Quaternary ammonium compounds

Details Quaternary ammonium compounds Quaternary ammonium compounds

2000-12-11

2002-04-30

Aulakh, Charanjit S. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S311100, C548S335100, C548S341500

Reexamination Certificate

active

06380396

ABSTRACT:

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
1
), neurokinin-2 (NK
2
) and neurokinin-3 (NK
3
) receptors.
These compounds are particularly useful as dual NK
1
and NK
2
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 (GI) 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 urease-positive 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:
wherein
R is phenyl, C
3
-C
7
cycloalkyl or heteroaryl, each of which being optionally benzo- or C
3
-C
7
cycloalkyl-fused and optionally substituted, including in the benzo- or C
3
-C
7
cycloalkyl-fused portion, by from 1 to 3 substituents each independently selected from C
1
-C
4
alkyl, fluoro(C
1
-C
4
)alkyl, C
1
-C
4
alkoxy, fluoro(C
1
-C
4
)alkoxy, phenoxy, C
2
-C
4
alkanoyl, halo, C
1
-C
4
alkoxycarbonyl, C
3
-C
7
cycloalkyl, —S(O)
m
(C
1
-C
4
alkyl), cyano, —NR
2
R
3
, —S(O)
m
NR
2
R
3
, —NR
4
(C
1
-C
4
alkanoyl) and —CONR
2
R
3
, or R is 2,3-dihydrobenzo[b]furanyl or chromanyl;
R
1
is H or C
1
-C
6
alkyl;
R
2
and R
3
are either each independently selected from H and C
1
-C
6
alkyl, or when taken together, represent C
4
-C
6
alkylene;
R
4
is H or C
1
-C
6
alkyl;
W is a direct link, methylene or ethylene;
X is unbranched C
2
-C
4
alkylene;
Y is phenyl, naphthyl, benzyl, pyridyl, thienyl or C
3
-C
7
cycloalkyl, each of which being optionally substituted by from 1 to 3 substituents each independently selected from C
1
-C
4
alkyl, fluoro(C
1
-C
4
)alkyl, C
1
-C
4
alkoxy, fluoro(C
1
-C
4
)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
1
-C
4
alkyl, fluoro(C
1
-C
4
)alkyl, C
1
-C
4
alkoxy, fluoro(C
1
-C
4
)alkoxy, halo and cyano, or Ar is 1,3-benzodioxolan4 or 5-yl or 1,4-benzodioxan-5 or 6-yl;
m is 0, 1 or 2;
Z
A
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.
Z
A
is a pharmaceutically acceptable anion such as chloride, bromide, nitrate, methanesulphonate, para-toluenesulphonate, benzenesulphonate, hydrogen sulphate or sulphate.
Preferably, Z
A
is chloride or methanesulphonate.
Most preferably, Z
A
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 C
3
-C
7
cycloalkyl-fused and optionally substituted, including in the benzo- or C
3
-C
7
cycloalkyl-fused portion, by 1, 2 or 3 substituents each independently selected from C
1
-C
4
alkyl, fluoro(C
1
-C
4
)alkyl, C
1
-C
4
alkoxy, fluoro(C
1
-C
4
)alkoxy, phenoxy and halo, or R is 2,3-dihydrobenzo[b]furanyl.
More preferably, R is phenyl which is optionally benzo- or C
3
-C
7
cycloalkyl-fused and optionally substituted, including in the benzo- or C
3
-C
7
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-yl, 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, R
1
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 C
1
-C
4
alkyl substituents.
More preferably, Y is phenyl, 3,5-dimethylphenyl, cyclohexyl or naphth-2-yl.
Most preferably, Y is phenyl.
Preferably, Ar is phenyl optionally substituted by 1, 2 or 3 halo substituents.
More preferably, Ar is phenyl substituted by 1

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