DE19711785A1 - Endothelin receptor antagonists - Google Patents

Abstract

The invention relates to novel compounds of formula (I) wherein X means N-R<3>, O or S, and R, R<1> and R<2> have the meaning cited in claim 1. The invention further relates to the salts thereof. Said compounds display endothelin-receptor antagonistic properties.

Description

The invention relates to compounds of the formula I.

wherein
X NR ³ , O or S,
R 2,1,3-benzothiadiazol-4- or 5-yl or 2,1-benzoisothiazol-5- or 6-yl, unsubstituted or mono- or disubstituted by R ² and / or R ^{2 '} , or unsubstituted or mono- phenyl which is substituted twice or three times by R ² and / or R ^{2 '} ,
R ¹ H or A,
R ² , R ^{2 '} each independently of one another H, A, OH, OA, Hal, OCF ₃ , OCHF ₂ , -O-CO-A, -O-alkylene-COOR ¹ , -O-alkylene-CH ₂ -OR ¹ , or unsubstituted or in the phenyl part mono- or disubstituted by R ⁴ and / or R ⁴ , OCH ₂ -phenyl or -O-CO-phenyl,
R ² and R ^{2 '} together also -OCH ₂ O-, -OCH ₂ CH ₂ O- or -OCH ₂ CH ₂ -,
R ^{3 is} H, A, alkylene-OA, -CO-OA or unsubstituted or in the phenyl part mono- or disubstituted by R ⁴ and / or R ^{4 '} substituted alkylene-phenyl,
R ⁴ , R ^{4 '} each independently of one another H, A, OH, OA, Hal, COOR ¹ or CH ₂ OR ¹ ,
A alkyl with 1-6 C atoms,
Hal fluorine, chlorine, bromine or iodine,
mean,
as well as their salts.

Similar connections with indane and inden backbones are from WO 93/08799, those with indole systems are from WO 94/14434, pyrimidine derivatives are from EP 0 526 708 A1 and phenyl and naphthyl compounds gen are known from EP 0 617 001 A1.

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 compounds show, among other things, a high affinity for the endothelin subreceptors ET _A and ET _B. These effects can be determined by conventional in vitro or in vivo methods, such as. B. described by PD 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, characterized in that

• a) a compound of formula II
  wherein
  R ¹ , R ² , R ^{2 '} and X have the meaning given in claim 1,
  with a compound of formula III
  R-CH ₂ -L III
  wherein
  L means Cl, Br, I or a free or reactively functionally modified OH group and
  R has the meaning given in claim 1,
  implements
  or
• b) a compound of formula IV
  wherein
  Q means Cl, Br or I and
  R, R ¹ and X have the meanings given in claim 1,
  with a boron compound of formula V
  wherein
  L, L 'each independently means OH, OCH ₃ , OC ₂ H ₅ or OC ₃ H ₇ , and
  R ² , R ^{2 'has} the meaning given in claim 1,
  implements
  and / or converting one or more radicals R, R ¹ and / or R ² into one or more radicals R, R ¹ and / or R ² in a compound of formula I,
  for example by
  hydrolyzed an ester group to a carboxy group,
  and / or converts a base or acid of the formula I into one of its salts.

For all residues that occur several times, such as B. A, R ² and R ⁴ , applies that their meanings are independent of each other.

Above and below, the radicals or parameters R, X, R ¹ , R ² , R ^{2 '} , R ³ , R ⁴ , L and Q have the meanings given in the formulas I to V, 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-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, more preferred is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Alkylene preferably means methylene, ethylene, propylene, butylene, also pentylene or hexylene. Alkylene may also be absent.

