KR987000970A - Piperazine derivatives, medicaments containing them, their use and methods for their preparation (Piperazine derivatives, medicaments containing the same, their use and process for preparing the same) - Google Patents

Abstract

Torn piperazine derivative is a compound of formula _{I, Ra, Y l, Y} 2, Y 3 and E are as defined in claim 1. Also encompassed by the present invention are the tautomers of the compounds having useful pharmacological properties, preferably exhibiting the effect of inhibiting flocculation, their stereoisomers including mixtures thereof and salts thereof, especially their physiologically acceptable salts with inorganic or organic acids, Its use and its production method are described.

(I)

Description

Piperazine derivatives, drugs containing them, uses thereof and methods for their production

The present invention relates to piperazine derivatives of the formula I, their tautomers, their stereoisomers including mixtures thereof, their salts, especially their pharmacological properties, preferably with physiologically tolerated acids or bases, Salts thereof, medicaments containing such compounds, their use and a process for their preparation.

In the above formula (I), Ra represents 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexamethyleneiminyl or 4-hexamethyleneiminyl group is, in each case, C _l-5 - alkyl or _aryl-l -C ₃ - alkyl group (wherein the alkyl moiety, in each case, carboxyl, C _l-3 - alrok when carbonyl, aminocarbonyl, NC N-di- ( _C1-3- alkyl) -aminocarbonyl, vinyl or ethynyl which may be substituted by _{1 to 3} -alkyl-aminocarbonyl, N, N-di- If not located atom, a hydroxyl, C _l-7 - alrok City, amino, C _1-3 - alkylamino or di - (C _l-3 - alkyl) may be substituted with may be substituted with amino group) or may be substituted with a radical which is pressed in the cleavage tanche; and, Rb and Ra are the same or different, hydrogen atom, C _l-5 - alkyl, aryl or ahring -C _1-5 - alkyl or him, Between them Together with an o-phenylene group in which one or two methylene groups in the 1,4-piperazinylene group of the formula (I) can be further substituted with a carbonyl, in each case by a carbonyl group, Y1 represents -Al-, -CO-, -CO-CO-, -Al-CO-, -CO-Al-, -502-A2-, -A2-502-, -CO- -CO-NRI-CO-, -CO-A2-0- or -CO-A2-CO-, -CO-NRI- Cl-3-alkyl, aryl or aryl-Cl-3-alkyl group, Al is optionally Cl-s-alkyl, cyclohexyl- Cl-3-alkylglycyl, or when n is not in the 7-position relative to the nitrogen atom, A2 is an optionally substituted Cl-5-alkyl, R-Cl-4-alkylene group substituted with aryl or aryl-Cl-3-alkyl group), Y2 is phenylene, cyclohexylene group, pyridinylene group, 3-piperidinylene, 4- Ridinylene or 1,4-piperazinylene (Provided that the methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group in each case and N, O-acetal or 0, 0-acetal and N, O defects or N2 bonds may be substituted for Y1 or Y3 4-piperidinylene may be further substituted in the RIO group at the 4-position, unless it is formed by a bond, 1,4-ketopiperazinylene group, with the exception that Cl Alkyl group, with the proviso that the alkyl group may be optionally substituted with R < 1 > O, phenylglycyl, Cl-3-alkoxycarbonyl or Cl-3-alkoxycarboxylyl, NRI-B- or -O-B- in which Yl is -NR1-bonded to the nitrogen atom of the -O-B-gulon, B is phenylene, cyclohexylene, Nylene or piperidinylene group (provided that the bond between the piperidinylene group and the -NRI-radical or the bond between the piperidinylene group and the oxygen atom 3-position or 4-position and the methylene group adjacent to the nitrogen atom may be further substituted with a carbonyl group), and Y3 is -CO-, -A2-CO-, -CH2-CH (NHR2 ) -CO-, -NR2-A3-CO-, -CH2-NR2-A3-CO-, -O-A3-CO-, -CO- With the proviso that R 1 and A 2 are as defined above and A 3 is an R-Cl-3-alkylene group optionally substituted with Cl-5-alkyl, aryl, pyridyl or aryl- Cl-7-alkyl, aryl-Cl-3-alkyl, aryl, Cl-5-aloxycarbonyl, Cl-7-alkylsulfonyl, aryl- - arylsulfonyl group or a formyl group optionally substituted with a Cl-4-alkyl, aryl or aryl-Cl-3-alkyl group, the -A7-CO- group and the radical Y2 are linked via the radical A2 and the group -NR2- A3-CO-Grunde and the radical Y2 are bonded through the NR2 group, -O-A3-CO- and the radical Y2 is bonded through an oxygen atom, and -NR2-A3-CO-, -CH2-NR2- CO- and -O-A3 And the -CO- group can not bind to the nitrogen atom of the radical Y2), E is hydroxyl group, an alkyl group having 1 to 6 carbon atoms, a phenylalkoxy group (the number of carbon atoms in the allyloxy moiety is 1 to 3) , A cycloalkoxy group having 3 to 9 carbon atoms (provided that the cycloalkyl moiety having 5 to 8 carbon atoms may be further substituted with 1 or 2 alkyl groups each having 1 to 3 carbon atoms), a cycloalkoxy group having 5 to 8 carbon atoms With the proviso that the methylene group at the 3-position or the 4-position of the cycloalkyl moiety is substituted with an oxygen atom or, optionally, an alkyl, phenylalkyl or phenalkoxycarbonyl, with the proviso that the alkyl moiety and the alkoxy moiety in each case , The number of carbon atoms may be from 1 to 3), or an imino group which is optionally substituted with alkanoyl having 2 to 6 carbon atoms, with the proviso that the cycloalkyl moiety in each case is an alkyl group having 1 to 3 carbon atoms Which may be further substituted with one or two substituents selected from the group consisting of 1, cycloalkenyloxy (wherein the cycloalkenyl moiety has 4 to 7 carbon atoms), alkenyloxy, phenylalkenyloxy, alkynyloxy or phenylalkynyloxy (In which the oxygen atom is not bonded to a carbon atom having a double bond or a triple bond, and the alkenyl moiety and the alkynyl moiety in each case have 3 to 5 carbon atoms), and a haloalkyloxy group Provided that the cycloalkyl moiety has 3 to 8 carbon atoms and the aryloxy moiety has 1 to 3 carbon atoms), bicyclic aryl groups having 8 to 10 carbon atoms in total (provided that the bicycloalkyl moieties are in each case, CO-O- (dyne CR4) -O-R < 1 >, wherein R & Cl-6 alkyl, C3-7-cycloalkyl or phenylgrile, R4 is a hydrogen atom or a Cl-6-alkyl group, R5 is Cl-5-alkyl, Cl- -Alkoxy, Cs-7-cyanoalkyl or Cs-l-cyclooxyglucose), or a long-amino group or esters of natural amino acids. Here, the term " aryl group "&Quot; Phenyl " and " phenylene group ", are in each case, in particular monosubstituted by fluorine, chlorine, bromine or iodine. Disubstituted or trisubstituted, or is alkyl, trifluoromethyl, nitro, amino, alkylamino. Di Dalyimino. Alkanoylamino. Which is optionally monosubstituted, disubstituted or trisubstituted by hydroxy, alkoxy, carboxyl, alkoxycarbonyl, hydroxycarbonylalkoxy, aryloxycarbonyloxy, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl groups (Wherein the substituents are the same or different and the alkyl moiety and the allyloxy moiety mentioned above, in each case, have 1 to 3 carbon atoms), natural α-aminoglyl is methyl, ethyl, n-propyl, isopropyl, tert-butyl. Refers to Cl-s-alkyl, C2-6-alkenyl, Cs-7-cycloalkyl, phenyl or phenyl-Cl-3-alkyl esters such as allyl, phenyl or benzyl esters, The radical may be an alkanoyl group having from 1 to 6 carbon atoms in total or a group selected from the group consisting of formyl, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, benzoyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl Such as benzyloxycarbonyl, such as benzyloxycarbonyl, benzyloxycarbonyl, benzyloxycarbonyl, phenylpropoxycarbonyl, phenylpropoxycarbonyl, tert-butyloxycarbonyl, , Allyloxycarbonyl, Cl-s-alkoxycarbonyl or phenyl-Cl-3-alkoxy monovanyl.

Preferred compounds of formula I are those, wherein 7 is 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexamethyleneiminyl or 4-hexamethyleneiminylglyle, The atoms are, in each case, Cl-s-alkyl or phenyl-Cl-3-alkyl groups wherein the alkyl moiety is in each case a carboxyl, 71-7-alkoxycarbonyl, aminocarbonyl, N- Alkyl-aminocarbonyl or N, N-di (Cl-3-alkyl) -aminocarbonyl groups, or where the substituents mentioned are not located at the a-carbon atom adjacent to the nitrogen atom, Which may be substituted by hydroxy, Cl-7-alkoxyamino, C7-7-alkylamino or di- (Cl-3-alkyl) aminoglycyl, or may be substituted by C1-4alkoxycarbonyl or benzyloxy Rb and 7 are the same or different and are selected from the group consisting of a hydrogen atom, Cl-3-alkyl or phenyl -Cl-3-alkyl, or together with an ethylene bridge therebetween, a 0-phenylene group wherein 1 or 2 methylene groups in the 1,4-piperazinylene group of the formula (I) -CO-Al-, -CO-Al-CO-, -CO-Al-, -CO-Al-, -CO-Al- , -CO-NRI-A2-, -CO-A2-0- or -CO-A2-NRI-group wherein R1 is a hydrogen atom, a 71-5-alkyl or a phenyl- Cl-5-alkylene group optionally substituted with a Cl-5-alkyl or cyano-Cl-3-alkyl group, or where Al is not 7-position to a nitrogen atom, With the proviso that phenyl may be substituted with a hydroxyl, Cl-3-aryloxy or benzyloxy group, A2 is optionally substituted with Cl-7-alkyl or phenyl- Cl-4-alkylene group, Y2 is a norbornylene, cyclomalcylene or pyridinylene group, 4-piperidinylene [but N, O- Acetyl or 0, 0-acetal and N, O defects or N bonds are not formed by a bond to Yl or Y3, then the piperidinylene group may be further substituted at R17 at the 4-position, or the -NR1-B- group (Provided that the Yl group is coordinated with the nitrogen atom of the -NR 1 -groom)] or 1,4-piperazinylene grule, except that methylene glycol adjacent to the nitrogen atom, in each case, Can be substituted with phenol, phenol, cyclohexylene. Piperidinylene or pyridinylene, wherein the piperidinylene group and the radical -NRI- can in each case be bonded through the 4-position and the methylene group adjacent to the nitrogen atom is further substituted in the carbonyl group Y3 is -CO-. ≪ / RTI > -CO-CO-, -O2-CO-, -CH2-CH (NHR2) -CO-, -NB2-A3-CO-, -CH2-NR2- Or -CO-NRI-A3-CO- wherein A3 is H-Cl-3-alkylene which is optionally substituted by Cl-s-alkyl, phenyl, pyridyl or phenyl- R2 is selected from the group consisting of hydrogen, C1-5-alkyl, phenyl-C1-3-alkyl, C1-5-alkoxycarbonyl, C1-5-alkylsulfonyl, phenyl- Phenylsulfonyl group or a formyl group substituted with a Cl-4-alkyl, phenyl or phenyl-Cl-3-alkyl group, the -A2-CO-group and the radical Y2 are linked via the radical A2 and the group -NR2- A3-CO- group and the radical Y2 are bonded through the NR2 group, and the -O-A3-CO- group and the radical Y2 are bonded through the oxygen atom, but -NR2-A3-CO-, -CH2- -CO-and -O-A3-CO- can not combine with the nitrogen atom of the silver radical Y7 and E is hydroxyl, Cl-6-alkyl 7.1, phenyl- (RS) -CO-O- (R3) -O-, wherein R3 is a hydrogen atom, , Cl-6-alkyl, C3-7-cycloalkyl or phenyl group, R4 is a hydrogen atom or a Cl-6-alkyl group and R5 is Cl-5-alkyl, Alkyl or C7-7-cyanoalkoxy group), or a 7-amino group of a natural amino acid, Cl7-alkyl or a benzyl ester thereof, its tautomers, mixtures thereof and mixtures thereof It is salt.

More preferred compounds of formula I are those, wherein Ra is 3-pyridinyl or 4-phenydridinyl group, with the proviso that the hydrogen atoms of the alkyleneimino ring in each case are Cl-5-alkyl or phenyl- -Alkyl < / RTI > group, or may be monosubstituted in a radical which may be cleaved in vivo, such as Cl-4-alkoxycarbonyl or benzyloxycarbonyl group, Rb and 17 are the same or different, Cl-3-alkyl or phenyl-Cl-3-alkyl group, or with a Hören-Brønge between them and a 0-clathrinene group (provided that in the 1,4- Two methylene groups may in each case be further substituted by a carbonyl group), and Yl is selected from the group consisting of -Al-, -CO-, -CO-CO-, -Al-CO-, -CO- Wherein R 1 is a hydrogen atom, Cl-s-alkyl or an ureido group, and R < 2 > -Cl-2-alkyl group, Al is optionally substituted by Cl-5-alkyl or < RTI ID = -Alkyl group substituted with an RIO group (provided that the phenyl group is substituted with a hydroxyl group or a hydroxy group, when the Al is not in the? -Position with respect to the nitrogen atom auth. And A2 is an n-Cl-3-alkylene group, and Y2 is 1,4-cyclohexylene, 1,4-pneumenylene, 4-per peridinylene, The methylene group may be substituted in each case by a carbonyl group and the 4-phenylidinylene group may be substituted by N, O-acetal or 0, 0-acetal and N, O bond or N & If the ring is not formed on the bond, it is substituted at the 4-position with the RIO group or with the -NR 1 -B- group (with the proviso that Y 1 group bonds with the nitrogen atom of the -NR 1 group)] or 1,4- Gululein, seedlings are selected from the group consisting of 1,3-phegene, 1,4-phenylene, 1,4-cyclohexylene or 4-phenylundinylene group, with the proviso that the piperidinylene group and the radical -NRI- And Y3 is -CO-, -A2-CO-, -NR2-A3-CO-, -CH2-NR2-A3-CO-, -O- , -CO-A3-CO- or -CO-NRI-A3-CO- group wherein A3 is n-Cl optionally substituted with Cl-5-alkyl, phenyl, pyridyl or phenyl- 3-alkylene group, R 2 is a hydrogen atom, C 1-3 -alkyl, phenyl-C 1-3 -alkyl, C 5 _ 5 -aroxycarbonyl, C 1-3 -alkanoyl, C 1-5 -alkylsulfonyl Or a Cl-5-pneumenylsulfonyl group, -A2-CO- and the radical Y2 is bonded through the radical A2, the -NR7-A3-CO-Grunde and the radical Y7 join together through the NR2 group, The group -NR2-A3-CO-, -CH2-NR2-A3-CO- and -O-A3-CO- are bonded to the nitrogen atom of the radical Ya, (R < 3 >) - O- group (provided that R3 is not R3), E is hydroxyl, C1-5-alkyl, Is a hydrogen straight, Cl-3-alkyl or C5-7-cycloalkyl group, R4 is a hydrogen atom, , R5 is Cl-5-alkyl or Cl-3-alkoxy group, or a compound of formula (I) in which the [alpha] -amino group of the natural amino acid is Cl7-alkyl or a benzyl ester thereof, Its stereoisomer and its salt.

Even more preferred compounds of formula (I) are those wherein Ra is a 3-alkynyl or 4-piperidinyl ring wherein the hydrogen atoms of the alkyleneimino ring in each case are Cl-3-alkyl, benzyl or tert- -CO-CO-, -Al-CO-, -CO < RTI ID = 0.0 > -CO-CH2-CO-, -CO-N] 7-A2-, -CO-CH7-O- or -CO-CH7-NH- group in which Al is optionally methyl or a carboxybenzyl group 2-alkylene group and A2 is Cl-7-alkylene group, Y2 is 1,4-cyclohexylene, 1,4-phenylene group, 4- Piperidinylene, 1,4-ricin ferrazinylene, 4-hydroxy-1,4-pheidylidene (provided that N, O-acetal or 0, 0-acetal and N, O bond or N, Yl or Y3) or -NH-B- group, with the proviso that Yl group binds to the nitrogen factor of the -NRI- group and the graft is a 1,3-phenyl 1,4-phenylene, 1,4-cyclohexylene or 4-piperidinylene group (in which the piperidinylene group and the radical -NH- in each case are bonded through the 4-position) And Y3 is -CO-, -A7-CO-, -NR2-A3-CO-. -CH2-NR7-A7-77-O-A3-CO-, -CO-A3-CO- or -CO-NRI-A3-CO-, wherein A3 is optionally a methyl, R2 is a hydrogen atom, a methyl, benzyl, acetyl or phenylsulfonyl group, a -A2-C7- group and a radical 7 " 2 are bonded through a radical A7, -NR2-A3- (-) - A7-7 () -Grun and Radigal 7'7 are linked through the oxygen atom, but are not bonded to each other through -NR2-A3-CO-, -CH2-NR2-A3- Cl-5-alkyl, benzyloxy or 75-7-cycloalkoxy < / RTI > f.1 group , Α-aminoglycine of natural amino acids, Cl-6-alkyl or its benzyl ester.

Particularly preferred compounds of formula are those wherein Ra is 4-piperidinyl, Rb and R are in each case hydrogen, Yl is -CO-, -COCH2-, -COCH2CH2- or -CO- Y2 is selected from the group consisting of 1,4-711 nylene, 4-piperidinylene, 1,4-piperazinylene or -NH-B- (wherein Y2 and Y1 are -NH- And B is 1,4-phenylene or 1,4-cyclohexylene, and Y3 is -CO-, -CHECO-, -Chino H7CO-. Of formula (I), cycloalkoxy geurun - -CH2CH2CH2CO-, -0-CH2-CO- or -CO-NH-CH2C him and deol -CO-, E is hydroxyl, C _1-7 - alrok state or C _5-7 Compound, its tautomer. Isomers, isomers and salts thereof, including mixtures thereof.

Particularly useful compounds mentioned above are, for example: (a) [4- trans- [3- [4- (4-piperidinyl) -piperazin- 1 -yl] propionyl 1 -amino] (4-piperidinyl) -piperazin-1-yl] carbonylamino] is obtained from cyclohexyl] propanoic acid Yl) carbonyl] -4- (4-piperidinyl) -butyric acid (d) N - [[4- ( (Piperidinyl) -piperazin-1-yl] carbonyl- (piperidinyl) -propionic acid e) N- [4- Yl) carbonyl] piperidinyl] -alanine 7 rl [4 - [[4- (4-piperidinyl) -piperazin- Yl) acetyl] phenoxy] acetic acid (h) [(4-Chloro-4-methylpiperazin- 4- [2 - [[4- (Piperidin-4-yl) -piperazin-l-yl] -carbonyl-Bethyl] -piperidin- l-yl] -acetic acid. And its Cl-5-alkyl esters and C5-6-cycloalkyl esters, especially the [4- [[4- (4-piperidinyl) -piperazin- 1- yl] carbonylamino] phenoxy] And their butyl esters, isobutyl esters, cyclopentyl esters or cyclohexyl esters, their tautomeric forms, their stereoisomers and their salts.

