UA80338C2 - N-pyrrolidin-3-yl-amide derivatives as serotonin and noradrenaline re-uptake inhibitors, processes for their preparation, pharmaceutical composition containing them - Google Patents

Abstract

A compound of Formula (I) and pharmaceutically and/or veterinarily acceptable derivatives thereof, wherein R1 is H, C1-6alkyl, -C(X)Y, C3-8cyc1oa1ky1, aryl, het, aryl-C1-4alkyl or het-C1-4alkyl, wherein the cycloalkyl, aryl or het groups are optionally substituted by at least one substituent independently selected from C1-8allkyl, C1-8alkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C1-6alkyl, C1-4alkaxy-C1-6alkyl and C1-4alkyl-S-C1-4alkyl; R2 is aryl or heteroaryl, each optionally substituted by at least one substituent independently selected from C1-8alkyl, C1-8alkoxy, OH, halo, CF3, OCF3 SCF3, hydroxy-C1-6alkyl, C1-4alkcoxy-C1-6alkyl and C1-4alkyl-S-C1-4alkyl; R3 is C1-6alkyl, C3-8cyc1oa1kcyl, C3-8cyc1oa1ky1-C1-4a1ky1, aryl, het, aryl-C1-4alkyl or het-C1-4alkyl, wherein the cycloalkyl, aryl or het groups are optionally substituted by at least one substituent independently selected from C1-6alkyl, C1-6alkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C1-6alkyl, C1-4alkoxy - C1-6alkyl and C1-4alkyl-SC1-4alkyl; X is S or O; Y is H, C1-6alkyl, aryl, het, aryl-C1-4alkyl or het-C1-4alkyl; and n is 1 or 2, provided that when n is 1, m is 0 or 1 and when n is 2, m is 0, wherein if m is 0, then * represents a chiral center. The compounds of the invention exhibit activity as both serotonin and noradrenaline re-uptake inhibitors and therefore have utility in a variety of therapeutic areas, for example urinary incontinence.

Description

Description of the invention

This invention relates to new amide compounds that inhibit the resorption of monoamines, methods of their preparation, 2 pharmaceutical compositions containing them, and their use in medicine.

The compounds of the invention show activity as serotonin and norepinephrine resorption inhibitors, and therefore have applications in various therapeutic areas, for example, the compounds of the invention are used in the treatment of disorders involving the regulation of monoamine transport function, more especially disorders involving the inhibition of serotonin or norepinephrine resorption; and especially disorders, disorders that involve 70 inhibition of serotonin and norepinephrine, such as urinary incontinence.

According to the first aspect, the invention relates to a compound of formula (1),

And even their VN is a "race" of the SN PITS

M

(8)

Shshsh, I

A c and its pharmaceutically and/or veterinary acceptable derivatives, where

В!-Н, Сі в-alkyl, -С(Х)М, Сз. β-cycloalkyl, aryl, Ni, aryl-C..4-alkyl, or pei-C. /-alkyl, where cycloalkyl, aryl Shk or Pei are optionally substituted with at least one substituent independently selected from the group: C 4.6-alkyl, co

Siv-Alkoxyl, OH, Halogen,. CEz, OSEz, ZSEz, hydroxy-C.-v-alkyl, C.sub.-alkoxy-C.-v-alkyl and

S. d-alkyl-in-S. -alkyl; at

IN? - aryl or heteroaryl, as an option, substituted by at least one substituent, independently selected from d) group: C 6 -alkyl, C 6 -alkyl, OH, halogen, CEz, OSEz, ZSE", hydroxy-C. C-alkyl, C.4.-Alkoxy-C. γ-alkyl and

Ci d-alkyl-5-C4 y-alkyl;

BZ - Ci c-alkyl, Xia c-cycloalkyl, Cz c-cycloalkyl-C. γ-alkyl, aryl, Nei, aryl-C. 4-alkyl or Ni-C. 4-alkyl, where "cycloalkyl, aryl, or Pei is optionally substituted with at least one substituent independently selected from the group: C 1 -alkyl, C 1 -C 6 -alkyl, OH, halogen, CE3, OSE3, ZCE3, hydroxy-C4 C-alkyl, C-4-Alkoxy-Ci-C-alkyl, and C-C, C-C-1-alkyl-5-C4-alkyl; "» X-5or 0; " U - H, S. valkil, Si. β-Alkoxyl, aryl, Ni, aryl-C../-alkyl or pei-C. /-alkyl; each - 1 or 2, provided that when n-1, t - 0 or 1, and when n-2, t-0, where if t-0, then " represents a chiral center; co aryl - phenyl, naphthyl, anthracyl or phenanthryl; o heteroaryl - aromatic 5- or b-membered heterocycle, which contains at least one heteroatom M, O or 5, as an option, condensed with aryl; a and Nei - aromatic or non-aromatic 4-, 5- or b --lene heterocycle containing at least one C 20 M, O or 5 heteroatom optionally fused with a 5- or β-lene carbocyclic group or a second 4-, 5- or 6β-lene heterocycle containing at least one heteroatom M, O or 5. co In the embodiment of the invention, B - H, and 27, EZ and t are defined above.

In a further embodiment of the invention, t-0, and VC", K2 and KZ are defined above. When t-0, " represents the VC or 5 enantiomeric configuration. Therefore, according to the following embodiment t-0, K 7, Kk? and KZ are as defined above, and "7 represents the C enantiomer. (F; In yet another embodiment, B", C, and t are as defined above, and 2 is phenyl, naphthyl, or quinolinyl, each of which is optionally substituted with at least one substituent , independently selected from the group: C-alkyl, C-alkyl, C-alkyl, OH, halogen, C-C, C-C, C-C, hydroxy-C-C-alkyl, C-C-Alkoxy-C-C-alkyl and C . "-alkyl-C-C4 /-alkyl. 60 In yet another embodiment, the substituents can be selected from the group: halogen, OH, C.. alkyl, C. -alkyloxy and

SEZ Alternatively, phenyl, naphthyl, or quinolinyl may be substituted with one, two, or three substituents each independently selected from the group consisting of halogen, OH, and C 1 -alkyl.

In the following embodiment, 22 is phenyl substituted with two substituents selected from the group consisting of chlorine, fluorine, OH and C-alkyl. 65 In yet another embodiment, 2 is dichlorophenyl.

In another embodiment of CT, V? and t are defined above, and 3 is C1-6-alkyl, C1-6-cycloalkyl or

C. vcycloalkyl-C. -alkyl

In the next embodiment, BZ is C3-alkyl, C3-6-cycloalkyl or C3-6-cycloalkyl-C. 4-alkyl.

In another embodiment, the invention relates to a compound of formula II and "A"

R

/5 t and | it and its pharmaceutically and/or veterinary acceptable derivatives, where

B - phenyl, naphthyl, or quinolinyl, each, as an option, substituted by at least one substituent independently selected from the group: C 1 -alkyl, C 1 -alkyloxy, OH, halogen, CEz, OSEz, ZSPE", hydroxy-C.4.v -alkyl, Ha

C.4-Alkoxy-C.4-C-alkyl and C..-C.-Alkyl-5-C.4-Alkyl; o 25 - C3-alkyl, C3-cycloalkyl, C3-cycloalkyl-C. C-alkyl, aryl or aryl-C. /-alkyl where cycloalkyl and aryl are optionally substituted with at least one substituent, each of which is independently selected from the group: C /4.alkyl,

Sivalkoxyl, OH, halogen, СЕз, ОСЕз5, ССЕ5, hydroxy-C4 6-alkyl, C/-Alkoxy-C- in-alkyl. and

C. .l-alkyl-5-C. /-alkyl; and c t - 0 or 1, where if t-0, then " represents K or 5 enantiomer.

In the next incarnation, B? and t are defined above, and K7 is phenyl, 1-naphthyl or 2-naphthyl, each of which, as an option, is substituted by at least one substituent independently selected from the group: C.-.v.-alkyl, C. β-Alkoxyl, OH, (ze) halogen, CEz, OSEz, ZSE»z, hydroxy-C.4 β-alkyl, C. -Alkoxy-C; c-alkyl and C. /-alkyl-C-C. /4-alkyl. Substituents о can, as an option, be selected from the group: C-1-6-alkyl, C-1-6-6-alkyl, OH, halogen and CE3. Phenyl or naphthyl can be substituted with one, two or three substituents. In an embodiment, the phenyl or naphthyls are substituted with two 99 substituents. In a further embodiment, the phenyl or naphthyls are substituted with two substituents independently selected from the group consisting of chlorine, fluorine, C 1-4 alkyl and OH. In yet another embodiment, the phenyl or naphthyls are substituted with two chlorines.

In yet another embodiment, B" and t are defined above, and B" is C-C-alkyl, C-C-cycloalkyl or "

S. d-"cycloalkyl-C,. ,-alkyl.

In the next embodiment, K" and K" are defined above, and t-0. In this embodiment, " represents K or the 5 enantiomer. c In the next embodiment, t:-0, and " represents the 5 enantiomer. :z" In yet another embodiment, a compound of the formula PI (ee) 7 («c) p Ch and is proposed,

Pho mi in (95)

IR e) 7 7 M

Ф) Кк я име) And its /ab Y and certain b - and bo quinolines Y vo and its pharmaceutically and/or veterinary acceptable derivatives, where phenyl, naphthyl or quinolinyl, each of which is optionally substituted with at least one substituent, regardless selected from the group: halogen, OH,

S. valkyl, S. β-alkyl and CE";

B - C3-alkyl, C3-cycloalkyl, C3-cycloalkyl-C. 4-alkyl, aryl or aryl-CH»o-; where cycloalkyl and aryl are optionally substituted with at least one substituent independently selected from the group consisting of halogen, OH, C 1-6 alkyl, 65 C 1-6 alkyl, and C 3 -a" represents the K or 5 enantiomer.

In a further embodiment, B/ and " are as defined above, and BE is phenyl, 1-naphthyl, or 2-naphthyl, each of which is optionally substituted with at least one substituent independently selected from the group: halogen, OH, C)-alkyl ,

Si. β-Alkoxyl and SEz. Substituents can, as an option, be selected from the group: chlorine, fluorine, C ..4-alkyl, OMe and

ON. Phenyl and naphthyl can be substituted with one, two or three substituents. In another embodiment, the phenyl and naphthyl are substituted with one, two, or three halogens independently selected from the group consisting of fluorine and chlorine.

In the next embodiment, 9 and "7 are defined above, and K" is C-C alkyl, C-C cycloalkyl or

S. vdcycloalkyl-S. /-alkyl. In yet another embodiment, B - C 3 c -alkyl is optionally C 3 alkyl. When K/ is Ca-C alkyl, it can be a branched C3-C alkyl.

In another embodiment, KU and K/ are defined above, and " represents the 5 enantiomer. In yet another embodiment, a compound of the formula is proposed

In H.

And S

IS

IR h s | n | o and its pharmaceutically and/or veterinary acceptable derivatives, where. BC Z - phenyl, as an option, substituted with 1-3 halogen substituents; (heh)

VZ - S. valkil; and co" represents K or 5 enantiomer.

Alternatively, KZ - dichlorophenyl, KU - C3 I-branched alkyl, and " represents the C enantiomer. EC? can be me) isobutyl. o

In the following embodiment, the invention relates to a compound selected from the group consisting of:

Zo 2,3-Dichloro-M-isobutyl-M-(35)-pyrrolidin-3-yl|benzamide; so 2,4-Dichloro-M-isobutyl-M-(35)-pyrrolidin-3-yl|benzamide; 2-Chloro-3-methyl-N-isobutyl-N-(35)-pyrrolidin-3-yl|benzamide; 3-Fluoro-2-methyl-N-isobutyl-N-(35)-pyrrolidin-3-yl|Ibenzamide; "3-Methoxy-2-methyl-N-isobutyl-N-(35)-pyrrolidin-3-yl|benzamide; 3-Chloro-M-isobutyl-M-((35)-pyrrolidin-3-yl|benzamide; With c 4-Chloro-M-isobutyl-M-((35)-pyrrolidin-3-yl|Senzamide; "» 3,4-Dichloro-M-isobutyl-M-(35)-pyrrolidin-3-yl|IbSenzamide; "M-2-Naphthylmethyl)-M-(35)-pyrrolidin-3-yl|Ibenzamide;

M-(2-Naphthylmethyl)-M-(35)-pyrrolidin-3-yl|Ibenzamide;

M-isobutyl-M-((35)-pyrrolidin-3-yl1-2-naphthamide; co M-butyl-M-(35)-pyrrolidin-3-yl|-1-naphthamide; o 4-Chloro-M- (3,4-dichlorobenzyl)-M-|(35)-pyrrolidin-3-yl|Ibenzamide; 4-Chloro-M-(2,3-dichlorobenzyl)-M-|((35)-pyrrolidin-3-yl |Ibenzamide; o and their pharmaceutically and/or veterinary acceptable derivatives. o 50 Further non-limiting examples of compounds include within the scope of the invention:

M-Pyrrolidin-3Z-yl-M-(5,6,7,8-tetrahydro-naphthalen-1-ylmethyl)-benzamide; co IM-42,4-Dichloro-benzyl)-M-pyrrolidin-3-yl-benzamide;

M-(3-Chloro-4-methyl-benzyl)-2-fluoro-M-pyrrolidin-3-yl-benzamide;

Naphthalene-2-carboxylic acid butyl-pyrrolidine-3-yl-amide; 59 Naphthalene-2-carboxylic acid isobutyl-pyrrolidine-3-yl-amide;

HF) Naphthalene-2-carboxylic acid (2,2-dimethyl-propyl)-pyrrolidin-3-yl-amide;

