Derivatives of adamantane, method for their preparing, pharmaceutical composition based on thereof and methods for treatment

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

EFFECT: improved method for preparing and treatment, valuable medicinal properties of compounds.

13 cl, 88 ex

 

The present invention relates to derivatives of adamantane, method of production thereof, pharmaceutical compositions containing them, process for the preparation of pharmaceutical compositions and their use in therapy.

Adamantane derivatives known in this field, for example, from WO 95/04720 for use as ligands receptor gastrin and cholecystokinin, Chem. Abs. (1977), Volume 86, No. 13 (86:89560d) for use as an analgesic funds and US-A-3464998 as antibiotics.

RH7-receptor (previously known as 2Z-receptor), which is logandarkrider ion channel present on various cell types, mainly on the types of cells, which are known to participate in inflammatory and immune process, especially macrophages, mast cells and lymphocytes (T and b). Activation RH7-receptor extracellular nucleotides, especially the ATP causes release of interleukin-1β (IL-1β) and the formation of giant cells (macrophages/glial macrophages), degranulation (mast cells) and proliferation (T-cells), apoptosis and L-seleccioneu terminal stage (lymphocytes). RH7receptors are also located on antigen presenting cells (APC), keratinocytes, salivary, acinar cells of the parotid cells), hepatocytes and mesangial cells.

<> It would be desirable to obtain compounds useful as antagonists of receptors RH7for use in the treatment of inflammatory, immune or cardiovascular diseases, the etiology of which RH7the receptor may play a role.

Therefore, in accordance with the present invention, the proposed compound of General formula

where m is 1, 2 or 3, preferably 1 or 2;

each R1independently represents a hydrogen atom or halogen (e.g. fluorine, chlorine, bromine or iodine), preferably, a hydrogen atom;

A represents C(O)NH, or, preferably, NHC(O);

Ar represents a group

X represents a bond, an oxygen atom or a group CO, (CH2)1-6, SN=, (CH2)1-6O(CH2)1-6, (CH2)2-6O(CH2)2-3O(CH2)1-3, CR'(OH), (CH2)1-3O(CH2)1-3, (CH2)1-3O(CH2)2-3O, NR5, (CH2)1-6NR5, NR5(CH2)1-6, (CH2)1-3NR5(CH2)1-3, O(CH2)2-6NR5, O(CH2)2-3NR5(CH2)1-3, (CH2)1-3NR5(CH2)2-3O, NR5(CH2)2-6O, NR5(CH2)2-3O(CH2)1-3, CONR5, NR5CO, (O) n, S(O)nCH2CH2S(O)n, SO2NR5or NR5SO2;

n is 0, 1 or 2;

R represents a hydrogen atom or a C1-C6-alkyl, preferably methyl group;

one of R2and R3represents halogen, cyano, nitro, amino, hydroxyl or a group selected from (i)1-C6-alkyl, optionally substituted by at least one3-C6-cycloalkyl, (ii)3-C8-cycloalkyl, (iii)1-C6-alkyloxy, optionally substituted by at least one3-C6-cycloalkyl, and (iv)3-C8-cycloalkane, and each of these groups optionally substituted by one or more fluorine atoms, and the other of R2and R3represents a hydrogen atom or halogen;

or R4is 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atom and optionally an oxygen atom, and the heterocyclic ring system optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6-alkyl, C1-C6-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7and-CONR6R7,

or R4represents a 3-8 member is nnow saturated carbocyclic ring system, substituted by one or more substituents independently selected from-NR6R7, -(CH2)rNR6R7and-CONR6R7also this ring system is optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl and C1-C6-alkyl;

r is 1, 2, 3, 4, 5 or 6;

R5represents a hydrogen atom or a C1-C6-alkyl or C3-C8-cycloalkyl group;

R6and R7each independently represents a hydrogen atom or a C1-C6-alkyl, C2-C6-hydroxyalkyl or3-C8-cycloalkyl group, or R6and R7together with the nitrogen atom to which they are attached, form a 3-8-membered saturated heterocyclic ring;

provided that

(a) when a represents C(O)NH and R4is unsubstituted 3-8-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, then X is other than a bond, and

(b) when a represents C(O)NH, and X represents a group (CH2)1-6or(CH2)1-6then R4is not unsubstituted imidazolines, unsubstituted morpholinyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl group, and

(C) when a represents NH(O) and R4before the hat unsubstituted 3-8-membered saturated aliphatic heterocyclic ring system, containing one nitrogen atom, then X is other than a bond, and

(d) when a represents NH(O) and X represents O(CH2)1-6, NH(CH2)1-6or S2then R4is not unsubstituted 1-piperidinyl or unsubstituted 1-pyrrolidinyl group, and

(e) when a represents NHC(O) and X represents O(CH2)2-3NH(CH2)2then R4is not imidazolidine group;

or its pharmaceutically acceptable salt or MES.

In the context of the present description, unless otherwise stated, the alkyl substituent or alkyl portion of the group-the Deputy may be straight or branched. Examples of alkyl groups/parts containing up to 6 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl. When one of R2and R3is1-C6-alkyl/S1-C6-alkyloxy, optionally substituted by at least one3-C6-cycloalkyl, it is understood that one or both of the alkyl and cycloalkyl parts can be optionally replaced by fluorine atoms. As for R4, 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atom and optionally an oxygen atom may be monocyclic or bicyclic number is zeway system. Further, as R4, 3-8-membered saturated carbocyclic ring system may be monocyclic or bicyclic ring system. When R6or R7is2-C6-hydroxyalkyl the Deputy NR6R7, -(CH2)rNR6R7or-CONR6R7you should take into account that the hydroxyl group could not be linked to the same carbon atom, and a nitrogen atom. When R6and R7together with the nitrogen atom to which they are attached, form a 3-8-membered saturated heterocyclic ring, the formed ring is monocyclic.

