IP Library › Patent Application 13185161

Patent Application

App. No. 13/185,161

Novel Compositions and Methods of Treating Diseases Using the Same

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Patent No.: US None
App. No.: 13/185,161

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Abstract

The invention includes compositions and methods for inhibiting proliferation and inducing apoptosis in activated lymphocytes, treating diseases associated with activated lymphocytes, or treating PAH.

Claims (171)

1 . A composition comprising a compound of formula II or a salt thereof:

wherein:

each occurrence of R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl; (C 1 -C 6 )alkenyl; (C 1 -C 6 )alkoxy; OH; NO 2 ; C≡N; C(═O)OR 7 ; C(═O)NR 7 2 ; NR 7 2 ; NR 7 C(═O)(C 1 -C 6 )alkyl; NR 7 C(═O)O(C 1 -C 6 )alkyl; NR 7 C(═O)NR 7 2 ; NR 7 SO 2 (C 1 -C 6 )alkyl; SO 2 NR 7 2 ; OC(═O)(C 1 -C 6 )alkyl; O(C 2 -C 6 )alkylene-NR 7 2 ; (C 2 -C 6 )alkylene-OR 7 ; and (C 1 -C 3 )perfluoroalkyl;

R 3 is hydrogen, C(═O)OR 7 , or C(═O)NR 7 2 ;

A 2 is CH or N;

R 5 is H or CR 8 R 9 R 10 ;

each occurrence of R 7 and R 10 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )cycloalkyl and (C 1 -C 6 )alkyl;

each occurrence of R 8 and R 9 is independently selected from the group consisting of (C 1 -C 6 )cycloalkyl and (C 1 -C 6 )alkyl; or R 8 and R 9 are bound to the same carbon atom and linked as to form a divalent group selected from the group consisting of ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl and heptane-17-diyl; wherein said bivalent group is optionally substituted with at least one (C 1 -C 6 )alkyl group;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2;

p is independently at each occurrence 2 or 3; and

q is independently at each occurrence 1 or 2.

2 . The composition of claim 1 , wherein R 2 is hydrogen.

3 . The composition of claim 1 , wherein R 3 is hydrogen.

4 . The composition of claim 1 , wherein A 2 is N.

5 . The composition of claim 1 , wherein R 5 is C(CH 3 ) 3 .

6 . The composition of claim 1 , wherein m is 2, n is 0, p is 2, and q is 1.

7 . The composition of claim 1 , wherein said compound is N-(2-(4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)piperazin-1-yl)ethyl)pivalamide (Compound 35b) or a salt thereof.

8 . A composition comprising a compound of formula III or a salt thereof:

wherein:

each occurrence of R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl; (C 1 -C 6 )alkenyl; (C 1 -C 6 )alkoxy; OH; NO 2 ; C≡N; C(═O)OR 5 ; C(═O)NR 5 2 ; NR 5 2 ; NR 5 C(═O)(C 1 -C 6 )alkyl; NR 5 C(═O)O(C 1 -C 6 )alkyl; NR 5 C(═O)NR 5 2 ; NR 5 SO 2 (C 1 -C 6 )alkyl; SO 2 NR 5 2 ; OC(═O)(C 1 -C 6 )alkyl; O(C 2 -C 6 )alkylene-NR 5 2 ; (C 2 -C 6 )alkylene-OR 5 ; and (C 1 -C 3 )perfluoroalkyl;

R 3 is hydrogen, C(═O)OR 5 , or C(═O)N(R 5 ) 2 ;

A 2 is CH or N;

R 4 is —(CR 5 2 ) p N(R 5 )C(═O)—CR 6 R 7 R 8 ; —(CR 5 2 ) p O(CR 5 2 ) p N(R 5 )C(═O)—CR 6 R 7 R 8 ; —(CR 5 2 ) p N(R 5 )(CR 5 2 ) p N(R 5 )C(═O)—CR 6 R 7 R 8 ; or —(CR 5 2 ) p N(R 5 )C(═O)(CR 5 2 ) p N(R 5 )C(═O)—CR 6 R 7 R 8 ;

each occurrence of R 5 and R 6 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl and (C 1 -C 6 )cycloalkyl;

R 7 is (C 1 -C 6 )alkyl or (C 1 -C 6 )cycloalkyl; or R 6 and R 7 are bound to the same carbon atom and linked as to form a divalent group selected from the group consisting of ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl and heptane-17-diyl; wherein said bivalent group is optionally substituted with at least one (C 1 -C 6 )alkyl group;

R 8 is (C 1 -C 6 )alkyl, —N(R 5 )C(═O)R 5 , or —N(R 5 )S(═O) 2 R 7 ;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2; and,

p is independently at each occurrence 1, 2 or 3.

