Method for the treatment or prevention of emesis in mammals and humans using some hinoksalinovym piperidinovyh, ethanolburning, ethylendiamine derivatives and related compounds

 

(57) Abstract:

The invention relates to pharmacology. The method includes the treatment or prevention of emesis in mammals using these compounds: (2S, 3S)-N-(5-tert. butyl-2-methoxyphenyl)-methyl-2-diphenylmethyl-1-azabicyclo(2,2,2)octane-3-amine; (2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)-methyl-2-diphenylmethyl-1-azabicyclo (2,2,2)octane-3-amine; (2S,3S)-2-phenyl-3-(2-methoxy-5-cryptomaterial)-aminopiperidin. The method allows to increase the effectiveness of the treatment. 3 C. p. F.-ly, 21 ill.

The invention relates to a method for the treatment and prevention of vomiting in mammals, including humans, using some hinoksalinovym derivatives, piperidinovyh derivatives, ethanolburning derivatives, ethylendiamine derivatives and related compounds.

Pharmaceutically active compounds used in accordance with the present invention are antagonists of P-receptor.

Hinoklidina, piperidine and userbalance derivatives and related compounds that exhibit activity P-receptor antagonists, are described in the following reference materials: U.S. patent 5162339, which was issued on 11 November 1992; in the application for Amey for review April 25, 1991; in the application of international patent application PCT/US 91/03369, filed may 14, 1991 ; the application of international patent application PCT/US 91/05776, filed August 20, 1991; the application of international patent application PCT/US 92/00113, submitted January 17, 1992; the application of international patent application PCT/US 92/03571, filed may 5, 1992; the application of international patent application PCT/US 92/03317, filed April 28, 1992 ; the application of international patent application PCT/US 92/04697, submitted 11 June 1992; in application for U.S. patent 766488, submitted on 26 September 1991; in application for U.S. patent 790934, submitted on 12 November 1991; in the application of international patent application PCT/US 92/04002, filed may 19, 1992; in the application for Japanese patent 065337/92, submitted on 23 March 1992; in application for U.S. patent 932392, submitted 19 August 1992; in application for U.S. patent 988653, submitted December 10, 1992; and in the application for U.S. patent 026328, filed March 4, 1993

In the description to the application for the European patent 533280 A1, published on 24 March 1993, describes the use of substances which are antagonists of P-receptor, in the treatment of vomiting.

In addition, the invention relates to a method of treating or preventing emesis in a mammal, including man, in the exercise of which is provided by the introduction into the organism referred to the mammal a certain number of compounds of formulas Ia-d,

where a is a cyclic system selected from phenyl, naphthyl, teinila, chinoline and indolinyl, and where a side chain that includes a group NR2R3associated with the carbon atom of the cyclic system A;

AA - aryl group selected from phenyl, naphthyl, teinila, dihydroquinoline and indolinyl, and a side chain that includes a group NR2R3associated with the carbon atom AA:

W is a hydrogen atom or halogen or (C1-C6)alkyl, S-(C1-C3)alkyl, halogen or (C1-C6)alkoxygroup, possibly substituted by 1 to 3 fluorine atoms,

W - hydrogen (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, -S(O) (C1-C6)alkyl 4-, 5 - or 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur (for example, thiazolyl, azetidine, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazolin, imidazolyl, isoxazolyl or oxazolyl), where the aforementioned heterocyclic ring may contain from 0 to 3 double bonds or may be substituted by 1-4 or more substituents, preferably 1 or 2 substituents, independently from each other selected from (C1-C6)Akilov, possibly substituted by 1-3 fluorine atoms, and (C1-C6)alkoxygroup, possibly substituted by 1-3 fluorine atoms;

R1chosen from amine, (C1-C6)alkylamine, di(C1-C6)alkylamine, -S(O)v(C1-C10)alkyl, where v is 0, 1 or 2, -S(O)v- aryl, where v is 0, 1 or 2, -O-aryl, -SO2-NR4R5where R4and R5independently marked alkyl(C1-C6or R4and R5together with the nitrogen atom to which they are linked, form a saturated ring containing 1 nitrogen atom and from 3 to 6 carbon atoms, groups where one or both of the alkyl portion can be substituted by 1-3 fluorine atoms, -N[SO2-(C1-C10)alkyl]2and where the aryl part is mentioned-S(O)vwhat about select from (C1-c4) alkyl, (C1-C4)alkoxygroup and halogen;

or R1group corresponding to the formula (F)

where a is 0,1 or 2, and the asterisk indicates the meta-position, R2R3NCH2relative to the side chain;

the dotted line in formula Ib indicate that one of the relations X-Y and Y-Z can be double;

X is chosen from =CH-, -CH2-, -O-, -S-, -SO-, -SO2-, -N(R4)-, -NH-, =N-, -CH[(C1-C6)alkyl],

=C-[(C1-C6)alkyl, -CH(C6H5)- =C(C6H5)-;

Y is selected from groups C=O, C=NR4C=S, =CH-, CH2-, =C-[(C1-C6)alkyl]-, -CH[(C1-C6)alkyl] , = C(C6H5)-, -CH(C6H5)-, =N-,-NH-,-N(R) =C(halogen)-, = C(OR4)-,

= C(SR4)-, = C(N-R4)-, -O-, -S -, and SO2where the phenyl part mentioned = C-(C6H5)- and-CH(C6H5) - groups can be substituted by 1-3 substituents, independently selected from trifloromethyl and halogen, and where the alkyl part of the mentioned groups = [(C1-C6)]alkyl and -- CH[(C1-C6)alkyl] can be substituted by 1-3 fluorine atoms;

Z is chosen from =CH-, -CH2-, =NH2, =N-, -NH-, -S-, -N(R4)-, =C(C6H5)-, -CH(C6H5)-, =C-(C1-C6)alkyl] -, and-CH[(C1-C6)alkalize, form a condensed pyridine or pyrimidine ring;

X1is hydrogen, (C1-C10)alkoxygroup, possibly substituted by 1-3 fluorine atoms, or (C1-C10)alkyl, possibly substituted by 1-3 fluorine atoms;

X2and X3independently selected from hydrogen or halogen, nitro, (C1-C10)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C10)alkoxygroup, possibly substituted by 1-3 fluorine atoms, trifloromethyl, hydroxyl group, phenyl group, ceanography, amine, (C1-C6)alkylamine, di(C1-C6)alkylamine, (C1-C4)oxaalkyl, (C1-C4)alkoxy, (C1-C4)alkyl, and

R4- (C1-C6)alkyl or phenyl;

R2- hydrogen or-CO2-(C1-C10)alkyl;

R3choose from the groups of formulas II-IX,

where R6and R10independently selected from Furie, teinila, pyridyl, indolyl, diphenyl and phenyl, where the specified phenyl may be substituted by one or two substituents, independently selected from halogen atoms, (C1-C10)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C10)alkoxygroup, possibly substituted by 1-3 fluorine atoms, carboxyl (C3-C4)alkyl, branched (C5-C6)alkenyl, (C5-C7) cycloalkyl and groups mentioned in the definition of values of R6;

R8is hydrogen or (C1-C6)alkyl;

R9and R19independently selected from phenyl, naphthyl, pyridyl, benzhydryl, tanila and Furie, and each of R9and R19may be substituted by 1-3 substituents, independently selected from halogen, (C1-C10)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C10)alkoxygroup, possibly substituted by 1-3 fluorine atoms;

Y1- is (CH2)Lwhere L is an integer from 1 to 3, or Y1group of the formula (J)

Z1oxygen, sulfur, amine, (C1-C3)alkylamino or (CH2)nwhere n is 0, 1 or 2;

x is an integer from 0 to 4;

Y is an integer from 0 to 4;

z is an integer from 1 to 6, and the ring comprising the group (CH2)zmay contain from 0 to 3 double bonds, and one of the carbon atoms of the group (CH2)zmay be replaced by oxygen atom, sulfur or nitrogen;

o - 2 to 3;

p is 0 or 1;

r - 1, 2 or 3;

R11- thienyl, diphenyl or phenyl, possibly substituted by one or two substituents, an>0)alkoxygroup, possibly substituted by 1-3 fluorine atoms;

X4group (CH2)qwhere q is an integer from 1 to 6, where any single carbon-carbon bonds in the specified group (CH2)qmay be substituted carbon-carbon double bond, where any of the carbon atoms of the aforementioned groups (CH2)qcan be substituted for R14and where any of the carbon atoms of the aforementioned groups (CH2)qcan be substituted for R15;

m is an integer from 0 to 8, and any carbon-carbon single links group (CH2)mwhere both carbon atom when such a link is connected between themselves and with other carbon atom (CH2)mthe chain may be substituted carbon-carbon double bond or carbon-carbon triple bond, and any one of carbon atoms of the aforementioned groups (CH2)mchain may be substituted by R17;

R12radical selected from hydrogen, straight or branched (C1-C6)alkyl, (C3-C7)cycloalkyl, where one of the carbon atoms may be replaced by nitrogen, oxygen or sulfur; aryl selected from diphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from tanila, furil, pyridyl, t is the alkyl, benzhydryl and benzyl, where the connection point is at R12is a carbon atom, where R12is not hydrogen, and where each of the aforesaid aryl and heteroaryl groups and the phenyl portions of the above-mentioned benzyl, phenyl(C2-C6)alkyl and benzhydryl may be substituted by one or more substituents, independently selected from halogen atoms, nitro, (C1-C10)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C10)alkoxygroup, possibly substituted by 1-3 fluorine atoms, amine, (C1-C6)oxaalkyl, (C1-C6)alkoxy, (C1-C6)alkyl, (C1-C6)alkylamine, di(C1-C6)alkylamine, and where one of the phenyl parts mentioned benzhydryl can be replaced by naphthyl, teinila, fullam or pyridium;

R13is hydrogen, phenyl or (C1-C6)alkyl;

or R12and R13together with the carbon atom to which they are linked, form a saturated carbocyclic ring containing from 3 to 7 carbon atoms, where one of the carbon atoms, which is neither a place of connection of piricola or related place, it may be replaced by oxygen, nitrogen or sulfur;

R141-C6)oxaalkyl, (C1-C6)alkoxy, (C1-C6)alkyl, (C1-C6)alkylamine, di(C1-C6)alkylamine, (C1-C6)alkoxy groups, (C1- C6)alkyl-CO-(C1-C6)alkyl-O-, and groups that are listed as values of R12;

R16group NHCH2- R18, SO2R18, GR20CO2H or one of the groups listed above when determining the values of any of R12, R14and R15;

R17- oxymyoglobin (=NOH) or one of the groups listed above when determining the values of any of R12, R14and R15;

and R18- (C1-C6)alkyl, hydrogen, phenyl or phenyl(C1-C6)alkyl;

G is chosen from the group consisting of CH2, nitrogen, oxygen and sulfur, and carbonyl;

R20is a monocyclic or bicyclic a heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro - 3-oxopentanoate-2-yl, motoline-1-yl, thiomorpholine-1-yl, benzofuranyl, benzothiazyl, indolyl, isoindolyl, izochinolina, furil, pyridyl, isothiazoline, oxazolyl, triazolyl, tetrazolyl, chinoline, thiazolyl, tanila and groups of the formulas (K)

erode;

E is a carbon atom or nitrogen;

n is an integer from 1 to 5; and any of the carbon atoms of the group (CH2)nor (CH2)n+1may be substituted (C1-C6)alkyl or (C2-C6)spiralcell, and any two of the carbon atoms of the above groups (CH2)nand (CH2)n+1can be connected to one or two carbon atoms, or any pair of adjacent carbon atoms of the above groups (CH2)nand (CH2)n+1together with 1-3 carbon atoms which are not members of carbonyl-containing ring, can form a condensed (C3-C5) carbocyclic ring; provided that (a) in the case when m is 0, one of R16and R17no, and the other represents hydrogen, (b) in the case when R3group of the formula VIII, R14and R15cannot be linked to the same carbon atom, (C) in the case when R14and R15linked to the same carbon atom or values of each of R14and R15independently selected from hydrogen atoms, fluorine, (C1-C6)alkyl, (C1- C6)oxyalkyl and (C1-C6)alkoxy-(C1-C6)alkyl, or R14and R15- ring, which forms spirochaetaceae with nitrogen-containing ring to which they are attached, (d) both R12and R13cannot be hydrogen; (e) in the case when R14and R15linked to the carbon atom of the group X4or (CH2)y, which is adjacent to the nitrogen atom of the ring, each R14and R15respectively must be a Deputy, and the place of attachment is a carbon atom, and (f) neither R14, R15, R16or R17can't form together with R13ring;

or its pharmaceutically acceptable salt, is effective for treatment or prevention of such diseases.

