Claims
- 1. A process for the preparation of trans keto acids of Formula I ##STR20## or a pharmaceutically acceptable salt thereof wherein: R.sub.1 is hydrogen,
- alkyl,
- alkoxy,
- O-allyl, or
- O-alkyl,
- R.sub.2 is hydrogen or
- alkoxy;
- R.sub.3 is hydrogen,
- alkyl, or
- alkoxy, or
- R.sub.2 and R.sub.3 together form
- --O--CH.sub.2 --O-- or
- --O--CH.sub.2 --CH.sub.2 --O--;
- R.sub.4 is hydrogen or
- alkoxy;
- R.sub.5 is hydrogen,
- alkoxy, or
- O-allyl;
- R.sub.6 is hydrogen,
- alkoxy, or
- O-allyl;
- R.sub.7 is hydrogen,
- alkoxy,
- O-allyl,
- --NH.sub.2,
- --NHMe,
- --NHEt,
- --N(Me).sub.2,
- --N(Et).sub.2, ##STR21## wherein n is an integer of from 4 to 5, --O(CH.sub.2).sub.m COOH, ##STR22## wherein m is an integer of from 2 to 5; R.sub.5 and R.sub.6 together can form --O--CH.sub.2 --O--;
- R.sub.6 and R.sub.7 together can form --O--CH.sub.2 --O--;
- R.sub.8 is hydrogen, or
- alkoxy;
- R.sub.9 is hydrogen,
- alkyl, or
- alkoxy;
- R.sub.10 is alkoxy or
- amino;
- R.sub.10 and R.sub.9 together can form --O--CH.sub.2 --O--;
- R.sub.11 is hydrogen,
- alkyl, or
- alkoxy; and
- R.sub.12 is hydrogen or
- alkoxy
- which are useful in treating conditions caused by elevated levels of endothelin which comprises
- 1) dissolving a .alpha.-hydroxy butenolide of Formula II ##STR23## in a solvent; 2) reacting it with one or more equivalents of a suitable base;
- 3) exposing the solution from Step 2) above to an ultraviolet light source for a sufficient time, acidifying it, and isolating a compound of Formula I above from the solution.
- 2. A process according to claim 1 wherein:
- R.sub.1 is hydrogen,
- methyl,
- methoxy, or
- O-allyl;
- R.sub.2 is hydrogen or
- methoxy;
- R.sub.3 is hydrogen,
- methyl, or
- methoxy;
- R.sub.2 and R.sub.3 form
- --O--CH.sub.2 --O-- or
- --O--CH.sub.2 --CH.sub.2 --O--;
- R.sub.4 is hydrogen or
- methoxy;
- R.sub.5 is hydrogen,
- methoxy, or
- ethoxy;
- R.sub.6 is methoxy,
- ethoxy, or
- O-allyl;
- R.sub.7 is methoxy,
- ethoxy,
- O-allyl,
- --NH.sub.2,
- --NHMe,
- --NHEt,
- --N(Me).sub.2,
- --N(Et).sub.2, ##STR24## wherein n is an integer of from 4 to 5, --O(CH.sub.2).sub.m COOH, ##STR25## wherein m is an integer of from 2 to 5; R.sub.8 is hydrogen;
- R.sub.9 is hydrogen,
- methyl, or
- methoxy;
- R.sub.10 is methoxy,
- ethoxy, or
- --N(CH.sub.3).sub.2 ;
- R.sub.10 and R.sub.9 together form --O--CH.sub.2 --O--;
- R.sub.11 is hydrogen,
- methyl, or
- methoxy; and
- R.sub.12 is hydrogen or
- methoxy.
- 3. A process according to claim 1 wherein:
- R.sub.1 is hydrogen or
- methoxy;
- R.sub.2 is methoxy;
- R.sub.3 is hydrogen; or
- R.sub.2 and R.sub.3 together form --O--CH.sub.2 --O--;
- R.sub.4 is hydrogen;
- R.sub.5 is hydrogen or
- methoxy;
- R.sub.6 is methoxy;
- R.sub.7 is methoxy; or
- R.sub.6 and R.sub.7 together form --O--CH.sub.2 --O--;
- R.sub.8 is hydrogen;
- R.sub.9 is hydrogen,
- methyl, or
- methoxy;
- R.sub.10 is methoxy or
- ethoxy;
- R.sub.11 is hydrogen or
- methoxy; or
- R.sub.12 is hydrogen.
