CN1216045A - N-(2,1,3-benzothia (oxa) diazolyl)-sulphonamides having endothelin receptor antagonistic effect - Google Patents
N-(2,1,3-benzothia (oxa) diazolyl)-sulphonamides having endothelin receptor antagonistic effect Download PDFInfo
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- CN1216045A CN1216045A CN97193775A CN97193775A CN1216045A CN 1216045 A CN1216045 A CN 1216045A CN 97193775 A CN97193775 A CN 97193775A CN 97193775 A CN97193775 A CN 97193775A CN 1216045 A CN1216045 A CN 1216045A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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Abstract
The invention concerns compounds of formula (I) and their salts, in which: -A=B-C=D- can be a -CH=CH-CH=CH group in which 1 or 2 CH can also be replaced by N; Het means an unsubstituted or substituted mono- or binuclear saturated, unsaturated or aromatic heterocycle having between 1 and 4 N, O and/or S atoms; R<1>, R<2>, R<3>, each being absent independently of one another, mean H or different substituents; and X means O or S. These compounds and their salts display endothelin receptor antagonistic properties.
Description
The present invention relates to the compound and the salt thereof of formula I:
I wherein
-A=B-C=D-is wherein 1 or 2 the also available N alternate of CH-CH=CH-CH=CH-bases,
Het has the monokaryon of 1～4 N, O and/or S atom or double-core is saturated, unsaturated or the heterocycle of aromatics, and it can be unsubstituted or with-Z-R
6Replace,
R
1, R
2And R
3Do not exist with being mutually independent or be H, Hal, A, CF
3, NO
2, NR
4R
5, CN, COOR
4Or NHCOR
4,
R
4And R
5Be H or A with being mutually independent, or also be-CH together
2-(CH
2)-CH
2-,
R
6For unsubstituted or single-, two-or three-R
7-, R
8-and/or R
9Phenyl, diazosulfide-5-base or the Ben Bing oxadiazole-5-base of-replacement,
R
7, R
8And R
9Be with being mutually independent A, O-A, CN, COOH, COOA, Hal, formyl radical ,-CO-A, diazosulfide-5-base or Ben Bing oxadiazole-5-base, R
7And R
8Also be together-O-(CH
2)
m-O-,
A is the alkyl with 1～6 carbon atom,
X is O or S,
Z is-CO-,-CONH-,-CO-(CH
2)
n-,-CH=CH-,-(CH
2)
n-,-CONHCO-,-NHCONH-,-NHCOO-,-O-CONH-,-CO-O-or-O-CO-,
Hal is F, Cl, Br or I,
M be 1 or 2 and
N is 1,2 or 3.
Similar compounds for example is disclosed among EP 0 558 258 A1, EP 0 569 193 A1 and the WO 94/27979.
The objective of the invention is to seek the novel cpd with useful performance, particularly those can be used for the compound of drug manufacture.
The compound and its esters that have been found that the formula I have very useful pharmacological properties and good tolerability.Particularly they show endothelin receptor antagonism performance, therefore can be used for the treatment of some diseases, as hypertension, cardiac insufficiency, coronary heart disease, kidney portion, brain and myocardial ischaemia, renal insufficiency, cerebral infarction, subarachnoid hemorrhage, arteriosclerosis, pulmonary hypertension, inflammation, asthma, hyperplasia of prostate, endotoxin shock and the complication after taking some materials such as ciclosporin, and other and endothelin activity diseases associated.
This compound especially shows the inferior acceptor ET of endothelin
AAnd ET
BHigh-affinity.These act in the external or body of available routine methods determines, for example P.D.Stein etc. the 329th～331 page of " medical chemistry magazine " 1994 the 37th volume and E.Ohlstein etc. 1994 " institute of NAS newspaper " the 91st roll up the 8052nd～8056 page described.
The proper method of determining hypotensive effect for example by M.K.Bazil etc. in explanations on 1991 " testing laboratory animal " the 20th volume application number 1016 such as 1993 " cardiovascular pharmacology magazine " the 22nd the 897th～905 page of volume and J.Lange.
The compound of formula I can be used as the pharmaceutical active compounds in people's medicine and the veterinary drug, is used in particular for preventing and/or treating heart, circulation and vascular disease, particularly hypertension and cardiac insufficiency.
The present invention relates to the compound and its esters of formula I, and, it is characterized in that according to the formula I compound of claim 1 and the preparation method of its esters:
(a) will be wherein-A=B-C=D-, R
1, R
2, R
3With the implication of X formula II as claimed in claim 1 compound
II is that the OH base of Cl, Br, I or free or reactive functional modification and the implication formula III as claimed in claim 1 compound of Het react with E wherein
Het-SO
2-E III, or
(b) X is the formula I compound of S in order to prepare wherein
Will be wherein-A=B-C=D-, Het, R
1, R
2And R
3Implication formula IV as claimed in claim 1 compound
The reactive derivatives reaction of IV and thionyl chloride or this compound, or
(c) X is the formula I compound of O in order to prepare wherein
Will be wherein-A=B-C=D-, Het, R
1, R
2And R
3Implication formula V as claimed in claim 1 compound reduction
V and/or it is characterized in that with the one or more radicals R in the formula I compound
1, R
2And/or R
3Be converted into one or more radicals R by the following method
1, R
2And/or R
3:
ⅰ) nitroreduction is become amino,
ⅱ) bromine substituent is substituted with cyano group,
Be carboxyl ⅲ) with cyan-hydrolysis,
ⅳ) with carboxyl esterification,
ⅴ) amino is converted into alkylated amines by reductive amination
And/or the alkali or the acid of formula I is converted into one of its salt.