Condensed bicyclic nucleus of the compounds of formula Ib, which are attached to W and a side chain-CN2-NR2R3may be one of the following groups (although their list is not limited to): benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazole, benzisothiazole, imidazolyl, indolyl, ethenolysis, benzofuran, benzothiazyl, oxindoles, benzoxazolinone, benzothiazolinone, benzimidazolinyl, benzimidazolinyl, dihydrobenzofuranyl-S, S-dioxide, benzotriazolyl, benzothiazolyl, benzoxazolyl and hintline.

(1) Compound of formula Ia or Ib, where the substituents at positions "2" and "3" of the nitrogen containing ring R3correspond to the CIS-configuration (when R3group of the formula VII or VIII, the term "CIS-configuration" used in this description to indicate that the non-hydrogen substituent in position "3" is in the CIS-position relative to the radical R13).

(2) Compound of formula Ia, where R3group of the formula III, VII or IX;

R2is hydrogen;

A - phenyl or indolinyl;

W - alkoxygroup C1-C3possibly substituted by 1-5 fluorine atoms;

a R - thiazolyl, imidazolyl, thiadiazolyl, pyrrolyl or oxazolyl, a R possibly substituted by one or two (C1-C3)alkyl residues.

(3) the Compound of formula Ib where R3group of the formula III, VII or IX;

R2is hydrogen; condensed bicyclic ring system, which linked the W and side chain-CH2NR2R3is cobourne substituted 1-5 fluorine atoms.

(4) the Compound according to the above p. 1, 2 or 3, where (a) R3is a group of formula III, a R9- benzhydryl;

(b) R3group of the formula VII, R12- phenyl, each of R13, R14, R15and R16hydrogen atom, m is 0, X4group - (CH2)3-; or

(C) R3group of the formula IX, r - 2, a R19- benzhydryl.

(5) the Compound of formula Ia, where:

(a) R3group of the formula III, where the substituents at positions "2" or "3" of the nitrogen containing ring are in the CIS-configuration, R9- benzhydryl, and - phenyl;

or (b) R3group of the formula VII, where R12and the substituent in position "3" of the nitrogen containing ring are in the CIS-configuration, And is phenyl, R12- phenyl, each of R2, R13, R14, R15and R16hydrogen atom, m is 0, W is methoxy or isopropoxy, X4group - (CH2)3- and R - thiazolyl, imidazolyl, pyrrolyl, oxazolyl or thiadiazolyl.

(6) the Compound of formula Ib where R3is a group of formula IX, where the substituents at positions "2" and "3" of the nitrogen containing ring are in the CIS-configuration, R19- benzhydryl, r - 2, and condensed bicyclic ring system, which linked the radical W and a side chain-CH2NR2/SUP> group of the formula IX, R19- benzhydryl, condensed bicyclic ring system, which linked the radical W and a side chain-CH2- NR2R3represents benzisoxazoles, and W is methoxy.

(8) the Compound of formula Ib, R3group of the formula VII, R12- phenyl, each of R13, R14, R15and R16hydrogen atom, m is 0, X4group -(CH2)3- and condensed bicyclic ring system, which linked the W side and the group - CH2NR2R3represents benzothiazolyl, benzoxazolyl or benzimidazolyl.

(9) the Compound of formula Ia, where R3group of the formula VII, each of R13, R14, R15and R16hydrogen atom, m is 0, X4group -(CH2)3-, And - phenyl, W is methoxy, and the symbol R is chosen from thiazolyl, imidazolyl, thiadiazolyl and isoxazolyl.

(10) Compound of formula Ia or Ib, which is chosen from:

(2S,3S)-3-[2-methoxy-5-(2-thiazolyl)benzyl]-amino-2-phenylpiperidine;

(2S, 3S)-3-[5-(2-imidazolyl)2-methoxybenzyl] -benzyl] -amino-2 - phenylpiperidine;

(2S, 3S)-3-[2-methoxy-5-(2-oxopyrrolidin)-benzyl] -amino - 2-phenylpiperidine;

(2S, 3S)-3-[2-methoxy-5-(4-methyl-2-thiazolyl)-benzo(2S, 3S)-(6-methoxy-2-methylbenzothiazol-5-ylmethyl)-(2 - phenylpiperidine-3-yl)amine;

(2S, 3S)-2[2,5-dimethylpyrrole-1-yl)-2-methoxybenzyl]-(2 - phenylpiperidine-3-yl)-amine;

(2S,3S)-3-[2-methoxy-5-(5-oxazolyl)-benzyl]-amino-2 - phenylpiperidine;

(2S, 3S)-(6-methoxy-2-methylbenzothiazol-5-ylmethyl)-(2 - phenylpiperidine-3-yl)-amine and

(1SR, 2SR, 3SR, 4SR)-3-[6-methoxy-3-methylbenzothiazol-5 - yl]-methylamino-2-benzhydrylidene Bornand.

(11) the Compound of formula Ic, where R3group of the formula II, III, VII or IX;

R2hydrogen atom;

ring AA is phenyl or indolinyl;

W1- (C1-C3)alkoxy, possibly substituted by 1-3 fluorine atoms;

a R1- S(O)v-(C1-C10)alkyl, where v is 0, 1 or 2, S(O)v- aryl, where v is 0, 1 or 2, -O-aryl group in which one or both of the alkyl residue can be substituted by 1-3 fluorine atoms, -N[SO2-(C1-C10)alkyl] or where specified aryl represents phenyl or benzyl and may be substituted by 1-3 substituents, independently from each other selected from (C1-C4)alkyl, (C1-C4)alkoxygroup and halogen.

(12) the Compound according to the above p. 11, where R3group of the formula II, o - 2, and each of R6and R7marked phenyl.

(13) the Connection is SUP> indicated hydrogen, R12- phenyl, m is 0, and X4group -(CH2)3-.

(14) the Compound according to the above p. 11, where R3group of the formula IX, R19- benzhydryl, and r - 2.

(15) the Compound according to the above p. 11, where R3group of the formula III, R8different from hydrogen, a R9- benzhydryl.

(16) the Compound of formula Ic, where the substituents at positions "2" and "3" of the nitrogen containing ring are in the CIS-configuration.

(17) the Compound of formula Ic, where R3group of the formula II, where the substituents at positions "2" and "3" of the nitrogen containing ring are in the CIS-configuration, o - 2, each of R6and R7marked phenyl, and ring AA is phenyl or indolinyl.

(18) the Compound of formula Ic, where R3group of the formula III, where the substituents at positions "2" and "3" of the nitrogen containing ring are in the CIS-configuration, the symbol R8other than hydrogen, R9- benzhydryl and ring AA is phenyl.

(19) the Compound of formula Ic, where R3group of the formula VII, where R12the substituent in position "3" of the nitrogen containing ring is in the CIS-configuration, ring AA is phenyl, R12- phenyl, each of R2R13, R14, R15and R16< 1 selected from S(O)v-(C1-C10)Akilov, where v is 0, 1 or 2, and di(C1-C10)alkylamine.

(20) a Compound defined by the above p. 19, where X4group -(CH2)2-, a W1-(C1-C6)alkoxy, possibly substituted by 1 to 3 fluorine atoms.

(21) a Compound defined by the above p. 19, where X4group -(CH2)3-, a W1- (C1-C6)alkoxy, possibly substituted by fluorine atoms.

(22) the Compound of formula Ic, where R3is a group of formula IX, where the substituents at positions "2" and "3" of the nitrogen containing ring are in the CIS-configuration, r - 2, a R19- benzhydryl.

(23) a Compound defined by the above p. 22, where the ring AA is phenyl, W1- (C1-C5)alkoxy, possibly substituted by 1-3 fluorine atoms, and R1selected from S(O)v-(C1-C10)Akilov, where v is 0, 1 or 2, di(C1-C10)alkylamine and

(24) a Compound defined by the above p. 15, where the ring AA is phenyl, W1- (C1-C6)alkoxy, possibly substituted by 1-3 fluorine atoms, and R1selected from S(O)v-(C1-C10)Akilov, where v is 0, 1 or 2, and

(25) the Connection specified by visor, and the values of R1chosen from amine, (C1-C6)alkylamine or di(C1-C6)alkylamine.

(26) a Compound defined by the above p. 12, where the ring AA is phenyl, W1- (C1-C6)alkoxy, possibly substituted by 1-3 fluorine atoms, and R1selected from S(O)v-(C1-C10)Akilov, where v is 0, 1 or 2,

(27) a Compound defined by the above p. 12, where the ring AA is phenyl, W1- (C1-C6)alkoxy, possibly substituted by 1-3 fluorine atoms, and R1chosen from amine, (C1-C6)alkylamine or di(C1-C6)alkylamine.

(28) a Compound defined by the above p. 24, where W1connected to the ring AA at position "2", a R1associated with the ring AA at position "5" on the point of attachment of the side chain containing the group NR2R3.

(29) a Compound defined by the above p. 25, where W1connected to the ring AA at position "2", a R1associated with the ring AA at position "5" on the point of attachment of the side chain containing the group NR2R3.

(30) the Compound defined by the above p. 26, where W1connected to the ring AA at position "2", a R13.

(31) the Compound defined by the above p. 27, where W1connected to the ring AA at position "2", a R1associated with the ring AA at position "5" on the point of attachment of the side chain containing the group NR2R3.

(32) a Compound defined by the above p. 13, where the ring AA is phenyl, W1choose from isopropoxide, groups OCF3, OCH3, OCHF2and OCH2CF3and the values of R1selected from - S(O)v-(C1-C10)Akilov, where v is 0, 1 or 2, and N-SO2-(C1-C10)Akilov.

(33) a Compound selected from a class which includes:

(2S, 3S)-N-(2-methoxy-5-methylsulfinylphenyl)-methyl-2 - diphenylmethyl-1-azabicyclo[2,2,2]Octan-3-amine;

(2S, 3S)-N-(2-methoxy-5-methylthiophenyl)-methyl-2 - diphenylmethyl-1-azabicyclo[2,2,2]Octan-3-amine;

(2S, 3S)-N-(2-methoxy-5-dimethylaminophenyl)-methyl-2 - diphenylmethyl-1-azabicyclo[2,2,2]Octan-3-amine and

(2S, 3S)-N-(5-triptorelin-2-methoxyphenyl)-methyl-2 - diphenylmethyl-1-azabicyclo[2,2,2]Octan-3-amine.

(34) the Compound of formula Ic, where R3group of the formula VII, m is 0, each of R13, R15, R16and R17the above - mentioned hydrogen, R12- phenyl, R14- group-CO-OH, ring AA is phenyl, WUB>3, SO2, SOCH3, (C1-C6)alkylamines followed and di(C1-C6)alkylamines followed.

(35) the Compound of the formula Ic, corresponding to the formula Ic'.

(36) the Compound of formula Id, where each of R6, R10, R11and R13marked phenyl, R8is hydrogen, R9- phenyl, possibly substituted by a chlorine atom or fluorine, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, or (C1-C6)alkoxy, possibly substituted by 1-3 fluorine atoms, m is 0 and n is 3 or 4.

(37) the Compound of formula Id, selected from a class which includes:

(2S, 3S)-3-(5-tert. butyl-2-methoxybenzyl)-amino-2 -(3 - trifloromethyl)-piperidine;

(2S, 3S)-3-(2-isopropoxy-5-cryptomaterial)-amino-2 - phenylpiperidine;

(2S,3S)-3-(2-ethoxy-5-cryptomaterial)-amino-2 - phenylpiperidine;

(2S,3S)-3-(2-methoxy-5-cryptomaterial)-amino-2 - phenylpiperidine;

(2S,3S)-3-(5-tert.butyl-2-cryptomaterial)-amino-2 - phenylpiperidine;

2-(diphenylmethyl)-N-(2-methoxy-5-trifloromethyl)- methyl-1-azabicyclo[2,2,2]Octan-3-amine;

(2S, 3S)-3-[5-chloro-2-(2,2,2-titerature)-benzyl] -amino - 2-phenylpiperidine;

(2S,3S)-3-(5-tert.butyl-2-cryptomaterial)-amino-2 - phenylpiperidine;

(2S, 3S)-3-(2-isopropoxy-5-tripto ridin;

(2S,3S)-2-phenyl-3-[2-(2,2,2-triptracker]- aminopiperidin and

(2S,3S)-2-phenyl-3-(2-cryptomaterial)-aminopiperidin.

