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WO1997014671A1 - Antagonistes des recepteurs de la cyclopentyle-tachykinine - Google Patents

Antagonistes des recepteurs de la cyclopentyle-tachykinine Download PDF

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Publication number
WO1997014671A1
WO1997014671A1 PCT/US1996/016489 US9616489W WO9714671A1 WO 1997014671 A1 WO1997014671 A1 WO 1997014671A1 US 9616489 W US9616489 W US 9616489W WO 9714671 A1 WO9714671 A1 WO 9714671A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
fluorophenyl
methyl
methoxy
cyclopentane
Prior art date
Application number
PCT/US1996/016489
Other languages
English (en)
Inventor
Paul E. Finke
Malcom Maccoss
Laura C. Meurer
Sander G. Mills
Charles G. Caldwell
Ping Chen
Philippe L. Durette
Jeffery Hale
Edward Holson
Ihor Kopka
Albert Robichaud
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9602853.5A external-priority patent/GB9602853D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU10497/97A priority Critical patent/AU722883B2/en
Priority to JP51592997A priority patent/JP2002534955A/ja
Priority to EP96941315A priority patent/EP0858444A4/fr
Priority to CA 2234913 priority patent/CA2234913A1/fr
Publication of WO1997014671A1 publication Critical patent/WO1997014671A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/006—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by sulfur as hetero atom
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P25/06—Antimigraine agents
    • 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
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    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
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    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
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    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • Analgesia has historically been achieved in the central nervous system by opiates and analogs which are addictive, and peripherally by cyclooxygenase inhibitors that have gastric side effects.
  • Substance P antagonists may induce analgesia both centrally and peripherally.
  • substance P antagonists are inhibitory of neurogenic inflammation.
  • the neuropeptide receptors for substance P are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev.. 1983, 21, 85-141).
  • the NK-1 and NK-2 receptor subtypes are implicated in synaptic transmission (Laneuville et al., Life Sci.. 42: 1295-1305 (1988)).
  • the receptor for substance P is a member of the superfamily of G protein-coupled receptors. This superfamily is an extremely diverse group of receptors in terms of activating ligands and biological functions. In addition to the tachykinin receptors, this receptor superfamily includes the opsins, the adrenergic receptors, the muscarinic receptors, the dopamine receptors, the serotonin receptors, a thyroid-stimulating hormone receptor, a luteinizing hormone-choriogonadotropic hormone receptor, the product of the oncogene ras, the yeast mating factor receptors, a Dictvostelium cAMP receptor, and receptors for other hormones and neurotransmitters (A.D. Hershey, et al., J. Biol. Chem.. 1991, 226, 4366-4373).
  • Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue.
  • the tachykinins are distinguished by a conserved carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH2.
  • the known mammalian tachykinins include neurokinin A and neurokinin B.
  • the current nonmenclature designates the receptors for SP, neurokinin A, and neurokinin B as NK-1, NK-2, and NK-3, respectively.
  • substance P is a neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence (Chang et al.. Nature New Biol. 232. 86 (1971); D.F. Veber et aL, U.S. Patent No. 4.680.283).
  • Substance P is a pharmacologically-active neuropeptide that is produced in mammals and acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R.C. A. Frederickson et al, Science. 199. 1359 (1978); P.
  • Tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease FNeuroscience. 25 (3), 817-37 (1988) and D. Regoli in "Trends in Cluster Headache” Ed. F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (1987)], and emesis [Trends Pharmacol. Sci..
  • substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis [O'Byrne et al, Arthritis and Rheumatism. 33 1023-8 (1990)].
  • tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Chrohn's disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyperreflexia is reviewed in "Tachykinin Receptors and Tachykinin Receptor Antagonists,"
  • Neurokinin- 1 receptor antagonists alone or in combination with bradykinin receptor antagonists may also be useful in the prevention and treatment of inflammatory conditions in the lower urinary tract, especially cystitis [Giuliani, et al., J. Urology. 150. 1014-1017 (1993)].
  • cystitis et al., J. Urology. 150. 1014-1017 (1993)
  • Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al., Can. J. Pharmacol. Physiol.
  • Substance P may also play a 5 role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod, et. al., poster C.I.N.P. XVIIIth Congress, 28th June-2nd July, 1992], and in disorders of bladder function such as bladder detrusor hyper-reflexia [Lancet, 16th May 1992, 1239].
  • NK-2 receptor may be useful in the treatment of asthmatic disease (Frossard et al.. Life Sci..49. 1941-1953 ( 1991 ); Advenier, et al., Biochem. Biophvs. Res. Comm.. 184(3). 1418- 1424 (1992); P. Barnes, et al., Trends Pharmacol. Sci.. H, 185-189 (1993)).
  • Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular
  • SCLC small cell lung cancer
  • tachykinin receptor antagonists have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders
  • vasospastic diseases such as angina and Reynauld's disease
  • f ⁇ brosing and collagen diseases such as scleroderma and eosinophillic fascioliasis
  • reflex sympathetic dystrophy such as shoulder/hand syndrome
  • addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorder related to
  • immune enhancement or suppression such as systemic lupus erythmatosus (EPO Publication No. 0,436,334), ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis (EPO Publication No. 0.394.989).
  • Substance P antagonists may be useful in mediating neurogenic mucus secretion in mammalian airways and hence provide treatment and symptomatic relief in diseases characterized by mucus secretion, in particular, cystic fibrosis [S. Ramnarine, et al., abstract presented at 1993 ALA/ATS Int'l Conference, 16-19 May, 1993, published in Am. Rev, of Respiratory Dis.. May 1993].
  • 4.680.283 also discloses peptidal analogs of substance P.
  • Certain inhibitors of tachykinins have been described in U.S. Patent No. 4.501.733. by - replacing residues in substance P sequence by T ⁇ residues.
  • a further class of tachykinin receptor antagonists comprising a monomeric or dimeric hexa- or heptapeptide unit in linear or cyclic form, is described in GB-A-2216529.
  • the peptide-like nature of such substances make them too labile from a metabolic point of view to serve as practical therapeutic agents in the treatment of disease.
  • the non-peptidic antagonists of the present invention do not possess this drawback, as they are expected to be more stable from a metabolic point of view than the previously-discussed agents.
  • baclofen [ ⁇ -(aminoethyl)-4-chlorobenzenepropanoic acid] effectively blocks the excitatory activity of substance P.
  • WIPO patent applications PCT Publication Nos. WO 90/05525.
  • WO 92/12151 and WO 92/12152 and publications (Science. 251. 435-437 (1991); Science. 251. 437-439 (1991); J. Med. Chem..