According to the invention, the novel compounds are obtained, for example, in the following way: (a) by reacting the product of formula (II) with a compound of formula (III) Y1 is -CO-CO-. CO-, -A2-502-, -CO-Al-CO-, -CO-NRI-A2-CO- or -CO-Az-NRI-CO-gulle, and the radical Yl carbonyl group is a radical Y2 Or a compound of formula II coupled to an oxygen atom or nitrogen atom of the formula II, or the reaction of a carboxylic acid of formula II may optionally be carried out in the presence of a base such as methylene chloride dimethylformamide, benzene, toluene, dichlorobenzene, tetrahydrofuran, A solvent or mixture of solvents such as furan or dioxane or a sultone amine of formula III or optionally a dehydrating agent such as isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl isoacetate, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxy-N, N'-dicyclohexylcarbodiimide, Succinimide, N, N'-dicycloxy: siluca bodymide , N-hydroxynitrozotriazole, 2- (IH-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, 2 - (IH-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxy-benzotriamine, N, N'- carbonyldi Dimethylpyridine, N-methylmorpholine or triethylamine in the presence of a base, such as triethylamine or triethylamine, in the presence of a base At the temperature of. Preferably at a temperature of 0 to 170 캜.

The reaction of a sulphuric reactive compound of formula 11 with an amine of formula III, such as an ester, imidazolide or halide thereof, is preferably carried out in the presence of a sulphonated amine as a solvent, optionally in the presence of an additional solvent such as methylene chloride or ether And is preferably carried out in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at a temperature of from 0 to 150 DEG C, preferably from 50 to 100 DEG C ≪ / RTI >

(7) converting a compound of formula (IV) to a compound of formula (I), wherein at least one of the radicals Ra, R2 and I must contain a semi- R3CR4) -O- group is excluded), or the preparation of a compound of formula I wherein the carboxyl group is protected with a protecting group for a hydroxyl group (for example, a substituted or unsubstituted amide, an ester, a thioester, Esters, ortho esters thereof or functional derivatives of carboxylic acids such as iminoesters) can be converted to carboxyl groups by hydrolysis.

Esters having tertiary alcohols (e.g., tertiary-butyl esters) can be converted to carboxyl groups by treatment with an acid or by pyrolysis.

An ester having an aralkanol (for example, benzyl ester) can be converted to a carboxyl group by the method of hydrolysis and decomposition.

To combine, the hydrolysis may be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, trifluoroacetic acid or mixtures thereof, or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide And is carried out at a temperature of -10 to 120 占 폚 (for example, at a temperature of from -10 to 120 占 폚, for example, at a temperature of from -10 to 120 占 폚, in a solvent such as water, , In practice the boiling point of the reaction mixture).

Under the above-mentioned countercyclical conditions, N-trifluoroacetylaminog or any N-acylamino such as a tert-butyloxycarbonyl group or Cl-5-aloxycarbonyl group can be converted to the corresponding amino group .

If I " in the water of formula (IV) is, for example, tertiary-butyloxypyryl, the tertiary butyl group is treated with an acid such as trifluoroacetic acid, formic acid, p- toluenesulfonic acid, sulfuric acid, hydrochloric acid or polyphosphoric acid And optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at a temperature of -10 to 120 ° C (for example, 0 In the presence of a base such as p-toluene, tetrahydrofuran or dioxane, in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, Preferably in the presence of a catalytic amount of acid such as sulfuric acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used (for example at a temperature of 40 to 120 DEG C) , The present N-epothilbutylthiocarbonyl amino group can be converted to the corresponding amino group.

If I in formula (VI) is, for example, benzyloxy, benzyl is reacted with methane, ethane, ethanol / water, glacial acetic acid in the presence of a hydrogenation catalyst such as palladium on carbon. Can be hydrolytically cleaved under a hydrogen pressure of 1 to Sbar at a temperature of 0 to 50 DEG C (for example, room temperature) in an equilibrated solvent such as heptyl acetate, dioxane or dimethylacetamide, preferably at 0 to 50 DEG C During the hydrochemical subdivision, other radicals can be simultaneously converted (for example, nitroglycine is reacted with amino group, benzyloxy group is replaced with hydroxyl group, and N-benzylamino, N-benzylimino, Carbonylamino or N-benzyloxycarbonylimino groups to an imino group)

(c) deprotecting a compound of formula (V) with a compound of formula (VI), wherein E is as defined above except for hydroxyl group and Y2 is selected from the group consisting of phenylene, cyclohexylene, Group wherein Y2 is bonded to Y3 by an oxygen atom of the radical Y3 or NR2 group and A3 is an ethylene group optionally substituted with Cl-5-alkyl, aryl, pyridyl or aryl-Cl-3-alkyl group Or a compound of formula (I) is prepared, or the methanol is preferably treated with methanol, ethanol, methylene chloride, tetrahydrofuran. Toluene, dioxane. In the presence of a tertiary organic base, such as N-ethyl-diisopropypidine or N-methyl-morpholine, in a solvent such as dimethylsulfoxide or dimethylformamide, Preferably at a temperature of 0 to 700 < 0 > C.

(d) reacting the water to be floated with a compound of formula (VIII) in a solvent, preferably methanol, ethane, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulfoxide or dimethylformamide In the presence of a dehydrating agent, in the presence or in the presence of a radical scavenger, the inorganic base is carried out at a temperature between 0 and 200 < 0 > C

The reaction of the compound of formula (VIII) wherein VI has a nucleophilic leaving group or an isocyanate of formula (VIII) is preferably carried out using methylene chloride, acetonitrile. Solvents such as tetrahydrofuran, dioxane, toluene, dimethylformamide or dimetal sulfoxide, optionally in the presence of sulphonated nitrone. In the presence of a salt, such as potassium tert-butoxide or N-ethyl-diisopropylamine, at a silver concentration of -20 to 107 < 0 > C. Preferably at 0 ° C and at a temperature of 60 ° C.

(e) reacting a compound of formula (IX) with an alcohol of formula (I) or a formamide acetal thereof, or a conversion product of formula (XI) to produce a compound of formula (I) as hereinbefore defined except for the hydroxyl group, The reaction of a compound of X with an alcohol is preferably carried out in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, In an alcohol, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent such as isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p- N, N'-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclopentylimidomide / N-hydroxysuccinimide, N, In this case, Is N7'-thionyldimide.

N-ethyl-diisopropylamine or N, N-dimethylamino-pyridine, optionally in the presence of a base such as triethylamine or triethylamine in the presence of a base, such as triphenylphosphine / carbon tetrachloride or triphenylphosphine / diethyl azodicarboxylate, In the presence of the same base, the temperature is preferably 0 to 15 ° C, preferably 0 ° C to 50 ° C.

The reaction with a compound of formula XI is suitably carried out in the presence of a base such as methylene chloride. Optionally in the presence of an antioxidant such as sodium iodide or iodine, and optionally in the presence of a base such as sodium carbonate or potassium carbonate, in a solvent such as tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or acetone, In the presence of a tertiary organic base such as N-ethyldiisopropylamine or N-methyl-morpholine, which may also be used as a solvent in the presence of base or simultaneously, or in the presence of carbonic acid silver or oxygen, At a temperature of 70 to 170 占 폚, preferably at a temperature of -10 to 80 占 폚.

(f) preparing a compound of formula (I) wherein n is an n-Cl-s-alkyl group substituted with a hydroxyl group by identifying a compound of formula (I) or a mixture of two or more methanol or ethanol. Is carried out in a solvent such as tetrahydrofuran, dioxane or water and mixtures thereof at a temperature of from 0 to 100 ° C, preferably from 0 ° C to the boiling point of the solvent used.

However, the reduction may be carried out in the presence of a hydrogenating gold complex such as sodium borohydride or sodium borohydride, at a pH of 6 to 7, at room temperature or, for example, in the presence of a hydrogenation catalyst , Under a hydrogen pressure of 1 to 5, preferably 20 ' to 7 '

(g) Reductively alkylating the compound of formula (X) with a long-chain monovanamine or reductive alkylation preferably with water or methanol, ethane, tetrahydrofuran, dioxane, formic acid, acetic acid, trifluoroacetic acid, In a solvent such as sulfuric acid or water and a mixture thereof. Is carried out at a temperature of from 7 to 100 DEG C, preferably from 20 DEG C. to the boiling point of the solvent used.

However, the reductive alkyl radicals Baran Geigae are sodium succinate, lithium borohydride, sodium cyanoborohydride, zinc borohydride. Optionally in the presence of a dehydrating agent such as a sieve or titanium (Iv) isopropylate, and at a temperature of from room temperature to about room temperature, optionally in the presence of a metal hydride complex such as sodium triacetaborohydride or borane / pyridine, Or in the presence of hydrogen and a hydrogenation catalyst (e.g. palladium / carbon), under a hydrogen pressure of 1 to Sbar, preferably at 20 ° C to the boiling point of the solvent used.

(h) alkylating a compound of formula (Xlfl) with a compound of formula (XIV) to produce a compound of formula (I) wherein R2 is n-Cl-s-alkyl or aryl- , Ethane is carried out in a solvent such as methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylbaroxy or dimethylformamide, optionally in the presence of an inorganic base or a tertiary organic base, When 23 is an oxygen atom together with the adjacent hydrogen atom, it is preferably carried out in the presence of a ring system at a temperature of 0 to 17 占 폚, preferably 20? Lt; RTI ID = 0.0 > boiling < / RTI > temperature of the solvent used.

The reaction with the compound of formula XIV, in which 23 is a nucleophilic leaving group, is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulfoxide, In the presence of a base such as sodium carbonate, potassium carbonate, tert-butyl acid chloride or N-ethyl-diisopropylamine at a temperature of 0 to 60 ° C.

Reductive aminoalkylation of a compound of formula XIV, wherein X < 23 > is an oxygen atom with hydrogen atoms attached to the carbon atom, is preferably selected from the group consisting of sodium borohydride, sodium borohydride, sodium cyanoborohydride, zinc borohydride, Preferably in the presence of a hydrogenation metal complex such as salicylic borohydride or borane / pyridine, suitably at a pH of 1 to 7, optionally in the presence of a molecular sieve or a dehydrating agent such as titanium (Iv) isopropylate, Is carried out in the presence of hydrogen and a hydrogenation catalyst (for example, palladium on carbon), under a hydrogen pressure of 1 to Sbar, preferably from 20 ° C to the boiling point of the solvent used. The methylation is also carried out in the presence of formaldehyde and formic acid as a reducing agent, at a temperature of between 60 and 120 [deg.] C.

(j) deprotecting a compound of formula (XV) with a compound of formula (III), wherein the radical Ra is substituted by n-Cl-5-alkyl or aryl- Cl-5-alkoxycarbonyl or furanyl-Cl-3-aloxycarbonyl group, or the compounds of formula I are preferably prepared by reacting methane with ethane, methylene chloride, tetrahydrofuran, In a solvent such as toluene, dioxane, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic base or a tertiary organic binder, and if the raw oxygen atom together with the hydrogen atom adjacent to the carbon atom is used, In the presence of 0 nee 1007, preferably 20? The boiling point of the solvent used is carried out in the silver halide.

The reaction of compound 24 with a compound of formula XIII wherein the 24 is a nucleofugic leaving group is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimetylformamide or dimethylsulfoxide, In the presence of a base such as potassium carbonate, potassium tert-butylate or N-ethyl-diisopropylamine at a temperature of 0 to 60 ° C.

The reaction with a compound of formula (XVI) wherein the tosus is an oxygen atom with a suzoline residue adjacent to the carbon atom is preferably selected from the group consisting of sodium borohydride, hydrogenated borohydride, sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride In the presence of a hydrogenation metal complex, such as a hydride or a borane / pyridine, suitably at a pH of 1 to 7, optionally in the presence of a molecular sieve or a dehydrating agent such as titanium (Iv) isopropyl levitate, In the presence of a catalyst (in the presence of palladium / carbon) under 1 to hydrogen pressure, To the boiling point temperature of the solvent used. The methylation is also carried out in the presence of formaldehyde and formic acid as a reducing agent, at a temperature of from 60 to 120 < 0 > C.

(k) reacting a compound of formula (VIII) to produce a compound of formula (I) wherein Ra is a 4-piperidinyl group, or the reaction is preferably carried out in the presence of water or a mixture of methanol, ethanol, tetrahydrofuran, dioxane, At a temperature of 0 to 100 ° C, preferably 20 ° C to the boiling point of the solvent used. However, the reaction is particularly preferably carried out without first separating the compound of formula XVll do.

(1) alkylating a compound of formula Xvlll reductively with glycidyl oxalic acid or a hydrate thereof, Y3 is -NR ₂ -CH ₂ -CO- group (where, R2 is hydrogen atom, C _l-5 - alkyl, aryl or aryl Lt; RTI ID = 0.0 > Cl _-3 -alkyl < / RTI > group).

The reductive alkylation is preferably water or methanol. In the presence of a solvent such as ethanol, tetrahydrofuran, dioxane or water and mixtures thereof in the presence of a base such as sodium borohydride at a temperature of from 0 to 100 ° C, preferably from 20 ° C to the boiling point of the solvent used ≪ / RTI >

HY ₂ '-Y ₃ -E'

A ₃ ' -CO-E

Z ₁ -Y ₁ -Y ₂ -Y ₃ -E

HO-R _d

Ra'-H

Z ₃ -R ₄

R _g -Z ₄

H, R, E, Y1, Y2 and Y are as defined in the above formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XHI, XIV, IV, XVI, XVH and XVIII Y3 is as defined above, with the proviso that in the formula n, the radicals aa, R2 and I (where E is as defined above but RS-CO-O- (R3CR4) The dog must contain a semirigid hydrogen atom and in formula Vl. E is as defined above, but the hydroxyl group is excluded]

Yl 'represents -CO-CO-, -Al-C7-, -717-502- -CO-Al-CO-, -CO-NRI-.772- Y7 'is the same as Y2 defined above when the hydrogen acceptor is in the basic nitrogen atom or the oxygen atom of the radical Y7', wherein Y2 'is phenylene, cyclohexylene, 3- Piperidinylene or 4-piperidinylene gum), E 'is as defined above, except R7-CO-O- (R3CR4) -O-, and long is a hydroxyl group , A group G3 which is adjacent to the carbonyl group of the radical Y3 and which can be converted into a carboxyl group by the hydrolysis, the treatment with an acid or a base, the decomposition of protective radicals which can be cleaved by pyrolysis or hydrolysis, (Provided that at least one of the radicals RA, R2 or I " contains a fissionable radical), X is hydroxyl or HNR2 and R2 is a hydrogen atom, Cl-5-alkyl, aryl-Cl-3-alkyl or arylgorm, A3 'is a vinyl group optionally substituted with Cl-5-alkyl, phenyl, A halogen atom (for example, a chlorine, bromine or iodine atom), a sulfonic acid ester group (for example, methanesulfonyloxy or p-toluenesulfonyloxy group), imidazolyl, triazolyl or 4-nitrophenyl And Yl is a carbonyl group, -NRI-B- is an additional carbon-nitrogen bond together with Rl of Rl, and Rd is an alkyl group having 1 to 6 carbon atoms, phenylalkyl (Provided that the number of carbon atoms in the alkyl moiety is 1 to 3), cycloalkyl having 3 to 9 carbon atoms (provided that the cycloalkyl moiety having 5 to 8 carbon atoms is in each case substituted with 1 or 2 alkyl groups having 1 to 3 carbon atoms) , A cycloalkyl group having 5 to 8 carbon atoms, Methylene group in the 3-position or 4-position in the alkyl moiety is optionally replaced by an oxygen atom or an optionally alkyl, perhalylalkyl or alkenyloxycarbonyl group in which the alkyl and alkoxy moieties are in each case 1 to 3 carbon atoms, To 7 carbon atoms, and the cycloalkyl moiety in each case may be further substituted with 1 or 2 alkyl groups of 1 to 3 carbon atoms. Wherein the oxygen atom is not bonded to a carbon atom having a double bond or a triple bond and the alkenyl moiety is bonded to the alkenyl moiety and the alkynyl group, (Wherein the cycloalkyl moiety has 3 to 8 carbon atoms and the alkyl moiety has 1 to 3 carbon atoms), an entire tango 8 to 10 bicycloalkylgulums in which the bicycloalkyl moieties may in each case be further substituted with one or two alkyl groups having 1 to 3 carbon atoms, or 1,3-dihydro-oxo-1, (R7, R4 and RS are as defined above), and 22 is halogen (R < 3 >) - Is an leaving group such as an atom (e.g., a chlorine or bromine atom), Al 'is an n-Cl-s-alkyl group (provided that the methylene group is substituted by a carbonyl group) (Provided that the ring methylene glycol is substituted with a carbonyl group),

Y3 'is -CHCH (Nl7) -CO- or -NH-A3-CO- group wherein A3 is as defined above and Rr is n-Cl-s-alkyl or aryl- 23 is a nucleofugal leaving group such as a halogen atom (e.g. a chlorine, bromine or iodine atom), a hydride or sulfonic acid ester thereof (for example methanesulfonyloxy or p -toluenesulfonyloxy) Group, or an oxygen atom of a carbonyl group with a hydrogen atom adjacent to the carbon atom, and R3 "is the same as R7 defined above (provided that the imino group is not substituted), R7 is H-C1-5-alkyl Group, an aryl-Cl-3-alkyl group or an aryl-Cl-3-alkyl group such as Cl-6-alkanoyl, benzoyl, allyloxycarbonyl, A radical which may be cleaved, 24 represents a halogen atom (e.g., chlorine, bromine or iodine atom), a sulfonic acid ester thereof (for example, methanesulfonyloxy Or p-toluenesulfonyloxyglucose), or when R7 is n-Cl-5-alkylglycyl or aryl-Cl-3-alkylsulphonyl, in addition to the hydrogen atom adjacent to the carbon atom, an oxygen atom , R7 '' is N-benzyl-pyridinium he and Rh is a hydrogen atom, Cl-5-alkyl, aryl or aryl-Cl-3-alkylgul.

In the reactions described above, the antimeric groups present, such as carboxyl, amino or imino groups, can be protected during antidepression as a conventional protective group that can be cleaved after repelling.

For example, possible protective groups for the carboxyl group are trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl groups.

Possible protection against amino or iminoglycine is in the form of a formyl, acetyl, trifluoroacetyl, allyloxycarbonyl, ethoxycarbonyl t-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-dimeroxybenzylglyle, and phthalyl group is added for the amino group.

