WO1993021181A1 - Composes azacycliques - Google Patents

Composes azacycliques Download PDF

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Publication number
WO1993021181A1
WO1993021181A1 PCT/GB1993/000788 GB9300788W WO9321181A1 WO 1993021181 A1 WO1993021181 A1 WO 1993021181A1 GB 9300788 W GB9300788 W GB 9300788W WO 9321181 A1 WO9321181 A1 WO 9321181A1
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WIPO (PCT)
Prior art keywords
methyloxy
phenyl
methyl
trifluoromethyl
phenylpiperidino
Prior art date
Application number
PCT/GB1993/000788
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English (en)
Inventor
Raymond Baker
Tamara Laddhwahetty
Eileen Mary Seward
Christopher John Swain
Original Assignee
Merck Sharp & Dohme Limited
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.)
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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 & Dohme Limited filed Critical Merck Sharp & Dohme Limited
Priority to AU40765/93A priority Critical patent/AU675786B2/en
Priority to EP93910151A priority patent/EP0636130A1/fr
Priority to JP5518131A priority patent/JPH07505648A/ja
Publication of WO1993021181A1 publication Critical patent/WO1993021181A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—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
  • 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 is believed inter alia to be involved in the neurotransmission of pain
  • GI disorders and diseases of the GI tract such as inflammatory bowel disease [Mantyh et al in Neuroscience (1988) 25 (3) 817-37 and D. Regoli in
  • 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) 33 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],
  • Substance P may also play a role in
  • demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J. Luber-Narod et. al., poster presented 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).
  • 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
  • peptide derivatives are likely to be of limited utility as therapeutic agents. It is for this reason that nonpeptide tachykinin antagonists are sought.
  • European patent application no. 0 436 334 discloses 4- to 7-membered azacyclic compounds
  • the compounds are said to be tachykinin
  • the present invention provides a compound of formula (I), or a salt or prodrug thereof:
  • n 1, 2 or 3;
  • 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 1, 2 or 3 groups selected from C 1-6 alkyl, C 2-6 alkenyl, C2-6alkynyl, halo, cyano, nitro, trifluoromethyl,
  • R 2 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl;
  • each aryl or heteroaryl moiety may be substituted by C 1-6 alkyl, C 1-6 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 1-6 alkyl, oxo, CH 2 OR a , CO 2 R a or
  • R 8 represents an optionally substituted
  • R a and R b each independently represent H, trifluoromethyl, C 1-6 alkyl or phenyl optionally
  • 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
  • suitable alkenyl groups include vinyl and allyl
  • suitable alkynyl groups include propargyl
  • halo as used herein includes fluoro, chloro, bromo 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
  • 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
  • n is 2 or 3, more preferably 3.
  • X represents O.
  • R 1 represents substituted phenyl.
  • suitable substituents include nitro, trifluoromethyl, trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, C 1-6 alkyl such as methyl, ethyl, i-propyl, i-butyl, t-butyl and cyclopropyl,
  • R 1 represents phenyl
  • C 1-4 alkyl 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,
  • R 1 represents phenyl substituted at the 3-position by trifluoromethyl or a C 1-6 alkyl group such as t-butyl, or 3,5-disubstituted phenyl wherein the
  • 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
  • Suitable values for R 4 and R 5 include H,
  • 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 R in question represents oxo, C-2 and C-3.
  • at least one of R 4 and R 5 represents H.
  • 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.
  • R represents a substituted aromatic heterocycle
  • suitable substituents in the heterocyclic ring include one or more of C 1-6 alkyl, C 1-6 alkoxy, phenyl, oxo, thioxo, halo, trifluoromethyl, NR a R b ,
  • NR a COR b CONR a R b , CO 2 R a , SR a , SO 2 R a and CH 2 OR a , where R a and R b are as previously defined.
  • suitable substituents include methyl, methoxy, phenyl, oxo, thioxo, bromo, iodo, NH 2 , SCH 3 , CONH 2 and cyano.
  • Particularly preferred substituents include oxo and NH 2 .
  • Suitable values for R 8 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,
  • benzimidazolyl benzoxazolyl, benzothiophenyl, benzofuranyl and indolyl, any of which may be
  • R 8 may represent optionally substituted thienyl, furyl, pyridyl, triazolyl,
  • R 8 represents optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,
  • R 8 represents a substituted or unsubstituted 5- or 6-membered nitrogen containing aromatic heterocycle such as for example oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, thiadiazolyl,
  • R 8 represents optionally substituted oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl,
  • R 8 represents substituted or
  • 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.
  • heterocyclic moiety R 8 is substituted by an oxo or thioxo substituent
  • n is 1, 2 or 3 and where any carbon atom of (CH 2 ) n may be substituted by R 12 and/or R 13 ;
  • X represents O or S
  • R 10 represents phenyl optionally substituted by 1, 2 or 3 groups selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, cyano, nitro, trifluoromethyl,
  • R 11 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl;
  • each aryl or heteroaryl moiety may be substituted by C 1-6 alkyl, C 1-6 alkoxy, halo or trifluoromethyl;
  • R 12 and R 13 each independently represent H, halo, C 1-6 alkyl, oxo, CO 2 R c or CONR c R d ;
  • R 14 represents C 1-4 alkyl, optionally substituted by oxo, substituted by an optionally
  • R c and R d each independently represent H
  • Suitable values for the heterocyclic moiety of R 14 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl,
  • R c and R d each independently represent H, C 1-6 alkyl, 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 1-6 alkyl,
  • R 14 represents C 1-4 alkyl substituted by an optionally substituted 5- or 6-membered aromatic heterocycle; and R c and R d each independently represent H, C 1-6 alkyl, phenyl or trifluoromethyl.
