Claims
- 1. A method of inhibiting production of TNF (tumor necrosis factor) in a mammal in need thereof which method comprises administering to said mammal an effective amount of a compound selected from the group consisting of compounds of the formula (I) ##STR40## the racemic, racemic-diastereomeric mixtures and optical isomers of said compounds, and the pharmaceutically acceptable salts thereof, wherein
- X.sup.1 is --(CH.sub.2).sub.q OH, --CHOHR.sup.5 or --(CH.sub.2).sub.m CON(R.sup.6)(OH);
- wherein q and m are each independently 0 or an integer from 1 to 5; R.sup.5 is (C.sub.1 -C.sub.4)alkyl; and R.sup.6 is hydrogen or (C.sub.1 -C.sub.3)alkyl;
- n is 0, 1, 2 or 3;
- Y.sup.1 and Y.sup.2 are independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, optionally substituted phenylalkyl having 1 to 6 carbons in the alkyl portion, optionally substituted phenoxyalkyl having 1 to 6 carbons in the alkyl portion, (C.sub.3 -C.sub.7)cycloalkyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, --OR.sup.1 and --OR.sup.2 ;
- wherein the aromatic portion of the optionally substituted phenylalkyl, and the aromatic portion of the optionally substituted phenoxyalkyl are optionally independently substituted with (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halogen or CF.sub.3 ;
- R.sup.1 is (C.sub.1 -C.sub.5)alkyl, phenylalkyl having one to four carbon atoms in the alkyl portion, fluoromethyl, difluoromethyl, trifluoromethyl, or --(CH.sub.2).sub.r -quinoline wherein r is 0 or an integer from 1 to 5;
- R.sup.2 is (C.sub.1 -C.sub.3)alkyl, (C.sub.3 -C.sub.7)cycloalkyl, alkoxyalkyl having 3 to 7 carbons in the alkoxy portion and 2 to 4 carbons in the alkyl portion, optionally substituted phenoxyalkyl having 2 to 6 carbons in the alkyl portion, optionally substituted phenylalkyl having 1 to 6 carbons in the alkyl portion, bicycloalkyl having 6 to 9 carbons or optionally substituted indanyl;
- wherein the aromatic portion of the optionally substituted phenylalkyl, the aromatic portion of the optionally substituted phenoxyalkyl and the optionally substituted indanyl are optionally substituted with (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halogen or CF.sub.3 ;
- R.sup.3 is hydrogen, (C.sub.1 -C.sub.3)alkyl, fluoro(C.sub.1 -C.sub.3)alkyl having 1 to 3 fluoro atoms, mono-hydroxyalkyl having 1 to 3 carbons or alkoxyalkyl having 1 to 3 carbons in the alkyl portion and 1 to 3 carbons in the alkoxy portion;
- R.sup.4 is hydrogen, (C.sub.1 -C.sub.5)alkyl, fluoro(C.sub.1 -C.sub.5)alkyl having 1 to 3 fluoro atoms, mono-hydroxyalkyl having 1 to 3 carbons, phenyl, alkoxyalkyl having 1 to 3 carbons in the alkyl portion and 1 to 3 carbons in the alkoxy portion, aminoalkyl having 1 to 3 carbons, ##STR41## wherein X.sup.2 is (C.sub.1 -C.sub.3)alkyl and t is an integer from 1 to 3, N-alkylaminoalkyl having 1 to 3 carbons in the alkylamino portion and 1 to 3 carbons in the alkyl portion, (C.sub.3 -C.sub.7)cycloalkyl or N,N-dialkylaminoalkyl having a total of 2 to 6 carbons in the dialkylamino portion and 1 to 3 carbons in the alkyl portion;
- or R.sup.3 and R.sup.4 are taken together with the carbon atoms to which they are attached and form a carbocyclic ring having 4 to 7 carbon atoms.