Except as otherwise noted, above and below the group of indication or parameter-A=B-C=D-, Het, R
1～R
9, A, X, Z, Hal, m and n implication described suc as formula I～V.
In following formula, A has 1～6 carbon atom, is preferably 1,2,3 or 4 carbon atom.A is preferably methyl, also is preferably ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl, and amyl group, 1-, 2-or 3-methyl butyl, 1,1-, 1,2-or 2,2-dimethyl propyl, 1-ethyl propyl, hexyl, 1-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethyl-butyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methyl-propyl, 1,1,2-or 1,2,2-trimethylammonium propyl group.
Hal is preferably F, Cl or Br, but also can be I.
Het is unsubstituted, and is preferred-Z-R
6-replace, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrryl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidyl also are preferably 1,2,3-triazole-1-,-4-or-the 5-base, 1,2,4-triazole-1-,-3-or-the 5-base, 1-or 5-tetrazyl, 1,2,3-oxadiazole-4-or-the 5-base, 1,2,4-oxadiazole-3-or-the 5-base, 1,3,4-thiadiazoles-2-or-the 5-base, 1,2,4-thiadiazoles-3-or-the 5-base, 1,2,3-thiadiazoles-4-or-the 5-base, 2-, 3-, 4-, 5-or 6-2H-thiapyran base, 2-, 3-or 4-H-thiapyran base, 3-or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6-or 7-benzofuryl, 2-, 3-, 4-, 5-, 6-or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl, 1-, 2-, 4-or 5-benzimidazolyl-, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzoisoxazole base, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazole base, 4-, 5-, 6-or 7-benzo-2,1,3-oxadiazole base, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolyl, 1,3-benzo dioxole-4-,-5-,-6-or-the 7-base, 1,4-benzodioxan-5-,-6-or-the 7-base.These heterocyclic groups are partly or entirely hydrogenation also.
Therefore Het for example also can be 2,3-dihydro-2-,-3-,-4-or-the 5-furyl, 2,5-dihydro-2-,-3-,-4-or-the 5-furyl, tetrahydrochysene-2-or-the 3-furyl, 1,3-dioxolane-4-base, tetrahydrochysene-2-or 3-thienyl, 2,3-dihydro-1-,-2-,-3-,-4-or-the 5-pyrryl, 2,5-dihydro-1-,-2-,-3-,-4-or-the 5-pyrryl, 1-, 2-or 3-pyrrolidyl, tetrahydrochysene-1-,-2-or-the 4-imidazolyl, 2,3-dihydro-1-,-2-,-3-,-4-or-the 5-pyrazolyl, tetrahydrochysene-1-,-3-or-the 4-pyrazolyl, 1,4-dihydro-1-,-2-,-3-or-the 4-pyridyl, 1,2,3,4-tetrahydrochysene 1-,-2-,-3-,-4-,-5-or-the 6-pyridyl, 1-, 2-, 3-or 4-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydrochysene-2-,-3-or-the 4-pyranyl, 1, the 4-alkyl dioxin, 1,3-diox-2-,-4-or-the 5-base, six hydrogen-1-,-3-or-the 4-pyridazinyl, six hydrogen-1-,-2-,-4-or-the 5-pyrimidyl, 1-, 2-or 3-piperazinyl, 1,2,3,4-tetrahydrochysene-1-,-2-,-3-,-4-,-5-,-6-,-7-or-the 8-quinolyl, 1,2,3,4-tetrahydrochysene-1-,-2-,-3-,-4-,-5-,-6-,-7-or-the 8-isoquinolyl.
Group-A=B-C=D-is preferably-CH=CH-CH=N-, also can be-CH=N-CH=CH-or-CH=N-CH=N-, be preferably especially-CH=CH-CH=CH-.
Radicals R
1, R
2And R
3Be preferably H, A (CH particularly with being mutually independent
3), Hal (being in particular chlorine or bromine), also be preferably NO
2Or CF
3
R
4And R
5Be preferably H, methyl with being mutually independent, can also be preferably for example ethyl, propyl group, sec.-propyl, butyl, also can be together-CH
2-CH
2-CH
2-,-CH
2-(CH
2)
2-CH
2Or-CH
2-(CH
2)
3-CH
2-.
R
6For unsubstituted, be preferably mono-substituted phenyl, specifically be preferably phenyl, adjacent-, between-or right-tolyl, adjacent-, between-or right-ethylphenyl, adjacent-, between-or right-propyl group phenyl, adjacent-, between-or right-isopropyl phenyl, adjacent-, between-or right-tert-butyl-phenyl, adjacent-, between-or right-cyano-phenyl, adjacent-, between-or right-p-methoxy-phenyl, adjacent-, between-or right-ethoxyl phenenyl, adjacent-, between-or right-carboxyl phenyl, adjacent-, between-or right-methoxycarbonyl phenyl, adjacent-, between-or right-carbethoxy phenyl, adjacent-, between-or right-fluoro phenyl, adjacent-, between-or right-bromo phenyl, adjacent-, between-or right-chlorophenyl, adjacent-, between-or right-formylphenyl, adjacent-, between-or right-acetyl phenyl, adjacent-, between-or right-propionyl phenyl, adjacent-, between-or right-butyryl phenyl, adjacent-, between-or right-valeryl phenyl, also be preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-phenyl-difluoride base, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dichloro-phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-or 3,5-dibromo-benzene base, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, the 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl-or 3-methyl-4-chloro-phenyl-, 2-bromo-3-methyl-, 2-bromo-4-methyl, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5-methyl-or 3-methyl-4-bromophenyl, 2,4-or 2, the 5-dinitrophenyl, 2,5-or 3,4-Dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6-or 3,4,5-trichlorophenyl, 2,4,6-three-tert-butyl-phenyl, 2, the 5-3,5-dimethylphenyl, to iodine substituted phenyl, 4-fluoro-3-chloro-phenyl-, 4-fluoro-3,5-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-two fluoro-4-bromophenyls, 2,4-two chloro-5-aminomethyl phenyls, 3-bromo-6-p-methoxy-phenyl, 3-chloro-6-p-methoxy-phenyl, 2-methoxyl group-5-aminomethyl phenyl, 2,4,6-triisopropyl phenyl, 1,3-benzo dioxole-5-base, 1,4-benzodioxan-6-base, diazosulfide-5-base or Ben Bing oxadiazole-5-base.
