Compounds and methods to inhibit or augment an inflammatory response

1. A method to modulate the migration or recruitment of leukocytes to a preselected physiological site, comprising: administering to a mammal a dosage form comprising an effective amount of a compound of formula (X):

wherein

R 1 is (C 1 -C 15 )alkyl, (C 2 -C 15 )alkenyl, (C 2 -C 15 )alkynyl, (C 1 -C 15 )alkoxy, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl; and

R 2 is hydrogen or (C 1 -C 15 )alkyl; or

R 1 and R 2 together with the atoms to which they are attached are a six membered heterocyclic ring comprising five carbon atoms, optionally substituted on carbon with oxo;

R 3 is hydroxy, (C 1 -C 6 )alkoxy, or N(R a )(R b ); and

R 4 is hydroxy, (C 1 -C 6 )alkoxy, or N(R a )(R b ); or

R 3 and R 4 together with the atoms to which they are attached are a five or six membered heterocyclic ring comprising four or five carbon atoms and N(R c );

R 5 is hydrogen or (C 1 -C 6 )alkyl;

R 6 is hydrogen or oxo;

X is a direct bond, N(H), or methylene (—CH 2 —);

each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, aryl(C 1 -C 6 )alkoxycarbonyl, heteroaryl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkanoyl, or heteroaryl(C 1 -C 6 )alkoxycarbonyl; and R c is hydrogen or (C 1 -C 6 )alkyl;

wherein any (C 1 -C 15 )alkyl, (C 2 -C 15 )alkenyl, (C 2 -C 15 )alkynyl, or (C 1 -C 15 )alkoxy of R 1 is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, hydroxy, oxo, and N(R a )(R b ); and

wherein any aryl, or heteroaryl of R 1 , R a , and R b , is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, sulfino (SO 2 H), sulfo (SO 3 H), and methylenedioxy;

or a pharmaceutically acceptable salt thereof;

wherein the dosage form is linked to a site targeting moiety.

2. The method of claim 1 wherein R 1 is selected from the group 9-decenyl, tert-butoxy, tert-butylcarbonyl-aminomethyl, benzoylaminomethyl, and 4-hydroxybenzyloxycarbonylaminomethyl; R 2 is hydrogen; R 3 is amino or hydroxy; and R 4 is selected from the group hydroxy, amino, or 4-hydroxybenzylamino; or R 3 and R 4 together with the atoms to which they are attached are a six membered heterocyclic ring comprising five carbon atoms and N(H); R 5 is hydrogen; R 6 is hydrogen; and the center marked * has the (S) absolute configuration.

3. A method of treating a mammal afflicted with atherosclerosis, osteoporosis, HIV infection, stroke, psoriasis, multiple sclerosis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus, wound, hypertension, asthma, endotoxemia, or acute ischemia, comprising: administering to the mammal an effective amount of a compound of formula (X):

wherein

R 1 is (C 1 -C 15 )alkyl, (C 2 -C 15 )alkenyl, (C 2 -C 15 )alkynyl, (C 1 -C 15 )alkoxy, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl; and

R 2 is hydrogen or (C 1 -C 15 )alkyl; or

R 1 and R 2 together with the atoms to which they are attached are a six membered heterocyclic ring comprising five carbon atoms, optionally substituted on carbon with oxo;

R 3 is hydroxy, (C 1 -C 6 )alkoxy, or N(R a )(R b ); and

R 4 is hydroxy, (C 1 -C 6 )alkoxy, or N(R a )(R b ); or

R 3 and R 4 together with the atoms to which they are attached are a five or six membered heterocyclic ring comprising four or five carbon atoms and N(R c );

R 5 is hydrogen or (C 1 -C 6 )alkyl;

R 6 is hydrogen or oxo;

