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US20080139552A1 - Indoles - Google Patents

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US20080139552A1
US20080139552A1 US11/947,877 US94787707A US2008139552A1 US 20080139552 A1 US20080139552 A1 US 20080139552A1 US 94787707 A US94787707 A US 94787707A US 2008139552 A1 US2008139552 A1 US 2008139552A1
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Prior art keywords
alkyl
halo
alkoxy
hydrogen
alkylene
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Inventor
Caterina Bissantz
Christophe Grundschober
Raffaello Masciadri
Hasane Ratni
Mark Rogers-Evans
Patrick Schnider
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Hoffmann La Roche Inc
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Individual
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Assigned to F. HOFFMANN-LA ROCHE AG reassignment F. HOFFMANN-LA ROCHE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MASCIADRI, RAFFAELLO, BISSANTZ, CATERINA, GRUNDSCHOBER, CHRISTOPHE, RATNI, HASANE, ROGERS-EVAN, MARK, SCHNIDER, PATRICK
Assigned to HOFFMAN-LA ROCHE INC. reassignment HOFFMAN-LA ROCHE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG
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    • 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
    • C07D401/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • Vasopressin is a 9 amino acid peptide mainly produced by the paraventricular nucleus of the hypothalamus. Three vasopressin receptors, all belonging to the class I G-protein coupled receptors, are known.
  • the V1a receptor is expressed in the brain, liver, vascular smooth muscle, lung, uterus and testis, the V1b or V3 receptor is expressed in the brain and pituitary gland, the V2 receptor is expressed in the kidney where it regulates water excretion and mediates the antidiuretic effects of vasopressin.
  • vasopressin acts as a neurohormone and stimulates vasoconstriction, glycogenolysis and antidiuresis.
  • vasopressin acts as a neuromodulator and is elevated in the amygdala during stress (Ebner, K., C. T. Wotjak, et al. (2002). “Forced swimming triggers vasopressin release within the amygdala to modulate stress-coping strategies in rats.” Eur J Neurosci 15(2): 384-8).
  • the V1a receptor is extensively expressed in the brain and particularly in limbic areas like the amygdala, lateral septum and hippocampus which are playing an important role in the regulation of anxiety.
  • V1a knock-out mouse show a reduction in anxious behavior in the plus-maze, open field and light-dark box (Bielsky, I. F., S. B. Hu, et al. (2003). “Profound Impairment in Social Recognition and Reduction in Anxiety-Like Behavior in Vasopressin V1a Receptor Knockout Mice.” Neuropsychopharmacology ).
  • the downregulation of the V1a receptor using antisense oligonucleotide injection in the septum also causes a reduction in anxious behavior (Landgraf, R., R. Gerstberger, et al. (1995). “V1 vasopressin receptor antisense oligodeoxynucleotide into septum reduces vasopressin binding, social discrimination abilities, and anxiety-related behavior in rats.” Regul Pept 59(2): 229-39).
  • the V1a receptor is also mediating the cardiovascular effects of vasopressin in the brain by centrally regulating blood pressure and heart rate in the solitary tract nucleus (Michelini, L. C. and M. Morris (1999). “Endogenous vasopressin modulates the cardiovascular responses to exercise.” Ann N Y Acad Sci 897: 198-211). In the periphery it induces the contraction of vascular smooth muscles and chronic inhibition of the V1a receptor improves hemodynamic parameters in myocardial infarcted rats (Van Kerckhoven, R., I. Lankhuizen, et al. (2002). “Chronic vasopressin V(1A) but not V(2) receptor antagonism prevents heart failure in chronically infarcted rats.” Eur J Pharmacol 449(1-2): 135-41).
  • the present invention provides novel indol-2-yl-carbonyl-piperidine derivatives as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use for the treatment of anxiety and depressive disorders and other diseases.
  • the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the text or in the examples, or by methods known in the art.
  • the compounds of formula (I) possess pharmaceutical activity, in particular they are modulators of V1a receptor activity. More particular, the compounds are antagonists of the V1a receptor.