X preferably represents a bond, an oxygen atom or a group CO, (CH2)1-6, SN=, (CH2)1-6, (CH2)2-6O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)nor S(O)nCH2.

One of R2and R3represents halogen (e.g. fluorine, chlorine, bromine or iodine), cyano, nitro, amino, hydroxyl or a group selected from (i)1-C6-alkyl, preferably With1-C4-alkyl, optionally substituted by at least one (e.g. 1, 2 or 3)3-C6-cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), (ii)3-C -cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), (iii)1-C6-alkyloxy, preferably, With1-C4-alkyloxy, optionally substituted by at least one (e.g. 1, 2 or 3)3-C6-cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and (iv)3-C8-cycloalkane (for example, cyclopropylamino, cyclobutylamine, cyclopentyloxy or cyclohexyloxy), and each of these groups optionally substituted by one or more (e.g. 1, 2, 3, or 4 fluorine atoms, and the other of R2and R3represents a hydrogen atom or halogen (e.g. fluorine, chlorine, bromine or iodine).

One of R2and R3preferably represents a halogen atom (especially chlorine or bromine) or a nitro, amino or1-C6is an alkyl group (especially methyl or ethyl) and the other of R2and R3represents a hydrogen atom.

R4can represent a 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atom and optionally an oxygen atom, and the heterocyclic ring system optionally substituted by one or more (e.g. 1, 2, 3, or 4) substituents independently selected from fluorine atoms, hydroxyl, carbon the sludge, cyano, C1-C6-alkyl, preferably With1-C4-alkyl, C1-C6-hydroxyalkyl, preferably, With1-C4-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7and-CONR6R7.

3-9-Membered saturated or unsaturated aliphatic heterocyclic ring system in the group R4may be a monocyclic ring system, such as pyrrolidinyl (for example, 1-pyrrolidinyl, 2-pyrrolidinyl or 3-pyrrolidinyl), piperidinyl (for example, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl), 4-piperidin-3-yl, piperazinil (for example, 1-piperazinil), homopiperazine,

or bicyclic ring system, such as

Alternative R4can represent a 3-8-membered saturated carbocyclic ring system, substituted with one or more (e.g. 1, 2 or 3) substituents, independently selected from NR6R7, -(CH2)rNR6R7and-CONR6R7and the ring system is optionally additionally substituted by one or more (e.g. 1, 2, 3, or 4) substituents independently selected from fluorine atoms, hydroxyl and C1-C6-alkyl, preferably With1-C4-alkyl.

3-8-Membered saturated carbocycles the second ring in the group R 4is preferably monocyclic ring system such as cyclopentene or tsiklogeksilnogo ring.

Specific examples of the groups R4include:

When X represents a bond or a group CO, (CH2)1-6, (CH2)2-6, (CH2)2-3O(CH2)2-3, (CH2)1-3O(CH2)2-3, NR5(CH2)2-6, (CH2)1-3NR5(CH2)2-3, O(CH2)2-3NR5(CH2)2-3, NR5(CH2)2-3O(CH2)2-3, NR5CO, SO2or NR5SO2, R4preferably represents a group:

When X represents an oxygen atom or sulfur or a group CH=, (CH2)1-6Oh, och2, (CH2)2-6O(CH2)2-3Och2, CR'(OH), (CH2)1-3Och2, (CH2)1-3O(CH2)2-3O, NR5, (CH2)1-6NR5, (CH2)2-6NR5, NR5CH2, (CH2)1-3NR5CH2, O(CH2)2-3NR5CH2, (CH2)1-3NR5(CH2)2-3O, NR5(CH2)2-6O, NR5(CH2)2-3Och2, CONR5, SO, S(O)nCH2 CH2S(O)nor SO2NR5, R4preferably represents a group:

R5represents a hydrogen atom or a C1-C6-preferably With1-C4-alkyl (e.g. methyl, ethyl, through boutelou, pentelow or hexoloy) or (C3-C8-preferably With3-C6-cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl or tsiklogeksilnogo) group.

R6and R7each independently represents a hydrogen atom or a C1-C6-preferably With1-C4-alkyl (e.g. methyl, ethyl, through boutelou, pentelow or hexoloy)2-C6-hydroxyalkyl or3-C8-preferably With3-C6-cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl or tsiklogeksilnogo) group, or R6and R7together with the nitrogen atom to which they are attached, form a 3-8-membered, preferably 3-6-membered saturated heterocyclic ring, such as pyrrolidinyl or piperidinyl ring.

