3-Azetidinylalkylpiperidines or -pyrrolidines as tachykinin...

Details 3-Azetidinylalkylpiperidines or -pyrrolidines as tachykinin... 3-Azetidinylalkylpiperidines or -pyrrolidines as tachykinin...

1998-06-01

2001-06-05

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S524000, C540S544000, C544S060000, C544S062000, C544S130000, C544S141000, C544S364000, C544S372000, C544S373000, C546S187000, C546S196000, C546S201000, C546S205000, C546S208000, C546S212000, C546S216000, C548S314700, C548S455000, C548S466000, C548S467000, C548S518000, C548S950000

Reexamination Certificate

active

06242438

ABSTRACT:

This invention relates to therapeutic agents, specifically azetidinylalkyl derivatives of N-substituted nitrogen heterocycles, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and uses of, such heterocycles.
International Patent Publication Number WO 96/05193 discloses various (azetidin-1-ylalkyl)lactams as tachykinin antagonists.
The present heterocycles 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. The heterocycles 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 gastrointestinal (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 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 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 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, 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 gastrointestinal (GI) disorder such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis or Crohn's disease, a urogenital tract disorder such as incontinence or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis or rhinitis, a hypersensitivity disorder such as poison ivy, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a bum, herpetic neuralgia or post-herpetic neuralgia, cough or acute or chronic pain.
The present invention provides compounds of the formula:
and the pharmaceutically acceptable salts thereof, wherein
R is C
3
-C
7
cycloalkyl, aryl or C
1
-C
6
alkyl, said C
1
-C
6
alkyl being optionally substituted by fluoro, —COOH, —COO(C
1
-C
4
) alkyl, C
3
-C
7
cycloalkyl, adamantyl, aryl or het
1
, and said C
3
-C
7
cycloalkyl being optionally substituted by 1 or 2 substituents each independently selected from C
1
-C
4
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
4
alkoxy, hydroxy, fluoro, fluoro(C
1
-C
4
) alkyl and fluoro(C
1
-C
4
)alkoxy;
A is CO or SO
2
;
R
1
is phenyl, benzyl, naphthyl, thienyl, benzothienyl or indolyl, each optionally substituted by 1 or 2 substituents each independently selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halo and trifluoromethyl;
R
2
is —CO
2
H, —CONR
3
R
4
, —CONR
5
(C
3
-C
7
cycloalkyl), —NR
5
(C
2
-C
5
alkanoyl), —NR
3
R
4
, —NR
5
CONR
5
R
6
, (C
3
-C
7
cycloalkyl-C
1
-C
4
alkyl)R
5
N—, (C
3
-C
7
cycloalkyl-C
1
-C
4
alkyl)
2
N—, —NR
5
COCF
3
, —NR
5
SO
2
CF
3
, —NR
5
(SO
2
C
1
—C
4
alkyl), —NR
5
SO
2
NR
5
R
6
, —NR
5
(SO
2
aryl), —N(aryl)(SO
2
C
1
-C
4
alkyl), —OR
5
, —O(C
3
-C
7
cycloalkyl), —SO
2
NR
5
R
6
, het
3
or a group of the formula:
R
3
and R
4
are each independently selected from H and C
1
-C
4
alkyl optionally substituted by hydroxy, C
1
-C
4
alkoxy, —S(O)
p
(C
1
-C
4
alkyl), amino, —NH(C
1
-C
4
alkyl), —N(C
1
-C
4
alkyl)
2
or het
2
;
R
5
and R
6
