DE2816863A1 - NEW DERIVATIVES OF 10-NITRO-7-OXO- 7H-INDOLIZINO SQUARE CLAMP ON 7,6,5-DE SQUARE BRACKET FOR ISOCHINOLINS, THEIR PRODUCTION AND THE COMPOSITIONS THAT CONTAIN THEM - Google Patents

Description

, EHONE-POÜLEHC IEDTJSiDRIES, Paris /! France

New derivatives of the

lins, their manufacture and the compositions containing them

The invention relates to new derivatives of 10-indolizino [7j6,5-de] isoquinoline the general formula

NO

where appropriate, their salts, their preparation and those containing them Compositions.

In the above general formula I, the symbol R denotes a straight-chain or branched alkyl radical which is at the terminal Carbon atom is substituted by a dialkylaminomethyl radical, the alkyl radicals of which, optionally together with the nitrogen atom, to which they are bound, and optionally with another heteroatom selected from nitrogen, oxygen or sulfur, can form a saturated heterocycle with 5 or 6 chain links (e.g. piperidino, morpholino or piperazin-1-yl, optionally N-methylated), the various alkyl radicals and alkyl parts contain 1 to 4 carbon atoms.

According to the invention, the products of general formula I can be prepared by nitration of the corresponding 7-0xo-7H-indolizino- [7,6,5-de] -isoquinoline the general formula

809842/1130

-OR

II

wherein R is as defined above, can be obtained.

The reaction is generally "at a lemperatur between 0 and 10 ⁰ C, using a at least 50 wt .- # - performed nitric acid as Hitrierungsmittel.

The 7-0xo-7H-indolizino [7,6,5-de] isoquinoline of the general Formula II can be obtained by reacting a derivative of letrahydrofuran of the general formula

III

wherein R ₁ denotes a methyl or ethyl radical, with a derivative of S-Amino- ^ carboxyisoquinoline of the general formula

OR

IY

COOH

wherein R is as defined above.

The reaction is generally carried out in an organic solvent such as acetic acid at a! Temperature between 90 and 10O ⁰ C.

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The derivative of 5-amino-4-carboxyisoquinoline of the general JOrmel IT can be obtained by reducing a derivative of 5-iTitro-4-carboxyisoquinoline the general formula

COOH

wherein R is as defined above.

It is particularly advantageous to use sodium borohydride in the presence of palladium. In general carried out under nitrogen atmosphere at a! Temperature 20-30 ⁰ C in an aqueous-alcoholic Gemiscn ^ Tireinem mixture of water and methanol. It is not absolutely necessary to purify the product obtained before the reaction with the product of the general formula III.

The derivative of 5-nitro-4-carboxyisoquinoline of the general Formula T can be obtained by nitrating a derivative of 4-carboxyisoquinoline the general formula

VI

COOH
wherein R is as defined above.

It is advantageous to use potassium nitrate in concentrated sulfuric acid as the nitrating agent and work at a temperature between 0 and 25 ^° C.

8 09842/1130

Derivative of 4-carboxyisoquinoline of the general formula TI can be obtained by reacting an alcohol of the general formula

R - OH, VII

where R is defined as given above, in the presence of an alkali base such as potassium or sodium hydroxide on 1-chloro-4-ethoxycarbonylisoquinoline. The reaction is advantageously carried out at a temperature between 100 and 110 ⁰ C.

The i-chloro ^ -ethoxycarbonylisocbinoline can after the of M.D. Fair and P.A. Malik, Indian J. Chem., 10, 341 (1972) described method.

The new products according to the invention can optionally by physical methods such as crystallization or chromatography getting cleaned.

The new products according to the invention can optionally be converted into addition salts with acids. The addition salts can be obtained in suitable acids by the action of the products Solvents are obtained; the organic solvents used are, for example, alcohols, ketones, Ether or chlorinated solvents .. The salt formed precipitates out of its solution after possible concentration and becomes separated by filtration or decantation.

The new products of the general formula I and, if appropriate, their salts are particularly effective as antimicrobial and antifungal agents. In addition, they are very little toxic.

The acute toxicity of these products was particularly evident Studied mouse, it is between 750 mg / kg and a dose of more than 1000 mg / kg when administered orally.

They show in vitro activity on gram-positive germs.

81) 9842/1 1 30

They have been shown to be effective on Staphylococcus aureus 209 P at concentrations between 0.1 and 2 µg / cm. The majority of the products according to the invention also show an in vitro activity on gram-negative germs. They have been shown to be effective in doses between 0.1 and 20yug / cm on Escherichia coli, strain Monod, in doses between 0.25 and 30 jag / cnP on Proteus vulgaris and in doses between 2 and 60yug / cnr on Pseudomonas aeruginosa.

Antifungal agents in particular have been canned

• z

between 1 and 1 25jag / cm ^ shown to be effective in Saccharomyces pastorianus.

Of particular interest are the compounds of the general formula I in which R is a straight alkyl radical having 1 to 4 carbon atoms, substituted on the terminal carbon atom by a dialkylaminomethyl radical having 1 to 4 carbon atoms in the alkyl part and especially those in which E is a dialkylaminoethyl radical.

