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WO1998017276A1 - Antagonistes heteroaryle spiroethercycloalkyle de recepteurs de la tachykinine - Google Patents

Antagonistes heteroaryle spiroethercycloalkyle de recepteurs de la tachykinine Download PDF

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Publication number
WO1998017276A1
WO1998017276A1 PCT/US1997/019359 US9719359W WO9817276A1 WO 1998017276 A1 WO1998017276 A1 WO 1998017276A1 US 9719359 W US9719359 W US 9719359W WO 9817276 A1 WO9817276 A1 WO 9817276A1
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WIPO (PCT)
Prior art keywords
fluorophenyl
trifluoromethyl
oxa
spiro
tetrazol
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PCT/US1997/019359
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English (en)
Inventor
Philippe Durette
Ihor Kopka
Malcolm Maccoss
Sander Mills
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from GBGB9702922.7A external-priority patent/GB9702922D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU49998/97A priority Critical patent/AU4999897A/en
Publication of WO1998017276A1 publication Critical patent/WO1998017276A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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

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, 35, 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.
  • 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 Dictyostelium 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 known mammalian tachykinins include neurokinin A and neurokinin B .
  • the current nomenclature 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.
  • 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. Oehme et al., Science. 208. 305 (1980)) and plays a role in sensory transmission and pain perception (T.M. Jessell, Advan. Biochem. Psychopharmacol. 28. 189 (1981)).
  • substance P is believed to be involved in the neurotransmission of pain sensations [Otsuka et al, "Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia” in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Transmitter?” TIPS. 8 506-510 (Dec. 1987)], specifically in the transmission of pain in migraine (see B.E.B. Sandberg et al., Journal of Medicinal Chemistry. 25, 1009 (1982); M. A. Moskowitz, Trends Pharmacol. Sci..
  • Tachykinins have also been implicated in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease [Neuroscience, 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. 9. 334-341 (1988), Eur. J. Pharmacol.. 249.
  • 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
  • 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 role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod, et.
  • Antagonists selective for the neurokinin- 1 (NK-1) and/or the neurokinin-2 (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.. ii, 185-189 (1993)).
  • Tachykinin antagonists may also be useful in the treatment of small cell carcinomas, in particular small cell lung cancer (SCLC) [Langdon et al. , Cancer Research. 52, 4554-7 (1992)].
  • tachykinin receptor antagonists have utility in the following disorders: depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing 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 ( ⁇ PO Publication No.
  • ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like
  • 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 Trp 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..
  • 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.
  • PCT Publication No. 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.
  • 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.
  • U.S. Patent No. 4.804.661 discloses certain piperazine compounds as analgesics.
  • U.S. Patent No. 4.943.578 discloses certain piperazine compounds useful in the treatment of pain.
  • WO 92/01679 discloses certain 1 ,4-disubstituted piperazines useful in the treatment of mental disorders in which a dopaminergic deficit is implicated.
  • EPO Publication No. 0.577.394 and PCT Publication No. WO 95/16679 disclose certain morpholine and thiomorpholine compounds as substance P antagonists.
  • U.S. Patent No. 5.387.595 and Bioorg. & Med. Chem. Lett.. 1345 (1995) disclose certain alicyclic compounds as tachykinin receptor antagonist.
  • PCT Publications WO 95/06645 and WO 95/08549 discloses certain 3-amino- piperidines as tachykinin antagonists.
  • the invention is also concerned with pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders.
  • the compounds of this invention are tachykinin receptor antagonists and are useful in the treatment of inflammatory diseases, pain or migraine, asthma and emesis. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention is directed to the novel compound of the structural formula I:
  • R3 is selected from the group consisting of:
  • R4 is selected from the group consisting of: (1) hydroxy,
  • halo is fluoro, chloro, bromo or iodo
  • R9 and RlO may be joined together to form a 3-8 membered heterocyclic ring which may contain another heterogroup selected from: -0-, -NH-, -
  • heterocycle wherein the heterocycle is selected from the group consisting of:
  • R6, R7 and R8 are independently selected from the group consisting of:
  • n is an integer selected from 1 or 2;
  • n is an integer selected from 0, 1 or 2;
  • each of the two dashed lines denotes the presence of either a single or a double bond between the indicated carbon atoms, with the proviso that at least one of the dashed lines indicates the presence of a single bond.
  • 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.
  • alkyl includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration.
  • alkyl examples 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.
  • Hydrogen or “halo”, as used herein, means 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,
  • 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 selected from the group consisting of -OH, -SH, -Cl-4-alkyl, - Cl-4-alkoxy, -CF3, halo, -N ⁇ 2, -CO2R9,-N(R9R10) and a fused benzo group.
  • pharmaceutically acceptable 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, lithium and ammonium.
  • a preferred embodiment of the present invention includes those compounds of structural formula I, or a pharmaceutically acceptable salt thereof, wherein:
  • R3 is selected from the group consisting of:
  • R4 is selected from the group consisting of:
  • heterocycle wherein the heterocycle is selected from the group consisting of:
  • the circle A is a heteroaryl moiety which is selected from the group consisting of:
  • 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:
  • Rl l, Rl2 and Rl3 are independently selected from: (1) hydrogen, and
  • n is an integer selected from 1 or 2;
  • each of the two dashed lines denotes the presence of either a single or a double bond between the indicated carbon atoms, with the proviso that at least one of the dashed lines indicates the presence of a single bond.
  • R is selected from the group consisting of:
  • R4 or Cl-6 alkyl substituted with -R4 it is preferred that R4 is selected from the group consisting of:
  • heterocycle wherein the heterocycle is selected from the group consisting of:
  • A is selected from the group consisting of:
  • R6, and R8 are independently selected from the group consisting of:
  • heterocycle wherein the heterocycle is selected from the group consisting of:
  • Rl 1, Rl2 and Rl3 are independently selected from:
  • m is 1 and n is 1.
