WO2004067546A1 - Carboxylic-acid-ester-type tetraalkyl ammonium salts, method for the production thereof and pharmaceutical compositions containing said compounds - Google Patents

Abstract

The invention relates to novel carboxylic-acid-ester-type tetraalkyl ammonium salts, the production thereof and the pharmaceutical use thereof in fungal and bacterial infections and as potential inhibitors in the biosynthesis of cholesterol. The compounds, which are produced by reacting aliphatic or phenolic alcohol functions with active chlorocarboxylic acid esters and amines, can contain one or several of said ammonium salts on a carrier molecule comprising a system of anellated rings or long-chained hydrocarbons. Said compounds are characterised by high and specific activity against Candida species, particularly when steroids are used as carriers.

Description

 Carbonic ester type tetraalkylammonium salts, processes for their preparation and pharmaceutical compositions containing them

compositions

The invention relates to tetraalkylammonium salts of the carbonic acid ester type of the general formula I,

worin

wherein

A = a carrier molecule consisting of fused rings, consisting of two or more rings, also spirostanes (with 3 to 7 C atoms), or a hydrocarbon residue

the carrier molecule may contain, in addition to the OH groups required for the attachment of the carbonyloxyalkylammonium radicals, further functional groups, and also alkyl side chains (having 1 to 12 carbon atoms, R = additional alkyl), with m = 5 to 24, n = 1 to 3,

R1 = H or methyl,

R2, R3 and R4 = alkyl (with 1 to 12 C atoms), cycloalkyl (with 2 to 8 C atoms), alkenyl (with 3 to 12 C atoms), cycloalkenyl (with 4 to 8 C atoms), Alkynyl (with 3 to 12 C atoms), aralkyl (with alkyl from 1 to 4 C atoms), alkyloxymethyl (with alkyl from 1 to 4) hydroxyethyl, hydroxypropyl and / or propargyl, where R3 and R4 can also be part of a nitrogen-containing heterocycle such as urotropin, orpholine, imidazolyl, oxazole, pyrazole, tamoxifen, pyrrolidine and - without the substituent R2 - can also be part of a nitrogen-containing aromatic immonium salt such as pyridine, dimethylaminopyridine or dipyridyl,

Y = bromide, iodide, chloride or tosyloxy.

Aryl in radicals such as aralkyl and the like means in particular phenyl or alkylphenyl (alkyl having 1 to 4 carbon atoms).

Compounds are known from the literature in combination with a local anesthetic (H. Kasch, C. Goldschmidt WO 2001, 01/45678 A3) or else of mono- and bis-tetraalkylammonium salts of long-chain aliphatic ethers, which, due to antibacterial activity but surface activity, are only for Disinfection purposes and can not be used for topical and systemic applications. The object of the invention is to provide new tetraalkylammonium salts of the carbonic acid ester type, and to show processes for their preparation, the biological activity of which is characterized by the carrier molecule and the characteristic ammonium structure, in which the surfactant effect to be expected per se is greatly suppressed and to pave the way for pharmacological use of this class of compounds.

The starting materials for the production are known from the literature. The compounds according to the invention are new, their biological activity has not yet been described.

The object is achieved in that new tetraalkylammonium salts of the carbonic acid ester type are made available.

Compounds preferred according to the invention are, for example:

N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-triethylammonium iodide,

N- (3ß-ethylidenoxycarbonyloxy-5-androsten-17-one), N, N, N-triethylammonium iodide, N- (3ß-methyleneoxycarbonyloxy-5-cholestene), N, N, N-triethylammonium bromide,

N- (3ß-methyleneoxycarbonyloxy-24-ethyl-5-cholestadiene), N, N, N-triethylammonium bromide, N- (3ß-methyleneoxycarbonyloxy-24-ethyl-5,22-cholestadiene), N, N, N- triethylammonium iodide,

N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-trimethylammonium chloride,

N, N-dimethyl, N-hexyl, N- (3ß-methylenoxycarbonyloxy-5-androsten-17-one) - ammonium iodide,

N, N-diethyl, N-methyl, N- (3ß-methylenoxycarbonyloxy-5-androsten ~ 17-one) - ammonium iodide,

