Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
  • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
  • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to melanocortin receptor agonists, and more particularly piperazine derivatives as melanocortin receptor agonists, which are useful for the treatment or prevention of diseases and disorders responsive to the activation of melanocortin receptors.
• Pro-opiomelanocortin (POMC) derived peptides are known to affect food intake.
• GPCRs G-protein coupled receptors
• M-R melanocortin receptor
• Evidence for the involvement of MC-R in obesity includes: i) the agouti (A V Y) mouse which ectopically expresses an antagonist of the MC-IR, MC-3R and MC-4R is obese, indicating that blocking the action of these three MC-Rs can lead to hyperphagia and metabolic disorders; ii) MC-4R knockout mice (Huszar et al., Cell, 88:131-141, 1997) recapitulate the phenotype of the agouti mouse and these mice are obese; iii) the cyclic heptapeptide MC-IR, MC-3R, MC-4R, and MC-5R agonist melanotanin-II (MT-II) injected intracerebroventricularly (ICV) in rodents, reduces food intake in several animal feeding models (NPY, oh/oh, agouti, fasted) while ICV injected SHU-9119 (MC-3R, MC-4R antagonist;
• MC-IR Five MC-Rs have thus far been identified, and these are expressed in different tissues.
• MC-IR was initially characterized by dominant gain of function mutations at the extension locus, affecting coat color by controlling phaeomelanin to eumelanin conversion through control of tyrosinase.
• MC-IR is mainly expressed in melanocytes.
• MC-2R is expressed in the adrenal gland and represents the ACTH receptor.
• MC-3R is expressed in the brain, gut and placenta and may be involved in the control of food intake and thermogenesis.
• MC-4R is uniquely expressed in the brain and its inactivation was shown to cause obesity.
• MC- 5R is expressed in many tissues including white fat, placenta and exocrine glands. A low level of expression is also observed in the brain. MC-5R knock out mice reveal reduced sebaceous gland lipid production (Chen et al., Cell, 91:789-798, 1997). MC-4R appears to play a role in other physiological functions as well, namely controlling grooming behavior, erection and blood pressure.
• Erectile dysfunction denotes the medical condition of inability to achieve penile erection sufficient for successful intercourse.
• the term "impotence" is often times employed to describe this prevalent condition.
• Synthetic melanocortin receptor agonists have been found to initiate erections in men with psychogenic erectile dysfunction (H. Wessells et al., "Synthetic Melanotropic Petide Initiates Erections in Men With Psychogenic Erectile Dysfunction: Double-Blind, Placebo Controlled Crossover Study," /. Urol, 160: 389-393, 1998).
• Activation of melanocortin receptors of the brain appears to cause normal stimulation of sexual arousal.
• Diabetes is a disease in which a mammal's ability to regulate glucose levels in the blood is impaired because the mammal has a reduced ability to convert glucose to glycogen for storage in muscle and liver cells. In Type I diabetes, this reduced ability to store glucose is caused by reduced insulin production.
• Type II Diabetes or “non-insulin dependent diabetes mellitus” (NEDDM) is the form of diabetes, which is due to a profound resistance to insulin stimulating or regulatory effect on glucose and lipid metabolism in the main insulin-sensitive tissues, muscle, liver and adipose tissue.
• Hyperinsulemia is associated with hypertension and elevated body weight. Since insulin is involved in promoting the cellular uptake of glucose, amino acids and triglycerides from the blood by insulin sensitive cells, insulin insensitivity can result in elevated levels of triglycerides and LDL which are risk factors in cardiovascular diseases.
• the constellation of symptoms which include hyperinsulemia combined with hypertension, elevated body weight, elevated triglycerides and elevated LDL is known as Syndrome X.
• the present invention relates to a compound of novel piperazine derivatives as melanocortin receptor agonists as shown formula I:
• L and L are independently: hydrogen or together oxo
• T is:
• R is independently: hydrogen, hydroxy, cyano, nitro, halo, Ci-Cg alkyl,
• Ri is independently: hydrogen, CONH(C ⁇ -Cg alkyl), C ⁇ Cg alkyl, (D)phenyl, (D)C3- ⁇ 7 cycloalkyl or oxo, provided that oxo is not attached to the same carbon that attached to nitrogen which forms an amide bond;
• R3 is independently: aryl or thienyl; wherein aryl and thienyl are optionally substituted with one to three substituents selected from the group consisting of: cyano, halo, C ⁇ -Cg alkyl, (D)C3- ⁇ 7 cycloalkyl, C1-C4 alkoxy, C1-C4 haloalkyl and
• R4 is independently: hydrogen, -C alkyl, C(O)R 9 , C(O)OR9, C3-C7 cycloalkyl or (CH 2 ) n O(C ⁇ -C 8 alkyl), wherein n is 2-8; each R8 is independently: hydrogen, halo, oxo
• each R9 is independently: hydrogen, C ⁇ -C 8 alkyl, C1-C4 haloalkyl, (D)C3-C7 cycloalkyl, (D)aryl, wherein aryl being phenyl or naphthyl,
• heterocyclyl excludes a heterocyclyl containing a single nitrogen
• aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of oxo, Cj-Cg alkyl,
• each RIO is independently: hydrogen, (C ⁇ -Cg)alkyl, C(O)C ⁇ -Cg alkyl, aryl or C3-C7 cycloalkyl;
• each RU is independently: hydrogen, Ci-C alkyl,
• each Ri 2 is independently: hydrogen, C!-C 8 alkyl,
• D is a bond or -(CH 2 ) n -; n is 0-8; p is 0-5; q is 0-1; and r is 1-2.
• the compounds of the present invention are useful in preventing or treating obesity or diabetes mellitus in a mammal comprising the administration of a therapeutically effective amount of the compound of formula I.
• the compounds of the present invention are also useful in preventing or treating male or female sexual dysfunction in mammal, more specifically erectile dysfunction, comprising the administration of a therapeutically effective amount of the compound of formula I.
• a pharmaceutical composition or formulation which comprises a pharmaceutical carrier and at least one compound of formula I or its pharmaceutically acceptable salts or stereoisomers thereof.
• the present invention further includes a process of making a pharmaceutical composition or formulation comprising a compound of formula I or its pharmaceutically acceptable salt or stereoisomers thereof and a pharmaceutically acceptable carrier.
• the present invention further includes a process of preparing a compound of formula I.
• the present invention relates to melanocortin receptor agonists, and more particularly piperazine derivatives as melanocortin receptor agonists.
• the compounds of present invention are useful for the treatment or prevention of diseases and disorders responsive to the activation of melanocortin receptors, such as obesity, diabetes and sexual dysfunction including erectile dysfunction and female sexual dysfunction.