  • the invention provides methods for the treatment of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders.
  • the preferred indications with regard to the present invention are the treatment of anxiety and depressive disorders.
  • alkyl refers to a branched or straight-chain monovalent saturated hydrocarbon radical.
  • C 1-6 -alkyl denotes a saturated straight- or branched-chain monovalent hydrocarbon group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, the isomeric pentyls and the like.
  • a preferred sub-group of C 1-6 -alkyl is C 1-4 -alkyl, i.e. with 1-4 carbon atoms.
  • alkylene refers to a linear or branched saturated divalent hydrocarbon radical.
  • C 1-6 -alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g. methylene, ethylene, 2,2-dimethylethylene, n-propylene, 2-methylpropylene, and the like.
  • alkoxy and C 1-6 -alkoxy refer to the group R′—O—, wherein R′ is C 1-6 -alkyl as defined above.
  • alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy and the like.
  • a preferred sub-group of C 1-6 -alkoxy, and still more preferred alkoxy groups are methoxy and/or ethoxy.
  • thioalkyl and “C 1-6 -thioalkyl” refer to the group R′—S—, wherein R′ is C 1-6 -alkyl as defined above.
  • C 1-6 -hydroxyalkyl and “C 1-6 -alkyl substituted by OH” denote a C 1-6 -alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a hydroxyl group.
  • C 1-6 -cyanoalkyl and “C 1-6 -alkyl substituted by CN” denote a C 1-6 -alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a CN group.
  • halo or halogen refer to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) with fluorine, chlorine and bromine being preferred.
  • halo-C 1-6 -alkyl denotes a C 1-6 -alkyl group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro.
  • halo-C 1-6 -alkyl include but are not limited to methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl or n-hexyl substituted by one or more Cl, F, Br or I atom(s) as well as those groups specifically illustrated by the examples herein below.
  • halo-C 1-6 -alkyl groups are difluoro- or trifluoro-methyl or -ethyl.
  • halo-C 1-6 -alkoxy denotes a C 1-6 -alkoxy group as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro.
  • halogenated alkoxy groups are difluoro- or trifluoro-methoxy or -ethoxy.
  • C 2-12 -alkenyl denotes a straight-chain or branched hydrocarbon residue of 2 to 12 carbon atoms comprising at least one double bond.
  • a preferred sub-group of C 2-12 -alkenyl is C 2-6 -alkyenyl.
  • Examples of the preferred alkenyl groups are ethenyl, propen-1-yl, propen-2-yl (allyl), buten-1-yl, buten-2-yl, buten-3-yl, penten-1-yl, penten-2-yl, penten-3-yl, penten-4-yl, hexen-1-yl, hexen-2-yl, hexen-3-yl, hexen-4-yl and hexen-5-yl, as well as those specifically illustrated by the examples herein below.
  • 5 or 6 membered heteroaryl means an aromatic ring of 5 or 6 ring atoms as ring members containing one, two, or three ring heteroatoms selected from N, O, and S, the rest being carbon atoms.
  • 5 or 6 membered heteroaryl can optionally be substituted with one, two, three or four substituents, wherein each substituent are independently selected from the group consisting of hydroxy, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, halo, cyano, nitro, halo-C 1-6 -alkyl, C 1-6 -hydroxyalkyl, C 1-6 -alkoxycarbonyl, amino, C 1-6 -alkylamino, di(C 1-6 )alkylamino, aminocarbonyl, and carbonylamino, unless otherwise specifically indicated.
  • Preferred substituents are halo, halo-C 1-6 -alkyl, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, nitro, or cyano.
  • heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted pyrazinyl, optionally substituted pyrrolyl, optionally substituted pyrazinyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted furanyl, and those which are specifically exemplified herein.
  • heterocycloalkyl means a monovalent saturated moiety, consisting of one ring of 3 to 7, preferably from 4 to 6 atoms as ring members, including one, two, or three heteroatoms chosen from nitrogen, oxygen and sulfur, the rest being carbon atoms.
  • 3 to 7 membered heterocycloalkyl can optionally be substituted with one, two, three or four substituents, wherein each substituent is independently hydroxy, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -thioalkyl, halo, cyano, nitro, halo-C 1-6 -alkyl, C 1-6 -hydroxyalkyl, C 1-6 -alkoxycarbonyl, amino, C 1-6 -alkylamino, di(C 1-6 )alkylamino, aminocarbonyl, or carbonylamino, unless otherwise specifically indicated.