  • a particularly preferred embodiment is directed to those compounds in which the phenyl ring bearing Rl 1, Rl2 and Rl is unsubstituted phenyl or is para- fluorophenyl.
  • Specific compounds within the present invention include:
  • PTC phase transfer catalyst prep. prepared or preparative Pr propyl rt room temperature
  • 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.
  • the triester can 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 can be formed from ketone IV by treatment with acidic methanol or diazomethane in ether.
  • ketone V may be accomplished with various reducing agents, for example, sodium borohydride, 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
  • the ratio of VI to VII thus obtained is dependent on the reducing agent employed.
  • 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-(-)- ⁇ - or S-(+)- -methylbenzylamine or other suitable chiral, non-racemic bases.
  • the l-oxaspiro[4.4]non-3-ene ring system is prepared as shown in Scheme 5.
  • the ketone V is treated with 2-(acetoxy- methyl)-3-(trimethylstannyl)propene and boron trifluoride etherate at low temperature in methylene chloride to provide the desired diastereomer X and lesser amounts of the epimeric product.
  • alcohol X is cyclized by treatment with tetrakis(triphenylphosphine)palladium in the presence of LiHMDS and ZnCl2, to provide the spirocycle XI.
  • a suitable strong base such as lithium, sodium, or potassium hexamethyldisilazide, lithium diisopropylamide, lithium tetramethylpiperidide, or similar agents, followed by treatment with N-phenyl triflimide, 2-[N,N-trifluoro- methylsulfonyl)-amino]-5-chloropyridine (or related agents designed to transfer a trifluorometfianesulfonyl group to an alkoxide or enolate oxygen), provided the enol triflate XIII.
  • 3-aryl derivative is carried out as described in Scheme 6.
  • Treatment of stannane XIV with an appropriate aryl halide or aryl trifluoromethanesulfonate in the presence of catalytic bis(triphenylphosphine) palladium dichloride or related palladium catalysts provides the unsaturated 3-aryl spirocycle XV.
  • XV may be prepared by coupling enol triflate and aryl boronic acids in the presence of one of the above described catalytic systems.
  • Hydrogenation of the double bond under standard conditions such as transfer hydrogenation by treatment with ammonium formate in the presence of palladium hydroxide on carbon at elevated temperature, or by exposure to hydrogen gas at or above atmospheric pressure in the presence of a precious metal catalyst (such as palladium on carbon, ruthenium on carbon, platinum on carbon, rhodium on carbon and the like) or Raney nickel catalyst, provided the saturated derivative XVI.
  • a precious metal catalyst such as palladium on carbon, ruthenium on carbon, platinum on carbon, rhodium on carbon and the like
  • Raney nickel catalyst Raney nickel catalyst
  • the alcohol can also be converted into a leaving group, for example by treatment with triphenylphosphine/carbon tetrabromide or by formation of the corresponding tosylate or mesylate, followed by displacement with sodium iodide, to give either the bromide or iodide XX (Scheme 8). Treatment with an appropriate amine would then provide compound XIX.
  • SCHEME 9
  • the second strategy places the amine directly on the C7 carbon (see Scheme 9).
  • Hydrolysis of ester XVI under standard conditions gives the corresponding acid XXI, which can be activated under a number of conditions, such as by treatment with oxalyl chloride or through mixed anhydride formation.
  • the activated acyl derivative can then be treated with an azide salt, to provide acyl azide XXII.
  • Thermolysis under anhydrous conditions provides the rearranged isocyanate XXIII, which can be treated with benzyl alcohol to give the CBZ protected amine XXIV.
  • acid XXI may be treated with Ph2P(0)N3 (diphenyl phosphoryl azide) followed by thermolysis to directly provide isocyanate XXIII.
  • This material can then be deprotected to provide the free amine XXV.
  • it can be treated with a strong base (such as sodium hydride, LDA or NaHMDS) followed by a suitable alkyl or aralkyl halide, to give protected amine XXVI (Scheme 10). Deprotection under standard conditions would then provide free amine XXVII.
  • a strong base such as sodium hydride, LDA or NaHMDS
  • the isomeric bromide XXXV can be prepared as described in Scheme 12.
  • Treatment of 2-bromo-3-methoxypyridine (XXXII) with warm fuming nitric acid provides 2-bromo-3-methoxy-6-nitropyridine (XXXIII).
  • Reduction of the nitro group with tin metal in concentrated hydrochloric acid provides aminopyridine XXXIV.
  • Conversion of this compound to the 5-(trifluoromethyl)tetrazole XXXV can be achieved by sequential treatment with trifluoroacetic anhydride, followed by triphenylphosphine in carbon tetrachloride (to provide the imino chloride), and finally exposure to sodium azide in DMF.
  • the 2-(trif uoromethyl)imidazole derivative XXXVI can be prepared by treating aminopyridine XXXIV with trifluoroacetic anhydride, followed by triphenylphosphine in carbon tetrachloride and then 2- aminoacetaldehyde diethyl acetal. Deprotection, cyclization and aromatization can then be achieved by heating with acetic acid.
  • Removal of the BOC protecting group in the assembled oxaspiro nonyl structure can be carried out, for example, with zinc bromide in methylene chloride.
  • reaction schemes may be varied to facilitate the synthesis or to avoid unwanted reaction products.
  • TACHYKININ ANTAGONISM ASSAY 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 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 serum, 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% C02 at 37°C until colonies were visible. Each colony was separated and propagated. The cell clone with the highest number of human NK1R was selected for subsequent applications such as drug screening.
  • CHO media 10 % fetal calf serum, 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)
  • the binding assay of human NK1R expressed in either COS or CHO cells is based on the use of 125i-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 NK1R.
  • 125i-substance P 125I-SP, from DU PONT, Boston, MA
  • 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
  • NK1R The activation of phospholipase C by NK1R may also be measured in CHO cells expressing the human NK1R 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.
