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US4801589A
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Method for suppressing the immune response
Assignee: Merck Sharp & Dohme LLC
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Filing: 1986-06-12
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Granted: 1989-01-31
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Expires: 2006-06-12
Abstract
Abstract A method and composition for suppressing the immune response are disclosed which employ an immunosuppressing effective amount of certain substituted quinoline, naphthyridine and pyrido-pyrazine derivatives.
Inventors
- 👤 Sidney R. Smith
- 👤 Marvin I. Siegel
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-27 07:25
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/33; A61K31/395; A61K31/495; A61K31/505; A61K31/435; A61K31/44; A61K31/47
Claims Analysis
Total Claims: 33
Claim 1
Independent Claim
409 words
A method of suppressing the T or B cell function of the immune response in a mammal which comprises administering to a mammal in need of such treatment an immunosuppressing effective amount of a compound having the structural formula I: ##STR4## wherein: A is ##STR5## B is independently oxygen or sulfur; R 1 -R 8 may be the same or different and are hydrogen or alkyl having from 1 to 6 carbon atoms or two adjacent R 1 -R 8 substituents may be combined to form an additional carbon to carbon bond; l and m may be the same or different and are 0 or one; the ring labelled, Q, may optionally contain up to two additional double bonds; n is 0, 1 or 2; W and X may be the same or different and are hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 cabon atoms, trifluoromethyl, cyano, cycloalkyl having from 3 to 7 carbon atoms, alkenyloxy having from 3 to 6 carbon atoms, alkynyloxy having from 3 to 6 carbon atoms, S(O) p --R a {wherein p is 0, 1 or 2 and R a is alkyl having from 1 to 6 carbon atoms}, NHSO 2 R a {wherein R a is defined herein}, NHSO 2 CF 3 , NHCOCF 3 , SO 2 NH 2 , COR b {wherein R b is OH, NH 2 or OR a (wherein R a is defined herein)}, O--D--COR b {wherein D is alkylene having from 1 to 4 carbon atoms and R b is defined herein}, NHCOR c {wherein R c is hydrogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, COR d (wherein R d is hydroxy or alkoxy having from 1 to 6 carbon atoms) or NHR e (wherein R e is hydrogen or alkyl having from 1 to 6 carbon atoms)}, or phenoxy {wherein the benzene ring may be substituted with any of the other substituents W and X}; Y and Z may be the same or different and are CH or N; V is phenyl, naphthyl, indenyl, indanyl, 2-, 3- or 4-pyridyl, 2-, 3- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl or 2-, 4- or 5-thiazolyl, any of which may be substituted with W and X as defined herein; and R 9 and R 10 are independently hydrogen or alkyl having from 1 to 6 carbon atoms.
Claim 2
Independent Claim
409 words
A method of suppressing the T or B cell function of the immune response in a mammal which comprises administering to a mammal in need of such treatment an immunosuppressing effective amount of a compound having the structural formula I: ##STR4## wherein: A is ##STR5## B is independently oxygen or sulfur; R 1 -R 8 may be the same or different and are hydrogen or alkyl having from 1 to 6 carbon atoms or two adjacent R 1 -R 8 substituents may be combined to form an additional carbon to carbon bond; l and m may be the same or different and are 0 or one; the ring labelled, Q, may optionally contain up to two additional double bonds; n is 0, 1 or 2; W and X may be the same or different and are hydrogen, hydroxy, alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy having from 1 to 6 cabon atoms, trifluoromethyl, cyano, cycloalkyl having from 3 to 7 carbon atoms, alkenyloxy having from 3 to 6 carbon atoms, alkynyloxy having from 3 to 6 carbon atoms, S(O) p --R a {wherein p is 0, 1 or 2 and R a is alkyl having from 1 to 6 carbon atoms}, NHSO 2 R a {wherein R a is defined herein}, NHSO 2 CF 3 , NHCOCF 3 , SO 2 NH 2 , COR b {wherein R b is OH, NH 2 or OR a (wherein R a is defined herein)}, O--D--COR b {wherein D is alkylene having from 1 to 4 carbon atoms and R b is defined herein}, NHCOR c {wherein R c is hydrogen, alkyl having from 1 to 6 carbon atoms, alkoxy having from 1 to 6 carbon atoms, COR d (wherein R d is hydroxy or alkoxy having from 1 to 6 carbon atoms) or NHR e (wherein R e is hydrogen or alkyl having from 1 to 6 carbon atoms)}, or phenoxy {wherein the benzene ring may be substituted with any of the other substituents W and X}; Y and Z may be the same or different and are CH or N; V is phenyl, naphthyl, indenyl, indanyl, 2-, 3- or 4-pyridyl, 2-, 3- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl or 2-, 4- or 5-thiazolyl, any of which may be substituted with W and X as defined herein; and R 9 and R 10 are independently hydrogen or alkyl having from 1 to 6 carbon atoms.
Claim 3
Dependent Claim
13 words
A method according to claim 1 wherein n in formula I is zero.
Claim 4
Dependent Claim
13 words
A method according to claim 2 wherein Y in formula I is CH.