  • a European patent application discloses various spirolactam- substituted amino acids and peptides which are antagonists or agonists of substance P.
  • a WIPO patent application (PCT Publication No. WO 92/06079) discloses fused-ring analogs of nitrogen-containing nonaromatic heterocycles as useful for the treatment of diseases mediated by an excess of substance P.
  • a WIPO patent application (PCT Publication No. WO 92/15585 discloses 1- azabicyclo[3.2.2]nonan-3-amine derivatives as substance P antagonists.
  • a WIPO patent application (PCT Publication No. WO 93/10073) discloses ethylenediamine derivatives as substance P antagonists.
  • WO 93/01169 discloses certain aromatic compounds as tachykinin receptor antagonists.
  • a publication (Life Sci.. 50. PL101- PL106 (1992)) discloses a 4-phenyl piperidine derivative as an antagonist of the neurokinin A (NK2) receptor. Howson et al. (Biorg. & Med. Chem. Lett.. 2 (6), 559-564
  • Publication 0.436.334 discloses certain 3-aminopiperidine compounds as substance P antagonists.
  • U.S. Patent No. 5.064.838 discloses certain 1,4- disubstituted piperidinyl compounds as analgesics.
  • PCT Publication No. WO 92/12128 discloses certain piperidine and pyrrolidine compounds as analgesics.
  • Peyronel, et al. (Biorg & Med. Chem. Lett.. 2 (1), 37-40 (1992)) disclose a fused ring pyrrolidine compound as a substance P antagonist.
  • EPO Publication No. 0.360.390 discloses certain spirolactam derivatives as substance P antagonists.
  • the present invention is directed to the novel compound of the structural formula I:
  • W is selected from the group consisting of: 10 (1) -0-,
  • X is selected from the group consisting of: 0 (1) hydrogen, and
  • Y is selected from the group consisting of: (1) a single bond, 5 (2) Cl-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
  • halo wherein halo is fluoro, chloro, bromo or iodo
  • R9 and R 10 are independently selected from:
  • Z is selected from the group consisting of:
  • Rl5 is selected from the group consisting of:
  • Rl5 and X may be joined together to form a 3- to 7-membered heterocyclic ring containing a group selected from: -NR3-, -CO-NR3-, -NR3- CO-, -S02-NR3-, -NR3-S02-,-S02-, -CO-0-, -0-C0-, -0-, and -CO-, and wherein the heterocyclic ring is optionally substituted with one or more of the substitutents selected from:
  • R3 is selected from the group consisting of: (1) hydrogen, (2) -R5, and
  • R5 is selected from the group consisting of:
  • heterocycle is selected from the group consisting of:
  • R6, R7 and R8 are independently selected from the group consisting of:
  • R l, Rl2 and Rl3 are independently selected from:
  • n is an integer selected from 1, 2 or 3.
  • Asymmetric centers may be present in the compounds of the instant invention depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixture and as pure or partially purified compounds are included within the ambit of this invention.
  • variable e.g., alkyl, aryl, Q, W, X, Y, Z, R5, R6, R7, R8, R9, RlO, Rl 1, Rl2, Rl3, Rl4, Rl5, etc.
  • alkyl includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration.
  • alkyl include methyl, ethyl, propyl, isopropyl, butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 3- ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
  • Alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy.
  • Alkenyl is intended to include hydrocarbon chains of a specified number of carbon atoms of either a straight- or branched- configuration and at least one unsaturation, which may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethylpentyl, and the like, and includes E and Z forms, where applicable.
  • Halogen or “halo”, as used herein, means 5 fluoro, chloro, bromo and iodo.
  • aryl means phenyl or naphthyl either unsubstituted or substituted with one or more substituents selected from the group consisting of halo, Cl-4-alkyl, Cl-4-alkoxy, -N02, -CF3, Cl-4-alkylthio, OH, -N(R9R10), -C02R9, C l -4-perfluoroalkyl,
  • heteroaryl means an unsubstituted, monosubstituted or disubstituted five or six membered aromatic heterocycle comprising from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are members
  • R3 is attached directly to the cyclopentyl ring.
  • salts include, but are not limited to salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate,
  • hydrobromide, and nitrate or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, pamoate, salicylate and stearate.
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum,
  • R° R7 and R ⁇ is heterocycle, -(Cl-6alkyl)-heterocycle, or -N(heterocycle)-S ⁇ 2Rl4, wherein heterocycle and R 14 are as defined above.
  • A is selected from the group consisting of:
  • n 1 or 2.
  • One embodiment of the present invention is directed to the compounds of structural formula I, or a pharmaceutically acceptable salt 0 thereof, in which A is phenyl and W is -O- of the formula:
  • R3, R6, R7, R8, Rl l, Rl2, Rl3, Q, X, Y and Z are as defined above.
  • One group within the embodiment of the compounds of the invention where W is -O- is that wherein Q is other than hydrogen.
  • Another group within the embodiment of the compounds of the invention where W is -O- is that wherein Y is a single bond.
  • W is -O-
  • X is other than hydrogen.
  • W is -O-
  • R6, R7 and R8 is heterocycle, -(Cl-6alkyl)-heterocycle, or -N(heterocycle)-S ⁇ 2Rl4, wherein heterocycle and Rl4 are as defined above.
  • Another embodiment of the present invention is directed to the compounds of structural formula I, or a pharmaceutically acceptable salt thereof, in which A is phenyl and W is -NH- or -N(Cl-6alkyl)- of the formula: wherein R3, R6, R7, R8, Rl l, Rl2, R13, Q, X, Y and Z are as defined above.
  • W is -NH- or -N(C l_6 alkyl)- is that wherein Q is other than hydrogen.
  • W is -NH- or -N(Cl-6 alkyl)- is that wherein Y is a single bond.
  • W is -NH- or -N(Cl-6 alkyl)- is that wherein X is other than hydrogen.
  • W is -NH- or -N(Cl-6 alkyl)- is that wherein at least one of R6, R7 and R° * is heterocycle, -(Cl-6alkyl)-heterocycle, or
  • heterocycle and Rl4 are as defined above.
  • a third embodiment of the present invention is directed to the compounds of structural formula I, or a pharmaceutically acceptable salt thereof, in which A is phenyl and W is -NHCO- or -N(Cl-6alkyl)- CO- of the formula:
  • R3, R6, R7, R8, Rl l, Rl2, R13, Q, X, Y and Z are as defined above.
  • a fourth embodiment of the present invention is directed to the compounds of structural formula I, or a pharmaceutically acceptable salt thereof, in which A is phenyl and W is -NH- or -N(Cl-6alkyl)-CO- and Q and the carbon atom to which it is attached are absent of the formula:
  • R3, R6, R7, R8, Rl 1, Rl2, Rl3, Q, ⁇ t y an d Z are as defined above.
