Thrombopoietin mimetics
View Patent ↗Invented are non-peptide TPO mimetics. Also invented are novel processes and intermediates used in the preparation of the presently invented compounds. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a selected hydroxy-1-azobenzene derivative.
1. A process for preparing a compound of the Formula:
by reaction of a compound of the formula or a salt thereof:
or a protected form thereof with a compound of Formula (VIII) or tautomeric equivalent (IX)
wherein
either:
R is a phenyl or pyridinyl ring substituted by one or more of the following: —(CH 2 ) g C(O)OR 8 , tetrazole, phosphonic acid, sulfonic acid, hydroxy, methyl, fluoro, NHSO 2 CF 3 , and C(O)NHSO 2 CH 3 , and R 1 is hydrogen,
where g is 0 to 6 and R 8 is hydrogen or alkyl,
or:
R is hydrogen; and R 1 is a phenyl or pyridinyl ring substituted by one or more of the following: —(CH 2 ) g C(O)OR 8 , tetrazole, phosphonic acid, sulfonic acid, hydroxy, methyl, fluoro, NHSO 2 CF 3 , and C(O)NHSO 2 CH 3 ,
where g is 0 to 6 and R 8 is hydrogen or alkyl,
and in either case:
R 2 and R 3 are independently selected from: hydrogen, C 1-6 alkyl and halogen;
R 15 is selected from the group consisting: of C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl and halogen;
Y is phenyl that is optionally substituted with from one to five substituents selected from the group consisting of: alkyl, substituted alkyl, trifluoromethyl and halogen; and m is 0
optionally followed by salt formation.
2. A process for preparing a compound of the Formula:
by reaction of a compound of the formula or a salt thereof:
or a protected form thereof with a compound of Formula (VIII) or tautomeric equivalent (IX)
wherein
either:
R is a phenyl or pyridinyl ring substituted by one or more of the following: —C(O)OH, tetrazole, phosphonic acid, sulfonic acid, hydroxy, methyl, fluoro, NHSO 2 CF 3 , and C(O)NHSO 2 CH 3 , and
R 1 is hydrogen,
or:
R is hydrogen; and
R 1 is a phenyl or pyridinyl ring substituted by one or more of the following: —C(O)OH, tetrazole, phosphonic acid, sulfonic acid, hydroxy, methyl, fluoro, NHSO 2 CF 3 , and C(O)NHSO 2 CH 3 ,
and in either case:
R 2 and R 3 are independently selected from: hydrogen, C 1-6 alkyl and halogen;
R 15 is selected from the group consisting: of C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl and halogen;
Y is phenyl that is optionally substituted with from one to five substituents selected from the group consisting of: alkyl, substituted alkyl, trifluoromethyl and halogen; and m is 0
optionally followed by salt formation.
3. The compound
3′-Amino-2′-hydroxybiphenyl-3-carboxylic acid.
4. A process for preparing the compound 3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid,
which process comprises converting the compound 3′-Amino-2′-hydroxybiphenyl-3-carboxylic acid into 3′-{N′-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2′-hydroxybiphenyl-3-carboxylic acid.