Soluble salts of thieno[2,3-d]pyrimidine derivatives
The present invention is directed to novel salts of thieno[2,3-d]pyrimidine derivatives, including 4-(2-fluorophenyl)-6-methyl-2-(piperazin-1-yl)thieno[2,3-d]pyrimidine salts. The present invention is also directed to compositions including such polymorphs and methods for using such salts, e.g., in the treatment of gastrointestinal and/or genitourinary disorders.
1 . A compound selected from the group consisting of highly soluble salts of Formula II:
wherein
R 1 and R 2 are each independently hydrogen, halogen or a C 1 -C 6 alkyl; or R 1 and R 2 are taken together with the carbons to which they are attached to form a 5 or 6 membered cycloalkylene group;
R 3 and R4 are each independently hydrogen or a C 1 -C 6 alkyl;
R 5 is hydrogen, C 1 -C 6 alkyl,
or —C(O)—NH—R 6 ;
m is an integer from 1 to 3; X is a halogen; and R6 is a C 1 -C 6 alkyl;
n is an integer of 2 or 3; and
Ar is a substituted or unsubstituted phenyl, 2-thienyl, or 3-thienyl group,
wherein the solubility of said salt is greater than about 2.0 mg/ml in water as quantified by HPLC.
2 . The compound of claim 1 , wherein R 1 is -CH 3 .
3 . The compound of any of the preceding claims, wherein R 2 is hydrogen.
4 . The compound of any of the preceding claims, wherein R 3 is hydrogen.
5 . The compound of any of the preceding claims, wherein R4 is hydrogen.
6 . The compound of any of the preceding claims, wherein R 5 is hydrogen.
7 . The compound of any of the preceding claims, wherein n is 2.
8 . The compound of any of the preceding claims, wherein Ar is ortho-fluorophenyl.
9 . The compound of any of the preceding claims, wherein the compound is a 4-(2-fluorophenyl)-6-methyl-2-(piperazin-1-yl)thieno[2,3-d] pyrimidine salt.
10 . The compound of any of the preceding claims, wherein a counterion of the salt has no additional acidic hydrogens.
11 . The compound of any of the preceding claims, wherein the salt is at least one salt selected from the group consisting of methane sulphonate, L-lactate, acetate and propionate.
12 . The compound of any of the preceding claims, wherein the solubility of the salt is greater than about 2.5 mg/ml in water.
13 . The compound of any of the preceding claims, wherein the solubility of the salt is greater than about 5.0 mg/ml in water.
14 . The compound of any of the preceding claims, wherein the solubility of the salt is greater than about 7.5 mg/ml in water.
15 . The compound of any of the preceding claims, wherein the solubility of the salt is greater than about 10.0 mg/ml in water.
16 . A pharmaceutical composition comprising at least one compound of any of the preceding claims and a pharmaceutically acceptable carrier.
17 . A method for treating a gastrointestinal tract disorder or a genitourinary disorder in a subject comprising administering to the subject a composition comprising a therapeutically effective amount of a composition of claim 16 , such that the gastrointestinal tract disorder or genitourinary disorder is treated.
18 . The method of claim 17 , wherein the disorder is a functional bowel disorder, irritable bowel syndrome, irritable bowel syndrome with diarrhea, chronic functional vomiting, overactive bladder or a combination thereof.
19 . A method for treating an MCI-225 responsive state comprising administering to the subject a therapeutically effective amount of a composition of claim 16 , such that the MCI-225 responsive state is treated.