Substituted propane phosphinic acid esters
View Patent ↗The present invention relates to certain esters of substituted 3-aminopropane phosphinic acid derivatives of formula I: wherein R, R 1 and R 2 are as defined herein. The compounds of this invention are useful in treating a variety of diseases including but not limited to depression, anxiety, certain psychiatric symptoms, cognitive impairment and schizophrenia.
1. A compound, including enantiomers, stereoisomers, and tautomers of said compound and pharmaceutically acceptable salts thereof, with said compound having the general structure shown in formula I:
wherein:
R is C 1-8 alkyl, C 3-8 cycloalkylC 1-4 alkyl, arylC 1-4 alkyl or fluoroalkyl of the formula C n H X F Y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1to 9 and sum of x and y is 2n+1;
R 1 is hydrogen or hydroxy;
R 2 is substituted or unsubstituted aryl, arylC 1-4 alkyl, heteroaryl or heteroarylalkyl, or CHWOCOX; wherein
W is hydrogen or C 1-4 alkyl;
X is C 1-4 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, NHY or OY; and
wherein
Y is C 1-4 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl.
2. The compound as set forth in claim 1 , wherein
R is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclohexylethyl, cyclohexylpropyl, benzyl, and phenylethyl;
R 1 is hydroxy; R 2 is substituted or unsubstituted phenyl, benzyl or oxo-1,3-dihydroisobenzofuranyl, 5-methyl-[1,3 ]dioxol-2-one-methyl, gamma-butyrolacton-4-yl, or CHWOCOX; wherein
W is hydrogen, methyl, ethyl, n-propyl or sec-butyl;
X is methyl, ethyl, n-propyl, n-butyl, sec-butyl, tert-butyl, cyclohexyl or OY; and wherein
Y is methyl, ethyl or n-propyl.
3. The compound as set forth in claim 1 , wherein R is C 3-8 cycloalkylC 1-4 alkyl and R 1 is hydroxy.
4. The compound as set forth in claim 1 , wherein R is arylC 1-4 alkyl and R 1 is hydroxy.
5. The compound as set forth in claim 1 , wherein R is C 5-7 cycloalkylC 1-4 alkyl and R 1 is hydroxy.
6. The compound as set forth in claim 1 , wherein R is phenylC 1-4 alkyl and R 1 is hydroxy.
7. The compound as set forth in claim 1 , wherein said compound is of the formula IB:
wherein
R 2 is substituted or unsubstituted phenyl, benzyl, oxo-1,3-dihydroisobenzofuranyl or 5-methyl-[1,3]dioxol-2-one-methyl, or CHWOCOX; wherein
W is hydrogen, methyl, ethyl, n-propyl or sec-butyl;
X is methyl, ethyl, n-propyl, n-butyl, sec-butyl, tert-butyl, cyclohexyl or OY; and wherein
Y is methyl, ethyl or n-propyl.
8. The compound as set forth in claim 1 , which is selected from the group consisting of:
((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid 3-oxo-1,3-dihydro-isobenzofuran-1-yl ester;
2,2-dimethyl-propionic acid ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinoyloxymethyl ester;
((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid ethoxycarbonyloxymethyl ester; and
((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid phenyl ester;
((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester;
(3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester; or
a pharmaceutically acceptable salt thereof.
9. The compound as set forth in claim 1 , which is 2,2-dimethyl-propionic acid ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinoyloxymethyl ester or a pharmaceutically acceptable salt thereof.
10. The compound as set forth in claim 1 , which is ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising one or more compounds of formula I, including enantiomers, stereoisomers, and tautomers of said compound and pharmaceutically acceptable salts, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients:
wherein:
R is C 1-8 alkyl, C 3-8 cycloalkylC 1-4 alkyl, arylC14alkyl or fluoroalkyl of the formula C n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from ito 9 and sum of x and y is 2n+1;
R 1 is hydrogen or hydroxy;
R 2 is substituted or unsubstituted aryl, arylC 1-4 alkky1, heteroaryl or heteroarylalkyl, or CHWOCOX; wherein
W is hydrogen or C 1-4 alkyl;
X is C 1-4 alkyl, C 3-8 cycloalkyl, aryl, heteroaryl, NHY or OY; and
wherein
Y is C 1-4 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl.
12. The composition as set forth in claim 11 , wherein said compound of formula I is having:
R is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclohexylethyl, cyclohexylpropyl, benzyl, and phenylethyl;
R 1 is hydroxy;
R 2 is substituted or unsubstituted phenyl, benzyl or oxo-1,3-dihydroisobenzofuranyl, 5-methyl-[1,3]dioxol-2-one-methyl, or CHWOCOX; wherein
W is hydrogen, methyl, ethyl, n-propyl or sec-butyl;
X is methyl, ethyl, n-propyl, n-butyl, sec-butyl, tert-butyl, cyclohexyl
or OY; and wherein
Y is methyl, ethyl or n-propyl.
13. The composition as set forth in claim 11 , wherein said compound is selected from the group consisting of:
((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid 3-oxo-1,3-dihydro-isobenzofuran-1-yl ester;
2,2-dimethyl-propionic acid ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinoyloxymethyl ester;
((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid ethoxycarbonyloxymethyl ester;
((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid phenyl ester;
((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester; and
(3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester; or
a pharmaceutically acceptable salt thereof.