DE19643331A1 - 1- (4-Piperidinyl) -piperidinylenes, medicaments containing these compounds, their use and process for their preparation - Google Patents

Abstract

The present invention relates to 1-(4-piperdinyl)-piperidinylene of the general formula (I), wherein Ra, Rb, A, B and D have the meaning given in claim 1, their stereoisomers, including their mixtures and their salts, specially their salts containing physiologically acceptable acids or bases possessing valuable pharmacological properties, preferably aggregation inhibiting effects. Also disclosed are medicaments containing said compounds and their use as well as the method for their production.

Description

The present invention relates to 1- (4-piperidinyl) -piperidylene of the general formula

 their stereoisomers, including their mixtures, and their Salts, especially their salts with physiologically compatible Acids or bases, which have valuable pharmacological properties have properties, preferably aggregation-inhibiting effects gen, drugs containing these compounds and their Ver application and process for their manufacture.

In the above general formula I means
R _{a is} a hydrogen atom, a C _1-5 alkyl or aryl C _1-3 alkyl group, in which the alkyl part is in each case represented by a carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 - Alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, ethenyl, ethynyl group or with the exception of the carbon atom which is linked to the ring nitrogen atom of the adjacent piperidinyl group, by a hydroxy, C _1-3 alkoxy -, Amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group, or a residue which can be split off in vivo,
R _{b is} a hydrogen atom, a C _1-6 -alkyl-, C _3-6 -cycloalkyl-, C _3-6 -cycloalkyl-C _1-3 -alkyl-, aryl-, aryl-C _1-3 -alkyl-, Pyridyl or pyridyl-C _1-3 alkyl group, a D-CO-CH ₂ group or a group of the formula

in which
R _{a are} as above and D are as defined below,
A a -CO-cyclohexylene-, -CH ₂ -cyclohexylene-, -CO-phenylene-, -CH ₂ -phenylene-, -CONR ₁ -cyclohexylene-, -CONR ₁ -phenylene-, -CO- (1-piperidinylene) - or -CH ₂ - (1-piperidinylene) group in which
R _{1 represents} a hydrogen atom, a C _1-6 -alkyl or aryl-C _1-3 -alkyl group and in each case the -CH ₂ - and -CO part of the above-mentioned groups are linked to the NR _b group,
B is a -CO-, -CHR ₂ -CO-, -CHR ₂ -CHR ₂ -CO-, -O-CHR ₂ -CO-, -NR ₃ -CHR ₂ -CO- or -OCH ₂ CH ₂ group, in which
R _{2 is} a hydrogen atom, a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, arylC _1-3 alkyl or pyridyl group and
R _{3 is} a hydrogen atom, a C _1-6 alkyl, aryl C _1-3 alkyl, C _1-6 alkanoyl, aryl C _1-6 alkanoyl, C _1-6 alkoxycarbonyl or Aryl-C _1-3 alkoxy group and the -O-CHR ₂ -, -NR ₃ -CHR ₂ - and -OCH ₂ part of the above-mentioned groups is linked with the proviso that the linkage is not via an oxygen or nitrogen atom of radical B with a nitrogen atom of radical A,
and D is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, which can be substituted in the 2-, 3-, 4-, 5- or 6-position by a hydroxyl group, a phenylalkoxy group in which the alkoxy part contains 1 to 3 carbon atoms can, a cycloalkoxy group with 3 to 9 carbon atoms, in which the cycloalkyl part with 5 to 8 carbon atoms can be additionally substituted by one or two alkyl groups each with 1 to 4 carbon atoms, a cycloalkoxy group with 5 to 8 carbon atoms, in the cycloalkyl part a methylene group in the 3- or 4-position through an oxygen atom or through an optionally through an alkyl, phenylalkyl or phenylalkoxycarbonyl group in which the alkyl and alkoxy part can each contain 1 to 3 carbon atoms, or through an alkanoyl group with 2 to 6 Carbon atoms sub substituted imino group is replaced and the cycloalkyl part in addition by one or two alkyl groups each with 1 to 3 carbon may be substituted, a cycloalkenyl oxy group in which the cycloalkenyl part can contain 4 to 7 carbon atoms, an alkenyloxy, phenylalkenyloxy, alkynyloxy or phenylalkynyloxy group, with the proviso that no bond to the oxygen atom originates from a carbon atom which is a Bears double or triple bond and in which the alkenyl and alkynyl part can each contain 3 to 5 carbon atoms, a cycloalkylalkoxy group in which the cycloalkyl part can contain 3 to 8 carbon atoms and the alkoxy part 1 to 3 carbon atoms, a bicycloalkoxy group with a total of 8 to 10 carbon atoms, which can additionally be substituted in the bicycloalkyl part by one or two alkyl groups each with 1 to 3 carbon atoms, a 1,3-dihydro-3-oxo-1-isobenzfuranyloxy group or an R ₆ -CO-O- (R ₄ CR ₅ ) -O group in which
R _{4 is} a hydrogen atom, a C _1-6 alkyl, C _3-7 cycloalkyl or phenyl group,
R _{5 is} a hydrogen atom or a C _1-6 alkyl group and
R _{6 represents} a C _1-5 alkyl, C _1-5 alkoxy, C _5-7 cycloalkyl or C _5-7 cycloalkoxy group,
and D is an amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, benzylamino or N- (C _1-6 alkyl) benzylamino group or an α-amino group of a natural amino acid and their esters.

The term "an aryl group" mentioned in the definition of the above radical R _b is to be understood in each case to mean a phenyl or naphthyl group which is in each case denoted by fluorine, chlorine or bromine atoms, by C _1-3 alkyl, trifluoromethyl, Amino, C _1-3 alkylamino, di (C _1-3 alkyl) amino, C _1-3 alkanoylamino, hydroxy, C _1-3 alkoxy, carboxy, C _{1 -3} -alk oxycarbonyl or D-CO-CH ₂ -O groups can be mono-, di- or tri-substituted, it being possible for the substituents to be identical or different and one of the substituents can also be a nitro group,
among the esters of a natural α-amino acid whose 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, isopropyl, tert-butyl, allyl, phenyl or benzyl ester and
an alkanoyl group with a total of 1 to 6 carbon atoms, a benzoyl, allyloxy carbonyl, C _1-9 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, octyloxycarbonyl, benzyloxycarbonyl To understand phenylethoxycarbonyl or phenylpropoxycarbonyl group.

Preferred compounds of the above general formula I are those in which
R _{a is} a hydrogen atom or a benzyl, benzyloxycarbonyl or C _1-9 alkoxycarbonyl group,
R _{b is} a hydrogen atom, a C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl methyl, phenyl, benzyl or pyridyl methyl group, a D-CO-CH ₂ group or a group of the formula

in which
R _{a are} as above and D are as defined below,
A a -CO-cyclohexylene-, -CH ₂ -cyclohexylene-, -CO-phenylene-, -CH ₂ -phenylene-, -CONR ₁ -cyclohexylene-, -CONR ₁ -phenylene-, -CO- (1-piperidinylene) - or -CH ₂ - (1-piperidinylene) group in which
R _{1 represents} a hydrogen atom, a C _1-6 alkyl or phenyl C _1-3 alkyl group, and in each case the —CH ₂ - and —CO part of the above-mentioned groups are linked to the NR _b group,
B is a -CO-, -CH ₂ -CO-, -CH ₂ -CH ₂ -CO-, -O-CH ₂ -CO-, -NR ₃ -CH ₂ -CO- or -OCH ₂ CH ₂ group, in which
R _{3 represents} a hydrogen atom, a C _1-6 alkyl, C _1-6 alkanoyl, phenyl C _1-6 alkanoyl, C _1-6 alkoxycarbonyl or phenyl C _1-3 alkoxycarbonyl group and the -O-CH ₂ - and -NR ₃ -CH ₂ part of the above-mentioned groups with the measure linked to the radical A that the link does not have an oxygen or nitrogen atom of the radical B with a nitrogen atom of the radical A. he follows,
and D is a hydroxy group, a C _1-6 alkoxy group which can be substituted in the 2-, 3-, 4-, 5- or 6-position by a hydroxyl group, one optionally substituted by a C _1-3 alkyl group C _5-7 cycloalkoxy group, which may be substituted by a further methyl group, a phenyl C _1-3 alkoxy group or an R ₆ -CO-O- (R ₄ CR ₅ ) -O group, in which
R _{4 is} a hydrogen atom, a C _1-6 alkyl, C _3-7 cycloalkyl or phenyl group,
R _{5 is} a hydrogen atom or a C _1-6 alkyl group and
R _{6 represents} a C _1-5 alkyl, C _1-5 alkoxy, C _5-7 cycloalkyl or C _5-7 cycloalkoxy group,
or D is a C _1-6 alkylamino, di (C _1-6 alkyl) amino, benzyl amino or N- (C _1-6 alkyl) benzylamino group or an α-amino group of a natural amino acid and whose C _1-6 alkyl and benzyl esters mean
where the phenyl nuclei mentioned in the definition of the abovementioned radical R _{b can} each be substituted by a fluorine, chlorine or bromine atom, by a methoxy or D-CO-CH ₂ -O group,
their stereoisomers, including their mixtures, and their salts.

Particularly preferred compounds of the general formula I above are those in which
R _{a is} a hydrogen atom or a benzyl, benzyloxycarbonyl or C _1-9 alkoxycarbonyl group,
R _{b is} a hydrogen atom, a C _1-6 alkyl, cyclohexyl, cyclohexylmethyl, phenyl or pyridylmethyl group, if appropriate in the phenyl nucleus by a fluorine or chlorine atom or by a methoxy or D-CO-CH ₂ - O group substituted benzyl group, a D-CO-CH ₂ group or a group of the formula

in which
R _{a are} as above and D are as defined below,
A is a -CO-phenylene, -CH ₂ -phenylene, CONH-cyclohexylene, -CO- (1-piperidinylene) or -CONH- (1-piperidinylene) group, where in each case the -CH ₂ - and - CO part of the above-mentioned groups is linked to the -NR _b group,
B is a -CO-, -CH ₂ -CO-, -CH ₂ -CH ₂ -CO-, -O-CH ₂ -CO-, -NR ₃ -CH ₂ -CO- or -OCH ₂ CH ₂ group, in which
R _{3 represents} a hydrogen atom or a C _1-3 alkanoyl group and the -O-CH ₂ - and -NR ₃ -CH ₂ part of the above-mentioned groups is linked with the proviso that the link does not have there is an oxygen or nitrogen atom of radical B with a nitrogen atom of radical A,
and D is a hydroxy group, a C _1-6 alkoxy group which can be substituted in the 2-, 3-, 4-, 5- or 6-position by a hydroxy group, a menthyloxy, phenyl-C _1-3 alkoxy - or C _5-7 cycloalkoxy group or an R ₆ -CO-O- (R ₄ CR ₅ ) -O group, in which
R _{4 is} a hydrogen atom, a C _1-3 alkyl or C _5-7 cycloalkyl group,
R _{5 is} a hydrogen atom and
R _{6 represents} a C _1-5 alkyl or C _1-3 alkoxy group,
or D is a C _1-6 alkylamino or benzylamino group or an α-amino group of a natural α-amino acid and its C _1-6 alkyl and benzyl esters,
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 hydrogen atom or a benzyl, benzyloxycarbonyl or C _1-3 alkoxycarbonyl group,
R _{b is} a hydrogen atom, a C _1-4 alkyl, cyclohexyl, cyclohexylmethyl, phenyl or pyridylmethyl group, one optionally in the phenyl nucleus in the 4-position by a fluorine or chlorine atom or by a methoxy or D-CO-CH ₂ -O group substituted benzyl group, a D-CO-CH ₂ group or a group of the formula

in which
R _{a are} as above and D are as defined below,
A is a -CO-phenylene-, -CH ₂ -phenylene-, -CONH-cyclohexylene-, -CO- (1-piperidinylene) - or -CONH- (1-piperidinylene) group, where in each case the -CH ₂ - and -CO part of the above-mentioned groups is linked to the NR _b group,
B is a -CO-, -CH ₂ -CO-, -CH ₂ -CH ₂ -CO-, -O-CH ₂ -CO-, -NR ₃ -CH ₂ -CO- or -OCH ₂ CH ₂ group, in which
R _{3 represents} a hydrogen atom or a C _1-3 alkanoyl group and the -O-CH ₂ - and -NR ₃ -CH ₂ part of the above-mentioned groups is linked with the proviso that the link does not have there is an oxygen or nitrogen atom of radical B with a nitrogen atom of radical A,
and D is a hydroxy group, a C _1-4 alkoxy group which can be substituted in the 2-, 3- or 4-position by a hydroxyl group, a menthyloxy, phenyl-C _1-3 alkoxy or C _5-6 - Cyclo alkoxy group or an R ₆ -CO-O- (R ₄ CR ₅ ) -O group in which
R _{4 is} a hydrogen atom, a C _1-3 alkyl or C _5-7 cycloalkyl group,
R _{5 is} a hydrogen atom and
R _{6 represents} a C _1-5 alkyl or C _1-3 alkoxy group,
or D is a C _1-3 alkylamino group or an amino group substituted by a carboxymethyl or C _1-3 alkoxycarbonylmethyl group,
especially those connections in which
R _{a is} a hydrogen atom, a benzyloxy or C _1-3 alkoxycarbonyl group,
R _{b is} a hydrogen atom, a C _1-4 alkyl, cyclohexyl, cyclohexylmethyl, phenyl or pyridylmethyl group, if appropriate in the phenyl nucleus in the 4-position by a fluorine or chlorine atom or by a methoxy or D- CO-CH ₂ -O group substituted benzyl group, a D-CO-CH ₂ group or a group of the formula

in which
R _{a are} as above and D are as defined below,
A is a -CO-phenylene-, -CH ₂ -phenylene-, -CONH-cyclohexylene-, -CO- (1-piperidinylene) - or -CONH- (1-piperidinylene) group, where in each case the -CH ₂ - and -CO part of the above-mentioned groups is linked to the NR _b group,
B is a -CO-, -CH ₂ -CO-, -CH ₂ -CH ₂ -CO-, -O-CH ₂ -CO-, -NR ₃ -CH ₂ -CO- or -OCH ₂ CH ₂ group, in which
R _{3 represents} a hydrogen atom or a C _1-3 alkanoyl group and the -O-CH ₂ - and -NR ₃ -CH ₂ part of the above-mentioned groups is linked with the proviso that the link does not have there is an oxygen or nitrogen atom of radical B with a nitrogen atom of radical A,
and D is a hydroxy group, a C _1-4 alkoxy group which can be substituted in the 2-, 3- or 4-position by a hydroxyl group, a menthyloxy, phenyl-C _1-3 alkoxy or C _5-6 - Cyclo alkoxy group or an R ₆ -CO-O- (R ₄ CR ₅ ) -O group in which
R _{4 is} a hydrogen atom, a C _1-3 alkyl or C _5-7 cycloalkyl group,
R _{5 is} a hydrogen atom and
R _{6 represents} a C _1-5 alkyl or C _1-3 alkoxy group,
mean,
their stereoisomers, including their mixtures, and their salts.

The following are mentioned as particularly valuable compounds:

• (a) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid,
• (b) 4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocar bonyl] phenoxyacetic acid,
• (c) 4- [N-Isobutyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
• (d) 4- [N- (4-pyridylmethyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid,
• (e) 4- [N-Phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
• (f) 4- [N- (4-Fluorobenzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,  
• (g) 4- [N-Cyclohexyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
• (h) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminomethylene] phenoxyacetic acid,
• (i) 4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino methylene] -phenoxyacetic acid and
• (j) 4- [N- (3-pyridylmethyl) -N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid,
  their C _1-5 alkyl and C _5-6 cycloalkyl esters as well as their stereoisomers and their salts,
  but especially the connections
  4- [N- (4-pyridylmethyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
  4- [N-phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid and
  4- [N- (3-pyridylmethyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
  their C _1-5 alkyl and C _5-6 cycloalkyl esters and their salts.

