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 compound represented by the following Formula (I):
wherein:
R, R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, —(CH 2 ) p OR 4 , —C(O)OR 4 , formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, —S(O) n R 4 , cycloalkyl, —NR 5 R 6 , protected —OH, —CONR 5 R 6 , phosphonic acid, sulfonic acid, phosphinic acid, —SO 2 NR 5 R 6 , a heterocyclic methylene substituent as represented by Formula (III),
and
a substituent as represented by Formula (VII),
where,
p is 0-6,
n is 0-2,
W and Z are each independently selected from O, S and NR 16 , where R 16 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl,
V and X are each independently selected from O, S and NR 16 , where R 16 is selected from:
hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl,
R 4 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl,
R 5 and R 6 are each independently selected from hydrogen, alkyl, substituted alkyl, C 3-6 cycloalkyl, and aryl,
or R 5 and R 6 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
T is selected from O, S and NR 16 , where R 16 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl,
P is selected from OR 4 , SR 4 , NR 5 R 6 , and R 4 , where R 4 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl,
R 25 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl, and
R 30 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl;
R 15 is selected from the group consisting of alkyl, C 1 -C 12 aryl, hydroxy, alkoxy, substituted alkyl, substituted C 1 -C 12 aryl and halogen;
m is 0-6; and
Y is a cyclic or polycyclic, unsaturated or saturated, non-aromatic ring containing from 3 to 16 carbon atoms and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, —C(O)OR 4 , —C(O)NR 10 R 11 , —S(O) 2 NR 10 R 11 , —S(O) n R 4 and protected —OH,
where n is 0-2,
R 4 is hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl, and
R 10 and R 11 are independently hydrogen, cycloalkyl, C 1 -C 12 aryl, substituted cycloalkyl, substituted C 1 -C 12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, —C(O)OR 4 , —S(O) n R 4 , —C(O)NR 4 R 4 , —S(O) 2 NR 4 R 4 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected —OH,
or R 10 and R 11 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
where R 4 is as described above and n is 0-2;
and pharmaceutically acceptable salts, and esters thereof;
provided that at least one of R, R 1 , R 2 and R 3 is a substituted aryl group or a heterocyclic methylene substituent as represented in Formula (III) or a substituent as represented in Formula (VII).
2. A compound of claim 1 represented by the following Formula (II):
wherein:
R, R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, —(CH 2 ) p OR 4 , —C(O)OR 4 , formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, —S(O) n R 4 , cycloalkyl, —NR 5 R 6 , protected —OH, —CONR 5 R 6 , phosphonic acid, sulfonic acid, phosphinic acid, —SO 2 NR 5 R 6 , a heterocyclic methylene substituent as represented by Formula (III),
and
a substituent as represented by Formula (VII),
where,
p is 0-6,
n is 0-2,
W and Z are each independently selected from O, S and NR 16 , where R 16 is selected from:
hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl,
V and X are each independently selected from O, S and NR 16 , where R 16 is selected from:
hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl,
R 4 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl,
R 5 and R 6 are each independently selected from hydrogen, alkyl, substituted alkyl, C 3-6 cycloalkyl, and aryl,
or R 5 and R 6 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
T is selected from O, S and NR 16 , where R 16 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl,
P is selected from OR 4 , SR 4 , NR 5 R 6 , and R 4 , where R 4 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl,
R 25 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl, and
R 30 is selected from: hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl;
R 15 is selected from the group consisting of alkyl, C 1 -C 12 aryl, hydroxy, alkoxy, substituted alkyl, substituted C 1 -C 12 aryl and halogen;
m is 0-6; and
Y is a cyclic or polycyclic, unsaturated or saturated, non-aromatic ring containing from 5 to 14 carbon atoms and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, —C(O)OR 4 , —C(O)NR 10 R 11 , —S(O) 2 NR 10 R 11 , —S(O) n R 4 and protected —OH,
where n is 0-2,
R 4 is hydrogen, alkyl, cycloalkyl, C 1 -C 12 aryl, substituted alkyl, substituted cycloalkyl and substituted C 1 -C 12 aryl, and
R 10 and R 11 are independently hydrogen, cycloalkyl, C 1 -C 12 aryl, substituted cycloalkyl, substituted C 1 -C 12 aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, —C(O)OR 4 , —S(O) n R 4 , —C(O)NR 4 R 4 , —S(O) 2 NR 4 R 4 , nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected —OH,
or R 10 and R 11 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen,
where R 4 is as described above and n is 0-2;
and pharmaceutically acceptable salts, and esters thereof;
provided that at least one of R, R 1 , R 2 and R 3 is a substituted aryl group or a heterocyclic methylene substituent as represented in Formula (III) or a substituent as represented in Formula (VII).