  • Rl5 and X may be joined together to form bicyclic compounds, for example, of the formula:
  • R3, R6, R7, R8, Rl 1, Rl2, Rl3, Q, w, X, Y and Z are as defined above.
  • a preferred embodiment of the present invention includes those compounds of structural formula I, or a pharmaceutically acceptable salt thereof, wherein:
  • 5 A is selected from the group consisting of:
  • Q is selected from the group consisting of: (1) hydrogen, and 0 (2) -CH3;
  • W is selected from the group consisting of:
  • X is hydrogen
  • Y is selected from the group consisting of: 0 (1) a single bond, and
  • Rl5 is selected from the group consisting of: hydrogen, -CH3, and -CH2CH2OCH3,
  • R3 is selected from the group consisting of:
  • R5 is selected from the group consisting of: (1) -NR9R10, wherein R9 and RlO are independently selected from:
  • heterocycle wherein the heterocycle is selected from the group consisting of: (A) imidazolyl,
  • heterocycle is unsubstituted or substituted with one or more substituent(s) selected from: (i) Cl-6 alkyl, unsubstituted or substituted with halo, -CF3, -OCH3, or phenyl, (ii) Cl-6 alkoxy, (iii) oxo, and (iv) hydroxy,
  • R6, R7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) -CF3,
  • Rl l, R 12 and Rl3 are independently selected from:
  • n 1 or 2; with the proviso that if W is -0-, -NH- or -N(CH3)-, then at least one of the following conditions must be met:
  • Y is a single bond, and/or (3) at least one of R6, R and R 0" is heterocycle, -(Cl-6alkyl)- heterocycle, or -N(heterocycle)-S ⁇ 2Rl4, wherein heterocycle and Rl4 are as defined above.
  • Q is selected from the group consisting of:
  • Y is selected from the group consisting of: (1) a single bond, and
  • Z is selected from the group consisting of: (1) -NR! 5-, wherein R 15 is selected from the group consisting of: hydrogen, -CH3, and -CH2CH2OCH3,
  • Z is optionally absent.
  • R3 is selected from the group consisting of: (1) -R5, and
  • R3 is absent.
  • R3 is -R5 or Cl-6 alkyl substituted with -R5, it is preferred that R5 is selected from the group consisting of:
  • heterocycle wherein the heterocycle is selected from the group consisting of:
  • -CO-heterocycle wherein heterocycle is as defined above.
  • a preferred embodiment is directed to those compounds in which R6, R7 and R8 are independently selected from the group consisting of: (1) hydrogen, (2) -CF3,
  • heterocycle wherein the heterocycle is selected from the group consisting of:
  • a particularly preferred embodiment is directed to those compounds in which the phenyl ring bearing R6, R7 and R8 is selected from:
  • a preferred embodiment is directed to those compounds in which Rl 1, Rl2 and R 13 are independently selected from: (1) hydrogen, and (2) fluoro.
  • a particularly preferred embodiment is directed to those compounds in which the phenyl ring bearing Rl 1, Rl2 and Rl3 is unsubstituted phenyl or is para-fluorophenyl.
  • Preferred compounds within the present invention include:
  • racemic mixture of A and B shown above can be named either as "(lRS,2RS,3RS)-2-(4-fluorophenyl)-3- azidocyclopentanecarboxylic acid methyl ester” or as "methyl 3-(SR)- azido-2-(SR)-(4-fluoro)phenyl-l-(SR)-carboxylate".
  • the preparation of compounds of Formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses detailing the preparation of the compounds of Formula I in a sequential manner are presented in the following reaction schemes. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures includes crystallization, normal phase or reverse phase chromatography. Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples wherein Rl, R2, R3, R4, R5, R6, R7, R8, R9, RlO, R l 1 , Rl2 and Rl3 are as defined above.
  • the triester may be cyclized by heating with sodium methoxide in dry methanol followed by treatment with aqueous HCl, to provide racemic cyclopentanone IV.
  • the methyl ester V may be formed from ketone IV by treatment with acidic methanol or diazomethane in ether.
  • ester V may be accomplished with various reducing agents, for example, sodium borohydride, lithium aluminum hydride, di-isobutyl aluminum hydride, lithium tri(sec-butyl)-borohydride and the like, or with hydrogen in the presence of a suitable catalyst, such as platinum oxide or 5% palladium on carbon, which provide the corresponding cis- and trans- alcohols VI and VII, respectively (Scheme 2).
  • a suitable catalyst such as platinum oxide or 5% palladium on carbon
  • Alcohols VI and VII may be interconverted by oxidation to ketone V with chromium trioxide, pyridinium chlorochromate, DMSO/oxalyl chloride/triethylamine or similar agents followed by reduction with one of the reagents given above. Separation of the enantiomers of esters VI and VII may be carried out by hydrolysis to the corresponding acids VIII and IX followed by fractional crystallization of the salts formed with R-(-)- ⁇ -methylbenzylamine or other suitable chiral, non-racemic bases.
  • O-alkylation of alcohols VI and VII may be carried out by several procedures, for example, treatment with sodium hydride followed by addition of a benzylic halide, alkylsulfonate or arylsulfonate; exposure of VI or VII to a benzylic trichloro-acetimidate in the presence of a strong acid such as trifluoromethane-sulfonic acid; or treatment with a benzylic trifluoromethansulfonic ester, to give ether XII.
  • Ester XII may be reduced with a hydride-reducing agent such as lithium aluminum hydride, lithium borohydride or di- isobutylaluminum hydride to provide the primary alcohol XIII, which may be further functionalized by standard acylation or etherification, reactions (Scheme 6).
  • a hydride-reducing agent such as lithium aluminum hydride, lithium borohydride or di- isobutylaluminum hydride
  • the hydroxyl group may be replaced by a leaving group such as a bromide (by exposure to tri- phenylphosphine-bromine or triphenylphosphine-carbon tetrabromide), an iodide (by treatment with methanesulfonyl chloride followed by sodium iodide) or a p-toluenesulfonate (by treatment with p-TsCl in the presence of a suitable base such as pyridine).
  • the leaving group may then be displaced by a variety of nucleophiles such as unsubstituted, mono- or disubstituted amines R9(RlO)NH, to give amine XIV.
  • a leaving group such as a bromide (by exposure to tri- phenylphosphine-bromine or triphenylphosphine-carbon tetrabromide), an iodide (by treatment with methanesulfonyl chlor
  • the leaving group may be displaced by azide anion and the azide group reduced by treatment with either triphenylphosphine/water or hydrogenation in the presence of a suitable metal catalyst to give the primary amine XV.