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

R ² , R ^{2 '} , each independently, preferably z. B. H, A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyclopentyloxy, cyclohexyloxy, trifluoromethoxy, difluoromethoxy, acetyloxy, propionyloxy, butyryloxy, carboxymethoxy, carboxyethoxy, methoxycarbonylyloxy, methoxycarbonyl Ethoxycarbonylmethoxy, ethoxycarbonylethoxy, hydroxymethoxy, hydroxyethoxy, methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy, benzyloxy, benzoyloxy, o-, m- or p-methyl- (benzyloxy- or benzoyloxy), o-, m- or p-ethyl- (benzyloxy- or benzoyloxy), o-, m- or p-propyl- (benzyloxy- or benzoyloxy), o-, m- or p-isopropyl- (benzyloxy- or benzoyloxy), o-, m- or p-tert-butyl - (benzyloxy- or benzoyloxy), o-, m- or p-hydroxy- (benzyloxy- or benzoyloxy), o-, m- or p-methoxy- (benzyloxy- or benzoyloxy), o-, m- or p- Ethoxy- (benzyloxy- or benzoyloxy), o-, m- or p-fluoro- (benzyloxy- or benzoyloxy), o-, m- or p-bromo- (benzyloxy- or benzoyloxy), o-, m- or p - Chlorine (benzyloxy or benzoylo xy), o-, m- or p- (hydroxymethyl) - (benzyloxy- or benzoyloxy), o-, m- or p-carboxy- (benzyloxy- or benzoyloxy), o-, m- or p-methoxycarbonyl- ( benzyloxy- or benzoyloxy), o-, m- or p-ethoxycarbonyl- (benzyloxy- or benzoyloxy).

R is preferably z. B. 2,1,3-benzothiadiazol-5- or 6-yl, o-, m- or p-methoxyphenyl, 2,5-dimethoxyphenyl, 1,3-benzodioxol-4-or 5-yl, 1,3-benzodioxol-6-methoxy-5-yl, 1,4-benzodioxan-5- or 6-yl, 2,1,3- Benzothiadiazol-6-methyl-5-yl, 2,1,3-benzothiadiazol-6-chloro-5-yl, 2,1- Benzoisothiazol-5- or 6-yl, 3,5-dimethoxyphenyl or 3,4,5- Trimethoxyphenyl.

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 Ie, which correspond to the formula I and in which the unspecified radicals have the meaning given for the formula I, but in which

in Ia R ² , R ^{2 '} each independently of one another H, A, OH, OA, Hal, -O-alkylene-COOR ¹ , -O-alkylene-CH ₂ -OR ¹ , or unsubstituted or in the phenyl part once or twice R ⁴ and / or R ^{4 '} substituted OCH ₂ -phenyl or -O-CO-phenyl and
R ² and R ^{2 '} together also -OCH ₂ O-, -OCH ₂ CH ₂ O- or -OCH ₂ CH ₂ -
mean;

in Ib R ² , R ^{2 '} each independently of one another H, A, OH, OA, Hal, -O-CH ₂ -COOR ¹ , -O-CH ₂ -CH ₂ -OR ¹ , or unsubstituted or in the phenyl moiety OCH ₂ -phenyl or -O-CO-phenyl substituted twice by R ⁴ and / or R ^{4 '} and
R ² and R ^{2 '} , together also -OCH ₂ O-, -OCH ₂ CH ₂ O- or -OCH ₂ CH ₂ - and
R ³ H or A,
mean;

in Ic X NR ³ ,
R ² , R ^{2 'are} each independently of one another H, A, OH, OA, Hal, -O-CH ₂ -COOR ¹ , -O-CH ₂ -CH ₂ -OR ¹ , or unsubstituted or in the phenyl part once or twice R ⁴ and / or R ^{4 '} substituted OCH ₂ -phenyl or -O-CO-phenyl and
R ² and R ^{2 '} together also -OCH ₂ O-, -OCH ₂ CH ₂ O- or -OCH ₂ CH ₂ - and
R ³ H or A,
mean;

in Id XO or S,
R ² , R ^{2 'are} each independently of one another H, A, OH, OA, Hal, -O-CH ₂ -COOR ¹ , -O-CH ₂ -CH ₂ -OR ¹ , or unsubstituted or in the phenyl part once or twice R ⁴ and / or R ^{4 '} , substituted OCH ₂ -phenyl or -O-CO-phenyl and
R ² and R ^{2 '} together also -OCH ₂ O-, -OCH ₂ CH ₂ O- or -OCH ₂ CH ₂ -,
mean;