• An embodiment of the present invention is a compound of formula I:
• L and lX are independently: hydrogen or together oxo; T is:
• R is independently: hydrogen, hydroxy, cyano, nitro, halo, C ⁇ -Cg alkyl, C ⁇ -Cg alkoxy,
• Ci -Cg alkyl, Ci -Cg alkoxy, C3-C7 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one to five substituents independently selected from R 8 ;
• Ri is independently: hydrogen, CONH(C ⁇ -Cg alkyl), Ci -Cg alkyl, (D)phenyl, (D)C3-C 7 cycloalkyl or oxo, provided that oxo is not attached to the same carbon that attached to nitrogen which forms an amide bond;
• R3 is independently: aryl or thienyl; wherein aryl and thienyl are optionally substituted with one to three substituents selected from the group consisting of: cyano, halo, Ci-Cg alkyl, (D)C3- ⁇ 7 cycloalkyl, Ci -C4 alkoxy, C1-C4 haloalkyl and
• R4 is independently: hydrogen, Ci -Cg alkyl, C(O)R 9 , C(O)OR 9 > C3-C7 cycloalkyl or (CH 2 ) n O(C ⁇ -Cg alkyl), wherein n is 2-8;
• each R 8 is independently: hydrogen, halo, oxo
• heterocyclyl excludes a heterocyclyl containing a single nitrogen, phenyl, (D)COR 9 ,
• aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of oxo, Ci -Cg alkyl,
• each R9 is independently: hydrogen, Ci-Cg alkyl,
• heterocyclyl excludes a heterocyclyl containing a single nitrogen
• aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl is optionally substituted with one to three substituents selected from the group consistmg of oxo, C ⁇ -Cg alkyl,
• each RlO is independently: hydrogen, (C ⁇ -Cg)alkyl, C(O)C ⁇ -Cg alkyl, aryl or C3-C7 cycloalkyl;
• each Ri 1 is independently: hydrogen, Ci-Cg alkyl, (D)aryl,
• each Rl2 1S independently: hydrogen, Ci-Cg alkyl,
• D is a bond or -(CH 2 ) n -; n is 0-8; p is 0-5; q is 0-1; and r is 1-2.
• R ⁇ is phenyl optionally para-substituted with chloro, bromo, fluoro, iodo, methoxy, benzyloxy or methyl.
• the preferred R ⁇ is phenyl para-substituted with chloro, fluoro or methoxy.
• the preferred embodiment of the present invention provides a compound of formula II,
• Yet another preferred embodiment of the present invention provides a compound of formula III,
• Yet another preferred embodiment of the present invention provides a compound of formula N,
• R is independently: hydrogen, hydroxy, cyano, nitro, halo, Ci-Cg alkyl,
• Ci-Cg alkyl, Ci-Cg alkoxy, C3-C7 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one to five substituents independently selected from R ;
• each R8 is independently: hydrogen, halo, oxo Ci-Cg alkyl, (D)C 3 -C 7 cycloalkyl, C1-C4 haloalkyl,
• each R is independently: hydrogen
• (D)aryl wherein aryl being phenyl or naphthyl heteroaryl or heterocyclyl; wherein heterocyclyl excludes a heterocyclyl containing a single nitrogen; and wherein aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of oxo, Ci-C alkyl,
• R 10 i s independently : hydrogen, (C ⁇ -Cg)alkyl, C(O)C ⁇ -Cg alkyl, aryl or C3-C7 cycloalkyl.
• the most preferred compound of the present invention is the compound listed below:
• a pharmaceutical composition or formulation which comprises a pharmaceutical carrier and at least one compound of formula I or its pharmaceutically acceptable salts or stereoisomers thereof.
• the pharmaceutical composition and or formulation may optionally further include a second active ingredient selected from the group consisting of an insulin sensitizer, insulin mimetic, sulfonylurea, alpha-glucosidase inhibitor, HMG-CoA reductase inhibitor, sequestrant cholesterol lowering agent, beta 3 adrenergic receptor agonist, neuropeptide Y antagonist, phosphodiester V inhibitor, and an alpha 2 adrenergic receptor antagonist.
• Yet another aspect of the present invention is a process of making a pharmaceutical composition
• a pharmaceutical composition comprismg a compound of formula I or its pharmaceutically acceptable salt or stereoisomers thereof as recited above and a pharmaceutically acceptable carrier.
• Yet another aspect of the present invention is a method of preventing or treating obesity or diabetes mellitus in mammal comprising the administration of a therapeutically effective amount of the compound of formula I.
• Yet anther aspect of the present invention is a method of preventing or treating male or female sexual dysfunction in mammal, more specifically the male or female sexual dysfunction, comprising the administration of a therapeutically effective amount of the compound of formula I.
• Yet anther aspect of the present invention is a process for preparing a compound of formula I,
• Ri is hydrogen, Ci-Cg alkyl, Boc, CBZ, phenyl, FMOC or (Ci-Cg alkyl)phenyl;
• R is independently: hydrogen, hydroxy, cyano, nitro, halo,
• Ci-C alkyl, Ci-Cg alkoxy, C3-C7 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one to five substituents independently selected from R8;
• R is independently: hydrogen, CONH(C ⁇ -Cg alkyl), Ci-Cg alkyl, (D)phenyl, (D)C3-C7 cycloalkyl or oxo, provided that oxo is not attached to the same carbon that attached to nitrogen which forms an amide bond;
• R3 is independently: aryl or thienyl; wherein aryl and thienyl are optionally substituted with one to three substituents selected from the group consisting of: cyano, halo, Ci ⁇ Cg alkyl, (D)C3- ⁇ 7 cycloalkyl, Ci-Cd. alkoxy, Ci-C4 haloalkyl and
• R4 is independently: hydrogen, Ci-Cg alkyl, C(O)R 9 , C(O)OR 9 > C3-C7 cycloalkyl or (CH 2 ) n O(C ⁇ -Cg alkyl), wherein n is 2-8; each R 8 is independently: hydrogen, halo, oxo
• each R9 is independently: hydrogen, Ci-Cg alkyl, C1-C4 haloalkyl, (D)C3-C7 cycloalkyl, (D)aryl, wherein aryl being phenyl or naphthyl,
• heterocyclyl excludes a heterocyclyl containing a single nitrogen
• aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of oxo, Ci-Cg alkyl,
• each Ri is independently: hydrogen, (C ⁇ -Cg)alkyl, C(O)C ⁇ -Cg alkyl, aryl or C3-C7 cycloalkyl;
• D is a bond or -(CH2) n n is 0-8; p is 0-5 q is 0-1 and r is 1-2;
• R a of compound 5 is C ⁇ Cg alkyl, to give a compound of formula 6;
• Step (a) is 2-boromobenzaldehydes.
• the catalyst in Step (a) is selected from the group consisting of: Pd(Ph P) 2 Cl2, Pd(Ph3P)4Cl 2 , Pd(Ph 3 P) 4 , Pd(Ph 3 P) 2 Cl 2 /CuI, Pd(OAc) 2 /Ph 3 P-Bu 4 NBr, Pd(Ph 3 P) 4 Cl 2 /H2 and Pd(OAc) 2 /P(O-tol) 3 ; and wherein the base in Step (a) is NR3 wherein R is hydrogen or Ci-Cg alkyl.
