DE19711428A1 - Endothelin receptor antagonists - Google Patents

Abstract

The invention relates to new compounds of the formula I wherein Z, R<1>, R<2>, R<3>, and R<3'> have the meaning given in Claim 1. Said compounds display endothelin receptor antagonistic properties.

Description

The invention relates to compounds of the formula I.

wherein
Z is a single or a double bond,
R ^{1 is} an unsubstituted or simply substituted in the phenyl part by R ⁷

an unsubstituted or substituted in the cyclohexadienyl part by R ⁷

R ² A, Ar- (CH ₂ ) _m , cycloalkyl- (CH ₂ ) _m , Het- (CH ₂ ) _m or R ¹ - (CH ₂ ) _m ,
R ³ , R ^{3 '} each independently of one another OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA',
R ³ and R ^{3 '} together also -O-, thereby forming a cyclic anhydride,
R ⁴ , R ^{4 '} each independently of one another H or A,
R ⁵ A or Ar,
R ^{6 is} phenyl or naphthyl which is unsubstituted or mono-, di- or trisubstituted by A, NH ₂ , NHA, NAA ', NO ₂ , CN or Hal,
R ⁷ A, COOR ⁴ , CN, 1H-tetrazol-5-yl, CONHSO ₂ R ⁵ , Hal, OR ⁴ , NO ₂ , NH ₂ , NHA, NAA ', NHCOR ⁴ , NHCOR ⁶ , NHSO ₂ R ⁴ , NHSO ₂ R ⁶ , S (O) _k R ⁴ , S (O) _k R ⁶ , SO ₂ NR ⁴ R ^{4 '} or formyl,
R ⁸ , R ^{8 '} each independently of one another are H or alkyl having 1-6 C atoms,
E CH ₂ or O,
D carbonyl or (CR ⁴ R ^{4 '} ) _n ,
E and D together also CR ⁴ = R ^{4 '} ,
XS or O,
A, A 'each independently of one another alkyl having 1-6 C atoms, in which one or two CH ₂ groups by O or S atoms or by -CR ⁸ = CR ^8' groups and / or 1-7 H- Atoms can be replaced by F,
or benzyl,
Ar unsubstituted or single, double or triple by A, OR ⁴ , NH ₂ , NHA, NAA ', NO ₂ , CN, Hal, NHCOR ⁴ , NHCOR ⁶ , NHSO ₂ R ⁴ , NHSO ₂ R ⁶ , COOR ⁴ , OPh, CONH ₂ , CONHA, CONAA ', COR ⁴ , CONHSO ₂ R ⁴ , CONHSO ₂ R ⁶ , O (CH ₂ ) _n COOR ⁴ , O (CH ₂ ) _n OR ⁴ , SO ₂ NR ⁴ R ^4' , p (O) _k R ⁶ or S (O) _k R ⁴ substituted phenyl or naphthyl,
Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1-4 N, O and / or S atoms, bonded via N or C, which is unsubstituted or mono-, di- or triple by Hal, A, COOR ⁴ , CN, 1H-tetrazol-5-yl, CONHSO ₂ R ⁵ , NH ₂ , NHA, NAA ', NO ₂ and / or = O may be substituted,
Hal fluorine, chlorine, bromine or iodine,
k 0, 1 or 2,
m 0, 1 or 2 and
n is 1 or 2,
as well as the (Z) and (E) isomers and the salts of all isomers.

The invention therefore relates to compounds substituted by the radicals R ¹ and R ² selected from the group of succinic acid, esters, mono- and diamide, anhydride, maleic acid, esters, mono- and diamide, anhydride, fumaric acid , esters, mono- and diamides.

Similar connections with Indian and Inden basic structures are e.g. B. from WO 93/08799, those with indole systems are from WO 94/14434, Pyrimi derivative derivatives are from EP 0 526 708 A1 and phenyl and naphthylver Bindings are known from EP 0 617 001 A1. Other acid derivatives are e.g. B. described in WO 95/05376.

The invention was based on the object, new compounds with valuable len properties to find, especially those that are used to manufacture of drugs can be used.

It has been found that the compounds of formula I and their salts good tolerance very valuable pharmacological properties Zen. In particular, they show endothelin receptor-antagonistic properties and can therefore be used to treat diseases such as hyper  tonie, heart failure, coronary heart disease, renal, cerebral and myocardial ischemia, renal failure, cerebral infarction, subarachnoid Hemorrhage, arteriosclerosis, pulmonary hypertension, inflammation, Asthma, prostatic hyperplasia, endotoxic shock and complications after the administration of substances such. B. cyclosporin, as well as other diseases associated with endothelin activities be used.

The connections show u. a. a high affinity for the endothelin ETA and ETB subreceptors. These effects can, according to usual in vitro or in vivo methods are determined, such as. B. described by P.D. Stein et al., J. Med. Chem. 37, 1994, 329-331 and E. Ohlstein et al., Proc. Natl. Acad. Sci. USA 91 1994, 8052-8056.

A suitable method for determining the hypotensive Effect is z. B. described by M.K. Bazil et al., J. Cardiovasc. Pharmacol 22 1993, 897-905 and J. Lange et al., Lab Animal 20 1991, Appl. Note 1016.

The compounds of formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used, especially for Prophylaxis and / or therapy of cardiovascular and vascular diseases diseases, especially hypertension and heart failure.

The invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim 1 and their salts,
wherein

• a) Z is a single bond and
  R ³ , R ^{3 '} each independently mean OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA',
  characterized in that a compound of formula II
  wherein
  R ^{2 has} the meaning given in claim 1,
  R ^{3 '} OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA' and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  with a compound of formula III
  wherein
  R ^{1 has} the meaning given in claim 1 and
  R ³ OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA ',
  implements
  or a compound of formula IV
  wherein
  R ^{1 has} the meaning given in claim 1,
  R ³ OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA 'and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  with a compound of formula V
  wherein
  R ^{2 has} the meaning given in claim 1 and
  R ³ OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA ',
  implements
  or that for the preparation of compounds of the formula I according to claim 1 and their salts,
  wherein
• b) Z is a double bond and
  R ³ , R ^{3 '} each independently mean OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA',
  a compound of the formula II with a compound of the formula IV, in which the radicals in II and IV have the meanings indicated,
  implements
  or that for the preparation of compounds of formula I according to claim 1 and their salts, wherein
• c) Z is a double bond and
  R ³ and R ^{3 '} together are -O-, thereby forming a cyclic anhydride,
  a compound of formula VI
  wherein
  R ^{2 has} the meaning given in claim 1 and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  with a compound of formula VII
  wherein
  R ^{1 has} the meaning given in claim 1 and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  implements
  or a compound of formula VIII
  wherein
  R ^{1 has} the meaning given in claim 1 and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  with a compound of formula IX
  wherein
  R ^{2 has} the meaning given in claim 1 and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  implements
  or that for the preparation of compounds of the formula I according to claim 1 and their salts,
  wherein
• d) Z is a double bond,
  R ³ and R ^{3 '} together are -O-, thereby forming a cyclic anhydride, and m is 1 or 2,
  a compound of formula III,
  wherein
  R ^{1 has} the meaning given in claim 1 and
  R ³ OR ⁴ means
  with a compound of formula X
  L-CH ₂ -COOA X
  wherein
  L Cl, Br, I or a free or reactive functionally modified OH group and
  A denotes alkyl with 1-6 C atoms or benzyl,
  to a compound of formula XI
  and then the compound of formula XI with a compound of formula XII
  R ² -CHO XII
  wherein
  R ² A, Ar- (CH ₂ ) _m , cycloalkyl- (CH ₂ ) _m , Het- (CH ₂ ) _m or R ¹ - (CH ₂ ) _m and
  m is 0 or 1,
  implements
  and / or that in a compound of the formula I one or more radicals R ¹ , R ² , R ³ and / or R ^{3 'are converted} into one or more radicals R ¹ , R ² , R ³ and / or R ^{3 '} converts
  for example by
• i) hydrolyzing an ester group to a carboxy group,
  ii) opens a cyclic anhydride structure to an open-chain dicarboxylic acid derivative,
  iii) reducing a nitro group,
  iv) acylated an amino group
  and / or converts a base or acid of the formula I into one of its salts.

