;
- R 3a and R 3b are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl or -COOR] 4 ; or any one of R 3a and the carbon to which it is attached taken together with any one of R 3D and the carbon atom to which it is attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring; or any one of R 3a and the carbon to which it is attached taken together with Ri and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring;
- R 4 is carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
- R 8 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle or substituted heterocycle; or R 8 and R 3a on the carbon atom adjacent the nitrogen atom bearing R 8 , taken together form a direct bond;
- R 9 and R 10 are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
- R ⁇ , R 12 and R 13 are the same or different and, at each occurrence, independently hydrogen, halogen, cyano, alkyl, substituted alkyl, carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; and R 14 is hydrogen, alkyl or substituted alkyl.
- Alkyl means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term
- lower alkyl has the same meaning as alkyl but contains from 1 to 6 carbon atoms.
- Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
- Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like.
- Cyclic alkyls are also referred to herein as a “homocycles” or “homocyclic rings.”
- Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl” or
- alkynyl Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-
- Carbocycle (also referred to herein as “carbocyclic ring”) means a 3- to 7- membered monocyclic, or a 7- to 10-membered bicyclic, homocyclic ring which is saturated, unsaturated or aromatic. Saturated and unsaturated carbocyclic rings are as defined above for saturated and unsaturated cyclic alkyls. Aromatic carbocyclic rings are as defined below for aryl.
- Carbocyclealkyl means an alkyl having at least one alkyl hydrogen atom replaced with a carbocycle moiety, such as -CH 2 cyclohexane, benzyl, and the like.
- Aryl means an aromatic carbocyclic moiety such as phenyl or naphthyl.
- Arylalkyl means an alkyl having at least one alkyl hydrogen atom replaced with an aryl moiety, such as benzyl, -(CH 2 ) 2 ⁇ henyl, -(CH 2 ) 3 phenyl, -CH(phenyl) 2 , and the like.
- Heteroaryl means an aromatic heterocycle ring of 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems.
- heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, triazolyl, tetrazolyl, oxadiazolyl and quinazolinyl.
- Heteroarylalkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH 2 pyridinyl, -CH 2 pyrimidinyl, and the like.
- Heterocycle (also referred to herein as a “heterocyclic ring”) means a 4- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is saturated, unsaturated, or aromatic, and which contains at least 1 carbon atom and from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring.
- the heterocycle may be attached via any heteroatom or carbon atom.
- Heterocycles include heteroaryls as defined herein.
- heterocycles also include morpholinyl, pyrrohdinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
- Heterocyclealkyl means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle moiety, such as -CH 2 morpholinyl, and the like.
- substituted means any of the above groups ⁇ i.e., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocycle, carbocyclealkyl, heterocycle and heterocyclealkyl) wherein at least one hydrogen atom is replaced with a substituent.
- Halogen means fluoro, chloro, bromo and iodo.
- Haloalkyl means an alkyl having at least one hydrogen atom replaced with halogen, such as trifluoromethyl and the like.
- Alkoxy means an alkyl moiety attached through an oxygen bridge (i.e., -O-alkyl) such as methoxy, ethoxy, and the like.
- Thioalkyl means an alkyl moiety attached through a sulfur bridge (i.e., -S-(alkyl)) such as methylthio, ethylthio, and the like.
- Alkylsulfonyl means an alkyl moiety attached through a sulfonyl bridge
- -S0 2 -(alkyl) such as methylsulfonyl, ethylsulfonyl, and the like.
- Alkylamino and dialkylamino mean one or two alkyl moiety attached through a nitrogen bridge ⁇ i.e., -N-(alkyl)) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like.
- Hydroalkyl means an alkyl substituted with at least one hydroxyl group.
- “Mono- or di(cycloalkyl)methyl” represents a methyl group substituted with one or two cycloalkyl groups, such as cyclopropylmethyl, dicyclopropylmethyl, and the like.
- Alkyloxyalkyl represents an alkyl substituted with a -O-(alkyl) group.
- Alkylthioalkyl represents a alkyl substituted with a -S-(alkyl) group.
- “Mono- or di(alkyl)amino represents an amino substituted with one alkyl or with two alkyls, respectively.
- “Mono- or di(alkyl)aminoalkyl” represents an alkyl substituted with a mono- or di(alkyl)amino.
- Alkylamino and dialkylamino mean one or two alkyl moiety attached through a nitrogen bridge ⁇ i.e., -N-(alky ⁇ )) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like.
- A is a direct bond
- the compounds of this invention have the following structure (II):
- Ri, R 2 , R 3a , R 3b , t , R 5 , R 6 , R and n are as defined above.
- A is -N(R 8 )-, and the compounds of this invention have the following structure (III):
- Ri , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 and n are as defined above.
- n 3 and the compounds of this invention have the following structure (V):
- any one of the R 3a moieties, such as those depicted in structure (V), taken together with Ri form a heterocycle or substituted heterocycle.
- the compounds of this invention have the following structure (VI):
- the compounds of the present invention may generally be utilized as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids.
- Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids.
- Base addition salts included those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like).
- the term "pharmaceutically acceptable salt" of structure (I) is intended to encompass any and all acceptable salt forms.
- prodrugs are also included within the context of this invention.
- Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient.
- Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
- Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups.
- prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I).
- esters may be employed, such as methyl esters, ethyl esters, and the like.
- the compounds of structure (I) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Compounds of structure (I) may also possess axial chirality which may result in atropisomers. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
- the compounds of this invention may be evaluated for their ability to bind to a MC receptor by techniques known in this field.
- a compound may be evaluated for MC receptor binding by monitoring the displacement of an iodonated peptide ligand, typically [ 125 I]-NDP- ⁇ -MSH, from cells expressing individual melanocortin receptor subtypes.
- an iodonated peptide ligand typically [ 125 I]-NDP- ⁇ -MSH
- cells expressing the desired melanocortin receptor are seeded in 96-well microtiter Primaria-coated plates at a density of 50,000 cells per well and allowed to adhere overnight with incubation at 37°C in 5% CO 2 .
- test compounds are diluted serially in binding buffer (D-MEM, 1 mg/ml BSA) containing [ 125 I]- NDP- ⁇ -MSH (10 5 cpm/ml). Cold NDP- ⁇ -MSH is included as a control.
- Cells are incubated with 50 ⁇ l of each test compound concentration for 1 hour at room temperature. Cells are gently washed twice with 250 ⁇ l of cold binding buffer and then lysed by addition of 50 ⁇ l of 0.5 M NaOH for 20 minutes at room temperature. Protein concentration is determined by Bradford assay and lysates are counted by liquid scintillation spectrometry. Each concentration of test compound is assessed in triplicate.
- ICs 0 values are determined by data analysis using appropriate software, such as GraphPad Prizm, and data are plotted as counts of radiolabeled NDP-MSH bound (normalized to protein concentration) versus the log concentration of test compound.
- MC receptors based on their coupling to G s proteins.
- the MC receptors couple to Gs and activate adenylyl cyclase resulting in an increase in cAMP production.
- Melanocortin receptor activity can be measured in HEK293 cells expressing individual melanocortin receptors by direct measurement of cAMP levels or by a reporter gene whose activation is dependent on intracellular cAMP levels.
- HEK293 cells expressing the desired MC receptor are seeded into 96-well microtiter Primaria-coated plates at a density of 50,000 cells per well and allowed to adhere overnight with incubation at 37°C in 5% CO 2 .
- Test compounds are diluted in assay buffer composed of D-MEM medium and 0.1 mM isobutylmethylxanthine and assessed for agonist and/or antagonist activity over a range of concentrations along with a control agonist ⁇ -MSH.
- medium is removed from each well and replaced with test compounds or ⁇ -MSH for 30 minutes at 37°C.
- Cells are harvested by addition of an equal volume of 100% cold ethanol and scraped from the well surface.
- the compounds of this invention function as ligands to one or more MC receptors, and are thereby useful in the treatment of a variety of conditions or diseases associated therewith. In this manner, the ligands function by altering or regulating the activity of an MC receptor, thereby providing a treatment for a condition or disease associated with that receptor.
- the compounds of this invention have utility over a broad range of therapeutic applications, and may be used to treat disorders or illnesses, including (but not limited to) eating disorders, cachexia, obesity, diabetes, metabolic disorders, inflammation, pain, skin disorders, skin and hair coloration, male and female sexual disfunction, erectile disfunction, dry eye, acne and/or Gushing' s disease.
- disorders or illnesses including (but not limited to) eating disorders, cachexia, obesity, diabetes, metabolic disorders, inflammation, pain, skin disorders, skin and hair coloration, male and female sexual disfunction, erectile disfunction, dry eye, acne and/or Gushing' s disease.
- the compounds of the present invention may also be used in combination therapy with agents that modify sexual arousal, penile erections, or libido such as sildenafil, yohimbine, apomorphine or other agents.
- agents that modify sexual arousal, penile erections, or libido such as sildenafil, yohimbine, apomorphine or other agents.
- Combination therapy with agents that modify food intake, appetite or metabolism are also included within the scope of this invention.
- agents include, but are not limited to, other MC receptor ligands, ligands of the leptin, NPY, melanin concentrating hormone, serotonin or B 3 adrenergic receptors.
- pharmaceutical compositions containing one or more compounds of this invention are disclosed.
- the compounds of the present invention may be formulated as pharmaceutical compositions.
- compositions of the present invention comprise a compound of structure (I) and a pharmaceutically acceptable carrier and/or diluent.
- the compound is present in the composition in an amount which is effective to treat a particular disorder of interest, and preferably with acceptable toxicity to the patient.
- the pharmaceutical composition may include a compound of this invention in an amount ranging from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
- compositions formulated as liquid solutions include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives.
- the compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a compound of this invention, dispersing and surface active agents, binders, and lubricants.
- One skilled in this art may further formulate the compound in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.
- the present invention provides a method for treating a condition related to an MC receptor.
- Such methods include administration of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition.
- "treat” includes prophylactic administration.
- Such methods include systemic administration of compound of this invention, preferably in the form of a pharmaceutical composition as discussed above.
- systemic administration includes oral and parenteral methods of administration.
- suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives.
- the compounds of the present invention can be prepared in aqueous injection solutions which may contain buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions. The following examples are provided for purposes of illustration, not limitation.
- HP 1100 series equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (electrospray); - HPLC column: YMC ODS AQ, S-5, 5 ⁇ , 2.0 x50 mm cartridge;
- HPLC gradients 1.5 mL/minute, from 10 % acetonitrile in water to 90 % acetonitrile in water in 2.5 minutes, maintaining 90 % for 1 minute.
- the diketone 3 was diluted with ethanol (0.5 mL), treated with the appropriate diamine (0.51 mmol) and toluenesulfonic acid monohydrate (13 mg, 0.068 mmol), and heated at 80 °C in a sealed vial for 20 h. A portion of this mixture was concentrated, diluted with dichloromethane (1 mL), washed with aqueous sodium bicarbonate, and concentrated. The residue was purified by preparative HPLC to afford amine 4. The remainder of the reaction mixture was treated with (lH)-pyrazole-l- carboxamidine hydrochloride (80 mg, 0.55 mmol) and triethylamine (0.5 mL) and heated at 80 °C for 25 min. Another portion of the carboxamidine (80 mg) was added and heating was continued for 25 min. Workup and purification as described above for 4 afforded the guanidine 5.
- the substituted acetophenone 12 (0.17 mol), paraformaldehyde (23 g, 0.77 mol), and N-methylanilinium trifluoroacetate (TAMA, 51 g, 0.23 mol) were combined in dioxane (210 mL) and the mixture was heated at 90 °C for 20 h. Additional paraformaldehyde (17 g, 0.55 mol) and TAMA (26 g, 0.12 mol) were added and heating was continued for 6 h. The mixture was cooled to room temperature, concentrated under vacuum, taken up in ethyl acetate (200 mL), washed with water and aqueous sodium chloride, and dried (MgSO 4 ). The solution was then concentrated and the residue purified by chromatography to afford the enone 13.