R
7, R
8And R
9Be preferably methyl independently of one another; also be preferably for example ethyl, propyl group, sec.-propyl, butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, CN, carboxyl, methoxycarbonyl, ethoxy carbonyl, fluorine, chlorine, formyl radical, ethanoyl, propionyl or butyryl radicals, R
7And R
8Also can be together-O-CH
2-O-or-O-CH
2-CH
2-O
Z is preferably-CO-,-CONH-,-CO-CH
2-,-CO-(CH
2)
2-,-CO-(CH
2)
3-, (E)-or (Z)--CH=CH-, methylene radical, ethylene, propylene ,-CO-NH-CO-,-NH-CO-NH-,-NH-CO-O-,-O-CO-NH-,-CO-O-or-O-CO-.
Parameter n is preferably 1 or 2, also is preferably 3.Parameter m is preferably 1 or 2.
The compound of formula I can have one or several chiral centre, therefore can exist with different stereoisomeric forms in any ratio.The compound of formula I comprises all these forms.
Therefore, the present invention is specifically related to the compound of formula I, and wherein at least one above-mentioned group has one of above-mentioned preferred meaning.Some preferred compounds can represent to I h with following minor I a, and they are corresponding to the formula I, and the implication of the group that wherein is not described in more detail is suc as formula described in the I, but therein in I a X be S; X is O in I b; In I c X be S and
-A=B-C=D-is-CH=CH-CH=CH-; In I d X be O and
-A=B-C=D-is-CH=CH-CH=CH-; In I e X be O and
-A=B-C=D-is-CH=CH-CH=N-; X is S in I f,
-A=B-C=D-is-CH=CH-CH=CH-,
R
1Be H
R
2For Hal and
R
3Be methyl; Het is a thienyl in I g; X is S in I h,
-A=B-C=D-is-CH=CH-CH=CH-,
R
1, R
2And R
3For hydrogen and
Het is a thienyl
The compound of formula I and the raw material for preparing it are with original known method, as in the literature (the Methoden der OrganischenChemie (organic chemistry method) that writes at classic such as Houben-Weyl for example, the Georg-Thieme-Verlag of Stuttgart publishes; Particularly in EP 0569193 A1 and WO 94/27979) the method preparation described, promptly known and be suitable under the reaction conditions of above-mentioned reaction.In this case, also can utilize original known improving one's methods, but here not mention in more detail.
If desired, raw material can form on the spot, thereby they is not separated from reaction mixture, but further reacts the compound that obtains the formula I at once.
The compound of formula I can preferably obtain with the compound of formula II and the compound reaction of formula III.
In the compound of formula III, the OH gene that E is preferably Cl, Br, I or reactivity (sic) modification is as alkylsulfonyloxy (preferable methyl sulfonyloxy) with 1～6 carbon atom or aryl-sulfonyl oxygen with 6～10 carbon atoms (be preferably phenyl-or p-methylphenyl sulfonyloxy).
Generally, this is reflected at one or more alkali and exists down and carry out in inert solvent, and alkali is preferably tertiary amine such as triethylamine, pyridine, 4-dimethylaminopyridine, and advantageously temperature of reaction is 0～150 ℃, is preferably 40～90 ℃.Excessive amine also can be used as solvent.
Suitable inert solvent for example is hydro carbons such as hexane, sherwood oil, benzene, toluene or dimethylbenzene; Chlorinated hydrocarbons such as trieline, 1,2-ethylene dichloride, tetracol phenixin, chloroform or methylene dichloride; Alcohols such as methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol or the trimethyl carbinol; Ethers such as ether, isopropyl ether, tetrahydrofuran (THF) (THF) Huo diox; Gylcol ether such as ethylene glycol monomethyl ether or single ether (methyl glycol or ethyl glycol), glycol dimethyl ether (diglyme); Ketone is sent out acetone or butanone; Amides such as ethanamide, N,N-DIMETHYLACETAMIDE or dimethyl formamide (DMF); Nitrile such as acetonitrile; Sulfoxide such as dimethyl sulfoxide (DMSO) (DMSO); Dithiocarbonic anhydride; Carboxylic acid such as formic acid or acetate; Nitro-compound such as Nitromethane 99Min. or oil of mirbane; The mixture of ester class such as ethyl acetate or above-mentioned solvent.
Generally, the initial compounds of formula II is novel.But they can prepare with the method for knowing originally.Therefore, 5-amino-6-methyl-2,1 for example, 3-diazosulfide can be in inert solvent such as methyl alcohol with Raney nickel with 5-nitro-6-methyl-2,1, the 3-diazosulfide carries out hydrogenation and makes.This can be to carry out under about 0～200 ℃ in temperature easily; Preferred 30～80 ℃.
