DE2733440A1 - BENZ SQUARE CLAMP ON CD SQUARE CLIP ON INDOLYL DERIVATIVES, THEIR USE AND MANUFACTURING - Google Patents

Description

SANDoz-PATENT-GMBH " ^{Case 1OO} ~ ⁴⁶³²

Loerrach <f 2733A40

Benz [cd] indolyl derivatives, their uses and Manufacturing

The invention relates to compounds of the formula I in which R _{1 is} in the 3- or 5-position and

a) -NHCOR. means in which R is hydrogen, alkyl with 1-4 carbon atoms, cycloalkyl with
3-7 carbon atoms, alkoxy with 1-4 carbon atoms, a 5- or 6-membered aromatic heterocycle with a nitrogen, oxygen or sulfur atom as a hetero atom, phenyl, phenylalkyl with 1-5 carbon atoms

in the alkyl part, by halogen with an atomic number of 9 to 35, alkyl with 1-4 carbon atoms, or alkoxy with 1-4 carbon atoms mono- or independently disubstituted phenyl or phenylalkyl with 1-5 carbon atoms
in the alkyl part or

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2733A40

b) -NR ₄ R ₅ , wherein

either R ₄ and R- independently represent hydrogen or alkyl having 1-4 carbon atoms

or R _{4 is} hydrogen and R_ is cycloalkyl

5-7 carbon atoms mean or

c) means halogen with an atomic number of 9 to 35, and

R-, hydrogen or -COR-, where R- has the above for R- * ο ο 3

may have given meaning, means, with the proviso that, if

R. means halogen in the 5-position,

II
R ₂ for -COR, wherein R- with the exception of

Hydrogen and alkyl having 1-4 carbon atoms have the meaning given _{above for R g}

owns, stands.

Alkyl and alkoxy preferably contain 1 or 2 carbon atoms, halogen preferably denotes chlorine or bromine, in particular chlorine. R. is preferably in the 5-position. R. preferably denotes -NHCOR- or halogen, in particular -NHCOR-. Suitable aromatic heterocycles are, for example, furyl, thienyl and pyridyl. If R- is -NR ₄ R ₅ , R ₄ and R _{5 are} preferably, preferably and independently of one another, hydrogen or alkyl. R ₀ preferably denotes -COR-. R, and / or R _c

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2733U0

mean preferably hydrogen, alkyl, cycloalkyl, alkoxy, unsubstituted or monosubstituted phenylalkyl, preferably alkyl, cycloalkyl or alkoxy, in particular alkyl or alkoxy, in particular ^ alkyl. If R and / or R _{g are} cycloalkyl, cycloalkyl preferably contains 3-6, in particular 3, carbon atoms. If R 1 and / or R 1 contain a disubstituted phenyl radical, the substituents on the phenyl radical are preferably identical.

The invention also relates to a process for the preparation of the compounds of the formula I, characterized in that that the primary amino group in corresponding compounds of the formula II in which R. has the above meaning has, with a corresponding group of the formula

-C-NHR,
NH

~ ^C ~ ^NHR 2, in which R has the above meaning, substituted.

The reaction according to the invention can be carried out under conditions which are analogous to known conditions for such substitutions with similar guanidine derivatives. For example, the compounds of the formula II are used with corresponding compounds of the formula III, in which R is as defined above, Y is a leaving group and R is hydrogen, or, for the preparation of compounds of the formula I in which R is hydrogen, with corresponding compounds of the formula III, wherein R _{2 has the} above meaning and Y and R- together represent a bond to.

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-y * - 100-4632

Y preferably denotes an aminolytically cleavable leaving group, such as alkoxy with 1-4 carbon atoms, unsubstituted 1-pyrazolyl or 1-pyrazolyl substituted on a ring carbon atom by at least one inert substituent, e.g. mono- or di (lower) alkyl-1-pyrazolyl, or alkylthio with 1-4 Carbon atoms. Y particularly denotes alkylthio.

The temperature is about 20 ° to about 170 ° C. It can be in the presence of a solvent, e.g. aprotic solvents, such as chloroform, are used; preferred if Y is alkoxy or Alkylthio is, for example, an alcohol such as isopropanol.

Especially if cyanamide is used as the compound of the formula III, it is also possible in the melt, e.g. be operated at about 80 ° to about 170 ° C. This embodiment is for making connections of the formula I, in which R- is hydrogen, are preferred.

The compounds of the formula II in which R ₁ denotes acylamino or alkylamino are obtained by known methods, for example by N-acylation or N-alkylation of 5-amino-1,2,6,7,8,8a- hexahydro-l-nitrosobenz [cd] indole and subsequent reduction of the nitroso group of the resulting N-acyl or N-alkyl compounds.

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The compounds of the formula I can be used in free form as a base or in the form of addition salts with Acids are present. Acid addition salts, for example the hydrochloride, the hydroiodide, the methanesulfonate or the naphthalene-l / 5-disulfonate produce and vice versa.