N, N-dimethyl, N-butyl, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one) - ammonium iodide, N, N-dimethyl, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one ), N-propargylammonium iodide,

N, N-dimethyl, N- (3ß-methylenoxycarbonyloxy-5-androsten-17-one), N-propynylammonium iodide,

N, N-dimethyl, N-dodecyl, N- (3ß-methylenoxycarbonyloxy-5-androsten-17-one) - ammonium iodide,

N, N-dimethyl, N- (3ß-methylenoxycarbonyloxy-5-androsten-17-one), N-propenylammonium iodide,

N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-tripropyl-ammonium iodide, N-methyl, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one) imidazolonium- iodide,

N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one) pyrrolidinium hydrochloride, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one) pyridinium iodide, N-methyl, N- (3ß-methyleneoxycarbonyloxy-5-androsten-

17-one) -pyrrolidinium iodide,

N- (3ß-methyleneoxycarbonyloxy-5-androsten-17ß-ol), N, N, N-triethylammonium iodide, N- (17ß-methyleneoxycarbonyloxy-5-androsten-3-one), N, N N-triethyl -ammonium- iodide,

N- (17β-methyleneoxycarbonyloxy-5-androsten-3ß-ol), N, N N-triethylammonium iodide,

N, N '- [3ß, 17ß- (dimethyleneoxycarbonyloxy) -5-androsten] - (N, N, N) -, (N', N 'N') - bis-triethylammonium diodide

N- [3-methoxy-17β-methyleneoxycarbonyloxy-estra-1,3,5 (10) -triene], N, N N-triethylammonium iodide,

N- [17ß-methyleneoxycarbonyloxy-3-sulfamoyloxy-estra-1, 3,5 (10) -triene], N, N, N-triethyl-ammonium iodide N- [17ß-methyleneoxycarbonyloxy-3-oxysulfonyloxy-estra-1 , 3,5 (10) -triene], N, N, N-triethylammonium iodide

N- [17ß-methyleneoxycarbonyloxy-3-oxysulfonylpropyl-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide

N- [3-methoxy-17β-methyleneoxycarbonyloxy-estra-1, 3.5 (10), 9 (11) -tetraen], N, N N-triethylammonium iodide,

N- (l-methyleneoxycarbonyloxy-dodecyl), N, N, N-triethyl-ammonium iodide

N, N '- [1, 12- (dimethyleneoxycarbonyloxy) dodecyl] - (N, N, N) -, (N', N 'N') - bis-triethylammonium diodide

The present invention furthermore relates to pharmaceutical compositions which contain at least one tetraalkylammonium salt of the carbonic acid ester type of the general formula I as active ingredient, suitable auxiliaries, excipients and additives and / or stabilizers being added to these compositions. In addition to an antibacterial, the compounds according to the invention have a preferred antifungal activity, the specific antcandida activity being emphasized. In addition, the compounds according to the invention are to be classified as potential HMG-Co-A reductase inhibitors which are able to regulate cholesterol biosynthesis. The reduced or, in some compounds, non-existent surfactant activity, which is greatly influenced by the carrier molecule used and the amine component, is surprising.

Due to their specific partial effects, the active ingredient components can be used for mycoses and as a cholesterol-lowering agent, not least because there are no hormonal side effects.

The pharmaceuticals of the invention are produced with the usual solid or liquid diluents and the commonly used pharmaceutical technical adjuvants according to the desired route of application with a suitable dosage in a manner known per se. The preferred preparations consist of dosage forms which exist for topical use in the form of transdermal systems. Oral applications in the form of tablets, coated tablets, pills, powder and depot forms are also suitable. To prepare the compounds according to the invention, compounds of the general formulas II,

wherein

A and n have the meanings given above, n = 1 to 3, in a manner known per se with methyl chloroformate or by reaction with phosgene and subsequent reaction with paraformaldehyde (acetaldehyde) according to the Henry method with ZnCl ₂ in carboxylic acid α -chloroalkyl ester (with alkyl = methyl or ethyl) converted and this with an amine, NR ₂ R3R4, in which R ₂ , R3 and R _{4 have} the meanings given above, in a suitable solvent, such as acetone, DMF, methylene chloride or a corresponding solvent combination, in the presence of iodide, bromide, tosylate or Chloride reacted in the form of salts, isolated and optionally oxidized, etherified, acylated in a manner known per se, for which purpose, inter alia, an acid derivative for esterifications, such as a carboxylic acid anhydride, carboxylic acid halide, such as carboxylic acid chloride or a sulfamoyl halide such as sulfamoyl chloride in the presence of a suitable solvent and a proton-emitting base can be used. The pharmaceutical preparations which contain at least one tetraalkylammonium salt of the carbonic acid ester type according to the invention comprise pharmaceutically acceptable auxiliaries, carriers and additives and / or stabilizers.