Preferred compounds of the invention include:

2-Nitro-3-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Dihydrochloride salt of 2-amino-3-piperazine-1-yl-N-(Tr is cyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide,

2-Chloro-3-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

2-Chloro-5-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 5-(4-amino-1-piperidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of (+/-)-5-(3-amino-1-pyrrolidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-piperazine-1-ylmethyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[(hexahydro-1H-1,4-diazepin-1-yl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1 - ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 5-[(4-amino-1-piperidinyl)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 5-[(3-amino-1-pyrrolidinyl)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of (R)-2-chloro-5-(2-pyrrolidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of (S)-2-chloro-5-(2-pyrrolidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(3-piperidinyloxy)-N-(tricyclo[3.3.1.1sup> 3,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of CIS-5-[(4-aminocyclohexane)oxy]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-methyl-5-(1-piperazinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(1-piperazinylmethyl)-N-(2-tricyclo[3.3.1.13,7]Oct-1-retil)benzamide,

Cleaners containing hydrochloride salt of (+/-)-2-chloro-5-(3-pyrrolidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of (+/-)-2-chloro-5-(3-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

TRANS-5-[(4-Aminocyclohexane)oxy]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

CIS-(+/-)-5-[(3-Aminocyclopent)oxy]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of (S,S)-2-chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(2-methyl-1-piperazinil)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of (+/-)-2-chloro-5-(3-pyrrolidinyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

(+/-)-5-(3-Amino-1-piperidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

(+/-)-2-Chloro-5-(3-piperidinylidene)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

2-Chloro-5-[hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzo the ID,

Cleaners containing hydrochloride salt of N-[2-methyl-5-(4-piperidinyloxy)phenyl]tricyclo[3.3.1.13,7]decane-1-acetamide", she

Cleaners containing hydrochloride salt of N-[2-chloro-5-(4-piperidinyloxy)phenyl]tricyclo[3.3.1.13,7]decane-1-acetamide", she

Dihydrochloride salt of 2-chloro-5-[(4-piperidylamine)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Dihydrochloride salt of 5-[[[4-(aminomethyl)cyclohexyl]amino]methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Dihydrochloride salt of 5-[[(4-aminocyclohexane)amino]methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

5-[(1-Azabicyclo[2.2.2]Oct-3-ylamino)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Dihydrochloride salt of N-[4-(3-aminopyrrolidine-1-yl)-2-were]-2-(tricyclo[3.3.1.13,7]Oct-1-yl)acetamide", she

Dihydrochloride salt of N-(2-methyl-4-piperazine-1-ylphenyl)-2-(tricyclo[3.3.1.13,7]Oct-1-yl)acetamide", she

Cleaners containing hydrochloride salt of CIS-4-(3-aminocyclopentane)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-4-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

(+/-)-2-Chloro-4-(pyrrolidin-3-yloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-4-(piperidine-3-yloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-4-(4-piperazine-1-yl)-N-(tricyclo[3.3.1.13,7Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-4-(3-pyrrolidinyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-4-(hexahydro-1H-1,4-diazepin-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt (±)-5-[(3-amino-1-piperidinyl)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of TRANS-2-chloro-5-[[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of CIS-2-chloro-5-[(hexahydrofuro[3,4-C]pyrrol-2(1H)-yl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinylidene)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(4-hydroxypiperidine-4-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(1,2,3,6-tetrahydropyridine-4-yl)-N-(Tris the CLO[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-ethyl-5-piperazine-1-ylmethyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

2-Chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-elmersolver)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-elmersolver)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(piperazine-1-carbonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-([1,4]diazepan-1-carbonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 4-chloro-N1-(piperidine-4-yl)-N2-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)isophthalamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(hydroxy-4-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt (±)-2-chloro-5-(hydroxy-3-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-bromo-5-piperazine-1-ylmethyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Hydrochloride the salt of 2-chloro-5-[2-(1-piperazinil)ethyl]-N-(tricyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 5-[2-(4-amino-1-piperidinyl)ethyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Dihydrochloride salt of 2-chloro-5-[2-(3-piperidylamine)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 5-[2-(3-amino-1-piperidinyl)ethyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Dihydrochloride salt of 2-chloro-5-[2-(3-pyrrolidinyl)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 5-[2-[(3R)-3-aminopyrrolidine)ethyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-[2-(hydroxymethyl)-1-piperazinil]ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(2-tricyclo[3.3.1.13,7]Oct-1-retil)benzamide,

Cleaners containing hydrochloride salt of (+/-)-5-(3-amino-1-pyrrolidinyl)-2-chloro-N-(2-tricyclo[3.3.1.13,7]Oct-1-retil)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinylcarbonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[1-hydroxy-1-(4-piperidinyl)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(1-piperazinil)ethoxy]-N-(tricyclo 3,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(4-piperidinyl)ethoxy]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(4-piperidinyloxy)ethoxy]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-[2-(1-piperazinil)ethoxy]ethoxy]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

2-Chloro-5-[(5,6-dihydro-1(4H)-pyrimidinyl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[[4-[(2-hydroxyethyl)amino]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

2-Chloro-5-[[4-hydroxy-4-[[(1-methylethyl)amino]methyl]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[(1,2,3,6-tetrahydro-3-pyridinyl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

The acetate salt of 2-chloro-5-(3-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

2-Bromo-5-[[4-[(2-hydroxyethyl)amino]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide and

2-Chloro-5-[(E)-3-piperidinylidene]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide.