C-Chloro-M-isobutyl-4-methyl-M-pyrrolidin-3-yl-benzamide; o M-isobutyl-2,3-dimethyl-M-pyrrolidin-3-yl-benzamide;

C-Chloro-M-(2,2-dimethyl-propyl)-2-methyl-M-pyrrolidin-3-yl-benzamide; 6o 2-Chloro-4-fluoro-M-isobutyl-M-pyrrolidine-3-yl-benzamide; 2-Chloro-M-isobutyl-M-pyrrolidin-3-yl-benzamide;

C-Chloro-2-fluoro-M-isobutyl-M-pyrrolidin-3-yl-benzamide;

C-Chloro-4-fluoro-M-isobutyl-M-pyrrolidin-3-yl-benzamide;

M-Butyl-2,4-dichloro-M-pyrrolidine-3-l-benzamide; bo 2,4-Dichloro-M-cyclobutylmethyl-M-pyrrolidin-3-yl-benzamide;

2,4-Dichloro-M-cyclopentylmethyl-M-pyrrolidine-3-yl-benzamide; 2,4-Dichloro-M-(2,2-dimethyl-propyl)-2-methyl-M-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-N'-2-ethyl-butyl)-N-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-M-(3-methyl-butyl)-M-pyrrolidin-3-yl-benzamide; 2,3,4-Trichloro-M-isobutyl-M-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-M-(2-cyclopropyl-ethyl)-M-pyrrolidin-3-yl-benzamide;

Naphthalene-1-carboxylic acid isobutyl-pyrrolidine-3-yl-amide; 2,4-Dichloro-5-fluoro-M-isobutyl-M-pyrrolidin-3-yl-benzamide; 70 2,3-Dichloro-M-12,2-dimethyl-propyl)-M-pyrrolidine-3-yl-benzamide; 2,3-Dichloro-M-(3-methyl-butyl)-M-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-M-cyclobutylmethyl-M-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-M-cyclopentyl-M-pyrrolidin-3-yl-benzamide; 3,4-Dichloro-M-cyclopentyl-M-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-M-(1,2-dimethyl-propyl)-M-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-M-11,2-dimethyl-propyl)-M-pyrrolidine-3-yl-benzamide; 2,3-Dichloro-M-cyclohexyl-M-pyrrolidine-3-yl-benzamide; 2(4-Dichloro-M-cyclopentyl-M-pyrrolidine-3-yl-benzamide; 3,4-Dichloro-M-cyclopentyl-M-pyrrolidine-3-yl-benzamide;

Naphthalene-1-carboxylic acid sec-butyl-pyrrolidin-3-yl-amide;

M-tert-Butyl-2,3-dichloro-M-pyrrolidin-3-yl-benzamide;

M-tert-Butyl-2,4-diphor-M-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-H-(1-ethyl-propyl)-M-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-M-(1-ethyl-propyl)-M-pyrrolidine-3-yl-benzamide; high school

Naphthalene-1-carboxylic acid (1-ethyl-propyl)-pyrrolidin-3-yl-amide; 2,3-Dichloro-M-cyclobutyl-M-pyrrolidin-3-yl-benzamide; (8) 2,4-Dichloro-M-cyclobutyl-M-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-M-cyclopentyl-M-pyrrolidin-3-yl-benzamide; 2,3-Dichloro-M-pyrrolidin-3-yl-M-(1,2,2-trimethyl-propyl)-benzamide; so zo N-tert-butyl-2,3-dichloro-N-pyrrolidin-3-yl-benzamide;

Naphthalene-1-carboxylic acid cyclopentyl-pyrrolidin-3-yl-amide; o 2,3-Dichloro-M-phenyl-M-pyrrolidin-3-yl-benzamide; c 3,4-Dichloro-M-(2,2-dimethyl-propyl)-2-methyl-M-pyrrolidin-3-yl-benzamide;

C-Chloro-M-isobutyl-2-methyl-M-pyrrolidin-3-yl-benzamide; at

M-Butyl-2,3-dichloro-M-pyrrolidin-3-yl-benzamide; co

M-Butyl-3,4-dichloro-M-pyrrolidin-3-yl-benzamide;

Naphthalene-2-carboxylic acid cyclobutylmethyl-pyrrolidine-3-yl-amide;

Naphthalene-1-carboxylic acid cyclobutylmethyl-pyrrolidine-3-yl-amide; 3,4-Dichloro-M-cyclobutylmethyl-M-pyrrolidine-3-yl-benzamide; « 4-Chloro-M-isobutyl-2-methoxy-M-pyrrolidin-3-yl-benzamide; with c 4-Chloro-M-isobutyl-3-methyl-M-pyrrolidin-3-yl-benzamide; . 2,4-Dichloro-M-isobutyl-3-methyl-M-pyrrolidin-3-yl-benzamide; and?" Naphthalene-1-carboxylic acid (3-methyl-butyl)-pyrrolidin-3-yl-amide;

Naphthalene-1-carboxylic acid (2,2-dimethyl-propyl)-pyrrolidin-3-yl-amide; 3,4-Dichloro-M-(3-methyl-butyl)-M-pyrrolidine-3-yl-benzamide;

Go! 2,3-Dichloro-M-(4-fluoro-phenyl)-M-pyrrolidin-3-yl-benzamide; 2,4-Dichloro-M-14-difluoro-phenyl)-M-pyrrolidin-3-yl-benzamide; o Naphthalene-1-carboxylic acid (4-fluoro-phenyl)-pyrrolidin-3-yl-amide; 2) M-Butyl-2,3,4-trichloro-M-pyrrolidin-3-yl-benzamide; 2,3,4-Trichloro-M-cyclobutylmethyl-M-pyrrolidin-3-yl-benzamide; o M-Pyrrolidin-3-yl-M-(3-trifluoromethyl-benzyl)-benzamide; c 2,4-Dichloro-M-phenyl-M-pyrrolidin-3-yl-benzamide; 3,4-Dichloro-M-phenyl-M-pyrrolidine-3-yl-benzamide; 2,3,4-Trichloro-M-(2,2-dimethyl-propyl)-M-pyrrolidin-3-yl-benzamide;

Naphthalene-1-carboxylic acid phenyl-pyrrolidin-3-yl-amide; 2,3,4-Trichloro-M-72-cyclopropyl-ethyl)-M-pyrrolidin-3-yl-benzamide;

F) 2,3-Dichloro-H-(2-cyclopropyl-ethyl)-M-pyrrolidin-3-yl-benzamide; ka 2-Bromo-4-chloro-M-zobutyl-M-pyrrolidin-3-yl-benzamide; 4-Chloro-2-ethoxy-M-isobutyl-M-pyrrolidin-3-yl-benzamide; 60 C-bromo-4-chloro-M-isobutyl-M-pyrrolidin-3-yl-benzamide; 3,4-Dichloro-M-isobutyl-2-methyl-M-pyrrolidine-3-yl-benzamide; 2,4-dichloro-3-fluoro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 2,3-dichloro-4-fluoro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 2,3-dichloro-5-fluoro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 65 2,4,5-trichloro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 2,5-dichloro-M-isobutyl-M-/pyrrolidine-3-yl|Senzamide;

2,5-dichloro-4-fluoro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 2(3,5-trichloro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 2,3-dichloro-6-fluoro-M-isobutyl-M-|pyrrolidin-3-yl|Ibenzamide; 3, 4-dichloro-6-fluoro-M-isobutyl-M-Ipyrrolidin-3-yl|IbSenzamide; 3,4-dichloro-2-fluoro-M-isobutyl-M-Ipyrrolidin-3-yl|IbSenzamide; 2-chloro- 3,6-difluoro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 2,A4-Dichloro-5-fluoro-M-isobutyl-M-((35)-pyrrolidin-3-yl|Senzamide; and their pharmaceutically and/or veterinary acceptable derivatives. 70 Pharmaceutically and/or veterinary acceptable derivatives mean any pharmaceutically or veterinary acceptable salt, solvate, ester or amide, or a salt or solvate of such an ester or amide of compounds of formulas (I), ( I), (I) or (IM) or any other compound which, when applied to the recipient, can give (directly or indirectly) a compound of the formula (I), (I), (IP) or (IM), or its active metabolite or residue.

For pharmaceutical or veterinary use, the above salts must be pharmaceutically or veterinary acceptable salts, but other salts may find use, for example, in the preparation of compounds of formulas (I), (II), (1) or (IM) and their pharmaceutically or veterinary acceptable salts .

The above pharmaceutically or veterinary acceptable salts include acid addition and base addition salts.

Suitable acid addition salts are formed with acids that form non-oxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, disulfate/sulfate, camsylate, citrate, edsylate, hemidesilate, hesylate, fumarate, glucoceptate, gluconate, glucuronate, gibenzate, chloride, bromide, iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, 2-napsylate, nicotinate, nitrate, orotate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, and tosylate. high school

Suitable base salts are formed with bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, (8)olamine, potassium, sodium, tromethamine and zinc salts.

For an introduction to suitable salts, see |"Naparsok oi RNpaptaseciisa! Zai(8: Rgoregiev. ZeIesiop, apa

Ove" ru gai and MUegtcy (MUNeu-MSN, U/eippeit, Septapu, 20023). so z A pharmaceutically acceptable salt of a compound of formula (1), (I), (II) or (IM) can be easily prepared by mixing together solutions of the compound and of the desired acid or base needed. The salt may precipitate out of solution and be collected by filtration, or it may be obtained by evaporation of the solvent. The degree of ionization of the salt may vary from fully ionized to nearly unionized.

Pharmaceutically acceptable solvates according to the invention include hydrates and solvates of compounds of the formulas (I), or CHO, (I) or (IM). co

Also within the framework of the invention E complexes, such as clathrates, drug-host inclusion complexes, where, unlike the above-mentioned solvates, the drug and the host are present in a stoichiometric or non-stoichiometric amount. Also covered by this invention are complexes of pharmaceutical drugs that contain two or more organic and/or inorganic components, which can be in stoichiometric or non-stoichiometric amounts. Formed "

Complexes can be ionized, partially ionized, or non-ionized. For a review of such complexes, see M RNagt zsi, 64 (8), 1285-1288 Bu Naieriyap (Aetsdivy 1975)).

Compounds of formula (U), (I), (I) or (IM) can be modified for their formation pharmaceutically and/or; veterinary acceptable derivatives with any functional group in compounds. Examples of such derivatives are described in: (Ogidvo oi Todau, Moiishte 19, Mitreg 9, 1983, pp. 499-538; Torisv ip SPetivigu, SParieg 31, pp. 306-316; and in "Oezvidp oi Rgodgodz" by N. Vypadaaga, EIvemieg , 1985, SPparieg 1 (disclosure of these documents

Go! entered as a reference)| and include: esters, carbonate esters, hemiesters, phosphate esters, nitroesters, sulfate esters, sulfoxides, amides, sulfonamides, carbamates, azo compounds, phosphamides, glycosides, ethers, acetals, and ketals. 2) It will be clear to those skilled in the art that some groups known in the art as "progroups", for example, described (N. 5o Vypddaaga in "Oevidp oi Rgodgydv" (ibid.)) can be placed into acceptable functional groups, when such o functional groups presented in the compounds of the invention. c Compounds of the formula (I), (I), (P) or (IM) may contain one or more chiral centers based on an asymmetric carbon atom defined by some values of B 71-29 (for example, sec-butyl) , or an integer value of t. Such compounds exist in a number of stereoisomeric forms (for example, in the form of a pair of optical isomers, or enantiomers). It is understood that the present invention encompasses all isomers of the compounds of the invention, including all geometric, tautomeric and optical forms, and mixtures thereof (eg, tautomeric or racemic mixtures).

F, Compounds of the invention can exist in one or more tautomeric forms. All tautomers and mixtures thereof are included within the scope of the present invention, for example, the name 2-hydroxypyridinyl may also refer to the tautomeric form co-pyridonyl. 60 It is clear that the present invention covers radiolabeled compounds of formulas (I), (I), (1) or (IM).

Compounds of formulas (1), (II), (I) or (IM) and their pharmaceutically and/or veterinary acceptable derivatives may also exist in more than one crystalline form, which is known as polymorphism. All such polymorphic forms ("polymorphs") are included within the scope of the invention. Polymorphism can usually occur as a result of changes in temperature or pressure, and can also result from variations in the crystallization process. Polymorphs can differ in 65 different physical characteristics, and usually in X-ray diffraction patterns, solubility, and melting point.

Unless otherwise stated, any alkyl may be linear or branched having 1-8 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or tert-butyl. When an alkyl contains more than one carbon atom, it can be unsaturated. Therefore, the term C1-6 alkyl covers C1-6 alkenyl and C1-6 alkynyl. Similarly, the term C 1-6 -alkyl encompasses C 1-6 -alkenyl and C 1-6-alkynyl, and the term C 1-6 -alkyl encompasses C 1-6 -alkenyl and C 1-6-alkynyl.

The term halogen is used to refer to fluorine, chlorine, bromine or iodine.

Unless otherwise stated, the term pei covers any aromatic, saturated or unsaturated 4-, 5- or b-membered heterocycle containing up to 4 heteroatoms selected from M, O and 5. Examples of such 70 heterocyclic groups include furyl, thienyl . , pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfozanyl, tetrazolyl, triazinyl, azepinyl, oxazapinyl, thiazepinyl, diazepinyl, and thiazolinyl. In addition, the term heterocycle encompasses fused heterocyclyls, such as benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazidinyl, benzothiazolyl, phthalimido, benzodiazepinyl, indolyl, and isoindolyl. The terms Pei, heterocyclyl, and heterocyclic are used similarly.

