EP0636130A1 - Azaclyclische Verbindungen - Google Patents

Azaclyclische Verbindungen

Info

Publication number
EP0636130A1
EP0636130A1 EP93910151A EP93910151A EP0636130A1 EP 0636130 A1 EP0636130 A1 EP 0636130A1 EP 93910151 A EP93910151 A EP 93910151A EP 93910151 A EP93910151 A EP 93910151A EP 0636130 A1 EP0636130 A1 EP 0636130A1
Authority
EP
European Patent Office
Prior art keywords
methyloxy
phenyl
methyl
trifluoromethyl
phenylpiperidino
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP93910151A
Other languages
English (en)
French (fr)
Inventor
Raymond Baker
Tamara Laddhwahetty
Eileen Mary Seward
Christopher John Swain
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Original Assignee
Merck Sharp and Dohme Ltd
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 GB929208323A external-priority patent/GB9208323D0/en
Priority claimed from GB929216065A external-priority patent/GB9216065D0/en
Priority claimed from GB929219686A external-priority patent/GB9219686D0/en
Priority claimed from GB929226069A external-priority patent/GB9226069D0/en
Application filed by Merck Sharp and Dohme Ltd filed Critical Merck Sharp and Dohme Ltd
Publication of EP0636130A1 publication Critical patent/EP0636130A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—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
    • C07D207/10—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 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • 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
    • C07D211/54—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to a class of azacyclic compounds, which are useful as tachykinin antagonists. More particularly, the compounds of the invention comprise an azacyclic ring system substituted by an arylmethyloxy or arylmethylthio moiety.
  • the tachykinins are a group of naturally- occurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in the-peripheral nervous and circulatory systems.
  • the structures of three known mammalian tachykinins are as follows: Substance P:
  • Neurokinin B Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH 2
  • substance P is believed inter alia 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 (Dec. 1987) 8.506-510], specifically in the transmission of pain in migraine (B.E.B. Sandberg et al, J. Med Chem, (1982) 25 1009; S.L. Shepheard et al.. Br. J. Pharmacol.
  • substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis [0'Byrne et al in Arthritis and Rheumatism (1990) 3J3 1023-8].
  • Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al Can. J. Pharmacol. Physiol. (1988) 66 1361-7], immunoregulation [Lotz et al Science (1988) 2411218-21 and Ki ball et al, J. Immunol.
  • Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., poster " resented at 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).
  • demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., poster " resented at C.I.N.P. XVIIIth Congress, 28th June- 2nd July, 1992]
  • disorders of bladder function such as bladder detrusor hyper-reflexia (Lancet. 16th May, 1992, 1239).
  • tachykinins 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, disorders related to immune enhancement or suppression such as systemic lupus erythmatosis (European patent application no.
  • ophthalmic disease such as conjuctivitis, vernal conjunctivitis, and the like
  • cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis (European patent application no. 0 394 989) and emesis (European patent application no. 0533 280) .
  • peptide derivatives are likely to be of limited utility as therapeutic agents. It is for this reason that non- peptide tachykinin antagonists are sought.
  • European patent application no. 0 436 334 discloses 4- to 7-membered azacyclic compounds substituted at the 3-position by a substituted amino moiety. The compounds are said to be tachykinin antagonists.
  • the present invention provides a compound of formula (I) , or a salt or prodrug thereof:
  • X represents O or S
  • Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which may optionally be substituted by oxo;
  • R 1 represents phenyl optionally substituted by l r 2 or 3 groups selected from Ci-galkyl, C2-6 alkenyl, C2-6alkyn l, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR a , SR a , SOR a , S0 2 R a , -NR a R b , -NR a C0R b , -NR a C0 2 R b , -C0 2 R a or -CONR a R b ;
  • R 2 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by C ⁇ _ ⁇ alkyl, C ⁇ _ ⁇ alkoxy, halo or trifluoromethyl;
  • R 4 and R 5 may be present on any available carbon atom of the azacyclic ring and each independently represent H, halo, C ⁇ _galkyl, oxo, CH2 ⁇ R a , C ⁇ 2R a or CONR a R b ;
  • R 8 represents an optionally substituted aromatic heterocycle; and R a and R b each independently represent H, trifluoromethyl, Ci-ealkyl or phenyl optionally substituted by Ci- ⁇ alkyl, halo or trifluoromethyl.
  • alkyl, alkenyl and alkynyl groups referred to with respect to the above formula may represent straight, branched or cyclic groups, or combinations thereof.
  • suitable alkyl groups include methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl-alkyl groups such as cyclopropylmethyl;
  • suitable alkenyl groups include vinyl and allyl; and suitable alkynyl groups include propargyl.
  • halo as used herein includes fluoro, chloro, bro o and iodo, especially chloro and fluoro.
  • the present invention includes within its scope prodrugs of the compounds of formula (I) above.
  • prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I) .
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the compounds according to the invention may exist both as enantiomers and as diastereomers.
  • the relative orientation of the 2- and 3- substituents on the azacyclic ring may give rise to cis and trans diastereoisomers, of which the cis stereochemistry is preferred. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • n is 2 or 3, more preferably 3.
  • X represents O.
  • a particularly preferred subgroup of compounds according to the invention is represented by compounds of formula (I) wherein Y is CH(CH 3 ) .
  • R 1 represents substituted phenyl.
  • suitable substituents include nitro, trifluoromethyl, trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, C ⁇ _galkyl such as methyl, ethyl, i-propyl, i-butyl, t-butyl and cyclopropyl, C2-6alkenyl such as vinyl, Ci-galkoxy such as methoxy, ethoxy and i-propoxy, phenoxy, amino, carboxamido and carbonylmethoxy.