(38) the Compound of formula Id, where R3group of the formula II, where about 2 or 3, and each of R6and R7marked phenyl or substituted phenyl.

(39) the Compound of formula Id, where R3group of the formula III, where R8is hydrogen, a R9is phenyl or substituted phenyl.

(40) the Compound of formula Id, where R3group of the formula IV, where l is 1 or 2, and each of R10and R11marked phenyl or substituted phenyl.

(41) the Compound of formula Id, where R3group of the formula V, where n is 0 or 1, and each of R10and R11marked phenyl or substituted phenyl.

(42) the Compound of formula Id, where R3group of the formula VI, where p is 1, and each of R10and R11marked phenyl or substituted phenyl.

(43) the Compound of formula Id, where R3group of the formula VII, where q is 2, 3 or 4, m is 0, a R12is phenyl or substituted phenyl.

(44) the Compound of formula Id, where R3group of the formula VIII, where y is 0, x is 0 or 1, z is 3 or 4, m is 0, and R12is phenyl or substituted phenyl.

(45) the Compound of formula Id, where R3group of the formula VII, each of R6, R14

2and X3independently selected from hydrogen atoms, chlorine or fluorine, methyl, (C1-C6)alkoxygroup and triptorelin, m is 0, and q is 3 or 4.

(46) the Compound of formula Id, where R3group of the formula VII, with the specified connection selected from the group consisting of:

CIS-3-(2-chlorobenzylamino)-2-phenylpiperidine;

CIS-3-(2-triphtalocyaninine)-2-phenylpiperidine;

CIS-3-(2-methoxybenzylamine)-2-(2-forfinal)-piperidine;

CIS-3-(2-methoxybenzylamine)-2-(2-chlorophenyl)-piperidine;

CIS-3-(2-methoxybenzylamine)-2-(2-were)-piperidine;

CIS-3-(2-methoxybenzylamine)-2-(3-were)-piperidine;

CIS-3-(2-methoxybenzylamine)-2-(3-forfinal)-piperidine;

CIS-3-(2-methoxybenzylamine)-2-(3-chlorophenyl)-piperidine;

CIS-3-(2-methoxybenzylamine)-2-phenylpiperidine;

CIS-3-(2-methoxybenzylamine)-2-(3-were)-piperidine;

CIS-3-(2-methoxybenzylamine)-2-(4-forfinal)-piperidine;

CIS-3-(2-methoxybenzylamine)-2-(3-thienyl)-piperidine;

CIS-3-(2-methoxybenzylamine)-2-phenylisocyanate;

3-(2-methoxybenzylamine)-4-methyl-2-phenylpiperidine;

3-(2-methoxybenzylamine)-5-methyl-2-phenylpiperidine;

3-(2-methoxybenzylamine)-6-methyl-2-phenylpiperidine;

(2S,3S)-3-(2-methoxybenzylamine)-sigex-1-yl)-3-(2-methoxybenzylamine)-2 - phenylpiperidine;

(2S, 3S)-1-(4-hydroxy-4-phenylbut-1-yl)-3-(2-methoxybenzylamine) - 2-phenylpiperidine;

(2S, 3S)-1-(4-oxo-4-phenylbut-1-yl)-3-(2 - methoxybenzylamine)-2-phenylpiperidine;

(2S, 3S)-1-(5,6-dioxygen-1-yl)-3-(2 - methoxybenzylamine) -2-phenylpiperidine;

CIS-3-(5-fluoro-methoxybenzylamine)-2-phenylpiperidine;

(2S, 3S)-1-[4-(4-forfinal)-4-exabot-1-yl] -3-(2 - methoxybenzylamine)-2-phenylpiperidine;

(2S, 3S)-1-[4-(4-forfinal)-4-occiput-1-yl] -3-(2 - methoxybenzylamine)-2-phenylpiperidine;

CIS-3-(2-methoxy-5-methylbenzylamino)-2-phenylpiperidine;

(2S,3S)-1-(4-benzamido-1-yl)-3-(2-methoxy-benzylamino)-2 - phenylpiperidine;

CIS-3-(2-metaxilat-1 ylmethylamino)-2 - phenylpiperidine;

(2S, 3S)-3-(2-methoxybenzylamine)-1-(5-N - methylcarbamic-aminophen - 1-yl)-2-phenylpiperidine;

(2S,3S)-1-(4-cyanobac-1-yl)-3-(2-methoxybenzylamine)-2 - phenylpiperidine;

(2S, 3S)-1-[4-(2-naphthalide)-buta-1-yl] -3-(2-methoxybenzylamine) -2-phenylpiperidine;

(2S, 3S)-1-(5-benzamidophenyl-1-yl)-3-(2 - methoxybenzylamine)-2 - phenylpiperidine;

(2S, 3S)-1-(5-aminophen-1-yl)-3-(2-methoxybenzylamine) - 2-phenylpiperidine;

(2S,3S)-3-(5-chloro-2-methoxybenzylamine)-2-phenylpiperidine;

(2S,3S)-3-(2,5-dimethoxyaniline)-2-phenylpiperidine;

CIS-3-(3,5-debtor-2-methoxybenzylamine)-2-phenylpiperidine;

CIS-3-(4,5-debtor-2-maipurean;

CIS-3-(5-chloro-2-methoxybenzylamine)-1-(5,6-di-oxygens-1-yl) - 2-phenylpiperidine;

CIS-1-(5,6-dioxygen-1-yl)-3-(2,5-dimethoxyaniline)-2 - phenylpiperidine;

CIS-2-phenyl-3-[2-(prop-2-yloxy)-benzylamino]-piperidine;

CIS-3-(2,5-dimethoxybenzyl)-amino-2-(3-methoxyphenyl)- piperidinedione;

CIS-3-(5-chloro-2-methoxybenzyl)-amino-2-(3-methoxyphenyl)- piperidinedione;

CIS-3-(5-chloro-methoxybenzyl)-amino-2-(3-chlorophenyl) -piperidinedione;

3-(2-methoxybenzylamine)-2,4-diphenylpiperazine;

CIS-3-(2-methoxybenzylamine)-2-phenylpyrrolidine;

(2S,3S)-3-(5-ethyl-2-methoxybenzyl)-amino-2-phenylpiperidine;

(2S,3S)-3-(5-n-butyl-2-methoxybenzyl)-amino-2 - phenylpiperidine;

(2S,3S)-3-(2-methoxy-5-n-propylbenzyl)-amino-2 - phenylpiperidine;

(2S,3S)-3-(5-isopropyl-2-methoxybenzyl)-amino-2 - phenylpiperidine;

(2S,3S)-3-(5-Deut.butyl-2-methoxybenzyl)-amino-2 - phenylpiperidine;

(2S,3S)-3-(5-tert.butyl-2-methoxybenzyl)-amino-2 - phenylpiperidine and

(2S,3S)-3-(2-methoxy-2-phenylbenzyl)-amino-2 - phenylpiperidine.

(47) the Compound of formula Id, where R3group of the formula II or III, and this compound selected from the group consisting of:

(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)-methyl-2-diphenylmethyl-1-azabicyclo(2,2,2)octane-3-amine;

(2S, 3S)-N-(5-ethyl-2-methoxyphenyl)-methyl-2-diphenylmethyl-1 - azabicyclo(2,2,2)octane-3-amine;

(2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)-methyl-2-diphenylmethyl - 1-azabicyclo(2,2,2)octane-3-amine;

(2S, 3S)-N-(5-Deut. butyl-2-methoxyphenyl)-methyl-2-diphenylmethyl-1-azabicyclo(2,2,2)octane-3-amine and

(2S, 3S)-N-(5-n-propyl-2-methoxyphenyl)-methyl-2-diphenylmethyl - 1-azabicyclo(2,2,2)octane-3-amine.

The present invention relates also to a method of treating or preventing emesis in a mammal, including man, in the exercise of which is provided by the introduction into the organism of these mammals appropriate number of compounds corresponding to the formula (X),

where W is Y or a group-X - (CH2)n;

Y - may be substituted (C1-C6)alkyl, possibly substituted (C2-C6)alkenyl or possibly substituted (C3-C8)cycloalkyl;

X - may be substituted (C1-C6)alkoxy, a group CONR1R2, CO2R1, CHR1OR2, CHR1NR2R3, COR1, CONR1OR2or maybe substituted aryl, where the specified aryl selected from phenyl, naphthyl, pyridyl, chinoline, teinila, furil, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n - n is specified, the aryl is selected from phenyl, naphthyl, pyridyl, chinoline, teinila, furil, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; the value of each of the symbols R1, R2and R3independently selected from hydrogen, possibly substituted (C1-C6)alkyl, possibly substituted (C1- C6)alkoxy, possibly substituted (C3-C8)cycloalkyl, possibly substituted aryl, where the specified aryl selected from phenyl, naphthyl, pyridyl, chinoline, teinila, furil, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and possibly substituted (C1-C5)heterocyclic groups, where these heterocyclic groups are selected from pyrrolidino, piperidino, morpholino, piperazinyl and thiomorpholine groups; where above substituents alkylene, alkenyl, cycloalkenyl and alkoxygroup independently selected from halogen atoms, nitro-, amino, (C1-C4)Akilov, (C1-C4)alkoxygroup, trifloromethyl and cryptometer; where the substituents of the above-mentioned substituted (C1-C5)heterocyclic groups attached to the sulfur atom or nitrogen in the ring, and is independently selected from sour>
independently selected from (C1-C6)alkyl, possibly substituted by 1-3 galoidsodyerzhascikh groups, (C1-C6)alkoxygroup, possibly substituted by 1-3 galoidsodyerzhascikh groups, (C1-C6)alkylsulfonyl, (C2-C6)alkenyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonamides and di(C1-C6)alkylamino, where one or both alkyl groups may be substituted (C1-C6) alkylsulfonyl, or (C1-C6)alkylsulfonyl group; where the substituents mentioned substituted groups Ar2Ar3independently from each other selected from (C1-C4)Akilov, (C1-C4)alkoxygroup, (C1-C4)alkylthio, (C1-C4)alkylsulfonyl groups, di(C1-C4)alkylamino, trifloromethyl cryptometer, provided that when Y is not substituted or substituted (C1-C4)alkyl, he joined hinoklidina ring in 4 - or 6 - position; or a pharmaceutically acceptable salt of such a compound, effective for the treatment or prophylaxis of the aforementioned diseases.

Preferred variants of the embodiment of the present sobre which includes the introduction in the body referred to mammals appropriate number of connections, defined in the following paragraphs. from (48) to (53), is effective for treatment or prevention of such diseases.

(48) the Compound of formula X, where W is the group X(CH).

(49) the Compound of formula X, where W is a y

(50) the Compound of formula X, where Ar1- substituted aryl, and W is a y

(51) the Compound of formula X, where Ar1mono - or disubstituted phenyl, and W is a y

(52) the Compound of formula X, where Ar1is phenyl, substituted in the 2 - and 5-th

provisions, and W is a y

(53) the Compound of formula X, where Ar1- parametersetter, each Ar2and Ar3is phenyl and W is a y

(54) the Compound of formula X, which is chosen from the group consisting of the following compounds:

(3R, 4S, 5S,6S)-N,N-diethyl-5-(5-isopropyl-2-methoxybenzylamine) -6-diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxamide;

(3R, 4S,5S,6S)-N,N-diethyl-5-(2,5-dimethoxyaniline)- 6-diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxamide;

(3R, 4S, 5S,6S)-5-(5-isopropyl-2-methoxybenzylamine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S, 5S,6S)-5-(2-methoxy-2-methylthiophenethylamine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic CI/BR> (3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylbenzylamino)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S, 5S,6S)-5-(5-ethyl-2-methoxybenzylamine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S, 5S,6S)-5-(2-methoxy-5-n-propylaniline)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(5-Deut.butyl-2-methoxybenzylamine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S, 5S,6S)-5-(5-N-methylmethanesulfonamide-2 - methoxybenzylamine)-6-diphenylmethyl-1-azabicyclo(2,2,2)octane-3 - carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzoyl)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-triphtalocyaninine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzoyl)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S,5S,6S)-5-(5-dimethylamino-5-methoxybenzylamine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S,5S,6S)-5-(5-isopropyl-5-methoxybenzylamine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S, 5S,6S)-5-(2-methoxy-5-methylthiophenethylamine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic sour(3R, 4S, 5S, 6S)-5-(2-methoxy-5-methylbenzylamino)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S, 5S,6S)-5-(5-ethyl-5-methoxybenzylamine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S, 5S,6S)-5-(2-methoxy-5-n-propylaniline)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid:

(3R, 4S,5S,6S)-5-(5-Deut.butyl-2-methoxybenzylamine)- 6-diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S, 5S,6S)-5-(5-N-methylmethanesulfonamide-2 - methoxybenzylamine)-6-diphenylmethyl-1-azabicyclo(2,2,2)octane-3 - carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzoyl)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-triphtalocyaninine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzoyl)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid;

(3R, 4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamine)-6 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-carboxylic acid.

