Claims for Patent: 6,020,358

Summary for Patent: 6,020,358

Title:	Substituted phenethylsulfones and method of reducing TNF.alpha. levels
Abstract:	Phenethylsulfones substituted in the position .alpha. to the phenyl group with a 1-oxoisoindoline or 1,3-dioxoisoindoline group reduce the levels of TNF.alpha. in a mammal. Typical embodiments are 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline- 1,3-dione and 2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline- 1,3-dione.
Inventor(s):	Muller; George W. (Bridgewater, NJ), Man; Hon-Wah (Neshanic Station, NJ)
Assignee:	Celgene Corporation (Warren, NJ)
Application Number:	09/183,049
Patent Claims:	1. A sulfone selected from the group consisting of (a) a compound of the formula: ##STR4## in which: the carbon atom designated * constitutes a center of chirality; Y is C.dbd.O, CH.sub.2, or CH.sub.2 C.dbd.O; each of R.sup.1, R.sup.2, R.sup.3, and R.sup.4, independently of the others, is hydrogen, halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro, cyano, hydroxy, or --NR.sup.8 R.sup.9 ; or any two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 on adjacent carbon atoms, together with the depicted phenylene ring are naphthylidene each of R.sup.5 and R.sup.6, independently of the other, is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, or cycloalkoxy of up to 18 carbon atoms; R.sup.7 is hydroxy, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, or NR.sup.8' R.sup.9' ; each of R.sup.8 and R.sup.9 taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R.sup.8 and R.sup.9 is hydrogen and the other is --COR.sup.10, or --SO.sub.2 R.sup.10, or R.sup.8 and R.sup.9 taken together are tetramethylene, pentamethylene, hexamethylene, or --CH.sub.2 CH.sub.2 X.sup.1 CH.sub.2 CH.sub.2 -- in which X.sup.1 is --O--, --S-- or --NH--; each of R.sup.8' and R.sup.9' taken independently of the other is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl, or one of R.sup.8' and R.sup.9' is hydrogen and the other is --COR.sup.10', or --SO.sub.2 R.sup.10', or R.sup.8' and R.sup.9' taken together are tetramethylene, pentamethylene, hexamethylene, or --CH.sub.2 CH.sub.2 X.sup.2 CH.sub.2 CH.sub.2 -- in which X.sup.2 is --O--, --S-- or --NH--; R.sup.10 is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl; and R.sup.10' is hydrogen, alkyl of 1 to 8 carbon atoms, or phenyl; and (b) the acid addition salts of said compounds which contain a nitrogen atom susceptible of protonation. 2. A sulfone according to claim 1 wherein in said compound, Y is C.dbd.O. 3. A sulfone according to claim 1 wherein in said compound, Y is CH.sub.2. 4. A sulfone according to claim 1 wherein in said compound, each of R.sup.1, R.sup.2, R.sup.3, and R.sup.4, independently of the others, is hydrogen, halo, methyl, ethyl, methoxy, ethoxy, nitro, cyano, hydroxy, or --NR.sup.8 R.sup.9 in which each of R.sup.8 and R.sup.9 taken independently of the other is hydrogen or methyl or one of R.sup.8' and R.sup.9' is hydrogen and the other is --COCH.sub.3. 5. A sulfone according to claim 1 wherein in said compound, one of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is --NH.sub.2 and the remaining of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen. 6. A sulfone according to claim 1 wherein in said compound, one of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is --NHCOCH.sub.3 and the remaining of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are hydrogen. 7. A sulfone according to claim 1 wherein in said compound, one of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is methyl or ethyl and the remaining of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are hydrogen. 8. A sulfone according to claim 1 wherein in said compound, one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is fluoro and the remaining of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen. 9. A sulfone according to claim 1 wherein in said compound, one of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is --N(CH.sub.3).sub.2 and the remaining of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are hydrogen. 10. A sulfone according to claim 1 wherein in said compound, each of R.sup.5 and R.sup.6, independently of the other, is hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopentoxy, or cyclohexoxy. 11. A sulfone according to claim 1 wherein in said compound, R.sup.5 is alkoxy and R.sup.6 is alkoxy, monocycloalkoxy, or bicycloalkoxy. 12. A sulfone according to claim 1 wherein in said compound, R.sup.5 is methoxy and R.sup.6 is ethoxy. 13. A sulfone according to claim 1 wherein in said compound, R.sup.7 is hydroxy, methyl, ethyl, phenyl, benzyl, or NR.sup.8' R.sup.9' in which each of R.sup.8' and R.sup.9' taken independently of the other is hydrogen or methyl. 14. A sulfone according to claim 1 wherein in said compound, R.sup.7 is methyl. 15. A sulfone according to claim 1 wherein in said compound, R.sup.7 is NR.sup.8' R.sup.9' in which each of R.sup.8' and R.sup.9' taken independently of the other is hydrogen or methyl. 16. A sulfone according to claim 1 which is 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindolin-1-one, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-(N,N-dimethylaminosulfonyl)ethyl]isoindo lin-1-one, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dion e, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-nitro-isoindoline -1,3-dione, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-nitroisoindoline- 1,3-dione, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-aminoisoindoline- 1,3-dione, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-methylisoindoline -1,3-dione, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-acetamidoisoindol ine-1,3-dione, 2-[1-(3-ethyoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethylaminoiso ndoline-1,3-dione, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-5-dimethylaminoisoi ndoline-1,3-dione, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]benzo[e]isoindoline- 1,3-dione, 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-methoxyisoindolin e-1,3-dione, 2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline- 1,3-dione, or 2-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-dimethyla minoisoindoline-1,3-dione. 17. A method of reducing undesirable levels of TNF.alpha. in a mammal which comprises administering thereto an effective amount of a compound according to claim 1. 18. A method of inhibiting PDE IV in a mammal which comprises administering thereto an effective amount of a compound according to claim 1. 19. A pharmaceutical composition comprising a quantity of a compound according to claim 1 sufficient upon administration in a single or multiple dose regimen to reduce levels of TNF.alpha. in a mammal in combination with a carrier.