  • 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 shown 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.
  • These conditions may include 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, emphy
  • 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 obstruction, 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: Recent Research and Clinical Advances", Eds. J. Kucharczyk, et al. , CRC Press Inc., Boca Raton, Florida, USA (1991), pages 177-203, especially page 188.
  • 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. J. Gralla, et al., Cancer Treatment Reports. 68(1), 163-172 (1984)].
  • 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 obstructive 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 postoperative 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 postoperative 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 external, 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, corn 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 manufacture 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 carrier or diluent.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn 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.
  • liquid forms in which the novel compositions of the present invention may be incorporated 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, polyvinylpyrrolidone 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, concurrent or subsequent to the administration of the other active agent(s).
  • the currently 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 preferred 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 10
  • 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 5HTl agonists, especially sumatriptan.
  • a compound of the present invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMD A), such as dizocilpine.
  • NMD A 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, concurrent 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
  • a mixture of 47 g of benzaldehyde and 50 g of ethyl cyanoacetate in 200 mL of absolute ethanol was treated with 2 mL of piperidine and the reaction was gently warmed. After the initial exothermic reaction had subsided, the reaction was heated to 60°C (internal temperature) and then allowed to cool to room temperature. After 1 h, 22 g of powdered sodium cyanide was added in portions over 25 min and a mild exotherm ensued.
  • the reaction was heated to an internal temperature of 80°C and then allowed to cool to 35°C before slow addition of 60 g of ethyl b-chloropropionate over 10 min. After heating in an oil bath at 80°C for 5 h, the reaction was cooled and filtered to remove the precipitated sodium chloride. The filtrate was concentrated and to the residue was added 250 mL of water and 500 mL of concentrated HCl. The mixture was heated at reflux for 48 h and, while still hot, was treated with charcoal and filtered through Celite to remove some insoluble tarry material. On cooling, 25.8 g of the title compound as a pale yellow solid was obtained after filtration and air drying. The filtrate was extracted with EtOAc, washed with brine, dried with sodium sulfate and evaporated to provide an additional 32.8 g of less pure product which could be used directly.
  • Step B Trimethyl ⁇ - ⁇ -dicarboxy- ⁇ -phenyl-n-valerate
  • Step C trans-(+/-)-2-Phenylcyclopentan-3-one-l -carboxylic acid To 50 mL of anhydrous methanol was added a solution of
  • Step D Methyl trans-(+/-)-2-phenylcyclopentan-3-one-l- carboxylate
  • Step A (R)- ⁇ -Methylbenzylammonium 3-(S)-(hydroxy)-2-(R)-
  • Step B (S)-(-)- ⁇ -Methylbenzylammonium 3-(R)-(hydroxy)-2-
  • the salt from Step A was dissolved in water and acidified with 2N HCl and was extracted with 3 portions of EtOAc. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give a white solid.
  • Step D 3-(R)-(Hydroxy)-2-(S)-(4-fluorophenyl)cyclopentane-l- (S)-carboxylic acid
  • Step E Methyl 3-(S)-(hydroxy)-2-(R)-(4-fluorophenyl)cyclo- pentane- 1 -(R)-carboxylate
  • Step C and dissolved in ether and a solution of diazomethane was added portionwise until the yellow color persisted. The excess diazomethane was quenched with acetic acid and the volatiles were removed in vacuo.
  • Step F Methyl 3-(R)-(hydroxy)-2-(S)-(4-fluorophenyl)cyclo- pentane-l-(S)-carboxylate
  • Step G Methyl 2-(S)-(4-fluorophenyl)cyclopentan-3-one-l-(S)- carboxylate
  • Step A Methyl [l-(RS), 2-(SR), 3-(SR)]-2-(4-fluorophenyl)-l-(2-
  • reaction was quenched with 40 mL of sat'd NH4CI; the resulting mixture was partitioned between 250 mL of ether and 150 mL of H2O and the layers were separated. The organic layer was washed with 200 mL sat'd KF, 200 mL sat'd NaCl, dried over MgS04 and concentrated in vacuo.
  • Step B Methyl [5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3- (methylene)- l-oxaspiro[4.4]nonane-7-carboxylate
  • Tetrakis(triphenylphosphine)- palladium(O) (230 mg, 0.2 mmol) was added and the resulting mixture was heated at reflux for 20 h.
  • the reaction was cooled, quenched with 50 mL of sat'd NH4CI, partitioned between 200 mL of ether and 50 mL of H2O and the layers were separated.
  • the organic layer was washed with 50 mL of sat'd NaHC03, 50 mL of sat'd NaCl, dried over MgS04 and concentrated in vacuo.
  • Step C Methyl [5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3- (oxo)-l-oxaspiror4.41nonane-7-carboxylate
  • reaction was quenched with 2.0 g of sodium bisulfite; the quenched mixture was partitioned between 200 mL of CH2CI2 and 100 mL of H2O and the layers were separated. The organic layer was dried over MgS04. The aqueous layer was extracted with 200 mL of
  • the crude diol was dissolved in 40 mL of 4: 1 v/v THF/H2O; the resulting solution was treated with 1.50 g (7.0 mmol) of sodium periodate and stirred for 20 h at rt.
  • the reaction mixture was partitioned between 250 mL of ether and 100 mL of H2O and the layers were separated.
  • the organic layer was dried over MgS04.
  • the aqueous layer was extracted with 250 mL of ether; the extract was dried and combined with the original organic layer.
  • the combined organics were concentrated in vacuo. Flash chromatography on 40 g of silica gel using 3: 1 v/v hexanes/ether afforded 1.02 g (92%) of the title compound as an oil.
