DE19526678A1 - New heterocyclic substd. piperazine derivs. - Google Patents

Abstract

Pyrrolidinyl-, piperidinyl- and hexamethyleneimino-substd. piperazine derivs. (I) and their tautomers, stereoisomers (including mixtures) and salts are new. Ra = 3-pyrrolidinyl, 3- or 4-piperidinyl or 3- or 4- hexamethyleneiminyl opt. monosubstd. by 1-5C alkyl or aryl-1-3C alkyl (opt. monosubstd. on or in alkyl part by COOH, 1-3C alkoxycarbonyl, CONH2, CONH(1-3C alkyl), CON(1-3C alkyl)2, vinyl or ethynyl); or, when this substit. is not on a C atom alpha to N, by OH, 1-3C alkoxy, NH2, NH(1-3C alkyl) or N(1-3C alkyl)2; or 1-6C alkanoyl; benzoyl; allyloxycarbonyl; 1-5C alkoxycarbonyl; or phenyl-1-3C alkoxycarbonyl; Rb, Rc = H; 1-5C alkyl; aryl; or aryl-1-5C alkyl; or together with the ethylene bridge between them form o-phenylene; and the piperazinylene gp. in (I) can contain 1 or 2 CO gps. in place of 1 or 2 CH2 gps.; Y1 = -A1-; -CO-; -CO-CO-; -A1-CO-; -CO-A1-; -SO2-A2-; -A2-SO2-; -CO-A1-CO-; -CO-NR1-CO-; -CO-NR1-A2-; -CO-NR1-A2-CO-; -CO-A2-NR1-CO-; -CO-A2-O-; or -CO-A2-NR1; R1 = H; 1-5C alkyl; aryl; or aryl-1-3C alkyl; A1 = 1-5C n-alkylene opt. monosubstd. by 1-5C alkyl, cyclohexyl-1-3C alkyl, aryl, aryl-1-3C alkyl or, when not alpha to a N atom, R1O; A2 = 1-4C n-alkylene opt. monosubstd. by 1-5C alkyl, aryl or aryl-1-3C alkyl; Y2= phenylene; cyclohexylene; pyridinylene; 3- or 4- piperidinylene or 1,4-piperazinylene opt. contg. 1 CO gp. in place of 1 CH2 gp. adjacent to a N atom, and in the case of 4-piperidinylene opt. 4-substd. by R1O (N, O or O,O acetal or N, O or N,N bond must not be formed in linkage with Y1 or Y3); 1,4-ketopiperazinylene opt. monosubstd. alpha to CO gp. by 1-5C alkyl (opt. substd. by phenyl, R1O-phenyl, 1-3C alkoxycarbonyl or COOH); -NR1-B- linked to Y1 via the N atom; or -O-B- linked to Y1 via the O atom; B = phenylene; cyclohexylene; pyridinylene; or piperidinylene linked via the 3- or 4-position with the NR1 or O of Y2 and opt contg. 1 CO gp. in place of 1 CH2 gp. adjacent to a N atom; Y3 = -CO-; -A2-CO-; -CH2-CH(NHR2)-CO-; -NR2-A3-CO-; -CH2-NR2-A3-CO-; -O-A3-CO-; -CO-A3-CO-; or -CO-NR1-A3-CO-; A3 = 1-3C n-alkylene opt. monosubstd. by 1-5C alkyl, aryl, pyridyl or aryl-1-3C alkyl; R2 = H; 1-5C alkyl; aryl-1-3C alkyl; aryl; 1-5C alkoxycarbonyl; 1-5C alkylsulphonyl; aryl-1-3C alkylsulphonyl or arylsulphonyl; formyl opt. monosubstd. by 1-4C alkyl, aryl or aryl-1-3C alkyl; and -A2-CO-, -NR2-A3-CO- and -O-A3-CO- are linked with Y2 via A2, NR2 and O, respectively, and -NR2-A3-CO-, -CH2-NR2-A3-CO- and -O-A3-CO- cannot be linked with a N atom of Y2; E = OH; 1-6C alkoxy; phenyl-1-3C alkoxy; 3-9C cycloalkoxy (in which a 5-8C cycloalkyl ring is opt. mono- or disubstd. by 1-3C alkyl); 5-8C cycloalkoxy where a CH2 gp. in the 3- or 4-position of the cycloalkyl ring is (a) replaced by O or (b) replaced by imino opt. monosubstd. by alkyl, phenyl-1-3C alkyl, phenyl-1-3C alkoxy-carbonyl or 2-6C alkanoyl (the cycloalkane ring can also be opt. mono- or disubstd. by 1-3C alkyl); 4-7C cycloalkenyloxy; or 3-5C alkenyloxy or alkynyloxy both opt. substd. by phenyl ("provided that no C-O bonds are present where the C carries a double or triple bond"); 3-8C cycloalkyl-1-3C alkoxy; 8-10C bicycloalkoxy opt. mono- or disubstd. in bicycloalkyl gp. by 1-3C alkyl; 1,3-dihydro-3-oxo-1-isobenzofuranyloxy; or R5-CO-O-C(R<3>R<4>)-O-; or alpha -amino gp. of a natural amino acid or its 1-6C alkyl, 2-6C alkenyl, 5-7C cycloalkyl, phenyl or phenyl-1-3C alkyl ester; R3 = H; 1=6C alkyl; 3-7C cycloalkyl; or phenyl; R4 = H or 1-6C alkyl; R5 = 1-5C alkyl; 1-5C alkoxy; 5-7C cycloalkyl; or 5-7C cycloalkoxy.

Description

The present invention relates to piperazine derivatives of the general my formula

their tautomers, their stereoisomers, including their Ge mix, and their salts, especially their salts with physiolo Gisch compatible acids or bases, which are valuable pharma have ecological properties, preferably aggregations inhibitory effects, medicinal products containing these compounds and their use as well as processes for their preparation.

In the above general formula I means
R _{a is} a 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexamethyleneiminyl or 4-hexamethyleneiminyl group, where in each case the hydrogen atom of the abovementioned alkylene imino rings may be replaced by an in vivo leaving group,
Y₁ is a -CO-, -A₁-CO- or -CO-A₁-CO- group in which
A₁ is an nC _1-5 -alkylene group optionally substituted by a C _1-5 -alkyl, aryl or aryl-C _1-3 -alkyl group and A₁ of the -A₁-CO group is attached to the nitrogen atom of the piperazino group,
Y₂ is a phenylene, 3-piperidinylene, 4-piperidinylene or 1,4-piperazinylene group or a -NR₁-B group, wherein the linkage with the Y₁ group is via the nitrogen atom of the -NR₁ group, as well as
R₁ is a hydrogen atom, a C _1-5 alkyl, aryl or aryl C₁-3 alkyl group and
B represents a phenylene, cyclohexylene or piperidinylene group, the linkage of the piperidinylene group in each case via the 3- or 4-position with the radical -NR₁- takes place,
Y₃ is a -CO-, -A₂-CO-, -NR₂-A₃-CO or -O-A₃-CO group, in which
A₂ is an optionally substituted by a C _1-5 alkyl, aryl or aryl-C _1-3 alkyl group nC _1-4 alkylene group,
A₃ is an optionally substituted by a C _1-5 alkyl, aryl or aryl-C _1-3 alkyl group substituted nC _1-3 alkylene group and
R₂ represents a hydrogen atom, a C _1-5 -alkyl, aryl-C _1-3 -alkyl, aryl, C _1-5 -alkoxycarbonyl or C _1-5 -alkanoyl group and the linkage of -A₂-CO Group on the radical A₂, the -NR₂-A₃-CO group via the NR₂ group and the -O-A₃-CO group via the oxygen atom with the radical Y₂ takes place, but where a -NR₂- or -O- A₃-CO group can not be linked to a nitrogen atom of the radical B,
and E is a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, a phenylalkoxy group in which the alkoxy part may contain 1 to 3 carbon atoms, a cycloalkoxy group having 3 to 9 carbon atoms, in which the cycloalkyl part having 5 to 8 carbon atoms is additionally represented by one or two Alkyl groups each having 1 to 3 carbon atoms may be substituted, a cycloalkoxy group having 5 to 8 Kohlenstoffato men, in which in the Cycloalkylteil a methylene group in the 3- or 4-position by an oxygen atom or by a given if by an alkyl, phenylalkyl or Phenylalkoxycarbo nylgruppe, in which the alkyl and alkoxy moiety may each contain 1 to 3 carbon atoms, or replaced by a Alkanoylgrup pe with 2 to 6 carbon atoms substituted imino group and the cycloalkyl moiety may be additionally tuiert by one or two alkyl groups each having 1 to 3 carbon atoms a cycloalkenyloxy group in which the cycloalkenylte il 4 to 7 carbon atoms, an alkenyloxy, phenylalkenyloxy, alkynyloxy or phenylalkyi nyloxygruppe with the proviso that no binding to the oxygen atom from a carbon atom, which carries a double or triple bond and in which the alkenyl and Alkynyl moiety each containing 3 to 5 carbon atoms, a cycloalkylalkoxy group in which the cycloalkyl moiety may contain 3 to 8 carbon atoms and the alkoxy moiety may contain 1 to 3 carbon atoms, a bicycloalkoxy group having a total of 8 to 10 carbon atoms, which in the bicycloalkyl moiety may additionally be substituted by one or two alkyl groups each 1 to 3 carbon atoms may be substituted, a 1,3-dihydro-3-oxo-1-isobenzfuranyloxygruppe or a R₅-CO-O- (R₃CR₄) -O- group, in the
R₃ represents a hydrogen atom, a C _1-6 -alkyl, C _3-7 -cycloalkyl or phenyl group,
R₄ is a hydrogen atom or a C _1-6 alkyl group and
R₅ represents a C _1-5 -alkyl, C _1-5 -alkoxy, C _5-7 -cycloalkyl or C _5-7 -cycloalkoxy group,
or E is an α-amino group of a natural amino acid and its esters.

Among the term "a phenyl group" mentioned in the definition of the above radicals is in particular a given case by fluorine, chlorine, bromine or iodine atoms, by alkyl, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, Alkanoylamino, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl mono-, di- or trisubstituted phenyl group, where the substituents may be the same or different and the abovementioned alkyl and alkoxy moieties each 1 may contain up to 3 carbon atoms,
among the esters of a natural α-amino group, their C _1-6 alkyl, C _2-6 alkenyl, C _5-7 cycloalkyl, phenyl or phenyl C _1-3 alkyl esters such as the methyl, ethyl , n-propyl, iso-propyl, tert-butyl, allyl, phenyl or benzyl esters and
an in vivo leaving group is an alkanoyl group having a total of 1 to 6 carbon atoms, a benzoyl, allyloxy carbonyl, C _1-5 alkoxycarbonyl or phenylC _1-3 alkoxy-carbonyl group such as the formyl, acetyl, propionyl , Butanoyl, pentanoyl, hexanoyl, benzoyl, allyloxycarbonyl, methoxy carbonyl, ethoxycarbonyl, propoxycarbonyl, Isopropoxycar bonyl, butoxycarbonyl, tert.butoxycarbonyl, Pentoxycar bonyl, hexoxycarbonyl, benzyloxycarbonyl, phenylethoxy carbonyl or phenylpropoxycarbonyl group.

Preferred compounds of the above general formula I are those in which
R _{a represents} a 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexamethyleneiminyl or 4-hexamethyleneiminyl group, in each case the hydrogen atom of the abovementioned alkylene imino rings being protected by an alkanoyl group having a total of 1 to 6 carbon atoms, a benzoyl group. , Allyloxycarbonyl, C _1-5 -alkoxycarbonyl or phenyl-C _1-3 -alkoxycarbonyl group may be replaced,
Y₁ is a -CO-, -A₁-CO- or -CO-A₁-CO- group in which
A₁ is an optionally substituted by a C _1-5 alkyl, phenyl or phenyl-C _1-3 alkyl group nC _1-5 alkylene group and A₁ of the -A₁-CO group is connected to the nitrogen atom of the piperazino group,
Y₂ is a 1,3-phenylene, 1,4-phenylene, 3-piperidinylene, 4-Pi peridinylene or 1,4-piperazinylene group or a -NR₁-B group, wherein the linkage with the Y₁ group via the nitrogen atom of the -NR₁ group takes place, as well as
R₁ represents a hydrogen atom, a C _1-5 alkyl, phenyl or phenyl C₁-3 alkyl group and
B represents a 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene, 1,4-cyclohexylene or piperidinylene group, where in the linking of the piperidinylene each via the 3- or 4-position with the Rest -NR₁- occurs,
Y₃ is a -CO-, -A₂-CO-, -NR₂-A₃-CO or -O-A₃-CO group, in which
A₂ is an optionally substituted by a C _1-5 alkyl, phenyl or phenyl-C _1-3 alkyl group nC _1-4 alkylene group,
A₃ is an optionally alkyl group by a C _1-5 alkyl, phenyl or phenyl-substituted C _1-3 -alkylene group, and nC _1-3
R₂ represents a hydrogen atom, a C _1-5 -alkyl, phenyl-C _1-3 -alkenyl, phenyl, C _1-5 -alkoxycarbonyl or C _1-5 -alkanoyl group and the linkage of the -A₂- CO group via the radical A₂, the -NR₂-A₃-CO group via the NR₂ Grup pe and the -O-A₃-CO group via the oxygen atom with the radical Y₂ takes place, but where a -NR₂- or - O-A₃-CO- group can not be linked ver with a nitrogen atom of the radical B,
and E is a hydroxy, C _1-6 alkoxy, phenylC _1-3 -alkoxy, C _5-7 cycloalkoxy or R₅-CO-O- (R₃CR₄) -O- group in which
R₃ represents a hydrogen atom, a C _1-6 -alkyl, C _3-7 -cycloalkyl or phenyl group,
R₄ is a hydrogen atom or C _1-6 alkyl group and
R₅ represents a C _1-5 alkyl, C _1-5 alkoxy, C _5-7 cycloalkyl or C _5-7 cycloalkoxy group, or
an α-amino group of a natural amino acid and its C _1-6 -alkyl or benzyl ester,
their tautomers, their stereoisomers, including their mixtures, and their salts.

Particularly preferred compounds of the above general formula I are those in which
R _{a is} a 3- or 4-piperidinyl group, wherein in each case the hydrogen atom of the abovementioned Alkyleniminoringe can be replaced by an allyloxycarbonyl, C _1-5 alkoxycarbonyl or phenyl-C _1-3 alkoxycarbonylgruppe,
Y₁ is a -CO-, -A₁-CO- or -CO-A₁-CO- group in which
A₁ is an nC _1-5 -alkylene group optionally substituted by a C _1-5 -alkyl, benzyl, 1-phenylethyl or 2-phenylethyl group and A₁ of the -A₁-CO group is attached to the nitrogen atom of the piperazino group,
Y₂ is a 1,4-phenylene, 4-piperidinylene or 1,4-piperazinylene group or a -NR₁-B group, linking with the Y₁ group via the nitrogen atom of the -NR₁ group, as well as
R₁ represents a hydrogen atom, a C _1-5 alkyl, benzyl, 1-phenylethyl or 2-phenylethyl group and
B represents a 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene, 1,4-cyclohexylene or piperidinylene group, where in the linking of the piperidinylene each via the 3- or 4-position with the Rest -NR₁- occurs,
Y₃ is a -CO-, -A₂-CO-, -NR₂-A₃-CO or -O-A₃-CO group, in which
A₂ is an optionally substituted by a C _1-3 alkyl, Ben zyl-, 1-phenylethyl or 2-phenylethyl substituted te n-C₁-4-alkylene group and
A₃ is an optionally substituted by a C _1-5 alkyl, benzyl, 1-phenylethyl or 2-phenylethyl group nC _1-3 alkylene group and
R₂ represents a hydrogen atom, a C _1-3 -alkyl, C _1-5 -alkoxycarbonyl or C _1-3 -alkanoyl group and the linking of the -A₂-CO group via the radical A₂, the -NR₂-A₃- CO group via the NR₂ group and the -O-A₃-CO- group via the oxygen atom with the radical Y₂ takes place, but with a -NR₂- or -O-A₃-CO group is not linked to a nitrogen atom of the radical B. can be,
and E is a hydroxy, C _1-5 alkoxy, C _5-7 cycloalkoxy or R₅-CO-O- (R₃CR₄) -O- group in which
R₃ represents a hydrogen atom, a C _1-3 -alkyl or C _5-7 -cycloalkyl group,
R₄ is a hydrogen atom and
R₅ represents a C _1-5 -alkyl or C _1-3 -alkoxy group, or an α-amino group of a natural amino acid and its C _1-6 -alkyl or benzyl ester,
their tautomers, their stereoisomers, including their mixtures, and their salts.

Very particularly preferred compounds of the above general formula I are those in which
R _{a is} a 4-piperidinyl group, where the hydrogen atom of the 4-piperidinyl group may be replaced by a C _1-5 -alkoxycarbonyl group,
Y₁ is a -CO-, -CH₂CO-, -CH₂CH₂CO-, -CH₂CH₂CH₂CO-, -CH₂CH₂CH₂CH₂CO-, -CH₂CH₂CH₂CH₂CH₂CO- or -CO-CH₂-CO- group,
Y₂ is a 1,4-phenylene, 4-piperidinylene, 1,4-piperazinylene or -NR₁-B group, linking to the Y₁ group via the nitrogen atom of the -NR₁ group, as well as
R₁ is a hydrogen atom and
B represents a 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene, 1,4-cyclohexylene or piperidinylene group, in which the linking of the piperidinylene group via the 4-position with the radical -NR₁- he follows,
Y₃ is a -CO-, -CH₂CO-, -CH₂CH₂CO-, -CH₂CH₂CH₂CO-, -NR₂-CH₂-CO-, -NR₂-CH₂CH₂-CO-, -O-CH₂-CO- or -O-CH₂CH₂-CO- group , in which
R₂ represents a hydrogen atom, a methyl, benzyl, 2-phenylethyl, tert.-butoxycarbonyl or acetyl group and the linking of the -CH₂CO-, -CH₂CH₂CO- or -CH₂CH₂CH₂CO group via the alkylene moiety, the -NR₂-CH₂- CO or -NR₂-CH₂CH₂-CO group via the -NR₂- group and the -O-CH₂-CO- or -O-CH₂CH₂-CO group via the oxygen atom with the radical Y₂ takes place, but where a -NR₂ or an oxygen atom can not be linked to a nitrogen atom of the radical B,
and E is a hydroxy, C _1-4 alkoxy, C _5-7 cycloalkoxy or R₅-CO-O- (R₃CR₄) -O- group in which
R₃ represents a hydrogen atom or a C _1-3 alkyl group,
R₄ is a hydrogen atom and
R₅ represents a C _1-5 alkyl or C _1-3 alkoxy group,
or a glycinyl group or its methyl ester,
their tautomers, their stereoisomers, including their mixtures, and their salts.