• Step (b) is selected from the group consisting of: benzylamine, alpha-methylbenzylamine and BocNH2-
• Step (b) further comprises reducing of intermediate imine compound in the presence of reducing agent, the reducing agent being selected from the group consisting of: NaCNBH3,
• Step (e) further comprises deprotecting or protecting of the compound of formula (4) at NRi.
• Yet another aspect of the present invention is a process for preparing a compound of formula I,
• .R is independently: hydrogen, hydroxy, cyano, nitro, halo, Ci-Cg alkyl,
• Ci-Cg alkyl, Ci-Cg alkoxy, C3-C7 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one to five substituents independently selected from R8;
• Ri is independently: hydrogen, CONH(C ⁇ -Cg alkyl), Ci-Cg alkyl, (D)phenyl, (D)C 3 -C 7 cycloalkyl or oxo, provided that oxo is not attached to the same carbon that attached to nitrogen which forms an amide bond;
• R3 is independently: aryl or thienyl; wherein aryl and thienyl are optionally substituted with one to three substituents selected from the group consisting of: cyano, halo, Ci-Cg alkyl, (D)C3-C7 cycloalkyl, C1-C4 alkoxy, Ci-C4 haloalkyl and
• R4 is independently: hydrogen, Ci-Cg alkyl, C(O)R 9 , C(O)OR9, C3-C7 cycloalkyl or (CH 2 ) n O(C ⁇ -Cg alkyl), wherein n is 2-8;
• each R is independently: hydrogen, halo, oxo
• heterocyclyl excludes a heterocyclyl containing a single nitrogen, phenyl, (D)COR 9 ,
• each R9 is independently: hydrogen
• (D)aryl wherein aryl being phenyl or naphthyl, (D)heteroaryl or (D)heterocyclyl; wherein heterocyclyl excludes a heterocyclyl containing a single nitrogen; and wherein aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of oxo, Ci-C alkyl,
• each RlO is independently: hydrogen, (C ⁇ -Cg)alkyl, C(O)C ⁇ -Cg alkyl, aryl or C3-C7 cycloalkyl;
• each RU is independently: hydrogen or (Ci-Cg)alkyl
• D is a bond or -(CH2) n n is 0-8; p is 0-5; q is 0-1; and r is 1-2; comprising the steps of: a) esterifying a compound of formula 1,
• R a is C 1 -C4 alkyl or (D)phenyl
• R 11 is independently hydrogen or -C 4 alkyl
• HA is an acidic and M is a univalent cation
• M is hydrogen and R a is H or R a ;
• Yet another aspect of the present invention is a process for preparing a compound of formula I,
• R is independently: hydrogen, hydroxy, cyano, nitro, halo, Ci-Cg alkyl,
• Ci-Cg alkyl, Ci-Cg alkoxy, C3-C7 cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one to five substituents independently selected from R8;
• R is independently: hydrogen, CONH(C ⁇ -Cg alkyl), Ci-C alkyl, (D)phenyl, (D)C3-C7 cycloalkyl or oxo, provided that oxo is not attached to the same carbon that attached to nitrogen which forms an amide bond;
• R3 is independently: aryl or thienyl; wherein aryl and thienyl are optionally substituted with one to three substituents selected from the group consisting of: cyano, halo, C -Cg alkyl, (D)C3- ⁇ 7 cycloalkyl, Ci-G alkoxy, C1-C4 haloalkyl and
• R4 is independently: hydrogen, Ci-Cg alkyl, C(O)R 9 , C(O)OR 9 , C3-C7 cycloalkyl or (CH 2 ) n O(Ci-Cg alkyl), wherein n is 2-8;
• each R8 is independently: hydrogen, halo, oxo
• each R9 is independently: hydrogen, Ci-Cg alkyl,
• heterocyclyl excludes a heterocyclyl containing a single nitrogen
• aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl is optionally substituted with one to three substituents selected from the group consisting of oxo, Ci-Cg alkyl,
• each RIO is independently: hydrogen, (C ⁇ -Cg)alkyl, C(O)C ⁇ -Cg alkyl, aryl or C3-C7 cycloalkyl;
• each RIO is independently: hydrogen or (C ⁇ -Cg)alkyl; D is a bond or -(CH 2 ) n -; n is 0-8; p is 0-5; q is 0-1; and r is 1-2;
• alkyl refers to those alkyl groups of a designated number of carbon atoms of either a straight or branched saturated configuration.
• alkyl includes, but are not limited to methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl and t-butyl, pentyl, hexyl, neopenyl, isopentyl and the like.
• Alkyl as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
• alkenyl means hydrocarbon chain of a specified number of carbon atoms of either a straight or branched configuration and having at least one carbon-carbon double bond, which may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, vinyl, alkyl, 2-butenyl and the like. Alkenyl as defined above may be optionally substituted with designated number of substituents as set forth in the embodiment recited above.
• haloalkyl is an alkyl group of indicated number of carbon atoms, which is substituted with one to five halo atoms selected from F, Br, CI and I.
• An example of a haloalkyl group is trifluoromethyl.
• alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and the like. Alkoxy as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
• cycloalkyl refers to a ring composed of 3 to 7 methylene groups, each of which may be optionally substituted with other hydrocarbon substituents.
• examples of cycloalkyl includes, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like. Cycloalkyl as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
• halo refers to fluoro, chloro, bromo and iodo.
• haloalkyloxy represents a haloalkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as OCF 3 .
• Haloalkyloxy as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
• aryl refers to phenyl, naphthyl, anthracenyl, phenanthrenyl and the like which is optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
• heteroaryl refers to monocyclic or bicyclic aromatic ring of 5- to 10-carbon atoms containing from one to four heteroatoms selected from O, N, or S, and the heteroaryl being optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
• heteroaryl examples include furanyl, thienyl, thiazolyl, imidazolyl, isoxazoyl, oxazoyl, pyrazoyl, pyrrolyl, pyrazinyl, pyridyl, pyrimidyl, and purinyl, cinnolinyl, benzothienyl, benzotriazolyl, benzoxazolyl, quinoline, isoquinoline and the like.
• heterocyclyl is defined as a monocyclic, bicyclic, or tricyclic ring of 5 to 14 carbon atoms which are saturated or partially saturated containing from one to four heteroatoms selected from N, O or S.
• the "heterocycly” includes "nitrogen containing heterocyclyl,” which contains from one to four nitrogen atoms and optionally further contains one other heteroatom selected from O or S. Heterocyclyl as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.
• a mammal as used in here includes a human and a warm-blooded animal such as a cat, a dog and the like.