- TAMA N-methylanilinium trifluoroacetate
- the aldehyde 28 (.071 mmol) was dissolved in 500 uL of acetonitrile, and the respective amines (0.142 mmol) were added to the solution. The mixtures were stirred for 10 minutes and sodium triacetoxyborohydride (0.142 mmol, 2.0 eq) was added. The reaction mixtures were stirred overnight at ambient temperature in capped vials. The mixtures were then diluted in 1 mL dichloromethane and were washed with 1 mL 10% aqueous sodium bicarbonate. The organic layer was concentrated under a stream of nitrogen, and the residual compound was then diluted in methanol, filtered, and purified via HPLC/MS to afford the desired aminoalkylpyrroles 29.
- Pyrrole 23 was prepared according to the procedure provided in example 18.
- Pyrrole 25 was prepared from 23 according to the same procedure as in the above conversion of 15 to 24.
- the selected N-Boc protected amino acid (0.217 mmol, 1.0 eq) was dissolved in dichloromethane (500 uL). Diisopropylethylamine (0.435 mmol, 2.0 eq) and HBTU (0.228 mmol, 1.05 eq) were added, and the mixture stirred for 30 min. The amine 30 (0.217 mmol, 1.0 eq) was dissolved in the minimum amount of dichloromethane and was added to the mixture. The solution stirred at ambient temperature overnight in a capped vial.
- the resulting secondary amine 35 (2.7 mmol, 1.5 eq) was dissolved in 10 mL methylene chloride.
- Di-tert-butyl dicarbonate (1.8 mmol, 1.0 eq) was dissolved in a minimum amount of methylene chloride and was added to the reaction mixture. The reaction stirred under nitrogen at ambient temperature for 3 hours. The mixture was concentrated in vacuo to afford 36.
- the aldehyde 37 (0.05 mmol, 1.0 eq) was dissolved in 500 uL acetonitrile, and the respective amine (O.lOmmol, 2.0eq) was added to the solution. The mixture stirred for 10 minutes and sodium triacetoxyborohydride (0.10 mmol, 2.0 eq) was added. The reaction mixture stirred 15 hours at ambient temperature in a capped vial. The mixture was then diluted in 1 mL methylene chloride and washed with 1 mL 10% sodium bicarbonate. The organic layer was concentrated under a stream of nitrogen to afford the desired oil.
- the compound was dissolved in 1 mL methylene chloride and 1 mL trifluoroacetic acid and stirred for 30 minutes, then concentrated under a stream of nitrogen. The compound was then diluted in methanol, filtered, and purified via HPLC/MS to produce diamine 38.
- the diamine 38 (0.198 mmol, 1.0 eq) was dissolved in 1 mL ethanol and was cooled to 0 °C.
- Cyanogen bromide (0.219 mmol, 2.0 eq) was dissolved in the minimum amount of ethanol and added slowly to the reaction solution under nitrogen. The reaction mixture was warmed over one half hour to 85 °C and then stirred for 2 hours.
- the resulting secondary amine 40 (0.333 mmol, 1.0 eq) was dissolved in 500 uL DMF.
- Dusopropylethylamine (0.667 mmol, 2.0 eq) was added to the solution.
- 1H- pyrazole-1-carboxamidine-HCl (0.667 mmol, 2.0 eq) was added to the mixture, and the reaction stirred 15 hours in a capped vial at 50 °C.
- the mixture was diluted with 3 mL methylene chloride and washed with 10% sodium bicarbonate.
- the organic layer was concentrated in vacuo and the resulting oil was diluted with acetonitrile, filtered and purified via HPLC/MS to yield the substituted guanidine 41.
- the piperidine 42 (1.31 mmol, 1.0 eq) was dissolved in 6 mL methylene chloride. To this solution, triethylamine (2.63 mmol, 2.0 eq) and dimethylaminopyridine (1.31 mmol, 1.0 eq) were added. Cyanogen bromide (1.98mmol, 1.5eq) was dissolved in a minimum amount of methylene chloride and added to the above mixture at 0 °C. The reaction was allowed to warm to room temperature and then was stirred for 15 hours under nitrogen atmosphere. The compound was concentrated in vacuo and purified via silica gel chromatography (1:1 hexanes: ethyl acetate) to afford the cyanamide 43 .
- Cyanamide 43 (0.108 mmol, 1.0 eq) was dissolved in 500 uL dry toluene.
- the appropriate amine (0.108 mmol, 3.0 eq) and p-toluenesulfonic acid (0.108 mmol, 1.0 eq) were added to the solution and the reaction was stirred at 85 °C in a capped vial for three days.
- the reaction mixture was concentrated under a stream of nitrogen, dissolved in acetonitrile, filtered and purified via HPLC/MS to yield substituted guanidine 44.
- Cyanamide 63 (0.128 mmole) was dissolved in toluene (500 uL) and 2.5 mmoles of the appropriate amine was added. The reaction was stirred at 50 °C for 72 hours. The reaction mixture was then concentrated in vacuo and purified by preparative
- Amine 46 (0.120 mmol, 1.0 eq) was dissolved in 1 mL DMF to which sodium hydride (0.598 mmol, 5.0 eq) was added. The reaction stirred for 5 min. and the appropriate N-(n-bromoalkyl)-phthalimide (0.180 mmol, 1.5 eq) was added. The reaction stirred overnight in a capped vial at ambient temperature. Another portion of both sodium hydride (5.0 eq) and bromoalkyl phthalimide (1.5 eq) was added and the reaction stirred for an additional 48 hours. The reaction was then diluted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under nitrogen.
- the alkylated product (0.08 mmol) was dissolved in 1 mL ethanol, and 6 drops hydrazine was added. The mixture stirred at 80 °C for 15 hours. The reaction was then diluted with methylene chloride, washed with 10% sodium bicarbonate solution, brine, and then was dried over anhydrous sodium sulfate.
- the methyl picolinimidate (0.132 mmol, 1.2 eq) was dissolved in 250 uL methanol, to which the amine 42 (0.103 mmol, 1.0 eq) was then added. The reaction was stirred overnight in a capped vial at ambient temperature. Another 1.2 eq of methyl picolinimidate was added and the reaction was stirred for 2 hours at 50 °C. The mixture was diluted with methylene chloride, washed with 10% sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated under nitrogen. The resulting oil was diluted in methanol, filtered and purified via HPLC/MS to yield amidine 48.
- Weinreb amides 53 were formed by dissolving the appropriate carboxylic acid in CH 2 C1 2 (-25 mL/g) and treating with three equivalents of DIEA followed by the addition of HBTU (1.0 eq). After 10 minutes N,O-dimethylhydroxylamine hydrochloride (1 eq) was added and the reaction stirred overnight at room temperature. The reaction mixture was diluted with CH 2 C1 2 and washed with saturated NaHCO 3 solution. The bicarbonate layers were extracted with CH 2 C1 2 ; all organic layers were collected, dried over anhydrous Na 2 SO and concentrated in vacuo to provide 53.
- Weinreb amides 53 were dissolved in dry THF (40 mL/g) and cooled to -78 °C.
- (l,3-Dioxan-2-ylethyl)magnesium bromide 1.3 eq of a 0.5 M solution in THF
- the reaction stirred at -78 °C for two hours, and was then quenched by the addition of water, followed by extraction with ethyl acetate.
- the organic layer was dried over anhydrous Na SO 4 and concentrated in vacuo to provide ketones 54.
- Ketones 54 were suspended in 80 % acetic acid/ H 2 O ( ⁇ 3 mL/g) and were heated in a sealed tube with stirring at 100 °C for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with H 2 O and saturated NaHC0 3 , then the organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo to provide keto- aldehydes 55.
- the crude keto-aldehydes 55 were dissolved in EtOH (30 mL/g ) in a sealed tube with the appropriate amine (1.3 eq) and p-toluene sulfonic acid (0.2 eq). The reaction was heated for 15 hours at 80 °C. Evaporation of solvent, extractive work-up, and purification by LC-MS provided the desired 2-aryl substituted pyrroles 56.
- the benzyl protected pyrrole 63 was dissolved in dry THF (10 mL/g) and was cooled to -78 °C. n-Butyllithium (1.3 eq) was added dropwise and the reaction mixture was stirred at -78 °C for 60 minutes. Quenching with water and extractive work- up followed by preparative HPLC-MS chromatography provided the desired N-benzyl, 2- aryl-5 benzyl pyrrole 64.
- Aminopyrrole 65 (0.082 mmol), the appropriate ketone (0.080 mmol), and toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) were dissolved in toluene and heated at reflux for 16 h.
- the material was concentrated under a stream of nitrogen, taken up in dichloromethane (1 mL), and washed with aqueous sodium bicarbonate.
- the organic layer was concentrated and the residue was taken up in acetonitrile, treated with TFA (0.020 mL, 0.026 mmol) and sodium borohydride (25 mg, 0.67 mmol), and stirred for 3 h.
- Compound 70 Aldehyde 70 was prepared from 14 using the same procedure as in the conversion of 14 to 17.
- Pyrrole 74 was prepared from the appropriate substituted hydrazine using the same procedure as in the conversion of 14 to 15.
- 3-Phenoxyphenyl bromide 78 (16.2 g, 64.8 mmol) was added to a clean flame-dried roundbottom flask along with 65 mL of dry tetrahydrofuran.
- magnesium 1.7 g, 71.3 mmol
- 25 mL of dry tetrahydrofuran were added.
- the phenoxyphenyl bromide-THF solution (prepared above) was added drop wise at room temperature.
- the reaction was heated to reflux and continued stirring under N 2 atmosphere for 4 hours.
- the reaction was monitored by quenching a small aliquot of the grignard and analyzed by GC-MS. After the reaction was completed, the grignard reagent 79 was stored under N atmosphere at room temperature for later use.
- D-Pyroglutamic acid ethyl ester (12 g, 76.4 mmol) was dissolved in 150 mL of dichloromethane along with triethylamine (12.64 mL) and 4-(dimethylamino)pyridine (9.3 g, 76.4 mmol).
- di-t-butyl dicarbonate (33.3 g, 152.7 mmol) was added in several portions and the reaction was allowed to stir at room temperature under N 2 atmosphere for 10 hours.
- 2-Bromothiazole (90.1 uL, 1 mmol) was added to a clean flame-dried reaction vial along with 1 mL of dry tetrahydrofuran.
- the reaction mixture was allowed to cool to -78°C and n-butyllithium (1.6M in hexanes, 812.5 uL, 1.3 mmol) was added.
- the reaction was allowed to stir under N 2 atmosphere for 10 minutes then warmed to 0°C.
- a solution of compound 85 (260 mg, 0.5 mmol) in 1 mL of tetrahydrofuran was added dropwise at 0°C. After the addition, the reaction was stirred at 0°C for 15 minutes, warmed to room temperature, and stirred for an additional 30 minutes.
- the reaction was then quenched with a small amount of trifluoroacetic acid and evaporated to dryness.
- the crude oil was dissolved in 2 mL of dichloromethane followed by 2 mL of trifluoroacetic acid. The reaction was allowed to stir at room temperature for 15 minutes then solvent and excess trifluoroacetic acid were removed by evaporation under vacuum.
- the crude pyrrole piperidine was dissolved in 4 mL of dichloromethane, washed with 3 x 5 mL of saturated NaHCO 3 solution, 5 mL of saturated NaCl solution, and dried over anhydrous Na 2 SO . The organic layer was filtered and solvent removed in vacuo. The residue was divided into two equal portions.
- the first portion was dissolved in 1 mL of methanol, filtered, and purified using preparative HPLC to yield compound 86.
- the second portion was dissolved in 1.2 mL of 1:1 ethanol/triethylamine along with lH-pyrazole-1-carboxamidine hydrochloride (64 mg, 0.44 mmol) and stirred at 80°C for 30 minutes. After 30 minutes, a second portion of lH-pyrazole-1-carboxamidine hydrochloride (64 mg, 0.44 mmol) was added and stirring was continued at 80°C for an additional 30 minutes. The solvent was then evaporated under a stream of nitrogen and the residue was dissolved in 4 mL of dichloromethane.
- compound 88 was prepared according to the procedures provided above.
- Compound 88 (0.12 g, 0.27 mmol) was dissolved in 0.55 mL of dichloromethane and diispropylethylamine (94 uL, 0.54 mmol).