As particularly valuable compounds are, for example fol mentioned above:

• (a) [4-trans- [3- [4- (4-piperidinyl) piperazin-1-yl] propionyl] amino] cyclohexane carboxylic acid,
• (b) [3- [4-trans- [4- (4-piperidinyl) -piperazin-1-yl] carbonylamine no] cyclohexyl] propionic acid,
• (c) N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] -4- (4-pipe ridinyl) butyric acid,
• (d) N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] -3- (piperi din-4-yloxy) propionic acid,
• (e) N - [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] piperi dinyl] -β-alanine,
• (f) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phen oxy] acetic acid,  
• (g) [4 - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] phenoxy] vinegar acid,
• (h) 3- [4-trans - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamine no] cyclohexyl] propionic acid cyclohexyl ester,
• (i) N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] -3- (pipe ridin-4-yloxy) -propionic acid ethyl ester,
• (j) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phen oxy] acetic acid methylester,
• (k) [4 - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] phenoxy] acetic acid methylester,
• (I) [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phen oxy] acetic acid isopropyl ester,
• (m) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid isobutyl ester,
• (n) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid neopentyl ester,
• (o) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid cyclopentyl,
• (p) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid cycloheptyl,
• (q) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid tert-butyl ester,
• (r) [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phen oxy] acetic acid cyclohexyl ester,  
• (s) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid ethyl ester,
• (t) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid tert-butyl ester,

their tautomers, their stereoisomers and their salts.

According to the invention, for example, the new compound is obtained tions according to the following procedures:

a. Reaction of a compound of the general formula

in the
R _a and Y₁ are as defined above, or their reactive derivatives with a compound of the general formula

H-Y₂¹-Y₃-E '(III)

in the
Y₃ is as defined above,
Y₂ 'with the exception of the phenylene group has the meanings for Y₂ at the beginning and th
E 'with the exception of the R₅-CO-O- (R₃CR₄) -O-group having the meanings mentioned for E above.

The reaction of a carboxylic acid of the general formula II, in the Y₁ represents an -A₁-CO or -CO-A₁-CO group is ge if necessary in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorine benzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane or in a corresponding amine of general formula III optionally in the presence of a dehydrating agent, z. In the presence of isobutyl chloroformate, Orthokoh Lentyl tetraethyl ester, trimethyl orthoacetate, 2,2-di  methoxypropane, tetramethoxysilane, thionyl chloride, trimethyl chlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclo hexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuc cinimide, N, N'-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate borate / 1-hydroxybenzotriazole, N, N'-carbonyldiimidazole or Triphenylphosphine / carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine expediently at Tem temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, performed.

The implementation of a corresponding reactive compound the general formula II such as their esters, imidazolides or Ha halogenides with an amine of the general formula III is present preferably in a corresponding amine as a solvent gege if appropriate in the presence of another solvent, such as Me thylene chloride or ether, and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopro pylamine or N-methyl-morpholine at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C, carried out.

b. For the preparation of a compound of general formula I in which at least one of the radicals R _a , R₂ and E must contain a reactive hydrogen atom with the proviso that E except the R₅-CO-O- (R₃CR₄) -O-group the for E mentioned above has:
Transfer of a compound of the general formula

in the
R _a and Y₁ to Y₃ are as defined above and
E '' is a hydroxy group or together with the adjacent Car bonylgruppe of the radical Y₃ by means of hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis cleavable Baren protective group in a carboxyl group group, but wherein at least one of the radicals R _a , NR₂ or E '' must contain a cleavable residue,
in a compound of general formula I in which at least one of the radicals R _a , R₂ and E must contain a reactive hydrogen atom with the proviso that E except for the R₅-CO-O- (R₃CR₄) -O- group for E has mentioned above conditions gene.

Examples of suitable protective groups for a hydroxy group of a carboxy group are the functional derivatives of a carboxyoxy group such as their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters by hydrolysis into a carboxyl group,
Esters with tertiary alcohols, e.g. For example, the tert.Butylester, with means of treatment with an acid or thermolysis in a Carb oxylgruppe and
Esters with aralkanols, e.g. As the benzyl ester, are converted by hydro genolysis in a carboxyl group.

The hydrolysis is conveniently carried out either in the presence an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, vinegar acid, trichloroacetic acid, trifluoroacetic acid or their Gemi or in the presence of a base such as lithium hydroxide, Natri hydroxide or potassium hydroxide in a suitable solvent tel such as water, water / methanol, water / ethanol, water / Isopro panol, methanol, ethanol, water / tetrahydrofuran or water / Dioxane at temperatures between -10 and 120 ° C, z. B. at Tem temperatures between room temperature and the boiling point of the Reaction mixture, carried out.

Under the above-mentioned reaction conditions, any existing N-acylamino or C _1-5 alkoxycarbonyl groups such as an N-trifluoroacetylamino or tert-butyloxy carbonyl group can be converted into the corresponding amino groups.

For example, E "in a compound of formula IV the tert-butyloxycarbonyl group, so the tert-butyl group also by treatment with an acid such as trifluoroacetic acid, Formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, Phosphoric acid or polyphosphoric acid optionally in one inert solvents such as methylene chloride, chloroform, benzene, Toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at temperatures between -10 and 120 ° C, z. At temperatures between 0 and 60 ° C, or thermally optionally in an inert solvent such as methylene chloride, chloroform, Benzene, toluene, tetrahydrofuran or dioxane and preferably in Presence of a catalytic amount of an acid such as p-toluene sulfonic acid, sulfuric acid, phosphoric acid or polyphosphorus acid preferably at the boiling point of Lö used agent, eg. B. at temperatures between 40 and 120 ° C, from be split. In the above-mentioned Reaktionsbedin may optionally be present N-tert.Butyloxycarbo nylaminogruppen converted into the corresponding amino groups become.

For example, E "in a compound of formula IV the benzyloxycarbonyl group, the benzyl group may also be hy drugolytically in the presence of a hydrogenation catalyst such as Palladium / carbon in a suitable solvent such as methanol, Ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ° C, z. At room temperature, and a hydrogen pressure be split off from 1 to 5 bar. In the hydrogenolysis Kings at the same time other radicals, eg. B. a nitro group in one Amino group, a benzyloxy group in a hydroxy group and an N-benzylamino, N-benzylimino, N-benzyloxycarbonylamino or N-Benzyloxycarbonyliminogruppe in a corresponding Amino or imino group are transferred.  

c. For the preparation of a compound of general formula I in which Y₂ is defined as mentioned above with the exception of the phenylene group, and Y₃ is an -A₂-CO group in which A₂ is optionally substituted by a C _1-5 alkyl, phenyl or Phenyl-C _1-3 -alkenyl substituted nC _2-4- alkenylene group, represent:
Reaction of a compound of the general formula

in the
R _a and Y₁ are as defined above and
Y₂ 'with the exception of the phenylene, 3-piperidinylene or 4-piperidinylene group has the meanings mentioned above for Y₂, with a compound of the general formula

A₂'-CO-E (VI)

in the
E as defined above and
A₂ 'represents an optionally substituted by a C _1-5 alkyl, phenyl or phenyl-C _1-3 alkyl group substituted nC _2-4 alkenylene group.

The reaction is preferably carried out in a solvent such as Me ethanol, methylene chloride, tetrahydrofuran, toluene, di oxane, dimethyl sulfoxide or dimethylformamide, optionally in Presence of a tertiary organic base such as N-ethyl-diiso propylamine or N-methyl-morpholine at temperatures between -30 and 150 ° C, but preferably at temperatures between 0 and 100 ° C, performed.

d. Reaction of a compound of the general formula

in the
R _{a is} as defined above, with a compound of the general my formula
Z₁-Y₁-Y₂-Y₃-E (VIII)
in the
Y₁, Y₂, Y₃ and E are as defined above and Z₁ is a nucleophilic leaving group such as a halogen atom, a hydroxy or sulfonic acid ester group, e.g. Example, a chlorine, bromine or iodine atom, a hydroxy, imidazolyl, 4-nitrophenyloxy, methanesulfonyloxy or p-toluenesulfonyloxy, or even if Y₁ represents a carbonyl group, Z₁ together with R₁ another carbon-nitrogen bond means.

The reaction is preferably carried out in a solvent such as Me ethanol, methylene chloride, tetrahydrofuran, toluene, di oxane, dimethyl sulfoxide or dimethylformamide, optionally in Presence of an inorganic or a tertiary organic Base or optionally in the presence of a dehydrating Conducted at temperatures between -30 and 200 ° C.

With a compound of the general formula VIII in which Z₁ represents a nucleophilic leaving group, or with a Isocyanate of the general formula VIII is the reaction before preferably in a solvent such as methylene chloride, aceto nitrile, tetrahydrofuran, toluene, dimethylformamide or dime thylsulfoxide optionally in the presence of a base such as Na triumhydride, potassium carbonate, potassium tert-butylate or N-ethyl diisopropylamine or optionally in the presence of a water withdrawing agent such as triphenylphosphine / azodicarboxylic acid Diethyl ester at temperatures between -20 and 100 ° C, preferably at temperatures between 0 and 60 ° C, carried out.

e. For the preparation of a compound of the general formula I, in which E, with the exception of the hydroxyl group as defined above:
Reaction of a compound of the general formula

in the
R _a and Y₁ to Y₃ are as defined above, with a connec tion of the general formula

HO-R _b (X)

or with a compound of the general formula

Z₂-R _c (XI)

in which
R _{b is} an alkyl group having 1 to 6 carbon atoms, a phenylalkyl group in which the alkyl part can keep 1 to 3 carbon atoms ent, a cycloalkyl group having 3 to 9 Kohlenstoffato men, in which the Cycloalkylteil with 5 to 8 Kohlenstoffato men additionally by one or two Alkyl groups each having 1 to 3 carbon atoms may be substituted, a Cycloal kylgruppe having 5 to 8 carbon atoms, in which in the cycloalkyl part of a methylene group in the 3- or 4-position by an oxygen atom or by an optionally represented by an alkyl, phenylalkyl or Phenylalkoxycarbonylgruppe in which the Al kyl- and alkoxy each containing 1 to 3 carbon atoms, or by an alkanoyl group with 2 to 6 carbon atoms substituted imino group is replaced and the Cycloal kylteil additionally be substituted by one or two alkyl groups each having 1 to 3 carbon atoms may, a Cycloal kenylgruppe in which the Cycloalkenylteil 4 to 7 carbon ato me, an alkenyl, phenylalkenyl, alkynyl or Phenylalkinylgruppe with the proviso that no bond to the oxygen atom emanates from a carbon atom which carries a double or triple bond and in which the Alke nyl- and alkynyl moiety each 3 to 5 Carbon atoms, a cycloalkylalkyl group in which the cycloalkyl moiety may contain from 3 to 8 carbon atoms and the alkyl moiety from 1 to 3 carbon atoms, a bicycloalkyl group having a total of from 8 to 10 carbon atoms, and in the bicycloalkyl moiety additionally one or two alkyl groups each having from 1 to 3 carbon atoms or a 1,3-dihydro-3-oxo-1-isobenzfuranyloxygruppe,
R _{c has} the meanings mentioned above for R _b and additionally an R₅-CO-O- (R₃CR₄) -O- group, in which
R₃ to R₅ are as defined above, and
Z₂ is a leaving group such as a halogen atom, e.g. As a chlorine or bromine, represent.

With an alcohol of the general formula X is the implementation conveniently in a solvent or solvent such as methylene chloride, benzene, toluene, chlorobenzene, tetra hydrofuran, benzene / tetrahydrofuran or dioxane, preferably however, in an alcohol of general formula X, given if in the presence of an acid such as hydrochloric acid or in the presence a dehydrating agent, for. In the presence of chlorine isobutyl isobutyl ester, thionyl chloride, trimethylchlorosilane, Hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfone acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexyl carbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or Triphenylphosphine / carbon tetrachloride, optionally in Ge present a base such as potassium carbonate, N-ethyl-diisopropylamine or N, N-dimethylamino-pyridine expediently at tempera temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, performed.

With a compound of general formula XI is the Umset Appropriately in a solvent such as methylene chloride chloride, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylform amide or acetone, if appropriate in the presence of a Reaktionsbe  accelerator such as sodium or potassium iodide and preferably in Presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl diisopropylamine or N-methyl-morpholine, which are simultaneously may also serve as a solvent, or optionally in Presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C, performed.

In the reactions described above can be given if existing reactive groups such as carboxy, amino or Imino groups during the reaction by conventional protecting groups be protected, which split off again after the implementation become.

For example, comes as a protective group for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or Te trahydropyranylgruppe and
as a protecting group for an amino or imino group, the formyl, acetyl, trifluoroacetyl, allyloxycarbonyl, ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group to addition the phthalyl group into consideration.

The optional subsequent cleavage of a used Protective residue is, for example, hydrolytically in an aqueous trigen solvent, z. In water, isopropanol / water, Es acetic acid / water, tetrahydrofuran / water or dioxane / water, in Presence of an acid such as trifluoroacetic acid, hydrochloric acid or Sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or by ether cleavage, z. B. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

However, the cleavage of a benzyl, methoxybenzyl or Benzyloxy carbonylrestes is carried out, for example hydrogenolytically, for. Example, with hydrogen in the presence of a catalyst such as Palla dium / carbon in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar. The cleavage of a 2,4-dimethoxybenzyl radical
however, it is preferably carried out in trifluoroacetic acid in the presence of anisole.

The cleavage of a tert-butyl or tert-butyloxycarbonylre Stes preferably takes place by treatment with an acid such as Trifluoroacetic acid or hydrochloric acid or by treatment with Iodotrimethylsilane optionally using a Lö such as methylene chloride, dioxane, methanol or ether.

The cleavage of a Trifluoracetylrestes is preferably carried out by treatment with an acid such as hydrochloric acid if necessary in the presence of a solvent such as acetic acid at tempera between 50 and 120 ° C or by treatment with soda lye or aqueous lithium hydroxide solution, optionally in Presence of a solvent such as tetrahydrofuran or metha nol at temperatures between 0 and 50 ° C.

The cleavage of an allyloxycarbonyl radical is carried out by Be treatment with a catalytic amount of tetrakis (triphenyl phosphine) -palladium (O) preferably in a solvent such as Tetrahydrofuran and preferably in the presence of an allyl group penakzeptors such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C, preferably at room temperature and below Inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (I) chloride in one Solvents such as aqueous ethanol and optionally in Ge present a base such as 1,4-diazabicyclo [2.2.2] octane at Tem temperatures between 20 and 70 ° C.  

The cleavage of a phthalyl radical is preferably carried out in Ge presently from hydrazine or a primary amine such as methylamine, Ethylamine or n-butylamine in a solvent such as methanol, Ethanol, isopropanol, toluene / water or dioxane at Temperatu between 20 and 50 ° C.

Further, the obtained compounds of the general For mel I, as already mentioned, in their enantiomers and / or diastereomers are separated. So can at For example, cis / trans mixtures into their cis and trans isomers, and compounds having at least one optically active Koh be separated into their enantiomers.

Thus, for example, the resulting cis- / trans Gemi by chromatography in their cis and trans isomers, the obtained compounds of general formula I, which in Racemates occur, according to known methods (see Allinger N.L. and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of the general formula I with at least 2 stereogenic centers due to their physicochemical Differences according to known methods, for. B. by Chro Matography and / or fractionated crystallization, in their Diastereomers, which, if they are in racemic form then, as mentioned above, into the enantiomers can be separated.

The enantiomer separation is preferably carried out by columns separation on chiral phases or by recrystallization an optically active solvent or by reacting with one, with the racemic compound salts or derivatives like z. As esters or amides-forming optically active substance, ins particular acids and their activated derivatives or alcohols, and separating the diastereomeric salt thus obtained mixed or derivative, e.g. B. due to different Lös from the pure diastereomeric salts or Derivatives the free antipodes by the action of appropriate Mit  tel can be released. Especially common, optical active acids are z. B. the D and L forms of tartaric acid or Dibenzoyltartaric acid, di-o-toluenoic acid, malic acid, almond acid, camphorsulfonic acid, glutamic acid, aspartic acid or China acid. For example, as an optically active alcohol (+) - or (-) - menthol and as an optically active acyl radical in Amides, for example, (+) - or (-) - menthyloxycarbonyl in Consideration.

Furthermore, the compounds of the formula I can be obtained in their salts, in particular for pharmaceutical use in their physiologically acceptable salts with inorganic or organic acids are transferred. As acids come here for example, hydrochloric acid, hydrobromic acid, sulfur acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, Citric acid, tartaric acid or maleic acid into consideration.

In addition, the new compounds thus obtained can be Formula I, if they contain a carboxyl group, desired then in their salts with inorganic or or ganic bases, in particular for pharmaceutical use into their physiologically acceptable salts. When Bases come here, for example, sodium hydroxide, Kaliumhy droxid, arginine, cyclohexylamine, ethanolamine, diethanolamine and Triethanolamine into consideration.

The compounds used as starting materials are partial known from the literature or obtained according to the literature Method (see Examples I to XXX).

As already mentioned, the new piperazinderi vate of the general formula I and their salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, valuable pharmacological Properties on, in addition to an anti-inflammatory and the Bone-degradation inhibiting effect especially antithrombotic,  antiaggregatory and tumor- or metastasis-inhibiting we fluctuations.