  • R ⁇ - represents phenyl substituted by one or more groups selected from
  • C _4alkyl such as methyl and t-butyl, trifluoromethyl and halo such as iodo, bromo chloro and fluoro.
  • R 1 represents monosubstituted phenyl, such as 3-substituted phenyl or, preferably, disubstituted phenyl, such as 3,5-disubstituted phenyl.
  • R 1 represents phenyl substituted at the 3- position by trifluoromethyl or a C ⁇ -galkyl group such as t-butyl, or 3,5-disubstituted phenyl wherein the substituents are independently selected from trifluoromethyl, chloro, fluoro, methyl and t-butyl.
  • R 1 Preferred values for R 1 include 3,5- bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl, 3-t- butyl-5-methylphenyl, 3-chloro-5-methylphenyl, 3-t-butyl- 5-chlorophenyl, 3-bis(trifluoromethyl)phenyl and 3-t- butylphenyl. Particularly preferred is 3,5- bis(trifluoromethyl)phenyl.
  • R 2 represents benzhydryl or optionally substituted phenyl, such as phenyl optionally substituted by halo such as fluoro or chloro, preferably in the 3- position.
  • R 2 represents unsubstituted phenyl or unsubstituted benzhydryl, more preferably unsubstituted phenyl.
  • Suitable values for R 4 and R 5 include H, Ci-galkyl, especially methyl, hydroxymethyl and oxo.
  • the substitutents R 4 and R 5 may be located on any available carbon atom of the azacyclic ring including, except in the case where the substituent R 4 or in question represents oxo, C-2 and C-3.
  • R 4 and R 5 both represent H.
  • one of R and R 5 is H and the other of R 4 and R 5 is methyl, preferably 2-methyl.
  • suitable substituents in the heterocyclic ring include one or more of Ci- ⁇ alkyl, Ci-galkoxy, phenyl, oxo, thioxo, halo, trifluoromethyl, NR a R b , NR a C0R b , C0NR a R b , C0 2 R a , SR a , S0 2 R a and CH 2 0R a , where R a and R b are as previously defined.
  • substituents include methyl, methoxy, phenyl, oxo, thioxo, bromo, iodo, NH2 SCH3, CO H2 and cyano.
  • substituents include oxo and NH2.
  • Suitable values for R 8 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl and indolyl, any of which may be substituted.
  • R 8 may represent optionally substituted thienyl, furyl, pyridyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl or benzoxazolyl.
  • R 8 represents optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl or indolyl.
  • R 8 represents a substituted or unsubstituted 5- or 6-membered nitrogen containing aromatic heterocycle such as for example oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl or triazinyl.
  • R 8 represents optionally substituted oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or tetrazolyl substituted by Ci-galkyl, preferably methyl.
  • R 8 represents substituted or unsubstituted oxadiazolyl, for example, oxadiazolyl substituted by halo, amino, dialkylamino or methyl. More preferably R 8 represents 5-(3-aminooxadiazolyl) .
  • R 8 represents substituted or unsubstituted triazolyl, for example, unsubstituted triazolyl or triazolyl subtituted by oxo or thioxo, more preferably, triazolyl substituted by oxo.
  • X represents 0 or S
  • R 10 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Ci-galkyl, C2-6 alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR c , SR C , SOR c , S0 2 R c , -NR c R d , -NR c COR d , -NR c C0 2 R d , -C0 2 R c or -CONR c R d ;
  • R ll represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by Ci-galkoxy, halo or trifluoromethyl; R 12 and R 13 each independently represent H, halo, Cx-ealkyl, oxo, C0 R c or CONR c R d ;
  • R 14 represents C1-4alkyl, optionally substituted by oxo, substituted by an optionally substituted aromatic heterocycle
  • R c and R d each independently represent H, Ci-gal l, phenyl optionally substituted by C ⁇ _galkyl or halo or trifluoromethyl.
  • Suitable values for the heterocyclic moiety of R 14 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, ⁇ .soxazolyl, quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl and indolyl. in one sub-class of compounds of formula (IA) ,
  • R c and R d each independently represent H, C ⁇ _galkyl, phenyl or trifluoromethyl.
  • a further subclass of compounds of formula (IA) is represented by compounds wherein n is 2 or 3; R 12 and R 13 each independently represent H, halo, C _galkyl,
  • R 14 represents C ⁇ _4alkyl substituted by an optionally substituted 5- or 6-membered aromatic heterocycle; and R c and R d each independently represent H, C ⁇ _galkyl, phenyl or trifluoromethyl.
  • suitable values for the heterocyclic moiety of R 14 include thienyl, furyl, pyrrolyl- pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl and imidazolyl.
  • a preferred sub-class of compounds according to the invention is represented by compounds of formula (IB) , and salts and prodrugs thereof: ,20
  • Y is as defined for formula (I) , preferably C ⁇ _2alkyl optionally substituted by oxo, more preferably CH 2 or CH(CH 3 ) ;
  • R 2 represents phenyl or benzhydryl wherein any of the phenyl rings of the phenyl or benzhydryl moieties may optionally be substituted by halo or trifluoromethyl, preferably unsubstituted phenyl;
  • R 8 is as defined for formula (I) ;
  • R 20 and R 21 independently represent H, C ⁇ _galkyl, C2-galkenyl, C2-galkynyl, bromo, chloro, fluoro, iodo, cyano, nitro, trifluoromethyl, trimethylsilyl, 0R a , SR a SOR a , S0 2 R a , NR a R b , NR a C0R , NR a C0 2 R b , COR a , C0 2 R a or C0NR a R b , where R a and R b are as previously defined; and z is- 1 or 2.
  • R 20 and R 21 include H, methyl, t-butyl, methoxy, i-propoxy, chloro, fluoro, nitro, amino, carbonylmethoxy, carboxamido and trifluoromethyl.
  • R 20 and R 21 are both other than H, more preferably C ⁇ _galkyl, halo or trifluoromethyl, and are located at the 3- and 5- positions of the phenyl ring.
  • R 8 is optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, indolyl, thiadiazolyl or oxadiazolyl, more preferably oxadiazolyl.
  • a further sub-class of compounds according to the invention are compounds of formula (IB) wherein R is optionally substituted oxadiazolyl, pyridinyl, benzimidazolyl, tetrazolyl, thiazolyl, furyl, thienyl, triazolyl, thiadiazolyl, benzoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, triazinyl, pyrimidinyl or imidazolyl.
  • a particularly preferred group of compounds according to the invention are compounds of formula (Ia) wherein R 8 is optionally substituted triazolyl, especially triazole substituted by oxo.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention (such as the dibenzoyltartrate salts) or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or p-toluenesulphonic acid.