  • Step D Methyl [5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3- (trifluoromethylsulfonyl-oxy)- 1 -oxaspiro[4.4]non-3-ene-7- carboxylate
  • Step E Methyl [5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3-
  • Step F Methyl [5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3-(2- methoxy-5-((5-trifluoromethyl)tetrazol- 1 -yl)phenyl)- 1 - oxaspiro[4.4]non-3-ene-7-carboxylate a) 2-Bromo-4-aminoanisole A mixture of 670 mg (2.9 mmol) of 2-bromo-4- nitroanisole and 1.20 g (21.1. mmol) of iron powder in 10 mL of 1 : 1 v/v HOAc/H2 ⁇ was heated at 80 °C for 1.5 h.
  • (Ph3P)2PdCl2 in toluene can be used in place of (Ph3P)4Pd and LiCl in dioxane.
  • the reaction mixture was cooled and partitioned between 40 mL of ether and 20 mL of H20 and the layers were separated. The organic layer was washed with 20 mL of sat'd KF, 20 mL of sat'd NaCl, dried over MgS ⁇ 4 and concentrated in vacuo. Flash chromatography on 12 g of silica gel using 10: 1 v/v hexanes/EtOAc as the eluant afforded 81 mg (65%) of the title compound as an oil.
  • Step G Methyl [3-(SR), 5-(RS), 6-(SR), 7-(SR)]-6-(4- fluorophenyl)-3-2-methoxy-5-((5-trifluoromethyl)tetrazol- 1 -vDphenyl)- 1 -oxaspiror4.41nonane-7-carboxylate
  • the catalyst was filtered onto a pad of Celite, the reaction flask and filter cake were rinsed with 100 mL of EtOAc and the filtrate was concentrated in vacuo. The residue was partitioned between 50 mL of ether and 25 mL of sat'd NaHC03 and the layers were separated. The organic layer was washed with 25 mL of sat'd NaCl, dried over MgS04 and concentrated in vacuo. Flash chromatography on 6 g of silica gel using 20:7:2 v/v/v hexanes/CH2C12/ether as the eluant afforded 36 mg (33%) of the title compound as an oil.
  • the title compound was synthesized from 2-hydroxy-3- bromo-5-nitropyridine by the method of H. J. W. van den Haak et al, Recl.Trav. Chim. Pays-Bas 99(3), p83-87 (1980) using trimethyloxonium tetrafluoroborate in methylene chloride.
  • the title compound was synthesized in 70% yield by a tin metal reduction in concentrated hydrochloric acid of the nitro group as described by T. Batkowski, Roczniki Chemii, 41, p729-740, (1967).
  • Step D 2-Methoxy-3-bromo-5-(5-trifluoromethyl-tetrazol-l-yl)- pyridine
  • Step E (5R,6S,7S)-6-(4-fluorophenyl)-3-[2-methoxy-5-(5- trifluoromethyl-tetrazol-l-yl)-pyridin-3-yl]-l- oxaspiro[4.41non-3-ene-7-carboxylic acid methyl ester
  • the title compound was synthesized according to the procedure given in Example 6, Step F d), wherein 2-methoxy-3-bromo- 5-(5-trifluoromethyl-tetrazol-l-yl)-pyridine replaced 2-bromo-4-(5- (trifluoromethyl)tetrazol-l-yl)anisole.
  • the title compound was synthesized in 80% yield by a tin metal reduction in concentrated hydrochloric acid as described by T. Batkowski, Roczniki chemii, 41, p729-740, (1967).
  • Step C 2-Bromo-3-methoxy-6-(5-trifluoromethyl-tetrazol-l-yl)- pyridine
  • the title compound was synthesized by the method described in Example 6, Steps F b) and F c), wherein the 6-amino group is transformed into 5-trifluoromethyl-tetrazol-l-yl via sequential trifluoroacetylation, iminochloride formation from triphenylphosphene in carbon tetrachloride and finally cyclization to the tetrazole with sodium azide in dimethylformamide.
  • Step D (5R,6S,7S)-6-(4-Fluorophenyl)-3-[2-methoxy-5-(5- trifluoromethyl-tetrazol- 1 -yl)-pyridin-2-yl]- 1 - oxaspiro[4.4]non-3-ene-7-carboxylic acid methyl ester
  • Step B (5R, 6S, 7S -6-(4-Fluorophenyl)-3-(5-trifluoromethyl- benzimidazol-7-yl)-l-oxaspiro[4.4]nonane-7-carboxylic acid methyl ester
  • a solution of (5R, 6S, 7S)-6-(4-fluorophenyl)-3-[l-(tert- butyloxycarbonyl)-6-trifluoromethyl-benzimidazol-4-yl)- 1 - oxaspiro[4.4]nonane-7-carboxylic acid methyl ester (13.5 mg, 0.024 mmol) in methylene chloride (1 mL) was treated with anhydrous zinc bromide (11 mg, 0.049 mmol) for 6 hours at room temperature.
  • Step B 7-Bromo-5-(5-trifluoromethyl-tetrazol-l-yl)-lJ7-indole
  • the title compound was prepared following the method described in Example 6, Steps F b) and F c), wherein the 5-amino group is transformed into 5-trifluoromethyl-tetrazol-l-yl via sequential trifluoroacetylation, treatment with triphenylphosphine in carbon tetrachloride to generate the imino chloride, and treatment with sodium azide in DMF to elaborate the tetrazole ring.
  • Step C (5R, 65", 7SJ-6-(4-Fluorophenyl)-3-(((5- trifluoromethyl)tetrazol- 1 -yl)- l/7-indol-7-yl)- 1 - oxaspiror4.4]non-3-ene-7-carboxylic acid methyl ester
  • the title compound was obtained pure by silica gel chromatography eluting initially with 5% MeOH/DCM, then with 5% MeOH/DCM containing 0.5% NH 4 OH, and finally with 10% MeOH/DCM containing 0.5% NH 4 OH; yield 11.5 mg.
  • the product was converted into the hydrochloride salt with 1M HCl in diethyl ether.