  • suitable values for the heterocyclic moiety of R 14 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,
  • a preferred sub-class of compounds according to the invention is represented by compounds of formula (IB), and salts and prodrugs thereof:
  • X represents O or S, preferably O
  • Y is as defined for formula (I), preferably C 1-2 alkyl 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 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, bromo, chloro, fluoro, iodo, cyano, nitro, trifluoromethyl,
  • 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
  • R 20 and R 21 are both other than H, more preferably C 1-6 alkyl, 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,
  • a further sub-class of compounds according to the invention are compounds of formula (IB) wherein R 8 is optionally substituted oxadiazolyl, pyridinyl,
  • pyrazinyl pyridazinyl, triazinyl, pyrimidinyl or
  • a particularly preferred group of compounds according to the invention are compounds of formula (Ia) wherein R 8 is optionally substituted triazolyl,
  • 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
  • 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 organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.
  • 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
  • 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
  • the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose. sucrose, sorbitol, talc, stearic acid, magnesium
  • 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
  • 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
  • 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, 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
  • 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. These may include 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
  • ALS Lou Gehrig's disease
  • peripheral neuropathological disorders such as peripheral obstructive sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral obstructive sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral obstructive sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral obstructive sclerosis (ALS; Lou Gehrig's disease) and other neuropathological disorders such as peripheral neuropathological disorders.
  • 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;
  • hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact
  • dermatitis atropic dermatitis, urticaria, and other eczematoid dermatitis
  • addiction disorders such as alcoholism
  • stress related somatic disorders such as reflex sympathetic dystrophy
  • reflex sympathetic dystrophy such as shoulder/hand syndrome
  • dysthymic disorders adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; 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; ernesis, including acute, delayed and anticipatory emesis, for example, induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, surgery, migraine and variations in intercranial pressure; disorders of bladder function such as bladder detrusor hyper-reflexia;
  • fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine.
  • 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.
  • respiratory diseases particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bron
  • 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
  • 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
  • tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I) is a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula (I) .
  • a compound of formula (I) may be used in conjunction with a bronchodilator, such as a ⁇ 2 -adrenergic receptor
  • bronchodilator may be administered to a patient
  • 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.
  • the present invention also provides a composition
  • a composition comprising a compound of formula (I), a bronchodilator, and a pharmaceutically acceptable
  • 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
  • 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 p- 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 p- toluenesulphonate,or any other suitable leaving group, in the presence of
  • Suitable bases of use in the reaction include inorganic bases such as alkali metal carbonates, for example, potassium carbonate.
  • reaction is effected in a suitable organic solvent, for example, dimethylformamide.
  • compounds of formula (I) wherein R 8 represents 5-oxadiazolyl may be prepared by reaction of a compound of formula (III) with a compound of formula (IV):
  • R 30 represents an alkyl group and R 31 represents H or a suitable substituent such as C 1-6 alkyl, C 1-6 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. Which solvents will be
  • suitable solvents will include alcohols, for example, ethanol, whereas where the base used is an alkali
  • suitable solvents will include ethers, for example, tetrahydrofuran.
  • reaction is conducted at
  • elevated temperature such as the reflux temperature of the chosen solvent.
  • R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) by treatment with an alkali metal azide, such as sodium azide.
  • reaction is conveniently effected in a high boiling organic solvent, such as, for example,
  • Hal-CH 2 C(O)-R 60 where Hal represents halo, such as bromo, chloro or iodo, and R 60 represents H or a suitable substituent such as C 1-6 alkyl.
  • the reaction is conveniently effected in a suitable organic solvent, such as a ketone, for example, acetone, or an alcohol, for example, methanol, or a mixture of solvents, preferably at elevated temperature, such as the reflux temperature of the chosen solvent.
  • R 61 NCS wherein R 61 represents H or a suitable
  • 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
  • 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, OCH 3 (which is converted to an oxo substituent under the reaction conditions) or CONH 2 .
  • reaction is conveniently effected in an anhydrous organic solvent, such as, for example, anhydrous dimethylformamide, preferably at elevated temperature, such as about 140oC.
  • anhydrous organic solvent such as, for example, anhydrous dimethylformamide
  • R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I), with substituted or unsubstituted 1,3,5-triazine.
  • reaction is conveniently effected in a suitable organic solvent, such as acetronitrile, at elevated temperature, such as 80-90oC, 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):