Claim 5
Dependent Claim
14 words
A method according to claim 3 wherein said compound has the structural formula: ##STR6##
Claim 6
Dependent Claim
13 words
A method according to claim 4 wherein Z in formula II is N.
Claim 7
Dependent Claim
16 words
A method according to claim 5 wherein l and m in formula II are both zero.
Claim 8
Dependent Claim
16 words
A method according to claim 5 wherein l and m in formula II are both one.
Claim 9
Dependent Claim
18 words
A method according to claim 5 wherein the sum of l and m in formula II is one.
Claim 10
Dependent Claim
10 words
A method according to claim 1 wherein B is oxygen.
Claim 11
Dependent Claim
10 words
A method according to claim 2 wherein B is oxygen.
Claim 12
Dependent Claim
10 words
A method according to claim 3 wherein B is oxygen.
Claim 13
Dependent Claim
13 words
A method according to claim 5 wherein V in formula II is ##STR7##
Claim 14
Dependent Claim
34 words
A method according to claim 1 wherein said compound has structural formula: ##STR8## wherein W, X, V, R 1 , R 2 , R 3 and R 4 are as defined in claim 1.
Claim 15
Dependent Claim
27 words
A method according to claim 1 wherein said compound has structural formula: ##STR9## wherein W, X, and R 1 -R 8 are as defined in claim 1.
Claim 16
Dependent Claim
15 words
A method according to claim 13 wherein R 1 -R 4 are hydrogen or methyl.
Claim 17
Dependent Claim
15 words
A method according to claim 14 wherein R 1 -R 8 are hydrogen or methyl.
Claim 18
Dependent Claim
22 words
A method according to claim 16 wherein zero or one of R 1 -R 8 is methyl and the rest are hydrogen.
Claim 19
Dependent Claim
17 words
A method according to claim 17 wherein W is 3-chloro and X is hydrogen, chlorine or fluorine.
Claim 20
Dependent Claim
16 words
A method according to claim 17 wherein W is 3-methoxy and X is hydrogen or fluorine.
Claim 21
Dependent Claim
13 words
A method according to claim 17 wherein W and X are both hydrogen.
Claim 22
Dependent Claim
35 words
A method according to claim 1 wherein said compound has the structural formula: ##STR10## wherein W, X, V, R 1 , R 2 , R 3 and R 4 are as defined in claim 1.
Claim 23
Dependent Claim
34 words
A method according to claim 1 wherein said compound has the structural formula: ##STR11## wherein W, X, R 1 , R 2 , R 3 and R 4 are as defined in claim 1.
Claim 24
Dependent Claim
17 words
A method according to claim 22 wherein W is 3-chloro and X is hydrogen, chlorine or fluorine.
Claim 25
Dependent Claim
16 words
A method according to claim 22 wherein W is 3-methoxy and X is hydrogen or fluorine.
Claim 26
Dependent Claim
13 words
A method according to claim 22 wherein W and X are both hydrogen.
Claim 27
Dependent Claim
14 words
A method according to claim 1 wherein said selected from the group consisting of:
Claim 28
Dependent Claim
17 words
5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin4[2H]-one; 3,5-dihydro-5-phenyl-thieno[3,2-c][1,8]-naphthyridin-4[2H]-one; 6-phenyl-2,3,4,6-tetrahydro-pyrano[3,2-c][1,8]naphthyridine-5-one; 2-methyl-3,5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-phenyl-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(p-methylphenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-2-methyl-9-phenyl-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(p-methylphenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(p-fluorophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(m-methoxyphenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(m-methylthiophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(p-fluorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(m-methoxyphenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(m-methylthiophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H-one;3,5-dihydro-5-(3,4-dichlorophenyl)-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3,4-dichlorophenyl)-2-methyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(4-chlorophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-chlorophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one;
Claim 29
Dependent Claim
17 words
5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin4[2H]-one; 3,5-dihydro-5-phenyl-thieno[3,2-c][1,8]-naphthyridin-4[2H]-one; 6-phenyl-2,3,4,6-tetrahydro-pyrano[3,2-c][1,8]naphthyridine-5-one; 2-methyl-3,5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-phenyl-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(p-methylphenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-2-methyl-9-phenyl-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(p-methylphenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(p-fluorophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(m-methoxyphenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(m-methylthiophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(p-fluorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(m-methoxyphenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(m-methylthiophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H-one;3,5-dihydro-5-(3,4-dichlorophenyl)-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3,4-dichlorophenyl)-2-methyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(4-chlorophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-chlorophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one;
Claim 30
Dependent Claim