Generally, the initial compounds of formula III is novel.But they can prepare with the method for knowing originally.Therefore, for example known 3-chlorosulfonyl-2-methoxycarbonyl thiophene-based is known.With to prepare ester with methyl alcohol similar, for example use 6-methyl phendioxin, 3-dioxole-5-base amine obtains acid amides.
With as similar at the currently known methods described in the document (as the 629th page of " heterocyclic chemistry magazine " 1970 the 7th volume), in the presence of one or more alkali in inert solvent, novel formula IV compound and thionyl chloride or its reactive derivatives such as thionyl aniline reaction under temperature is 0～150 ℃ easily will be generally, also obtaining wherein, X is the formula I compound of S, alkali is preferably tertiary amine such as triethylamine, pyridine, 4-dimethylaminopyridine, and temperature of reaction is preferably 40～90 ℃.Excessive amine also can be used as solvent.
With as document (as the 1656th page of 1963 the 28th volume of the 257th page of 1980 the 20th volume of the 8199th page of 1992 the 48th volume of the 5209th page of " tetrahedron " 1988 the 44th volume, " tetrahedron ", " The Chemicals ", " organic chemistry magazine " nineteen eighty-two the 47th the 1774th page of volume, " organic chemistry magazine " or " medical chemistry magazine " nineteen sixty-eight the 11st the 305th page of volume) described in currently known methods similar, will be generally novel formula V compound and reductibility compound such as Cl-SO
2-N=C=O, POCl
3, PCl
3, Na
2S
2O
4, Ph
3P or P (OC
2H
5)
3React, also obtaining wherein, X is the formula I compound of O.
The initial compounds of formula V can prepare with original known method.Therefore, for example the 4-tertiary butyl-N-(4-chloro-3-nitro) benzsulfamide warp is obtained the 4-tertiary butyl-N-(4-azido--3-nitro) benzsulfamide with reaction of sodium azide under phase transfer catalysis condition, in Glacial acetic acid, carry out cyclisation subsequently, can prepare the 4-tertiary butyl-N-(2,1,3-Ben Bing oxadiazole-1-N-oxygen-5-yl) benzsulfamide.
Can also pass through one or several radicals R
1, R
2And/or R
3Change one or several other radicals R into
1, R
2And/or R
3Thereby change the compound of formula I the compound of another kind of formula I into, for example nitroreduction (for example hydrogenation on Raney nickel or Pd-carbon in inert solvent such as methyl alcohol or ethanol) is become amino and/or for example bromine substituent is converted into cyano group and/or is the COOH group with cyan-hydrolysis and/or with carboxyl esterification and/or under the hydrogenolysis condition 4-nitro alkylization is obtained alkylated amines with pure with the cupric cyanide reaction.
At inert solvent such as methylene dichloride or THF and/or in the presence of alkali such as triethylamine or pyridine; temperature is under-60～+ 30 ℃, can also easily free amine group be carried out acidylate in the usual way or carry out alkylation with the alkyl halide that does not replace or replace with acyl chlorides or acid anhydrides.
If desired, the method according to commonly used by solvolysis or hydrogenolysis, can discharge the amino and/or the hydroxyl of the functionalization and modification in the formula I compound.Therefore, for example contain NH-COR
4Or COOR
4The formula I compound of group can be converted into and contain NH
2Or the corresponding formula I compound of HOOC group.In water, water-THF or water-dioxs, temperature is 0～100 ℃, can be with NaOH or KOH with COOR
4The base hydrolysis.
The alkali of formula I can be converted into associating acid salt with acid, for example the alkali with equivalent reacts in inert solvent such as ethanol with acid, evaporates subsequently.The suitable acid that is used for this reaction is in particular the acid that those can generate physiologically acceptable salt.So available mineral acid such as sulfuric acid, nitric acid, haloid acid example hydrochloric acid or Hydrogen bromide, phosphoric acid such as ortho-phosphoric acid, thionamic acid, also available organic acid, particularly aliphatic, alicyclic, araliphatic, aromatics or heterocycle family monobasic or polycarboxylic acid, sulfonic acid or sulfuric acid, for example formic acid, acetate, propionic acid, PIVALIC ACID CRUDE (25), diethyl acetate, propanedioic acid, succsinic acid, pimelic acid, fumaric acid, toxilic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, glyconic acid, xitix, nicotinic acid, Yi Yansuan, methylsulfonic acid, ethyl sulfonic acid, ethionic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, tosic acid, naphthalene monosulfonic acid and naphthalene disulfonic acid and lauryl sulfate.The salt such as the picrate that form with the unacceptable acid of physiology can be used for separating and/or purifying of formula I compound.
On the other hand, available bases (as sodium hydroxide or potassium, yellow soda ash or potassium) is converted into corresponding metal salt, particularly an alkali metal salt or alkaline earth salt with formula I compound, or is converted into corresponding ammonium salt.
The invention further relates to the production that compound and/or its physiologically acceptable salt with the formula I are used for medicament, particularly use method non-chemically.In this, they can be made suitable agent shape with at least a solid, liquid and/or semiliquid vehicle or auxiliary agent,, can combine with one or more other active compounds if suitable.
The invention still further relates to pharmaceutical preparation, it comprises compound and/or a kind of its physiologically acceptable salt of at least a formula I.
