Novel carboxylic acid derivatives, their preparation and use

1 . (canceled)

2 . A method to prevent or treat a disease mediated by inhibition of binding of endothelin to endothelin-receptor in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound which is selective for inhibition of endothelin-binding to sub-type-A endothelin-receptor over sub-type-B endothelin-receptor.

3 . The method of claim 2 , wherein said endothelin is endothelin isoform-type-1.

4 . The method of claim 2 , wherein said disease is selected from hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, acute kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, and hypertension caused by ischemia or intoxication, kidney failure caused by ischemia or intoxication, Raynaud's syndrome, and asthmatic airway condition

5 . The method of claim 4 , wherein said disease is hypertension.

6 . The method of claim 2 , wherein said compound is 2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid.

7 . The method of claim 6 , wherein said compound is a racemate.

8 . The method of claim 6 , wherein said compound is an enantiomerically-pure form.

9 . The method of claim 8 , wherein said enantiomerically-pure form has superior selectivity for inhibition of said sub-type-A endothelin-receptor over sub-type-B endothelin-receptor.

10 . The method of claim 2 , further characterized by administering said compound orally or parenterally.

11 . The method of claim 10 , wherein said compound is administered orally in a daily dose of about 0.5 mg/kg to about 50 mg/kg of body weight.

12 . The method of claim 10 , wherein said compound is administered parenterally in a daily dose of about 0.1 mg/kg to about 10 mg/kg of body weight.

13 . The method of claim 10 wherein said compound is in solid or liquid pharmaceutical form

14 . The method of claim 10 , wherein said compound is orally administered with vapor or spray means through nasopharyngeal space.

15 . The method of claim 10 , wherein said compound is parenterally administered by subcutaneous, intravenous, intramuscular or intraperitoneal means.

16 . The method of claim 2 , wherein said compound is a carboxylic derivative, or salt thereof, of a compound of Formula I:

where R is formyl, tetrazole, nitrile, a COOH group or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings:

R 2 is hydrogen, hydroxyl, NH 2 , NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 , halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio;

R 3 is hydrogen, hydroxyl, NH 2 , NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 , halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, NH—O—C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio or CR 3 is linked to CR 14 as indicated above to give a 5- or 6-membered ring;

R 4 and R 5 , which can be identical or different, are phenyl or naphthyl, which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 - haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C 4 -alkylthio, amino, C 1 -C 4 -alkylamino or C 1 -C 4 -dialkylamino; or

phenyl or naphthyl, which are connected together in the ortho position via a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO 2 , NH or N-alkyl group; or C 3 -C 7 -cycloalkyl;

R 6 is hydrogen, C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or C 3 -C 8 -cycloalkyl, where each of these radicals can be substituted one or more times by: halogen, nitro, cyano, C 1 -C 4 -alkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 -alkynyloxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 8 -alkylcarbonylalkyl, C 1 -C 4 -alkylamino, di-C 1 -C 4 -alkylamino, phenyl or phenoxy which is substituted one or more times by halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio;

phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, amino, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylamino, C 1 -C 4 -dialkylamino or dioxomethylene or dioxoethylene;

a five or six-membered heteroaromatic moiety containing one to three nitrogen atoms and/or one sulfur or oxygen atom, which can carry one to four halogen atoms and/or one or two of the following radicals: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possible for the phenyl radicals in turn to carry one to five halogen atoms and/or one to three of the following radicals: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and/or C 1 -C 4 -alkylthio;

X is CR 14 where R 14 is hydrogen or C 1 -C 5 -alkyl;

Y is sulfur or oxygen or a single bond; and

Z is sulfur, oxygen, —SO— or —SO 2 —.

17 . The method of claim 16 , wherein X is CR 14 and R 14 is hydrogen.

18 . The method of claim 17 , wherein R is CO 2 H.

19 . The method of claim 17 , wherein in R 2 and R 3 each is methoxy.

20 . The method of claim 17 , wherein in R 4 and R 5 each is phenyl.

21 . The method of claim 17 , wherein in R 6 is C 1 -C 8 -alkyl.

22 . The method of claim 17 , wherein in Y is oxygen.

23 . The method of claim 17 , wherein in Z is oxygen or sulfur.

24 . The method of claim 23 , wherein in Z is oxygen.

