# US 5,703,098 A · Immunotherapeutic imides/amides

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- Number: US 5,703,098 A
- Document ID: US5703098A
- Status: Granted
- Kind: A
- Application number: 08/759,788
- Filed: 1996-12-03
- Granted: 1997-12-30
- Earliest claimed: 1994-12-30
- Assignees: Celgene Corporation
- Inventors: George W. Muller; Mary Shire; David I. Stirling
- Web page: https://patentgrep.com/patent/US5703098A

## CPC

- C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide
- A61K 31/4035: Isoindoles, e.g. phthalimide
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61P 11/06: Antiasthmatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/18: for HIV
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/46: with an oxygen atom in position 1
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Imide/amide ethers and alcohols are inhibitors of cytokines including tumor necrosis factor .alpha. and can be used to combat cachexia, endotoxic shock, arthritis, asthma, and retrovirus replication. A typical embodiment is 3-Phthalimido-3-(3', 4'-dimethoxyphenyl)propan-1-ol.

## Claims

### Claim 1

A compound having the formula: ##STR3## wherein R.sup.1 is (i) straight, branched, or cyclic, unsubstituted alkyl of 1 to 12 carbon atoms; (ii) straight, branched, or cyclic, substituted alkyl of 1 to 12 carbon atoms; (iii) phenyl; or (iv) phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, acylamino, alkylamino, di(alkyl)amino, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, bicycloalkyl of 5 to 12 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkoxy of 3 to 10 carbon atoms, bicycloalkoxy of 5 to 12 carbon atoms, and halo;
R.sup.2 is hydrogen, alkyl of 1 to 8 carbon atoms, benzyl, pyridylmethyl, or alkoxymethyl;
R.sup.3 is (i) ethylene, (ii) vinylene, (iii) a branched alkylene of 3 to 10 carbon atoms, (iv) a branched alkenylene of 3 to 10 carbon atoms, (v) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (vi) cycloalkenylene of 4 to 9 carbon atoms unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (vii) o-phenylene unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 6 carbon atoms, amino substituted with acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, and halo, (viii) naphthyl, or (ix) pyridyl;
R.sup.4 is --CX--, --CH.sub.2 -- or --CH.sub.2 CX--;
X is O or S; and,
n is 0, 1, 2, or 3.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein
R.sup.1 is (i) straight, branched, or cyclic, unsubstituted alkyll of 1 to 12 carbon atoms; (ii) straight, branched, or cyclic, substituted alkyl of 1 to 12 carbon atoms; (iii) phenyl; or (iv) phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or halo;
R.sup.2 is hydrogen or alkyl of 1 to 8 carbon atoms;
R.sup.3 is (i) ethylene, (ii) vinylene, (iii) a branched alkylene of 3 to 10 carbon atoms, (iv) a branched alkenylene of 3 to 10 carbon atoms, (v) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, and halo, (vi) cycloalkenylene of 4 to 9 carbon atoms unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, and halo, or (vii) o-phenylene unsubstituted or substituted with one or more substituents each selected independently from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, amino substituted with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, and halo; and
R.sup.4 is --CX-- or --CH.sub.2 --.

### Claim 3 (depends on 2)

A compound claim 2 wherein R.sup.4 is --CO-- and R.sup.1 is 3,4-diethoxyphenyl.

### Claim 4 (depends on 2)

A compound of claim 2 wherein R.sup.4 is --CO-- and R.sup.1 is 3-ethoxy-4-methoxyphenyl.

### Claim 5 (depends on 2)

A compound of claim 2 wherein R.sup.4 is --CO-- and R.sup.1 is 3-cyclopentoxy-4-methoxyphenyl.

### Claim 6 (depends on 2)

A compound of claim 2 wherein R.sup.1 is 3,4-dimethoxyphenyl.

### Claim 7 (depends on 2)

A compound of claim 2 wherein R.sup.1 is 3-ethoxy-4-methoxyphenyl.

### Claim 8 (depends on 2)

A compound of claim 2 wherein R.sup.1 is 3-isopropoxy-4-methoxyphenyl.