in Ie X NR ³ , O or S,
R 2,1,3-benzothiadiazol-5- or 6-yl, o-, m- or p-methoxyphenyl, 2,5-dimethoxyphenyl, 1,3-benzodioxol-4- or 5-yl, 1,3-benzodioxole -6-methoxy-5-yl, 1,4-benzodioxan-5- or 6-yl, 2,1,3-benzothiadiazol-6-methyl-5-yl, 2,1,3-benzothiadiazol-6-chloro 5-yl, 2,1-benzoisothiazol-5- or 6-yl, 3,5-dimethoxyphenyl or 3,4,5-trimethoxyphenyl
R ¹ H or A,
R ² , R ^{2 'are} each independently of one another H, A, OH, OA, Hal, -O-CH ₂ -COOR ¹ , -O-CH ₂ -CH ₂ -OR ¹ , or unsubstituted or in the phenyl part once or twice R ⁴ and / or R ⁴ , substituted OCH ₂ -phenyl or -O-CO-phenyl and
R ² and R ^{2 '} together also -OCH ₂ O-, -OCH ₂ CH ₂ O- or -OCH ₂ CH ₂ -,
R ³ H or A and
R ⁴ , R ^{4 '} each independently of one another H, A, OH, OA, Hal, COOR ¹ or CH ₂ OR ¹ ,
mean.

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 can preferably be obtained by reacting compounds of formula II with compounds of formula III.

In the compounds of formula III, L is preferably Cl, Br, I or a reactively modified OH group such as alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C- Atoms (preferably phenyl or p-tolylsulfonyloxy).

The reaction is usually carried out in an inert solvent, in Ge presence of an acid-binding agent, preferably an alkali or Alkaline earth metal hydroxides, carbonates or bicarbonates or another  salt of a weak acid of the alkali or alkaline earth metals preferably potassium, sodium, calcium or cesium. The Zu too set of an organic base such as triethylamine, dimethylaniline, pyridine or Quinoline or an excess of the heterocycle component of the Formula II or the alkylation derivative of formula III 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, trifluoromethylbenzene, 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 monomethyl or -monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (Diglyme); Ketones such as acetone or butanone; Amides such as acetamide, Dimethylacetamide 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 like Nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of mentioned solvents.

The starting compounds of formula II are usually new, while which are generally known in Formula III.

However, the compounds of formula II can be prepared by methods known per se. So z. B., analogous to the regulation by Yokoe et al. in Chem. Pharm. Bull. Jpn. 1989, 529, 1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene-2-carboxylic acid ethyl ester by reacting 1-bromo-8-methyl-3, 8-dihydro-3,8-diaza-cyclopenta- [a] inden-2-carboxylic acid ethyl ester with 4-methoxyphenyl-boronic acid with the addition of a noble metal catalyst such as PdCl ₂ (dppf) = palladium (II) - [1,1- bis- ( diphenyl-phosphino) -ferrocene] chloride and an acid-binding agent. This is expediently carried out at temperatures between 0 and approximately 200 °; preferably one works between 30 and 80 °.

Suitable inert solvents are those already mentioned above.

Compounds of formula I can also be obtained by Reacts compounds of formula IV with compounds of formula V. The starting compounds of the formula IV and V are generally new, but can be prepared by methods known per se.

In the compounds of the formula IV, Q is preferably Cl, Br or I. The implementation is carried out analogously to the regulation by Yokoe et al. in Chem. Pharm. Bull. Jpn. 1989, 529, as described above.

The reaction is usually carried out in an inert solvent, in Ge presence of an acid-binding agent and at temperatures as above specified.

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, R ¹ and / or R ² into one or more radicals R, R ¹ and / or converts R ² , e.g. B. by hydrolyzing an ester group to a carboxy group.