For the avoidance of doubt, unless otherwise specified, the term substitution means substitution with one or more specified substituents. In the case where the substituents may be selected from a number of alternative groups, the selected groups may be the same or different. The term independently means that, where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

Further, the compounds of formulas (I), (I), (I) and (IM) and their pharmaceutically and veterinary acceptable derivatives, their radiolabeled analogs, isomers, and polymorphs, are designated as "compounds of the invention." high school

In one embodiment of the invention, the compounds of the invention are pharmaceutically and veterinary acceptable derivatives of the compounds of formula (1), (I), (PI) or (IM), as pharmaceutically or veterinary acceptable salts or solvates and) compounds of formula (1), ( I), (I) or (IM), (for example, pharmaceutically or veterinary acceptable salts of compounds of formula (1), (1), (1) or (IM)).

In another embodiment of the invention, a compound of the invention is proposed, which is an inhibitor of resorption of the monoamine sosoberotonin and/or norepinephrine, having an IC50 value for ZKI or MK! of 200 nM or less. In a further embodiment, the compound has an IC50 value for ZKI and/or MKI T0ONM or less In another embodiment, the compound has an IR 50 value for C5KI or MKI 5ONM or less In another embodiment, the compound has an IR 50 value for ZKI and c

MK BONM or less. In yet another embodiment, the compound has an ICeo value for ZKI and MKI of 25 nm or less.

According to scheme 1, compounds of formula (M) can be obtained from compounds of formula (MI) by reaction with aldehyde KZ about

CHO, and then reaction with an acid or halogen anhydride B2COX (where X represents OH or halogen) and deprotection. " - with ;" (ee) («c) (95) at 50

IR e)

F) name) 60 b5

Scheme 1. Zh m o snu "MK sn) (c) - HER chv. I y p Ram mi payu zh (Khan oye payu) o s lne Shk y M A s dergabossop o "dent Pn» s Her t (ee)

VI ni t (o z Ra no - well MV . "" In the above scheme BC? and t are defined above, RO is a protective group, and the group -"SNoK satisfies the definition

Kk (a) Reductive amination (ee) The reaction of amine 12 (MI) with aldehyde to form amine 2 2 (MII) is a reductive amination reaction in which dehydration of the amine and aldehyde is followed by reduction of the formed imine with a metal hydride or hydrogenation, in a suitable solvent at room temperature temperature In this reaction, equimolar amounts of the amine and (9) aldehyde are usually treated with sodium triacetoxyborohydride (STAB), Masm(Bn)' or Mavn, in a suitable solvent (e.g. DCM, THF) at room temperature in a suitable solvent (e.g. DCM, THF) at room temperature for 1-24 hours. Alternatively, an excess of a reducing agent (e.g., Mavn, HIAIN,

IR e) ZTAV) in a suitable solvent (for example, THF, Meon, EUN) is added after mixing the amine and aldehyde for 1-18 hours, as an option, in the presence of a drying agent (for example, molecular sieves) or by removing water using the Dyna apparatus Stark with a suitable solvent (for example, toluene, xylene).

A further alternative is catalytic hydrogenation in the presence of a palladium or nickel catalyst (e.g. Pa/C, Mi KapeuF) under a hydrogen atmosphere, optionally at elevated temperature and pressure, in a suitable solvent (e.g. EN). A more specific example of reductive amination is to treat an aldehyde with an amine in the presence of 1095 Pa/sC, alternatively in the presence of triethylamine, in ethanol at about 415 kPa (about bOpsi) of hydrogen at 60 room temperature for 18 hours, or with excess sodium borohydride in methanol at room temperature for 6 hours. (B) Amide formation

The formation of a peptide bond between an acid or anhydride and an amine (MI) can be carried out using: 65 (Y) an acyl halide and an amine (MI), with an excess of an acid acceptor in a suitable solvent, or (its) acid, alternatively, a conventional coupling agent and amine (MI), optionally in the presence of a catalyst, with an excess of acid acceptor in a suitable solvent.

Examples of such reactions are: () Halide (optionally formed in situ) reacts with an excess of amine (MI), optionally with an excess of an amine Zo, such as EEZM, Hunig's base, or MMM, in DCM or dioxane, optionally, at elevated temperature for 1-24 hours; (i) acid, MZSO1/OSSI/TVT and NOVT/NOAT reacts with an excess of amine (MII) and an excess of NMUMI, EBM, Hunig's base in THF, DCM or EUdAs, at room temperature, for 4-48 hours; or (ii) acid and RUVORF/RUVGORF/Mukaiyama's reagent react with excess amine (MII) and excess MMM, 7/0. EM, Hunig's base in THF, DCM or EAs, at room temperature, for 4-24 hours.

When the halide is chloride (ie, X-CI), this can be generated in situ by standard methods and then reacted with amine (MI) and triethylamine in dichloromethane at 7023 for 90 minutes. (c) Withdrawal of protection

When RO is a suitable amino-protecting group, preferably BOC, trifluoroacetate or benzyl, removal of RO 75 From (MI) to form the unprotected amine (M) is carried out by a protective group-selective method, as detailed in ", Z'Ya edyiop, Bu TU OSgeepe and ROM UUtsiv. dopp Umieu and

Bopv, Ips., 1959, which is included as a reference).

Examples of such deprotection reactions are:

When PO is VOC, deprotection consists in treating (MIII) with an excess of a strong acid (for example, HCI, TFOK) at room temperature in a suitable solvent (for example, DCM, E(Ac, dioxane).

When PO is trifluoroacetate, the removal of protection consists in treating (MIII) with a base (for example, K 2CO3, Ma»CoO»3,

MH», Ba(onH)”) in alcohol (for example, MeonH, ЕІН), optionally with water and, optionally, at an elevated temperature.

When Po is B2, deprotection consists in transferable hydrogenation catalyzed by a transition metal or a transition metal salt (for example, Pa/C, RY(OH)") in the presence of a hydrogen donor (for example, MNANSO.) in a polar liquid SM solvent (for example, tetrahydrofuran, ethanol, methanol), optionally at elevated temperature and/or (5) pressure, or catalytic hydrogenation in the presence of a palladium or nickel catalyst (e.g., Pa/cC,

Dripping Mi) in a hydrogen atmosphere, alternatively, at elevated temperature and pressure, in a suitable solvent.

More specifically:

When PO is VOC, deprotection consists of treatment with an excess of 4M hydrochloric acid in dioxane for 18 (ee) hours at room temperature. Or with TFOK in DM for 4.5 hours at room temperature. with

When PO is trifluoroacetate, the removal of protection consists in processing K 2СО3 in a mixture of methanol: water (5:1-10:1) at room temperature for 18 hours. (ze)

When РО is B2, deprotection consists in the treatment of МН /"HCО"- and 10965 Pa/C in ethanol with careful boiling under reflux for 6-20 hours. 3о According to scheme 2, compounds of formula (IX) can be obtained from compounds of formula (MI) by reaction with KZ-I, where I is a leaving group, under suitable conditions. The compound of formula (IX) formed can then be converted into a compound of formula (II) by amide formation and deprotection in a manner similar to that described above , according to Scheme 1. and s;" (ee) («c) (95) at 50

IR e)

F) name) 60 b5

Scheme 2

IN

Br | . o Te t y de t pn adnnn nn nn sho y

Re | . and THEM

Y ve v x "H-ON og payu! sch (8)

LYA and / co

With -B8 (ze) with "in N M p M SHY o

Chergoieschop dream about "Dnieper urni iii drink iii t."

SN, (2,0) in t p. in her RO h nn Ii | | хи - с In the above scheme, B, VZ and t are defined above, RO is a suitable protecting group, and I is a leaving group, which one will depend, among other things, on the nature of the reaction and the specific reaction conditions. Suitable leaving groups will be apparent to one of ordinary skill in the art and are described in many standard reference books on organic chemistry, for example: | Admapsea Ogdapis Spetizigu", degtu Magspy, 39 Ediiop, Umieu (1985), rade 587, introduced as a reference); they

Ho) include halogen (e.g. Bg) and sulfonate esters (e.g. methanesulfonate or trifluoromethanesulfonate). Conveniently, KZ is aryl, I is Bg, and reaction (4) is carried out in a suitable solvent at elevated temperature in (4) the presence of a palladium catalyst. Such palladium-mediated aryl amination reactions are well known to those skilled in the art.

A more specific example of the method according to scheme 2 consists in the treatment of aryl bromide with an amine of the formula (MI) in

Che) in the presence of trisidibenzylideneacetone)dipalladium 2,2'-bis(diphenylphosphino)-1,1-dinaphthyl and sodium tert-butoxide in toluene at 1002 for 18 hours.

According to scheme C, compounds of formula (IX) can be obtained from ketone of formula (XII) by reaction with primary 22 amine vUZ-MNo under suitable conditions. The resulting compound of formula (IX) can then be converted into a compound of formula

Gee! (I) amide formation and deprotection in a manner analogous to that described above in Scheme 1. ime) 60 b5

Scheme Z

And we" I-mn, then t I pn vynna vnysh and Du. 2) t

Ra | ! и хи Ра их и Ж (ХаОН ог паб) sm shchi 6) . 1 p. 1 2 I. p

App

M so! Sn.) that "iy apa

Her" t u t d) ! Ra " nn Y hi - s "" In the above scheme K7, EZ and t are defined above, and RO is a suitable protecting group. The reaction (e) of the primary amine KZ-MNO with a ketone (XII) can be conveniently carried out by reductive amination, in which the dehydration of the amine and ketone is accompanied by the reduction of the formed imine, for example, with a metal hydride or hydrogenation under suitable conditions. The reaction of the amine and the ketone is conveniently carried out in the presence titanium (IM) of tetraisopropoxide in THF at room temperature for 18 hours, and then by reduction with excess sodium borohydride in methanol at room temperature for 5 hours. o A person skilled in the art simply chooses the most acceptable route for the synthesis of the desired compound of formula (I), (I), (I ) or (MI).

Ha 20 The above schemes can be unconditionally modified according to the usual general level of specialists.

For example, it will be clear to a person skilled in the art that the hydrogen attached to the piperidine or pyrrolidine nitrogen (depending on the value of t) of the unprotected amide (II) or (M) can be replaced by alternative groups that are required for the formation of compounds of formula (I), where n-1 and t-0 or 1 using conventional methods of synthesis.

In addition, compounds of formula (I) where n is 2 and m is 0 can be obtained by methods similar to those described above, using acceptable starting materials.

GF) It is clear to those skilled in the art that one or more sensitive functional groups may require protection and deprotection during the synthesis of a compound of formula (I), (II), (PI) or (IM). This can be achieved in the usual ways, for example, as described in Hrgoyesiime Sgoyrz ip Ogdapis Zupipeviv, Z'Ya eaiiop, Bu TM Sgeepe and ROM UUtsiv. Dope

UMPeu and Zopzv, Ips., 1999, incorporated by reference), which also describes methods for removing such groups. 60 It will be apparent to those skilled in the art that some protected derivatives of the compounds of the invention that can be produced prior to ultimate deprotection may not exhibit pharmacological activity as such, but may in some cases be administered orally or parenterally and then metabolized in the body to form a compound of the invention that is pharmacologically active. So derivatives can be described as prodrugs. Furthermore, some compounds of the invention may act as prodrugs for other compounds of the invention. Therefore, according to the following aspect of the invention, a method of obtaining compounds of formula (1), (II) is proposed,

(PI) or (IM), which consists in the reaction of a compound of formula (X): y sucro de KZ, n and t are defined above, and U represents K' or a protecting group, with an acid or an acyl halide

B2COX, where X represents OH or halogen, and deprotection if necessary.

When KZ includes a methylene group, which is directly attached to a nitrogen atom, then the compound of formula (X) can be obtained by the reaction of the compound of formula (XXI) with the aldehyde KUSNO (where -СНоВ"! satisfies the 29 definition of ВЗ).

MN, so ra her and ; so o p t "c)

M d) and XXI 5 s Alternatively, the compound of the formula (X) can be obtained by the reaction of the compound of the formula (XXI) with the compound KZ-Y, :z» where I is a leaving group, as an option, selected from halide, methanesulfonate and trifluoromethanesulfonate.

Further, the compound of the formula (X) can be obtained by the reaction of the compound of the formula (XXIII) with the compound KZ-MN". (ee) («c) t (C o 50 p t

IR e)

Some of the intermediates described above are novel compounds and it is understood that all novel intermediates form aspects of the present invention.

Racemic compounds can be separated using preparative HPLC and a column with a chiral stationary phase, or separated to obtain individual enantiomers using methods known to those skilled in the art. In addition, chiral intermediates can be resolved and used to prepare chiral compounds b5 of the invention.

According to the following aspect of the invention, one or more metabolites of the compounds of the invention are proposed in the formation of ip mimo.

Compounds of the invention may have advantages in that they are more potent, have a longer duration of action, have a wider range of activity, are more stable, have a reduced side effect or are more selective, or have other beneficial properties compared to compounds of the prior art.

The compounds of the invention are useful because they have pharmacological activity in mammals, including humans. Thus, they are useful in the treatment or prevention of disorders involving the regulation of monoamine transport function, more specifically, disorders involving inhibition of serotonin or norepinephrine, and especially those involving inhibition of serotonin and norepinephrine reuptake. 70 Accordingly, the compounds of the invention are useful in the treatment of urinary incontinence, such as true stress incontinence (51), stress incontinence (05I), or urinary incontinence in the elderly; overactive bladder (OAB), including idiopathic detrusor instability, detrusor overactivity secondary to neurological disease (eg, Parkinson's disease, multiple sclerosis, spinal cord injury, and stroke), and detrusor overactivity secondary to bladder outflow obstruction (eg, benign 7/5 Prostatic hyperplasia (BPH), urethral stricture or stenosis); nocturnal enuresis; urinary incontinence due to a combination of the above conditions (for example, true stress incontinence associated with an overactive bladder); and urinary symptoms such as frequency and urgency.