### Claim 9 (depends on 2)

A compound of claim 2 wherein R.sup.1 is 3-cyclopentoxy-4-methoxyphenyl.

### Claim 10 (depends on 2)

A compound of claim 2 wherein R.sup.1 is 3-ethoxy-4-ethylphenyl.

### Claim 11 (depends on 2)

A compound of claim 2 wherein R.sup.4 is --CO-- and R.sup.1 is substituted phenyl.

### Claim 12 (depends on 2)

A compound of claim 2 wherein R.sup.4 is --CH.sub.2 -- and R.sup.1 is substituted phenyl.

### Claim 13 (depends on 2)

A compound of claim 2 wherein R.sup.4 is --CH.sub.2 CO-- and R.sup.1 is substituted phenyl.

### Claim 14 (depends on 1)

The method of reducing levels of TNF.sub..alpha. in a mammal which comprises administering thereto an effective amount of a compound of claim 1.

### Claim 15

The method of reducing levels of TNF.sub..alpha. in a mammal which comprises administering thereto an effective amount of a compound of the formula: ##STR4## wherein R.sup.1 is (i) straight, branched, or cyclic, unsubstituted alkyl of 1 to 12 carbon atoms; (ii) straight, branched, or cyclic, substituted alkyl of 1 to 12 carbon atoms; (iii) phenyl; or (iv) phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, acylamino, alkyl(dialkyl)amino, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, bicycloalkyl of 5 to 12 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkoxy of 3 to 10 carbon atoms, bicycloalkoxy of 5 to 12 carbon atoms, or halo;
R.sup.2 is --H, alkyl of 1 to 8 carbon atoms, benzy, pyridylmethyl, or alkoxymethyl;
R.sup.3 is i) ethylene, ii) vinylene, iii) a branched alkylene of 3 to 10 carbon atoms, iv) a branched alkenylene of 3 to 10 carbon atoms, v) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with 1 or more substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino alkyl of 1 to 6 carbon atoms, substituted amino acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, or halo, vi) cycloalkenylene of 4 to 9 carbon atoms unsubstituted or substituted with 1 or more substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino alkyl of 1 to 6 carbon atoms, substituted amino acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, or halo, vii) o-phenylene unsubstituted or substituted with 1 or more substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino alkyl of 1 to 6 carbon atoms, substituted amino acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, or halo, viii) napthyl, or ix) pyridyl;
R.sup.4 is --CX--, --CH.sub.2 -- or --CH.sub.2 CX--;
X is O or S; and,
n is 0, 1, 2, or 3.

### Claim 16 (depends on 1)

The method of inhibiting TNF.alpha.-activated retrovirus replication in a mammal which comprises administering thereto an effective amount of a compound according to claim 1.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising an amount of a compound according to claim 1 effective upon single or multiple dosage to inhibit TNF.alpha. and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 2)

A pharmaceutical composition comprising an amount of a compound according to claim 2 effective upon single or multiple dosage to inhibit TNF.alpha. and a pharmaceutically acceptable carrier.

### Claim 19

The method of inhibiting phosphodiesterases in a mammal which comprises administering thereto an effective amount of a compound of the formula: ##STR5## wherein R.sup.1 is (i) straight, branched, or cyclic, unsubstituted alkyl of 1 to 12 carbon atoms; (ii) straight, branched, or cyclic, substituted alkyl of 1 to 12 carbon atoms; (iii) phenyl; or (iv) phenyl substituted with one or more substituents each selected independently of the other from the group consisting of nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino, acylamino, alkyl(dialkyl)amino, alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, bicycloalkyl of 5 to 12 carbon atoms, alkoxy of 1 to 10 carbon atoms, cycloalkoxy of 3 to 10 carbon atoms, bicycloalkoxy of 5 to 12 carbon atoms, or halo;
R.sup.2 is --H, alkyl of 1 to 8 carbon atoms, benzy, pyridylmethyl, or alkoxymethyl;
R.sup.3 is i) ethylene, ii) vinylene, iii) a branched alkylene of 3 to 10 carbon atoms, iv) a branched alkenylene of 3 to 10 carbon atoms, v) cycloalkylene of 4 to 9 carbon atoms unsubstituted or substituted with 1 or more substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino alkyl of 1 to 6 carbon atoms, substituted amino acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, or halo, vi) cycloalkenylene of 4 to 9 carbon atoms unsubstituted or substituted with 1 or more substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino alkyl of 1 to 6 carbon atoms, substituted amino acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, or halo, vii) o-phenylene unsubstituted or substituted with 1 or more substituents each selected independently from nitro, cyano, trifluoromethyl, carbethoxy, carbomethoxy, carbopropoxy, acetyl, carbamoyl, acetoxy, carboxy, hydroxy, amino, substituted amino alkyl of 1 to 6 carbon atoms, substituted amino acyl of 1 to 6 carbon atoms, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 12 carbon atoms, or halo, viii) napthyl, or ix) pyridyl;
R.sup.4 is --CX--, --CH.sub.2 -- or --CH.sub.2 CX--;
X is O or S; and
n is 0, 1, 2, or 3.