You can also free hydroxyl groups in the usual way with a Acyl 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 compound of the formula I can be functional modified hydroxy group by solvolysis or hydrogenolysis usual methods-to be set free. COOA groups can e.g. B. with NaOH or KOH in water, water-THF or water-dioxane Temperatures between 0 and 100 ° are saponified.  

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 In particular acids are considered, the physiologically harmless Deliver salts. So inorganic acids can be used, e.g. B. Sulfuric acid, nitric acid, hydrohalic acids such as chlorine 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, Ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfone acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfone acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. B. Picrates, can be used to isolate and / or purify the compounds of formula I can be used.

On the other hand, compounds of the 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 position of pharmaceutical preparations, especially on non-chemical ischemic way. 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.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, 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, dried organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization. Rf values on silica gel; 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 1.0 g of 8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester (described in Synth. Commun., 1990, 2011-2017) in 10 ml of THF, 0.74 g of N-bromosuccinimide is added and 15 are stirred Minutes after. After the usual work-up, 1.1 g of 1-bromo-8- methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester ("A"), mp 197-198 °.

A solution of 1.0 g of "A" in 100 ml of ethylene glycol dimethyl ether is mixed with 0.74 g of 4-methoxyphenylboronic acid, 15 ml of 2N sodium carbonate solution and 20 mg of PdCl ₂ (dppf) catalyst and heated under reflux for 2 hours. After customary working up, 0.76 g of 1- (4-methoxyphenyl) - 8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene-2-carbonic acid ethyl ester ("B"), F . 198-199 °.

Analogously, by converting "A"
with 1,3-benzodioxol-5-boronic acid
1- (1,3-Benzodioxol-5-yl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 2,3-dihydrobenzofuran-5-boronic acid
1- (2,3-Dihydrobenzofuran-5-yl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1,4-benzodioxane-6-boronic acid
1- (1,4-Benzodioxan-6-yl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with (3-fluoro-4-methoxyphenyl) boronic acid
1- (3-Fluoro-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with (2-carboxymethoxy-4-methoxyphenyl) boronic acid
1- (2-Carboxymethoxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene-2-carboxylic acid ethyl ester;
with (2-hydroxyethoxy-4-methoxyphenyl) boronic acid
1- (2-Hydroxyethoxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with [2- (2-carboxy-benzyloxy) -4-methoxyphenyl] boronic acid
1- [2- (2-Carboxy-benzyloxy) -4-methoxyphenyl] -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene-2-carboxylic acid ethyl ester;
with [2- (2-hydroxymethyl-benzyloxy) -4-methoxyphenyl] boronic acid 1- [2- (2-hydroxymethyl-benzyloxy) -4-methoxyphenyl] -8-methyl-3,8-dihydro-3,8- diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with (2-hydroxy-4-methoxyphenyl) boronic acid
1- (2-Hydroxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester and
with (2-benzyloxy-4-methoxyphenyl) boronic acid
1- (2-Benzyloxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester.

Analogously, 1-bromo-8-oxa-3-aza-cyclopenta is obtained by reaction [a] Inden-2-carboxylic acid ethyl ester ("C") [obtainable by bromination of 8- Oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester (described in Oh one. Lett., 1977, 401-404) with 4-methoxyphenylboronic acid the compound 1- (4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2- carboxylic acid ethyl ester.

Analogously, the following compounds are obtained by reacting "C" with the above-mentioned boronic acid derivatives
1- (1,3-Benzodioxol-5-yl) -8-oxa-3-aza-cyclopenta [a] inden-2-carbonate, ethyl ester;
1- (2,3-Dihydrobenzofuran-5-yl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
1- (1,4-Benzodioxan-6-yl) -8-oxa-3-aza-cyclopenta [a] inden-2-carbonate, ethyl ester;
1- (3-Fluoro-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
1- (2-Carboxymethoxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
1- (2-Hydroxyethoxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
1- [2- (2-Carboxy-benzyloxy) -4-methoxyphenyl] -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
Ethyl 1- [2- (2-hydroxymethylbenzyloxy) -4-methoxyphenyl] -8-oxa-3-aza-cyclopenta [a] indene-2-carboxylate;
1- (2-Hydroxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester and
1- (2-Benzyloxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester.