For all residues that occur several times, their meanings apply are independent of each other.

Above and below, the radicals or parameters Z, R ¹ , R ² , R ³ and R ^{3 'have} the meanings given in the formulas I to IX, unless expressly stated otherwise.

In the above formulas, A is alkyl and has 1 to 6, preferred wise 1, 2, 3 or 4 carbon atoms. A is preferably methyl, furthermore Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,  2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methyl propyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl Trifluoromethyl, pentafluoroethyl, allyl or crotyl.

Cycloalkyl preferably means z. B. cyclopropyl, cyclobutyl, cyclo pentyl, cyclohexyl or cycloheptyl.

Acyl preferably means formyl, acetyl, propionyl, also butyryl, Pentanoyl or hexanoyl.

Hal is preferably F, Cl or Br, but also I.

Ar means z. B. unsubstituted phenyl or naphthyl, preferably through A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, Butoxy, pentyloxy, hexyloxy, benzyloxy, phenethyloxy, methylthio, Ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, Phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, Dimethylamino, diethylamino, formamido, acetamido, propionylamino, Butyrylamino, methylsulfonamido, ethylsulfonamido, propylsulfonamido, Butylsulfonamido, phenylsulfonamido, (4-methylphenyl) sulfonainido, Carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxy carbonylethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, Carboxy, methoxycarbonyl or ethoxycarbonyl mono-, di- or trisub substituted phenyl or naphthyl.

Ar therefore preferably means z. B. o-, m- or p-tolyl, o-, m- or p-ethyl phenyl, o-, m- or p-propylphenyl, o-, in- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitro phenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- (N, N-Di methylamino) phenyl, o-, m- or p- (N-ethylamino) phenyl, o-, m- or p- (N, N-diethylamino) phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromine phenyl, o-, m- or p- chlorophenyl, o-, m- or p- (phenylsulfonamido) - phenyl, o-, m- or p- (methylsulfonamido) phenyl, o-, m- or p-methyl thiophenyl, o, m or p- (hydroxymethyl) phenyl, o-, m- or p- (methoxy  methyl) -phenyl, 2,3-, 2,4- 2,5-, 2,6-, 3,4- or 3,5- (difluoromethoxy) - (carb oxymethyloxy) phenyl, 2,3-, 2,4- 2,5-, 2,6-, 3,4- or 3,5-methoxy- (carb oxymethyloxy) phenyl, 2,3-, 2,4- 2,5-, 2,6-, 3,4- or 3,5-hydroxy- (carboxy methyloxy) phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-di fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 2-amino-3-chloro, 2- Amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4- N, N-dimethylamino- or 3-nitro-4-N, N-dimethylaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,3-, 2,4- 2,5-, 2,6-, 3, 4- or 3,5-dimethoxyphenyl, 3,4,5- or 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-di chlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorine phenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxy phenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl or 3-fluoro-4-methoxyphenyl.

Het preferably means z. B. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 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-pyrimidinyl preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3- Thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 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-quinazolinyl, 5- or 6- Quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, further before adds 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals can also be partially or completely hydrogenated be.  

Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxo lan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5- pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrole dinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3- Piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2 -, - 3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5- , 6-, 7- or 8- 3,4-dihydro-2H-benzo [1,4] oxazinyl, more preferably 2,3- Methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydro benzofuran-5- or 6-yl, 2,3- (2-oxo-methylenedioxy) phenyl or also 3,4- Dihydro-2H-1,5-benzodioxepin-6- or -7-yl, further preferably 2,3-dihydro benzofuranyl or 2,3-dihydro-2-oxo-furanyl.

R ¹ preferably denotes an unsubstituted or in the phenyl part simply by A, COOH, COOCH ₃ , COOC ₂ H ₅ , CN, CONHSO ₂ phenyl, CONHSO ₂ CH ₃ , Hal, OH, OCH ₃ , NO ₂ , NH ₂ , NHCOCH ₃ , NHCOPhenyl, NHSO ₂ CH ₃ , NHSO ₂ phenyl, SO ₂ CH ₃ , SO ₂ phenyl substituted

in which E is preferably O, furthermore CH ₂ , and D is preferably CH ₂ ,
or
an unsubstituted or in the cyclohexadienyl part simply by A, COOH, COOCH ₃ , COOC ₂ H ₅ , CN, CONHSO ₂ phenyl, CONHSO ₂ CH ₃ , Hal, OH, OCH ₃ , NO ₂ , NH ₂ , NHCOCH ₃ , NHCOPhenyl, NHSO ₂ CH ₃ , NHSO ₂ phenyl, SO ₂ CH ₃ , SO ₂ phenyl substituted

where X is preferably S.

The compounds of formula I can have one or more chiral centers possess and therefore occur in different stereoisomeric forms. Formula I encompasses all of these forms.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ic, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in Ia Z a single or a double bond,
R ^{1 is} an unsubstituted or in the phenyl part simply by A, COOH, COOCH ₃ , COOC ₂ H ₅ , CN, CONHSO ₂ phenyl, CONHSO ₂ CH ₃ , Hal, OH, OCH ₃ , NO ₂ , NH ₂ , NHCOCH ₃ , NHCOPhenyl, NHSO ₂ CH ₃ , NHSO ₂ phenyl, SO ₂ CH ₃ , SO ₂ phenyl substituted

an unsubstituted or in the cyclohexadienyl part simply by A, COOH, COOCH ₃ , COOC ₂ H ₅ , CN, CONHSO ₂ phenyl, CONHSO ₂ CH ₃ , Hal, OH, OCH ₃ , NO ₂ , NH ₂ , NHCOCH ₃ , NHCOPhenyl, NHSO ₂ CH ₃ , NHSO ₂ phenyl, SO ₂ CH ₃ , SO ₂ phenyl substituted

R ² A, Ar- (CH ₂ ) _m , cycloalkyl- (CH ₂ ) _m , 1,3-benzodioxol-5-yl, 2,1,3-benzothiadiazol-5-yl, 1,3-benzodioxol-5- yl-methyl, 2,1,3-benzothiadiazol-5-ylmethyl, thiophene-2-yl, thiophene-2-ylmethyl,
R ³ , R ^{3 '} each independently of one another OR ⁴ , NHSO ₂ A, NHSO ₂ phenyl, NH ₂ , NHA or NAA',
R ³ and R ^{3 '} together also -O-, thereby forming a cyclic anhydride,
means;
in Ib Z a single or a double bond,
R ^{1 is} an unsubstituted or in the phenyl part simply by A, COOH, COOCH ₃ , COOC ₂ H ₅ , CN, CONHSO ₂ phenyl, CONHSO ₂ CH ₃ , Hal, OH, OCH ₃ , NO ₂ , NH ₂ , NHCOCH ₃ , NHCOPhenyl, NHSO ₂ CH ₃ , NHSO ₂ phenyl, SO ₂ CH ₃ , SO ₂ phenyl substituted 1,3-benzodioxol-5-yl
or
an unsubstituted or in the cyclohexadienyl part simply by A, COOH, COOCH ₃ , COOC ₂ H ₅ , CN, CONHSO ₂ phenyl, CONHSO ₂ CH ₃ , Hal, OH, OCH ₃ , NO ₂ , NH ₂ , NHCOCH ₃ , NHCOPhenyl, NHSO ₂ CH ₃ , NHSO ₂ phenyl, SO ₂ CH ₃ , SO ₂ phenyl substituted 2,1,3-benzothiadiazol-5-yl,
R ² A, Ar- (CH ₂ ) _m , cycloalkyl- (CH ₂ ) _m , 1,3-benzodioxol-5-yl, 2,1,3-benzothiadiazol-5-yl, 1,3-benzodioxol-5- yl methyl, 2,1,3-benzothiadiazol-5-ylmethyl, thiophene-2-yl, thiophene-2-ylmethyl,
R ³ , R ^{3 '} each independently of one another OR ⁴ , NHSO ₂ A, NHSO ₂ phenyl, NH ₂ , NHA or NAA',
R ³ and R ^{3 '} together also -O-, thereby forming a cyclic anhydride,
means;
in Ic Z a single or a double bond,
R ^{1 is} an unsubstituted or 1,3-benzodioxol-5-yl or 1,4-benzodioxan-6-yl which is simply substituted by A or Hal in the phenyl part
or
an unsubstituted 2,1,3-benzothiadiazol-5-yl or 2,1,3-benzoxadiazol-5-yl,
R ² A, Ar- (CH ₂ ) _m , cycloalkyl- (CH ₂ ) _m , 1,3-benzodioxol-5-yl, 2,1,3-benzothiadiazol-5-yl, 1,3-benzodioxol-5- yl-methyl, 2,1,3-benzothiadiazol-5-ylmethyl, thiophene-2-yl, thiophene-2-ylmethyl,
R ³ , R ^{3 '} each independently of one another OR ⁴ , NHSO ₂ A, NHSO ₂ phenyl, NH ₂ , NHA or NAA',
R ³ and R ^{3 '} together also -O-, thereby forming a cyclic anhydride,
Ar phenyl or naphthyl which is unsubstituted or mono-, di- or trisubstituted by OCH ₃ , NH ₂ , NHA, NAA 'or Hal
means.

