Methods of using N-alkyl-hydroxamic acid-isoindolyl compounds

1. A method of treating arthritis, inflammatory bowel disease, Crohn's disease, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disorder, or psoriasis, comprising administering to a patient in need thereof an effective amount of a compound of formula I:

wherein:

Y is —C(O)—, —CH 2 —, or —CH 2 C(O)—

R 1 and R 2 are each independently C 1-8 -alkyl, CF 2 H, CF 3 , CH 2 CHF 2 , cycloalkyl, or (C 1-8 -alkyl) cycloalkyl;

Z 1 is H, C 1-6 -alkyl, NH 2 , NR 3 R 4 or OR 5 ;

Z 2 is H or C(O)R 5 ;

X 1 , X 2 , X 3 and X 4 are each independently H, halogen, NO 2 , OR 3 , CF 3 , C 1-6 -alkyl, (C 0-4 -alkyl) -(C 3-6 -cycloalkyl), (C 0-4 -alkyl)-N—(R 8 R 9 ), (C 0-4 -alkyl)- NHC(O)—(R 8 ), (C 04 -alkyl) -NHC(O)CH(R 8 )(R 9 ), (C 0-4 -alkyl)-NHC(O)N(R 8 R 9 ), (C 0-4 -alkyl)-NHC(O)O(R 8 ), (C 0-4 -alkyl)-O—R 8 , (C 0-4 -alkyl)-imidazolyl, (C 0-4 -alkyl)-pyrrolyl, (C 0-4 -alkyl)-oxadiazolyl, (C 0-4 -alkyl)-triazolyl or (C 0-4 -alkyl)-heterocycle;

R 3 , R 4 , and R 5 are each independently H, C 1-6 -alkyl, O—C 1-6 -alkyl, phenyl, benzyl, or aryl;

R 6 and R 7 are independently H or C 1-6 -alkyl;

R 8 and R 9 are each independently H, C 1-9 -alkyl, C 3-6 -cycloalkyl, (C 1-6 -alkyl)-(C 3-6 -cycloalkyl), (C 0-6 -alkyl)-N(R 4 R 5 ),(C 1-6 -alkyl)-OR 5 , phenyl, benzyl, aryl, piperidinyl, piperizinyl, pyrolidinyl, morpholino, or C 3-7 -heterocycloalkyl;

or a pharmaceutically acceptable salt thereof;

or an enantiomer or diastereomer thereof.

2. The method of claim 1 , wherein the arthritis is rheumatoid arthritis.

3. The method of claim 1 , wherein adult respiratory distress syndrome disease is treated.

4. The method of claim 1 , wherein chronic obstructive pulmonary disorder is treated.

5. The method of claim 1 , wherein inflammatory bowel disease is treated.

6. The method of claim 1 , wherein Crohn's disease is treated.

7. The method of claim 1 , wherein asthma is treated.

8. The method of claim 1 , wherein psoriasis is treated.

9. The method of claim 1 , wherein said 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](tert-butoxy) carbonylamino (tert-butoxy)formate;

(1R)-Cyclopropanecarboxylic acid {2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy -amino)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol-4-yl}-amide;

(1R)-N-{2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-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)-propyl]-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)-propyl]-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)-propyl]-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-formyi-N-hydroxy -amino)-propyl]-3-oxo-2,3-dihydro-1H-Isoindol- 4 -yl}-amide;

(N-{3-[7-(Cyciopropylcarbonylamino)-1-oxoisoindolin-2-yl]-3 -(3-ethoxy-4-methoxyphenyl) propyl}acetylamino) acetate;

(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; or

(3R)-(tert-Butoxy)-N-{3-(3-ethoxy- 4 -methoxyphenyl)-3-[7-nitro-1-oxoisoindolin-2-yl]-propyl}carbonylamino (tert-butoxy)formate.