The present invention relates to a method for obtaining compounds of formula (I)as defined above, which includes:

(i) when X is CH2group, R4is 3-9-membered saturated or nenasi the military aliphatic heterocyclic ring system, containing one or two nitrogen atom and optionally an oxygen atom, and the heterocyclic ring system optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6-alkyl, C1-C6-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7and-CONR6R7and R4linked to X via a nitrogen atom, the interaction of the compounds of General formula

where one of R10and R11represents a hydrogen atom and the other of R10and R11represents a group-CH2L1in which L1represents a leaving group (e.g. halogen atom, and m, A, R1, R2and R3have the meanings indicated in the formula (I), with the compound of General formula

R4'-H (III)

in the presence of a base (for example, diisopropylethylamine), where R4'is 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atom and optionally an oxygen atom, and the heterocyclic ring system optionally substituted by one or more substituents independently selected from fluorine atoms, hydroxyl, carboxyl, cyano, C1-C6-alkyl, C1-C6-hydroxyalkyl, -NR6R 7, -(CH2)rNR6R7and-CONR6R7and where R6and R7have the meanings indicated in the formula (I); or

(ii) when X represents an oxygen atom or a group O(CH2)1-6, (CH2)2-6O(CH2)2-3O(CH2)1-3, (CH2)2-6NR5or O(CH2)2-3NR5(CH2)1-3the interaction of the compounds of General formula

where one of R12and R13represents a hydrogen atom and the other of R12and R13represents a hydroxyl group, and m, A, R1, R2and R3have the meanings indicated in the formula (I), with the compound of General formula

R4-Y-OH (V)

where Y represents a bond or a group (CH2)1-6, (CH2)2-6, (CH2)1-3O(CH2)2-3, NR5(CH2)2-6or (CH2)1-3NR5(CH2)2-3and R4has the values listed in the formula (I), in the presence of 1,1-(azodicarbon)dipiperidino and tributylphosphine (under the reaction conditions, Mitsunobu: Tetrahedron Lett. (1993), 34, 1639); or

(iii) when X represents a bond, an oxygen atom or a group O(CH2)1-6, (CH2)2-6O(CH2)2-3O(CH2)1-3, NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)-3 and a represents NHC(O), the interaction of the compounds of General formula

where one of R14and R15represents a group-X'-R4and the other of R14and R15represents a hydrogen atom, X' represents a bond, an oxygen atom or a group O(CH2)1-6, (CH2)2-6O(CH2)2-3O(CH2)1-3, NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3L2represents a leaving group (e.g. hydroxyl or chloride leaving group and R2, R3, R4and R5have the meanings indicated in the formula (I), with the compound of General formula

where m and R1have the meanings indicated in the formula (I), optionally in the presence of the agent combinations (for example, 1,1'-carbonyldiimidazole); or

(iv) when X represents a bond, an oxygen atom or a group O(CH2)1-6, (CH2)2-6O(CH2)2-3O(CH2)1-3, NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3and a represents C(O)NH, interaction of the compounds of General formula

where R2and R3have the meanings indicated in the formula (I), and R14and R1 have the meanings indicated in the formula (VI) in the above (iii), with the compound of General formula

where m and R1have the meanings indicated in the formula (I), in the presence of a base (for example, Diisopropylamine); or

(v) when X represents a bond or a group NR5, NR5(CH2)1-6, NR5(CH2)2-6O or NR5(CH2)2-3O(CH2)1-3the interaction of the compounds of General formula

where one of R16and R17represents a leaving group L3such as halogen atom, and the other of R16and R17represents a hydrogen atom, and m, A, R1, R2and R3have the meanings indicated in the formula (I), with the compound of General formula

R4-Z (XI)

where Z represents a hydrogen atom or a group NR5, (CH2)1-6Other5, O(CH2)2-6Other5or group (CH2)1-3O(CH2)2-3Other5and R4and R5have the meanings defined in formula (I), optionally in the presence of a palladium catalyst (e.g. palladium acetate), phosphine ligand (e.g., BINAP) and a base (e.g. cesium carbonate); or

(vi) when X represents a group CH2Oh, the interaction of the compounds of formula II, as defined above in (i)with the compound of the formula (V)as defined is but above in (ii), where Y represents a bond, in the presence of a base (e.g. sodium hydride) or in the presence of a metal salt (for example, triftoratsetata silver); or

(vii) when X represents a group CH2NR5the interaction of the compounds of formula (II)as defined above in (i)with the compound of the formula (XI)as defined above in (v), where Z represents a group other5; or

(viii) when X represents a group CH2O(CH2)1-3or CH2O(CH2)2-3Oh, the interaction of the compounds of formula (II)as defined above in (i)with the compound of the formula (V)as defined above in (ii), where Y represents the group (CH2)1-3or(CH2)2-3in the presence of a base (e.g. sodium hydride) or in the presence of a metal salt (for example, triftoratsetata silver); or

(ix) when X represents a group CH2NR5CH2or CH2NR5(CH2)2-3O, the interaction of the compounds of formula (II)as defined above in (i)with the compound of the formula (XI)as defined above in (v), where Z represents the group CH2Other5or O(CH2)2-3Other5; or

(x) when X represents a group CH2and R4is unsubstituted 4-6 membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, the interaction of the compounds of formula (II), the AK defined above in (i), with a compound of General formula

where s and t, independently, is 1 or 2; or

(xi) when X represents a group WITH, NR5, NR5CO, SO2, NR5SO2or SO2NR5and a represents NHC(O), the interaction of the compounds of General formula

where one of R18and R19represents a group-S-R4and the other of R18and R19represents a hydrogen atom, X represents a group WITH, NR5, NR5CO, SO2, NR5SO2or SO2NR5L4represents a leaving group (e.g. hydroxyl or chloride leaving group and R2, R3, R4and R5have the meanings indicated in the formula (I)with the compound of the formula (VII)as defined above in (iii), optionally in the presence of the agent combinations (for example, 1,1'-carbonyldiimidazole); or