For example, the compounds of general formula I examined for their biological effects as follows:

1. Inhibition of the binding of 3 H-BIBU 52 to human platelets

A suspension of human platelets in plasma is with 3 H-BIBU 52 [= (3S, 5S) -5 - [(4'-amidino-4-biphenylyl) oxymethyl] - 3 - [(carboxyl) methyl] -2-pyrrolidinone [3-³H-4-biphenylyl]] replaced the literature known ligand ¹²⁵J-fibrinogen, (see DE-A-4,214,245) and various concentrations of te incubated substance. The free and bound ligand becomes separated by centrifugation and by scintillation counting determined quantitatively. From the measured values, the inhibition of 3 H-BIBU 52 binding determined by the test substance.

For this purpose, donor blood is taken from an anticancer vein and anticoagulated with trisodium citrate (final concentration 13 mM). The blood is centrifuged for 10 minutes at 170 x g and the supernatant platelet-rich plasma (PRP) was removed. The rest Blood is again sharply abzentri for the production of plasma fugue. The PRP is diluted 1:10 with autologous plasma. 750 μl are mixed with 50 μl physiological saline, 100 μl Test substance solution, 50 μl of ¹⁴C-sucrose (3700 bq) and 50 μl 3 H-BIBU 52 (final concentration: 5 nM) at room temperature for 20 min incubated. To measure the non-specific binding is on place the test substance 5 μl BIBU 52 (final concentration: 30, LM) used. The samples are centrifuged at 10,000 xg for 20 seconds fugiert and the supernatant subtracted. 100 μl of these become the Determination of the free ligand measured. The pellet is in Dissolve 500 μl of 0.2N NaOH, add 450 μl to 2 ml of scintillator and 25 .mu.l 5N HCl added and measured. The ver still in the pellet remaining residual plasma is determined from the ¹⁴C content, the bound ligand from the 3 H-measurement. After deduction of unspe zifischen binding is the pellet activity against the Konzen  concentration of the test substance and the concentration for determined a 50% inhibition of binding.

2. Antithrombotic effect methodology

Platelet aggregation is determined by the method of Born and Cross (J. Physiol 170, 397 (1964)) in platelet-rich plasma measured by healthy subjects. For clotting inhibition is the blood with sodium citrate 3.14% in the volume ratio 1: 10 added.

Collagen-induced aggregation

The course of decrease of the optical density of the platelets pension becomes after adding the aggregation-triggering substance Measured and registered photometrically. From the angle of inclination the density curve is ge on the aggregation speed closed. The point of the curve where the largest light transmission permeability is used to calculate the "optical densi ty ".

The amount of collages is chosen as low as possible, but that results in an irreversible reaction curve. The commercial collagen from Hormonche is used Munich, Munich.

The collagen is added to the plasma for 10 minutes before the collagen is added the substance is incubated at 37 ° C.

From the obtained measurement numbers, an EC₅₀ is determined graphically, referring to a 50% change in the optical density in the sin ne an aggregation inhibition relates.  

The following table contains the results found:

In addition, the compounds of Examples 4 (6) to 4 (13) in rhesus monkeys after peroral administration of 1 mg / kg high plasma level of the corresponding acid (see Example 1 (23)) a period of more than 8 hours.

The new compounds are well tolerated because, for example after intravenous administration of 30 mg / kg of the inventive Ver No toxic side effects were observed in the mouse could become.  

Due to their inhibitory effect on cell-cell or cell-matrix Interactions are the new piperazine derivatives of general formula I and their physiologically acceptable salts for the control or prevention of diseases in which klei larger or larger cell aggregates occur or cell ma trix interactions play a role, eg. B. in the fight or prevention of venous and arterial thrombosis, from cerebrovascular diseases, pulmonary embolism, heart infarction, arteriosclerosis, osteoporosis and meta stasis of tumors and the therapy of genetic conditions or also acquired disorders of the interactions of cells with each other or with solid structures. Furthermore suitable These are concomitant with the thrombolysis therapy Fibrinolytica or vascular interventions such as transluminal Angioplasty or also in the treatment of shock states, psoriasis, diabetes and inflammation.

For the control or prevention of the abovementioned Diseases, the dose is between 0.1 .mu.m and 30 mg / kg Kör per weight, preferably at 1 μg to 15 mg / kg body weight, with up to 4 doses per day. For this purpose, the invention can be according to compounds of formula I, optionally in combination with other active substances such as thromboxane-Re zeptor antagonists and thromboxane synthesis inhibitors or their Combinations, serotonin antagonists, α-receptor antagonists, Alkyl nitrates such as glyceryl trinitrate, phosphodiesterase inhibitors, Prostacyclin and its analogs, fibrinolytics such as tPA, Prouro kinase, urokinase, streptokinase, or anticoagulants like Heparin, dermatan sulfate, activated protein C, vitamin K-Anta gonisten, hirudin, inhibitors of thrombin or other acti fourth coagulation factors, along with one or more inert customary carriers and / or diluents, z. B. with corn starch, lactose, cane sugar, microcrystalline Cellulose, magnesium stearate, polyvinylpyrrolidone, lemons acid, tartaric acid, water, water / ethanol, water / glycerine, what ser / sorbitol, water / polyethylene glycol, propylene glycol, stearyl  alcohol, carboxymethylcellulose or fatty substance such as Hard fat or its suitable mixtures, in usual galenic Preparations such as tablets, dragees, capsules, powders, suspensions instructions, solutions, sprays or suppositories.

The following examples are intended to explain the invention in more detail tern:  

Preparation of the starting compounds Example I 4-Amino-piperidin-1-yl-acetic acid methylester dihydrochloride a) 4-tert-Butyloxycarbonylamino-N-benzyl-piperidine

To a solution of 50 g (0.26 mol) of 4-amino-1-benzyl-piperidine in 300 ml of dry dioxane is added dropwise with stirring and cooling with water, a solution of 60 g (0.276 mol) of di-tert.Butyldi carbonate in 150 ml of dry dioxane. The mixture is stirred for 4 hours at room temperature and concentrated to dryness under vacuum. The residue which remains is triturated with a little ether and petroleum ether, filtered off with suction and washed with petroleum ether.
Yield: 70.6 g (92.6% of theory),
Melting point: 114-115 ° C
R _f value: 0.6 (silica gel, methylene chloride / methanol = 9: 1)

b) 4-tert-Butyloxycarbonylamino-piperidine

A solution of 5 g (0.017 mol) of 4-tert-butyloxycarbonylamino-N-benzyl-piperidine in 50 ml of methanol is acidified with ethereal hydrochloric acid until pH 6 and over palladium on carbon (10%) under a hydrogen pressure of 50 psi at room temperature exhaustively hydrogenated. 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⁺ = 200
R _f value: 0.13 (silica gel, methylene chloride / methanol = 9: 1)

c) 4-tert-Butyloxycarbonylamino-piperidin-1-yl-acetic acid methylester

A solution of 3.0 g (0.013 mol) of 4-tert-butyloxycarbonyl-amino-piperidine, 1.9 g (0.13 mol) of methyl bromoacetate (1.2 ml) and 2.6 g (0.025 mol) of triethylamine ( 3.4 ml) is stirred overnight at room temperature. The mixture is then concentrated to dryness under vacuum and the residue is partitioned between ethyl acetate and water. The organic phase is dried over sodium sulfate and concentrated.
Yield: 3.1 g (89.8% of theory),
Mass spectrum: M⁺ = 272
R _f value: 0.43 (silica gel, methylene chloride / methanol = 9: 1)

d) 4-aminopiperidin-1-yl-acetic acid methyl ester dihydrochloride

A solution of 3.1 g (0.011 mol) of 4-tert-butyloxycarbonyl-amino-piperidine-acetic acid methyl ester in 30 ml of methanol is acidified with 30 ml of ethereal hydrochloric acid and allowed to stand overnight at room temperature. It is then 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
R _f value: 0.1 (silica gel, methylene chloride / methanol = 9: 1)

Example II 3- (4-piperidinyl) -propionic acid methylester a) 3- (4-piperidinyl) -propionic acid

50 g (0.335 mol) of 3- (4-pyridyl) -acrylic acid are hydrogenated in 800 ml of 50% acetic acid with the addition of 10 g of platinum dioxide as a catalyst at room temperature and under 50 psi hydrogen pressure until the hydrogen absorption is complete. After filtering off the catalyst, the mixture is concentrated to dryness in vacuo and the remaining residue is crystallized from a little methanol after the addition of ether.
Yield: 47 g (89.2% of theory),
Mass spectrum: M⁺ = 157

b) Methyl 3- (4-piperidinyl) propionate

500 ml of methanol are slowly added at -20 ° C and with stirring with 46.7 g (0.39 mol) of thionyl chloride. After the end of the addition is stirred for a further 20 minutes and then, just if at -20 ° C, slowly added to 56.1 g (0.357 mol) of 3- (4-piperidinyl) propionic acid. The mixture is stirred for a further hour at -20 ° C and then allowed with stirring overnight, the temperature Tempe rise to room temperature. The clear solution thus obtained is concentrated to dryness under vacuum and the rear was crystallized from acetone.
Yield: 57 g (77.2% of theory)
Mass spectrum: M⁺ = 171

Example III N- [4-nitrophenyloxycarbonyl] -3- (4-piperidinyl) propionic acid methylester

To a solution of 4.75 g (0.0229 mol) of methyl 3- (4-piperidinyl) propionate and 4.93 g (0.0229 mol) of p-nitrophenyl chloroformate in 200 ml of dry tetrahydrofuran are added dropwise at 0 ° C and with stirring 8 ml (0.0573 mol) of triethylamine and allowed to stir overnight at room temperature. The mixture is then heated to room temperature for 4 hours and concentrated to dryness under vacuum. The residue is partitioned between methylene chloride and water, the organic phase separated, dried and concentrated. The remaining residue is purified on a silica gel column using methylene chloride as the eluent.
Yield: 9 g of oil containing 4-nitrophenol as impurity.
Mass spectrum: M⁺ = 336
R _f value: 0.93 (silica gel, methylene chloride / methanol = 9: 1)

Example IV N- (4-nitrophenyloxycarbonyl) -4- (4-piperidinyl) -butyric acid methylester

Prepared from 4- (4-piperidinyl) -butyric acid methyl ester hydrochloride, p-nitrophenyl chloroformate and N-ethyl diisopropylamine analogously to Example III.
Oil that slowly crystallizes.
R _f value: 0.11 (silica gel, methylene chloride / methanol = 9: 1)

Example V [4 - [[4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] carbonyl amino] phenoxy] acetic acid methylester

Prepared by reacting 4-methyloxycarbonylmethyloxy aniline with p-nitrophenyl chloroformate in the presence of triethylamine in 4- (4-nitrophenyloxycarbonylamino) -phenoxy-acetic acid methyl ester and then reacting this intermediate with N- [4- (1-benzyl-piperidinyl )] piperazine in the presence of triethylamine analogously to Example 5.
Yield: 1.2 g of oil (37.3% of theory),
Mass spectrum: M⁺ = 466
R _f value: 0.4 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example VI N-t-butyloxycarbonyl-N- (4-piperidinyl) -β-alanine methyl ester hydrochloride a) N- [1-Benzyl-4-piperidinyl] -β-alanine methyl ester hydro chloride

A solution of 50 g (0.263 mol) of 4-amino-1-benzyl-piperidine and 28.5 ml (0.263 mol) of ethyl acrylate in 300 ml of methanol is heated for 4 hours at reflux temperature. It is then concentrated to dryness under vacuum, the residue is dissolved in acetone, acidified to pH 3 with ethereal hydrochloric acid and concentrated again under reduced pressure to dryness. The remaining residue is triturated with acetone. The separated crystalline product is filtered off with suction and dried.
Yield: 48.7 g (50.2% of theory),
Melting point: 172-180 ° C (decomp.)
R _f value: 0.6 (silica gel, methylene chloride / methanol = 9: 1)

b) N- [1-Benzyl-4-piperidinyl] -N-tert -butyloxycarbonyl-β-ala ninmethylester hydrochloride

A solution of 25 g (0.0716 mol) of N- [1-benzyl-4-piperidinyl] β-alanine methyl ester hydrochloride, 15.8 g (0.072 mol) of di-tert-butyl dicarbonate and 20 ml (0.138 mol). Triethylamine in 100 ml of dioxane and 100 ml of water is allowed to stand for 48 hours at room temperature. It is then concentrated to dryness under vacuum and the residue is partitioned between ethyl acetate and water. The organic phase is dried over sodium sulfate and concentrated. The remaining residue is dissolved in ethanol and acidified to pH 6 with ethereal 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: 24.1 g (81.5% of theory),
Melting point: 196-197 ° C (decomp.)
R _f value: 0.8 (silica gel, methylene chloride / methanol = 9: 1)

c) N-tert-butyloxycarbonyl-N- (4-piperidinyl) -β-alanine-methyl ester hydrochloride

24 g (0.05 mol) of N- [1-benzyl-4-piperidinyl] -N-tert-butyloxy-carbonyl-β-alanine methyl ester hydrochloride are dissolved in 900 ml of methanol at room temperature and a hydrogen pressure of 50 psi over palladium Coal (10%) as the catalyst hydrogenated exhaustively. The catalyst is filtered off with suction and the solution is concentrated to dryness in vacuo.
Yield: 20.4 g of oil,
R _f value: 0.17 (silica gel, methylene chloride / methanol = 9: 1)

Example VII N-t-butyloxycarbonyl-N- (4-piperidinyl) -glycine methylester hydrochloride a) N- [1-Benzyl-4-piperidinyl] glycine methyl ester dihydro chloride

Prepared from 4-aminop-1-benzyl-piperidine, bromoacetic acid methyl ester and N-ethyldiisopropylamine.

b) N- [1-Benzyl-4-piperidinyl] -N-tert-butyloxycarbonyl-glycine methylester dihydrochloride

Prepared from N- [1-benzyl-4-piperidinyl] glycine methyl ester hydrochloride, di-tert-butyl dicarbonate and triethylamine.

c) N-tert-butyloxycarbonyl-N- (4-piperidinyl) -glycine methyl ester hydrochloride

Prepared from N- [1-benzyl-4-piperidinyl] glycine methyl ester hydrochloride by exhaustive hydrogenation over palladium Coal (10%)

Example VIII N-methyl-N- (4-piperidinyl) -β-alanine methyl ester dihydrochloride a) N- [1-Benzyl-4-piperidinyl] -N-methyl-β-alanine methyl ester di- hydrochloride

A suspension of 28.8 g (0.026 mole) of N- [1-benzyl-4-piperidinyl] -β-alanine methyl ester dihydrochloride, 2.7 g (0.09 mole) of paraformaldehyde and 5.2 g (0.083 mole). Sodium cyanoborohydride in 100 ml of ethanol is stirred for 24 hours at room temperature. It is then diluted with water and acidified to pH 2 with 1N hydrochloric acid. It is extracted with ethyl acetate, makes the aqueous phase with dilute sodium hydroxide solution and extracted exhaustively with methylene chloride. The combined methylene chloride phases are dried and concentrated to dryness under vacuum. The residue is purified on a silica gel column using methylene chloride with 3% and with 5% methanol as eluent. The combined eluates are acidified to pH3 with ethereal hydrochloric acid and concentrated to dryness under vacuum. The residue is mixed with acetone and filtered with suction.
Yield: 20.8 g (69.5% of theory)
Melting point: 224-227 ° C
R _f value: 0.60 (silica gel, methylene chloride / methanol = 4: 1)

b) N-methyl-N- (4-piperidinyl) -β-alanine methyl ester dihydro chloride

Prepared by hydrogenating N- [1-benzyl-4-piperidinyl] -N-methyl-β-alanine methyl ester dihydrochloride with palladium on carbon (10%).
Yield: 15.8 g (95.4% of theory)
Melting point: 194-195 ° C (decomp.)
R _f value: 0.09 (silica gel, methylene chloride / methanol = 9: 1)
The following compound can be prepared analogously to Example VIII:

(1) N-methyl-N- (4-piperidinyl) -glycine methyl ester dihydro chloride a) N- [1-Benzyl-4-piperidinyl] -N-methyl-glycine methyl ester di hydrochloride

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

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

Prepared from N- [1-benzyl-4-piperidinyl] -N-methyl-glycine methyl ester dihydrochloride by exhaustive hydrogenation over Palladium on charcoal (10%).  

Example IX N-Acetyl-N- (4-piperidinyl) -β-alanine methylester hydrochloride a) N-acetyl-N- [1-benzyl-4-piperidinyl] -β-alanine methyl ester hydrochloride

A solution of 25 g (0.0716 mol) of N- (1-benzyl-4-piperidinyl) β-alanine methyl ester hydrochloride, 20 ml (0.143 mol) of triethylamine and 8.1 ml (0.0859 mol) of acetic anhydride in 300 ml of methanol is allowed to stand overnight at room temperature and then concentrated under vacuum. The residue is dissolved in water, adjusted to pH 8 with 2N sodium hydroxide solution and exhaustively extracted with ethyl acetate. The combined ethyl acetate extracts are dried and concentrated to dryness under vacuum. The residue is purified over a silica gel column containing methylene chloride containing 3% methanol. The eluates are concentrated, the residue is dissolved in acetone, acidified to pH 6 with etheric hydrochloric acid and concentrated. The residue is crystallized with acetone / ether.
Yield: 19 g (74.7% of theory),
Melting point: 138-140 ° C (decomp.)
R _f value: 0.5 (silica gel, methylene chloride / methanol = 9: 1)

b) N-acetyl-N- (4-piperidinyl) -β-alanine methyl ester-hydro chloride

Prepared analogously to Example VIc by hydrogenation with palladium on carbon (10%).
Yield: 13.2 g (93.2% of theory),
Very hygroscopic solid
Mass spectrum: M⁺ = 228
R _f value: 0.09 (silica gel, methylene chloride / methanol = 9: 1)

Example X N-Acetyl-N- (4-piperidinyl) -glycine methylester hydrochloride a) N-acetyl-N- [1-benzyl-4-piperidinyl] -glycine-methyl ester hydrochloride

Prepared from N- [1-benzyl-4-piperidinyl] glycine methyl ester hydrochloride and acetic anhydride.

b) N-acetyl-N- (4-piperidinyl) -glycine methyl ester hydrochloride

Prepared from N-acetyl-N- [1-benzyl-4-piperidinyl] glycine methyl ester hydrochloride by exhaustive hydrogenation over Palladium on charcoal (10%).