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
  • suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • Preferred salts of the compounds according to the invention include the hydrochloride and p- toluenesulphonic acid salts.
  • compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation.
  • the invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I) , or a salt or prodrug thereof, and a pharmaceutically acceptable carrier, which process comprises bringing a compound of formula (I) , or a salt or prodrug thereof into association with a pharmaceutically acceptable carrier.
  • 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 solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, 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, polyvinyl- pyrrolidone 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 adminsitered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably- sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising 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 formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised 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; 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 amyotropic lateral sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral neuropathy, for example, diabetic or chemotherapy-induced neuropathy, and postherpetic and other neuralgias; respiratory diseases such as chronic obstructive airways disease, bronchopneumonia, bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis;
  • the compounds of formula (I) may suitably be used in the 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, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; 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 in migraine.
  • GI gastrointestinal
  • the compounds of formula (I) are particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and especially migraine.
  • neuropathy such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and especially migraine.
  • the present invention further provides a compound of formula (I) for use in therapy.
  • the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
  • the present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I) .
  • a compound according to the present invention for the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another pharmacologically active agent.
  • a compound of formula (I) may be used in conjunction with a bronchodilator, such as a -adrenergic receptor antagonist or tachykinin antagonist which acts at NK-2 receptors.
  • the compound of formula (I) and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination.
  • the present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula (I) and an effective amount of a bronchodilator.
  • a respiratory disease such as asthma
  • the present invention also provides a composition comprising a compound of formula (I) , a bronchodilator, and a pharmaceutically acceptable carrier.
  • a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg of a compound of formula (I) per day.
  • a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula (II) :
  • R 1 , R 2 , R 4 , R 5 , X and n are as defined for formula (I) above, with a reagent suitable to introduce the group Y-R 8 , for example, a halide or acyl halide, or corresponding mesylate or tosylate, of formula R 8 -Y-L, where L represents halo, such as chloro, bromo or iodo, methylsulphonate or ⁇ - toluenesulphonate,or any other suitable leaving group, in the presence of a base.
  • a reagent suitable to introduce the group Y-R 8 for example, a halide or acyl halide, or corresponding mesylate or tosylate, of formula R 8 -Y-L, where L represents halo, such as chloro, bromo or iodo, methylsulphonate or ⁇ - toluenesulphonate,or any other suitable leaving group, in the
  • Suitable bases of use in the reaction include inorganic bases such as alkali metal carbonates, for example, potassium carbonate.
  • R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I)
  • R 30 represents an alkyl group and R 31 represents H or a suitable substituent such as C ⁇ _galkyl, Cx- alkoxy, halo, NR a R b or NR a COR b , where R a and R b are as previously defined, in the presence of a base.
  • Suitable bases of use in the reaction include alkali metals, such as, for example, sodium, and alkali metal hydrides, such as, for example, sodium hydride.
  • reaction is conveniently effected in a suitable organic solvent.
  • suitable solvents will include alcohols, for example, ethanol, whereas where the base used is an alkali hydride, suitable solvents will include ethers, for example, tetrahydrofuran.
  • reaction is conducted at elevated temperature, such as the reflux temperature of the chosen solvent.
  • reaction is conveniently effected in a high boiling organic solvent, such as, for example, N-methylpyrrolidinone.
  • R 61 NCS wherein R 61 represents H or a suitable substituent such as C ⁇ -galkyl, in the presence of a base.
  • Suitable bases of use in the reaction include organic bases such as, for example, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) .
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • the reaction is conveniently effected in a suitable orgainc solvent, such as alcohol, e.g. butanol.
  • compounds of formula (I) wherein R 8 represents unsubstituted or substituted triazolyl may be prepared by reaction of intermediates of formula (II) with a compound of formula
  • VAM wherein Y and Hal are as previously defined and R 18 is H or a group suitable as a substituent of the triazole ring, or convertible to such a group under the reaction conditions, in the presence of a base.
  • Suitable bases of use in the reaction include alkali metal carbonates, such as, for example, potassium carbonate.
  • R 18 represents H, OCH3 (which is converted to an oxo substituent under the reaction conditions) or CONH2.
  • reaction is conveniently effected in an anhydrous organic solvent, such as, for example, anhydrous dimethylformamide, preferably at elevated temperature, such as about 140 ⁇ C.
  • anhydrous organic solvent such as, for example, anhydrous dimethylformamide
  • reaction is conveniently effected in a suitable organic solvent, such as acetronitrile, at elevated temperature, such as 80-90 ⁇ C, preferably about