The present invention relates also to a method for treatment and prevention of vomiting in mammals, including man, in the exercise of which is provided by the introduction into the organism of these mammals is Ohm, straight or branched alkyl, (C3-C7)cycloalkyl, where one of the carbon atoms may be substituted by a nitrogen atom, oxygen or sulfur; aryl selected from phenyl, diphenyl, indanyl and naphthyl; heteroaryl selected from tanila, furil, pyridyl, thiazolyl, isothiazoline, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and chinoline; (C2-C6)phenylalkyl, benzhydryl and benzyl, where each of these aryl and heteroaryl groups and the phenyl residue of the above-mentioned benzyl, (C2-C6)phenylalkyl and benzhydryl may be substituted by 1-3 substituents, independently from each other selected from halogen atoms, nitro, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C6)alkoxygroup, amino, trihaloacetic (for example, cryptometer), (C1-C6)alkylamino, (C1-C6)alkyl-O-C-, (C1-C6)alkyl-O-C-(C1-C6)alkyl,

(C1-C6)alkyl-C-O-, (C1-C6)alkyl-C-, (C1-C6)alkyl-O-, (C1-C6)alkyl -, C-,

(C1-C6)alkyl-C-, (C1-C6)alkyl, di(C1-C6)alkylamino, -C-NH-(C1-C6)alkyl, (C1-C6
R3aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, teinila, furil, pyridyl, thiazolyl, isothiazoline, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and chinoline; or cycloalkyl containing from 3 to 7 carbon atoms, where one of the carbon atoms may be substituted by a nitrogen atom, oxygen or sulfur, where each of these aryl and heteroaryl radicals may be substituted by one or more substituents, and specified (C3-C7)cycloalkyl may be substituted by one or two substituents, each of these substituents independently selected from halogen atoms, nitro, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C6)alkoxygroup, possibly substituted by 1-3 fluorine atoms, amino, phenyl, trihaloacetic (for example, cryptometer), (C1-C6)alkylamino, NH-(C1-C6)alkyl, and one of R5and R6indicated hydrogen, and the other values are chosen from oximetry, hydrogen (C1-C3)alkyl, (C1-C8)aryloxyalkyl(C1-C3)alkyl, (C1-C8)alkoxymethyl, gasoline is 9
selected from methyl, oxymethyl, groups, R16OCO2CH2-, (C1-C4)alkyl-CO2CH2-, CONR17R18, R17R18NCO2-, R19OCO2C6H5CH2CO2CH2-,

C6H5CO2CH2-, (C1-C4)alkyl-CH(OH)-, C6H5CH(OH)-, C6H5CH2CH(OH)-,

CH2-halogen, R20SO2OCH2, -CO2R16and R21CO2-;

R10, R11independently selected from hydrogen, (C1-C3)alkyl and phenyl;

R12is hydrogen, benzyl or a group of the formula (L),

where m is an integer from 0 to 12, any of the carbon-carbon single links group (CH2)mwhere both carbon atom of such a link is connected between themselves and with other carbon atom in the chain (CH2)mmay be substituted carbon-carbon double bond or triple bond, and any one of carbon atoms of the group (CH2)mcan be substituted for R23;

the values of each of R13, R14, R15, R16, R17, R18, R19, R20, R21and R24independently selected from hydrogen, (C1-C3)alkyl and phenyl;

R22and R23independently selected from the a, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxygroup,

straight or branched (C1-C6)alkyl, (C3-C7)cycloalkyl, where one of the carbon atoms may be substituted by a nitrogen atom, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, teinila, furil, pyridyl, thiazolyl, isothiazoline, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and chinoline; and (C2-C6)phenylalkyl, benzhydryl and benzyl, where each of the foregoing aryl and heteroaryl groups and the phenyl residue of the above-mentioned benzyl, (C2-C6)phenylalkyl and benzhydryl may be substituted by one or two substituents, independently selected from halogen, nitro, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C6)alkoxygroup, possibly substituted by 1-3 fluorine atoms, trifloromethyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, groups, and where one of the phenyl residues mentioned benzhydryl can be replaced by naphthyl, teinila, fullam or pyridium; or R9together with the carbon atom to which he mω which is associated with R5and R6forms pyrolidine ring; provided that when R9together with the carbon atom to which it is linked, nitrogen atom pyrolidine ring, the carbon atom bound to R7and the carbon atom, which is associated with R5and R6forms a second pyrolidine ring (forming, thus, a bicyclic structure, including associated main bridge nitrogen atom), then R12absent or present, and the nitrogen atom of this second pyrolidine ring is positively charged; or pharmaceutically acceptable salts of such compounds effective for the treatment or prophylaxis of the aforementioned diseases.

The compounds of formula XI, which contain two pyrrolidinone rings, depending on the presence or absence of R12I can answer one of structural formulae XI', XI".

Preferred variants of the embodiment of the present invention encompass methods of treating or preventing emesis in a mammal, including humans, the implementation of which is provided by the introduction into the organism of these mammals appropriate number of connections, which is defined in digiprep the e formula XI, where R' is benzhydryl.

(56) the Compound of formula XI, where R' is diphenylmethyl, R3aryl selected from phenyl or indanyl, where each of the aryl groups may be substituted by one, two or three substituents, each R5, R6, R7, R8, R10and R11indicated hydrogen, R9choose from oximetry, methoxymethyl, groups,- CO2R16, -CONR17R18, R14R15N-CO2CH2-, R16CO2CH2-, (C1-C4)alkyl-CO2CH2-,

C6H5CH2CO2CH2-, -CH2-halogen and R20SO2OCH2-, a R12is hydrogen or benzyl.

(57) a Compound of formula XI, where R1- phenyl, R3aryl selected from phenyl or indanyl, where each of the aryl groups may be substituted by one, two or three substituents, each R5, R6, R7, R8, R10and R11indicated hydrogen, R9choose from oximetry, methoxymethyl, groups, - CO2R18, -CONR17R18, R14R15N-CO2CH2CH2-, R16OCO2CH2-, (C1-C4)alkyl-CO2CH2-, -CH2-halogen and R20SO2OCH2-, and R125, R6, R7, R8, R10, R11and R13indicated hydrogen, where R9together with the carbon atom to which it is linked, nitrogen atom pyrolidine ring, the carbon atom bound to R7and the carbon atom, which is associated with R5and R6forms a second pyrolidine ring (forming, thus, a bicyclic structure, including associated main bridge nitrogen atom).

(59) a Compound of formula XI, which are selected from the group consisting of:

(2S, 3S,4R)-2-diphenylmethyl-3-[(2-methoxy-4,5-di - were-methylamino] -4-(2-oxyethyl)-pyrrolidin;

(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-4,5-dimetilfenil) -methylamino]-4-(2-oxyethyl)-pyrrolidin;

(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)- phenylethylamine]-4-(carbomethoxyamino)-pyrrolidin;

(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)- phenylethylamine)]-4-(carboxymethyl)-pyrrolidin;

(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)- phenylethylamine)]-4-(2 - dimethylaminocarbonylmethyl)-pyrrolidin;

(2SR, 3SR,4RS)-2-diphenylmethyl-3-[(2-trifloromethyl)- methylamino]-4-(2-oxyethyl)-p;

(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1 - dimethylethyl)-phenylethylamine)]-4-(2-methoxyethyl)-pyrrolidin;

(2S,3S,4R)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)- phenylethylamine)] -4-(2-oxyethyl)-pyrrolidin;

(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)- phenylethylamine]-4-(2-methoxyethyl)-pyrrolidin;

(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methyl-5-(1,1 - dimethylethyl)-phenyl)methylamino]-4-(2-oxyethyl)-pyrrolidin;

(1SR, 2SR, 3SR, 4RS)-1-Aza-2-diphenylmethyl-3-[(2-methoxy-4,5 - dimetilfenil)-methylamino]-bicyclo(2,2,1)heptane;

(1SR, 2SR,3SR,4RS)-1-Aza-2-diphenylmethyl-3-[(2-methoxyphenyl)- methylamino] -bicyclo(2,2,1)heptane;

(1SR,2SR,3SR,4RS)-1-Aza-2-diphenylmethyl-3-[(2-methoxy-5- (1,1-dimethylethyl)-phenyl)-methylamino]-bicyclo(2,2,1)heptane;

(1SR,2SR,3SR,4RS)-1-Aza-2-diphenylmethyl-3-[(2-methoxy-5 - trifloromethyl)-methylamino]-bicyclo(2,2, 1)heptane;

(1SR, 2SR,3SR,4RS)-1-Aza-2-diphenylmethyl-3-[(2-methoxy-5-(1 - methylethyl)-phenyl)-methylamino]-bicyclo(2,2,1)heptane;

(1SR,2SR,3SR,4RS)-1-Aza-2-diphenylmethyl-3-[(2-methoxy-5 - propylphenyl)-methylamino]-bicyclo(2,2,1)heptane;

(1SR, 2SR, 3SR, 4RS)-1-Aza-2-diphenylmethyl-3-[(2-methoxy-5-1 - methylpropyl)-phenyl)-methylamino]-bicyclo(2,2,1)heptane;

(1SR, 2SR, 3SR, 4RS)-1-Aza-2-phenyl-3-[(2-methoxyphenyl)- methylamino]-bicyclo(2,2,1)heptane;

(1SR, 2SR,3SR,4SR)-1-Aza-2-phenyl-3-[(2-methoxy-5 - Trife)-methylamino]-4-(2-oxyethyl)pyrrolidin;

(2SR,3SR,4SR)-2-diphenylmethyl-3-[(2-methoxyphenyl)-methylamino]- 4-(2-oxyethyl)pyrrolidin;

(2SR, 3SR, 4SR)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1 - dimethylethyl)-phenyl)-methylamino]-4-(2-oxyethyl)pyrrolidin;

(2SR, 3SR, 4RS)-2-diphenylmethyl-3-[(2-methoxy-5 - trifloromethyl)-methylamino]-4-(2-oxyethyl)pyrrolidin;

(2SR, 3SR, 4SR)-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylethyl)- phenyl)-methylamino]-4-(2-oxyethyl)pyrrolidin;

(2SR, 3SR, 4SR)-2-diphenylmethyl-3-[(2-methoxy-5-propylphenyl)- methylamino] -4-(2-oxyethyl)-pyrrolidin;

(2SR, 3SR, 4SR)-2-diphenylmethyl-3-[(2-methoxy-5-(1 - methyl-1-propyl)-phenyl)-methylamino]-4-(2-oxyethyl) pyrrolidin;

(2SR, 3SR, 4SR)-2-diphenylmethyl-3-[(2-triptoreline-5- (1,1-dimethylethyl)-phenyl)-methylamino]-4-(2-oxyethyl)pyrrolidin;

(2SR, 3SR,4SR)-2-diphenylmethyl-3-[(2-methoxy-5-chlorophenyl) - methylamino]-4-(2-oxyethyl)pyrrolidin;

(2SR, 3SR, 4SR)-2-phenyl-3-[(2-methoxyphenyl)-methylamino] -4-(2 - oxyethyl)pyrrolidin;

(2SR, 3SR, 4SR)-2-phenyl-3-[(2-methoxy-5-(1,1 - dimethylethyl)-phenyl)-methylamino]-4-(2-oxyethyl)pyrrolidin and

(2SR, 3SR,4RS)-2-phenyl-3-[(2-methoxy-5-trifloromethyl)- methylamino] -4-(2-oxyethyl)pyrrolidin.