According to the invention, for example, the new compounds are obtained by the following methods:
a. For the preparation of a compound of the general formula I in which R _a, with the exception of the hydrogen atom and a group which contains a reactive hydrogen atom of an amino group, has the meanings mentioned above for R _a :
Reductive alkylation of a compound of the general formula

in the
A, B, D and R _b are defined as mentioned above, with a piperidinone of the general formula

in the
R _a 'with the exception of the hydrogen atom and a group which contains a reactive hydrogen atom of an amino group which has the meanings mentioned for R _a at the outset.

The reductive alkylation is preferably carried out in a solution agents such as water or methanol, ethanol, tetrahydrofuran, Dioxane, formic acid, acetic acid, trifluoroacetic acid, sulfur acid or mixtures thereof with water in the presence of a reduc tion agent at temperatures between 0 and 100 ° C, preferably at temperatures between 20 ° C and the boiling point of ver applied solvent.

However, the reductive alkylation is preferably carried out in the presence a complex metal hydride such as sodium borohydride, lithium boron hydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxy borohydride or borane / pyridine conveniently at one pH of 1-7 optionally in the presence of a water ent pulling agents such as molecular sieve or titanium IV isopropylate and at room temperature or with hydrogen in the presence of a Hydrogenation catalyst, e.g. B. in the presence of palladium / coal, at a hydrogen pressure of 1 to 5 bar, preferably at Temperatures between 20 ° C and the boiling point of the use deten solvent. In the implementation it can be further advantageous if reactive groups during the Implementation are protected by usual protective residues, which after  who split off the implementation again using usual methods the.

b. To prepare a compound of the general formula I in which R _a is defined as mentioned at the beginning and D represents a hydroxy group,
D with the exception of the R ₆ -CO-O- (R ₄ CR ₅ ) -O group has the meanings mentioned for D and R _{a represents} a hydrogen atom or
R _{a represents} a hydrogen atom and D represents a hydroxy group:
Conversion of a compound of the general formula

in the
A, B and R _b are defined as mentioned at the outset, D 'has the meanings mentioned for D at the outset or a carboxyl group protected by a protective radical which can be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis , and
R _a 'has the meanings mentioned for R _a or is a protective radical for an imino group which can be removed by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, but at least R _a ' is a protective radical which can be split off or D 'together with the adjacent one Carbonyl group of the radical B must represent a carboxyl group protected by a protective radical,
into a compound of the general formula I, in which R _{a is defined} as one mentioned above and D represents a hydroxyl group, D with the exception of the R ₆ -CO-O- (R ₄ CR ₅ ) -O group, those mentioned above for D Has meanings and R _{a represents} a hydrogen atom or
R _{a represents} a hydrogen atom and D represents a hydroxy group.

As a group which can be converted into a carboxy group, for example a carboxyl group protected by a protective radical, such as its functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters, which are conveniently converted into a carboxyl group by means of hydrolysis,
whose esters with tertiary alcohols, e.g. B. the tert-butyl ester, which are conveniently converted into a carboxyl group by treatment with an acid or thermolysis, and
whose esters with aralkanols, e.g. B. the benzyl ester, which are advantageously converted into a carboxyl group by means of hydrogenolysis,
as protective residues for an imino group, the benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, which are expediently converted into a hydrogen atom by means of hydrogenolysis,
or the formyl, acetyl, trifluoroacetyl, allyloxycarbonyl, ethoxycarbonyl, tert.butoxycarbonyl or benzyloxycarbonyl group, which are expediently converted into a hydrogen atom by hydrolysis.

The hydrolysis is advantageously carried out either in the presence an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, vinegar acid, trichloroacetic acid, trifluoroacetic acid or cross-Gemi or in the presence of a base such as lithium hydroxide, sodium umhydroxid or potassium hydroxide in a suitable solution with 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, e.g. B. at Tem temperatures between room temperature and the boiling point of Reaction mixture carried out.  

If D 'or R _a ' in a compound of the formula IV is, for example, the tert-butyl or tert-butyloxycarbonyly group, these can also be treated by treatment with an acid such as tri-fluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane, preferably at temperatures between -10 and 120 ° C, e.g. B. 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 the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or Polyphosphoric acid preferably at the boiling point of the solvent used, e.g. B. at temperatures between 40 and 120 ° C, split off.

If D 'and R _a ' in a compound of the formula IV are, for example, the benzyloxy or benzyloxycarbonyl group, these can also be hydrogenolytically 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. B. at room temperature, and a hydrogen pressure of 1 to 5 bar.

For the preparation of a compound of the general formula I in which D, with the exception of the hydroxyl group, has the meanings mentioned for D:
Implementation of a compound of the general formula

in the
A, B and R _b are defined as mentioned at the beginning and
R _a 'is a protective radical for an imino group or has one of the meanings mentioned for R _a , or their reactive derivatives with a compound of the general formula

HO-R ₇ (VI),

or with its formamide acetal,
with an amine of the general formula

HR ₈ (VII),

or with a compound of the general formula Z ₁ -R ₉ (VIII),

in which
R _{7 is} an alkyl group with 1 to 6 carbon atoms, which can be substituted in the 2-, 3-, 4-, 5- or 6-position by a hydroxyl group, a phenylalkyl group in which the alkyl part can contain 1 to 3 carbon atoms, one Cycloalkyl group with 3 to 9 carbon atoms, in which the cycloalkyl part with 5 to 8 carbon atoms can additionally be substituted by one or two alkyl groups with 1 to 3 carbon atoms each, a cycloalkyl group with 5 to 8 carbon atoms, in which in the cycloalkyl part a methylene group in 3- or 4-Stel ment by an oxygen atom or by an optionally substituted by an alkyl, phenylalkyl or phenylalkoxycarbonyl group, in which the alkyl and alkoxy part can each contain 1 to 3 carbon atoms, or by an alkanoyl group having 2 to 6 carbon atoms substituted imino group is and the cycloalkyl part may additionally be substituted by one or two alkyl groups each having 1 to 3 carbon atoms nn, a cycloalkenyl group in which the cycloalkenyl part can contain 4 to 7 carbon atoms, an alkenyl, phenyl alkenyl, alkynyl or phenylalkynyl group with the proviso that no bond to the oxygen atom originates from a carbon atom which has a double or triple bond and in which the alkenyl and alkynyl part can each contain 3 to 5 carbon atoms, a cycloalkylalkyl group in which the cycloalkyl part can contain 3 to 8 carbon atoms and the alkyl part can contain 1 to 3 carbon atoms, a bicycloalkyl group with a total of 8 to 10 carbon atoms, which can additionally be substituted in the bicycloalkyl part by one or two alkyl groups each having 1 to 3 carbon atoms, a 1,3-dihydro-3-oxo-1-isobenzfuranyl group,
R _{8 is} an amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, benzylamino or N- (C _1-6 alkyl) benzylamino group or an α-amino group of a natural α -Amino acid and its esters.

R _{9 has} the meanings mentioned above for R ₇ and additionally an R ₆ -CO-O- (R ₄ CR ₅ ) -O group in which
R ₄ to R ₆ are defined as mentioned at the beginning,
and Z _{1 is} a leaving group such as a halogen atom, e.g. B. represent a chlorine or bromine atom.

The reaction with an alcohol of the general formula VI or with an amine of the general formula VII is more appropriate wise in a solvent or solvent mixture such as Me ethylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, Benzene / tetrahydrofuran or dioxane, but preferably in an excess of the general compound used Formula VI or VII, in the presence of a dehydrating agent tels, e.g. B. in the presence of hydrochloric acid, sulfuric acid, chlorine isobutyl formate, thionyl chloride, trimethylchlorosilane, Hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfone acid, phosphorus trichloride, phosphorus pentoxide, 2- (1H-benzotria zol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate, N, N'-Di cyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxy succinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimida  zole, triphenylphosphine / carbon tetrachloride or triphenyl phosphine / Azodicarbonsäurediethylester optionally in counter was a base like potassium carbonate, N-ethyl-diisopropylamine or N, N-dimethylamino-pyridine expediently at tempera doors between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C.

With a compound of general formula VIII, the order conveniently in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethyl formamide or acetone, optionally in the presence of a reak tion accelerator such as sodium or potassium iodide and before preferably in the 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 can also serve as a solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C, stirred.

The implementation of a corresponding reactive connection the general formula V such as their esters, imidazolides or Ha logenides with a compound of general formula VI or VII is preferably in a corresponding excess of used compound of general formula VI or VII as Solvent optionally in the presence of another Lö solvents such as methylene chloride or ether and preferably in Presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at tempera doors between 0 and 150 ° C, preferably at temperatures between between 50 and 100 ° C, carried out.

d. To prepare a compound of the general formula I in which R _{b is defined} with the proviso that when A is a -CH ₂ -cyclohexylene, -CH ₂ -phenylene- or -CH ₂ - (1-piperidinylene) Represents a group, R _b does not represent a hydrogen atom or a group containing a reactive hydrogen atom, and R _{a represents} a radical which can be split off in vivo:
Implementation of a compound of the general formula

in the
A, B and D and R _b are defi ned with the proviso that when A represents a -CH ₂ -cyclohexylene, -CH ₂ -phenylene or -CH ₂ - (1-piperidinylene) group, R _b does not represent a hydrogen atom and a group containing a reactive hydrogen atom, with a compound of the general formula

Z ₂ -R ₁₀ (X),

in the
Z _{2 is} a nucleofugic leaving group such as a halogen atom, e.g. B. a chlorine, bromine or iodine atom, a sulfonic acid ester group, for. B. a methanesulfonyloxy or p-toluenesulfonyloxy group, and
R _{10 represent} a residue which can be split off in vivo.

The reaction is preferably carried out in a solvent such as Methylene chloride, acetonitrile, tetrahydrofuran, toluene, dime thylformamide or dimethyl sulfoxide, optionally in the presence a base such as sodium hydride, potassium carbonate, potassium tert.bu tylate or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C.

e. For the preparation of a compound of general formula I in which B represents an -OCH ₂ CH ₂ group and D represents a hydroxy group:
Reduction of a compound of the general formula

in the
A, B, R _a and R _b are defined as mentioned at the beginning and D ″ together with the carbonyl group of the radical B represents a carboxylic acid ester group, preferably an ester which contains one of the alkoxy groups mentioned for D at the beginning.

The reduction is preferably carried out in the presence of an appropriate one complex metal hydride such as lithium borohydride or borane / pyridine at temperatures between 20 ° C and the boiling point of solvent used, but preferably at room temperature temperature in a solvent such as tetrahydrofuran or dioxane, carried out.

In the implementations described above, given if existing reactive groups such as carboxy, amino or Imino groups during the implementation by conventional protective groups protected, which split off after the implementation will.

For example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group and comes as a protective radical for a carboxyl group
as a protective radical 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 additionally the Phthalyl group into consideration.

The subsequent subsequent splitting off of one used Protective residue takes place, for example, hydrolytically in an aqueous solution Rigen solvent, for. B. 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 base such as sodium hydroxide or potassium hydroxide or by ether cleavage, e.g. B. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.

The removal of a benzyl, methoxybenzyl or benzyloxy However, carbonyl radical is carried out, for example, by hydrogenolysis, e.g. B. with hydrogen in the presence of a catalyst such as Palla dium / coal in a solvent such as methanol, ethanol, vinegar acid ethyl ester or glacial acetic acid, optionally with the addition of a Acid such as hydrochloric acid at temperatures between 0 and 100 ° C preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar. The cleavage of a 2,4-dimethoxybenzyl radical however, it is preferably carried out in the presence of trifluoroacetic acid of anisole.

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

A trifluoroacetyl radical is preferably cleaved off by treatment with an acid such as hydrochloric acid if necessary in the presence of a solvent such as acetic acid at tempera tures between 50 and 120 ° C or by treatment with sodium bicarbonate 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.

An allyloxycarbonyl radical is split off by Be deal 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 pen acceptor 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 presence of a base such as 1,4-diazabicyclo [2.2.2] octane at tem temperatures between 20 and 70 ° C.

A phthalyl radical is preferably split off in Ge presence of 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 temperature ren between 20 and 50 ° C.

Furthermore, the compounds of general form mel I, as already mentioned at the beginning, in their enantiomers and / or diastereomers are separated. So at for example connections with at least one optically active Carbon atom are separated into their enantiomers.

For example, the compounds obtained from general formula I, which occur in racemates, according to known methods (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and connections of the general my formula I with at least 2 stereogenic centers on the ground according to their physical and chemical differences ten methods, e.g. B. by chromatography and / or fractionated Crystallization, separate into their diastereomers, which, if they are obtained in racemic form, then as mentioned above can be separated into the enantiomers.

Furthermore, the compounds of formula I obtained in their salts, especially for pharmaceutical use in their physiologically compatible salts with inorganic or organic acids. 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.

In addition, the new compounds of Formula I, if they contain a carboxyl group, desired if necessary then in their salts with inorganic or ganic bases, especially for pharmaceutical use convert them into their physiologically acceptable salts. As Bases come here, for example, sodium hydroxide, potassium hy hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and Triethanolamine into consideration.

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

As already mentioned at the beginning, the new 1- (4-piperidi nyl) -piperidinylenes of the general formula I and their salts, in particular their physiologically tolerable salts with anor ganic or organic acids or bases, valuable pharma ecological properties, in addition to an anti-inflammatory and the bone loss inhibiting effect, especially antithroma botical, antiaggregatory and tumor or metastasis inhibitors effects.

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

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

A suspension of human platelets in plasma is mixed with ³ H-BIBU 52 [= (3S, 5S) -5 - [(4'-amidino-4-biphenylyl) oxymethyl] -3 - [(car boxyl) methyl] -2-pyrrolidinone [3- ³ H-4-biphenylyl]], which replaces the ligand ¹²⁵ J-fibrinogen known from the literature (see DE-A-4,214,245) and incubates various concentrations of the substance to be tested. The free and bound ligand is separated by centrifugation and quantified by scintillation counting. The inhibition of the ³ H-BIBU 52 binding by the test substance is determined from the measured values.

For this purpose, donor blood is drawn from an anti-cubital vein and anticoagulated with trisodium citrate (final concentration 13 mM). The blood is centrifuged at 170 × g for 10 minutes and the supernatant platelet-rich plasma (PRP) is removed. The rest of the blood is sharply centrifuged again to obtain plasma. The PRP is diluted 1:10 with autologous plasma. 750 ml are incubated with 50 ml of physiological saline, 100 ml of test substance solution, 50 ml of ¹⁴ C sucrose (3700 Bq) and 50 ml of ³ H-BIBU 52 (final concentration: 5 nM) at room temperature for 20 minutes. To measure the non-specific binding, 5 ml BIBU 52 (final concentration: 30 mM) is used instead of the test substance. The samples are centrifuged at 10,000 × g for 20 seconds and the supernatant is removed. 100 ml of this are measured to determine the free ligand. The pellet is dissolved in 500 ml of 0.2N NaOH, 450 ml are mixed with 2 ml of scintillator and 25 ml of 5N HCl and measured. The remaining plasma remaining in the pellet is determined from the ¹⁴ C content, the bound ligand from the ³ H measurement. After subtracting the non-specific binding, the pellet activity is plotted against the concentration of the test substance and the concentration is determined for a 50% inhibition of binding.

2. Antithrombotic effect methodology

Platelet aggregation is performed using the Born and Cross (J. Physiol. 170, 397 (1964)) in platelet-rich plasma healthy subjects measured. For anticoagulation the blood with sodium citrate 3.14% in a volume ratio of 1:10 transferred.  

Collagen-induced aggregation

The course of the decrease in the optical density of the platelets pension is added after the addition of the aggregation-triggering substance measured and registered photometrically. From the angle of inclination the density curve is based on the rate of aggregation closed. The point of the curve at which the greatest light passes Reliability is used to calculate the "optical densi ty ".

The amount of collagen is chosen to be as small as possible, but in such a way that there is an irreversible response curve. The standard collagen from Hormonche is used mie, Munich.

Before adding the collagen, the plasma is added for 10 minutes the substance incubated at 37 ° C.

An EC _{50 is} determined graphically from the measurement numbers obtained, which relates to a 50% change in the "optical density" in the sense of an inhibition of aggregation.

The following table contains the results found:

In addition, some esters of the general formula I have Rhe Sus monkeys after oral administration of 1 mg / kg high plasma levels the corresponding acid.