### Claim 20 (depends on 19)

A compound according to claim 19 which is 3-phthimido-3-(3,4-dimethoxy-phenyl)propan-1-ol; 2-phthimidodo-2-(3,4-dimethoxyphenyl)ethanol; 3-phthalimido-3-(3,4-diethoxyphenyl)propan-1-ol; 3-phthalimido-3-(3,4-dimethoxyphenyl)-1-methoxy-propane; 2-phthalimido-2-(3,4-dimethoxyphenyl)-1-methoxyethane; 3-phthalimido-3-(3,4-diethoxyphenyl)-1-methoxypropane; 3-phthalimido-3-(3,4-dimethoxyphenyl)-1-ethoxypropane; 3-phthalimido-3-(3,4-dimethoxyphenyl)-1-(3-pyridylmethoxy)propane; 3-phthalimido-3-(3,4-diethoxyphenyl)-1-(3-pyridylmethoxyl)propane; 3-phthalimido-3-naphthylpropan-1-ol; 3-phthalimido-3-(3,4-diethylphenyl)propan-1-ol; 3-phthalimido-3-(3,4-dipropylphenyl)propan-1-ol; 3-phthimido-3-(3,4-diethylphenyl)-1-methoxypropane; 3-phthalimido-3-(3,4-diethoxyphenyl)-1-ethoxypropane; 3-phthalimido-3-cyclohexyl-1-methoxypropane-, 3-phthalimido-3-(3,4-diethylcyclohexyl)-1-methoxypropane; 3-(1-oxoisoindolinyl)-3-(3,4-dimethoxyphenyl)propan-1-ol; 2-(1-oxoisoindolinyl)-2-(3,4-di-methoxyphenyl)ethanol; 3-(1-oxoisoindolinyl)-3-(3,4-diethoxyphenyl)propan-1-ol; 3-(1-oxoisoindolinyl-3-(3,4-dimethoxyphenyl)-1-methoxypropane; 2-(1-oxoisoindolinyl)-2-(3,4-dimethoxyphenyl)-1-methoxyethane; 3-(1-oxoisoindolinyl)-3-(3,4-diethoxyphenyl)-1-methoxypropane; 3-(1-oxoisoindolinyl)-3-(3,4-dimethoxyphenyl)-1-ethoxypropane; 3-(1-oxoisoindolinyl)-3-(3,4-dimethoxyphenyl)-1-(3-pyridylmethoxy)propane; 3-(1-oxo-isoindolinyl)-3-(3,4-diethoxyphenyl)-1-(3-pyridylmethoxyl)propane ; 3-(1-oxoisoindolinyl)-3-naphthylpropan-1-ol; 3-(1-oxoisoindolinyl)-3-(3,4-diethylphenyl)propan-1-ol; 3-(1-oxoisoindolinyl)-3-(3,4-dipropylphenyl)propan-1-ol; 3-(1-oxoisoindolinyl)-3-(3,4-diethylphenyl)-1-methoxypropane; or 3-(1-oxoisoindolinyl)-3-(3,4-diethoxyphenyl)-1-ethoxypropane.