  • compounds of formula (I) wherein R represents substituted or unsubstituted 1,2,5-triazine may be prepared by reaction of an intermediate of formula (X) with a dicarbonyl compound of formula (XI) :
  • reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g. tetrahydrofuran, conveniently at ambient temperature.
  • a suitable organic solvent such as an ether, e.g. tetrahydrofuran, conveniently at ambient temperature.
  • Compounds of formula (I) may also be prepared from other compounds of formula (I) using suitable interconversion procedures.
  • compounds of formula (I) wherein Y represents C ⁇ _4alkyl substituted by an aromatic heterocycle may be prepared from compounds of formula (I) wherein Y represents C1-.4alkyl substituted by oxo by reduction, for example, using borane.
  • Suitable interconversion procedures are described in the accompanying Examples, or will be readily apparent to those skilled in the art.
  • Intermediates of formula (III) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C ⁇ 2R 30 , where Hal represents halo such as chloro, bromo or iodo and R ° and Y are as above defined, in the presence of a base.
  • Suitable bases include tertiary amines, for example, triethylamine.
  • the reaction is effected in a suitable organic solvent, such as an ether, for example, tetrahydrofuran, at elevated temperature, such as the reflux temperature of the solvent.
  • Intermediates of formula (V) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-CN, wherein Hal is halo such as bromo, chloro or iodo and Y is as previously defined.
  • Intermediates of formula (VI) may be prepared from intermediates of formula (V) by treatment with an alkylthioamide, such as, for example, thioacetamide.
  • an alkylthioamide such as, for example, thioacetamide.
  • Intermediates of formula (VII) may be prepared from intermediates of formula (III) by treatment with hydrazine.
  • the reaction is conveniently effected in a suitable organic solvent, such as an alcohol, for example, ethanol, at elevated temperature.
  • Intermediates of formula (IX) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C(NH)NH2 where Hal and Y are as previously defined.
  • Intermediates of formula (X) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C(NH)NHNH-Boc, wherein Hal and Y are as previously defined and Boc stands for t-butoxycarbonyl, followed by deprotection under acidic conditions.
  • any suitable intermediates may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric esters or amides, followed by chromatographic separation or separation by fractional crystallization and removal of the chiral auxiliary.
  • the diastereomeric intermediates can then be used to prepare optically pure compounds of formula (I) .
  • the substance P antagonising activity of the compounds described herein was evaluated using the human NK1R assay described in published European patent application no. 0 528 495.
  • the method essentially involves determining the concentration of the test compound required to reduce by 50% the amount of radiolabelled substance P binding to human NK1R, thereby affording an IC50 value for the test compound.
  • the compounds of Examples 1-10, for example, were found to have IC50 . values less than 500nM.
  • DESCRIPTION 1 s-3-((3.5-Bisf1-rifluoromethyl)phenvDmethv ⁇ oxv;-2-phenvh)iperidine hydrochloride salt a) A solution of methyl 4-nitrobutyrate (23g) and benzaldehyde (16ml) in acetic acid (39ml) containing ammonium acetate (12.12g) was heated at reflux under nitrogen for 2h.
  • DESCRTPTTON 2 (2R*.3R* 3-f.3.5-Bis(trifluoromethyl)phenyl methvloxv.-l-(carbomethoxv)methvl-2-phenvlpiperidine cis-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-pheny lpiperidine hydrochloride (Description 1, lg) was Uberated from the hydrochloride salt by partitioning between ethyl acetate and 2M sodium hydroxide. The organic phase was washed successively with water, saturated brine, dried (MgS0 4 ) and evaporated in vacuo.
  • (+)-cis-3-Hydroxy-2-phenylpiperidine was reacted according to the procedure detailed in Description lc-e to give (+)-cJs-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy-2- phenylpiperidine hydrochloride as a crystalline solid: mp 215-216°C.
  • DESCRIPTION 8 (2S.3S).3-((3.5-Bisftrifl ⁇ oromethy1 nhe ⁇ yl methyloxy)-l-(carboxyhvdrazidomethyl)-2-phenylpiperidinium hydrochloride
  • the title compound was prepared according to the procedure outlined in Description 7 using the compound of Description 4 as a starting material.
  • (+)-cis-3-Hydroxy-2-phenylpiperidine (Description 3c) was reacted with 3-£-butyl-5-chlorobenzyl bromide (Description 15d above) according to the procedure detailed in Description lc-d to afford the title compound.
  • the compound of Description 19 (0.342g) was dissolved in methanol (20ml) with hydrochloric add (1ml, 2N). Palladium on charcoal (50mg) was added and the mixture placed under an atmosphere of hydrogen for lh at room temperature. The solvent was removed in vacuo and the residue basified with sodium hydroxide (2M). This solution was extracted with ethyl acetate and the organic extracts were dried (MgS0 4 ) and concentrated to leave a brown oil; this was purified by column chromatography on siHca using 8% methanol in dichloromethane as eluent. The resulting oil was characterised as the salt prepared by treatment with methanolic hydrogen chloride: mp 241-243°C.
  • the foUowing piperidines were prepared according to the procedures outlined in Descriptions 1 and 3, using the appropriate benzyl hahde.
  • DESCRIPTION 28 (3R* 3-. te. ⁇ -Bisftrifluoromethyl fohenyl ) methyloxy)-2-methyl-2-(2R*)-2-phenvIpiperidine
  • Hydroxyguanidine sulphate hydrate (2.3g) was dissolved in water and freeze-dried overnight. Ethanol (35ml) and powdered molecular sieves (lg) were added to the sohd hydroxyguanidine and the suspension was stirred under nitrogen for 1 hour. Sodium (670mg) was added to the mixture whidi was stirred until aH sodium had reacted. The suspension assumed an orange colour at this time and was placed in an ultrasound bath for 15 min. The ester of Description 2 (1.4g) was added to the mixture which was then heated at reflux for 2h. The reaction mixture was cooled and filtered through ceHte.
  • Acetamideoxime (117mg) and powdered molecular sieves were suspended in dry tetrahydrofuran (10ml) and stirred under nitrogen for 1 hour.
  • Sodium hydride 63mg of 60% suspension in oil
