Pharmaceutically active compounds and methods of use
View Patent ↗The invention provides substituted pyrazole compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for the treatment of mammalian infertility.
1. A compound of the following Formula I;
wherein R 1 is optionally substituted alkyl or para substituted phenyl;
R 2 is pyridyl, quinoline or isoquinoline;
R 3 is hydrogen;
X is optionally substituted alkylene; optionally substituted alkenylene; optionally substituted alkynylene; optionally alicyclic, optionally substituted carbocyclic aryl;
Y is optionally substituted amino; optionally substituted methylene; carbonyl; or sulfonyl;
Z is an alkylamine substituted with a phenolic group on the alkyl chain; an amino acid selected from the group consisting of tyrosine, homo-tyrosine, β-homo-tyrosine, meta-tyrosine, threonine, serine, 4-hydroxymethyl-phenylalanine, 4-amino-phenylalanine, 4-acetyl-amino-phenylalanine, and 4-hydroxy-α-phenylglycine; m is 0 or 1; n is 0 or 1; and pharmaceutically acceptable salts thereof.
2. A compound of claim 1 wherein the compound is of the following Formula IA:
wherein R 1 is optionally substituted alkyl or para substituted phenyl;
R 2 is pyridyl, quinoline or isoquinoline;
R 3 is hydrogen;
X is optionally substituted alkylene; optionally substituted alkenylene; optionally substituted alkynylene; optionally alicyclic, optionally substituted carbocyclic aryl;
Y is optionally substituted amino; optionally substituted methylene; carbonyl; or sulfonyl;
Z is an alkylamine substituted with a phenolic group on the alkyl chain; an amino acid selected from the group consisting of tyrosine, homo-tyrosine, β-homo-tyrosine, meta-tyrosine, threonine, serine, 4-hydroxymethyl-phenylalanine, 4-amino-phenylalanine, 4-acetyl-amino-phenylalanine, and 4-hydroxy-α-phenylglycine; m is 0 or 1; n is 0 or 1; and pharmaceutically acceptable salts thereof.
3. A compound of claim 1 wherein R 1 is optionally substituted alkyl.
4. A compound of claim 1 wherein R 1 is arylalkyl.
5. A compound of claim 1 wherein R 1 is para substituted phenyl.
6. A compound of claim 1 wherein R 1 is phenyl substituted by alkyl in the 4-position.
7. A compound of claim 1 wherein R 2 is pyridyl.
8. A compound of claim 1 wherein R 2 is quinoline.
9. A compound of claim 1 wherein R 2 is isoquinoline.
10. A compound of claim 1 wherein X is an optionally substituted alkylene group.
11. A compound of claim 1 wherein X is an optionally substituted carbocyclic aryl.
12. A compound of claim 1 wherein X is —CH 2 CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 CH 2 —.
13. A compound of claim 1 wherein the compound is selected from the group consisting of:
N-{5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]pentanoyl}tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-5-pyridin-4-yl-1H-pyrazol-3-yl]pentanoyl}tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}-N,N-dimethyltyrosinamide;
N-3-[1-(4-tert-butylphenyl)-5-pyridin-3-yl-1H-pyrazol-3-yl]propanoyl)tyrosinamide;
N-3-[1-(4-tert-butylphenyl)-3-pyridin-5-yl-1H-pyrazol-3-yl]propanoyl)tyrosinamide;
N-[4-(1-butyl-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide;
N-{5-[1-(4-isopropylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-{6-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide;
N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-3-hydroxyphenylalaninamide;
N-[5-(1-butyl-isoquinolin-3-yl-1H-pyrazol-5-yl)pentanoyl]tyrosinamide;
N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}serinamide;
N-{6-[1-(4-iso-propylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}serinamide;
N-{6-[1-(4-iso-propylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}threonamide;
N-{5-[1-(4-isopropylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]-N-[2-4-hydroxyphenyl)ethyl]hexanamide;
N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-{6-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide;
N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-N-methyltyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}-4-(hydroxymethyl)phenylalaninamide;
4-amino-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide;
4-(acetylamino)-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide;
4-(aminocarbonyl)-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}phenylalaninamide;
N-butyl-N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}tyrosinamide;
N-{6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanoyl}threonamide;
N-[2-amino-1-(4-hydroxyphenyl)-2-oxoethyl]-6-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]hexanamide;
N-[2-amino-1-(4-hydroxyphenyl)-2-oxoethyl]-4-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]benzamide;
4-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]-N-[2-(4-hydroxyphenyl)ethyl]benzamide;
N-{3-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-{3-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;
N-{3-[1-(4-tert-butylphenyl)-3-isoquinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;
N-{3-[1-(4-tert-butylphenyl)-3-quinolin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;
N-{3-[3-isoquinolin-3-yl-1-(4-propylphenyl)-1H-pyrazol-5-yl]benzoyl}tyrosinamide;
N-{3-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;
N-{4-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-{3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]benzoyl}tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-3-pyridin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-[3-(1-butyl-3-isoquinolin-3-yl-1H-pyrazol-5-yl)benzoyl]tyrosinamide;
N-{3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}tyrosinamide;
N-acetyl-N-{3-[1-(4-tert-butylphenyl)-3-pyridin-4-yl-1H-pyrazol-5-yl]propyl}tyrosinamide;
N-[1-(aminocarbonyl)-3-(4-hydroxyphenyl)propyl]-5-[1-(4-tert-butylphenyl)-3-pyridin-2-yl-1H-pyrazol-5-yl]pentanamide;
N-{5-[1-(4-tert-butylphenyl)-3-quinolin-3-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-[5-(1-butyl-3-quinolin-6-yl-1H-pyrazol-5-yl)pentanoyl]tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-3-quinolin-6-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide;
N-{5-[1-(4-tert-butylphenyl)-3-quinolin-6-yl-1H-pyrazol-5-yl]pentanoyl}tyrosinamide; or an optical isomer, racemate or tautomer of any one thereof or a pharmaceutically acceptable salt of any one thereof.
14. A compound that is:
15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds as in claim 1 or 14 .
16. A pharmaceutical composition comprising one or more compounds as in claim 1 or 14 wherein the composition is in an oral dosage form.
17. A compound of claim 1 , wherein Z is tyrosine.
18. A compound of claim 1 , wherein Z is selected from —NHCH(CH 2 C 6 H 4 OH)C(═O)NH 2 , —NH{CH 2 C 6 H 3 —(N═C—NH—)}C(═O)NH 2 , and —NH{CH 2 C 6 H 3 —(N═N—NH—)}C(═O)NH 2 .
19. A compound of claim 1 , wherein Z is —NHCH(CH 2 C 6 H 4 OH)C(O)NH 2 .