Analogously, 1-bromo-8-thia-3-aza-cyclopenta is obtained by reaction [a] Inden-2-carboxylic acid ethyl ester ("D") [obtainable by bromination of 8- Thixa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester (described in Chem. Abstr., 1968, 69, 27290) with 4-methoxyphenylboronic acid the compound 1- (4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2- carboxylic acid ethyl ester.

Analogously, the following compounds are obtained by reacting "D" with the above-mentioned boronic acid derivatives
1- (1,3-Benzodioxol-5-yl) -8-thia-3-aza-cyclopenta [a] inden-2-carbonate, ethyl ester;
1- (2,3-Dihydrobenzofuran-5-yl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
1- (1,4-Benzodioxan-6-yl) -8-thia-3-aza-cyclopenta [a] inden-2-carbonate, ethyl ester;
1- (3-Fluoro-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
1- (2-Carboxymethoxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
1- (2-Hydroxyethoxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
1- [2- (2-Carboxy-benzyloxy) -4-methoxyphenyl] -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
1- [2- (2-hydroxymethyl-benzyloxy) -4-methoxyphenyl] -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
1- (2-Hydroxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester and
1- (2-Benzyloxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester.

Example 2

A solution of 0.7 g "B" in 20 ml DMF is mixed with 0.82 g cesium carbonate added and stirred for 30 minutes. After adding 0.58 g of 5-bromo methyl- (2,1,3-benzothiadiazole) is stirred for a further 3 hours. After The usual work-up gives 0.96 g of 3- (2,1,3-benzothiadiazol-5-yl methyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] Inden-2-carboxylic acid ethyl ester, mp 124-125 °.