In some cases, the continuous cleavage of the protecting radicals used is preferably carried out in the presence of a transition metal such as trifluoroacetic acid in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or an aqueous solvent such as dioxane / In the presence of an acid such as hydrochloric acid or sulfuric acid, or in the presence of an alkali metal base, such as sodium hydroxide or a hydroxide, or in the presence of, for example, iodotrimethylsilane at a temperature of from 0 to 120 < Preferably at a temperature of 10 to 100 < 0 > C.

However, the benzyl, carboxybenzyl or benzyloxycarbonyl radical may be reacted in the presence of a catalyst such as, for example, lalidium / carbon, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, The acid is added and cleaved by hydrogenolysis at a temperature of 0 to 100 ° C, preferably at a temperature of 70 to 607, at a pressure of 1 to 7 bar, preferably at a pressure of 3 to Sbar. However, the 2,4-dimercovibenzyl radical is preferably cleaved to trifluoroacetic acid in the presence of anisole.

The tert-butyl or tertiary-butyloxycarbonyl radical is preferably treated with an acid such as trifluoroacetic acid or hydrochloric acid, or with iodotrimethylsilane, optionally with methylene chloride, dioxane, methane or Using a solvent such as ether.

The trifluoroacetyl radical is preferably treated with an acid such as hydrochloric acid, optionally in a solvent such as acetic acid, at a temperature of 50 to 120 < 0 > C, or, optionally, in a solvent such as tetrahydrofuran or methanol, Lt; RTI ID = 0.0 > 50 C < / RTI > with sodium hydroxide solution or with a solution of lithium hydroxide.

The allyloxycarbonyl radical is preferably treated in a solvent bath such as tetrahydrofuran and preferably in the presence of allylgalline such as morpholine or 1,3-dimethone at a temperature of 0 to 700 < 0 > C, (Triphenylphosphine) -radalate (0), preferably at room temperature and with a catalytic amount of tetrakis- (triphenylphosphine) -radalate (0) under an uncertain gas, or in a solvent such as ethanol, (Triphenylphosphine) rhodium (I) chloride at a temperature of 20 ° C and 77 ° C in the presence of a base such as sodium bicarbonate,

The phthalyl radical is preferably in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent bath such as methanone, ethanol, isopropanol, toluene / water or dioxane, 50 C < / RTI >

The resulting compounds of the compounds of formula I already mentioned above can be further separated into their enantiomers and / or diastereomers. Thus, for example, the sheath / trans mixture can be separated into its cis and trans isomeric forms, and optionally the cis / trans horns having at least one active carbon can be separated into their enantiomers.

Thus, the resulting cis / trans mixture can be separated into its cis and trans isomers by chromatography, for example, and the compound of formula (I) produced as a racemate can be obtained from Allingel'NL and Eliel EL in Topics in Stei et al., Vol. 6, Wiley Irlterscience, 1971). A compound of formula (1) containing two or more stereochemical centers can be isolated by a method known in the literature Based on the physical and chemical differences in its nature, can be separated into its diastereoisomers and the enantiomers obtained from racemic semisomers (ill) Lt; / RTI >

The separation of the enantiomers is preferably carried out by column separation in a clliral phase, recrystallization from an optically active solvent, or purification of the enantiomerically active substance, such as, for example, ethers or amides, Semi-compounds, in particular acids and their dilated derivatives or alcohols, and f.1. The diastereomeric salt mixtures or derivatives obtained in such a way and in such manner, for example on the basis of different monographs, Free isomeric knee pure diastereomeric salt or derivative thereof. Particularly conventional optically active acids are, for example, D-form or L-form of tartaric acid, dibenzoyl tartaric acid, di-o-tolyl-tartaric acid, maleic acid, mandelic acid, camptothecin acid, glutamic acid, aspartic acid or jucan acid. Possible optically active alcohols are, for example, (+) - menthol or (-) - menthol, and the possible optically active acyl radicals in the amide are, for example, (+) - methyloxycarbonyl or (-) - methyloxycarbonyl to be.

In addition, the resulting compounds of formula I can be converted into their salts, in particular their physiologically acceptable salts with inorganic or organic acids, for pharmaceutical use. For this purpose, the possible acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, , Fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In some cases, if the novel compounds of formula I obtained contain carboxyl groups, they can be further converted into their salts with inorganic or organic acids and, in particular for pharmaceutical uses, can be converted into their physiologically acceptable salts . Possible bases for this are, for example, sodium hydroxide, cuprous oxide, arginine, cyclohexylamine, ethanolamine, diethanolamine or triethanolamine.

Compounds used as starting materials may in some cases be obtained by methods known in the literature or known in the art (see Examples I to XLVI)

As already mentioned above, the novel piperazine derivatives of the formula I and their salts, especially the physiologically acceptable salts thereof with inorganic acids, organic acids or bases, have valuable pharmaceutical properties and are characterized by anti-inflammatory action and inhibition of bone destruction In addition to its action, in particular, antithrombotic action, anti-amyloid action and tumor inhibition action or metastasis inhibition action.

The biological action of the compounds of formula (I) was observed as follows.

Platelet-derived human platelet suspensions were incubated with the ligand 177-fibrinogen-substituted 3H-BIBU 52 [= (35,55) -5-f (4'-amidino-4- biphenylyl) oxymethyl] 3 - [(carboxyl) methyl1-2-pyrridinone f3-3H-4-biphenylyl] and various concentrations of material are tested. The free ligand and bound ligand are separated by centrifugation and quantitated by scintillation counting. The inhibition of 3H-BIBU 52 deficiency by the test substance is determined by the measurement value.

For this purpose, the blood is drawn from the vein opposite the elbow and anticoagulated with trisodium citrate (final concentration 13 mM). Centrifuge the blood for 10 min at 170 x g and remove platelet-rich plasma (PRP). To separate plasma, residual blood is centrifuged one more time under vigorous conditions. PRP is autoclaved at a ratio of 1:10 to autologous plasma. 7507 is cultured at room temperature for 20 minutes with physiological saline 5 tin, test substance solution 100, 14C-sucrose (3,700Bq) 50 and 3R-BIBU 52 (final concentration: 5 nM) To measure non-specific binding, BIBU 52 (final concentration: 307 M) 17071 is used in place of the test substance. The sample is centrifuged at 10 x 10 g for 20 seconds and the supernatant is removed. Determine the free ligand by measuring its 1007. The pellet is dissolved in 0.2N NaOH 5007, 2 ml of scintillator and 5N HCl 2577 are added to 4507 and the sample is measured. Residual plasma still remaining in the pellet is determined from the t4C content and the defective ligand is determined by 3H measurement. After subtraction of non-specific binding, the activity is plotted against the test material and a 50% inhibition concentration is determined.

Platelet aggregation is measured by the Born and Cross method (J. Physiol. 77, 397 (1964)), which refers to platelet-rich plasma of healthy persons. To prevent sputum, 3.14% sodium citrate is added to the blood at a volume ratio of 1:10.

Optical recording and recording of the process of decreasing the optical density of the gypsum board suspension after addition of agglomerated material. The velocity of the curve is determined by the inclination angle of the density curve. The point of the curve where the highest light transmission appears is used to calculate the "cross-correlation density".

The amount of lolagen is as low as possible but is sufficient to indicate the reaction curve progressing with irreversible process. Commercial collagen (manufactured by Hormonchemie, Munich) is used.

Plasma is incubated with the material at 37 ° C for 10 minutes in each case before adding collagen.

The ECe based on the% change in "optical density" in the sense of cohesion inhibition is determined from the measurement graph taken

The following table shows the results:

In addition, the compounds of Examples 4 (6) to 4 (13) were obtained from oral administration of Img / kg to Rhesus monkeys High plasma lettuce.

The novel compounds are well tolerated, for example, since no toxic side effects have been observed after intravenous administration of 7 g 200 mg to the compound of Example 1 (23) according to the invention.

The novel piperazine derivatives of formula (I) and their physiologically acceptable salts, based on their inhibitory effects on cell / cell and cell / cell interleukin interactions, are useful for the treatment of large or small cell populations, Which is suitable for the treatment or prevention of a disease for which the action is to be treated (for example, venous thrombosis, arterial thrombosis, cerebral hemorrhage, pulmonary embolism, myocardial infarction, arteriosclerosis, osteoporosis, It is also suitable for the treatment of genetic disorders due to interactions between cells or interactions of cells with solid constructs, as well as acquired disorders. They are also suitable for the treatment of shock, psoriasis, diabetes and saline conditions as well as incidental treatment of vascular intervention such as thrombolysis or vascular angioplasty with vascular injury.

The dose for treating or preventing the above-mentioned diseases is 0.lng to 30 yg / kg of body weight, preferably 1 mg to 15 mg of body weight, and is administered 4 times or more per day. To this end, according to the invention, the compounds of the formula I are optionally administered in combination with other active substances such as thromboxane receptor antagonists and thromboxane synthesis lowering agents or mixtures thereof, serotonin antagonists,? -Receptor antagonists, glycerol trinitrate, A fibrinolytic agent such as hyaluronic acid, salicylate protein C, a vitamin K antagonist, hirudin, thrombin, a thrombin inhibitor, a fosetin inhibitor, a prostacyclin and its analogs, (E.g., corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, and the like) in combination with conventional antioxidants and / or excipients such as anticoagulants, Citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbic, water / polyethylene Capsules, powders, suspensions, solutions, sprays or suppositories, together with one or more of the above-mentioned ingredients, such as, for example, recol, a propylene glycol, stearyl alcohol, carboxymethylcellulose or fat- Can be prepared in the same conventional pharmaceutical formulation.

The following examples further illustrate the present invention:

A solution of 609 (0.276 mol) of tert-butyl dicarbonate in 150 ml of anhydrous dioxane is added dropwise to a solution of 4-amino-1-benzyl-piperidine 509 (0.25 mol) in 300 ml of anhydrous dioxane while stirring and cooling. When the addition is complete, the mixture is concentrated to dry under vacuum at room temperature for 4 hours. The remaining residue was polished with a small amount of ether and petroleum ether, filtered by suction

Wash with petroleum ether.

Yield: 70.6 g (92.6% of theory)

Melting point. 114-112

Rf value: 0.60 (silica gel, methylene chloride / methane = 9: 1)

Methane was treated with a solution of 5 g (0.717 mol) of tert-butyloxycarbonylamino-N-benzyl-piperidine in tin of 501 with ethereal hydrochloric acid to pH 6 and poured into a solution of carbon- 10%). The catalyst is filtered off, the filtrate is concentrated to dryness in vacuo, the residue is triturated with ether and the solid is filtered off with suction.

Yield: 3.3 g (95.7% of theory)

Mass spectrum: M '=? 00

Rf value: 0.13 (silica gel: methylene chloride / methane = 7: 1)

A solution of 3. 0 g (0.013 mol) of tert-butyloxycarbonylamino-piperidine, 1.9 g (0.13 mmol, 1.2 ml) of methyl bromoacetate and 2.6 g (0.025 mol, 3.4 i long) Lt; / RTI > overnight. The concentrated residue was dissolved in ethyl acetate and water. The organic layer is dried with sodium sulfate and concentrated

yield. 3.Is (89.8% of theory)

Mass spectrum: M '= 272

Rf value: 0.43 (silica gel, methylene chloride / methane = 9: 1)

Methane was acidified with 30 ml of a solution of methyl tert-butyloxycarbonyl-amino-piperidine acetate (3.71 g, 0.71 mmol) in ethereal hydrochloric acid 301 and allowed to stand overnight at room temperature. It is concentrated to dryness under vacuum, the residue is triturated with ether and the solid is filtered off with suction.

Yield: 2.4 g (100% of theory)

Mass spectrum: M '= 140

Rr value: 0.10 (silica gel; methylene chloride / methane = 9: 1)

3- (4-Pyridyl) -acrylic acid 509 (0.335 in 1) is hydrogenated in 500 ml of acetic acid at 50 똔 concentration under a hydrogen pressure of 50 psi, until the hydrogen is completely dissolved in the acetic acid, as a catalyst, The catalyst is filtered off, the filtrate is concentrated to dryness under vacuum, and the residue is crystallized by adding a small amount of methane and ether.

Yield: 47 g (59 of theory)

Mass spectrum: M '= 157

46.7 g (0.39 mol) of thionyl chloride was stirred at -20 ° C, and methane was stirred at 500 m / sec. Upon completion, the mixture is further stirred for 20 minutes and then 56. Is (0.357 mol) of 3- (4-piperidinyl) -protonic acid is also slowly added dropwise

The mixture is further stirred at 0.7 for a time, then the temperature is raised to room temperature overnight with further stirring. The resulting clear solution is then concentrated to dryness under vacuum and the residue is crystallized from acetone.

Yield: 57 g (77.277 of theory)

Mass spectrum: M ' = 171

(0.0227 mol) of methyl 3-4-piperidinyl) -propionate and 4.73 g (0.0229 mol) of p-nitrophenyl fluoroformate while stirring 5 mol (0.0573 mol) of triethylamine at 0 ° C. The solution is added dropwise and the mixture is stirred at room temperature. It was allowed to warm at room temperature for 4 hours and then concentrated to dryness in vacuo. The residue was partitioned between methylene chloride and water. The organic layer was separated, dried and concentrated. The remaining residue is fixed on a silica gel column and methylene chloride is used as a non-releasing agent.

Yield: 9 g of oily substance, 4-nitrophenol as fire tear

Mass spectrum: M ' = 335

Rr value: 0.93 (silica gel; methylene chloride / methane = 9: 1)

Prepared similarly to Example m from 4- (4-piperidinyl) -butyrate hydrochloride, p-nitrophenyl chloroformate and N-ethyl diisopropylamine. Oily substances that slowly crystallize.

Rr value; 0.11 (silica gel; film methylene / methane = 9: 1)

Example V

Methane is heated at reflux temperature for 4 hours in a solution of 4-amino-1-indole-piperidine 509 (0.263 mol) and 28.5 ml (0.263 mol) of ethyl acrylate in a volume of 300 ml. Concentrate under vacuum, dissolve the residue in acetone, acidify the solution to pH 3 with ethereal hydrochloric acid, and concentrate to dryness under vacuum. The remaining residue is polished with acetone. The separated crystalline product is impregnated and dried.

Yield: 45.7 g (50.27 of theory)

Melting point: 172-180 占 폚 (decomposition)

Rr value: 0.60 (silica gel; methylene chloride / methane = 7: 1)

259 (0.0716 mol) of N-fl-benzyl-4-piperidinyl] -? - alaninyl methyl ester hydrochloride in dioxane 1001 residue, 15.8 g (0.772 mol) of diglyme-butyl dicarbonate and 20 ml 0.138 mol) and 1701 l of water are left at room temperature for 48 hours. Concentrated to dryness in vacuo and the residue is partitioned between ethyl acetate and water. The organic layer is dried with sodium sulfate and concentrated. The remaining residue is dissolved in ethane and acidified to pH 6 with ether hydrochloric acid. The solution is concentrated to dryness under vacuum, the residue is stirred with acetone and the solid is filtered off with suction.

Yield: 24.Is (81.5% of theory)

Melting point: 196-197 占 폚 (decomposition)

Rf value: 0.50 (silica gel; methylene chloride / methane = 9: 1)

Methane was prepared by reacting N- (1-benzyl-4-piperidinyl) -N-butyloxycarbonyl- beta -alanine methyl ester hydrochloride 249 (0.05 mol) - palladium (10%) catalyst. The catalyst is filtered off and the solution is concentrated to dryness under vacuum.

Yield: 27.4g

Rf value: 0.17 (silica gel, methylene chloride / methane = 9: 1)

From 4-amino-1-benzyl-piperidine, methyl bromoacetate and N-ethyl-diisopropylamine

Prepared from N- (1-benzyl-4-piperidinyl) -glycine methylassdere hydrochloride, di-tert-butyl dicarbonate and triethylamine.

Complete hydrogenation from N- (1-benzyl-4-piperidinyl) glycine methyl ester hydrochloride to carbon-azide-lalidium (10%).

Ethane was added to a solution of 28.8 g (0.0261 nio) of N- (1-benzyl-piperidinyl) -? - alanine methyl ester dihydrochloride in 100 ml of ethyl acetate, 0.09 mol of paraformaldehyde? And 5.2 g of sodium cyanoborohydride (0.03 mol) of the above compound are stirred at room temperature for 247,1 minutes. Quench with water and acidify with pouter 2 with IN hydrochloric acid. Extract the common water with ethyl acetate, make the worms alkaline with diluted Na2CO3 solution and completely extract with methylene chloride. The combined methylene chloride layers are dried and concentrated to dryness under vacuum. The residue was purified by silica gel column using 37% methylene chloride and 5% methanol as eluent. The combined extracts are acidified with Pdyn 3 with etheric HCl and concentrated to dryness under vacuum. Acetone is added to the residue, and the sieve is filtered by suction.

Yield: 20.8 g (69.5% of theory)

Melting point: 224-227'c

Rf value of 0.60 (silica gel; methylene chloride / methane = 4: 1)

Prepared by hydrogenating N- (1-benzyl-4-piperidinyl) -N-methyl- beta -alanine methyl ester dihydrochloride with carbon-iodine-palladium (10%).

Yield: 15.89 (95.47 of theory)

Melting point: 194-195 DEG C (decomposition)

Rf value: 0.09 (silica gel; methylene chloride / methane = 9: 1)

The following excipients can be prepared analogously to Example VII:

a) N- (1-Benzyl-piperidinyl) -N-methyl-glycine methyl ester dihydrochloride

Prepared from N- (1-benzyl-4-piperidinyl) glycine methyl ester dihydrochloride, paraformaldehyde and sodium cyanoborohydride.

b) Preparation of N-methyl-N- (4-piperidinyl) -glycine methyl ester dihydrochloride

Prepared by complete hydrogenation from N- (1-tinyl-4-piperidinyl) -h-methyl-glycine methyl ester to carbon-iodide-laladium (10%).

Methane was added to a solution of N- (1-benzyl-4-piperidinyl) -f-alanine methyl ester hydrolyzate 259 (0.0716 rno1), triethylamine 20m1 (0.143mol) and acetic anhydride 5.lnl (0.0s59mo1 ) The suspension is left overnight at room temperature and concentrated under vacuum. The residue is dissolved in water and the solution is brought to pH S with 2N sodium hydroxide solution and completely extracted with ethyl acetate. The combined ethyl acetate extracts are dried and concentrated to dryness under vacuum. The residue is purified by silica gel column with methylene chloride containing 3% methane. The effluent is concentrated and the residue is dissolved in acetone, the solution is acidified with p-Bu 6 with ethereal hydrochloric acid and concentrated. The residue is crystallized from acetone / ether.

Yield: 19 g (74.7% of theory)

Melting point: 138-140 캜 (decomposition)

Rf value: 0.50 (silica gel; methylene chloride / methane = 9: 1)

(10%) in the same manner as in Example Vc.