  • R 1 , R 2 , R 4 , R 5 , X, Y and n are as defined for formula (I) and R 35 and R 36 each independently represnt H or a suitable substituent such as C 1-6 alkyl, e.g. methyl.
  • reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g.
  • 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 1-4 alkyl substituted by an aromatic heterocycle may be prepared from compounds of formula (I) wherein Y represents C 1-4 alkyl substituted by oxo by reduction, for example, using borane.
  • Suitable interconversion procedures are described in the
  • Intermediates of formula (III) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-CO 2 R 30 , where Hal represents halo such as chloro, bromo or iodo and R 30 and Y are as above defined, in the presence of a base.
  • Suitable bases include tertiary amines, for example, triethylamine.
  • reaction is effected in a suitable organic solvent, such as an ether, for example,
  • 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
  • Intermediates of formula (IX) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C(NH)NH 2 , 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
  • 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) .
  • protecting groups may be removed at a convenient
  • the method essentially involves determining the concentration of the test compound required to reduce by 50% the amount of
  • DESCRIPTION 8 (2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl) methyloxy)-1-(carboxyhydrazidomethyl)-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.
  • 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 (MgSO 4 ) and concentrated to leave a brown oil; this was purified by column chromatography on silica 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 following piperidines were prepared according to the procedures outlined in Descriptions 1 and 3, using the appropriate benzyl halide.
  • Hydroxyguanidine sulphate hydrate (2.3g) was dissolved in water and freeze-dried overnight. Ethanol (35ml) and powdered molecular sieves (1g) 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 celite.
  • 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 (MgSO 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 (MgSO 4 ) and evaporated.
  • borane-dimethyl sulfide complex 0.18ml of 10M solution
  • the compound of Description 1 was reacted with 2-thiophenecarbonyl chloride as outlined in Example 9.
  • the oil obtained after work-up and removal of solvent was purified by chromatography on silica, eluting with 10% ethyl acetate in petroleum ether to afford the pure product as a dear oil.
  • Example 13 The compound of Example 13 was reacted with borane dimethylsulfide as described in Example 10. The free base was recrystallised from ether and hexane to give the product as a white crystalline sohd.
  • 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.1ml) was added and the reaction mixture was heated under reflux for 2.5h. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was dried (MgSO 4 ) and evaporated. The residue was purified on silica using 5% methanol in dichloromethane as eluant to give the title compound. The product (470mg) was characterised as the hydrochloride salt.
  • 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 allowed to stir under nitrogen at 96°C for 1h 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 (MgSO 4 ) and evaporated. The residue was purified on silica using medium pressure chromatography (Lobar), and eluted with 25% ethyl acetate in petrol.
  • Libar medium pressure chromatography
  • 1,3-Oxazole-4-carboxaldehyde (0.38g) was dissolved in anhydrous methanol and stirred under nitrogen; sodium borohydride (0.074g) was added carefully. After 1 hour no starting material was present by TLC using 50% ethyl acetate in hexane as eluent. The methanol was removed by rotary evaporator (water bath temp 40°C). The residue was purified by chromatography on silica eluting with 100% diethyl ether. This afforded the alcohol (0.27g) as a white sohd.
  • Example 32 The compound of Example 32 was dissolved in dichloromethane and ethereal hydrogen chloride was added.
  • 1,2-pyridazine-3-carboxaldehyde (0.89g) (G. Heimsch, E. Luszczak and M. Paller, Mh. Chem 104, 1372 (1973)) was dissolved in water and sodium iiorohydride (0.081g) was added carefully. After 1 hour no starting material was present by TLC using 10% methanol in dichloromethane as eluent. The water was removed in vacuo to afford a gum. The gum was extracted with dichloromethane, the combined organics were dried (MgSO 4 ) and concentrated in vacuo to afford the alcohol as a sohd, which was used in the following experiment without further purification.
  • the titie compound was prepared according to the procedure described in Example 35, using the compound of Description 3 as starting material.
  • the hydrochloride salt was recrystallised from ethyl acetate-methanol to give a white crystalline solid: mp 265-266°C.
  • Example 30 The compound of Example 30 (0.5g) was dissolved in methanol in a tube. Sodium (0.03g) and iodomethane (0.075ml) were added and the container was sealed. The resulting solution was heated at 65°C for 1h, cooled and evaporated. The residue was suspended between water and ethyl acetate. The organic layer was dried (MgSO 4 ), filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica using ethyl acetate as eluent. This afforded the product as a colourless oil, which was converted to the hydrochloride salt by addition of ethereal hydrogen chloride. The salt was recrystallised from ether/petrol.
  • Example 59 The compound of Example 59 (0.61g) was dissolved in chloroform (10ml) and the resulting solution was cooled to 0°C in an ice bath. Triethylamine (2ml) was added followed by phosphorus oxychloride (1.2ml), dropwise. The solution was stirred at room temperature for lh. The solvent was removed in vacuo and the residue was dispersed between chloroform and sodium hydrogen carbonate. The organic layer was washed with brine, dried (MgSO 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 hydrochloride salt using ethereal hydrogen chloride: mp 81°C. MS (CI + ) m/z 510 (M++1, 60%).
  • 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 1.0mg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and 100mg 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.

