AP947A - Quaternary ammonium compounds as tachykinin antagonists. - Google Patents
Quaternary ammonium compounds as tachykinin antagonists. Download PDFInfo
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- AP947A AP947A APAP/P/1998/001262A AP9801262A AP947A AP 947 A AP947 A AP 947A AP 9801262 A AP9801262 A AP 9801262A AP 947 A AP947 A AP 947A
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Abstract
The present invention provides a compound of the formula: wherein R is phenyl, C3-C7 cycloalkyl or heteroaryl, each of which being optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by from 1 to 3 substituents each independently selected from C,-C4 alkyl, fluoro(C1-C4)alkyl, C,-C4 alkoxy, fluoro(C,-C4)alkoxy, phenoxy, C2-C4 alkanoyl, halo, C,-C4 alkoxycarbonyl, C3-C7 cycloalkyl, -S(O)m(CrC4 alkyl), cyano, -NR2R3, -S(O)mNR2R3, -NR4(C,-C4 alkanoyl) and -CONR2R3, or R is 2,3-dihydrobenzo[b]furanyl or chromanyl; R1 is H or C,-C6 alkyl; X is unbranched C2-C4 alkylene; Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C3-C7 cycloalkyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C,-C4 alkyl, fluoro(CrC4)alkyl, C,-C4 alkoxy, fluoro(C,-C4)alkoxy, halo and cyano; Ar is phenyl, naphthyl, benzyl, thienyl, benzo[b]thienyl or indolyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C,-C4 alkyl, fluorofCrC^alkyl, C,-C4 alkoxy, fluoro(C,-C4)alkoxy, halo and cyano, or Ar is 1,3-benzodioxolan-4 or 5-yl or 1,4-benzodioxan-5 or 6-yl; ZA is a pharmaceutically acceptable anion; with the proviso that when W is a direct link and R is optionally fused and optionally substituted heteroaryl, said heteroaryl is linked by a ring carbon atom to the carbonyl group. The compounds are tachykinin antagonists. W is a direct link, methylene or ethylene;
Description
QUATERNARY AMMONIUM COMPOUNDS
This invention relates to quaternary ammonium compounds. More particularly, this invention relates to 1-(2-acylimidazol-1-ylalkyl)quinuclidinium salts and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such salts.
The present compounds are antagonists of tachykinins, including NKA (neurokinin A), NKB (neurokinin B) and Substance P, acting at the human neurokinin-1 (NK^, neurokinin-2 (NK2) and neurokinin-3 (NK3) receptors.
These compounds are particularly useful as dual NK·, and NK2 receptor antagonists and can therefore be used for treating an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a central nervous system (CNS) disorder such as anxiety, depression, dementia or psychosis, a gastro-intestinal (Gl) disorder such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis or Crohn’s disease, a disease caused by Helicobacter pylori or another ureasepositive Gram negative bacteria, a urogenital tract disorder such as incontinence, impotence, hyperreflexia or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis, atopic dermatitis, urticaria, eczematoid dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a proliferative disorder such as a cancer or a disorder involving fibroblast proliferation, a vasospastic disease such as angiogenesis, angina or Reynaud’s disease, a fibrosing or collagen disease such as atherosclerosis, scleroderma or eosinophilic fascioliasis, reflux sympathetic dystrophy such as shoulder/hand syndrome, an addiction disorder such as alcoholism, a stress-related somatic disorder, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia or post-herpetic neuralgia, a neuropathological disorder such as Alzheimer’s disease or multiple sclerosis, a disorder related to immune enhancement or suppression such as systemic lupus erythematosis, a rheumatic disease such as fibrositis, emesis, cough, acute or chronic pain, migraine, an ophthalmic disease such as proliferative retinopathy, influenza or a cold. EP-A-680962 and EP-A-0739891 disclose heterocyclic compounds which are non-peptide antagonists of NKA and that are useful for the treatment of diseases such as asthma. EP-A-0591040 discloses quaternary compounds with tachykinin antagonist activity.
The present invention provides compounds of the formula:
-Z* (I) wherein R is phenyl, C3-C7 cycloalkyl or heteroaryi, each of which being optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by from 1 to 3 substituents each independently selected from CrC4 alkyl, fluoro(C1-C4)alkyl, CrC4 alkoxy, fluoro(C1-C4)alkoxy, phenoxy, C2-C4 alkanoyl, halo, Ο·,-Ο4 alkoxycarbonyl, C3-C7 cycloalkyl, -5(0)^,(0^04 alkyl), cyano, -NR2R3, -S(O)mNR2R3, -NR4(CrC4 alkanoyl) and -CONR2R3, or R is 2,3-dihydrobenzo[b]furanyl or chromanyl; R1 is H or CrC6 alkyl;
R2 and R3 are either each independently selected from H and C.,-C6 alkyl, or when taken together, represent C4-C6 alkylene; R4 is H or CrC6 alkyl; W is a direct link, methylene or ethylene; X is unbranched C2-C4 alkylene; Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C3-C7 cycloalkyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from CrC4 alkyl, fluoro(C1-C4)alkyl, CrC4 alkoxy, fluoro(C.,-C4)alkoxy, halo and cyano;
Ar is phenyl, naphthyl, benzyl, thienyl, benzo[b]thienyl or indolyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from CrC4 alkyl, fluoro(C1-C4)alkyl, CrC4 alkoxy, fluoro(C.,-C4)alkoxy, halo and cyano, or Ar is 1,3-benzodioxolan-4 or 5-yl or 1,4-benzodioxan-5 or 6-yl; m is 0, 1 or 2; ZA is a pharmaceutically acceptable anion; and “heteroaryl”, used in the definition of R, means thienyl or a 5- or 6-membered ring heteroaryl group containing either from 1 to 4 nitrogen heteroatoms, or 1 or 2 nitrogen heteroatom(s) and 1 oxygen or sulphur heteroatom, with the proviso that when W is a direct link and R is optionally fused and optionally substituted heteroaryl, said heteroaryl is linked by a ring carbon atom to the carbonyl group.