3. A compound represented by Formula (II), as defined in claim 2 , wherein:
R is a substituted aryl; and R 1 is hydrogen;
R is hydrogen; and R 1 is a substituted aryl;
R is a hydrogen; and R 1 is a substituent as represented in Formula (III); or
R is a hydrogen; and R 1 is a substituent as represented in Formula (VII);
and in each of the above cases:
R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, cycloalkyl, phosphonic acid, phosphinic acid and sulfonic acid;
R 15 is selected from the group consisting of alkyl, substituted alkyl, C 1 -C 12 aryl, alkoxy and halogen;
m is 0-4; and
Y is selected from, cyclohexyl, cyclopentyl and cycloheptyl, where the cyclohexyl, cyclopentyl and cycloheptyl are optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, substituted C 1 -C 12 aryl, alkoxy and halogen;
and pharmaceutically acceptable salts, and esters thereof.
4. A compound represented by Formula (II), as defined in claim 2 , wherein:
R is a substituted C 1 -C 12 aryl; and R 1 is hydrogen;
R is a hydrogen; and R 1 is a substituent as represented in Formula (III); or
R is a hydrogen; and R 1 is a substituent as represented in Formula (VII);
and in each of the above cases:
R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, nitro, cyano, halogen, substituted alkyl and cycloalkyl;
R 15 is selected from the group consisting of alkyl, substituted alkyl, C 1 -C 12 aryl, alkoxy and halogen;
m is 0-2; and
Y is selected from,
cyclohexyl, cyclopentyl and cycloheptyl, where the cyclohexyl, cyclopentyl and cycloheptyl are optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, substituted C 1 -C 12 aryl, alkoxy and halogen;
and additionally, when R is a hydrogen; and R 1 is a substituent as represented in Formula (VII);
R 25 and R 30 are each selected from: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, substituted C 1-6 alkyl and cycloalkyl;
and additionally, when R is a hydrogen; and R 1 is a substituent as represented in Formula (VII); and when R is a hydrogen; and R 1 is a substituent as represented in Formula (III);
R 4 is selected from: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, substituted C 1-6 alkyl and cycloalkyl;
and pharmaceutically acceptable salts, and esters thereof.
5. A compound represented by Formula (II), as defined in claim 2 , wherein:
R is a substituted phenyl ring and R 1 is hydrogen; or
R is a hydrogen; and R 1 is a substituent as represented in Formula (III);
and in either of the above cases:
R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, substituted alkyl and halogen;
R 15 is selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, C 1 -C 12 aryl and halogen;
m is 0; and
Y is selected from, cyclohexyl, cyclopentyl and cycloheptyl, where cyclohexyl, cyclopentyl and cycloheptyl are optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, substituted C 1 -C 12 aryl, alkoxy and halogen;
and additionally, when R is a hydrogen; and R 1 is a substituent as represented in Formula (III);
R 4 is selected from: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, substituted C 1-6 alkyl and cycloalkyl;
and pharmaceutically acceptable salts, and esters thereof.
6. A compound of claim 1 selected from:
3′-(1-Cyclohexyl-5-hydroxy-3-methyl-1H-pyrazol-4-ylazo)-2′-hydroxy-biphenyl-3- carboxylic acid;
3′-[1-(4-tert-Butyl-cyclohexyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylazo]-2′-hydroxy-biphenyl-3-carboxylic acid;
3′-[1-(3,4-Dimethyl-cyclohexyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylazo]-2′-hydroxy-biphenyl-3-carboxylic acid;
3′-[1-(3,4-Dichloro-cyclohexyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylazo]-2′-hydroxy-biphenyl-3- carboxylic acid;
5-[4-(1-Cyclohexyl-5-hydroxy-3-methyl-1H-pyrazol-4-ylazo)-3-hydroxy-benzylidene]-thiazolidine-2,4-dione;
5-{4-[1-(4-tert-Butyl-cyclohexyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylazo]-3-hydroxy-benzylidene}-thiazolidine-2,4-dione;
5-{4-[1-(3,4-Dimethyl-cyclohexyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylazo]-3-hydroxy-benzylidene}-thiazolidine-2,4-dione;
5-{4-[1-(3,4-Dichloro-cyclohexyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylazo]-3-hydroxy-benzylidene}-thiazolidine-2,4-dione;
(E)-3-{4-[1-(4-tert-butylcyclohexyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-ylazo]-3-hydroxyphenyl}-2- methylacrylic acid;
(E)-3-(4-{N′-3-Ethylcyclopentyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]-hydrazino}-3-hydrophenyl-2- methylacrylic acid; and
(E)-3-[4-(N′-{1-[3-(1,1-Dimethylpropyl)-cyclopentyl]-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene}-hydrazino)-3-hydroxyphenyl]-2-methylacrylic acid;
and pharmaceutically acceptable salts, and esters thereof.