(xii)when X represents a group WITH, NR5, NR5CO, SO2, NR5SO2or SO2NR5and a represents C(O)NH, interaction of the compounds of General formula

where R2and R3have the meanings indicated in the formula (I), and R18and R19have the meanings indicated in the formula (XIII)above (xi)with the compound of the formula (IX)as defined above in (iv), in the presence of a base (for example, disop is pilipina), or

(xiii) when X represents a sulfur atom, the interaction of the compounds of formula (X)as defined above in (v), with an organolithium reagent such as n-utility (e.g., at -70° (C) and then with a compound of General formula

R4-S-SO2Tol (XV)

where Tol is calilou group (4-methylphenylene) and R4has the values listed in the formula (I), or

(xiv) when X represents a group SNON or CH2the interaction of the compounds of formula (X)as defined above in (v), with an organolithium reagent (e.g. methyllithium/ tert-butyllithium or n-butyllithium at -70° (C) and then with a compound of General formula

R4-CHO (XVI)

where R4has the values listed in the formula (I), optionally followed by reduction, for example, methylacetylene or triethylamine and then with tributyltinhydride in the presence of azobisisobutyronitrile; or

(xv) when X represents a bond, the interaction of the compounds of formula (X)as defined above in (v), with an organolithium reagent such as n-utility (e.g., at -70° (C) and then with a compound of General formula

R4=O (XVII)

where R4has the values listed in the formula (I), optionally followed by reduction, for example, methylacetylene and triethylamine and then tributyltinhydride in the presence of and the of abyssalchronicles; or

(xvi) when X represents a group SO that oxidation of the corresponding compounds of formula (I)in which X represents a sulfur atom (for example, using as the oxidizing agent 3-chloroperoxybenzoic acid or peroxymonosulfate potassium (commercially sold under the trademark "OXONE"); or

(xvii) when X represents a group SCH2the interaction of the compounds of formula (X)as defined above in (v), with an organolithium reagent (e.g. methyllithium and/or tert-butyllithium at -70° (C) and then with a compound of General formula

where R4has the values listed in the formula (I); or

(xviii) when X represents a group SOCH2or SO2CH2the oxidation of the corresponding compounds of formula (I)in which X represents a group SCH2(for example, using as the oxidizing agent 3-chloroperoxybenzoic acid or peroxymonosulfate potassium (commercially sold under the trademark "OXONE"); or

(xix) when X represents the group CH=, the interaction of the compounds of formula (II)as defined above in (i), with trimethylphosphite and then with the compound of the formula (XVII)as defined above in (xv)in the presence of a base (for example, diisopropylamide lithium); or

(XX) when X represents a group (CH2)1-6the interaction of the compounds of obatala

where one of R20and R21represents a group Cho or a group (CH2)1-5SNO and the other of R20and R21represents a hydrogen atom, and m And R1, R2and R3have the meanings indicated in the formula (I), with the compound of General formula (XX), R4-H, where R4has the values listed in the formula (I), in the presence of a reducing agent (for example, triacetoxyborohydride sodium in a suitable solvent, such as dichloromethane); or

(xxi) when X represents a group (CH2)1-6NR5, (CH2)1-3NR5(CH2)1-3or (CH2)1-3NR5(CH2)2-3O, the interaction of the compounds of formula (XIX)as defined above in (XX)with a compound of General formula (XXI), R4-Z, where Z' represents a group other5, (CH2)1-3Other5, O(CH2)2-3Other5and R4and R5have the meanings indicated in the formula (I), in the presence of a reducing agent (for example, triacetoxyborohydride sodium in a suitable solvent, such as dichloromethane); or

(xxii) when X represents a group (CH2)1-3O(CH2)1-3or (CH2)1-3O(CH2)2-3Oh, the interaction of the compounds of formula (XIX)as defined above in (XX), in which one of R20and R21represents a group Cho Il the group (CH 2)1-2SNO and the other of R20and R21represents a hydrogen atom, with a regenerating agent (such as borohydride sodium) with subsequent interaction with the compound of General formula (XXII), R4-E, where E represents a group (CH2)1-3L5or(CH2)2-3L5L5represents a leaving group (such as halogen atom or a sulphonate ether group, for example, p-toluensulfonate) and R4has the values listed in the formula (I), in the presence of a base (such as sodium hydride); or

(xxiii) when X represents a group (CH2)1-6the interaction of the compounds of formula (II)as defined above in (i), with trimethylphosphite and then with the compound of the formula (XVI)as defined above in (xiv)with a compound of formula (XVII)as defined above in (xv), or a compound of General formula (XVIA), R4(CH2)1-4CHO, in which R4has the values listed in the formula (I), in the presence of a base (for example, diisopropylamide lithium) followed by reduction (for example, with hydrogen and platinum oxide as catalyst); or

(xxiv) when X represents a group (CH2)2-6Oh, the interaction of the compounds of General formula

where one of R22and R23represents a group (CH2)2-6L6and the other of R22/sup> and R23represents a hydrogen atom, L6represents a leaving group (e.g. halogen atom or a sulphonate ester group, such as p-toluensulfonate) and (m, A, R1, R2and R3have the meanings indicated in the formula (I)with the compound of the formula (V)as defined above in (ii)in which Y represents a bond; or

(xxv) when X represents a group CR'(OH)in which R' represents a C1-C6is an alkyl group, oxidation of the corresponding compounds of formula (I)in which X represents CH(OH) (for example, using as oxidant combination of dimethyl sulfoxide/oxalicacid) with subsequent interaction with1-C6-alkyllithium reagent; or