Insofar as the production of the starting products is not described, these are known or can according to methods known per se or analogously to those described here or analogously to those known per se Process to be manufactured and cleaned.

The compounds of the formula I in free form or in the form of their physiologically acceptable acid addition salts have interesting pharmacological properties. They can therefore be used as a remedy will.

The compounds have a salidiuretic effect. It is because of this effect that they are ready for use suitable as salidiuretics.

They also have antihypertensive properties. It is because of this effect that they are ready for use suitable as antihypertensive drugs.

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The compound of Example 1 is of particular pharmacological interest.

A group of compounds of the formula I consists of the compounds of the formula I in which R ₁ a) -NHCOR *, in which R * is hydrogen, alkyl with 1-4

Carbon atoms, cycloalkyl with 3-7 carbon atoms, alkoxy with 1-4 carbon atoms, furyl, thienyl, pyridyl, phenyl, phenyl mono- or independently disubstituted by

Halogen with an atomic number from 9 to 35, alkyl with 1-4 carbon atoms, or alkoxy with 1-4 carbon atoms or

b) -NR ₄ R ₅ , in which R. and R _{5 are as defined} above, and

R ₂ -CORg, in which Rg has the above meaning. R- preferably stands for -NHCOR.

Another group of compounds of the formula I consists of the compounds of the formula I in which

R. a) -NHCOR-, in which R _{3 has the} above meaning, or

b) -NR ₄ R ₅ , in which R ₄ and R _{5 are as defined} above, and

R. mean hydrogen.

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R, preferably represents -NHCOR-

The invention also relates to remedies that have a compound of formula I in free form or in the form of a physiologically acceptable acid addition salt contain. These remedies, for example a solution or a tablet, can be used according to known Methods, using the usual auxiliaries and carriers, are produced.

The compounds of the formula I or their physiologically acceptable acid addition salts can be used as medicaments be administered alone or in a suitable dosage form.

In the following examples, all temperatures are given in degrees Celsius and are uncorrected.

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Example 1 ; N-acetyl-N '- (1,2,6,7,8,8a-hexahydro-5-propionamido-1-benz [cd] indolyl) guanidine

To a stirred mixture of 15.3 g of 1-amino-1,2,6,7,8,8ahexahydro-5-propionamidobenz [cd] indole and 181 ml of isopropanol are added in portions and at 30-35 ° C. 14.2 g of 1-acetyl-2-methylisothiourea methanesulfonate added within 1 hour while passing nitrogen through. The reaction mixture will stirred for a further 22 hours, the crude product obtained was filtered off and treated with carbon from methanol / isopropanol recrystallized. After drying in a high vacuum for 18 hours at room temperature and 8 hours at 100.degree the title compound is obtained (melting point of the methanesulphonate 184-186 ° C. [decomp.]).

The starting material is obtained as follows:

a) To a stirred mixture of 34 g of 5-amino-l, 2,6,7,8,8a-hexahydro-l-nitrosobenz [cd] indole and 340 ml of pyridine under ice cooling at 10 to 20 ^e C 51.9 g propionyl chloride was added dropwise over the course of 25 minutes. The reaction mixture is stirred for a further 16 hours at room temperature, 850 ml of Hasser are added and the mixture is extracted four times with chloroform. The combined extracts are washed with 2N acetic acid and then with 10% potassium carbonate solution, dried over magnesium sulfate, evaporated and the residue

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Adhering pyridine is removed azeotropically with toluene. The remaining 1,2,6,7,8,8a-hexahydro-1-nitroso-5-propionamidobenz [cd] indole is crystallized from ethyl acetate and dried in a high vacuum at 80 ° C. for 17 hours (melting point 2O1-2O4 ° C.).

b) To a stirred mixture of 24.75 g of zinc dust and 35 ml of water is added dropwise at 10 - 20 ⁰ C for 30 minutes, a solution of 21.4 g of the above product in 109 ml of glacial acetic acid. The reaction mixture is stirred for 1 hour at room temperature, filtered and the filtrate is evaporated to dryness at 90 ° C. The residue is concentrated with 400 ml. Rubbed ammonia. This mixture is extracted in ether for 2 days in a Kutscher-Steudel extraction apparatus. After evaporation of the ether extract, l-amino-1,2,6,7,8,8a-hexahydro-5-propionamidobenz [cd] indole of melting point 184-187 ° C. (from alcohol / ether) is obtained.

The following compounds of the formula I are obtained in an analogous manner, starting from corresponding compounds of formula II, by reaction with corresponding 2-methylisothiourea methanesulfonates (such as described in Example 1) or hydroiodides (in isopropanol at reflux temperature) of the formula III or with corresponding compounds of the formula III in which Y is pyrazolyl (in chloroform at Reflux temperature, as the hydrochloride salt).