In view of their above-mentioned pharmacological activity, the compounds of the invention are also useful in the treatment of depression, such as adult depression, recurrent depression, single episode depression, subsyndromal symptomatic 20 depression, depression in cancer patients, depression in parkinsonism patients, depression after myocardial infarction, childhood depression, child abuse-induced depression, infertile depression, postpartum depression, premenstrual dysphoria, and geriatric grumpy syndrome.

In view of their aforementioned pharmacological activity, the compounds of the invention are also useful in the treatment of cognitive disorders such as dementia, especially degenerative dementia (including senile dementia, Alzheimer's disease

Alzheimer's disease, Pick's disease, Gentinton's chorea, Parkinson's disease and Creutzfeldt-Jakob disease) and vascular dementia (including multi-infarct dementia) and dementia associated with intracranial lesions and) trauma, infections and associated conditions (including HIV infection), metabolism , toxins, anoxia and vitamin deficiency; moderate cognitive impairment associated with aging, especially age-associated memory impairment (AAMI), a disorder causing memory impairment and age-related cognitive decline (ACO); psychotic disorders such as schizophrenia and mania; disorders with an anxiety component, such as generalized anxiety disorder, phobias (eg, agoraphobia, social phobia, and mild phobias), o panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, mixed anxiety disorders (in and depression; disorders personality disorders, such as non-contact personality disorder and attention deficit hyperactivity disorder (ADHD); sexual dysfunctions, such as premature ejaculation, male erectile dysfunction (MED) and female sexual dysfunction (E5O) (eg, sexual arousal disorder in females (ESAB)); co-premenstrual syndrome; seasonal affective disorder (SAD); eating disorders, such as anorexia nervosa and bulimia nervosa; obesity; appetite suppression; chemical drug or substance abuse dependencies, such as a tendency to nicotine, alcohol, cocaine, heroin, phenobarbital, and benzodiazepines; withdrawal syndromes such as those that can occur from the aforementioned chemical dependence; "headache such as migraine, cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with chemical dependencies or syndromes. weaning from chemical dependence, and headache with increased pressure; pain; Parkinson's disease, or something?" dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesia); endocrine disorders, such as hyperprolactinemia; vasospasm, as in the cerebral vascular system; cerebellar ataxia; Tourette syndrome; trichotillomania; kleptomania; emotional instability; pathological sobbing; sleep disorder

Go! (cataplexy); and shock

In view of their aforementioned pharmacological activity, the compounds of the invention are also useful in the treatment of a number of other conditions or disorders, including hypotension; disorders of the gastrointestinal tract (including changes in 2) motility and secretion), such as irritable bowel syndrome (IBS), ileus (eg, postoperative 5or ileus and ileus in sepsis), gastroparesis (eg, diabetic gastroparesis), peptic ulcer tract, o gastroesophageal reflux disease (GERD, or its synonym SECO), flatulence and other functional disorders from the intestines, such as dyspepsia (for example, non-ulcer dyspepsia (NOD) and non-cardiac chest pain (NSCP); and fibromyalgia syndrome.

In view of the above pharmacological activity, the compounds of the invention may also be useful in the 5B treatment of pain such as, exertional/strain pain, post-operative pain (pain after any surgical procedure), post-traumatic pain, burns, myocardial infarction, acute pancreatitis , and renal

F) colic. Also, acute pain syndromes associated with cancer, usually as a result of therapy, such as toxic chemotherapy, immunotherapy, hormonal therapy and radiotherapy. Further examples include pain associated with tumors (eg, bone pain, headache and facial pain, visceral pain) or, associated with cancer therapy (eg, post-chemotherapy syndromes, chronic post-surgical pain syndromes, post-gradation syndromes), back pain that may be due to herniated or ruptured intervertebral discs, or abnormalities of the joint surface, sacroiliac joints, paraspinal muscles, or posterior longitudinal ligament.

In addition, the compounds of the invention may be useful in the treatment of neuropathic pain, defined as pain caused by a primary lesion or dysfunction of the nervous system (definition IA5P). Nerve damage can be caused by trauma and disease, and thus the term "neuropathic pain" encompasses many disorders of various etiologies including, but not limited to, diabetic neuropathy, postherpetic neuralgia, back pain, cancer neuropathy, chemotherapy-induced neuropathy, HIV neuropathy , phantom limb pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, trauma-induced neuropathy, or vitamin deficiency.

Other types of pain include, but are not limited to: inflammatory pain, such as arthritic pain, including rheumatoid arthritis (RA) and osteoarthritis (OA), and inflammatory bowel disease (IBD); musculoskeletal disorders, including but not limited to myalgia, fibromyalgia, spondylitis, seronegative 70 (non-rheumatoid) arthropathies, non-articular rheumatism, dystophinopathy, glycogenolysis, polymyositis, pyomyositis;.

Central pain or thalamic pain, which is defined as pain caused by damage or dysfunction of the nervous system, including but not limited to central pain after stroke, multiple sclerosis, spinal cord injury, Parkinson's disease, and epilepsy;

Cardiac and vascular pain, including but not limited to angina pectoris, myocardial infarction, myocardial /5 btenosis, pericarditis, Raynaud's phenomenon, sclerodoma, skeletal muscle ischemia;

Visceral pain and gastrointestinal disorders, including pain associated with dysmenorrhea, pelvic pain, cystitis, and pancreatitis;

Headache, including but not limited to migraine, migraine with seizure precursor, migraine without seizure precursor, recurrent headache, tension headache; 200.78

Rotofacial pain, including but not limited to toothache, temporomandibular myofacial pain.

Disorders of particular interest include urinary incontinence such as mixed incontinence, true stress incontinence, stress incontinence; pain; depression; disorders with an anxiety component, such as obsessive-compulsive disorder and post-traumatic stress disorder; with personality disorders, such as ASNO); sexual dysfunction; and chemical dependence and chemical dependence withdrawal syndromes.

Therefore, according to the following aspects, the invention relates to: i) compounds of the invention for use in human medicine or veterinary medicine; i) compounds of the invention for use in the treatment of a disorder involving the regulation of the function of monoamine transport, such as urinary incontinence; ii) use of the compound of the invention in the production of a medication for the treatment of a disorder involving the regulation of monoamine transport function; with them) compounds of the invention for use in the treatment of a disorder in which the regulation of serotonin or norepinephrine is involved; at

M) use of the compound of the invention in the production of a medication for the treatment of a disorder involving the co-regulation of serotonin or norepinephrine; mi) compounds of the invention for use in the treatment of a disorder involving the regulation of serotonin or norepinephrine; mii) use of the compound of the invention in the production of a medicine for the treatment of a disorder involving the regulation of serotonin or norepinephrine; (c) compounds of the invention for use in the treatment of urinary incontinence, such as true stress incontinence or stress incontinence; ;" i) use of the compound of the invention in the production of a medicine for the treatment of urinary incontinence, such as true stress incontinence or stress incontinence; x) a method of treating a disorder involving the regulation of monoamine transport function, which

Go! consists in administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment; o xi) a method of treating a disorder involving the regulation of serotonin or norepinephrine, which consists in 2) administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment; xii) a method of treating a disorder involving the regulation of serotonin or norepinephrine, which consists in applying a therapeutically effective amount of a compound of the invention to a patient in need of such treatment;

IR e) and xiii) of a method of treating urinary incontinence, such as true stress incontinence or stress incontinence, which consists in applying a therapeutically effective amount of the compound of the invention to a patient in need of such treatment.

It is understood that all references to treatment include curative, palliative and prophylactic treatment, unless otherwise specified. The compounds of the invention can be used alone or as part of a combination therapy. If a combination of therapeutic agents is used, then the active ingredients can be used sequentially or simultaneously in boron in separate or combined pharmaceutical compositions.

Examples of suitable agents for adjunctive therapy include: an estrogen agonist or selective estrogen receptor modulator, such as NCT therapy or lasofoxifene; an alpha-adrenergic receptor agonist such as phenylpropanolamine or K-450; an alpha-adrenergic receptor antagonist (eg, phenylolamine, doxasazine , tamsulosin, terazazine, and prazazine), including the selective alpha-adrenergic receptor antagonist I, for example, Example 19

U/098/30560); a beta-adrenergic agonist (eg, clenbuterol); a muscarinic receptor antagonist (eg, tolterodine or oxybutynin) including an M3Z muscarinic receptor antagonist (eg, darifenacin); a Cox inhibitor, such as a Cox-2 inhibitor (eg, celecoxib, rofecoxib, valdecoxib, parecoxib, or etoricoxib); a tachykinin receptor antagonist, such as a neurokinin antagonist (for example, an antagonist of MK», MK», MKU); beta 3 receptor agonist; 70 5NT ligands. (for example, buspirone); a 5HT agonist, such as a triptan (for example, sumatriptan or naratriptan); a dopamine receptor agonist (e.g., apomorphine, the instructions for use of which as a pharmaceutical agent can be found in (O5-A-5345117|І), including a dopamine 02 receptor agonist (e.g., pramiprixal, a compound of MIAORMO95686RHagtasia Oriopp; or ropinirole); a melanocortin receptor agonist ( eg, melanotan I); a ROE receptor antagonist; a ROE1 agonist (eg, alprostadil); a subsequent monoamine transport inhibitor such as a norepinephrine reuptake inhibitor (eg, reboxetine), a serotonin reuptake inhibitor (eg, sertraline, fluoxetine, or paroxetine), or dopamine reuptake inhibitors a 5-NTZ receptor antagonist (eg, ondapsetron, granisetron, tropisetron, azasetron, dolasetron, or alosetron) a phosphodiesterase (POE) inhibitor such as a POE2 inhibitor (eg, erythro-9-(2-hydroxyl-3 -ponyl)-adenine or Example 100 of EP 0771799, incorporated as a reference|), and in particular a POE5 inhibitor (for example, sildenafil; ch 141843; 4-dihydro-5-methyl-4-oxo-7-propylimidazoi|5,1- il| -astrazin-2-yl)-4-ethoxyphenyl|sulfonyl)-4-ethylpiperazine, and) i.e., vardenafil, also known as Waweg VA 38-9456; or Isoz I PShu'z IKz5i, see the structure below). s n so so and | "in)

And d) « - p. y Qui (sov Qi y) (ee) The invention thus relates, according to the following aspect, to a combination comprising a compound of the invention together with the following therapeutic agent. AND

In humans, the compounds of the invention may be administered alone, but in human therapy they are usually administered in (95) admixture with a suitable pharmaceutical excipient, diluent, or carrier selected in view of the route of administration and standard pharmaceutical practice.

For example, compounds of the invention can be administered orally, buccally, or sublingually

IR e) tablets, capsules (including soft gelatin capsules), elixirs, solutions or suspensions that may contain flavorings or dyes, for immediate, prolonged, modified, sustained, dual, controlled-release or pulsatile delivery. The compounds of the invention can also be used by intracavernous injections. The compounds of the invention can also be used by rapid dispersion or rapid dissolution of dosage forms. o Such tablets may contain excipients, such as microcrystalline cellulose, lactose, sodium citrate, i.e.) calcium carbonate, dibasic calcium phosphate, glycine, and starch (mainly corn, potato or tapioca starch), disintegrants, such as sodium starch glycolate, croscarmellose sodium and some 60 complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, and gum acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be covered.

Solid compositions of this type can also be used as fillers in gelatin capsules. Preferred excipients include lactose, starch, cellulose, milk sugar, or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of the invention and their pharmaceutically acceptable salts can be combined with various sweetening or flavoring agents, colorants, emulsifiers and/or suspending agents and diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

Dosage forms with modified or pulsatile release may contain excipients as described

The above is for an immediate release form, along with additional excipients acting as release rate modifiers that are coated or incorporated into the device substance. Release rate modifiers include, but are not limited to, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, polyethylene oxide, xanthan gum, carbomer, ammonium methacrylate copolymer, hydrogenated castor oil, carnuba wax, paraffin wax, acetate phthalate 7/ 0 Cellulose, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer and their mixtures. Dosage forms with modified or pulsatile release may contain one or a combination of excipients. Excipients that are modifiers of the release rate can be in the dosage form, that is, in the matrix, and/or on the dosage form, that is, on the surface or in the coating.

Dosage compositions with rapid dispersion or rapid dissolution may contain the following 7/5 Ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropyl methyl cellulose, magnesium stearate, mannitol, methyl methacrylate, m' aromatic flavoring, polyethylene glycol, Aerosil, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The terms dispersion or dissolution used to describe fast-dispersing or fast-dissolving formulations depend on the drug substance, i.e., when the drug substance is insoluble, a fast-dispersing dosage form can be made, and when the drug substance is soluble, a fast-dissolving dosage form can be made. dissolving

The compounds of the invention can also be administered parenterally, for example, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly, subcutaneously, or they can also be administered by infusion. For such parenteral use, it is better to use them in a form that may contain other substances, for example, salt or glucose before rendering the solution isotonic with blood. Aqueous solutions should be buffered and) (preferably to pH 3-9) if necessary. Preparation of a suitable parenteral formulation under sterile conditions is readily accomplished by standard pharmaceutical methods well known to those skilled in the art.

For oral and parenteral administration to humans, the daily dose level of the compound of the invention or its salt or solvate is usually 10-500 mg (in single or divided doses).