The compounds of formula I and also the starting materials for their manufacture position are otherwise produced by methods known per se, as described in literature (e.g. in standard works such as Houben-Weyl,  Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions for the ge mentioned implementations are known and suitable. You can also do that use of known variants not mentioned here do.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.

Compounds of formula I, wherein
Z is a single bond and R ³ , R ³ , each independently of one another OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA ', can preferably be obtained by combining compounds of the formula II or IV with compounds of the formula III or V, and then optionally cleaves the ester or amides.

The reaction is usually carried out in an inert solvent Presence of an acid-binding agent, preferably an alkali or Alkaline earth metal hydroxides, carbonates or bicarbonates or one other weak acid salt of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium. Also the Addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the compound of formula III or V or the alkylation derivative of formula II or IV can be favorable. The response time is between depending on the conditions used a few minutes and 14 days, the reaction temperature between about 0∘ and 150 °, usually between 20 ° and 130 °.

Suitable inert solvents are, for. B. hydrocarbons such as hexane Petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as Trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or Dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol mono methyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene  glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or Dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

The starting compounds of the formula II, III, IV and V are generally known. If they are new, they can be used according to methods known per se getting produced.

Compounds of formula I, wherein
Z denotes a double bond and R ³ , R ³ , each independently of one another OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA ',
can preferably be obtained by reacting compounds of the formula II with compounds of the formula IV and, if appropriate, subsequently cleaving the ester or amides.

The reaction takes place under conditions as described above.

Compounds of formula I, wherein
Z is a double bond and R ³ , R ³ , together are -O-, thereby forming a cyclic anhydride,
can preferably be obtained by reacting compounds of the formulas VI and VIII with compounds of the formulas VII and IX. The reaction is preferably carried out in the presence of acetic anhydride at temperatures as described above.

The starting compounds of formula VI, VII, VIII and IX are in the Usually known. If they are new, they can be made according to known ones Methods are made.

Compounds of formula I, wherein
Z is a double bond, R ³ , R ³ , together -O-, thereby forming a cyclic anhydride, and in 1 or 2,
can in particular also be obtained by reacting compounds of the formula III with compounds of the formula X to give compounds of the formula XI and then reacting them with compounds of the formula XII, analogously to the known Stobbe condensation.

The compounds of the formulas X, XI and XII are generally known. are they are new, but can be produced according to methods known per se will.

The reaction conditions for the implementation of the compounds of Formula III with the compounds of formula X are the same as for the Reaction of the compounds of formula III with those of formula II.

The reaction of the compounds of formula XI with the compounds of Formula XII is usually carried out in an inert solvent with addition preferably in the presence of a base. As a base z. B. a potassium or Sodium alcoholate such as potassium or sodium methylate, ethylate or tert-butoxide.

The response time is between depending on the conditions used a few minutes and 14 days, the reaction temperature between about -78 ° and 150 °, usually between -20 ° and 50 °.

Esters can e.g. B. with acetic acid or with NaOH or KOH in water Water-THF or water-dioxane at temperatures between 0 and 100 ° be saponified.

It is also possible to convert a compound of the formula I into another compound of the formula I by one or more radicals R ¹ , R ² , R ³ and / or R ³ , in one or more radicals (e ) R ¹ , R ² , R ³ and / or R ³ , converted, for. B. by nitro groups (for example by hydrogenation on Raney nickel or Pd carbon in an inert solvent such as methanol or ethanol) reduced to amino groups.

A maleic anhydride derivative of formula I can e.g. B. by implementation with an amine in an inert solvent to a maleic acid mono- or diamide can be implemented.

The above-mentioned are suitable as inert solvents. The Response time is between depending on the conditions used  a few minutes and 14 days, the reaction temperature between about 0 ° and 150 °, usually between 20 ° and 130 °.

You can also free amino groups in the usual way with an acid chloride or anhydride or with an unsubstituted or Alkylate substituted alkyl halide, advantageously in an inert Solvents such as dichloromethane or THF and / or in the presence of one Base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

If desired, a functionally modified amino and / or hydroxyl group in a compound of the formula I can be liberated by solvolysis or hydrogenolysis by customary methods. So z. B. a compound of formula I, which contains an NH-acyl or a COOA group, can be converted into the corresponding compound of formula I, which instead contains an NH ₂ - or a HOOC group.

A base of formula I can with an acid in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. For this implementation men in particular acids, the physiologically harmless Deliver salts. So inorganic acids can be used, e.g. B. Sulfuric acid, nitric acid, hydrohalic acids such as chlorwas hydrochloric acid or hydrobromic acid, phosphoric acids such as ortho phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascor bic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, Ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p- Toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfur acid. Salts with physiologically unacceptable acids, e.g. B. picrates,  can be used to isolate and / or purify the compounds of the Formula I can be used.

On the other hand, compounds of formula I with bases (e.g. sodium or Potassium hydroxide or carbonate) in the corresponding metal, ins special alkali metal or alkaline earth metal, or in the corresponding Ammonium salts are converted.

The invention further relates to the use of the compounds of formula I and / or their physiologically acceptable salts Provision of pharmaceutical preparations, especially on non-chemical Ways. You can do this together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and counter possibly in combination with one or more other active ingredients be brought into a suitable dosage form.

The invention furthermore relates to pharmaceutical preparations, containing at least one compound of formula I and / or one of them physiologically acceptable salts.

These preparations can be used as medicinal products in human or veteri used in medicine. Organic or inorganic substances in question that are suitable for enteral (e.g. oral), parenteral or topical application and with the new compound not react, e.g. water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, coated tablets, Capsules, powder, granules, syrups, juices or drops, for rectal application application suppositories, for parenteral application solutions, preferred wise oily or aqueous solutions, further suspensions, emulsions or implants, for topical application of ointments, creams or powder. The new compounds can also be lyophilized and the Lyo obtained philisate z. B. can be used for the preparation of injectables. The specified preparations can be sterilized and / or Auxiliaries such as lubricants, preservatives, stabilizers and / or mesh  agents, emulsifiers, salts to influence the osmotic pressure, Buffer substances, color, taste and / or several other active ingredients contain substances, e.g. B. one or more vitamins.

The compounds of formula I and their physiologically acceptable Salts can help fight diseases, especially those of Hypertension and heart failure can be used.

The substances according to the invention are generally preferred wise in dosages between about 1 and 500 mg, in particular administered between 5 and 100 mg per dosage unit. The daily Dosage is preferably between about 0.02 and 10 mg / kg body Weight. However, the specific dose for each patient depends on the various factors, for example the effectiveness of used special connection, of age, body weight, general my state of health, gender, food, enjoyment time and route of excretion, Drug combination and severity of the disease, which the therapy applies. Oral application is preferred.

Compounds of formula I according to the invention, for. B. succinic acid derivatives, because of their molecular structure, can and can be chiral accordingly in two enantiomeric or more diastereoisomers Shapes occur. You can therefore due to one or more chiral centers are present in racemic or optically active form.

Since the pharmaceutical effectiveness of the Racemate or the Stereo can differentiate isomers of the compounds according to the invention, it may be desirable to add the diastereomers or enantiomers use. In these cases the end product or already the Intermediates in enantiomeric compounds, by the expert known chemical or physical measures, separated or can already be used as such in the synthesis.