Analogously, the reaction of 5-bromomethyl- (2,1,3-benzothiadiazole)
with 1- (1,3-benzodioxol-5-yl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (1,3-benzodioxol-5-yl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] ethyl indene-2-carboxylate;
with 1- (2,3-dihydrobenzofuran-5-yl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2,3-dihydrobenzofuran-5-yl) - 8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- (1,4-benzodioxan-6-yl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (1,4-benzodioxan-6-yl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] ethyl indene-2-carboxylate;
with 1- (3-fluoro-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (3-fluoro-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden- 2-carboxylic acid ethyl ester;
with 1- (2-carboxymethoxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden- 2-carboxylic acid ethyl ester;
with 1- (2-hydroxyethoxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-hydroxyethoxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden- 2-carboxylic acid ethyl ester;
with 1- [2- (2-carboxy-benzyloxy) -4-methoxyphenyl] -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene-2-carboxylic acid ethyl ester
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- [2- (2-carboxy-benzyloxy) -4-methoxyphenyl] -8-methyl-3,8-dihydro-3,8-diaza- cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- [2- (2-hydroxymethyl-benzyloxy) -4-methoxyphenyl] -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- [2- (2-hydroxymethylbenzyloxy) -4-methoxyphenyl] -8-methyl-3,8-dihydro-3,8-diaza- cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- (2-hydroxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-hydroxy-4-methoxyphenyl) - 8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene- 2-carbonic acid ethyl ester;
with 1- (2-benzyloxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-benzyloxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden- 2-carboxylic acid ethyl ester;
with 1- (4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carbonic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] indene-2-carboxylic acid ethyl ester, mp 144-145 °;
with 1- (1,3-benzodioxol-5-yl) -8-oxa-3-aza-cyclopenta [a] inden-2-carbonic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (1,3-benzodioxol-5-yl) -8-oxa- 3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- (2,3-dihydrobenzofurnn-5-yl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2,3-dihydrobenzofuran-5-yl) - 8-oxa-3-aza-cyclopenta [a] indene-2-carboxylic acid ethyl ester;
with 1- (1,4-benzodioxan-6-yl) -8-oxa-3-aza-cyclopenta [a] inden-2-carbonic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (1,4-benzodioxan-6-yl) -8-oxa- 3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- (3-fluoro-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (3-fluoro-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- (2-carboxymethoxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] indene-2-carboxylic acid ethyl ester;
with 1- (2-hydroxyethoxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-hydroxyethoxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] indene-2-carboxylic acid ethyl ester;
with 1 [2- (2-carboxy-benzyloxy) -4-methoxyphenyl] -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester 3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- [2- (2-carboxy-benzyloxy) -4-methoxyphenyl] -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- [2- (2-hydroxymethyl-benzyloxy) -4-methoxyphenyl] -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- [2- (2-hydroxymethylbenzyloxy) -4-methoxyphenyl] -8-oxa-3-aza-cyclopenta [a] inden-2- carbonic acid ethyl ester;
with 1- (2-hydroxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-hydroxy-4-methoxyphenyl) - 8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1 (2-benzyloxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-benzyloxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] indene-2-carboxylic acid ethyl ester;
with 1- (4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carbonic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] indene-2-carboxylic acid, ethyl ester F. 176-177 °;
with 1- (1,3-benzodioxol-5-yl) -8-thia-3-aza-cyclopenta [a] inden-2-carbonic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (1,3-benzodioxol-5-yl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- (2,3-dihydrobenzofuran-5-yl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2,3-dihydrobenzofuran-5-yl) - 8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid, ethyl ester;
with ethyl 1- (1,4-benzodioxan-6-yl) -8-thia-3-aza-cyclopenta [a] indene-2-carbon
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (1,4-benzodioxan-6-yl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- (3-fluoro-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (3-fluoro-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- (2-carboxymethoxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] indene-2-carboxylic acid ethyl ester;
with 1- (2-hydroxyethoxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-hydroxyethoxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester;
with 1- [2- (2-carboxy-benzyloxy) -4-methoxyphenyl] -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- [2- (2-carboxy-benzyloxy) -4-methoxyphenyl] -8-thia-3-aza-cyclopenta [a] inden-2- carboxylic acid ethyl ester;
with 1- [2- (2-hydroxymethyl-benzyloxy) -4-methoxyphenyl] -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- [2- (2-hydroxymethylbenzyloxy) -4-methoxyphenyl] -8-thia-3-aza-cyclopenta [a] inden-2- carbonic acid ethyl ester;
with 1- (2-hydroxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-hydroxy-4-methoxyphenyl) - 8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester and
with 1- (2-benzyloxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-benzyloxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester.

Analogously, by converting "B"
with 2-methoxybenzyl bromide
3- (2-methoxybenzyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene-2-carboxylic acid ethyl ester, mp 144-145 °;
with 2,5-dimethoxybenzyl bromide
3- (2,5-Dimethoxybenzyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene-2-carboxylic acid ethyl ester, mp 169-170 ° ;
with (1,3-benzodioxol-5-yl) methyl bromide
3- (1,3-Benzodioxol-5-ylmethyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester, F. 139-140 °;

Analogously, ethyl 1- (4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] is obtained by reacting 1- (4-methoxyphenyl)
with 2-methoxybenzyl bromide
3- (2-methoxybenzyl) -1- (4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester, mp 107-108 ° and
with 2,5-dimethoxybenzyl bromide
3- (2,5-Dimethoxybenzyl) -1- (4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid ethyl ester, mp 109-110 °.

Example 3

A solution of 0.5 g of 3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (4-methoxy phenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carbon Acid ethyl ester in 25 ml THF / ethanol (1: 1) with 25 ml 1 N sodium hydroxide solution added and heated under reflux for 5 hours. The solvent will removed and refurbished as usual. 0.36 g of 3- (2,1,3-benzo thiadiazol-5-ylmethyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza- cyclopenta [a] inden-2-carboxylic acid, mp 172-173 °.

