KR100349209B1 - Adhesive receptor antagonist - Google Patents

Abstract

The present invention provides novel compounds of the general formula (I) and salts thereof.

(Wherein

X is O, S, NH or NA,

Y is an aziridino, agentidino, pyrrolidino, piperidino, 1-oxa-8-azas pyro [4.5] deck-8-yl, hexahydroazino or 4-R ⁴ -piperazino group, Wherein these groups may be unsubstituted or substituted once with R ² , and further substituted with OZ, SZ or N (Z) ₂ groups, and / or with carbonyl oxygen,

Z is in each case H, A, phenyl-C _k H _2k or Ac,

R ¹ is CN, H ₂ N-CH _2- , (A) ₂ N-CH _2- , H ₂ NC (= NH)-, H ₂ NC (= NH) -NH-, H ₂ Nl-C (= NH) -NH-CH _2- , phenyl group once substituted with HO-NH-C (= NH)-or HO-NH-C (= NH) -NH-,

R ² is —C _m H _2m —COOR ³ or —C _n H _2n —0-C _P H _2P —COOR ³ ol,

R ³ is H, A or benzyl,

R ⁴ is H, A, benzyl or -C _m H _2m , -COOR ³ ,

A is in each case alkyl of 1 to 6 carbon atoms,

Ac is acyl having 1 to 11 carbon atoms,

k and m are in each case 0, 1, 2 or 3,

n is 0, 1 or 2,

p is 1, 2 or 3. ) And a method of manufacturing the same.

The novel compounds of the present invention inhibit fibrinogen binding to fibrinogen receptors and can therefore be used to treat thrombosis, heart attack, myocardial infarction, anti-inflammatory, arteriosclerosis, osteoporosis and tumors.

Description

Adhesive receptor antagonist

The present invention relates to novel compounds of the general formula (I) and salts thereof.

(In the above formula,

X is O, S, NH or NA,

Y is an aziridino, azetidino, pyrrolidino, piperidino, 1-oxa-8-azaspiro [4,5] dec-8-yl, hexahydroazino or 4-R ⁴ -piperazino group Wherein these groups may be unsubstituted or substituted once with R ² , and further substituted with OZ SZ or N (Z) ₂ groups and / or with carbonyl oxygen, where Z is in each case H, A, phenyl-C _k H _zk or Ac,

R ¹ is CN, H ₂ N-CH _2- , (A) ₂ N-CH _2- , H ₂ NC (= NH)-, H ₂ NC (= NH) -NH-,

H ₂ NC (= NH) -NH-CH _2- , a phenyl group once substituted with HO-NH-C (= NH)-or HO-NH-C (= NH) -NH-,

R ² is -C _m H _2m -COOR ³ or -C _n H _2n -0-C _p H _2p -COOR ³ ,

R ³ is H, A or benzyl,

R ⁴ is H, A, benzyl or -C _m H _2m -COOR ³ ,

A is in each case alkyl of 1 to 6 carbon atoms,

Ac is acyl having 1 to 11 carbon atoms,

k and m are in each case 0, 1, 2 or 3,

n is 0, 1 or 2,

p is 1, 2 or 3.

Compounds similar to this are known from European Patent Application Publication No. 0 381 033.

The present invention is based on the purpose of finding novel compounds with valuable properties, in particular novel compounds that can be used for the manufacture of a drug.

This object has been achieved by the present invention. The inventors have found that the compounds of formula (1) and their solvates and salts are resistant and have valuable pharmacological properties. In particular, they inhibit the binding of fibrinogen, fibronectin and von Willebrand factors to these proteins as well as to the binding of fibrinogen receptors (glycoprotein IIb / IIIa) on platelets, furthermore vitronectin, collagen and laminin Sticky proteins such as these inhibit the binding of corresponding receptors present on various types of cell surfaces. Because of this, these compounds affect cell-cell and cell-matrix interactions. These compounds can be used in the treatment of thrombosis, heart attack, myocardial infarction, inflammation, arteriosclerosis, etc., especially because they inhibit the production of platelet thrombin. In addition, these compounds affect tumor cells by inhibiting the cells from forming metastases. Thus, these compounds can also be used as anti-tumor agents.

The compound is also suitable as an antimicrobial active substance that can prevent infection by, for example, bacteria, fungi or yeasts. Therefore, the present substance can be preferably used as an antimicrobial active substance in the case of inserting an exogenous substance into an organism, for example, a bio substance, an implant substance, a catheter or a pacemaker. They act as preservatives.

The properties of the compounds can be demonstrated by the method described in European Patent Application Publication No. 0 462 960. Inhibition of the binding of fibrinogen to fibrinogen receptors can be demonstrated by the method described in Published Patent Application No. 0 381 033, and the inhibitory effect on platelet aggregation is as follows (Born, Nature 4832, 927-929, 1962). This can be demonstrated by in vitro testing.

The present invention also provides a process for preparing the compounds of the general formula (I) and salts thereof,

(a) a compound of formula (I) is isolated from one of its functional derivatives by treatment with a solvolysis or hydrogenolysis agent, or

(b) a compound of the following general formula (II):

(Meal,

E is C1, Br, I or a reactive esterified OH group,

R ¹ and X are as defined above) wherein the amino compound of formula (III)

H-Y (Ⅲ)

(Wherein Y is as defined above), or

(c) a compound of the following general formula (IV):

R ¹ -NH-CH ₂ -CH (XH) -CH ₂ -Y (IV)

(Wherein R ¹ , X and Y are as defined above) or one of its reactive derivatives, or reacting with a reactive derivative of carboxylic acid, or

(d) To prepare a guanidino compound of formula (I), wherein R ¹ is a phenyl radical once substituted with H ₂ NC (= NH) -NH, corresponds to formula (I), wherein the radical R ¹ Instead treating an amino compound containing an amino-phenyl group with an amidinating agent, and / or in a compound of formula (I), one or both of R ¹ and / or Y radicals are substituted with other radical (s) R ¹ and And / or to Y and / or to a compound of formula (I) which is treated with an acid or a base and converted to one of its salts.

Compounds of formula (I) contain one or more chiral centers, resulting in several enantiomeric forms. Thus, the ordinary stone (I) includes all these forms (e.g., D and L forms) and mixtures thereof (e.g., DL forms).

Above and below, radicals or parameters X, Y, Z, R ¹ to R ⁴ , A, Ac, k, m, n, p and E, unless otherwise stated, are of general formula (I) or ( II).

When several groups A and / or Z are present in compounds (I), (II) and / or (III), they may be the same or different from one another.

In the above formulas, the A group has 1 to 6 carbon atoms, preferably 1, 2, 3 or 4. Specifically, A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl or tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl, 1,1 -, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl or 1-, 2-, 3- or 4-methylpentyl.

X is preferably 0, and S, NH or NA (e.g., N-CH ₃ ) is also preferred.

Y is preferably 3- (R ³ OOC-)-azetidino, 3- (R ³ OOC-CH2-0-)-azetidino, 2- (R ³ OOC-)-pyrrolidino, 3- (R ³ OOC-)-pyrrolidino, 2- (R ³ OOC-)-piperidino, 3- (R ³ OOC-)-piperidino, 4- (R ³ OOC-)-piperidino 2 -(R ³ OOC-CH ₂ -)-piperidino, 3- (R ³ OOC-CH ₂ -)-piperidino, 4- (R ³ OOC-CH ₂ -)-piperidino, 4- ( R ³ OOC-CH ₂ CH ₂ -)-piperidino, 4-hydroxy-4- (R ³ OOC-)-piperidino, 4-hydroxy-4- (R ³ OOC-CH ₂ -)- Piperidino, 4-amino-4- (R ³ OOC-)-piperidino, 4-amino-4- (R-OOC-CH ₂ ) -piperidino, 3-oxo-4- (R ³ OOC -CH ₂ -)-piperidino, 2- (R ³ OOC-CH ₂ -O-)-piperidino, 3- (R ³ OOC-CH ₂ -O-)-piperidino, 4- (R ³ OOC-CH ₂ -O-)-piperidino, 1-oxa-2-oxo-8-azaspiro [4,5] -deck-8-yl, 2-, 3- or 4- (R ³ OOC -)-Hexahydroazenono, 4- (R ³ OOC-CH ₂ -)-piperidino, 4- (R ³ OOC-CH ₂ CH ₂ -)-piperidino, 2- (R ³ OOC-) -Piperidino, 3- (R ³ OOC-)-piperazino or 4-benzyl-3- (R ³ OOC-)-piperazino.