• compositions or “formulation”, as in pharmaceutical composition or formulation, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention (a compound of formula I) and a pharmaceutically acceptable carrier.
• pharmaceutical when used herein as an adjective means substantially non-deleterious to the recipient mammal.
• unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other non-human animals such as warm-blooded animals each unit containing a predetermined quantity of active ingredient (a compound of formula I) calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical carrier.
• Erectile dysfunction is a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejaculatory failure, premature ejaculation, inability to achieve an orgasm. An increase in erectile dysfunction is often associated with age and is generally caused by a physical disease or as a side effect of drug treatment.
• Female sexual dysfunction encompasses, without limitation, conditions such as a lack of sexual desire and related arousal disorders, inhibited orgasm, lubrication difficulties, and vaginismus.
• the compound of formula I may exist as a pharmaceutical base addition salt thereof.
• Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like.
• the compound of formula I can also exist as a pharmaceutical acid addition salt.
• Such salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono- hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2- butyne-1,4 dioate, 3-hexyne-2, 5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate
• Compounds of formula I are effective as melanocortin receptor modulators, particularly as agonists of the human MC-4 receptor.
• melanocortin receptor agonists the compounds of formula I are useful in the treatment of diseases, disorders or conditions responsive to the activation of one or more of the melanocortin receptors including, but not limited to, MC-1, MC-2, MC-3, MC-4, and MC-5.
• Diseases, disorders or conditions receptive to treatment with a MC-4 agonist include those mentioned above and those described in WO 00/74679, the teachings of which are herein incorporated by reference.
• diseases, disorders or conditions receptive to treatment with a MC-4 agonist include obesity or diabetes mellitus, male or female sexual dysfunction, more specifically erectile dysfunction.
• a domain The following listing provides some of examples "A domain”, “B domain” and “C domain” of the compound of formula I. These listings are provided as illustrative purposes and as such are not meant to be limiting.
• the compound of formula I is preferably formulated in a unit dosage form prior to administration. Accordingly the present invention also includes a pharmaceutical composition comprising a compound of formula I and a suitable pharmaceutical earner.
• the active ingredient (a compound of formula I) is usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper or other container.
• a carrier which may be in the form of a capsule, sachet, paper or other container.
• the earner serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle, excipient or medium for the active ingredient.
• compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosol (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
• Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
• the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
• the compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
• the specific dose administered is determined by the particular circumstances surrounding each situation. These circumstances include, the route of administration, the prior medical history of the recipient, the pathological condition or symptom being treated, the severity of the condition/symptom being treated, and the age and sex of the recipient. Additionally, it would be understood that the therapeutic dosage administered can be determined by the physician in the light of the relevant circumstances.
• an effective minimum daily dose of a compound of formula I is about 1, 5, 10, 15, or 20 mg.
• an effective maximum dose is about 500, 100, 60, 50, or 40 mg.
• the suitable dose may be determined in accordance with the standard practice in the medical arts of "dose titrating" the recipient, which involves administering a low dose of the compound initially and then gradually increasing the does until the desired therapeutic effect is observed.
• the compounds may be administered by a variety of routes including the oral, rectal, transdermal, subcutaneous, topical, intravenous, intramuscular or intranasal routes.
• Combination Therapy Compounds of formula I may be used in combination with other drugs that are used in the treatment of the diseases or conditions for which compounds of formula I are useful. Such other drugs may be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of formula I.
• a pharmaceutical composition containing such other drugs in addition to the compound of formula I is prefened.
• the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients in addition to a compound of formula I. Examples of other active ingredients that may be combined with a compound of formula I, either administered separately or in the same pharmaceutical compositions, include but are not limited to:
• insulin sensitizers including (i) PPAR ⁇ agonists such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like) and compounds disclosed in WO97/27857, WO 97/28115, WO 97/28137 and WO97/27847; (ii) biguanides such as metformin and phenformin; (b) insulin or insulin mimetics;
• PPAR ⁇ agonists such as the glitazones (e.g., troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like) and compounds disclosed in WO97/27857, WO 97/28115, WO 97/28137 and WO97/27847;
• biguanides such as metformin and phenformin;
• insulin or insulin mimetics insulin or insulin mimetics
• ⁇ -glucosidase inhibitors such as acarbose
• cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol and a dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol nicotinic acid or a salt thereof, (iv) proliferator-activater receptor - agonists such as fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), (v) inhibitors of cholesterol absorption such as ⁇ -sitosterol and acyl CoA:cholesterol acylfransferase inhibitors such as melinamide, (vi) probucol, (vii) vitamin E, and (viii) thyrom
• antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, and ⁇ -3 adrenergic receptor agonists
• feeding behavior modifying agents such as neuropeptide Y antagonists (e.g., neuropeptide Y5) as disclosed in WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822 and WO 97/20823;
• PPAR ⁇ agonists as described in WO 97/36579
• PPAR ⁇ antagonists as described in WO97/10813
• serotonin reuptake inhibitors such as fluoxetine and sertraline
• growth hormone secretagogues such as MK-0677.
• agents useful in the treatment of male and/or female sexual dysfunction such as phosphodiester V inhibitors including sildenafil and ICI-351, and ⁇ -2 adrenergic receptor antagonists including phentolamine mesylate; and dopamine-receptor agonists, such as apomorphine.
• the radioligand binding assay is used to identify competitive inhibitors of l 5l-NDP- ⁇ -MSH binding to cloned human MCRs using membranes from stably transfected human embryonic kidney (HEK) 293 cells.
• HEK 293 cells transfected with human or rat melanocortinin receptors are grown either as adherent monolayers or suspension culture.
• Monolayer cells are grown in roller bottle cultures at 37°C and 5% CO 2 /air atmosphere in a 3:1 mixture of Dulbecco's modified Eagle medium (DMEM) and Ham's F12 containing 25 mM L-glucose, 100 units/ml penicillin G, 100 microgram/ml streptomyocin, 250 nanogram/ml amphoterin B, 300 microgram/ml genticin and supplemented with 5% fetal bovine serum.
• DMEM Dulbecco's modified Eagle medium
• Ham's F12 containing 25 mM L-glucose, 100 units/ml penicillin G, 100 microgram/ml streptomyocin, 250 nanogram/ml amphoterin B, 300 microgram/ml genticin and supplemented with 5% fetal bovine serum.
• the cell pellets are resuspended in 10 volumes of membrane preparation buffer (i.e., 1 g pellet to 10 ml buffer) having the following composition: 50 mM Tris pH 7.5 @ 4°C, 250 mM sucrose, 1 mM MgCl 2 , Complete® EDTA-free protease inhibitor tablet (Boehringer Mannheim), and 24 micrograms/ml DNase I (Sigma, St. Louis, MO).
• the cells are homogenized with a motor-driven dounce using 20 strokes, and the homogenate is centrifuged at 38,000 x g at 4°C for 40 minutes.