  • Step A 7-Bromo-5-(5-trifluoromethyl-tetrazol- 1 -yl)- 1 - methvindole
  • sodium hydride 80% dispersion in mineral oil
  • iodomethane 33 ⁇ L, 0.530 mmol
  • Step B (5R, 65, 75)-7-6-(4-Fluorophenyl)-3-(((5- trifluoromethyl)tetrazol- 1 -yl)- 1 -methyl-indol-7-yl)- l-oxaspiro[4.41non-3-ene-7-methanol
  • the title compound was prepared following the procedure described in Example 15, Step C, using 7-bromo-5-(5- trifluoromethyl-tetrazol-l-yl)-l-methyl-indole and (5R, 65, 75)-6-(4- fluorophenyl)-3-(trimethylstannyl)- 1 -oxaspiro[4.4]non-3-ene-7- methanol as substrates for the cross-coupling reaction.
  • Step D 2-Bromo-3-methoxy-6-(2-(trifluoromethyl)imidazol-l- yPpyridine
  • the title compound was prepared by using the procedure given in Example 48, Step A, replacing N-(3-bromo-4-methoxyphenyl)- trifluoroacetamide with N-(2-bromo-3-methoxy)-6-trifluoroacetamido- pyridine (from Step C above).
  • *H NMR (CDCI3, 400 MHz) ⁇ 7.35 (m, 2H), 7.27 (m, IH), 7.19 (s, IH), 3.99 (s, 3H) ppm.
  • Step E Methyl [5(R),6(S),7(S)]-6-(4-fluorophenyl)-3-(3-methoxy-
  • Example 1 Example 1 (IEK) was substituted in place of methyl [3- (SR), 5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3-2-methoxy-5-((5- trifluoromethyl)tetrazol-l-yl)phenyl)-l-oxaspiro[4.4]non-3-ene-7- carboxylate.
  • Example 22 The title compound was prepared as the lower R f of two products obtained using the procedure in Example 6, Step G, except that 40 mg of methyl [5(R),6(S),7(S)]-6-(4-fluorophenyl)-3-(3-methoxy-6- (2-trifluoromethyl-imidazol-l-yl)-pyridin-2-yl)-l-oxa-spiro[4.4]non-3- ene-7-carboxylate (Example 22) was substituted in place of methyl [3- (SR), 5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3-2-methoxy-5-((5- trifluoromethyl)tetrazol-l-yl)phenyl)-l-oxaspiro[4.4]non-3-ene-7- carboxylate.
  • Step A [5(R),6(S),7(S)]-6-(4-Fluorophenyl)-3-[3-methoxy-6-(2- trifluoromethyl-imidazol- 1 -y l)-pyridin-2-y 1] - 1 -oxa- spiror4.4]non-3-ene-7-carbonyl hydrazoic acid
  • Step B [5(R),6(S),7(S)]-6-(4-Fluorophenyl)-3-[3-methoxy-6-(2- trifluoromethy 1-imidazol- 1 -yl)-pyridin-2-yl] - 1 -oxa- spiro[4.4]non-3-ene-7-carbonyl azide
  • Step C I5(R),6(S),7(S)]-6-(4-Fluorophenyl)-3-[3-methoxy-6-(2- trifluoromethylimidazol- 1 -yl)-pyridin-2-yl]- 1 -oxa- spiro[4.4]non-3-en-7-amine
  • a 10 mL round bottom flask fitted with a stirred bar and reflux condenser is added the carbonyl azide from Example 26, Step B to 3 mL of 35% acetic acid. The solution is refluxed until nitrogen evolution has ceased.
  • Step A [3(S),5(R),6(S),7(S)]-6-(4-Fluorophenyl)-3-[3- methoxy-6-(2-trifluoromethyl-imidazol- 1 -yl)-pyridin-2- yl]-l-oxa-spiror4.41nonane-7-carbaldehyde
  • Step B [3(S),5(R),6(S),7(S)]-6-(4-Fluoro-phenyl)-3-[3-methoxy-6-
  • the title compound was prepared by taking 620 mg (1.9 mmol) of 2-bromo-3-methoxyoxy-6-(2-(trifluoromethyl)imidazol-l- yl)pyridine (described in Example 22 Step D) and heating it at 160 °C in 2.0 gm (15.7 mmole) of anhydrous pyridinium hydrochloride under nitrogen for.3 hours. By TLC (70/30 hexane/ethyl acetate) no starting material was seen. The pyridine hydrochloride was removed by sublimation under high vacuum at 130 °C. The product remained in the flask and was dissolved in 2 mL of methanol. This was slowly dropped into 150 mL of ice water with stirring.
  • Step B Methyl [5(R),6(S),7(S)]-6-(4-fluorophenyl)-3-(3-hydroxy-
  • Step A [5(R),6(S),7(S)]-6-(4-Fluorophenyl)-3-[3-methoxy-6-(2- trifluoromethy 1-imidazol- 1 -y l)-pyridin-2-yl] - 1 -oxa- spiro[4.41non-2-en-7-yl [-methanol
  • the title compound was prepared using the procedure given in Example 6, Step G, except that 98 mg of [5(R),6(S),7(S)]-6-(4- fluorophenyl)-3-[3-methoxy-6-(2-trifluoromethyl-imidazol-l- yl)pyridin-2-yl]-l-oxa-spiro[4.4]non-3-en-7-methanol (from Example 4 (IEK)) was substituted in place of methyl [3-(SR), 5-(RS), 6-(SR), 7- (SR)]-6-(4-fluoropheny
  • Step B [3(S),5(R),6(S),7(S)]-6-(4-Fluorophenyl)-3-[3-methoxy-6-
  • the compound was prepared by taking 2-bromo-3- hydroxy-6-(2-(trifluoromethyl)imidazol-l-yl)pyridine (330 mg, l .lmmol from Example 31 Step B), dissolving it in 2 mL of dimethylformamide, then adding 1 g of anhydrous potassium carbonate (7 mmol) and 2 -iodopropane (640 mg, 4.0 mmol) to the solution. The mixture was stirred at room temperature overnight. The next day no starting material was seen by TLC (70/30 hexane/ethyl acetate). The reaction was worked up by removing the solvent under reduced pressure and purifying the residue by flash chromatography (70/30 hexane/ethyl acetate).
