Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-10
2001-07-17
Shah, Mukund J. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217040, C514S219000, C514S235500, C514S252180, C514S316000, C514S326000, C540S544000, C540S575000, C540S597000, C544S129000, C544S360000, C546S187000, C546S208000
Reexamination Certificate
active
06262046
ABSTRACT:
This invention relates to therapeutic agents of the azetidine family. More particularly, this invention relates to azetidinylpropylpiperidine derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and uses of, such derivatives.
International Patent Application Publication Number WO 96/05193 discloses various (azetidin-1-ylalkyl)lactams as tachykinin antagonists.
International Patent Application Publication Number WO97/25322 discloses various azetidinylalkyl derivatives of N-substituted nitrogen heterocycles as tachykinin antagonists. Certain of the compounds and salts of this invention are generically but not specifically described therein.
The present azetidinylpropylpiperidine derivatives are antagonists of tachykinins, including neurokinin A (NKA), neurokinin B (NKB) and Substance P, acting at the human neurokinin-1 (NK
1
), neurokinin-2 (NK
2
) or neurokinin-3 (NK
3
) receptor, or a combination of two or more thereof. They are therefore useful for preventing or 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, dyspepsia, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis, ulcerative colitis or Crohn's disease, a disease caused by
Helicobacter pylori
or other urease positive Gram negative bacteria, a urogenital tract disorder such as incontinence, hyperreflexia, impotence 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 vasospastic disease such as angina or Reynaud's disease, a proliferative disorder such as cancer or a disorder involving fibroblast proliferation, a fibrosing or collagen disease such as scleroderma or eosinophillic 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 Parkinson's disease, 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 opthalmic disease such as proliferative retinopathy, occular inflammation, conjunctivitis, a bladder disorder, or a viral disease such as influenza or a cold.
The present derivatives are particularly potent and selective antagonists of tachykinins, including NKA, NKB and Substance P, acting at the human NK
1
, NK
2
and NK
3
receptors or combinations of two or more thereof. They are particularly useful for treating or preventing 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, dyspepsia, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis, ulcerative colitis or Crohn's disease, a urogenital tract disorder such as incontinence or cystitis, a neuropathological disorder such as Parkinson's disease, Alzheimer's disease or multiple sclerosis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, occular inflammation, conjunctivitis, a bladder disorder, a burn, herpetic neuralgia or post-herpetic neuralgia, cough or acute or chronic pain.
The present invention provides compounds of the formula (I):
and the pharmaceutically-acceptable salts thereof,
wherein
A is CO, SO
2
or CH
2
;
Ar
1
is phenyl optionally substituted by one or more substituents independently selected from halogen, C
1-6
alkoxy optionally substituted by one or more halogen, and C
1-6
alkyl optionally substituted by one or more halogen;
X
1
is C
3-7
cycloalkyl, aryl or C
1-6
alkyl,
said C
1-6
alkyl being optionally substituted by fluoro, CO
2
H, CO
2
(C
1-4
alkyl), C
3-7
cycloalkyl, adamantyl, aryl or het,
and said C
3-7
cycloalkyl being optionally substituted by 1 or 2 substituents each independently selected from C
1-4
alkyl, C
3-7
cycloalkyl, C
1-4
alkoxy, OH, F, fluoro(C
1-4
alkyl) and fluoro(C
1-4
alkoxy);
X is a direct link or NR
1
;
R is SO
2
aryl, SO
2
(C
1-6
alkyl optionally substituted by one or more halogen),
R
1
is H or C
1-6
alkyl optionally substituted by one or more halogen,
or R
1
is phenyl optionally substituted by one or more substituents independently selected from halogen, C
1-6
alkoxy optionally substituted by one or more halogen, or C
1-6
alkyl optionally substituted by one or more halogen;
Y is O, NCO(C
1-6
alkyl optionally substituted by one or more halogen), NCO
2
(C
1-6
alkyl optionally substituted by one or more halogen), NSO
2
(C
1-6
alkyl optionally substituted by one or more halogen), NCOaryl, NCO
2
aryl, NSO
2
aryl, NSO
2
(C
1-6
alkyl optionally substituted by one or more halogen), CH
2
, CHF, CF
2
, NH, NCH
2
aryl, N(C
1-6
alkyl optionally substituted by one or more halogen), or NCH
2
(C
3-7
cycloalkyl);
with the proviso that X is not NR
1
when R is
wherein “aryl” used in all the above definitions represents phenyl or naphthyl each optionally substituted with one or more substituents independently selected from halogen, C
1-6
alkoxy optionally substituted by one or more halogen, and C
1-6
alkyl optionally substituted by one or more halogen;
and “het” used in the definition of X
1
means thienyl or a 5- or 6-membered ring heteroaryl group containing either 1 or 2 nitrogen heteroatoms or 1 nitrogen heteroatom and one oxygen or sulphur heteroatom, each optionally substituted by 1 or 2 substituents each independently selected from C
1-4
alkyl, C
1-4
alkoxy, halogen, fluoro(C
1-4
alkyl) and fluoro(C
1-4
alkoxy),
hereinafter referred to as “substances of the invention”.
“Alkyl” groups can be straight or branched chain.
“Halogen” means fluorine, chlorine, bromine or iodine.
“Ph” means phenyl.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19 (1977).
Preferably, A is CO or SO
2
. More preferably, A is CO.
Preferably, Ar
1
is phenyl optionally substituted by one or more halogen atoms. More preferably, Ar
1
is phenyl optionally substituted by up to two halogen atoms. Yet more preferably, Ar
1
is phenyl optionally substituted by one or two chlorine atoms. Most preferably, Ar
1
is phenyl, 4-chlorophenyl or 3,4-dichlorophenyl.
Preferably X
1
is aryl or C
1-6
alkyl, said C
1-6
alkyl being optionally substituted by fluoro, CO
2
H, CO
2
(C
1-4
alkyl, C
3-7
cycloalkyl, adamantyl, aryl or het, and said C
3-7
cycloalkyl being optionally substituted by 1 or 2 substituents each independently selected from C
1-4
alkyl, C
3-7
cycloalkyl, C
1-4
alkoxy, OH, F, fluoro(C
1-4
alkyl) and fluoro(C
1-4
al
Alker David
Magee Thomas Victor
Maw Graham Nigel
Middleton Donald Stuart
Benson Gregg C.
McKenzie Thomas
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
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