Yield: 13.2 g (93.2% of theory),

Very hygroscopic solid

Mass spectrum: = 228

Rf value: 0.09 (silica gel; methylene chloride / methane = 9: 1)

Preparation from N- (1-benzyl-4-pyridinyl) glycine methyl ester hydrochloride and acetic anhydride.

(10%) from N-acetyl-N-11-benzyl-4-piperidinyl] glycine methyl ester hydrochloride to give

Prepared from N-benzyl-piperazine and methyl acrylate analogously to example Va.

Yield: 14.7 g (71.5% of theory)

Mass spectrum 'M' = 262

Rf value: 0.42 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Prepared by hydrogenation of 3- [4- (1-benzyl) -piperazin-1-yl] propionate dihydrochloride to carbon-ad-palladium (10%) in analogy to example V7.

Yield: 10.5 g (99% of theory)

Mass spectrum: M '= 172 < RTI ID = 0.0 >

Rf value: 0.13 (silica gel, methylene chloride / methane / ammonia ammonia = 9: 1: 0.1)

About 4 g of 3A molecular sieve was charged with 1.9 g (0.01 mole, 1.9 ml) of N-benzyl-4-piperidone in 27 tin and 2.5 g of methyl 3- (piperazin- 1 -yl) -propionate dihydrofluoride (0.01 mol) solution. 1.2 g (0.03 mol) of sodium cyanoborohydride are added and the mixture is stirred at room temperature overnight. After this, the molecular sieve is suction filtered and the solution is concentrated to dry under vacuum. The remaining residue is partitioned between ethyl acetate and water. The ethyl acetate solution is dried and concentrated to dryness under vacuum. The remaining residue is purified with a silicapel column using methylene chloride / methane = 20: 1 to methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1 as an eluent.

Yield: 2 g of oily substance (57.7 of theory)

Rr value: 0.25 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Prepared from methyl 3- [l- [4- (l-wyll) -piperidinyl] -piperazin-l-yl 1 propionate and semi-concentrated hydrochloric acid in analogy to example 1.

Yield: 2.2 g (94.0% of theory)

Mass spectrum; M '= 331

Rf value: 0.17 (silica gel; methylene chloride / ethanoxime / concentrated ammonia = 4: 1: 0.1)

Methane was allowed to stand at room temperature overnight at room temperature, to which were added 6 g (0.034 mol, 6 ml) of N-benzyl-piperazine in the long chain, 5.2 g (0.037 mol, 3.3 rnl) of methyl bromoacetate and 3.5 g The solution is concentrated to dryness under vacuum and the residue is purified on a silica gel column (eluent: methylene chloride containing 2% methanol).

Yield: 7 g of oil (82.5% of theory)

Rr value: 0.60 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

7 g (0.028 mol) of methyl (4-benzyl-piperazin-1-yl) -Agatate are hydrogenated under a hydrogen pressure of 50 psi with methane containing 1 ml of ethereal hydrochloric acid in the presence of catalytic carbon- Lt; / RTI > When the pollution of hydrogen is terminated

The catalyst is removed and the residue is concentrated to dryness.

Yield: 4.5 g of amorphous solid (10077 of theory)

Rr value: 0.26 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

A solution of 4.5 g (7.00 smol) of methylpiperadino acetate dihydrofluoride in 100 ml of anhydrous methane and 5.4 g (0.028 mol, 5.31 ng) of N-permutant-4-piperidone was acidified with PH 6 with ethereal hydrochloric acid. 1.8 g (0.028 mol) of sodium anoborohydride and about 4 g of 3-molecular sieves are added to this solution with stirring at room temperature and stirred overnight. After filtering off the molecular sieves, the solution is concentrated to dryness under vacuum and the residue is partitioned between ethyl acetate and water. The combined organics are dried and concentrated to dryness under vacuum. The residue is purified on a silica gel column (eluent: methylene chloride / methanol / conc. Ammonia = 30: 1: 0.1).

Yield: 6.4 g (81.2% of theory)

Mass spectrum: M ' = 331

Rf value: 0.65 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(0.0471 nio) was added to a solution of 7.1 g (0.0074 mmol) of methyl 4-74- (1-benzyl) -piperidinyl] piperazinoacetate in 30 ml of tetrahydrofuran and water 351111, and the mixture was stirred at room temperature for 6 I will teach for the time. Then 2.5 g (0.07 mol) of ammonium chloride are added and the solution is concentrated under reduced pressure. The residue is extracted twice with distilled ethanol. The combined ethane extract is dried under vacuum. Purify the remaining residue with a silica-fritted wood (Texture: methylene chloride / methanol / conc. Ammonia = 4: 1: 0.1).

Yield: 2 g (67.4% of theory)

Mass spectrum: M < + > = 317

Rf value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Prepared analogously to Example c from N-butyloxycarbonyl-4-piperidine, N-benzyl-piperazine and sodium cyanoborohydride.

Yield: 4.Sg (83.1% of theory)

R 1 value: 0.45 (silica gel, methylene chloride / methane = 9: 1)

Prepared by hydrogenation of 1-benzyl-4- [4- (1-tert-butyloxycarbonyl) -piperidinyl] piperazine with a carbon-iodine-palladium dihydroxide catalyst analogously to example 3.

Yield: 3.Og (83.3% of theory)

Rf value: 0.13 (silica gel, methylene chloride / methane = 9: 1)

2.8 g (0.0104 mol) of N- [4- (tert-butyloxycarbonyl) -piperidinyl 1 piperazine), 1.8 g (0.0107 nio) of malonic acid monoethyl ester potassium salt, (IH-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (3.3 g, 0.01 mmol) and 1-hydroxy-1-H-benzotriazole 0.0107 < / RTI > no 1) and N-methyl-morpholine Is (0.01 mol) in toluene. The solution is concentrated to dryness under vacuum and the residue is purified by chromatography on a silica gel column (eluent: methylene chloride containing 2% to 4% of methane).

Yield: 1.5 g (37.1% of theory)

Rf value: 0.45 (silica gel; methylene chloride / methane = 9: 1)

IN sodium hydroxide solution 5 (0.042 mol) was dissolved in 50 ml of ethyl f4 - [(4- (tert-butyloxycarbonyl) -piperidinyl] piperazin-1-yl] malonate The solution is then concentrated to dryness under vacuum. The anhydrous ethanol is added to the residue and the mixture is concentrated in vacuo 3 times. The residue was stirred with anhydrous ethane and methylene chloride (1: 1), the undissolved inorganic salt was filtered off with suction, and the solution was concentrated to dryness under vacuum

Yield: 1.2 g of bubbles (87.4% of theory)

Rf value. 0.11 (silica gel; methylene chloride / methane = 4: 1)

In the same manner as in Example 6, the title compound was obtained from 4-amino-N-benzyl-caffeferidine, N- [4- (1-butyloxycarbonyl) -piperidinyl] -piperazine, N, N'-carbonyldiimidazole And imidazole.

Yield: 5.7B (63.5% of theory)

Rf value '0.40 (silica gel; strongly methylene / methanol / concentrated ammonia = 9: 1: 0.1)

Piperazin-1-yl] was prepared from N-benzyl- [4- [4- (4- (tert-butyloxycarbonyl) Prepared by hydrogenation to hydroxide.

Yield: 4.3 g (92.677 of theory)

Rf value: 0.11 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

13.4 g (0.583 mol) of sodium are dissolved in 18 ml of dry ethane and 204 ml (1.35 mol) of diethyl malonate are added in portions to the solution resulting from the colorless precipitation. This precipitate is heated to 30 to 40 占 폚, and dissolved by dissolving in ethanol, and anhydrous ethane is added dropwise over 1.5 hours while stirring a solution of 4-vinylpyridine 631n1 (0.553 mol) in 12 ml with stirring. After the addition, the reaction mixture is heated to reflux for 3 hours, then concentrated to a small volume and poured into 450 ml of semi-concentrated hydrochloric acid. Extracted twice with ether to remove excess diethylmalonate, the bacterium is made alkaline with sodium carbonate and is completely extracted with methylene chloride. The combined organic extracts are dried and concentrated. Purify the residue with a silica column (eluent: ethyl acetate / cyclohexane = 1: 1). The oil residue (78.6 g = 50.8 of the theoretical amount) is dissolved in acetone and the solution is acidified with 7H 3.5 with ethereal hydrochloric acid and concentrated. Crystallize overnight in the residue and grind with acetone / ether and filter by suction.

Yield: 65 g (37% of theory)

at value: 0.80 (silica gel; methylene chloride / methane = 9: 1)

b) Diethyl 2- [2- (4-piperidinyl) -ethyl] malonate hydrochloride

64.5 g (0.21 mol 1) of diethyl 2- [2- (1-pyridyl) ethyl] malonate hydrochloride was thoroughly hydrogenated in 400 ml of dry ethane under hydrogen pressure of 50 psi with a platinum dioxide catalyst at room temperature . After the catalyst is filtered off, the remaining solution is concentrated to dryness under vacuum. Rinse the residue with acetone and filter in hob.

Yield: 62.8 g (75.5% of the theoretical amount) of crystals of very hygroscopic crystals,

Rf value: 0.22 (silica gel; methylene chloride / methane = 9: 1)

A solution of diethyl 2- [2- (4-piperidinyl) -ethyl] -malonate hydrochloride 629 (0.201 m71) in 607 ml of concentrated hydrochloric acid was concentrated to dryness under heating in vacuo at reflux temperature for 24 hours. Toluene is added to the residue and the fractions are concentrated. This operation is repeated three more times.

Yield: 44.3 g of a colorless crystal containing a small amount of toluene

Rr value: 0.197 silica gel; Methylene chloride / methane = 9: 1)

18m1 (0.242mol) of thionyl chloride was stirred at -17 ° C and the reaction was stopped when SOOm was removed. A solution of 44.3 (0.20 mmol) of 4-14-piperidinyl) -butyric acid hydrofluoride in 100 ml of methanol was added dropwise to the stirred solution and stirred at room temperature overnight, then the mixture was concentrated to dryness under vacuum. The residue is partitioned into 50 똔 concentrated potassium carbonate solution and ether.

The water is extracted twice more with ether. The combined ether extracts are dried and concentrated. The residue is dissolved in methanol and the solution is acidified to pH 6 with ethereal hydrochloric acid and concentrated to dryness under vacuum. The remaining residue is polished with acetone. The separated crystals are filtered by suction.

Weight: 35.5 g (88.7% of boron)

Melting point: 99-105 DEG C (decomposition)

2.3 g (0.05 mol) of sodium hydride (50% concentration in oil) were added to a solution of N-tert-butyloxycarbonyl-4-p ypyridinol 109 (0.05 mol) in 100 ml of anhydrous tetrahydrofuran with stirring and the mixture was stirred for 2 hours While stirring further. 7.6 g (0.05 mol, 5 ml) of methyl bromoacetate was added dropwise with further stirring and stirred overnight. The sodium hydride of Miwaeng is decomposed by adding water. The mixture is extracted with ethyl acetate and the combined ethyl acetate extracts are dried and concentrated to dryness under vacuum. The residue is purified on a silica gel column (eluent: methylene chloride containing 1% of methane).

Yield: 4.9 g (36.1% of theory)

Mass spectrum: M '= 273

Rr value: 0.50 (silica gel; methylene chloride / methane = 9.5: 0.5)

Ethereal hydrochloric acid 3 긴 Long-lasting methane is added to a solution of 4.9 g (0.018 mol) of methyl N 2 급-tert-butyloxycarbonyl-4-piperidinyloxyacetate of the genus 10 ml and the mixture is left at room temperature for 4 hours. It is concentrated to dryness under vacuum, ether is added to the residue and the solid is suction filtered

Yield: colorless solid (82.5% of theory)

Mass spectrum: M ' = 173

Rr value: 0.10 (silica gel; methylene chloride / methane = 9: 1)

9 g (0.06 mol, 5.6 ml) of methyl bromoacetate and 8 g (0.7 mol) of calcium carbonate are added to a solution of 8 g (0.06 mol) of 4-hydroxy-acetophenone in 100 ml of anhydrous dimethylformamide. Heat the mixture at reflux temperature for 5 h and then stir at room temperature overnight. The solution was concentrated to dryness under vacuum and the residue was partitioned between ethyl acetate and water. The organic extracts were dried and concentrated to dryness under vacuum. The residue is triturated with ether, suction filtered and dried

Yield: 8.6 g of an amorphous solid (70.3% of theory)

Mass spectrum: M ' = 208 < RTI ID = 0.0 >

Rf value: 0.45 (silica gel; ethyl acetate / cyclohexane = 1: 1)

0.0106 mol (from bromine 1.79 and 8 ml of dioxane) suspension of bromodioxane in dioxane was added dropwise to a solution of 4 g of ether and 2 g (0.0096 mol) of 4-mexylocarbonylmethyloxy-acetophenone in 1 ml of dioxane while stirring at room temperature do. After completion of the addition, the mixture was further stirred at room temperature for 2 hours and then concentrated to dryness under vacuum.

Yield: 1.3 g of crude product

Rr value: 0.60 A double sword (silica gel, ethyl acetate / cytohexane = 1: 1)

The following compounds can be prepared analogously to the examples.

Prepared from methyl 4-acetyl-phenylacetate and bromodioxane.

5. Sg (0.065 mol) of potassium carbonate are added to a solution of 7 g (0.0651 nio) of m-nitrophenol in 100 ml of anhydrous dimethylformamide, and the mixture is stirred at room temperature for 1/2 hour. 10.9 g (0.07 mol, 6.7 ml) of methyl bromoacetate are added and the mixture is heated at 80 for 5 hours. The solution is concentrated to dryness under vacuum and the residue is partitioned between ethyl acetate and water. The combined organic layers are dried and concentrated to dryness under vacuum. The residue is triturated with ether, suction filtered and dried.

Yield: 7.2 g (67.3% of theory)

Rf value: 0.55 (silica gel; methylene chloride)

7.2 g (0.0461 nio) of 3-methoxycarbonylmethyl-nitrobindine were hydrogenated in situ in methane with 1.5 g of Raney nickel under a hydrogen pressure of 50 psi at room temperature. The catalyst is filtered off with suction and the solution is concentrated.

Yield: 7.0 g of oily substance (85.7% of theory)

Rf value: 0.50 (silica gel; ethyl acetate / cyclohexane = 1: 1)

Prepared similarly to Example XVIIIa from 4-nitrophenol, methyl bromo a gateate and cesium carbonate.

Yield: 10.4 g (91.0 of theory)

Gradient: 86-88 ° C

Prepared by hydrogenation of 4-mepicycarbonylmethyloxy-nitrobenzene to Raney nickel analogously to Example XVIIIb.

Yield: 9.5 g of dendritic material (95.4 of theory)

R1 value; 0.67 (silica gel, chloromethylmethane = 7: 1)

Methanol and 177111 g of 3- (4-amino-phenyl) -propyl are added to the acid 159 (0.0991 mol) solution in water while stirring with 12.77 g (0.lllnol) thionyl chloride and cooling with methanol / ice. After completion of the addition, the mixture is further stirred for 30 minutes while cooling, and then stirred overnight at room temperature. The mixture is concentrated to dryness in vacuo and the residue is crystallized from methanol / ether

Yield: 15.8 g (85.6% of theory)

Melting point: 165-167 ° C

(0.0027 mol) was added to a solution of N-tert-butyloxycarbonyl-4-piperidinol 109 (0.0497 mol) in 20 ml of dioxane, and 13.5 ml (0.127 mol) of ethyl acrylate was added dropwise And the mixture is heated at reflux for 7 hours. The mixture is stirred overnight in vacuo, concentrated to dryness under vacuum and the residue is partitioned between ethyl acetate and water. The organic layer is dried and concentrated to dryness under vacuum. The residue was purified on a silica gel column (eluent: cyclohexane / ethyl acetate = 10: 3).

Yield: 4.5 g of oily material (30% of theory)

Rf value: 0.80 (silica gel; methylene chloride / methane = 7: 1)

4.5 g (0.015 mol) of 4- (ethoxycarbonyl-2-ethyloxy) -N-tert-butyloxycarbonylpiperidine were added to a solution of 30 ml of methylene chloride and 20 ml of trifluoroacetic acid Leave in the mixture for 4 hours. The mixture is concentrated to dryness under vacuum and 4.5 g of colorless oil are obtained.

A solution of 4-nitrobenzocatechol 109 (0.0645 mol), methyl bromoacetate 12.8 ml (0.135 mol) and potassium carbonate 18.79 (0.135 mol) in 100 ml of dimethylformamide is heated at 80 t for 5 hours. After cooling, the residue is partitioned between water and ethyl acetate and the organic layer is dried and concentrated in vacuo. The residue is polished with ether and filtered.

Yield: 11.4 g (59% of theory)

Rf value: 0.70 (silica gel; methylene chloride)

11.4 g (0.0381 mol) of dimethyl 4-nitro-1,2-phenylenedioxy-diacetate were hydrogenated under a hydrogen pressure of 50 psi at room temperature with carbon-chilled-lalidium (10 ml catalyst with 160 ml of methane and 40 ml of IN hydrochloric acid, The catalyst is suction filtered, and the remaining solution is concentrated to dryness under vacuum. The residue is polished with acetone and suction filtered.

Yield: 10.69 (93.7% of theory)

Rf value: 0.70 (silica gel, methylene chloride / methane = 9: 1)

A suspension of p-Nitrophenol 109 (0.0179 mol), 2 ml of Triton B and 20 ml of methyl acrylate (0.1797 mol) was heated at reflux temperature for 20 hours and then concentrated to dryness under reduced pressure. The residue is partitioned between water and ethyl acetate. The organic layer is dried and concentrated to dryness under reduced pressure. The residue is chromatographed on a silica gel column using methylene chloride as an eluent. The remaining residue is polished with petroleum ether and filtered by impregnation.

Melting point: 50-53 DEG C

R 1 value: 0.65 (silica gel; methylene chloride)

Prepared by complete hydrogenation of ethyl 3- (4-nitro-phenyloxy) -propionate analogously to Example XXIIb, using ethanol as the working-up.

1-yl] acetyl] amino] -cyclohexanecarboxylate trihydrochloride. ≪ Desc / Clms Page number 30 >

Amorphous solid

Mass spectrum: M ^< ^{+ &} gt ^; = 352

R _f value: 0.85 (reverse phase plate RP18; methanol / 5% strength sodium chloride solution = 3: 2)

Prepared from methyl N - [[4- (4-piperidinyl) -piperazin-1-yl] acetyl] -3- (4- piperidinyl) -propionate trihydrochloride.

Amorphous solid.

Mass spectrum: (M + H) < + > = 367

Rf value: 0.63 (reverse phase plate RPIS; methanol / 5% strength sodium chloride solution = 3: 2)

Methyl [4- [[4- (4-piperidinyl) -piperazin-1-yl] acetyl] phenoxy] -acetate trihydrochloride.