  • Primary amine XV may also be prepared by the route shown in Scheme 8. Hydrolysis of ester XII to the acid XVI, followed by formation of the acid chloride and exposure to aqueous ammonia, provides primary amide XVII. Reduction with borane-methyl sulfide, lithium aluminum hydride, or a similar reagent then gives amine XV.
  • the isocyanate may be treated with a chiral, non-racemic alcohol such as (R)-(+)-alpha-methylbenzyl alcohol to form diastereomeric carbamates XXIII, which after diastereomer separation by, for example, fractional crystallization or chromatography, may be converted to the non-racemic primary amine XXII by reduction or hydrolysis (Scheme 11).
  • a chiral, non-racemic alcohol such as (R)-(+)-alpha-methylbenzyl alcohol
  • Alkylation of amine XXII or amine XXVI may be carried out by treatment with a number of reagents, such as iodoacetamide or t- butyl bromoacetate (Scheme 13). With the latter compound, the t-butyl ester may be cleaved by exposure to trifluoroacetic acid, to provide the carboxylic acid XXVII, which after treatment with coupling reagents such as oxalyl chloride, DCC or EDAC/HOBt, followed by addition of a primary or secondary amine R9(RlO)NH gives carboxamide XXVIIl.
  • coupling reagents such as oxalyl chloride, DCC or EDAC/HOBt
  • the bromides produced above may be employed to alkylate amine XXII and XXVI.
  • treatment of amine XXVI with bromide XXXII in acetonitrile in the presence of a suitable base such as di-isopropylethylamine affords the N-alkylated product XXXIII (Scheme 15).
  • a suitable base such as di-isopropylethylamine
  • the cyclopentyl amines XXII and XXVI may also be alkylated with heteroarylalkyl subunits (Scheme 16).
  • Scheme 16 For example, treatment of amines XXII or XXVI with 4-(bromomethyl)-l,3-diacetyl- lH,3H-2-oxo-imidazole (prepared according to the procedure of R. Duschinsky and L. A. Dolan, J. Am. Chem. Soc. 70, 657 (1948)) followed by de-acetylation with methylamine gives the cyclopentylamine derivative XXXII.
  • Benzylamine derivatives may be prepared as shown in Scheme 18.
  • Treatment of ketone X with 4-methoxybenzylamine in the presence of a suitable reducing agent such as sodium cyanoborohydride provides a mixture of the cis and trans amines XXXIX and XL.
  • Alkylation with a benzyl halide, benzyl alkylsulfonate or benzyl arylsulfonate followed by acidic methanolysis and then hydrogenolysis with 10% Pd C provides the N-benzylated derivatives XLI and XLII.
  • Amide derivatives may be prepared as shown in Scheme 19. Methanolysis of ester XXXIX, followed by removal of the para- methoxybenzyl protecting group with hydrogen and palladium on carbon and then acylation with an activated acyl derivative such as an acid chloride, provides amide XLIII.
  • the amide nitrogen may be alkylated with an alkyl halide such as methyl iodide in the presence of sodium hydride, to give tertiary amide XLIV.
  • Derivatives with an additional substituent at the ring carbon to which Y is attached may be prepared as shown in Scheme 20.
  • XLV which can be intermediates XII, XLI, or XLII
  • a strong anhydrous base such as lithium diisopropylamide, LHMDS, sodium hydride, or potassium hydride
  • an electrophile such as an alkyl halide or alkyl sulfonate ester, or an allylic halide or allylic sulfonate ester, provides a compound with the alkyl group linked to the ring.
  • an electrophile such as an alkyl halide or alkyl sulfonate ester, or an allylic halide or allylic sulfonate ester, provides a compound with the alkyl group linked to the ring.
  • allyl bromide is employed, compound XL VI may be obtained by this procedure.
  • the olefin can be hydroborated under standard conditions and the trialkylborane oxidized with hydrogen peroxide to provide the 3-hydroxy ⁇ ropyl substituent. Heating this compound with or without strong acid catalysis may provide the lactone XLVII.
  • allyl-ester XL VI can be exposed to oxidizing conditions such as osmium tetroxide and then sodium periodate, or ozone gas at low temperature followed by dimethyl sulfide, or potassium permanganate, to provide the corresponding 2-oxo-ethyl substituent.
  • the azides XLIX and L can be converted directly to the primary amines LI and LII by either catalytic reduction, for example, with hydrogen and 10% Pd C in methanol, or by treatment with a trialkyl- or triaryl- phosphine, followed by hydrolysis (Scheme 22).
  • azides XLIX and L can be treated with trimethylphosphine in THF in the presence of 4 A molecular sieves followed by direct addition of an aryl or heteroaryl aldehyde, to produce the intermediate imine.
  • heteroaryl substituted benzaldehydes are described in Scheme 23.
  • the desired heteroaryl boronic acids LV are commercially available, they can be coupled directly with 3- bromobenzaldehyde derivatives LVI, by treatment with a palladium (0) reagent, such as tetrakis(triphenylphosphine)palladium, in the presence of aqueous sodium carbonate in dimethoxyethane, to give the biaryl product LVII.
  • a palladium (0) reagent such as tetrakis(triphenylphosphine)palladium
  • the bromide can be converted into the desired boronic acid by treatment with an alkylhthium reagent in THF at low temperature followed by addition of trimethyl or triisopropyl borate.
  • Hydrolysis to the boronic acid can be effected by treatment of the intermediate with aqueous base and then acid.
  • Preparation of some heteroaryl bromides can be ca ⁇ ied out by removing unneeded functionality from available precursors.
  • 5-bromothiazole can be prepared by diazotizing 2-amino-5-bromothiazole, followed by reduction with hypophosphorus acid. Treatment of 2,4-thiazolidinedione with phosphorus oxybromide, followed by selective reduction with zinc in acetic acid provides the isomeric 4-bromothiazole.
  • heteroaryl boronic acids can be prepared by direct metallation of the parent heterocycle.
  • furan can be metallated with n-butyllithium at the 2-position.
  • Treatment with triisopropyl borate and workup as above provides the desired boronic acid LIX.
  • the 3-bromobenzaldehyde LVI can be converted into the co ⁇ esponding boronic acid LX by protection of the aldehyde functionality, for example as the diethyl acetal LXI, followed by metal-halogen exchange with n-butyllithium and then treatment with a trialkyl borate. Hydrolytic workup then yields LX, which can then be coupled directly with heteroaryl bromides under the palladium catalyzed conditions given above.
  • the benzothiazole carboxaldehyde LXV can be prepared as shown in Scheme 27.