  • the ester of Description 2 500mg was dissolved in tetrahydrofuran (2ml) and added to the above mixture. This mixture was heated at reflux for 2h, cooled, filtered through celite and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water and then brine.
  • the organic layer was dried (MgS0 4 ) and evaporated in vacuo.
  • Example 9 The compound of Example 9 (340mg) was dissolved in tetrahydrofuran. To this solution was added borane-dimethyl sulfide complex (0.18ml of 10M solution) and the resulting solution was heated at reflux for 8h. The mixture was cooled, methanol added to quench excess borane, and the solvents were removed in vacuo. The residue was dissolved in methanol (10ml) and potassium carbonate was added (238mg). This mixture was heated at reflux for 1 hour; the methanol was removed in vacuo and the residue was dispersed between ethyl acetate and brine. The ethyl acetate layer was dried (MgS0 4 ) and evaporated.
  • Example 13 The compound of Example 13 was reacted with borane dimethylsulfide as described in Example 10. The free base was recrystalHsed from ether and hexane to give the product as a white crystalline sohd.
  • Example 7 The compound of Example 7 (500mg) was suspended in water (4ml) and sodium hydroxide (44mg) added. This was heated to an external temperature of 96°C and dimethyl sulphate (65mg) added. The reaction mixture was aUowed to stir under nitrogen at 96°C for lh after which time stirring was continued for 24h at 5°C. After this time, the product was extracted into dichloromethane and washed with water and brine. The organic layer was dried (MgS0 4 ) and evaporated. The residue was purified on siHca using medium pressure chromatography (Lobar), and eluted with 25% ethyl acetate in petrol.
  • Libar medium pressure chromatography
  • Example 32 The compound of Example 32 was dissolved in ⁇ dichloromethane and ethereal hydrogen chloride was added.
  • TMs compound was prepared according to the procedure described in Example 7, using the compound of Description 9 as a starting material: mp 179-181°C. MS (CI + ) m/z 486 (MH + ,
  • TMs compound was prepared according to the procedure described in Example 18 using the compound of Example 37 as a starting material. TMs afforded the title compound as a wMte crystalline material: mp 158-l ⁇ 9°C. MS (CI + ) m/z ⁇ OO (MH + , 70%). Found: C, ⁇ 5.84; H, 4.66, N, 14.13. Calcd. for C, 5 ⁇ .31; H, 4.64; N, 14.02%.
  • TMs compound was prepared according to the procedure l ⁇ described in Example 19 using the compound of Example 37 as a starting material. TMs afforded the title compound as a dear oU. MS (Cl*) ⁇ OO (MH + , 40%). Found: C, ⁇ .27; H 4.69; N,
  • TMs was purified by chromatography on silica gel using a gradient elution of 10-30% ethyl acetate in petrol. ⁇ Further purification was carried out by medium pressure chromatography; elution with ⁇ O/ ⁇ O ethyl acetate/petrol afforded the title compound as a wMte solid: mp 111-113°C.
  • the titie compound was prepared according to the procedure described in Example 3 ⁇ , using the compound of Description 3 as starting material.
  • the hydrocMoride salt was
  • Example 30 The compound of Example 30 (O. ⁇ g) was dissolved in methanol in a tube. Sodium (0.03g) and iodomethane (0.075ml) 0 were added and the container was sealed. The resulting solution was heated at 65°C for lh, cooled and evaporated. The residue was suspended between water and ethyl acetate. The organic layer was dried (MgS0 4 ), filtered and the solvent removed in vacuo. The residue was purified by chromatography on siHca using ethyl acetate as eluent. TMs afforded the product as a 5 colourless oU, wMch was converted to the hydrocMoride salt by addition of ethereal hydrogen cMoride.
  • Example 59 The compound of Example 59 (0.61g) was dissolved in cMoroform (10ml) and the resulting solution was cooled to 0°C in an ice bath. Triethylamine (2ml) was added followed by phosphorus oxycMoride (1.2ml), dropwise. The solution was stirred at room temperature for lh. The solvent was removed in vacuo and the residue was dispersed between cMoroform and sodium hydrogen carbonate. The organic layer was washed with brine, dried (MgS0 4 ), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica using 30% petrol in ethyl acetate as eluent. The product was isolated as the hydrocMoride salt using ethereal hydrogen cMoride: mp 81°C. MS (CI + ) m/z 510 (M++1, 60%).
  • the foUowing compounds were prepared by the procedure described in Example 35.
  • TMs was prepared from the compound of Description 3 and N-formyl-2-cMoropropionamidohydrazone foUowing the procedure described in Example 61.
  • the first compound to be eluted from the column (using 3% methanol in dicMoromethane as eluant on siHca) was isolated and characterised as the title compound: mp 66-68°C.
  • TMs compound was prepared according to the procedure described in Example 35 using the compound of Description 3 and N-carbomethoxy-2-cMoropropionamidohydrazone
  • TMs compound was prepared according to the procedure described in Example 35 using the compound of Description 29 as starting material. *H NMR (CDC1 3 ) ⁇ 1.37-1.55 (2H, m), 1.9-
  • TMs was prepared from the compo ⁇ md of Description 28 according to the procedure outiined in Example 3 ⁇ .
  • the compound of formula (X) , cellulose, lactose and a portion of the corn starch are mixed and granulated with
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing l.Omg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and lOOmg of the active compound per tablet.
  • the sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water.
  • the compound of formula (I) is dissolved or suspended in the solution and made up to volume.
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the compound of formula (I) is added and stirring continued until dispersed. The mixture is then cooled until solid.
EP93910151A 1992-04-15 1993-04-14 Azaclyclische Verbindungen Withdrawn EP0636130A1 (de)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
GB9208323 1992-04-15
GB929208323A GB9208323D0 (en) 1992-04-15 1992-04-15 Therapeutic agents
GB9216065 1992-07-28
GB929216065A GB9216065D0 (en) 1992-07-28 1992-07-28 Therapeutic agents
GB9219686 1992-09-17
GB929219686A GB9219686D0 (en) 1992-09-17 1992-09-17 Therapeutic agents
GB9226069 1992-12-14
GB929226069A GB9226069D0 (en) 1992-12-14 1992-12-14 Therapeutic agents
PCT/GB1993/000788 WO1993021181A1 (en) 1992-04-15 1993-04-14 Azacyclic compounds