25 . The method of claim 16 , wherein

X is CH;

Y is oxygen;

Z is oxygen;

R is CO 2 H;

R 2 is methoxy;

R 3 is methoxy;

R 4 is phenyl;

R 5 is phenyl; and

R 6 is methyl, ethyl or iso-propyl.

26 . The method of claim 16 , wherein R is tetrazole, nitrile or a group

where R 1 has the following meanings:

a) hydrogen;

b) succinylimidoxy;

c) a five-membered heteroaromatic ring linked by a nitrogen atom, selected from the group consisting of: pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which ring can carry one or two halogen atoms and or one or two of the following radicals: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio;

d) a radical

where m is 0 or 1 and R 7 and R 8 , which can be identical or different, have the following meanings:

hydrogen,

C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, where these alkyl, cycloalkyl, alkenyl and alkynyl groups can each carry one to five halogen atoms and/or one or two of the following groups: C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -haloalkoxy, C 3 -C 6 -alkenyloxy, C 3 -C 6 - alkenylthio, C 3 -C 6 -alkynyloxy or C 3 -C 6 -alkynylthio,

C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 6 -alkenylcarbonyl, C 3 -C 6 -alkynylcarbonyl, C 3 - C 6 -alkenyloxycarbonyl or C 3 -C 6 -alkynyloxycarbonyl,

phenyl, which can be substituted one or more times by halogen, nitro, cyano, C 3 -C 6 -alkenylcarbonyl, C 3 -C 6 -alkynylcarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio,

di-C 1 -C 4 -alkylamino, or

R 7 and R 8 together form a C 4 -C 7 -alkylene chain which can be substituted by C 1 -C 4 -alkyl, and may contain a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen, or R 7 and R 8 together form a CH 2 —CH═CH—CH 2 or CH═CH-(CH 2 ) 3 chain;

e) a radical

where k is 0, 1 and 2, p is 1, 2, 3 and 4, and R 9 is C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl or phenyl, which can be substituted one or more times by halogen, nitro, cyano, C 3 -C 6 -alkenylcarbonyl, C 3 -C 6 -alkynylcarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio;

f) a radical OR 10 , where R 10 is

hydrogen, the cation of an alkali metal or an alkaline earth metal or an environmentally compatible organic ammonium ion;

C 3 -C 8 -cycloalkyl which may carry one to three C 1 -C 4 -alkyl groups;

C 1 -C 8 -alkyl which may carry one to five halogen atoms and/or one of the following radicals: C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, cyano, C 1 -C 4 -alkylcarbonyl, C 3 -C 8 -cycloalkyl, C 1 -C 4 -alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, where the aromatic radicals in turn may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and/or C 1 -C 4 -alkylthio;

C 1 -C 8 -alkyl which may carry one to five halogen atoms and which carries one of the following radicals: a 5-membered heteroaromatic ring containing one to three nitrogen atoms or a nitrogen atom and an oxygen or sulfur atom, which may carry one to four halogen atoms and/or one or two of the following radicals: nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, phenyl, C 1 -C 4 -haloalkoxy and/or C 1 -C 4 -alkylthio;

C 2 -C 6 -alkyl which carries one of the following radicals in position 2: C 1 -C 4 -alkoxyimino, C 3 -C 6 -alkynyloxyimino, C 3 -C 6 -haloalkenyloxyimino or benzyloxyimino;

C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl which may carry one to five halogen atoms;

phenyl which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and/or C 1 -C 4 -alkylthio;

a 5-membered heteroaromatic ring which is bonded via a nitrogen atom and containing one to three nitrogen atoms, which may carry one or two halogen atoms and or one or two of the following radicals: C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, phenyl, C 1 -C 4 -haloalkoxy and/or C 1 -C 4 -alkylthio;

a radical

where R 11 and R 2 , which may be identical or different are: C 1 -C 8 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, it being possible for these radicals to carry a C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio and/or phenyl which may carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and/or C 1 -C 4 -alkylthio; phenyl which may carry one or more of the following radicals: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio; or R 11 and R 12 together form a C 3 -C 12 -alkylene chain which may carry one to three C 1 -C 4 -alkyl groups and which may contain a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur;

g) a radical

where R 13 is C 1 -C 4 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, it being possible for these radicals to carry a C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio and/or a phenyl radical, or

phenyl which may carry one or more of the following radicals: halogen, nitro, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy or C 1 -C 4 -alkylthio.