Benzofuran and method of production thereof

 

(57) Abstract:

Describes new benzofuran formula I, where R1denotes NH2, 1-piperazinil or 4-R3-piperazinil; R2denotes H; R3denotes benzyl or is itself known to be protective amine function group; X represents COOH, cooa or CONR4R5; R4and R5each independently of one another represent H; And denotes alkyl with 1-4 C-atoms; and their salts, useful as intermediates in the synthesis of drugs and possessing properties effects on the Central nervous system. Describes how they are received. 2 S. and 2 C.p. f-crystals.

The invention relates to benzofuran formula I

< / BR>
where R1denotes NH2, 1-piperazinil or 4-R3-piperazinil;

R2denotes H, Cl, Br, OH or OA;

R3denotes benzyl or itself known protective for the amine function group;

X denotes a CN, COON, COOA, COOPh, COOCH2Ph, COOPy, CONR4R5or CO-Het;

R4and R5each independently of one another denotes H, A or benzyl;

A denotes alkyl with 1-4 C-atoms;

Ph denotes phenyl;

Het denotes imidate connection is known from the patent Germany 4333254.

The basis of the invention is to obtain new compounds, which, in particular, can be used as intermediates in the synthesis of medicines, but also they can be used directly for the preparation of drugs.

It was found that the compounds of formula I and their salts are important intermediates for the preparation of drugs and simultaneously possess pharmacological properties. So, they have, for example, properties, effects on the Central nervous system.

The subject invention are derivatives of benzofuran formula I and their salts.

Above and below the remains of R1, R2, R3, R4, R5, R6X, X1, A, Ph, Het and Py are defined for formulas I - VI values, unless nothing else.

In the above formulas, A is 1-4, preferably 1, 2 or 3 C-atoms. Preferably A represents methyl or ethyl, then, propyl, isopropyl, also referred to as butyl, isobutyl, sec-butyl or tert-butyl.

The balance Ph denotes phenyl.

The rest Gets denotes substituted in position 1 imidazole, triazole or tetrazole.

OST is the Remainder of X denotes a CN, COOH, COOA, COOPh, COOCH2Ph, COOPy, CONR4R5or CO-Gets.

The remainder R1denotes NH2, 1-piperazinil or substituted in position 4 by using the radical R31-piperazinilnom the rest.

The remainder R2denotes H, Cl, Br, OH or OA.

The remainder R3denotes benzyl, preferably, however, in itself known, for protective amine function group.

The expression "protection for the amino function group" is well known and relates to groups which are suitable for protecting (blocking) an amino group from chemical interactions, which, however, can be easily removed after in other parts of the molecule was desired chemical reaction. Typical of such groups are, in particular, unsubstituted acyl, aryl, arelaxation or kalkilya group. As for protective amine function group after the desired reaction (or sequence of reactions) are removed, they were kind and magnitude, however, is not critical; however, a preferred group with 1-20, in particular 1-8, C atoms.

The expression "azalina group" in connection with the present method and existing connections need to be understood in its broadest sense. It covers produced from Alif the e group, and in particular alkoxycarbonyl group. Examples of such acyl groups are alkanoyl as acetyl, propionyl, butyryl; arcanol as phenylacetyl; aroyl as benzoyl or toluyl; aryloxyalkanoic as phenoxyacetyl; alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, 2,2,2-trichlorocyanuric, BOC (tert-butoxycarbonyl), 2-iodine-etoxycarbonyl; Uralelectromed as CBZ (carbobenzoxy, also called "Z"), 4-methoxybenzeneboronic, FMOC (9-fluorenylmethoxycarbonyl); arylsulfonyl as Mtr (4-methoxy-2,3,6-trimethylphenylsulfonyl). Preferred protective for amine-function groups are BOC and Mtr, then, CBZ or FMOC.

The compounds of formula (I) can have one or more chiral centers and therefore may exist in different stereoisomeric forms. Formula I encompasses all these forms.