9 . The composition of claim 8 , wherein R 3 is hydrogen.

10 . The composition of claim 8 , wherein A 2 is N.

11 . The composition of claim 8 , wherein R 4 is —(CR 5 2 ) p N(R 5 )C(═O)—CR 6 R 7 R 8 .

12 . The composition of claim 8 , wherein m is 2, n is 0, p is 2, and q is 1.

13 . The composition of claim 8 , wherein said compound is selected from the group consisting of 2-amino-2-methyl-N-(2-(4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)piperazin-1-yl)ethyl)propanamide (Compound 36a), 2-formamido-N-(2-(4-(3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)piperazin-1-yl)ethyl)acetamide (Compound 37b), a salt thereof, and mixtures thereof.

14 . A method of inducing apoptosis in an immune cell or lymphocyte, said method comprising contacting said immune cell or lymphocyte with a composition comprising a compound selected from the group comprising:

a compound of formula II:

wherein:

each occurrence of R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )alkyl; (C 1 -C 6 )alkenyl; (C 1 -C 6 )alkoxy; OH; NO 2 ; C≡N; C(═O)OR 7 ; C(═O)NR 7 2 ; NR 7 2 ; NR 7 C(═O)(C 1 -C 6 )alkyl; NR 7 C(═O)O(C 1 -C 6 )alkyl; NR 7 C(═O)NR 1 2 ; NR 7 SO 2 (C 1 -C 6 )alkyl; SO 2 NR 7 2 ; OC(═O)(C 1 -C 6 )alkyl; O(C 2 -C 6 )alkylene-NR 7 2 ; (C 2 -C 6 )alkylene-OR 7 ; and (C 1 -C 3 )perfluoroalkyl;

R 3 is hydrogen, C(═O)OR 7 , or C(═O)NR 7 2 ;

A 2 is CH or N;

R 5 is H or CR 8 R 9 R 10 ;

each occurrence of R 7 and R 10 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )cycloalkyl and (C 1 -C 6 )alkyl;

each occurrence of R 8 and R 9 is independently selected from the group consisting of (C 1 -C 6 )cycloalkyl and (C 1 -C 6 )alkyl; or R 8 and R 9 are bound to the same carbon atom and linked as to form a divalent group selected from the group consisting of ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl and heptane-17-diyl; wherein said bivalent group optionally substituted is with at least one (C 1 -C 6 )alkyl group;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2;

p is independently at each occurrence 2 or 3; and

q is independently at each occurrence 1 or 2;

a compound of formula III:

wherein:

R 3 is hydrogen, C(═O)OR 5 , or C(═O)N(R 5 ) 2 ;

A 2 is CH or N;

each occurrence of R 5 and R 6 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl and (C 1 -C 6 )cycloalkyl;

R 8 is (C 1 -C 6 )alkyl, —N(R 5 )C(═O)R 5 , or —N(R 5 )S(═O) 2 R 7 ;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2; and,

p is independently at each occurrence 1, 2 or 3;

a salt thereof and mixtures thereof, thereby inducing apoptosis in said immune cell or lymphocyte.

15 . The method of claim 14 , wherein said lymphocyte is selected from the group consisting of a T cell and a B cell.

16 . The method of claim 15 , wherein said B cell is a plasma cell.

17 . The method of claim 16 , wherein said plasma cell is a multiple myeloma cell.

18 . A method of inhibiting proliferation of a lymphocyte, said method comprising contacting said lymphocyte with a composition comprising a compound selected from the group comprising:

a compound of formula H:

wherein:

R 3 is hydrogen, C(═O)OR 7 , or C(═O)NR 7 2 ;

A 2 is CH or N;

R 5 is H or CR 8 R 9 R 10 ;

each occurrence of R 7 and R 10 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )cycloalkyl and (C 1 -C 6 )alkyl;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2;

p is independently at each occurrence 2 or 3; and

q is independently at each occurrence 1 or 2;

a compound of formula III:

wherein:

R 3 is hydrogen, C(═O)OR 5 , or C(═O)N(R 5 ) 2 ;

A 2 is CH or N;

each occurrence of R 5 and R 6 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl and (C 1 -C 6 )cycloalkyl;

R 8 is (C 1 -C 6 )alkyl, —N(R 5 )C(═O)R 5 , or —N(R 5 )S(═O) 2 R 7 ;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2; and,

p is independently at each occurrence 1, 2 or 3;

a salt thereof and mixtures thereof, thereby inhibiting proliferation of said lymphocyte.