In addition, the scope of this invention covers also a method for the treatment or prevention of emesis in mammals, including humans, when osushestvleniya formula XII,

where R1is hydrogen, (C1-C3)alkyl, saturated (C6-C10)carbocyclic ring system comprising two condensed rings, saturated (C6-C10)carbocyclic ring system with the ring with an internal bridge that includes two rings, or benzyl, where the phenyl residue of the above-mentioned benzyl may be substituted by one or more substituents, independently selected from halogen atoms, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms;

R2is hydrogen, benzyl or a group of formula (M)

where m is an integer from 0 to 12, any of the carbon-carbon single links group (CH2)mwhere both carbon atom of such a link is connected between the self and the other carbon atom of this group (CH2)mmay be substituted carbon-carbon double or triple bond, and any one of carbon atoms of the group (CH2)mcan be substituted for R9; the values of each of R8and R9independently selected from hydrogen atom, hydroxyl group, halogen atoms, amino groups, (C1-C6)carboxyamide, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C12-C6)phenylalkyl, benzhydryl and benzyl, where each of these aryl and heteroaryl radicals and phenyl residues specified benzyl, (C2-C6)phenylalkyl and benzhydryl may be substituted by one or two substituents, independently from each other selected from halogen atoms, nitro, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C6)alkoxygroup, possibly substituted by 1-3 fluorine atoms, trifloromethyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, and where one of the phenyl residues mentioned benzhydryl can be replaced by naphthyl, tanila or pyridium;

or R1and R2together with the nitrogen atom to which they are linked, form a saturated or unsaturated monocyclic ring containing from 3 to 8 carbon atoms, condensed bicyclic ring containing from 6 to 10 operon R4selected from phenyl or naphthyl; heteroaryl selected from indanyl, teinila, furil, pyridyl, thiazolyl, isothiazoline, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl and chinoline; and cycloalkyl containing from 3 to 7 carbon atoms, where one of these carbon atoms may be substituted by a nitrogen atom, oxygen or sulfur, where each of the above-mentioned aryl and heteroaryl groups may be substituted by one or more substituents, as indicated (C3-C7)cycloalkyl may be substituted by one, two or three substituents, each of these substituents independently selected from halogen atoms, nitro, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C6)alkoxygroup, possibly substituted by 1-3 fluorine atoms, phenyl, amino, (C1-C6)alkylamino, NH2-(C1-C6)alkyl, NH-SO2-(C1-C6)alkyl, (C1-C6)alkyl-N-SO2-(C1-C6)alkyl;

R3is hydrogen, (C3-C8)cycloalkyl, straight or branched (C1-C6)alkyl or phenyl, possibly substituted by one or more substituents, independently selected from halogen atoms, (C1
R5is hydrogen, (C1-C6)alkyl or phenyl, possibly substituted by one or more substituents, independently selected from halogen, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C6)alkoxygroup, possibly substituted by 1-3 fluorine atoms;

R6selected from hydrogen, straight or branched (C1-C6)alkyl, (C3-C7)cycloalkyl, where one of the carbon atoms may be substituted by a nitrogen atom, oxygen or sulfur; aryl selected from phenyl, diphenyl, indanyl and naphthyl; heteroaryl selected from tanila, furil, pyridyl, thiazolyl, isothiazoline, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and chinoline; (C2-C6)phenylalkyl, benzhydryl and benzyl, where each of these aryl and heteroaryl radicals and phenyl residues specified benzyl, (C2-C6)phenylalkyl and benzhydryl may be substituted by one or more substituents, independently selected from halogen, nitro, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C6)alkoxygroup, trifloromethyl, aminogroup, trihaloacetic (for example, cryptometer), (C1-C6is hydrilla can be replaced by naphthyl, tanila, fullam or pyridium;

a R12is hydrogen, (C1-C3)alkyl or phenyl; or pharmaceutically acceptable salts of such compounds effective for the treatment or prophylaxis of the aforementioned diseases.

Preferred variants of the embodiment of the present invention encompass methods of treating or preventing emesis in a mammal, including humans, the implementation of which is provided by the introduction into the organism of these mammals appropriate number of connections, which is defined in the following paragraphs. from (60) to (62), is effective for treatment or prevention of such diseases.

(60) a Compound of formula XII, where R2is hydrogen or R2and R1together with the nitrogen atom to which they are attached, form a monocyclic ring containing 5 to 7 carbon atoms; R3is hydrogen, methyl or phenyl; R5is hydrogen; R4is phenyl or indanyl where specified phenyl or indanyl may be substituted by 1-3 substituents, independently from each other selected from halogen atoms, nitro, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C6)alkoxygroup, trihaloacetic (for example, triptoreline the C1-C6)alkyl and (C1-C6)alkyl-N-SO2-(C1-C6)alkyl; R6is phenyl. (61) the Compound of formula XII, where R1- alkyl, R6is unsubstituted phenyl, R4- monosubstituted or disubstituted aryl group which is substituted in position C-2 alkoxygroup or substituted at position C-5 alkyl, alkoxy or trigonometrictype, or substituted therefore in both positions C-2 and C-5 (alkoxygroup in position C-2 and alkyl, alkoxy or trigonometrictype in position C-5), and each of R2, R3and R5indicated hydrogen.

(62) the Compound of formula XII, which are selected from a class which includes:

1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxyphenyl)-methyl]- 1,2-amandemen;

1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5 - trifloromethyl)-methyl] -1,2-amandemen;

1-N-pyrrolidin-1-phenyl-2-N'-[(2-methoxyphenyl)-methyl]- 1,2-amandemen;

1-N-methyl-1-phenyl-2-N'-[(2-methoxyphenyl)-methyl]-1,2 - amandemen;

1-N-cyclopentyl-1-phenyl-2-N'-[(2-methoxyphenyl)-methyl]- 1,2-amandemen;

1-N-propyl-1-phenyl-2-N'-[(2-methoxyphenyl)-methyl]-1,2 - amandemen;

1-N-phenylmethyl-1-phenyl-2-N'-[(2-methoxyphenyl)-methyl]- 1,2-amandemen;

1-N-cyclooctyl-1-phenyl-2-N'-[(2-methoxyphenyl)-methyl]-1,2 - e is 2-methoxyphenyl)- methyl]-1,2-amandemen;

1-N-(1,1-dimethylethyl)-1-phenyl-2-N'-[(2-methoxyphenyl)- methyl] -1,2-amandemen;

1-N-cyclopropyl-1-phenyl-2-N'-[(2-methoxyphenyl)- methyl]-1,2-amandemen;

1-N-isopropyl-1-phenyl-2-N'-[(2-methoxyphenyl)-methyl]-1,2 - amandemen;

1-N-(1-phenylethyl)-1-phenyl-2-N'-[(2-methoxyphenyl)-methyl]-1,2 - amandemen;

1-N-(2-norbornyl)-1-phenyl-2-N'-[(2-methoxyphenyl)-methyl]-1,2 - amandemen;

1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-tert. butyl - phenyl)-methyl]-1,2-amandemen;

1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-isopropylphenyl) - methyl] -1,2-amandemen;

1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5,5 - dimetilfenil)-methyl] -1,2-amandemen;

1-N-cyclohexyl-1-N-(6-oxohexyl)-1-phenyl-2-N'-[(2 - methoxyphenyl)-methyl]-1,2-amandemen.

The scope of this invention covers also a method for the treatment or prevention of emesis in a mammal, including man, in the exercise of which is provided by the introduction into the organism of these mammals corresponding number of the compounds of formula XIII,

where R1- cycloalkyl containing from 5 to 7 carbon atoms, pyrrolyl, thienyl, pyridyl, phenyl or substituted phenyl, where the specified substituted phenyl substituted by 1-3 substituents, independently selected from fluorine atoms, chlorine, bromine, trifloromethyl, alkyl,group, alkoxycarbonyl containing about 1 to 3 carbon atoms in alkoxyalkane, and benzyloxycarbonyl;

R2- furyl, thienyl, pyridyl, indolyl, diphenyl, phenyl or substituted phenyl, where the specified substituted phenyl substituted by 1 or 2 substituents, independently from each other selected from fluorine atoms, chlorine and bromine, trifloromethyl, alkyl containing from 1 to 3 carbon atoms, alkoxyalkyl containing from 1 to 3 carbon atoms, carboxypropyl, alkoxycarbonyl containing from 1 to 3 carbon atoms in alkoxyalkane, and benzyloxycarbonyl;

a R3- thienyl, phenyl, forfinal, chlorophenyl or bromophenyl, or pharmaceutically acceptable salts of such compounds effective for the treatment or prophylaxis of the aforementioned diseases.

Preferred variants of the embodiment of the present invention encompass methods of treating or preventing emesis in a mammal, including humans, the implementation of which is provided by the introduction into the organism of these mammals appropriate number of connections defined in the following paragraphs. from (63) to (65), is effective for treatment or prevention of such diseases.

(63) the Compound of formula XIII, where R1- phenyl, or C is ormula XII, where the specified connection is a ()-CIS-9-diphenylmethyl-N-[2-(methoxyphenyl)- methyl]-10-azatricyclo(4,4,1,05,7)undecane-8-amine.

The scope of the present invention is covered, in addition, a method of treating or preventing emesis in a mammal, including man, in the exercise of which is provided by the introduction into the organism of these mammals corresponding number of the compounds of formula XIV,

where m is a positive integer from 0 to 8, and any carbon-carbon single links group (CH2)mwhere both carbon atom of such a link is connected between themselves and with other carbon atom in the chain (CH2)mmay be substituted carbon-carbon double bond or carbon-carbon triple bond, and any one of carbon atoms of the aforementioned groups (CH2)mmay be substituted by the radical R8;

W is an integer from 0 to 2;

Y is an integer from 1 to 4;

z is an integer from 1 to 4, and where any of the carbon atoms of the groups listed above (CH2)zmay be substituted by the radical R4;

R1is hydrogen or (C1-C8)alkyl, possibly substituted by a hydroxyl group, alkoxygroup or fluorine atom;

R2group, ueberla, where one of the carbon atoms may be substituted by a nitrogen atom, oxygen or sulfur; aryl selected from phenyl, indanyl and naphthyl; heteroaryl selected from tanila, furil, pyridyl, thiazolyl, isothiazoline, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and chinoline; (C2-C6)phenylalkyl, benzhydryl and benzyl, where the phenyl residues mentioned benzhydryl can be replaced by naphthyl, teinila, fullam or pridiom and where each of these aryl and heteroaryl radicals and phenyl residues mentioned benzyl, (C2-C6)phenylalkyl and benzhydryl may be substituted by one or more substituents, independently from each other selected from halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxyalkyl, trifloromethyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, or R2and R5together with the carbon atom to which they are linked, form a saturated carbocyclic ring containing from 3 to 7 carbon atoms, where one of the carbon atoms may be replaced by oxygen atom, nitrogen or sulfur; R3aryl selected from phenyl, indanyl and naphthyl; hetero, societally, oxazolyl, triazolyl, tetrazolyl and chinoline; and cycloalkyl containing from 3 to 7 carbon atoms, where one of the carbon atoms may be substituted by a nitrogen atom, oxygen or sulfur, where each of these aryl and heteroaryl radicals may be substituted by one or more substituents, as indicated (C3-C7)cycloalkyl may be substituted by one or two substituents, each of these substituents independently selected from halogen atoms, nitro, (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C6)alkoxygroup, possibly substituted by 1-3 fluorine atoms, trifloromethyl, phenyl, amino, (C1-C6)alchemyapi, di(C1-C6)alkylamino, and the values of R4independently selected from hydrogen, hydroxyl, halogen atoms, amino group, carbonyl group (=O), nitrile, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxygroup, alkyl, (C1-C6)oxaalkyl, (C1-C6)alkoxy(C1-C6)alkyl, and the groups listed above when determining the values of R2; R6group NHCH2R9, NHP>4
; R8- oxymyoglobin (=NOH) or one of the groups listed above when determining the values of any of R2and R4; R9- (C1-C6)alkyl, hydrogen, phenyl or (C1-C6)phenylalkyl; provided that (a) when m is 0, R8no, a R6- hydrogen, (b) any R4and R6or R8can't together with the carbon atom to which they are bound, form together with R5ring, (C) the sum of y and z must be less than 7;

or its pharmaceutically acceptable salt, is effective for treatment or prevention of such diseases.