These preparations can be used as people's medicine or veterinary drug.Possible vehicle is the organic or inorganic thing, they are suitable for intestines portion (as oral) or administered parenterally or topical, and do not react, water, vegetables oil, benzylalcohol, alkylene dihydric alcohol, polyoxyethylene glycol, Vanay, gelatin, carbohydrate such as lactose or starch, Magnesium Stearate, talcum and Vaseline are for example arranged with this novel compound.Particularly, be used for oral be tablet, pill, coated tablet, capsule, pulvis, particle, syrup, juice or drop, the suppository that is that is used for rectal administration, the solution that is that is used for administered parenterally, the preferred oily or the aqueous solution, also have suspension, emulsion or implant, local application be ointment, creme or pulvis.Also can be with novel compound freeze-drying, the lyophilized products that obtains for example can be used for the production of injection formulations.Described preparation can be sterilized and/or they can comprise auxiliary agent such as lubricant, sanitas, stablizer and/or wetting agent, emulsifying agent, the salt that influences osmotic pressure, buffer substance, tinting material, seasonings and/or one or more other active compounds such as one or more VITAMIN.
The compound of formula I and physiologically acceptable salt thereof can be used for control disease, particularly hypertension and cardiac insufficiency.
In this case, the general preferred dosage of material according to the present invention is about 1～500mg/ dose unit, is preferably 5～100mg/ dose unit especially.Day obey dosage and be preferably about 0.02～10mg/kg body weight.But, concrete dosage for each patient depends on multiple factor, the activity of for example used particular compound, age, body weight, common healthy state, sex, diet, administration time and approach, discharge rate, the combination of medicine and the severity of the specified disease that treatment relates to.The preferred oral administration.
Above and below the temperature unit given be ℃.In the following embodiments, " conventional processing " refers to: if desired, add entry, if desired, according to the composition of the finished product mixture being adjusted to pH is 2～10, with ethyl acetate or dichloromethane extraction, isolate organic phase, use dried over sodium sulfate, evaporation is used the silica gel chromatography method and/or is used the crystallization process purifying.Rf is on the silica gel; Eluent: ethyl acetate/methanol 9: 1.Embodiment 1
The 10ml pyridine solution of 4g 3-chlorosulfonyl-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides (" A ") is joined 1.52g 5-amino-2,1,3-diazosulfide (deep green solid, 148 ℃ of fusing points; Can pass through 5-nitro-2,1, the 3-diazosulfide carries out hydrogenation and obtains on Raney nickel in methyl alcohol; 5-nitro-2,1, the fusing point of 3-diazosulfide is 130 ℃, it can pass through 2,3,5-diamino oil of mirbane and thionyl chloride are reacted in toluene and triethylamine and are obtained) the 15ml pyridine solution in, at 60 ℃ mixture was stirred 24 hours, join then in the hydrochloric acid of 75ml 2N, handle with usual manner.The 3-that obtains (2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides is a solid.
Similarly, with following mQ-5-amino-2,1, the 3-diazosulfide is a raw material with " A ", and wherein mQ is
The 4-methyl
The 6-methyl
The 7-methyl
4, the 6-dimethyl
4, the 7-dimethyl
6, the 7-dimethyl
The 4-trifluoromethyl
The 6-trifluoromethyl
The 7-trifluoromethyl
The 4-bromine
The 6-bromine
The 7-bromine
4, the 6-dibromo
4, the 7-dibromo
6, the 7-dibromo
4-bromo-6-methyl
4-bromo-7-methyl
6-bromo-7-methyl
4-methyl-6-bromine
4-methyl-7-bromine
6-methyl-7-bromine
4-bromo-6-ethyl
4-bromo-7-ethyl
6-bromo-7-ethyl
4-ethyl-6-bromine
4-ethyl-7-bromine
6-ethyl-7-bromine
4-bromo-6-trifluoromethyl
4-bromo-7-trifluoromethyl
6-bromo-7-trifluoromethyl
4-trifluoromethyl-6-bromine
4-trifluoromethyl-7-bromine
6-trifluoromethyl-7-bromine
4-chlorine
6-chlorine
7-chlorine
The 4-nitro
The 6-nitro
The 7-nitro
The 4-bromo-6-tertiary butyl
The 4-bromo-7-tertiary butyl
The 6-bromo-7-tertiary butyl
The 4-tertiary butyl-6-bromine
The 4-tertiary butyl-7-bromine
The 6-tertiary butyl-7-bromine
4-chloro-6-methyl
4-chloro-7-methyl
6-chloro-7-methyl
4-methyl-6-chlorine
4-methyl-7-chlorine
6-methyl-7-chlorine
The 4-dimethylamino
The 6-dimethylamino
The 7-dimethylamino
4-cyano group
6-cyano group
7-cyano group
The 4-methoxycarbonyl
The 6-methoxycarbonyl
The 7-methoxycarbonyl
The 4-ethoxy carbonyl
The 6-ethoxy carbonyl
The 7-ethoxy carbonyl
The 4-kharophen
The 6-kharophen
The 7-kharophen obtains 3-(mQ-2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides, and wherein mQ is
The 4-methyl
The 6-methyl
The 7-methyl
4, the 6-dimethyl
4, the 7-dimethyl
6, the 7-dimethyl
The 4-trifluoromethyl
The 6-trifluoromethyl
The 7-trifluoromethyl
The 4-bromine
The 6-bromine
The 7-bromine
4, the 6-dibromo
4, the 7-dibromo
6, the 7-dibromo
4-bromo-6-methyl
4-bromo-7-methyl
6-bromo-7-methyl
4-methyl-6-bromine
4-methyl-7-bromine
6-methyl-7-bromine
4-bromo-6-ethyl
4-bromo-7-ethyl
6-bromo-7-ethyl
4-ethyl-6-bromine
4-ethyl-7-bromine
6-ethyl-7-bromine
4-bromo-6-trifluoromethyl
4-bromo-7-trifluoromethyl
6-bromo-7-trifluoromethyl
4-trifluoromethyl-6-bromine
4-trifluoromethyl-7-bromine
6-trifluoromethyl-7-bromine
4-chlorine
6-chlorine
7-chlorine
The 4-nitro
The 6-nitro
The 7-nitro
The 4-bromo-6-tertiary butyl
The 4-bromo-7-tertiary butyl
The 6-bromo-7-tertiary butyl
The 4-tertiary butyl-6-bromine
The 4-tertiary butyl-7-bromine
The 6-tertiary butyl-7-bromine
4-chloro-6-methyl
4-chloro-7-methyl
6-chloro-7-methyl
4-methyl-6-chlorine
4-methyl-7-chlorine
6-methyl-7-chlorine
The 4-dimethylamino
The 6-dimethylamino
The 7-dimethylamino
4-cyano group
6-cyano group
7-cyano group
The 4-methoxycarbonyl
The 6-methoxycarbonyl
The 7-methoxycarbonyl
The 4-ethoxy carbonyl
The 6-ethoxy carbonyl
The 7-ethoxy carbonyl
The 4-kharophen
The 6-kharophen
The 7-kharophen.