- 2. A method of inhibiting production of TNF in a mammal in need thereof according to claim 1 wherein Y.sup.1 is --OR.sup.1 and is attached to the 4-position of the phenyl ring and Y.sup.2 is --OR.sup.2 and is attached to the 3-position of the phenyl ring.
- 3. A method of inhibiting production of TNF in a mammal in need thereof according to claim 2 wherein X.sup.1 is --(CH.sub.2).sub.m CON(R.sup.6)(OH), R.sup.1 is (C.sub.1 -C.sub.4)alkyl, phenylalkyl having one to four carbon atoms in the alkyl portion or --(CH.sub.2).sub.r -quinoline; and n is 0.
- 4. A method of inhibiting production of TNF in a mammal in need thereof according to claim 3 wherein R.sup.2 is phenylalkyl having 1 to 6 carbons in the alkyl portion, (C.sub.3 -C.sub.7)cycloalkyl or (C.sub.1 -C.sub.3)alkyl and m is 0.
- 5. A method of inhibiting production of TNF in a mammal in need thereof according to claim 4 wherein R.sup.2 is 5-phenylpentyl, benzyl, cyclopentyl or methyl.
- 6. A method of inhibiting production of TNF in a mammal in need thereof according to claim 5 wherein R.sup.3 is hydrogen.
- 7. A method of inhibiting production of TNF in a mammal in need thereof according to claim 6 wherein R.sup.4 is hydrogen or (C.sub.1 -C.sub.5)alkyl.
- 8. A method of inhibiting production of TNF in a mammal in need thereof according to claim 7 wherein R.sup.6 is hydrogen or (C.sub.1 -C.sub.3)alkyl.
- 9. A method of inhibiting production of TNF in a mammal in need thereof according to claim 8 wherein R.sup.1 is methyl; R.sup.2 is cyclopentyl; R.sup.4 is hydrogen; and R.sup.6 is hydrogen.
- 10. A method of inhibiting production of TNF in a mammal in need thereof according to claim 9 wherein the levorotatory (negative rotation) enantiomer of the compound is used.
- 11. A method of inhibiting production of TNF in a mammal in need thereof according to claim 8 wherein R.sup.1 is methyl; R.sup.2 is cyclopentyl; R.sup.4 is methyl; and R.sup.6 is hydrogen.
- 12. A method of inhibiting production of TNF in a mammal in need thereof according to claim 11 wherein the levorotatory (negative rotation) enantiomer of the compound is used.
- 13. A method of inhibiting production of TNF in a mammal in need thereof according to claim 1 wherein X.sup.1 is --(CH.sub.2).sub.q OH, or --CH(OH)CH.sub.3 wherein q is 0, 1 or 2; Y.sup.1 is methoxy or --OCH.sub.2 -2-quinoline and is attached to the 4-position of the phenyl ring; R.sup.3 is hydrogen, methyl or ethyl; n is 0; Y.sup.2 is hydrogen, cyclopentyloxy or --O(CH.sub.2).sub.5 phenyl and is attached to the 3-position of the phenyl ring; and R.sup.4 is hydrogen, methyl or ethyl.
- 14. A method of inhibiting production of TNF in a mammal in need thereof according to claim 1 wherein X.sup.1 is --CONHOH; Y.sup.1 is --OCH.sub.2 -2-quinoline and is attached to the 4-position of the phenyl ring; R.sup.3 is hydrogen, methyl or ethyl; n is 0; Y.sup.2 is hydrogen or --O(CH.sub.2).sub.5 phenyl and is attached to the 3-position of the phenyl ring; and R.sup.4 is ethyl.