X is a direct bond, N(H), or methylene (—CH 2 —);

each R a and R b is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, aryl(C 1 -C 6 )alkoxycarbonyl, heteroaryl, heteroaryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkoxy, heteroaryl(C 1 -C 6 )alkanoyl, or heteroaryl(C 1 -C 6 )alkoxycarbonyl; and R c is hydrogen or (C 1 -C 6 )alkyl;

wherein any (C 1 -C 15 )alkyl, (C 2 -C 15 )alkenyl, (C 2 -C 15 )alkynyl, or (C 1 -C 15 )alkoxy of R 1 is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, carboxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, hydroxy, oxo, and N(R a )(R b ); and

wherein any aryl, or heteroaryl of R 1 , R a , and R b , is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, cyano, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, sulfino (SO 2 H), sulfo (SO 3 H), and methylenedioxy;

or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 wherein R 1 is selected from the group 9-decenyl, tert-butoxy, tert-butylcarbonyl-aminomethyl, benzoylaminomethyl, and 4-hydroxybenzyloxycarbonylaminomethyl; R 2 is hydrogen; R 3 is amino or hydroxy; and R 4 is selected from the group hydroxy, amino, or 4-hydroxybenzylamino; or R 3 and R 4 together with the atoms to which they are attached are a six membered heterocyclic ring comprising five carbon atoms and N(H); R 5 is hydrogen; R 6 is hydrogen; and the center marked * has the (S) absolute configuration.

5. The method of claim 1 wherein R 1 is 9-decenyl, 9-decanyl, 7-octenyl, 5-hexenyl, 3-butenyl, ethenyl, tert-butyl, benzoylaminomethyl, or 4-hydroxybenzyloxycarbonylaminomethyl.

6. The method of claim 1 wherein R 2 is hydrogen or methyl, R 3 is N(R a )(R b ), R 4 is hydroxy, amino, or 4-hydroxybenzylamino, R 5 is hydrogen and R 6 is hydrogen or oxo.

7. The method of claim 1 wherein R 3 and R 4 together with the atoms to which they are attached are a five or six membered heterocyclic ring comprising four or five carbon atoms and N(R c ).

8. The method of claim 1 wherein X is a direct bond, N(H) or methylene (—CH 2 —).

9. The method of claim 1 wherein R 1 is (C 1 -C 15 )alkyl, (C 2 -C 15 )alkenyl, (C 2 -C 15 )alkynyl, (C 1 -C 15 )alkoxy, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl;

R 2 is hydrogen;

R 3 and R 4 together with the atoms to which they are attached are a six-membered heterocyclic ring comprising five carbon atoms and N(R c ), wherein R c is hydrogen or (C 1 -C 6 )alkyl;

X is methylene (—CH 2 —);

R 5 is hydrogen; and

R 6 is hydrogen.

10. The method of claim 1 wherein the compound of formula (X) is racemic or optically active 3-(undec-10-enoylamino)piperidine-2,6-dione.

11. The method of claim 1 wherein the compound of formula (X) is [3S]-3-(undec-10-enoylamino)piperidine-2,6-dione.

12. The method of claim 3 wherein R 1 is 9-decenyl, 9-decanyl, 7-octenyl, 5-hexenyl, 3-butenyl, ethenyl, tert-butyl, benzoylaminomethyl, or 4-hydroxybenzyloxycarbonylaminomethyl.

13. The method of claim 3 wherein R 2 is hydrogen or methyl, R 3 is N(R a )(R b ), R 4 is hydroxy, amino, or 4-hydroxybenzylamino, R 5 is hydrogen and R 6 is hydrogen or oxo.

14. The method of claim 3 wherein R 3 and R 4 together with the atoms to which they are attached are a five or six membered heterocyclic ring comprising four or five carbon atoms and N(R c ).

15. The method of claim 3 wherein X is a direct bond, N(H) or methylene (—CH 2 —).

16. The method of claim 3 wherein R 1 is (C 1 -C 15 )alkyl, (C 2 -C 15 )alkenyl, (C 2 -C 15 )alkynyl, (C 1 -C 15 )alkoxy, heteroaryl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl;

R 2 is hydrogen;

R 3 and R 4 together with the atoms to which they are attached are a six-membered heterocyclic ring comprising five carbon atoms and N(R c ), wherein R c is hydrogen or (C 1 -C 6 )alkyl;

X is methylene (—CH 2 —);

R 5 is hydrogen; and

R 6 is hydrogen.

17. The method of claim 3 wherein the compound of formula (X) is racemic or optically active 3-(undec-10-enoylamino)piperidine-2,6-dione.

18. The method of claim 3 wherein the compound of formula (X) is [3S]-3-(undec-10-enoylamino)piperidine-2,6-dione.