The subject invention further is a method of obtaining benzofuranol formula I and their salts, characterized in that a compound which corresponds to formula I, where R1denotes the nitrogroup itself in the usual way restore, or

the connection that corresponds to the formula I, where R1denotes NH2-the group will enter into vsenachal H or benzyl and X1denotes Cl, Br, I, OH or a reactive functionally modified OH-group; or

the connection that corresponds to the formula I, where R1denotes 1-piperazinilnom balance, by introducing itself is known to be protective amine function group is transformed into another compound of formula I, in which R1denotes 4-R3-piperazinilnom balance, where R3has the specified value, or

the connection that corresponds to the formula I, where X denotes COOA group, in which A in turn has the specified value is converted into another compound of formula I in which X is CONR4R5where R4and R5have the specified values, or

the connection that corresponds to the formula I, where X denotes COOH group is converted into another compound of formula I, in which X denotes CO-Het, where Het has the specified value, or

the connection that corresponds to the formula I, where R1denotes 4-R3-piperazinilnom group, in which R3has a specified value, by removal of a protective group into a compound of formula I, in which R1denotes 1-piperazinil; and/or

the basis of the formula I by treatment with acid pre is eat, get itself known in ways that are described in the literature (for example in standard works, as Houben-Weil, Methods of organic chemistry, ed. Georg-Thime, Stuttgart), namely under reaction conditions which are known and suitable for the specified transformations (interactions). You can also use themselves known here more not mentioned options.

The source of the substance, if desired, can also be obtained in situ, so they are not isolated from the reaction mixture, and immediately injected into the interaction further, to obtain compounds of formula I.

In compounds of formula II the remainder of X1means preferably Cl or Br; however, it can refer also I, OH or a reactive modified OH group, as alkylsulfonates with 1-6 C atoms (preferably methylsulfonylamino) or arylsulfonate with 6-10 C atoms (preferably phenyl, p-tolilsulfonil-, 1 - or 2-naphthalenesulfonate).

In compounds of formula II, the remainder R6denotes H or benzyl. The compounds of formula II are partly known, unknown compounds can be easily obtained analogously to known compounds.

The interaction of compounds stny from the literature for the alkylation of amines. You can fuse the components with each other in the absence of a solvent, if necessary in a sealed tube or in an autoclave.

However, you can also connect to enter into interaction in the presence of an inert solvent.

As inert solvents are suitable, for example, hydrocarbons as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloroethane, alcohols like methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers like diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; a simple glycol ethers, as etilenglikolevye or monotropy simple ether (methylglycol or ethylglycol), etilenglikolevye simple ether (diglyme); ketones, such as acetone or butanone; amides, as ndimethylacetamide, dimethylacetamide or dimethylformamide (DMF); NITRILES like acetonitrile; sulfoxidov as dimethylsulfoxide (DMSO), carbon disulfide; nitro compounds, as nitromethane or nitrobenzene; esters as ethyl acetate; and, if necessary, also mixtures of these solvents with one another or mixtures with water.

Can be beaten alkaline-earth metal or of another salt of a weak acid of the alkali or alkaline-earth metals, preferably potassium, sodium or calcium, or the addition of organic bases like triethylamine, dimethylamine, pyridine or quinoline, or an excess terminal of amine component. The reaction time, depending on the applied conditions, ranges from a few minutes up to 14 days; the reaction temperature is from 0oC to 150oC, usually from 20 to 130oC.

The transformation of compounds of formula I in which R1denotes a nitro-group in the compound of the formula I, in which R1denotes the amino group, preferably carried out using hydrogen gas in catalysis using a catalyst based on a transition metal (for example by hydrogenation on Raney Nickel or Pd-fired in an inert solvent like methanol or ethanol).

The transformation of compounds of formula I, where R1denotes 1-piperazinilnom residue in the compound of the formula I, in which R1denotes 4-R3-piperazinilnom balance, carried out by known methods, which are described in the literature (for example in standard works, as Houben-Weil, Methods of organic chemistry, ed. Georg-Thieme, Stuttgart), for example, alkylation or acylation of amines, namely under reaction conditions which are known and suitable drobney not mentioned options.

The transformation of compounds of formula I, where X denotes the carboxyl group, the compound of formula I, in which X denotes COOA, COOPh, COOCH2Ph, COOPy or CO-Het, exercise itself known in ways that are described in the literature (for example in standard works, as Houben-Weil, Methods of organic chemistry, ed. Georg-Thieme, Stuttgart) for such terifically to esters or amidarone; namely under reaction conditions which are known and suitable for the specified transformations (interactions). You can also use itself known here more not mentioned options.

The conversion of compounds of formula I, in which X denotes COOA, in the compounds of formula I in which X is COOH, implement, for example, using NaOH or KOH in water, mixtures of water with THF or water with dioxane at temperatures of 0 - 100oC.