- 15. A method of treating or alleviating sepsis, septic shock, inflammatory bowel disease, tuberculosis, graft versus host disease or cachexia associated with AIDS or cancer in a mammal in need thereof which method comprises administering to said mammal an effective amount of a compound selected from the group consisting of compounds of the formula (I) ##STR42## the racemic, racemic-diastereomeric mixtures and optical isomers of said compounds, and the pharmaceutically acceptable salts thereof, wherein
- X.sup.1 is --(CH.sub.2).sub.q OH, --CHOHR.sup.5 or --(CH.sub.2).sub.m CON(R.sup.6)(OH);
- wherein q and m are each independently 0 or an integer from 1 to 5; R.sup.5 is (C.sub.1 -C.sub.4)alkyl; and R.sup.6 is hydrogen or (C.sub.1 -C.sub.3)alkyl;
- n is 0, 1, 2 or 3;
- Y.sup.1 and Y.sup.2 are independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, optionally substituted phenylalkyl having 1 to 6 carbons in the alkyl portion, optionally substituted phenoxyalkyl having 1 to 6 carbons in the alkyl portion, (C.sub.3 -C.sub.7)cycloalkyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, --OR.sup.1 and --OR.sup.2 ;
- wherein the aromatic portion of the optionally substituted phenylalkyl, and the aromatic portion of the optionally substituted phenoxyalkyl are optionally independently substituted with (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halogen or CF.sub.3 ;
- R.sup.1 is (C.sub.1 -C.sub.5)alkyl, phenylalkyl having one to four carbon atoms in the alkyl portion, fluoromethyl, difluoromethyl, trifluoromethyl, or --(CH.sub.2).sub.r -quinoline wherein r is 0 or an integer from 1 to 5;
- R.sup.2 is (C.sub.1 -C.sub.3)alkyl, (C.sub.3 -C.sub.7)cycloalkyl, alkoxyalkyl having 3 to 7 carbons in the alkoxy portion and 2 to 4 carbons in the alkyl portion, optionally substituted phenoxyalkyl having 2 to 6 carbons in the alkyl portion, optionally substituted phenylalkyl having 1 to 6 carbons in the alkyl portion, bicycloalkyl having 6 to 9 carbons or optionally substituted indanyl;
- wherein the aromatic portion of the optionally substituted phenylalkyl, the aromatic portion of the optionally substituted phenoxyalkyl and the optionally substituted indanyl are optionally substituted with (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halogen or CF.sub.3 ;
- R.sup.3 is hydrogen, (C.sub.1 -C.sub.3)alkyl, fluoro(C.sub.1 -C.sub.3)alkyl having 1 to 3 fluoro atoms, mono-hydroxyalkyl having 1 to 3 carbons or alkoxyalkyl having 1 to 3 carbons in the alkyl portion and 1 to 3 carbons in the alkoxy portion;
- R.sup.4 is hydrogen, (C.sub.1 -C.sub.5)alkyl, fluoro(C.sub.1 -C.sub.5)alkyl having 1 to 3 fluoro atoms, mono-hydroxyalkyl having 1 to 3 carbons, phenyl, alkoxyalkyl having 1 to 3 carbons in the alkyl portion and 1 to 3 carbons in the alkoxy portion, aminoalkyl having 1 to 3 carbons, ##STR43## wherein X.sup.2 is (C.sub.1 -C.sub.3)alkyl and t is an integer from 1 to 3, N-alkylaminoalkyl having 1 to 3 carbons in the alkylamino portion and 1 to 3 carbons in the alkyl portion, (C.sub.3 -C.sub.7)cycloalkyl or N,N-dialkylaminoalkyl having a total of 2 to 6 carbons in the dialkylamino portion and 1 to 3 carbons in the alkyl portion;
- or R.sup.3 and R.sup.4 are taken together with the carbon atoms to which they are attached and form a carbocyclic ring having 4 to 7 carbon atoms.
