IP Library › Granted Patent US 9,725,427

Granted Patent B2

US 9,725,427 · App. 14/385,551 · Granted Aug 8, 2017

Prodrugs of riluzole and their method of use

Inventors: Garry R. Smith (Royersford, PA); Allen B. Reitz (Lansdale, PA); Mark McDonnell (Lansdale, PA); Suzie Chen (Highland Park, NJ); Matthew D. Vera (Collegeville, PA); Benjamin E. Blass (Eagleville, PA); Jeffery C. Pelletier (Lafayette Hill, PA); Venkata N. Velvadapu (Philadelphia, PA); Jay E. Wrobel (Lawrenceville, NJ)

Assignees: Biohaven Pharmaceutical Holding Company Limited; Rutgers, The State University of New Jersey

C07D277/82 A61K31/428 A61K45/06 C07D417/12

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Quick Facts

Patent No.: US 9,725,427
App. No.: 14/385,551
Granted: Aug 8, 2017
Kind: B2

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Abstract

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

Claims (86)

1. A compound having formula (I):

including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:

R 1 is selected from the group consisting of OR 2 , CR 3a R 3b NH 2 , CH 2 CH 2 CO 2 R 4 , CH 2 CH 2 CONHR 5 , (CR 6a R 6b ) m NR 7a R 7b , and CH 2 Ar;

R 2 is selected from the group consisting of C1-C6 alkyl and CH 2 (CH 2 ) n NR 8a R 8b ;

n =1 or 2;

R 3a and R 3b are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted CH 2 CH 2 Ar, CH 2 OR 9 ,

R 4 is selected from the group consisting of hydrogen and optionally substituted C1-C6 Alkyl;

R 5 is selected from the group consisting of hydrogen, optionally substituted C1-C6 Alkyl, CH 2 CH 2 NR 10a R 10b , and CH 2 R 11 ;

R 6a and R 6b are, at each occurrence, independently selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl; or

R 6a and R 6b are taken together with the atom to which they are bound to form an optionally substituted 6 membered ring;

m =3 or 4;

R 7a and R 7b are each independently selected from the group consisting of hydrogen methyl,

R 8a and R 8b are each independently C1-C6 alkyl;

R 9 is selected from the group consisting of hydrogen, optionally substituted phenyl, optionally substituted benzyl, and optionally substituted CH 2 CH 2 Ar;

R 10a and R 10b are each independently is selected from the group consisting of hydrogen and optionally substituted C1-C6 alkyl; or

R 10a and R 10b and are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms; or

R 10a and R 10b and are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms containing an oxygen; or

R 10a and R 10b and are taken together with the atom to which they are bound to form an optionally substituted ring having 5 to 6 ring atoms containing two nitrogen atoms;

R 11 is selected from the group consisting of optionally substituted phenyl and optionally substituted heteroaryl;

Ar is selected from the group consisting of optionally substituted phenyl and optionally substituted naphthyl ring; wherein

the phenyl or naphthyl ring is optionally substituted with 0-5 moieties selected from the group consisting of deuterium, halogen, trifluoromethyl, triflouromethoxy, C1-C6 alkyl, and C2-C6 alkoxy.

2. The compound of claim 1 having the formula (III)

including hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein R 12a , R 12b , R 12c , R 12d , and R 12e are each independently selected from the group consisting of hydrogen, deuterium, halogen, trifluoromethyl, triflouromethoxy, optionally substituted C1-C6 alkyl, and optionally substituted C1-C6 alkoxy.

3. The compound selected from the group consisting of:

2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-acetamide;

(R)-2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;

(R)-2-Amino-3-phenyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;

(R)-2-Amino-3-benzyloxy-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;

(S)-2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;

(S)-2-Amino-3-methyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-butyramide;

(S)-2-Amino-3-phenyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;

(S)-2-Amino-3-benzyloxy-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;

(S)-2-amino-3-(4-fluorobenzyloxy)-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propanamide;

(S)-2-amino-3-(2,4-difluorobenzyloxy)-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propanamide;

(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid methyl ester;

(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid ethyl ester;

(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid propyl ester;

(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid butyl ester;

(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid isobutyl ester;

(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid hexyl ester;

(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid 2-dimethylamino-ethyl ester;

(6-Trifluoromethoxy-benzothiazol-2-yl)-carbamic acid 3-dimethylamino-propyl ester;

N-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid;

N-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid methyl ester;

N-(6-Trifluoromethoxy-benzothiazol-2-yl)-succinamic acid tert-butyl ester;

N-Pyridin-3-ylmethyl-N′-(6-trifluoromethoxy-benzothiazol-2-yl)-succinamide;

N-(2-Morpholin-4-yl-ethyl)-N′-(6-trifluoromethoxy-benzothiazol-2-yl)-succinamide;

5-Methylamino-pentanoic acid (6-trifluoromethoxy-benzothiazol-2-yl)-amide;

5-Amino-pentanoic acid (6-trifluoromethoxy-benzothiazol-2-yl)-amide;

2-(1-Aminomethyl-cyclohexyl)-N-(6-trifluoromethoxy-benzothiazol-2-yl)-acetamide;

or a pharmaceutically acceptable salt form thereof.

4. A composition comprising an effective amount of at least one compound according to claim 1 .

5. The composition according to claim 4 , further comprising at least one excipient.

6. A composition comprising at least one excipient and an effective amount of at least one compound selected from the group consisting of:

2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-acetamide;

(R)-2-Amino-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;

(R)-2-Amino-3 -phenyl-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;

(R)-2-Amino-3 -benzyloxy-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;