  • Step B Methyl [5(R),6(S),7(S)]- 6-(4-fluoro-phenyl)-3-[3- isopropoxy-6-(2-trifluoromethyl-imidazol- 1 -yl)-pyridin-2- yl]-l-oxa-spiror4.41non-3-ene-7-carboxylate
  • the title compound was prepared by using the procedure given in Example 6, Step F d, except that methyl 2-(S)-(4-fluoro- phenyl)cyclopentanone-3-(S)-carboxylate (from Example 5) was substituted for methyl 2-(RS)-(4-fluorophenyl)cyclopentanone-3-(RS)- carboxylate in Step A along with replacing 2-bromo-4-(5-(trifluoro- methyl)tetrazol-l-yl)anisole with 180 mg (0.51 mmol) of 2-bromo-3- isopropoxy-6-(2-
  • Example 34 Step B was substituted in place of methyl [3-(SR), 5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3-2- methoxy-5-((5-trifluoromethyl)tetrazol-l-yl)phenyl)-l- oxaspiro[4.4]nonane-7-carboxylate.
  • Example34 Step B was substituted in place of methyl [3-(SR), 5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)- 3-2-methoxy-5-((5-trifluoromethyl)tetrazol- 1 -yl)phenyl)- 1 - oxaspiro[4.4]nonane-7-carboxylate.
  • Step A [3(S),5(R),6(S),7(S)]-6-(4-Fluorophenyl)-3-[3-isopropoxy-
  • the title compound was prepared by using the standard reduction procedures with 1.5 M DIBALH solution in toluene, usingl lO mg of methyl [3(S),5(R),6(S),7(S)]-6-(4-fluorophenyl)-3-[3-isopropoxy- 6-(2-trifluoromethylimidazol-l-yl)-pyridin-2-yl]-l -oxaspiro ⁇ .4]nonane-7-carboxylate (from Example 36). After flash chromatography (70/30 hexane/ethyl acetate) we recovered 76 mg of product(70% yield).
  • the title compound was prepared using standard procedure for reductive amination with sodium triacetoxyborohydride and 3 A molecular sieves in methanol, using 41 mg of [3(S),5(R),6(S),7(S)]-6- (4-fluorophenyl)-3-[3-isopropoxy-6-(2-trifluoromethyl-imidazol- l-yl)- pyridin-2-yl]-l-oxa-spiro[4.4]nonane-7-carbaldehyde (from Example 37 Step B) and dimethylamine hydrochloride.
  • Step A 2-Hydroxy-3-bromo-5-nitropyridine
  • 2-hydroxy-3- bromo-5-nitropyridine 7.0 g, 50 mmol
  • bromine 14 g, 88 mmol
  • 200 mL of glacial acetic acid 200 mL
  • the mixture is refluxed for 18 hr, then another 7.5 g ( 47 mmol) of bromine is added and the mixture is heated for an additional 4 hrs.
  • the solvent and excess bromine were removed under reduced pressure.
  • the precipitate was suspended in water and filtered. It was wash with 3 x 25 mL of water, sucked dry, then washed with 3 x 30 mL of toluene.
  • the precipitate was dried under reduced pressure at 70 °C. Recovered 9.0 g of product. The yield is 86%.
  • the title compound derived from Example 38 Step A, is prepared by suspending 12 g (55 mmol) of 2-hydroxy-3-bromo ⁇ 5- nitropyridine in 100 mL of dimethylformamide. Add 25 g (165 mmol) of anydrous cesium fluoride and 2 iodopropane (28 g, 165 mmol). Heat the mixture with vigorous stirring at 70 ° C for 18 hr. By TLC, no starting material is observed, only a high and low R f product. Pour the reaction mixure into 1 liter of cold water.
  • the title compound derived from Example 38 Step B, is prepared by dissolving 1.0 g (3.9 mmol) of 2-isopropoxy-3-bromo-5- nitropyridine in 10 mL of concentrated hydrochloric acid and 5 mL of methanol. Metallic tin (1.5g, 2.6 mmol) is added portion-wise with vigorous stirring until TLC (95/5 methylene chloride/ethyl acetate) indicates that all the starting material is consumed. Add 25 mL of water and basify with aqueous sodium carbonate (pH-9). Extract the product with methylene chloride.
  • Step E 2-Isopropoxy-3-bromo-5-(5-(trifluoromethyl)tetrazol-l- yDpyridine
  • the title compound was prepared by using the procedure given in Example 6, Step F c, replacing replacing N-(3-bromo-4- methoxyphenyl)-trifluoroacetamide with 200 mg (0.61 mmol) of 2- isopropoxy-3-bromo-5-trifluoroacetamidopyridine (from Example 15 (IEK) Step E). Chromatography (90/10 hexane/ethyl acetate) gave 190 mg of product (90% yield).