Example XI N- [4-trans- [3- [4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] - propionyl] amino] cyclohexanecarboxylic acid-methylester a) methyl 3- [4- (1-benzyl) -piperazin-1-yl] -propionate hydrochloride

Prepared from N-benzyl-piperazine and acrylic acid methyl ester analogously to Example VIa.
Yield: 14.7 g (71.5% of theory),
Mass spectrum: M⁺ = 262
R _f value: 0.42 (silica gel, methylene chloride / methanol / conc.
Ammonia = 9: 1: 0.1)

b) 3- (piperazin-1-yl) -propionic acid methyl ester dihydrochloride

Prepared from methyl 3- [4- (1-benzyl) -piperazin-1-yl] propionate dihydrochloride by hydrogenation over palladium on carbon (10%) analogously to Example VIc.
Yield: 10.5 g (99% of theory),
Mass spectrum: M⁺ = 172
R _f value: 0.13 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

c) 3- [4- [4- (1-Benzyl) piperidinyl] piperazin-1-yl] propion acid methylester

To a solution of 1.9 g (0.01 mol) of N-benzyl-4-piperidone (1.9 ml) and 2.5 g (0.01 mol) of methyl 3- (piperazin-1-yl) propionate Dihydrochloride in 200 ml of methanol are about 4 g of molecular sieve 3 A. It is treated with 1.2 g (0.03 mol) of sodium bicarbonate borohydride and stirred overnight at room temperature. Thereafter, the molecular sieve is sucked off and the solution is concentrated to dryness 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 on a silica gel column, with methylene chloride / methanol = 20: 1 and methylene chloride / methanol / conc. Ammonia = 9: 1: 0.1 can be used as Elutionsmitel.
Yield: 2 g of oil (57.7% of theory),
R _f value: 0.25 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

d) 3- [4- [4- (1-Benzyl) piperidinyl] piperazin-1-yl] propion acid dihydrochloride

Prepared from methyl 3- [4- [4- (1-benzyl) piperidinyl] piperazin-1-yl] propionate and semi-concentrated hydrochloric acid analogously to Example 1.
Yield: 2.2 g (94.0% of theory),
Mass spectrum: M⁺ = 331
R _f value: 0.17 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.1)

e) N- [4-trans- [3- [4- (4- (1-benzyl) piperidinyl] piperazine 1-yl] propionyllamino] cyclohexanecarboxylic acid-methylester

Prepared from 3- [4- [4- (1-benzyl) -piperidinyl] -piperazin-1-yl] -propionic acid dihydrochloride, 4-trans-aminocyclohexylcarboxylic acid methyl ester hydrochloride, 2- (1H-benzotriazol-1-yl) - 1,1,3,3-tetramethyluronium tetrafluoroborate, 1-hydroxy-1H-ben zotriazol and N-methyl-morpholine analogously to Example XXVIIIa.
Yield: 0.9 g (70.3% of theory),
Mass spectrum: (M + + H) = 471
R _f value: 0.65 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Example XII N - [[4 - [(4- (1-benzyl) piperidinyl) piperazin-1-yl] acetyl] - 4-piperidinyl] oxyacetate methylester trihydrochloride a) (4-Benzyl-piperazin-1-yl) -acetic acid methyl ester

A solution of 6 g (0.034 mol) of N-benzyl-piperazine (6 ml), 5.2 g (0.034 mol) of methyl bromoacetate (3.3 ml) and 3.5 g (0.034 mol) of triethylamine (4.8 ml) in 100 ml of methanol is allowed to stand overnight at room temperature. Finally, the solution is concentrated to dryness under vacuum and the residue is purified on a silica gel column (eluant: methylene chloride containing 2% methanol).
Yield: 7 g of oil (82.8% of theory),
R _f value: 0, 6 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

b) Piperazinoacetic acid methyl ester dihydrochloride

7 g (0.028 mol) of (4-benzyl-piperazin-1-yl) -acetic acid methyl ester in 100 ml of methanol containing 1 ml of ethereal hydrochloric acid over palladium on carbon (10%) as a catalyst at room temperature and under exhaustively hydrogenated at a hydrogen pressure of 50 psi. After completion of hydrogen uptake and removal of the catalyst is concentrated to dryness.
Yield: 4.5 g of amorphous solid (100% of theory),
R _f value: 0.26 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

c) 4- [4- (1-Benzyl) -piperidinyl] -piperazinoacetic acid-methyl ester

A solution of 4.5 g (0.028 mole) of methyl piperazinoacetate diester and 5.4 g (0.028 mole) of N-benzyl-4-piperidine (5.3 ml) in 100 ml of dry methanol is added with ethereal hydrochloric acid acidified pH 6. With stirring and at room temperature, 1.8 g (0.028 mol) of sodium cyanoborohydride and about 4 g of molecular sieve 3 A are added to this solution and stirring is continued overnight. After filtering off the molecular sieve, the solution is concentrated to dryness in vacuo and the residue is partitioned between ethyl acetate and water. The combined organic phases are dried and concentrated to dryness under vacuum. The remaining 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
R _f value: 0.65 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

d) 4- [4 - [(1-Benzyl) piperidinyl] piperazin-1-yl] acetic acid

To a solution of 3.1 g (0.0094 mol) of methyl 4- [4- (1-benzyl) piperidinyl] piperazinoacetate in 30 ml of tetrahydrofuran and 35 ml of water is added 2 g (0.047 mol) of lithium hydroxide and stirred for 6 hours at room temperature. Thereafter, 2.5 g (0.047 mol) of ammonium chloride are added and the solution is concentrated to dryness in vacuo. The residue is extracted twice with absolute ethanol. The combined ethanol extracts are evaporated to dryness under vacuum. The remaining residue is purified over a silica gel column (elution medium: methylene chloride / methanol / concentrated ammonia = 4: 1: 0.1).
Yield: 2 g (67.4% of theory),
Mass spectrum: M⁺ = 317
R _f value: 0.35 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

e) N - [[4- (4- (1-Benzyl) piperidinyl) piperazin-1-yl] acetyl] - 4-piperidinyloxyessigsäure-methylester trihydrochloride

Prepared from 4 - [(4- (1-benzyl) piperidinyl) piperazin-1-yl] acetic acid, 4-piperidinyloxyacetic acid methyl ester hydrochloride, 2- (1H-Benzotriazol-1-yl) -1,1 , 3,3-tetramethyluronium te trafluoroborate and triethylamine analogously to Example XVIIIa.
Yield: 0.7 g (40.7% of theory),
Mass spectrum: M⁺ = 472
R _f value: 0.4 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XIII N - [[4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] acetyl] -4-pi piperidinyl-acetic acid-methylester trihydrochloride

Prepared from 4 - [(4- (1-benzyl) -piperidinyl) -piperazin-1-yl] -acetic acid, 4-piperidinylacetic acid methyl ester hydrochloride, 2- (1H-Benzotriazol-1-yl) -1.1, 3,3-tetramethyluronium tetrafluoroborate and triethylamine analogously to Example XVIIIa.
Yield: 1 g (59.9% of theory),
Mass spectrum: M⁺ = 456
R _f value: 0.38 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XIV N - [[[4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] acetyl] pi perazine-1-yl] acetic acid methylester tetrahydrochloride

Prepared from 4- [4- (1-benzyl-piperidinyl) -piperazin-1-yl] - acetic acid, piperazinoacetic acid methyl ester dihydrochloride, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium fluoroborate and triethylamine analogously to Example XVIIIa.

Example XV [4-trans- [4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] acetyl amino] cyclohexanecarboxylic acid ethyl ester trihydrochloride

Prepared from 4- [4- (1-benzyl-piperidinyl) -piperazin-1-yl] - acetic acid, methyl 4-trans-amino-cyclohexanecarboxylate hydrochloride, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluro nium tetrafluoroborate and triethylamine analogously to Example XVIIIa.  

Example XVI N - [[4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] acetyl] - 3- (4-piperidinyl) -propionic acid methylester trihydrochloride

Prepared from 4- [4- (1-benzyl-piperidinyl) -piperazin-1-yl] - acetic acid, 3- [4-piperidinyl] -propionic acid methyl ester-hydro chloride, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate and triethylamine analogously to Example XVIIIa.

Example XVII N- [4- (1-t-butyloxycarbonyl) piperidinyl] piperazine a) 1-Benzyl-4- [4- (1-tert-butyloxycarbonyl) -piperidinyl] piperazine

Prepared from N-benzyl-4-piperidone, N-benzyl-piperazine and sodium cyanoborohydride analogously to Example XIIc.
Yield: 4.8 g (83.1% of theory),
R _f value: 0.45 (silica gel, methylene chloride / methanol = 9: 1)

b) N- [4- (1-tert-Butyloxycarbonyl) piperidinyl] piperazine

Prepared from 1-benzyl-4- [4- (1-tert-butyloxycarbonyl) -pipe-ridinyl] -piperazine by hydrogenation with palladium dihydroxide on carbon as catalyst analogously to Example 3.
Yield: 3.0 g (83.3% of theory),
R _f value: 0.13 (silica gel, methylene chloride / methanol = 9: 1)

Example XVIII [4 - [(4- (1-t-butyloxycarbonyl) piperidinyl] piperazine-1-yl] - malonate a) [4- [4- (1-tert-butyloxycarbonyl) piperidinyl] piperazine 1-yl] ethyl malonate

A solution of 2.8 g (0.0104 mol) of N- [4- (1-tert-butyloxycarbonyl) -piperidinyl] -piperazine, 1.8 g (0.0104 mol) of malonic acid monoethyl ester potassium salt, 3.3 g (0.0104 mol) of 2- (1H-Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, 1.4 g (0.0104 mol) of 1-hydroxy-1-H-benzotriazole and 1 g (0.01 mol) of N-methylmorpholine in 100 ml of dry dimethylformamide is allowed to stand overnight at room temperature. The solution is then concentrated to dryness in vacuo and the residue is purified by chromatography on a silica gel column (eluent: methylene chloride containing 2% and 4% methanol, respectively).
Yield: 1.5 g (37.1% of theory),
R _f value: 0.45 (silica gel, methylene chloride / methanol = 9: 1)

b) [4 - [(4- (1-tert-Butyloxycarbonyl) piperidinyl] piperazine 1-yl] malonic acid

A solution of 1.5 g (0.039 mol) of ethyl [4 - [(4- (1-tert-butyloxycarbonyl) piperidinyl] piperazin-1-yl] malonate in 50 ml of methanol is treated with 5 ml of a 1N sodium hydroxide solution ( 0.042 mol) and allowed to stand at room temperature for 24 hours, then 5 ml of 1N hydrochloric acid are added and the solution is evaporated to dryness in vacuo, the residue is added 3 times with absolute ethanol and concentrated in vacuo with a mixture of abso lutem ethanol and methylene chloride (1: 1), the undissolved inorganic salts are filtered off and the solution is concentrated to dryness under vacuum.
Yield: 1.2 g of foamy substance (87.4% of theory),
R _f value: 0.11 (silica gel, methylene chloride / methanol = 4: 1)

Example XIX [4- [4- (4- (1-t-butyloxycarbonyl) piperidinyl) -piperazine 1-yl] carbonylamino] piperidine a) N-Benzyl [4- [4- (4- (1-tert-butyloxycarbonyl) -piperidinyl] piperazin-1-yl] carbonylaminopiperidin

Prepared from 4-amino-N-benzyl-piperidine, N- [4- (1-tert-butyloxycarbonyl) -piperidinyl] -piperazine, N, N'-carbonyldiimi dazol and imidazole analogously to Example 6.
Yield: 5.7 g (63.8% of theory),
R _f value: 0.4 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

b) [4- [4- (4- (1-tert-Butyloxycarbonyl) -piperidinyl] -piperazine- 1-yl] carbonylaminolpiperidin

Prepared from N-benzyl- [4- [4- (4- (1-tert-butyloxycarbonyl) piperidinyl) piperazin-1-yl] carbonylamino] piperidine by hydrogenation over palladium dihydroxide on carbon analogously to Example 3.
Yield: 4.3 g (92.6% of theory),
R _f value: 0.11 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example XX 3- [4- [4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] carbonyl piperidinyl] propionic acid methylester dihydrochloride

A solution of 0.7 g (0.0018 mol) of 3- [4- [4- (4-pyridyl) -piperazin-1-yl] carbonylpiperidinyl] -propionic acid methyl ester hydrochloride and 0.3 ml of N-ethyl -diisoproylamine in 30 ml of acetonitrile is heated for 2 hours at reflux temperature. The solution is concentrated to dryness under vacuum and the residue is dissolved in 30 ml of methanol. The solution is mixed with 1 g of sodium borohydride and stirred for 48 hours at room temperature. Thereafter, 0.6 g of sodium borohydride are again added and the mixture is stirred overnight. It is concentrated to dryness in vacuo and the residue is partitioned between ethyl acetate and water. The ethyl acetate phase is separated, dried and concentrated. The remaining residue is purified on a silica gel column, with methylene chloride with 5% methanol as Elutionsmitel served. Evaporation of the eluates gives a residue which is taken up in methanol and acidified with ethereal hydrochloric acid. After evaporation, a colorless foam remains.
Yield: 0.3 g (36.6% of theory),
Mass spectrum: M⁺ = 456
R _f value: 0.37 (silica gel, methylene chloride / methanol = 9: 1)

Example XXI 4- (4-piperidinyl) -butyric acid methyl ester hydrochloride a) 2- [2- (4-pyridyl) ethyl] malonic acid diethyl ester hydrochloride

13.4 g (0.583 mol) of sodium are dissolved in 180 ml of absolute ethanol, and 204 ml (1.35 mol) of malonic acid diethyl ester are added in portions to the resulting solution, forming a colorless precipitate. This precipitate is brought by He warm to 30-40 ° C and dilution with absolute ethanol in solution and added dropwise within 1.5 hours with stirring, a solution of 63 ml (0.583 mol) of 4-vinylpyridine in 120 ml absolu tem ethanol. After completion of the addition, the mixture is heated at reflux temperature for 3 hours, then concentrated to a small volume and diluted with 450 ml of half-concentrated hydrochloric acid. It is extracted twice with ether to remove excess malonic acid diethyl ester, the aqueous phase is rendered alkaline with sodium carbonate and exhaustively extracted with methylene chloride. The combined organic phases are dried and concentrated. The residue is purified on a silica gel column using ethyl acetate / cyclohexane = 1: 1 as eluent. The oily residue (78.6 g = 50.8% of theory) is dissolved in acetone and acidified to pH 3.5 with ethereal hydrochloric acid and concentrated. The residue crystallizes overnight, is triturated with acetone / ether and filtered with suction.
Yield: 65 g (37% of theory),
R _f value: 0.8 (silica gel, methylene chloride / methanol = 9: 1)

b) 2- [2- (4-piperidinyl) ethyl] malonic acid diethyl ester-hydro chloride

64.5 g (0.21 mol) of 2- [2- (4-pyridyl) ethyl] malonic acid diethyl ester hydrochloride are exhausted in 400 ml of absolute ethanol at room temperature and a hydrogen pressure of 50 psi over platinum dioxide as a catalyst hydrogenated. After sucking off the catalyst, the remaining solution is concentrated to dryness under vacuum. The residue is crystallized with acetone and filtered with suction.
Yield: 56378 00070 552 001000280000000200012000285915626700040 0002019526678 00004 56259 62.8 g (95.5% of theory) very hygroscopic
Crystals that melt in the air,
R _f value: 0.22 (silica gel, methylene chloride / methanol = 9: 1)

c) 4- (4-piperidinyl) -butyric acid hydrochloride

A solution of 62 g (0.201 mol) of 2- [2- (4-piperidinyl) ethyl] malonic acid diethyl ester hydrochloride in 600 ml of concentrated hydrochloric acid is heated for 24 hours at reflux temperature and then concentrated to dryness under vacuum. The residue is treated with toluene and concentrated. This operation is repeated three more times.
Yield: 44.3 g of colorless crystals which still contain some toluene,
R _f value: 0.19 (silica gel, methylene chloride / methanol = 9: 1)

d) 4- (4-piperidinyl) -butyric acid methyl ester hydrochloride

In 800 ml of methanol are slowly added dropwise with stirring at -10 ° C 18 ml (0.242 mol) of thionyl chloride. A solution of 44.3 g (0.201 mol) of 4- (4-piperidinyl) -butyric acid hydrochloride in 100 ml of methanol is then added dropwise at the same temperature, the mixture is stirred overnight at room temperature and then concentrated to dryness in vacuo. The residue is partitioned between 50% potassium carbonate solution and ether. The aqueous phase is extracted twice more with ether. The combined ether extracts are dried and concentrated. The residue is dissolved in methanol, acidified to pH 6 with ethereal hydrochloric acid and concentrated to dryness in vacuo. The remaining residue is triturated with acetone. The precipitated crystals are sucked off.
Weighing: 35.5 g (88.7% of theory)
Melting point: 99-105 ° C (decomp.)