- the reaction mixture was cooled to 0°C and cyanogen bromide (28.6 mg, 0.27 mmol) was added in one portion.
- the reaction was allowed to stir at 0°C for 1 hour then room temperature for 1 hour.
- Compound 89 a brown oil, was isolated in quantitative yield (0.13g).
- EXAMPLE 29 The representative compounds listed in the following Table were made according the above procedures.
- the column titled “Ex” indicates the synthesis route by the corresponding Example number.
- “Ex. 2” means that the compounds were made according to the procedure of Example 2 above.
Abstract
Compounds which function as melanocortin receptor ligands and having utility in the treatment of melanocortin receptor-based disorders. The compounds having the following structure (I): including stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein A, n, R1, R2, R3a, R3b, R4, R5, R6 and R7 are as defined herein. Pharmaceutical compositions containing a compound of structure (I), as well as methods relating to the use thereof, are also disclosed.
Description
PYRROLE DERIVATIVES AS LIGA DS OF MELANOCORTIN RECEPTORS
BACKGROUND OF THE INVENTION
Field of the Invention This invention is generally directed to ligands of a melanocortin receptor, specifically pyrrole-based ligands, and to compositions and methods for using such ligands to alter activity of a melanocortin receptor.
Description of the Related Art
Melanocortin (MC) receptors are members of the family of G-protein coupled receptors. To date, five distinct MC receptors {i.e., MC1-R, MC2-R, MC3-R,
MC4-R and MC5-R) have been identified in a variety of tissues and these receptors have been shown to mediate a number of physiological processes. Ligands, including peptides and small molecules, have been shown to act as agonists or antagonists at these receptors.
The role of specific MC receptors in physiological processes has been the object of intense study since their discovery and cloning. These receptors are expressed in a variety of tissues including melanocytes, adrenal cortex, brain, gut, placenta, skeletal muscle, lung, spleen, thymus, bone marrow, pituitary, gonads and adipose tissue. A putative role of MC receptors has been shown in melanocytes, stimulatory actions on learning, attention and memory, motor effects, modification of sexual behavior, facilitation of nerve regeneration, anti-inflammatory and antipyretic effects, and the regulation of food intake and body weight.
The pro-opiomelanocortin (POMC) gene product is processed to produce a number of biologically active peptides that are expressed in the pituitary, and two locations in the brain: the arcuate nucleus of the hypothalamus and the solitary tract nucleus of the brain stem. These peptides elicit a range of biological activities. Two POMC peptides,
α-melanocyte stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH), control melanocyte and adrenocortical function, respectively, in the periphery.
Cloning studies have defined a family of five melanocortin (MC) receptors that respond to POMC peptides (reviewed in Rec. Prog. Hor. Res. 51, 287-318, 1996). Each receptor in this family is pharmacologically distinct in its particular response to the POMC peptides α-MSH, γ-MSH and ACTH and to two peptide antagonists. Among the five receptors, MC4-R has the highest affinity for α-MSH. MC4-R differs from the other MC receptors in that it binds both natural melanocortin antagonists, agouti (Nature 371, 799-802, 1994) and αgøwtz-related protein (AgRP) {Biochem. Biophys. Res. Commun. 237, 629-631, 1997). In contrast, MCl-R only binds agouti, MC2-R does not bind AgRP, MC3-R only binds AgRP, and MC5-R has only low affinity binding for AgRP {Mol. Endocrinology 13, 148-155, 1999).
The expression of specific MC receptors is restricted anatomically. MCl-R is expressed primarily in melanocytes, while MC2-R is expressed in adrenocortical cells. MC3-R is expressed in brain, placenta and gut, and MC4-R is expressed primarily in the brain where its mRNA can be detected in nuclei that bind α-MSH. MC4-R is notably absent from adrenal cortex, melanocyte and placental tissues. Both MC3-R and MC4-R are expressed in arcuate and paraventricular neurons. MC5-R is expressed in brain, adipose tissues, muscle and exocrine glands. α-Melanocyte stimulating hormone (α-MSH) is a tridecapeptide whose principal action {i.e., the activation of a set of G-protein coupled melanocortin receptors), results in a range of physiological responses including pigmentation, sebum production and feeding behavior. Cyclized peptide derivatives of α-MSH are potent modulators of these receptors. When administered by intracerebroventricular (i.c.v) injection into fasted animals, peptides exhibiting MCR-4 antagonist activity increase food intake and body weight. Moreover, overexpression of a naturally occurring peptide antagonist, agouti- related peptide (AgRP) has a similar effect on food intake and body weight. The development of small molecule antagonists of the MC4-R would selectively enhance the feeding response. MC4-R antagonists have a unique clinical potential because such
compounds would stimulate appetite as well as decrease metabolic rate. Additionally, chronic MC4-R blockade causes an increase in lean body mass as well as fat mass, and the increase in lean body mass is independent of the increase in fat mass. Orally active forms of a small molecule MC4-R antagonist would provide a novel therapeutic strategy for indications in which cachexia is a symptom.
The MC receptors are also key mediators of steroid production in response to stress (MC2-R), regulation of weight homeostasis (MC4-R), and regulation of hair and skin pigmentation (MCl-R). They may have additional applications in controlling both insulin regulation (MC4-R) and regulation of exocrine gland function (MC5-R) {Cell 91, 789-798, 1997); the latter having potential applications in the treatment of disorders such as acne, dry eye syndrome and blepharitis. Melanocortin peptides have also been reported to have anti-inflammatory activity, although the receptor(s) involved in mediating these effects have not yet been determined. Endocrine disorders such as Gushing 's disease and congenital adrenal hyperplasia, which are characterized by elevated levels of ACTH, could be effectively treated with ACTH receptor (MC2-R) antagonists. Some evidence suggests that depression, which is characterized by elevated levels of glucocorticoids, may also be responsive to these same compounds. Similarly, elevated glucocorticoids can be an etiological factor in obesity. Synthetic melanocortin receptor agonists have been shown to initiate erections in men (J. Urol. 160, 389-393, 1998). An appropriate MC receptor agonist could be an effective treatment for certain sexual disorders.
MCl-R provides an ideal target for developing drugs that alter skin pigmentation. MCl-R expression is localized to melanocytes where it regulates eumelanin pigment synthesis, hi fact, two small clinical trials indicate that broad-spectrum melanocortin agonists induce pigmentation with limited side effects. The desired compound would have a short half-life and be topically applied. Applications include skin cancer prevention, UV-free tanning, inhibition of tanning and treatment of pigmentation disorders, such as tyrosinase-positive albinism.
Due to their important biological role, a number of agonists and antagonists of the MC receptors have been suggested. For example, U.S. Patent No. 6,054,556 is
directed to a family of cyclic heptapeptides which act as antagonists for MCI, MC3, MC4 and MC5 receptors; U.S. Patent No. 6,127,381 is directed to isoquinoline compounds which act upon MC receptors for controlling cytokine-regulated physiologic processes and pathologies; and published PCT Application No. WO 00/74679 is directed to substituted piperidine compounds which act as selective agonists of MC4-R.
Accordingly, while significant advances have been made in this field, there is still a need in the art for ligands to the MC receptors and, more specifically, to agonists and/or antagonists to such receptors, particularly small molecules. There is also a need for pharmaceutical compositions containing the same, as well as methods relating to the use thereof to treat conditions associated with the MC receptors. The present invention fulfills these needs, and provides other related advantages.
BRIEF SUMMARY OF THE INVENTION
In brief, this invention is directed to compounds which function as melanocortin (MC) receptor ligands. In this context, the term "ligand" means a molecule that binds or forms a complex with one or more of the MC receptors. This invention is also directed to compositions containing one or more MC receptor ligands in combination with one or more pharmaceutically acceptable carriers, as well as to methods for treating conditions or disorders associated with MC receptors.
In one embodiment, this invention is directed to MC receptor ligands that may be characterized as "substituted pyrroles" and having the following structure (I):
including stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein A, n, Rls R2, R3a, R3b, R4, R5, Re and R are as defined herein. The MC receptor ligands of this invention have utility over a broad range of therapeutic applications, and may be used to treat disorders or illnesses, including (but not limited to) eating disorders, cachexia, obesity, inflammation, pain, skin disorders, skin and hair coloration, sexual disfunction, dry eye, acne and/or Cushing's disease. A representative method of treating such a disorder or illness includes administering an effective amount of a ligand of this invention, preferably in the form of a pharmaceutical composition, to an animal (also referred to herein as a "patient", including a human) in need thereof. The ligand may be an antagonist or agonist or may stimulate a specific melanocortin receptor while functionally blocking a different melanocortin receptor. Accordingly, in another embodiment, pharmaceutical compositions are disclosed containing one or more ligands of this invention in combination with a pharmaceutically acceptable carrier.
These and other aspects of this invention will be apparent upon reference to the following detailed description and attached figures. To that end, certain patent and other documents are cited herein to more specifically set forth various aspects of this invention. Each of these documents are hereby incorporated by reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, in one embodiment the present invention is generally directed to compounds having the following structure (I):
(I)
including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein:
A is a direct bond or -N(R8)-; n is 3, 4, 5 or 6;
Ri and R2 are the same or different and independently hydrogen, alkyl, substituted alkyl, carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -(alkyl)-NR9R10, -(alkyl)-NHC(-NRπ)NR9R10, -C(Rπ)(=NR12) or -C(Z)Y; or Ri and R2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring or a substituted heterocyclic ring;
Y is -NR9R10, -C(R11)(R12)NR9R10, -C(Rπ)(R12)-NR9-C(=O)R13, -(alkyl)- NR9R10, -NR11-(alkyi)-NR9R1o, alkyl, substituted alkyl, carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
Z is =O or =NRπ;
R3a and R3b are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl or -COOR]4; or any one of R3a and the carbon to which it is attached taken together with any one of R3D and the carbon atom to which it is attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring; or any one of R3a and the carbon to which it is attached taken together with Ri and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring;
R4 is carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
R5, R6 and R7 are the same or different and independently hydrogen, halogen, alkyl, substituted alkyl, carbocycle, -C(=O)-carbocycle, substituted carbocycle,
-C(=O)-(substituted carbocycle), carbocyclealkyl, substituted carbocyclealkyl, heterocycle,
-C(=O)-heterocycle, substituted heterocycle, -C(=O)-(substituted heterocycle), heterocyclealkyl or substituted heterocyclealkyl;
R8 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle or substituted heterocycle; or R8 and R3a on the carbon atom adjacent the nitrogen atom bearing R8, taken together form a direct bond;
R9 and R10 are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
Rπ, R12 and R13 are the same or different and, at each occurrence, independently hydrogen, halogen, cyano, alkyl, substituted alkyl, carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; and
R14 is hydrogen, alkyl or substituted alkyl.
As used herein, the above terms have the following meaning:
"Alkyl" means a straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10 carbon atoms, while the term
"lower alkyl" has the same meaning as alkyl but contains from 1 to 6 carbon atoms.
Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclic alkyls are also referred to herein as a "homocycles" or "homocyclic rings." Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl" or
"alkynyl", respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-
1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1 -butynyl, 2-butynyl,
1-pentynyl, 2-pentynyl, 3 -methyl- 1 -butynyl, and the like.
"Carbocycle" (also referred to herein as "carbocyclic ring") means a 3- to 7- membered monocyclic, or a 7- to 10-membered bicyclic, homocyclic ring which is saturated, unsaturated or aromatic. Saturated and unsaturated carbocyclic rings are as defined above for saturated and unsaturated cyclic alkyls. Aromatic carbocyclic rings are as defined below for aryl.
"Carbocyclealkyl" means an alkyl having at least one alkyl hydrogen atom replaced with a carbocycle moiety, such as -CH2cyclohexane, benzyl, and the like.
"Aryl" means an aromatic carbocyclic moiety such as phenyl or naphthyl.
"Arylalkyl" means an alkyl having at least one alkyl hydrogen atom replaced with an aryl moiety, such as benzyl, -(CH2)2ρhenyl, -(CH2)3phenyl, -CH(phenyl)2, and the like.
"Heteroaryl" means an aromatic heterocycle ring of 5 to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, triazolyl, tetrazolyl, oxadiazolyl and quinazolinyl.