Preferred variants of the embodiment of the present invention encompass methods of treating or preventing emesis in a mammal, including humans, the implementation of which is provided by the introduction into the organism of these mammals appropriate number of connections, which is defined in the following paragraphs. (66) to (68), is effective for treatment or prevention of such diseases.

(66) the Compound of formula XIV, where R2is selected from a hydrogen atom, phenyl, naphthyl and benzhydryl; where each of the phenyl, naphthyl and benzhydryl may be substituted by one or more substituents, ntauxhpm, trifloromethyl, amino, (C1-C6)alkylamino, -O-, (C1-C6)alkyl, di(C1-C6)alkylamino, and where one of the phenyl residues mentioned benzhydryl can be replaced by naphthyl, teinila, fullam or pyridium.

(67) the Compound of formula XIV, where R2is selected from hydrogen, phenyl, naphthyl and benzhydryl; where each of the above-mentioned phenyl, naphthyl and benzhydryl may be substituted by one or more substituents, independently from each other selected from halogen atoms, nitro, (C1-C6)alkyl, (C1-C6)alkoxygroup, trifloromethyl, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, and

and where one of the phenyl residues mentioned benzhydryl can be replaced by naphthyl, teinila, fullam or pyridium; and R4independently selected from hydrogen, hydroxyl, halogen, amino, carbonyl group (=O), nitrile, (C1-C6)alkylamine, di(C1-C6)alkylamino, (C1-C6)alkoxygroup,

(C1-C6)oxaalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl and phenyl.

(68) the Compound of formula XIV, where

In addition, the scope of this invention covers a method of treating or preventing emesis in a mammal, including man, in the exercise of which is provided by the introduction into the organism of these mammals of the compounds of formula XV,

where X1- (C1-C5)alkoxygroup or galizana (C1-C5)alkoxygroup;

X2is hydrogen or halogen, (C1-C5)alkyl, (C2-C5)alkenyl, (C2-C5)quinil, (C1-C5)alkoxygroup, (C1-C5)allylthiourea, (C1-C5)alkylsulfonyl, (C1-C5)alkylsulfonyl, galijasevic (C1-C5)alkyl, galizana (C1-C5)alkoxygroup, (C1-C5)alkylamino, dialkylamino containing 1-5 carbon atoms in each alkyl residue, (C1-C5) alkylsulfonamides (which may be substituted by halogen atom), N-alkyl(C1-C5)-N-alkyl (C1-C5)sulfonylamino (which may be substituted in alkylsulfonyl balance a halogen atom), (C1-C5)alkanolamine (which may be substituted by halogen atom), or N-alkyl(C1-C5)-N-(C1-C5)alkanolamide the performance of the designated thienyl, phenyl, forfinal, chlorophenyl or bromophenyl;

A - group Y-(CH2)m-CH(R2-(CH2)n-NR1-;

R1- hydrogen (C1-C5)alkyl, benzyl or a group -(CH2)p-Y-;

R2- hydrogen (C1-C5)alkyl (which may be substituted by the Deputy selected from a class which includes hydroxyl, amino, methylaminopropyl and the mercaptan group), a benzyl, 4-oxybenzyl, 3-indoleacetic or the group - (CH2)p-Y-; Y is a group-CN, -CH2Z or-COZ; Z is hydroxyl, amine, (C1-C5)alkoxygroup, (C1-C5)alkylamino or dialkylamino containing 1-5 carbon atoms in each alkyl residue;

m, n and p independently is 0, 1, 2 or 3;

R1and R2can be linked in such a way that forms a ring;

or pharmaceutically acceptable salts of such compounds effective for the treatment or prophylaxis of the aforementioned diseases.

Preferred variants of the embodiment of the present invention encompass methods of treating or preventing emesis in a mammal, including humans, the implementation of which is provided by the introduction into the organism of these mammals corresponding Kalicha disease.

(69) the Compound of formula XV, where the specified connection selected from the group consisting of:

(3R, 4S, 5S,6S)-N-carbamoylmethyl-5-(5-isopropyl-2 - methoxybenzylamine)-6-diphenylmethyl-1-azabicyclo(2,2,2)octane-3 - carboxamide;

(3R, 4S,5S,6S)-N-carbosulcis-5-(5-isopropyl-2 - methoxybenzylamine)-6-diphenylmethyl-1-azabicyclo(2, 2,2) Octan-3 - carboxamide;

(3R, 4S,5S,6S)-3-(2-carbamoylation-1-yl)-carbonyl-5- (5-isopropyl-2-methoxybenzylamine)-6-diphenylmethyl-1 - azabicyclo(2,2,2)octane-3-carboxamide;

(3R*4S*, 5S*,6S*)-N-(1-carbamoylethyl)- 5-(5-isopropyl-2 - methoxybenzylamine)-6-diphenylmethyl-1-Aza-bicyclo (2,2,2)octane-3-carboxamide;

(3R,4S,5S,6S)-N-(1-carbarnoyl-3-methylbutyl) -5-(5 - isopropyl-2-methoxybenzylamine)-6-diphenylmethyl - 1-azabicyclo(2,2,2)octane-3-carboxamide and

(3R, 4S, 5S, 6S)-N-(2-carbamoylethyl)-5-(5-isopropyl-2 - methoxybenzylamine)-6-diphenylmethyl-1-azabicyclo(2,2,2)octane-3 - carboxamide.

The scope of this invention covers also a method for the treatment or prevention of emesis in a mammal, including man, in the exercise of which in the organism of these mammals enter the appropriate number of compounds of formula XVI,

where R1- phenyl, possibly substituted by one or more of the Deputy, is itagroup, (C1-C10)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C10)alkoxygroup, possibly substituted by 1-3 fluorine atoms, trifloromethyl, hydroxyl, phenyl, cyano, amino, (C1-C6)alkylamino-, di(C1-C6)alkylamino, (C1-C4)oxaalkyl, (C1-C4)alkoxy(C1-C4)alkyl, -S(O)v- (C1-C10)alkyl, where v is 0, 1 or 2, -S(O)v-aryl, where v is 0, 1 or 2, -O-aryl, -SO2NR4R5where each of R4and R5independently from each other - (C1-C6) alkyl, or R4and R5together with the nitrogen atom to which they are linked, form a saturated ring containing one nitrogen atom and from 3 to 6 carbon atoms, groups where one or both of the alkyl residue can be substituted by 1-3 fluorine atoms, N[SO2[(C1-C10)alkyl]2and where the aryl residues mentioned-S(O)v-aryl, -O-aryl and independently from each other selected from phenyl and benzyl, each of which may be substituted by 1-3 substituents, independently selected from each other from a (C1-C4)alkyl, (C1-C4)alkoxygroup and halogen atoms;

or R1is phenyl, substituted by a group corresponding to the formula (F)1;

R2choose from straight or branched (C1-C6)alkyl, (C3-C7)cycloalkyl, where one of the carbon atoms may be substituted by a nitrogen atom, oxygen or sulfur; aryl selected from diphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from tanila, furil, pyridyl, thiazolyl, isothiazoline, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and chinoline;

(C2-C6)phenylalkyl, benzhydryl and benzyl, where each of the above-mentioned aryl and heteroaryl and phenyl residues mentioned benzyl, (C2-C6)phenylalkyl and benzhydryl may be substituted by one or more substituents, preferably 1 to 3 substituents selected from halogen atoms, nitro, (C1-C10)alkyl, possibly substituted by 1-3 fluorine atoms, (C1-C10)alkoxygroup, possibly substituted by 1-3 fluorine atoms, amino groups, (C1-C10)oxaalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, and where one of the phenyl groups mentioned benzhydryl can be replaced by naphthyl, teinila, fullam or pyridium; m is an integer from 0 to 8, and any carbon-coal the other carbon atom in the chain (CH2)mmay be substituted carbon-carbon double bond or carbon-carbon triple bond, and any one of carbon atoms of the aforementioned groups (CH2)mcan be substituted for R4;

R3choose from groups NHCH2R8, SO2R8, AR9, CO2H and the radicals listed above in the definition of R2, R6and R7;

A - methylene, nitrogen atom, oxygen or sulfur, or carbonyl;

R8- (C1-C6)alkyl, hydrogen, phenyl or (C1-C6)phenylalkyl;

R4choose from oxymyoglobin (=NOH) and groups listed above when determining the values of R2, R6and R7;

R9- monocyclic or disilicate a heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro - 3-oxopentanoate-2-yl, morpholine-1-yl, thiomorpholine-1-yl, benzofuranyl, benzothiazyl, indolyl, isoindolyl, izochinolina, furil, pyridyl, isothiazoline, oxazolyl, triazolyl, tetrazolyl, chinoline, thiazolyl, tanila and groups of formula (K),

where the values of b and D are selected from carbon, oxygen and nitrogen, with values of at least one of b and D non-carbon atom;

E - atom UB> and (CH2)n+1; can be replaced by (C1-C6)alkyl or (C2-C6)piroumian; or any pair of carbon atoms of the above groups (CH2)nand (CH2)n+1may be related to bridge communication with one or two carbon atoms, one or any pair of adjacent carbon atoms of the above groups (CH2)nand (CH2)n+1may together with 1 to 3 carbon atoms which are not members of carbonyl-containing ring to form a condensed carbocyclic (C3-C5a ring;

X - band (CH2)qwhere q is 2 or 3, where one of the carbon-carbon single bonds in the specified group (CH2)qmay be substituted carbon-carbon double bonds, and where any carbon atom of the specified group (CH2)qcan be substituted for R6and where any of the carbon atoms of the specified group (CH2)qcan be substituted for R7; the values of R6and R7independently selected from hydrogen, hydroxyl, halogen, amino-, oxo- (=O), cyano groups, (C1-C6)oxaalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylamino,

di(C1-C6)alkylamino, (C1 is PAP (CH2)zwhere z is 0 or 1; provided that: (a) when a is methylene or carbonyl, R9can't be fullam, pyridium, isothiazolines, oxazolium, triazolium, tetrazolium, chinaillon, thiazolium or tanilo; (b) when m is O, one of R6and R7no, and the other is hydrogen atom; and (C) when R6or R7linked to the carbon atom of X, which is adjacent to the ring nitrogen atom corresponding to R6or R7must be a Deputy, the place of attachment is a carbon atom;

or pharmaceutically acceptable salts of such compounds effective for the treatment or prophylaxis of the aforementioned diseases.

Preferred variants of the embodiment of the present invention encompass methods of treating or preventing emesis in a mammal, including humans, the implementation of which is provided by the introduction into the organism of these mammals appropriate number of connections, which is defined in the following p. (69), is effective for treatment or prevention of such diseases.

(70) the Compound of formula XVI, where z - 1.

(71) the Compound of formula XVI, where q - 3.

(72) the Compound of formula XVI, where q is 3, m is 0, R3- hydrogen representatives, independently from each other selected from (C1-C6)alkyl, possibly substituted by 1-3 fluorine atoms, and (C1-C6)alkyloxy, possibly substituted by 1-3 fluorine atoms.

(74) the Compound of formula XVI, where z is 1, m is 0, R4is absent, and each of R3, R6and R7indicated hydrogen.

(75) the Compound of formula XVI, which is selected from a class which includes:

(){3R-[3-alpha,6-alpha(R*)]}-3-phenyl-7-phenyl-1,8 - diazaspiro(5,5)undecane and

(){ 3R-[3-alpha, 6-alpha(R*)] }-3-(methoxyphenyl)-7-phenyl - 1,8-diazaspiro(5,5)undecane.

