Derivatives of 1-[(1-substituted-4-piperidinyl)methyl]-4 - piperidine derivatives, methods for their preparation, pharmaceutical compositions on their basis and intermediate substances

 

The invention relates to new derivatives of 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine F.-ly (I), where Ar is a group of the formula (Ar-1) or (Ar-2), where R1is a halogen, R2represents hydrogen or lower alkyl, R3represents hydrogen, lower alkyl or lower alkanoyl, R4represents hydrogen or lower alkyl, R5and R6are the same or different and represent hydrogen or lower alkyl, n is 1, 2 or 3, And represents a group of formula (a-1), (a-2) or (a-3): -Z-N(Q1)(Q2) (A-1), where Z represents-CO -, - CS-or-SO2-, Q1and Q2are the same or different and represent hydrogen, lower alkyl, cycloalkyl, unsubstituted or substituted phenyl or phenyl(lower alkyl), or Q1and Q2together with the nitrogen atom form a pyrolidine, piperidine, hexahydroazepin, morpholino, thiomorpholine or pieperazinove ring; -CO-R7(A-2), where R7represents hydrogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl, substituted lower alkyl; -(CH2)p-CH(R8)-COR9(A-3), where p has a value 0, 1, 2, 3, 4 5; R8represents hydrogen or lower alkyl; R9politicheskoi activity against serotonin receptors 4 and can be used for the treatment of gastrointestinal disorders. 9 C. and 16 h.p. f-crystals, 9 PL.

Description text in facsimile form (see graphic part)and

Claims

1. The compound of formula (I):where AG is a group of formula (AG-1 or AG-2):where R1represents a halogen atom; R2represents a hydrogen atom or a lower alkyl group;
R3represents a hydrogen atom, a lower alkyl group or lower alkanoyloxy group;
R4represents a hydrogen atom or a lower alkyl group;
R5and R6are the same or different and each represents a hydrogen atom or a lower alkyl group;
n = 1, 2, or 3;
A represents a group of formula (a-1), (a-2) or (a-3):
-Z-N(Q1)(Q2) (A-1),
where Z represents-CO-, -CS - or-SO2-;
Q1and Q2are the same or different and each represents a hydrogen atom, a lower alkyl group, cycloalkyl group, substituted or unsubstituted fineliners together with the nitrogen atom, with which they are associated, with the formation of the pyrolidine ring, piperidino rings, hexahydroazepin rings, morpholino rings, thiomorpholine rings or piperazinovogo ring, optionally containing lower alkyl or benzyl substituents on the other nitrogen atom;
-CO-R7(A-2),
where R7represents a hydrogen atom, a lower alkyl group, lower alkoxygroup, lower alkoxycarbonyl group, a lower alkyl group, a substituted hydroxy, lower alkoxy or lower alkoxycarbonyl group or a substituted or unsubstituted phenyl group;
-(CH2)p-CH(R8)-COR9(A-3)
where p= 0, 1, 2, 3, 4 or 5;
R8represents a hydrogen atom or a lower alkyl group;
R9represents a lower alkyl group or lower alkoxy group,
or its pharmaceutically acceptable acid additive salt.

2. Connection on p. 1, where AG is the value defined in paragraph 1, and a represents a group of formula (a-1)
-Z-N(Q1)(Q2) (A-1),
where Z represents-CO-, -CS - or-SO2-;
Q1and Q2are the same or different and each represents a hydrogen atom, a lower alkyl group(lower alkyl) group, or Q1and Q2may be combined together with the nitrogen atom to which they relate, with the formation of the pyrolidine ring, piperidino rings, hexahydroazepin rings, morpholino rings or piperazinovogo ring, optionally containing lower alkyl or benzyl substituents on another nitrogen atom,
or its pharmaceutically acceptable acid additive salt.

3. Connection on p. 1, where AG is the value defined in paragraph 1, and a represents a group of formula (a-2) or (a-3):
-CO-R7(A-2),
where R7represents a hydrogen atom, a lower alkyl group, lower alkoxygroup, lower alkoxycarbonyl group, a lower alkyl group, a substituted lower alkoxy or lower alkoxycarbonyl group or a substituted or unsubstituted phenyl group;
-(CH2)p-CH(R8)-COR9(A-3)
where p= 0, 1, 2, 3, 4 or 5;
R8represents a hydrogen atom or a lower alkyl group;
R9represents a lower alkyl group or lower alkoxy group,
or its pharmaceutically acceptable acid additive salt.