Therefore, for example, tablets or capsules of the compound of the invention or its salt or solvate may contain about

Bmg-250mg of the active compound to be used singly, twice or more at a time as appropriate. In any case, the doctor will determine the most suitable dose for any particular patient, it will depend on the age, weight and reaction of the particular patient. The above doses are average. Of course, there may be individual cases where higher or lower doses are better, and such are within the scope of the present invention. One skilled in the art will appreciate that in the co-treatment of certain conditions (including PE), the compounds of the invention may be administered as a single dose on an "as needed" basis.

An example of the composition of tablets

In general, tablet compositions usually contain approximately 0.01mg-5000mg of a compound according to the present invention (or a salt thereof), the total weight of the tablet may be 50mg-1000mg. An example of a composition for a tablet of 10 mg is illustrated: :» in so

F

I x THIS QUANTITY IS USUALLY PROVEN ACCORDING TO DRUG ACTIVITY based on the mass of the free base. at 50

The compounds of the invention may also be administered intranasally or by inhalation and conveniently delivered in dry powder form by inhaler or aerosol spray from a pressurized container, pump or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, hydrofluoroalka, such as 1,1 ,1,2-tetrafluoroethane (NEA 134А 29 (trade mark)) or 1,1,1,2,3,3,3-heptafluoropropane (NEA 227EA Gtrade mark)), carbon dioxide or other

HF) suitable gas. In the case of a pressurized aerosol, the dose can be determined by a dosing valve. A pressurized container, pump or spray can contain a solution or suspension of the active compound, for example, using a mixture of ethanol and propellant as a solvent, which may additionally contain a lubricant, for example, sorbitan trioleate. Capsules and cartridges (made, for example, of gelatin) for use in the inhaler or insufflator 60 may contain a powder mixture of a compound of the invention and a suitable powder base, such as lactose or starch.

An aerosol or dry powder composition is preferably obtained in such a way that each measured dose contains 1-50 mg of the compound of the invention. The full daily dose from an aerosol should be in the range of 1-5Omg, it can be used during the day in a single dose or more, of course, in divided doses.

The compounds of the invention may also be formulated for nebulizer delivery. Compositions for bo nebulizers may contain the following ingredients as solubilizers, emulsifiers or suspending agents:

water, ethanol, glycerin, propylene glycol, low molecular weight polyethylene glycols, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.

Alternatively, the compounds of the invention may be administered in the form of a suppository or pessary, or they may be administered topically in the form of a gel, hydrogel, lotion, solution, cream, ointment, or spray powder.

The compounds of the invention can also be applied dermally or transdermally, for example by applying a skin patch. they can also be administered by ocular, pulmonary, or rectal routes.

For ophthalmic use, the compounds may be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline, or preferably as solutions in isotonic, pH-adjusted, 7/0 sterile saline, optionally in combination with a preservative such as is benzylalkonium chloride.

Alternatively, they can be formed in ointments, such as petroleum jelly.

For topical application to the skin, the compounds of the invention may be formulated as a suitable ointment containing the active compound suspended or dissolved, for example, in admixture with one or more of the following: mineral oil, liquid petroleum jelly, white petroleum jelly, propylene glycol, polyoxyethylene polyoxypropylene, emulsifying wax and /5 Water. Alternatively, they may be formulated as a suitable lotion or cream, suspended or dissolved, for example in admixture with one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 50, cetyl esters, wax cetearyl alcohol, 2-octyldodecanol , benzyl alcohol and water.

The compounds of the invention can also be used in combination with cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drugs. The formation of a drug-cyclodextrin complex can modify the solubility, dissolution rate, bioavailability and/or stability of drug molecules. Drug-dcyclodextrin complexes are generally useful for most dosage forms and routes of administration. As an alternative to direct complexation with drugs, cyclodextrin can be used as an auxiliary additive, for example, as a carrier, diluent or solubilizer. Alpha-, beta-, and gamma-cyclodextrins are the most commonly used, and suitable examples are described in (|MO-A-91/11172, UUO-A-94/02518 and

UKO-A-98/551481. and)

For oral or parenteral administration to humans, the levels of daily doses of compounds of formula (I) and their pharmaceutically acceptable salts are 0.01-3Omg/kg (in single or divided doses), and preferably 0.01-5mg/kg.

Thus, the tablets contain 1 mg-0.4 g of the compound for single or double or more administration, as appropriate. co

The physician will determine the appropriate dose for any particular patient in any case based on the age, weight and response of the particular patient. The above doses are average. Of course, there may be cases where higher or lower doses are better, and such are within the scope of the present invention. Oral use is preferred. with

For veterinary use, the compound of the invention is used as a suitable acceptable composition in accordance with normal veterinary practice, and the veterinarian will determine the most acceptable dosage regimen and route of administration for a particular animal. co

Thus, according to the following aspect, the invention relates to a pharmaceutical composition containing a compound of the invention and a pharmaceutically acceptable adjuvant, diluent or carrier.

The above combinations may also conveniently be used in the form of a pharmaceutical composition, and thus pharmaceutical compositions containing the combination as defined above together with a pharmaceutically acceptable adjuvant, diluent or carrier form a further aspect of the invention. Individual components of such 7-3 combinations can be used sequentially or simultaneously in separate or combined pharmaceutical compositions. ;" When a compound of the invention is used in combination with another, the therapeutic dose of each compound may be different than when the compound is used alone. Acceptable doses are clear to experts.

The invention is illustrated by the following non-limiting examples, where the following abbreviations and

Go! definition: (ав) HIAT chemical ionization at atmospheric pressure with Agrasea filter medium g wide and95) vos tert-butoxycarbonyl CO CO carbonyldiimidazole 5 chemical shift a doublet

A heat of dew dicyclohexylcarbodiimide iF) dhm dichloromethane ko dMF M,M-dimethylformamide

DMSO / dimethylsulfoxide 60 EP" electrospray ionization positive scanning

ER- ionization by electrospray negative scanning

NOAT 1-hydroxy-7-azabenzotriazole new 1-hydroxybenzotriazole

HPLC high performance liquid chromatography b5 t/x peak mass spectrum

Mo mass spectrum

MM M-methylmorpholine

NM nuclear magnetic resonance and a quartet with a singlet

And triplet tvty 2-(1H-benzotril-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate te trifluoromethanesulfonyl tek trifluoroacetic acid tgF tetrahydrofuran

TLC thin-layer chromatography, thermospray ionization, positive scanning

M/5SOI 0/0 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide chloride

The invention and Examples illustrating the invention are not intended to limit the invention in any way. All temperatures are given in EC.

Flash chromatography was performed using silica gel Megsk 60 (9385). Chromatography by solid phase extraction (PE) was performed using Magiap Meda Wopa Eishi cartridges (51) (Apaspet) under a vacuum of 15 mm Na.

Thin-layer chromatography (TLC) was performed on silica gel tablets Megsk 60 (5729). The melting point was determined using the Sayepkatr MROZBO apparatus and was not corrected. NMR was performed using a 400MHz Magiap-Opiu oIpsma spectrometer or a 400MHz Magiap Megsigu spectrometer.

Mass spectroscopy was performed using a Rippidap Mamidag single-quadrupole mass spectrometer with electrospraying or a Rippidap aSa ARSI mass spectrometer.

Obtaining 1 cm of tert-butyl (35)-1-"(trifluoroacetyl)pyrrolidin-3-ylcarbamate (5) with

(3K)-3-(tert-butoxycarbonylamino)pyrrolidine (3.0g, 16b, 1mmol), which is commercially available from Kygospept), sv) c and pyridine (3, 87 ml, 48.3 mmol) was dissolved in dichloromethane (55 ml) and the reaction mixture was stirred under nitrogen. at 02 for 1 hour. A solution of trifluoroacetic anhydride (2.64 mL, 32.2 mmol) in dichloromethane (bmL) was added dropwise to the reaction mixture over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was diluted with dichloromethane (1000 OmL) and washed with saturated sodium hydrogencarbonate solution, water and then brine.The organic layer

Ge | separated, dried over magnesium sulfate and concentrated in vacuo. The crude product was azeotropically distilled with otoluene (2x3Oml), obtaining the title product. NMR (DMSO-O5, 400MHz): 1.40 (in, 9H), 1.82 (44, 71H), 2.08 (da, yin), 3.33 (t, 1H), 3.46 (t, 1H), (95) 3.59-3.67 (rpt, 2H), 4.06 (t, 1H), 7.22 (t, 1H) syu 50 MS ER» t/z 281 (MNI "

Receiving 2

IR e) (3K)-1-"Trifluoroacetyl)pyrrolidin-3-amine chloride

F) name)

The Bos-protected amine from the preparation of 1 (4.59g, 16.1mmol) was dissolved in dichloromethane (100ml) and the reaction mixture was stirred at 02C for 1 hour. Hydrogen chloride gas was then bubbled through the solution for 10 minutes and the reaction mixture was allowed to warm to room temperature. Hydrogen chloride gas and nitrogen gas were then bubbled through the solution for 15 and 10 minutes, respectively, and the reaction mixture was concentrated in vacuo to give the title product.

T"H NMR (SOCI5, 400 MHz): 1.27 (t, 2H), 1.65 (t, 1H), 1.81 (t, 1H), 2.10 (t, 2H), 3.32 ( t, 2H), 3.61 (t, 1H)

MS ER" t/z 183 (MNI"

Obtaining tert-butyl (35)-3-(isobutylamino)pyrrolidine-1-carboxylate p 18 sn, .

U-c (8) (35)-3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (Zg, 16b, 1mmol) was added to a solution of isobutyraldehyde (1.61ml, 17.bmmol) and 1095 Pa/C ( 3bOmg) in ethanol (bOml) and the reaction mixture was allowed to stand at about 415 kPa (about bOlbs/sq.in.) of hydrogen for 18 hours. The reaction mixture was filtered through Agrosey?, washed well with ethyl acetate. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate: pentane 1:11, to give the title product, 2.8 g, (7390). "YAN NMR (SOSI5, 400 MHz): 0.92 (9, 6H), 1.44 (z, 9H), 1.83 (t, 2H), 2.00 (t, 1H), 2.39 (t , 2H), 3.02 (t, (F 1H), 3.25 (t, 2H), 3.48 (t, 2H), 3.6O(t, 1H) so

MS HIAT"- 243 MN")

Preparation of 4 (35)-M-butyl-1-trifluoroacetyl)pyrrolidin-3-amide « z - c . su and SU and o («c) oz 2. syu 20 E Ya

IR e)

Triethylamine (1.9 ml, 13.62 mmol) and butanal (1.3 ml, 14.4 mmol) were added to a solution of (5)-1-trifluoroacetyl)pyrrolidin-3-ylamine (33.0 g, 13.62 mmol) U. May Spet., 1996, 39(14), ro, 2771, Mob) in ethanol (bOml). The reaction mixture was treated with 1095 Pa/C (30 Ωg) and held at about 415 kPa (about 415 kPa) of hydrogen at room temperature for 18 hours. The reaction mixture was filtered through

Agrose!F, washed with ethyl acetate. The filtrate was washed with saturated sodium hydrogen carbonate solution, dried with 60% magnesium sulfate and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with a mixture of ethyl acetate:pentane:triethylamine 25:75:0-100:0:0-99:0:1, to give the title product.

TN NMR (SOCIz, 400 MHz): 1.01 (5 ЗН), 1.38 (t, 2Н), 1.47 (t, 2Н), 1.86-2.09 (t, 2Н), 2.62 (t, 2H), 3.38-3.87 (rgt, 6H)

MS HIAT t/2 239 МН 65 Obtaining 5 (35)-M-zobutyl-1--'trifluoroacetyl)pyrrolidin-3-amine with 70 U-

OH

This compound was prepared in a manner similar to that described for 4 using isobutyraldehyde. "IN NMR (SOSIz, 400 MHz): 0.91 (, 6H), 1.26 (a, 2H), 1.47 (t, 2H), 1.62 (t, 1H), 2.42 (t, 2H), 3.39 (t, 2H), 3.67 (t, 1H), 4.09 (171, 1H)

MS HIAT pt/ 239 (MN

Preparation of 6 (35)-1-Benzyl-M-(2-naphthylmethyl)pyrrolidin-3-amine from 7 to 7 "c) d) ; "shi s. » A solution of 2-naphthaldehyde (2.0g, 12.8mmol) and (35)-benzyl-3-amino-pyrrolidine (2.37g, 13.4mmol) in methanol (30ml) was stirred under nitrogen at room temperature for b hours. Sodium borohydride (969mg, 25.mmol) was added and the reaction mixture was left at room temperature for 18 hours. The reaction (ee) was diluted with water and extracted into ethyl acetate (x3) and the organic products were combined, dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with dichloromethane:methanol 100:0 to 97:3, to give the title product, 4.01 g. o "YAN NMR (SOSIv, 400 MHz): 1.62 (t, 1H), 2.19 (t, 1H), 2.48 (t, 2H), 2.80 (t, 2H), 3.42 ( t, 1H), 3.63 (z, oo 20 2H), 3.92 (t, 2H), 7.26 (t, 5H), 7.44 (t, ЗН), 7.68 (t, 4H )

MS HIAT m/z 317 МН" so Preparation of 7 (3K)-1-Benzyl-M-(2-naphthylmethyl)pyrrolidin-3-amine

F) name) 60 b5 r pe o

The title compound was prepared in a manner similar to that described for 6 using (35)-1-benzyl-3-amino-pyrrolidine.