• the pellets are resuspended in membrane preparation buffer at a concentration of 2.5-7.5 mg/ml and 1 milliliter aliquots of membrane homogenates are quickly frozen in liquid nitrogen and then stored at -80°C.
• the membrane binding buffer has the following composition: 25 mM HEPES pH 7.5; 10 mM CaCl 2 ; 0.3%
• Functional cell based assays are developed to discriminate agonists and antagonists.
• HEK 293 cells stably expressing a human melanocortin receptor are dissociated from tissue culture flasks using a trypsin/EDTA solution(0.25%; Life Technologies, Rockville, MD). Cells are collected by centrifugation and resuspended in DMEM (Life Technologies, Rockville, MD) supplemented with 1% L-glutamine and 0.5% fetal bovine serum. Cells are counted and diluted to 4.5xlONml.
• a compound of formula I is diluted in dimethylsulfoxide (DMSO) (3 x 10" ⁇ to 3 x 10 ⁇ 10 M final concentrations) and 0.05 volume of compound solution is added to 0.95 volumes of cell suspension; the final DMSO concentration is 0.5%.
• DMSO dimethylsulfoxide
• luciferin solution 50 mM Tris, 1 mM MgCl 2 , 0.2 % Triton-XlOO, 5 mM DTT, 500 micromolar Coenzyme A, 150 micro
• Luciferase activity is measured from the cell lysate using a Wallac Victor 2 luminometer.
• the amount of lumen production which results from a compound of formula I is compared to that amount of lumens produced in response to NDP- ⁇ -MSH, defined as a 100% agonist, to obtain the relative efficacy of a compound.
• the EC50 is defined as the compound concentration that results in half maximal stimulation, when compared to its own maximal level of stimulation.
• the compounds are prepared as lOmM and NDP-alpha- MSH (control) as 33.3 ⁇ M stock solutions in 100 % DMSO. These are serially diluted in 100 % DMSO. The compound plate is further diluted 1:200 in compound dilution buffer (HBSS-092, 1 mM Ascorbic Acid, 1 mM IBMX, 0.6% DMSO, 0.1% BSA). The final concentration range being 10 ⁇ M-100 pM for compound and 33.33 nM-0.3 pM for control in 0.5 % DMSO. Transfer 20 ⁇ l from this plate into four PET 96-well plates (all assays are performed in duplicate for each receptor). Cell Culture and Cell Stimulation
• HEK 293 cells stably transfected with the MC3R and MC4R were grown in DMEM containing 10% FBS and l%Antibiotic/Antimycotic Solution. On the day of the assay the cells were dislodged with enzyme free cell dissociation solution and resuspended in cell buffer (HBSS-092, 0.1% BSA, 10 mM HEPES) at 1 x e6 cells/ml. Add 40 ⁇ l of cells/well to the PET 96-well plates containing 20 microliter diluted compound and control. Incubate @ 37°C in a waterbath for 20 minutes. Stop the assay by adding 50 ⁇ l Quench Buffer (50 mM Na Acetate, 0.25% Triton X-100). Radioligand Binding Assays
• Radioligand binding assays were run in SPA buffer (50mM Sodium Acetate, 0.1% BSA). The beads, antibody and radioligand were diluted in SPA buffer to provide sufficient volume for each 96-well plate. To each quenched assay well was added 100 microliter cocktail containing 33.33 microliter of beads, 33.33 microliter antibody and 33.33 microliter 125 I-cAMP. This was based on a final concentration of 6.3 mg/ml beads, 0.65 % anti-goat antibody and 61 pM of 125 I-cAMP (containing 25000-30000 CPM) in a final assay volume of 210 microliter. The plates were counted in a Wallac MicroBeta counter after a 12- hour incubation.
• Rats are administered test compound by subcutaneous injection, intramuscular injection, intravenous injection, intraperitoneal injection, ICV injection or by oral gavage between 0 and 5 hours after the onset of the dark cycle. Rats are placed into a calorimetry chamber and the volume of oxygen consumed and volume or carbon dioxide exhaled are measured each hour for 24 hours. Food intake is measured for the 24 hour period as described in C.1). Locomoter activity is measured when the rat breaks a series of infrared laser beams when in the calorimeter. These measurements permit calculation of energy expenditure, respiratory quotient and energy balance.
• Rats are gently restrained in a supine position with their anterior torso placed inside a cylinder of adequate size to allow for normal head and paw grooming. For a 400-500 gram rat, the diameter of the cylinder is approximately 8 cm.
• the lower torso and hind limbs are restrained with a non-adhesive material (vetrap).
• An additional piece of vetrap with a hole in it, through which the glans penis will be passed, is fastened over the animal to maintain the preputial sheath in a retracted position. Penile responses will be observed, typically termed ex copulu genital reflex tests.
• a series of penile erections will occur spontaneously within a few minutes after sheath retraction.
• the types of normal reflexogenic erectile responses include elongation, engorgement, cup and flip.
• An elongation is classified as an extension of the penile body.
• Engorgement is a dilation of the glans penis.
• a cup is defined as an intense erection where the distal margin of the glans penis momentarily flares open to form a cup ' .
• a flip is a dorsiflexion of the penile body.
• Baseline and/or vehicle evaluations are conducted to determine how and if an animal will respond. Some animals have a long duration until the first response while others are non-responders altogether.
• Rodent assays relevant to female sexual receptivity include the behavioral model of lordosis and direct observations of copulatory activity. There is also a urethrogenital reflex model in anesthetized spinally transected rats for measuring orgasm in both male and female rats. These and other established animal models of female sexual dysfunction are described in McKenna, et al., Am. J. Physiol, (Regulatory Integrative Comp. Physiol 30):R1276-R1285, 1991; McKenna, et al., Pharm. Bioch. Behav., 40:151-156, 1991; and Takahashi, et al., Brain Res., 359:194-207, 1985.
• Preparation of the compounds of the present invention may be carried out via sequential or convergent synthetic routes.
• the skilled artisan will recognize that, in general, the three domains of a compound of formula I are connected via amide bonds.
• the B and C domains are optionally connected via a reduced or partially reduced amide bond (e.g., via reductive animation).
• the skilled artisan can, therefore, readily envision numerous routes and methods of connecting the three domains via standard peptide coupling reaction conditions.
• standard peptide coupling reaction conditions means coupling a carboxylic acid with an amine using an acid activating agent such as EDC, dicyclohexylcarbodiimide, and benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate in a inert solvent such as DCM in the presence of a catalyst such as HOBT.
• an acid activating agent such as EDC, dicyclohexylcarbodiimide, and benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate
• a catalyst such as HOBT.
• CBZ, Boc and FMOC protecting groups are used extensively in the synthesis, and their removal conditions are well known to those skilled in the art.
• removal of CBZ groups can he achieved by catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide such as palladium on activated carbon in a protic solvent such as ethanol.