Similarly, with 5-amino-2,1,3-diazosulfide and 3-chlorosulfonyl-N-(6-ethanoyl-1,3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides reaction obtains
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-ethanoyl-1,3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides; Obtain with 3-chlorosulfonyl-N-(6-cyano group-1,3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides reaction
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-cyano group-1,3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides; Obtain with the reaction of 3-chlorosulfonyl-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-ylmethyl carbonyl) thiophene
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-2-(6-cyano group-1,3-benzo dioxole-5-ylmethyl carbonyl) thiophene; Obtain with the reaction of 3-chlorosulfonyl-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-ylmethyl) thiophene
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-ylmethyl) thiophene; Obtain with 3-chlorosulfonyl-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-base ethyl) thiophene reaction;
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-base ethyl) thiophene; Obtain with 3-chlorosulfonyl-N-(4-tolyl) thiophene-2-carboxylic acid amides reaction
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(4-tolyl) thiophene-2-carboxylic acid amides; Obtain with 3-chlorosulfonyl-N-(4-p-methoxy-phenyl) thiophene-2-carboxylic acid amides reaction
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(4-p-methoxy-phenyl) thiophene-2-carboxylic acid amides; Obtain with 3-chlorosulfonyl-N-(4-cyano-phenyl) thiophene-2-carboxylic acid amides reaction
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(4-cyano-phenyl) thiophene-2-carboxylic acid amides; Obtain with 3-chlorosulfonyl-N-(4-methoxycarbonyl phenyl) thiophene-2-carboxylic acid amides reaction
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(4-methoxycarbonyl phenyl) thiophene-2-carboxylic acid amides; Obtain with 3-chlorosulfonyl-N-(4-chloro-phenyl-) thiophene-2-carboxylic acid amides reaction
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(4-chloro-phenyl-) thiophene-2-carboxylic acid amides; Obtain with 3-chlorosulfonyl-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-base carbonyl) thiophene reaction
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-base carbonyl) thiophene; Obtain with the reaction of 3-chlorosulfonyl-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-base-oxygen carbonyl) thiophene
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-base oxygen carbonyl) thiophene; Obtain with the reaction of 3-chlorosulfonyl-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-base-vinyl) thiophene
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-2-(6-methyl isophthalic acid, 3-benzo dioxole-5-base vinyl) thiophene; Obtain with 3-chlorosulfonyl-N-(6-ethanoyl-1,3-benzo dioxole-5-base-carbonyl) thiophene-2-carboxylic acid amides reaction
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-ethanoyl-1,3-benzo dioxole-5-base carbonyl) thiophene-2-carboxylic acid amides; Embodiment 2
The solution of 3g thionyl chloride in 15ml toluene is joined 3g 3-(1; 2-diamino-4-amino-sulfonyl)-N-(6-methyl isophthalic acid; 3-benzo dioxole-5-yl) in thiophene-2-carboxylic acid amides and the solution of 4.1g triethylamine in 100ml toluene; at 110 ℃ with mixture heating up 1 hour; handle with usual manner then, obtain 3-(2,1; 3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides.Embodiment 3
Under 75 ℃; with 1g 3-(2; 1; 3-Ben Bing oxadiazole-5-amino-sulfonyl-1-or-the 3-N-oxide compound)-N-(6-methyl isophthalic acid; 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides (can pass through in Glacial acetic acid 3-(1-azido--2-nitrophenyl-4-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides heating to be obtained) and the solution heating of 5ml triethyl-phosphite in the 50ml dehydrated alcohol are 30 minutes.After solvent being removed and handling, obtain 3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides with usual manner.Embodiment 4
Under normal pressure and 20 ℃,, 1g 3-(4-nitro-2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, the 3-benzo dioxole-5-yl) thiophene-solution of 2-carboxylic acid amides in 25ml methyl alcohol is hydrogenated to fully with 1g Raney nickel.Filtering mixt, evaporated filtrate obtains 3-(4-amino-2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides.Embodiment 5
Under 120 ℃, with 4.6g 3-(4-bromo-2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides and the mixture heating up of 1.3g cupric cyanide in the 30ml pyridine 8 hours.Be poured in the ammonia soln, handle, obtain 3-(4-cyano group-2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides with usual manner.Embodiment 6
1g 3-(4-cyano group-2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides and the solution of 0.7g potassium hydroxide in 20ml ethanol and 5ml water were under agitation boiled 8 hours.Solvent is removed, and water dissolves resistates, uses the salt acid treatment, obtains 3-(4-carboxyl-2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides.Embodiment 7