TN NMR (SOCI3, 400 MHz): 1.65 (t, 1H), 2.18 (t, 1H), 2.51 (t, 2H), 2.68 (t, 2H), 3.41 (t, 1H), 3.63 (t, 2H), 3.94 (v, 2H), 7.22 (t, 1H), 7.28 (t, 4H), 7.43 (t, ЗН), 7, 69 (t, 4H)

MS HIAT t/2 317 MN

Preparation of 8 (35)-M4-(3,4-Dichlorobenzyl)-1-(trifluoroacetyl)pyrrolidin-3-amine c a (8) c so co «c) d) o « shi c This compound was obtained by a method similar to that described in obtaining 6, using the amine from obtaining 2 and c 3,4-dichlorobenzaldehyde. ,» "IN NMR (DMSO-Ov, 400 MHz): 1.88 (t, 2H), 2.63 (t, 1H), 3.36-3.68 (t, 7H), 7.32 (t, 1H), 7.59 (t.2H)

MS HIAT p/g 341 (MN

Preparation of 9 (ee) (35)-M-(2,3-Dichlorobenzyl)-1--'trifluoroacetyl)pyrrolidin-3-amine («c) (95) o 50 so "Y 25 | p

F) "E 60 E b5

This compound was prepared in a manner similar to that described for 6, using the amine from 2 and 2,3-dichlorobenzaldehyde. "IN NMR (DMSO-O,, 400 MHz): 1.92 (t, 2H). 3.25-3.64 (t, 7H), 3.83 (t, 1H), 7.27 (t, 1H ), 7.51 (t, 2H)

MS HIAT p/g 341 (MN

Receiving 10-12

Х сн, че m сн, | her village

The acceptable carboxylic acid KSO2H (mmol) was dissolved in dichloromethane (5 mL), cooled in an ice bath (He) and the solution was cooled and treated with oxalyl chloride (0.248 mL, 2.bmmol) and 1 drop

M,M-dimethylformamide. The ice was removed and the reaction mixture was allowed to warm to room temperature and then stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the product was added to a solution of triethylamine (0.229 mL, 1.64 mmol) and the amine from the preparation of C (200 µg, 0.8 µmol) in dioxane (1 µl). co

The reaction mixture was heated to 702 for 45 minutes and then allowed to cool to room temperature.

The reaction mixture was concentrated in vacuo and the product was taken up in dichloromethane and washed with 1095% citric acid solution and 2M sodium hydroxide solution. The organic layer was separated and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with a mixture

From dichloromethane:methanol 100:0 to 98:2 to give the title products. so sv 00060000

MO HIAtT I tig 295 1MNI « s ;» " M, NYAMe (SOS. 400 MHz): A mixture of Goyamara

E O,68, 0,98 (min, VN), 1,42,1,44 (Zk, ZN), so 7T,58-2,50 (t, VNU 2,58-4,65 (t, 6H ), 4.08, o « MZa (2kht, 7H), 8.96 (t, 1), 7.03 (t, 1H), io 7.20 (ti NI) o 50

MO HIT those 279 |MNI"

IR e) sn Y. MO HIT bird 291 IMNG

Gee!

F) name)

Preparation of 13 60 tert-Butyl (35)-3-(2,3-dichlorobenzoyl)(isobutyl)amino|pyrrolidine-1-carboxylate b5 yiv sy, -

Kk p

The amine from C (200 mg, 0.82 mmol) was added to a solution of triethylamine (0.229 mL, 1.652 mmol) in dioxane (b mL), and the reaction mixture was treated with 2,3-dichlorobenzoyl chloride (207 mg, 0.99 mmol). The reaction mixture was heated to 702 and stirred for 90 minutes. The reaction mixture was concentrated in vacuo and the product was taken up in dichloromethane and washed with 2M sodium hydroxide and 1095 citric acid solution. Organic products were carefully separated and concentrated in a vacuum. The crude product was purified by silica gel column chromatography eluting with dichloromethane to give the title product, 278 mg, (81905). at

MS HIAT t/2 315 |MNI

Obtaining 14-17 s so

In o ni sia so , n shi s z . and at sleep

With n, (ee) o The following compounds of the general formula above were obtained by a method similar to that described in the preparation of 13, c using the amine from the preparation of C and an acceptable halogen chloride: o 50

IR e)

F) name) 60 b5

Because NNYA s; MON

WHAT | What | "I NMR (SOSI;, 400 MGu): poor resolution: 0.68 (68, 8H), 1.37

FI (in, 9H), 2.00 (Bgp, ЗН), 2.41 (8, 1Н), 3.04 (bt, ЗН), 3.43 (bt, 2Н), 4.19 (bit, 1Н ), 7.14(d, 1), 7.23 (t, ЗН) more MS HIAT t/x 281 (MH "H NMR (SOS, 400 MG): poor resolution 0.68 (z, 8H), 1 ... rt, 2H), 4.20 (bt, 18), 7.21 (y, 2H), 7.28 (d, 24) MS HIAT" t/2 281 ; part of division: MS HIAT--t/2315IMNI v z g so so "c) d)

Preparation of 18 -(35)-1-Benzylpyrrolidin-3-yl|-M-(2-naphthylmethyl)benzamide "shi c"" 7 (ee) («c) (95) o 50

IR e)

Benzoyl chloride (0.12 mL, 1.043 mmol) was added to a solution of the amine from 8 (30 mg, 0.948 mmol) and triethylamine (0.2 mmol, 1.89 mmol) in dichloromethane (mL), and the reaction mixture was left under nitrogen at room temperature at 60 temperature for 18 hours. The reaction mixture was washed with water and then brine, dried over magnesium sulfate and concentrated in vacuo to give the title product, 38Omg. "YAN nMR (SOSI5, 400 MHz): 1.83-2.62 (rpt, 4H), 2.84 (t, 2H), 3.62 (t, 2H), 4.56 (t, 1H), 5 .05 (t, 2H), 7.24 (t, 4H), 7.31-7.60 (t, 9H), 7.68 (t, 4H)

MS ER t/72 421 |MNI bo Receiving 19

IM-(35)-1-Benzylpyrrolidin-3-yl-N-(2-naphthylmethyl)benzamide

WITH

The title compound was prepared using a method similar to that described for the preparation of 18 using amine 75 from the preparation of 7.

TN nMR (SOSIS, 400 MHz): 1.94-2.58 (rgt, EN), 2.86 (t, 2H), 3.62 (t, 1H), 5.08 (t, 2H), 7, 23 (t, 4H), 7.34-7.60 (t, 9H), 7.69 (t, 4H)

MS HIAT t/2 421 |NAMES

Receiving 20

M-butyl-M-((35)-1-"trifluoroacetyl)pyrrolidin-3-yl|-1-naphthamide

She is with so

And with "c) d)

E « - ZHE - c This compound was obtained by a method similar to that described for the preparation of 18, using the amine from the preparation of 4: c» and 1-naphthoyl chloride.

TN nMR (SOCI3, 400 MHz): 0.61 (t, 2H), 0.98 (t, 3H), 1.32-1.80 (rgt, 4H), 3.06 (t, 2H), 3, 27-3.66 (t,

ЗН), 5.28 (t, 1Н), 7.39 (t, 1Н), 7.45 (t, ЗН), 7.62 (t, 1Н), 7.89 (t, 2Н) about MS HIAT pt/: 393 (MN

Obtaining 21 o M-isobutyl-M-((35)-1-"trifluoroacetyl)pyrrolidin-3-yl|-2-naphthamide (95) o 50 a so | sn, 2 -

F) has) 60 in still

This compound was prepared in a manner similar to that described for 18, using 1-naphthoyl chloride and the amine from 3. "NMR (SOS, 400 MHz): 0.84 (t, 8H), 2.00 (t, 1H), 3 .25 (t, 2H), 3.93 (t, 2H), 4.38 (rgt, 1H), 5.31 (t, 2H), 7.24 (t, 2H), 7.38-7, 82 (t, 5H)

MS HIAT t/:2 393 MNI"

Preparation of 22 4-Chloro-M-(3,4-dichlorobenzyl)-M-((3K)-1-"-trifluoroacetylpyrrolidin-3-ylIsSenzamide chigoryo

The amine from 8 (180mg, 0.58mmol) was dissolved in dichloromethane (3ml) and the reaction mixture was treated with triethylamine (0.1bml, 1.1bmmol). The reaction mixture was cooled to 09C and 4-chlorobenzoyl chloride (0.08 ml, 0.6 mmol) was added dropwise. The reaction mixture was stirred under nitrogen for 18 hours. co

The reaction mixture was further diluted with dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane:methanol 100:0-95:5, obtaining the title product. co "IN NMR (DMSO-O5, 400 MHz): 2.02 (t, 2H), 3.37-3.62 (t, AN), 4.61 (t, 2H), 5.68 (t, 1H ), 7.22-7.59 (t, 7Н)

MS HIAT t/2 479 MH" o z Obtaining 23 so 4-Chloro-M-(2,3-dichlorobenzyl)-M-|((35)-1-"-trifluoroacetyl)pyrrolidin-3-yl|IbSenzamide « shi with ;" This compound was obtained by a method similar to that described for the preparation of 22, using the amine from the preparation of 9. H NMR (DMSO-O5, 400 MHz): 2.04 (t, 2H), 3.37-3.68 (t, 4H), 4.46-4.66 (t, ZH), 7.22-7.58 (bgt, 7H)

MS HIAT t/: 479 MNI"

Example 1

HF) 2,3-Dichloro-M-isobutyl-M-(35)-pyrrolidin-3-yl|IbSenzamide citrate ime) 60 b5 o chX "ek van . -

The Bos-protected product from 13 (10.55g, 25.4mmol) was dissolved in dichloromethane (20ml) under nitrogen and the reaction mixture was treated with trifluoroacetic acid (20ml, 260.5mmol). The reaction mixture was then stirred at room temperature for 4.5 hours. The reaction mixture was concentrated in vacuo and the residue was taken up in dichloromethane (200ml) and washed with 1M sodium hydroxide solution (100ml). The organic phase was separated, dried with magnesium sulfate and concentrated in vacuo. The residue was azeotroped with ethyl acetate (10x) and then dried in vacuo to give the free base of the title product as a colorless oil, 7.281g (91965). Another portion of this product (3.327g, 10.5bmmol) was treated with a solution of citric acid (2.028g, 10.5bmmol) in methanol, concentrated in vacuo and dried under high vacuum to give the title product as a pink solid, 4.61g. "NN NMR (MeO0, 400 MHz): 0.80 (Hi, 6H), 1.89 (t, 2H), 2.11 (rgt, 2H), 2.53 (t, 2H), 2.68-2 .91 (t, 4H), 3.59 s 29 (t, 1H), 3.82 (t, 2H), 4.37 (t, 1H), 7.40 (t, 2H), 7.61 ( t, 1H) Ge)

MS HIAT t/z 315 MN"

Example 2 2,4-Dichloro-M-zobutyl-M-(35)-pyrrolidin-3-yl|Ibsenzamide hydrochloride so so . so with | "c) 7 so m SU nOe " " and o s. ;" The BOC-protected product from 14 (157mg, 0.561mmol) was added to a solution of 4M hydrochloric acid in dioxane (1ml) in dichloromethane (bml) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the product was azeotroped with dichloromethane and ether, and then triturated with ether to give the title product, 103 mg, (87905). av) NMR (MeO0O, 400MHz): 0.80 (t, 6H), 1.89 (t, 1H), 2.51 (t, 2H), 2.90 (t, 1H), 3.20 (t, 2H), 3.52 (t, o 1H), 3.68 (t, 2H), 4.30 (t, 1H), 7.40 (t, 1H), 7.46 (y, 1H ), 7.58 (in, 1H)

MS HIAT t/2 315 | MNI oz 20 Examples 3-8

IR e) x

Ф) and not 60 The following compounds of the general formula above were obtained by a method similar to that described in example 2, obtaining the chloride of the compound: b5

BsKSVY NNNNNNNNNYA NNNNNNNo ; i "NO NMR (MeO0, 400 MHz): 0.80 (t, 6H), 1.91 (t, 1H), 2.41 (8,

ZN), 2.54 (t, 2H), 2.88 (t, 1H), 3.20 (t, 2H), 3.53 (t, 1H), phi 3.69 (t, 2H), 4 .34 (ha, 1H), 7.20 (a, 1H), 7.32 (KN), 7.41 (a, o 1n)

MS HIAT - t/h 295 (MN

H, "H NMR (MeO0, 400 MHz): 0.80 (a, 6H), 1.90 (ip, 1H),

E 2.20 (8, ЗН), 2.53 (t, 2Н), 2.97 (t, 1Н), 3.20 (t, ЗН), 3.54 (I, 1Н), 3.69 ( t, 1H), 4.32 (t, 1H), 7.06 (685, 1H), 7.16 (, 1H), 7.30 (d, 1H)

MS HIAT" t/2 279 (MH tv, "NA NMR (MeO0, 400 MgHu): 0.88 (a, EN), 1.88 (ip, 1H), se; 2.12 (a, ZN), 2.53 (t, 2H), 2.38 (t, 1H), 3.16 (p, 1H), sc 3.22 (t, 1H), 3.52 (t, 1H), 3.68 ( t, 2H), 3.88 (c, ЗН), o 4.30 (t, 1H), 6.80 (a, 1n), 7.00 sa, 1H), 7.23 (0 18)

MO-HIAT t/2291 (MH so that CHU TN-NMR (meО0b, 400 MHz): 0.83(4. 6), 1.91(t, 1Н), so

Shchi 2.52(t, 2H), 3.15(y, 2H), 3.22(t, 1H), 3.55(1, 1H), She

Z,bb(t, 2H), 4.32(etc, 1H), 7.38(d, 1H), 7.50(pt, ZY) o r)