Z is preferably H, more preferably A, for example methyl or ethyl phenyl, benzyl, acetyl or benzoyl.

R ¹ is preferably a phenyl radical substituted at the 4-position, otherwise at the 2- or 3-position as described above, specifically 2-, 3- or (particularly) 4-cyanophenyl, 2-, 3- or (particularly) 4-aminomethylphenyl, 2-, 3- or (particularly) 4-dimethylaminophenyl, 2-, 3- or (particularly) 4-amidinophenyl, 2-, 3- or 4-sphere Anidinophenyl or 2-, 3- or 4-guanidinomethylphenyl, 2-, 3- or (particularly) 4-hydroxyamidinophenyl.

R ² is preferably —COOR ³ , —CH ₂ COOR ³ or —O—CH ₂ COOR ³ .

R ³ is preferably H, methyl, ethyl, tert-butyl or benzyl.

R ⁴ is preferably H, methyl, ethyl, benzyl or CH ₂ COOR ³ .

Ac is preferably an alkanoyl having 1 to 6 carbon atoms, for example formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl or caproyl and also benzoyl, tolyl, 1- or 2-naphthoyl or Phenylacetyl.

The parameters k and m are preferably 0 or 1. The parameter n is preferably O, and p is preferably 1.

Preference is given to compounds having one of the groups in which at least one of the radicals, groups and / or parameters mentioned above of the compounds of formula (I) is mentioned as preferred. These preferred compounds can be represented by compounds of the general formulas (Ia) to (Id), corresponding to general formula (I):

(I a), X is 0,

In (I b), X is 0,

R ¹ is cyanophenyl,

In (IC) X is 0,

R ¹ is aminomethylphenyl,

In (I d), X is 0,

R ¹ is amidinophenyl.

Also corresponding to general formulas (I), (I a), (I b), (I c) and (I d), as well as general formula (I e) having the following groups, (I ae), ( Preferred are the compounds of I be), (I ce) and (I de):

Y is 3-R ² -azetidino, 2-R ² -pyrrolidino, 2-R ² -piperidino, 3-R ² -piperidino, 4-R ² -piperidino, 4-R ² -piperidino or 3-R ² -4-R ⁴ -piperazino,

R ² is —COOR ³ , —CH ₂ COOR ³ or —OCH ₂ COOR ³ ,

R ⁴ is -CH ₂ COOR ³ .

Preferred compounds which are rarely selected are compounds of the general formulas (I f) and (I g), which correspond to the general formula (I) with the following groups.

In (I f), X is 0, Y is 3- (R ³ OOC—CH ₂ —O —)-azetidino, 2- (R ³ OOC —)-pyrrolidino, 2-, 3- or 4- (R ³ OOC-)-piperidino, 4- (R ³ OOC-CH ₂ -)-piperidino, 3- or 4- (R ³ OOC-CH ₂ -O-) piperidino, 4 -(R ³ OOC-CH ₂ ) -piperazino or 3- (R ³ OOC-)-4-R ⁴ -piperazino,

R ¹ is 4-cyanophenyl, 4-aminomethylphenyl, 4-amidinophenyl, or 4-guanidinomethylphenyl,

R ³ is H, C ₁ -C ₄ -alkyl or benzyl,

R ⁴ is H or benzyl,

In (I g), X is 0,

Y is 4- (R ³ OOC —)-piperidino or 4- (R ³ OOC—CH ₂ O —)-piperidino,

R ¹ is 4-cyanoferyl, 4-aminomethylphenyl or 4-amidinophenyl,

R ³ is H, C ₁ -C ₄ -alkyl or benzyl.

Compounds of general formula (I) and starting materials for their preparation are described in, for example, Houben-Wey1, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme Verlag, Stuttgart and European Patent Application Publications. 0 381 033 and Published Application 0 462 960 may be prepared differently, especially under reaction conditions known to be most appropriate thereto. Although not described in detail herein below, known variations may be used.

If desired, starting materials can be prepared and reacted immediately to produce compounds of formula (I) without separation from the reaction system.

Compounds of general formula (I) can also be obtained by liberation from their functional derivatives by solvolysis (particularly hydrolysis) or hydrogenolysis.

Starting compounds suitable for solvolysis or hydrogenolysis contain corresponding protected amino and / or hydroxy groups in place of one or more free amino and / or hydroxy groups, while particularly preferably in place of H atoms bonded to N atoms Accompanying amino protecting groups, for example, corresponding to general formula (I), containing -COOR "groups, where R" is a hydroxy protecting group, instead of -COOH groups.

Several -identical or different-protected amino and / or hydroxy can be present in the molecule of the starting compound. If the protecting groups present are different, in many cases they can be selectively removed.

The expression 'amino protecting group' is generally used in connection with functional groups which are suitable for protecting (blocking) the amino group from chemical reactions and which can be easily removed after the desired chemical reaction is carried out at another position in the molecule. Typical groups of this type are, in particular, substituted or unsubstituted acyl, aryl (eg 2,4-dinitrophenyl (DNF), aralkoxymethyl (eg benzyloxymethyl (BOM) or aralkyl (eg benzyl, 4) -Nitrobenzyl or triphenylmethyl) groups, amino protecting groups are removed after the desired reaction (or series of reactions), so their properties and size are not a problem, but those containing 1-20 carbon atoms, especially 1-8 carbon atoms, In the context of the process, the expression “acyl group” is used in its broadest sense, including acyl groups derived from aliphatic, aromatic aliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, in particular alkoxy. Carbonyl groups, aryloxycarbonyl groups and, above all, aralkoxy carbonyl groups Examples of acyl groups in this form include alkanoyls such as acetyl, propionyl or butyryl; phenyl Aralkanoyl like cetyl: Arylyl like benzoyl or tolyl: Aryloxyalkanoyl like phenoxyacetyl: methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopro Alkoxycarbonyls such as foxoxycarbonyl, tert-butoxycarbonyl (BOC) or 2-iodoethoxycarbonyl: benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, or 9-flu Aralkyloxycarbonyl such as orenylmethoxycarbonyl (FMOC) Preferred amino protecting groups are EOC, DNP and BOM, with CBZ, benzyl and acetyl also being preferred.

The expression 'hydroxyprotecting group' is also used in connection with functional groups which are suitable for protecting the hydroxy group from chemical reactions and which can be easily removed after the desired chemical reaction is carried out at another position in the molecule. Typical groups of this nature include substituted or unsubstituted aryl, aralkyl or acyl groups as mentioned above and also include alkyl groups. The hydroxy protecting groups are removed at the end of the desired reaction or series of reactions, so the nature or size thereof is not a problem, but those having 1-20 carbon atoms, particularly 1-10 carbon atoms, are preferred. Examples of hydroxy protecting groups include tert-butyl, benzyl, p-nitrobenzoyl, P-toluenesulfonyl, and acetyl, among which benzyl and acetyl are particularly preferred.

Functional derivatives of the compounds of the general formula (I) to be used as starting compounds may be prepared by conventional methods (e.g., by the methods described in the above standard documents and patent applications), for example in general formulas (II) and (III). Correspondingly, but can be prepared by reacting one or more compounds containing protecting groups instead of H atoms.

Depending on the type of protecting group used, strong acids can be used to liberate compounds of formula (I) from their functional derivatives. Suitable strong acids are trifluoroacetic acid or perchloric acid, but other strong inorganic acids such as hydrochloric acid, sulfuric acid, carboxylic acids such as trichloroacetic acid, benzenesulfonic acid, or sulfonic acids such as p-toluene sulfonic acid may be used. Additional inert solvents may be used but are not always necessary.