Melting point: 265-270 占 폚 (decomposition)

Mass spectrum: (M + H) < + > = 362

Rf value: 0.075 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Prepared from methyl [3 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] phenoxy] acetate dihydrochloride.

Melting point: 240-242 占 폚 (decomposition)

Mass spectrum: (M + H) < + > = 363

Rr value: 0.07 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Prepared from methyl 4 - [[4- (4-piperidinyl) -piperazin-1-yl] acetyl) phenyl- acetate trihydrochloride.

Prepared from methyl [3 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] phenyl] propionate dihydrochloride.

Melting point: 289-292 占 폚 (decomposition)

Mass spectrum: M < + > = 360

Rf value: 0.80 (reverse phase plate RP18; methanol / 5% strength sodium sulphate solution = 6: 4)

Prepared from methyl [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] phenoxy] acetic acid dihydrochloride.

Melting point 263-265 DEG C (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 362

R _f value: 0.75 (reverse phase plate RP18; methanol / 5% strength sodium chloride solution = 6: 4)

(41) N- [4 - [[4- (4-Piperidinyl) -piperazin-1-yl] carbonyl] phenyl] -? - alanine dihydrochloride

Prepared from N- [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl] phenyl] - [beta] -alanine ethyl ester dihydrochloride.

Amorphous solid.

Mass spectrum: (M + H) < ⁺ & gt ^; = 361

R _f value: 0.52 (reverse phase plate RP18; methanol / 5% strength sodium chloride solution = 3: 2)

(42) N- [3 - [[4- (4-Piperidinyl) -piperazin- 1-yl] carbonyl] phenyl] -? - alanine dihydrochloride

Prepared from N- [3 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl] phenyl] - [beta] -alanine ethyl ester dihydrochloride.

Amorphous solid.

Mass spectrum: M ^< ^{+ &} gt ^; = 360

R _f value: 0.75 (reverse phase plate RP18; methanol / 5% strength sodium chloride solution = 3: 2)

(43) 3- [3 - [[4- (4-Piperidinyl) -piperazin-1-yl] carbonyl] phenyloxy] propionic acid dihydrochloride

Prepared from ethyl 3- [3 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl] phenyloxy] propionate dihydrochloride.

Melting point: 262-264 DEG C (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 362

_Rf value: 0.10 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Preparation from ethyl N-4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylethyl] piperidinyl acetate trihydrochloride.

Mass spectrum: M ^< ^{+ &} gt ^; = 366

_Rf value: 0.19 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Prepared from methyl N-4 - [[4- (4-piperidinyl) -piperazin-1-yl] -malonyl] piperidinyl acetate dihydrochloride.

Amorphous solid

Mass spectrum: M ^< ^{+ &} gt ^; = 380

_Rf value: 0.13 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Preparation from methyl N-4 - [[4- (4-piperidinyl) -piperazin-1-yl] -ethylcarbonyl] piperidinyl acetate trihydrochloride.

Melting point: 229-233 DEG C (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 367

R _f value: 0.55 (reversed phase RP18; methanol / 5% NaCl solution = 3: 2)

Prepared from methyl [4-trans- [2S- (4- (4-piperidinyl) -piperazin- 1 -yl] propionylamino] cyclohexanecarboxylate trihydrochloride.

Amorphous solid.

Mass spectrum: M ^< ^{+ &} gt ^; = 366

Rf value: 0.70 (reverse phase plate RP18; methanol / 5% strength sodium chloride solution = 3: 2)

Yl)] - (3- (4-methoxyphenol)) propionylamino] cyclohexanecarboxylate trihydrochloride (prepared as described in Example 1) .

Amorphous material.

Mass spectrum: M ^< ^{+ &} gt ^; = 472

R _f value: 0.55 (reverse phase plate RP-8; methanol / 5% strength sodium chloride solution = 3: 2)

Prepared from methyl N - [[2S- (4- (4-piperidinyl) -piperazin-1-yl] propionyl] -4-piperidinyloxyacetate trihydrochloride.

Yl)] - (3- (4-methoxyphenyl)) propionyl] -4-piperidinyloxy-acetate The title compound was prepared from ethyl N - [[2S- (4- (4-piperidinyl) -piperazin- Trihydrochloride.

Mass spectrum: (M + H) < ⁺ & gt ^; = 489

R _f value: 0.68 (reverse phase plate RP18: methanol / 5% strength sodium chloride solution = 3: 2)

Prepared from methyl [4-trans- [4- (4-piperidinyl) -piperazin-1-yl] oxalylamino] -cyclohexanecarboxylate dihydrochloride.

Prepared from methyl N - [[4- (4-piperidinyl) -piperazin-1-yl] oxalyl-4-piperidinyl oxyacetate dihydrochloride.

Prepared from methyl 4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylmethyl] -phenoxy] acetate dihydrochloride.

Melting point: 148 deg. C (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 361

R _f value: 0.25 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Methyl [4 - [(4- (4-piperidinyl) -piperazin-1-yl] -2-ethyl] phenoxy] acetate trihydrochloride

Melting point: 312-315 DEG C (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 348

_Rf value: 0.25 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(55) N- [4- (4- (1-Benzyl) -piperidinyl) -piperazin-1-yl] carbonyl] -piperidine-

Butyloxycarbonyl-N- [4 - [[4- (4- (tert-butyloxycarbonyl) -piperidinyl) -piperazin-1-yl] -Carbonyl] piperidinyl] glycine methyl ester with 50% strength trifluoroacetic acid.

Piperidine-1-yl] carbonyl] piperidinyl] -N- (4-fluorophenyl) Prepared from methyl-glycine methyl ester and 50% strength trifluoroacetic acid.

(4- (4- (tert-butyloxycarbonyl) -piperidinyl) -piperazin-1-yl] carbonyl] -piperid in the presence of N- ≪ / RTI > yl] -glycine methyl ester with 50% strength trifluoroacetic acid.

Yl) carbonyl] -4- (4-piperidinyl) -piperazin-1-yl] carbonyl] ) -Butyrate with 50% strength trifluoroacetic acid.

Melting point: 306-307 占 폚 (decomposition)

R _f value: 0.15 (reverse phase plate RP18; methanol / 5% strength sodium chloride solution = 6: 4)

-Piperazin-1-yl] acetyl] phenoxy] acetate and ethereal hydrochloric acid in the presence of a base.

Melting point: 245-247 DEG C

Mass spectrum: M ^< ^{+ &} gt ^; = 375

_Rf value: 0.095 (silica gel; methylene chloride / methanol = 9: 1)

-Piperazin-1-yl] acetyl] phenoxy] acetate and ethereal hydrochloric acid in an analogous manner as described for the preparation of the title compound.

Melting point: 250-252 DEG C

Mass spectrum: M < ^{+ &} gt ^; = 376

_Rf value: 0.095 (silica gel; methylene chloride / methanol = 9: 1)

(13) methyl 4 - [[4- (4-piperidinyl) -piperazin-1-yl] -acetyl] phenylacetate trihydrochloride

Prepared from methyl 4 - [[4- (4- (1-tert-butyloxycarbonyl) -piperidinyl) -piperazin-1-yl] -acetyl] phenylacetate and ephedrine hydrochloride.

Prepared from methyl [3 - [[4- (4- (1-tert-butyloxycarbonyl) -piperidinyl) -piperazin- 1-yl] carbonylamino] phenyl] propionate and ethereal hydrochloric acid .

Melting point: 292-295 占 폚 (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 374

R _f value: 0.80 (reverse phase plate RP18; methanol / 5% strength sodium chloride = 3: 2)

(Tert-butyloxycarbonyl) -piperidinyl) -piperazin-1 -yl] carbonyl] -3- (piperidin-4-ylmethyl) -Yloxy) -propionate < / RTI > and trifluoroacetic acid in 50% strength.

Amorphous solid

Mass spectrum; M @ ⁺ = 390

R _f value: 0.12 (silica gel; methylene chloride / methanol = 9: 1)

1-yl] carbonyl] -piperidin-4-yl) -carbamoyl] -piperidine-1-carboxylic acid in methanol Ethyl] - [beta] -alanine methyl ester and ethereal hydrochloric acid.

Melting point: 288-290 DEG C

Mass spectrum: M ^< ^{+ &} gt ^; = 409

_Rf value: 0.50 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Yl] carbonylamino] phenylenedioxy] di (tert-butyloxycarbonyl) -piperidinyl) -piperazin-1-yl] Acetate and 50% strength trifluoroacetic acid.

Melting point: 240-242 DEG C

Mass spectrum: (M + H) < ⁺ & gt ^; = 465

Piperidine-1-yl] carbonylamino] phenoxy] propyl) -piperidine in the presence of ethyl 3- [4 - [[4- Nate and 50% strength trifluoroacetic acid.

Melting point: 245-250 占 폚 (decomposition)

Mass spectrum M ^< ^{+ &} gt ^; = 404

R _f value: 0.85 (silica gel; methylene chloride / methanol = 9: 1)

In the methylene chloride, ethyl 3- [4 - [[4- (4- (tert-butyloxycarbonyl) -piperidinyl) -piperazin-1-yl] carbonyl] phenoxy] propionate And 50% strength trifluoroacetic acid.

Melting point: 304-306 占 폚 (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 389

R _f value: 0.09 (silica gel; methylene chloride / methane = 9: 1)

A solution of ethyl 4 - [[4- (4- (1-tert-butyloxycarbonyl) -piperidinyl) -piperazin- 1-yl] carbonylamino] phenylacetate in 50% Manufactured from roaset acid.

Piperazinyl) -piperazin-1-yl] carbonylamino] cyclohexyl] acetate with 50 [beta] - [4- % Strength from trifluoroacetic acid.

Phenyl] - [beta] -alanine in the presence of N- [3 - [[4- (4- (tert- butyloxycarbonyl) -perperidinyl) -piperazin- 1 -yl] carbonyl] Ethyl ester and 50% strength trifluoroacetic acid.

Amorphous solid

Mass spectrum M ^< ^{+ &} gt ^; = 388

In the methylene chloride, ethyl 3- [3 - [[4- (4- (tert-butyloxycarbonyl) -piperidinyl) -piperazin- 1-yl] carbonyl] phenyloxy] propionate And 50% strength trifluoroacetic acid.

Melting point: 290-296 DEG C (decomposition)

Mass spectrum M ^< ^{+ &} gt ^; = 389

Rf value: 0.1 (silica gel; methylene chloride / methanol = 9: 1)

Piperazine-1-yl] carbonylethyl] piperidineacetate and 50 < RTI ID = 0.0 > % Strength from trifluoroacetic acid.

Amorphous solid.

Mass spectrum: M ^< ^{+ &} gt ^; = 380

R _f value: 0.13 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Piperazine-1-yl] malonyl] piperidinyl acetate in 50% methylene chloride in the presence of methyl N-4 - [[4- (4- (tert- butyloxycarbonyl) -piperidinyl) Concentration Prepared from trifluoroacetic acid

Bubble substance

Mass spectrum: M ^< ^{+ &} gt ^; = 394

R _f value: 0.13 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Piperazine-1-yl] ethylcarbonyl] piperidinylacetate and 50 < RTI ID = 0.0 > % Strength from trifluoroacetic acid.

Bubble substance

Mass spectrum: M ^< ^{+ &} gt ^; = 394

_Rf value: 0.095 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(Tert-butyloxycarbonyl) -piperidinyl) -piperazin-1-yl)] propionylamino] is obtained from methyl [4- trans- [2S- Cyclohexanecarboxylate and 50% strength trihydro acetic acid.

Melting point: 262-266 占 폚 (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 380

_Rf value: 0.06 (silica gel: methylene chloride / methanol = 9: 1)

(3- (4-methoxyphenyl) -piperazin-1 -yl) - (3- (4- Phenyl))] - propionylamino] cyclohexanecarboxylate with 50% strength trifluoroacetic acid.

Amorphous solid.

Mass spectrum: M ^< ^{+ &} gt ^; = 486

_Rf value: 0.21 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Piperazinyl) -piperazin-1-yl) -propionyl] -4-piperidinyl (2-methylpiperazin-1 -yl) Prepared with oxyacetate and 50% strength trifluoroacetic acid.

(30) Synthesis of methyl N - [[2S- (4- (4-piperidinyl) -piperazin-1-yl)] - (3- (4- methoxyphenyl)) propionyl] -4piperidinyloxy Acetate trihydrochloride.

Piperazin-1-yl)] - (3- (4-methoxyphenyl) -piperazin-1 -yl) Phenyl)) propionyl] -4-piperidinyloxyacetate and 50% strength trifluoroacetic acid.

1-yl)] oxalylamino] cyclohexanecarboxylate with ethereal hydrochloric acid in an analogous manner to that described in Example < RTI ID = 0.0 > Produce.

Melting point: 325 캜 (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 380

R _f value: 0.10 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Prepared from methyl N - [[4- (4- (1-tert-butyloxycarbonyl) -piperidinyl) -piperazin-1yl] oxalyl] -4-piperidinyl oxyacetate and ethereal hydrochloric acid .

Melting point: 280-282 DEG C

Mass spectrum: M ^< ^{+ &} gt ^; = 396

1-yl] carbonyl] -4-piperidinyl oxyacetate with ethereal hydrochloric acid to give the title compound as a light brown solid; MS: m / e = Produce.

Yl) carbonylmethyl]] phenoxy] acetate dihydroacetate A mixture of methyl [4 - [[4- (4 - ((4-methyl- 1-tert-butyloxycarbonyl) -piperidinyl) -piperazin-1-yl] carbonylmethyl]] phenoxy] acetate and hydrochloric acid.

Melting point: 265-267 DEG C (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 375

_Rf value: 0.55 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Prepared from methyl [4 - [[4- (4- (tert-butyloxycarbonyl) -piperidinyl) -piperazin- 1-yl] -2-eth yl] phenoxy] acetate and ethereal hydrochloric acid .

Melting point: 182-188 占 폚 (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 362

R _f value: 0.25 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.1)

To a solution of N-benzyl-N- [4-trans- [4- (4- (tert-butyloxycarbonyl) -piperidinyl) -piperazin- 1 -yl] -carbonylaminocyclo Hexyl] glycine with 50% strength trifluoroacetic acid. Oil matter.

R _f value: 0.19 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Prepared from N- [4- [4- (4- (1-tert-butyloxycarbonyl) -piperidinyl) -piperazin-1-yl] carbonylaminophenyl] glycine methyl ester and ethereal hydrochloric acid .

Mass spectrum: M ^< ^{+ &} gt ^; = 375

Prepared from N- [4- [4- (4- (1-tert-butyloxycarbonyl) -piperidinyl) -piperazin-1-yl] -carbonylaminophenyl] sarcosine methyl ester and ethereal hydrochloric acid .

Prepared from N-benzyl-N- [4- [4- (1-tert-butyloxycarbonyl) -piperidinyl) -piperazin-1-yl] carbonylaminophenyl] glycine methyl ester and ethereal hydrochloric acid .

The reaction is carried out in dioxane / ethereal hydrochloric acid (3: 1). The precipitate is suction filtered and dried.

Mass spectrum: M ^< ^{+ &} gt ^; = 448

R _f value: 0.36 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

The reaction is carried out in a mixture of anhydrous methanol / dioxane / ethereal hydrochloric acid (1: 1: 1). After 1.5 hours, the precipitate is suction filtered and dried.

Melting point: 302-306 ° C

Mass spectrum: M ^< ^{+ &} gt ^; = 394

_Rf value: 0.23 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

The crude product is chromatographed on silica gel with methylene chloride / methanol / concentrated ammonia (4: 1: 0.25).

Mass spectrum: M ^< ^{+ &} gt ^; = 382

R _f value: 0.36 (silica gel; methylene chloride / methane / concentrated ammonia = 4: 1: 0.25)

The reaction is carried out in a mixture of anhydrous dioxane / anhydrous ethanol / ethereal hydrochloric acid (1: 1: 2). Filter the precipitate by hobbing and drying.

Melting point: Sintering from 288 ° C

Mass spectrum: M ^< ^{+ &} gt ^; = 395

_Rf value: 0.23 (silica gel: methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Butyl-N - [[trans-4 - [[4- [1- (tert- butyloxycarbonyl) -piperidin-4-yl] -piperazin- Carbonyl] -cyclohexyl] -methyl] -N- (phenylsulfonyl) -aminoacetate and 50% strength trifluoroacetic acid.

The crude product is chromatographed on silica gel with methylene chloride / methanol / concentrated ammonia (2: 1: 0.2).

Melting point: 298 占 폚 (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 507

R _f value; 0.22 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

The reaction is carried out in a mixture of dry methane / dioxane / ethereal hydrochloric acid (1: 1: 1). After 4 h, the precipitate is filtered off with suction and dried.

Melting point: 290-300 DEG C (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 484

R _f value: 0.45 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(46) Synthesis of [4-hydroxy-1- [2- [(4-piperidin-4- yl) -piperazin- 1- yl] -carbonyl] -ethyl] -piperidin- - acetic acid trihydrochloride

1-yl] -carbonyl] -ethyl] -4-hydroxy-piperidine < / RTI > 4-yl] acetate and 50% strength trifluoroacetic acid. The trihydrochloride is prepared with 1N hydrochloric acid.

Dark spectrum: M ^< ^{+ &} gt ^; = 348

R _f value; 0.12 (silica gel; absolute methylene / methanol / concentrated ammonia = 2: 1: 0.25)

[Example 3]

(0.0017 mol) of methyl [4-trans- [3- [4- (4- (1-benzyl) -piperidinyl) -piperazin- 1 -yl] propionyl] amino] cyclohexanecarboxylate 0.0 > 50ml < / RTI > hydrogen pressure as a carbon-on-palladium dihydroxide catalyst. The catalyst is filtered off with suction and the solvent is concentrated to a small volume. The separated catalyst is suction filtered.

Yield: 0.42 g (65% of theory)

Melting point: 173-178 DEG C

Mass spectrum: M ^< ^{+ &} gt ^; = 380

R _f value: 0.18 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

The following compounds were prepared in the same manner as in Example 3.

Yl] carbonyl] -3- (4-piperidinyl) -propionate dihydrochloride was prepared as described for the synthesis of methyl N- [[4- (4- (1- benzyl) -piperidinyl) -piperazin- - < / RTI > by hydrogenation in vacuo (10%).

Melting point: 284-286 DEG C (decomposition)

_Rf value: 0.10 (silica gel; methylene chloride / methanol = 9: 1)

1-yl] acetyl] -4-piperidinyl oxyacetate was hydrogenated with carbon-mis-palladium (10%) to give the title compound .

Amorphous solid

Mass spectrum: M ^< ^{+ &} gt ^; = 382

_Rf value: 0.32 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Piperidine-1-yl] acetyl] -4-piperidinyl acetate was hydrogenated with carbon-mis-palladium (10%) to give methyl N- [[4- Produce.