4. The compound according to any one of paragraphs.1-3, where in the formula (Ar-1) R2and R3both represent hydrogen atoms, or in formula (AG-2), R2and R3are both hydrogen atoms; R5and R6are both hydrogen atoms or one of them represents a metal group and the other represents a hydrogen atom, n = 1,
or its pharmaceutically acceptable acid additive salt.

5. The compound according to any one of paragraphs.1-3, which is a compound of the formula (I-1)

where R1represents a halogen atom;
R41represents a methyl group, ethyl group, through group or isopropyl group;
And1represents a group of formula (A1-1), (A1-2) or (A1-3):
-Z-N(Q11)(Q21) (A-1),
where Z represents-CO-, -CS - or-SO2-;
Q11and Q21are the same or different and each represents a methyl group, ethyl group, through group or isopropyl group, or Q11represents a hydrogen atom and Q21represents cyclopentyloxy group, tsiklogeksilnogo group, cycloheptyl group or a substituted or unsubstituted phenyl group, where these substituents may be a halogen atom, a C1-C4alkyl grouppolicy they are connected, with the formation of the pyrolidine ring or morpholino ring;
-CO-R71(A1-2),
where R71represents a hydrogen atom, methyl group, ethyl group, through the group, a methoxy group, ethoxypropan, C1-C4alkyl group, a substituted methoxy, ethoxy, methoxycarbonyl or ethoxycarbonyl group or a substituted or unsubstituted phenyl group, where the substituents can be from 1 to 3 groups selected from halogen atoms, C1-C4alkyl group, a C1-C4alkoxy group and amino group;
-(CH2)p'-CH(R81)-COR91(A1-3),
where p' = 0, 1, or 2;
R81represents a hydrogen atom, methyl group or ethyl group;
R91represents a methyl group, ethyl group, methoxy group or ethoxypropan,
or its pharmaceutically acceptable acid additive salt.

6. Connection on p. 5, where R1and R41have the meanings defined in paragraph 5, and1represents a group of formula (A1-2) or (A1-3):
-CO-R71(A1-2),
where R71represents a hydrogen atom, methyl group, ethyl group, through the group, a methoxy group, ethoxypropan, C11-C4alkyl group, a C1-C4alkoxygroup and amino;
-(CH2)p'-CH(R81)-COR91(A1-3),
where p' = 0, 1, or 2;
R81represents a hydrogen atom, methyl group or ethyl group;
R91represents a methyl group, ethyl group, methoxy group or ethoxypropan,
or its pharmaceutically acceptable acid additive salt.

7. The compound according to any one of paragraphs.1-3, which is a compound of the formula (I-1')

where R1represents a halogen atom;
And1represents a group of formula (A1-1), (A1-2) or (A1-3):
-Z-N(Q11)(Q21). (A1-1),
where Z represents-CO-, -CS - or-SO2-, Q11and Q21are the same or different and each represents a methyl group, ethyl group, through group or isopropyl group, or Q11represents a hydrogen atom and Q21represents cyclopentyloxy group, tsiklogeksilnogo group, cycloheptyl group or a substituted or unsubstituted phenyl group, where alkoxy group, or Q11and Q21may be combined together with the nitrogen atom to which they relate, with the formation of the pyrolidine ring or morpholino ring;
-CO-R71(A1-2),
where R71represents a hydrogen atom, methyl group, ethyl group, through the group, a methoxy group, ethoxypropan, C1-C4alkyl group, a substituted methoxy, ethoxy, methoxycarbonyl or ethoxycarbonyl group, or substituted or unsubstituted phenyl group, these substituents may be from 1 to 3 groups selected from a halogen atom, a C1-C4alkyl group, a C1-C4alkoxygroup and amino;
-(CH2)p'-CH(R81)-COR91(A1-3),
where p' is 0, 1 or 2;
R81represents a hydrogen atom, methyl group or ethyl group;
R91represents a methyl group, ethyl group, methoxy group or ethoxypropan,
or its pharmaceutically acceptable acid additive salt.

8. Connection on p. 6, which is a compound of the formula (I-2):

where R11represents a chlorine atom or a bromine atom;
R41represents a methyl group, etileno group or ethyl group;
R92represents a methyl group, ethyl group or ethoxy group;
p = 0, 1, or 2,
or its pharmaceutically acceptable acid additive salt.