Other compounds of formula I include:

(){ 3R-[3-alpha, 6-alpha(R*)] }-3-(2 - trifloromethyl)-7-phenyl-1,8 - diazaspiro(5,5)undecane;

(){3R-[3-alpha,6-alpha(R*)]}-3-(5-chloro-2-methoxyphenyl)-7 - phenyl-1,8-diazaspiro(5,5)undecane;

(){ 3R-[3-alpha, 6-alpha(R*)]}-3-(5-isopropyl-methoxyphenyl) - 7-phenyl-1,8-diazaspiro(5,5)undecane;

(){ 3R-[3-alpha, 6-alpha(R*)]}-3-(5-tert.butyl-methoxyphenyl) -7-phenyl-1,8-diazaspiro(5,5)undecane;

(){ 3R-[3-alpha, 6-alpha(R*)] }-3-(2-methoxy-5-(N - methyl-N-methylsulfonylamino)-7-phenyl-1,8 - diazaspiro(5,5)undecane;

(){ 3R-[3-alpha, 6-alpha(R*)] } -3-(2-itfeel) -7-phenyl-1,8 - diazaspiro(5,5)undecane;

(){ 3R-[3-alpha, 6-alsoproperty) - 7-phenyl-1,8-diazaspiro(5,5)undecane;

(){ 3R-[3-alpha, 6-alpha(R*)] }-3-(2-deformedarse-5 - trifloromethyl)-7-phenyl-1,8-diazaspiro(5,5)undecane;

(){ 3R-[3-alpha,5 alpha(R*)]}-3-(2-methoxyphenyl)-6-phenyl - 1,7-diazaspiro(4,5)decane;

(){ 3R-[3-alpha,5 alpha(R*)]}-3-(2-methoxy-5 - trifloromethyl) -6-phenyl-1,7-diazaspiro(4,5)decane;

(){ 3R-[3-alpha,5 alpha(R*)]}-3-(5-chloro-2-methoxyphenyl) - 6-phenyl-1,7-diazaspiro(4,5)decane;

(){ 3R-[3-alpha, 5 alpha(R*)] } -3-(5-isopropyl-2 - methoxyphenyl) -6-phenyl-1,7-diazaspiro(4,5)decane;

(){ 3R-[3-alpha, 5 alpha(R*)] } -3-(5-tert.butyl-2 - methoxyphenyl)-6-phenyl-1,7-diazaspiro(4,5)decane.

Used in this description, the term "halogen" in all cases, except as specifically stated, is used to denote the atoms of chlorine, fluorine, bromine and iodine.

The term "alkyl" used in this description, in all cases, except as expressly provided, includes saturated monovalent hydrocarbon radicals containing straight, branched or cyclic residues or combinations thereof.

As used in this description, the term "alkenyl" in all cases, unless otherwise specified, refers to straight or branched hydrocarbon radicals which rapinyl, 1 - and 2-butenyl. Used in this description, the term "alkoxy" in all cases, unless otherwise specified, refers to-O-alkyl, where the meaning of the term "alkyl" defined above, and covers, though the list is not limited to, methoxy, ethoxy-, propoxy-, isopropoxy, h-butoxy, isobutoxy - and tert. butoxypropyl.

Used in this description, the term "alkylthio" in all cases, unless otherwise specified, refers to-S-alkyl, where the meaning of the term "alkyl" defined above, and covers, though the list is not limited to, methylthio, ethylthio, h-propylthio, isopropylthio, h-butylthio, isobutylic - and tert.butylthiourea.

Used in this description, the term "cycloalkyl" in all cases, except as specifically stated, is used to denote a cyclic hydrocarbon radicals, covering, though the list is not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Used in this description, the term "one or more substituents" in all cases, except as specifically modified, means from one to the maximum number of deputies, which is determined by the number of possible centers of communication.

Connection of different forms.

The above definition of these compounds encompass all optical isomers and all stereoisomers of such compounds, and mixtures thereof.

Treatment of vomiting involves the treatment of nausea, vomiting and retching and vomiting. The term "vomiting" covers profuse vomiting, delayed vomiting and premature vomiting.

For the treatment of vomiting regardless of the cause of its reasons can be used P-receptor antagonists.

So, for example, vomiting can be caused by drugs, particularly chemotherapeutics for the treatment of cancer (e.g., cyclophosphamide, carmustine, lomustine and hlorambuzila), cytotoxic antibiotics (for example, dactinomycin, doxorubicin, mitomycin-C and bleomycin), opioid analgesics (eg, morphine), antimetabolites (e.g., citarabinom, methotrexate and 5-fluorouracil), Vinca alkaloids (for example, etoposide, vinblastine and vincristine) and other drugs, in particular cisplatin, dacarbazine, procarbazine and oximosilane.

Vomiting can also be caused by radiation sickness, radiation therapy, toxic substances, toxins, in particular those which are formed in disorders of the exchange rate up to the first apparatus, for example, violation of coordination of movements, postoperative complications, gastrointestinal obstruction, reduced gastrointestinal motility, visceral pain (e.g. myocardial infarction or peritonitis), migraines, increased intracranial pressure or low intracranial pressure (for example, when altitude sickness).

Proposed in accordance with the present invention methods can also be used to treat and prevent vomiting caused by drug gag root.

The compounds of formula Ia, Ib, Ic, Id, X, XI, XII, XIII and XIV can be obtained by methods described below. In all cases, except as specifically allowed in the following description of structural formula Ia, Ib, Ic, Id, X, XI, XII, XIII and XIV, and groups of formulae II, III, IV, V, VI, VII, VIII and IX are defined as described above.

Compounds of formulas Ia and Ib can be obtained as presented in the application for U.S. patent 988653, which was submitted on 10 December 1992, the application referred to in this description as a reference.

The compounds of formula Ic can be obtained as described in U.S. patent application 932392, which was submitted on August 19, 1992, e is in compliance with the set forth in the application for international patent application PCT/US 92/03571, USA, which was submitted to the patent service of the United States on may 5, 1992, the application referred to in this description as a reference.

In the case when R3group of the formula II, the starting materials of the formula NH2R3used for obtaining the compounds of formulas Ia, Ib, Ic and Id can be obtained as described in U.S. patent 5162339, which was issued on 11 November 1992, the patent referred to in this description as a reference.

When R3group of the formula III, the starting materials of the formula NH2R3used for obtaining the compounds of formulas Ia, Ib, Ic and Id can be obtained as described in the application for international patent application PCT/US 91/02853, USA, which was submitted to the patent office of the United States on April 25, 1991, and published international patent office under the number WO 91/18899 12 December 1991 the application referred to in this description as a reference.

When R3group of the formula IV, V or VI, the starting materials of the formula NH2R3used for obtaining the compounds of formulas Ia, Ib, Ic and Id can be obtained as described in the application for international patent application PCT/US 91/03369, With the international patent office under the number WO 92/01688 February 6, 1992 This application is referred to in this description as a reference.

When R3group of the formula VII, starting materials of the formula NH2R3used for obtaining the compounds of formulas Ia, Ib, Ic and Id can be obtained as described in application for U.S. patent 724268, submitted July 1, 1991, in the application for U.S. patent 800667, submitted on 27 November 1991 and in the application of international patent application PCT/US 92/00065, USA, which was submitted to the patent office of the United States January 14, 1991, and published international patent office under the number WO 92/17449 October 15, 1992, the application referred to in this description as a reference.

When R3group of the formula VIII, starting materials of the formula NH2R3used for obtaining the compounds of formulas Ia, Ib, Ic and Id can be obtained as described in the application for international patent application PCT/US 91/05776, USA, which was filed in the U.S. patent office on August 20, 1991, and published international patent office under the number WO 92/06079 April 16, 1992, in the application for U.S. patent 800667, submitted on 27 November 1991 and in the application of mizunara 1992 published international patent office under the number WO 92/17449 October 15, 1992, the applications mentioned in this specification as a reference.

When R3group of the formula IX, starting materials of the formula NH2R3used for obtaining the compounds of formulas Ia, Ib, Ic and Id can be obtained as described in application for U.S. patent serial number 719884, filed June 21, 1991, and in the application of international patent application PCT/US 92/04697, USA, which was submitted to the patent office of the United States on June 11, 1992, the applications mentioned in this specification as a reference.

The compounds of formula X can be obtained as described in the application for international patent application PCT/US 92/04002, USA, which was submitted to the patent office of the United States on may 19, 1992, and published international patent office under the number WO 92/15585 September 17, 1992, the application referred to in this description as a reference.

The compounds of formula XI can be obtained as described in the description of the application of international patent application PCT/US 92/04697, USA, which was submitted to the patent office of the United States on June 11, 1992 Eni as described in the application for international patent application PCT/US 92/07730, USA, which was submitted to the patent office of the United States on September 18, 1992, the application referred to in this description as a reference.

The compounds of formula XIII can be obtained as described in the application for international patent application PCT/US 92/06819, USA, which was submitted to the patent office of the United States August 20, 1992, the application referred to in this description as a reference.

The compounds of formula XIV can be obtained as described in application for U.S. patent 885110, which was filed may 18, 1992, the application referred to in this description as a reference.

The compounds of formula XV can be obtained by the method described in the application for Japanese patent 065337/92, which was submitted on March 23, 1992

These methods are reflected in schemes 1, 2 and 3 and discussed below. Values used in these reaction schemes and the discussion below, the symbols A, X1X2, Ar1and Ar2a similar definition of the compounds of the above formula XV.

With regard to scheme 1, the starting materials of the formula (i) can be obtained by methods which set out the data description as a reference.

The introduction of protected amino acids in the compound of formula (i), giving the compound of formula (ii) can be carried out in accordance with various known methods of peptide synthesis, as described in "Peptide synthesis, the basis and experiments", published by N. Izumiyo, 1985 (Maruzen).

Such methods include a method of activated complex ether, in the exercise of which is used as the acid chloride or a mixed acid chloride, and the method of condensation, according to which use of an appropriate condensing agent selected from dicyclohexylcarbodiimide (DCC), water soluble carbodiimide, 2-ethoxy-N-etoxycarbonyl-1,2-dihydroquinoline, agent BOP (Bopagent), diethylthiophosphate acid and diphenylphosphonate.

If desired, the flow velocity, the condensation reaction can be accelerated by adding a tertiary amide. To prevent racemization can be used N-oxysuccinimide, N-oxybisethanol or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazin.

Typically, the compound of formula (ii) can be obtained from the compounds of formula (i) and the amino acid or its salt, which is a protected amino group or a mono - or dialkylamino amino group, using the peptide reagent of combination reaction, in the East of methylene, THF or DMF, in the presence of triethylamine.

By reductive amination can hold the conversion of the compounds of the formula (ii) in the compound of formula (iii). This path involves the direct introduction of an appropriate benzylamine in 3rd position in the molecule of hinoklidina, which is usually carried out in two stages.

In the first stage receiving imine of the compounds of formula (ii) and benzylamine conducting exposure of the reactants at the boiling point under reflux in a reaction inert solvent such as toluene or benzene, in the presence of catalytic amount of acid (e.g. p-toluensulfonate or camphorsulfonic acid (CSC) in legalpolitical conditions.

According to another variant as the acid catalyst can be used Lewis acid, in particular aluminium chloride or titanium tetrachloride.

In such catalytic conditions and at a temperature from about -78oC to room as solvent, it is preferable to use acetonitrile or methylene chloride together with a dehydrating agent, in particular molecular sieve.

In the second stage Imin restore with obtaining the corresponding hydride, as a reagent, in particular with borohydride, borane or aluminum hydride.

Usually use NaBH4, NaBH3CN or NaBH(OAc)3in the presence of acetic acid.

Both the above reaction stage can be performed simultaneously. In such cases, the reaction is preferably conducted using NaBH3CN in methanol in the presence of acetic acid.

Acidic hydrolysis with mineral acid, in particular hydrochloric acid, at a temperature from about room temperature up to the boiling point of the reaction mixture for from about 30 minutes to several hours can be the conversion of compounds of formula (iii) into the corresponding carboxylic acid of formula (iv).

By heating the obtained carboxylic acid in an alcohol solvent in the presence of acid catalyst can exercise its conversion into the corresponding ester.

Alternatively the compound of formula (iii) can be obtained according to the method, which is illustrated in scheme 2.

With regard to scheme 2, the compound of formula (iii) can be obtained peptide condensation of the compounds of formula (iv) and amino acids, the carboxyl group of which is protected.

In the course of the peptide synthesis, outlined in the discussion above scheme 1.

Upon receipt of the compounds of the formula (iii) can also be used in the manner which is illustrated in figure 3.

When implementing this method, the compound of formula (iii) can be obtained by reductive amination of 3-aminoquinuclidine formula (v) having the amino acid as Deputy And with the appropriate substituted benzaldehyde.

This reaction reductive amination easily proceeds in the standard reaction conditions, the intermediate product of this reaction is stable Imin.

It is preferable to use bananowy recovery agent (for example, NaBH3CN or NaBH(OAc), and the like).

The initial product of the formula (v) can be obtained by dibenzylammonium the compounds of formula (iii). This dibenzylamine preferably carried out by hydrogenolysis using a palladium catalyst (e.g. palladium or palladium oxide hydrate), which is unlikely to affect other functional groups in the molecule of the compounds of formula (v).