Melting point: 250-253 DEG C

Mass spectrum: M ^< ^{+ &} gt ^; = 366

R _f value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Prepared by hydrogenating methyl N - [[4- (4- (1-benzyl) -piperidinyl) -piperazin-1-yl] acetyl] piperazinoacetate with carbon-ad-palladium (10%).

Melting point: 130-135 占 폚 (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 367

R _f value: 0.065 (silica gel, methylene chloride / methanol = 9: 1)

1-yl] acetyl] amino] -cyclohexanecarboxylate trihydrochloride is reacted with carbon-ad-palladium ((1-benzyl) -piperidinyl) 10%).

Melting point: 275-277 占 폚 (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 366

1-yl] acetyl] -3- (4-piperidinyl) -propionate trihydrochloride is reacted with carbon- Prepared by hydrogenation with palladium-palladium.

Melting point: 247-249 占 폚 (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 380

1-yl] carbonylamino] phenoxy] acetate was hydrogenated with a carbon-m-palladium dihydroxide to give methyl [4- (4- Produce.

Melting point: 266-269 DEG C

Mass spectrum: M < ^{+ &} gt ^; = 376

Rf value: 0.65 (reverse phase FFP RP18: methanol / 5% sodium chloride solution)

- [(piperidin-4-yl) -carbonyl] glycine ethyl ester and a catalyst such as N, N-dihydroxybenzoic acid, (10%) as a white solid.

Melting point: 295-296 DEG C (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 409

_Rf value: 0.50 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(9) Synthesis of pivaloyloxymethyl [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] phenoxy] acetate Pivaloyloxymethyl [ -Piperazin-l-yl] carbonylamino] phenoxy] acetate with carbon-m-palladium dihydroxide.

(1-ethoxy) - carbonyloxy] - [4- (4- (4- (1-benzyl) -piperidinyl) -piperazin- 1 -yl] carbonylamino] - < / RTI > complex-palladium dihydroxide.

Piperazine-1-yl] carbonylamino] -phenoxy] acetate was reacted with carbon-mis-palladium (III) (10%).

Melting point: 288-290 占 폚 (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 419

_Rf value: 0.08 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

1-yl] carbonyl] -phenyl] - [beta] -alanine ethyl dihydrochloride is reacted with a carbon-to- Prepared by hydrogenation with lalidadium (10%).

Melting point: 286-290 DEG C

Mass Spec Trim: M ^< ^{+ &} gt ^; = 388

(3- (4-methoxyphenyl)) - propionyl] - < / RTI > -4-piperidinyloxyacetate with carbon-on-palladium (10%).

1-yl] carbonylamino] cyclohexyloxy] acetate was reacted with carbon-mis-palladium ((2-fluoro-phenyl) 10%).

Melting point: 139-141 占 폚 (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 424

Yl)] carbonylaminocyclohexyl] glycine trihydrochloride with carbon-chiral-lalidium (10%) as a colorless oil Prepared by hydrogenation.

Amorphous solid

Mass spectrum: (M + H) < ⁺ & gt ^; = 368

_Rf value: 0.095 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

1-yl)] carbonylamino] cyclohexyl] propionate was prepared in a manner similar to that described for the synthesis of example 1, but starting from tert-butyl 3- [4-trans- [[4- Prepared by hydrogenation with carbon-on-palladium (10%).

_Rf value: 0.16 (silica gel; methyl chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(17) The ethyl [4 - [[4- (3-pyrroladinyl) -piperazin-1-yl] -carbonylamino] -phenoxy] acetate solvent is evaporated and the crude product is chromatographed on silica gel.

Mass spectrum: M < ^{+ &} gt ^; = 376

R _f value: 0.30 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(18) A mixture of ethyl 4- [4 - [[4- (piperidin-4-yl) piperazin-1-yl] -carbonyl] -piperidin-

To a solution of ethyl 4- [4 - [[4- (1 -benzyl-piperidin-4-yl) -piperazin- 1 -yl] -carbonyl] -piperidin-

0.65 g of the solution is hydrogenated at room temperature under a hydrogen pressure of 50 psi in the presence of 0.2 g of carbon-on-palladium. The catalyst is filtered off and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with methylene chloride / methanol / concentrated ammonia (4: 1: 0.2).

Yield: 0.3 lg (59% of theory)

Mass spectrum: M ^< ^{+ &} gt ^; = 394

R _f value: 0.40 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(19) Ethyl [4- [2- [[4- (piperidin-4-yl) -piperazin- 1-yl] -carbonyl] -ethyl] -piperidin-

[Prepared in the same manner as in Example 3 (17)

Melting point: Sintered at 240 ° C

Mass spectrum: M ^< ^{+ &} gt ^; = 394

R ^f value: 0.39 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(20) Methyl 3 - [[4 - [[4- (Pyrrolidin-4-yl) -piperazin] -yl] carbonyl] -piperidin- l-yl] -carbonyl] propionate Hydrochloride Chloride

1 molar equivalent of 1 M hydrochloric acid in methanol is hydrogenated. The residue is polished with a small amount of ethyl acetate / methane and suction filtered.

Melting point: Sintering from 275 ° C

Mass spectrum: M ^< ^{+ &} gt ^; = 394

_Rf value: 0.41 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(21) Methyl [4- [[4- (piperidin-4-yl) -piperazin-3-one-1-yl] -carbonylamino] -phenoxy] acetate

(22) Ethyl [4 - [[2-methyl-4- (piperidin-4-yl) -piperazin-3-one- 1 -yl] -carbonylamino] -phenoxy]

(23) Ethyl [4 - [[2-methyl-4- (piperidin-4-yl) -piperazin- 1- yl] -carbonylamino] -phenoxy] acetate

(24) Methyl [4 - [[2- [[4-methoxy-phenyl] -methyl] -4- (piperidin- 4- yl) -piperazin- Amino] -phenoxy] < / RTI > acetate

(25) Methyl [4 - [[4- (piperidin-4-yl) -tetrahydroquinoxalin-l-yl] -carbonylamino] -phenoxy] acetate

(26) Methyl 4 - [[4- (piperidin-4-yl) -piperazine-2,5-dione- l-yl] -methylcarbonyl] -phenoxy]

Prepared in the same manner as in Example 3 (18).

Mass spectrum: M ^< ^{+ &} gt ^; = 434

R _f value: 0.45 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

Prepared in the same manner as in Example 3 (18).

Mass spectrum: M ^< ^{+ &} gt ^; = 438

_Rf value: 0.27 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

[Example 4]

A weak hydrochloric acid gas stream was bubbled through a solution of 3- [4-trans-1- [4- (4-piperidinyl) -piperazin- 1 -yl] carbonylamino] cyclohexyl] propionic acid dihydrochloride Is passed through a 300 mg (0.7 mmol) suspension. A clear solution is formed after about 5 minutes. The solution is allowed to stand at room temperature overnight and then heated to reflux temperature for 2 hours.

After cooling, the mixture is triturated with ether and suction filtered.

Yield: 240 mg (67.4% of theory)

Melting point: 324-326 DEG C

Mass spectrum: M ^< ^{+ &} gt ^; = 448

R _f value: 0.55 (silica gel, methylene chloride / ethanol / concentrated ammonia = 2: 1: 0.25)

The following compounds can be prepared analogously to Example 4:

Prepared from 3- [4-trans - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] cyclohexyl] propionic acid dihydrochloride and isobutanol.

Melting point:> 315 ° C

Mass spectrum: M ^< ^{+ &} gt ^; = 422

R _f value: 0.47 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Prepared from 3- [4- [4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] piperidinopropionic acid dihydrochloride and isobutanol.

Prepared from 3- [4- [4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] piperidinopropionic acid dihydrochloride and cyclohexanol.

Prepared from 4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] piperidino acetic acid dihydrochloride and isobutanol.

Prepared from 4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] piperidino acetic acid dihydrochloride and cyclohexanol.

Prepared from 4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy] acetic acid dihydrochloride and isopropane.

Melting point: 296-298 占 폚 (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 405

R _f value: 0.38 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

-Piperazin-1-yl] carbonylamino] -phenoxy] acetic acid dihydrochloride and isobutanol.

Melting point: 308-310 DEG C (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 419

_Rf value: 0.50 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Prepared from [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy] acetic acid dihydrochloride and neopentyl alcohol.

Melting point: 250-252 占 폚 (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 433

R _f value: 0.45 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Prepared from [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy] acetic acid dihydrochloride and cyclopentanol.

Melting point: 298-300 DEG C (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 431

R _f value: 0.65 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

Prepared from [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy] acetic acid dihydrochloride and cycloheptanol.

Dendritic material

Mass spectrum: (M + H) < ⁺ & gt ^; = 459

R _f value: 0.65 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

Prepared from [4- [14- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy] acetic acid dihydrochloride and 1-butanol.

Melting point: 300-301 占 폚 (decomposition)

Mass spectrum (M + H) < ⁺ & gt ^; = 419

_Rf value: 0.50 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Prepared from [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy] acetic acid dihydrochloride and cyclohexanol.

Melting point: 291-293 占 폚 (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 445

_Rf value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

[4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy] acetic acid dihydrochloride and ethanol.

Melting point: 288-290 占 폚 (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 391

_Rf value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Prepared from [4-trans- [4- (4-piperidinyl) -piperazin-l-yl] carbonylaminocyclohexyloxy] acetic acid dihydrochloride and methanol.

(3- (4-methoxyphenyl)) propionyl] -4-piperidinyloxyacetic acid < / RTI & Prepared from chloride and ethanol.

Melting point:

Mass spectrum: (M + H) < ⁺ & gt ^; = 517

_Rf value: 0.15 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Prepared from [4-trans- [4- (4-piperidinyl) -piperazin-l-yl] carbonylamino-cyclohexyloxy] acetic acid dihydrochloride and ethanol.

Prepared from [4-trans- [4- (4-piperidinyl) -piperazin-l-yl] carbonylaminocyclohexyloxy] acetic acid dihydrochloride and isopropanol.

Prepared from [4-trans- [4- (4-piperidinyl) -piperazin-l-yl] carbonylamino-cyclohexyloxy] acetic acid dihydrochloride and isobutanol.

Melting point: 316-320 占 폚 (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 425

R _f value: 0.40 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Prepared from [4-trans- [4- (4-piperidinyl) -furan-l-yl] carbonylaminocyclohexyloxy] acetic acid dihydrochloride and cyclohexanol.

Melting point: 311-314 占 폚 (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 451

R _f value: 0.40 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Prepared from [4-trans- [4- (4-piperidinyl) -piperazin-l-yl] carbonylaminocyclohexyloxy] acetic acid dihydrochloride and cyclopentanol.

Melting point: 309-311 DEG C (decomposition)

Mass spectrum: (M + H) < ⁺ & gt ^; = 437

R _f value: 0.40 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

1-yl] carbonylamino-cyclohexyloxy] acetic acid dihydrochloride and 1-butanol in a similar manner to that described in Example < RTI ID = 0.0 &

[Example 5]

(0.0068 mol) of N-tert-butyloxycarbonyl-N- [4- [1- (4-nitrophenyloxycarbonyl) -piperidinyl]] - (0.0068 mol) and N-ethyl-diisopropylamine (2.3 ml, 0.0136 mol) was heated at 140 < 0 > C for 4 hours do. After cooling, the mixture is partitioned between ethyl acetate and water, and the organic layer is washed with sodium bicarbonate solution, dried and concentrated. The residue is purified on a silica gel column (eluent: methylene chloride containing 2.5%, 3% and 4% methanol).

Yield: 1.3 g (colorless vapor phase material, 33.6% of theory)

Mass spectrum: M ^< ^{+ &} gt ^; = 581

R _f value: 0.48 (silica gel; methylene chloride / methane = 9: 1)

The following compounds were prepared in the same manner as in Example 5.

Alanine methyl ester (prepared as in Example III) and N- [4- (1 (4-nitrophenyloxycarbonyl) -piperidinyl] -3-tert-butyloxycarbonyl) -piperidyl] -piperazine.

Yield: 500 mg (9.1% of theory)

Rf value: 0.52 (silica gel: methylene chloride / methanol = 9: 1)

(Prepared as described in Example III) and N- [4- (1 (4-nitrophenyloxycarbonyl) -piperidinyl] -3-tert-butyloxycarbonyl) -piperidinyl] -piperazine.

(Prepared as described in Example III) and N- [4 - [(4-nitrophenyloxycarbonyl) -piperidinyl]] glycine methyl ester - (l-tert-butyloxycarbonyl) -piperidinyl] -piperazine and N-ethyl-diisopropylamine.

(Prepared as described in Example III) and N- [4- (1-3 < RTI ID = 0.0 > Tert-butyloxycarbonyl) -piperidinyl] -piperazine and N-ethyl-diisopropylamine.

N- [4- (1- (4-nitrophenyloxycarbonyl) -piperidinyl]] - glycine methyl ester (prepared as in Example III), N- [4- Tert-butyloxycarbonyl) -piperidinyl] -piperazine and N-ethyl-diisoproylamine

Prepared from methyl N- (4-nitrophenyloxycarbonyl) -4- (4-piperidinyl) -butyrate and N- [4- (l-tert-butyloxycarbonyl) -piperidinyl] piperazine .

R _f value: 0.48 (silica gel; methylene chloride / methanol = 9: 1)

(Prepared as in Example III) and N- [4- (l-tert-butoxycarbonylamino) -3- Butyl < / RTI > oxycarbonyl) -piperidinyl] piperazine.

Oil matter

R _f value: 0.60 (silica gel; methylene chloride / methanol = 9: 1)

(Prepared as in Example III) and N - [- (1- (4-nitrophenyloxycarbonyl) Tert-butyloxycarbonyl) -piperidinyl] -piperazine. ≪ / RTI >

Amorphous material

R _f value: 0.39 (silica gel; methylene chloride / methanol = 9: 1)

4-Methyloxycarbonylmethyloxy-aniline was reacted with p-nitrophenyl chloroformate in the presence of triethylamine in methyl 4- (4-nitrophenyloxycarbonylamino) -phenoxyacetate, and then the intermediate product (4- (1-benzyl-piperidinyl)] piperazine in the presence of triethylamine.

The following compound can be prepared in the same manner as in Example 19.

-Piperazin-1-yl] carbonylamino] -purinoxy] acetic acid with 1-chloroethyl ethyl carbonate.

[Example 20]

(4 mmol) of N, N-dimethylformamide di-tert-butyl acetal were added to a solution of 3- [4-trans- [[4- (4- -Piperazin-l-yl] -carbonylamino] cyclohexyl] propionic acid and the mixture was further stirred at 80 ° C for 1 hour. 0.8 ml of N, N-dimethylformamide di-tert-butyl acetal are further added and the mixture is further heated at 80 DEG C for 1 hour. The residue was concentrated under reduced pressure. The residue was purified by silica gel chromatography using methylene chloride / methanol / concentrated ammonia = 95: 5: 0.5 as an eluent.

Yield 0.5 g (49.5% of theory)

R _f value: 0.50 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

[Example 21]

1-yl] carbonylamino] phenoxy] acetate To a solution of 1- (4- (1-benzyl) -piperidin-4- (0.172 mol) of piperazine xH2Cl are dissolved in 500 ml of a saturated sodium carbonate solution and methylene chloride is extracted five times with 200 ml each time. The combined organic layers are dried over sodium sulfate and concentrated. The residue is dissolved in 200 ml of dioxane and the solution is added dropwise to a solution of 44 g (0.155 mol) of benzyl 2- (4-isocyanate-phenoxy) -acetate in 100 ml of dioxane at room temperature with vigorous stirring. After completion of the addition, the reaction solution is further stirred at 60 DEG C (oil bath temperature) for 3 hours and at room temperature overnight. The solvent is evaporated under vacuum and the residue is stirred with ether. The undissolved material is filtered by suction and dried.

Yield: 72.0 g (85.4% of theory)

Mass spectrum: M ^< ^{+ &} gt ^; = 542

The following compounds may be prepared analogously to example 21:

Substituting the corresponding ethyl ester for benzyl 2- (4-isocyanato-phenoxy) -acetate. The crude product is chromatographed on silica gel.

Mass spectrum: (M + H) < ⁺ & gt ^; = 467

Rf value: 0.48 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

[Example 22]

Methanol was added to a solution of ethyl [4 - [[4- (1-benzyl-3-pyrrolidinyl) -piperazin- 1-yl] -carbonylamino] -phenoxy] -acetate and 1M sodium hydroxide solution in 10 ml of tetrahydrofuran Add 2.5 ml of emulsion by an amount that makes the solution clear. After the solution was stirred at room temperature for 2 hours, 2.5 ml of 1M hydrochloric acid was added and the solvent was evaporated under reduced pressure. The residue is polished with a mixture of absolute ethanol / methylene chloride and filtered. The filtrate is evaporated to dry the residue.

Yield: 280 mg (99% of theory)

Mass spectrum: (M + H) < ⁺ & gt ^; = 439

_Rf value: 0.18 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

The following compounds may be prepared analogously to example 22:

(1) [4- [[4- (3-Pyrrolidinyl) -piperazin-1-yl] -carbonylamino] -phenoxy] -acetic acid residue is polished with a mixture of methanol / methylene chloride.

Mass spectrum: (M + H) < ⁺ & gt ^; = 349

Rf value: 0.11 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(2) Synthesis of [4 - [[4- (1-methyl-3-pyrrolidinyl-piperazin- 1 -yl] -carbonylamino] -phenoxy-

The residue is ground with a mixture of anhydrous methanol / methylene chloride.

Mass spectrum: (M + H) < ⁺ & gt ^; = 363

R _f value: 0.30 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

The reaction solution is acidified with 1M hydrochloric acid, and the solvent is subjected to repeated extraction under reduced pressure. The residue is chromatographed on silica gel with methylene chloride / methanol / concentrated ammonia (4: 1: 0.25).

Mass spectrum: M ^< ^{+ &} gt ^; = 456

R _f value: 0.30 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

Mass spectrum (M + H) < ⁺ & gt ^; = 381

Rf value: 0.31 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

The reaction solution is extracted with ether and the aqueous layer is evaporated. The residue was polished with anhydrous ethanol / methylene chloride, the suspension was filtered, and the residue was subjected to rotary evaporation. The residue is polished with ether and filtered by suction.

Mass spectrum: M ^< ^{+ &} gt ^; = 442

R _f value: 0.30 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

The reaction solution is extracted with ether and the aqueous layer is evaporated. The residue is polished with absolute ethanol / methylene chloride, the suspension is filtered and the filtrate is evaporated on a rotary evaporator. The residue is polished with ether and filtered by suction.

Mass spectrum: (M + H) < ⁺ & gt ^; = 353

Rf value: 0.12 (silica gel; methylene chloride / methanol / diluted ammonia = 2: 1: 0.25)

The reaction solution is poured into water, extracted with ether, and the aqueous layer is extracted. The residue is polished with anhydrous ethanol / methylene chloride and suction filtered.