9. Connection on p. 2, which is a compound of the formula (I-3)

where R11represents a chlorine atom or a bromine atom;
Z2represents-CO - or-CS-;
Q12represents a hydrogen atom, methyl group or ethyl group, Q22represents a methyl group, ethyl group, or phenyl group, or Q12and Q22can be combined with the nitrogen atom to which they relate, with the formation of the pyrolidine ring,
or its pharmaceutically acceptable acid additive salt.

10. Connection on p. 2, which is a compound of the formula (I-4)

where R11represents a chlorine atom or a bromine atom;
R42represents a methyl group, ethyl group or isopropyl group;
Z2represents-CO - or-CS-;
Q12represents a hydrogen atom, methyl group or ethyl group;
Q22represents a methyl group, ethyl group labratories pyrolidine ring,
or its pharmaceutically acceptable acid additive salt.

11. Connection on p. 2 or 9, which is selected from the following substances:
4-amino-5-chloro-N-[1-(1-dimethylcarbamoyl-4-piperidinylmethyl)-4-piperidinyl]-2,3-dihydrobenzo[b]furan-7-carboxamide;
4-amino-5-chloro-N-[1-(1-diethylcarbamoyl-4-piperidinylmethyl)-4-piperidinyl]-2,3-dihydrobenzo[b]furan-7-carboxamide;
4-amino-5-chloro-N-[1-(1-dimethylthiocarbamyl-4-piperidinylmethyl)-4-piperidinyl]-2,3-dihydrobenzo[b]furan-7-carboxamide;
4-amino-5-chloro-N-[1-[1-(1-pyrrolidinecarbonyl)-4-piperidinylmethyl)-4-piperidinyl]-2,3-dihydrobenzo[b]furan-7-carboxamide; and
4-amino-5-chloro-N-[1-(1-phenylcarbamoyl-4-piperidinylmethyl)-4-piperidinyl] -2,3-dihydrobenzo[b]furan-7-carboxamide,
or its pharmaceutically acceptable acid additive salt.

12. Connection on p. 2, which is selected from the following substances:
4-amino-5-chloro-N-[1-(1-dimethylcarbamoyl-4-piperidinylmethyl)-4-piperidinyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[1-(1-(N-ethyl-N-methylcarbamoyl)-4-piperidinylmethyl] -4-piperidinyl]-2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N-[1-[1-(N-methyl-N-phenylcarbamoyl)-4-piperidinylmethyl]-4-piperidinyl]benzamide;
4-amino-5-chloro-N-[1-(1-dimethylthiocarbamyl-4-piperidinylmethyl)-4-piperidinyl]-2-methoxybenzamide; 4-amino-5-bromo-N-[1-(1-dimethylcarbamoyl-4-piperidinylmethyl)-4-piperidinyl]-2-methoxybenzamide;
4-amino-5-chloro-N-[1-(1-diethylcarbamoyl-4-piperidinylmethyl)-4-piperidinyl]-2-ethoxybenzene;
4-amino-5-chloro-N-[1-(1-dimethylcarbamoyl-4-piperidinylmethyl)-4-piperidinyl]-2-isopropoxybenzoic;
4-amino-5-bromo-2-methoxy-N-[1-[1-(1-pyrrolidinecarbonyl)-4-piperidinylmethyl]-4-piperidinyl]benzamide;
4-amino-5-chloro-2-methoxy-N-[1-(1-phenylcarbamoyl-4-piperidinylmethyl)-4-piperidinyl]benzamide,
or its pharmaceutically acceptable acid additive salt.

13. Connection on p. 3, which is N-[1-(acetyl-4-piperidinylmethyl)-4-piperidinyl] -4-amino-5-chloro-2-methoxybenzamide or its pharmaceutically acceptable acid additive salt.

14. The compound according to any one of paragraphs.1, 4, 5, or 7, having agonistic activity against serotonin receptors 4.

15. The compound according to any one of paragraphs.3, 6, 8, or 13, having agonistic activity against serotonin receptors 4.