• removal of CBZ can also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide.
• Removal of Boc protecting groups is carried out in a solvent such as methylene chloride, methanol or ethyl acetate with a strong acid, such as TFA or HCI or hydrogen chloride gas.
• the compounds of formula I when exist as a diastereomeric mixture, may be separated into diastereomeric pairs of enantiomers by fractional crystallization from a suitable solvent such as methanol, ethyl acetate or a mixture thereof.
• a suitable solvent such as methanol, ethyl acetate or a mixture thereof.
• the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means by using an optically active acid as a resolving agent.
• any enantiomer of a compound of the formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
• the compounds of the present invention can be prepared according to the procedure of the following schemes and examples, which may further illustrate details for the preparation of the compounds of the present invention.
• the compounds illustrated in the examples are, however, not to be construed as forming the only genus that is considered as the present invention. h the Schemes, Preparations and Examples below, various reagent symbols and abbreviations have the following meanings:
• an appropriate A domain e.g., piperazine
• B domain e.g., D-Boc-p-Cl-Phe-OH
• EDC/HOBt e.g., D-Boc-p-Cl-Phe-OH
• the coupled AB compound is then coupled to an appropriate C domain followed by deprotection of Boc group and salt formation.
• C domain is not protected with Boc group, the final compound can be obtained without the deprotection step.
• an appropriate A domain e.g., piperazine
• an appropriate BC domain in the presence of HATU followed by deprotection of Boc group and salt formation.
• BC domain is not protected with Boc group, the final compound can be obtained without the deprotection step.
• an appropriate BC domain is coupled to an appropriate A domain in the presence of EDC HOBT followed by deprotection of Boc group and salt formation.
• C domain is not protected with Boc group, the final compound can be obtained without the deprotection step.
• EDC/HOAT for coupling of A with Boc-B, EDC/HOAT, EDC/HOBT or DCC/HOBT can be used.
• the starting material of Boc-protected piperazine (A domain) can be deprotected in the presence of TFA/CH 2 C1 2 , HCl/EtOAc, HCl/dioxane, or HCI in MeOH/Et 2 O with or without a cation scavenger, such as dimethyl sulfide (DMS) before being subjected to the coupling procedure. It can be freebased before being subjected to the coupling procedure or in some cases used as the salt.
• a cation scavenger such as dimethyl sulfide (DMS)
• a suitable solvent such as CH 2 C1 2 , DMF, THF or a mixture of the above solvents can be used for the coupling procedure.
• Suitable base includes triethyl amine (TEA), diisopropyethyl amine (DJPEA), N-methymorpholine, collidine, or 2,6-lutidine. Base may not be needed when EDC HOBt is used.
• the reaction mixture can be diluted with an appropriate organic solvent, such as EtOAc, CH 2 C1 2 , or Et 2 O, which is then washed with aqueous solutions, such as water, HCI, NaHSO 4 , bicarbonate, NaH 2 PO , phosphate buffer (pH 7), brine or any combination thereof.
• the reaction mixture can be concentrated and then be partitioned between an appropriate organic solvent and an aqueous solution.
• the reaction mixture can be concentrated and subjected to chromatography without aqueous workup.
• Protecting group such as Boc or CBZ, FMOC, CF 3 CO and H 2 /Pd-C can be deprotected in the presence of TFA/CH 2 C1 2 , HCl EtOAc, HCI/ dioxane, HCI in MeOH/Et 2 O, NH3/MeOH, or TBAF with or without a cation scavenger, such as thioanisole, ethane thiol and dimethyl sulfide (DMS).
• the deprotected amines can be used as the resulting salt or are freebased by dissolving in CH 2 C1 2 and washing with aqueous bicarbonate or aqueous NaOH.
• the deprotected amines can also be freebased by ion exchange chromatography.
• the compounds of the present invention can be prepared as salt, such as TFA, hydrochloride or succinate salts by using known standard methods.
• the A domains of the present invention may be prepared from commercially available starting materials via known chemical transformations.
• the preparation of A domain of the compound of the present invention is illustrated in the reaction scheme below.
• the "A domain" of the compounds of the present invention can be prepared by coupling halo-substituted aryl 1 (X-Q) with piperazines 2 in the presence of tris(dibenzylideneacetone) dipalladium (Pd 2 (dba) 3 ), l,l'-Bi[(2- diphenylphosphines) naphthalene] (BINAP) and sodium t-butoxide (NaO'Bu) or cesium carbonate (Cs 2 CO 3 ) in an organic solvent such as toluene at a suitable temperature. More detailed examples of A Domain preparation are described below.
• E G electron withdrawing group
• the "A domain" of the compounds of the present invention can be prepared by heating appropriately substituted fluoro-aryl compounds 4 and piperazines 2 neat or with an appropriate solvent and with or without an appropriate base.
• the "A domain" of the compounds of the present invention can be prepared by heating l-bromo-2-fluoro-benzene 6 with various alcohols (R 9 -OH) in the presence of NaH to give ortho-substituted bromobenzenes 7 which can then be subjected to Buchwald conditions as shown in Reaction Scheme 4 above.
• A is aryl or heteroaryl.
• the "A domain" of the compounds of the present invention can be prepared by heating 2-bromophenol 9 with various aryl and heteroaryl boronates (X-OH) in the presence of Cu(OAc) 2 and pyridine to give ortho- substituted bromobenzenes 10 which can then be subjected to Buchwald conditions.
• Reaction Scheme 6 Benzylamines 6A. Nitrile reduction
• A SO 2 R 9 , SO 2 N(R 9 ) 2 , C(O)R 9 , C(O)OR 9 , C(O)SR 9 , C(O)N(R 9 ) 2 and etc.
• the "A domain" of the compounds of present invention can be prepared by reducing the nitrile of (2-cyano-phenyl)-piperazine 12 to the corresponding benzyl amine 13 with either NaBH 4 and TFA or H 2 and Raney nickel.
• Benzyl amine 13 can be transformed to other benzyl amine derivatives 14 using various methods known to the skilled artisan.
• the "A domain" of the compounds of present mvention can be prepared by hydrolyzing the nitrile of (2-cyano-phenyl)-piperazine 12 to the conesponding carboxylic acid 15 with KOH followed by reduction to benzyl alcohol 16 with BH 3 -THF.
• Benzyl alcohol 16 can be transformed to benzyl amines 17 either using Mitsunobu conditions or by activating the alcohol as the mesylate followed by nucleophilic displacement.
• A SO 2 R , SO 2 N(R ) 2 , C(O)R 9 , C(O)OR ⁇ , C(O)SR 9 , C(O)N(R 2 and etc.
• the "A domain" of the compounds of present invention can be prepared from l-Boc-4-(2-amino-phenyl)-piperazine 19 which is prepared from 4-(2-nitro-phenyl)-piperazine 18 by Boc protection followed by nitro reduction.