Examples of suitable inert solvents include carboxylic acids such as acetic acid, ethers such as tetrahydrofuran, dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, sulfoxides such as dimethyl sulfoxide (DMSO) And alcohols such as methanol, ethanol, isopropanol and water are also preferred. Mixtures of the above solvents may also be suitable solvents. It is preferable to use trifluoroacetic acid in excess, without adding another solvent, and perchloric acid is preferably used in the form of a 9: 1 mixture of acetic acid and 70% perchloric acid. The reaction temperature for decomposition is preferably between about 0 ° and about 50 °, preferably between 15 and 30 ° (room temperature).

The BOC group can be removed at 15 to 60 ° using 40% trifluoroacetic acid in dichloromethane or using about 3 to 5 N HCI in dioxane and the FMOC group at 15 to 50 ° in dimethylamine, diethyl in DMF It can be removed using about 5-20% solution of amine or piperidine.

In addition, DNP groups can be removed, for example, at 15-30 ° using a solution of about 3-10% 2-mercaptoethanol in DMF / water.

Protecting groups (eg BOU, CBZ or benzyl) that can be removed by hydrogenolysis are hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium; advantageously on a carrier such as carbon) Remove by treating with. Suitable solvents for this are as described above, but alcohols such as methanol or ethanol and amides such as DMF are particularly preferred. Hydrolysis is usually carried out at a temperature of about 0 to 100 ° and a pressure of about 1 to 200 bar, but is preferably carried out at 20 to 30 ° and 1 to 10 bar. Hydrolysis of the CBZ groups can be satisfactorily carried out on 5 to 10% Pd-carbon phase in methanol at 20 to 30 °.

The compound of general formula (I) may preferably be obtained by reacting a compound of general formula (II) with a base of general formula (III). Known N-alkylation methods can then be advantageously used.

The leaving group E is preferably Cl, Br, I, C ₁ -C ₆ -alkylsulfonyloxy (eg methanesulfonyloxy or ethanesulfonyloxy), or C ₆ -C ₁₀ -arylsulfonyloxy (eg Benzenesulfonyloxy, P-toluenesulfonyloxy or 1- or 2-naphthalenesulfonyloxy).

The reaction is carried out, for example, in the presence of a base such as an alkali metal or alkaline earth metal hydroxide or a carbonate, such as sodium hydroxide, potassium hydroxide or calcium hydroxide, or sodium carbonate, potassium carbonate or calcium carbonate, a halogenated hydrocarbon such as dichloromethane, In ethers such as THF or dioxane, amides such as DMF or dimethylacetamide, or nitriles such as acetonitrile, it is preferably carried out at a temperature of about -10 to 200, preferably 0 to 120 °. When the leaving group E of (I) is different, it is preferable to add an iodide like potassium iodide.

Starting compounds of economy stone (II) are generally novel compounds. These compounds include, for example, substituted anilines of the general formula R ¹ -NH ₂ with the general formula R ⁵ CH ₂ -CHR ⁶ -CH ₂ OH, wherein R ⁵ is E, R ⁶ is XR ⁷ , and R ⁷ is a protecting group and R ⁵ and R ⁶ together are also 0 to react with a compound of the general formula R ¹ -NH-CH ₂ -CHR ⁸ -CH ₂ OH, wherein R ⁸ is XR ⁷ or OH ), And if necessary, a compound of the general formula R ¹ -NH-CH ₂ -CH (XH) -CH ₂ OH obtained by removing the protecting group R ⁷ is reacted with a derivative of carbonic acid such as diethyl carbonate to give 3- Obtain R ¹ -5-hydroxymethyl-2-oxazolidinone and then convert the hydroxymethyl group to a CH ₂ E group using, for example, SOCl ₂ , SOBr ₂ , methanesulfonylchloride or p-toluenesulfonyl chloride Can be prepared by Compounds of Economy HY (III) are generally known or can be prepared analogously to known compounds.

In addition, the compound of general formula (I) can be obtained by reacting a compound of general stone (IV) (or a reactive derivative thereof) with a reactive derivative of carbonic acid.

Suitable carbonic acid derivatives are in particular dialkyl carbonates such as diethyl carbonate and other alkyl esters of chloroformic acid such as ethyl chloroformate. Preferably, carbonic acid derivatives which are advantageously used in excess also act as solvents or suspending agents. One of the above solvents may be contained under conditions inert to this reaction. It is also preferable to add bases, in particular alkali metal alcoholates such as potassium tert-butylate. As reaction temperature, 0-150 degree, Preferably 70-120 degree is used advantageously.

Starting compounds of general formula (IV) are generally novel substances. These compounds are functionalized with compounds of the general formula R ¹ -NH-CH ₂ -CH (XH) -CH ₂ OH as described above, for example, and general formula R ¹ -NH-CH ₂ -CH (XH) -CH _2- . After obtaining the compound of E, it can be obtained by reacting with the compound of general formula HY (III).

In order to manufacture the compound of general stone (I) whose R <^1> is a guanidinophenyl group, it can obtain by processing a corresponding aminophenyl compound with an amidinizing agent. 1-amidino-3,5-dimethylpyrazole, especially used in its nitrate form, is preferred as an amidine agent. The reaction is advantageously carried out in the presence of a base such as triethylamine or ethyl diisopropylamine, at a temperature of 0 to 120 °, preferably 60 to 120 ° in an inert solvent or solvent mixture, for example water / dioxane. do.

Also in the compounds of formula (I), one or both of the radicals R ^l and / or Y may be converted to the other radical (s) R ¹ and / or Y.

In particular, the cyano group is reduced to an aminomethyl group, converted to an amidino group or a hydroxyamidino group, esterified with a carboxyl group, an ester group is separated, or a benzyl group is hydrolyzed, or an aminomethyl group is guanidinomethyl group. You can switch to

Reducing the cyano group to the aminomethyl group is preferably carried out by catalytic hydrogenation, for example on Raney nickel, at a temperature of 0 to 100 °, preferably at a temperature of 10 to 30 °, under a pressure of 1 to 200 bar, preferably Is preferably carried out under atmospheric pressure, in an inert solvent such as lower alcohols such as methanol or ethanol, advantageously in the presence of ammonia. For example, when the reaction is performed at about 20 ° and 1 bar, the benzyl ester group or N-benzyl group present in the starting material is preserved as is. If these groups are to be hydrolytically separated, it is preferred to use a noble metal catalyst, preferably Pd-carbon, in which acid and water such as acetic acid can be added to the solution.

In order to manufacture the amidine of general formula (I) whose R <^1> is amidinophenyl, ammonia can be added to the nitrile of general formula (I) whose R <^1> is cyanophenyl. Such addition is carried out by known per se methods, i.e. in multiple stages,

a) nitrile is converted to thioamide using H ₂ S and this compound is converted to the corresponding S-alkyl imidothioester using an alkylating agent such as CH ₃ l. React with NH ₃ to obtain amidine,

b) converting the nitrile to the corresponding imido ester in the presence of HCl using an alcohol such as ethanol and treating this compound with ammonia, or

c) Preferably, the nitrile is reacted with lithium bis (trimethylsilyl) amide followed by hydrolysis of the product.

The corresponding N-hydroxyamidines of formula (I), wherein R ¹ is phenyl substituted with HO-NH-C (= NH)), are hydrates instead of ammonia, according to a) or b) from nitrile It can be obtained by a similar method using a siloxane.

For esterification, an acid of general formula (I) in which R ³ is H and an alcohol of general formula R ³ -OH in which R ³ is A or benzyl, in the presence of a strong acid, advantageously hydrochloric acid or sulfuric acid Under the treatment, it can be treated at a temperature of 0 to 100 °, preferably at a temperature of 20 to 50 °.

Alternatively R ³ is A or benzyl. The ester of general formula (I) is advantageously subjected to a temperature of 0 to 40 °, preferably 10 to 30 "in water / dioxane, for example using NaOH or KOH, according to one of the methods described above. Solubilization at a temperature of can convert to the corresponding acid of formula (I), wherein R ³ is H.