  • Preferred substituents are halo, halo-C 1-6 -alkyl, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, nitro, or cyano.
  • heterocyclic moieties include, but are not limited to, optionally substituted tetrahydro-furanyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted morpholinyl, optionally substituted piperazinyl, and the like or those which are specifically exemplified herein.
  • heterocycle in the definition “R a and R b , R c and R d , R g and R h , R i and R j , together with the nitrogen to which they are bound form a five- or six-membered heterocycle comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur” means either heterocycloalkyl or heteroaryl in the above-given sense which may optionally be substituted as described above.
  • the “heterocycle” may optionally be substituted with one, two or three substituents selected from halo, halo-C 1-6 -alkyl, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, nitro, and cyano.
  • Preferred heterocycles are piperazine, N-methylpiperazine, morpholine, piperidine and pyrrolidine.
  • substituents preferably means one, two or three substituents per ring.
  • cycloalkyl means a cycloalkyl group containing 3 to 6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkyl containing 3 to 4 carbon atoms are the most preferred.
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • pharmaceutically acceptable acid addition salt embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • R a and R b , R c and R d , R i and R j , or R g and R h together with the nitrogen to which they are bound may form piperazine, 4-(C 1-6 -alkyl)-piperazine, 4-methylpiperazine, morpholine, piperidine or pyrrolidine.
  • R a and R b , R c and R d , R i and R j , or R g and R h together with the nitrogen to which they are bound may form 4-methylpiperazine, or morpholine.
  • R m is a 5- to 6-membered heteroaryl
  • the preferred heteroaryl is selected from the group consisting of pyridine, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole, oxazole, and isoxazole.
  • R m is a 4- to 6-membered heterocycloalkyl
  • the preferred heterocycloalkyl is selected from the group consisting of pyrrolidine, oxethane, tetrahydropyrane, piperidine, morpholine, and piperazine.
  • compounds of formula (I) according to the invention are those wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are not all hydrogen at the same time.
  • R 12 and R 12′ are each independently hydrogen, C 1-6 -alkoxy, C 1-6 -alkyl, halo, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, or nitro;
  • R 2 is hydrogen, or C 1-6 -alkyl.
  • R 3 is hydrogen
  • R 4 is hydrogen, halo, C 1-6 -alkyl, halo-C 1-6 -alkyl or C 1-6 -alkoxy, preferably, R 4 is hydrogen or halo, more preferably, R 4 is hydrogen or chloro.
  • R 5 is hydrogen, halo, C 1-6 -alkyl, halo-C 1-6 -alkyl or C 1-6 -alkoxy; preferably, R 5 is hydrogen.
  • R 1 to R 11 are as defined herein above.
  • A is (a), X is CH 2 and Y is O, i.e. a compound of formula (I-a′′):
  • R 1 to R 11 are as defined herein above.
  • A is (a), X is CH 2 and Y is CH 2 , i.e. a compound of formula (I-a′′′):
  • R 1 to R 11 are as defined herein above.
  • R 1 to R 14 are as defined herein above.
  • R 1 to R 11 are as defined herein above.
  • the invention also encompasses methods for the treatment of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders which comprises administering a therapeutically effect amount of a compound of formula (I), (Ia), (Ib), or (Ic).
  • the invention also encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), or (Ic) and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can further comprise at least one pharmaceutically acceptable excipient.
  • the compound of the invention can be manufactured according to a process comprising reacting a compound of formula (II):
  • the compounds of the invention can be manufactured according to a process comprising reacting a compound of formula (I-1):
  • Compounds of formula (I) can be prepared via an amide coupling between an indole 2-carboxylic acid (II) and a compound of formula (A-H), wherein A is defined as hereinabove.
  • the usual reagents and protocols known in the art can be used to effect the amide coupling.
  • Indole 2-carboxylic acids (II) are either commercially available or readily prepared using procedures described hereinafter.