The following example is intended to explain the invention in more detail.

example

To 18.2 cnr about 50 weight percent nitric acid (density = 1.33), which is cooled by an ice bath, is added 5.20 g 4- (2-Diethylaminoethoxy) -7-oxo-7H-indolizino [7,6,5-de] isoquinoline. After dissolution, the urate of the base precipitates and a viscous crystalline broth is obtained.

Is then poured dropwise while maintaining the iDemperatur of Reaktionsminlieus of about 20 ⁰ C a mixture of 10.3 cnr nitric acid of density 1.33 and 10.3 cm nitric acid of about 97 wt .- # (density = 1.52) to.

After completion of the addition, which takes about 20 minutes, a clear red-orange-colored solution is obtained. One stirs

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another 1. hour 20 minutes while maintaining the temperature at 20 ^° C., then 30 cm- ^{5 of} water are added dropwise, being careful not to exceed this temperature ",

The brown-orange-colored crystals which have precipitated out are suctioned off. They were washed three times with 5 cur distilled water, then dried under reduced pressure (0.5 mm Hg) at 20 ⁰ G. are thus obtained 5.1 g of 4- (2-Diäthylaminoäthoxy) -10-nitro-7- oxo-7H-indolizino [7,6,5-de] isoquinoline as ifitrate.

This salt is vigorously stirred with 240 cnr of ethyl acetate and 24 cnr normal liatron lye. After filtering something off The organic phase is decanted and washed with insolubles

• z

then successively with 50 cm of 0.2 N sodium hydroxide solution and then three times with 50 cm of aqueous 5% sodium chloride solution. This solution was then dried over magnesium sulfate and the solvent ealciniertem then evaporated under reduced pressure (30 mm Hg) at 20 ⁰ C.

The yellow-ocher-colored crystalline residue is suspended in 20 cm of isopropyl ether, then filtered off with suction and washed three times with 5 cm of this solvent. Tray drying, obtained under reduced pressure (0.5 mm Hg) at 45 ⁰ C. 2.92 g of 4- (2-Diäthylaminoäthoxy) -10-nitro-7-oxo-7H-indolizino [7,6,5-de ] - isoquinoline from Έ. = 102 ⁰ C.

The 4- (2-Diäthylaminoäthoxy) -7-oxo-7H-indolinzino [7,6,5-de] isoquinoline can be prepared in the following manner: The mixture is stirred for 10 minutes between 95 and 100 ⁰ C.A solution of 7 , 4 g of 2,5-dimethoxytetrahydrofuran and crude amine derived from the reduction of 15.51 g of 5-bitro-4-carboxy-1- (2-diethylaminoethoxy) isoquinoline in 70.5 cnr acetic acid. The reaction mixture is cooled down to 20 ^° C., then it is poured into 350 cm ^{5 of} ice water.

To the brown solution thus obtained, 120 cnr 10 ^ are added

8U 9 B Λ 2/11 3 0

lye (density = 1.33). The tanned crystals which have separated out are filtered off with suction, washed four times with 25 cm of water and then dried under reduced pressure. Are thus obtained 4.81 g of 4- (2-Diäthylaminoäthoxy) -7 - oxo - 7H - indolizino- [7,6,5-de] isoquinoline from P. = 171 ⁰ C.

The 5 - amino-4-carbo3qy-1- (2-diethylaminoethoxy) -isoquinoline can be made in the following ways:

To a mixture of 0.8 g of catalyst with 3% palladium on carbon, 3.52 g Uatriumborhydrid and 155 cnr water was added within 1 hour with stirring and under a nitrogen atmosphere, a solution of 15.51 g of 4-carboxy-1- ( 2-diethylaminoethoxy) -5-nitroisoquinoline in 155 cnr methanol and 51.5 cm 1 η-sodium hydroxide solution. During the addition, the temperature is kept between 27 and 30 ^° C.

Stirring is continued between 25 and 27 ^° C. for 2 hours 30 minutes after the addition has ended. The catalyst is filtered, then (0.5 mm Hg) evaporated off the solvent under reduced pressure at a temperature of about 20 ⁰ C., thus obtaining a yellow brittle foam which a mixture of the Uatriumsalzes of 5-amino-4-carboxy -1- (2-diethylaminoethoxy) -isoquinoline and mineral salts. This mixture can be used as such in the following synthesis stage.

The 4-carboxy-1- (2-diethylaminoethoxy) -5-nitroisoquinoline can be prepared in the following way:

To 156.6 cnr concentrated sulfuric acid are added little by little 26.1 g of 4-carboxy-1- (2-diäthylaminoätho: xy) -isochinolindihydrochlorid. When the evolution of hydrogen chloride has ended, a brownish solution is obtained, which is cooled down ^{to 20 ° C.} To this solution is added dropwise in 50 minutes and while maintaining the temperature of the medium 15 to 20 ⁰ C a solution of 7.3 g of potassium nitrate

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in, 58.4 cnr concentrated sulfuric acid. Bach 16 hours of contact time, the yellowish solution is poured onto 430 g of crushed ice. It is slowly made alkaline with 750 cnr 11 n-ammonia (density = 0.92). The pale yellow crystals which have precipitated out are suctioned off and washed three times with 30 cubic centimeters of ice water. ITach drying under reduced pressure (0.5 mm Hg) at 5O ⁰ C is obtained 17.82 g of 4-carboxy-1- (2-diäthylaminoäthoxy) -5-nitroisoquinoline from P. = 205 ⁰ C.