Publications (1)

Publication Number Publication Date
EP0636130A1 true EP0636130A1 (de) 1995-02-01

Family

ID=27450859

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93910151A Withdrawn EP0636130A1 (de) 1992-04-15 1993-04-14 Azaclyclische Verbindungen

Country Status (5)

Country Link
EP (1) EP0636130A1 (de)
JP (1) JPH07505648A (de)
AU (1) AU675786B2 (de)
CA (1) CA2133077A1 (de)
WO (1) WO1993021181A1 (de)

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2700472B1 (fr) 1993-01-19 1995-02-17 Rhone Poulenc Rorer Sa Association synergisante ayant un effet antagoniste des récepteurs NK1 et NK2.
US5633266A (en) * 1993-02-18 1997-05-27 Merck Sharp & Dohme Ltd. Azacyclic compounds compositions containing them and their use as tachykinin antagonists
WO1995019344A1 (en) * 1994-01-13 1995-07-20 Merck Sharp & Dohme Limited Gem-disubstituted azacyclic tachykinin antagonists
US5728716A (en) * 1994-01-28 1998-03-17 Merck Sharp & Dohme Limited Aralkylamino substituted azacyclic therapeutic agents
RU2309953C2 (ru) 1999-11-03 2007-11-10 Эймр Текнолоджи, Инк. Арил- и гетероарилзамещенные тетрагидроизохинолины, фармацевтическая композиция и способ лечения на их основе
ZA200701232B (en) 2004-07-15 2008-08-27 Amr Technology Inc Aryl-and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin
ES2382814T3 (es) 2005-05-17 2012-06-13 Merck Sharp & Dohme Ltd. Ácido cis-4-[(4-clorofenil)sulfonil]-4-(2,5-difluorofenil)ciclohexanopropanoico para el tratamiento del cáncer
EP1904069B1 (de) 2005-07-15 2018-06-13 Albany Molecular Research, Inc. Aryl- und heteroarylsubstituierte tetrahydrobenzazepine und verwendung damit zur wiederaufnahmeblockierung von norepinephrin, dopamin und serotonin
US8293900B2 (en) 2005-09-29 2012-10-23 Merck Sharp & Dohme Corp Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
GB0603041D0 (en) 2006-02-15 2006-03-29 Angeletti P Ist Richerche Bio Therapeutic compounds
CA2664113C (en) 2006-09-22 2013-05-28 Merck & Co., Inc. Use of platencin and platensimycin as fatty acid synthesis inhibitors to treat obesity, diabetes and cancer
US20110218176A1 (en) 2006-11-01 2011-09-08 Barbara Brooke Jennings-Spring Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
BRPI0806245B1 (pt) 2007-01-10 2022-01-25 Msd Italia S.R.L. Compostos de fórmula i e seus usos
CA2682727C (en) 2007-04-02 2016-03-22 Banyu Pharmaceutical Co., Ltd. Indoledione derivative
EP2170076B1 (de) 2007-06-27 2016-05-18 Merck Sharp & Dohme Corp. 4-carboxybenzylamino-derivate als histondeacetylase-hemmer
US8598184B2 (en) 2008-03-03 2013-12-03 Tiger Pharmatech Protein kinase inhibitors
US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
US8691825B2 (en) 2009-04-01 2014-04-08 Merck Sharp & Dohme Corp. Inhibitors of AKT activity
KR20120034644A (ko) 2009-05-12 2012-04-12 알바니 몰레큘라 리써치, 인크. 아릴, 헤테로아릴, 및 헤테로사이클 치환된 테트라하이드로이소퀴놀린 및 이의 용도
CN102638982B (zh) 2009-05-12 2015-07-08 百时美施贵宝公司 (S)-7-([1,2,4]三唑并[1,5-a]吡啶-6-基)-4-(3,4-二氯苯基)-1,2,3,4-四氢异喹啉的晶型及其用途
CA2760837C (en) 2009-05-12 2018-04-03 Albany Molecular Research, Inc. 7-([1,2,4]triazolo[1,5-.alpha.]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
WO2011046771A1 (en) 2009-10-14 2011-04-21 Schering Corporation SUBSTITUTED PIPERIDINES THAT INCREASE p53 ACTIVITY AND THE USES THEREOF