The new compounds are well tolerated, for example after intravenous administration of 200 mg / kg of ver binding to the mouse no toxic side effects observed could become.

Due to their inhibitory effect on cell-cell or cell matrix  The new piperazine derivatives are suitable for interactions general formula I and its physiologically tolerable salts to combat or prevent diseases in which small nere or larger cell aggregates occur or cell Ma trix interactions play a role, e.g. B. in the fight or prevention of venous and arterial thrombosis, of cerebrovascular diseases, of pulmonary embolism, of the heart infarct, arteriosclerosis, osteoporosis and meta staging of tumors and therapy of genetically determined or acquired disorders of cell interactions with each other or with solid structures. Also suitable this is the accompanying therapy for thrombolysis with Fi brinolytica or vascular interventions such as transluminal angio plastie or also in the therapy of shock states, the Psoriasis, diabetes and inflammation.

For the control or prevention of the aforementioned Diseases the dose is between 0.1 mg and 30 mg / kg body weight per weight, preferably at 1 mg to 15 mg / kg body weight, with up to 4 doses per day. For this purpose, the fiction according to compounds of formula I prepared, if appropriate in combination with other active substances such as Thromboxan-Re zeptor antagonists and thromboxane synthesis inhibitors or their Combinations, serotonin antagonists, α-receptor antagonists, Alkyl nitrates such as glycerol trinitrate, phosphodiesterase inhibitors, Prostacyclin and its analogues, fibrinolytics such as tPA, Prouro kinase, urokinase, streptokinase, or anticoagulants such as Heparin, dermatan sulfate, activated protein C, vitamin K anta gonists, hirudin, inhibitors of thrombin or other acti fourth coagulation factors, together with one or more inert customary carriers and / or diluents, e.g. B. with corn starch, milk sugar, cane sugar, microcrystalline Cellulose, magnesium stearate, polyvinylpyrrolidone, lemons acid, tartaric acid. Water, water / ethanol, water / glycerin, what water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethyl cellulose or retentive substances such as Hard fat or their suitable mixtures, in conventional galenic  Preparations such as tablets, dragees, capsules, powders, suspensions Work in sions, solutions, sprays or suppositories.

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

Production of the starting products Example I 4- [N- (4-methoxybenzyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxy methyl acetate a) N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -4-methoxy benzylamine

To a solution of 6.0 g (0.043 mol) of 4-methoxybenzylamine, 8.71 g (0.043 mol) of 1-tert-butyloxycarbonyl-piperidin-4-one and 2.4 ml of glacial acetic acid in 150 ml of dry tetrahydrofuran are added with stirring and nitrogen 10.2 g (0.048 mol) of sodium triacet oxyborohydride and stirred for a further 24 hours at room temperature. After this time, the mixture is concentrated to dryness in vacuo and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The combined organic extracts are dried and concentrated to dryness in vacuo.
Yield: 13.7 g (97.7% of theory), oil.
R _f value: 0.50 (silica gel; methylene chloride / methanol = 9: 1).

b) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N- (4-methoxy methyl benzyl) aminocarbonyl] phenoxyacetate

To a solution of 3.2 g (0.01 mol) of N- (1-tert-butyloxycar bonyl-piperidin-4-yl) -4-methoxybenzylamine, 2.1 g (0.01 mol) of 4-hydroxycarbonyl-phenoxyacetic acid, methyl ester and 3.2 g (0.01 mol) of 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluro nium tetrafluoroborate in 100 ml of dry tetrahydrofuran are added at room temperature and with stirring 1.3 g (0.01 mol) of N-ethyldiisopropylamine and heated at 80 ° C for 6 hours. The solution is then evaporated to dryness in vacuo and the residue is purified on a silica gel column, methylene chloride containing 1% methanol being used as the eluent.
Yield: 1.4 g (27.3% of theory), oil.
R _f value: 0.9 (silica gel; methylene chloride / methanol = 9: 1).

c) 4- [N- (4-Methoxybenzyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxy methyl acetate

A solution of 3.6 g (7.0 mmol) of 4- [N- (1-tert-butyloxycarbonylpiperidin-4-yl) -N- (4-methoxybenzyl) aminocarbonyl] phenoxyacetic acid methyl ester and 20 ml of trifluoroacetic acid in 20 ml of methylene chloride for one hour at room temperature and then evaporate the solution to dryness under vacuum. The residue is mixed with ether and concentrated again. The remaining residue is distributed between saturated sodium bicarbonate solution and ethyl acetate. The combined organic extracts are dried and evaporated to dryness in vacuo.
Yield: 1.4 g (48.3% of theory), amorphous solid.
R _f value: 0.15 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

Example II 4- [N-Benzyl-N- (piperidin-4-yl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester a) N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) benzylamine

Made from 1-tert-butyloxycarbonyl-piperidin-4-one and benzylamine analogously to Example Ia. Purification by chromatography on a silica gel column using methylene chloride containing 1% methanol as the eluent.
Yield: 14.2 g (48.9% of theory), oil.
R _f value: 0.45 (silica gel; methylene chloride / methanol = 9: 1).

b) 4- [N-Benzyl-N- (1-tert-butyloxycarbonyl-piperidin-4-yl) amino carbonyl] phenoxyacetic acid cyclohexyl ester

Made from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) benzyl amine, 4-hydroxycarbonyl-phenoxyacetic acid cyclohexyl ester and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetra fluoroborate analogous to Example Ib.
Yield: 9.5 g (100% of theory), oil.
R _f value: 0.55 (silica gel; methylene chloride / methanol = 9.5: 0.5).

c) 4- [N-Benzyl-N- (1-piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate

Prepared from 4- [N-benzyl-N- (1-tert-butyloxycarbonyl-pipe ridin-4-yl) -aminocarbonyl] -phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 4.9 g (100% of theory), oil.
R _f value: 0.38 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

Example III 4- [N-Benzyl-N- (piperidin-4-yl) aminomethylene] phenoxyacetic acid cyclohexyl ester a) 4- [N-Benzyl-N- (1-tert-butyloxycarbonyl-piperidin-4-yl) amino methylene] phenol

A solution of 5.0 g (0.017 mol) of N- (1-tert-butyloxycarbonylpiperidin-4-yl) benzylamine, 2.1 g (0.017 mol) of 4-hydroxybenzaldehyde, 4.4 g (0.02 mol ) Sodium triacetoxyborohydride and 0.9 ml glacial acetic acid in 200 ml dry tetrahydrofuran is left overnight at room temperature under a nitrogen atmosphere and then evaporated to dryness under vacuum. The residue is purified by chromatography on a silica gel column using methylene chloride, which contains 1% methanol, as the eluent.
Yield: 2.4 g (33.7% of theory), oil.
R _f value: 0.75 (gravels; methylene chloride / methanol = 9: 1).

b) 4- [N-Benzyl-N- (1-tert-butyloxycarbonyl-piperidin-4-yl) amino methylene] -phenoxyacetic acid cyclohexyl ester

A suspension of 2.4 g (6.1 mmol) of 4- [N-benzyl-N- (1-tert-butyloxycarbonyl-piperidin-4-yl) aminomethylene] phenol and 0.84 g (6.1 mmol) of potassium carbonate (anhydrous) in 50 ml of dimethylformamide is stirred for 30 minutes at room temperature. Then 1.3 g (7.2 mmol) of chloroacetic acid cyclohexyl ester are added and stirring is continued overnight at room temperature. The mixture is concentrated to dryness in vacuo and the residue is purified by chromatography on a silica gel column, methylene chloride being used as the eluent.
Yield: 2.2 g (67.7% of theory).
Melting point: 104-106 ° C
R _f value: 0.27 (silica gel; methylene chloride)
Mass spectrum: M⁺ = 536.

c) 4- [N-Benzyl-N- (piperidin-4-yl) aminomethylene] phenoxyacetic acid cyclohexyl ester

Made from 4- [N-benzyl-N- (1-tert.butyloxycarbonyl-pipe ridin-4-yl) aminomethylene] phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 1.8 g (97% of theory), oil.
R _f value: 0.4 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

Example IV 4- [N- (4-methoxybenzyl) -N- (piperidin-4-yl) aminomethylene] phen methyl oxyacetate a) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N- (4-methoxy benzyl) aminomethylene] phenol

Made from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -4-methoxybenzylamine, 4-hydroxybenzaldehyde and sodium triacet oxyborohydride analogously to Example IIIa.
Yield: 1.3 g (25.7% of theory), oil.
R _f value: 0.60 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 426.

b) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N- (4-methoxy benzyl) aminomethylene] phenoxyacetic acid methyl ester

Prepared from 4- [N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -N- (4-methoxybenzyl) aminomethylene] phenol, and methyl bromoacetate analogously to Example IIIb.
Yield: 820 mg (46.7% of theory), oil.
R _f value: 0.42 (silica gel; methylene chloride / methanol = 9.5: 0.5)
Mass spectrum: M⁺ = 498.

c) 4- [N- (4-Methoxybenzyl) -N- (piperidin-4-yl) aminomethylene] phenoxy methyl acetate

Prepared from 4- [N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -N- (4-methoxybenzyl) -aminomethylene] -phenoxyacetic acid methyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 0.75 g (100% of theory), oil.
R _f value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 398.

Example V 4- [N- (4-methoxybenzyl) -N- (piperidin-4-yl) aminocarbonyl] phen cyclohexyl oxyacetate a) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N- (4-methoxy benzyl) aminocarbonyl] phenoxycyclohexyl ester

Made from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -4-methoxy benzylamine, 4-hydroxycarbonyl-phenoxyacetic acid cyclohexyl ester and 2- (1H-benzotriazol-1-yl) -1,1,3,3- tetra methyluronium tetrafluoroborate analogous to Example Ib. Purification by chromatography on a silica gel column, using methylene chloride, which contains 1% methanol, as eluent.
Yield: 2.4 g (28.2% of theory), foam.
R _f value: 0.45 (silica gel; methylene chloride / methanol = 9.5: 0.5)
Mass spectrum: M⁺ = 580.

b) 4- [N- (4-Methoxybenzyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate

Prepared from 4- [N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -N- (4-methoxy benzyl) aminocarbonyl] phenoxycyclohexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 1.7 g (85.6% of theory), oil.
R _f value: 0.32 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

Example VI 4-Hydroxycarbonyl-phenoxyacetic acid- (1R, 2S, 5R) - (-) - menthyl ester a) Chloroacetic acid (1R, 2S, 5R) - (-) - menthyl ester

A solution of 15.6 g (0.1 mol) of (1R, 2S, 5R) - (-) - menthol and 45 mg (3.6 mmol) of dimethylaminopyridine in 200 ml of absolute toluene is added dropwise over the course of 20 minutes 12 , 4 g (0.12 mol) chloroacetyl chloride (8.8 ml), the temperature rising from + 16 ° C to + 23 ° C. The mixture is left to stand at room temperature for 2 days and concentrated to dryness under vacuum. The residue is mixed with ether, the precipitated dimethylaminopyridine hydrochloride is filtered off and the mother liquor is concentrated to dryness in vacuo.
Yield: 23.3 g (100% of theory), oil.
R _f value: 0.7 (silica gel; cyclohexane / ethyl acetate = 2: 1).

b) 4-Benzyloxycarbonyl-phenoxyacetic acid (1R, 2S, 5R) - (-) - men thylester

3.6 g (0.026 mol) of dried potassium carbonate are added to a solution of 5.0 g (0.022 mol) of benzyl 4-hydroxybenzoate in 50 ml of absolute dimethylformamide at room temperature and with stirring and the mixture is stirred for a further 30 minutes. Then 5.2 g (0.022 mol) of chloroacetic acid (1R, 2S, 5R) - (-) - menthyl ester are added and the mixture is stirred overnight. It is then concentrated to dryness in vacuo, the residue is partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution, the combined organic extracts are dried and concentrated to dryness in vacuo.
Yield: 9.3 g (100% of theory), oil.
R _f value: 0.72 (silica gel; ethyl acetate / cyclohexane = 1: 2).

c) 4-Hydroxycarbonyl-phenoxyacetic acid (1R, 2S, 5R) - (-) - men thylester

9.3 g (0.02 mol) of 4-benzyloxycarbonyl-phenoxyacetic acid (1R, 2S, 5R) - (-) - menthyl ester were dissolved in 100 ml of methanol over 1 g of palladium on carbon (10%) at room temperature and under a Hydrogen pressure of 50 psi exhaustively hydrogenated. The catalyst is filtered off and the filtrate is concentrated to dryness in vacuo.
Yield: 7.3 g (100% of theory).
Melting point: 64-84 ° C (sintering)
Mass spectrum: M⁺ = 334.

Example VII 4- [N- (4-methoxybenzyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxy acetic acid (1R, 2S, 5R) - (-) - menthyl ester a) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N- (4-meth oxybenzyl) aminocarbonyl] phenoxyacetic acid (1R, 2S, 5R) - (-) - men hylester

Made from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -4-methoxy benzylamine, 4-hydroxycarbonyl-phenylacetic acid- (1R, 2S, 5R) - (-) - menthyl ester and 2- (1H-benzotriazole- 1-yl) -1,1,3,3-tetra methyluronium tetrafluoroborate analogous to Example Ib. Purification by chromatography on a silica gel column using methylene chloride, which contains 1% methanol, as the elution medium.
Yield: 3.9 g (78.8% of theory).
Melting point 56-60 ° C
R _f value: 0.6 (silica gel; methylene chloride / methanol = 9.5: 0.5)
Mass spectrum: M⁺ = 636.

b) 4- [N- (4-Methoxybenzyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxy acetic acid (1R, 2S, 5R) - (-) - menthyl ester

Made from 4- [N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -N- (4-methoxybenzyl) aminocarbonyl] phenoxyacetic acid- (1R, 2S, 5R) - (-) - menthyl ester and trifluoroacetic acid analogous to Example Ic.
Yield: 3.3 g (100% of theory), oil.
R _f value: 0.28 (silica gel; methylene chloride / methanol = 9: 1).

Example VIII 4- [N-isobutyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester a) N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -isobutylamine

Manufactured from 1-tert-butyloxycarbonyl-piperidin-4-one and isobutylamine analogously to Example Ia.
Yield: 5.7 g (88.6% of theory), oil.
R _f value: 0.48 (silica gel; methylene chloride / methanol = 9: 1).

b) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N-isobutyl aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Made from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -iso-butylamine, 4-hydroxycarbonyl-phenoxyacetic acid cyclohexyl ester and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate analogous to Example Ib. Purification by chromatography on a silica gel column using methylene chloride, which contains 1.5% methanol, as the eluent.
Yield: 5.1 g (97.7% of theory), oil.
R _f value: 0.68 (silica gel; methylene chloride / methanol = 9: 1).

c) 4- [N-isobutyl-N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate

Prepared from 4- [N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -N-isobutylaminocarbonyl] phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 3.8 g (92.7% of theory), oil.
R _f value: 0.20 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

Example IX N-Benzyl-N- (piperidin-4-yl) -N '- (trans-4-methoxycarbonylcyclo hexyl) urea a) N-Benzyl-N- (1-tert.butyloxycarbonyl-piperidin-4-yl) -N '- (trans- 4-methoxycarbonylcyclohexyl) urea

To a solution of 2.3 g (0.0119 mol) of methyl trans-4-aminocyclohexanecarboxylate hydrochloride in 100 ml of dry dimethylformamide, 4.2 ml (0.0297 mol) of triethylamine and 1.94 g ( 0.0119 mol) 1,1'-carbonyl-di- (1.2.4-triazole) and stirred for a further hour. Then 3.44 g (0.0119 mol) of N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -benzylamine are added and the mixture is stirred overnight at room temperature. The mixture is concentrated to dryness in vacuo and the residue is partitioned between ethyl acetate and a 0.5 molar potassium hydrogen sulfate solution, the organic phase is extracted with saturated sodium bicarbonate solution, the organic phase is dried and concentrated to dryness in vacuo. The residue is purified by chromatography on a silica gel column using methylene chloride with 2% and 3% methanol as the eluent. The residue is crystallized from ether / petroleum ether.
Yield: 2.56 g (45.4% of theory).
R _f value: 0.5 (silica gel; methylene chloride / methanol = 9: 1).

b) N-Benzyl-N- (piperidin-4-yl) -N '- (trans-4-methoxycarbonyl cyclohexyl) urea trifluoroacetate

Made from N-benzyl-N- (1-tert.butyloxycarbonyl-piperidin-4-yl) -N '- (trans-4-methoxycarbonylcyclohexyl) urea and trifluoroacetic acid analogously to Example Ic.
Yield: 2.45 g (93% of theory).
Melting point: 175-178 ° C
R _f value: 0.27 (silica gel; methylene chloride / methanol = 9: 1).