(xxvi) when X represents a group CH2S, the interaction of the compounds of formula (II)as defined above in (i), with the compound of General formula (XXIV), R4-SH, where R4has the values listed in the formula (I), in the presence of a base (e.g. sodium hydride); or

(xxvii) when X represents a group CH2SO or CH2SO2the oxidation of the corresponding compounds of formula (I)in which X represents the group CH2S (for example, using as the oxidizing agent 3-chloroperoxybenzoic acid or peroxymonosulfate potassium (commercially sold under the trade mark "OXONE"); or

(xxviii) when X pre who is the group CH 2and R4is 3-piperidinyl or 2-piperazinilnom group, the interaction of the compounds of formula (II)as defined above in (i)with a reagent formed by the combination of pyridine or pyrazine with aluminohydrides reagent (for example, sociallyengaged), followed by reaction of recovery (for example, hydrogen and a platinum catalyst); or

(xxix) when X represents the group CH= and R4is 3-piperidinyloxy group, the interaction of the compounds of General formula

where one of R24and R25represents an aldehyde group-Cho and the other of R24and R25represents a hydrogen atom, and m, A, R1, R2and R3have the meanings indicated in the formula (I), 2,3,4,5-tetrahydropyridine (Bull. Chem. Soc. Jpn. 1983, 56, 3199) followed by reduction (for example, with sodium borohydride in proton solvent such as methanol); or

(xxx) when X represents a bond, NR5or NR5(CH2)1-6and R4is linked via a carbon piperidino or piperazinilnom group, the recovery of the compounds of General formula

where one of R26and R27is pyridinol, personilnya, NR5-pyridinol, NR5-personilnya, NR5(CH2)1-6-pyridinoyl NR 5(CH2)1-6-personilnya group and the other of R26and R27represents a hydrogen atom, and m, A, R1, R2and R3have the meanings indicated in the formula (I), the source of hydrogen and a hydrogenation catalyst (such as platinum oxide); or

(xxxi) when X represents a group CH2O(CH2)1-3or CH2O(CH2)2-3O and a represents NHC(O), the interaction of the compounds of General formula

where one of R28and R29represents a group-X′′′R4and the other of R28and R29represents a hydrogen atom, X′′′ represents the group CH2O(CH2)1-3or CH2O(CH2)2-3Oh, L7represents a leaving group (e.g. hydroxyl or chloride leaving group and R2, R3and R4have the meanings indicated in the formula (I)with the compound of the formula (VII)as defined above in (iii), optionally in the presence of the agent combinations (for example, 1,1'-carbonyldiimidazole); or

(xxxii) when X represents a group CH2O(CH2)1-3or CH2O(CH2)2-3O and a represents C(O)NH, interaction of the compounds of General formula

where R2and R3have the meanings indicated in the formula (I), and R28and R29have meaning to the Oia, specified in the formula (XXVII)above (xxxi), with the compound of formula (IX)as defined above in (iv), in the presence of a base (for example, Diisopropylamine);

and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), (xvii), (xviii), (xix), (xx), (xxi), (xxii), (xxiii), (xxiv), (xxv), (xxvi), (xxvii), (xxviii), (xxix), (xxx), (xxxi) or (xxxii) the conversion of compounds of formula (I) in the following compound of formula (I) and, optionally, education pharmaceutically acceptable salt or MES the compounds of formula (I).

The methods of the invention can be suitably carried out in a solvent, for example, an organic solvent, such as dichloromethane, dichloroethane, tetrahydrofuran, dioxane, xylene or dimethylformamide, at a temperature of, for example, in the range from 0 to 200°preferably in the range from 0 to 150°C.

The compounds of formula (II)in which a represents NHC(O), can be obtained by the interaction of the compounds of General formula

where L10represents a leaving group (e.g. hydroxyl or chloride leaving group and R2, R3, R10and R11have the meanings indicated in the formula (II)with the compound of the formula (VII)as defined above, optionally in the presence of the agent combinations (for example, 1,1'-carbonyldiimidazole).

The compounds of formula (XXX), in which one of R10and R11pre is is a hydrogen atom and the other of R 10and R11represents a group-CH2L1and L1represents a bromine atom, can be obtained by the interaction of the compounds of General formula

where one of R30and R31represents a hydrogen atom and the other of R30and R31represents a methyl group and R2and R3have the meanings indicated in the formula (I), N-bromosuccinimide and a catalytic azobisisobutyronitrile or Dibenzoyl peroxide, optionally followed by chlorination with oxalylamino and catalytic dimethylformamide or thionyl chloride.

The compounds of formula (II)in which a represents C(O)NH and L1is, for example, a bromine atom, can be obtained by the interaction of the compounds of General formula

where R2and R3have the meanings indicated in the formula (I), and R30and R31have the values listed in the above formula (XXXI)with a compound of formula (IX)as defined above, in the presence of a base (for example, diisopropylethylamine) followed by interaction with N-bromosuccinimide and a catalytic azobisisobutyronitrile or Dibenzoyl peroxide.

The compounds of formula (IV)in which a represents NHC(O), can be obtained in a manner analogous to the formation of compounds of formula (II)in which a represents NHC(O), use the instead of the intermediate compounds of formula (XXX) intermediate compounds of General formula

where L11represents a leaving group (e.g. hydroxyl or chloride leaving group and R2, R3, R12and R13have the meanings indicated in the formula (IV).