In the case of racemic amines, the mixture is reacted formed with an optically active release agent diastereomers. As a separator agents are suitable for. B. optically active acids, such as the R and S forms  of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, Malic acid, lactic acid, suitable N-protected amino acids (e.g. N- Benzoylproline or N-benzenesulfonylproline) or the different optically active camphorsulfonic acids. A chromato is also advantageous graphic separation of enantiomers using an optically active separation means (e.g. dinitrobenzoylphenylglycine, cellulose triacetate or others Derivatives of carbohydrates or chiral derivatized ones fixed on silica gel Methacrylate polymers). Aqueous or alcoholic solvent mixtures such. B. Hexane / Isopropanol / Aceto nitrile z. B. in the ratio 82: 15: 3.

In the case of racemic acids, optically active ones can be used in an analogous manner Bases such as B. the R and S form of 1-phenylethylamine, 1-naphthyl ethylamine, dihydroabietylamine, cinchonine or cinchonidines used will.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, and if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated off and dried the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1.
Mass spectrometry (MS): EI (electron impact ionization) M⁺
FAB (Fast Atom Bombardment) (M + H) ⁺

example 1

To a solution of 2.49 g of 2- (2,1,3-benzothiadiazol-5-yl) -acetic acid ethyl ester ("A") in 50 ml of DMF are added 3.0 g of 2- (1,3-benzodioxol-5-yl) -2-bromo methyl acetate and 3.60 g of cesium carbonate. Then turns 16 Stirred for hours at room temperature. You remove the solvent works up as usual and receives 2- (2,1,3-benzothiadiazol-5-yl) -3- (1,3-benzo dioxol-5-yl) -3-methoxycarbonyl-propionic acid ethyl ester as colorless Crystals (mixture of diastereomers), EI 414.  

Analogously, by converting "A"
with methyl 2- (2,1,3-benzothiadiazol-5-yl) -2-bromoacetate 2- (2,1,3-benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) ) -3-meth oxycarbonylpropionic acid ethyl ester;
with methyl 2- (4-methoxyphenyl) -2-bromoacetate 2- (2,1,3-benzothiadiazol-5-yl) -3- (4-methoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2-phenyl-2-bromoacetate, ethyl 2- (2,1,3-benzothiadiazol-5-yl) -3-phenyl-3-methoxycarbonylpropion;
with methyl 2- (3,4-dimethoxyphenyl) -2-bromoacetate 2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4-dimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (2,4-dimethoxyphenyl) -2-bromoacetate 2- (2,1,3-benzothiadiazol-5-yl) -3- (2,4-dimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (thiophene-2-yl) -2-bromoacetate 2- (2,1,3-benzothiadiazol-5-yl) -3- (ethyl thiophene-2-yl) -3-methoxycarbonyl propionate;
with methyl 2- (3,4,5-trimethoxyphenyl) -2-bromoacetate 2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4,5-trimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (4-dimethylaminophenyl) -2-bromoacetate 2- (2,1,3-benzothiadiazol-5-yl) -3- (4-dimethylaminophenyl) -3-methoxy carbonylpropionate and
with methyl 2- (4-chlorophenyl) -2-bromoacetate 2- (2,1,3-benzothiadiazol-5-yl) -3- (4-chlorophenyl) -3-methoxycarbonyl propionate.

Analogously, ethyl acetate is obtained by reacting 2- (1,3-benzodioxol-5-yl) acetic acid;
with methyl 2- (1,3-benzodioxol) -2-bromoacetate 2- (1,3-benzodioxol-5-yl) -3- (1,3-benzodioxol-5-yl) -3-methoxycarbonyl propionic acid ethyl ester;
with 2- (2,1,3-benzothiadiazol-5-yl) -2-bromoacetic acid methyl ester 2- (1,3-benzodioxol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) - 3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (4-methoxyphenyl) -2-bromoacetate 2- (1,3-benzodioxol-5-yl) -3- (4-methoxyphenyl) -3-methoxycarbonyl propionic acid ethyl ester;
with 2-phenyl-2-bromoacetic acid methyl ester 2- (1,3-benzodioxol-5-yl) -3-phenyl-3-methoxycarbonylpropionic acid ethyl ester;
with methyl 2- (3,4-dimethoxyphenyl) -2-bromoacetate 2- (1,3-benzodioxol-5-yl) -3- (3,4-dimethoxyphenyl) -3-methoxycarbonyl propionic acid ethyl ester;
with methyl 2- (2,4-dimethoxyphenyl) -2-bromoacetate 2- (1,3-benzodioxol-5-yl) -3- (2,4-dimethoxyphenyl) -3-methoxycarbonyl propionic acid ethyl ester;
with methyl 2- (thiophene-2-yl) -2-bromoacetate 2- (1,3-benzodioxol-5-yl) -3- (ethyl thiophene-2-yl) -3-methoxycarbonylpropionate;
with methyl 2- (3,4,5-trimethoxyphenyl) -2-bromoacetate 2- (1,3-benzodioxol-5-yl) -3- (3,4,5-trimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (4-dimethylaminophenyl) -2-bromoacetate 2- (1,3-benzodioxol-5-yl) -3- (4-dimethylaminophenyl) -3-methoxy carbonylpropionate and
with methyl 2- (4-chlorophenyl) -2-bromoacetate 2- (1,3-benzodioxol-5-yl) -3- (4-chlorophenyl) -3-methoxycarbonyl propionate.

Analogously, ethyl acetate is obtained by reacting 2- (1,4-benzodioxan-6-yl) acetic acid
with methyl 2- (1,3-benzodioxol) -2-bromoacetate 2- (1,4-benzodioxan-6-yl) -3- (1,3-benzodioxol-5-yl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (2,1,3-benzothiadiazol-5-yl) -2-bromoacetate 2- (1,4-benzodioxan-6-yl) -3- (2,1,3-benzothiadiazol-5-yl) - 3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (4-methoxyphenyl) -2-bromoacetate 2- (1-4-benzodioxan-6-yl) -3- (4-methoxyphenyl) -3-methoxycarbonyl propionate;
with methyl 2-phenyl-2-bromoacetate 2- (1-4-benzodioxan-6-yl) -3-phenyl-3-methoxycarbonylprnpionic acid ethyl ester;
with methyl 2- (3,4-dimethoxyphenyl) -2-bromoacetate 2- (1,4-benzodioxan-6-yl) -3- (3,4-dimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (2,4-dimethoxyphenyl) -2-bromoacetate 2- (14-benzodioxan-6-yl) -3- (2,4-dimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (thiophene-2-yl) -2-bromoacetate 2- (1,4-benzodioxan-6-yl) -3- (thiophene-2-yl) -3-methoxycarbonyl propionic acid ethyl ester;
with methyl 2- (3,4,5, trimethoxyphenyl) -2-bromoacetate 2- (1,4-benzodioxan-6-yl) -3- (3,4,5-trimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (4-dimethylaminophenyl) -2-bromoacetate 2- (1,4-benzodioxan-6-yl) -3- (4-dimethylaminophenyl) -3-methoxy carbonylpropionate and
with methyl 2- (4-chlorophenyl) -2-bromoacetate 2- (1,4-benzodioxan-6-yl) -3- (4-chlorophenyl) -3-methoxycarbonyl propionate.

Analogously, ethyl acetate is obtained by reacting 2- (2,1 3-benzoxadiazol-5-yl) acetic acid
with methyl 2- (1,3-benzodioxol) -2-bromoacetate 2- (2,1,3-benzoxadiazol-5-yl) -3- (1,3-benzodioxol-5-yl) -3-methoxy carbonylpropionic acid ethyl ester;
with 2- (2,1,3-benzothiadiazol-5-yl) -2-bromoacetic acid methyl ester 2- (2,1,3-benzoxadiazol-5-yl) -3- (2,1 3-benzothiadiazol-5-yl) Ethyl -3-meth oxycarbonylpropionate;
with methyl 2- (4-methoxyphenyl) -2-bromoacetate 2- (2,1,3-benzoxadiazol-5-yl) -3- (4-methoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2-phenyl-2-bromoacetate, ethyl 2- (2,1,3-benzoxadiazol-5-yl) -3-phenyl-3-methoxycarbonylpropion;
with methyl 2- (3,4-dimethoxyphenyl) -2-bromoacetate 2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4-dimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (2,4-dimethoxyphenyl) -2-bromoacetate 2- (2,1,3-benzoxadiazol-5-yl) -3- (2,4-dimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (thiophene-2-yl) -2-bromoacetate 2- (2,1,3-benzoxadiazol-5-yl) -3- (ethyl thiophene-2-yl) -3-methoxycarbonyl propionate;
with methyl 2- (3,4,5-trimethoxyphenyl) -2-bromoacetate 2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4,5-trimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (4-dimethylaminophenyl) -2-bromoacetate 2- (2,1,3-benzoxadiazol-5-yl) -3- (4-dimethylaminophenyl) -3-methoxy carbonylpropionate and
with methyl 2- (4-chlorophenyl) -2-bromoacetate 2- (2,1,3-benzoxadiazol-5-yl) -3- (4-chlorophenyl) -3-methoxycarbonyl propionate.