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Ex. No.

43

^R 2

2 5-NHCOCH ₃ COOC ₂ H ₅ hj V 180-182 ° [decomp.] 3 5-HH ₂ COCH ₃ hj ^> ms 230-232 ° [decomp.] 4th 5-NHCOCH ₃ COC ₆ H ₅ hj hj 205-208 [decomp.] 5 3-NHCOCH ₃ COOC ₂ H ₅ b b 217 ° [decomp.] 6th 3-NH ₂ COCH ₃ hj 222-224 ° 7th 5-NH-CO-C ₆ H ₅ COCH ₃ hj 252-255 ° 8th 5-N (CH ₃ J ₂ COCH ₃ nd 282 ° [decomp.] 9 5-NHCOCH ₃ COCH ₃ hj 216-219 ° [decomp.] 10 3-NHCOCH ₃ COC ₆ H ₅ hj 155 ° 11 5-NHCOCH ₃ H hj 186-189 ° [decomp.] 12th 5-NHCOC ₂ H ₅ H. hcl 268 ° [decomp.] 13th 5-NHCHO H hcl 280-283 ° [decomp.] 14th 5-NHCOOC ₂ H ₅ H hcl 267 ° [decomp.] 15th 5-NHCOC ₆ H ₅ H b 200-202 ° 16 5-Br COC ₆ H ₅ hj 257-259 ° [decomp.] 17th 3-Cl COOC ₂ H ₅ b 191-193 ° 18th 5-Cl COC ₆ H ₅ hj 206-209 ° 19th 3-Cl H hcl 247 ° [decomp.] 20th 5-NHCOC ₂ H ₅ COOC ₂ H ₅ ms 153 ° [decomp.] 21 5-NHCOC ₀ H COC (CH) ms 153-156 ° [decomp.] 22nd 5-NHCOC ₂ H ₅ CO-CH ₂ -V 197 ° [decomp.] 23 5-Br COOC ₀ H ₁ . 191-193 ° [decomp.] 24 5-Cl COOC ₂ H ₅ 187-189 °

b »in free form

hcl «hydrochloride

hj - hydroiodide

ma ■ methanesulfonate

nd «naphthalene-1,5-disulfonate

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-NH-C-NHR,

-NH.

II

R ₇ N = C - NHR ₂ Y

III

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Claims (5)

Germany-West 100-4632 Patent claims: Benz [cd] indolyl derivatives of the formula I, wherein R _{1 is} in the 3- or 5-position and a) -NHCOR- means in which R is hydrogen, alkyl with 1-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, alkoxy with 1-4 carbon atoms, a 5- or 6-membered aromatic Heterocycle with a nitrogen, oxygen or sulfur atom as a hetero atom, Phenyl, phenylalkyl with 1-5 carbon atoms in the alkyl part, through halogen with an atomic number from 9 to 35, alkyl with 1-4 carbon atoms, or alkoxy of 1-4 carbon atoms mono- or independently disubstituted phenyl or phenylalkyl of 1-5 carbon atoms in the alkyl part or b) -NR ₄ R ₅ , wherein either R and R independently of one another represent hydrogen or alkyl with 1-4 Carbon atoms 7098 86/0709 ORIGINAL INSPECTED Germany-West 100-4632 or R _{4 is} hydrogen and R is cycloalkyl 5-7 carbon atoms mean or c) means halogen with an atomic number from 9 to, and R is hydrogen or -COR, in which R _g can have the meaning given above for R_, with the proviso that, if R is halogen in the 5-position, II
R ₂ for -COR, in which R, with the exception of hydrogen and alkyl having 1-4 carbon atoms has the meaning given above for R., ο and their acid addition salts. 2. The N-acetyl-N '- (1,2,6,7,8,8a-hexahydro-5-propionamido-1-benz [cd] indolyl) guanidine and its acid addition salts. 3. A process for the preparation of the compounds of the formula I, wherein R and R are those in claim 1 Have given meaning, and their acid addition salts, characterized in that the primary Amino group in corresponding compounds of formula II, II 709886/0709 Germany West - YA - 100-4632 wherein R _{1 has the} above meaning with a corresponding group of the formula -C-NHR NH wherein R, has the above meaning, substituted, and the compounds of formula I in free form or in the form thus obtained gains of acid addition salts. 4. The method according to claim 3 for the preparation of N-acetyl-N '- (1,2,6,7,8, ea-hexahydro-S-propionamido-1-benz [cd] indolyl) guanidine, characterized in that one the primary amino group of l-amino-1,2,6,7,8,8a-hexahydro-5-propionamidobenz [cd] indole is substituted with a group of the formula -C-NHCOCH CH-. NH 5. Remedies, characterized in that they contain compounds of the formula I or their physiologically acceptable acid addition salts. 37OO / VA / GD 709886/0709