"Heteroarylalkyl" means an alkyl having at least one alkyl hydrogen atom replaced with a heteroaryl moiety, such as -CH2pyridinyl, -CH2pyrimidinyl, and the like.
"Heterocycle" (also referred to herein as a "heterocyclic ring") means a 4- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is saturated, unsaturated, or aromatic, and which contains at least 1 carbon atom and from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls as defined herein. Thus, in addition to the heteroaryls listed above, heterocycles also include morpholinyl, pyrrohdinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
"Heterocyclealkyl" means an alkyl having at least one alkyl hydrogen atom replaced with a heterocycle moiety, such as -CH2morpholinyl, and the like.
The term "substituted" as used herein means any of the above groups {i.e., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocycle, carbocyclealkyl, heterocycle and heterocyclealkyl) wherein at least one hydrogen atom is replaced with a substituent. In the case of a keto substituent ("= ") two hydrogen atoms are replaced. When substituted,
"substituents" within the context of this invention include halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy, alkylthio, haloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb -NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, -S(=O)2Ra, -OS(=O)2Ra, -S(=O)2ORa, -CH2S(=O)2Ra, -CH2S(=O)2N(Ra)2, =NS(=O)2Ra, - S(=O)2N(Ra)2 wherein Ra and Rb are the same or different and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, carbocycle, substituted carbocycle, carbocyclealkyl or substituted carbocyclealkyl.
"Halogen" means fluoro, chloro, bromo and iodo.
"Haloalkyl" means an alkyl having at least one hydrogen atom replaced with halogen, such as trifluoromethyl and the like.
"Alkoxy" means an alkyl moiety attached through an oxygen bridge (i.e., -O-alkyl) such as methoxy, ethoxy, and the like.
"Thioalkyl" means an alkyl moiety attached through a sulfur bridge (i.e., -S-(alkyl)) such as methylthio, ethylthio, and the like. "Alkylsulfonyl" means an alkyl moiety attached through a sulfonyl bridge
{i.e., -S02-(alkyl)) such as methylsulfonyl, ethylsulfonyl, and the like.
"Alkylamino" and "dialkylamino" mean one or two alkyl moiety attached through a nitrogen bridge {i.e., -N-(alkyl)) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like. "Hydroxyalkyl" means an alkyl substituted with at least one hydroxyl group.
"Mono- or di(cycloalkyl)methyl" represents a methyl group substituted with one or two cycloalkyl groups, such as cyclopropylmethyl, dicyclopropylmethyl, and the like.
"Alkylcarbonylalkyl" represents an alkyl substituted with a -C(=O)(alkyl) group.
"Alkylcarbonyloxyalkyl" represents an alkyl substituted with a -C(=O)O(alkyl) group or a -OC(=O)(alkyl) group. "Alkyloxyalkyl" represents an alkyl substituted with a -O-(alkyl) group.
"Alkylthioalkyl" represents a alkyl substituted with a -S-(alkyl) group.
"Mono- or di(alkyl)amino represents an amino substituted with one alkyl or with two alkyls, respectively.
"Mono- or di(alkyl)aminoalkyl" represents an alkyl substituted with a mono- or di(alkyl)amino.
"Alkylamino" and "dialkylamino" mean one or two alkyl moiety attached through a nitrogen bridge {i.e., -N-(alkyι)) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like.
In one embodiment of this invention, A is a direct bond, and the compounds of this invention have the following structure (II):
(II)
wherein Ri, R2, R3a, R3b, t, R5, R6, R and n are as defined above.
In another embodiment, A is -N(R8)-, and the compounds of this invention have the following structure (III):
(III)
wherein Ri, R2, R3a, R3b, R4, R5, R6, R7 and n are as defined above. In a more specific embodiment of structure (III) R8 and R3a (i.e., the R3a on the carbon adjacent to the nitrogen atom bearing R8) taken together form a direct bond, and the compounds of this invention have the following structure (IV):
(IV)
wherein Ri , R2, R3a, R3b, R4, R5, R6, R7 and n are as defined above.
In another embodiment, n is 3 and the compounds of this invention have the following structure (V):
In a further embodiment, any one of the R3a moieties, such as those depicted in structure (V), taken together with Ri form a heterocycle or substituted heterocycle. For example, when the R3a group adjacent the A moiety of structure (V) taken together with Rj forms a heterocycle or substituted heterocycle, the compounds of this invention have the following structure (VI):
(VI) wherein W represents one or more optional heterocycle substituents as defined above.
The compounds of the present invention may generally be utilized as the free acid or free base. Alternatively, the compounds of this invention may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present invention may be prepared by methods well known in the art, and may be formed
from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Base addition salts included those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like). Thus, the term "pharmaceutically acceptable salt" of structure (I) is intended to encompass any and all acceptable salt forms.
In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently bonded carriers that release a compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this invention wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of structure (I). Further, in the case of a carboxylic acid, esters may be employed, such as methyl esters, ethyl esters, and the like.
With regard to stereoisomers, the compounds of structure (I) may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Compounds of structure (I) may also possess axial chirality which may result in atropisomers. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present
invention. In addition, some of the compounds of structure (I) may also form solvates with water or other organic solvents. Such solvates are similarly included within the scope of this invention.
The compounds of this invention may be evaluated for their ability to bind to a MC receptor by techniques known in this field. For example, a compound may be evaluated for MC receptor binding by monitoring the displacement of an iodonated peptide ligand, typically [125I]-NDP-α-MSH, from cells expressing individual melanocortin receptor subtypes. To this end, cells expressing the desired melanocortin receptor are seeded in 96-well microtiter Primaria-coated plates at a density of 50,000 cells per well and allowed to adhere overnight with incubation at 37°C in 5% CO2. Stock solutions of test compounds are diluted serially in binding buffer (D-MEM, 1 mg/ml BSA) containing [125I]- NDP-α-MSH (105 cpm/ml). Cold NDP-α-MSH is included as a control. Cells are incubated with 50 μl of each test compound concentration for 1 hour at room temperature. Cells are gently washed twice with 250 μl of cold binding buffer and then lysed by addition of 50 μl of 0.5 M NaOH for 20 minutes at room temperature. Protein concentration is determined by Bradford assay and lysates are counted by liquid scintillation spectrometry. Each concentration of test compound is assessed in triplicate. ICs0 values are determined by data analysis using appropriate software, such as GraphPad Prizm, and data are plotted as counts of radiolabeled NDP-MSH bound (normalized to protein concentration) versus the log concentration of test compound.
In addition, functional assays of receptor activation have been defined for the MC receptors based on their coupling to Gs proteins. In response to POMC peptides, the MC receptors couple to Gs and activate adenylyl cyclase resulting in an increase in cAMP production. Melanocortin receptor activity can be measured in HEK293 cells expressing individual melanocortin receptors by direct measurement of cAMP levels or by a reporter gene whose activation is dependent on intracellular cAMP levels. For example, HEK293 cells expressing the desired MC receptor are seeded into 96-well microtiter Primaria-coated plates at a density of 50,000 cells per well and allowed to adhere overnight with incubation at 37°C in 5% CO2. Test compounds are diluted in assay buffer composed
of D-MEM medium and 0.1 mM isobutylmethylxanthine and assessed for agonist and/or antagonist activity over a range of concentrations along with a control agonist α-MSH. At the time of assay, medium is removed from each well and replaced with test compounds or α-MSH for 30 minutes at 37°C. Cells are harvested by addition of an equal volume of 100% cold ethanol and scraped from the well surface. Cell lysates are centrifuged at 8000 x g and the supernatant is recovered and dried under vacuum. The supernatants are evaluated for cAMP using an enzyme-linked immunoassay such as Biotrak, Amersham. EC50 values are determined by data analysis using appropriate software such as GraphPad Prizm, and data are plotted as cAMP produced versus log concentration of compound. As mentioned above, the compounds of this invention function as ligands to one or more MC receptors, and are thereby useful in the treatment of a variety of conditions or diseases associated therewith. In this manner, the ligands function by altering or regulating the activity of an MC receptor, thereby providing a treatment for a condition or disease associated with that receptor. In this regard, the compounds of this invention have utility over a broad range of therapeutic applications, and may be used to treat disorders or illnesses, including (but not limited to) eating disorders, cachexia, obesity, diabetes, metabolic disorders, inflammation, pain, skin disorders, skin and hair coloration, male and female sexual disfunction, erectile disfunction, dry eye, acne and/or Gushing' s disease.
The compounds of the present invention may also be used in combination therapy with agents that modify sexual arousal, penile erections, or libido such as sildenafil, yohimbine, apomorphine or other agents. Combination therapy with agents that modify food intake, appetite or metabolism are also included within the scope of this invention. Such agents include, but are not limited to, other MC receptor ligands, ligands of the leptin, NPY, melanin concentrating hormone, serotonin or B3 adrenergic receptors. In another embodiment, pharmaceutical compositions containing one or more compounds of this invention are disclosed. For the purposes of administration, the compounds of the present invention may be formulated as pharmaceutical compositions. Pharmaceutical compositions of the present invention comprise a compound of structure (I) and a pharmaceutically acceptable carrier and/or diluent. The compound is present in the
composition in an amount which is effective to treat a particular disorder of interest, and preferably with acceptable toxicity to the patient. Typically, the pharmaceutical composition may include a compound of this invention in an amount ranging from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to 60 mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
Pharmaceutically acceptable carrier and/or diluents are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a compound of this invention, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the compound in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.
In another embodiment, the present invention provides a method for treating a condition related to an MC receptor. Such methods include administration of a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the condition. In this context, "treat" includes prophylactic administration. Such methods include systemic administration of compound of this invention, preferably in the form of a pharmaceutical composition as discussed above. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parental administration, the compounds of the present invention can be prepared in aqueous injection solutions which may contain buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
The following examples are provided for purposes of illustration, not limitation.
EXAMPLES
Analytical HPLC-MS (LC-MS)
HP 1100 series: equipped with an auto-sampler, an UV detector (220 nM and 254 nM), a MS detector (electrospray); - HPLC column: YMC ODS AQ, S-5, 5μ, 2.0 x50 mm cartridge;
HPLC gradients: 1.5 mL/minute, from 10 % acetonitrile in water to 90 % acetonitrile in water in 2.5 minutes, maintaining 90 % for 1 minute.
Prep. HPLC-MS
Gilson HPLC-MS equipped with Gilson 215 auto-sampler/fraction collector, an UV detector and a ThermoFinnigan AQA Single QUAD Mass detector (electrospray); HPLC column: BHK ODS-O/B, 5 μ, 30x75 mm HPLC gradients: 35 mL/minute, 10 % acetonitrile in water to 100 % acetonitrile in 7 minutes, maintaining 100 % acetonitrile for 3 minutes
EXAMPLE 1
Compound 2 - 4-Arylbut-3-en-2-ones
The appropriate aldehyde (39 mmol) was dissolved in acetone-water (5:2, 42 mL) and treated with 15% aqueous sodium hydroxide (0.30 mL). The mixture was stirred
for 4 h, concentrated under vacuum, taken up in dichloromethane (30 mL), washed with aqueous sodium chloride, dried (MgSO4), and concentrated. The residue was purified by column chromatography to afford the enone 2.
Compound 3 Enone 2 (0.33 mmol), the appropriate aldehyde (0.33 mmol), 3-benzyl-5-(2- hydroxyethyl)-4-methylthiazolium chloride (27 mg, 0.10 mmol), dioxane (0.5 mL), and triethylamine (0.5 mL) were combined and heated at 60°C for 16 h. The mixture was concentrated under a stream of nitrogen, diluted with dichloromethane (1 mL), washed with aqueous sodium bicarbonate, and again concentrated to afford the crude 1,4-diketone 3.