Example XXII 4-Piperidinyloxyessigsäure-methylester hydrochloride a) N-tert-butyloxycarbonyl-4-piperidinyloxyacetic acid methyl ester

To a solution of 10 g (0.05 mol) of N-tert-butyloxycarbonyl-4-piperidinol in 100 ml of dry tetrahydrofuran is added with stirring 2.3 g (0.05 mol) of sodium hydride (50% in oil) and stirred another 2 hours. 7.6 g (0.05 mol) of methyl bromoacetate (5 ml) are then added dropwise with continued stirring, and stirring is continued overnight. The unreacted sodium hydride is destroyed by the addition of water. It is extracted with ethyl acetate, the combined ethyl acetate extracts are dried and concentrated to dryness under vacuum. The residue is purified over a silica gel column (eluant: methylene chloride containing 1% methanol).
Yield: 4.9 g (36.1% of theory),
Mass spectrum: M⁺ = 273
R _f value: 0.5 (silica gel, methylene chloride / methanol = 9.5: 0.5)

b) methyl 4-piperidinyloxyacetate hydrochloride

A solution of 4.9 g (0.018 mol) of N-tert-butyloxycarbonyl-4-piperidinyloxy-acetic acid methyl ester in 10 ml of methanol is mixed with 30 ml of ethereal hydrochloric acid and allowed to stand for 4 hours at room temperature. It is then concentrated to dryness under vacuum, the residue is mixed with ether and the solid is filtered off with suction.
Yield: 3.1 g of colorless solid (82.5% of theory),
Mass spectrum: M⁺ = 173
R _f value: 0.1 (silica gel, methylene chloride / methanol = 9: 1)

Example XXIII α-Bromo-4-methoxycarbonylmethyloxy-acetophenone a) 4-Methoxycarbonylmethyloxy-acetophenone

To a solution of 8 g (0.06 mol) of 4-hydroxy-acetophenone in 100 ml of dry dimethylformamide are added 9 g (0.06 mol) of methyl bromoacetate (5.6 ml) and 8 g (0.06 mol) Potassium carbonate. The mixture is heated for 5 hours at reflux temperature and then stirred overnight at room temperature. The solution is concentrated to dryness under vacuum and the residue was distributed between ethyl acetate and water. The combined organic extracts are dried and concentrated to dryness in vacuo. The residue is triturated with ether, filtered off with suction and dried.
Yield: 8.6 g of amorphous solid (70.3% of theory),
Mass spectrum: M⁺ = 208
R _f value: 0.45 (silica gel, ethyl acetate / cyclohexane = 1: 1)

b) α-bromo-4-methoxycarbonylmethyloxy-acetophenone

To a solution of 2 g (0.0096 mol) of 4-methoxycarbonylmethyl oxy-acetophenone in 40 ml of ether and 10 ml of dioxane is added dropwise with stirring and at room temperature, a suspension of 0.0106 mol of bromodioxane (prepared from 1.7 g of bromine and 8 ml dioxane) in dioxane. After completion of the addition, the mixture is stirred for a further 2 hours at room temperature and then concentrated to dryness under vacuum.
Yield: 1.3 g of crude product,
R _f value: 0.6 double spot (silica gel, ethyl acetate / cyclohexane = 1: 1)
The following compound can be prepared analogously to Example XXIII:

(1) 4- (α-bromo-acetyl) -phenylacetic acid methyl ester

Prepared from 4-acetyl-phenylacetic acid methyl ester and Bromdioxan.

Example XXIV 3-methoxycarbonylmethyloxy-aniline a) 3-Methoxycarbonylmethyloxy-nitrobenzene

To a solution of 9 g (0.065 mol) of m-nitrophenol in 100 ml of dry dimethylformamide is added 8.8 g (0.065 mol) of potassium carbonate and stirred for 1/2 hour at room temperature. Then, 10.9 g (0.07 mol) of methyl bromoacetate (6.7 ml) are added and the mixture is heated at 80 ° C. for 5 hours. The solution is then concentrated to dryness under vacuum and the residue is partitioned between ethyl acetate and water. The combined organic phases are dried and concentrated to dryness under vacuum. The residue is triturated with ether, filtered off with suction and dried.
Yield: 9.2 g (67.3% of theory),
R _f value: 0.55 (silica gel, methylene chloride)

b) 3-Methoxycarbonylmethyloxy-aniline

9.2 g (0.046 mol) of 3-methoxycarbonylmethoxy-nitrobenzene are exhaustively hydrogenated in methanol over 1.5 g of Raney nickel at a hydrogen pressure of 50 psi and at room temperature. After suctioning off the catalyst, the solution is concentrated.
Yield: 7.0 g of oil (88.7% of theory),
R _f value: 0.5 (silica gel, ethyl acetate / cyclohexane = 1: 1)

Example XXV 4-Methyloxycarbonylmethyloxy-aniline a) 4-Methoxycarbonylmethyloxy-nitrobenzene

Prepared from 4-nitrophenol, methyl bromoacetate and cesium carbonate analogously to Example XXIVa.
Yield: 10.4 g (91.2% of theory),
Melting point: 86-88 ° C

b) 4-Methoxycarbonylmethyloxy-aniline

Prepared from 4-methoxycarbonylmethyloxy-nitrobenzene by hydrogenation over Raney nickel analogously to Example XXIVb.
Yield: 9.5 g of resin (98.4% of theory),
R _f value: 0.6 (silica gel, methylene chloride / methanol = 9: 1)

Example XXVI 3- (4-amino-phenyl) -propionic acid methylester hydrochloride

A solution of 15 g (0.0991 mol) of 3- (4-amino-phenyl) -propionic acid in 100 ml of methanol is added dropwise with stirring and cooling with methanol / ice with 12.96 g (0.11 mol) thionyl chloride (7.93 ml). After completion of the addition, stirring is continued for 30 minutes with cooling and then overnight at room temperature. It is then concentrated to dryness under vacuum and the residue is crystallized from methanol / ether.
Yield: 16.8 g (85.6% of theory),
Melting point: 165-167 ° C

Example XXVII [N- [4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] carbonyl] - [(Piperidin-4-yl) carbonyl] glycine methylester a) [N- [4- (4- (1-benzyl) -piperidinyl) -piperazin-1-yl] carbonyl] - piperidine-4-carboxylic acid methylester

Prepared by reacting piperidine-4-carboxylic acid methyl ester with chloroformic acid p-nitro-phenyl ester in the presence from triethylamine to N- (4-nitrophenyloxycarbonyl) piperidine 4-carboxylic acid methyl ester and subsequent reaction of this Intermediate with (4- (1-benzyl) -piperidinyl) -piperazine analogously to Example 5.

b) [N- [4- (4- (1-benzyl) -piperidinyl) -piperazin-1-yl] carbonyl] - piperidine-4-carboxylic acid

Prepared by reaction of [N- [4- (4- (1-benzyl) -piperi dinyl) -piperazin-1-yl] carbonyl] -piperidine-4-carboxylic acid-me methyl ester with half-concentrated hydrochloric acid analogously to Example 1.

c) [N- [4- (4- (1-Benzyl) -piperidinyl) -piperazin-1-yl] carbonyl] - (Piperidin-4-yl) carbonyl] -glycine methyl ester

Prepared by reaction of [N- [4- (4- (1-benzyl) -piperidi nyl) -piperazin-1-yl] carbonyl] piperidine-4-carboxylic acid, glycine methyl ester hydrochloride, 2- (1H-benzotriazol-1-yl) -1,1,3,3- tetramethyluronium tetrafluoroborate and 1-hydroxy-1H-benzotria zol analogously to Example XVIIIa.

Example XXVIII 4- (Ethoxycarbonyl-2-ethyloxy) -piperidine trifluoroacetate a) 4- (ethoxycarbonyl-2-ethyloxy) -N-tert-butyloxycarbonyl- piperidine

To a solution of 10 g) 0.0497 mol) of N-tert-butyloxycarbonyl-4-piperidinol in 20 ml of dioxane is added 0.3 g (0.0027 mol) of potassium tert-butylate and then dropwise and with stirring 13, 5 ml (0.124 mol) of ethyl acrylate and heated for 7 hours at reflux temperature. After stirring overnight at room temperature, it is concentrated to dryness under vacuum and the residue is partitioned between ethyl acetate and water. The organic phase is dried and concentrated to dryness in vacuo. The residue is purified over a silica gel column (eluent: cyclohexane / ethyl acetate = 10: 3).
Yield: 4.5 g of oil (30% of theory),
R _f value: 0.8 (silica gel, methylene chloride / methanol = 9: 1)

b) 4- (ethoxycarbonyl-2-ethyloxy) -piperidine trifluoroacetate

4.5 g (0.015 mol) of 4- (ethoxycarbonyl-2-ethyloxy) -N-tert-butyl oxycarbonyl-piperidine are allowed to stand in a mixture of 30 ml of methylene chloride and 20 ml of trifluoroacetic acid for 4 hours at room temperature. It is concentrated to dryness under vacuum and receives 4.5 g of a colorless oil.
R _f value: 0.20 (silica gel, methylene chloride / methanol = 9: 1)

Example XXIX [4 - [[4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] carbonylami no] phenoxy] acetic acid pivaloyloxymethyl ester

A mixture of equimolar parts of [4 - [[4- (4- (1-benzyl) piperidinyl) -piperazin-1-yl] carbonylamino] phenoxy] acetic acid, Pivaloyl chloromethyl ester, potassium iodide and potassium carbonate is stirred in dimethylformamide at room temperature for 2 days. Then it is poured into water and with ethyl acetate extra hiert. The combined organic phases are dried and concentrated to dryness under vacuum. The remaining residue is gerei by chromatography on a silica gel nigt.  

Example XXX [4 - [[4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] carbonylami no] phenoxy] acetic acid, ethyl (1-ethoxy) -carbonyloxyethylester

Prepared from [4 - [[4- (4- (1-benzyl) -piperidinyl] -piperazine-1 yl] carbonylamino] phenoxy] acetic acid and 1-chloroethyl-ethylcar Bonate analogous to Example XXIX.

Production of final products example 1 [4-trans- [3- [4- (4-piperidinyl) -piperazin-1-yl] propionyl] amino] cyclohexane carboxylic acid dihydrochloride

A solution of 0.22 g (0.00058 mol) of [4-trans- [3- [4- (piperidinyl) -piperazin-1-yl] -propionyl] -amino] cyclohexanecarboxylic acid methyl ester in 20 ml of half-concentrated hydrochloric acid is added during 4 hours allowed to stand at room temperature and then concentrated to dryness under vacuum. The remaining residue is mixed with acetone and concentrated again to dryness. The residue is triturated with acetone, filtered off with suction and dried.
Yield: 0.21 g (82.7% of theory),
Melting point: 286-288 ° C
R _f value: 0.1 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
The following compounds can be prepared analogously to Example 1:

(1) [3- [4-trans- [4- (4-piperidinyl) piperazin-1-yl) carbonyl amino] cyclohexyl] propionic acid dihydrochloride

Prepared from [3- [4-trans- [4- [4- (piperidinyl) -piperazin-1-yl] carbonylamino] cyclohexyl] -propionic acid methyl ester dihydrochloride.
Melting point: 318-320 ° C
Mass spectrum: M⁺ = 366
R _f value: 0.1 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(2) [4-trans- [4- (4-piperidinyl) piperazin-1-yl] malonylamino] cyclohexane dihydrochloride

Prepared from [4-trans- [4- (piperidinyl) piperazin-1-yl] malonylamino] cyclohexanecarboxylic acid methyl ester dihydrochloride.
Melting point: 256-258 ° C
Mass spectrum: M⁺ = 380
R _f value: 0.07 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(3) 3- [4- [4- (4-piperidinyl) piperazin-1-yl] carbonylamino] pi peridino-propionic acid dihydrochloride

Prepared from 3- [4- [4- (4-piperidinyl) piperazin-1-yl] carbo nylamino] piperidinopropionic acid methyl ester dihydrochloride.
Melting point: 281-283 ° C
Mass spectrum: M⁺ = 335
R _f value: 0.1 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(4) [4- [4- (4-piperidinyl) piperazin-1-yl] carbonylamino] piperidinoessigsäure trihydrochloride

Prepared from [4- [4- (4-piperidinyl) -piperazin-1-yl] carbo nylamino] -piperidinoacetic acid methyl ester trihydrochloride.
Mass spectrum: M⁺ = 353
R _f value: 0.1 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.25)

(5) N- [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] piperi dinyl] -β-alanine trihydrochloride

Prepared from N- [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] piperidinyl] -β-alanine methyl ester trihydrochloride.
Melting point: 282-284 ° C (decomp.)
Mass spectrum: M⁺ = 367
R _f value: 0.6 (reversed phase plate RP18, methanol / 5% sodium chloride solution = 6: 4)

(6) N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] -3- (4-pi piperidinyl) propionic acid dihydrochloride

Prepared from N - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl] -3- (4-piperidinyl) -propionic acid methyl ester dihydrochloride.
Melting point: 293-294 ° C (decomp.)
R _f value: 0.57 (reversed phase plate RP18, methanol / 5% sodium chloride solution = 6: 4)

(7) N-Acetyl-N- [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbo nyl] piperidinyl] -β-alanine dihydrochloride

Prepared from N-acetyl-N- [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] piperidinyl] -β-alanine methyl ester dihydrochloride. Oil,
Mass spectrum: M⁺ = 409
R _f value: 0.7 (Reversed phase plate RP18, methanol / 5% sodium chloride solution = 3: 2)

(8) N-methyl-N- [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbo nyl] piperidinyl] -β-alanine trihydrochloride

Prepared from N-methyl-N- [4 - [[4- (4-piperidinyl) -piperazine 1-yl] carbonyl] piperidinyl] -β-alanine-methylester-trihydro chloride.

(10) N- [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] piperi dinyl] glycine trihydrochloride

Prepared from N- [4 - [[4- (4-piperidinyl) -piperazin-1-yl] car carbonyl] piperidinyl] glycine methylester trihydrochloride.

(11) N-methyl-N- [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbo nyl] piperidinyl] glycine trihydrochloride

Prepared from N-methyl-N- [4 - [[4- (4-piperidinyl) -piperazine 1-yl] carbonyl] piperidinyl] glycine trihydrochloride methylester.

(12) N-acetyl-N- [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbon yl] piperidinyl] glycine dihydrochloride

Prepared from N-acetyl-N- [4 - [[4- (4-piperidinyl) -piperazine 1-yl] carbonyl] piperidinyl] glycine methylester dihydrochloride.

= (13) N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] -4- (4-pipe ridinyl) butyric acid dihydrochloride

Prepared from N - [[4- (4-piperidinyl) -piperazin-1-yl] -carboxyl] -4- (4-piperidinyl) -butyric acid methyl ester dihydrochloride.
Melting point: 296-298 ° C (decomp.)
R _f value: 0.45 (reversed phase plate RP18, methanol / 5% sodium chloride solution = 6: 4)

(14) N - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] -4-piperi dinyloxyessigsäure trihydrochloride

Prepared from N - [[4- (4-piperidinyl) -piperazin-1-yl] acetyl] -4-piperidinyloxyacetic acid methyl ester trihydrochloride.
Amorphous solid.
Mass spectrum: M⁺ = 368
R _f value: 0.24 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(15) N - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] -4-piperi dinylessigsäure trihydrochloride

Prepared from N - [[4- (4-piperidinyl) -piperazin-1-yl] acetyl] -4-piperidinylacetic acid methyl ester trihydrochloride.
Amorphous solid.
Mass spectrum: M⁺ = 352
R _f value: 0.15 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(16) N - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] piperazino acetic acid tetrahydrochloride

Prepared from N - [[4- (4-piperidinyl) -piperazin-1-yl] acetyl] -piperazinoacetic acid methyl ester tetrahydrochloride.
Amorphous solid.
Mass spectrum: (M + H) ⁺ = 354

(17) [4-trans - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] amino] cyclohexanecarboxylic trihydrochloride

Prepared from [4-trans - [[4- (4-piperidinyl) -piperazin-1-yl] -acetyl] -amino] cyclohexanecarboxylic acid methyl ester trihydrochloride.
Amorphous solid.
Mass spectrum: M⁺ = 352
R _f value: 0.85 (reversed phase plate RP18, methanol / 5% sodium chloride solution = 3: 2)

(18) N - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] -3- (4-piper Diny) -propionic acid trihydrochloride

Prepared from N - [[4- (4-piperidinyl) -piperazin-1-yl] acetyl] -3- (4-piperidinyl) -propionic acid methyl ester trihydrochloride.
Amorphous solid.
Mass spectrum: (M + H) ⁺ = 367
R _f value: 0.63 (reversed phase plate RP18, methanol / 5% sodium chloride solution = 3: 2)

(19) [4 - [[4- (4-piperidinyl) piperazin-1-yl] acetyl) phenoxy] acetic acid trihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] phenoxy] acetic acid methyl ester trihydrochloride.
Melting point: 265-270 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 362
R _f value: 0.075 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(20) [3 - [[4- (4-piperidinyl) piperazin-1-yl) carbonylamino] phen oxyiessigsäure dihydrochloride

Prepared from [3 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid methyl ester dihydrochloride.
Melting point: 240-242 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 363
R _f value: 0.07 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(21) 4 - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] phenylacetic acid acid trihydrochloride

Prepared from 4 - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] phenylacetic acid methylester trihydrochloride.

(22) [3 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phe nyl] propionic acid dihydrochloride

Prepared from methyl 3- [4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenyl] propionate dihydrochloride.
Melting point: 289-292 ° C (decomp.)
Mass spectrum: M⁺ = 360
R _f value: 0.8 (reversed phase plate RP18, methanol / 5% sodium chloride solution = 6: 4)

(23) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phen oxy] acetic acid dihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid methyl ester dihydrochloride.
Melting point: 263-265 ° C (decomp.)
Mass spectrum: M⁺ = 362
R _f value: 0.75 (reversed phase plate RP18, methanol / 5% sodium chloride solution = 6: 4)

(24) N- [4-trans- [4- (4-piperidinyl) -piperazin-1-yl] carbonyl aminocyclohexyl] glycine trihydrochloride

Prepared from N- [4-trans- [4- (4-piperidinyl) piperazin-1-yl] carbonylaminocyclohexyl] glycine methyl ester trihydrochloride. Amorphous solid.
Mass spectrum: (M + H) ⁺ = 368
R _f value: 0.095 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(25) N- [4-trans- [4- (4-piperidinyl) piperazin-1-yl] carbonyl aminocyclohexyl] sarcosine trihydrochloride

Prepared from N- [4-trans- [4- (4-piperidinyl) -piperazin-1-yl] carbonylaminocyclohexyl] sarcosine methylester-trihydrochloride.

(26) N-acetyl-N- [4-trans- [4- (4-piperidinyl) -piperazin-1-yl] carbonylaminocyclohexyl] glycine dihydrochloride

Made from N-acetyl-N- [4-trans- [4- (4-piperidinyl)] -pipe Razin-1-yl] carbonylaminocyclohexyl] glycine methyl ester-dihydro chloride.

(27) N- [4- [4- (4-piperidinyl) piperazin-1-yl] carbonylamino phenyl] glycine dihydrochloride

Prepared from N- [4- [4- (4-piperidinyl) piperazin-1-yl] car bonylaminophenyl] glycine methyl ester dihydrochloride.
Amorphous solid.
Mass spectrum: (M + H) ⁺ = 362

(28) N- [4- [4- (4-piperidinyl) piperazin-1-yl] carbonylaminophe nyl] sarcosine dihydrochloride

Prepared from N- [4- [4- (4-piperidinyl) -piperazin-1-yl] carbo nylaminophenyl] sarcosine methylester-dihydrochloride.