WO2011163330A1 (en) 2010-06-24 2011-12-29 Merck Sharp & Dohme Corp. Novel heterocyclic compounds as erk inhibitors
CA2805265A1 (en) 2010-08-02 2012-02-09 Merck Sharp & Dohme Corp. Rna interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (ctnnb1) gene expression using short interfering nucleic acid (sina)
WO2012024170A2 (en) 2010-08-17 2012-02-23 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF HEPATITIS B VIRUS (HBV) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US8883801B2 (en) 2010-08-23 2014-11-11 Merck Sharp & Dohme Corp. Substituted pyrazolo[1,5-a]pyrimidines as mTOR inhibitors
US8946216B2 (en) 2010-09-01 2015-02-03 Merck Sharp & Dohme Corp. Indazole derivatives useful as ERK inhibitors
EP2615916B1 (de) 2010-09-16 2017-01-04 Merck Sharp & Dohme Corp. Kondensierte pyrazolderivate als neue erk-hemmer
WO2012058210A1 (en) 2010-10-29 2012-05-03 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACIDS (siNA)
WO2012087772A1 (en) 2010-12-21 2012-06-28 Schering Corporation Indazole derivatives useful as erk inhibitors
JP2014514321A (ja) 2011-04-21 2014-06-19 メルク・シャープ・アンド・ドーム・コーポレーション インスリン様増殖因子１受容体阻害剤
US9023865B2 (en) 2011-10-27 2015-05-05 Merck Sharp & Dohme Corp. Compounds that are ERK inhibitors
US9505728B2 (en) 2012-03-09 2016-11-29 Inception 2, Inc. Triazolone compounds and uses thereof
US20150299696A1 (en) 2012-05-02 2015-10-22 Sirna Therapeutics, Inc. SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS
WO2014052563A2 (en) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Novel compounds that are erk inhibitors
MX363243B (es) 2012-11-28 2019-03-14 Merck Sharp & Dohme Composiciones para tratar cáncer y usos de dichas composiciones.
RU2690663C2 (ru) 2012-12-20 2019-06-05 Мерк Шарп И Доум Корп. Замещенные имидазопиридины в качестве ингибиторов hdm2
AU2013363398B2 (en) 2012-12-20 2017-06-01 Tempest Therapeutics, Inc. Triazolone compounds and uses thereof
US9540377B2 (en) 2013-01-30 2017-01-10 Merck Sharp & Dohme Corp. 2,6,7,8 substituted purines as HDM2 inhibitors
US20160194368A1 (en) 2013-09-03 2016-07-07 Moderna Therapeutics, Inc. Circular polynucleotides
EA201690230A1 (ru) 2013-09-06 2016-07-29 Инсепшн 2, Инк. Соединения триазолона и их применения
JP6563017B2 (ja) 2014-08-28 2019-08-21 エースニューロン・ソシエテ・アノニム グリコシダーゼ阻害剤
TW201726678A (zh) 2015-10-30 2017-08-01 赫孚孟拉羅股份公司 嘧啶酮衍生物及其於治療、改善或預防病毒性疾病之用途
CN108884078A (zh) 2016-02-25 2018-11-23 阿森纽荣股份公司 糖苷酶抑制剂
EA201891438A1 (ru) 2016-02-25 2019-01-31 Асенейрон С. А. Кислотно-аддитивные соли производных пиперазина
US11261183B2 (en) 2016-02-25 2022-03-01 Asceneuron Sa Sulfoximine glycosidase inhibitors
WO2017144633A1 (en) 2016-02-25 2017-08-31 Asceneuron S. A. Glycosidase inhibitors
AU2017378186A1 (en) 2016-12-16 2019-06-13 Janssen Pharmaceutica Nv Monocyclic OGA inhibitor compounds
US11213525B2 (en) 2017-08-24 2022-01-04 Asceneuron Sa Linear glycosidase inhibitors
US10947234B2 (en) 2017-11-08 2021-03-16 Merck Sharp & Dohme Corp. PRMT5 inhibitors
WO2020033284A1 (en) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Prmt5 inhibitors
EP3833668A4 (de) 2018-08-07 2022-05-11 Merck Sharp & Dohme Corp. Prmt5-inhibitoren
WO2020039029A1 (en) 2018-08-22 2020-02-27 Asceneuron S. A. Spiro compounds as glycosidase inhibitors
US11795165B2 (en) 2018-08-22 2023-10-24 Asceneuron Sa Tetrahydro-benzoazepine glycosidase inhibitors