The base of formula (I) can be converted to the corresponding acid addition salt by addition of an acid. Particularly suitable acids for this reaction are those that produce physiologically harmless salts. Therefore, inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrochloric acid such as hydrobromic acid, phosphoric acid such as orthophosphoric acid, and sulfamic acid, and also aliphatic, alicyclic, aromatic aliphatic, aromatic, heterocyclic monobasic or polybasic carboxylic acids. , Sulfonic acid or sulfuric acid such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Organic acids such as ascorbic acid, nicotinic acid, isnicotinic acid, methanesulfonic acid or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic acid and naphthalenedisulfonic acid and lauryl sulfate have. In order to isolate and / or purify the compound of formula (I), salts with acids which are not physiologically harmless, for example picric acid salts, can also be used.

The free base of general formula (I) can be separated from these salts by treatment with a strong base such as sodium hydroxide or potassium hydroxide or sodium carbonate or potassium carbonate, if necessary.

It is also possible to convert carboxylic acids of the general formula (I), in which R ³ is H, to their metal salts or ammonium salts, such as sodium, potassium or calcium salts, by reaction with the corresponding bases.

Since the compounds of formula (I) have one or more chiral centers, they may exist in racemic or optically active forms. The obtained racemates can be cleaved mechanically or chemically into enantiomers according to methods known in the art. Preferably, the diastereomer is formed by reaction with the optically active splitting agent from the racemic mixture. Suitable splitting agents are, for example, optically active acids such as D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid or lactic acid and various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Enantiomeric splitting using a column packed with an optically active splitting agent (e.g., dinitrobenzoyl phenylglycine) is also advantageous, in which the eluent is a mixture of hexane / isopropanol / acetonitrile, for example a mixture of 82: 15: 3 volume ratios. This is suitably used.

It is also possible to obtain an optically active compound of the general formula (I) according to the above-mentioned method using a starting compound (e.g., a compound of the general formula (II)) already optically active.

The novelized heaps of formula (I) and their physiologically harmless salts can be converted into suitable formulations with one or more excipients or auxiliaries, if necessary, together with one or more other active compound (s) to form a pharmaceutical formulation. The formulation thus obtained can be used for human or veterinary medicine. Suitable excipients are organic or inorganic compounds which are suitable for administration in the form of intestinal (eg oral or rectal) or parenteral administration or inhalation for inhalation and do not react with new compounds, for example water, vegetable oils. Benzyl alcohol, polyethylene glycol, glycerol triacetate and other fatty acid glycerin, gelatin, soya lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc and cellulose.

In particular, tablets, coatings, capsules, syrups, juices or drops are used for oral use, with lacquer tablets and gastric acid-resistant coatings or capsule casing containing capsules being particularly advantageous. Suppositories can be used for rectal use, and liquids, preferably oily or aqueous solutions and suspensions, emulsions or implants, etc. can be used for parenteral administration.

As a spray for inhalation, a spray can be used in which the active ingredient is dissolved or suspended in a propeller gas mixture. Advantageously, the active ingredient is used in particulate form, preferably with the addition of one or more physiologically acceptable solvents such as ethanol. Inhalation solutions can be administered using conventional inhalers. These new compounds can be lyophilized and the resulting lyophilisates can be used, for example, in preparations for injection. Such formulations may be sterile and / or may contain the following auxiliaries. Such adjuvants include preservatives, stabilizers and / or wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants and / or flavors and the like. They may also contain one or more other active ingredients, such as one or more vitamins, if desired.

The dosage of the substance according to the invention is administered in a similar way generally to other known commercially available drugs, but in particular similarly to the compounds described in EP 459256, preferably from about 5 mg to 1 g per unit of dosage, in particular 50 It is preferred to have a daily dosage of about 0,1 to 20 mg, especially 1 to 10 mg per kg of body weight. However, the specific dosage of each patient depends on a number of factors, including, for example, the activity, age, weight, health and sex, diet, time and route of administration, rate of excretion of the compound being used. Combination of drugs and the severity of the disease being treated. Oral administration is preferred.

All temperatures above and below are degrees Celsius. In the examples, " normal reaction finish " means that water is added if necessary, the pH is adjusted to 2-8 depending on the composition of the final product, extracted with ethyl acetate or dichloromethane, the phases are separated and the organic phase is sodium sulfate. And evaporated and purified by chromatography and / or crystallization on silica gel.

FAB = (M ++ 1) peak in the mass spectrum was obtained by fast-atom bombardment method.

Next, the Example of this invention is described. However, these examples are provided only to facilitate the understanding of the present invention, the present invention is not limited to these examples.

Example 1

Ethyl 1-3-butoxycarbonyl-4- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-2-carboxylate [method as described in Example 3 Obtained by reacting 3- (4-cyanophenyl) -5-bromomethyl-2-oxazolidinone with ethyl 1-3 tert-butoxycarbonylpiperazine-2-carboxylate] The solution dissolved in 12 ml of dichloromethane and 12 ml of trifluoroacetic acid was left at 20 ° C. for 1 hour, and then concentrated by evaporation to ethyl 1- (3- (4-cyanophenyl) -2-oxo-5- Oxazolidinylmethyl) piperazine-3-carboxylate (FAB.359) was obtained.

By the same method as described above, 1-3-tert-butoxycarbonyl-4- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-2-carboxyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-3-carboxylic acid and its benzyl esters were obtained from the acid or benzyl esters thereof.

Example 2

Tert-butyl 1- (3- (4-benzyloxycarbonylaminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-oxyacetate [3- according to the method described in Example 3 Obtained by reacting (4-benzyloxycarbonylaminomethylphenyl) -5-chloromethyl-2-oxazolidinone with tert-butyl piperidine-4-oxyacetate] 1 g of 38 ml of methanol, 6 ml of water, and The solution dissolved in a mixture of 6 ml of acetic acid was hydrogenated on 0.6 g of 5% Pd-carbon at a temperature of 20 ° C. and 1 bar of pressure until H ₂ absorption ceased. The mixture was filtered and the filtrate was then concentrated by evaporation to tert-butyl1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-oxyacetate (melting point 95 FAB 420) was obtained.

Example 3

3- (4-cyanophenyl) -5-methanesulfonyloxymethyl-2-oxazolidinone (melting point 162-163 ° C) [4-aminobenzonitrile is reacted with 2,3-epoxypropanol to give 4- (2 , 3-dihydroxypropylamino) benzonitrile (oily) was obtained, which was then reacted with diethyl carbonate / potassium tert-butylate at 110 ° C. to 3- (4-cyanophenyl) -5-hydroxymethyl 2.96 g of 2-oxazolidinone (melting point 130-131 ° C.), followed by esterification with methanesulfonyl chloride), 1.69 g of ethyl piperidine-4-carboxylate, 70 ml of potassium acetonitrile A mixture of 1,38 g and 1.65 g of potassium iodide was boiled for 25 hours, followed by normal reaction finishing to afford ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) Ferridine-4-carboxylate (called "IA") (FAB 358) was obtained.