Compounds 4 and 5 - Aminoalkylpyrroles and Guanidines
The diketone 3 was diluted with ethanol (0.5 mL), treated with the appropriate diamine (0.51 mmol) and toluenesulfonic acid monohydrate (13 mg, 0.068 mmol), and heated at 80 °C in a sealed vial for 20 h. A portion of this mixture was concentrated, diluted with dichloromethane (1 mL), washed with aqueous sodium bicarbonate, and concentrated. The residue was purified by preparative HPLC to afford amine 4. The remainder of the reaction mixture was treated with (lH)-pyrazole-l- carboxamidine hydrochloride (80 mg, 0.55 mmol) and triethylamine (0.5 mL) and heated at 80 °C for 25 min. Another portion of the carboxamidine (80 mg) was added and heating was continued for 25 min. Workup and purification as described above for 4 afforded the guanidine 5.
EXAMPLE 2
Acetophenone 6 (5.0 mmol) and the appropriate aldehyde (5.0 mmol) were dissolved in ethanol-water (10:1, 10 mL), treated with 15% aqueous sodium hydroxide, and stirred at rt for 16 h. Reactions producing a precipitate were filtered and the resulting solid was washed with cold ethanol to afford the product 7. The remaining reactions were concentrated, diluted with dichloromethane (20 mL), washed with aqueous sodium chloride, dried (MgSO4), and concentrated to afford the crude chalcone 7, which was used in the next step without further purification.
Compounds 9 and 10 - Aminoalkylpyrroles and Guanidines Pyrroles 9 and 10 were prepared from the appropriate enone 7 using the same procedure as in the conversion of 2 to 4 and 5.
EXAMPLE 3
12
Compound 13 - Aryl Vinyl Ketones (Method A)
Vinylmagnesium bromide in THF (1.0 M, 110 mL, 0.11 mol) was added to a stirred solution of aldehyde 11 (0.10 mol) in THF (400 mL) at -78 °C. After 20 min, the reaction was carefully quenched with water (100 mL) and allowed to warm to room temperature. The solution was diluted with 10% aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were dried (MgSO4), concentrated under vacuum, and the residue was purified by column chromatography to afford the allylic alcohol. This material (33 mmol) was dissolved in acetone (140 mL), cooled to 0 °C, and
treated drop wise with 1.0 M Jones reagent. After 20 min, methanol (5 mL) was added and the mixture was stirred for 5 min. It was then decanted into a separatory funnel and the solid residue was washed with three 100 mL portions of ether. All layers were combined, washed with water, dried (MgSO4) and concentrated under vacuum to afford the enone 13.
Compound 13 - Aryl Vinyl Ketones (Method B
The substituted acetophenone 12 (0.17 mol), paraformaldehyde (23 g, 0.77 mol), and N-methylanilinium trifluoroacetate (TAMA, 51 g, 0.23 mol) were combined in dioxane (210 mL) and the mixture was heated at 90 °C for 20 h. Additional paraformaldehyde (17 g, 0.55 mol) and TAMA (26 g, 0.12 mol) were added and heating was continued for 6 h. The mixture was cooled to room temperature, concentrated under vacuum, taken up in ethyl acetate (200 mL), washed with water and aqueous sodium chloride, and dried (MgSO4). The solution was then concentrated and the residue purified by chromatography to afford the enone 13.
Compounds 15 and 16 - Aminoalkylpyrroles and Guanidines Pyrroles 15 and 16 were prepared from the appropriate enone 13 using the same procedure as in the conversion of 2 to 4 and 5.
EXAMPLE 3A
Compound 79 - N-Aryl and Heteroaryl pyrroles
Pyrrole 79 was prepared from the appropriate diketone 14 using the same procedure as in the conversion of 14 to 15 .
EXAMPLE 4
Compound 17 - Oxyalkylpyrroles The diketone (115 mmol) and an aminoalkanol (173 mmol) were combined with toluenesulfonic acid monohydrate (4.37 g, 23.0 mmol) and ethanol 400 mL and heated at 80 °C for 2 days. The mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (400 mL), washed with aqueous sodium bicarbonate, dried (MgSO ) and concentrated under vacuum. The residue was purified by column chromatography to afford the hydroxyalkylpyrrole. This alcohol (6.8 mmol), N-methylmorpholine N-oxide (1.19 g, 10.2 mmol), 4A molecular sieves (2.8 g), and dichloromethane (75 mL) were combined and stirred for 20 min. Tetrapropylammonium perruthenate (118 mg) was added and stirring was continued for 90 min. The mixture was filtered (Celite), concentrated under vacuum, and the residue was purified by column chromatography to afford the aldehyde 17.
Compound 18 - Aminoalkylpyrrole
Aldehyde 17 (0.048 mmol) was dissolved in acetonitrile (0.5 mL), treated with the appropriate amine (ca. 0.18 mmol) and sodium triacetoxyborohydride (21 mg, 0.099 mmol) and stirred at room temperature for 20 hours. The mixture was concentrated under a stream of nitrogen and the residue taken up in dichloromethane (1 mL), washed with aqueous sodium bicarbonate and again concentrated. The residue was purified by preparative HPLC to afford pyrrole 18.
EXAMPLE 4A
Compound 27 - Aminoalkylpyrroles Aldehyde 26 (0.071 mmol) was dissolved in acetonitrile (500 uL), and the respective amine (0.142mmol) was added to the solution. The mixture was stirred for 10 minutes and sodium triacetoxyborohydride (0.142 mmol) was added. The reaction mixture stirred overnight at ambient temperature in a capped vial. The mixture was then diluted in 1 mL methylene chloride and washed with 1 mL 10% aqueous sodium bicarbonate. The organic layer was concentrated under a stream of nitrogen to afford the desired oil. The compound was then diluted in methanol, filtered, and purified via HPLC/MS.
EXAMPLE 4B
Compound 29 - Alkylaminopyrroles
The aldehyde 28 (.071 mmol) was dissolved in 500 uL of acetonitrile, and the respective amines (0.142 mmol) were added to the solution. The mixtures were stirred for 10 minutes and sodium triacetoxyborohydride (0.142 mmol, 2.0 eq) was added. The
reaction mixtures were stirred overnight at ambient temperature in capped vials. The mixtures were then diluted in 1 mL dichloromethane and were washed with 1 mL 10% aqueous sodium bicarbonate. The organic layer was concentrated under a stream of nitrogen, and the residual compound was then diluted in methanol, filtered, and purified via HPLC/MS to afford the desired aminoalkylpyrroles 29.
EXAMPLE 5
Compound 19 - Methylisothiourea Hydroxyalkylpyrrole prepared from compound 14 as described above (22 mmol), triphenylphosphine (7.39 g, 28.2 mmol), and diisopropylazodicarboxylate (5.5 mL, 28 mmol) were stirred in THF (200 mL) for 5 min. l,3-Bis(t-butoxycarbonyl)-2-methyl-2- fhiopseudour'ea (6.93 g, 23.9 mmol) was added and the mixture was stirred for 20 h. A second equal portion of all three reagents was added and stirring was continued for 4 h. The mixture was diluted with ethyl acetate (100 mL), washed with aqueous sodium bicarbonate, dried (MgSO4), and concentrated under vacuum. The residue was purified by column chromatography to afford 19.
Compound 20 - Substituted Guanidines
Isothiourea 19 (0.048 mmol) was dissolved in dichloromethane (0.5 mL), treated with the appropriate amine (ca. 0.18 mmol) and stirred at room temperature for 20 h. TFA (0.5 mL) was added and stirring was continued for 4 hours. The mixture was concentrated under a stream of nitrogen and the residue was purified by preparative HPLC to afford guanidine 20.
EXAMPLE 5A
Compound 34 - N-Alkylguanidines Compound 33 (0.055 mmol) was dissolved in 500 uL methylene chloride to which the amine (0.109 mmol ) was added. The reactions were stirred overnight at ambient temperature in capped vials. If starting material was still present by TLC (50:50 hexanes:ethylacetate), triethylamine (0.273 mmol, 5.0 eq) was added and the reactions were allowed to stir an additional 15 hours. 300 uL trifluoroacetic acid was added; the reactions stirred for 4 hours and were then concentrated in v cuo. The compounds were then dissolved in acetonitrile, filtered and purified via HPLC/MS to provide N-alkylguanidines 34.
EXAMPLE 6
Pyrrole 15 (0.14 mmol), carboxylic acid 21 (0.14 mmol) and HOBT (19 mg, 0.14 mmol) were dissolved in 7:3 dichloromethane-NMP (1 mL) and stirred for 5 min. EDC (27 mg, 0.14 mmol) was added and stirring was continued for 20 h. The mixture was diluted with dichloromethane (1 mL) and washed with aqueous sodium bicarbonate. At this stage compounds containing a BOG protecting group (22, Rio = t-Boc) were treated with TFA (1 mL) and stirred for 1 h. The mixture was concentrated under a stream of nitrogen, taken up in methanol, filtered, and purified by preparative HPLC to afford pyrrole 22. EXAMPLE 7
IS 24
Compound 24 - Aminoalkylpyrroles
The appropriate amine (ca. 0.2 mmol) was dissolved in acetic acid (0.5 mL) and treated with 37% aqueous formaldehyde. Pyrrole 15 (0.075 mmol) was added and stirring was continued for 4 h. The mixture was concentrated under a stream of nitrogen, taken up in dichloromethane (1 mL) and washed with aqueous sodium bicarbonate. The
organic extract was concentrated and the residue was purified by preparative HPLC to afford pyrrole 24.
Compound 25 - Aminoalkylpyrroles
Pyrrole 23 was prepared according to the procedure provided in example 18. Pyrrole 25 was prepared from 23 according to the same procedure as in the above conversion of 15 to 24.
EXAMPLE 8
Compound 31 - N-Acylated aminoalkylpyrroles
The selected N-Boc protected amino acid (0.217 mmol, 1.0 eq) was dissolved in dichloromethane (500 uL). Diisopropylethylamine (0.435 mmol, 2.0 eq) and HBTU (0.228 mmol, 1.05 eq) were added, and the mixture stirred for 30 min. The amine 30 (0.217 mmol, 1.0 eq) was dissolved in the minimum amount of dichloromethane and was added to the mixture. The solution stirred at ambient temperature overnight in a capped vial. The mixture was diluted with 1 mL dichloromethane, washed with 10% sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated under a stream of nitrogen. The resulting oil was then diluted in 1 mL methylene chloride and 1 mL trifluoroacetic acid and was stirred for 30 min. The mixture was concentrated under nitrogen to afford the deprotected amine as TFA salt. The residue was then diluted in methanol, filtered, and purified via HPLC/MS to provide the title compounds 31.
EXAMPLE 9
Compound 32 - Amidinalkylpyrroles The imidate ester hydrochloride salt (0.130 mmol, 1.2 eq) was dissolved in
250 uL methanol to which dusopropylethylamine (0.109 mmol, 1.0 eq) was added. The amine 30 (0.109 mmol, 1.0 eq) was dissolved in 250 uL methanol and was added to the reaction mixture. The reactions stirred overnight at ambient temperature in capped vials. The methanol was evaporated under a stream of nitrogen. The resulting residue was dissolved in 1 mL methylene chloride and washed with 1 mL 10% sodium bicarbonate. The organic layer was concentrated under nitrogen. The compounds were then dissolved in methanol, filtered and purified via HPLC/MS to provide the desired amidines 32.
EXAMPLE 10
Aldehyde 26 (3.27 mmol, 1.0 eq) was dissolved in 15 mL acetonitrile. Ethanolamine (6.53 mmol, 2.0 eq) was added and the mixture stirred for 10 min. Sodium triacetoxyborohydride (6.53 mmol, 2.0 eq) was added and the reaction stirred at ambient temperature under nitrogen overnight. The solution was diluted with methylene chloride, washed with 10%) sodium bicarbonate, washed with brine and dried over sodium sulfate. The organic layer was concentrated in vacuo to give compound 35.
Compound 36
The resulting secondary amine 35 (2.7 mmol, 1.5 eq) was dissolved in 10 mL methylene chloride. Di-tert-butyl dicarbonate (1.8 mmol, 1.0 eq) was dissolved in a minimum amount of methylene chloride and was added to the reaction mixture. The reaction stirred under nitrogen at ambient temperature for 3 hours. The mixture was concentrated in vacuo to afford 36.