Example X N-Benzyl-N- (piperidin-4-yl) -N '- (1-methoxycarbonylmethylene piperidin-4-yl) urea a) N-Benzyl-N- (1-tert.butyloxycarbonyl-piperidin-4-yl) -N '- (1-methoxy carbonylmethylene-piperidin-4-yl) urea

Made from 1-methoxycarbonylmethylene-4-amino-piperidine hydrochloride, N- (1-tert-butyloxycarbonyl-piperidin-4-yl) benzyl amine and 1,1'-carbonyl-di- (1,2,4-triazole) analogous to example IXa.
Yield: 2.2 g (62.5% of theory).
Melting point 117-121 ° C
R _f value: 0.57 (silica gel; methylene chloride / methanol = 9: 1).

b) N-Benzyl-N- (piperidin-4-yl) -N '- (1-methoxycarbonylme ethylene-piperidin-4-yl) urea

Made from N-benzyl-N- (1-tert.butyloxycarbonyl-piperidin-4-yl) -N '- (1-methoxycarbonylmethylene-piperidin-4-yl) urea and trifluoroacetic acid analogously to Example Ic.
Yield: 1.88 g (100% of theory), amorphous solid.
R _f value: 0.11 (silica gel; methylene chloride / methanol = 9: 1).

Example XI 4- [N-methyl-N- (piperidin-4-yl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester a) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N-methyl aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Manufactured from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) methyl amine, 4-hydroxycarbonyl-phenoxyacetic acid cyclohexyl ester and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate analog Example Ib.
Yield: 4.4 g (92.7% of theory), oil.
R _f value: 0.55 (silica gel; methylene chloride / methanol = 9: 1).

b) 4- [N-Methyl-N- (piperidin-4-yl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Prepared from 4- [N- (1-tert-butyloxycarbonyl-diperidin-4-yl) -N-methyl aminocarbonyl] phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 3.5 g (quantitative), oil.
R _f value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

Example XII 4- [N-phenyl-N- (piperidin-4-yl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester a) N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) aniline

Manufactured from 1-tert-butyloxycarbonyl-piperidin-4-one and aniline analogously to Example Ia. Purification by chromatography on a silica gel column using methylene chloride as the elution medium.
Yield: 2.6 g (62.4% of theory), oil.
R _f value: 0.75 (silica gel; methylene chloride / methanol = 9.5: 0.5).

b) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N-phenyl aminocarbonyl] phenoxyacetic acid cyclohexyl ester

A suspension of 2.6 g (9.5 mmol) of cyclohexyl 4-hydroxycarbonyl-phenoxyacetic acid in 10 ml of thionyl chloride is heated to 50 ° C., a clear solution being formed. Then it is stirred for an hour at room temperature, then concentrated to dryness in vacuo and the residue is dissolved in 50 ml of methylene chloride. 2.6 g (9.5 mmol) of N- (1-tert-butyloxycarbonylpiperidin-4-yl) aniline and 1.2 g (9.5 mmol) of N-ethyl-diisopropylamine are added to this solution with stirring and keeps stirring overnight. The mixture is then evaporated to dryness in vacuo and the residue is purified by chromatography on a silica gel column using methylene chloride as the eluent.
Yield: 3.7 g (73.5% of theory), oil.
R _f value: 0.61 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 536.

c) 4- [N-phenyl-N- (piperidin-4-yl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Prepared from 4- [N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -N-phenyl aminocarbonyl] phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 3.0 g (quantitative), foam.
R _f value: 0.35 (silica gel; methylene chloride / methanol = 9: 1).

Example XIII 4- [N-Cyclohexyl-N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate a) N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) anilin-4-yl) cyclo hexylamine

Manufactured from 1-tert-butyloxycarbonyl-piperidin-4-one and cyclohexylamine analogously to Example Ia. Purification by chromatography on a silica gel column using methylene chloride containing 1% methanol as the eluent.
Yield: 4.2 g (98.7% of theory), oil.
R _f value: 0.59 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

b) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N-cyclohexyl aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Prepared from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -cyclohexylamine, 4-hydroxycarbonyl-phenoxyacetic acid cyclohexyl ester and thionyl chloride as in Example XIIb. Purification by means of chromatography on a silica gel column, using methylene chloride which contains 1% methanol as the eluent.
Yield: 2.5 g (76.5% of theory), oil.
R _f value: 0.38 (silica gel; methylene chloride / methanol = 9.5: 0.5).

c) 4- [N-Cyclohexyl-N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate

Prepared from 4- [N- (1-tert-butyloxycarbonyl-diperidin-4-yl) -N-cyclohexyl-aminocarbonyl] -phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 2.0 g (quantitative), oil.
R _f value: 0.35 (silica gel; methylene chloride / methanol = 9: 1).

Example XIV 4- [N- (4-fluorobenzyl) -N- (piperidin-4-yl) aminocarbonyl] phen cyclohexyl oxyacetate a) N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) - (4-fluor benzylamine

Manufactured from 1-tert-butyloxycarbonyl-piperidin-4-one and 4-fluorobenzylamine analogously to Example Ia.
Yield: 4.4 g (94.8% of theory), oil.
R _f value: 0.45 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

b) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N- (4-fluor benzyl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Prepared from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -4-fluorobenzylamine, 4-hydroxycarbonyl-phenoxyacetic acid cyclo hexyl ester and thionyl chloride analogously to Example XIIb. Purification by chromatography on a silica gel column, using methylene chloride, which contains 1% methanol, as eluent.
Yield: 5.1 g (98.8% of theory), oil.
R _f value: 0.45 (silica gel; methylene chloride / methanol = 9.5: 0.5)
Mass spectrum: M⁺ = 568.

c) 4- [N- (4-Fluorobenzyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate

Made from 4- [N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -N- (4-fluorobenzyl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 4.2 g (quantitative), oil.
R _f value: 0.27 (silica gel; methylene chloride / methanol = 9.5: 0.5).

Example XV 4- [N-Cyclohexylmethyl-N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate a) N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) aminomethylene cyclohexane

Manufactured from 1-tert-butyloxycarbonyl-piperidin-4-one and aminomethylene cyclohexane analogously to Example Ia.
Yield: 5.9 g (quantitative), oil.
R _f value: 0.38 (silica gel; methylene chloride / methanol = 9: 1).

b) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N-methylene cyclohexyl cyclohexyl aminocarbonyl] phenoxyacetic acid

Prepared from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -amino methylene cyclohexane, 4-hydroxycarbonyl-phenoxyacetic acid cyclohexyl ester and thionyl chloride analogously to Example XIIb. Purification by means of chromatography on a silica gel column, where methylene chloride, which contains 1.5% methanol, is used as the elution medium 63910 00070 552 001000280000000200012000285916379900040 0002019643331 00004 63791d.
Yield: 3.5 g (62.9% of theory), oil.
R _f value: 0.78 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 556.

c) 4- [N-Cyclohexylmethyl-N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate

Prepared from 4- [N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -N-cyclohexylmethyl-aminocarbonyl] -phenoxyacetic acid cyclo hexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 2.9 g (quantitative), oil.
R _f value: 0.29 (silica gel; methylene chloride / methanol = 9: 1).

Example XVI 4- [N- (3-pyridylmethyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate a) N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -3-aminomethylene pyridine

Manufactured from 1-tert-butyloxycarbonyl-piperidin-4-one and 3-aminomethylene pyridine analogously to Example Ia.
Yield: 5.8 g (quantitative), oil.
R _F value: 0.44 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 291.

b) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N- (3-methy len-pyridyl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Prepared from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -3-amino methylene pyridine, 4-hydroxycarbonyl-phenoxyacetic acid, cyclohexyl ester and thionyl chloride as in Example XIIb. Cleaning by chromatography on a silica gel column, where methylene chloride containing 2% methanol is used as the elution medium.
Yield: 4.1 g (74.5% of theory), oil.
R _f value: 0.46 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 551.

c) 4- [N- (3-Pyridylmethyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate

Prepared from 4- [N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -N- (3-pyridylmethyl) -aminocarbonyl] -phenoxyacetic acid cyclo hexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 3.4 g (quantitative), oil.
R _f value: 0.19 (silica gel; methylene chloride / methanol = 9: 1).

Example XVII 4- [N- (4-pyridylmethyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate a) N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) aminomethylene pyridine

Prepared from 1-tert-butyloxycarbonyl-piperidin-4-one and 4-aminomethylene pyridine analogously to Example Ia.
Yield: 4.8 g (65.6% of theory).
Melting point: 75-77 ° C
R _f value: 0.45 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

b) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N- (4-methy len-pyridyl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Prepared from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -4-amino methylene pyridine, 4-hydroxycarbonyl-phenoxyacetic acid, cyclohexyl ester and thionyl chloride as in Example XIIb. Purification by chromatography on a silica gel column, where methylene chloride, which contains 1% methanol, is used as the eluent.
Yield: 2.9 g (52.1% of theory), foam.
R _f value: 0.51 (silica gel; methylene chloride / methanol = 9: 1).

c) 4- [N- (4-Pyridylmethyl) -N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate

Prepared from 4- [N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -N- (4-pyridylmethyl) -aminocarbonyl] -phenoxyacetic acid cyclo hexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 2.4 g (quantitative), oil.
R _f value: 0.3 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

Example XVIII 4- [N-ethoxycarbonylmethyl-N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate a) N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -glycine ethyl ester

Prepared from 1-tert-butyloxycarbonyl-piperidin-4-one and glycine ethyl ester hydrochloride analogously to Example Ia.
Yield: 5.7 g (quantitative), oil.
R _f value: 0.44 (silica gel; methylene chloride / methanol = 9: 1).

b) 4- [N- (1-tert-Butyloxycarbonyl-piperidin-4-yl) -N-ethoxy carbonylmethyl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Prepared from N- (1-tert-butyloxycarbonyl-piperidin-4-yl) -glycine ethyl ester, 4-hydroxycarbonyl-phenoxyacetic acid cyclo hexyl ester and thionyl chloride analogously to Example XIIb. Purification by chromatography on a Kieseigel column, using methylene chloride, which contains 2% methanol, as eluent.
Yield: 3.6 g (66.7% of theory), oil.
R _f value: 0.67 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 546.

c) 4- [N-Ethoxycarbonylmethyl-N- (piperidin-4-yl) amino carbonyl] phenoxyacetic acid cyclohexyl ester

Made from 4- [N-1-tert-butyloxycarbonyl-piperidin-4-yl) -N-ethoxy carbonylmethyl-aminocarbonyl] -phenoxyacetic acid cyclo hexyl ester and trifluoroacetic acid analogously to Example Ic.
Yield: 2.9 g (quantitative), oil.
R _f value: 0.28 (silica gel; methylene chloride / methanol = 9: 1).

Example XIX 4- [N-benzyl-N- (piperidin-4-yl) aminocarbonyl] -N-phenyl glycine methyl ester a) 4- [N-Benzyl-N- (1-benzyloxycarbonyl-piperidin-4-yl) amino carbonyl] -N-tert.butyloxycarbonylaniline

Made from 1-benzyloxycarbonyl-piperidin-4-yl) -benzyl amine, 4-tert-butyloxycarbonylamino-benzoic acid and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate analogously to the example Ib. Purification by chromatography on a silica gel column using methylene chloride, which contains 2% methanol, as the eluent.
Yield: 8.4 g (63.3% of theory).
R _f value: 0.4 (silica gel; ethyl acetate / cyclohexane = 1: 1).

b) 4- [N-Benzyl-N- (1-benzyloxycarbonyl-piperidin-4-yl) amino carbonyl] aniline

Made from 4- [N-benzyl-N- (1-benzyloxycarbonyl-piperidin-4-yl) aminocarbonyl] -N-tert.butyloxycarbonylaniline and trifluoroacetic acid analogously to Example Ic.
Yield: 5.26 g (77.5% of theory).
R _f value: 0.11 (silica gel; ethyl acetate / cyclohexane = 1: 1).

c) 4- [N-Benzyl-N- (1-benzyloxycarbonyl-piperidin-4-yl) amino carbonyl] -N-phenylglycine methyl ester

A solution of 5.2 g (0.0117 mol) of 4- [N-benzyl-N- (1-benzyloxycarbonyl-piperidin-4-yl) aminocarbonyl] aniline, 1.22 ml (0.00129 mol) Methyl bromoacetate and 1.9 ml (0.0129 mol) of N-ethyldiisopropylamine in 200 ml of dry dimethylformamide are left at room temperature for 12 days. The mixture is then evaporated to dryness in vacuo and the residue was distributed between ethyl acetate and saturated sodium bicarbonate solution. The combined organic extracts are dried and evaporated to dryness in vacuo. The remaining residue is cleaned on a silica gel column, using ethyl acetate / cyclohexane = 1: 1 as the eluent.
Yield: 5.2 g (86.2% of theory), foam.
R _f value: 0.21 (silica gel; ethyl acetate / cyclohexane = 1: 1).

d) 4- [N-Benzyl-N- (piperidin-4-yl) aminocarbonyl] -N-phenyl glycine methyl ester

4.1 g (0.005 mol) of 4- [N-benzyl-N- (1-benzyloxycarbonyl-pipe ridin-4-yl) aminocarbonyl] -N-phenylglycine methyl ester are dissolved in 160 ml of methanol at room temperature and under a hydrogen pressure exhaustively hydrogenated from 50 psi over 0.8 g palladium on carbon (10%). The catalyst is filtered off and the mother liquor is evaporated to dryness in vacuo.
Yield: 3 g (98.5% of theory) of foam.
R _f value: 0.14 (silica gel; methylene chloride / methanol = 9: 1).

Manufacture of end products example 1 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidine- 4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxyacetic acids thylester

To a solution of 1.4 g (3.5 mmol) of 4- [N- [4-methoxybenzyl) -N- (piperidine-4-yl) aminocarbonyl] phenoxyacetic acid methyl ester, 0.7 g (3.5 mmol) 1-tert-butyloxycarbonyl-piperidin-4-one and 0.25 ml glacial acetic acid in 50 ml dry tetrahydrofuran, 0.9 g (4.3 mmol) sodium tri acetoxyborohydride are added with stirring and nitrogen and the mixture is stirred for a further 16 hours at room temperature . After this time, the mixture is concentrated to dryness in vacuo and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The combined organic extracts are dried and evaporated to dryness in vacuo. The remaining residue is purified on a silica gel column using methylene chloride, which contains 2% and subsequently 3% methanol, as the eluent.
Yield: 0.4 g (19% of theory).
Melting point: 57-60 ° C
R _f value: 0.42 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 595.

The following compounds can be prepared analogously to Example 1 will:

(1) 4- [N-Benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) pipe ridin-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Made from 4- [N-benzyl-N- (piperidin-4-yl)] - aminocarbonyl] -phenoxyacetic acid cyclohexyl ester and 1-tert-butyloxycar bonyl-piperidin-4-one. Purification by chromatography on a silica gel column using methylene chloride containing 1% methanol as the eluent.
Yield: 4.6 g (66.7% of theory), oil.
R _f value: 0.53 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 633.

(2) 4- [N-Benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) pipe ridin-4-yl] aminomethylene] phenoxyacetic acid cyclohexyl ester

Made from 4- [N-benzyl-N- (piperidin-4-yl] aminomethylene] phenoxy cyclohexyl acetate and 1-tert-butyloxycarbonyl piperidin-4-one.Purification by chromatography on a silica gel column, using methylene chloride, the 1st % Contains methanol, is used as eluent.
Yield: 1.7 g (63% of theory), oil.
R _f value: 0.52 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 619.