  • the compounds of formula (A-H) are either commercially available or prepared using methods known in the art starting from commercially available materials.
  • General scheme A is hereinafter further illustrated with general procedure I.
  • Compounds of formula (I-2) (compounds of formula (I) wherein R 1 is different from H), can be prepared by alkylation of the indole derivative of formula (I-1), with an electrophile of formula R 1 -hal (commercially available, wherein hal is halo, preferably Cl or Br) using standard procedures.
  • Derivatives (I-1) are prepared using the amide coupling as described in the general scheme A.
  • Substituted indole 2-carboxylic acids can be prepared according to the general scheme C.
  • Indoles V are obtained by a Fischer indole synthesis from an aryl hydrazine III and a ⁇ -ketoester IV. Saponification gives an acid of formula II-a.
  • Boc protection of the indole nitrogen gives VI.
  • Selective bromination of the methyl group in the 7-position of the indole using NBS affords VII.
  • Subsequent nucleophilic substitution of 7-bromomethyl indole intermediate VII with NaCN or a secondary amine yields intermediates VIII and IX, respectively.
  • the corresponding carboxylics acids II-b and II-c are obtained.
  • the compounds of the present invention exhibit V1a activity, which may be detected as described below:
  • the human V1a receptor was cloned by RT-PCR from total human liver RNA.
  • the coding sequence was subcloned in an expression vector after sequencing to confirm the identity of the amplified sequence.
  • Cell membranes were prepared from HEK293 cells transiently transfected with the expression vector and grown in 20 liter fermenters with the following protocol.
  • the pellet was resuspended in 12.5 ml Lysis buffer+12.5ml Sucrose 20% and homogenized using a Polytron for 1-2 min.
  • the protein concentration was determined by the Bradford method and aliquots were stored at ⁇ 80° C. until use.
  • 60 mg Yttrium silicate SPA beads (Amersham) were mixed with an aliquot of membrane in binding buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, 10 mM MgCl2) for 15 minutes with mixing.
  • the present invention also provides pharmaceutical compositions containing compounds of the invention or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the pharmaceutical compositions also can be in the form of suppositories or injectable solutions.
  • compositions of the invention in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragées and hard gelatine capsules.
  • Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
  • Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
  • Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
  • Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
  • compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • a daily dosage of about 10 to 1000 mg per person of a compound of general formula (I) should be appropriate, although the above upper limit can also be exceeded when necessary.
  • Capsules of the following composition can be manufactured:
  • the active substance, lactose and corn starch can be firstly mixed in a mixer and then in a comminuting machine. The mixture then can be returned to the mixer, the talc can be added thereto and mixed thoroughly. The mixture can be filled by machine into hard gelatine capsules.
  • the suppository mass can be melted in a glass or steel vessel, mixed thoroughly and cooled to 45° C. Thereupon, the finely powdered active substance can be added thereto and stirred until it has dispersed completely.
  • the mixture can be poured into suppository moulds of suitable size, left to cool; the suppositories then can be removed from the moulds and packed individually in wax paper or metal foil.
  • the compounds of formula I may be prepared in accordance with the process variants as described above.
  • the starting materials described in the Example section are either commercially available or are otherwise known or derived from the chemical literature, for instance as cited below, or may be prepared as described in the Examples section.
  • the title compound is prepared by saponification of 3,7-dimethyl-1H-indole-2-carboxylic acid ethyl ester (prepared by Fischer indole synthesis as described in Tetrahedron Lett. 2003, 44, 5665) using the procedure described above for the synthesis of 5-chloro-7-cyanomethyl-1H-indole-2-carboxylic acid (acid 1, step g)).