  • the commercially available benzothiazole LXVI is first demethylated with HBr in acetic acid. Reaction with hexamethylenetetramine in TFA followed by reformation of the methyl ether with trimethylsilyldiazomethane provides aldehyde LXV.
  • LXVI I The indole derivative LXVII is prepared by esterification of 5-methoxy-indole-2-carboxylic acid (LXVIII), bromination and then hydrolysis to provide the 4-bromo derivative LXIX (Scheme 28). Sequential treatment with copper cyanide in refluxing dimethyl ⁇ acetamide, then hydrogenation in the presence of Raney nickel and semicarbazide, and finally hydrolysis with pyruvic acid in acetic acid yields the desired aldehyde intermediate LXVII.
  • the 2-substituted thiazole LXX is prepared as outlined in Scheme 29. Condensation of the pyridine derivative LXXI and diethyl bromomalonate yields the thiazole LXXI Alkylation of the hydroxyl group under standard conditions, followed by reduction and mild reoxidation then provides the aldehyde LXX. SCHEME 30
  • Benzothiophene LXXIII is synthesized according to the route given in Scheme 30. S-alkylation of thiol LXXIV with methyl bromoacetate provides the benzothiophene LXXV. Alkylation of the hydroxyl under standard conditions followed by reduction and mild reoxidation then provides the aldehyde LXXIII.
  • the indole derivative LXXXII is prepared according to the procedure of Dobson et. al (Dobson, D. R.; Gilmore, J. Long, D. A. Syn. Lett. 1992, 79) outlined in Scheme 34. Protection of the aldehyde in 2- nitrobenzaldehyde by ketal formation under standard conditions provides the dibutyl acetal LXXXIII. Treatment with vinyl magnesium bromide followed by aqueous acid then yields the desired aldehyde.
  • the tetrazole intermediate LXXXIV was prepared as shown in Scheme 35.
  • the commercially available amino acid LXXXV is treated with triethyl orthoformate in warm acetic acid followed by addition of sodium azide to give tetrazole acid LXXXVl.
  • Esterification and then reduction with lithium borohydride provided the alcohol, which was converted to the bromide LXXXIV with triphenylphosphine dibromide.
  • the synthesis of the thioalkyl intermediate CII is described in Scheme 41.
  • the methyl benzoate derivative CI was alkylated under standard basic conditions, the ester was reduced, and the primary alcohol was brominated to yield the desired benzyl bromide CII.
  • Oxidation to the sulfoxide CIII or to the sulfone CIV can be carried out by treatment with different ratios of Oxone® (potassium peroxy monosulfate).
  • Alkylation under basic conditions provides a mixture of 1- alkyl- and 2-alkyl tetrazoles CXXXV, which can be converted to the desired azide intermediates by hydrogenolytic deprotection and then by treatment with zinc diazide bis(pyridine) complex and imidazole in the presence of diethylazodicarboxylate and triphenylphosphine to provide azido tetrazoles CXXXVI.
  • the compounds of this invention are useful for antagonizing tachykinins, in particular substance P and neurokinin A in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, pain or migraine and asthma in a mammal in need of such treatment. This activity can be demonstrated by the following assays.
  • the cDNA for the human NK1R was cloned into the expression vector pCDM9 which was derived from pCDM8 (INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+) into the Sac II site.
  • Transfection of 20 ug of the plasmid DNA into 10 million COS cells was achieved by electroporation in 800 ul of transfection buffer (135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 uF using the IBI GENEZAPPER (IBI, New Haven, CT).
  • the cells were incubated in 10% fetal calf semm, 2 mM glutamine, lOOU/ml penicillin-streptomycin, and 90% DMEM media (GIBCO, Grand Island, NY) in 5% C ⁇ 2 at 37°C for three days before the binding assay.
  • the cDNA was subcloned into the vector pRcCMV (INVITROGEN).
  • Transfection of 20 ug of the plasmid DNA into CHO cells was achieved by electroporation in 800 ul of transfection buffer suplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 uF using the IBI GENEZAPPER (IBI).
  • the transfected cells were incubated in CHO media [10 % fetal calf se m, 100 U/ml pennicilin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml G418 (GIBCO)] in 5% C ⁇ 2 at 37°C until colonies were visible. Each colony was separated and propagated. The cell clone with the highest number of human NKIR was selected for subsequent applications such as dmg screening.
  • the binding assay of human NKIR expressed in either COS or CHO cells is based on the use of 125l-substance P (125I-SP, from DU PONT, Boston, MA) as a radioactively labeled ligand which competes with unlabeled substance P or any other ligand for binding to the human NKIR.
  • 125I-SP 125l-substance P
  • Monolayer cell cultures of COS or CHO were dissociated by the non-enzymatic solution (SPECIALTY MEDIA, Lavallette, NJ) and resuspended in appropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon) such that 200 ul of the cell suspension would give rise to about 10,000 cpm of specific 125I-SP binding (approximately 50,000 to 200,000 cells).
  • the binding buffer 50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon
  • the binding assay 200 ul of cells were added to a tube containing 20 ul of 1.5 to 2.5 nM of 125I-SP and 20 ul of unlabeled substance P or any other test compound. The tubes were incubated at 4°C or at room temperature for 1 hour with gentle shaking. The bound radioactivity was separated from unbound radioactivity by GF/C filter (BRANDEL, Gaithersburg, MD) which was pre-wetted with 0.1 % polyethylenimine. The filter was washed with 3 ml of wash buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl) three times and its radioactivity was determined by gamma counter.
  • wash buffer 50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl
  • NKIR The activation of phospholipase C by NKIR may also be measured in CHO cells expressing the human NKIR by determining the accumulation of inositol monophosphate which is a degradation product of IP3.
  • CHO cells are seeded in 12- well plate at 250,000 cells per well. After incubating in CHO media for 4 days, cells are loaded with 0.025 uCi/ml of 3H-myoinositol by ovemight incubation. The extracellular radioactivity is removed by washing with phosphate buffered saline. LiCl is added to the well at final concentration of 0.1 mM with or without the test compound, and incubation is continued at 37°C for 15 min.
  • Substance P is added to the well at final concentration of 0.3 nM to activate the human NKIR. After 30 min of incubation at 37°C, the media is removed and 0.1 N HCl is added. Each well is sonicated at 4°C and extracted with CHCl3/methanol (1 : 1). The aqueous phase is applied to a 1 ml Dowex AG 1X8 ion exchange column. The column is washed with 0.1 N formic acid followed by 0.025 M ammonium formate-0.1 N formic acid. The inositol monophosphate is eluted with 0.2 M ammonium formate-0.1 N formic acid and quantitated by beta counter.
  • the intrinsic tachykinin receptor antagonist activities of the compounds of the present invention may be demonstrated by this assay.