Under 80 ℃, 1g 3-(4 carboxyls-2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides, the 0.5ml vitriol oil and 30ml alcoholic acid solution were heated 6 hours.Remove and desolvate, handle resistates, obtain 3-(4-ethoxy carbonyl-2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides with usual manner.Embodiment 8
6g 3-(4-amino-2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides and the solution of 0.5g titanium tetrachloride in 100ml methyl alcohol are handled with the acetaldehyde that 1ml distillation just obtains.Add the 4g sodium cyanoborohydride then, mixture was stirred 30 hours.Add half cold dense (half-concentrated) hydrochloric acid; use the usual manner treating mixture, obtain 3-(4-ethylamino-2,1; 3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides.Embodiment 9
Similar to embodiment 1, with 5-amino-[1,2,5] thiadiazoles-[3,4-b] pyridine and " A " reaction, obtain
3-([1,2,5] thiadiazoles is [3,4-b] pyridine-5-amino-sulfonyl also)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides reaches
5-amino-2,1,3-diazosulfide and 3-chlorosulfonyl-N-(2,1,3-diazosulfide-5-yl) thiophene-2-carboxylic acid amides reaction obtains
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(2,1,3-diazosulfide-5-yl) thiophene-2-carboxylic acid amides, its fusing point is 267 ℃ (decomposition).
Similarly, with 5-amino-2,1,3-diazosulfide and 3-chlorosulfonyl-N-(1,3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides reaction obtains
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(1,3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides, its fusing point are 235 ℃ and obtain with the reaction of 3-chlorosulfonyl-N-(2,4, the 6-trimethylphenyl) thiophene-2-carboxylic acid amides
3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(2,4, the 6-trimethylphenyl) thiophene-2-carboxylic acid amides.
Following embodiment relates to pharmaceutical preparation:
Embodiment A: injection small jar
With 2N hydrochloric acid the active compound of 100g formula I and the solution of 5g Sodium phosphate dibasic in 3 liters of redistilled waters being adjusted to pH is 6.5, and sterilising filtration divides to install in the injection small jar freeze-drying under aseptic condition, and sterile seal.Each injection small jar contains the 5mg active compound.
Embodiment B: suppository
The active compound of 20g formula I and the mixture of 100g soybean lecithin and 1400g theobroma oil are merged, be poured in the mould cooling.Each suppository contains the 20g active compound.
Embodiment C: solution
Active ingredient, the 9.38g NaH of preparation 1g formula I
2PO
42H
2O, 28.48gNa
2HPO
412H
2O and the solution of 0.1g Zephiran chloride in the 940ml redistilled water.With the pH regulator of solution is 6.8, is made into 1 liter, and passes through sterilization by irradiation.This solution can use with the form of collyrium.
Embodiment D: paste
The active compound of 500mg formula I is mixed under aseptic condition with 99.5g Vaseline.
Embodiment E: tablet
With common mode, the mixture compression with active compound, 4kg lactose, 1.2kg yam starch, 0.2kg talcum and the 0.1kg Magnesium Stearate of 1kg formula I obtains tablet, and each tablet contains the 10mg active compound.
Embodiment F: coated tablet
Similar with embodiment E, with tablet press, coat with the coating of common mode then with sucrose, yam starch, talcum, tragacanth gum and tinting material.
Embodiment G: capsule
In common mode, the active compound of 2kg formula I is filled in the hard gelatine capsule, each capsule contains the 20mg active compound as a result.
Embodiment H: ampoule
The solution sterilization of active compound in 60 liters of redistilled waters of 1kg formula I filtered, divide to install in the ampoule freeze-drying under aseptic condition, sterile seal.Each ampoule contains the 10mg active compound.
Claims (9)
1. the compound of formula I and salt thereof:
I wherein
-A=B-C=D-is wherein 1 or 2 the also available N alternate of CH-CH=CH-CH=CH-bases,
Het has the monokaryon of 1～4 N, O and/or S atom or double-core is saturated, unsaturated or the heterocycle of aromatics, and it can be unsubstituted or with-Z-R
6Replace,
R
1, R
2And R
3Do not exist with being mutually independent or be H, Hal, A, CF
3, NO
2, NR
4R
5, CN, COOR
4Or NHCOR
4,
R
4And R
5Be H or A with being mutually independent, or also be-CH together
2-(CH
2)
n-CH
2-,
R
6For unsubstituted or single-, two-or three-R
7-, R
8-and/or R
9Phenyl, diazosulfide-5-base or the Ben Bing oxadiazole-5-base of-replacement,
R
7, R
8And R
9Be with being mutually independent A, O-A, CN, COOH, COOA, Hal, formyl radical ,-CO-A, R
7And R
8Also be together-O-(CH
2)
m-O-,
A is the alkyl with 1～6 carbon atom,
X is O or S,
Z is-CO-,-CONH-,-CO-(CH
2)
n-,-CH=CH-,-(CH
2)
n-,-CONHCO-,-NHCONH-,-NHCOO-,-O-CONH-,-CO-O-or-O-CO-,
Hal is F, Cl, Br or I,
M be 1 or 2 and
N is 1,2 or 3.