The compounds of formula (IV)in which a represents C(O)NH, can be obtained by the interaction of the compounds of General formula

where R2, R3, R12and R13have the meanings indicated in the formula (IV)with the compound of the formula (IX)as defined above, optionally in the presence of a base (for example, diisopropylethylamine).

The compounds of formula (VI) can be obtained by the interaction of the compounds of General formula

where R32represents a hydrogen atom or a C1-C6is an alkyl group, one of R33and R34represents a leaving group L12such as halogen atom (e.g. bromine or iodine) or triftormetilfosfinov group and the other of R33and R34represents a hydrogen atom and R2and R3have the meanings indicated in the formula (VI)with a compound of General formula

N-X'-R4(XXXVI)

where X' and R4have the meanings indicated in the formula (VI), in the presence of a palladium catalyst (e.g. palladium acetate), phosphine ligand (e.g., BINAP) and a base (e.g. cesium carbonate) (196, J. Am. Chem. Soc., 7215-6; 1997, J. Am. Chem. Soc., 3395) followed by hydrolysis (e.g., sodium hydroxide) and optional chlorination reaction (for example, oxalylamino and catalytic dimethylformamide or thionyl chloride).

The compound of formula (VIII) can suitably be obtained by the coupling of compounds of formula (VI), in which L2represents a hydroxyl group, with diphenylphosphorylacetate in the presence of a base such as triethylamine.

The compound of formula (X)in which a represents NHC(O), can be obtained in a manner analogous to the formation of compounds of formula (II)in which a represents NHC(O), using together the intermediate compounds of formula (XXX) intermediate compounds of General formula

where L13represents a leaving group (e.g. hydroxyl or chloride leaving group and R2, R3, R16and R17have the meanings indicated in the formula (X).

The compounds of formula (X)in which a represents C(O)NH, can be obtained in a manner analogous to the formation of compounds of the formula (IV)in which a represents C(O)NH, using instead the intermediate compounds of formula (IV) intermediate compounds of General formula

where R2, R3, R16and R17have the values listed in the ormula (X).

The compounds of formula (XII) can be obtained as described in Syn. Lett. (1998) 379-380.

The compounds of formula (XIII), in which X represents a group CO, CONR5, SO2or SO2NR5you can get by the interaction of the compounds of General formula

where one of R35and R36represents a group COL14or SO2L14and the other of R25and R26represents a hydrogen atom, L14represents a leaving group (e.g. halogen atom), R37represents a hydrogen atom or a C1-C6is an alkyl group, and R2and R3have the meanings indicated in the formula (XIII)with a compound of formula (XXXVI)in which X' represents a bond or a group NR5in the presence of a base, such as diisopropylethylamine, and catalytic dimethylaminopyridine followed by hydrolysis (e.g., sodium hydroxide) and optional chlorination reaction (for example, oxalylamino and catalytic dimethylformamide or thionyl chloride).

The compounds of formula (XIII), in which X represents a group NR5CO or NR5SO2you can get by the interaction of the compounds of General formula

where one of R38and R39represents a group other5and the other of R38and R39represents a hydrogen atom, R372and R3have the meanings indicated in the formula (XIII)with a compound of General formula (LI), R4-J, where J represents a group COCl or SO2Cl and R4has the values listed in the formula (I), in the presence of a base, such as diisopropylethylamine.

The compounds of formula (XIV) can be conveniently obtained by the interaction of the compounds of formula (XIII), in which L4represents a hydroxyl group, with diphenylphosphorylacetate in the presence of a base such as triethylamine.

The compounds of formula (XIX), in which one of R20and R21represents a group (CH2)1-5SNO and the other of R20and R21represents a hydrogen atom, can be obtained by oxidation of compounds of General formula

where one of R40and R41represents a group (CH2)2-6HE and the other R40and R41represents a hydrogen atom, and m, A, R1, R2and R3have the meanings indicated in the formula (I), using as the oxidizing agent, for example, reagent Dess Martin Periodinan.

The compounds of formula (XLII)in which one of R40and R41represents a group (CH2)2HE and the other R40and R41represents a hydrogen atom, can be obtained from compounds of General formula (X), as defined above, interaction with l reorganizes reagent, such as motility (at -70° (C), and then n-butyllithium (at -70°) and then treatment with ethylene oxide.

The compounds of formula (XLII)in which one of R40and R41represents a group (CH3)3-6HE and the other R40and R41represents a hydrogen atom, can be obtained by the interaction of the compounds of General formula (X), as defined above, with a compound of General formula

in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), and subsequent reduction, for example, hydrogen and platinum oxide as a catalyst.

The compounds of formula (XIX), in which one of R20and R21represents a group Cho and the other of R20and R21represents a hydrogen atom (which are equivalent to compounds of formula (XXV)can be obtained from compounds of General formula (X), as defined above, interaction with the organolithium reagent, such as motility (at -70°C), then with n-butyllithium (at -70° (C) and then with dimethylformamide.

The compounds of formula (XXIII), in which L6represents an iodine atom or C-toluensulfonate, can be obtained by the coupling of compounds of formula (XLII), as defined above, with a mixture of iodine/triphenylphosphine/imidazole or sulphonylchloride, such as p-toluensulfonate, in the presence of the tvii Foundation, such as diisopropylethylamine.