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Cited By (7)

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WO2014152013A1 (fr) * 2013-03-14 2014-09-25 The Trustees Of Columbia University In The City Of New York 4-phénylpipéridines, leur préparation et leur utilisation
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use

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US20070197603A1 (en) * 2003-07-04 2007-08-23 Alessandra Consonni Substituted indole ligands for the orl-1 receptor
US7781436B2 (en) * 2005-07-29 2010-08-24 Hoffmann-La Roche Inc. Indol-3-y-carbonyl-piperidin and piperazin-derivatives

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CO5150201A1 (es) 1998-09-07 2002-04-29 Hoffmann La Roche Derivados de piperidina
IL152177A0 (en) 2000-05-12 2003-05-29 Solvay Pharm Bv Piperazine and piperidine compounds
HU227197B1 (en) * 2000-10-24 2010-10-28 Richter Gedeon Nyrt Nmda receptor antagonist carboxylic acid amide derivatives and pharmaceutical compositions containing them
WO2004035549A1 (fr) 2002-10-17 2004-04-29 Amgen Inc. Derives de benzimidazoles et utilisation de ceux-ci en tant que ligands du recepteur vanilloide
WO2008068184A1 (fr) * 2006-12-08 2008-06-12 F. Hoffmann-La Roche Ag Indoles agissant comme des antagonistes du récepteur v1a

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US20070197603A1 (en) * 2003-07-04 2007-08-23 Alessandra Consonni Substituted indole ligands for the orl-1 receptor
US7781436B2 (en) * 2005-07-29 2010-08-24 Hoffmann-La Roche Inc. Indol-3-y-carbonyl-piperidin and piperazin-derivatives

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8980924B2 (en) 2010-11-24 2015-03-17 The Trustees Of Columbia University In The City Of New York Non-retinoid RBP4 antagonist for treatment of age-related macular degeneration and stargardt disease
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US9926271B2 (en) 2013-03-14 2018-03-27 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US12473302B2 (en) 2013-03-14 2025-11-18 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
WO2014152013A1 (fr) * 2013-03-14 2014-09-25 The Trustees Of Columbia University In The City Of New York 4-phénylpipéridines, leur préparation et leur utilisation
US10787453B2 (en) 2013-03-14 2020-09-29 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US11919913B2 (en) 2013-03-14 2024-03-05 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10273243B2 (en) 2013-03-14 2019-04-30 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US11028098B2 (en) 2013-03-14 2021-06-08 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
US10421720B2 (en) 2013-03-14 2019-09-24 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US10570148B2 (en) 2013-03-14 2020-02-25 The Trustees Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
US9777010B2 (en) 2014-04-30 2017-10-03 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10913746B2 (en) 2014-04-30 2021-02-09 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10407433B2 (en) 2014-04-30 2019-09-10 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US11649240B2 (en) 2014-04-30 2023-05-16 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US10072016B2 (en) 2014-04-30 2018-09-11 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US12404277B2 (en) 2014-04-30 2025-09-02 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use
US9434727B2 (en) 2014-04-30 2016-09-06 The Trustees Of Columbia University In The City Of New York Substituted 4-phenylpiperidines, their preparation and use

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CL2007003504A1 (es) 2008-07-04
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US20080139550A1 (en) 2008-06-12
AU2007328993B2 (en) 2012-05-10
AU2007328993A1 (en) 2008-06-12
KR20120055716A (ko) 2012-05-31
EP2102186A1 (fr) 2009-09-23
US8026259B2 (en) 2011-09-27
JP2010511659A (ja) 2010-04-15
TWI349667B (en) 2011-10-01
CA2670139A1 (fr) 2008-06-12
US8076360B2 (en) 2011-12-13
MX2009005544A (es) 2009-06-05

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