16. Pharmaceutical composition having agonistic activity against serotonin receptor 4, containing as active ingredient a compound according to any one of paragraphs.1-13 or its pharmaceutically acceptable acid-establet a group of the formula (AG-1 or AG-2):


where R1represents a halogen atom;
R2represents a hydrogen atom or a lower alkyl group;
R3represents a hydrogen atom, a lower alkyl group or lower alkanoyloxy group;
R4represents a hydrogen atom or a lower alkyl group;
R5and R6are the same or different and each is a hydrogen atom or a lower alkyl group;
n = 1, 2, or 3;
A represents a group of formula (a-1)
-Z-N(Q1)(Q2) (A-1),
where Z represents-CO-, -CS - or-SO2;
Q1and Q2are the same or different and each represents a hydrogen atom, a lower alkyl group, cycloalkyl group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenyl(lower alkyl) group, or Q1and Q2may be combined together with the nitrogen atom to which they relate, with the formation of the pyrolidine ring, piperidino rings, hexahydroazepin rings, morpholino rings or piperazinovogo ring, optionally containing lower alkyl or benzyl substituents on dinene formula (II):

where AG shall have the meaning given above,
with the compound of the formula (III)
X-Z-N(Q1)(Q2) (III),
where X represents a halogen atom;
Z, Q1and Q2such as defined above,
and, if necessary, subsequent transformation of the product into its pharmaceutically acceptable acid additive salt.

18. The method of obtaining the compounds of formula (I)

where AG is a group of formula (AG-1 or AG-2):


where R1represents a halogen atom;
R2represents a hydrogen atom or a lower alkyl group;
R3represents a hydrogen atom, a lower alkyl group or lower alkanoyloxy group;
R4represents a hydrogen atom or a lower alkyl group;
R5and R6are the same or different and each is a hydrogen atom or a lower alkyl group;
n = 1, 2, or 3;
A represents a group of formula (a-2)
-CO-R7(A-2),
where R7represents a hydrogen atom, a lower alkyl group, lower alkoxygroup, lower alkoxycarbonyl group, nizzamudin phenyl group,
or its pharmaceutically acceptable acid additive salt
by reacting the compounds of formula (II)

where AG shall have the meaning given above,
with the compound of the formula (a-2')
HO-CO-R72(A-2'),
where R72has the same meaning as R7,
or its reactive derivative, with the proviso that when R72represents a lower alkoxygroup, then use the acid chloride of compound (a-2') and, if applicable, the subsequent transformation of the product into its pharmaceutically acceptable acid additive salt.

19. Agonist serotonin receptor 4, containing as active ingredient a compound as defined in any of paragraphs.1, 3-8, or 13, or its pharmaceutically acceptable acid additive salt.

20. The method of treatment of diseases caused by the lack of stimulation of serotonin receptors 4 patients, including the introduction of an effective amount of a compound as defined in any of paragraphs.1, 3-8, or 13, or its pharmaceutically acceptable acid salt additive, the patient suffering from these diseases.

21. The method according to p. 20 for the treatment of disorders of the gastrointestinal peristalsis, or gastrointestinal symptoms such the and connection as defined in any of paragraphs.1, 3-8, or 13, or its pharmaceutically acceptable acid additive salt.

23. The compound of the formula (II-2)

where R1represents a halogen atom;
R2represents a hydrogen atom or a lower alkyl group;
R3represents a hydrogen atom, a lower alkyl group or lower alkanoyloxy group;
R5and R6are the same or different and each represents a hydrogen atom or a lower alkyl group;
n = 1, 2, or 3,
or its acid additive salt.

24. The compound of formula (VIII)

where a represents a group of formula (a-1), (a-2) or (a-3):
Z-N(Q1)(Q2) (A-1),
where Z represents-CO-, -CS - or-SO2-;
Q1and Q2are the same or different and each represents a hydrogen atom, a lower alkyl group, cycloalkyl group, a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenyl(lower alkyl) group, or Q1and Q2may be combined together with the nitrogen atom to which they relate, with the formation of the pyrolidine ring, piperidino rings, Stateline containing lower alkyl or benzyl substituents on the other nitrogen atom;
-CO-R7(A-2),
where R7represents a hydrogen atom, a lower alkyl group, lower alkoxygroup, lower alkoxycarbonyl group, a lower alkyl group, a substituted hydroxy, lower alkoxy or lower alkoxycarbonyl group or a substituted or unsubstituted phenyl group;
-(CH2)p-CH(R8)-COR9(A-3)
where p= 0, 1, 2, 3, 4 or 5;
R8represents a hydrogen atom or a lower alkyl group;
R9represents a lower alkyl group or lower alkoxygroup,
or its pharmaceutically acceptable acid additive salt.