The following carboxylic acids are obtained analogously from the carboxylic acid esters obtained in Example 2 by hydrolysis
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (1,3-benzodioxol-5-yl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2,3-dihydrobenzofuran-5-yl) - 8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (1,4-benzodioxan-6-yl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (3-fluoro-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden- 2-carboxylic acid;
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden- 2-carboxylic acid;
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-hydroxyethoxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden- 2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- [2- (2-carboxy-benzyloxy) -4-methoxyphenyl] -8-methyl-3,8-dihydro-3,8-diaza- cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- [2- (2-hydroxymethylbenzyloxy) -4-methoxyphenyl] -8-methyl-3,8-dihydro-3,8-diaza- cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-hydroxy-4-methoxyphenyl) - 8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene- 2-carboxylic acid;
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-benzyloxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden- 2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid, mp 155-156 °;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (1,3-benzodioxol-5-yl) -8-oxa- 3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2,3-dihydrobenzofuran-5-yl) - 8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (1,4-benzodioxan-6-yl) -8-oxa- 3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (3-fluoro-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2-hydroxyethoxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- [2- (2-carboxy-benzyloxy) -4-methoxyphenyl] -8-oxa-3-aza-cyclopenta [a] inden-2- carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- [2- (2-hydroxymethylbenzyloxy) -4-methoxyphenyl] -8-oxa-3-aza-cyclopenta [a] inden-2- carbon acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2-hydroxy-4-methoxyphenyl) - 8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2-benzyloxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid, potassium salt, mp 303-305 ° (Decomposition);
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (1,3-benzodioxol-5-yl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2,3-dihydrobenzofuran-5-yl) - 8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (1,4-benzodioxan-6-yl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (3-fluoro-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (2-carboxymethoxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) - 1- (2-hydroxyethoxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- [2- (2-carboxy-benzyloxy) -4-methoxyphenyl] -8-thia-3-aza-cyclopenta [a] inden-2- carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- [2- (2-hydroxymethylbenzyloxy) -4-methoxyphenyl] -8-thia-3-aza-cyclopenta [a] inden-2- carbon acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2-hydroxy-4-methoxyphenyl) - 8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2-benzyloxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid;
3- (2-methoxybenzyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene-2-carboxylic acid, mp 141-142 °;
3- (2,5-Dimethoxybenzyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid, mp 133-134 ° ;
3- (1,3-benzodioxol-5-ylmethyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid, F. 253-254 °;
3- (2-methoxybenzyl) -1- (4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid, mp 173-174 ° and
3- (2,5-Dimethoxybenzyl) -1- (4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid, mp 159-160 °.

Example 4

Analogously to Example 1, reaction of 3- (2,1,3-benzothia diazol-5-ylmethyl) -1-bromo-8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester with 4-methoxyphenyl boronic acid Compound 1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza- cyclopenta [a] inden-2-carboxylic acid ethyl ester, mp 198-199 °.

Example 5

For the preparation of compounds of the formula I in which R ² , R ^{2 '} OH, -O-alkylene-COOH, -O-alkylene-CH ₂ -OH or in the phenyl part mono- or disubstituted by OH, CH ₂ OH or COOH ₂ -phenyl or -O-CO-phenyl and R is a COOH-functionalized radical, the method of preparation listed below offers itself.

A solution of 1 g of 1- (2-benzyloxy-4-methoxyphenyl) -8-methyl-3,8- dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester in 25 ml Methanol is at normal pressure and 200 to a standstill on 1 g of Raney Nickel hydrogenated. The mixture is filtered, the solvent is removed and 1- (2- Hydroxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester.

Equimolar amounts of the hydroxy compound obtained, chloroacetic acid ethyl ester and sodium carbonate in DMF are stirred for 3 hours. After usual work-up gives 1- (2-ethoxycarbonylmethoxy-4- methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2- carboxylic acid ethyl ester.

Analogous to Example 2, subsequent reaction with 5- Bromomethyl (2,1,3-benzothiadiazole) the compound 3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (2-ethoxycarbonylmethoxy-4- methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2- carboxylic acid ethyl ester.