33 words
5-dihydro-5-(3-chlorophenyl)-2-methyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(4-fluorophenyl)-2-methyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-methoxyphenyl)-2-methyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3,5-dichlorophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(3,5-dichlorophenyl)-2-methyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-phenyl-2,2-dimethyl-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-methylsulfonylaminophenyl)-2-methylfuro[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-methylsulfonylaminophenyl)-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(3,4-dichlorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(4-chlorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(3-chlorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(3-chlorophenyl)-2-methyl-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(4-fluorophenyl)-2-methyl-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(3-methoxyphenyl)-2-methyl-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(3,5-dichlorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(3,5-dichlorohenyl)-2-methyl-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(3-methylsulfonylaminophenyl)-2-methyl-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 6-(4-chlorophenyl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c]-[1,8]naphthyridin-5-one; 6-(3,4-dichlorophenyl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one; 6-(4-methoxyphenyl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one; 6-(4-methylphenyl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one; 10-(3,4-dichlorophenyl)-2,3,4,10-tetrahydro-5H-pyrano-[2,3-b][1,8]naphthyridin-5-one; 10-(4-methoxyphenyl)-2,3,4,10-tetrahydro-5H-pyrano[2,3-b][1,8]naphthyridin-5-one; 10-(4-chlorophenyl)-2,3,4,10-tetrahydro-5H-pyrano(2,3-b][1,8]naphthyridin-5-one; 10-(4-methylphenyl)-2,3,4,10-tetrahydro-5H-pyrano(2,3-b][1,8]naphthyridin-5-one; 10-phenyl-2,3,4,10-tetrahydro-5H-pyrano-[2,3-b][1,8]-naphthyridin-5-one; 7-phenyl-3,4,5,7-tetrahydro-oxepino[3,2-c][1,8]naphthyridin-6[2H]-one; 7-(4-chlorophenyl)-3,4,5,7-tetrahydro-oxepino[3,2-c][1,8]-naphthyridin-6[2H]-one; 7-(3-chlorophenyl)-3,4,5,7-tetrahydro-oxepino[3,2-c][1,8]-naphthyridin-6[2H]-one; 7-(3-methoxyphenyl)-3,4,5,7-tetrahydro-oxepino[3,2-c][1,8 -naphthyridin-6[2H]-one; and 7-(3-hydroxyphenyl)-3,4,5,7-tetrahydro-oxepino[3,2-c][1,8]-naphthyridin-6[2H]-one.
Claim 31
Dependent Claim
33 words
5-dihydro-5-(3-chlorophenyl)-2-methyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(4-fluorophenyl)-2-methyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-methoxyphenyl)-2-methyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3,5-dichlorophenyl)-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(3,5-dichlorophenyl)-2-methyl-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-phenyl-2,2-dimethyl-furo[3,2-c][1,8]naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-methylsulfonylaminophenyl)-2-methylfuro[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,5-dihydro-5-(3-methylsulfonylaminophenyl)-furo[3,2-c][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(3,4-dichlorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(4-chlorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(3-chlorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(3-chlorophenyl)-2-methyl-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(4-fluorophenyl)-2-methyl-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(3-methoxyphenyl)-2-methyl-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(3,5-dichlorophenyl)-furo[2,3-b][1,8]naphthyridin-4[2H]-one; 3,9-dihydro-9-(3,5-dichlorohenyl)-2-methyl-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 3,9-dihydro-9-(3-methylsulfonylaminophenyl)-2-methyl-furo[2,3-b][1,8]-naphthyridin-4[2H]-one; 6-(4-chlorophenyl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c]-[1,8]naphthyridin-5-one; 6-(3,4-dichlorophenyl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one; 6-(4-methoxyphenyl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one; 6-(4-methylphenyl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one; 10-(3,4-dichlorophenyl)-2,3,4,10-tetrahydro-5H-pyrano-[2,3-b][1,8]naphthyridin-5-one; 10-(4-methoxyphenyl)-2,3,4,10-tetrahydro-5H-pyrano[2,3-b][1,8]naphthyridin-5-one; 10-(4-chlorophenyl)-2,3,4,10-tetrahydro-5H-pyrano(2,3-b][1,8]naphthyridin-5-one; 10-(4-methylphenyl)-2,3,4,10-tetrahydro-5H-pyrano(2,3-b][1,8]naphthyridin-5-one; 10-phenyl-2,3,4,10-tetrahydro-5H-pyrano-[2,3-b][1,8]-naphthyridin-5-one; 7-phenyl-3,4,5,7-tetrahydro-oxepino[3,2-c][1,8]naphthyridin-6[2H]-one; 7-(4-chlorophenyl)-3,4,5,7-tetrahydro-oxepino[3,2-c][1,8]-naphthyridin-6[2H]-one; 7-(3-chlorophenyl)-3,4,5,7-tetrahydro-oxepino[3,2-c][1,8]-naphthyridin-6[2H]-one; 7-(3-methoxyphenyl)-3,4,5,7-tetrahydro-oxepino[3,2-c][1,8 -naphthyridin-6[2H]-one; and 7-(3-hydroxyphenyl)-3,4,5,7-tetrahydro-oxepino[3,2-c][1,8]-naphthyridin-6[2H]-one.
Claim 32
Dependent Claim
12 words
The method according to claim 1 wherein the compound is administered orally.
Claim 33
Dependent Claim
12 words
The method according to claim 26 wherein the compound is administered orally.
References Cited (Backward Citations)
EP0127135A2
Cited
US4680298A
Cited
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