The conversion of compounds of formula I, in which X denotes a CN, COOH, COOA, COOPh, COOCH2Ph, COOPy or Co-Het in the compounds of formula I in which X is CONR4R5carry out, for example, using HCONR4R5in an inert, as mentioned above, the solvent, if necessary with the addition of the base. As bases are, for example, alcohol from the compounds of formula I is carried out depending on the protective group, for example using strong acids, expediently using TFA (triperoxonane acid or perchloric acid, but also using other strong inorganic acids as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, as trichloroacetic acid, or sulfonic acids, as benzoyl or p-toluensulfonate. The presence of an additional inert solvent may, however, not always required. As inert solvents suitable preferred organic, for example carboxylic acids, as acetic acid; ethers, like tetrahydrofuran or dioxane; amides as dimethylformamide; halogenated hydrocarbons like dichloromethane; hereinafter, also alcohols as methanol, ethanol or isopropanol, and also water. Next, apply a mixture of the above solvents. TFA is preferably used in excess without the addition of another solvent; perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperature is expediently approximately 0 to 50oC, preferably operate at 15 - 30- 5 N. hydrochloric acid in dioxane at 15 - 30oC.

Hydrogenations removable protective group (for example, CBZ or benzyl) can be split, for example, by treatment with hydrogen in the presence of a catalyst (for example, a catalyst based on a noble metal, such as palladium, expediently on the media, as coal). As solvents, and the fit of the above, in particular, for example, alcohols, like methanol or ethanol, or amides, as DMF. Hydrogenolysis carried out usually at a temperature of from about 0oC to 100oC and pressures from about 1 to 200 bar, preferably at 20 to 30oC and a pressure of 1-10 bar.

The base of formula I with acids can be converted to the corresponding salt accession acid, for example, by reacting equivalent amounts of base and acid in an inert solvent like ethanol and subsequent evaporation. For this transformation change, in particular acids, which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, halogen acids as hydrochloric acid or Hydrobromic acid, phosphoric acid, like phosphoric acid; the Kie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, etandisulfonata, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalene mono - and di-sulfonic acids, louisanna acid. Salts with physiologically unacceptable acids, for example the picrate, can be used for isolation and/or purification of the compounds of formula I.

On the other hand, the compounds of formula I with bases (for example, hydroxide or carbonate of sodium or potassium) can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline-earth metals, or into the corresponding ammonium salts.

The subject invention are also medicines on the basis of the compounds of formula I and their fiziologicheskii intermediate products for the synthesis of medicines. Medications are described, for example, in the patent Germany 4333254.

The subject invention accordingly is, in particular, the use of compounds of formula I on p. 1 of the claims in the synthesis of 1-[4-(5-cyan-indol-3-yl)butyl] -4-(2-carbarnoyl-benzofuran-5-yl)- piperazine and its salts, characterized in that

nitrous 2-(2-formylphenoxy)acetic acid;

cyclist thus obtained 2-(2-formyl-4-nitrophenoxy)-acetic acid;

atrificial to complex ester thus obtained 5-nitrobenzophenone-2-carboxylic acid;

the thus obtained compound of formula III

< / BR>
where X denotes COOA, COOPh or COOCH2Ph, restore;

the thus obtained compound of formula I, where R1denotes NH2and X denotes COOA, COOPh or COOCH2Ph is converted into its salt accession acid and is driven into engagement with salt accession acid compounds of formula II

NH(CH2CH2X1)2,

where X1denotes Cl, Br, I, OH or a reactive functionally modified OH-group,

obtaining a derivative of piperazine of formula IV

< / BR>
where X denotes COOA, COOPh or COOCH2Ph;

TAC in cooperation with the connection, which is suitable for introduction for protective amine group functions;

the thus obtained compound of the formula V

< / BR>
where R3means in itself known protective for the amine function group and X has the specified value is converted into a compound of formula VI

< / BR>
where R3has the above meaning;

the thus obtained compound of the formula VI by removal of protective for the amine function group converted into 5-(1-piperazinil)-benzofuran-2-carboxamide or salt accession acid; and

5-(1-piperazinil)-benzofuran-2-carboxamide or the corresponding salt is introduced into an interaction with 3-(4-chlorobutyl)-5-cyan-indol obtaining 1-[4-(5-cyan-indol-3-yl)butyl] -4-(2-carbarnoyl-benzofuran-5-yl)piperazine and, if necessary, and then transferred to salt accession acid.