• 1-Boc- 4-(2-amino-phenyl)-piperazine 19 can be transformed to other aniline derivatives 20 using various methods known to the skilled artisan.
• Sulfonamides 21 could be prepared from 1- Boc-4-(2-amino-phenyl)-piperazine 19 by reaction with various sulfonyl chlorides.
• the resulting sulfonamides 21 could then be deprotonated with NaH or K 2 CO 3 in DMF followed by alkylation with various alkyl halides (R 9 X) to afford alkylated sulfonamides 22.
• l-Boc-4- (2-amino-phenyl)-piperazine could also be acylated with various acid chlorides to give acetamides 23.
• the acetamides 23 could be reduced with BH 3 -THF to give alkyl amines 24 which can be transformed to other amine derivatives 25 using various methods known to the skilled artisan.
• the "A domain" of the compounds of present invention can be prepared by reducing the nitrile of (2-cyano-phenyl)-piperazine 12 to the conesponding aldehyde 26 with DIBAL.
• Aldehyde 26 can be transformed to benzyl amines 27 by reductive amination with various amines including nitrogen containing heterocycles. These benzyl amines 27 can be transformed to other amine derivatives using various methods known to the skilled artisan.
• Aldehyde 26 can also be reacted with various organolithium reagents
• a domain of the compounds of present invention can be prepared by treating l-Boc-(2-hydroxy-phenyl)-piperazine 31 with a base and an alkyl halide (RX) or subjected to Mitsunobu conditions with R 9 OH to give ortho- substituted aryl piperazines 32.
• RX alkyl halide
• A heterocyclyl, N(R 9 )2, OR 9 or SR 9 and etc.
• "A domain" of the compounds of present invention can be prepared by hydrolyzing the nitrile of (2-cyano-phenyl)-piperazine 12 to the conesponding carboxylic acid 15 with KOH followed by transformation to other carboxylic acid derivatives 33 using various methods known to the skilled artisan.
• a domain of the compounds of present invention can be prepared by reacting the nitrile of (2-cyano-phenyl)-piperazine 12 with tributyltin azide to give tetrazoles 34.
• the tetrazoles can be further transformed to 35 using various methods known to the skilled artisan.
• the present invention also provides a novel process for preparing certain intermediates and/or compounds of the invention as shown in Reaction Schemes 12-14.
• the isoindoline compounds of the present invention may be prepared from 2-halobenzaldehyde 1 or substituted analog thereof.
• Prefened starting material is 2-bromobenzaldehyde or substituted analog thereof.
• amines, 3 or carbamates where is for example, Boc.
• Various Heck coupling reagents and conditions were found suitable to effect the coupling reaction.
• Suitable catalysts and ligands include Pd(OAc) 2 /PPh 3 , Pd(OAc)PPh 3 /BU 4 NBr, Pd(PPH 3 ) 2 Cl 2 /CUI, Pd(OAC) 2 /P(O-Tol) 3 .
• Suitable solvent or solvent systems for the Heck coupling reaction include DMF, toluene and ethyl acetate. More prefened base is triethylamine.
• Reductive amination of the aldehyde functionality of 2 to amines is accomplished in good yields by reaction with benzylamine or alpha-methylbenzylamine in acidic conditions, followed by in situ reduction of the incipient imines with NaCNBH 3 at about pH 5.
• Other reducing agents including Na(OAc) 3 BH and NaBHj/H may also be used to effect reduction of the incipient imines.
• the resulting amines immediately cyclized to the isoindoline compounds under the same acidic conditions for the reduction.
• Direct preparation of compound 4 may also be effected by use of BocNH 2 instead of benzylamine in the reductive amination step. Screening of various reducing agents demonstrated that the combination of Et 3 SiH and TFA in CH 3 CN represents the prefened method for effecting reductive amination using BocNH .
• the N-Boc isoindolinecarboxylic acid 5 may also be prepared from 3 as the carbamate, by an intra-molecular Michael addition and ester hydrolysis. The resolution of the isoindolinecarboxylic acids 4 by crystallization afforded enantio-pure compounds 5.
• m-tyrosine ester or analogs, including substituted analogs thereof may be esterified by forming the acid halide followed by nucleophilic displacement of halide by the alkoxy group from an alcohol, i.e., methanol or ethanol. Where thionyl chloride or other halide source is used the product may be isolated as the acid addition salt (2).
• the resulting ester (2) is subjected to a Pictet-Spengler reaction by heating with a suitable ketone or aldehyde in refluxing conditions.
• a suitable ketone or aldehyde in refluxing conditions.
• an unsubstituted isoquinoline backbone (3) may be formed by employing formaldehyde in the pictet-Spengler reaction.
• a gem-dimethyl substituted isoquinoline wherein R is methyl may be formed by using acetone as the ketone source and solvent.
• Other less reactive substituents may be substituted as the R 11 group for the practice of the present invention.
• the product isoquinoline (3) may be isolated preferably as the acid addition salt. Where m-tyrosine is used as the starting material, the free hydroxyl group is removed first by protection activation with a good leaving group such as, for example, reaction with triflic anhydride (trifluoromethane sulfonic anhydride) or methanesulfonic acid to form the triflate or mesylate in the presence of a base.
• a good leaving group such as, for example, reaction with triflic anhydride (trifluoromethane sulfonic anhydride) or methanesulfonic acid to form the triflate or mesylate in the presence of a base.
• the triflate is a prefened group used to set up the compound (3) for deoxygenation because of the extra electron withdrawing effect of the trifluoromethane substituent.
• the deoxygenation reaction is effected by hydrogenation at pressures of about 50psi.
• the product (4) may be isolated as
• the product (4) is hydrolyzed under basic conditions to afford the acid salt.
• Suitable bases for the above hydrolysis include aqueous sodium hydroxide, potassium hydroxide and sodium lithium hydroxide.
• the reaction is preferably performed in a mixture of aqueous and organic solvents. An exotherm during addition of base may be regulated (i.e., less than about 35°C) to avoid overheating or "runaway reactions.”
• the reaction product may be isolated by aqueous work up. Alternatively, the entire mixture may be concentrated and washed with organic solvents to afford the desired product (6) after crystallization.
• the product (6) is then reacted with a "B" domain substrate such as, for example, 4-chloro-D-phenylalanine as described previously and in the experimental section.
• a "B” domain substrate such as, for example, 4-chloro-D-phenylalanine as described previously and in the experimental section.
• the resulting "BC” combination product is then reacted with an "A” domain piece to form the respective compound of formula I.
• the product (6) may be reacted with an "AB” domain combination product to afford a compound of formula I.
• the isoquinoline product i.e., compound (3) or (5) including their N-protected analogs may be resolved by reaction with a resolving agent such as for example, L-tartaric acid, dehydroabietylamine or other resolving agents known to one of skill in the art.
• a resolving agent such as for example, L-tartaric acid, dehydroabietylamine or other resolving agents known to one of skill in the art.
