Claims for Patent: 6,911,464

Summary for Patent: 6,911,464

Title:	N-alkyl-hydroxamic acid-isoindolyl compounds and their pharmaceutical uses
Abstract:	The invention encompasses novel N-alkyl-hydroxamic acid-isoindolyl compounds, pharmaceutical compositions of these compounds, and methods of using these compounds and compositions for treatment or prevention of various diseases and disorders, for example, diseases associated with PDE4.
Inventor(s):	Man; Hon-Wah (Princeton, NJ), Muller; George W. (Bridgewater, NJ)
Assignee:	Celgene Corporation (Summit, NJ)
Application Number:	10/798,372
Patent Claims:	1. A compound of formula (I): ##STR31## wherein: Y is --C(O)--, --CH.sub.2 --, --CH.sub.2 C(O)-- or --SO.sub.2 --; R.sub.1 and R.sub.2 are each independently C.sub.1-8 -alkyl, CF.sub.2 H, CF.sub.3, CH.sub.2 CHF.sub.2, cycloalkyl, or (C.sub.1-8 -alkyl)cycloalkyl; Z.sub.1 is H, C.sub.1-6 -alkyl, NH.sub.2, NR.sub.3 R.sub.4 or OR.sub.5 ; Z.sub.2 is H or C(O)R.sub.5 ; X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are each independently H, halogen, NO.sub.2, OR.sub.3, CF.sub.3, C.sub.1-6 -alkyl, (C.sub.0-4 alkyl)-(C.sub.3-6 -cycloalkyl), (C.sub.0-4 -alkyl)-N--(R.sub.8 R.sub.9), (C.sub.0-4 -alkyl)-NHC(O)--(R.sub.8), (C.sub.0-4 -alkyl)-NHC(O)CH(R.sub.8)(R.sub.9), (C.sub.0-4 -alkyl)-NHC(O)N(R.sub.8 R.sub.9), (C.sub.0-4 -alkyl)-NHC(O)O(R.sub.8), (C.sub.0-4 -alkyl)-O--R.sub.8, (C.sub.0-4 -alkyl)-imidazolyl, (C.sub.0-4 -alkyl)-pyrrolyl, (C.sub.0-4 -alkyl)-oxadiazolyl, (C.sub.0-4 -alkyl)-triazolyl (C.sub.0-4 -alkyl)-heterocycle or NHCOCH(R.sub.8)N(R.sub.7 R.sub.8); R.sub.3, R.sub.4, and R.sub.5 are each independently H, C.sub.1-6 -alkyl, O--C.sub.1-6 -alkyl, phenyl, benzyl, or aryl; R.sub.6 and R.sub.7 are independently H or C.sub.1-6 -alkyl; R.sub.8 and R.sub.9 are each independently H, C.sub.1-9 -alkyl, C.sub.3-6 -cycloalkyl, (C.sub.1-6 -alkyl)-(C.sub.3-6 -cycloalkyl), (C.sub.0-6 -alkyl)-N(R.sub.4 R.sub.5), (C.sub.1-6 -alkyl)-OR.sub.5, phenyl, benzyl, aryl, piperidinyl, piperizinyl, pyrolidinyl, morpholino, or C.sub.3-7 -heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. 2. The compound of claim 1 wherein Y is --CH.sub.2 -- or --C(O)--. 3. The compound of claim 1 wherein Z.sub.1 is H. 4. The compound of claim 3 wherein R.sub.6 is C.sub.1-6 -alkyl and R.sub.7 is H. 5. The compound of claim 1 wherein Z.sub.2 is H, --C(O)CH.sub.3 or --C(O)CH.sub.2 CH.sub.3. 6. The compound of claim 5 wherein X.sub.4 is NHC(O)R.sub.8. 7. The compound of claim 5 wherein R.sub.1 is CH.sub.3 or CF.sub.2 H and R.sub.2 is C.sub.1-8 -alkyl. 8. The compound of claim 5 wherein Z.sub.2 is H. 9. The compound of claim 1 wherein R.sub.1 is CH.sub.3 or CF.sub.2 H. 10. The compound of claim 1 wherein R.sub.2 is CH.sub.2 CH.sub.3, CH.sub.3, CF.sub.2 H, CH.sub.2 -cyclopropyl, or cyclopentyl. 11. The compound of claim 1 wherein R.sub.6 and R.sub.7 are both H or one of R.sub.6 and R.sub.7 is H and the other is CH.sub.3. 12. The compound of claim 1 wherein X.sub.4 is --NHC(O)R.sub.8 and X.sub.1 is H or halogen. 13. The compound of claim 1 wherein one of X.sub.1, X.sub.2, X.sub.3, and X.sub.4 is NHCOCH.sub.2 N(CH.sub.3).sub.2, NHCON(CH.sub.3).sub.2, NHCONH.sub.2, NHCOCH.sub.3, NHCOCH(R.sub.8)N(R.sub.7 R.sub.8) or OCH.sub.3, and the rest of X.sub.1, X.sub.2, X.sub.3, and X.sub.4 are H. 14. The compound of claim 1, wherein the configuration of stereocenter a is (S). 15. The compound of claim 1, wherein the configuration of stereocenter a is (R). 16. The compound of claim 1, wherein R.sub.6 and R.sub.7 are not the same, and the configuration of stereocenter b is (S). 17. The compound of claim 1, wherein R.sub.6 and R.sub.7 are not the same, and the configuration of stereocenter b is (R). 18. A diastereomerically pure SS isomer of a compound of claim 1, substantially free of other diasteriomers, or a pharmaceutically acceptable salt, or solvate. 19. A diastereomerically pure RS isomer of a compound of claim 1, substantially free of other diasteriomers, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. 