Analogously, ethyl acetate is obtained by reacting 2- (1,3-benzodioxol-6-chloro-5-yl) acetic acid
with methyl 2- (1,3-benzodioxol) -2-bromoacetate 2- (1,3-benzodioxol-6-chloro-5-yl) -3- (1,3-benzodioxol-5-yl) -3-methoxy carbonylpropionate ;
with methyl 2- (2,1,3-benzothiadiazol-5-yl) -2-bromoacetate 2- (1,3-benzodioxol-6-chloro-5-yl) -3- (2,1,3-benzothiadiazol-5) -yl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (4-methoxyphenyl) -2-bromoacetate 2- (1,3-benzodioxol-6-chloro-5-yl) -3- (4-methoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2-phenyl-2-bromoacetate, ethyl 2- (1,3-benzodioxol-6-chloro-5-yl) -3-phenyl-3-methoxycarbonylpropion;
with methyl 2- (3,4-dimethoxyphenyl) -2-bromoacetate 2- (1,3-benzodioxol-6-chloro-5-yl) -3- (3,4-dimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (2,4-dimethoxyphenyl) -2-bromoacetate 2- (1,3-benzodioxol-6-chloro-5-yl) -3- (2,4-dimethoxyphenyl) -3-methoxy carbonylpropionic acid ethyl ester;
with methyl 2- (thiophene-2-yl) -2-bromoacetate 2- (1,3-benzodioxol-6-chloro-5-yl) -3- (ethyl thiophene-2-yl) -3-methoxycarbonyl propionate;
with methyl 2- (3,4,5-trimethoxyphenyl) -2-bromoacetate 2- (1,3-benzodioxol-6-chloro-5-yl) -3- (3,4,5-trimethoxyphenyl) -3-methoxycarbonylpropionic acid ethyl ester ;
with 2- (4-dimethylaminophenyl) -2-bromoacetic acid, ethyl 2- (1,3-benzodioxol-6-chloro-5-yl) -3- (4-dimethylaminophenyl) -3-meth oxycarbonylpropionate and
with methyl 2- (4-chlorophenyl) -2-bromoacetate 2- (1,3-benzodioxol-6-chloro-5-yl) -3- (4-chlorophenyl) -3-methoxy carbonylpropionate.

Example 2

Analogously to Example 1, reaction of methyl 2- (2,1,3-benzothia diazol-5-yl) -2-bromoacetate ("B") with 2- (2,1,3-benzothiadiazol-5-yl) ) -2-Bromoacetic acid methyl ester
2- (2,1,3-Benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) fumaric acid dimethyl ester.

Analogously, methyl 2- (1,3-benzodioxol-5-yl) -2-bromoacetate is obtained by reacting methyl 2- (1,3-benzodioxole) -2-bromoacetate
2- (1,3-Benzodioxol-5-yl) -3- (1,3-benzodioxol-5-yl) fumaric acid dimethyl ester.

Example 3

To a suspension of 0.34 g of 2- (2,1,3-benzothiadiazol-5-yl) -3- (1,3-benzo dioxol-5-yl) -3-methoxycarbonyl-propionic acid ethyl ester in 50 ml Methanol is added to 2.0 ml of 32% aqueous NaOH and stirred for 16 hours at room temperature after. After removing the solvent and Conventional work-up gives 2- (2,1,3-benzothiadiazol-5-yl) -3- (1,3-benzo dioxol-5-yl) succinic acid, EI 354.

The following compounds are obtained analogously by hydrolysis of the 3-methoxycarbonyl-propionic acid ester or fumaric acid dimethyl ester derivatives obtained in Examples 1 and 2
2- (2,1,3-benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) succinic acid;
[The diastereomer mixture of the two 2- (2,1,3-benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) succinic acids was separated due to different crystallization properties of the two isomers. A diastereomer has a melting point of 259∘.]
2- (2,1,3-benzothiadiazol-5-yl) -3- (4-methoxyphenyl) succinic acid;

2- (2,1,3-benzothiadiazol-5-yl) -3-phenyl succinic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4-dimethoxyphenyl) succinic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (2,4-dimethoxyphenyl) succinic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (thiophene-2-yl) succinic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4,5-trimethoxyphenyl) succinic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (4-dimethylaminophenyl) succinic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (4-chlorophenyl) succinic acid;
2- (1,3-benzodioxol-5-yl) -3- (1,3-benzodioxol-5-yl) succinic acid;
2- (1,3-benzodioxol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) succinic acid;
2- (1,3-benzodioxol-5-yl) -3- (4-methoxyphenyl) succinic acid;
2- (1,3-benzodioxol-5-yl) -3-phenyl succinic acid;
2- (1,3-benzodioxol-5-yl) -3- (3,4-dimethoxyphenyl) succinic acid;
2- (1,3-benzodioxol-5-yl) -3- (2,4-dimethoxyphenyl) succinic acid;
2- (1,3-benzodioxol-5-yl) -3- (thiophene-2-yl) succinic acid;
2- (1,3-benzodioxol-5-yl) -3- (3,4,5-trimethoxyphenyl) succinic acid;
2- (1,3-benzodioxol-5-yl) -3- (4-dimethylaminophenyl) succinic acid;
2- (1,3-benzodioxol-5-yl) -3- (4-chlorophenyl) succinic acid;
2- (1,4-benzodioxan-6-yl) -3- (1,3-benzodioxol-5-yl) succinic acid;
2- (1,4-benzodioxan-6-yl) -3- (2,1,3-benzothiadiazol-5-yl) succinic acid;
2- (1,4-benzodioxan-6-yl) -3- (4-methoxyphenyl) succinic acid;
2- (1,4-benzodioxan-6-yl) -3-phenyl succinic acid;
2- (1,4-benzodioxan-6-yl) -3- (3,4-dimethoxyphenyl) succinic acid;
2- (1,4-benzodioxan-6-yl) -3- (2,4-dimethoxyphenyl) succinic acid;
2- (1,4-benzodioxan-6-yl) -3- (thiophene-2-yl) succinic acid;
2- (1,4-benzodioxan-6-yl) -3- (3,4,5-trimethoxyphenyl) succinic acid;
2- (1,4-benzodioxan-6-yl) -3- (4-dimethylaminophenyl) succinic acid;
2- (1,4-benzodioxan-6-yl) -3- (4-chlorophenyl) succinic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (1,3-benzodioxol-5-yl) succinic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) succinic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-methoxyphenyl) succinic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3-phenyl succinic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4-dimethoxyphenyl) succinic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (2,4-dimethoxyphenyl) succinic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (thiophene-2-yl) succinic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4,5-trimethoxyphenyl) succinic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-dimethylaminophenyl) succinic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-chlorophenyl) succinic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (1,3-benzodioxol-5-yl) succinic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) succinic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (4-methoxyphenyl) succinic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3-phenyl succinic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (3,4-dimethoxyphenyl) succinic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (2,4-dimethoxyphenyl) succinic acid;
2- (1,3-Benzodioxol-6-chloro-5-yl) -3- (thiophene-2-yl) succinic acid
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (3,4,5-trimethoxyphenyl) succinic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (4-dimethylaminophenyl) succinic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (4-chlorophenyl) succinic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) fumaric acid;
2- (1,3-benzodioxol-5-yl) -3- (1,3-benzodioxol-5-yl) fumaric acid.