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4968678A (en) * 1988-02-19 1990-11-06 Eli Lilly And Company Tetrazole excitatory amino acid receptor antagonists
MX18467A (es) * 1988-11-23 1993-07-01 Pfizer Agentes terapeuticos de quinuclidinas
UA41251C2 (uk) * 1990-01-04 2001-09-17 Пфайзер, Інк. Гідровані азотвмісні гетероциклічні сполуки, похідні піперидину, фармацевтична композиція та спосіб пригнічення активності речовини р в організмі
DE69220258T2 (de) * 1991-02-11 1997-12-18 Merck Sharp & Dohme Azabicyclische Verbindungen, diese enthaltende pharmazeutische Zubereitungen und ihre therapeutische Verwendung
EP0600952B1 (de) * 1991-08-20 1996-04-17 MERCK SHARP & DOHME LTD. Azacyclische verbindungen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische zubereitungen
IL111730A (en) * 1993-11-29 1998-12-06 Fujisawa Pharmaceutical Co Piperazine derivatives, processes for their preparation and pharmaceutical preparations containing them

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9321181A1 *

Also Published As

Publication number Publication date
JPH07505648A (ja) 1995-06-22
WO1993021181A1 (en) 1993-10-28
CA2133077A1 (en) 1993-10-28
AU675786B2 (en) 1997-02-20
AU4076593A (en) 1993-11-18

Similar Documents

Publication Publication Date Title
US5496833A (en) Piperidine tachykinin receptor antagonists
EP0636130A1 (de) Azaclyclische Verbindungen
EP0666856B1 (de) 4-arylmethyloxymethyl piperidine als tachykinin antagonisten
US5633266A (en) Azacyclic compounds compositions containing them and their use as tachykinin antagonists
US5561130A (en) Azacyclic compounds
US5665883A (en) Aralkoxy and aralkylthio substituted azacyclic compounds as tachykinin antagonists
US5728716A (en) Aralkylamino substituted azacyclic therapeutic agents
EP0600952B1 (de) Azacyclische verbindungen, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische zubereitungen
US5612362A (en) Imidazolinone derivatives as tachykinin receptor antagonists
US5760018A (en) Gem-disubstituted azacyclic tachykinin antagonists
US5624947A (en) Phenyl derivatives useful as tachykinin antagonists
WO1993024465A1 (en) 2/3-(heterocyclic alkyl amino)-1-(subst.-phenyl-methoxy)-ethanes/propanes as tachykinin-receptor antagonists
JP2002534955A (ja) シクロペンチルタキキニン受容体アンタゴニスト
AU714701B2 (en) Novel thiophene derivative and pharmaceutical composition thereof
US5444074A (en) Piperidine tachykinin receptor antagonists
JP2840288B2 (ja) 置換１―（１ｈ―イミダゾール―４―イル）アルキル―ベンズアミド
JPH10513172A (ja) ５−ｈｔ▲下１ｄ▼受容体アゴニストとしての置換１，４−ピペラジン−ヘテロアリール誘導体
KR19980702304A (ko) 장운동 촉진성 옥사디아졸
EP1773823A1 (de) 4-arylmorpholin-3-onderivate, herstellung und therapeutische verwendung dafür
JPS60158172A (ja) グリセリン誘導体
JPH04210970A (ja) ベンズアミド誘導体及びその中間体

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19941115

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU NL PT SE

17Q First examination report despatched

Effective date: 19980123

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20010302