In a similar manner the following compounds are obtained:

Using benzyl piperidine-4-carboxylate

Benzyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylate (melting point 96 ° C., FAB 420);

Using tert-butyl piperidine-4-carboxylate

Tert-butyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidanylmethyl) piperidine-4-carboxylate;

Using ethyl piperidine-3-carboxylate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-carboxylate;

Using benzyl piperidine-2-carboxylate

Benzyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-carboxylay (FAB 420);

Using tert-butyl piperidine-3-carboxylate

Tert-butyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-carboxylate:

Using ethyl piperidine-2-carboxylate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-2-carboxylate;

Using benzyl piperidine-2-carboxylate

Benzyl 1- (3- (4-cyanoferyl) -2-oxo-5-oxazolidinylmethyl) piperidine-2-carboxylate (FAB 420);

Using tert-butyl piperidine-2-carboxylate

Tert-butyl 1- (3- (4-cyanoferyl) -2-oxo-5-oxazolimonylmethyl) piperidine-2-carboxylate:

Using ethyl pyrrolidine-2-carboxylate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) pyrrolidine-2-carboxylate;

Using benzyl pyrrolidine-2-carboxylate

Benzyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) pyrrolidine-2-carboxylate;

Using tert-butyl pyrrolidine-3-carboxylate

Tert-butyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) pyrrolidine-2-carboxylate;

Using ethyl piperidine-4-acetate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-aceteart;

Using benzyl piperidine-4-acetate

Benzyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-acetate;

Using tert-butyl piperidine-4-acetate

Tert-butyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-acetate;

Using ethyl piperidine-4-oxyacetate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-oxyacetate:

Using benzyl piperidine-4-oxyacetate

Benzyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-oxyacetate;

Using tert-butyl piperidine-4-oxyacetate

Tert-butyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-oxyacetate (melting point 88-89 ° C., FAB 416);

Using ethyl piperidine-3-oxyacetate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-oxyacetate;

Using benzyl piperidine-3-oxyacetate

Benzyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-oxyacetate;

Using tert-butyl piperidine-3-oxyacetate

Tert-butyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-oxyacetate;

Using ethyl piperazine-1-acetate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-4-acetate;

Using benzyl piperazine-1-acetate

Benzyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-4-acetate;

Using tert-butyl piperazine-1-acetate

Tert-butyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-4-acetate;

Using ethyl azetidine-3-oxyacetate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) azetidine-3-oxyacetate;

Using benzyl azetidine-3-oxyacetate

Benzyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) azetidine-3-oxyacetate;

Tert-butyl azetidine-3-oxyacetate

Tert-butyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) azetidine-3-oxyacetate;

Using ethyl 1-benzyl piperazine-2-carboxylate

Ethyl 1-benzyl-4- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinyl) piperazine-2-carboxylate;

Using benzyl 1-benzyl piperazine-2-carboxylate

Benzyl 1-benzyl-4- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinyl) piperazine-2-carboxylate;

Using tert-butyl 1-benzyl piperazine-2-carboxylate

Tert-butyl 1-benzyl-4- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinyl) piperazine-2-carboxylate was obtained, respectively.

3- (4-cyanophenyl) -5S-methanesulfonyloxymethyl2-oxazoladinone (melting point 141-142 ° C; [α] ²⁰ _D + 75,3 ° (c = 3.9 mg) in the same manner as described above / Ml in methanol)) [4-aminobenzonitrile with 2R-2,3-epoxypropanol to give 4- (2S, 3-dihydroxypropylamino) benzonitrile, which in turn is diethyl carbonate / potassium Reaction with tert-butylate to give 3- (4-cyanophenyl) -5S-hydroxymethyl-2-oxazolidinone, which is then esterified with methanesulfonyl chloride] and benzyl piperidine- 4-carboxylate is reacted to yield benzyl1- (3- (4-cyanophenyl) -2-oxo-5S-oxazolidinylmethyl) piperidine-4-carboxylate (melting point 87-88 ° C .; α] ²⁰ _D 43.0 ° (c = 9.8 mg / ml, methanol) was obtained.

In a similar manner the following compounds are obtained:

Using yetin piperidine-4-carboxylate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5S-oxazolidinylmethyl) piperidine-4-carboxylate;

Using tert-butyl piperidine-4-carboxylate

Tert-butyl 1- (3- (4-cyanophenyl) -2-oxo-5S-oxazolidinylmethyl) piperidine-4-carboxylate was obtained, respectively.

4- (2R, 3-dihydroxypropyl from 3- (4-cyanophenyl) -5R-methanesulfonyloxymethyl-2-oxazolidinone (2S-2,3-epoxypropanol) in the same manner as described above Obtained via amino) benzonatril and 3- (4-cyanophenyl) -5R-hydroxy methyl-2-oxazolidinone]] benzyl 1- (3- (4-cyanophenyl) -2-oxo -5R-oxazolidinylmethyl) piperidine-4-carboxylate, the corresponding ethyl ester and the corresponding tert-butyl ester, were obtained.

Example 4

In a similar manner to Example 3, 3- (4-dimethylaminomethylphenyl) -5-bromomethyl-2-oxazolidinone [4-dimethylaminomethylaniline was reacted with 2,3-epoxypropanol to give 3- (4 -Dimethylaminomethylphenylamino) -1,2-propanediol, which is then reacted with diethyl carbonate / potassium tert-butylate to give 3- (4-dimethylaminomethylphenyl) -5-hydroxymethyl-2-oxa Obtained by reaction with SOBr ₂ ] and tert-butyl piperidine-4-carboxylate to react tert-butyl 1- (3- (4-dimethylaminomethylphenyl) -2- Oxo-5-oxazolidinylmethyl) piperidine-4-carboxylate (FAB 432) was obtained.

Example 5

1- (3- (4-cyanophenyl) -2-hydroxypropyl) piperidine-4-carboxylate [3- (4-cyanophenyl) -1,2-propanediol-1-methanesulfo Obtained by reacting an acetate with ethyl piperidine-4-carboxylate.] A mixture of 3.31 g, 15 ml of diethyl carbonate and 0.1 g of potassium tert-butylate was stirred at a bath temperature of 110 ° C. for 2 hours. The mixture was evaporated to concentration and the usual reaction finish to afford the "IA" (FAB 358) compound.

Example 6

0.17 ml of ethyl diisopropylamine was added to a solution of 201 mg of 1-amidino-3,5-dimethylpyrazole nitrate in 17 ml of dioxane and 5 ml of water, and the mixture was stirred for 15 minutes. Then to this mixture was tert-butyl 1- (3- (4-aminophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylate [4-aminoacetanilide and 2, 3-epoxypropanol is reacted to obtain 4- (2,3-dihydroxypropylamino) acetanilide, which is then reacted with diethyl carbonate to react with 3- (4-acetamidophenyl) -5-hydroxymethyl- 2-oxazolidinone was obtained, which was then converted to methane sulfonate and obtained by reaction with tert-butyl piperidine-4-carboxylate] 375 mg was added and the mixture was boiled for 45 hours. Concentration by evaporation and the usual reaction finishing gave tert-butyl 1- (3- (4-guanidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylate.

In the same manner as above, tert-butyl 1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylate and 1-amidino-3 , 5-dimethylpyrazole nitrate was reacted to give tert-butyl 1- (3- (4-guanidinomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylate ( FAB 432).

Example 7

A solution of 1 g of “IA” compound dissolved in 40 ml of 10% methanolic NH ₃ solution was hydrogenated at 0.6 ° C. on nickel at a temperature of 20 ° C. and pressure 1 bar until H ₂ absorption ceased. Filtration and evaporation concentrated to give ethyl 1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylate (FAB 362).

In the same manner as described above, the corresponding nitrile compound is hydrogenated to give the following 1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine compound:

-4-carboxylic acid tert-butyl ester,

3-carboxylic acid ethyl ester,

3-carboxylic acid tert-butyl ester,

2-carboxylic acid ethyl ester,

2-carboxylic acid tert-butyl ester,

-4-acetic acid ethyl ester,

-4-acetic acid tert-butyl ester,

-4-oxyacetic acid ethyl ester,

4-oxyacetic acid tert-butyl ester (melting point 95-96 ° C., FAB 420),

-3-oxyacetic acid ethyl ester,

3-oxyacetic acid tert-butyl ester:

In the manner as described above,

The following 1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) pyrrolidine compound is obtained:

2-carboxylic acid ethyl ester,

2-carboxylic acid tert-butyl ester:

In the manner as described above,

The following 1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperazine compound is obtained:

-4-acetic acid ethyl ester,

4-Acetic acid tert-butyl ester:

In the manner as described above,

The following 1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) azetidine compound is obtained:

-3-oxyacetic acid ethyl ester,

-3-oxyacetic acid tert-butyl ester;

In the manner as described above,

The following 1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) -4-benzylpiperazine compound is obtained:

3-carboxylic acid ethyl ester,

3-carboxylic acid tert-butyl ester;

In the manner as described above,

The following 1- (3- (4-aminomethylphenyl) -2-oxo-5S-oxazolidinylmethyl) piperidine compound is obtained:

-4-carboxylic acid ethyl ester,

-4-carboxylic acid tert-butyl ester,

In the manner as described above,

The following 1- (3- (4-aminomethylphenyl) -2-oxo-5R-oxazolidinylmethyl) piperidine compound is obtained:

-4-carboxylic acid ethyl ester,

4-carboxylic acid tert-butyl ester.