  • the compounds of the following examples have activity in the aforementioned assay in the range of 0.05 nM to 10 ⁇ M.
  • the activity of the present compounds may also be demonstrated by the assay disclosed by Lei, et al., British J. Pharmacol.. 105. 261-262 (1992).
  • the compounds of the present invention are useful in the prevention and treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin, in particular substance P, activity.
  • disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; epilepsy; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral neuropathy, for example AIDS related neuropathy, diabetic neuropathy, chemotherapy- induced neuropathy, and postherpetic and other neuralgias; small cell carcinomas such as small cell lung cancer; respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, acute bronchitis, diffuse panbronchilitis, emphysema, cystic fibrosis, asthma, and bronchospasm; airways disease modulated by neurogenic inflammation; laryngopharhngitis; bronchiectas
  • these compounds may be readily adapted to therapeutic use for the treatment of physiological disorders associated with an excessive stimulation of tachykinin receptors, especially neurokinin- 1 , and as neurokinin- 1 antagonists in the control and/or treatment of any of the aforesaid clinical conditions in mammals, including humans.
  • the compounds of the present invention are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
  • the compounds of the present invention are particularly useful in the treatment of nausea or emesis, including acute, delayed, post-operative, late-phase, and anticipatory emesis, such as emesis or nausea induced by for example chemotherapy, radiation, surgery, migraine, toxins, such as metabolic or microbial toxins, viral or bacterial infections, pregnancy, vestibular disorder, motion, mechanical stimulation, gastrointestinal obstmction, reduced gastrointestinal motility, visceral pain, psychological stress or disturbance, high altitude, weightlessness, opioid analgesics, intoxication, resulting for example from consumption of alcohol, and variations in intercranial pressure.
  • the compounds are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy.
  • chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, alkyl sulfonates and other compounds with an alkylating action such as nitrosoureas, cisplatin, and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
  • alkylating agents for example, nitrogen mustards, ethyleneimine compounds, alkyl sulfonates and other compounds with an alkylating action such as nitrosoureas, cisplatin, and dacarbazine
  • antimetabolites for example, folic acid, purine or pyrimidine antagonists
  • mitotic inhibitors for example, vinca alkaloids and derivatives of podophyllotoxin
  • cytotoxic antibiotics include cytotoxic antibiotics.
  • chemotherapeutic agents are described, for example, by D. J. Stewart in "Nausea and Vomiting:
  • chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, and chlorambucil [R.
  • the compounds of the present invention are also of use in the treatment of emesis induced by radiation including radiation therapy such as in the treatment of cancer, or radiation sickness, and in the treatment of post-operative nausea and vomiting.
  • the compounds of the present invention are also of use in the prevention or treatment of disorders of the central nervous system such as anxiety, psychosis and schizophrenia; neurodegenerative disorders such as senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstmctive airways disease, broncho-pneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, osteoarthritis, rheumatoid arthritis and fibromyalgia; adverse immunological reactions such as rejection of transplanted tissues; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; disorders of blood flow caused by vasodilation; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions or the transmission of pain
  • the compounds of the present invention are also particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example: neuropathy, such as diabetic or peripheral neuropathy and chemotherapy-induced neuropathy; postherpetic and other neuralgias; inflammatory bowel disease; acute and chronic pain, such as post-operative pain, cancer-related pain, neuritic pain syndromes, and fibromyalgia; asthma; osteoarthritis; rheumatoid arthritis; psoriasis; and especially migraine, either alone or in combination or co-administration with other antiinflammatory or analgesic agents.
  • neuropathy such as diabetic or peripheral neuropathy and chemotherapy-induced neuropathy
  • postherpetic and other neuralgias such as inflammatory bowel disease
  • acute and chronic pain such as post-operative pain, cancer-related pain, neuritic pain syndromes, and fibromyalgia
  • asthma osteoarthritis
  • rheumatoid arthritis psoriasis
  • the compounds of the present invention are also particularly useful in the treatment of diseases characterized by neurogenic mucus secretion, especially cystic fibrosis.
  • the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for extemal, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non- toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, com starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
  • the present invention is further directed to a method for the manufacmre of a medicament for antagonizing the effect of substance P or another tachykinin at its receptor site or for the blockade of neurokinin- 1 receptors or other tachykin receptors in a mammal comprising combining a compound of the present invention with a pharmaceutical canier or diluent.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present - invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • the liquid forms in which the novel compositions of the present invention may be inco ⁇ orated for administration orally or by injection include aqueous solution, suitably flavoured syrups, aqueous or oil suspensions, and emulsions with acceptable oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, or with a solubilizing or emulsifying agent suitable for intravenous use, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpy ⁇ olidone or gelatin.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
  • Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the compounds of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • a compound of the present invention for the treatment of certain conditions it may be desirable to employ a compound of the present invention in conjunction with another pharmacologically active agent(s).
  • a compound of the present invention and the other pharmacologically active agent(s) may be administered to a patient simultaneously, sequentially or in combination.
  • the present compound may employed directly in combination with the other active agent(s), or it may be administered prior, concu ⁇ ent or subsequent to the administration of the other active agent(s).
  • the cu ⁇ ently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
  • a compound of the present invention may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate, or sequential use for the relief of emesis.
  • Such combined preparations may be, for example, in the form of a twin pack.
  • a prefe ⁇ ed combination comprises a compound of the present invention with a chemotherapeutic agent such as an alkylating agent, antimetabolite, mitotic inhibitor, or cytotoxic antibiotic, as described above.
  • the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5- lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin- 1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenid
  • an antiinflammatory or analgesic agent such as an
  • the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextrametho ⁇ han; a diuretic; and a sedating or non-sedating antihistamine.
  • a pain reliever such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide
  • a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephine
  • a compound of the present invention may be used in conjunction with a bronchodilator, such as a ⁇ 2-adrenergic receptor agonist or a tachykinin antagonist which acts at neurokinin-2 receptors.
  • a bronchodilator such as a ⁇ 2-adrenergic receptor agonist or a tachykinin antagonist which acts at neurokinin-2 receptors.
  • Suitable ⁇ 2- adrenergic receptor agonist include: Bambuterol (US 4,419,364 issued to Draco on 12/6/83); Bitolterol mesylate (US 4,138,581 issued to Sterling 2/6/79); Brosaterol (US 4,276,299 issued to Zambon 6/30/81 and US 4,520,200 issued to Zambon 5/28/85); Carbuterol (US 3,763,232 issued to Smith Kline 10/2/73); Clenbuterol (US 3,536,712 issued to Boehringer Ingelheim 10/27/70); Cimaterol (US 4,407,819 issued to American Cyanamid 10/4/83); Doca ⁇ amine (US 4,228,183 issued to Tanabe 10/14/80); Dopexamine (US 4,645,768 issued to Fisons 2/24/87); Formoterol (US 3,994,974 issued to Yamanouchi 11/30/76); Mabuterol (US 4,119,710 issued to Boehringer Ingelheim
  • a compound of the present invention may be used in conjunction with a tachykinin antagonist which acts at neurokinin-2 receptors, or with tachykinin receptor antagonist which acts at both neurokinin- 1 and neurokinin-2 receptors.