The 4-carboxy-1- (2-diethylaminoethoxy) -isoquinoline dihydrochloride can be obtained in the following way: A mixture of 20 g of i-chloro-4-ethoxycarbonylisoquinoline, 160 cnr of 2-diethylaminoethanol and 10.45 g of potassium hydroxide lozenges is stirred during 6 hours at 100 ⁰ C. Uach cooling to 20 ⁰ C is filtered, the mineral salts, which are precipitated, and washed then the filter cake with

3 ··
twice 20 cm ethanol. The filtrate is concentrated ^{at 70 °} C. under reduced pressure (1 mm Hg). The syrupy brown-orange residue is dissolved in 160 cnr ethanol and then 70 cnr of an ethereal 5N hydrochloric acid solution is added.

The crystalline precipitate is then suctioned off and washed then with three times 30 cm of a mixture of ethanol and Ether (3/1 in YoI.) And then twice with 50 cm of ether. To drying under reduced pressure (0.5 mm Hg) gives 26.13 g of 4-carboxy-1- (2-diethylaminoethosy) isoquinoline dihydrochloride in the form of cream-colored crystals which melt with decomposition at "227 ° C.

The 1-chloro-4-ethoxycarbonylisoquinoline can be obtained by the method described by MD Hair and PA Malik, Indian J. Chem., W, 341 (1972).

Since the products of general formula I and their non-toxic salts are active through contact, they are used as agents of choice as topical antiseptic use. You can in the Dermatology, Ophthalmology, Gynecology, Urology, Oto ^ Rhino-

8Ü9842 / 1130

Laryngology, stomatology or surgery can be used.

The invention also relates to the medicaments which consist of the products of the general formula I and the pharmaceutical ones Compositions which the products of general formula I together with one or more compatible, pharmaceutically contain acceptable diluents or auxiliaries. These compositions can be used by topical application will.

The most common liquid compositions for local application are pharmaceutically acceptable emulsions, solutions and suspensions, which include diluents such as water or Contain alcohol. These compositions can also contain substances other than diluents, for example wetting agents, Contain dyes or perfumes.

The most common semi-solid compositions for local application are pomades and creams. In addition to the antiseptic product, these compositions may contain wetting agents, coloring agents, perfumes, Mineral salts such as calcium carbonate or magnesium carbonate or tricalcium phosphate and diluents such as starch or ! DaIk included.

The most common solid compositions for topical application are powders. These compositions can besides the antiseptic Product contain thinners, colourants and perfumes. In general, these powders are used after dissolution or Suspended in a sterile liquid such as water or alcohol, or used directly for dusting.

In these compositions the content of active product is generally between 0.01% and $ 0.5.

example

A solution is prepared according to the usual methods, which

809842/1130

Oy5056 contains active ingredient and has the following composition: Methanesulfonate des 4- (2-diethylaminoethosy) -10-nitro-7-oxo-7H-indolizino [7,6,5-de] -

isoquinolines 0.64 g

Fill up with water to 100 ml.

8098 42/1 130

Claims (2)

Dr. F. Zumstein Sr. - Or R. Αδβιτεηη - Dr. R. Koenigsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. F. Klingseisen - Dr. F. Zumstein jun. PATENTANWÄLTE 8000 Munich 2 ■ BrauhausstraBe 4 ■ Telephone collection no. 225341 - Telegrams Zumpot ■ Telex 529979 SO 4626 10 / bs 1. New derivative of 10-Fitro-7-oxo-7H-indolizino [7,6,5-de] -isoquinoline the general formula -o-R where R denotes a straight-chain or branched alkyl radical which is substituted on the terminal carbon atom by a dialkylaminomethyl radical, the alkyl radicals of which are optionally saturated with the nitrogen atom to which they are bonded and optionally with a further heteroatom selected from nitrogen, oxygen or sulfur with 5 or 6 chain links, which is optionally ii-methylated, the various alkyl radicals and alkyl parts containing 1 to 4 carbon atoms, in the state of the base or as an addition salt with an acid. 2. A method for producing a product according to claim 1, characterized in that 7-oxo-7H-indolizino [7> 6,5-de] -isoquinoline the general formula 809842/1 13Q 281R863 wherein R is as defined in claim 1, nitrated and the product obtained optionally in an addition salt with transferred to an acid. 3 «Medicines," consisting of a product according to claim 1 or from a pharmaceutical composition with at least one product according to claim 1 together with one or more compatible and pharmaceutically acceptable diluents or auxiliaries. 8Ü9842 / 1130