- 4. A compound selected from:
- (E)-2-(3,5-Dimethoxy-phenyl)-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-4-(4-methoxy-3-methyl-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-2-(7-Methoxy-benzo[1,3]dioxol-5-yl)-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-(4-ethoxy-carbonylmethoxy-3,5-dimethoxy-benzyl)-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-4-Benzo[1,3]dioxol-5-yl-2-(7-methoxy-benzo[1,3]dioxol-5-yl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-3-(3-Allyloxy-4,5-dimethoxy-benzyl)-2-benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-(3-ethoxy-4,5-dimethoxy-benzyl)-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-4-(2,4-dimethoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-2-(7-Allyloxy-benzo[1,3]dioxol-5-yl)-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-4-oxo-3-(3,4,5-trimethoxy-benzyl)-4-(3,4,5-trimethoxy-phenyl)-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-(4-ethoxy-3,5-dimethoxy-benzyl)-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-3-(4-Allyloxy-3,5-dimethoxy-benzyl)-2-benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5-triethoxy-benzyl)-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-(7-methoxy-benzo[1,3]dioxol-5-ylmethyl)-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-(3,4-bis-allyloxy-5-methoxy-benzyl)-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-4-(3,4-dimethoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-(3-dimethyl-amino-benzyl)-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-[3-(3-carboxy-propoxy)-4,5-dimethoxy-benzyl]-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-(3,5-Dimethyl-phenyl)-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-2-Indan-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-4-(4-ethoxy-3-methyl-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-3-[3-(3-Carboxy-propoxy)-4,5-dimethoxy-benzyl]-2-(3,5-dimethyl-phenyl)-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-[3-(4-carboxy-butoxy)-4,5-dimethoxy-benzyl]-4-(4-methoxyphenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-[3,4-dimethoxy-5-(2-morpholin-4-yl-ethoxy)-benzyl]-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-[3-(3-dimethyl-amino-propoxy)-4,5-dimethoxy-benzyl]-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid
- (E)-2-Benzo[1,3]dioxol-5-yl-3-[3,4-dimethoxy-5-(3-sulfo-propoxy)-benzyl]-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-3-(3-Amino-benzyl)-2-benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-3-(3-methylamino-benzyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-[3-(2-dimethyl-amino-ethoxy)-4,5-dimethoxy-benzyl]-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-[3,4-dimethoxy-5-(3-morpholin-4-yl-propoxy)-benzyl]-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-2-Benzo[1,3]dioxol-5-yl-3-{3,4-dimethoxy-5-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzyl}-4-(4-methoxy-phenyl)-4-oxo-but-2-enoic acid;
- (E)-4-(4-Amino-phenyl)-2-benzo[1,3]dioxol-5-yl-4-oxo-3-(3,4,5-trimethoxy-benzyl)but-2-enoic acid; and
- (E)-2-Benzo[1,3]dioxol-5-yl-4-(4-dimethyl-amino-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid.
- 5. A compound selected from:
- (E)-2-Benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid;
- (E)-3-Benzo[1,3]dioxol-5-ylmethyl-2-(4-methoxy-phenyl)-4-oxo-4-(3,4,5-trimethoxy-phenyl)-but-2-enoic acid; and
- (E)-4-(4-Ethoxy-3-methyl-phenyl)-2-(7-methoxy-benzo[1,3]dioxol-5-yl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoic acid.
- 6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 4 in admixture with a pharmaceutically acceptable excipient, diluent, and/or carrier.
- 7. A method of inhibiting elevated levels of endothelin comprising administering to a host suffering therefore a therapeutically effective amount of a composition according to claim 4 in unit dosing form.
- 8. A method of treating vascular diseases comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claims 4 and 5 in unit dosage form.
- 9. A method of treating mild or severe congestive heart failure comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 10. A method of treating cerebral ischemia, cerebral infarction, or embolic stroke, comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 11. A method of treating cerebral vasospasm, subarachnoid hemorrhage or hemorrhagic stroke comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 12. A method of treating diabetes comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 13. A method of treating gastric ulceration and mucosal damage, ischemic bowel disease, or Chrohn's disease comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 14. A method of treating essential and malignant hypertension comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 15. A method of treating pulmonary hypertension or pulmonary hypertension after bypass surgery comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 16. A method of treating cancer selected from human meningiomas, malignant hemangioendothelioma, metastatic prostate cancer, and benign prostatic hyperplasia comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage from.
- 17. A method of treating myocardial infarction or ischemia comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 18. A method of treating acute or chronic renal failure, renal ischemia, or radiocontrast-induced nephrotoxicity comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 19. A method of treating endotoxic, septic or hemorrhagic shock comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 20. A method of treating angina comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 21. A method of treating preeclampsia comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 22. A method of treating asthma comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 23. A method of treating arrhythmias comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 24. A method of treating benign prostatic hyperplasia comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 25. A method of treating glaucoma comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 26. A method of treating male penile erectile dysfunction comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 27. A method of treating acute respiratory distress syndromes (ARDS) comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 28. A method of treating chronic obstructive pulmonary diseases comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 29. A method of treating cryptogenic fibrosing alveolitis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to claim 4 in unit dosage form.
- 30. A method of treating atherosclerosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to one of claims 4 and 5 in unit dosage form.
- 31. A method of treating restenosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to one of claims 4 and 5 in unit dosage form.
- 32. A method of treating Raynaud's phenomenon comprising administering to a host suffering therefrom a therapeutically effective amount of a compound according to one of claims 4 and 5 in unit dosage form.
Parent Case Info
This application claims priority from copending provisional application Ser. No. 60/015,269 filed Apr. 10, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US97/03959 |
3/12/1997 |
|
|
7/31/1998 |
7/31/1998 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO97/37987 |
10/16/1997 |
|
|
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
5559105 |
Bryan et al. |
Sep 1996 |
|
5691373 |
Berryman et al. |
Nov 1997 |
|