The following examples serve to explain the invention in more detail without restricting it in any way.

Experimental part

For example, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one) -N, N, N-triethylammonium iodide

300 mg of 3β-hydroxy-5-androsten-17-one are reacted with 1.2 mmol of chloromethyl chloroformate and 3 mmol of triethylamine in the presence of 3 mmol of sodium iodide in 3 ml of acetone. The ammonium salt crystallizes out of the acetone solution and can be purified by recrystallization from methylene chloride / n-hexane.

F: 208-211 ° C

IR [cιτf ¹ ]: 1635 (CO)

MS [m / z]: ES ⁺ 446.6 [M ⁺ ] Example 2

N- (3ß-Methylenoxycarbonyloxy-5-cholesten) -N, N, N-triethylammonium chloride 300 mg 3ß-Hydroxy-5-cholesten are with 1, 2 mmol triphosgene in the presence of triethylamine in 3ß-chlorocarbonyloxy-5- Cholesten transferred and then converted with 2 mmol paraformaldehyde in DMF in the presence of anhydrous ZnCl ₂ with brief heating in 3ß-chloromethyleneoxycarbonyloxy-5-choleste. The chloromethyl ester obtainable by chromatographic purification is converted into the ammonium salt with 3 mmol of triethylamine and the salt is crystallized from methylene chloride / n-hexane.

MS [m / z]: ES ⁺ 544.9 [M ⁴ ]

Example 3 N- (17β-methyleneoxycarbonyloxy-5-androsten-3-one) -N, N, .N-triethylammonium-. iodide

200 mg of 17β-iodomethyleneoxycarbonyloxy-5-androsten-3-one, prepared from 17ß-chloromethyleneoxycarbonyloxy-5-androsten-3-one by reaction with sodium iodide in acetone, are dissolved in 2 ml of acetone and mixed with 3 mmol of triethylamine at room temperature. The crystallizing ammonium salt is separated off and crystallized from methylene chloride / n-hexane.

F: 208 to 311 ° C

Claims

Expectations: (1) carbonic ester type tetraalkylammonium salts of the formula I,

wherein A = a carrier molecule consisting of fused rings, consisting of two or more rings, also spirostanes (with 3 to 7 C atoms), or a hydrocarbon residue