Example 4

A solution of 5.0 g (1,3-benzodioxol-5-yl) glyoxylic acid and 5.0 g 2- (2,1,3- Benzothiadiazol-5-yl) acetic acid ("C") in 50 ml acetic anhydride is boiled under reflux for 3 hours. After usual work-up 2- (2,1,3-Benzothiadiazol-5-yl) -3- (1,3-benzodioxol-5-yl) maleic acid anhydride.

Analogously, by converting C "
with (2,1,3-benzothiadiazol-5-yl) glyoxylic acid 2- (2,1,3-benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) maleic anhydride;
with (4-methoxyphenyl) glyoxylic acid 2- (2,1,3-benzothiadiazol-5-yl) -3- (4-methoxyphenyl) maleic anhydride;
with phenyl-glyoxylic acid 2- (2,1,3-benzothiadiazol-5-yl) -3-phenyl-maleic anhydride;
with (3,4-dimethoxyphenyl) glyoxylic acid 2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4-dimethoxyphenyl) maleic anhydride;
with (thiophene-2-yl) glyoxylic acid 2- (2,1,3-benzothiadiazol-5-yl) -3- (thiophene-2-yl) maleic anhydride;
with (3,4,5-trimethoxyphenyl) glyoxylic acid 2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4,5-trimethoxyphenyl) maleic anhydride;
with (2,4-dimethoxyphenyl) glycoyl acid 2- (2,1,3-benzothiadiazol-5-yl) -3- (2,4-dimethoxyphenyl) maleic anhydride;
with (4-chlorophenyl) glyoxylic acid 2- (2,1,3-benzothiadiazol-5-yl) -3- (4-chlorophenyl) maleic anhydride and
with (4-dimethylaminophenyl) glyoxylic acid 2- (2,1,3-benzothiadiazol-5-yl) -3- (dimethylaminophenyl) maleic anhydride.

Analogously, the following compounds are obtained by reacting 2- (1,3-benzodioxol-5-yl) -acetic acid with the glyoxylic acids mentioned
2- (1,3-benzodioxol-5-yl) -3- (1,3-benzodioxol-5-yl) maleic anhydride, mp 148 °;
2- (1,3-benzodioxol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (4-methoxyphenyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3-phenyl-maleic anhydride, mp 244 °;
2- (1,3-benzodioxol-5-yl) -3- (3,4-dimethoxyphenyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (thiophene-2-yl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (3,4,5-trimethoxyphenyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (2,4-dimethoxyphenyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (4-chlorophenyl) maleic anhydride and
2- (1,3-Benzodioxol-5-yl) -3- (dimethylaminophenyl) maleic anhydride.

Analogously, the following compounds are obtained by reacting 2- (1,4-benzodioxan-6-yl) acetic acid with the glyoxylic acids mentioned
2- (1,4-benzodioxan-6-yl) -3- (1,3-benzodioxol-5-yl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (2,1,3-benzothiadiazol-5-yl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (4-methoxyphenyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3-phenyl-maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (3,4-dimethoxyphenyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (thiophene-2-yl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (3,4,5-trimethoxyphenyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (2,4-dimethoxyphenyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (4-chlorophenyl) maleic anhydride and
2- (1,4-Benzodioxan-6-yl) -3- (dimethylaminophenyl) maleic anhydride.

Analogously, the following compounds are obtained by reacting 2- (2,1,3-benzoxadiazol-5-yl) acetic acid with the glyoxylic acids mentioned
2- (2,1,3-benzoxadiazol-5-yl) -3- (1,3-benzodioxol-5-yl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-methoxyphenyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3-phenyl-maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4-dimethoxyphenyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (thiophene-2-yl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4,5-trimethoxyphenyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (2,4-dimethoxyphenyl) maleic anhydride;
2- (2,1,3-Benzoxadiazol-5-yl) -3- (4-chlorophenyl) maleic anhydride
and
2- (2,1,3-Benzoxadiazol-5-yl) -3- (dimethylaminophenyl) maleic anhydride.

The following compounds are obtained analogously by reacting 2- (1,3-benzodioxol-6-chloro-5-yl) acetic acid with the glyoxylic acids mentioned
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (1,3-benzodioxol-5-yl) maleic anhydride;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) maleic anhydride;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (4-methoxyphenyl) maleic anhydride;
2- (1,3-benzodioxol-6-chloro-5-yl) -3-phenyl-maleic anhydride;
2- (1-3-benzodioxol-6-chloro-5-yl) -3- (3,4-dimethoxyphenyl) maleic anhydride;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (thiophene-2-yl) maleic anhydride;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (3,4,5-trimethoxyphenyl) maleic anhydride;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (2,4-dimethoxyphenyl) maleic anhydride;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (4-chlorophenyl) maleic anhydride and
2- (1,3-Benzodioxol-6-chloro-5-yl) -3- (dimethylaminophenyl) maleic anhydride.

Example 5

The ring opening of the maleic anhydride derivatives obtained in Example 4 is carried out analogously to Example 3 with NaOH, the disodium salts of the corresponding maleic acids being obtained:
2- (2,1,3-benzothiadiazol-5-yl) -3- (1,3-benzodioxol-5-yl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (4-methoxyphenyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3-phenyl-maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4-dimethoxyphenyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (thiophene-2-yl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4,5-trimethoxyphenyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (2,4-dimethoxyphenyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (4-chlorophenyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (dimethylaminophenyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (1,3-benzodioxol-5-yl) maleic acid, FAB 401;
2- (1,3-benzodioxol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (4-methoxyphenyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3-phenyl-maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (3,4-dimethoxyphenyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (thiophene-2-yl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (3,4,5-trimethoxyphenyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (2,4-dimethoxyphenyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (4-chlorophenyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (dimethylaminophenyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (1,3-benzodioxol-5-yl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (2,1,3-benzothiadiazol-5-yl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (4-methoxyphenyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3-phenyl-maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (3,4-dimethoxyphenyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (thiophene-2-yl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (3,4,5-trimethoxyphenyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (2,4-dimethoxyphenyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (4-chlorophenyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (dimethylaminophenyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (1,3-benzodioxol-5-yl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-methoxyphenyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3-phenyl-maleic acid;
2- (2,1,3-benzoxadiazol-5-l) -3- (3,4-dimethoxyphenyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (thiophene-2-yl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4,5-trimethoxyphenyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (2,4-dimethoxyphenyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-chlorophenyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (dimethylaminophenyl) maleic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (1,3-benzodioxol-5-yl) maleic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) maleic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (4-methoxyphenyl) maleic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3-phenyl-maleic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (3,4-dimethoxyphenyl) maleic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (thiophene-2-yl) maleic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (3,4,5-trimethoxyphenyl) maleic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (2,4-dimethophenyl) maleic acid;
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (4-chlorophenyl) maleic acid and
2- (1,3-benzodioxol-6-chloro-5-yl) -3- (dimethylaminophenyl) maleic acid.

Example 6

A solution of 2- (1,3-benzodioxol-5-yl) -3- (1,3-benzodioxol-5-yl) -malein Acid anhydride in toluene is mixed with dibutylamine and 2 hours heated. After the usual work-up, 2- (1,3-benzodioxol-5-yl) -3- (1,3-benzo dioxol-5-yl) -maleic acid-N, N-dibutyl-monoamide, dibutylammon iumsalz, FAB 597.

Analogously, 2- (2,1,3-benzothiadiazol-5-yl) -3- (2,1,3-benzo) is obtained thiadiazol-5-yl) maleic anhydride 2- (2,1,3-Benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) -malein acid-N, N-dibutyl-monoamide.

Example 7

A solution of 1 g of 2- (1,3-benzodioxol-5-yl) -3- (3-nitrophenyl) maleic acid in 25 ml of methanol is at normal pressure and 20 ° to Standstill hydrogenated on 1 g of Raney nickel. Filter, remove Solvent and receives 2- (1,3-benzodioxol-5-yl) -3- (3-aminophenyl) -malein acid.

Example 8

By reaction with equimolar amounts of acetyl chloride in pyridine and catalytic amounts of dimethylaminopyridine, one obtains
from 2- (1,3-benzodioxol-5-yl) -3- (3-aminophenyl) maleic acid 2- (1,3-benzodioxol-5-yl) -3- (3-acetamidophenyl) maleic acid.