(29) N-Acetyl-N- [4- [4- (4-piperidinyl) piperazin-1-yl] carbonyl aminophenyl] glycine dihydrochloride

Prepared from N-acetyl-N- [4- [4- (4-piperidinyl) -piperazine 1-yl] carbonylaminophenyl] glycine methylester dihydrochloride.

(30) N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] -3- (piperi din-4-yloxy) propionic acid dihydrochloride

Prepared from N - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl] -3- (piperidin-4-yloxy) -propionic acid, ethyl ester dihydrochloride.
Melting point: 288-290 ° C (decomp.)
Mass spectrum: M⁺ = 368
R _f value: 0.65 (reversed phase plate RP 18, methanol / 5% sodium chloride solution = 3: 2)

(31) [4-trans- [4- (4-piperidinyl) piperazin-1-yl] carbonylamino cyclohexyloxy] acetic acid dihydrochloride

Prepared from [4-trans- [4- (4-piperidinyl) piperazin-1-yl] car bonylaminocyclohexyloxy] acetic acid methyl ester dihydrochloride.
Melting point: 290-296 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 369
R _f value: 0.75 (reversed phase plate RP 18, methanol / 5% sodium chloride solution = 3: 2)

(32) N - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl] - (piperidine) 4-yloxy) -acetic acid dihydrochloride

Prepared from N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] - (Piperidin-4-yloxy) -acetic acid methylester dihydrochloride.  

(33) N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] - (piperidine) 4-yl) carbonyl] glycine dihydrochloride

Prepared from N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] - (piperidin-4-yl) carbonyl] glycine ethyl ester dihydrochloride.
Melting point: 276-278 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 382
R _f value: 0.21 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(34) N-Benzyl-N- [4- [4- (4-piperidinyl) piperazin-1-yl] carbonyl aminophenyl] glycine dihydrochloride

Prepared from N-benzyl-N- [4- [4- (4-piperidinyl) -piperazine 1-yl] carbonylaminophenyl] glycine methylester dihydrochloride.

Example 2 3- [4-trans - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl amino] cyclohexyl] propionic acid methylester dihydrochloride

To a solution of 1.6 g (0.0033 mol) of 3- [4-trans- [4- [4- (1-tert-butyloxycarbonyl) piperidinyl] piperazin-1-yl] carbonylamino] cyclohexyl] propionic acid Methyl ester in 10 ml of methanol is added 20 ml of ethereal hydrochloric acid and allowed to stand overnight at room temperature. It is then concentrated to dryness under vacuum, the residue is mixed with acetone and concentrated again to dryness. The solid residue is sealed with acetone, filtered off with suction and dried.
Melting point: 311-313 ° C
Mass spectrum: M⁺ = 380
R _f value: 0.09 (silica gel, methylene chloride / methanol = 9: 1)
The following compounds can be prepared analogously to Example 2:

(1) [4-trans- [4- (4-piperidinyl) piperazin-1-yl] malonylamino] cyclohexyl carboxylic acid-methylester dihydrochloride

Prepared from [4-trans- [4- (4- (1-tert-Butyloxycarbonyl) -pi-peridinyl) -piperazin-1-yl] malonylamino] cyclohexylcarboxylic acid methyl ester and ethereal hydrochloric acid in methanol.
Melting point: 254-256 ° C
Mass spectrum: M⁺ = 394
R _f value: 0.08 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(2) 3- [4- [4- (4-piperidinyl) piperazin-1-yl] carbonylamino] pipe ridinopropionsäure-methylester trihydrochloride

Prepared from methyl 3- [4- [4- (4- (1-tert-butoxycarbonyl) -piperidininyl) piperazin-1-yl] carbonylamino] piperidinopropionate and ethereal hydrochloric acid in methanol.
Melting point: 275-277 ° C
Mass spectrum: M⁺ = 381
R _f value: 0.08 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

(3) [4- [4- (4-piperidinyl) piperazin-1-yl] carbonylamino] piperi dino acetic acid methylester trihydrochloride

Prepared from [4- [4- (4- (1-tert-Butyloxycarbonyl) -piperidinyl] -piperazin-1-yl] carbonylamino] -piperidinoacetic acid methyl ester and ethereal hydrochloric acid in methanol.
Melting point: 260-265 ° C (decomp.)
Mass spectrum: M⁺ = 367
R _f value: 0.1 (silica gel, methylene chloride / methanol = 9: 1)

(4) N- [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] piperi dinyl] -β-alanine methylester trihydrochloride

Prepared from N-tert-butyloxycarbonyl-N- [4- [4- [4- (1-tert-butyloxycarbonyl-piperidinyl) -piperazin-1-yl] carbonyl] piperi-dinyl] -β-alanine methyl ester and 50% Trifluoroacetic acid in methylene chloride.
Melting point: 273-275 ° C (decomp.)
Mass spectrum: M⁺ = 381

(5) N-acetyl-N- [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl] piperidinyl] -β-alanine methylester dihydrochloride

Prepared from N-acetyl-N- [4 - [[4- (4- (1-tert-butyloxycarbonyl-piperidinyl) -piperazin-1-yl] -carbonyl] -piperidinyl] -β-alanine methyl ester and 50% trifluoroacetic acid in methylene chloride.
Melting point: 260-262 ° C (decomp.)

(6) N-methyl-N- [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbo nyl] piperidinyl] -β-alanine methylester trihydrochloride

Made of N- [4 - [[4- (4- (1-tert-butyloxycarbonyl)] -pipe ridinyl) -piperazin-1-yl] carbonyl] piperidinyl] -N-methyl-β- alanine methyl ester and 50% trifluoroacetic acid in methyl lenchlorid.

(7) N- [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] pi piperidinyl] glycine methylester trihydrochloride

Prepared from N-tert-butyloxycarobyl-N- [4 - [[4- (4- (1-tert. butyloxycarbonyl) piperidinyl) -piperazin-1-yl] carbonyl] pi peridinyl] glycine methyl ester and 50% trifluoroacetic acid in Methylene chloride.

(8) N-methyl-N- [4 - [[4- (4-piperidinyl) -piperazin-1-yl] car carbonyl] piperidinyl] glycine methylester trihydrochloride

Made of 4- [4 - [[4- (4- (1-tert-butyloxycarbonyl)] -pipe ridinyl) -piperazin-1-yl] carbonyl] piperidinyl] -N-methyl-glycine methyl ester and 50% trifluoroacetic acid in methylene chloride.

(9) N-acetyl-N- [4 - [[4- (4-piperidinyl) -piperazin-1-yl] car carbonyl] piperidinyl] glycine methylester dihydrochloride

Prepared from N-acetyl-N- [4 - [[4- (4- (1-tert.butyloxycar carbonyl) piperidinyl) -piperazin-1-yl] carbonyl] - (piperidinyl] glycine methyl ester and 50% trifluoroacetic acid in methyl lenchlorid.  

(10) N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] -4- (4-pi piperidinyl) -butyric acid methylester dihydrochloride

Prepared from N - [[4- (4- (1-tert-Butyloxycarbonyl) -piperidinyl] -piperazin-1-yl] carbonyl] -4- (4-piperidinyl) -butyrate methyl ester and 50% trifluoroacetic acid in methylene chloride.
Melting point: 306-307 ° C (decomp.)
R _f value: 0.15 (reversed phase plate RP18; methanol / 5% sodium chloride solution = 6: 4)

(11) [4 - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] phenoxy] acetic acid methylester trihydrochloride

Prepared from [4 - [[4- (4- (1-tert-Butyloxycarbonyl) piperidinyl] piperazin-1-yl] acetyl] phenoxy] acetic acid methyl ester and ethereal hydrochloric acid.
Melting point: 245-247 ° C
Mass spectrum: M⁺ = 375
R _f value: 0.095 (silica gel, methylene chloride / methanol = 9: 1)

(12) [3 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phen oxy] acetic acid methylester dihydrochloride

Prepared from [3 - [[4- (4- (1-tert-Butyloxycarbonyl) -piperi-dinyl) -piperazin-1-yl] -acetyl] -phenoxy] -acetic acid methyl ester and ethereal hydrochloric acid.
Melting point: 250-252 ° C
Mass spectrum: M⁺ = 376
R _f value: 0.095 (silica gel, methylene chloride / methanol = 9: 1)

(13) 4 - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] phenylacetic acid acid methylester trihydrochloride

Prepared from 4 - [[4- (4- (1-tert-Butyloxycarbonyl) piperidi nyl) -piperazin-1-yl] acetyl] phenylacetic acid methyl ester and ethereal hydrochloric acid.  

(14) [3 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phe nyl] propionic acid methylester dihydrochloride

Prepared from [3 - [[4- (4- (1-tert-Butyloxycarbonyl) piperidinyl) -piperazin-1-yl] carbonylamino] phenyl] propionic acid methyl ester and ethereal hydrochloric acid.
Melting point: 292-295 ° C (decomp.)
Mass spectrum: M⁺ = 374
R _f value: 0.80 (reversed phase plate RP 18, methanol / 5% sodium chloride solution = 3: 2)

(15) N - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl] -3- (pipe ridin-4-yloxy) -propionic acid ethyl ester dihydrochloride

Prepared from N - [[4- (4- (1-tert-Butyloxycarbonyl) -piperidinyl) -piperazin-1-yl] carbonyl] -3- (piperidin-4-yloxy) -propionic acid ethyl ester and 50% Trifluoroacetic acid in methylene chloride.
Amorphous solid
Mass spectrum: M⁺ = 390
R _f value: 0.12 (silica gel, methylene chloride / methanol = 9: 1)

Example 3 [4-trans- [3- [4- (4-piperidinyl) -piperazin-1-yl] propionyl] amino] cyclohexanecarboxylic acid-methylester

0.8 g (0.0017 mol) of [4-trans- [3- [4- (4- (1-benzyl) -piperidinyl) -piperazin-1-yl] propionyl] -amino] cyclohexanecarboxylic acid methyl ester are dissolved in 20 ml Methanol exhaustively hydrogenated at room temperature and a hydrogen pressure of 50 psi over palladium on carbon hydroxide as a catalyst. The catalyst is filtered off with suction and the solution is concentrated to a small volume. The precipitated crystals are sucked off.
Yield: 0.42 g (65% of theory),
Melting point: 173-178 ° C
Mass spectrum: M⁺ = 380
R _f value: 0.18 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
The following compounds can be prepared analogously to Example 3:

(1) N - [[- (4-piperidinyl) piperazin-1-yl] carbonyl] -3- (4-piperi dinyl) -propionic acid methylester dihydrochloride

Prepared from N - [[4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] carbonyl] -3- (4-piperidinyl) -propionic acid methyl ester dihydrochloride by hydrogenation over palladium on carbon (10%). ig).
Melting point: 284-286 ° C (decomp.)
R _f value: 0.10 (silica gel, methylene chloride / methanol = 9: 1)

(2) N - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] -4-piperi dinyloxyessigsäure-methylester trihydrochloride

Prepared from N - [[4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] acetyl] -4-piperidinyloxyacetic acid methyl ester by hydrogenation over palladium on carbon (10%).
amorphous solid
Mass spectrum: M⁺ = 382
R _f value: 0.32 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(3) N - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] -4-piperi dinylacetic acid methyl ester trihydrochloride

Prepared from N - [[4- (4- (1-benzyl) -piperidinyl) -piperazin-1-yl] -acetyl] -4-piperidinylacetic acid methyl ester by hydrogenation over palladium on carbon (10%).
Melting point: 250-253 ° C
Mass spectrum: M⁺ = 366
R _f value: 0.35 (silica gel, methylene chloride / methanol, concentrated ammonia = 2: 1: 0.25)

(4) N - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] piperazino acetic acid methylester tetrahydrochloride

Prepared from N - [[4- (4- (1-benzyl) -piperidinyl) -piperazin-1-yl] -acetyl] -piperazinoacetic acid methyl ester by hydrogenation over palladium on carbon (10%).
Melting point: 130-135 ° C (decomp.)
Mass spectrum: M⁺ = 367
R _f value: 0.065 (silica gel, methylene chloride / methanol = 9: 1)

(5) [4-trans - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] amino] cyclohexane-methylester trihydrochloride

Prepared from [4-trans [[4- (4- (1-benzyl) -piperidinyl) -pipera-zin-1-yl] -acetyl] -amino] cyclohexanecarboxylic acid methyl ester trihydrochloride by hydrogenation over palladium on carbon (10%) ,
Melting point: 275-277 ° C (decomp.)
Mass spectrum: M⁺ = 366

(6) N - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] -3- (4-piperi dinyl) -propionic acid methylester trihydrochloride

Prepared from N - [[4- (4- (1-benzyl) -piperidinyl) -piperazin-1-yl] acetyl] -3- (4-piperidinyl) -propionic acid methyl ester trihydrochloride by hydrogenation over palladium on carbon.
Melting point: 247-249 ° C (decomp.)
Mass spectrum: M⁺ = 380

(7) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phen oxy] acetic acid methylester dihydrochloride

Prepared by [4- [4- (4- (1-benzyl) -piperidinyl) -piperazin-1-yl] carbonylamino] phenoxy] -acetic acid methyl ester by heating over palladium hydroxide on carbon.
Melting point: 266-269 ° C
Mass spectrum: M⁺ = 376
R _f value: 0.65 (reversed phase plate RP18, methanol / 5% saline solution)

(8) 1 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl] - [(piperi din-4-yl) -carbonyl] glycine ethyl ester dihydrochloride

Prepared from N - [[4- (4- (1-benzyl) piperidinyl) piperazin-1-yl] carbonyl] - [(piperidin-4-yl) carbonyl] glycine ethyl ester and palladium on carbon (10%). ig) as a catalyst.
Melting point: 295-296 ° C (decomp.)
Mass spectrum: M⁺ = 409
R _f value: 0.50 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(9) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phen oxy] acetic acid pivaloyloxymethyl ester

Prepared from [4 - [[4- (4- (1-benzyl) -piperidinyl] -piperazine- 1-yl] carbonylamino] phenoxy] acetic acid pivaloyloxymethyl ester by hydrogenating over palladium dihydroxide on carbon.

(10) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phen oxy] acetic acid, ethyl (1-ethoxy) -carbonyloxyethylester

Prepared from [4 - [[4- (4- (1-benzyl) -piperidinyl] -piperazine- 1-yl] carbonylamino] phenoxy] acetic acid 1-ethoxy) -carbonyloxy ethyl ester by hydrogenation over palladium dihydroxide on carbon.

(11) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid tert-butyl ester dihydrochloride

Prepared from [4 - [[4- [4- (1-benzyl) -piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy] -acetic acid tert -butyl ester by hydrogenation over palladium on carbon (10%) in water ,
Melting point: 288-290 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 419
R _f value: 0.08 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example 4 3- [4-trans - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] cyclohexyl] propionic acid cyclohexyl ester dihydrochloride

By a suspension of 300 mg (0.7 mmol) of 3- [4-trans - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] cyclohexyl] propionic acid dihydrochloride in 20 ml of cyclohexanol is passed during half a hour a faint stream of hydrochloric acid gas. After about 5 minutes, clear solution occurs. It is allowed to stand overnight at room temperature and then heated for two hours at reflux temperature. After cooling, it is poured into ether and the precipitate is filtered off with suction.
Yield: 240 mg (67.4% of theory),
Melting point: 324-326 ° C
Mass spectrum: M⁺ = 448
R _f value: 0.55 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
The following compounds can be prepared analogously to Example 4:

(1) 3- [4-trans - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl amino] cyclohexyl] propionic acid isobutyl ester dihydrochloride

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⁺ = 422
R _f value: 0.47 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(2) 3- [4- [4- (4-piperidinyl) piperazin-1-yl] carbonylamino] pi peridinopropionsäure isobutyl trihydrochloride

Prepared from 3- [4- [4-piperidinyl] piperazin-1-yl] carbonyl amino] piperidinopropionic acid dihydrochloride and isobutanol.

(3) 3- [4- [4- (4-piperidinyl) piperazin-1-yl] carbonylamino] pi peridinopropionsäure cyclohexyl ester trihydrochloride

Prepared from 3- [4- [4- (4-piperidinyl) -piperazin-1-yl] car bonylamino] piperidinopropionic acid dihydrochloride and cyclo hexanol.

(4) 4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] pi peridinoessigsäure isobutyl trihydrochloride

Prepared from 4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl amino] piperidinoacetic acid dihydrochloride and isobutanol.  

(5) 4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] pi peridinoessigsäure cyclohexyl ester trihydrochloride

Prepared from 4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl amino] piperidinoacetic acid dihydrochloride and cyclohexanol.

