Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-21
2002-11-12
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S239000, C546S210000, C544S172000, C544S399000, C548S252000, C548S254000, C548S572000, C562S512000, C564S163000, C564S164000, C514S237500, C514S255030, C514S381000, C514S423000, C514S561000, C514S613000
Reexamination Certificate
active
06479518
ABSTRACT:
BACKGROUND OF THE INVENTION
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3), respectively.
Evidence has been reviewed for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Chrohn's disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyperreflexia.
It has furthermore been suggested that tachykinin receptor antagonists have utility in the following disorders: anxiety, depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorder related to immune enhancement or suppression such as systemic lupus erythmatosus, ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Attempts have been made to provide antagonists for the receptors of substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases mentioned above. For example, U.S. Pat. Nos. 5,387,595, 5,750,549 and
Bioorg
. &
Med. Chem. Lett.,
1345 (1995) disclose certain alicyclic compounds as tachykinin receptor antagonists.
SUMMARY OF THE INVENTION
This invention is concerned with novel compounds represented by structural formula I:
or a pharmaceutically acceptable salt thereof, wherein R
3
, R
5
, R
6
, R
7
, R
8
, R
11
, R
12
, R
13
, Q, W, X, Y and Z are defined herein. The invention is also concerned with pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders. The compounds of this invention are tachykinin receptor antagonists and are useful in the treatment of psychiatric disorders including depression and anxiety.
DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of the structural formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Q is selected from the group consisting of:
(1) hydrogen,
(2) C
1-6
alkyl,
(3) C
1-6
alkyl-OH, and
(4) C
1-6
alkyl-O—C
1-6
alkyl;
W is selected from the group consisting of:
(2) —NH—, and
(3) —N(C
1-6
alkyl)-;
X is selected from the group consisting of:
(1) hydrogen, and
(2) C
1-6
alkyl, and
(3) C
1-6
alkyl-OH;
Y is selected from the group consisting of:
(1) a single bond, and
(2) C
1-6
alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C
1-6
alkoxy,
(d) phenyl-C
1-3
alkoxy,
(e) phenyl,
(f) —CN,
(g) halo, wherein halo is fluoro, chloro, bromo or iodo,
(h) —NR
9
R
10
, wherein R
9
and R
10
are independently selected from:
(I) hydrogen,
(II) C
1-6
alkyl,
(III) phenyl,
(IV) (C
1-6
alkyl)-phenyl,
(V) (C
1-6
alkyl)-hydroxy, and
(VI) (C
1-6
alkyl)-(C
1-4
alkoxy),
(i) —NR
9
—COR
10
,
(j) —NR
9
—CO
2
R
10
,
(k) —CO—NR
9
R
10
,
(l) —COR
9
, and
(m) —CO
2
R
9
;
Z is selected from the group consisting of:
C
1-6
alkyl,C
3-6
cycloalkyl and C
1-6
alkyl(C
3-6
cycloalkyl), which is unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C
1-6
alkoxy,
(d) phenyl-C
1-3
alkoxy,
(e) phenyl,
(f) —CN,
(g) halo,
(h) —NR
9
R
10
,
(i) —NR
9
—COR
10
,
(j) —NR
9
—CO
2
R
10
,
(k) —CO—NR
9
R
10
,
(l) —COR
9
, and
(m) —CO
2
R
9
;
R
3
is selected from the group consisting of:
(1) —CO
2
H,
(2) -tetrazolyl, and
(3) —CO—NH—SO
2
—CH
3
;
R
5
is selected from the group consisting of:
(1) hydrogen,