Example 8

3.57 g of "IA" compound was dissolved in 50 ml of pyridine and 6.6 ml of triethylamine, and N ₂ S was introduced at -10 ° C for 45 minutes. The mixture was then stirred at 20 ° C. for 14 hours, then evaporated to concentration, the residue was dissolved in 50 ml of acetone and 9 ml of methyl iodide was added to this solution. The solution was stirred at 20 ° C. for 6 hours, then filtered, the residue was washed with a small amount of acetone and then dissolved in 30 ml of methanol, then 4.6 g of ammonium acetate was added and the mixture was stirred at 20 ° C. for 30 hours Stirred. The obtained ethyl 1- (3- (4-aminophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylate was filtered and chromatographed on silica gel (dichloromethane / methanol / acetic acid, 70: 30: 2) (melting point, 200 ° C. (decomposition), FAB 375).

In a similar manner, the following 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine compound is obtained from the corresponding nitrile:

4-carboxylic acid benzyl ester, melting point 204 DEG C (decomposition), FAB 437: dihydrochloride (melting point 182 DEG C),

-4-carboxylic acid tert-butyl ester,

3-carboxylic acid ethyl ester,

3-carboxylic acid benzyl ester, acetate (FAB 437),

3-carboxylic acid tert-butyl ester,

2-carboxylic acid ethyl ester,

2-carboxylic acid benzyl ester (FAB 437),

2-carboxylic acid tert-butyl ester,

-4-acetic acid ethyl ester,

-4-acetic acid benzyl ester,

-4-acetic acid tert-butyl ester,

-4-oxyacetic acid ethyl ester,

4-oxyacetic acid benzyl ester (acetate, melting point 206 ° C.),

4-oxyacetic acid tert-butyl ester, melting point 187 ° C. (decomposition), FAB 433,

-3-oxyacetic acid ethyl ester,

3-oxyacetic acid benzyl ester,

-3-oxyacetic acid tert-butyl ester;

In the same manner as described above, the following 1- (3- (4-amidinophenyl) 2-oxo-5-oxazolidinylmethyl) pyrrolidine compound is obtained:

2-carboxylic acid ethyl ester,

2-carboxylic acid benzyl ester,

2-carboxylic acid tert-butyl ester;

In the same manner as described above, the following 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine compound is obtained:

-4-acetic acid ethyl ester,

4-acetic acid benzyl ester, FAB 452,

-4-acetic acid tert-butyl ester;

In the same manner as described above, the following 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) azetidine compound is obtained:

-3-oxyacetic acid ethyl ester,

-3-oxyacetic acid benzyl ester,

-3-oxyacetic acid tert-butyl ester;

In the same manner as described above, the following 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -4-benzylpiperazine compound is obtained:

3-carboxylic acid ethyl ester,

3-carboxylic acid benzyl ester,

3-carboxylic acid tert-butyl ester;

In the same manner as described above, the following 1- (3- (4-amidinophenyl) -2-oxo-5S-oxazolidinylmethyl) piperidine compound is obtained:

-4-carboxylic acid ethyl ester,

-4-carboxylic acid benzyl ester,

-4-carboxylic acid tert-butyl ester;

In the same manner as described above, the following 1- (3- (4-amidinophenyl) -2-oxo-5R-oxazolidinylmethyl) piperidine compound is obtained:

-4-carboxylic acid ethyl ester,

-4-carboxylic acid benzyl ester,

4-carboxylic acid tert-butyl ester.

Example 9

In a similar manner as in Example 8 except that an equivalent amount of hydroxyammonium acetate is used instead of ammonium acetate, ethyl 1- (3- (4-hydroxyamidinophenyl) -2-oxo- 5-oxazolidinylmethyl) piperidine-4-carboxylate was obtained.

Example 10

1 g of tert-butyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylate was dissolved in 12 ml of dichloromethane, and this solution To the mixture was added 12 ml of trifluoroacetic acid, the mixture was allowed to stand for 5 minutes, concentrated by evaporation, and subjected to the usual reaction reaction to give 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl. ) Piperidine-4-carboxylic acid (FAB 330) was obtained.

In a similar manner, the following acid is obtained from the corresponding tert-butyl ester:

1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-carboxylic acid,

1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-2-carboxylic acid,

1- (3- (4-cyanophenyl) -2-oxo-5-oxolidinylmethyl) pyrrolidine-2-carboxylic acid,

1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-acet

1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-oxyacetic acid,

1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-oxyacetic acid,

1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-4-acetic acid,

1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) azetidine-3-oxyacetic acid,

1-benzyl-4- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-2-carboxylic acid,

1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylic acid (melting point 190 ° C. (decomposition), FAB 334),

1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-carboxylic acid,

1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-2-carboxylic acid,

1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) pyrrolidine-2-carboxylic acid,

1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-acetic acid,

1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-oxyacetic acid (melting point 135 ° C., FAB 364),

1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-oxyacetic acid,

1- (3- (1-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-4-acetic acid,

1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) azetidine-3-oxyacetic acid,

1-benzyl-4- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-2-carboxylic acid,

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylic acid (melting point 265 ° C (decomposition), FAB 347, dihydrochloride (melting point 142 ° C) )),

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-carboxylic acid,

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-2-carboxylic acid (melting point 198 ° C., FAB 347),

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) pyrrolidine-2-carboxylic acid,

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-acetic acid (melting point 256 ° C.),

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-oxyacetic acid (oil, FAB 377),

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-oxyacetic acid (melting point 167-168 ° C.),

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-4-acetic acid (FAB 362),

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) azetidine-3-oxyacetic acid,

1-benzyl-4- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-2-carboxylic acid,

1- (3- (4-guanidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylic acid,

1- (3- (4-guanidinomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylic acid (FAB 376),

1- (3- (4-cyanophenyl) -2-oxo-5S-oxazolidinylmethyl) piperidine-4-carboxylic acid,

1- (3- (4-cyanophenyl) -2-oxo-5R-oxazolidinylmethyl) piperidine-4-carboxylic acid,

1- (3- (4-aminomethylphenyl) -2-oxo-5S-oxazolidinylmethyl) piperidine-4-carboxylic acid,

1- (3- (4-aminomethylphenyl) -2-oxo-5R-oxazolidinylmethyl) piperidine-4carboxylic acid,

1- (3- (4-amidinomethylphenyl) -2-oxo-5S-oxazolidinylmethyl) piperidine-4-carboxylic acid,

1- (3- (4-amidinomethylphenyl) -2-oxo-5R-oxazolidinylmethyl) piperidine-4-carboxylic acid,

1- (3- (4-dimethylaminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylic acid.

Example 11

1 g of benzyl 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylate was dissolved in 100 ml of methanol, 17 ml of acetic acid and 17 ml of water. The solution was hydrogenated over 0.7 g of 5% Pd-carbon at a temperature of 20 ° C. and 1 bar of pressure until hydrogen absorption ceased. The mixture was filtered, concentrated by evaporation and the residue treated with diethyl ether to give 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4- Carboxylic acid (melting point 265 degreeC, FBA 347, dihydrochloride (fusion | melting 142 degreeC)) was obtained.

Example 12

Similar to Example 11, 1-benzyl-4- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-2-carboxylic acid (referred to as "IB", Or “IB” benzyl ester) to give 1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-3-carboxylic acid.

In a similar way,

1-benzyl-4- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-2-carboxylic acid (or benzyl ester thereof) was hydrogenated to give the same material as described above. .

In a similar manner, each ethyl 1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-3-carboxyl from the ethyl and tert-butyl esters of the "IB" compound The rate and tert-butyl 1- (3- (4-aminomethylphenyl) -2-oxo-5-oxazolidinylmethyl) piperazine-3-carboxylate were obtained.