Compound 37 The N-t-Boc-protected amino alcohol 36 (2.8 mmol, 1.0 eq) was dissolved in 30 mL methylene chloride, to which 4 A molecular sieves were added. To this mixture, N-methylmorpholine N-oxide (4.2 mmol, 1.5 eq) was added. The reaction stirred for 30 minutes under nitrogen, then TPAP (0.141 mmol, 0.05 eq) was added, and the reaction stirred for 2 hours under nitrogen at ambient temperature. The mixture was filtered through celite and concentrated in vacuo. The residue was purified via silica gel chromatography (30:70 hexanes:ethyl acetate) to afford the aldehyde 37.
Compound 38
The aldehyde 37 (0.05 mmol, 1.0 eq) was dissolved in 500 uL acetonitrile, and the respective amine (O.lOmmol, 2.0eq) was added to the solution. The mixture stirred for 10 minutes and sodium triacetoxyborohydride (0.10 mmol, 2.0 eq) was added. The reaction mixture stirred 15 hours at ambient temperature in a capped vial. The mixture was
then diluted in 1 mL methylene chloride and washed with 1 mL 10% sodium bicarbonate. The organic layer was concentrated under a stream of nitrogen to afford the desired oil. The compound was dissolved in 1 mL methylene chloride and 1 mL trifluoroacetic acid and stirred for 30 minutes, then concentrated under a stream of nitrogen. The compound was then diluted in methanol, filtered, and purified via HPLC/MS to produce diamine 38.
Compound 39
The diamine 38 (0.198 mmol, 1.0 eq) was dissolved in 1 mL ethanol and was cooled to 0 °C. Cyanogen bromide (0.219 mmol, 2.0 eq) was dissolved in the minimum amount of ethanol and added slowly to the reaction solution under nitrogen. The reaction mixture was warmed over one half hour to 85 °C and then stirred for 2 hours.
The solution was then filtered and purified via HPLC/MS to produce cyclic guanidine 39.
EXAMPLE 11
Compound 40
Aldehyde 28 (0.065 mmol, 1.0 eq) was dissolved in 500 uL acetonitrile, and the appropriate amine (0.131 mmol, 2.0 eq) was added to the solution. The mixture stirred for 10 minutes, then sodium triacetoxyborohydride (0.131 mmol, 2.0 eq) was added The reaction mixture stirred overnight at ambient temperature in a capped vial. The mixture was then diluted in 1 mL methylene chloride and was washed with 1 mL 10% sodium bicarbonate solution. The organic layer was concentrated under a stream of nitrogen to afford the desired oil 40.
Compound 41
The resulting secondary amine 40 (0.333 mmol, 1.0 eq) was dissolved in 500 uL DMF. Dusopropylethylamine (0.667 mmol, 2.0 eq) was added to the solution. 1H- pyrazole-1-carboxamidine-HCl (0.667 mmol, 2.0 eq) was added to the mixture, and the reaction stirred 15 hours in a capped vial at 50 °C. The mixture was diluted with 3 mL methylene chloride and washed with 10% sodium bicarbonate. The organic layer was concentrated in vacuo and the resulting oil was diluted with acetonitrile, filtered and purified via HPLC/MS to yield the substituted guanidine 41.
EXAMPLE 12
Compound 43
The piperidine 42 (1.31 mmol, 1.0 eq) was dissolved in 6 mL methylene chloride. To this solution, triethylamine (2.63 mmol, 2.0 eq) and dimethylaminopyridine (1.31 mmol, 1.0 eq) were added. Cyanogen bromide (1.98mmol, 1.5eq) was dissolved in a minimum amount of methylene chloride and added to the above mixture at 0 °C. The reaction was allowed to warm to room temperature and then was stirred for 15 hours under nitrogen atmosphere. The compound was concentrated in vacuo and purified via silica gel chromatography (1:1 hexanes: ethyl acetate) to afford the cyanamide 43 .
Compound 44
Cyanamide 43 (0.108 mmol, 1.0 eq) was dissolved in 500 uL dry toluene. The appropriate amine (0.323 mmol, 3.0 eq) and p-toluenesulfonic acid (0.108 mmol, 1.0 eq) were added to the solution and the reaction was stirred at 85 °C in a capped vial for
three days. The reaction mixture was concentrated under a stream of nitrogen, dissolved in acetonitrile, filtered and purified via HPLC/MS to yield substituted guanidine 44.
EXAMPLE 12A
Compound 63
Compound 62 (0.51 mmole) was dissolved in dichloromethane (2 mL). TEA (181 uL) and dimethylaminopyridine (62 mg) were added and the solution was cooled to 0 °C. Cyanogen Bromide (81 mg) was added. The reaction was allowed to warm to room temperature and was stirred for 15 hours. The reaction mixture was concentrated in vacuo to yield cyanamide 63 which was used in subsequent steps without further purification.
Compounds 64, 65
Cyanamide 63 (0.128 mmole) was dissolved in toluene (500 uL) and 2.5 mmoles of the appropriate amine was added. The reaction was stirred at 50 °C for 72 hours. The reaction mixture was then concentrated in vacuo and purified by preparative
HPLC to afford compound 64 as the major product, the minor product 65 was also isolated.
EXAMPLE 13
Compound 45 Aldehyde 26 (0.108 mmol, 1.0 eq) and the 3,4-dimethoxy phenethyl amine
(0.218 mmol, 2.0 eq) were dissolved in 250 uL methylene chloride. Trifluoroacetic acid (0.327 mmol, 3.0 eq) was added to the mixture and the reaction stirred in a capped vial at ambient temperature for four hours. An excess of trifluoroacetic acid (~9.0 eq) was then added and the reaction stirred for 72 hours. The reaction mixture was diluted with methylene chloride, washed with 10% sodium bicarbonate, washed with brine, dried over sodium sulfate and concentrated under nitrogen. The residue was then diluted in acetonitrile, filtered and purified via HPLC/MS to yield tetrahydroisoquinoline 45.
EXAMPLE 14
Compound 46
The amine 46 was formed by reaction with 4-methylsulfonyl- phenylhydrazine according to Example 3.
Compound 47
Amine 46 (0.120 mmol, 1.0 eq) was dissolved in 1 mL DMF to which sodium hydride (0.598 mmol, 5.0 eq) was added. The reaction stirred for 5 min. and the appropriate N-(n-bromoalkyl)-phthalimide (0.180 mmol, 1.5 eq) was added. The reaction stirred overnight in a capped vial at ambient temperature. Another portion of both sodium hydride (5.0 eq) and bromoalkyl phthalimide (1.5 eq) was added and the reaction stirred for an additional 48 hours. The reaction was then diluted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under nitrogen.
The alkylated product (0.08 mmol) was dissolved in 1 mL ethanol, and 6 drops hydrazine was added. The mixture stirred at 80 °C for 15 hours. The reaction was then diluted with methylene chloride, washed with 10% sodium bicarbonate solution, brine, and then was dried over anhydrous sodium sulfate.
The resulting free amine (0.061 mmol, 1.0 eq) was dissolved in 250 uL DMF. Dusopropylethylamine (0.123 mmol, 2.0 eq) and lH-pyrazole-1-carboxamidine- HCl (0.123 mmol, 2.0 eq) were added and the reaction stirred in a capped vial at ambient temperature for 15 hours. The reaction was diluted in methylene chloride, washed with 10%) sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated under nitrogen. The compound was dissolved in acetonitrile, filtered and purified via HPCL/MS to yield compounds 47. EXAMPLE 15
The methyl picolinimidate (0.132 mmol, 1.2 eq) was dissolved in 250 uL methanol, to which the amine 42 (0.103 mmol, 1.0 eq) was then added. The reaction was stirred overnight in a capped vial at ambient temperature. Another 1.2 eq of methyl picolinimidate was added and the reaction was stirred for 2 hours at 50 °C. The mixture was diluted with methylene chloride, washed with 10% sodium bicarbonate, washed with brine, dried over sodium sulfate, and concentrated under nitrogen. The resulting oil was diluted in methanol, filtered and purified via HPLC/MS to yield amidine 48.
EXAMPLE 16
Compound 49
Dimethyl cyanodithioiminocarbonate (0.205 mmol, 1.0 eq) was dissolved in 500 uL dry acetonitrile to which the piperidine 42 (0.205 mmol, 1.0 eq) was added. The reaction stirred overnight in capped vial at 85 °C, and was then concentrated under nitrogen to afford 49.
EXAMPLE 16A
Compound 50
Compound 49 (0.086 mmol, 1.0 eq) is dissolved in 250 uL dry acetonitrile to which N,N-dimethylethylenediamine is added. The reaction stirred overnight in a capped vial at ambient temperature and was then filtered and purified via HPLC/MS to produce 50.
EXAMPLE 16 B
Compound 51
Compound 49 (0.205 mmol, 1.0 eq) was treated with 7M ammonia in methanol (5.14 mmol, 25 eq). The reaction stirred overnight in a capped vial at 60 °C. The mixture was then concentrated under nitrogen, dissolved in acetonitrile, filtered and purified via HPLC/MS to produce compound 51.
EXAMPLE 17
Compound 52 Compound 42 (0.10 mmole) was dissolved in acetonitrile (3 mL). The appropriate aldehyde (0.2 mmoles) was added and the mixture was stirred at room temperature for 1 hour. Triacetoxyborohydride (1 mmole) was added and the reaction mixture was shaken overnight at room temperature. The reaction mixture was partitioned with ethyl acetate and saturated sodium bicarbonate solution. The sodium bicarbonate layer was washed a second time with ethyl acetate and the organic layers were combined, concentrated in vacuo and purified by preparative HPLC to afford N-substituted amines 52.
EXAMPLE 18
Compound 53
Weinreb amides 53 were formed by dissolving the appropriate carboxylic acid in CH2C12 (-25 mL/g) and treating with three equivalents of DIEA followed by the addition of HBTU (1.0 eq). After 10 minutes N,O-dimethylhydroxylamine hydrochloride (1 eq) was added and the reaction stirred overnight at room temperature. The reaction mixture was diluted with CH2C12 and washed with saturated NaHCO3 solution. The
bicarbonate layers were extracted with CH2C12; all organic layers were collected, dried over anhydrous Na2SO and concentrated in vacuo to provide 53.
Compound 54
Weinreb amides 53 were dissolved in dry THF (40 mL/g) and cooled to -78 °C. (l,3-Dioxan-2-ylethyl)magnesium bromide (1.3 eq of a 0.5 M solution in THF) was added dropwise. The reaction stirred at -78 °C for two hours, and was then quenched by the addition of water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous Na SO4 and concentrated in vacuo to provide ketones 54.
Compound 55 Ketones 54 were suspended in 80 % acetic acid/ H2O (~3 mL/g) and were heated in a sealed tube with stirring at 100 °C for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with H2O and saturated NaHC03, then the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to provide keto- aldehydes 55.
Compound 56
The crude keto-aldehydes 55 were dissolved in EtOH (30 mL/g ) in a sealed tube with the appropriate amine (1.3 eq) and p-toluene sulfonic acid (0.2 eq). The reaction was heated for 15 hours at 80 °C. Evaporation of solvent, extractive work-up, and purification by LC-MS provided the desired 2-aryl substituted pyrroles 56.
EXAMPLE 19
Compound 57 Aminopyrroles 56 were dissolved in CH2C12 and treated with DIEA (2.0 eq) and di-tert-butyl dicarbonate (2.0 eq). The reaction stirred overnight. The solvent was removed in vacuo. Extractive work-up provided the Boc-protected aminopyrroles 57 which were used without further purification.
Compound 58 The pyrroles 57 were dissolved in dry THF (10 mL/g ) and cooled to -78 °C under an inert atmosphere. BuLi (1.6 M in hexanes, 1.3 eq) was added dropwise. The reaction stirred at -78 °C for 20 minutes, 0 °C for 2 hours, was warmed to room temperature for 20 minutes and then was subsequently cooled back down to °0. The metalated pyrrole was treated with 2 equivalents of an aldehyde, acid chloride, or benzyl bromide. After stirring for 30 to 60 minutes at 0 °C, the reaction was quenched with water and the product partitioned into ethyl acetate. Drying over anhydrous sodium sulfate and removal of the solvent in vacuo produced the desired ketone, alcohol or benzylated pyrroles 58.