(3) 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidine- 4-yl] -N- (4-methoxybenzyl) aminomethylene] phenoxyacetic acids thylester

Made from methyl 4- [N- (4-methoxybenzyl) -N- (piperidin-4-yl] -amino methylene] -phenoxyacetic acid and 1-tert-butyl oxycarbonyl-piperidin-4-one, purified by chromatography on a silica gel column using methylene chloride containing 1.5% methanol as the eluent.
Yield: 500 mg (45.7% of theory), oil.
R _f value: 0.42 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 581.

(4) 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidine- 4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Made from 4- [N- (4-methoxybenzyl) -N- (piperidin-4-yl] -amino carbonyl] -phenoxyacetic acid cyclohexyl ester and 1-tert-butyloxycarbonyl-piperidin-4-one. Purification by chromatography on a silica gel Column, where methylene chloride containing 2 or 5% methanol is used as the eluent.
Yield: 450 mg (19.2% of theory).
Melting point: 64-69 ° C
R _f value: 0.63 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: (M⁺H) ⁺ = 664.

(5) 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidine- 4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxyacetic acid - (1R, 2S, 5R) - (-) - menthyl ester

Made from 4- [N- (4-methoxybenzyl) -N- (piperidin-4-yl) amino carbonyl] phenoxyacetic acid- (1R, 2S, 5R) - (-) - menthyl ester and 1-tert-butyloxycarbonyl-piperidine -4-one. Purification by chromatography on a silica gel column, methylene chloride / methanol / conc. Ammonia = 99: 1: 0.1 is used as the eluent.
Yield: 1.3 g (29.4% of theory), oil.
R _f value: 0.55 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 599.

(6) 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidine- 4-yl] -N-isobutylaminocarbonyl] phenoxyacetic acid cyclohexyl ester

Prepared from 4- [N-isobutyl-N- (piperidin-4-yl] aminocar bonyl] phenoxyacetic acid cyclohexyl ester and 1-tert-butyloxy carbonyl-piperidin-4-one. Purification by chromatography on a silica gel column, methylene chloride, containing 1% methanol as eluent.
Yield: 3.2 g (58.5% of theory), oil.
R _f value: 0.48 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 599.

(7) 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidine- 4-yl] -N- (4-methoxybenzyl) aminomethylene] phenoxyacetic acid cyclohexyl ester

Made from 4- [N- (4-methoxybenzyl) -N- (piperidin-4-yl] amino methylene] phenoxyacetic acid cyclohexyl ester and 1-tert-butyloxycarbonyl-piperidin-4-one. Purification by chromatography on a silica gel Column using methylene chloride containing 1% methanol as the eluent.
Yield: 850 mg (40.7% of theory), oil.
R _f value: 0.55 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 649.

(8) N-Benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] -N '- (trans-4-methoxycarbonylcyclohexyl) urine material

Made from N-benzyl-N- (piperidin-4-yl] -N '- (trans- 4-methoxycarbonylcyclohexyl) urea trifluoroacetate and 1-tert-butyloxycarbonyl-piperidin-4-one. Purification by chromatography on a silica gel Column using methylene chloride containing 2.5% methanol as the eluent.
Yield: 1.68 g (61.6% of theory), foam.
R _f value: 0.5 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1).

(9) N-Benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] -N '- (1-methoxycarbonylmethylene-piperidin-4-yl) urine material

Made from N-benzyl-N- (piperidin-4-yl] -N '- (1-methoxy carbonylmethylene-piperidin-4-yl) urea and tert-butyloxycarbonyl-piperidin-4-one.Purification by chromatography on a silica gel Column, using methylene chloride containing 2.5% methanol as the eluent.
Yield: 1.64 g (59.7% of theory), oil.
R _f value: 0.41 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 571.

(10) 4- [N- [1- (1-Benzyl-4-piperidinyl) piperidin-4-yl] -N-methyl aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Made from 4- [N-methyl-N- (piperidin-4-yl) aminocarbonyl] phenoxy cyclohexyl acetate and 1-benzyl-piperidin-4-one. Purification by chromatography on a silica gel column, methylene chloride / methanol / conc. Ammonia = 98: 2: 0.2 is used as the eluent. After evaporation under vacuum, the oily residue is crystallized from ether.
Yield: 1.9 g (37.1% of theory).
Melting point: 112-115 ° C
R _f value: 0.43 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 547.

(11) 4- [N- [1- (1-tert-Butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] -N-phenylaminocarbonyl] phenoxyacetic acid cyclohexyl ester

Prepared from 4- [N-phenyl-N- (piperidin-4-yl] aminocarbonyl] phenoxy cyclohexyl acetate and 1-tert-butyloxycarbonyl piperidin-4-one.Purification by chromatography on a silica gel column, using methylene chloride, the 2nd , Contains 5% methanol, is used as eluent.
Yield: 2.55 g (58.5% of theory).
R _f value: 0.53 (silica gel, methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 619.

(12) 4- [N- [1- (1-tert-Butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] -N-cyclohexylaminocarbonyl] phenoxyacetic acid cyclohexyl ester

Prepared from 4- [N-cyclohexyl-N- (piperidin-4-yl] amino carbonyl] phenoxyacetic acid cyclohexyl ester and 1-tert-butyloxycarbonyl-piperidin-4-one.Cleaning by means of chromatography on a silica gel column where methylene chloride / Methanol / concentrated ammonia = 99: 1: 0.1, is used as the eluent.
Yield: 1.8 g (62.3% of theory).
Melting point: 53-56 ° C
R _f value: 0.47 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 625.

(13) 4- [N- [1- (1-tert-Butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] -N- (4-fluorobenzyl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Made from 4- [N- [1- (4-fluorobenzyl) -N- (piperidin-4-yl) amino carbonyl] phenoxyacetic acid cyclohexyl ester and 1-tert-butyloxycarbonyl-piperidin-4-one. Purification by means of chromatography on a silica gel column, methylene chloride / methanol / conc. Ammonia = 9: 1: 0.1 is used as the eluent.
Yield: 3.5 g (59.4% of theory).
Melting point: 50-53 ° C
R _f value: 0.57 (silica gel methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 651.

(14) 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) pipe ridin-4-yl] -N-cyclohexylmethyl-aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Made from 4- [N-cyclohexylmethyl-N- (piperidin-4-yl) amino carbonyl] phenoxyacetic acid cyclohexyl ester and 1-tert-butyloxycarbonyl-piperidin-4-one. Purification by chromatography on a silica gel column using methylene chloride containing 2% methanol as the eluent.
Yield: 1.9 g (46.8% of theory), foam.
R _f value: 0.62 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 639.

(15) 4- [N- [1- (1-tert-Butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] -N- (3-pyridylmethyl) aminocarbonyl] phenoxy cyclohexyl acetate

Made from 4- [N- (3-pyridylmethyl) -N- (piperidin-4-yl) amino carbonyl] phenoxyacetic acid cyclohexyl ester and 1-tert-butyloxycarbonyl-piperidin-4-one. Purification using chromatography on a silica gel column. using methylene chloride containing 2% methanol as the eluent.
Yield: 2.6 g (54.4% of theory), foam.
R _f value: 0.47 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 634.

(16) 4- [N- [1- (1-tert-Butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] -N- (4-pyridylmethyl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Made from 4- [N- (4-pyridylmethyl) -N- (piperidin-4-yl) amino carbonyl] phenoxyacetic acid cyclohexyl ester and 1-tert-butyloxycarbonyl-piperidin-4-one. Purification by means of chromatography on a silica gel column, methylene chloride / methanol / conc. Ammonia = 98: 2: 0.2 is used as the eluent.
Yield: 1.7 g (50.4% of theory), oil.
R _f value: 0.45 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 634.

(17) 4- [N- [1- (1-tert-Butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] -N-ethoxycarbonylmethyl-aminocarbonyl] phenoxy cyclohexyl acetate

Prepared from 4- [N-ethoxycarbonylmethyl-N- (piperidin-4-yl] amino carbonyl] phenoxyacetic acid cyclohexyl ester and 1-tert-butyloxycarbonyl-piperidin-4-one. Purification by chromatography on a silica gel column, methylene chloride, containing 2% methanol is used as the eluent.
Yield: 3.1 g (75.8% of theory), oil.
R _f value: 0.49 (silica gel; methylene chloride = 9: 1)
Mass spectrum: M⁺ = 629.

(18) 4- [N-Benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] aminocarbonyl] -N-phenylglycine methyl ester

Made from 4- [N-benzyl-N- (piperidin-4-yl) aminocarbonyl] -N-phenyl glycine methyl ester and 1-tert-butyloxycarbonyl-piperidine-4-one. Purification by chromatography on a silica gel column using methylene chloride containing 2.5% methanol as the eluent.
Yield: 460 mg (44.4% of theory), foam.
R _f value: 0.45 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 564.

(19) 4 - [[N-Benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperi dinyl) -piperidin-4-yl] aminocarbonyl] -N-phenyl] -N-formylgly cinemethyl ester

Made from 4 - [[N-benzyl-N- (piperidin-4-yl) aminocar bonyl] -N-phenyl] -N-formylglycine methyl ester and 1-tert-butyl oxycarbonyl-piperidin-4-one.

(20) 4 - [[N-Benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperi dinyl) -piperidin-4-yl] aminocarbonyl] -N-phenyl] -N-acetylgly cinemethyl ester

Made from 4 - [[N-benzyl-N- (piperidin-4-yl) aminocar bonyl] -N-phenyl] -N-acetylglycine methyl ester and 1-tert-butyl oxycarbonyl-piperidin-4-one.

(21) 1 - [[N-Benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperi dinyl) -piperidin-4-yl] aminocarbonyl] -piperidin-4-yl] -3-pro ethyl pionate

Made from 1 - [[N-benzyl-N- (piperidin-4-yl) aminocar bonyl] -piperidin-4-yl] -3-propionic acid ethyl ester and 1-tert.Bu tyloxycarbonyl-piperidin-4-one.

(22) 4- [N-Benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenyl-3-propionic acid ethyl ester

Made from 4- [N-benzyl-N- (piperidin-4-yl] aminocarbonyl] phenyl- 3-propionic acid ethyl ester and 1-tert-butyloxycarbonyl piperidin-4-one.

(23) 4- [N - [, 1- (1-tert-butyloxycarbonyl-4-piperidinyl) pipe ridin-4-yl] -N- (4-ethoxycarbonylmethyleneoxy-benzyl) aminocar bonyl] -phenoxyacetic acid benzyl ester

Made from 4- [N- (4-ethoxycarbonylmethyleneoxy-benzyl) -N- (pipe ridin-4-yl) aminocarbonyl] phenoxyacetic acid benzyl ester and 1-tert-butyloxycarbonyl-piperidin-4-one.  

Example 2 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid methyl ester dihydrochloride

A solution of 0.4 g (0.67 mmol) of 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidin-4-yl] -N- (4-methoxy benzyl) is left -aminocarbonyl] -phenoxyacetic acid methyl ester and 10 ml ethereal hydrochloric acid in methanol for 2 hours at room temperature and then concentrated to dryness under vacuum. The residue is triturated with ether, suction filtered and dried.
Yield: 350 mg (91.7% of theory), amorphous solid.
R _f value: 0.06 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 495.

The following compounds can be prepared analogously to Example 2 will:

(1) 4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid cyclohexyl ester bistrifluoroacetate

Made from 4- [N-benzyl-N- [1- (1-tert-butyloxycarbonyl- 4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid, cyclohexyl acid and trifluoroacetic acid.
Yield: 2.4 g (43.4% of theory).
Melting point: 220-222 ° C
R _f value: 0.55 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 533.

(2) 4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino methylene] phenoxyacetic acid cyclohexyl ester tristrifluoroacetate

Made from 4- [N-benzyl-N- [1- (1-tert-butyloxycarbonyl) - (4-piperidinyl) piperidin-4-yl] aminomethylene] phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid.
Yield: 1.9 g (80.4% of theory).
Melting point: 60-62 ° C
R _f value: 0.52 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 519.

(3) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminomethylene] phenoxyacetic acid methyl ester tristri fluoroacetate

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidyl nyl) piperidin-4-yl] -N- (4-methoxybenzyl) aminomethylene] phenyl methyl oxyacetate and trifluoroacetic acid.
Yield: 520 mg (85.3% of theory).
Melting point: 72-80 ° C
R _f value: 0.46 (silica gel methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: (M⁺H) ⁺ = 482.

(4) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Made from 4- [N- [l- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidin-4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxy methyl acetate and trifluoroacetic acid. Purification by chromatography on a Kieseigel column, with methylene chloride / methanol / conc. Ammonia = 6: 1: 0.2 is used as the eluent.
Yield: 150 mg (39.3% of theory), foam.
Melting point: 208-210 ° C
R _f value: 0.57 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 563.

(5) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetyl-N-glycine ethyl ester dihydro chloride

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) -piperidin-4-yl) -N-methoxybenzyl) -aminocarbonyl] -phen oxyacetyl-N-glycine ethyl ester and trifluoroacetic acid. Purification by chromatography on a silica gel column, with methylene chloride / methanol / conc. Ammonia = 6: 1: 0.2 is used as the eluent.
Yield: 0.9 g (49.4% of theory), foam.
R _f value: 0.66 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 566.

(6) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid (1R, 2S, 5R) - (-) - men thylester

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-pipe ridinyl) piperidin-4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxy acetic acid- (1R, 2S, 5R ) - (-) - menthyl ester and trifluoroacetic acid. Purification by chromatography on a silica gel column, methylene chloride / methanol / conc. Ammonia = 6: 1: 0.1 is used as the eluent.
Yield: 300 mg (26.8% of theory).
Melting point: 60-62 ° CR _f value: 0.66 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 619.

(7) 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid cyclohexyl ester trifluoroacetate

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) -piperidin-4-yl] -N-isobutyl-aminocarbonyl] -phen oxyacetic acid cyclohexyl ester and trifluoroacetic acid.
Yield: 3.1 g (79.8% of theory).
Melting point: 191-193 ° C
R _f value: 0.22 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 499.

(8) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetyl-N-ethylamide

Made from 4- [N- (1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidin-4-yl) -N- (4-methoxybenzyl) aminocarbonyl] phenoxy acetyl-N-ethylamide and trifluoroacetic acid. Purification by chromatography on a silica gel column, with methylene chloride / methanol / conc. Ammonia = 6: 1: 0.2 is used as the eluent.
Yield: 600 mg (57.1% of theory), amorphous solid.
R _f value: 0.44 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 508.

(9) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminomethylene] phenoxyacetic acid cyclohexyl ester tristri fluoroacetate

Made from 4- [N- [1-tert-butyloxycarbonyl-4-piperidinyl) piperidine-4-yl] -N- (4-methoxybenzyl) aminomethylene] phenoxy cyclohexyl acetate and trifluoroacetic acid.
Yield: 850 mg (88.7% of theory).
Melting point: 82-84 ° C
R _f value: 0.50 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: (M + H) ⁺ = 550.

(10) N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] -N '- (trans- 4-methoxycarbonylcyclohexyl) urea dihydrochloride

Made from N-benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidin-4-yl] -N '- (trans-4-methoxycarbonylcyclohexyl) urea and trifluoroacetic acid.
Yield: 1.73 g (100% of theory), amorphous solid.
R _f value: 0.09 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 456.

(11) N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] -N '- (1-methoxy carbonylmethylene-piperidin-4-yl) urea trihydrochloride

Made from N-benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidin-4-yl] -N '- (1-methoxycarbonylmethylene-pipe ridin-4-yl) urea and trifluoroacetic acid .
Yield: 1.56 g (96% of theory), amorphous solid.
R _f value: 0.05 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 581.

(12) 4- [N-Phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid cyclohexyl ester bistrifluoroacetate

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) -piperidin-4-yl] -N-phenyl-aminocarbonyl] phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid.
Yield: 1.7 g (82.9% of theory).
Melting point: 176-178 ° C
R _f value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 519.

(13) 4- [N-Cyclohexyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid cyclohexyl ester dihydrochloride

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) -piperidin-4-yl] -N-cyclohexyl-aminocarbonyl] phenoxy cyclohexyl acetate.
Yield: 1.3 g (75.5% of theory).
Melting point: 80-82 ° C
R _f value: 0.25 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 525.