MS ER» t/x 281 IMNI 7 "N YAME (MeObr, 400 MHzxuh 0.82(a, 6H), 1.92(t, 1H), f 2.53(t, 2H), 3.29(a, 2H ), 3.25(t, 18), 3.54(, МН), 47 of them with 3.v6(t, 2Н), 4.30(t, 1Н), 7.25(99, 4Н) :» MO ER t/h 281 (MNI" 7 "I NMR (MeO0, 400 MHz): 0.82(4, 6H), 1.91(t, tn), o fi 2.8tst, 2), 31590, ZN ), 3.51 (i TTN), 3.620(t, 2H), o C Az (li, NU, 7, Z5(, 1H,, 7, bB(t, 2H) with 50 so MO ER nt/2315IMNG

Example 9

M-(2-Naphthylmethyl)-M-|((35)-pyrrolidin-3-ylIbSenzamide chloride

F) name) 60 b5

-

A solution of the benzyl-protected product from 18 (37Omg, 8v8mmol), aminonium formate (555mg, 8.798mmol) and 10965 Ra/C (40mg) in ethanol (bml) was heated at reflux under nitrogen for 8 hours. The reaction mixture was filtered through Agrosey?, washed with ethanol, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with a mixture of dichloromethane:methanol:0.88 ammonia 100:0:0-90:10:1. The product was dissolved in a minimum solution of ethereal hydrochloric acid in dichloromethane and concentrated in vacuo. The product was triturated with ether (x3) and dried in vacuo to give the title product, 12Omg, (38905). NMR (DMSO-O5, 400MHz): 2.08 (t, 2H), 2.98 (rg5, 1H), 3.69 (t, 3H), 4.43 (t, 1H), 4.61 (t, 2H), 7.25-7.59 (t, 9H), 7.68 (t, 1H), 7.93 (t, ЗН) s

MS HIAT t/z 331 MN" o

Example 10

M-(2-Naphthylmethyl)-M-|((35)-pyrrolidin-3-ylIbSenzamide chloride c so co «c) d) for 4 sh s The title compound was obtained using a method similar to that described in, for example, 9, using h » benzyl-protected product of obtaining 19 as starting material, 1bOmg, (4795), the title product was collected. " TN nMR (DMSO-O5, 400 MHz): 2.11 (t, 2H), 3.00 (t, 1H), 3.35 (rgt, ЗН), 4.44 (t, 1H), 4.68 (t, 2H), 7.28-7.56 (rgt, 9H), 7.81 (t, 1H), 7.96 (t, ЗН)

MS ER" t/g2 331 MNI" because Example 11 av! M-isobutyl-M-((35)-pyrrolidin-3-yn-2-naphthamide hydrochloride o g syu so sn, 2 i on,

GF) and name)

BUT

60 J

Potassium carbonate (92 mg, 0.6 mmol) was added to a solution of the trifluoroacetate-protected product 21 (130 mg, 0.3 mmol) in water (0.0 mmol) and methanol (bmL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product was dissolved in a mixture of b5 1095 potassium carbonate solution: ethyl acetate 1:1 (25 ml). The organic phase was dried with magnesium sulfate and concentrated in vacuo. The crude product was dissolved in ethyl acetate, treated with 1M hydrochloric acid in ether and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to give the title product.

TN NMR (MmeO0, 400 MHz): 0.69 (9, 6H), 1.93 (t, 1H), 2.56 (t, 2H), 3.25 (t, ZN), 3.55 (I, 1H), 3.30 (t, 2H), 4.36 (t, 1H), 7.48 (y, 1H), 7.59 (t, 2H), 7.96 (t, 4H)

MS ER" t/:2 298 MN"

Example 12

M-Butyl-M-(35)-pyrrolidin-3-yl|-1-naphthamide hydrochloride o

F U ten

CHO, no 'M

This compound was obtained by a method similar to that described in Example 11, using the trifluoroacetate-protected product from 20 as starting material. sc "YAN NMR (meO0b, 400 MHz): 0.62 (t, ЗН), 1.04 (t, 2Н), 1.62 (t, 2Н), 2.65 (t, 2Н), 3.07 ( t, 2H), 3.21 (t, 1H), 3.59 (t, 1H), 3.87 (t, 2H), 4.42 (t.1H), 7.30 (v, t, 1H ), 7.57 (t, ZN), 7.68 (t, 1H), 8.00 (t, 2H) and)

MS ER" t/z 297 |MNI"

Example 13 4-Chloro-M-(3,4-dichlorobenzyl)-M-(ZK)-pyrrolidin-3-yl|IbSenzamide chloride (ee) yl paio PP CHI chn. so a so o | "c) d) "I " shi s p n (ee)

This compound was obtained by a method similar to that described in example 11, using trifluoroacetate-protected product 22 as starting material. Collected 75mg, (4795), of the title product. o "YAN NMR (DMSO-Ov, 400MHz): 1.5 8(t, 1H), 1.83 (t, 1H), 2.60 (t, 1H), 2.81 (t, 2H), 3 .42 (t, 2H), 4.61 50. (t, 2H), 7.25 (t, 1H), 7.39-7.59 (t, 7H) o Example 14 (Che 4-Chlor-M -(2,3-dichlorobenzyl)-M-(35)-pyrrolidin-3-yl|IsSenzamide chloride m

F) then she is 60

This compound was prepared in a manner similar to that described in Example 11, using the trifluoroacetate protected product of 23 as starting material, 9Omg, (52905), the title product was collected. "H NMR (DMSO-O5, 400 MHz): 1.62 (t, 1H), 1.88 (t, 1H), 2.61 (t, 2H), 2.85 (t, 2H), 4.28 (t, 1H); 4.59 c; (2H), 7.24 (t, 1H), 7.36 (t, 1H), 7.42-7.58 (t, 6H)

MS ER" t/: 385 |MNI"

Example 15 2,4-Dichloro-5-fluoro-M-isobutyl-M-((35)-pyrrolidin-3-yl|IsSenzamide chloride and nature» sn, - . g tu h ) o sv,

Tert-butyl 1351-3-(2,4-dichloro-5-fluorobenzoyl)(isobutyl)amino|pyrrolidine-1-carboxylate was obtained by a method similar to that described for the preparation of 13, using the amine from the preparation of 3 and 2 ,4-dichloro-5-fluorobenzoyl chloride, obtaining the desired product, 34Omg.

MS ER t/: 455 |MMa/)". 2,4-Dichloro-5-fluoro-M-isobutyl-M-((35)-pyrrolidin-3-yl|isenzamide chloride was obtained from the above compound by a method similar to that described in example 2 to form the title product as a whitish solid product, 10Omg.

MS HIAT t/: 333 MNI.

Found: C, 47.22; H, 5.87; M, 7.0895. Calculated for C 45NloSiOEM20. NSI.O,6NhO: C, 47.17; H, 5.64; M, Ge! 7,339.

Example 16 Fr

IR value 50 MK! and IR;o ZKI of the compounds of examples 1-14 were determined as follows. The results are presented in the table below.

Biological activity of

The compounds were tested for biological activity by their ability to inhibit the uptake of serotonin and/or norepinephrine by human serotonin and/or norepinephrine transporters as follows. (Y) Cell cultivation (ze)

Human embryonic kidney cells (NEK-293) stably transfected with human serotonin transporter (YAZECT), norepinephrine transporter (MET) or dopamine transporter (PSAT) were cultured by standard cell culture methods (cells were grown at 372C and 595 СО» in modified 0

Dulbecco's Eagle's culture medium (OMEM) supplemented with 1095 dialyzed fetal calf serum (FSC), 2 mM I-glutamine and 250 μg/ml geneticin (AYAZECT and PMET cells) or culture medium

OMEM supplemented with 595 NWT, 596 serum of a newborn calf, 2MM I! -glutamine and 2.5 mg/ml puromycin (NBAT cells). Before the study, cells were collected by separation using cell separation solution (Zidta) and centrifugation and resuspended in standard study buffer (see below) at a viable cell density of 75,000 cells/ml. h (Y) Determination of inhibitor potency All test compounds were dissolved in 100956 DMSO at 4 mM and diluted with 195 DMSO in water, obtaining acceptable test concentrations. The research was carried out in 96-cell tablets with a filter bottom. Cells expressing acceptable human transporter protein (75,000 cells/cell) were preincubated at 259C in standard assay buffer containing test compound, standard inhibitor (positive control), or vehicle compound (DMSO in water; final DMSO concentration was 0.195 in each cell) for 5 minutes. The reactions were started by adding the substrates НН-serotonin, НН-norepinephrine or НН-dopamine. All reactions were carried out at 25202 in an incubator with shaking. The incubation time is 5 minutes for the AZECT and PAT studies and 15 minutes for the 20 TENT study. Reactions were stopped by adding ice-cold wash buffer (see below), after co-filtering the mixture using a vacuum manifold and quickly washing with ice-cold wash buffer. The amount of ZN substrate introduced into the cells was then determined: Filtered/washed tablets were dried at 459C for 1 hour, scintillation liquid was added, and radioactivity was measured by scintillation counting. The potency of the test compounds was determined as the IR 50 value (the concentration of the test compound required to inhibit the specific uptake of the radiolabeled substrate by cells by 5095 relative to the maximum (only (F) vehicle compound) and the minimum response (complete inhibition by the standard inhibitor). d (ii) Composition standard buffer for research:

Tris(hydroxymethyl)aminomethane chloride (2b6mM) by weight (124mM)

KSI (4.5 mm)

KNoRO, (1.2 mM)

MasI".-6NoO (1.3MM)

Ascorbic acid (1.13 mM) v5 Glucose (5.55 mM) pH 7.40

Sasi. (2.8mm)

Pargipine (10µM)

Note: The pH of the buffer was adjusted to 7.40 with 1M Mahon prior to the addition of Sasi' and pargyline.

The composition of the washing buffer:

Tris(hydroxymethyl)methylamine (2bmM) mass (124mM)

KSI (4.5 mm)

KNoRO, (1.2 mm) 70 Mass", 6H2O (1.3 mm)

Ascorbic acid (1.13bmM) pH 7.40 at 42С with EM NOSI (m) Summary of parameters of the study и5 00000001 Study p8ECT Study LOAT | NMET research

Priledg| 96 | вв сч о со зо о ne о з5 со

It is convenient to isolate the compounds of the invention in the form of a free base, but it is possible to obtain pharmaceutically acceptable acid-addition salts of the compounds of the invention using conventional means. Solvates (for example, hydrates) of compounds of the invention can be formed in one of the above-mentioned steps of the method.

Claims (1)