EXAMPLE 20
A: X= 0 A: X= 0 A: X= 0
B: X= CHOH B: X= CHOH B: X= CHOH
C: X= CH C: X= CH, C: X= CH,
Compound 60 Pyrroles 58 were treated with a 5-50% solution of TFA in dichloromethane
15 (mL/g), and the removal of the t-Boc-group monitored by TLC. The solvent was removed in vacuo to give compound 60.
Compound 61
Compound 60 was treated with approximately two equivalents of DIEA to provide a pH of at least 9 when tested with wet pH paper. The residue was dissolved in ethanol (10 mL/g); lH-pyrazole-1-carboxamidine hydrochloride (2 eq) was added and the reaction mixture was stirred at room temperature for 15 hours. Removal of the solvent and preparative HPLC chromatography provided the desired pyrrole 61.
EXAMPLE 21
62 63 64
Compound 63
Pyrrole 62 (3 mmol) was dissolved in CH2C12 and DIEA (6 mmol) was added, followed by benzyl bromide (3.9 mmol). The reaction mixture was stirred for 15 hours at room temperature. Extractive work up provided the N-benzylamino pyrrole 63.
Compound 64
The benzyl protected pyrrole 63 was dissolved in dry THF (10 mL/g) and was cooled to -78 °C. n-Butyllithium (1.3 eq) was added dropwise and the reaction mixture was stirred at -78 °C for 60 minutes. Quenching with water and extractive work- up followed by preparative HPLC-MS chromatography provided the desired N-benzyl, 2- aryl-5 benzyl pyrrole 64.
EXAMPLE 22
Compound 65 - N- Aminopyrroles The diketone (1.42 mmol), N-aminophthalimide (281 mg, 1.73 mmol), and toluenesulfonic acid monohydrate (65 mg, 0.34 mmol) were heated in ethanol (5 mL) for 18 h. Hydrazine (1 mL) was added and heating was continued for 20 h. The mixture was cooled to room temperature and concentrated under vacuum. It was then taken up in dichloromethane (5 mL), washed with aqueous sodium bicarbonate, dried (MgSO4), and concentrated to afford 65.
Compounds 66, 67 - Imines
Aminopyrrole 26 (0.082 mmol), the appropriate ketone (0.080 mmol), and toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) were dissolved in toluene and heated at reflux for 16 h. The material was concentrated under a stream of nitrogen, taken up in dichloromethane (1 mL), and washed with aqueous sodium bicarbonate. The organic layer was treated with TFA (1 mL) and stirred for 1 h. It was then concentrated, and a portion of this residue was purified by preparative HPLC to afford imine 66. The remainder was guanylated as previously described to afford guanidine 67.
EXAMPLE 23
Compounds 68, 69 - N-(Alkylamino^pyrroles
Aminopyrrole 65 (0.082 mmol), the appropriate ketone (0.080 mmol), and toluenesulfonic acid monohydrate (5 mg, 0.026 mmol) were dissolved in toluene and heated at reflux for 16 h. The material was concentrated under a stream of nitrogen, taken up in dichloromethane (1 mL), and washed with aqueous sodium bicarbonate. The organic layer was concentrated and the residue was taken up in acetonitrile, treated with TFA (0.020 mL, 0.026 mmol) and sodium borohydride (25 mg, 0.67 mmol), and stirred for 3 h. The mixture was concentrated and partitioned between dichloromethane (1 mL) and aqueous sodium bicarbonate. The organic layer was treated with TFA (1 mL) and stirred for 1 h. The mixture was concentrated, and a portion of this residue was purified by preparative HPLC to afford imine 68. The remainder was guanylated as previously described to afford guanidine 69.
EXAMPLE 24
Compound 70 Aldehyde 70 was prepared from 14 using the same procedure as in the conversion of 14 to 17.
Compound 71, 72
Aldehyde 70 (0.11 mmol) and the appropriate amine (0.12 mmol) were combined in acetonitrile and treated with sodium cyanoborohydride (25 mg, 0.39 mmol). The mixture was stirred for 2 h, concentrated, and the residue was partitioned between dichloromethane (1 mL) and aqueous sodium bicarbonate. The organic layer was concentrated and the residue was stirred in a thioanisole-TFA solution (7%, 0.5 mL) for 2 h. The mixture was concentrated and a portion of this residue was purified by preparative HPLC to afford pyrrole 71. The remainder was guanylated as previously described to afford guanidine 72.
EXAMPLE 25
15 73
Compound 73 - Amidines
Pyrrole 15 (0.080 mmol), the alkyl acetimidate hydrochloride (0.19 mmol) and triethylamine (0.2 mL) were dissolved in methanol and stirred for 1 h. The mixture was concentrated under a stream of nitrogen, taken up in dichloromethane (1 mL), washed with aqueous sodium bicarbonate, and again concentrated. The residue was purified by preparative HPLC to afford the amidine 73.
EXAMPLE 26
76: R, = C(NH)NH2
Compound 74 - N-(Alkylamino pyrroles
Pyrrole 74 was prepared from the appropriate substituted hydrazine using the same procedure as in the conversion of 14 to 15.
Compounds 75, 76
Pyrrole 74 (0.067 mmol) was dissolved in DMF (0.5 mL) and was treated with sodium hydride (5 mg, 0.21 mmol). After 5 min, the appropriate alkyl bromide (0.067 mmol) was added and stirring was continued for 18 h. The mixture was cautiously treated with water (1 mL), taken up in ethyl acetate (1 mL), washed three times with aqueous sodium chloride and concentrated. The residue was taken up in ethanol (1 mL), treated with hydrazine (0.1 mL), and heated at reflux for 18 h. The mixture was concentrated under vacuum and a portion of this residue was purified by preparative HPLC to afford pyrrole 75. The remainder was guanylated as previously described to afford guanidine 76.
EXAMPLE 27
Compound 77
The appropriate carbodiimide (0.22 mmol, 1.0 eq) was dissolved in 250uL DMF or CH2C12 to which the amine 30 (0.22 mmol, 1.0 eq) was added. The reaction mixture was stirred for 15 hours at 40 °C in a capped vial. The reaction was cooled to ambient temperature, diluted with methylene chloride and washed once with water. The organic layer was concentrated under a stream of nitrogen. The resulting oil was diluted in 1 mL of methanol, filtered, and purified via HPLC/MS to provide di-substituted guanidines 77.
EXAMPLE 28
Compound 78 - 3-Phenoxyphenyl Bromide
A mixture of 3-phenoxyaniline (25 g, 135 mmol) and 47.5 mL of 48% hydrobromic acid was cooled in an ice-salt bath to 0 - 5 °C. To the reaction mixture, a solution of sodium nitrite (9.3 g, 135 mmol) in 19 mL of water was added slowly with stirring. The temperature of the reaction mixture was maintained below 10 °C at all times during the addition (Note: temperature controlled by rate of addition of nitrite solution). The resulting diazonium salt was kept at 0 °C until needed. In a separate flask, copper(I)
bromide (19.4 g, 135 mmol) and 16.5 mL of 48% hydrobromic acid were heated with constant stirring to 100 °C. To the acidic copper bromide mixture, the diazonium salt (prepared above) was added in several portions to the refluxing reaction mixture. After the addition, the reaction was allowed to stir at 100 °C for 1 hour. The reaction was then cooled to room temperature, quenched with NaOH, and extracted with 4 x 100 mL of ether. The ethereal extracts were combined, washed with 3 x 100 mL of saturated NaHCO3 solution followed by washing with 100 mL saturated NaCl solution. The organic layer was dried over anhydrous MgSO4, filtered, and solvent removed in vacuo. The resulting dark black-brown residue was purified by column chromatography on silica using 100% hexanes as the eluent (Rf = 0.8, collected first spot). The solvent was removed by evaporation and the compound 78 was isolated as a clear liquid in 50% yield (16.9g).
Compound 79 - 3-Phenoxyphenyl Magnesium Bromide
3-Phenoxyphenyl bromide 78 (16.2 g, 64.8 mmol) was added to a clean flame-dried roundbottom flask along with 65 mL of dry tetrahydrofuran. In a separate clean flame-dried roundbottom flask, magnesium (1.7 g, 71.3 mmol) and 25 mL of dry tetrahydrofuran were added. To the magnesium mixture, the phenoxyphenyl bromide-THF solution (prepared above) was added drop wise at room temperature. The reaction was heated to reflux and continued stirring under N2 atmosphere for 4 hours. The reaction was monitored by quenching a small aliquot of the grignard and analyzed by GC-MS. After the reaction was completed, the grignard reagent 79 was stored under N atmosphere at room temperature for later use.
80 8hrs.
Compound 80 - Boc-Protected 4-(bromomethyl piperidine
4-Piperidinemethanol (6 g, 52 mmol) was protected by mixing with di-t- butyl dicarbonate (15.2g, 69.6 mmol) in 105 mL of dichloromethane and stirring under N2 atmosphere at room temperature for 2 hours (reaction checked by GC-MS). The reaction mixture was then washed with 100 mL of water, 3 x 100 mL of saturated NaHCO3 solution, 100 mL of saturated NaCl solution, and dried over anhydrous Na2SO4. The organic layer was filtered and solvent was removed in vacuo. The crude residual oil was then dissolved in 132 mL of tetrahydrofuran and triethylamine (9.7 mL, 69.6 mmol). The reaction mixture was allowed to stir at 0 °C for 30 minutes then methanesulfonyl chloride (5.2 mL, 66.8 mmol) was added. After the addition, the mixture was warmed to room temperature and continued stirring for an additional hour. The mixture was then filtered through celite and solvent was removed in vacuo. The resulting mesylate was stirred at room temperature in 205 mL of acetone along with lithium bromide (17.9 g, 206 mmol) for 8 hours. The reaction mixture was then filtered through celite and solvent was removed by evaporation under vacuum. The product was recovered as a clear slightly yellow oil in 66% yield (9.5g). No further purification was needed.
Compound 81 - Boc-Protected Pyroglutamic Acid Ethyl Ester
D-Pyroglutamic acid ethyl ester (12 g, 76.4 mmol) was dissolved in 150 mL of dichloromethane along with triethylamine (12.64 mL) and 4-(dimethylamino)pyridine (9.3 g, 76.4 mmol). To the reaction flask, di-t-butyl dicarbonate (33.3 g, 152.7 mmol) was added in several portions and the reaction was allowed to stir at room temperature under N2 atmosphere for 10 hours. Solvent was then removed in vacuo and the dark red oil was
purified by column chromatography on silica using 10% methanol/dichloromethane as the eluent (Rf = 0.8, collected the first spot). Solvent was removed and the compound 81 was isolated as a clear dark red oil in quantitative yield (20 g).
Compound 82
A solution of 3-phenoxyphenyl magnesium bromide 79 (64.8 mmol, prepared above) in tetrahydrofuran was cooled to 0 °C then added dropwise to a solution of Boc-protected pyroglutamic acid ethyl ester 81 (15.2 g, 58.9 mmol) in 107 mL of dry tetrahydrofuran at -40 °C. After stirring under N2 atmosphere for 1 hour at -40 °C and 1 hour at 0 °C, the reaction was quenched with a 1:1 acetic acid/methanol solution. The reaction mixture was diluted with water and extracted with 3 x 150 mL of ether. The ethereal extracts were combined, washed with 3 x 150 mL of water, 150 mL of saturated NaCl solution, and dried over anhydrous Na2SO The organic mixture was then filtered and solvent was removed by evaporation under vacuum to give the intermediate. The intermediate was dissolved in 63.6 mL of dichloromethane, cooled to 0 °C, and trifluoroacetic acid (49 mL, 636 mmol) was added. The reaction was allowed to stir at 0 °C under N atmosphere for 2 hours. Solvent and residual trifluoroacetic acid were then removed in vacuo. The residue was redissolved in dichloromethane, washed with 3 x 150 mL of saturated NaHCO3 solution, 150 mL of saturated NaCl solution, and dried over anhydrous Na2SO4. Solvent was removed by evaporation and compound 82 was collected as a oil in 89% yield (17.82 g).