7. A method of treating of thrombocytopenia in a mammal, including a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), as described in claim 1 .
8. A method as claimed in claim 7 , wherein the mammal is a human.
9. A pharmaceutical composition for use in enhancing platelet production which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.
10. A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of the Formula (I) as described in claim 1 and pharmaceutically acceptable salts, hydrates, solvates and esters thereof which process comprises bringing the compound of the Formula (I) into association with the pharmaceutically acceptable carrier or diluent.
11. A process for preparing a compound of Formula (II) by reaction of a compound of Formula (XX)
or a protected form thereof with a compound of Formula (XXI) or tautomeric equivalent (XXII)
wherein
R is a substituted aryl; and R 1 is hydrogen;
R is hydrogen; and R 1 is a substituted aryl;
R is a hydrogen; and R 1 is a substituent as represented in Formula (III); or
R is a hydrogen; and R 1 is a substituent as represented in Formula (VII);
and in each of the above cases:
R 2 and R 3 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, nitro, cyano, halogen, aryl,.substituted aryl, substituted alkyl, cycloalkyl, phosphonic acid, phosphinic acid and sulfonic acid;
R 15 is selected from the group consisting of alkyl, substituted alkyl, C 1 -C 12 aryl, alkoxy and halogen;
m is 0-4; and
Y is selected from,
cyclohexyl, cyclopentyl and cycloheptyl, where the cyclohexyl, cyclopentyl and cycloheptyl are optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C 1 -C 12 aryl, substituted C 1 -C 12 aryl, alkoxy and halogen;
followed if necessary or desired by salt formation.
12. A method of claim 7 wherein said thrombocytopenia is due to myelosuppression caused by chemotherapy or radiation therapy.
13. A method of claim 7 wherein said thrombocytopenia is due to an organ transplant.
14. A method of claim 7 wherein said thrombocytopenia is due to bone marrow, stem cell, or liver transplant.
15. A method of claim 7 wherein said thrombocytopenia is due to idiopathic thrombocytopenia purpura (ITP).
16. A method of claim 7 wherein said thrombocytopenia is due to myelodysplastic syndromes (MDS), aplastic anemia or leukemia.
17. A method of claim 7 wherein said thrombocytopenia is due to viral, fungal, microbial or parasitic infection.
18. A method of claim 7 wherein said thrombocytopenia is due to liver dysfunction.
19. A method of claim 7 wherein said thrombocytopenia is due to surgical procedures.
20. A method of claim 7 wherein said thrombocytopenia is due to treatment with antiviral or antibiotic agents.
21. A compound of claim 6 selected from:
3′-[N′-(1-cyclohexyl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene)-hydrazino]-2′-hydroxy-biphenyl-3- carboxylic acid;
or pharmaceutically acceptable salt, hydrate, solvate and ester thereof.
22. A compound of claim 1 selected from:
3′-(1-Cyclohexyl-5-hydroxy-3-methyl-1H-pyrazol-4-ylazo)-2′-hydroxy-biphenyl-3- carboxylic acid;
5-{4-[1-(4-tert-Butyl-cyclohexyl)-5-hydroxy-3-methyl-1H-pyrazol-4-ylazo]-3-hydroxy-benzylidene}-thiazolidine-2,4-dione;
(E)-3-{4-[1-(4-tert-butylcyclohexyl)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-ylazo]-3-hydroxyphenyl}-2- methylacrylic acid;
(E)-3-(4-{N′-3-Ethylcyclopentyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]-hydrazino}-3-hydrophenyl-2-methylacrylic acid; and
(E)-3-[4-(N′-{1-[3-(1,1-Dimethylpropyl)-cyclopentyl]-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene}-hydrazino)-3-hydroxyphenyl]-2-methylacrylic acid;
and pharmaceutically acceptable salts, and esters thereof.