;" The formula of the invention Ge | 1. The compound of the formula (I) o , y 0) c shk c: "pk o edu i pr, c I e and its pharmaceutically and/or veterinary acceptable derivatives, where F) B71- n; ko B? - aryl or heteroaryl , each of which, as an option, is substituted by at least one substituent independently selected from the group: C.v.-alkyl, C.v.-alkyloxy, OH, halogen, CEz, OSEz, ZSE", hydroxy-C.4v-alkyl, 60 Ci 4-Alkoxy-C4-alkyl and C-4-Alkyl-C-C-4-alkyl; BZ -- C-C-alkyl, C-C-cycloalkyl, C-C-cycloalkyl-C-C-alkyl , aryl, C 1 , aryl-C 4 -alkyl or C 1 -C 4 -alkyl, where the cycloalkyl, aryl, or Her group is optionally substituted with at least one substituent independently selected from the group: C 1 -C 4 -alkyl, C 1 -C 4 -alkyl, OH, halogen, CEz, OSE5, ZSE»z, hydroxy-C-C-alkyl, C-C-Alkoxy-C 6-Alkyl and C-D-Alkyl-5-C4 y-Alkyl; 65 p - 1 or 2, provided that when n-1, t-0 or 1, and when n-2, t-0, where if t-0, then " represents a chiral center; aryl - phenyl, naphthyl, anthracil or phenanthryl; heteroaryl - an aromatic 5- or β-ene heterocycle, which contains at least one M, O or 5 heteroatom, and, as an option, is condensed with an aryl; It is an aromatic or non-aromatic 4-, 5- or b-lene heterocycle containing at least one M, O or 5 heteroatom, and optionally fused with a 5- or b-lene carbocyclic group or a second 4-, 5 - or b--len heterocycle, which contains at least one M, O or 5 heteroatom; provided that: the compound is not M-methyl-M-piperidin-4-ylbenzamide or M-ethyl-M-piperidin-4-ylbenzamide; and when 2 /o represents mei | Omme Omme? OSE then VZ does not represent sm d red o Y I (ee) OMe , shi so (ze) I OoMme «v) sha; and E , - s -- o . I» Y Z ee) A --y-y o M; c 2. The compound according to claim 1, where t is 0, and " represents the K or 5 enantiomer. C. The compound according to claim 2, where " represents the 5 enantiomer. (65) 4. The compound according to any of the preceding clauses, where K 2 is phenyl, naphthyl or quinolinyl, each of which is optionally substituted with at least one substituent , independently selected from the group: C.-.v-alkyl, C.-v.-alkyl, OH, halogen, CEz, OSEZ, ZSE", hydroxy-C.v-alkyl, C.-4-alkyl-C..v- alkyl and C./-alkyl-5-C.4.-alkyl. 5. The compound according to claim 4, where b2 is phenyl or naphthyl, each of which is optionally substituted with one, two or three substituents independently selected from the group: halogen, OH, C-4-alkyl and CE3. 6. A compound according to any of the previous clauses, where C is C.sub.6-alkyl, C.sub.6-cycloalkyl, C.sub.4-cycloalkyl-C.sub.4-alkyl or aryl-C..sub.-alkyl. ko 7. The compound according to item b, where BZ is C 1 -alkyl, C 6 -cycloalkyl, C 6 -cycloalkyl-C 4 o -alkyl, phenyl-CH»o- or naphthyl-CH»o-. 60 8. Compound according to claim 1, where Kk - N; 2 - phenyl or naphthyl, each of which, as an option, is replaced by one, two or three substituents independently selected from the group: halogen, OH, C..4-alkyl and CE"; 23 - Si. c-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C4.3-alkyl, phenyl-CH»- or naphthyl-CH»-; because the so-called 9. The compound according to claim 1, selected from the group: 2,3-dichloro-M-isobutyl-M-((35)-pyrrolidin-3-yl|Senzamide; 2,4-dichloro-M-isobutyl-M-(( 35)-pyrrolidin-3-yl|Senzamide; 2-chloro-3-methyl-M-isobutyl-M-((35)-pyrrolidin-3-yl|Senzamide; 3-fluoro-2-methyl-M-isobutyl-M-((35)-pyrrolidin-3- 3-methoxy-2-methyl-N-isobutyl-N-(35)-pyrrolidin-3-ylbenzamide; C-chloro-N-isobutyl-N-(35)-pyrrolidin-3-yl|Ibenzamide; 4-chloro-N-isobutyl-N-(35)-pyrrolidin-3-yl|benzamide; 70 3,4-dichloro-M-isobutyl-M-(35)-pyrrolidin-3-yl|benzamide; M-(2-naphthylmethyl)-M-(35)-pyrrolidin-3-yl|benzamide; M-(2-naphthylmethyl)-M-(35)-pyrrolidin-3-yl|benzamide; M-isobutyl-M-((35)-pyrrolidin-3-yl|-2-naphthamide; M-butyl-M-((35)-pyrrolidin-3-yl|-1-naphthamide; 4-chloro-M-(3,4-dichlorobenzyl)-M-((ZK)-pyrrolidin-3-yl|benzamide; M-pyrrolidin-3-yl-M-(5,6,7,8-tetrahydronaphthalen-1-ylmethyl)-benzamide; IM-(2,4-dichlorobenzyl)-M-pyrrolidin-3-ylbenzamide; M-(3-chloro-4-methylbenzyl)-2-fluoro-M-pyrrolidin-3-ylbenzamide; naphthalene-2-carboxylic acid butylpyrrolidine-3-ylamide; naphthalene-2-carboxylic acid isobutylpyrrolidine-3-ylamide; naphthalene-2-carboxylic acid (2,2-dimethylpropyl)-pyrrolidin-3-ylamide; C-chloro-M-isobutyl-4-methyl-M-pyrrolidin-3-ylbenzamide; M-isobutyl-2,3-dimethyl-M-pyrrolidin-3-ylbenzamide; C-chloro-M-(2,2-dimethylpropyl)-2-methyl-M-pyrrolidin-3-ylbenzamide; high school 2-chloro-4-fluoro-M-isobutyl-M-pyrrolidin-3-ylbenzamide; 2-chloro-M-isobutyl-M-pyrrolidin-3-ylbenzamide; (8) C-chloro-2-fluoro-M-isobutyl-M-pyrrolidin-3C-ylbenzamide; C-chloro-4-fluoro-M-isobutyl-M-pyrrolidin-3C-ylbenzamide; M-butyl-2,4-dichloro-M-pyrrolidin-3-ylbenzamide; 2,4-dichloro-N-cyclobutylmethyl-N-pyrrolidin-3-ylbenzamide; 2,4-dichloro-M-cyclopentylmethyl-M-pyrrolidin-3-ylbenzamide; and 2,4-dichloro-M-(2,2-dimethylpropyl)-2-methyl-M-pyrrolidin-3-ylbenzamide; with 2,4-dichloro-M-(2-ethylbutyl)-M-pyrrolidin-3-ylbenzamide; 2,4-dichloro-M-(3-methylbutyl)-M-pyrrolidin-3-ylbenzamide; at 2,3,4-trichloro-M-isobutyl-M-pyrrolidin-3-ylbenzamide; so 2,4-dichloro-M-(2-cyclopropylethyl)-M-pyrrolidin-3-ylbenzamide; naphthalene-1-carboxylic acid isobutylpyrrolidine-3-ylamide; 2,4-dichloro-5-fluoro-M-isobutyl-M-pyrrolidin-3-ylbenzamide; 2,3-dichloro-M-(2,2-dimethylpropyl)-M-pyrrolidin-3-ylbenzamide; " 2,3-dichloro-M-(3-methylbutyl)-M-pyrrolidin-3-ylbenzamide; with c 2,3-dichloro-M-cyclobutylmethyl-M-pyrrolidin-3-ylbenzamide; 2,3-dichloro-M-cyclopentyl-M-pyrrolidin-3-ylbenzamide; ; t 3,4-dichloro-M-cyclopentyl-M-pyrrolidin-3-ylbenzamide; 2,3-dichloro-M-(1,2-dimethylpropyl)-M-pyrrolidin-3-ylbenzamide; 2,4-dichloro-M-(1,2-dimethylpropyl)-M-pyrrolidin-3-ylbenzamide; Go! 2,3-dichloro-M-cyclohexyl-M-pyrrolidin-3-ylbenzamide; 2,4-dichloro-M-cyclopentyl-M-pyrrolidin-3-ylbenzamide; o 3,4-dichloro-M-cyclopentyl-M-pyrrolidin-8-ylbenzamide; 2) naphthalene-1-carboxylic acid sec-butylpyrrolidin-3-ylamide; M-tert-butyl-2,3-dichloro-M-pyrrolidin-3-ylbenzamide; and N-tert-butyl-2,4-dichloro-N-pyrrolidin-3-ylbenzamide; c 2,3-dichloro-M-(1-ethylpropyl)-M-pyrrolidin-33-ylbenzamide; 2,4-dichloro-M-(1-ethylpropyl)-M-pyrrolidin-33-ylbenzamide; naphthalene-1-carboxylic acid (1-ethylpropyl)-pyrrolidin-3-ylamide; 2,3-dichloro-M-cyclobutyl-M-pyrrolidin-3-ylbenzamide; 2,4-dichloro-M-cyclobutyl-M-pyrrolidin-3-ylbenzamide; (F) 2,4-dichloro-M-cyclopentyl-M-pyrrolidin-3-ylbenzamide; ka 2,3-dichloro-M-pyrrolidin-3-yl-M-(1,2,2-trimethylpropyl)-benzamide; M-tert-butyl-2,3-dichloro-M-pyrrolidin-3-ylbenzamide; in naphthalene-1-carboxylic acid cyclopentylpyrrolidin-3-ylamide; 2,3-dichloro-M-phenyl-M-pyrrolidin-3-ylbenzamide; 3,4-dichloro-M-(2,2-dimethylpropyl)-2-methyl-M-pyrrolidin-3-ylbenzamide; C-chloro-M-isobutyl-2-methyl-M-pyrrolidin-3-ylbenzamide; M-butyl-2,3-dichloro-M-pyrrolidin-3-ylbenzamide; 65 M-butyl-3,4-dichloro-M-pyrrolidin-3-ylbenzamide; naphthalene-2-carboxylic acid cyclobutylmethylpyrrolidin-3-ylamide; naphthalene-1-carboxylic acid cyclobutylmethylpyrrolidin-3-ylamide; 3,4-dichloro-M-cyclobutylmethyl-M-pyrrolidin-3-ylbenzamide; 4-chloro-M-isobutyl-2-methoxy-M-pyrrolidin-3-ylbenzamide; 4-chloro-M-isobutyl-3-methyl-M-pyrrolidin-3-ylbenzamide; 2,4-dichloro-M-isobutyl-3-methyl-M-pyrrolidin-3-ylbenzamide; naphthalene-1-carboxylic acid (3-methylbutyl)-pyrrolidine-3-ylamide; naphthalene-1-carboxylic acid (2,2-dimethylpropyl)-pyrrolidin-3-ylamide; 3,4-dichloro-M-(3-methylbutyl)-M-pyrrolidin-3-ylbenzamide; 70 2,3-dichloro-M-(4-fluorophenyl)-M-pyrrolidin-3-ylbenzamide; 2,4-dichloro-M-(4-fluorophenyl)-M-pyrrolidin-3-ylbenzamide; naphthalene-1-carboxylic acid (4-fluorophenyl)-pyrrolidine-3-ylamide; M-butyl-2,3,4-trichloro-M-pyrrolidin-3-ylbenzamide; 2,3,4-trichloro-M-cyclobutylmethyl-M-pyrrolidin-3-ylbenzamide; M-pyrrolidin-3-yl-M-(3-trifluoromethylbenzyl)-benzamide; 2,4-dichloro-M-phenyl-M-pyrrolidin-3-ylbenzamide; 3,4-dichloro-M-phenyl-M-pyrrolidin-3-ylbenzamide; 2,3,4-trichloro-M-(2,2-dimethylpropyl)-M-pyrrolidin-3-ylbenzamide; naphthalene-1-carboxylic acid phenyl-pyrrolidin-3-ylamide; 2,3,4-trichloro-M-(2-cyclopropylethyl)-M-pyrrolidin-3-ylbenzamide; 2,3-dichloro-M-(2-cyclopropylethyl)-M-pyrrolidin-3-ylbenzamide; 2-bromo-4-chloro-M-isobutyl-M-pyrrolidin-3-ylbenzamide; 4-chloro-2-ethoxy-M-isobutyl-M-pyrrolidin-3-ylbenzamide; C-bromo-4-chloro-M-isobutyl-M-pyrrolidin-3-ylbenzamide; c 2,4-dichloro-5-fluoro-N-isobutyl-N-(35)-pyrrolidin-3-yl|Ibenzamide; 3,4-dichloro-M-isobutyl-2-methyl-M-pyrrolidin-3-ylbenzamide; (8) 2,4-dichloro-3-fluoro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 2,3-dichloro-4-fluoro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 2,3-dichloro-5-fluoro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 2,4,5-trichloro-N-isobutyl-N-|pyrrolidin-3-yl|benzamide; 2,5-dichloro-M-isobutyl-M-Ipyrrolidin-3-yl|Ibenzamide; and 2,5-dichloro-4-fluoro-N-isobutyl-N-|pyrrolidin-3-yl|benzamide; c 2,3,5-trichloro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; 2,3-dichloro-6-fluoro-M-isobutyl-M-|pyrrolidin-3-yl|benzamide; o 3,4-dichloro-6-fluoro-M-isobutyl-M-Ipyrrolidin-3-yl|IbSenzamide; so 3,4-dichloro-2-fluoro-M-isobutyl-M-Ipyrrolidin-3-yl|IbSenzamide; 2-chloro-3,6-difluoro-M-isobutyl-M-|pyrrolidin-3-yl|IbSenzamide and 4-chloro-M-(2,3-dichlorobenzyl)-M-(ZK)-pyrrolidin-3-yl ISenzamid, or their pharmaceutically and/or veterinary acceptable derivatives. " 10. The compound according to claim 9, which is 2,3-dichloro-M-isobutyl-M-((35)-pyrrolidine-Z-yl|bPhenzamide or its pv) with pharmaceutically and/or veterinary acceptable derivatives. . 11. A pharmaceutical composition containing a compound according to any one of claims 1 - 10 and a pharmaceutically acceptable i? adjuvant, diluent or carrier. 12. A compound according to any one of claims 1-10 for use as a medicament. 13. Use of a compound according to any one of claims 1-10 in the manufacture of a medicament for the treatment of a disorder, in Go! which is involved in the regulation of monoamine transport function in a mammal. 14. Use of a compound according to any one of claims 1-10 in the manufacture of a medicament for the treatment of a disorder involving the regulation of serotonin or norepinephrine in a mammal. 2) 15. Application according to claim 14, where the regulation of serotonin and norepinephrine is involved. 16. Use of a compound according to any one of claims 1-10 in the manufacture of a medicament for the treatment of disorders of the urinary system, depression, pain, premature ejaculation, attention deficit hyperactivity disorder (ADHD) or fibromyalgia in a mammal. 17. Use of a compound according to claim 16 for the treatment of urinary incontinence, such as true stress incontinence (O51I) or stress incontinence (051), in a mammal. 18. A method of treating a disorder involving the regulation of monoamine transport function, wherein a therapeutically effective amount of a compound according to any one of paragraphs is administered to a patient in need of such treatment. iF) 1-10. 19. A method of treating a disorder involving the regulation of serotonin or norepinephrine, which comprises administering a therapeutically effective amount of the compound according to any one of claims 1-10 to a patient in need of such treatment. 20. The method according to claim 19, in which the regulation of serotonin and norepinephrine is covered. 21. A method of treating urinary disorders, depression, pain, premature ejaculation, attention deficit hyperactivity disorder (ADHD), or fibromyalgia, wherein a therapeutically effective amount of a compound according to any one of claims 1-10 is administered to a patient in need of such treatment. 65 22. The method according to claim 21, where the disorder of the urinary system is urinary incontinence, such as C5I or BI. 23. The method of obtaining a compound according to any of claims 1-10, in which the reaction of the compound of formula (X) is carried out: y Y shk ГГ" и Ки de Ку, п and т are defined above, and У is ВЕ" or a protecting group, with an acid or an acyl halide: KoСОХ, where Х - ОН is either a halogen, and deprotection, if it is mandatory or necessary. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 14, 10.09.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s o s so so "c) d) - s;" (ee) («c) (95) o 50 IR e) F) name) 60 b5