are each independently selected from H, C
1
-C
4
alkyl and C
3
-C
7
cycloalkyl-C
1
-C
4
alkyl, said C
1
-C
4
alkyl and C
3
-C
7
cycloalkyl-C
1
-C
4
alkyl being optionally substituted by fluoro;
R
7
is H, C
1
-C
4
alkyl, hydroxy, fluoro(C
1
-C
4
)alkyl or phenyl, said phenyl being optionally substituted by 1 or 2 substituents each independently selected from C
1
-C
4
alkyl, fluoro(C
1
-C
4
)alkyl, halo, C
1
-C
4
alkoxy and fluoro (C
1
-C
4
)alkoxy;
R
8
is H, fluoro, hydroxy, C
1
-C
4
alkoxy, C
2
-C
5
alkanoyl or C
2
-C
5
alkanoyloxy;
R
9
is —NR
5
R
6
, —NR
5
COR
5
, —NR
5
SO
2
CF
3
, —NR
5
(SO
2
C
1
-C
4
alkyl), —NR
5
SO
2
NR
5
R
6
, —NR
5
COO(C
1
-C
4
alkyl), —NR
5
CONR
5
R
6
, —NR
5
(SO
2
morpholino), —NR
5
(SO
2
aryl), —N(aryl)(SO
2
C
1
-C
4
alkyl) or a group of the formula:
X is C
1
-C
4
alkylene;
X
1
is a direct link or C
1
-C
6
alkylene;
X
2
is a direct link, CO, SO
2
or NR
5
CO;
W is methylene, CO, CH(OH), C(OH)
2
, CH(C
1
-C
4
alkoxy), CHCO
2
H, CHCO
2
(C
1
-C
4
alkyl), CHCONR
5
R
6
, CHF, CF
2
, CH(azetidin-1-yl), CH(pyrrolidin-1-yl), CH(piperidin-1-yl), CH(morpholino), CH(benzoxazol-2-yl), CHR
9
, O, S(O)
p
, NR
5
, N(C
3
-C
7
cycloalkyl), NSO
2
(C
1
-C
4
alkyl), NSO
2
NR
5
R
6
, NSO
2
CF
3
, NSO
2
(morpholino), NSO
2
(aryl),
NCONR
5
R
6
, NCOR
5
, NCO(aryl) or NCO
2
(C
1
-C
4
alkyl);
W
1
is methylene, CO, CH(OH), C(OH)
2
, CH(C
1
-C
4
alkoxy), CHCO
2
H, CHCO
2
(C
1
-C
4
alkyl), CHCONR
5
R
6
, CHF, CF
2
, CH(azetidin-1-yl), CH(pyrrolidin-1-yl), CH(piperidin-1-yl), CH(morpholino) or CHR
9
;
W
2
is W
1
, —CH
2
W
1
—, —CH
2
WCH
2
— or —CH
2
CH
2
WCH
2
—;
m is 0, 1 or2;
n is 1 or 2 when W is other than methylene and is 0, 1 or 2 when W is methylene;
p is 0, 1 or2;
q is1 or2;
r is 1,2,3 or4;
“aryl”, used in the definition of R, R
2
, R
9
and W, means naphthyl or phenyl, each optionally substituted by C
1
-C
4
alkyl, halo, —OR
5
, fluoro(C
1
-C
4
)alkyl, C
2
-C
5
alkanoyl, —CONR
5
R
6
, —SO
2
NR
5
R
6
or phenyl;
“het”, used in the definition of R, means thienyl or a 5- or 6- membered ring heteroaryl group containing either 1 or 2 nitrogen heteroatoms or one nitrogen heteroatom and one oxygen or sulphur heteroatom, each optionally substituted by 1 or 2 substituents each independently selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy, halo, fluoro(C
1
-C
4
alkyl) and fluoro(C
1
-C
4
alkoxy);
“het”, used in the definitions of R
3
and R
4
, means a 4- to 7- membered ring, non-aromatic, heterocyclic group containing 1 or 2 heteroatoms each independently selected from nitrogen, oxygen and S(O)
p
, said group being optionally C-substituted by 1 or 2 substituents each independently selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy and fluoro(C
1
-C
4
)alkyl, and said ring nitrogen heteroatom optionally bearing a H, C
1
-C
4
alkyl, C
2
-C
5
alkanoyl, —CONR
5
R
6
or —SO
2
NR
5
R
6
substituent;
and “het”, used in the definition of R
2
means an optionally benzo-fused, N-linked, 5-membered ring heteroaryl group containing from 1 to 4 nitrogen heteroatoms, which is optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from C
1
-C
4
alkyl, fluoro and fluoro(C
1
-C
4
)alkyl.
In the above definitions, the term “halo” means fluoro, chloro,

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