3-(4-Chlorobutyl)-5-cyan-indole is known from the patent Germany 4101686; 1-[4-(5-cyan-indol-3-yl)butyl] -4-(2-carbarnoyl-benzofuran-5-yl)piperazine is known from the patent Germany 4333254.

The subject of the invention, then, is the use of compounds of the formula I as intermediates for the synthesis of drugs that affect the Central nervous system.

Pri for the preparation of pharmaceutical compositions in particular, non-chemical way. While their together with at least one solid, liquid and/or semi-liquid carrier or auxiliary substance and, if necessary, in combination with one or more other biologically active substances can be brought to a suitable dosage forms.

The subject of the invention, further, are pharmaceutical compositions containing at least one compound of the formula I and/or one of its physiologically acceptable salts.

These compositions can be used as drugs in medicine or veterinary medicine. As carriers to apply an organic or inorganic substances which are suitable for intestinal (e.g. oral), parenteral or topical administration and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkalophile, glycols, glyceryltrinitrate, gelatin, carbohydrate as lactose or starch, magnesium stearate, talc, vaseline. For oral administration are, in particular, tablets, pills, coated tablets, capsules with the medicine, powders, granules, syrups, juices or drops; for rectal use candles; for parenteral use cases the practical application are ointments, creams or powders. The new compounds can also be liofilizirovanny and received lyophilizate to apply, for example, for the preparation of drugs for injection. These compositions can be sterilized and/or may contain auxiliary substances, as imparting lubricity means, preservatives, stabilizers and/or wetting, emulsifying agents, salts for influencing the osmotic pressure, buffer substances, colorants, flavorings and/or some other biologically active substances, for example one or more vitamins.

The compounds of formula I and their physiologically acceptable salts can be used in the fight against diseases.

All above - and below the temperature specified inoC. In the following examples, the expression "conventional treatment" means add, if required, water; establish, if required, depending on the structure of the target product, the pH-value of from 2 to 10; extracted with ethyl acetate or dichloromethane; separated, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and/or by crystallization. Rfvalues are determined on silica gel.

Example 1

A solution of 2.3 g of ethyl EF is filtrowa and the solution concentrated. After the usual processing gain ethyl ester 5-aminobenzophenone-2-carboxylic acid; Rf= 0,1 (dichloromethane/ethanol = 9,5:0,5); hydrochloride; so pl. 246-248oC.

Example 2

A solution of 2.05 g of ethyl ester of 5-aminobenzophenone-2-carboxylic acid in 80 ml of dichloromethane is mixed with 1.5 g of N,N-bis(2-chloroethyl)-amine and stirred for 10 hours. Process as usual and get ethyl ester 5-(1-piperazinil)benzofuran-2-carboxylic acid. Rf=0,55 (isopropanol/water= 95:5).

Example 3

A solution of 1 g of ethyl ester of 5-(1-piperazinil)benzofuran-2-carboxylic acid in 50 ml of THF together with 1 g of di-tert-butyl-dicarbonate stirred for 3 hours. After the usual processing gain ethyl ester 5-(4-tert-butylcarbamoyl-1-piperazinil)benzofuran-2-carboxylic acid; so pl. 116 - 118oC.

Example 4

A solution of 3 g of ethyl ester of 5-(4-tert-butyloxycarbonyl-1 - piperazinil)benzofuran-2-carboxylic acid in 100 ml of N-methylpyrrolidone together with 1 g of formamide and 3 g of sodium alcoholate is stirred for 5 hours. After conventional treatment receive 5-(4-tert-butyloxycarbonyl-1-piperazinil)benzofuran-2-carboxamide; so pl. 198 - 200oC.

Example 5

A solution of 1 g of ethyl ether out within 2 hours. After the usual processing gain ethyl ester 5-(4-benzyl-1-piperazinil)benzofuran-2-carboxylic acid; so pl. = 219 - 222oC.

Example 6

1 g of 5-(4-tert-butyloxycarbonyl-1-piperazinil)benzofuran-2 - carboxamide are dissolved in 50 ml of methanolic HCl solution and stirred for 1 hour. After conventional treatment receive 5-(1 - piperazinil)benzofuran-2-carboxamide. So pl. 252 - 255oC.

The following examples relate to pharmaceutical compositions:

Example A. Vials of drugs for injection

A solution of 100 g of biologically active substances of the formula I and 5 g of the secondary acid phosphate in 3 l of double-distilled water using 2 N. hydrochloric acid to establish a pH = 6.5, the solution is sterile filtered, filled their bottles for injectables, lyophilizer in sterile sterile conditions and closed. Each bottle of medication for injection contains 5 mg of biologically active substances.