(14) 4- [N- (4-fluorobenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester bistri fluoroacetate

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) -piperidin-4-yl] -N- (4-fluorobenzyl) aminocarbonyl] phenoxy cyclohexyl oxyacetate and trifluoroacetic acid.
Yield: 3.5 g (97.5% of theory).
Melting point: 210-212 ° C
R _f value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 551.

(15) 4- [N-Cyclohexylmethyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester bistri fluoroacetate

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-pipe ridinyl) piperidin-4-yl] -N-cyclohexylmethyl-aminocarbonyl] phenoxy cyclohexyl acetate and trifluoroacetic acid.
Yield: 2.0 g (92.6% of theory).
Melting point: 223-226 ° C
R _f value: 0.20 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 539.

(16) 4- [N- (3-pyridylmethyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester tristri fluoroacetate

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-pipe ridinyl) piperidin-4-yl] -N- (3-pyridylmethyl) aminocarbonyl] phenoxy cyclohexyl acetate and trifluoroacetic acid.
Yield: 3.0 g (83.5% of theory), amorphous solid.
R _f value: 0.22 (gravels; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 534.

(17) 4- [N- (4-pyridylmethyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester trihy hydrochloride

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-pipe ridinyl) piperidin-4-yl] -N- (4-pyridylmethyl) aminocarbonyl] phenoxy cyclohexyl acetate and trifluoroacetic acid.
Yield: 1.9 g (93% of theory), amorphous solid.
R _f value: 0.63 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 534.

(18) 4- [N-ethoxycarbonylmethyl) -N- [1- (4-piperidinyl) pipe ridin-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester bistrifluoroacetate

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidin-4-yl] -N-ethoxycarbonylmethylamino carbonyl] phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid.
Yield: 2.7 g (72.4% of theory).
Melting point: 185-187 ° C
R _f value: 0.25 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 529.

(19) 4- [N-ethoxycarbonylmethyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid benzyl ester

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-pipe ridinyl) piperidin-4-yl] -N-ethoxycarbonylmethyl aminocar bonyl] -phenoxyacetic acid benzyl ester and trifluoroacetic acid.

(20) 4- [N-Benzyl-N - [, 1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] -N-phenyl-glycine methyl ester trihydrochloride

Made from 4- [N-benzyl-N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidin-4-yl] aminocarbonyl] -N-phenylglycine methyl ester and trifluoroacetic acid.
Yield: 430 mg (quantitative), amorphous solid.
R _f value: 0.06 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum: M⁺ = 464.

(21) 4 - [[N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] -N-phenyl] -N-formylglycine methyl ester dihydrochloride

Made from 4 - [[N-benzyl-N- [1- (1-tert.butyloxycarbonyl- 4-piperidinyl) -piperidin-4-yl] aminocarbonyl] -N-phenyl] -N-for methylglycine methyl ester and trifluoroacetic acid.

(22) 4 - [[N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] -N-phenyl] -N-acetylglycine methyl ester dihydrochloride

Made from 4 - [[N-benzyl-N- [1- (1-tert.butyloxycarbonyl- 4-piperidinyl) -piperidin-4-yl] aminocarbonyl] -N-phenyl] -N-acetyl glycine methyl ester and trifluoroacetic acid.

(23) 1 - [[N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] -piperidin-4-yl] -3-propionic acid ethyl ester trihydro chloride

Made from 1 - [[N-benzyl-N- [1- (1-tert.butyloxycarbonyl- 4-piperidinyl) piperidin-4-yl] aminocarbonyl] piperidin-4-yl] -3-propion acid ethyl ester and trifluoroacetic acid.

(24) 4 - [[N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenyl] -3-propionic acid ethyl ester dihydrochloride

Made from 4 - [[N-benzyl-N- [1- (1-tert.butyloxycarbonyl- 4-piperidinyl) -piperidin-4-yl] aminocarbonyl] phenyl] -3-pro ethyl pionate and trifluoroacetic acid.

(25) 4- [N- (4-Ethoxycarbonylmethyleneoxy-benzyl) -N- [1- (4-piperi dinyl) -piperidin-4-yl] aminocarbonyl] phenoxyacetic acid benzyl ester

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperi dinyl) -piperidin-4-yl] -N- (4-ethoxycarbonylmethylenoxy-benzyl) amino carbonyl] phenoxyacetic acid benzyl ester and trifluoroacetic acid acid.  

(26) 4- [N, N-bis- [1- (4-piperidinyl) piperidin-4-yl] aminocar bonyl] -phenoxyacetic acid cyclohexyl ester

Made from 4- [N, N-bis- [1- (1-tert-butyloxycarbonyl-4-pi peridinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester and trifluoroacetic acid.

Example 3 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid dihydrochloride

A solution of 120 mg (0.2 mmol) of 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxy methyl acetate dihydrochloride is left and 0.84 ml (0.84 mmol) of 1N sodium hydroxide solution in 4 ml of tetrahydrofuran and 4 ml of water for 2 hours at room temperature, then mixed with 0.84 ml (0.84 mmol) of 1N hydrochloric acid and evaporated to dryness under vacuum a. The remaining residue is mixed three times with absolute ethanol and each time concentrated to dryness under vacuum. The residue is triturated with methylene chloride / methanol = 1: 1. The solid which has separated out is filtered off with suction and the mother liquor is evaporated to dryness in vacuo.
Yield: 100 mg (85.4% of theory), amorphous solid.
R _f value: 0.11 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: (M + H) ⁺ = 482.

The following connection can be established analogously to Example 3:

(1) 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidine- 4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxyacetic acid

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-pipe ridinyl) piperidin-4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxy acetic acid methyl ester and 1N sodium hydroxide solution.
Yield: 4.3 g (89.9% of theory).
R _f value: 0.48 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2).

Example 4 4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocar bonyl] phenoxyacetic acid dihydrochloride

A solution of 2.0 g (2.6 mmol) of 4- [N-benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid cyclo hexyl ester bistrifluoroacetate in 30 ml conc . Hydrochloric acid / water = 1: 1 is left to stand for 3 hours at room temperature and then concentrated to dryness in vacuo. The residue is mixed three times with acetone and again evaporated to dryness under vacuum.
Yield: 1.3 g (94.4% of theory), amorphous solid.
R _f value: 0.4 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
Mass spectrum: M⁺ = 451.

The following compounds can be prepared analogously to Example 4 will:

(1) 4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino methylene] phenoxyacetic acid trihydrochloride

Made from 4- [N-benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminomethylene] phenoxyacetic acid cyclohexyl ester tristri fluoroacetate and conc. Hydrochloric acid / water = 1: 1.
Yield: 520 mg (91% of theory), amorphous solid.
R _f value: 0.54 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
Mass spectrum: M⁺ = 437.

(2) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminomethylene] phenoxyacetic acid trihydrochloride

Made from 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine-4-yl] aminomethylene] phenoxyacetic acid methyl ester tristrifluoroacetate and conc. Hydrochloric acid / water = 1: 1.
Yield: 180 mg (94.5% of theory), amorphous solid.
R _f value: 0.42 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: (M + H) ⁺ = 468.

(3) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetyl-N-glycine dihydrochloride

Made from 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidine-4-yl] aminocarbonyl] phenoxyacetyl-N-glycinethyl ester dihydrochloride and conc. Hydrochloric acid / water = 1: 1.
Yield: 300 mg (78.4% of theory).
Melting point 141-143 ° C
R _f value: 0.37 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
Mass spectrum: M⁺ = 538.

(4) N-benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] -N '- (trans- 4-hydroxycarbonylcyclohexyl) urea dihydrochloride

Made from N-benzyl-N- [1- (4-piperidinyl) -piperidin-4-yl] -N '- (trans- 4-methoxycarbonylcyclohexyl) urea dihydrochloride and conc. Hydrochloric acid / water = 1: 1.
Yield: 1.03 g (79.9% of theory).
R _f value: 0.5 (reversed phase plate RP18; methanol / 5% sodium chloride solution = 3: 2)
Mass spectrum: M⁺ = 442.

(5) N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] -N '- (1-hy hydroxycarbonylmethylene-piperidin-4-yl) urea trihydro chloride

Made from N-benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] -N '- (1-methoxy carbonylmethylene-piperidin-4-yl) urea tri hydrochloride and conc. Hydrochloric acid / water = 1: 1.
Yield: 0.83 g (77.3% of theory), amorphous solid.
R _f value: 0.06 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 457.

(6) 4- [N- [1- (4-Piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxy acetic acid dihydrochloride

Made from 4- [N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid methyl ester dihydrochloride and conc. Hydrochloric acid / water = 1: 1.
Mass spectrum: M⁺ = 361.

(7) 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid dihydrochloride

Made from 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester and conc. Hydrochloric acid / water = 1: 1.
Yield: 600 mg (89% of theory).
Melting point: 256-258 ° CR _f value: 0.15 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 417.

(8) 4- [N-Methyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid dihydroctiloride

Made from 4- [N-methyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester and conc. Hydrochloric acid / water = 1: 1.
Yield: 260 mg (88.4% of theory).
Melting point: 278-280 ° C
R _f value: 0.19 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
Mass spectrum: M⁺ = 375.

(9) 4- [N-Phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid dihydrochloride

Made from 4- [N-phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester bistri fluoroacetate and conc. Hydrochloric acid / water = 1: 1.
Yield: 420 mg (87.9% of theory).
Melting point: 290-293 ° C
R _f value: 0.18 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.25)
Mass spectrum: M⁺ = 437.

(10) 4- [N-Cyclohexyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid dihydrochloride

Made from 4- [N-cyclohexyl-N- [1- (4-piperidinyl) piperidine-4-yl] aminocarbonyl] phenoxyacetic acid cyclo hexyl ester dihydrochloride and conc. Hydrochloric acid / water = 1: 1.
Yield: 400 mg (77.3% of theory).
Melting point: 63-71 ° C
R _f value: Ö, 35 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
Mass spectrum: M⁺ = 443.

(11) 4- [N- (4-fluorobenzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride

Made from 4- [N- (4-fluorobenzyl) -N- [1- (4-piperidinyl) piperidine-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester-bistrifluoroacetate and conc. Hydrochloric acid / water = 1: 1.
Yield: 900 mg (86.2% of theory).
Melting point: 230-235 ° C
R _f value: 0.25 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
Mass spectrum: M⁺ = 469.

(12) 4- [N-cyclohexylmethyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride

Made from 4- [N-cyclohexylmethyl) -N- [1- (4-piperidinyl) -piperidine-4-yl] aminocarbonyl] -phenoxyacetic acid cyclohexyl ester-bistrifluoroacetate and conc. Hydrochloric acid / water = 1: 1.
Yield: 620 mg (89.7% of theory).
Melting point: 89-101 ° C
R _f value: 0.20 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 457.

(13) 4- [N- (3-pyridylmethyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid trihydrochloride

Made from 4- [N- (3-pyridylmethyl) -N- [1- (4-piperidinyl) piperidine-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester tristrifluoroacetate and conc. Hydrochloric acid / water = 1: 1.
Yield: 580 mg (90.5% of theory).
Melting point: 70-81 ° C
R _f value: 0.35 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
Mass spectrum: M⁺ = 452.

(14) 4- [N- (4-pyridylmethyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid trihydrochloride

Made from 4- [N- (4-pyridylmethyl) -N- [1- (4-piperidinyl) piperidine-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester trihydrochloride and conc. Hydrochloric acid / water = 1: 1.
Yield: 200 mg (70.0% of theory), amorphous solid.
R _f value: 0.22 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
Mass spectrum: M⁺ = 452.

(15) 4- [N-Carboxylmethyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid dihydrochloride

Made from 4- [N-ethoxycarbonylmethyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid cyclo hexyl ester bistrifluoroacetate and conc. Hydrochloric acid / water = 1: 1.
Yield: 610 mg (93.9% of theory).
Melting point: 70-81 ° C
R _f value: 0.38 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.25)
Mass spectrum: M⁺ = 419.

(16) 4- [N-Benzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] -N-phenyl-glycine trihydrochloride

Made from 4- [N-benzyl) -N- [1- (4-piperidinyl) -piperidin-4-yl] aminocarbonyl] -N-phenyl-glycine methyl ester trihydrochloride and conc. Hydrochloric acid / water = 1: 1.
Yield: 251 mg (quantitative), amorphous solid.
R _f value: 0.38 (reversed phase plate RP18; methanol / 5% saline = 3: 2)
Mass spectrum: M⁺ = 450.

(17) 4 - [[N-Benzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] -N-phenyl] -N-formylglycine dihydrochloride

Made from 4 - [[N-benzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] -aminocarbonyl] -N-phenyl] -N-formylglycine methyl ester di hydrochloride and conc. Hydrochloric acid / water = 1: 1.

(18) 4 - [[N-Benzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] -N-phenyl] -N-acetylglycine dihydrochloride

Made from 4 - [[N-benzyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] -N-phenyl] -N-acetylglycine methyl ester dihy hydrochloride and conc. Hydrochloric acid / water = 1: 1.

(19) 1 - [[N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] piperidin-4-yl] -3-propionic acid trihydrochloride

Made from 1 - [[N-benzyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] piperidin-4-yl] -3-propionic acid ethyl ester trishydrochloride and conc. Hydrochloric acid / water = 1: 1.  

(20) 4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenyl-3-propionic acid dihydrochloride

Made from 4- [N-benzyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenyl-3-propionic acid ethyl ester dihydro chloride and conc. Hydrochloric acid / water = 1: 1.

(21) 4- [N, N-bis- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid tetrahydrochloride

Made from 4- [N, N-bis- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] -phenoxyacetic acid cyclohexyl ester and conc. Hydrochloric acid / water = 1: 1.

Example 5 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidine- 4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxyacetyl-N-gly cinethyl ester

To a solution of 2.5 g (4.3 mmol) of 4- [N- [1- (1-tert-butyloxy carbonyl-4-piperidinyl) piperidin-4-yl] -N- (4-methoxybenzyl) - amino carbonyl] phenoxyacetic acid, 0.6 g (4.3 mmol) glycine ethyl ester hydrochloride and 1.1 g (8.5 mmol) N-ethyldiiso propylamine (1.5 ml) in 100 ml dry tetrahydrofuran are added with stirring 1.4 g (4.3 mmol) of 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate at room temperature and stirring continues overnight. The mixture is then concentrated to dryness in vacuo and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The combined organic phases are dried and evaporated to dryness in vacuo. The residue is purified by chromatography on a silica gel column, using methylene chloride, which contains 1.5% methanol, as the eluent.
Yield: 1.8 g (62.8% of theory), foam.
R _f value: 0.55 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 666.

The following connection can be established analogously to Example 5:

(1) 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidine- 4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxyacetyl- N-ethylamide

Made from 4- [N- [1- (1-tert-butyloxycarbonyl-4-piperidinyl) piperidin-4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxyacetic acid, ethylamine and 2- (1H -Benzotriazol-1-yl) -1,1,3,3-tetra methyluronium tetrafluoroborate. Purification by chromatography on a silica gel column, methylene chloride containing 1% methanol being used as the eluent.
Yield: 1.1 g (58.4% of theory), amorphous solid.
R _f value: 0.50 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 608.

Example 6 4- [N-benzyl-N- [1- (1-methoxycarbonyl-4-piperidinyl) piperidine- 4-yl] aminomethylene] phenoxyacetic acid cyclohexyl ester

To a solution of 0.3 g (0.3 mmol) of 4- [N-benzyl-N- [1- (4-pi peridinyl) piperidin-4-yl] aminomethylene] phenoxyacetic acid cyclohexyl ester tristrifluoroacetate in 30 ml Methylene chloride is added to 0.03 g (0.3 mmol) of methyl chloroformate and 1.4 ml (1.4 mmol) of 1N sodium hydroxide solution and stirred overnight at room temperature. After adding water, the mixture is extracted twice with methylene chloride. The combined organic extracts are dried and evaporated to dryness in vacuo.
Yield: 140 mg (69.6% of theory), amorphous solid.
R _f value: 0.64 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 577.

The following compounds can be prepared analogously to Example 6 will:

(1) 4- [N- (4-methoxybenzyl) -N- [1- (1-methoxycarbonyl- 4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Made from 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl esters and methyl chloroformate.