In the above definitions, “halo” means fluoro, chloro, bromo or iodo and alkyl and alkoxy groups having three or more carbon atoms, alkanoyl groups having four carbon atoms and alkylene groups having two or more carbon atoms (except where stated) may be unbranched- or branched-chain. ZA is a pharmaceutically acceptable anion such as chloride, bromide, nitrate, methanesulphonate, para-toluenesulphonate, benzenesulphonate, hydrogen sulphate or sulphate.
Preferably, ZA is chloride or methanesulphonate.
Most preferably, ZA is methanesulphonate. A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) and mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid.
Preferably, R is phenyl which is optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by 1, 2 or 3 substituents each independently selected from CrC4 alkyl, fluoro(C1-C4)alkyl, CrC4 alkoxy, fluoro(C1-C4)alkoxy, phenoxy and halo, or R is 2,3-dihydrobenzo[b]furanyl.
More preferably, R is phenyl which is optionally benzo- or C3-C7 cycloalkyl-fused and optionally substituted, including in the benzo- or C3-C7 cycloalkyl-fused portion, by 1, 2 or 3 substituents each independently selected from methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, phenoxy, fluoro and chloro, or R is 2,3-dihydrobenzo[b]furanyl.
Yet more preferably, R is phenyl, naphthyl or tetrahydronaphthyl, each of which being optionally substituted by 1, 2 or 3 substituents each independently selected from methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, trifluoromethoxy, phenoxy, fluoro and chloro, or R is 2,3-dihydrobenzo[b]furanyl.
Yet further preferably, R is phenyl, 3,5-dimethylphenyl, 2,3-dimethylphenyl, 2-trifluoromethoxyphenyl, 2-methoxy-3-methylphenyl, 2,3-dihydrobenzo[b]furan-7-yl, naphth-2-yt, 4-fluoro-3-trifluoromethylphenyl, 1,2,3,4-tetrahydronaphth-5-yl, 1,2,3,4-tetrahydronaphth-6-yl, 5-chloro-2-methoxyphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-isopropoxyphenyl, 2-ethylphenyl, 2-phenoxyphenyl or 3,5-bis(trifluoromethyl)phenyl.
Most preferably, R is 2,3-dimethylphenyl, naphth-2-yl, 1,2,3,4-tetrahydronaphth-5-yl or 2-methoxyphenyl.
Preferably, R1 is H.
Preferably, W is a direct link or methylene.
Most preferably, W is a direct link.
Preferably, X is 1,2-ethylene.
Preferably, Y is phenyl, naphthyl or cyclohexyl, each of which being optionally substituted by 1, 2 or 3 CrC4 alkyl substituents.
More preferably, Y is phenyl, 3,5-dimethylphenyl, cyclohexyl or naphthoyl-
Most preferably, Y is phenyl. c
Preferably, Ar is phenyl optionally substituted by 1, 2 or 3 halo 4 substituents. *
More preferably, Ar is phenyl substituted by 1 or 2 chloro substituents. < Most preferably, Ar is 3,4-dichlorophenyl. ( <
Preferred examples of compounds of the formula (I) are compounds of ( the formula: ί
I
.ZA (IA) wherein 1) R-W- is 3,5-dimethylphenyl, Y is phenyl and ZA is CH3SO3‘; 2) R-W- is 2,3-dimethylphenyl, Y is phenyl and ZA is CH3SO3';
3) R-W- is 2-trifluoromethoxyphenyl, Y is phenyl and ZA is CH3SO3'; 4) R-W- is 2-methoxy-3-methylphenyl, Y is phenyl and ZA is CH3SO3'; 5) R-W- is 2,3-dihydrobenzo[b]furan-7-yl, Y is phenyl and ZA is CH3SO3"; 6) R-W- is naphth-2-yl, Y is phenyl and ZA is CH3SO3'; 7) R-W- is 4-fluoro-3-trifluoromethylphenyl, Y is phenyl and ZA is CH3SO3'; 8) R-W- is 1,2,3,4-tetrahydronaphth-5-yl, Y is phenyl and ZA is CH3SO3'; 9) R-W- is 1,2,3,4-tetrahydronaphth-6-yl, Y is phenyl and ZA is CH3SO3'; 10) R-W- is 5-chloro-2-methoxyphenyl, Y is phenyl and ZA is CH3SO3'; 11) R-W- is 2-methoxyphenyl, Y is phenyl and ZA is CH3SO3'; 12) R-W- is 2-trifluoromethylphenyl, Y is phenyl and ZA is CH3SO3'; 13) R-W- is 2-isopropoxyphenyl, Y is phenyl and ZA is CH3SO3'; 14) R-W- is 2-ethylphenyl, Y is phenyl and ZA is CH3SO3"; 15) R-W- is 2-phenoxyphenyl, Y is phenyl and ZA is CH3SO3'; 16) R-W- is benzyl, Y is phenyl and ZA is CH3SO3'; 17) R-W- is 3,5-bis(trifluoromethyl)phenyl, Y is phenyl and ZA is Cl'; 18) R-W- is 2-methoxyphenyl, Y is cyclohexyl and ZA is CH3SO3'; 19) R-W- is 4-fluoro-3-trifluoromethylphenyl, Y is cyclohexyl and ZA is CH3SO3'; 20) R-W- is 2-methoxyphenyl, Y is 3,5-dimethylphenyl and ZA is CH3SO3'; or 21) R-W- is 2-methoxyphenyl, Y is naphth-2-yl and ZA is CH3SO3': or an alternative pharmaceutically acceptable salt of any thereof (re ZA).