Mass spectrum: M ^< ^{+ &} gt ^; = 366

R _f value 0.12 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(8) [4 - [[[4- (piperidin-4-yl) -piperazin-l-yl] -carbonyl] -methyloxy] -piperidin- l-yl] -acetic acid

Mass spectrum: M ^< ^{+ &} gt ^; = 369

R _f value: 0.12 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

[Example 23]

Ethyl [4- [[4- (1-methyl-3-pyrrolidinyl) -piperazin- 1-yl] -carbonylamino] -phenoxy] -acetate

320 mg of 37% strength formalin and 270 mg of sodium cyanoborohydride were added to a solution of ethyl [4 - [[4- (3-pyrrolidinyl) -piperazin- 1 -yl] carbonylamino] -phenoxy] Acetate < / RTI > The mixture is acidified with ethereal hydrochloric acid and stirred at room temperature for 1 hour. The solvent was evaporated and the residue was chromatographed on silica gel with methylene chloride / methanol / concentrated ammonia (9: 1: 0.1).

Yield: 250 mg (34% of theory)

Mass spectrum: M ^< ^{+ &} gt ^; = 390

_Rf value: 0.54 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

The following compounds are obtained analogously to example 23:

Mass &^lt; ^{RTI ID} = 0.0 &^gt;

_Rf value: 0.26 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

[Example 24]

To a solution of ethyl 3 - [[4 - [[4- (1-benzyl-piperidin-4-yl) -piperazin- 1- yl] -carbonyl] -piperidine -1-yl] -carbonyl] -propionate and 42 mg of lithium hydroxide hydrate are stirred at room temperature for 4 hours. The reaction mixture was neutralized with 1N hydrochloric acid and the solvent was distilled off under reduced pressure. The residue is chromatographed on silica gel with methylene chloride / methanol / concentrated ammonia (4: 1: 0.2).

Yield: 70 mg (52% of theory)

Mass spectrum: (M + H) < ⁺ & gt ^; = 471

_Rf value: 0.23 (silica gel; methylene chloride / methanol / concentrated ammonia 14: 1: 0.25)

The following compounds are obtained analogously to Example 24:

The reaction solution is acidified with 1M hydrochloric acid and evaporated under reduced pressure. The residue is polished several times with acetone and dried.

Mass spectrum: (M + H) < ⁺ & gt ^; = 367

_Rf value: 0.06 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

The reaction solution is acidified with 1M hydrochloric acid and subjected to repeated blowing under reduced pressure. The residue is polished several times with acetone and dried.

Mass spectrum: (M + H) < ⁺ & gt ^; = 367

_Rf value: 0.46 (silica gel, methylene chloride / methanol / concentrated ammonia = 1: 3: 0.2)

(3) [trans-4 - [[4- (piperidin-4-yl) -piperazin- 1-yl] -carbonyl] -cyclohexylcarbonylamino]

Melting point: 260-270 占 폚 (sintering)

Mass spectrum: M ^< ^{+ &} gt ^; = 380

_Rf value: 0.08 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

Mass spectrum: (M + H) < ⁺ & gt ^; = 381

R _f value: 0.05 (silica gel; methylene chloride / methanol / concentrated ammonia = 3: 1: 0.2)

Melting point: 239-244 DEG C (decomposition)

Mass spectrum: M ^< ^{+ &} gt ^; = 367

_Rf value: 0.33 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

[Example 25]

A dry ampule containing 2.5 mg of active compound per ml

Composition water:

2.5 mg

Mannose 50.0 mg

Distilled water for injection 1.0ml

Produce:

Liquor and mannitol are dissolved in water. After the ampoules are filled, the solution is lyophilized. Dissolve in main use water to make a ready-to-use solution.

[Example 26]

A dry ampule containing 35 mg of drug per 2 ml

Composition:

Liquor 35.0 mg

Mannitol 100.0 mg

Feeding water for main use 2.0ml

Produce:

Liquor and mannitol are dissolved in water. After the ampoules are filled, the solution is lyophilized. Dissolve in main use water to make a ready-to-use solution.

[Example 27]

Tablets containing 50 mg of drug

Composition water:

(1) Tablets 50.0 mg

(2) Lactose 98.0 mg

(3) corn starch 50.0 mg

(4) Polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mg

215.0 mg

Produce:

(1), (2) and (3) are mixed and the mixture is granulated together with the aqueous solution of (4). (5) is added to the dry granules and mixed. It is manufactured by extruding this mixture with two sides facing each other and dividing grooves on one side.

Tablet diameter: 9mm

[Example 28]

Tablets containing 350 mg liquor

Composition:

(1) Liquor 350.0 mg

(2) Lactose 136.0 mg

(3) corn starch 80.0 mg

(4) Polyvinylpyrrolidone 30.0 mg

(5) Magnesium stearate 4.0 mg

600.0 mg

Preparation:

(1), (2) and (3) are mixed and the mixture is granulated together with the aqueous solution of (4). (5) is added to the dry granules and mixed. A two-layer tablet with a side-to-side and split-on-one flaws is prepared by squeezing this mixture.

Tablet diameter: 12mm

[Example 29]

Capsules containing 50 mg of drug

Composition:

(1) Tablets 50.0 mg

(2) dried corn starch 58.0 mg

(3) Powdered lactose 50.0 mg

(4) Magnesium stearate 2.0 mg

160.0 mg

pharmacy:

(1) is polished to (3). The polished mixture is added to the mixture of (2) and (4) with vigorous mixing.

The powder mixture is filled into a size 3 hard gelatin capsule with a capsule filling machine.

[Example 30]

Capsules containing 350 mg of drug

Composition:

(1) Liquor 350.0 mg

(2) dried oyster starch 46.0 mg

(3) Powdered lactose 30.0 mg

(4) Magnesium stearate 4.0 mg

430.0 mg

Preparation:

(1) is polished to (3). The polished mixture is added to the mixture of (2) and (4) with vigorous mixing.

The powder mixture is filled into a size 3 hard gelatin capsule with a capsule filling machine.

Claims (12)