Example B. Candles

Melt a mixture of 20 g of biologically active substances of formula I with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and leave to cool. Each suppository contains 20 mg of biologically active substances.

Example Century. RAS,48 g of Na2HPO412H2O and 0.1 g of benzylaniline in 940 ml of double-distilled water. Set pH 6.8, made up to a total volume of 1 liter and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example, Ointment

Mix 500 mg of biologically active substances of formula I with 99.5 g of vaseline under aseptic conditions.

Example D. Tablets

A mixture of 1 kg of biologically active substances of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate as usual pressed into tablet so that the tablet contains 10 mg of biologically active substances.

Example E. Bean

Analogously to example D is pressed tablets, then the usual way is applied a coating of sucrose, potato starch, talc, tragant and dye.

Example J. Capsules

2 kg of biologically active substances of the formula I in the usual way bring into hard gelatin capsules so that each capsule contains 20 mg of biologically active substances.

Example z Capsules

A solution of 1 kg of biologically active substances of the formula I in 60 l of double-distilled water is sterile filtered, dispensed into ampoules, leofiles the VA.

Example 7

Getting 5-{4-[4-(5-cyano-3-indolyl) -butyl]-1-piperazinil}- benzofuran-2-carboxamide hydrochloride

To a mixture of 75 g of dimethylformamide and 15 g of K2CO3in an atmosphere of nitrogen was added 2.5 g of 3-(4-chlorobutyl)-indole-5 - carbonitrile and 2.5 g of 5-(1-piperazinil)-benzofuran-2-carboxamide and was stirred for 12 hours at 110oC and then was filtered, not cooling. The liquid phase was freed from solvent in vacuo at a temperature of 60oC and the residue was mixed with 80 g of ethanol. The precipitate was separated, was dried at 40oC, was dissolved in 130 g of ethyl acetate and again filtered.

The solution under stirring was mixed with 15 g of 1 N. hydrochloric acid and then was stirred for one hour.

The resulting pale yellow precipitate was isolated by filtration and dried in vacuum at 60oC.

Yield 3.0 g (61%). Melting point 285 - 295oC (decomposition).

1. Benzofuran formula I

< / BR>
where R1denotes NH2, 1-piperazinil or 4-R3-piperazinil;

R2denotes H;

R3denotes benzyl or is itself known to be protective amine function group;

X is COOH, COOA, or CONR4R5;

R4and R

2. The compound of formula I on p. 1, representing a)Ethyl ester 5-aminobenzophenone-2-carboxylic acid and its salts; b) 5-(1-piperazinil)benzofuran-2-carboxylic acid and its salts; C) ethyl ester 5-(1-piperazinil)benzofuran-2-carboxylic acid and its salts; d) ethyl ester 5-(4-tert. -butyloxycarbonyl-1-piperazinil)-benzofuran-2-carboxylic acid; d) 5-(4-tert. -butyloxycarbonyl-1-piperazinil)benzofuran-2-carboxamide; e) 5-(1-piperazinil)benzofuran-2-carboxamide.

3. The method of producing benzofuranol formula I under item 1, and their salts, characterized in that the compound of formula I, where R1denotes 1-piperazinilnom balance, by introducing aminosidine group is converted into a compound of formula I, in which R1denotes 4-R3-piperazinilnom balance, where R3has the specified values.

4. The compound of formula I under item 1 as intermediate products for the synthesis of medicines.

 

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EFFECT: preparation of new compounds.

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (II-A) or pharmaceutically acceptable salt thereof: [in which symbols denote the following: R10-R12: are identical or different and each denotes halogen, lower alkyl, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, R13: R0, halogen, halogen-lower alkyl, -OR0, -O-halogen-lower alkyl or -CN, ring B: benzene ring or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from O, S and N, R14: R0, halogen or -OR0, R0: are identical or different and each denotes H or lower alkyl, Y1: a single bond, lower alkylene, lower alkenylene or O-lower alkylene-, and Z1: -CO2R0 or -C0-NH-SO2-lower alkyl]. The invention also relates to a pharmaceutical composition based on the said compound, having antagonistic effect on the EP1 receptor.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in a medicinal agent for treating lower urinary tract symptoms.

6 cl, 56 tbl, 231 ex

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