86 87
Compound 83 - Pyrrole Carboxylic Acid
Compound 82 (4.0 g, 12.9 mmol) and 2,3-dichloro-5,6-dicyano-l,4- benzoquinone (2.9 g, 12.91 mmol) were allowed to stir in 129 mL of dichloromethane at room temperature for 2 hours. The reaction was followed by GC-MS (mixture becomes darker during the progress of the reaction). After the reaction was completed, the mixture was filtered through celite and solvent was removed in vacuo. The residue was suspended in 260 mL of a 10% sodium hydroxide solution and refluxed for 12 hours. The solution was then poured into cold water and neutralized with 10% hydrochloric acid solution. The crude product was extracted with 3 x 150 mL of dichloromethane and the combined organic extracts were washed with 3.x 150 mL of saturated NaHCO3 solution followed by 150 mL of saturated NaCl solution. The organic layer was dried over anhydrous Na2SO4, filtered, and solvent was removed by evaporation. The product was obtained in 84% crude yield (3 g). The crude product was used for later reactions without further purification. H- NMR.(300 MHz) δ 9.31 (s, IH), 7.3-6.9 (m, 10H), 6.5 (s, IH)
Compound 84 - Pyrrole Amide
Compound 83 (0.33 g, 1.19 mmol) was dissolved in 5.5 mL of dichloromethane and 0.1 mL of dimethylformamide. Oxalyl chloride (10.6 mL, 121.7 mmol) was added dropwise to the reaction mixture at room temperature and the reaction was allowed to stir at room temperature for 4 hours then solvent and excess oxalyl chloride were, removed in vacuo. The resulting acid chloride was redissolved in 6 mL of dichloromethane along with triethylamine (366 uL, 2.6 mmol) and N,O- dimethylhydroxylamine hydrochloride (0.13 g, 1.31 mmol). The reaction mixture was allowed to stir at room temperature for 1 hour then solvent and triethylamine were removed by evaporation under vacuum. The resulting residue was dissolved in 5 mL of dichloromethane, washed with washed with 3 x 5 mL of saturated NaHCO3 solution, 5 mL of saturated NaCl solution, and dried over anhydrous Na2SO4. The solvent was removed and the brown residue was purified by column chromatography on silica using 10%> methanol/dichloromethane (Rf = 0.5-0.6). The product was recovered in 93% yield as a brown solid (0.36 g). 1H-NMR (300 MHz) δ 9.7 (s, IH), 7.83-6.54 (m, 10H), 6.52-6.55 (m, IH), 3.79 (s, 3H), 3.35 (s, 3H)
1 ArLi or ArM Br
Compound 85 - Pyrrole Piperidine Amide
Compound 84 (0.7 g, 2.2 mmol), Compound 80 (3 g, 10.9 mmol), and potassium carbonate (1.5g, 10.9 mmol) were mixed in 22 mL of dimethylformamide. The reaction mixture was allowed to stir under N2 atmosphere at 70 °C for 12-24 hours (reaction followed by LC-MS). Then, the mixture was cooled to room temperature and filtered (dichloromethane used for rinse). The filtrant was collected and solvent was evaporated under vacuum. The residue was purified by column chromatography on silica using 3% methanol/dichloromethane. Removal of the solvent in vacuo afforded the product as a brown oil in 97% yield (1. lg)
Compounds 86 and 87 — Pyrrole Piperidine and Pyrrole Guanidine
2-Bromothiazole (90.1 uL, 1 mmol) was added to a clean flame-dried reaction vial along with 1 mL of dry tetrahydrofuran. The reaction mixture was allowed to cool to -78°C and n-butyllithium (1.6M in hexanes, 812.5 uL, 1.3 mmol) was added. The reaction was allowed to stir under N2 atmosphere for 10 minutes then warmed to 0°C. A solution of compound 85 (260 mg, 0.5 mmol) in 1 mL of tetrahydrofuran was added dropwise at 0°C. After the addition, the reaction was stirred at 0°C for 15 minutes, warmed to room temperature, and stirred for an additional 30 minutes. The reaction was then quenched with a small amount of trifluoroacetic acid and evaporated to dryness. The crude oil was dissolved in 2 mL of dichloromethane followed by 2 mL of trifluoroacetic acid. The reaction was allowed to stir at room temperature for 15 minutes then solvent and excess trifluoroacetic acid were removed by evaporation under vacuum. The crude pyrrole piperidine was dissolved in 4 mL of dichloromethane, washed with 3 x 5 mL of saturated NaHCO3 solution, 5 mL of saturated NaCl solution, and dried over anhydrous Na2SO . The organic layer was filtered and solvent removed in vacuo. The residue was divided into two equal portions. The first portion was dissolved in 1 mL of methanol, filtered, and purified using preparative HPLC to yield compound 86. The second portion was dissolved in 1.2 mL of 1:1 ethanol/triethylamine along with lH-pyrazole-1-carboxamidine hydrochloride (64 mg, 0.44 mmol) and stirred at 80°C for 30 minutes. After 30 minutes, a second portion of lH-pyrazole-1-carboxamidine hydrochloride (64 mg, 0.44 mmol) was added and stirring was continued at 80°C for an additional 30 minutes. The solvent was then evaporated under a stream of nitrogen and the residue was dissolved in 4 mL of dichloromethane. The organic layer was washed with 3 x 5 mL of saturated NaΗCO3 solution, 5 mL of saturated NaCl solution, and dried over anhydrous Na2SO4. The organic layer was filtered and solvent was removed under vacuum. The residue was dissolved in 1 mL of methanol, filtered, and purified using preparative HPLC to yield compound 87.
Compounds 88 and 89 - Pyrrole Pyridine and Pyrrole Cyanamide
Using 2-bromopyridine as starting material, compound 88 was prepared according to the procedures provided above. Compound 88 (0.12 g, 0.27 mmol) was dissolved in 0.55 mL of dichloromethane and diispropylethylamine (94 uL, 0.54 mmol). The reaction mixture was cooled to 0°C and cyanogen bromide (28.6 mg, 0.27 mmol) was added in one portion. The reaction was allowed to stir at 0°C for 1 hour then room temperature for 1 hour. Solvent was then removed in vacuo and the residue was purified by column chromatography on silica using 10%) methanol/dichloromethane as the eluent (Rf = 0.8, collected first spot). Compound 89, a brown oil, was isolated in quantitative yield (0.13g).
Compound 90 - Pyrrole Guanidine Compound 89 (0.13g, .27 mmol) was mixed with p-TsOH (154 mg, 0.81 mmol) in 540 uL of toluene. To the reaction vial, 2-(diisopropylamino)ethylamine (94 uL, 0.54 mmol) was added and the reaction was heated at 100°-110°C for 12 hours. Solvent was then removed by evaporation under a stream of nitrogen. The residual oil was dissolved in 1 mL of methanol, filtered, and purified by preparative HPLC. 1H-NMR (300
MHz) δ 8.7 (d, IH), 7.91-7.86 (m, 3H), 7.47-7.31 (m, 4H), 7.17-6.99 (m, 5H), 6.26 (d, 1H), 6.16 (d, IH), 3.77 (d, 2H), 3.05-2.98 (m, 4H), 2.86-2.77 (m, 4H), 1.53-1.25 (m, 3H)
EXAMPLE 29 The representative compounds listed in the following Table were made according the above procedures. In this regard, the column titled "Ex" indicates the synthesis route by the corresponding Example number. Thus, "Ex. 2" means that the compounds were made according to the procedure of Example 2 above.
Table
(CR3aR3b)n
R, 2
(i)
It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made
without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.
Claims
1. A compound having the following structure:
(I)
or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein:
A is a direct bond or -N(R8)-; n is 3, 4, 5 or 6;
Ri and R2 are the same or different and independently hydrogen, alkyl, substituted alkyl, carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -(alkyl)- NR9R10, -(alkyl)-NHC(=NRπ)NR9R10, -C(Rn)(=NR12) or -C(Z)Y; or R\ and R2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring or a substituted heterocyclic ring;
Y is -NR9R10, -C(Rπ)(R12)NR9RI0, -C(R„)(R12)-NR9-C(=O)R13, -(alkyl)-NR9Rlθ5 -NRπ-(alkyl)-NR9R10, alkyl, substituted alkyl, carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
Z is =O or =NRπ;
R3a and R31) are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, alkylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl or -COORπ; or any one of R a and the carbon to which it is attached taken together with any one of R3b and the carbon atom to which it is attached form a homocyclic ring, substituted homocyclic ring, heterocyclic ring or substituted heterocyclic ring; or any one of R3a and the carbon to which it is attached taken together with Rj and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring;
R4. is carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
R5, R6 and R7 are the same or different and independently hydrogen, halogen, alkyl, substituted alkyl, carbocycle, -C(=O)-carbocycle, substituted carbocycle, -C(=O)- (substituted carbocycle), carbocyclealkyl, substituted carbocyclealkyl, heterocycle, -C(=O)- heterocycle, substituted heterocycle, -C(=O)-(substituted heterocycle), heterocyclealkyl or substituted heterocyclealkyl;
Rg is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle or substituted heterocycle; or R8 and the R3a:on the carbon atom adjacent the nitrogen atom bearing R8, taken together form a direct bond;
R9 and Rio are the same or different and, at each occurrence, independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl;
Rn, Rι2 and ι3 are the same or different and, at each occurrence, independently hydrogen, halogen, cyano, alkyl, substituted alkyl, carbocycle, substituted carbocycle, carbocyclealkyl, substituted carbocyclealkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl; and
R1 is hydrogen, alkyl or substituted alkyl.
2. The compound of claim 1 wherein A is a direct bond.
3. The compound of claim 1 wherein A is -N(R8)-.
4. The compound of claim 3 wherein R8 and R3a on the carbon atom adjacent the nitrogen atom bearing R8 taken together form a direct bond.
5. The compound of claim 1 wherein R is substituted heteroaryl or substituted aryl.
6. The compound of claim 1 wherein R4 is substituted heterocycle or substituted carbocycle.
7. The compound of claim 1 wherein n is 3, 4 or 5.
8. The compound of claim 2 wherein R4 is carbocycle, substituted carbocycle, heterocycle, or substituted heterocycle.
9. The compound of claim 8 wherein R5 is carbocycle, substituted carbocycle, heterocycle, substituted heterocycle, -C(=O)carbocycle, -C(=O)(substituted carbocycle), -C(=O)heterocycle, or -C(=O)(substituted heterocycle).
10. The compound of claim 9 wherein R2 is substituted alkyl, -(alkyl)-NR9R10, -(alkyl)-NHC(=NR11)NR9R10, -C(Rn)(=NR12) or -C(Z)Y.
11. The compound of claim 1 wherein R5 is carbocycle, substituted carbocycle, heterocycle, substituted heterocycle, -C(=O)carbocycle, -C(=O)(substituted carbocycle), -C(=O)heterocycle, or -C(=O)(substituted heterocycle).
12. The compound of claim 1 wherein R2 is substituted alkyl, -(alky -NRgRio, -(alkyl)-NHC(-NR11)NR9R10, -C(Rπ)(=NR12) or -C(Z)Y.
13. The compound of claim 1 wherein R3a and the carbon to which it is attached taken together with Ri and the nitrogen to which it is attached form a heterocyclic ring or substituted heterocyclic ring.
14. The compound of claim 1 wherein the compound is an agonist of a melanocortin receptor.
15. The compound of claim 1 wherein the compound is an antagonist of a melanocortin receptor.
16. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
17. A method for altering a disorder associated with the activity of a melanocortin receptor, comprising administering to a patient an effective amount of the pharmaceutical composition of claim 16.
18. The method of claim 17 wherein the disorder is an eating disorder.
19. The method of claim 17 wherein the disorder is a skin disorder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003216274A AU2003216274A1 (en) | 2002-02-11 | 2003-02-11 | Pyrrole derivatives as ligands of melanocortin receptors |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35586702P | 2002-02-11 | 2002-02-11 | |
| US60/355,867 | 2002-02-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2003068738A1 true WO2003068738A1 (en) | 2003-08-21 |
Family
ID=27734573
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2003/004455 WO2003068738A1 (en) | 2002-02-11 | 2003-02-11 | Pyrrole derivatives as ligands of melanocortin receptors |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2003216274A1 (en) |
| WO (1) | WO2003068738A1 (en) |
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