By hydrolysis analogously to Example 3, 3- (2,1,3-benzothiadiazole-5- ylmethyl) -1- (2-carboxymethoxy-4-methoxyphenyl) -8-methyl-3,8-dihydro- 3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ethyl ester.  

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 Dragees

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 (9)

1. Compounds of formula I.
wherein
X NR ³ , O or S,
R 2,1,3-benzothiadiazol-4- or 5-yl or 2,1-benzoisothiazol-5- or 6-yl, unsubstituted or mono- or disubstituted by R ² and / or R ^{2 '} , or unsubstituted or mono- phenyl which is substituted twice or three times by R ² and / or R ^{2 '} ,
R ¹ H or A,
R ² , R ^{2 '} each independently of one another H, A, OH, OA, Hal, OCF ₃ , OCHF ₂ , -O-CO-A, -O-alkylene-COOR ¹ -O-alkylene-CH ₂ -OR ¹ , or unsubstituted or in the phenyl part mono- or disubstituted by R ⁴ and / or R ⁴ , OCH ₂ -phenyl or -O-CO-phenyl,
R ² and R ^{2 '} , together also -OCH ₂ O-, -OCH ₂ CH ₂ O- or -OCH ₂ CH ₂ -,
R ^{3 is} H, A, alkylene-OA, -CO-OA or unsubstituted or in the phenyl part mono- or disubstituted by R ⁴ and / or R ^{4 '} substituted alkylene-phenyl,
R ⁴ , R ^{4 '} each independently of one another H, A, OH, OA, Hal, COOR ¹ or CH ₂ OR ¹ ,
A alkyl with 1-6 C atoms,
Hal fluorine, chlorine, bromine or iodine,
mean,
as well as their salts. 2. Compounds of formula I according to claim 1

• a) 3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2- carbon acid;
• b) 3- (2-methoxybenzyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] indene-2-carboxylic acid;
• c) 3- (2,5-dimethoxybenzyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid;
• d) 3- (1,3-Benzodioxol-5-ylmethyl) -1- (4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid ;
• e) 3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid;
• f) 3- (2,1,3-benzothiadiazol-5-ylmethyl) -1- (4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid;
• g) 3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (3-carboxymethoxy-4-methoxyphenyl) -8-methyl-3,8-dihydro-3,8-diaza-cyclopenta [a] inden-2-carboxylic acid;
• h) 3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (3-carboxymethoxy-4-methoxyphenyl) -8-oxa-3-aza-cyclopenta [a] inden-2-carboxylic acid;
• i) 3- (2,1,3-Benzothiadiazol-5-ylmethyl) -1- (3-carboxymethoxy-4-methoxyphenyl) -8-thia-3-aza-cyclopenta [a] inden-2-carboxylic acid.

3. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that

• a) a compound of formula II
  wherein
  R, R ² , R ^{2 '} and X have the meaning given in claim 1, with a compound of the formula III
  R-CH ₂ -L III
  wherein
  L means Cl, Br, I or a free or reactively functionally modified OH group and
  R has the meaning given in claim 1,
  implements
  or
• b) a compound of formula IV
  wherein
  Q means Cl, Br or I and
  R, R ¹ and X have the meanings given in claim 1,
  with a boron compound of formula V
  wherein
  L, L 'each independently means OH, OCH ₃ , OC ₂ H ₅ or OC ₃ H ₇ , and
  R ² , R ^{2 'has} the meaning given in claim 1,
  implements
  and / or in a compound of the formula I one or more radicals R ¹ R ^{1 '} and / or R ^{2 are converted} into one or more radicals R, R ¹ and / or R ² ,
  for example by
  hydrolyzed an ester group to a carboxy group,
  and / or converts a base or acid of the formula I into one of its salts.

4. 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. 5. 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. 6. 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. 7. Medicament of formula I according to claim 1 and its physiological harmless salts as endothelin receptor antagonists. 8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a drug. 9. 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.