• asymmetric analogs of product (6) may be prepared by using asymmetric starting materials.
• L-DOPA may be used in place of m-tyrosine ester in reactions essentially similar to those described and illustrated in Reaction Scheme 13, and in the examples, to afford the asymmetric analog of compound (6).
• Tetrahydroisoquinoline acetic acid derivatives may be prepared and utilized as shown in Reaction Scheme 14 below:
• the compound of formula 10b may be protected as the compound 10c with a suitable protecting group (Pg) and then subjected to hydrogenation conditions including for example asymmetric hydrogenation to form a compound of formula lOd, which may be chiral (depending on hydrogenation conditions, i.e., asymmetric versus non-asymmetric hydrogenation).
• the compound of formula lOd or stereoisomer thereof is reacted with a B-domain piece such as, for example, 4-chloro-D-phe to afford a BC piece (lOe).
• the compound of formula lOe is then reacted with an A-domain piece to afford a compound of formula I.
• the details of the specific reaction steps are similar to or analogous to reactions taught herein, and in the experimental section.
• one of skill in the art is aware of that such intermediate reactions as hydrolysis and deprotection may be necessary to achieve optimum yields in certain steps of the scheme as shown.
• One of skill in the art is also aware of further common manipulations such as N-alkylation, or N-acylation, and alkylations on the benzene ring to afford other compounds of formula I.
• the title compound was prepared in a manner similar to Preparation 1 A except that piperazine was coupled to l-bromo-5-methyl-2-isopropyl-benzene.
• l-Boc-4-(2-aminomethyl-phenyl)-piperazine (2.09 g, 7.18 mmol) was dissolved in methylene chloride (50 mL), cooled to 0°C and treated with triethylamine (1.5 mL, 10.8 mmol) followed by methanesulfonyl chloride (0.67 mL, 8.61 mmol).
• the resulting mixture was stined for about 3 hours at r.t., and then diluted with ether (200 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), which is then dried over anhydrous magnesium sulfate.
• the title compound was Prepared in a similar manner to Preparation 39A except isobutyryl chloride was used instead of methanesulfonyl chloride and diisopropylethylamine was used as the base.
• l-Boc-4-(2-aminomethyl-phenyl)-piperazine (0.75 g, 2.6 mmol) was dissolved in methylene chloride (20 mL), treated with DIPEA (2.3 mL, 13 mmol), and cooled to about 0°C.
• Propionyl chloride (0.20 mL, 2.34 mmol) was added and the mixture was stined for about 1 hour at 0°C and subsequently stirred overnight at r.t.
• the title compound was prepared in the following procedure: About 0.40 g (1.37 mmol) of l-Boc-4-(2-aminomethyl-phenyl)-pi ⁇ erazine, 0.11 ml of (1.51 mmol) propionic acid, 0.22g (1.64 mmol) of HOBt, 0.31g (1.64 mmol) of EDC, and 0.24 ml (1.37 mmol) of DIEA were mixed in 30 ml THF under nitrogen and stined overnight at r.t. The reaction was concentrated to dryness and ethyl acetate was added. The mixture was washed with saturated bicarbonate and brine, and then dried with sodium sulfate.
• l-Boc-4-(2-Aminomethyl-phenyl)-piperazine (0.47 g, 1.6 mmol) was dissolved in methylene chloride (20 mL). DIPEA (1.5 mL, 8.5 mmol) was added, and the mixture was cooled to about 0°C. The mixture was treated with benzoyl chloride (0.20 g, 0.16 mL, 1.4 mmol). The resulting mixture was stined for about 1 hour at 0°C, and then warmed to r.t. and stined overnight.
• Step 1 1 -Boc-4-(2-carboxy- ⁇ henyl)-piperazine boc
• Step 3 To a solution of l-Boc-4-(hydroxymethyl-phenyl)-piperazine (300 mg, 1.02 mmol, 1.0 eq.), 1,2,4 triazole (104 mg, 1.53 mmol, 1.5 eq.), triphenylphosphine (535 mg, 2.04 mmol, 2.0 eq.) and THF at 0°C under nitrogen was added DEAD (0.321 mL, 2.04 mmol, 2.0 eq.) slowly so that temperature of reaction does not rise above 10°C. After addition was completed, the ice bath was removed and the reaction mixture was stined at r.t. overnight. Methanol was added and the mixture was stined for about 15 minutes. The mixture was then concentrated.
• DEAD 0.321 mL, 2.04 mmol, 2.0 eq.
• l-Boc-4-(2-Hydroxymethyl-phenyl)-piperazine (4.59 g, 15J mmol) was dissolved in toluene (75 mL).
• Triphenylphosphine (8.3 g, 31.6 mmol) was added followed by zinc azide pyridine salt (3.61g, 11.72 mmol).
• Diisopropyl azodicarboxylate (6.27 mL, 31.6 mmol) was added dropwise, and the solution was stined at r.t. for about 12 hours.
• l-Boc-4-(2-Azidomethyl-phenyl)-piperazine (0.25 g, 0.79 mmol) was dissolved in deuterated chloroform (3 mL). Methyl propiolate (0.35 mL, 3.9 mmol) was added, and the mixture was heated to reflux for about 4 hours and then cooled to r.t. The mixture was concentrated under reduced pressure and purified using silica chromatography (50% ethyl acetate in hexanes) to give the title compound (0.155 g, 49%) as an oil.
• 4-(2-cyano-3-frifluoromethyl-phenyl)piperazine was prepared in a manner similar to 4-(2-cyano-5-trifluoromethyl-phenyl)piperazine described above except that 2- fluoro-6-frifluoromethylbenzonitrile was used as the starting material.
• 4-(2- cyano-3-trifluoromethyl-phenyl)piperazine (1.35 g, 5.29 mmol, 1.0 eq.) in dioxane (40 mL) was added a solution of DIBAL in heptane (1.0 M in heptane, 13.2 mL, 13.22 mmol, 2.5 eq.).
• the resulting mixture was stined at r.t. for about 3 days.
• the mixture was transfened via cannula to 0.5 M Rochelle salt and stirred for about 2 hours.
• NaHCO 3 1.3 g, 15.9 mmol, 3.0 eq
• di-tert-butyl dicarbonate 1.7 g, 7.29 mmol, 1.5 eq.
• the mixture was stirred at r.t. overnight.
• the mixture was partitioned between EtOAc (100 mL) and brine (50 mL). The organic layer was separated, and aqueous layer was extracted with EtOAc (2x).
• l-Boc-4-[2-(isopropylamino-methyl)-phenyl]-piperazine (0.325 g, 0.975 mmol) was dissolved in tefrahydrofuran (5 mL) and cooled to about 0°C.
• TEA (0.54 mL, 3.9 mmol) was added followed by dropwise addition of acetyl chloride (0.2 mL, 2.93 mmol).

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