(2) 4- [N- [1- (1-Ethoxycarbonyl-4-piperidinyl) piperidin-4-yl] -N- (4-methoxy benzyl) aminocarbonyl] phenoxyacetic acid cyclo hexyl ester

Made from 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl esters and ethyl chloroformate.

(3) 4- [N- [1- (1-benzyloxycarbonyl-4-piperidinyl) piperidine- 4-yl] -N- (4-methoxybenzyl) aminocarbonyl] phenoxyacetic acid cyclohexyl ester

Made from 4- [N-methoxybenzyl-N- [1- (4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenoxyacetic acid cyclohexyl esters and benzyl chloroformate.

(4) 4- [N-Benzyl-N- [1- (1-n-butyloxycarbonyl-4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenoxyacetic acid cyclo pentyl ester

Made from 4- [N-benzyl-N- [1- (4-piperidinyl) piperidine- 4-yl] -aminocarbonyl] -phenoxyacetic acid cyclopentyl ester and N-butyl chloroformate.

(5) 4- [N-Benzyl-N- [1- (1-n-octyloxycarbonyl-4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenoxyacetic acid isopropyl ester

Made from 4- [N-benzyl-N- [1- (4-piperidinyl) piperidine- 4-yl] -aminocarbonyl] -phenoxyacetic acid isopropyl ester and N-octyl chloroformate.  

(6) 4- [N-isobutyl-N- [1- (1-methoxycarbonyl-4-piperidinyl) pipe ridin-4-yl] aminocarbonyl] phenoxyacetic acid ethyl ester

Made from 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid ethyl ester.

Example 7 2- [4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino methylene] phenoxy] ethanol

To a solution of 0.3 g (0.3 mmol) of 4- [N-benzyl-N- [1- (4-pi peridinyl) piperidin-4-yl] aminomethylene] phenoxyacetic acid cyclohexyl ester tristrifluoroacetate in 20 ml absolute tetra hydrofuran is added at room temperature and with stirring 0.03 g (1.3 mmol) of lithium borohydride, stirring is continued for half an hour and then heated to reflux temperature for 2 hours. Then 10 ml of methanol are added and the mixture is left to stand overnight. After this, acidify with 1N hydrochloric acid to pH 4-5 and concentrate to dryness under vacuum. The remaining oily residue is mixed twice with absolute ethanol and evaporated to dryness. The residue is purified by chromatography on a silica gel column, methylene chloride / methanol / conc. Ammonia = 97: 3: 0.3 serves as the eluent.
Yield: 120 mg (81.4% of theory).
Melting point: 152-154 ° C
R _f value: 0.51 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)
Mass spectrum: M⁺ = 423.

Example 8 4- [N-Methyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbon yl] -phenoxyacetic acid cyclohexyl ester

1.5 g of 4- [N- [1- (1-benzyl-4-piperidinyl) piperidin-4-yl] -N-methyl aminocarbonyl] phenoxyacetic acid cyclohexyl ester in 50 ml of methanol are added over 1.5 g of palladium hydroxide on carbon Room temperature and a hydrogen pressure of 50 psi he hydrogenated exhaustively. After removing the catalyst, the mother liquor is evaporated to dryness in vacuo. The residue is triturated with ether and filtered off.
Yield: 0.5 g (39.9% of theory).
Melting point: 140-142 ° C
R _f value: 0.38 (silica gel; methylene chloride / methanol / concentrated ammonia = 4: 1: 0.2)
Mass spectrum: M⁺ = 457.

The following compounds can be prepared analogously to Example 8 will:

(1) 4- [N-ethoxycarbonylmethyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid

Made from 4- [N-ethoxycarbonylmethyl-N- [1- (4-pipe ridinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid benzyl ester and palladium on carbon (10%).

(2) 4- [N- (4-Ethoxycarbonylmethyleneoxy-benzyl) -N- [1- (4-piperi dinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid

Made from 4- [N- (4-ethoxycarbonylmethyleneoxy-benzyl) -N- [1- (4-piperi dinyl) piperidin-4-yl] aminocarbonyl] phen benzyl oxyacetate and palladium on carbon (10%).

Example 9 4- [N-Methyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbon yl] -phenoxyacetic acid methyl ester dihydrochloride

A suspension of 1 mmol of 4- [N-methyl-N- [1- (4-piperi dinyl) -piperidin-4-yl] aminocarbonyl] phenoxyacetic acid dihy drochloride in 30 ml of methanol is passed for half a hour Hour a weak stream of hydrochloric acid gas. One leaves over Stand at room temperature overnight and then warm up At reflux temperature for 2 hours. After cooling, pour on ether and the precipitate is filtered off with suction.  

The following compounds can be prepared analogously to Example 9 will:

(1) 4- [N-Methyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid ethyl ester dihydrochloride

Made from 4- [N-methyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and Ethanol.

(2) 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid methyl ester dihydrochloride

Made from 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and Me ethanol.

(3) 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid ethyl ester dihydrochloride

Made from 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and Ethanol.

(4) 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid isopropyl ester dihydrochloride

Made from 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and iso propanol.

(5) 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid isobutyl ester dihydrochloride

Made from 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and iso butanol.  

(6) 4- [N-phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid methyl ester dihydrochloride

Made from 4- [N-phenyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and Methanol.

(7) 4- [N-phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid ethan-2-ol ester dihydrochloride

Made from 4- [N-phenyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and Ethylene glycol.

(8) 4- [N- (4-pyridylmethyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] -aminocarbonyl] -phenoxyacetic acid methyl ester trihydro chloride

Made from 4- [N- (4-pyridylmethyl) -N- [1- (4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenoxyacetic acid trihydro chloride and methanol.

(9) 4- [N- (4-Fluorobenzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid methyl ester dihydrochloride

Made from 4- [N- (4-fluorobenzyl) -N- [1- (4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenoxyacetic acid dihydrochlo rid and methanol.

(10) 4- [N-Cyclohexyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid methyl ester dihydrochloride

Made from 4- [N-cyclohexyl) -N- [1- (4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenoxyacetic acid dihydro chloride and methanol.

(11) 4- [N-Cyclohexylmethyl-N- [1- (4-piperidinyl) piperidine- 4-yl] -aminocarbonyl] -phenoxyacetic acid methyl ester dihydrochlo rid

Made from 4- [N-cyclohexylmethyl-N- [1- (4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and methanol.  

(12) 4- [N- (3-pyridylmethyl) -N- [1- (4-piperidinyl) piperidine- 4-yl] -aminocarbonyl] -phenoxyacetic acid methyl ester trihydro chloride

Made from 4- [N- (3-pyridylmethyl) -N- [1- (4-piperidinyl) piperi din-4-yl] aminocarbonyl] phenoxyacetic acid trihydro chloride and methanol.

(13) 4- [N, N-bis- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid methyl ester tetrahydrochloride

Made from 4- [N, N-bis- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid tetrahydrochloride and metha nol.

(14) 4- [N- (4-Ethoxycarbonylmethyleneoxy-benzyl) -N- [1- (4-pi peridinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid ethyl dihydrochloride

Made from 4- [N- (4-ethoxycarbonylmethyleneoxy-benzyl) -4- [1- (4-piperi dinyl) piperidin-4-yl] aminocarbonyl] phenoxy acetic acid and ethanol.

(15) 4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] -phenoxyacetic acid cyclopentyl ester dihydro chloride

Made from 4- [N-benzyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and Cy clopentanol.

(16) 4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid isopropyl ester dihydrochloride

Made from 4- [N-benzyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and iso propanol.  

(17) N- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid n-butyl ester dihydrochloride

Made from 4- [N-benzyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and n-butanol.

(18) 4- [N-Phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid ethyl ester dihydrochloride

Made from 4- [N-phenyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and Ethanol.

(19) 4- [N-Phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid isobutyl ester dihydrochloride

Made from 4- [N-phenyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and iso butanol.

(20) 4- [N-Phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid isopropyl ester dihydrochloride

Made from 4- [N-phenyl-N- [1- (4-piperidinyl) piperidine- 4-yl] aminocarbonyl] phenoxyacetic acid dihydrochloride and iso propanol.

Example 10 Dry ampoule with 2.5 mg active ingredient per 1 ml

Composition:

Active ingredient 2.5 mg Mannitol 50.0 mg Water for injections ad 1.0 ml

Manufacturing:
Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.

Example 11 Dry ampoule with 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 ingredient and mannitol are dissolved in water. After filling, freeze-drying.

The ready-to-use solution is dissolved with water for injections.

Example 12 Tablet with 50 mg of active ingredient

Composition:

(1) Active ingredient 50.0 mg (2) milk sugar 98.0 mg (3) corn starch 50.0 mg (4) polyvinyl pyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg           215.0 mg         

Manufacturing:
(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). The dried granules are mixed (5). Tablets are pressed from this mixture, biplan with facets on both sides and partial notch on one side. Tablet diameter: 9 mm.

Example 13 Tablet with 350 mg of active ingredient

Composition:

(1) Active ingredient 350.0 mg (2) milk sugar 136.0 mg (3) corn starch 80.0 mg (4) polyvinyl pyrrolidone 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). Tablets are pressed from this mixture, biplan with facets on both sides and partial notch on one side. Tablet diameter: 12 mm.

Example 14 Capsules with 50 mg of active ingredient

Composition:

(1) Active ingredient 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 is added to the mixture of (2) and (4) with intensive mixing.

This powder mixture is in a capsule filling machine Bottled hard gelatin capsules size 3.

Example 15 Capsules with 350 mg of 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 is added to the mixture of (2) and (4) with intensive mixing.

This powder mixture is in a capsule filling machine Bottled hard gelatin capsules size 0.

Claims (13)