Abstract

L'invention concerne des composés de la formule (I) et les sels et les précurseurs dans laquelle n est égal à 1, 2 ou 3; X représente O ou S; Y représente une chaîne hydrocarbonée à 1, 2, 3 ou 4 atomes de carbone, le cas échéant avec une substitution oxo; R1 est un phényle, le cas échéant substitué avec 1, 2 ou 3 groupes (C¿1?-C6)alkyle, (C2-C6)alcényle, (C2-C6)alcynyle, halo, cyano, nitro, trifluorométhyle, triméthylsilyle, -OR?a, SRa, SORa, SO¿2R?a, -NRaRb, -NRaCORb, -NRaCO¿2Rb, -CO2Ra ou -CONRaRb; R2 est un groupe phényle, indazolyle, thiényle, furyle, pyridyle, thiazolyle, tétrazolyle, quinolyle, benzhydryle ou benzyle; R4 et R5 représentent chacun d'une manière indépendante un H, un halo, un groupe (C¿1?-C6)alkyle, oxo, CH2OR?a, CO¿2Ra ou CONRaRb; R8 représente un hétérocycle aromatique, le cas échéant substitué; et Ra et Rb sont chacun d'une manière indépendante un H, un groupe trifluorométhyle, (C¿1?-C6)alkyle ou phényle, le cas échéant substitué par unou des groupes (C1-C6)alkyle, halo ou trifluorométhyle; ces produits sont des antagonistes de la tachykinine et sont utiles en médecine.
PCT/GB1993/000788 1992-04-15 1993-04-14 Composes azacycliques WO1993021181A1 (fr)

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JP5518131A JPH07505648A (ja) 1992-04-15 1993-04-14 アザサイクリック化合物

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GB929208323A GB9208323D0 (en) 1992-04-15 1992-04-15 Therapeutic agents
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GB9216065.4 1992-07-28
GB9219686.4 1992-09-17
GB929219686A GB9219686D0 (en) 1992-09-17 1992-09-17 Therapeutic agents
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AU4076593A (en) 1993-11-18
EP0636130A1 (fr) 1995-02-01
CA2133077A1 (fr) 1993-10-28
JPH07505648A (ja) 1995-06-22
AU675786B2 (en) 1997-02-20

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