19 . The method of claim 18 , wherein said lymphocyte is selected from the group consisting of a T cell and a B cell.

20 . The method of claim 19 , wherein said B cell is a plasma cell.

21 . The method of claim 20 , wherein said plasma cell is a multiple myeloma cell.

22 . A method of treating a disease characterized by abnormal lymphocyte proliferation in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a pharmaceutically acceptable composition comprising a compound selected from the group comprising:

a compound of formula II:

wherein:

R 3 is hydrogen, C(═O)OR 7 , or C(═O)NR 7 2 ;

A 2 is CH or N;

R 5 is H or CR 8 R 9 R 10 ;

each occurrence of R 7 and R 10 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )cycloalkyl and (C 1 -C 6 )alkyl;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2;

p is independently at each occurrence 2 or 3; and

q is independently at each occurrence 1 or 2;

a compound of formula III:

wherein:

R 3 is hydrogen, C(═O)OR 5 , or C(═O)N(R 5 ) 2 ;

A 2 is CH or N;

each occurrence of R 5 and R 6 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl and (C 1 -C 6 )cycloalkyl;

R 8 is (C 1 -C 6 )alkyl, —N(R 5 )C(═O)R 5 , or —N(R 5 )S(═O) 2 R 7 ;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2; and,

p is independently at each occurrence 1, 2 or 3;

a salt thereof and mixtures thereof, thereby treating said disease in said mammal.

23 . A method of treating a disease selected from the group consisting of asthma and rheumatoid arthritis in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a pharmaceutically acceptable composition comprising a compound selected from the group comprising:

a compound of formula II:

wherein:

R 3 is hydrogen, C(═O)OR 7 , or C(═O)NR 7 2 ;

A 2 is CH or N;

R 5 is H or CR 8 R 9 R 10 ;

each occurrence of R 7 and R 10 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )cycloalkyl and (C 1 -C 6 )alkyl;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2;

p is independently at each occurrence 2 or 3; and

q is independently at each occurrence 1 or 2;

a compound of formula III:

wherein:

R 3 is hydrogen, C(═O)OR 5 , or C(═O)N(R 5 ) 2 ;

A 2 is CH or N;

each occurrence of R 5 and R 6 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl and (C 1 -C 6 )cycloalkyl;

R 8 is (C 1 -C 6 )alkyl, —N(R 5 )C(═O)R 5 , or —N(R 5 )S(═O) 2 R 7 ;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2; and,

p is independently at each occurrence 1, 2 or 3;

a salt thereof and mixtures thereof thereby treating said disease in said mammal.

24 . A method of preventing or treating PAH in a mammal, said method comprising to said mammal a therapeutically effective amount of a pharmaceutically acceptable composition comprising a compound selected from the group comprising:

a compound of formula II:

wherein:

R 3 is hydrogen, C(═O)OR 7 , or C(═O)NR 7 2 ;

A 2 is CH or N;

R 5 is H or CR 8 R 9 R 10 ;

each occurrence of R 7 and R 10 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )cycloalkyl and (C 1 -C 6 )alkyl;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2;

p is independently at each occurrence 2 or 3; and

q is independently at each occurrence 1 or 2;

a compound of formula III:

wherein:

R 3 is hydrogen, C(═O)OR 5 , or C(═O)N(R 5 ) 2 ;

A 2 is CH or N;

each occurrence of R 5 and R 6 is independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl and (C 1 -C 6 )cycloalkyl;

R 8 is (C 1 -C 6 )alkyl, —N(R 5 )C(═O)R 5 , or —N(R 5 )S(═O) 2 R 7 ;

m is independently at each occurrence 1, 2, or 3;

n is 0, 1, or 2; and,

p is independently at each occurrence 1, 2 or 3;

a salt thereof and mixtures thereof, thereby preventing or treating PAH in said mammal.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 27, 2011

From: ROTH, STEPHEN; TOMCZUK, BRUCE E.

To: CORRIDOR PHARMACEUTICALS, INC.

Reel/Frame 027135/0010 →

MERGER Recorded Oct 26, 2011

From: IMMUNE CONTROL INC.; ARGINETIX, INC.

To: CORRIDOR PHARMACEUTICALS, INC.

Reel/Frame 027121/0692 →