Example 13

Similar to Example 3, the following compounds are obtained from 3- (4-cyanophenyl) -5-methanesulfonyloxymethyl-2-oxazolidinone:

Using benzyl piperidine-3-acetate

Benzyl 1- (3- (4-anophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-acetate (FAB 434):

Using methyl 3- (1-piperazinyl) propionate

Methyl 3- (4- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) -1-piperazinyl) propionate (FAB 373):

Using ethyl 3- (1-piperazinyl) propionate

Ethyl 3- (4- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) -1-piperazinyl) propionate (FAB 387):

Using ethyl 2-oxopiperazine-1-acetate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) -3-oxo-piperazine-4-acetate (FAB 387);

Using ethyl 3- (2-oxo-1-piperazinyl) propionate

Ethyl 3- (4- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) -2-oxo-1-piperazinyl) propionate (FAB 401):

Using ethyl 4-hydroxypiperidine-4-carboxylate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) -4-hydroxypiperidine-4-carboxylate (FAB 374);

Using ethyl 4-hydroxypiperidine-4-acetate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) -4-hydroxypiperidine-4-acetate (FAB 388):

Using 1-oxa-8-azaspiro [4.5] decan-2-one (lactone of = 3- (4-hydroxy-4-piperidyl) propionic acid)

8- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) -1-oxa-8-azaspiro [4.5] decan-2-one (FAB 356) was obtained, respectively.

In a similar way,

The following compounds are obtained from 3- (4-cyanophenyl) -5R- or -5S-methanesulfonyloxymethyl-2-oxazolidinone;

Using benzyl piperidine-4-carboxylate

Benzyl 1- (3- (4-cyanophenyl) -2-oxo-5R-oxazolidinylmethyl) piperidine-4-carboxylate,

Benzyl 1- (3- (4-cyanophenyl) -2-oxo-5S-oxazolidinylmethyl) piperidine-4-carboxylate;

Using ethyl piperazine-4-acetate

Ethyl 1- (3- (4-cyanophenyl) -2-oxo-5R-oxazolidinylmethyl) piperazine-4-acetate (FAB 373);

With ethyl 1- (3- (4-cyanophenyl) -2-oxo-5S-oxazolidinylmethyl) piperazine-4-acetate (FAB 373),

Using benzyl 3- (1-piperazinyl) propionate

Benzyl 3- (4- (3- (4-cyanophenyl) -2-oxo-5R-oxazolidinylmethyl) -1-piperazinyl) propionate (melting point 90 ° C.),

Benzyl 3- (4- (3- (4-cyanophenyl) -2-oxo-5S-oxazolidinylmethyl) -1-piperazinyl) propionate (melting point 90 ° C.) was obtained, respectively.

Example 14

Similar to Example 8, the following compounds are obtained from the corresponding nitrile (see Example 13):

Benzyl 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-3-acetate (diacetate, melting point 287-288 ° C.),

Ethyl 3- (4- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -1-piperazinyl) propionate (condensing point 206 ° C.),

Ethyl 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -3-oxo-piperazine-4-acetate (melting point 224 ° C.),

Ethyl 3- (4- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -2-oxo-1-piperazinyl) propionate (FAB 418),

Ethyl 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -4-hydroxypiperidine-4-carboxylate,

Ethyl 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -4-hydroxypiperidine-4-acetate (acetate, melting point 108 ° C.),

8- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -1-oxa-8-azaspiro- [4.5] decan-2-one (FAB 373),

Benzyl 1- (3- (4-amidinophenyl) -2-oxo-5R-oxazolidinylmethyl) piperidine-4-carboxylate (acetate, melting point 225 ° C .: [α] ²⁰ _D + 40.5 ° (c = 1, methanol), benzyl 1- (3- (4-amidinophenyl) -2-oxo-5S-oxazolidinylmethyl) piperidine 4-carboxylate (acetate, melting point 225 ° C .: [ α] ²⁰ _D -41 ° (c = 1, methanol), ethyl 1- (3- (4-amidinophenyl) -2-oxo-5R-oxazolidinylmethyl) piperazine-4-acetate (FAB 390) ,

Ethyl 1- (3- (4-amidinophenyl) -2-oxo-5S-oxazolidinylmethyl) piperazine-4-acetate (FAB 390).

Example 15

Similar to Example 9, the following compounds are obtained from the corresponding nitrile:

Ethyl 1- (3- (4-hydroxyamidinophenyl) -2-oxo-5-oxazolidinylmethyl) -4-hydroxypiperidine-4-acetate (acetate, melting point 178-180 ° C.),

Methyl 3- (4- (3- (4-hydroxyamidinophenyl) -2-oxo-5-oxazolidinylmethyl) -1-piperazinyl) propionate (melting point 202 ° C.),

Benzyl 3- (4- (3- (4-hydroxyamidinophenyl) -2-oxo-5R-oxazolidinylmethyl) -1-piperazinyl) propionate (condensation point 159 ° C.),

Benzyl 3- (4- (3- (4-hydroxyamidinophenyl) -2-oxo-5S-oxazolidinylmethyl) -1-piperazinyl) propionate (melting point 159 ° C.).

Example 16

1 g of ethyl 3- (4- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -1-piperazinyl) propionate, 0.2 g NaOH, 8 ml dioxane and water 2 ml of the mixture was stirred at 20 ° C. for 5 hours. Subsequently, after acidification, normal reaction was completed to obtain 3- (4- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -1-piperazinyl) propionic acid (melting point 269 ° C). )

In the same manner as described above, hydrolysis of the corresponding ester yields the following compounds:

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -3-oxo-piperazin-4-acetic acid (monohydrate, melting point 261 ° C.),

3- (4-3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -2-oxo-1-piperazinyl) propionic acid (FAB 390),

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -4-hydroxypiperidine-4-carboxylic acid,

1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -4-hydroxypiperidine-4-acetic acid (melting point 230 ° C.),

1- (3- (4-amidinophenyl) -2-oxo-5R-xaxazolidinylmethyl) piperazine-4-acetic acid (acetate, FAB 362, [α] ²⁰ _D -28.0 ° (c = 1, DMSO),

1- (3- (4-amidinophenyl) -2-oxo-5S-oxazolidinylmethyl) piperazine-4-acetic acid (acetate, FAE 362, [α] ²⁰ _D + 24.0 ° (c = 1, DMSO),

Example 17

a) using ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) -4-methanesulfonyloxypiperidine-4-acetate [methanesulfonyl chloride / pyridine Obtained from 4-hydroxy compound (see Example 13)] was dissolved in a 2% NH ₃ solution in 10 mL of a mixture of ethanol and THF 1: 1, and the solution was left at 20 ° C. for 2 hours. Subsequently, the mixture was evaporated to concentration, and the reaction reaction was completed and ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidinylmethyl) -4-aminopiperidine-4-acetate (FAB 387 )

b) The obtained compound was carried out in a similar manner to Example 8, to obtain ethyl 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -4-aminopiperidine- 4-acetate (FAB 404) was obtained.

c) The obtained compound was hydrolyzed in a similar manner to Example 16 to give 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -4-aminopiperidine-4 Acetic acid (FAB 376) was obtained.

Example 18

a) Similar to Example 17 a), ethyl 1- (3- (4-cyanophenyl) -2-oxo-5-oxazolidineethylyl) -4-methanesulfonyloxypy using NH ₃ From ethyl 1- (3- (4-cyanophenyl) -2- from ferridine-4-carboxylate [obtained from 4-hydroxy compound (see Example 13) using methanesulfonyl chloride / pyridine chloride)] Oxo-5-oxazolidinylmethyl) -4-aminopiperidine-4-carboxylate (FAB 373) was obtained.

b) The obtained compound was carried out in a similar manner to Example 8, to obtain ethyl 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -4-aminopiperidine- 4-carboxylate (FAB 390) was obtained.

c) The obtained compound was hydrolyzed in a similar manner to Example 16 to give 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) -4-aminopiperidine-4 -Carboxylic acid (FAB 362) was obtained.