The compounds of formula (iii) obtained by the above methods, you can select and clear of known ability, the ut can be obtained as described in application for U.S. patent 026382, which was submitted on 7 April 1993, the application referred to in this description as a reference.

Compounds of formulas Ia, Ib, Ic, Id, X, XI, XII, XIII, XIV, XV and XVI (hereinafter collectively called "therapies") and their pharmaceutically acceptable salts can be used as a P-receptor antagonists, meaning they have the ability to counteract the effects of tachykinins on the P-receptor sites in a mammal, whereupon they are able to function as therapeutic agents in the treatment and prevention of vomiting in suffering from this disease mammals.

Therapeutic agents, which by their nature exhibit basicity, capable of combining with various mineral and organic acids with a variety of salts.

Examples of acids that form the corresponding pharmaceutically acceptable salts suitable for use according to the present invention are those that form non-toxic acid adducts, that is, salts whose molecules include pharmaceutically acceptable anions, in particular cleaners containing hydrochloride, hydroiodide, nitrate, sulfate, bisulfate, phosphate, kaliee, fumaric, gluconate sahabatnya, benzoate, methanesulfonate, econsultancy, benzosulfimide, p-toluensulfonate and pamoate [that is, 1,1-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Although such salts must be pharmaceutically acceptable for administration to animals, in practice it is often desirable to first highlight therapeutic agent from the reaction mixture in the form of pharmaceutically acceptable salts, and then make a simple conversion again in this last connection in the free base form of processing an alkaline agent with subsequent conversion of the latter free base in a pharmaceutically acceptable acid adduct.

Acid adducts of major therapeutic agents of the present invention can easily be obtained by processing the primary connection is practically the equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent, in particular methanol or ethanol.

Careful evaporation of the solvent can easily obtain the desired solid salt.

therapeutic agents of the present invention, which are by their nature cyclothymics Foundation, which are used as reagents for producing pharmaceutically acceptable basic salts of these therapeutic agents are such compounds which are acid therapeutic agents form a non-toxic basic salts.

Such non-toxic basic salts include derivatives such pharmaceutically acceptable cations as sodium, potassium, calcium, magnesium and the like.

These salts can be easily obtained by treating the corresponding acid compounds with an aqueous solution containing the desired pharmaceutically acceptable cation, followed by evaporation of the solution to dryness, preferably under reduced pressure.

Another option can be obtained by mixing solutions of lower alcohols of these acidic compounds with the desired alkoxides of alkali metals with subsequent evaporation of the resulting solution to dryness similar to the foregoing.

In any case, in order to achieve completeness of reaction and maximum yield of the desired target product, it is preferable to use stoichiometric amounts of reactants.

Therapeutic agents and their pharmaceutically acceptable is opractice vomiting in mammals, including humans.

Therapeutic agents and their pharmaceutically acceptable salts can be introduced into the body, either oral, topical, rectal or parenteral routes.

In General, such compounds are most preferable to introduce into the body in doses that are in the range from about 5.0 to 1500 mg/day, although depending on the weight and condition of the patient being treated and the particular route of administration into the body, it may be necessary variation in dose.

However, the most desirable of the applied dose should be in the range from about 0.07 to 21 mg/kg body weight/day.

However, depending on the kind of animal being treated and its individual response to the specified medication, as well as the type of the selected pharmaceutical product, time period and the intervals at which this organism produce, can be non-bypass variation.

In some cases the dose that is below the lower limit of the above interval, may be more than adequate, while in other cases without any harmful side effects, the dose may exceed maximalizing for introduction into the body throughout the day.

Therapeutic agents and their pharmaceutically acceptable salts can be introduced into the body either individually or in combination with pharmaceutically acceptable carriers or diluents by any of the above ways, and this organism can be realized in the form of single or multiple doses.

More specifically, new therapeutic agents of the present invention can be entered in a variety of dosage forms, i.e. they can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, pellets, wafers, hard candy, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups and the like.

Such carriers include solid diluents or fillers, sterile aqueous medium and various non-toxic organic solvents and the like.

Moreover, the oral pharmaceutical compositions can to sweeten and/or flavored. Usually, therapeutic compounds of the present invention are contained in such dosage forms in concentrations of from about 5.0 to 70 wt.%.

Tablets for oral administration in the body, which include reset calcium, dicalcium phosphate and glycine, can be used in combination with various agents, giving friability, in particular with starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with a binder for granulation such as polyvinylpyrrolidone, sucrose, gelatin and gum Arabic.

In addition, in order tabletting often very useful lubricating agents, in particular magnesium stearate, sodium lauryl sulfate and talc.

Solid compositions of a similar type can also be used as fillers in gelatin capsules. In these cases, the preferred materials include lactose or milk sugar and, in addition, high molecular weight polyethylene glycols.

When oral ingestion is desirable aqueous suspensions and/or elixirs, its active component can be combined with various sweetening or flavoring agents, coloring materials or dyes, and if desired, with emulsifying and/or suspendresume agents, together with such diluents as water, ethanol, propylene glycol, glycerin and works therapeutic agent or sesame oil or peanut oil, or in aqueous propylene glycol.

Aqueous solutions should contain an appropriate buffer, if necessary and the liquid diluent first to report isotonicity.

Such aqueous solutions can be used for intravenous injection. Oil solutions acceptable for intra-articular, intramuscular and subcutaneous injections.

Preparation of all these solutions under sterile conditions is easily achieved using standard pharmaceutical techniques well known to any expert in this field.

The activity of therapeutic agents as antagonists of P-receptors can be identified by their ability to inhibit the binding of substance P at its receptor sites in the tissue of the bovine tail with radioactive ligands for observation tachykinin receptors through auto-Radiolaria.

Antagonistic activity against P-receptor compounds described herein can be assessed using standard techniques described by M. A. Cascieri and others in the Journal of Biological Chemistry, vol 258, pp. 5158 (1983).

This method essentially involves determining the concentration of an individual link is castco in the above-mentioned selected bovine tissues, which allows to obtain the characteristic value of the IC50for each test compound.

In this method, the fabric bullish tail extract out of the freezer with a temperature of -70oC and homogenized in 50 volumes (weight/volume) ice cleaners containing hydrochloride 50 mm Tris buffer (i.e tromethamine, which is 2 - amino-2-oxymethyl-1,3 - propandiol), with pH of 7.7.

This homogenate was centrifuged at 30,000 G for 20 minutes. Again in 50 volumes of Tris buffer, and suspended the tablet, re-homogenized and centrifuged again at 30,000 G for another 20 minutes.

Next, the tablet again suspended in 50 volumes of ice 50 mm Tris-buffer (pH of 7.7) containing 2 mm calcium chloride, 2 mm magnesium chloride, 4 μg/ml bacitracin, 4 µg/ml leupeptin, 2 IYP of hemostasia and 200 g/ml of bovine serum albumin.

This stage completes the process of obtaining the drug tissue. Then the binding of the radioactive ligand carried out as follows, namely: initiation of reaction by adding 100 ál of the test compound, the concentration of which was brought to 1 μm, followed by addition of 100 μl of the radioactive ligand final concentration of which was brought to 0.5 mm,ecny volume is thus, 1.0 ml; then the reaction mixture was subjected to vortex-mixed and incubated at room temperature (approximately at

20oC) for 20 minutes

Then the contents of the test tubes was filtered using a collection of cells and filters glass fibre (grade Whatman GF/B) four times washed with 50 mm Tris-buffer (pH of 7.7), with filters pre-soaked for 2-hour time period before filtering.

Then using a counter of beta particles in 53% efficient counting define radioactivity and in accordance with standard statistical methods calculate the value of the IC50.

The ability of therapeutic agents to inhibit induced by substance P effects in vivo may be determined by the implementation of methods from "a" to "C" [methods from "a" to "C" are given in Nagahiga et al. European Journal of Pharmacology, 217, 191-5 (1992), which is referred to in this description as a reference].

A. Radiolabeled plasma in the skin

The radiolabeled plasma cause intradermal introduction substance P (50 μl of 0.01% BSC-saline) using skin back male Guinea pigs, Hartley weighing 450-500 g, which was anestesiologi inside the e methylcellulose (MC) in water and orally dosed for 1 h before injection of substance P (3 pmol. /plot).

For 5 min before the intravenous injection 30 mg/kg of a blue dye Evans. After 10 min, the animals are killed, remove the skin of the back and with a punch for punching holes in the tubes of skin cut blue spots [11.5 mm, oral dose (p. D.)].

The content in the tissues of the dye quantify upon completion of the extraction formamide overnight at 600 nm absorption.

b. Radiolabeled plasma caused by capsaicin

The radiolabeled plasma cause intraperitoneal injection of 10 ml of 30 μm solution of capsaicin 0.1% solution of a BSC/salt) Guinea pigs after anesthesia by intraperitoneal injection of pentobarbital 25 mg/kg

The test compound is dissolved in a 0.1% solution of MC and dosed orally 1 h before injection of capsaicin.

For 5 min before the intravenous injection of 30 mg/kg of a blue dye Evans. After 10 min, the animals are killed and removed from them as the right and left ureters. The content of the dye in the fabric quantify similar to above in paragraph "a".

C. Abdominal stretching caused by acetic acid

Male ddY mice (SLC, Japan) weighing 14-18 g not give for 0.5 h before the injection of 0.7% acetic acid (CA) (0.16 ml/10 g body weight).

Animals are placed in a transparent chemical glasses (one glass) and after 10-20 min after injection of the criminal code (10-minute interval) calculate the reaction sipping.

Antiemetic action of compounds that are P-receptor antagonists may be determined by assessing their ability to reduce the percentage vomiting caused vomiting in ferrets impact of cisplatinum (10 mg/kg intraperitoneally).

The compound (2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)-methyl-2 - diphenylmethyl-1-azabicyclo(2,2,2)octane-3-amine inhibited caused by cisplatinum vomiting in ferrets percutaneously into the body at a dose of 1 mg/kg 30 min prior to the introduction of cisplatinum.

The compound (2S, 3S)-3-(2-methoxy-5-cryptomaterial)- amino-2-phenylpiperidine inhibited caused by cisplatinum vomiting in ferrets percutaneously into the body at a dose of 1 mg/kg 30 min prior to the introduction of cisplatinum.

The compound CIS-3-[(2-methoxyphenyl)-methylamino] -2 - benzhydrylidene inhibited caused by cisplatinum vomiting in ferrets percutaneously into the body at a dose of 10 mg/kg 30 min prior to the introduction of cisplatinum.

1. A method of treating or preventing emesis in a mammal, comprising entered is eception substance P injected (2S, 3S)-2-phenyl-3-(2-methoxy-5-cryptomaterial)-aminopiperidin or its pharmaceutically acceptable salt in an effective amount for the treatment or prevention of a specified disease.

2. A method of treating or preventing emesis in a mammal, comprising the introduction of a specified mammal of the receptor antagonist of the substance P, characterized in that as a receptor antagonist of the substance P injected (2S, 3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenyl-methyl-1-azabicyclo[2.2.2] Octan-3-amine or its pharmaceutically acceptable salt in an effective amount for the treatment or prevention of a specified disease.

3. A method of treating or preventing emesis in a mammal, comprising the introduction of a specified mammal of the receptor antagonist of the substance P, characterized in that as receptor antagonists of substance P injected (2S, 3S)-N-(5-tertbutyl-2-methoxyphenyl)methyl)-2-diphenyl-methyl-1-azabicyclo[2.2.2] -Octan-3-amine or its pharmaceutically acceptable salt in an effective amount for the treatment or prevention of a specified disease.

 

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Drug // 2121347

FIELD: medicine, phthisiology.

SUBSTANCE: one should lymphotropically introduce the mixture of 5.0 ml 0.25%-novocaine solution and 2.0 ml 1%-dioxidine solution or the mixture of 5.0 ml 0.25%-novocaine solution and 0.5 g cefazoline subcutaneously into jugular cavity and deeply behind xiphoid process, successively 1 point once daily, 5-7 injections/course. After injection the site of injection should be treated either with heparin ointment or ultrasound (1-3 MHz, PPM 0.2 W/sq. cm, for 2 min, through Vaseline oil) followed by evaluating roentgenological dynamics of the process 10-14 d later.

EFFECT: higher efficiency of differential diagnostics.

3 ex

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