Example 9

By reaction with equimolar amounts of phenylsulfonyl chloride in pyridine
from 2- (1,3-benzodioxol-5-yl) -3- (3-aminophenyl) maleic acid 2- (1,3-benzodioxol-5-yl) -3- (3-phenylsulfonamido-phenyl) maleic acid .

Example 10

To a solution of "A" in DMF, ethyl 2-bromoacetate and Close. The mixture is then stirred at room temperature for 16 hours. Man removes the solvent, works up as usual and receives 2- (2,1,3- Benzothiadiazol-5-yl) succinic acid diethyl ester ("D").

The compound is dissolved together with piperonal in ether and to a added to -10 ° cooled suspension of sodium ethylate in ether. Man stir for 6 hours, work up as usual and obtain 2- (2,1,3-benzothia diazol-5-yl) -3- (1,3-benzodioxol-5-ylmethyl) maleic anhydride.

Analogously, by converting "D"
with (2,1,3-benzothiadiazol-5-yl) carbaldehyde 2- (2,1,3-benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-ylmethyl) maleic anhydride ;
with 4-methoxybenzaldehyde 2- (2,1,3-benzothiadiazol-5-yl) -3- (4-methoxybenzyl) maleic anhydride;
with 3,4-dimethoxybenzaldehyde 2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4-dimethoxybenzyl) maleic anhydride;
with 2,4-dimethoxybenzaldehyde 2- (2,1,3-benzothiadiazol-5-yl) -3- (2,4-dimethoxybenzyl) maleic anhydride;
with thiophene-2-carbaldehyde 2- (2,1-3-benzothiadiazol-5-yl) -3- (thiophene-2-ylmethyl) maleic anhydride;
with 3,4,5-trimethoxybenzaldehyde 2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4,5-trimethoxybenzyl) maleic anhydride;
with 4-dimethylaminobenzaldehyde 2- (2,1,3-benzothiadiazol-5-yl) -3- (4-dimethylaminobenzyl) maleic anhydride;
with benzaldehyde 2- (2,1,3-benzothiadiazol-5-yl) -3-benzyl-maleic anhydride and
with 4-chlorobenzaldehyde 2- (2,1,3-benzothiadiazol-5-yl) -3- (4-chlorobenzyl) maleic anhydride.

Analogously, diethyl 2- (1,3-benzodioxol-5-yl) -bers gives diethyl stony acid [obtainable from ethyl 2- (1,3-benzodioxol-5-yl) -acetate and ethyl bromoacetate] and the aldehydes mentioned the connections below
2- (1,3-benzodioxol-5-yl) -3- (1,3-benzodioxol-5-ylmethyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (2,1,3-benzothiadiazol-5-ylmethyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (4-methoxybenzyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (3,4-dimethoxybenzyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (2,4-dimethoxybenzyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (thiophene-2-ylmethyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (3,4,5-trimethoxybenzyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3- (4-dimethylaminobenzyl) maleic anhydride;
2- (1,3-benzodioxol-5-yl) -3-benzyl-maleic anhydride and
2- (1,3-Benzodioxol-5-yl) -3- (4-chlorobenzyl) maleic anhydride.

Analogously, diethyl 2- (1,4-benzodioxan-6-yl) is obtained from diethyl ethylsuccinate [obtainable from ethyl 2- (1,4-benzodioxan-6-yl) -acetate and ethyl bromoacetate] and the aldehydes mentioned the connections below
2- (1,4-benzodioxan-6-yl) -3- (1,3-benzodioxol-5-ylmethyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (2,1,3-benzothiadiazol-5-ylmethyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (4-methoxybenzyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (3,4-dimethoxybenzyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (2,4-dimethoxybenzyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (thiophene-2-ylmethyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (3,4,5-trimethoxybenzyl) maleic anhydride;
2- (1,4-benzodioxan-6-yl) -3- (4-dimethylaminobenzyl) maleic anhydride;
2- (1, -Benzodioxan-6-yl) -3-benzyl-maleic anhydride and
2- (1,4-Benzodioxan-6-yl) -3- (4-chlorobenzyl) maleic anhydride.

Analogously, diethyl 2- (2,1,3-benzoxadiazol-5-yl) -berins gives diethyl stony acid [obtainable from ethyl 2- (2,1,3-benzoxadiazol-yl) -acetate and ethyl bromoacetate] and mentioned aldehydes the following compounds
2- (2,1,3-benzoxadiazol-5-yl) -3- (1,3-benzodioxol-5-ylmethyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-ylmethyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-methoxybenzyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4-dimethoxybenzyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (2,4-dimethoxybenzyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (thiophene-2-ylmethyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4,5-trimethoxybenzyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-dimethylaminobenzyl) maleic anhydride;
2- (2,1,3-benzoxadiazol-5-yl) -3-benzyl-maleic anhydride and
2- (2,1,3-Benzoxadiazol-5-yl) -3- (4-chlorobenzyl) maleic anhydride.

Example 11

The ring opening of the maleic anhydride derivatives obtained in Example 11 is carried out analogously to Example 3 with NaOH, the disodium salts of the corresponding maleic acids being obtained:
2- (2,1,3-benzothiadiazol-5-yl) -3- (1,3-benzodioxol-5-ylmethyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-ylmethyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (4-methoxybenzyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4-dimethoxybenzyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (2,4-dimethoxybenzyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (thiophene-2-ylmethyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (3,4,5-trimethoxybenzyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (4-dimethylaminobenzyl) maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3-benzyl-maleic acid;
2- (2,1,3-benzothiadiazol-5-yl) -3- (4-chlorobenzyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (1,3-benzodioxol-5-ylmethyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (2,1,3-benzothiadiazol-5-ylmethyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (4-methoxybenzyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (3,4-dimethoxybenzyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (2,4-dimethoxybenzyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (thiophene-2-ylmethyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (3,4,5-trimethoxybenzyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (4-dimethylaminobenzyl) maleic acid;
2- (1,3-benzodioxol-5-yl) -3-benzyl-maleic acid;
2- (1,3-benzodioxol-5-yl) -3- (4-chlorobenzyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (1,3-benzodioxol-5-ylmethyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (2,1,3-benzothiadiazol-5-ylmethyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (4-methoxybenzyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (3,4-dimethoxybenzyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (2,4-dimethoxybenzyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (thiophene-2-ylmethyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (3,4,5-tn.methoxybenzyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (4-dimethylaminobenzyl) maleic acid;
2- (1,4-benzodioxan-6-yl) -3-benzyl-maleic acid;
2- (1,4-benzodioxan-6-yl) -3- (4-chlorobenzyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (1,3-benzodioxol-5-ylmethyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-ylmethyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-methoxybenzyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4-dimethoxybenzyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (2,4-dimethoxybenzyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (thiophene-2-ylmethyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (3,4,5-trimethoxybenzyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-dimethylaminobenzyl) maleic acid;
2- (2,1,3-benzoxadiazol-5-yl) -3-benzyl-maleic acid and
2- (2,1,3-benzoxadiazol-5-yl) -3- (4-chlorobenzyl) maleic acid.

Example 12

A solution of 3.0 g of ethyl 2- (2,1,3-benzothiadiazol-5-yl) -acetate in 20 ml of DMF, 0.41 g of NaH is added and the mixture is stirred for 20 minutes. Then 0.7 ml of bromine are added and it is 3 hours stirred at room temperature. You work up as usual and get 2- (2,1,3- Benzothiadiazol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) succinic acid diethyl ester as a mixture of diastereomers.  

Analogously, ethyl 2- (1,3-benzodioxol-5-yl) is obtained 2- (1,3-benzodioxol-5-yl) -3- (1,3-benzodioxol-5-yl) succinic acid diethyl ester as a mixture of diastereomers.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium Hydrogen phosphate is dissolved in 3 liters of double distilled water with 2N salt acid adjusted to pH 6.5, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Every In jection glass contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and leave cool down. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ PO ₄ .2 H ₂ O, 28.48 g of Na ₂ HPO ₄ .12 H ₂ O and 0.1 g of benzalkonium chloride in 940 ml double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.  

Example E: tablets

A mixture of 1 kg of active ingredient of formula I, 4 kg lactose, 1.2 kg kar Potato starch, 0.2 kg talc and 0.1 kg magnesium stearate are common Formed into tablets in such a way that each tablet contains 10 mg of active ingredient contains.

Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.

Example G: capsules

2 kg of active ingredient of formula I are in the usual way in hard gelatin capsules filled so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of active ingredient of formula I in 60 l of double distilled Water is sterile filtered, filled into ampoules, under sterile conditions lyophilized and sealed sterile. Each ampoule contains 10 mg Active ingredient.

Claims (10)

1. Compounds of formula I.
wherein
Z is a single or a double bond,
R ^{1 is} an unsubstituted or simply substituted in the phenyl part by R ⁷
an unsubstituted or substituted in the cyclohexadienyl part by R ⁷
R ² A, Ar- (CH ₂ ) _m , cycloalkyl- (CH ₂ ) _m , Het- (CH ₂ ) _m or R - (CH ₂ ) _m ,
R ³ , R ^{3 '} each independently of one another OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA',
R ³ and R ^{3 '} together also -O-, thereby forming a cyclic anhydride,
R ⁴ , R ^{4 '} each independently of one another H or A,
R ⁵ A or Ar,
R ^{6 is} phenyl or naphthyl which is unsubstituted or mono-, di- or trisubstituted by A, NH ₂ , NHA, NAA ', NO ₂ , CN or Hal,
R ⁷ A, COOR ⁴ , CN, 1H-tetrazol-5-yl, CONHSO ₂ R ⁵ , Hal, OR ⁴ , NO ₂ , NH ₂ , NHA, NAA ', NHCOR ⁴ , NHCOR ⁶ , NHSO ₂ R ⁴ , NHSO ₂ R ⁶ , S (O) _k R ⁴ , S (O) _k R ⁶ , SO ₂ NR ⁴ R ⁴ , or formyl,
R ⁸ , R ^{8 '} each independently of one another are H or alkyl having 1-6 C atoms,
E CH ₂ or O,
D carbonyl or (CR ⁴ R ^{4 '} ) _n ,
E and D together also CR ⁴ = R ^{4 '} ,
XS or O,
A, A 'each independently of one another alkyl having 1-6 C atoms in which one or two CH ₂ groups by O or S atoms or by -CR ⁸ = CR ^8' groups and / or 1-7 H atoms can be replaced by F,
or benzyl,
Ar unsubstituted or single, double or triple by A, OR ⁴ , NH ₂ , NHA, NAA ', NO ₂ , CN, Hal, NHCOR ⁴ , NHCOR ⁶ , NHSO ₂ R ⁴ , NHSO ₂ R ⁶ , COOR ⁴ , OPh, CONH ₂ , CONHA, CONAA ', COR ⁴ , CONHSO ₂ R ⁴ , CONHSO ₂ R ⁶ , O (CH ₂ ) _n COOR ⁴ , O (CH ₂ ) _n OR ⁴ , SO ₂ NR ⁴ R ^4' , p (O) _k R ⁶ or S (O) _k R ⁴ substituted phenyl or naphthyl,
Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1-4 N, O and / or S atoms, bonded via N or C, which is unsubstituted or mono-, di- or triple by Hal, A, COOR ⁴ , CN, 1H-tetrazol-5-yl, CONHSO ₂ R ⁵ , NH ₂ , NHA, NAA ', NO ₂ and / or = O may be substituted,
Hal fluorine, chlorine, bromine or iodine,
k 0, 1 or 2
m 0, 1 or 2 and
n is 1 or 2,
as well as the (Z) and (E) isomers and the salts of all isomers. 2. Enantiomers and diastereomers of the compounds of formula I. according to claim 1. 3. Compounds according to claim 1

• a) 2- (1,3-benzodioxol-5-yl) -3- (2,1,3-benzothiadiazol-5-yl) succinic acid;
• b) 2,3-bis (1,3-benzodioxol-5-yl) maleic acid;
• c) 2,3-bis (1,3-benzodioxol-5-yl) maleic acid-N, N-dibutyl monoamide;
• d) 2,3-bis (1,3-benzodioxol-5-yl) maleic anhydride;
• e) 2- (1,3-benzodioxol-5-yl) -3-phenyl-maleic anhydride;
  as well as their salts.

4. A process for the preparation of compounds of the formula I as claimed in claim 1 and their salts,
wherein

• a) Z is a single bond and R ³ , R ³ , each independently of one another OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA ',
  characterized in that a compound of formula II
  wherein
  R ^{2 has} the meaning given in claim 1,
  R ^{3 '} OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA' and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  with a compound of formula III
  wherein
  R ^{1 has} the meaning given in claim 1 and
  R ³ OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA ',
  implements
  or a compound of formula IV
  wherein
  R ^{1 has} the meaning given in claim 1,
  R ³ OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA 'and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  with a compound of formula V
  wherein
  R ^{2 has} the meaning given in claim 1 and
  R ³ OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA ',
  implements
  or that for the preparation of compounds of the formula I according to claim 1 and their salts,
  wherein
• b) Z is a double bond and
  R ³ , R ³ , each independently of one another, mean OR ⁴ , NHSO ₂ R ⁵ , NH ₂ , NHA or NAA ',
  reacting a compound of the formula II with a compound of the formula IV in which the radicals in II and IV have the meanings indicated,
  or that for the preparation of compounds of the formula I according to claim 1 and their salts,
  wherein
• c) Z is a double bond and
  R ³ and R ^{3 '} together are -O-, thereby forming a cyclic anhydride,
  a compound of formula VI
  wherein
  R ^{2 has} the meaning given in claim 1 and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  with a compound of formula VII
  wherein
  R ^{1 has} the meaning given in claim 1 and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  implements
  or a compound of formula VIII
  wherein
  R ^{1 has} the meaning given in claim 1 and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  with a compound of formula IX
  wherein
  R ^{2 has} the meaning given in claim 1 and
  L denotes Cl, Br, I or a free or reactively functionally modified OH group,
  implements
  or that for the preparation of compounds of the formula I according to claim 1 and their salts,
  wherein
• d) Z is a double bond,
  R ³ and R ³ , together -O-, thereby forming a cyclic anhydride, and in 1 or 2 mean
  a compound of formula III,
  wherein
  R ^{1 has} the meaning given in claim 1 and
  R ³ OR ⁴ means
  with a compound of formula X
  L-CH ₂ -COOA X
  wherein
  L Cl, Br, I or a free or reactive functionally modified OH group and
  A denotes alkyl with 1-6 C atoms or benzyl,
  to a compound of formula XI
  and then the compound of formula XI with a compound of formula XII
  R ² -CHO XII
  wherein
  R ² A, Ar- (CH ₂ ) _m , cycloalkyl- (CH ₂ ) _m , Het- (CH ₂ ) _m or R 1 - (CH ₂ ) _m and
  in 0 or 1 mean
  implements
  and / or that in a compound of the formula I one or more radicals R ¹ , R ² , R ³ and / or R ^{3 'are converted} into one or more radicals R ¹ , R ² , R ³ and / or R ^{3 '} converts
  for example by
• i) hydrolyzing an ester group to a carboxy group,
  ii) opens a cyclic anhydride structure to an open chain dicarboxylic acid derivative
  iii) reducing a nitro group,
  iv) acylated an amino group
  and / or converts a base or acid of the formula I into one of its salts.

5. Process for the preparation of pharmaceutical preparations, thereby characterized in that a compound of formula I according to Claim 1 and / or one of their physiologically acceptable Salts together with at least one solid, liquid or semi liquid carrier or auxiliary in a suitable dosage form brings. 6. Pharmaceutical preparation, characterized by a content on at least one compound of the formula I according to claim 1 and / or one of their physiologically acceptable salts. 7. Compounds of formula I according to claim 1 and their physiological harmless salts to combat hypertension, heart failure efficiency, renal failure, cerebral infarction, coronary heart disease, renal, cerebral and myocardial ischemia, subarachnoid Hemorrhage, inflammation, asthma and endotoxic shock. 8. Medicament of formula I according to claim 1 and their physiological harmless salts as endothelin receptor antagonists 9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a drug. 10. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the Combating hypertension, heart failure, kidney failure, Cerebral infarction, coronary heart disease, renal, cerebral and myocardial ischemia, subarachnoid hemorrhage, Inflammation, asthma and endotoxic shock.