Example 19

Benzyl 3- (4- (3- (4-hydroxyamidinophenyl) -2-oxo-5R- or -5S-oxazolidinylmethyl) -1-piperazinyl) propionate (see Example 15) A solution of 1 g dissolved in 30 ml of acetic acid was hydrogenated at a temperature of 20 ° C. and 1 bar of pressure on 0,2 g of 10% Pd-carbon until the calculated amount of hydrogen was absorbed with the addition of 1 ml of acetic anhydride. After filtration, the reaction is completed in the usual manner to obtain the following compound:

3- (4- (3- (4-amidinophenyl) -2-oxo-5R-oxazolidinylmethyl) -1-piperazinyl) propionic acid (acetate, melting point 200-220 ° C. (decomposition), [α ²⁰ _D + 9 ° (c = 0.5, DMSO),

3- (4- (3- (4-amidinophenyl) -2-oxo-5S-oxazolidinylmethyl) -1-piperazinyl) propionic acid (acetate, melting point 200-220 ° C. (decomposition), [α ] ²⁰ _D -8 ° (c = 0.5, DMSO).

The following examples relate to pharmaceutical formulations.

Example A : Tablet

A mixture of 1 kg of the active compound represented by the general formula (I), 4 kg of lactose, 1.2 kg of corn starch, 200 g of talc and 100 g of magnesium stearate was pressed by a conventional method to obtain each tablet containing 100 mg of the active compound.

Example B

The tablets were compressed similarly to Example A, and then subjected to conventional methods using a coating consisting of sucrose, corn starch, talc, tragacanth and a colorant to obtain individual tablets.

Example C : Capsule

A hard gelatine capsule was filled with 500 g of the active compound represented by the general formula (I) by a conventional method to obtain each capsule containing 500 mg of the active compound.

Example D : Injection Vials

The solution obtained by dissolving 100 g of the active compound represented by Formula (I) in 4 L of secondary distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, then sterilized by filtration and filled into an injection vial. The vial contents were lyophilized and the vials were sealed under sterile conditions. Each injection vial containing 50 mg of the active compound was obtained.

Example E : Suppositories

A mixture of 50 g of the active compound represented by the general formula (I), 10 g of soya lecithin, and 140 g of cacao butter was melted, poured into a mold, and cooled to obtain each suppository containing 250 mg of the active compound.

Claims (11)

New compounds of the general formula (I) and salts thereof. (Wherein X is O, S, NH or NA, Y is an azirinino, azetidino, pyrrolidino, piperidino, 1-oxa-8-azaspiro [4.5] deck-8-yl, hexahydroazino or 4-R ⁴ -piperazino group These groups may be unsubstituted or substituted once with R ² , and further substituted with OZ groups, SZ groups, N (Z) ₂ groups or carbonyl oxygen, or with OZ, SZ or N (Z) ₂ groups and carbonyl oxygen. Can and Z is in each case H, A, phenyl-C _k H _2k or Ac, R ¹ is CN, H ₂ N-CH _2- , (A) ₂ N-CH _2- , H ₂ NC (= NH)-, H ₂ NC (= NH) -NH-, H ₂ NC (= NH) -NH-CH _2- , phenyl group once substituted with HO-NH-C (= NH)-or HO-NH-C (= NH) -NH-, R ² is —C _m H _2m —COOR ³ or —C _n H _2n —OC _p H _2p —COOR ³ , R ³ is H, A or benzyl, R ⁴ is H, A, benzyl or -C _m H _2m -COOR ³ , A is in each case alkyl of 1 to 6 carbon atoms, Ac is acyl having 1 to 11 carbon atoms, k and m are in each case 0, 1, 2 or 3, n is 0, 1 or 2, p is 1, 2 or 3.) 1- (3- (4-amidinophenyl) -2-oxo-5-oxazolidinylmethyl) piperidine-4-carboxylic acid. In the process for preparing the compound of formula (I) and salts thereof according to claim 1, A process according to claim 1, wherein the compound of formula (I) is treated with a solubilizer or a hydrogenolysis agent to separate from one of its functional derivatives. In the process for preparing the compound of formula (I) and salts thereof according to claim 1, Compounds of the general formula (II) Wherein E is Cl, Br, I or a reactive esterified OH group, R ¹ and X are as defined above, wherein the amino compound of formula III: H-Y (Ⅲ) Wherein Y is as defined above And reacting with the preparation method. In the process for preparing the compound of formula (I) and salts thereof according to claim 1, Compounds of the general formula (IV) R ¹ -NH-CH ₂ -CH (XH) -CH ₂ -Y (IV) Wherein R ¹ , X and Y are as defined above. Or reacting one of the reactive derivatives thereof with a reactive derivative of carbonic acid. In the process for preparing the compound of formula (I) and salts thereof according to claim 1, For R ¹ is H ₂ NC (= NH) is a phenyl radical substituted once by -NH producing a guanidino compound of the formula (I), but correspond to the general formula (I), in place of the amino radical R ¹ - A process for producing an amino compound containing a phenyl group with an amidine agent. In the process for preparing the compound of formula (I) and salts thereof according to claim 1, The compounds of formula (I), the radical R ¹ and one or the other of both the radical of Y (s) R ^1, Y, or R ¹ and changed to Y, or an acid or base of a compound of formula (I) To one of its salts, or to one or both radicals R ¹ and Y in the compound of formula (I) to the other radical (s) R ¹ , Y or R ¹ and Y A process according to claim 1, wherein the compound of I) is treated with an acid or a base and converted to one of its salts. In the process for preparing the compound of formula (I) and salts thereof according to claim 1, The compound of formula (I) is treated with a solubilizer or a hydrogenolysis weight to separate from one of its functional derivatives, The compounds of formula (I), the radical R ¹ and one or the other of both the radical of Y (s) R ^1, Y, or R ¹ and changed to Y, or an acid or base of a compound of formula (I) To one of its salts, or to one or both radicals R ¹ and Y in the compound of formula (I) to the other radical (s) R ¹ , Y or R ¹ and Y A process according to claim 1, wherein the compound of I) is treated with an acid or a base and converted to one of its salts. In the process for preparing the compound of formula (I) and salts thereof according to claim 1, Compounds of the general formula (II) Wherein E is Cl, Br, I or a reactive esterified OH group, R ¹ and X are as defined above, wherein the amino compound of formula III: H-- Y (Ⅲ) (Wherein Y is as defined above), The compounds of formula (I), the radical R ¹ and one or the other of both the radical of Y (s) R ^1, Y, or R ¹ and changed to Y, or an acid or base of a compound of formula (I) To one of its salts, or to one or both radicals R ¹ and Y in the compound of formula (I) to the other radical (s) R ¹ , Y or R ¹ and Y A process characterized by the conversion of the compound of I) to one of its salts under treatment with an acid or a base. In the process for preparing the compound of formula (I) and salts thereof according to claim 1, A compound of formula (IV) R ¹ -NH-CH ₂ -CH (XH) -CH ₂ -Y (IV) Wherein R 1, X and Y are as defined above, or one of its reactive derivatives is reacted with a reactive derivative of carbonic acid, The compounds of formula (I), the radical R ^1, and Y of one or both other radicals both (s) R ^1, switch to a Y, or R ¹ and Y, or the general formula (I) an acid or yeomkeo a compound of To one of its salts, or to one or both radicals R ¹ and Y in the compound of formula (I) with the other radical (s) R ¹ , Y or R ¹ and Y A process according to claim 1, wherein the compound of I) is treated with an acid or a base and converted to one of its salts. In the process for preparing the compound of formula (I) and salts thereof according to claim 1, To prepare a guanidino compound of formula (I) wherein R ¹ is a phenyl radical once substituted with H ₂ NC (= NH) -NH, it corresponds to formula (I) with amino- instead of radical R ¹ An amino compound containing a phenyl group is treated with an amidine agent, In compounds of formula (I), one or both radicals R ¹ and Y are replaced with other radical (s) R ¹ , Y, or R ¹ and Y, or compounds of formula (I) with acids or bases Treatment to convert to one of its salts, or wherein Formula (I) replaces one or both of the radicals R ¹ and Y in the compound with other radical (s) R ¹ , Y, or R ¹ and Y and A process for treating a compound of) with an acid or a base and converting it into one of its salts.