  • Step F Methyl[5(R),6(S),7(S)]-6-(4-fluorophenyl)-3-[2- isopropoxy-5-(5-trifluoromethyl-tetrazol- 1 -yl)-pyridin-3- yl]-l-oxa-spiro[4.41non-3-ene-7-carboxylate
  • Step A [5(R),6(S),7(S)]-[6-(4-fluoro-phenyl)-3-[2-isopropoxy-5- (5-trifluoromethyl-tetrazol- 1 -yl)-pyridin-3-yl]- 1 -oxa- spiro[4.41non-3-en-7-yll-methanol
  • Step B [5(R),6(S),7(S)]- 6-(4-Fluorophenyl)-3-[2-isopropoxy-5-(5- trifluoromethyl-tetrazol- 1 -yl)-pyridin-3-yl]- 1 -oxa- spiro[4.4]non-3-ene-7-carbaldehyde
  • Step C [5(R),6(S),7(S)]-(2-Fluoro-l,l-dimethyl-ethyl)-[6-(4- fluoro-phenyl)-3-[2-isopropoxy-5-(5-trifluoromethyl- tetrazol-l-yl)-pyridin-3-yl]-l-oxa-spiro[4.4]non-3-en-7- ylmethyll-amine
  • the title compound was prepared by dissolving 25 mg (0.05 mmol) of [5(R),6(S),7(S)]- 6-(4-fluorophenyl)-3-[2-isopropoxy-5- (5-trifluoromethyl-tetrazol-l-yl)-pyridin-3-yl]-l-oxa-spiro[4.4]non-3- ene-7-carbaldehyde (from Example 41 Step B) in 500 ⁇ l of THF. Then ⁇ , ⁇ -dimethylamino-2-fluoroethane hydrochloride (16 mg, 0.12 mmol) was added and the mixture stirred for 15 minutes at 0 °C.
  • Step A [5(R),6(S),7(S)]- [6-(4-fluorophenyl)-3-(2-isopropoxy-5- trifluoromethylpyridin-3-yl)-l-oxa-spiro[4.4]non-3-ene-7- yl]-methanol
  • Step B [5(R),6(S),7(S)]- 6-(4-fluorophenyl)-3-[2-isopropoxy-5- trifluoromethylpyridin-3-yl]-l-oxa-spiro[4.4]non-3-ene-7- carbaldehyde
  • the title compound was prepared by oxidation with Dess- Martin reagent in methylene chloride, using 38 mg (0.084 mmol) of [5(R),6(S),7(S)]-[6-(4-fluorophenyl)-3-[2-isopropoxy-5- trifluoromethyl-pyridin-3-yl]-l-oxa-spiro[4.4]non-3-en-7-yl]-methanol (from Example 46 Step A).
  • the product was flash chromatographed using 80/20 hexane/ethyl acetate to give 25 mg of product (65% yield).
  • Step C [5(R),6(S),7(S)]-(2-Fluoro- 1,1 -dimethyl-ethyl)- [6-(4- fluoro-phenyl)-3-(2-isopropoxy-5-trifluoromethylpyridin- 3-yl)-l-oxa-spiror4.41non-3-en-7-yl-methyn-amine
  • the title compound was prepared by the procedure described in Example 41 Step C, except that 21 mg (0.05 mmol) of [5(R),6(S),7(S)]- 6-(4-fluorophenyl)-3-[2-isopropoxy-5- trifluoromethylpyridin-3-yl]-l-oxa-spiro[4.4]non-3-ene-7-carbaldehyde (from Example 22 (IEK) Step B) was substituted for [5(R),6(S),7(S)]- 6-(4-fluorophenyl)-3-[2-is
  • Example 46 Step C was substituted in place of methyl [3-(SR), 5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3-2- methoxy-5-((5-trifluoromethyl)tetrazol-l-yl)phenyl)-l-oxaspiro[4.4]- nonane-7-carboxylate.
  • Step A l-(3-Bromo-4-methoxyphenyl)-2-(trifluoromethyl)- imidazole
  • Triphenylphosphine (2.1 g, 8.0 mmol) was added in portions to a suspension of N-(3-bromo-4-methoxyphenyl)-2,2,2- trifluoroacetamide (2.0 g, 6.7 mmol) in 40 mL of carbon tetrachloride at 80 °C, and stirring was continued at 80 °C overnight. An additional portion of triphenylphosphine (2.1 g, 8.0 mmol) was added and stirring was continued for 2.5 h at 80 °C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was treated with 50 mL of boiling hexane and filtered.
  • the mixture was concentrated in vacuo, and the residue was dissolved in 55 mL of acetic acid and heated at reflux for 1.5 h. After cooling to room temperature, the acetic acid was removed in vacuo. The residue was partitioned between 100 mL of ethyl acetate and 50 mL of 2.5 N aq. sodium hydroxide, and the aqueous layer was then extracted with 2 x 100 mL of ethyl acetate. The combined ethyl acetate layers were washed with 100 mL of brine, dried over sodium sulfate, and evaporated.
  • Step B (5R,65,75)-6-(4-Fluorophenyl)-3-(2-methoxy-5-(2-
  • Step B N-f2-bromo-6-methoxy-4-nitrophenyl)acetamide
  • a solution of 23 g of 2-bromo-6-methoxy-4-nitro- phenylamine in 125 mL of acetic anhydride and 100 mL of AcOH was refluxed at 110 °C. Following reflux for 5 h, mixture was dumped into 1.5 L of ice water. A precipitate formed, and was collected via filtration. The precipitate was then placed in EtOH and refluxed for 15 min.. 9 mL of cone. NH 4 OH was then added to the hot mixture. The solution was then cooled, and a precipitate formed and collected again via filtration. The solid was washed with ethanol(2x) and ether, and allowed to air dry. 21.5 g of title compound as a tan powder was collected.
  • Step E 4-Bromo-2-methyl-6-amino-benzooxazole To a solution of 720 mg of 4-bromo-2-methyl-6-nitro- benzooxazole in 45 mL EtOH was added 642 mg of iron powder and 8.5 mL of AcOH. Solution was refluxed for 2.5 h, during which a chalky white color formed. Solvent was removed, solid was dissolved back into DCM and filtered through Celite. The filtrate was washed with satd. NaHC0 3 and brine, dried over MgS0 4 and solvent evaporated. 690 mg of title compound as a brown solid was recovered.
  • Step F 4-Bromo-2-methyl-6-(5-trifluoromethyl-tetrazol- 1 -yl)- benzooxazole
  • Step G (3S,5R,6S,7S)-6-(4-Fluoro-phenyl)-3-[2-methyl-6-(5- trifluromethy 1-tetrazol- 1 -yl)-benzooxazol-4-y 1] - 1 -oxa- spiror4.41non-3-ene-7-carboxylic acid methyl ester
  • Step B 7-bromo-2-methyl-5-trifluoromethyl-benzooxazole Compound was prepared according to the procedure given in Example Steps B and D using 2-bromo-4-trifluoromethyl-6-nitro- phenol in place of 2-bromo-6-methoxy-4-nitro-phenylamine.