- 16. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a tumor necrosis factor inhibiting amount of a compound selected from the group consisting of compounds of the formula (I) ##STR44## the racemic, racemic-diastereomeric mixtures and optical isomers of said compounds, and the pharmaceutically acceptable salts thereof, wherein
- X.sup.1 is --(CH.sub.2).sub.q OH, --CHOHR.sup.5 or --(CH.sub.2).sub.m CON(R.sup.6)(OH);
- wherein q and m are each independently 0 or an integer from 1 to 5; R.sup.5 is (C.sub.1 -C.sub.4)alkyl; and R.sup.6 is hydrogen or (C.sub.1 -C.sub.3)alkyl;
- n is 0, 1, 2 or 3;
- Y.sup.1 and Y.sup.2 are independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, optionally substituted phenylalkyl having 1 to 6 carbons in the alkyl portion, optionally substituted phenoxyalkyl having 1 to 6 carbons in the alkyl portion, (C.sub.3 -C.sub.7)cycloalkyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, --OR.sup.1 and --OR.sup.2 ;
- wherein the aromatic portion of the optionally substituted phenylalkyl, and the aromatic portion of the optionally substituted phenoxyalkyl are optionally independently substituted with (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halogen or CF.sub.3 ;
- R.sup.1 is (C.sub.1 -C.sub.5)alkyl, phenylalkyl having one to four carbon atoms in the alkyl portion, fluoromethyl, difluoromethyl, trifluoromethyl, or --(CH.sub.2).sub.r -quinoline wherein r is 0 or an integer from 1 to 5;
- R.sup.2 is (C.sub.1 -C.sub.3)alkyl, (C.sub.3 -C.sub.7)cycloalkyl, alkoxyalkyl having 3 to 7 carbons in the alkoxy portion and 2 to 4 carbons in the alkyl portion, optionally substituted phenoxyalkyl having 2 to 6 carbons in the alkyl portion, optionally substituted phenylalkyl having 1 to 6 carbons in the alkyl portion, bicycloalkyl having 6 to 9 carbons or optionally substituted indanyl;
- wherein the aromatic portion of the optionally substituted phenylalkyl, the aromatic portion of the optionally substituted phenoxyalkyl and the optionally substituted indanyl are optionally substituted with (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy, halogen or CF.sub.3 ;
- R.sup.3 is hydrogen, (C.sub.1 -C.sub.3)alkyl, fluoro(C.sub.1 -C.sub.3)alkyl having 1 to 3 fluoro atoms, mono-hydroxyalkyl having 1 to 3 carbons or alkoxyalkyl having 1 to 3 carbons in the alkyl portion and 1 to 3 carbons in the alkoxy portion;
- R.sup.4 is hydrogen, (C.sub.1 -C.sub.5)alkyl, fluoro(C.sub.1 -C.sub.5)alkyl having 1 to 3 fluoro atoms, mono-hydroxyalkyl having 1 to 3 carbons, phenyl, alkoxyalkyl having 1 to 3 carbons in the alkyl portion and 1 to 3 carbons in the alkoxy portion, aminoalkyl having 1 to 3 carbons, ##STR45## wherein X.sup.2 is (C.sub.1 -C.sub.3)alkyl and t is an integer from 1 to 3, N-alkylaminoalkyl having 1 to 3 carbons in the alkylamino portion and 1 to 3 carbons in the alkyl portion, (C.sub.3 -C.sub.7)cycloalkyl or N,N-dialkylaminoalkyl having a total of 2 to 6 carbons in the dialkylamino portion and 1 to 3 carbons in the alkyl portion;
- or R.sup.3 and R.sup.4 are taken together with the carbon atoms to which they are attached and form a carbocyclic ring having 4 to 7 carbon atoms.
Parent Case Info
This is a division of application Ser. No. 08/700,431, filed on Sep. 5, 1996, now U.S. Pat. No. 5,869,511 which is the national stage of International Application No. PCT/IB95/00078, filed Feb. 3, 1995 which is a continuation-in-part of U.S. Ser. No. 08/209,125, filed Mar. 9, 1994, now abandoned.
Foreign Referenced Citations (1)
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0026928 |
Apr 1981 |
EPX |
Divisions (1)
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