25. Connection on p. 24, where a represents a group of formula (a-2) or (a-3):
-CO-R7(A-2),
where R7represents a hydrogen atom, a lower alkyl group, lower alkoxygroup, lower alkoxycarbonyl group, a lower alkyl group, a substituted lower alkoxy or lower alkoxycarbonyl group or a substituted or unsubstituted phenyl group;
-(CH2)p-CH(R8)-COR9(A-3)
where p= 0, 1, 2, 3, 4 or 5;
R8represents a hydrogen atom or a lower alkyl group;
R9represents a lower alkyl group or lower alkoxygroup,
1) is a group of formula (a-1) (or (A1-1));
24.06.1998 is set to compounds of formula (I), (I-1), (I-1') or (VIII) And (or And1) is a group of formula (a-2), or (a-3) (or (A1-2), or (A1-3)).

 

Same patents:

The invention relates to the field of organic chemistry and relates to compounds of formula (I) and their pharmaceutically acceptable salts and difficult ether derivatives

< / BR>
where Ar represents a phenyl group which may be optionally substituted from 1 to 3 substituents selected from the group consisting of halogen atoms and triptorelin groups having antifungal activity

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to the derivatives of hintline formula I, where m is an integer from 1 to 2; R1represents hydrogen, nitro or1-3alkoxy; R2represents hydrogen or nitro; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano; X1represents-O-, -S-, -SO - or-SO2-; R4is one of 13 groups described in paragraph 1 of the claims

The invention relates to an improved process for the preparation of dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione used as antifibrillatory and antiarrhythmic agent, the General formula

< / BR>
incorporating the following stages: a) interaction 1- [[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-2,4-imidazolidinedione formula

< / BR>
with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichlorobutane, 1,4-dibromobutane and their mixtures, in the presence of a weak base selected from the group comprising potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione 4-methylpiperazine education 1-[[[5-(4-chlorophenyl)-2-furanyl] the methylene]amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione

The invention relates to an improved process for the preparation of 1,3-disubstituted 4-oxocyclohexa ureas used as antifibrillatory and antiarrhythmic agents, the General formula

< / BR>
where R1, R2and R3independently selected from the group consisting of H, Cl, F, Br, NH2, NO2, COOH, CH3SO2NH, SO3H, HE, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, acyloxy; R4selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, quinil, alkylaryl and heteroalkyl; and a represents a substituted or unsubstituted, saturated or unsaturated, unbranched or branched alkyl or alkenylamine, containing 1-7 carbon atoms; or a represents a substituted or unsubstituted, saturated or unsaturated heterocycle having 5, 6 or 7 members containing at least one nitrogen, and R4attached to the nitrogen; incorporating the following stages: a) the interaction of 1-substituted 4-oxocyclohexa urea having the formula

< / BR>
with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichloro is tons of potash, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione; and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione with amine with the formation of 1,3-disubstituted 4-oxocyclohexa urea

The invention relates to new derivatives of pyrimidinediamine General formula I and fungicides for agriculture or horticulture on the basis of their

The invention relates to new Amida acids of the formula I

< / BR>
where R1- C1-C6alkanoyl,1-C6alkoxycarbonyl, benzoyl, benzoyl substituted halogen (C1-C6)-alkoxy, C1-C6alkylsulfonyl, phenylsulfonyl, phenylsulfonyl, substituted with halogen, or cyclo (C3-C6) alkylsulphonyl, R2- phenyl, phenyloxy or phenylamino, where each phenyl may be substituted with halogen; pyridyl or pyridylamino, a represents a single bond, E is ethylene, X represents CH, Y is-NR5where R5is hydrogen, Q is-C(O)- or-SO2-, R3and R4together form ethylene, or their pharmaceutically acceptable salts

The invention relates to derivatives of 5-areolation formula I, where a represents-CH2-, -C(O)- or-S(O)2-; Z denotes a group of formula b or D:

< / BR>
where X is O or S; R6and R7independently from each other selected from the group including hydrogen, C1-C6alkyl, CF3WITH1-C6alkylthio,1-C6alkoxy, halogen, nitro, hydroxy, and-NR9R10where R9and R10independently of one another denote hydrogen or C1-C6alkyl; R1means hydrogen, C1-C6alkyl, C1-C6alkoxy, hydroxy2-C6alkyloxy, hydroxy, halogen, cyano, carboxy, co2SOP(CH3)2, -СОNR9R10, -ОСОNR9R10or ОSO2R11where R9and R10have the meanings indicated above, and R11means1-C6alkyl or CF3; R3means-SO2R12or-SO2NR13R14where R12means1-C6alkyl; R13means hydrogen or C1-C6alkyl, and R14means hydrogen, C1-C6alkyl, C3-C6cycloalkyl,2-C6alkenyl, hydroxy SS1-C6alkyl, benzyl, phenethyl, naphtalate, acyl, morpholino-C1-C6alkyl, pyrrolidino-C1-C6alkyl, pyridyl-C1-C6alkyl, furanyl-C1-C6alkyl, or R13and R14together with the nitrogen atom to which they are attached, optionally form heterocyclization selected from piperidino, morpholino, di-(C1-C6alkyl)morpholino, pyrrolidino, methylpiperazine, phenylpiperazine, forfilipino; and their pharmaceutically acceptable salts or their esters or carbamates, individual isomers and mixtures of isomers and method thereof

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of railbirding formula I, where X and Y independently of one another denote N or CH; ring a is an unsubstituted or substituted benzene ring, or their salts

The invention relates to 4-amino-1-piperidinecarbonitrile formula (I):

< / BR>
where R1and R2each independently of one another denote H, A, Ph, Ph-ALK, CO-A, CO-Het, or known of the chemistry of protective peptides for amino group;

R1and R2together also denote alkylene with 4-5 C atoms, and one or two CH2- groups may be replaced by-O-, -S-, -CO-, -NH-, -NA - and/or N-CH2-Ph and, if necessary, the benzene ring may be precondensation so that the formed dihydroindole, tetrahydropyrimidines, tetrahydroisoquinolinium or dehydrobenzperidol the rest;

R3and R4each independently of one another denote H, A, Gal, -X-R5, CN, NO2, CF3CH2-CF3, SOn-R7or SO2-NR5R6;

R5denotes H, A, CF3CH2-CF3Ph, Ph-alk, C5-C7- cycloalkyl or C5-C7-cycloalkyl-alk;

R6denotes H or A, or

R5and R6together also denote alkylene with 4-5 C atoms, and one CH2group can be replaced by-O-, -S-, -NH-or-N-CH2-Ph;

R7denotes A or Romani;

Gal denotes F, Cl, Br or I;

Ph denotes unsubstituted or one-or two-, or three times substituted by A, OA, Gal, CF3, NH2, NHA or NA2phenyl;

Het denotes a saturated or unsaturated five - or six-membered heterocyclic residue with 1 to 4 atoms of nitrogen, oxygen and/or sulfur; and

"n" represents 1 or 2;

and their physiologically acceptable salts

The invention relates to novel 1,2,4-substituted piperidines formula 1, where R1is unsubstituted or substituted with halogen and/or trifluoromethyl phenyl or diphenyl-C1-C4-alkyl, ; 9-fluorenyl, pyridil-C1-C4-alkyl; chinolin-C1-C4-alkyl; 5-chloro-2-[1H-1,2,4-triazolyl-1-yl]-phenoxy-C1-C4-alkyl, unsubstituted or substituted C1-C4-alkyl, C1-C4-alkoxyl, hydroxyl, halogen, trifluoromethyl, di-C1-C4-alkylamino-group and/or cyano benzoyl; naphtol; 2-fluorenyl; phenyl - or diphenyl-C2-C4-alkanoyl; naphthyl-C2-C4-alkanoyl; dimethylcyclohexanols; hinolincarbonova; pyridyl-C2-C4-alkanoyl; benzyloxycarbonyl, unsubstituted or substituted by acetyl or 4-carboxymethylation phenylalanine or phenylcarbamoyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-3-yl-carbonyl; R2is unsubstituted or substituted with halogen phenyl or naphthyl; R3is hydrogen, C1-C4-alkyl, cyclohexyl or phenylcarbamoyl, or 3-aminocarbonylmethyl; R4- if necessary substituted C1-C4-alkyl or C1-C4-alkoxyl phenyl, naphthyl, benzyl, pyridyl, if necessary, C-Zam the sludge; if necessary substituted C1-C4the alkyl benzothiophenes, dihydrobenzofuranyl or aniline group, X1- simple bond, methylene, hydroxymethylene or carbonyl, X2- a simple link, X3- simple bond, methylene, ethylene, benzylidene or carbonyl or their salts
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