2. according to the compound of claim 1
A) 3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides;
B) 3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-ethanoyl-1,3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides;
C) 3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-cyano group-1,3-benzo dioxole-5-yl) thiophene-2-carboxylic acid amides;
D) 3-(2,1,3-diazosulfide-5-amino-sulfonyl)-N-(6-methyl isophthalic acid, 3-benzo dioxole-5-ylmethyl carbonyl) thiophene.
3. preparation is characterized in that according to the formula I compound of claim 1 and the method for its esters
(a) will be wherein-A=B-C=D-, R
1, R
2, R
3With the implication of X formula II as claimed in claim 1 compound
II is that the OH base of Cl, Br, I or free or reactive functional modification and the implication formula III as claimed in claim 1 compound of Het react with E wherein
Het-SO
2-E III, or
(b) X is the formula I compound of S in order to prepare wherein
Will be wherein-A=B-C=D-, Het, R
1, R
2And R
3Implication formula IV as claimed in claim 1 compound
The reactive derivatives reaction of IV and thionyl chloride or this compound, or
(c) X is the formula I compound of O in order to prepare wherein
Will be wherein-A=B-C=D-, Het, R
1, R
2And R
3Implication formula V as claimed in claim 1 compound reduction
V and/or it is characterized in that with the one or more radicals R in the formula I compound
1, R
2And/or R
3Be converted into one or more radicals R by the following method
1, R
2And/or R
3:
ⅰ) nitroreduction is become amino,
ⅱ) bromine substituent is substituted with cyano group,
Be carboxyl ⅲ) with cyan-hydrolysis,
ⅳ) with carboxyl esterification,
ⅴ) amino is converted into alkylated amines by reductive amination
And/or the alkali or the acid of formula I is converted into one of its salt.
4. the method for useful in preparing drug formulations is characterized in that formula I compound and/or a kind of its physiologically acceptable salt according to claim 1 are made suitable agent shape with at least a solid, liquid or semiliquid vehicle or auxiliary agent.
5. pharmaceutical preparation is characterized in that it contains at least a formula I compound and/or a kind of its physiologically acceptable salt according to claim 1.
6. according to the formula I compound and the physiologically acceptable salt thereof of claim 1, be used for the treatment of hypertension, cardiac insufficiency, renal insufficiency, cerebrum block, coronary heart disease, kidney portion, brain and myocardial ischaemia, subarachnoid hemorrhage, inflammation, asthma and endotoxin shock.
7. according to the formula I medicine and the physiologically acceptable salt thereof of claim 1, as endothelin-receptor antagonists.
8. according to the formula I compound and/or the purposes of its physiologically acceptable salt in drug manufacture of claim 1.
9. controlling hypertension, cardiac insufficiency, renal insufficiency according to formula I compound and/or its physiologically acceptable salt of claim 1, cerebrum block, coronary heart disease, kidney portion, brain and myocardial ischaemia, subarachnoid hemorrhage, inflammation, the purposes in asthma and the endotoxin shock.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19606980.7 | 1996-02-24 | ||
| DE19606980A DE19606980A1 (en) | 1996-02-24 | 1996-02-24 | Endothelin receptor antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1216045A true CN1216045A (en) | 1999-05-05 |
Family
ID=7786338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97193775A Pending CN1216045A (en) | 1996-02-24 | 1997-02-20 | N-(2,1,3-benzothia (oxa) diazolyl)-sulphonamides having endothelin receptor antagonistic effect |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0885219A1 (en) |
| CN (1) | CN1216045A (en) |
| AR (1) | AR005946A1 (en) |
| AU (1) | AU1875697A (en) |
| DE (1) | DE19606980A1 (en) |
| WO (1) | WO1997030996A1 (en) |
| ZA (1) | ZA971474B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6678669B2 (en) | 1996-02-09 | 2004-01-13 | Adeza Biomedical Corporation | Method for selecting medical and biochemical diagnostic tests using neural network-related applications |
| DE10155076A1 (en) * | 2001-11-09 | 2003-05-22 | Merck Patent Gmbh | Use of endothelin receptor antagonists for the treatment of tumor diseases |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5591761A (en) * | 1993-05-20 | 1997-01-07 | Texas Biotechnology Corporation | Thiophenyl-, furyl-and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin |
| DE19509950A1 (en) * | 1995-03-18 | 1996-09-19 | Merck Patent Gmbh | Endothelin receptor antagonists |
-
1996
- 1996-02-24 DE DE19606980A patent/DE19606980A1/en not_active Withdrawn
-
1997
- 1997-02-20 EP EP97905064A patent/EP0885219A1/en not_active Withdrawn
- 1997-02-20 CN CN97193775A patent/CN1216045A/en active Pending
- 1997-02-20 AU AU18756/97A patent/AU1875697A/en not_active Abandoned
- 1997-02-20 ZA ZA9701474A patent/ZA971474B/en unknown
- 1997-02-20 WO PCT/EP1997/000817 patent/WO1997030996A1/en not_active Application Discontinuation
- 1997-02-21 AR ARP970100702A patent/AR005946A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR005946A1 (en) | 1999-07-21 |
| EP0885219A1 (en) | 1998-12-23 |
| AU1875697A (en) | 1997-09-10 |
| ZA971474B (en) | 1997-08-28 |
| DE19606980A1 (en) | 1997-08-28 |
| WO1997030996A1 (en) | 1997-08-28 |
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