(6) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid isopropyl ester dihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid dihydrochloride and isopropanol.
Melting point: 296-298 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 405
R _f value: 0.38 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(7) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid isobutyl ester dihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid dihydrochloride and isobutanol.
Melting point: 308-310 ° C (decomp.)
Mass spectrum: (M⁺H) + = 419
R _f value: 0.5 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(8) [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phen oxy] acetic acid neopentyl dihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid dihydrochloride and neopentyl alcohol.
Melting point: 250-252 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 433
R _f value: 0.45 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(9) [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phen oxy] acetic acid cyclopentyl dihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid dihydrochloride and cyclopentanol.
Melting point: 298-300 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 431
R _f value: 0.65 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

(10) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid cycloheptyl dihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid dihydrochloride and cycloheptanol.
resin
Mass spectrum: (M + H) ⁺ = 459
R _f value: 0.65 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.2)

(11) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenol oxy] acetic acid butyl ester dihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid dihydrochloride and 1-butanol.
Melting point: 300-301 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 419
R _f value: 0.5 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

(12) [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phen oxy] acetic acid cyclohexyl ester dihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid dihydrochloride and cyclohexanol.
Melting point: 291-293 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 445
R _f value: 0.35 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

(13) [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phen oxy] acetic acid ethyl ester dihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid dihydrochloride and ethanol.
Melting point: 288-290 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 391
R _f value: 0.35 (silica gel, methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)

Example 5 N-t-butyloxycarbonyl-N - [[4- [4- (4- (1-t-butyloxycarbonyl) piperidinyl) -piperazin-1-yl] carbonyl] piperidinyl] -β-alanine methylester

A mixture of 4.2 g (0.0068 mol) of crude N-tert-butyloxycarbonyl-N- [4- [1- (4-nitrophenyloxycarbonyl) -piperidinyl] -β-alanine methyl ester, 1.8 g (0 , 0068 mol) of N- [4- (1-tert-butyl-oxycarbonyl) -piperidinyl] -piperazine and 2.3 ml (0.0136 mol) of N-ethyl-diisopropylamine is heated at 140 ° C for 4 hours. After cooling, the mixture is partitioned between ethyl acetate and water, the organic phase is washed with sodium bicarbonate solution, dried and concentrated. The residue is purified over a silica gel column (eluant: methylene chloride with 2.5%, 3%, 4% methanol).
Yield: 1.3 g of colorless foam (33.6% of theory),
Mass spectrum: M⁺ = 581
R _f value: 0.48 (silica gel, methylene chloride / methanol = 9: 1)
The following compounds can be prepared analogously to Example 5:

(1) N-Acetyl-N - [[4- [4- (4- (1-tert-butyloxycarbonyl) -piperidine] nyl) piperazin-1-yl] carbonyl] piperidinyl] -β-alanine methylester

Prepared from N-acetyl-N- [4- [1- (4-nitrophenyloxycarbonyl) piperidinyl] -β-alanine methyl ester (prepared analogously to Example III) and N- [4- (1-tert-butyloxycarbonyl) -piperidyl ] -pipe razin.
Yield: 500 mg (9.1% of theory),
R _f value: 0.52 (silica gel, methylene chloride / methanol = 9: 1)

(2) N - [[4- [4- (4- (1-tert-Butyloxycarbonyl) -piperidinyl] piperazin-1-yl] carbonyl] piperidinyl] -N-methyl-β-alanine methylester

Prepared from N-methyl-N- [4- [1- (4-nitrophenyloxycarbonyl) piperidinyl]] - β-alanine methyl ester (preparation analogous to Game III) and N- [4- (1-tert-Butyloxycarbonyl) -piperidinyl] piperazine

(3) N-tert-butyloxycarbonyl-N - [[4- [4- (4- (1-tert.butyloxycar carbonyl) piperidinyl) -piperazin-1-yl] carbonyl] piperidinyl] glycine methylester

Prepared from N-tert-butyloxycarbonyl-N- [4- [1- (4-nitro phenyloxycarbonyl) piperidinyl]] glycine methyl ester (Herstel analogous to Example III) and N- [4- (1-tert-butyloxycarbonyl) piperidinyl] piperazine and N-ethyl-diisopropylamine.

(4) N - [[4- [4- (4- (1-tert-Butyloxycarbonyl) -piperidinyl] -pipera zin-1-yl] carbonyl] piperidinyl] -N-methyl-glycine methylester

Prepared from N-methyl-N- [4- [1- (4-nitrophenyloxycarbonyl) piperidinyl]] - glycine methyl ester (preparation analogous to Example III) and N- [4- (1-tert-butyloxycarbonyl) piperidinyl] piperazine and N-ethyl-diisopropylamine.

(5) N-Acetyl-N - [[4- [4- (4- (1-tert-butyloxycarbonyl) -piperidine] nyl) piperazin-1-yl] carbonyl] piperidinyl] glycine methylester

Prepared from N-acetyl-N- [4- [1- (4-nitrophenyloxycarbonyl) piperidinyl]] - glycine methyl ester (preparation analogous to Example III), N- [4- (1-tert-butyloxycarbonyl) piperidinyl] piperazine and N-ethyl-diisopropylamine.

(6) N - [[4- (4- (1-tert-Butyloxycarbonyl) -piperidinyl] -piperazine 1-yl] carbonyl] -4- (4-piperidinyl)] butyric acid methylester

Prepared from N- (4-nitrophenyloxycarbonyl) -4- (4-piperidinyl) -butyric acid methyl ester and N- [4- (1-tert-butyloxycarbonyl) piperidinyl] piperazine.
R _f value: 0.48 (silica gel, methylene chloride / methanol = 9: 1)

(7) N - [[4- (4- (1-tert-Butyloxycarbonyl) -piperidinyl] -piperazine 1-yl] carbonyl] -3- (piperidin-4-yloxy) -propionic acid ethyl ester

Prepared from ethyl N- (4-nitro-phenyloxycarbonyl) -3- (piperidine-4-yloxy) -propionate (prepared analogously to Example III) and N- [4- (1-tert-butyloxycarbonyl) -piperidinyl] -piperazine. Oil.
R _f value: 0.6 (silica gel, methylene chloride / methanol = 9: 1: 0.1)

Example 6 [3- [4-trans- [4- [4- (1-t-butyloxycarbonyl) piperidinyl] pipe Razin-1-yl] carbonylamino] cyclohexyl] propionic acid methylester

To a solution of 2 g (0.0123 mol) of N, N'-carbonyldiimidazole and 1.2 g (0.0176 mol) of imidazole in 150 ml of absolute dimethyl formamide is added dropwise with stirring and at -5 ° C, a solution of 2 , 5 g (0.0093 mol) of methyl 3- [4-trans-amino-cyclohexyl] propionate in 20 ml of absolute dimethylformamide and stirred for a further hour at -5 ° C and then at room temperature for 3 hours. Now added dropwise to a solution of 3 g (0.0135 mol) of N- [4- (1-tert-butyloxycarbonyl) piperidinyl] piperazine in 20 ml of absolute dimethylformamide and allowed to stir overnight at room temperature. It is concentrated to dryness in vacuo and the residue is purified on a silica gel column, with methylene chloride containing 2% and 4% of methanol as the eluent.
Yield: 1.75 g (32.3% of theory),
Mass spectrum: M⁺ = 480
R _f value: 0.5 (silica gel, methylene chloride / methanol = 9: 1)
The following compound can be prepared analogously to Example 6:

(1) [4- [4- (4- (1-tert-Butyloxycarbonyl) piperidinyl] piperazine 1-yl] carbonylamino] piperidinoessigsäure-methylester

Prepared from N- [4- (1-tert-Butyloxycarbonyl) piperidinyl] piperazine, 4-aminopiperidinoacetic acid methyl ester dihydrochloride, N, N'-carbonyldiimidazole and imidazole.
R _f value: 0.3 (silica gel, methylene chloride / methanol = 9: 1)

Example 7 [4-trans- [4- (4- (1-t-butyloxycarbonyl) -piperidinyl) -pipera zin-1-yl] malonylamino] cyclohexyl carboxylic acid-methylester

Prepared from 4 - [(4- (1-tert-Butyloxycarbonyl) piperidinyl) piperazin-1-yl] malonic acid, trans-4-aminocyclohexylcarboxylic acid methyl ester hydrochloride, 2- (1H-Benzotriazol-1-yl) -1,1 , 3,3-th tramethyluronium tetrafluoroborate, 1-hydroxy-1H-benzotriazole and triethylamine in dry dimethylformamide analogous to Example XVIIIa.
Yield: 0.6 g (35.9% of theory),
Mass spectrum: (M + H) ⁺ = 495
R _f value: 0.48 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example 8 3- [4- [4- (4- (1-t-butyloxycarbonyl) piperidinyl) -piperazine 1-yl] carbonylamino] -piperidinopropionsäure-methylester

To a solution of 4.3 g (0.011 mol) of 4- [4- [4- (4- (1-tert-Bu tyloxycarbonyl) piperidinyl) piperazino] carbonylamino) piperidin in 100 ml of methanol are added with stirring and at room temperature 1 g (0.011 mol) of methyl acrylate (1 ml) and allowed to stand for 4 hours at room temperature. The mixture is then concentrated to dryness under reduced pressure and the residue is purified by chromatography on a silica gel column (elution medium: methylene chloride / methanol / concentrated ammonia = 9: 0.5: 0.05).
Yield: 2.5 g (47.8% of theory),
Mass spectrum: M⁺ = 481
R _f value: 0.37 (silica gel, methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Example 9 [4- [4- (4- (1-t-butyloxycarbonyl) piperidinyl) -piperazine 1-yl] acetyl] phenoxyacetic acid methylester

A solution of 1.3 g (0.0048 mol) of α-bromo-4-methoxycarbonylmethyloxy-acetophenone, 1.3 g (0.0048 mol) of N- (4- (1-tert-butyl-oxycarbonyl) -piperidinyl) -piperazine and 0.62 g (0.0048 mol) of N-ethyl-diisopropylamine (0.82 ml) in 50 ml of methylene chloride is allowed to stand overnight at room temperature. The mixture is then concentrated to dryness under vacuum and the remaining residue is partitioned between ethyl acetate and water. The combined organic extracts are dried and concentrated to dryness in vacuo. The remaining residue is purified on a silica gel column (eluant: methylene chloride containing 3% methanol). The substance-containing eluates are evaporated. The residue is dissolved in a little methanol, this solution is acidified to pH 6 with ethereal hydrochloric acid and evaporated. The residue is triturated with acetone, filtered off with suction and dried.
Yield: 350 mg of colorless solid (15.3% of theory),
Mass spectrum: M⁺ = 475
R _f value: 0.6 (silica gel, methylene chloride / methanol = 9: 1).

The following compound can be prepared analogously to Example 9:

(1) [4- [4- [4- (1-tert-butyloxycarbonyl) piperidinyl] piperazine 1-yl] acetyl] phenylacetic acid

Prepared from N- [4- (1-tert-butyloxycarbonyl) -piperidinyl] piperazine and 4- (α-bromo-acetyl) -phenylacetic acid methyl ester.

Example 10 [3- [4- (4- (1-t-butyloxycarbonyl) piperidinyl) -piperazine 1-yl] acetyl] phenoxyacetic acid methylester

To a solution of 1.8 g (0.011 mol) of 1,1'-carbonyldi (1,2,4-triazole) in 50 ml of absolute tetrahydrofuran, which is cooled to -5 ° C is added dropwise with stirring, a solution of 2 g (0.011 mol) of 3-methoxycarbonylmethyloxy-aniline in 20 ml of absolute tetrahydrofuran. The mixture is stirred for a further half hour at -5 ° C and then for 1 hour at room temperature and then treated with a solution of 2.95 g (0.011 mol) of N- [4- (1-tert.butyloxycarbonyl) piperidinyl] piperazine in 20 ml of tetrahydrofuran and then heated for 2.5 hours at reflux temperature. After stirring overnight at room temperature, it is concentrated under vacuum and the residue is partitioned between ethyl acetate and water. The organic phase is separated, dried and concentrated. The resulting residue is purified over a silica gel column using methylene chloride containing 2.5% methanol as the eluent.
Yield: 1.8 g (34.2% of theory),
Mass spectrum: M⁺ = 476
R _f value: 0.5 (silica gel, methylene chloride / methanol = 9: 1)
The following compounds can be prepared analogously to Example 10:

(1) [3- [4- (4- (1-tert-Butyloxycarbonyl) -piperidinyl] -piperazine- 1-yl] carbonylamino] phenylpropionic acid methylester

Prepared from methyl 3- [4-amino-phenyl] -propionate hydrochloride, N- [4- (1-tert-butyloxycarbonyl) -piperidinyl] piperazine, N-ethyl-diisopropylamine and 1,1-carbonyldi (1,2,4- triazole)

(2) [4 - [[4- (4- (1-Benzyl) -piperidinyl) -piperazin-1-yl] carbonyl amino] phenoxy] acetic acid tert-butyl ester

Prepared from N- (4- (1-benzyl) piperidinyl) piperazine, 4-tert. Butyloxycarbonylmethyloxyaniline, 1,1-carbonyldi (1,2,4-triazole) and triethylamine.
Melting point: 295-298 ° C (decomp.)
R _f value: 0.43 (silica gel, methylene chloride / methanol = 9: 1)

Example 11 [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy] acetic acid, ethyl (R) -sec.butylester dihydrochloride

A suspension of 0.5 g (13 mmol) of [4 - [[4- (4-piperidinyl) -pi-perazin-1-yl] carbonylamino] -phenoxy] -acetic acid dihydrochloride and 10 ml of thionyl chloride is stirred for 2 hours at room temperature and then heated to reflux temperature for 2 more hours. The excess thionyl chloride is then distilled off under reduced pressure and the residue is suspended in 40 ml of methylene chloride. Add 1 ml of (R) -butan-2-ol and heated for 6 hours at reflux temperature. After distilling off the solvent, the rear is triturated in acetone and filtered with suction. The solid substance thus obtained is purified by chromatography on silica gel, with methylene chloride / methanol / conc. Ammonia = 2: 1: 0.25 is used as the eluent. The solid obtained after evaporation of the solid is dissolved in methylene chloride, converted with ethereal hydrochloric acid into the dihydrochloride and triturated after re-evaporation with ether.
Yield: 120 mg (21% of theory),
Melting point: 294-296 ° C (decomp.)
Mass spectrum: (M + H) ⁺ = 419
R _f value: 0.4 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
The following compound is prepared analogously to Example 11:

11 (1) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid, ethyl (S) -sec.butylester dihydrochloride

Prepared from [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid dihydrochloride, thionyl chloride and (S) -butan-2-ol.
Amorphous solid
Mass spectrum: (M + H) ⁺ = 419
R _f value: 0.4 (silica gel, methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)

Example 12 Dry ampoule containing 2.5 mg of active ingredient per 1 ml

composition Active ingredient | 2.5 mg mannitol 50.0 mg Water for injections ad 1.0 ml

manufacturing

Active substance and mannitol are dissolved in water. After bottling is freeze-dried. The resolution for ready to use Solution is with water for injections.

Example 13 Dry ampoule containing 35 mg of active ingredient per 2 ml

composition Active ingredient | 35.0 mg mannitol 100.0 mg Water for injections ad 2.0 ml

manufacturing

Active substance and mannitol are dissolved in water. After bottling is freeze-dried.

The solution to the ready-to-use solution is water for injections.  

Example 14 Tablet with 50 mg active ingredient

composition (1) Active substance | 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

manufacturing

(1), (2) and (3) are mixed and treated with an aqueous solution granulated by (4). The dried granules are added (5) mixed. From this mixture tablets are pressed biplan with double-sided facet and one-sided part notch. Diameter of the tablets: 9 mm.

Example 15 Tablet with 350 mg active ingredient

composition (1) Active ingredient | 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

manufacturing

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are mixed (5). From this mixture tablets are pressed, biplan with double-sided facet and one-sided part score.
Diameter of the tablets: 12 mm.

Example 16 Capsules with 50 mg active ingredient

composition (1) Active substance | 50.0 mg (2) dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg (4) magnesium stearate  2.0 mg 160.0 mg

manufacturing

(1) is triturated with (3). This trituration becomes the mix from (2) and (4) with intensive mixing.

This powder mixture is placed on a capsule filling machine in Hard gelatine capsules size 3 bottled.

Example 17 Capsules with 350 mg active ingredient

composition (1) Active ingredient | 350.0 mg (2) dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) magnesium stearate  4.0 mg 430.0 mg

manufacturing

(1) is triturated with (3). This trituration becomes the mix from (2) and (4) with intensive mixing.

This powder mixture is placed on a capsule filling machine in Hard gelatine capsules size 0 filled.

Claims (11)