  • Step C (3S,5R,6S,7S)-6-(4-Fluoro-phenyl)-3-(2-methyl-5- trifluromethyl- benzooxazol-7-yl)-l-oxa-spiro[4.4]non-3- ene-7-carboxylic acid methyl ester
  • Step C (3S,5R,6S,7S)-6-(4-Fluorophenyl)-3-[2-methyl-5-(5- trifluromethyl-tetrazol- 1 -yl)-benzooxazol-7-yl]- 1 -oxa- spiro[4.4]non-3-ene-7-carboxylic acid methyl ester
  • Example 6 employing (3S,5R,6S,7S)-6-(4-fluoro-phenyl)-3-[2- methyl-6-(5-trifluromethyl-tetrazol-l-yl)-benzooxazol-4-yl]-l-oxa- spiro[4.4]non-3-ene-7-carboxylic acid methyl ester in place of methyl [5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3-(2-methoxy-5-((5- trifluoromethyl)tetrazol-l-yl)phenyl)-l-oxaspiro[4.4]non-3-ene-7- carboxylate, except reaction was placed on hydrogenator at 45 p.s.i for 32 h..
  • Example 6 employing (3S,5R,6S,7S)-6-(4-fluoro-phenyl)-3-[2- methyl-6-(5-trifluromethyl-tetrazol-l-yl)-benzooxazol-4-yl]-l -oxaspiro ⁇ .4]non-3-ene-7-carboxylic acid methyl ester in place of methyl [5-(RS), 6-(SR), 7-(SR)]-6-(4-fluorophenyl)-3-(2-methoxy-5-((5- trifluoromethyl)tetrazol-l-yl)phenyl)-l-oxaspiro[4.4]non-3-ene-7- carboxylate, except reaction was placed on hydrogenator at 45 p.s.i for 32 h.

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Abstract

L'invention a pour objet certains composés nouveaux, représentés par la formule générale (I), ou un de leurs sels pharmaceutiquement acceptables. Dans ladite formule, R?3, R6, R7, R8, R11, R12, R13¿, A, m, n et les liaisons sont définis dans l'invention. L'invention se rapporte également à des formulations pharmaceutiques contenant ces composés nouveaux en tant qu'ingrédients actifs et à l'utilisation desdits composés et de leurs formulations dans le traitement de certains troubles. Lesdits composés sont des antagonistes de récepteurs de la tachykinine et sont utilisés dans le traitement de maladies inflammatoires, de douleurs, de migraines, d'asthme ou de vomissement.
PCT/US1997/019359 1996-10-25 1997-10-22 Antagonistes heteroaryle spiroethercycloalkyle de recepteurs de la tachykinine Ceased WO1998017276A1 (fr)

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Cited By (11)

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WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
US10730863B2 (en) 2017-11-01 2020-08-04 Bristol-Myers Squibb Company Bridged bicyclic compounds as farnesoid X receptor modulators
US11078198B2 (en) 2017-11-01 2021-08-03 Bristol-Myers Squibb Company Spirocyclic compounds as farnesoid X receptor modulators
US11168079B2 (en) 2017-11-01 2021-11-09 Bristol-Myers Squibb Company Alkene compounds as farnesoid x receptor modulators
US11254663B2 (en) 2019-02-15 2022-02-22 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US11286252B2 (en) 2017-11-01 2022-03-29 Bristol-Myers Squibb Company Alkene spirocyclic compounds as farnesoid X receptor modulators
US11370785B2 (en) 2017-11-01 2022-06-28 Bristol-Myers Squibb Company Multicyclic compounds as farnesoid X receptor modulators
US12030835B2 (en) 2019-02-15 2024-07-09 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators
US12227496B2 (en) 2019-02-15 2025-02-18 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US12319676B2 (en) 2019-02-15 2025-06-03 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators

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US5300524A (en) * 1991-03-06 1994-04-05 British Bio-Technology Limited Spirocyclic PAF antagonists
US5641883A (en) * 1993-07-22 1997-06-24 American Cyanamid Co. Fungicidal spiroheterocyclic derivatives

Patent Citations (2)

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US5300524A (en) * 1991-03-06 1994-04-05 British Bio-Technology Limited Spirocyclic PAF antagonists
US5641883A (en) * 1993-07-22 1997-06-24 American Cyanamid Co. Fungicidal spiroheterocyclic derivatives

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
US10730863B2 (en) 2017-11-01 2020-08-04 Bristol-Myers Squibb Company Bridged bicyclic compounds as farnesoid X receptor modulators
US11078198B2 (en) 2017-11-01 2021-08-03 Bristol-Myers Squibb Company Spirocyclic compounds as farnesoid X receptor modulators
US11168079B2 (en) 2017-11-01 2021-11-09 Bristol-Myers Squibb Company Alkene compounds as farnesoid x receptor modulators
US11286252B2 (en) 2017-11-01 2022-03-29 Bristol-Myers Squibb Company Alkene spirocyclic compounds as farnesoid X receptor modulators
US11370785B2 (en) 2017-11-01 2022-06-28 Bristol-Myers Squibb Company Multicyclic compounds as farnesoid X receptor modulators
US11254663B2 (en) 2019-02-15 2022-02-22 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US11713312B2 (en) 2019-02-15 2023-08-01 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US12030835B2 (en) 2019-02-15 2024-07-09 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators
US12227496B2 (en) 2019-02-15 2025-02-18 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US12319676B2 (en) 2019-02-15 2025-06-03 Bristol-Myers Squibb Company Substituted amide compounds useful as farnesoid X receptor modulators

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