  • a compound of the present invention may be employed with a leucotriene antagonist, such as a leucotriene D4 antagonist, exemplfied by those disclosed in Patent Pub. EP 0,480,717, published April 15, 1992; Patent Pub. EP O 604,114, published June 1994; US Patent No. 5,270,324, issued December 14, 1993; and US Patent No. 4,859,692, issued August 22, 1989.
  • a leucotriene antagonist such as a leucotriene D4 antagonist
  • a compound of the present invention further may be used in conjunction with a corticosteroid such as Dexamethasone, Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent Nos. 2,789,118, 2,990,401, 3,048,581 , 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712.
  • a corticosteroid such as Dexamethasone, Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.Patent Nos. 2,789,118, 2,990,401, 3,048,581 , 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712.
  • a compound of the present invention may be used in conjunction with other anti-emetic agents, especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, decadron, and zatisetron, or GABA ⁇ receptor agonists, such as baclofen.
  • 5HT3 receptor antagonists such as ondansetron, granisetron, tropisetron, decadron, and zatisetron
  • GABA ⁇ receptor agonists such as baclofen.
  • a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5HT ⁇ agonists, especially sumatriptan.
  • a compound of the present invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine.
  • NMDA N-methyl D-aspartate
  • a compound of the present invention may be used in conjunction with an antiinflammatory agent, such as a bradykinin receptor antagonist.
  • the compound of the present invention and the other pharmacologically active agent may be administered to a patient simultaneously, sequentially or in combination.
  • the compounds of this invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concu ⁇ ent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
  • an appropriate dosage level will generally be about 0.001 to 50 mg per kg patient body weight per day which may be administered in single or multiple doses.
  • the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.05 to 10 mg/kg per day, and especially about 0.1 to 5 mg/kg per day.
  • a compound may be administered on a regimen of multiple times per day, such as 1 to 4 times per day, preferably once or twice per day.
  • a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially about 0.05 to 5 mg/kg per day.
  • a compound may be administered on a regimen of multiple times per day, such as 1 to 4 times per day, preferably once or twice per day.
  • Step A ⁇ - ⁇ -Dicarboxy- ⁇ -phenyl-n-valeric acid
  • Step B Trimethyl ⁇ - ⁇ -dicarboxy- ⁇ -phenyl-n- valerate Into a solution of 21.2 g of the above triacid dissolved in 200 mL of methanol was bubbled 48.6 g of HCl gas. After heating at reflux ovemight, the cooled reaction was concentrated and diluted with toluene. Most of the aqueous bottom phase was removed via pipette and the toluene was evaporated. The residue was taken up in 200 mL of methanol and resaturated with HCl gas (53.5 g).
  • Step C trans-(-t-/-)-2-Phenylcyclopentan-3-one- 1 -carboxylic acid
  • Step D Methyl trans-(+/-)-2-phenylcyclopentan-3-one-l- carboxylate
  • Step D n 5 mL of dry THF under N2 and cooled in a dry ice/acetone bath was added 5 dropwise 0.55 mL of IM L-Selectride in THF. After 1 h, the reaction was quenched with dilute HCl. The mixture was extracted twice with ether and the organic layers were washed with brine, combined, dried with sodium sulfate and evaporated.
  • Example 2 Method A and 525 mg of 3,5-bis(trifluoromethyl)-benzyl bromide in 5 mL of DMF at room temperature was added 91 mg of 60% NaH in mineral oil. After 3 h, the reaction was quenched with dilute HCl and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried with sodium sulfate and evaporated.
  • Step A 3-(SR)-(3 ,5-Bis(trifluoromethyl)phenyl)methoxy )-2-(RS)- phenylcyclopentane- 1-(RS .-carboxylic acid
  • Step B 3-(SR)-(3,5-Bis(trifluoromethyl)phenyl)methoxy)-2-(SR)- phenylcyclopentyl- 1 -(RS V isocyanate
  • Step A l-(SR)-(3,5-Bis(trifluoromethyl)phenyl)methoxy-2-(SR)- phenyl-3-(RS)-(N-(benzyloxycarbonyl)-N-methylamino) cyclopentane
  • Step B l-(SR)-(3,5-Bis(trifluoromethyl)phenyl)methoxy-2-(SR)- phenyl-3-(RS)-(methylamino)cyclopentane
  • Step A (+/-)- 1 -(3.5-Bis(trifluoromethv)phenyl)- 1 -hvdroxyethane
  • Step B (+/-)-( 1 -(3, 5-Bis(trifluoromethyl)phenyl)ethyl) trichloroacetamidate
  • anhydrous ether 160 mg of 60% sodium hydride in mineral oil.
  • 10.3 g of the above racemic alcohol dissolved in 25 mL of ether was added.
  • the reaction was warmed slightly and sti ⁇ ed until a homogeneous solution was obtained.
  • the solution was added via canula to a solution of 4.0 mL of trichloroacetonitrile in 10 mL of ether cooled in an ice bath. After 1 h an amber color was produced and the reaction was concentrated to give 15.6 g of the title product as an amber oil.
  • Step C (+/-)- 1 -(3.5-Bis(trifluoromethyl)phenyl)ethyl bromide 7/14671 PC77US96/16489
  • Step D Methyl 3-(SR)-(l-(SR)-(3,5-bis(trifluoromethyl) phenylethoxy)-2-(RS)-phenylcyclopentane- 1 -(RS)- carboxylate (higher Rf ⁇ -methyl isomer)and methyl 3-(SR)- (l-(RS)-(3,5-bis(trifluoromethyl)phenyl)-ethoxy)-2-(RS)- phenylcyclopentane- 1 -(RS)-carboxylate (lower Rf ⁇ -methyl isomer) (Racemic 2.3-trans isomers)
  • Step D Another 40 mL of dry benzene was added to the above solution of acyl azide and the solution was heated at 80°C for 2 h and then evaporated to give cmde isocyanate as an oil.