Particularly preferred examples of the compounds of the formula (I) are 4-phenyl-1-(3(S)-[3,4-dichlorophenyl]-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)-imidazol-1-yl]butyl)quinuclidinium methanesulphonate and 4-phenyl-1-(3(R)-[3,4-dichlorophenyl]-4-[2-(1,2,3,4-tetrahydro-5-naphthoyl)imidazol-1-yl]butyl)quinuclidinium methanesulphonate.
All the compounds of the formula (I) can be prepared by reaction of a compound of the formula;
(II) wherein R, R1, Ar, W and X are as previously defined for a compound of the formula (I), Z is a suitable leaving group capable of forming a pharmaceutically acceptable anion (ZA) and Z1 is a suitable leaving group, with a compound of the formula:
(III) wherein Y is as previously defined for a compound of the formula (I), said process being followed by either (a), where Z1 is a suitable leaving group, exchange for a pharmaceutically acceptable anion (ZA), or (b), optionally, where ZA is a pharmaceutically acceptable anion, exchange for another pharmaceutically acceptable anion.
Preferred examples of Z are alkanesulphonyloxy, benzenesulphonyloxy, para-toluenesulphonyloxy, chloro, bromo and iodo.
An example of Z1 is trifluoromethanesulphonyloxy.
Preferably, the leaving group in the compound of the formula (II) forms a pharmaceutically acceptable anion (Z/ZA), e.g. methanesulphonyloxy/ methanesulphonate, and therefore anion exchange at the end of the process is unnecessary.
It is possible to exchange pharmaceutically acceptable anions (ie ZA) in the work-up procedure, e.g. methanesulphonate may be exchanged to chloride by treatment of the isolated compound or the crude mixture with aqueous hydrochloric acid solution.
The reaction of the compounds (II) and (III) is generally carried out in a suitable solvent, e.g. acetonitrile, at elevated temperatures, preferably at the reflux temperature thereof.
The starting materials of the formula (II) can be prepared as shown in Scheme 1.
Scheme 1
Claims (1)
- Original document published without claims.
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| GBGB9712882.1A GB9712882D0 (en) | 1997-06-18 | 1997-06-18 | Quaternary ammonium compounds |
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| WO1999033489A1 (en) * | 1997-12-26 | 1999-07-08 | Yamanouchi Pharmaceutical Co., Ltd. | Sustained release medicinal compositions |
| JP4546589B2 (en) * | 1998-04-23 | 2010-09-15 | 武田薬品工業株式会社 | Naphthalene derivatives |
| NZ523310A (en) * | 2000-06-12 | 2005-07-29 | Univ Rochester | Tachykinin receptor antagonist to block receptors NK1, NK2, and NK3 and treat symptoms of hormonal variation |
| WO2002046156A2 (en) * | 2000-12-06 | 2002-06-13 | Sepracor, Inc. | 4,4-disubstituted piperidines for use as dopamine, serotonin and norepinephrine ligands |
| AU2003243353A1 (en) * | 2002-05-29 | 2003-12-19 | The Regents Of The University Of California | Antagonizing nk1 receptors inhibits consumption of substances of abuse |
| WO2004091597A2 (en) * | 2003-04-15 | 2004-10-28 | Pharmacia & Upjohn Company Llc | Method of treating irritable bowel syndrome (ibs) |
| WO2005110998A1 (en) * | 2004-05-07 | 2005-11-24 | Janssen Pharmaceutica N.V. | Scalable synthesis of imidazole derivatives |
| WO2008090114A1 (en) | 2007-01-24 | 2008-07-31 | Glaxo Group Limited | Pharmaceutical compositions comprising 2-methoxy-5- (5-trifluoromethyl-tetrazol-i-yl-benzyl) - (2s-phenyl-piperidin-3s-yl-) |
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