1. piperazine derivatives of the general formula in the
R _{a is} a 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexamethyleneiminyl or 4-hexamethyleneiminyl group, where in each case the hydrogen atom of the abovementioned alkylene imino rings may be replaced by an in vivo cleavable radical,
Y₁ is a -CO-, -A₁-CO- or -CO-A₁-CO- group in which
A₁ is an nC _1-5 -alkylene group optionally substituted by a C _1-5 -alkyl, aryl or aryl-C _1-3 -alkyl group and A₁ of the -A₁-CO group is attached to the nitrogen atom of the piperazino group,
Y₂ is a phenylene, 3-piperidinylene, 4-piperidinylene or 1,4-piperazinylene group or a -NR₁-B group, wherein the linkage with the Y₁ group is via the nitrogen atom of the -NR₁ group, as well as
R₁ represents a hydrogen atom, a C _1-5 alkyl, aryl or aryl C _1-3 alkyl group and
B represents a phenylene, cyclohexylene or piperidinylene group, wherein the linkage of the piperidinylene group takes place via the or 4-position with the radical -NR₁-,
Y₃ is a -CO-, -A₂-CO-, -NR₂-A₃-CO or -O-A₃-CO group, in which
A₂ is an optionally substituted by a C _1-5 alkyl, aryl or aryl-C _1-3 alkyl group nC _1-4 alkylene group,
A₃ is an optionally substituted by a C _1-5 alkyl, aryl or aryl-C _1-3 alkyl group substituted nC _1-3 alkylene group and
R₂ represents a hydrogen atom, a C _1-5 -alkyl, aryl-C _1-3 -alkyl, aryl, C _1-5 -alkoxycarbonyl or C _1-5 -alkanoyl group and the linkage of -A₂-CO Group on the radical A₂, the -NR₂-A₃-CO group via the NR₂ group and the -O-A₃-CO group via the oxygen atom with the radical Y₂ takes place, but where a -NR₂- or -O- A₃-CO group can not be linked to a nitrogen atom of the radical B,
and E is a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, a phenylalkoxy group in which the alkoxy part may contain 1 to 3 carbon atoms, a cycloalkoxy group having 3 to 9 carbon atoms, in which the cycloalkyl part having 5 to 8 carbon atoms is additionally represented by one or two Alkyl groups each having 1 to 3 carbon atoms may be substituted, a cycloalkoxy group having 5 to 8 Kohlenstoffato men, in which in the Cycloalkylteil a methylene group in the 3- or 4-position by an oxygen atom or by a given if by an alkyl, phenylalkyl or Phenylalkoxycarbo nylgruppe, in which the alkyl and alkoxy moiety may each contain 1 to 3 carbon atoms, or replaced by a Alkanoylgrup pe with 2 to 6 carbon atoms substituted imino group and the cycloalkyl moiety may be additionally tuiert by one or two alkyl groups each having 1 to 3 carbon atoms a cycloalkenyloxy group in which the cycloalkenylte il 4 to 7 carbon atoms, an alkenyloxy, phenylalkenyloxy, alkynyloxy or phenylalkyi nyloxygruppe with the proviso that no binding to the oxygen atom from a carbon atom, which carries a double or triple bond and in which the alkenyl and Alkynyl moiety each containing 3 to 5 carbon atoms, a cycloalkylalkoxy group in which the cycloalkyl moiety may contain 3 to 8 carbon atoms and the alkoxy moiety may contain 1 to 3 carbon atoms, a bicycloalkoxy group having a total of 8 to 10 carbon atoms which in the bicycloalkyl moiety may additionally be substituted by one or two alkyl groups each 1 to 3 carbon atoms may be substituted, a 1,3-dihydro-3-oxo-1-isobenzfuranyloxygruppe or a R₅-CO-O- (R₃CR₄) -O- group, in the
R₃ represents a hydrogen atom, a C _1-6 -alkyl, C _3-7 -cycloalkyl or phenyl group,
R₄ is a hydrogen atom or a C _1-6 alkyl group and
R₅ represents a C _1-5 -alkyl, C _1-5 -alkoxy, C _5-7 -cycloalkyl or C _5-7 -cycloalkoxy group,
or E represents an α-amino group of a natural amino acid and its esters,
their tautomers, their stereoisomers, including their mixtures, and their salts,
wherein, under the term "a phenyl group" mentioned in the definition of the above radicals, one optionally substituted by fluorine, chlorine, bromine or iodine atoms, by alkyl, trifluoromethyl, nitro, amino, alkylamino, dialkylamino, Al kanoylamino, hydroxy, alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl mono-, di- or trisubstituted phenyl group, wherein the substituents may be the same or different and the abovementioned alkyl and alkoxy moieties each 1 may contain up to 3 carbon atoms,
among the esters of a natural α-amino group, their C _1-6 alkyl, C _2-6 alkenyl, C _5-7 cycloalkyl, phenyl or phenyl C _1-3 alkyl esters such as the methyl, ethyl , n-propyl, iso-propyl, tert-butyl, allyl, phenyl or benzyl esters and
an in vivo leaving group is an alkanoyl group having a total of 1 to 6 carbon atoms, a benzoyl, allyloxy carbonyl, C _1-5 alkoxycarbonyl or phenylC _1-3 alkoxy-carbonyl group such as the formyl, acetyl, propionyl , Butanoyl, pentanoyl, hexanoyl, benzoyl, allyloxycarbonyl, methoxy carbonyl, ethoxycarbonyl, propoxycarbonyl, Isopropoxycar bonyl, butoxycarbonyl, tert.butoxycarbonyl, Pentoxycar bonyl, hexoxycarbonyl, benzyloxycarbonyl, phenylethoxy carbonyl - or phenylpropoxycarbonyl to understand. 2. piperazine derivatives of the general formula I according to claim 1, in which
R _{a represents} a 3-pyrrolidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexamethyleneiminyl or 4-hexamethyleneiminyl group, in each case the hydrogen atom of the abovementioned alkylene imino rings being protected by an alkanoyl group having a total of 1 to 6 carbon atoms, a benzoyl group. , Allyloxycarbonyl, C _1-5 -alkoxycarbonyl or phenyl-C _1-3 -alkoxycarbonyl group may be replaced,
Y₁ is a -CO-, -A₁-CO- or -CO-A₁-CO- group in which
A₁ is an optionally substituted by a C _1-5 alkyl, phenyl or phenyl-C _1-3 alkyl group nC _1-5 alkylene group and A₁ of the -A₁-CO group is connected to the nitrogen atom of the piperazino group,
Y₂ is a 1,3-phenylene, 1,4-phenylene, 3-piperidinylene, 4-Pi peridinylene or 1,4-piperazinylene group or a -NR₁-B group, wherein the linkage with the Y₁ group via the nitrogen atom of the -NR₁ group takes place, as well as
R₁ is a hydrogen atom, a C _1-5 alkyl, phenyl or phenyl C₁-3 alkyl group and
B represents a 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene, 1,4-cyclohexylene or piperidinylene group, where in the linking of the piperidinylene each via the 3- or 4-position with the Rest -NR₁- occurs,
Y₃ is a -CO-, -A₂-CO-, -NR₂-A₃-CO or -O-A₃-CO group, in which
A₂ is an optionally substituted by a C _1-5 alkyl, phenyl or phenyl-C _1-3 alkyl group nC _1-4 alkylene group,
A₃ is an optionally alkyl group by a C _1-5 alkyl, phenyl or phenyl-substituted C _1-3 -alkylene group, and nC _1-3
R₂ represents a hydrogen atom, a C _1-5 -alkyl, phenyl-C _1-3 -alkenyl, phenyl, C _1-5 -alkoxycarbonyl or C _1-5 -alkanoyl group and the linkage of the -A₂- CO group via the radical A₂, the -NR₂-A₃-CO group via the NR₂ Grup pe and the -O-A₃-CO group via the oxygen atom with the radical Y₂ takes place, but where a -NR₂- or - O-A₃-CO- group can not be linked ver with a nitrogen atom of the radical B,
and E is a hydroxy, C _1-6 alkoxy, phenylC _1-3 -alkoxy, C _5-7 cycloalkoxy or R₅-CO-O- (R₃CR₄) -O- group in which
R₃ represents a hydrogen atom, a C _1-6 -alkyl, C _3-7 -cycloalkyl or phenyl group,
R₄ is a hydrogen atom or C _1-6 alkyl group and
R₅ represents a C _1-5 alkyl, C _1-5 alkoxy, C _5-7 cycloalkyl or C _5-7 cycloalkoxy group, or
an α-amino group of a natural amino acid and its C _1-6 -alkyl or benzyl ester,
their tautomers, their stereoisomers, including their mixtures, and their salts. 3. piperazine derivatives of the general formula I according to claim 1, in which
R _{a is} a 3- or 4-piperidinyl group, wherein in each case the hydrogen atom of the abovementioned Alkyleniminoringe can be replaced by an allyloxycarbonyl, C _1-5 alkoxycarbonyl or phenyl-C _1-3 alkoxycarbonylgruppe,
Y₁ is a -CO-, -A₁-CO- or -CO-A₁-CO- group in which
A₁ is an nC _1-5 -alkylene group optionally substituted by a C _1-5 -alkyl, benzyl, 1-phenylethyl or 2-phenylethyl group and A₁ of the -A₁-CO group is attached to the nitrogen atom of the piperazino group,
Y₂ is a 1,4-phenylene, 4-piperidinylene or 1,4-piperazinylene group or a -NR₁-B group, linking with the Y₁ group via the nitrogen atom of the -NR₁ group, as well as
R₁ represents a hydrogen atom, a C _1-5 alkyl, benzyl, 1-phenylethyl or 2-phenylethyl group and
B represents a 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene, 1,4-cyclohexylene or piperidinylene group, where in the linking of the piperidinylene each via the 3- or 4-position with the Rest -NR₁- occurs,
Y₃ is a -CO-, -A₂-CO-, -NR₂-A₃-CO or -O-A₃-CO group, in which
A₂ is optionally substituted by a C _1-3 alkyl, benzyl, 1-phenylethyl or 2-phenylethyl group substituted te C _1-4 alkylene group and
A₃ is an optionally substituted by a C _1-5 alkyl, benzyl, 1-phenylethyl or 2-phenylethyl group nC _1-3 alkylene group and
R₂ represents a hydrogen atom, a C _1-3 -alkyl, C _1-5 -alkoxycarbonyl or C _1-3 -alkanoyl group and the linking of the -A₂-CO group via the radical A₂, the -NR₂-A₃- CO group via the NR₂ group and the -O-A₃-CO- group via the oxygen atom with the radical Y₂ takes place, but with a -NR₂- or -O-A₃-CO group is not linked to a nitrogen atom of the radical B. can be,
and E is a hydroxy, C _1-5 alkoxy, C _5-7 cycloalkoxy or R₅-CO-O- (R₃CR₄) -O- group in which
R₃ represents a hydrogen atom, a C _1-3 -alkyl or C _5-7 -cycloalkyl group,
R₄ is a hydrogen atom and
R₅ represents a C _1-5 alkyl or C _1-3 alkoxy group,
or an α-amino group of a natural amino acid and its C _1-6 -alkyl or benzyl ester,
their tautomers, their stereoisomers, including their mixtures, and their salts. 4. piperazine derivatives of the general formula I according to claim 1, in which
R _{a is} a 4-piperidinyl group, where the hydrogen atom of the 4-piperidinyl group may be replaced by a C _1-5 -alkoxycarbonyl group,
Y₁ is a -CO-, -CH₂CO-, -CH₂CH₂CO-, -CH₂CH₂CH₂CO-, -CH₂CH₂CH₂CH₂CO-, -CH₂CH₂CH₂CH₂CH₂CO- or -CO-CH₂-CO- group,
Y₂ is a 1,4-phenylene, 4-piperidinylene, 1,4-piperazinylene or -NR₁-B group, linking to the Y₁ group via the nitrogen atom of the -NR₁ group, as well as
R₁ is a hydrogen atom and
B represents a 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene, 1,4-cyclohexylene or piperidinylene group, in which the linking of the piperidinylene group via the 4-position with the radical -NR₁- he follows,
Y₃ is a -CO-, -CH₂CO-, -CH₂CH₂CO-, -CH₂CH₂CH₂CO-, -NR₂-CH₂-CO-, -NR₂-CH₂CH₂-CO-, -O-CH₂-CO- or -O-CH₂CH₂-CO- group , in which
R₂ represents a hydrogen atom, a methyl, benzyl, 2-phenylethyl, tert.-butoxycarbonyl or acetyl group and the linking of the -CH₂CO-, -CH₂CH₂CO- or -CH₂CH₂CH₂CO group via the alkylene moiety, the -NR₂-CH₂- CO or -NR₂-CH₂CH₂-CO group via the -NR₂- group and the -O-CH₂-CO- or -O-CH₂CH₂-CO group via the oxygen atom with the radical Y₂ takes place, but where a -NR₂ or an oxygen atom can not be linked to a nitrogen atom of the radical B,
and E is a hydroxy, C _1-4 alkoxy, C _5-7 cycloalkoxy or R₅-CO-O- (R₃CR₄) -O- group in which
R₃ represents a hydrogen atom or a C _1-3 alkyl group,
R₄ is a hydrogen atom and
R₅ represents a C _1-5 alkyl or C _1-3 alkoxy group,
or a glycinyl group or its methyl ester,
their tautomers, their stereoisomers, including their mixtures, and their salts. 5. The following piperazine derivatives of the general formula I according to claim 1:

• (a) [4-trans- [3- [4- (4-piperidinyl) piperazin-1-yl] propionyl] amino] cyclohexane carboxylic acid,
• (b) [3- [4-trans- [4- (4-piperidinyl) piperazin-1-yl] carbonylamino] cyclohexyl] propionic acid,
• (c) N - [[4- (4-piperidinyl) -piperazin-1-yl] carbonyl] -4- (4-piperidinyl) -butyric acid,
• (d) N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] -3- (piperidin-4-yloxy) propionic acid,
• (e) N- [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] piperidinyl] -β-alanine,
• (f) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy] acetic acid,
• (g) [4 - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] phenoxy] acetic acid,
• (h) cyclohexyl 3- [4-trans - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] cyclohexyl] propionate;
• (i) ethyl N - [[4- (4-piperidinyl) piperazin-1-yl] carbonyl] -3- (piperidine-4-yloxy) propionate,
• (j) [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] phenoxy] -acetic acid methyl ester,
• (k) [4 - [[4- (4-piperidinyl) piperazin-1-yl] acetyl] phenoxy] acetic acid methyl ester,
• (l) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy oxyacetate,
• (m) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] -phenoxy] -acetic acid isobutyl ester,
• (n) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxy oxy] acetic acid,
• (o) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxycyclopentyl oxyacetate,
• (p) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxycyclohexyl oxyacetate,
• (q) [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy oxy] -acetate,
• (r) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] phenoxycyclohexyl oxyacetate,
• (s) [4 - [[4- (4-piperidinyl) -piperazin-1-yl] carbonylamino] -phenoxy oxy] -acetate,
• (t) [4 - [[4- (4-piperidinyl) piperazin-1-yl] carbonylamino] -phenoxy oxy] -acetate,

their tautomers, their stereoisomers and their salts. 6. Physiologically acceptable salts of the compounds after min at least one of claims 1 to 5 with inorganic or or ganic acids or bases.   7. A pharmaceutical composition containing a compound after at least one of claims 1 to 5 or a physiologically acceptable Lich salt according to claim 6 in addition to optionally one or several inert carriers and / or diluents. 8. Use of a compound according to at least one of Claims 1 to 6 for the manufacture of a medicament intended for Combating or preventing diseases in which smaller or larger cell aggregates occur or cell matrix inter actions play a role. 9. A process for the preparation of a medicament according to claim 7, characterized in that non-chemically A compound according to any one of claims 1 to 6 in one or more inert carriers and / or diluents is incorporated. 10. A process for the preparation of the compounds of general formula I according to claims 1 to 6, characterized in that

• a. a compound of the general formula in the
  R _a and Y₁ are as defined in claims 1 to 5, or their reactive derivatives with a compound of the general formula H-Y₂'-Y₃-E '(III) in the
  Y₃ is as defined in claims 1 to 5,
  Y₂ 'with the exception of the phenylene group has the meanings mentioned for Y₂ in the Ansprü Chen 1 to 6, and
  E 'is reacted with the exception of the R₅-CO-O- (R₃CR₄) -O- group having the meanings mentioned for E in claims 1 to 5, or
• b. for the preparation of a compound of the general formula I in which at least one of the radicals R _a , R₂ and E must contain a reactive hydrogen atom with the proviso that E with the exception of the R₅-CO-O- (R₃CR₄) -O-group for E in the claims 1 to 5 mentioned meanings, a United bond of the general formula in the
  R _a and Y₁ to Y₃ are as defined in claims 1 to 5 and
  E '' is a hydroxy group or together with the adjacent Car bonylgruppe of the radical Y₃ by means of hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis cleavable Baren protective group in a carboxyl group group, but wherein at least one of the radicals R _a , NR₂ or E '' must contain a cleavable residue,
  in a compound of general formula I in which at least one of the radicals R _a , R₂ and E must contain a reactive hydrogen atom with the proviso that E except for the R₅-CO-O- (R₃CR₄) -O- group for E has in the claims 1 to 5 mentioned meanings, is converted or
• c. for the preparation of a compound of the general formula I in which Y₂ is defined as mentioned in claims 1 to 5 with the exception of the phenylene group and Y₃ is an -A₂-CO group in which A₂ is optionally substituted by a C _1-5 -alkyl group , Phenyl or phenyl-C _1-3 -alkyl group substituted nC _2-4- alkenylene group, represent a compound of the general formula in the
  R _a and Y₁ are as defined in claims 1 to 5 and Y₂ 'with the exception of the phenylene, 3-piperidinylene or 4-piperidinylene group has the meanings mentioned for Y₂ in claims 1 to 5, with a compound of general For melA₂'-CO-E (VI) in the
  E as defined in claims 1 to 5 and
  A₂ 'represents an optionally substituted by a C _1-5 alkyl, phenyl or phenyl-C _1-3 alkyl group substituted nC _2-4 alkenylene, is reacted or
• d. a compound of the general formula in the
  R _{a is} as defined in claims 1 to 5, with a compound of the general formula Z₁-Y₁-Y₂-Y₃-E (VIII) in the
  Y₁, Y₂, Y₃ and E are as defined in claims 1 to 5 and
  Z₁ is a nucleophilic leaving group or else when Y₁ represents a carbonyl group,
  Z₁ together with R₁ represents another carbon-nitrogen bond is reacted or
• e. for the preparation of a compound of the general formula I in which E, with the exception of the hydroxy group, is defined as in claims 1 to 5, a compound of the general formula in the
  R _a and Y₁ to Y₃ are as defined in claims 1 to 6, with a compound of the general formula HO-R _b (X) or with a compound of the general formula Z₂-R _c (XI) in which
  R _{b is} an alkyl group having 1 to 6 carbon atoms, a phenylalkyl group in which the alkyl part can keep 1 to 3 carbon atoms ent, a cycloalkyl group having 3 to 9 Kohlenstoffato men, in which the Cycloalkylteil with 5 to 8 Kohlenstoffato men additionally by one or two Alkyl groups each having 1 to 3 carbon atoms may be substituted, a Cycloal kylgruppe having 5 to 8 carbon atoms, in which in the cycloalkyl part of a methylene group in the 3- or 4-position by an oxygen atom or by an optionally represented by an alkyl, phenylalkyl or Phenylalkoxycarbonylgruppe in which the Al kyl- and alkoxy each containing 1 to 3 carbon atoms, or by an alkanoyl group with 2 to 6 carbon atoms substituted imino group is replaced and the Cycloal kylteil additionally be substituted by one or two alkyl groups each having 1 to 3 carbon atoms may, a Cycloal kenylgruppe in which the Cycloalkenylteil 4 to 7 carbon ato me, an alkenyl, phenylalkenyl, alkynyl or Phenylalkinylgruppe with the proviso that no bond to the oxygen atom emanates from a carbon atom which carries a double or triple bond and in which the Alke nyl- and alkynyl moiety each 3 to 5 Carbon atoms, a cycloalkylalkyl group in which the cycloalkyl moiety may contain from 3 to 8 carbon atoms and the alkyl moiety from 1 to 3 carbon atoms, a bicycloalkyl group having a total of from 8 to 10 carbon atoms, and in the bicycloalkyl moiety additionally one or two alkyl groups each having from 1 to 3 carbon atoms or a 1,3-dihydro-3-oxo-1-isobenzfuranyloxygruppe,
  R _{c has} the meanings mentioned above for R _b and additionally an R₅-CO-O- (R₃CR₄) -O- group, in which
  R₃ to R₅ are as defined in claims 1 to 5,
  and Z₂ represent a leaving group, is reacted and
  if desired, a compound of general formula I thus obtained is separated into its stereoisomers and / or
  a compound of the general formula I thus obtained is converted into its salts, in particular for the pharmaceutical application, into its physiologically tolerated salts.