Phenylketone carboxylate compounds and pharmaceutical uses thereof
Phenylketone carboxylate compounds of Formula I, wherein n=2-6; R═C(0); —OC(O)— or —CH(OH)—; A is (CH2)mCOOH, W(CH2)mCOOH or YCH(COOH)((CH2)pCH3) when B is Ft B is (CH2)mCOOH, W(CH2)mCOOH or YCH(COOH)((CH2)pCH3) when A is Ft or A and B form a 5-7 membered cycloalkyl substituted with COOFt W=0, S or NFt Y=0,S,NH or CH2; m=0-2; p=1-7; have been prepared. These compounds and their pharmaceutically acceptable salts have beneficial therapeutic effects to prevent or treat a condition related to (l) blood disorders, (ii) inflammation related diseases, (iii) renal disorders and/or renal disorders complications, or (iv) fibrosis-related organ dysfunction.
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
wherein:
n is 2-6;
R is —C(O)—,—OC(O)—, or —CH(OH)—;
A is
when B is H;
B is
when A is H;
where:
Y is O, S, NH, or CH 2 ; and
p is 3-7.
2. The compound of claim 1 , wherein R is —C(O)—.
3. The compound of claim 1 , wherein the salt is a base addition salt.
4. The compound of claim 3 , wherein the base addition salt comprises a metal counterion selected from sodium, potassium, magnesium, calcium and lithium.
5. The compound of claim 4 , wherein the metal counterion is calcium.
6. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is any one of Compounds I, III-XIV and XVI:
Compound No.
Structure
I
III
IV
V
VI
VII
VIII
IX
X
XI
XII
XIII
XIV
XVI
7. The compound of claim 6 , wherein the compound is Compound I, III or X.
8. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier.
9. A method for ameliorating: (i) anemia induced by chemotherapy, (ii) neutropenia induced by chemotherapy, (iii) a renal disorder or a renal disorder complication, or (iv) a fibrosis-related organ dysfunction wherein said method comprises administering, to a patient in need of such treatment, a compound of claim 1 .
10. The method of claim 9 , wherein the renal disorder is a nephropathy.
11. The method of claim 9 , used for nephroprotection of a subject in need thereof against toxic effects arising from a treatment with a chemotherapeutic agent.
12. The method of claim 9 , used for improving clearance of creatinine or clearance of uric acid.
13. The method of claim 9 , wherein the fibrosis-related organ dysfunction is a fibrosis-related kidney dysfunction, a fibrosis-related heart dysfunction, a fibrosis-related lung dysfunction, a fibrosis-related liver dysfunction, nephropathy or a fibrosis-related brain dysfunction.
14. A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:
wherein:
n is 2-6;
R is —C(O)—, —OC(O)—, or —CH(OH)—;
A is
when B is H;
B is
when A is H; or
A and B are covalently bonded to form a six (6) or seven (7)-membered cycloalkyl substituted with COOH;
where:
Y is O, S, NH, or CH 2 ; and
p is 3-7.
15. The compound of claim 14 , wherein R is —C(O)—.
16. The compound of claim 14 , wherein the salt is a base addition salt.
17. The compound of claim 16 , wherein the base addition salt comprises a metal counterion selected from sodium, potassium, magnesium, calcium, and lithium.
18. The compound of claim 17 , wherein the metal counterion is calcium.
19. A pharmaceutical composition comprising a compound according to claim 14 , and a pharmaceutically acceptable carrier.
20. A method for ameliorating: (i) anemia induced by chemotherapy, (ii) neutropenia induced by chemotherapy, (iii) a renal disorder or a renal disorder complication, or (iv) a fibrosis-related organ dysfunction wherein said method comprises administering, to a patient in need of such treatment, a compound of claim 14 .
21. The method of claim 20 , wherein the renal disorder is a nephropathy.
22. The method of claim 20 , used for nephroprotection of a subject in need thereof against toxic effects arising from a treatment with a chemotherapeutic agent.
23. The method of claim 20 , used for improving clearance of creatinine or clearance of uric acid.
24. The method of claim 20 , wherein the fibrosis-related organ dysfunction is a fibrosis-related kidney dysfunction, a fibrosis-related heart dysfunction, a fibrosis-related lung dysfunction, a fibrosis-related liver dysfunction, nephropathy or a fibrosis-related brain dysfunction.