1. 1- (4-piperidinyl) piperidinylenes of the general formula
in the
R _{a is} a hydrogen atom, a C _1-5 alkyl or aryl C _1-3 alkyl group, in which the alkyl part is in each case represented by a carboxy, C _1-3 alkoxycarbonyl, aminocarbonyl, C _1-3 - Alkylaminocarbonyl, di (C _1-3 alkyl) aminocarbonyl, ethenyl, ethynyl group or with the exception of the carbon atom which is linked to the ring nitrogen atom of the adjacent piperidinyl group, by a hydroxy, C _1-3 alkoxy -, Amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group, or a residue which can be split off in vivo,
R _{b is} a hydrogen atom, a C _1-6 -alkyl-, C _3-6 -cycloalkyl-, C _3-6 -cycloalkyl-C _1-3 -alkyl-, aryl-, aryl-C _1-3 -alkyl-, Pyridyl or pyridyl-C _1-3 alkyl group, a D-CO-CH ₂ group or a group of the formula
in which
R _{a are} as above and D are as defined below,
A a -CO-cyclohexylene-, -CH ₂ -cyclohexylene-, -CO-phenylene-, -CH ₂ -phenylene-, -CONR ₁ -cyclohexylene-, -CONR ₁ -phenylene-, -CO- (1-piperidinylene) - or -CH ₂ - (1-piperidinylene) group in which
R _{1 represents} a hydrogen atom, a C _1-6 -alkyl or aryl-C _1-3 -alkyl group and in each case the -CH ₂ - and -CO part of the above-mentioned groups are linked to the NR _b group,
B is a -CO-, -CHR ₂ -CO-, -CHR ₂ -CHR ₂ -CO-, -O-CHR ₂ -CO-, -NR ₃ -CHR ₂ -CO- or -OCH ₂ CH ₂ group, in which
R _{2 is} a hydrogen atom, a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, arylC _1-3 alkyl or pyridyl group and
R _{3 is} a hydrogen atom, a C _1-6 alkyl, aryl C _1-3 alkyl, C _1-6 alkanoyl, aryl C _1-6 alkanoyl, C _1-6 alkoxycarbonyl or Aryl-C _1-3 alkoxy group and the -O-CHR ₂ -, -NR ₃ -CHR ₂ - and -OCH ₂ part of the above-mentioned groups is linked with the proviso that the linkage is not via an oxygen or nitrogen atom of radical B with a nitrogen atom of radical A,
and D is a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, which can be substituted in the 2-, 3-, 4-, 5- or 6-position by a hydroxyl group, a phenylalkoxy group in which the alkoxy part contains 1 to 3 carbon atoms can, a cycloalkoxy group with 3 to 9 carbon atoms, in which the cycloalkyl part with 5 to 8 carbon atoms can be additionally substituted by one or two alkyl groups each with 1 to 4 carbon atoms, a cycloalkoxy group with 5 to 8 carbon atoms, in the cycloalkyl part a methylene group in the 3- or 4-position through an oxygen atom or through an optionally through an alkyl, phenylalkyl or phenylalkoxycarbonyl group in which the alkyl and alkoxy part can each contain 1 to 3 carbon atoms, or through an alkanoyl group with 2 to 6 Carbon atoms sub substituted imino group is replaced and the cycloalkyl part in addition by one or two alkyl groups each with 1 to 3 carbon may be substituted, a cycloalkenyl oxy group in which the cycloalkenyl part can contain 4 to 7 carbon atoms, an alkenyloxy, phenylalkenyloxy, alkynyloxy or phenylalkynyloxy group, with the proviso that no bond to the oxygen atom originates from a carbon atom which is a Bears double or triple bond and in which the alkenyl and alkynyl part can each contain 3 to 5 carbon atoms, a cycloalkylalkoxy group in which the cycloalkyl part can contain 3 to 8 carbon atoms and the alkoxy part 1 to 3 carbon atoms, a bicycloalkoxy group with a total of 8 to 10 carbon atoms, which can additionally be substituted in the bicycloalkyl part by one or two alkyl groups each with 1 to 3 carbon atoms, a 1,3-dihydro-3-oxo-1-isobenzfuranyloxy group or an R ₆ -CO-O- (R ₄ CR ₅ ) -O group in which
R _{4 is} a hydrogen atom, a C _1-6 alkyl, C _3-7 cycloalkyl or phenyl group,
R _{5 is} a hydrogen atom or a C _1-6 alkyl group and
R _{6 represents} a C _1-5 alkyl, C _1-5 alkoxy, C _5-7 cycloalkyl or C _5-7 cycloalkoxy group,
and D is an amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, benzylamino or N- (C _1-6 alkyl) benzylamino group or an α-amino group of a natural amino acid and their esters mean
whereby the expression "an aryl group" mentioned in the definition of the above radical R _{b is} to be understood in each case to mean a phenyl or naphthyl group, each of which is represented by fluorine, chlorine or bromine atoms, by C _1-3 alkyl, trifluoromethyl or amino -, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) -amino-, C _1-3 -Al kanoylamino-, hydroxy-, C _1-3 -alkoxy-, carboxy-, C _{1- 3} -alk oxycarbonyl or D-CO-CH ₂ -O groups can be mono-, di- or tri-substituted, where the substituents can be identical or different and one of the substituents can also represent a nitro group,
among the esters of a natural α-amino acid whose 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, isopropyl, tert-butyl, allyl, phenyl or benzyl ester and
an alkanoyl group with a total of 1 to 6 carbon atoms, a benzoyl, allyloxy carbonyl, C _1-9 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, octyloxycarbonyl, benzyloxycarbonyl , Phenylethoxycarbonyl or phenylpropoxycarbonyl group is to be understood,
their stereoisomers, including their mixtures, and their salts. 2. 1- (4-piperidinyl) -piperidinylenes of the general formula I according to claim 1, in which
R _{a is} a hydrogen atom or a benzyl, benzyloxycarbonyl or C _1-9 alkoxycarbonyl group,
R _{b is} a hydrogen atom, a C _1-6 alkyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl methyl, phenyl, benzyl or pyridyl methyl group, a D-CO-CH ₂ group or a group of the formula
in which
R _{a are} as above and D are as defined below,
A a -CO-cyclohexylene-, -CH ₂ -cyclohexylene-, -CO-phenylene-, -CH ₂ -phenylene-, -CONR ₁ -cyclohexylene-, -CONR ₁ -phenylene-, -CO- (1-piperidinylene) - or -CH ₂ - (1-piperidinylene) group in which
R _{1 represents} a hydrogen atom, a C _1-6 alkyl or phenyl C _1-3 alkyl group, and in each case the —CH ₂ - and —CO part of the above-mentioned groups are linked to the NR _b group,
B is a -CO-, -CH ₂ -CO-, -CH ₂ -CH ₂ -CO-, -O-CH ₂ -CO-, -NR ₃ -CH ₂ -CO- or -OCH ₂ CH ₂ group, in which
R _{3 represents} a hydrogen atom, a C _1-6 alkyl, C _1-6 alkanoyl, phenyl C _1-6 alkanoyl, C _1-6 alkoxycarbonyl or phenyl C _1-3 alkoxycarbonyl group and the -O-CH ₂ - and -NR ₃ -CH ₂ part of the above-mentioned groups with the measure linked to the radical A that the link does not have an oxygen or nitrogen atom of the radical B with a nitrogen atom of the radical A. he follows,
and D is a hydroxy group, a C _1-6 alkoxy group which can be substituted in the 2-, 3-, 4-, 5- or 6-position by a hydroxyl group, one optionally substituted by a C _1-3 alkyl group C _5-7 cycloalkoxy group, which may be substituted by a further methyl group, a phenyl C _1-3 alkoxy group or an R ₆ -CO-O- (R ₄ CR ₅ ) -O group, in which
R _{4 is} a hydrogen atom, a C _1-6 alkyl, C _3-7 cycloalkyl or phenyl group,
R _{5 is} a hydrogen atom or a C _1-6 alkyl group and
R _{6 represents} a C _1-5 alkyl, C _1-5 alkoxy, C _5-7 cycloalkyl or C _5-7 cycloalkoxy group,
or D is a C _1-6 alkylamino, di (C _1-6 alkyl) amino, benzyl amino or N- (C _1-6 alkyl) benzylamino group or an α-amino group of a natural amino acid and whose C _1-6 alkyl and benzyl esters mean
where the phenyl nuclei mentioned in the definition of the abovementioned radical R _{b can} each be substituted by a fluorine, chlorine or bromine atom, by a methoxy or D-CO-CH ₂ -O group,
their stereoisomers, including their mixtures, and their salts. 3. 1- (4-piperidinyl) -piperidinylenes of the general formula I according to claim 1, in which
R _{a is} a hydrogen atom or a benzyl, benzyloxycarbonyl or C _1-9 alkoxycarbonyl group,
R _{b is} a hydrogen atom, a C _1-6 alkyl, cyclohexyl, cyclo hexylmethyl, phenyl or pyridylmethyl group, if appropriate in the phenyl nucleus by a fluorine or chlorine atom or by a methoxy or D-CO-CH ₂ -O -Group-substituted benzyl group, a D-CO-CH ₂ group or a group of the formula
in which
R _{a are} as above and D are as defined below,
A is a -CO-phenylene-, -CH ₂ -phenylene-, -CONH-cyclohexylene-, -CO- (1-piperidinylene) - or -CONH- (1-piperidinylene) group, where in each case the -CH ₂ - and -CO part of the above-mentioned groups is linked to the NR _b group,
B is a -CO-, -CH ₂ -CO-, -CH ₂ -CH ₂ -CO-, -O-CH ₂ -CO-, -NR ₃ -CH ₂ -CO- or -OCH ₂ CH ₂ group, in which
R _{3 represents} a hydrogen atom or a C _1-3 alkanoyl group and the -O-CH ₂ - and -NR ₃ -CH ₂ part of the above-mentioned groups is linked with the proviso that the link does not have there is an oxygen or nitrogen atom of radical B with a nitrogen atom of radical A,
and D is a hydroxy group, a C _1-6 alkoxy group which can be substituted in the 2-, 3-, 4-, 5- or 6-position by a hydroxy group, a menthyloxy, phenyl-C _1-3 alkoxy - or C _5-7 cycloalkoxy group or an R ₆ -CO-O- (R ₄ CR ₅ ) -O group, in which
R _{4 is} a hydrogen atom, a C _1-3 alkyl or C _5-7 cycloalkyl group,
R _{5 is} a hydrogen atom and
R _{6 represents} a C _1-5 alkyl or C _1-3 alkoxy group,
or D is a C _1-6 alkylamino or benzylamino group or an α-amino group of a natural α-amino acid and its C _1-6 alkyl and benzyl esters,
their stereoisomers, including their mixtures, and their salts. 4. 1- (4-piperidinyl) -piperidinylenes of the general formula I according to claim 1, in which
R _{a is} a hydrogen atom or a benzyl, benzyloxycarbonyl or C _1-3 alkoxycarbonyl group,
R _{b is} a hydrogen atom, a C _1-4 alkyl, cyclohexyl, cyclohexylmethyl, phenyl or pyridylmethyl group, one optionally in the phenyl nucleus in the 4-position by a fluorine or chlorine atom or by a methoxy or D-CO-CH ₂ -O group substituted benzyl group, a D-CO-CH ₂ group or a group of the formula
in which
R _{a are} as above and D are as defined below,
A is a -CO-phenylene-, -CH ₂ -phenylene-, -CONH-cyclohexylene-, -CO- (1-piperidinylene) - or -CONH- (1-piperidinylene) group, where in each case the -CH ₂ - and -CO part of the above-mentioned groups is linked to the NR _b group,
B is a -CO-, -CH ₂ -, CO-, -CH ₂ -CH ₂ -CO-, -O-CH ₂ -CO-, -NR ₃ -CH ₂ -CO- or -OCH ₂ CH ₂ group , in which
R _{3 represents} a hydrogen atom or a C _1-3 alkanoyl group and the -O-CH ₂ - and -NR ₃ -CH ₂ part of the above-mentioned groups is linked with the proviso that the link does not have there is an oxygen or nitrogen atom of radical B with a nitrogen atom of radical A,
and D is a hydroxy group, a C _1-4 alkoxy group which can be substituted in the 2-, 3- or 4-position by a hydroxyl group, a menthyloxy, phenyl-C _1-3 alkoxy or C _5-6 - Cyclo alkoxy group or an R ₆ -CO-O- (R ₄ CR ₅ ) -O group in which
R _{4 is} a hydrogen atom, a C _1-3 alkyl or C _5-7 cycloalkyl group,
R _{5 is} a hydrogen atom and
R _{6 represents} a C _1-5 alkyl or C _1-3 alkoxy group,
or D is a C _1-3 alkylamino group or an amino group substituted by a carboxymethyl or C _1-3 alkoxycarbonylmethyl group,
their stereoisomers, including their mixtures, and their salts. 5. 1- (4-piperidinyl) -piperidinylenes of the general formula I according to claim 1, in which
R _{a is} a hydrogen atom, a benzyloxy or C _1-3 alkoxycarbonyl group,
R _{b is} a hydrogen atom, a C _1-4 alkyl, cyclohexyl, cyclohexylmethyl, phenyl or pyridylmethyl group, if appropriate in the phenyl nucleus in the 4-position by a fluorine or chlorine atom or by a methoxy or D- CO-CH ₂ -O group substituted benzyl group, a D-CO-CH ₂ group or a group of the formula
in which
R _{a are} as above and D are as defined below,
A is a -CO-phenylene-, -CH ₂ -phenylene-, -CONH-cyclohexylene-, -CO- (1-piperidinylene) - or -CONH- (1-piperidinylene) group, where in each case the -CH ₂ - and -CO part of the above-mentioned groups is linked to the NR _b group,
B is a -CO-, -CH ₂ -CO-, -CH ₂ -CH ₂ -CO-, -O-CH ₂ -CO-, -NR ₃ -CH ₂ -CO- or -OCH ₂ CH ₂ group, in which
R _{3 represents} a hydrogen atom or a C _1-3 alkanoyl group and the -O-CH ₂ - and -NR ₃ -CH ₂ part of the above-mentioned groups is linked with the proviso that the link does not have there is an oxygen or nitrogen atom of radical B with a nitrogen atom of radical A,
and D is a hydroxy group, a C _1-4 alkoxy group which can be substituted in the 2-, 3- or 4-position by a hydroxyl group, a menthyloxy, phenyl-C _1-3 alkoxy or C _5-6 - Cyclo alkoxy group or an R ₆ -CO-O- (R ₄ CR ₅ ) -O group in which
R _{4 is} a hydrogen atom, a C _1-3 alkyl or C _5-7 cycloalkyl group,
R _{5 is} a hydrogen atom and
R _{6 represents} a C _1-5 alkyl or C _1-3 alkoxy group,
their stereoisomers, including their mixtures, and their salts. 6. The following compounds of general formula I according to claim 1:

• (a) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid,
• (b) 4- [N-benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocar bonyl] phenoxyacetic acid,
• (c) 4- [N-isobutyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
• (d) 4- [N- (4-pyridylmethyl) -N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid,
• (e) 4- [N-phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
• (f) 4- [N- (4-fluorobenzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
• (g) 4- [N-cyclohexyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
• (h) 4- [N- (4-methoxybenzyl) -N- [1- (4-piperidinyl) piperidin-4-yl] aminomethylene] phenoxyacetic acid,
• (i) 4- [N-Benzyl-N- [1- (4-piperidinyl) piperidin-4-yl] amino methylene] phenoxyacetic acid and
• (j) 4- [N- (3-pyridylmethyl) -N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid,
  their C _1-5 alkyl and C _5-6 cycloalkyl esters and their stereoisomers and their salts.

7. The following compounds of general formula I according to claim 1:
4- [N- (4-pyridylmethyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
4- [N-phenyl-N- [1- (4-piperidinyl) piperidin-4-yl] aminocarbonyl] phenoxyacetic acid and
4- [N- (3-pyridylmethyl) -N- [1- (4-piperidinyl) piperidin-4-yl] amino carbonyl] phenoxyacetic acid,
their C _1-5 alkyl and C _5-6 cycloalkyl esters and their salts. 8. Physiologically acceptable salts of the compounds after min at least one of claims 1 to 7 with inorganic or ganic acids or bases. 9. Medicament containing a compound according to at least one of claims 1 to 7 or a physiologically tolerated Lich salt according to claim 8 in addition to optionally one or several inert carriers and / or diluents. 10. Use of a connection according to at least one of the An Proverbs 1 to 8 for the manufacture of a medicinal product for  Combat or prevent diseases in which minor or larger cell aggregates occur or cell matrix inter actions play a role is suitable. 11. A method for producing a medicament according to An Proverb 9, characterized in that in a non-chemical way a connection according to at least one of claims 1 to 8 in one or more inert carriers and / or diluents tel is incorporated. 12. A process for the preparation of the compounds of general formula I according to claims 1 to 8, characterized in that
a. for the preparation of a compound of the general formula I in which R _a, with the exception of the hydrogen atom and a group which contains a reactive hydrogen atom of an amino group which has the meanings mentioned for R _a in claims 1 to 7, a compound of the general formula
in the
A, B, D and R _{b are} as defined in claims 1 to 7, with a piperidinone of the general formula
in the
R _a 'with the exception of the hydrogen atom and a group which contains a reactive hydrogen atom of an amino group which has the meanings for R _{a mentioned} in claims 1 to 7, is reductively alkylated or
b. for the preparation of a compound of the general formula I in which R _{a is} as defined in claims 1 to 7 and D represents a hydroxy group,
D with the exception of the R ₆ -CO-O- (R ₄ CR ₅ ) -O group has the meanings mentioned for D in claims 1 to 7 and R _{a represents} a hydrogen atom or
R _{a represents} a hydrogen atom and D represents a hydroxy group, a compound of the general formula
in the
A, B and R _{b are} as defined in claims 1 to 7,
D 'has the meanings mentioned for D in claims 1 to 7 or a carboxyl group protected by a protective radical which can be converted into a carboxyl group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, and
R _a 'has the meanings given for R _a in claims 1 to 7 or is a protective radical for an imino group which can be removed by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, but at least R _a ' is a removable protective radical or D ' together with the adjacent carbonyl group of radical B must represent a carboxyl group protected by a protective radical,
into a compound of the general formula I in which R _{a is} as defined in claims 1 to 7 and D represents a hydroxyl group,
D with the exception of the R ₆ -CO-O- (R ₄ CR ₅ ) -O group has the meanings mentioned for D in claims 1 to 7 and R _{a represents} a hydrogen atom or
R _{a represents} a hydrogen atom and D represents a hydroxy group, is converted or
c. for the preparation of a compound of general formula I, in which D, with the exception of the hydroxyl group, has the meanings mentioned for D in claims 1 to 7, a compound of the general formula
in the
A, B and R _{b are} as defined in claims 1 to 7 and
R _a 'is a protective radical for an imino group or has the meanings mentioned for R _a in claims 1 to 7, or its reactive derivatives with a compound of the general formula HO-R ₇ (VI), or with its formamide acetal,
with an amine of the general formula H-R ₈ (VII), or with a compound of the general formula Z ₁ -R ₉ (VIII), in which
R _{7 is} an alkyl group with 1 to 6 carbon atoms, which can be substituted in the 2-, 3-, 4-, 5- or 6-position by a hydroxyl group, a phenylalkyl group in which the alkyl part can contain 1 to 3 carbon atoms, one Cycloalkyl group with 3 to 9 carbon atoms, in which the cycloalkyl part with 5 to 8 carbon atoms can additionally be substituted by one or two alkyl groups with 1 to 3 carbon atoms each, a cycloalkyl group with 5 to 8 carbon atoms, in which in the cycloalkyl part a methylene group in 3- or 4-Stel ment by an oxygen atom or by an optionally substituted by an alkyl, phenylalkyl or phenylalkoxycarbonyl group, in which the alkyl and alkoxy part can each contain 1 to 3 carbon atoms, or by an alkanoyl group with 2 to 6 carbon atoms substituted imino group is and the cycloalkyl part may additionally be substituted by one or two alkyl groups each having 1 to 3 carbon atoms nn, a cycloalkenyl group in which the cycloalkenyl part can contain 4 to 7 carbon atoms, an alkenyl, phenyl alkenyl, alkynyl or phenylalkynyl group, with the proviso that no bond to the oxygen atom originates from a carbon atom which has a double or triple bond and in which the alkenyl and alkynyl part can each contain 3 to 5 carbon atoms, a cycloalkylalkyl group in which the cycloalkyl part can contain 3 to 8 carbon atoms and the alkyl part can contain 1 to 3 carbon atoms, a bicycloalkyl group with a total of 8 to 10 carbon atoms, which can additionally be substituted in the bicycloalkyl part by one or two alkyl groups each having 1 to 3 carbon atoms, a 1,3-dihydro-3-oxo-1-isobenzfuranyl group,
R _{8 is} an amino, C _1-6 alkylamino, di (C _1-6 alkyl) amino, benzylamino or N- (C _1-6 alkyl) benzylamino group or an α-amino group of a natural α -Amino acid and its esters. R _{9 has} the meanings mentioned above for R ₇ and additionally an R ₆ -CO-O- (R ₄ CR ₅ ) -O group in which
R ₄ to R _{6 are defined} as mentioned in claims 1 to 7,
and Z _{1 represent} a leaving group, is implemented or
d. for the preparation of a compound of the general formula I in which R _{b is defined} with the proviso as mentioned in claims 1 to 7 that if A is a -CH ₂ -cyclohexylene-, -CH ₂ -pheny len- or -CH ₂ - (1-piperidinylene) group, R _b does not represent a hydrogen atom or a group containing a reactive hydrogen atom, and R _a denotes a radical which can be split off in vivo, a compound of the general formula
in the
A, B and D and R _{b are defined} with the proviso as mentioned in claims 1 to 7 that when A is a -CH ₂ -cyclohexylene-, -CH ₂ -phenylene- or -CH ₂ - (1-piperidinylene) Group represents. R _b does not represent a hydrogen atom or a group containing a reactive hydrogen atom, with a compound of the general formula Z ₂ -R ₁₀ (X), in which
Z _{2 is} a nucleofugic leaving group and
R _{10 represent} a residue which can be split off in vivo, is reacted or
e. for the preparation of a compound of general formula I, in which B represents an -OCH ₂ CH ₂ group and D represents a hydroxy group, a compound of general formula
in the
A, B, R _a and R _{b are} as defined in claims 1 to 7 and
D '' together with the carbonyl group of the radical B represents a carboxylic acid ester group
and if necessary a protective residue used in the reactions described above is split off again and / or
if desired, a compound of the 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 its pharmaceutical use into its physiologically tolerable salts.