A gemepelazine derivative of formula (I), a tautomer thereof, a stereoisomer thereof including a conjugate, and a salt thereof. (I) In the above formulas, Ra represents 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexamethyleniminimyl or 4-hexamethyleniminimyl, with the proviso that the hydrogen atom of the alkylenimino ring is , in each case, C _l-5 - alkyl or _aryl-l -C ₃ - alkyl geureup (wherein the alkyl moiety, each occurrence, a carboxyl C _l-3 - alkoxycarbonyl, aminocarbonyl, NC _l-3 - alkyl-aminocarbonyl, N, N- di - (C _l-3 -alkyl) aminocarbonyl, or can be substituted with vinyl or ethynyl Gruul, the mentioned substituents located at the α- carbon atom adjacent to the nitrogen factor (C ₁ -C ₃ -alkyl) amino group, which may be substituted by hydroxyl, C _1-3 -alkoxy, amino, C _1-3 -alkylamino or di- (C _1-3 -alkyl) amino groups, may be substituted with a radical which can be split in] a, R _b and R _c are the same or different, hydrogen winja, C _l-5 - alkyl, aryl or _aryl-l -C ₅ - alkyl group, these four With an ethylene bridge of an o-phenylgene group (with the proviso that 1 or 7 methylene groups in the 1,4-piperazinylene group of the formula I can in each case be further substituted by a carbonyl group) and, Yl is -Al-, -CO-, -CO-CO-, -Al-CO-, -CO-Al-, -SO 2 -A 2 -, -A 2 -SO 2 -, -CO-Al -CO-, -CO-NR ₁ -CO-, -CO-NR ₁ -A ₂ -, -CO-NR ₁ -A ₂ -CO-, -CO-A ₂ -NR _{1 1} -CO-, a ₂ -0- or -CO-a ₂ -NR ₁ - geureup (where, R _l is hydrogen, C _l-5 - alkyl, aryl or _aryl-l -C ₃ - alkyl group, a is an optionally C _{l l-5} - alkyl, _cyclohexyl-l -C ₃ - alkyl, aryl or -C _l-3 - or substituted with an alkyl group, a _l is the case not in the α- position to the nitrogen atom, R ₁ O group _l in a _{RC-5-substituted-alkylene} group, A2 is an optionally C _l-5-alkyl, aryl or -C _l-3-a RC _l-4 alkyl substituted with geureup - and the alkylene him), Y ₂ is a phenylene, cyclohexylene geureup, pyridinium alkenylene geureup, 3-piperidinyl Piperylene or 1,4-piperazinylene group, provided that the methylene group adjacent to the nitrogen atom may in each case be substituted with a carbonyl group and may be substituted by N, O-acetal or 0,0 - acetal and the N, O bond or the N, N bond is not formed by a bond with Y _l or Y ₃ , the 4-piperidinylene group may be further substituted with R ₁ O at the 4-position), 1 , 4-cake toffee piperazinyl alkylene him [stage, C _l-5 in the α- position to the carbonyl hair geureup -alkyl geureup (where alkyl geureup is optionally substituted with R _I groups O-phenyl group, C _l-3- Alkoxycarbonyl or C _1-13 -alkoxycarboxyl group], or -NR ₁ -B- or -O-B- group (provided that Y 1 group is -NR _I - group And B is a group selected from the group consisting of phenylene, cyanohexylene, piperidinylene or piperidinylene with the proviso that the piperidinylene group and -NR ₁ - Is a bond or torn piperidinyl alkenylene engagement with him and an oxygen atom of the radical may be a result from the 3-position or 4-position, a methylene group adjacent to the nitrogen atom is that it can be further substituted with a carbonyl group)], Y ₃ -CO-, -A ₂ -CO-, -CH ₂ -CH (NHR ₂ ) -CO-, -NR ₂ -A ₃ -CO-, -CH ₂ -NR ₂ -A ₃ -CO-, -O -A ₃ -CO-, -CO-A ₃ -O- or -CO-NR ₁ -A ₃ -CO- group in which R ₁ and A ₂ are as defined above and A ₃ is optionally C _{1 5} - alkyl, aryl, pyridyl or _aryl-l -C ₃ - alkylene group, R ₂ is hydrogen, C _l-5--alkyl geureup the HC _{l-3-substituted} by alkyl, aryl, -C _{l- 3-alkyl,} aryl, C _{l-5-alkoxy-carbonyl,} C _{l-15-alkyl-sulfonyl, aryl-l} -C ₁₃ -alkyl sulfonyl, aryl, -C _{l-3-arylsulfonyl} him or optionally C _{l 4} - alkyl, aryl or _aryl-l -C ₃ - alkyl and the Gruul substituted formyl group, -A ₂ -CO- group, and Y _f radical is bonded via the radical and a _2, -NR ₂ -A ₃ - CO- group and radical Y ₂ Group is bonded through an NR ₂ group, a -O-A ₃ -CO- group and a radical Y ₂ are bonded via an oxygen atom, and -NR ₂ -A ₃ -CO-, -CH ₂ -NR ₂ -A ₃ - CO- and -O-A ₃ -CO- group can not combine with the nitrogen atom of radopope Y ₂ ), E represents a hydrosilyl group, an alkyloxy group having 1 to 6 carbon atoms, a cyano group, And the number of carbon atoms in the moiety is from 1 to 3), a cycloalkyl group having from 3 to 9 carbon atoms (provided that the cycloalkyl moiety having 5 to 8 carbon atoms is in each case 1 or 2 alkyl groups having 1 to 3 carbon atoms A cycloalkoxy group having 5 to 8 carbon atoms, with the proviso that the methylene group at the 3-position or the 4-position of the alkyl moiety is substituted with an oxygen atom or is optionally substituted with an alkyl, an arylalkyl or a fused alkoxycarbonyl group With the proviso that the alkyl moiety and the alkoxy moiety in each case may have from 1 to 3 carbon atoms, With an imino group substituted with an alkanoyl group of 1 to 6 carbon atoms, and the cycloalkyl moiety may be further substituted with 1 or 2 alkyl groups of 1 to 3 carbon atoms in each case), cycloalkenyloxy groups ( (Wherein the haloalkenyl moiety has 4 to 7 carbon atoms), alkenyloxy, phenylalkenyloxy, alkynyloxy or phenylalkynyloxy, provided that the oxygen atom is a double bond or a carbon atom having a triangle or And the alkenyl moiety and the alkynyl moiety in each case have 3 to 5 carbon atoms), cycloalkylalkoxy, wherein the cycloalkyl moiety has 3 to 8 carbon atoms and the alkoxy moiety has 1 to 3 carbon atoms , A bicycloalkoxy group having a total of 8 to 10 carbon atoms (provided that the bicycloalkyl moiety in each case may be further substituted with 1 or 2 alkyl groups having 1 to 3 carbon atoms), 1,3-dihydro -3-ox Isobenzofuranyloxy or R ₅ -CO-O- (R ₃ CR ₄ ) -O- wherein R ₃ is a hydrogen atom, C _1-6 -alkyl, C _3-7 -cyclo Alkyl or phenyl group, R ₄ is a hydrogen atom or a C _1-6 -alkyl group and R ₅ is C _1-5 -alkyl, C _1-5 -alkoxy, C _5-7 -cycloalkyl or C _5-7 -Cyclooxy group), or an α-amino glycine of a natural amino acid or an ester thereof (wherein the "aryl group", "phenyl group" and "phenylene group" mentioned in the radical definition above are, in each case, Especially fluorine, chlorine, bromine or iodine atoms, optionally monosubstituted, disubstituted or trisubstituted, or substituted by one or more substituents selected from the group consisting of alkyl, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, hydroxyl, aryloxy, Alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, Disubstituted or disubstituted phenyl group or phenylene group (provided that the substituents are the same or different and the alkyl and aryloxy moieties mentioned above, in each case, have 1 to 3 carbon atoms) C _1-7 -alkyl such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, allyl, phenyl or benzyl ester, C _2-7 -alkenyl, C _5-7 Phenyl-Ci _-3 -alkyl ester, wherein the radical which can be cleaved in vivo is an alkanoyl group having from 1 to 6 carbon atoms in total, or a formyl, acetyl, propionyl, butanoyl , Pentanoyl, hexanoyl, benzoyl, allyloxycarbonyl, carboxycarbonyl, eroxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, amoxycarbonyl, tertiary-cyclohexanecarbonyl, phenoxy Carbonyl, hexoxycarbonyl, benzyloxycarbonyl, furanyloxycarbonyl, or phenyl Benzyl, allyloxycarbonal, CI _-5 -alkoxycarbonyl or phenyl-CI _-13 -alkoxycarbonyl group such as N-propoxycarbonyl group. The compound according to claim 1, wherein Ra is 3-pyridinyl, 3-piperidinyl, 4-piperidinyl, 3-hexamethyleneiminyl or 4-hexamethyleneiminyl group The atom is. In each case, C _l-5 - alkyl or _phenyl-l -C ₃ - alkyl Gruul (provided that the alkyl moiety, in each case, carboxyl, C _l-13 - alrok when carbonyl, aminocarbonyl, NC _{l- 3} -alkyl-aminocarbonyl or N, N-di- ( _C1-3- alkyl) -aminocarbonyl group, or the substituent mentioned is not located at the a-carbon atom adjacent to the nitrogen atom , hydroxy reuksil, C _l-13 - alrok City, amino, C _l-3 - alkylaminocarbonyl or di - (C _l-3 - alkyl), or amino can be substituted with may be substituted him), C _l-4 -Alkoxycarbonyl or benzyloxycarbonyl group, R _b and R _c are the same or different and represent a hydrogen atom, a C _1-3 -alkyl or a phenyl -C _l-3 - alkyl group or, together with the ethylene bridge between these o- phenylene him (provided that 1,4-piperazinyl alkylene one or two methylene groups of formula (I) in him, each Cases, to form a may be further substituted with a carbonyl group), Y ₁ is -Al-, -CO -, - CO- CO-, -A l -CO-, -CO-A l -, - CO-Al-CO-, -CO- NR 1 -A 2 -, -CO-A 2 -0- or -CO-A ₂ -NR _I - group (where, R _l is a hydrogen atom, C _1-5 - Alkyl or phenyl-C _1-13 -alkyl group, and Al is optionally substituted with C _1-5 -alkyl or phenyl-C _1-3 -alkyl, or where Al is not in the [alpha] -position with respect to the nitrogen atom , R _I O the ₅ nC _{l-substituted} with geureup-alkylene group, - a (where, phenyl geureup is hydroxyl, C _l-13 may be substituted with alrok state or benzyloxy group), A2 is an optionally C _{l- 5-alkyl} or _phenyl-l -C ₃ - the RC _l-4 alkyl substituted with geureup-alkylene is him), Y ₂ is a phenylene, cyclohexylene, or is a pyridinyl alkenylene geureup, 4-piperidinyl alkenylene [ Provided that if N, O-acetal or O, O-acetal and N, O bond or N, N bond is not formed by bonding with Y _l or Y ₃ , then 4-piperidinylene Groups can be further substituted with R _I O group in the 4-position or can be substituted with -NR ₁ -B- group (where, Y is the group _l -NR ₁ - is bonded and the nitrogen atom of the group), or 1 , A 4-piperazinylene group, with the proviso that the methylene group adjacent to the nitrogen atom may in each case be substituted by a carbonyl group and B represents a phenylene, cyclohexylene, piperidinylene or pyridinylene group ( With the proviso that the piperidinylene group and the radical -NR < ₁ > may in each case be bonded through the 4-position and the methylene group adjacent to the nitrogen atom may be further substituted with a carbonyl group) ₃ is _{-CO-, -A 2 -CO-, -CH 2} -CH (NHR 2) -CO-, -NR 2 -A 3 -CO -, - CH 2 -NR 2 -A 3 -C0-, - A ₃ -CO-, -CO-A ₃ -CO- or -CO-NR ₁ -A ₃ -CO- group, wherein A ₃ is optionally C _{1 -5} -alkyl, phenyl, C _l-3 - alkylene geureup, R ₂ is hydrogen, C _l-5 - - nC a _l-3 alkyl group substituted with an alkyl, pyenil -C _l-3 - alkyl, C _l-5 - alkoxycarbonyl, C _l-5 - alkylsulfonyl, _phenyl-l -C ₃ - alkylsulfonyl, phenyl, -C _l-13 - phenylsulfonyl geureup or an optionally C _l-4 - alkyl, phenyl or pyenil -C _l-3 - is a formyl group substituted with alkyl geureup, -A ₂ -CO- geureup the radical Y ₂ is bonded through a radical a _2, and -NR ₂ -A ₃ -CO- group and the radical Y ₂ is bonded through an NR ₂ group, a -O-A ₃ -CO- group and a radical Y ₂ are bonded through an oxygen atom, but -NR ₂ -A ₃ -CO-, -CH ₂ -NR ₂ -A ₃ -CO- and -OA ₃ -CO- group can not combine with the nitrogen atom of the radical Y ₂ and E is hydroxyl, C _1-6 -alkoxy, cyano _- C _1-3 -alkoxy, C ₅ -alkoxy, _-7 -cycloalkoxy group or R ₅ -CO-O- (R ₃ CR ₄ ) -O- group wherein R ₃ is a hydrogen atom, C _1-6 -alkyl, C _3-7- and pyenil him, R ₄ is a hydrogen atom or a C _l-6 - geureup alkyl, R ₅ is C _l-7 - alkyl, C _l-5 - alkoxy, C _7-7 - cycloalkyl or C _5-7 - between Alkoxy Comes to a), or α- amino group, C _l-6 of natural amino acids - stereoisomer thereof and a salt thereof comprising piperazine derivatives, their tautomers, mixed land of formula I is an alkyl or benzyl ester thereof). According to claim 1, Ra is 4-piperidinyl or piperidinyl torn geureup (where this alkylene ring unexposed hydrogen atom with a 3-blood is, in each case, C _l-5 - alkyl, -C _l-3 pyenil -Alkyl group, or may be substituted in vivo by a fissionable radical such as a C _1-4 -alkoxycarbonyl or a benzylic acycarbonyl group, and R b and R c are the same or different a hydrogen atom, C _l-3 - alkyl or pyenil -C _l-3 - alkyl group or, together with the ethylene bridge in between the O-phenylene Gruul (where, in the alkylene geureup possess La 1,4 exhaustion of formula (I) One or two methylene groups may in each case be further substituted by a carbonyl group), Y ₁ -A ₁ -, -CO-, -CO-CO-, -A ₁ -CO- , -CO-A ₁ -, -CO-CH ₂ -CO-, -CO-NR ₂ -A ₂ -, -CO-A ₂ -O- or -CO-A _a -NR _I - group _l is a hydrogen atom, C _l-5 - alkyl geureup, a _l is an optionally C _l-5 - - alkyl or _phenyl-l -C ₂ alkyl or pyenil -C _{l-2-substituted} with alkyl geureup, in addition to A _l is not the case apneun daehem α- position to the nitrogen atom, R ₁ O substituted nC _l-5 Groom-alkylene geureup (where pyenil geureup is hydroxy ₃ -alkylene group) and Y ₂ is 1,4-cyclohexylene, 1,4-phenylene, 4-phenylene, 4-phenylene, The methylene group adjacent to the nitrogen atom may in each case be replaced by a carbonyl group and the 4-pyrrolidinylene group may be N, O-acetal or O, O-acetal and N, O bond or If the N, N bond is not formed by a bond with Y ₁ or Y ₃ , then it is substituted at the 4-position with an R ₁ O group or with a -NR ₁ -B- group (provided that Y ₁ is -NR ₁ - Or a 1,4-piperazinylene group, wherein B is a group selected from the group consisting of 1,3-phenylene, 1,4-phenylene, 1,4-cyprohexylene or 4-piperidylene Group (however, -NR _l - is, in each case, the defect through the 4-position) is] a, Y ₃ is _{-CO-, -A 2 -CO-, -NR 2} -A 3 -CO-, -CH 2 -NR _2- A ₃ -CO-, -OA ₃ -CO-, -CO-A ₃ -CO- or -CO-NR ₁ -A ₃ -CO- group wherein A ₃ is optionally C _1- phenyl, pyridyl or _phenyl-l -C ₂ - alkyl substituted by geureup HC _l-3 - alkylene Gruul, R ₂ is hydrogen, C _l-3 - alkyl, _phenyl-l -C ₃ - alkyl, C _l-5 - alkoxycarbonyl, C _l-3 - alkanoyl, C _l-5 - alkylsulfonyl, or C _l-5 - phenyl and sulfonyl group, -A ₂ -CO- radical and Y ₂ is a radical A him ₂ , the radical -N ₂ -A ₃ -CO- group and the radical Y ₂ are bonded through the NR ₂ group and the radical -OA ₃ -CO- group and the radical Y ₂ are bonded through an oxygen atom, ₂ -A ₃ -CO-, -CH ₂ -NR ₂ -A ₃ -CO- and -OA ₃ -CO- group can not combine with the nitrogen atom of the radical Y ₂ , and E is hydroxyl, C _{1 -5} -alkoxy, phenyl-Ci _-3 -alkyl, C _5-7 -cycloalkoxy or R ₅ -CO-O- (R ₃ CR ₄ ) -O - group (provided that R ₃ is a hydrogen atom, C _1-3 -alkyl or C _5-17 -cycloalkyl group, R ₄ is a hydrogen atom and R ₅ is C _1-5 -alkyl or C _1-3- Alkoxy group), or a piperazine derivative of formula (I), a tautomeric mixture thereof, and a salt thereof, wherein the compound is an a-amino group of a natural amino acid, Cl-6-alkyl or benzyl ester thereof. A compound according to claim 1, wherein Ra is 3-pyrrolidinyl or 4-piperidinyl grl, with the proviso that the hydrogen atoms of the alkylenimino ring are in each case Ci _-3 -alkyl, benzyl or tert- R _b and R _c are each in each case a hydrogen atom and Y ₁ is optionally hydroxyl, -CO-, -CO-CO-, -A ₁ -CO-, _{-CO-A l -, -CO-} CH 2 -CO-, -CO-NH-A 2 -, - CO-CH 2 -O- or -CO-CH ₂ -NH- him (where, A _l is an optionally ₂ -alkylene group substituted with a methyl or a hydroxybenzyl group, and A ₂ is a C _1-2 -alkylene group), Y ₂ is an ethylene group substituted with 1,4- 1,4-phenylene group, 4-piperidinylene, 1,4-phenalazine, 4-hydroxy-1,4-piperidylene (provided that N, O- An acetal and an N, O bond or an N, N bond can not be formed by a bond with Y ₁ or Y ₃ ) or -NH-B group (with the proviso that the Yl group is bonded to the nitrogen atom of the -NR 1 - group , B is a 1,3-f 1,4-phenylene, 1,4-cyclohexylene or 4-piperidinylene group with the proviso that the perferredynylene group and the radical -NH- are in each case via 4-position ] a, Y ₃ is _{-CO-, -A 2 -CO -, -} NR 2 -A 3 -CO-, -CH 2 -NR 2 -A 3 -CO-, -OA 3 -CO- -CO-a ₃ -CO- or -CO-NR _I -A ₃ -CO- group wherein A ₃ is a C _1-2 -alkyl group optionally substituted with methyl or phenyl group, R ₂ is hydrogen, methyl, benzyl, An acetyl or phenylsulfonyl group, a -A ₂ -CO- group and a radical Y ₂ are bonded via a radical A ₂ , a -NR ₂ -A ₃ -CO- group and a radical Y ₂ are bonded via an NR ₂ group , The -OA ₃ -CO- group and the radical Y ₂ are bonded through an oxygen atom, but the group -NR ₂ -A ₃ -CO-, -CH ₂ -NR ₂ -A ₃ -CO- and -OA ₃ -CO- group May not be bonded to the nitrogen atom of the radical Y ₂ ) and E is hydroxyl, C _{1- 5} -alkoxy, benzyloxy or C _5-7 -cycloalkyloxy, or the α-amyl of the natural amino acid No geureup, C _l-6 - stereoisomer thereof and a salt thereof containing a piperazine derivative, its tautomeric common compound of formula (I), alkyl or benzyl ester thereof. The method of claim 1, wherein, R is _a 4-piperidinyl geureup and, in the case of R _b and 17 a, respectively, a hydrogen atom, Y _l is _{-CO -, - COCH 2 -,} -COCH 2 CH 2 - or -CO-CH ₂ -O- group and Y ₂ is 1,4-phenylene, 4-piperidinylene, 1,4-piperazinylene or -NH-B-group (Y ₂ group and Y ₁ group is bonded through the nitrogen atom of -NH- group and B is 1,4-phenylene or 1,4-cyclohexylene group), Y ₃ is -CO-, -CHECO-, -CH _{2 CH 2 CO-, -CH 2 CH 2} CH 2 CO-, -O-CH 2 -CO- or -CO-NH-CH ₂ CH ₂ -CO- and geureup, E is hydroxyl, C _l-5 - alrok Or a C _1-5 -cycloalkoxy group, a tautomer thereof, a stereoisomer thereof and a salt thereof. 2. The piperazine derivative of claim 1, its tautomer, its stereoisomer and its salt. (b) Synthesis of [3- [4-trans- [4 ' - [4- (4-piperidinyl) -piperazin- 1 -yl] propionyl] -amino} cyclohexanecarboxylic acid - (4-piperidinyl) -piperazin-1-yl] carbonylamino] cyclohexyl] propionic acid (c) ] - 4- (4-piperidinyl) -butyric acid d) Preparation of N - [[4- (4-piperidinyl) -piperazin- 1- yl] carbonyl] -3- (piperidinyl) (f) < RTI ID = 0.0 > [4 - [[4- (4 (4- (4-fluorophenyl) -piperazin- (4-r4- (4-piperidinyl) -piperazin-1-yl] acetyl] phenoxy < / RTI > ] Acetic acid (h) [4- [2 - [[4- (Piperidin-4-yl) -piperazin- 1- yl] -carbonyl] -ethyl] -piperidin- , And C _1-5 -alkyl esters and C _5-6 -cycloalkyl esters thereof. Phenoxy] acetic acid, its butyl ester, isobutyl ester, cyclopentyl ester or cyclohexyl ester, its tautomeric form, or its tautomeric form, , A stereoisomer thereof and a salt thereof. 8. A physiologically acceptable salt of a compound according to any one of claims 1 to 7 with an inorganic acid, an organic acid or a base. 9. A medicament comprising at least one compound according to any one of claims 1 to 7 or a physiologically acceptable salt according to claim 8, and optionally an inert carrier and / or an excipient. 9. The use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament suitable for the treatment or prevention of diseases in which large or small cell vacuoles occur or where cell / 10. A process for the preparation of a medicament according to claim 9, characterized in that the compound according to any one of claims 1 to 8 is introduced into the at least one inert carrier and / or excipient by a non-chemical route. (a) reacting a compound of the formula III a compound of Formula II, Y _l is _{-CO-CO-, A l -CO-,} -A 2 -SO 2 -, - CO-A l -CO-, -CO -NR ₁ -A ₂ -CO- or -CO-a ₂ -NR ₁ -CO- group and prepare a compound of formula I is bonded to an oxygen atom or a nitrogen atom of the carbonyl group of the radical Y _l Y ₂ radical or (b) converting a compound of formula (IV) to a compound of formula (I), wherein one or more of the radicals R _a , R ₂ and I must contain a reactive hydrogen atom, with the proviso that E is as defined in _{but, R 5 -CO-O- (R} 3 CR 4) -O- group is excluded) preparing a compound of formula (I) or, (c) by banung with a compound of formula Vl with a compound of formula V, E is hydroxyl Wherein Y ₂ is phenylen, interstitial cyclohexylene, 3-piperidinylene or 4-piperidinylene group, with the proviso that Y ₂ is a radical Y ₃ of oxygen or NR ₂ Is coupled by a flow in the Y _{3) 3,} and A is optionally C _l-5 - alkyl, aryl, pyridyl or _aryl-l -C ₃ - Preparation of an ethylene group, a compound of formula (I) substituted with an alkyl group, or ( d) reacting a compound of formula (VI) with a compound of formula (VIII), or (e) reacting a compound of formula (IX) with an alcohol of formula (X) or a formamide acetal thereof, and the claim 1 to prepare a compound of formula (I) as defined in claim 7 or 8, or, (f) reducing a compound of formula X, A1 is a hydroxyl group substituted nC _l-5 - alkyl him formula I Preparation of the compound, or, (g) alkylating the compound of formula (XI) reductively with amines of the formula XII, or, (h) by alkylating the compound of formula XIII to the compound of formula XIV, R2 is nC _l-5 - alkyl, _aryl-l -C ₁₃ - alkyl group of the general formula I Preparation of the compound, or, (i) reacting a compound of formula XVI The compound of formula XV, the radicals Ra RC _l-5 - alkyl or _aryl-l -C ₃ - alkyl substituted him or C _l-6 - Al alkanoyl, benzoyl, allyloxy-carbonyl, C _l-7 - alkoxycarbonyl or _phenyl-l -C ₃ - alkoxycarbonyl radical producing a compound of formula (I) substituted by such as geureup or, (k) a compound of formula XVII by reduction, by Ra is manufactured, or (1) alkylating a compound of formula XVIII by a reductive glycidyl oxalic acid or a hydrate of the compound of formula I 4- piperidinyl group, Y ₃ is -NR ₂ -CH ₂ Groom -CO- (where, R ₂ is hydrogen, C _l-5 - alkyl, aryl or _aryl-l -C ₃ - alkyl is him) in accordance with the preparing a compound of the hakhak formula I, and if, so to give A compound of formula (I) is isolated by its stereoisomer and / or is obtained by reacting a compound of formula And a conversion, in particular a process for preparing a compound of formula (I) according to the pharmaceutical use in the reukjing the Sikkim converted to its salt physiologically acceptable for, any one of claims 1 to 8. ≪ RTI ID = 0.0 & (III) HY ₂ '-Y ₃ -E' (IV) (V) (VI) A ₃ ' -CO-E (VII) (VIII) Z ₁ -Y ₁ -Y ₂ -Y ₃ -E (IX) (X) HO-R _d (XI) Z ₂ -Re (X) (XI) Ra'-H (XII) (XIII) (XIV) Z ₃ -R _f (XV) (XVI) R _g -Z ₄ (XVII) (XVIII) Rb, Rc, E, Y ₁ , Y, and Y in the above formulas II, III, IV, V, VI, VII, VIII, IX, X, Xl, XII, XIII, XIV, XV, XVI, XVII and XVIII ₂ and Y ₃ are the same as defined 1 to in claim 7, wherein [stage, the same as defined in formula IV, the radical Ra, R ₂ and E (stage, E is any one of claims 1 to 7, wherein, R ₅ - CO-O- (R ₃ CR ₄ ) -O- group is excluded), at least one of which must contain a reactive hydrogen atom, E in formula (VI) is as defined in any of claims 1 to 7, Y ₁ 'represents -CO-CO-, -A ₁ -CO-, -A ₂ -SO ₂ -, -CO-Al ₁ -CO-, -CO-NR ₁ -A ₂ - CO- or -CO-A ₂ -NR ₁ -CO- or a reactive derivative thereof, Y ₂ 'is a hydrogen atom or a group represented by any of the formulas (1) to (7) when a hydrogen atom is bonded to a basic nitrogen atom or an oxygen atom of the radical Y _Z ' defined the same as Y ₂ (however, in the formula V, Y2 'is a phenylene, cyclohexylene, 3-piperidinyl or 4-piperidinyl alkenylene an alkenylene group), E' is Were _{R 5 -CO-O- (R 3} CR 4) equal to E-0-group and defined in claim 1 to claim 7, wherein except for the case of, E "is a hydroxyl group or, the carbonyl group of the radical Y3 A group capable of being converted into a carboxyl group by the elimination of a protecting radical which can be cleaved by a method of hydrolysis, treatment with an acid or a base, thermal decomposition or hydrolysis, provided that the radicals RA and R ₂ or E "must contain a radical which can be cleaved), X is a hydroxyl or HNR ₂ group and R ₂ is a hydrogen atom, C _1-5 -alkyl, aryl-C _1-3 A ₃ 'is a vinyl group optionally substituted with C _{1 -5} -alkyl, phenyl, pyridyl or phenyl-C _1-3 -alkyl groups, Z ₁ is a binuclear leaving group or -NR 1 -B- in addition to R < 1 > is further a carbon-nitrogen bond, Rd is an alkyl group having 1 to 7 carbon atoms, (Wherein the cycloalkyl moiety having 5 to 8 carbon atoms is further substituted with 1 or 2 of alkyl groups having 1 to 3 carbon atoms), and the alkyl group having 3 to 9 carbon atoms A cycloalkyl group having 5 to 5 carbon atoms, provided that the methylene group at the 3-position or the 4-position in the cycloalkyl moiety is an oxygen atom or optionally an alkyl, phenylalkyl or phenylalkoxycarbonyl group (provided that the alkyl moiety and the alkoxy The moiety is in each case substituted with an imino group substituted with an alkanoyl group having from 1 to 3 carbon atoms, or alternatively from 2 to 6 carbon atoms, and the cycloalkyl moiety in each case has 1 to 3 carbon atoms , A cycloalkenyl group having 4 to 7 carbon atoms, an alkenyl group, a phenylalkenyl group, an alkynyl group, a phenylalkynyl group (provided that the oxygen atom is doubly substituted) The alkenyl moiety and the alkynyl moiety in each case having from 3 to 5 carbon atoms), a cycloalkylalkyl group in which the alkyl moiety is not bonded to a carbon atom having a carbon number of 3 To 8, and the alkyl moiety has from 1 to 3 carbon atoms), a bis-alkyl group having a total of from 8 to 10 carbon atoms (provided that the non-cyprofluoroalkyl moiety in each case is an alkyl group having 1 to 3 carbon atoms, Or a 1,3-dihydro-3-oxo-1-isobenzofuranyloxy group, R a is the same as R _d , and further R ₅ -CO-O- (R ₃ CR ₄ ) -O- group (wherein R ₃ , R ₄ and R ₅ are as defined in any one of claims 1 to 7), Z ₂ is a leaving _group and A ₁ 'is HCl _-5 -alkyl group With the proviso that the methylene group is substituted by a carbonyl group, and Ra 'is the same as Ra defined in claims 1 to 7, provided that the ring methylene group is substituted with a carbonyl group It), Y ₃ 'are as defined -CH ₂ CH (NH ₂₎ -CO- or -NH-A ₃ -CO- geureup (where, A ₃ is in any one of claims 1 to 7), and, R _f is RC _l-5 - alkyl or _aryl-l -C ₃ - alkyl geureup, Z ₃ is a nucleofugic leaving geureup or, in addition to the oxygen atom of the hydrogen atoms and the carbonyl hamre Groom adjacent to the carbon atom, Ra "is the first Bg is HCl _-5 -alkyl group, aryl-Cl _-3 -alkyl group or Cl _-6 -alkanoyl _{group as defined in} claim _7, C _1-4 -alkyloxycarbonyl, benzoyl, allyloxycarbonyl, C _1-7 -aroxycarbonyl or fused-C _1-3 -alkoxycarbonyl group lock, Z ₄ is a nucleophilic leaving group, Rg is other than HC _l-5-alkyl or aryl GRONLUND -C _l-3 - if ahkil group, an oxygen atom with hydrogen atoms adjacent to the carbon atom, Ra '"is N- benzyl-a pyridinium group, Rh is hydrogen atoms, C _l-5 - alkyl, aryl or _Reel-l -C ₃ - alkyl group.