(2) C
1-6
alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C
1-6
alkoxy,
(d) phenyl-C
1-3
alkoxy,
(e) phenyl,
(f) —CN,
(g) halo,
(h) —NR
9
R
10
,
(i) —NR
9
—COR
10
,
(j) —NR
9
—CO
2
R
10
,
(k) —CO—NR
9
R
10
,
(l) —COR
9
, and
(m) —CO
2
R
9
,
or R
5
and Z may be joined together to form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring which is substituted with R
3
and further substituted with one or more of the substituents selected from:
(a) C
1-6
alkyl,
(b) (C
1-6
alkyl)-phenyl,
(c) (C
1-6
alkyl)-hydroxy,
(d) (C
1-6
alkyl)-(C
1-4
alkoxy),
(e) hydroxy,
(f) oxo,
(g) C
1-6
alkoxy,
(h) phenyl-C
1-3
alkoxy,
(i) phenyl,
(j) —CN,
(k) halo,
(l) —NR
9
R
10
,
(m) —NR
9
—COR
10
,
(n) —NR
9
—CO
2
R
10
,
(o) —CO—NR
9
R
10
,
(p) —COR
9
, and
(q) —CO
2
R
9
,
R
6
, R
7
and R
8
are independently selected from the group consisting of:
(1) hydrogen,
(2) C
1-6
alkoxy,
(3) halo,
(4) C
1-6
alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C
1-6
alkoxy,
(d) phenyl-C
1-3
alkoxy,
(e) phenyl,
(f) —CN,
(g) halo,
(h) —NR
9
R
10
,
(i) —NR
9
—COR
10
,
(j) —NR
9
—CO
2
R
10
,
(k) —CO—NR
9
R
10
,
(l) —COR
9
,
(m) —CO
2
R
9
,
(n) heterocycle, wherein heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) benzofuranyl,
(C) benzothiophenyl,
(D) benzoxazolyl,
(E) furanyl,
(F) imidazolyl,
(G) indolyl,
(H) isooxazolyl,
(I) isothiazolyl,
(J) oxadiazolyl,
(K) oxazolyl,
(L) pyrazinyl,
(M) pyrazolyl,
(N) pyridyl,
(O) pyrimidyl,
(P) pyrrolyl,
(Q) quinolyl,
(R) tetrazolyl,
(S) thiadiazolyl,
(T) thiazolyl,
(U) thienyl,
(V) triazolyl,
(W) azetidinyl,
(X) 1,4-dioxanyl,
(Y) hexahydroazepinyl,
(Z) piperazinyl,
(AA) piperidinyl,
(AB) pyrrolidinyl,
(AC) morpholinyl,
(AC) thiomorpholinyl,
(AD) dihydrobenzimidazolyl,
(AE) dihydrobenzofuranyl,
(AF) dihydrobenzothiophenyl,
(AG) dihydrobenzoxazolyl,
(AH) dihydrofuranyl
(AI) dihydroimidazolyl,
(AJ) dihydroindolyl,
(AK) dihydroisooxazolyl,
(AL) dihydroisothiazolyl,
(AM) dihydrooxadiazolyl,
(AN) dihydrooxazolyl,
(AO) dihydropyrazinyl,
(AP) dihydropyrazolyl,
(AQ) dihydropyridinyl,
(AR) dihydropyrimidinyl,
(AS) dihydropyrrolyl,
(AT) dihydroquinolinyl,
(AU) dihydrotetrazolyl,
(AV) dihydrothiadiazolyl,
(AW) dihydrothiazolyl,
(AX) dihydrothienyl,
(AY) dihydrotriazolyl,
(AZ) dihydroazetidinyl,
(BA) dihydro-1,4-dioxanyl,
(BB) tetrahydrofuranyl, and
(BC) tetrahydrothienyl,
and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C
1-6
alkyl, unsubstituted or substituted with halo, —CF
3
—OCH
3
, or phenyl,
(ii) C
1-6
alkoxy,
(iii) oxo,
(iv) hydroxy,
(v) thioxo,
(vi) —SR
9
,
(vii) halo,
(viii) cyano,
(ix) phenyl,
(x) trifluoromethyl,
(xi) —(CH
2
)
m
—NR
9
R
10
,
(xii) —NR
9
COR
10
,
(xiii) —CONR
9
R
10
,
(xiv) —CO
2
R
9
, and
(xv) —(CH
2
)
m
—OR
9
,
(5) hydroxy,
(6) —CN,
(7) —CF
3
,
(8) —NO
2
,
(9) —SR
14
, wherein R
14
is hydrogen or C
1-6
alkyl,
(10) —SOR
14
,
(11) —SO
2
R
14
,
(12) —NR
9
—COR
10
,
(13) —CO—NR
9
—COR
10
,
(14) —NR
9
R
10
,
(15) —NR
9
—CO
2
R
10
,
(16) —COR
9
,
(17) —CO
2
R
9
,
(18) heterocycle, wherein heterocycle is as defined above,
(19) —(C
1-6
alkyl)-heterocycle, wherein heterocycle is as defined above,
(20) —N(hete
Finke Paul E.
MacCoss Malcolm
Meurer Laura C.
Mills Sander G.
Qi Hongbo
Aulakh Charanjit S.
Merck & Co. , Inc.
Thies J. Eric
Winokur Melvin
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