the carrier molecule may contain, in addition to the OH groups required for the attachment of the carbonyloxyalkylammonium radicals, further functional groups, and also alkyl side chains (having 1 to 12 carbon atoms, R = additional alkyl), with m = 5 to 24, n = 1 to 3, R1 = H or methyl, R2, R3 and R4 = alkyl (with 1 to 12 C atoms), cycloalkyl (with 2 to 8 C atoms), alkenyl (with 3 to 12 C atoms), cycloalkenyl (with 4 to 8 C atoms), Alkynyl (with 3 to 12 C atoms), aralkyl (with alkyl from 1 to 4 C atoms), alkyloxymethyl (with alkyl from 1 to 4) hydroxyethyl, hydroxypropyl and / or propargyl, where R3 and R4 are also part of a nitrogen-containing heterocycle such as urotropin, morpholine, imidazolyl, oxazole, pyrazole, tamoxifen, pyrrolidine and - without the substituent R2 - also part of a nitrogenous one aromatic immonium salt such as pyridine, dimethylaminopyridine or dipyridyl, Y = bromide, iodide, chloride or osyloxy. 2. carbonic acid ester type tetraalkylammonium salts according to claim 1 selected from the group N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-triethylammonium iodide, N- (3ß-ethylidenoxycarbonyloxy-5-androsten-17-one), N, N, N-triethylammonium iodide, N- (3ß-methyleneoxycarbonyloxy-5-cholestene), N, N, N-triethylammonium bromide, N- (3ß-methyleneoxycarbonyloxy-24-ethyl-5-cholestene), N, N, N-triethylammonium bromide, N- (3ß-methyleneoxycarbonyloxy-24-ethyl-5,22-cholestadiene), N, N, N-triethylammonium iodide, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-trimethylammonium chloride, N, N-dimethyl, N-hexyl, N- (3ß-methylenoxycarbonyloxy-5-androsten-17-one) - ammonium iodide, N, N-diethyl, N-methyl, N- (3ß-methylenoxycarbonyloxy-5-androsten -17-one) - ammonium iodide, N, N-dimethyl, N-butyl, N- (3ß-methylenoxycarbonyloxy-5-androsten-17-one) - ammonium iodide, N, N-dimethyl, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one), N-propargylammonium iodide, N, N-dimethyl, N- (3ß-methylenoxycarbonyloxy-5-androsten-17-one), N-propynylammonium iodide, N, N-dimethyl, N-dodecyl, N- (3ß-methylenoxycarbonyloxy-5-androsten- 7-one) - ammonium iodide, N, N-dimethyl, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one), N-propenylammonium-iodide, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one), N, N, N-tripropyl-ammonium iodide, N-methyl, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one) -imidazolonium iodide, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one) pyrrolidinium hydrochloride, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17-one) pyridinium iodide, N-methyl, N- (3ß-methylenoxycarbonyloxy-5-androsten-17-one) -pyrrolidinium iodide, N- (3ß-methyleneoxycarbonyloxy-5-androsten-17ß-ol), N, N, N-triethylammonium iodide, N- (17ß-methyleneoxycarbonyloxy-5-androsten-3-one), N, N N-triethylammonium iodide, N- (17β-methyleneoxycarbonyloxy-5-androsten-3ß-ol), N, N N-triethylammonium iodide, N, N '- [3ß, 17ß- (dimethyleneoxycarbonyloxy) -5-androstenHN, N, N) -, (N', N 'N') - bis-triethylammonium d iodide N- [3-methoxy -17ß-methyleneoxycarbonyloxy-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide, N- [17β-methyleneoxycarbonyloxy-3-sulfamoyloxy-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide N- [17ß-methyleneoxycarbonyloxy-3-oxysulfonyloxy-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide N- [17β-methyleneoxycarbonyloxy-3-oxysulfonylpropyl-estra-1,3,5 (10) -triene], N, N, N-triethylammonium iodide N- [3-methoxy-17β-methyleneoxycarbonyloxy-estra-1, 3.5 (10), 9 (11) -tetraen], N, N N-triethylammonium iodide, N- (l-methyleneoxycarbonyloxy-dodecyl), N, N, N-triethylammonium iodide N, N '- [1, 12- (di-methyleneoxycarbonyloxy) -dodecyl] - (N, N, N) -, ( N ', N' N ') - bis-triethylammonium diodide. 3. Process for the preparation of tetraalkylammonium salts from Carbonic acid ester type of formula I according to claim 1, characterized in that compounds of general formulas II,

wherein A and n have the meanings given above, n = 1 to 3, in a manner known per se with methyl chloroformate or by reaction with phosgene and subsequent reaction with paraformaldehyde (acetaldehyde) according to the Henry method with ZnCl ₂ in Carboxylic acid-α-chloroalkyl ester (with alkyl = methyl or ethyl) converted and this with an amine, NR ₂ R ₃ R ₄ , wherein R ₂ , R ₃ and R _{4 are} the above Have meanings in a suitable solvent, such as acetone, DMF, methylene chloride or a corresponding solvent combination, in Reacting the presence of iodide, bromide, tosylate or chloride in the form of salts, isolating them and optionally oxidizing, etherifying, acylating them in a manner known per se, including an acid derivative for esterifications, such as a Carboxylic acid anhydride, carboxylic acid halide such as carboxylic acid chloride or a sulfamoyl halide such as sulfamoyl chloride in the presence of a suitable one Solvent and a proton-emitting base can be used. 4. Pharmaceutical composition containing at least one Tetraalkylammonium salt of carbonic acid ester type according to claim 1, optionally with pharmaceutically acceptable auxiliaries, carriers or additives and / or stabilizers.