20. A diastereomerically pure SR isomer of a compound of claim 1, substantially free of other diasteriomers, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. 21. A diastereomerically pure RR isomer of a compound of claim 1, substantially free of other diasteriomers, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. 22. A compound, where the compound is: (3R)-(tert-Butoxy)-N-{3-[7-(cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl] -3-(3-ethoxy-4-methoxyphenyl)propyl}carbonylamino (tert-butoxy)formate; N-[3-(7-Amino-1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propyl](ter t-butoxy)carbonylamino (tert-butoxy)formate; (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-o xo-2,3-dihydro-1H-isoindol-4-yl}-amide; (1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propy l]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide; (1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propy l]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide; (1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propy l]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide; (1R)-N-{2-[3-(N-Acetoxy-N-formyl-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propy l]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide; (1R)-N-{2-[3-(N-Aminocarbonyl-N-hydroxy-amino)-1-(3-ethoxy-4-methoxy-phenyl )-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide; (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-o xo-2,3-dihydro-1H-isoindol-4-yl}-amide; (N-{3-[7-(Cyclopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3-(3-ethoxy-4-met hoxyphenyl)propyl}acetylamino) acetate; or (1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(formyl-hydroxy-amino)-butyl]-3-oxo-2, 3-dihydro-1H-isoindol-4-yl}-amide. 23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent and a compound of formula (I): ##STR32## wherein: Y is --C(O)--, --CH.sub.2 --, --CH.sub.2 C(O)-- or --SO.sub.2 --; R.sub.1 and R.sub.2 are each independently C.sub.1-8 -alkyl, CF.sub.2 H, CF.sub.3, CH.sub.2 CHF.sub.2, cycloalkyl, or (C.sub.1-8 -alkyl)cycloalkyl; Z.sub.1 is H, C.sub.1-6 -alkyl, NH.sub.2, NR.sub.3 R.sub.4 or OR.sub.5 ; Z.sub.2 is H or C(O)R.sub.5 ; X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are each independently H, halogen, NO.sub.2, OR.sub.3, CF.sub.3, C.sub.1-6 -alkyl, (C.sub.0-4 alkyl)-(C.sub.3-6 -cycloalkyl), (C.sub.0-4 -alkyl)-N--(R.sub.8 R.sub.9), (C.sub.0-4 -alkyl)-NHC(O)--(R.sub.8), (C.sub.0-4 -alkyl)-NHC(O)CH(R.sub.8)(R.sub.9), (C.sub.0-4 -alkyl)-NHC(O)N(R.sub.8 R.sub.9), (C.sub.0-4 -alkyl)-NHC(O)O(R.sub.8), (C.sub.0-4 -alkyl)-O--R.sub.8, (C.sub.0-4 -alkyl)-imidazolyl, (C.sub.0-4 -alkyl)-pyrrolyl, (C.sub.0-4 -alkyl)-oxadiazolyl, (C.sub.0-4 -alkyl)-triazolyl or (C.sub.0-4 -alkyl)-heterocycle; R.sub.3, R.sub.4, and R.sub.5 are each independently H, C.sub.1-6 -alkyl, O--C.sub.1-6 -alkyl, phenyl, benzyl, or aryl; R.sub.6 and R.sub.7 are independently H or C.sub.1-6 -alkyl; R.sub.8 and R.sub.9 are each independently H, C.sub.1-9 -alkyl, C.sub.3-6 -cycloalkyl, (C.sub.1-6 -alkyl)-(C.sub.3-6 -cycloalkyl), (C.sub.0-6 -alkyl)-N(R.sub.4 R.sub.5), (C.sub.1-6 -alkyl)-OR.sub.5, phenyl, benzyl, aryl, piperidinyl, piperizinyl, pyrolidinyl, morpholino, or C.sub.3-7 -heterocycloalkyl; or a pharmaceutically acceptable salt or solvate thereof. 24. The pharmaceutical composition of claim 23 further comprising an additional therapeutic agent. 25. The pharmaceutical composition of claim 24 wherein the additional therapeutic agent is an anti-cancer agent or an anti-inflammatory agent. 26. The pharmaceutical composition of claim 25 wherein the anti-cancer agent is paclitaxel, cisplatin, tamoxifen, docetaxel, pirubicin, doxorubicin, irinotecan, leuprolide, bicalutamide, a goserlin implant, gemcitabine, sargramostim or a steroid.

Details for Patent 6,911,464

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Partner Therapeutics, Inc.	LEUKINE	sargramostim	For Injection	103362	03/05/1991		2023-03-12
Partner Therapeutics, Inc.	LEUKINE	sargramostim	Injection	103362	03/05/1991		2023-03-12