  • Step E The above isocyanate was dissolved in 8 mL of toluene and treated with 1 g of (S)-(-)- ⁇ -methylbenzyl alcohol, 0.66 mL of diisopropylamine and 15 mg of dimethylaminopyridine. The resulting solution was heated at 100°C ovemight and then evaporated. Purification on a silica gel flash column (5 to 20% ethyl acetate in hexanes) gave 193 mg of pure higher Rf isomer and 180 mg of pure lower Rf isomer. Higher Rf isomer.
  • Example 27 and iodoacetamide using essentially the same procedure as Example 10. Mass spec (NH3/CI): 475 (M+l ).
  • Step A (R)-(+/-)- ⁇ -Methylbenzylammonium 3-(S)-(hydroxy)-2-
  • Step B (S)-(-)- ⁇ -Methylbenzylammonium 3-(R)-(hydroxy)-2-(S)-
  • Step C 3-(S)-(Hydroxy)-2-(R)-(4-fluorophenyl)cyclopentane-l-£RJt carboxylic acid
  • Step D 3-(R)-(Hydroxy)-2-(S)-(4-fluoro ⁇ henyl)cyclopentane- 1 -(S)- carboxylic acid
  • the salt from Step B was dissolved in water and acidified with 2N HCl and was extracted with 3 portions of ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give a white solid.
  • Step E Methyl 3-(S)-(hydroxy)-2-(R)-(4-fluorophenyl)cyclo- pentane- 1 -(R)-carboxylate
  • Step F Methyl 3-(R)-(hydroxy)-2-(S)-(4-fluorophenyl)cyclo- pentane- l-(S)-carboxylate
  • Example 33 Using essentially the same procedures as in Example 33, the title compounds were prepared from the higher Rf 2,3-cis alcohol from Example 32.
  • Step A (R)-(+/-)- ⁇ -Methylbenzylammonium 3-(S)-(hydroxy)-2- (S)-(4-fluorophenyl)cyclopentane- 1 -(S)-carboxylate
  • Step B (S)-(-)- ⁇ -Methylbenzylammonium 3-(R)-(hydroxy)-2-(R)- (4-fluorophenyl)cvclopentane- 1 -(R)-carboxylate
  • Step C 3-(S)-(Hydroxy)-2-(S)-(4-fluorophenyl)cyclopentane-l-(S)- carboxylic acid
  • Step D 3-(R)-(Hydroxy)-2-(R)-(4-fluorophenyl)cyclopentane- 1 -(R)- carboxylic acid
  • Step A Methyl 2-(S)-(4-fluorophenyl)cyclopentan-3-one-l-(S)- carboxylate Method A:
  • Step B Methyl 3-(S)-(hydroxy)-2-(S)-(4-fluorophenyl)- cyclopentane- 1 -(S)-carboxylate
  • a solution of 0.55 g of crude ketone prepared as in Step A in 30 mL of THF was cooled in an ice bath and 3.2 mL of IM L-Selectride was added. The ice bath was removed and the reaction was sti ⁇ ed at room temperature for 2 h before being quenched with 2N HCl. The mixture was extracted twice with ethyl acetate and the organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated.
  • Example 5 Following essentially the same procedures as in Example 5, 8, 9 (Method B), 11, 19, 20 and 21, but using non-racemic ether from Example 37 (lower Rf ⁇ -methyl isomer), the title compounds were prepared.
  • Example 5 Following essentially the same procedures as in Example 5, 8, 9 (Method B), 11, 19, 20 and 21, but using non-racemic ether from Example 38 (lower Rf ⁇ -methyl isomer), the following compounds were prepared.
  • Method A To a solution of 1.9 g of alcohol from Example 41 in 50 mL of dry acetonitrile at room temperature was added 2.0 g of triphenylphosphine dibromide. After 1 h an additional 700 mg of triphenylphosphine dibromide was added and the reaction was sti ⁇ ed a further 1 h. The reaction was quenched with sodium bicarbonate solution and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 10% ethyl acetate in hexanes to obtain 708 mg of title compound and 484 mg of recovered strating material.

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Abstract

L'invention concerne de nouveaux composés représentés par la formule développée (I) ou leurs sels pharmaceutiquement acceptables. Dans ladite formule, R?3, R6, R7, R8, R11, R12, R13¿, A, Q, W, X, Y, Z et n correspondent à la définition donnée dans la description. L'invention concerne également des formulations pharmaceutiques comportant comme ingrédients actifs ces composés, ainsi que l'utilisation de ces composés et de leurs formulations dans le traitement de certains troubles. Les composés selon l'invention sont des antagonistes des récepteurs des tachykinines et sont utiles dans le traitement des maladies inflammatoires, des douleurs et des migraines, de l'asthme et des vomissements.
PCT/US1996/016489 1995-10-18 1996-10-15 Antagonistes des recepteurs de la cyclopentyle-tachykinine WO1997014671A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU10497/97A AU722883B2 (en) 1995-10-18 1996-10-15 Cyclopentyl tachykinin receptor antagonists
JP51592997A JP2002534955A (ja) 1995-10-18 1996-10-15 シクロペンチルタキキニン受容体アンタゴニスト
EP96941315A EP0858444A4 (fr) 1995-10-18 1996-10-15 Antagonistes des recepteurs de la cyclopentyle-tachykinine
CA 2234913 CA2234913A1 (fr) 1995-10-18 1996-10-15 Antagonistes des recepteurs de la cyclopentyle-tachykinine

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US555895P 1995-10-18 1995-10-18
US60/005,558 1995-10-18
GBGB9602853.5A GB9602853D0 (en) 1996-02-13 1996-02-13 Treatment of hyperandrogenic conditions
GB9602853.5 1996-02-13

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US5929094A (en) * 1996-10-25 1999-07-27 Merck & Co., Inc. Heteroaryl spiroethercycloalkyl tachykinin receptor antagonists
US5877191A (en) * 1996-10-25 1999-03-02 Merck & Co., Inc. Phenyl spiroethercycloalkyl tachykinin receptor antagonists
EP1126833A4 (fr) * 1998-10-29 2004-09-08 Trega Biosciences Inc Derives oxadiazole, thiadiazole et triazole et bibliotheques combinatoires contenant ces derives
US7612090B2 (en) 1999-11-03 2009-11-03 Albany Molecular Research, Inc. Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof
US7163949B1 (en) 1999-11-03 2007-01-16 Amr Technology, Inc. 4-phenyl substituted tetrahydroisoquinolines and use thereof
US7265116B2 (en) 1999-11-03 2007-09-04 Arm Technology, Inc. Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof
US7309789B2 (en) 2000-07-11 2007-12-18 Amr Technology, Inc. 4-phenyl substituted tetrahydroisoquinolines and therapeutic use thereof
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JP2002534955A (ja) 2002-10-15
AU722883B2 (en) 2000-08-10

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