The compounds of formula (XXVI), in which one of R26and R27is pyridyloxy or personilnya group and the other of R26and R27represents a hydrogen atom, can be obtained from the compounds of formula (X), as defined above, interaction with the pyridyl - or personalbramwell acid in the presence of palladium catalyst such as tetrakis(triphenylphosphine)palladium(0).

The compounds of formula (XXVI), in which one of R26and R27is NR5-pyridinol, NR5-personilnya, NR5(CH2)1-6-pyridinol or NR5(CH2)1-6-personilnya group and the other of R26and R27represents a hydrogen atom, can be obtained from the compounds of formula (X), as defined above, interaction, and connection with other5-pyridyl, NR5-pyrazinyl, NR5(CH2)1-6-pyridyl or other5(CH2)1-6-pyrazinyl in the presence of a palladium catalyst (e.g. palladium acetate), phosphine ligand (e.g., BINAP) and a base (e.g. cesium carbonate).

Compounds of formula (III), (V), (VII), (IX), (XI), (XV), (XVI), (XVIA), (XVII), (XVIII), (XX), (XXI), (XXII), (XXIV), (XXVII), (XXVIII), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XL), (XLI), (XLII) and (XLIII) are either commercially available, are well known in the literature, or they can be obtained easily using the receiving of the known methods.

The compounds of formula (I) can be converted into the following compounds of formula (I) using standard procedures. For example, the compounds of formula (I)in which one of R2and R3is the nitro-group, can be converted into compounds of formula (I)in which one of R2and R3represents an amino group, restoring the use of iron powder and ammonium chloride in a mixture of ethanol/water by boiling under reflux. The latter compounds can, in turn, be converted into compounds of formula (I)in which one of R2and R3represents a halogen atom, e.g. chlorine, diazotization (for example, sodium nitrite) and interaction with the chloride of copper. The compounds of formula (I)in which R6or R7represents a hydrogen atom, can be converted into compounds of formula (I)in which R6or R7is1-C6-alkyl, C2-C6-hydroxyalkyl,3-C8-cycloalkyl or 3-8-membered saturated heterocyclic ring, standard chemical procedures.

The person skilled in the art it will be obvious that the methods of the present invention certain functional groups such as hydroxyl or amino groups, in the original reactants or intermediate compounds may need to be protected with protective groups. So about the time, obtaining compounds of formula (I) may include, at an appropriate stage, removing one or more protective groups.

Protect and unprotect functional groups described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973) and ' Protective Groups in Organic Synthesis", 2ndedition, by T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991).

Compounds of the above formula (I) can be transformed into its pharmaceutically acceptable salt or MES, preferably, an acid additive salt, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluensulfonate, or salt of an alkali metal such as sodium or potassium salt.

Some compounds of formula (I) can exist in stereoisomeric forms. It should be clear that the invention encompasses all geometric and optical isomers of compounds of formula (I) and mixtures thereof, including racemates. The tautomers and their mixtures also form an aspect of the present invention.

Compounds of the present invention possess pharmacological activity. They, therefore, serve as pharmaceuticals for use in the treatment of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), increased susceptibility to respiratory p is TEI, septic shock, glomerulonephritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastoma leukemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischemic heart disease, stroke and varicose veins.

Accordingly, the present invention relates to the compound of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, for use in therapy.

In another aspect, the invention relates to the use of compounds of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, for preparing a medicinal product for use in therapy.

In the context of the present invention, the term "therapy" includes "prevention"only if, in contrast, does not include specific instructions. The term "therapeutic" and "therapeutically" shall be construed accordingly.

The invention further relates to a method of immunosuppression (for example, in the treatment of rheumatoid arthritis, inflammatory bowel disease, atherosclerosis or psoriasis), which includes an introduction to the patient a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or salt is ATA, as specified above.

The invention relates also to a method for the treatment of obstructive Airways disease (e.g. asthma or COPD), which includes an introduction to the patient a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or MES, as defined above.

For the above mentioned therapeutic uses the entered dose, of course, will vary depending on the compound, the route of administration, the desired treatment such violations. Daily dose of the compounds of formula (I)/salt/MES (active ingredient) may be in the range from 0.001 mg/kg to 30 mg/kg

The compounds of formula (I) and their pharmaceutically acceptable salt and solvate can be used as such, but they are usually administered in the form of pharmaceutical compositions in which the compound of formula (I)/Sol/MES (active ingredient) is in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the method of administration, the pharmaceutical composition will preferably include from 0.05 to 99 wt.% (percent by weight), more preferably from 0.10 to 70 wt.%, the active ingredient and from 1 to 99.95 wt.%, more preferably, from 30 to 99,90% of the mass. pharmaceutically acceptable adjuvant, diluent or carrier, all weight percents OS is ofany on the total composition.

Thus, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further relates to a method for producing a pharmaceutical composition of the invention, which involves mixing the compounds of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition of the invention can be entered locally (for example, in the lungs and/or Airways or to the skin) in the form of solutions, suspensions, heptapteridae aerosols or ready preparative forms in the form of a dry powder, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral introduction, in the form of solutions or suspensions, or subcutaneous injection, or rectally introduction in the form of suppositories, or percutaneous.

The present invention is hereinafter explained with reference to the following illustrative examples.

Example 1

2-Nitro-3-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 3-Chloro-2-nitro-N-(tricyclo[3.3.1.13,7]the EC-1-ylmethyl)benzamide

To a suspension of 3-chloro-2-nitrobenzoic acid (2,68 g) in dichloromethane (10 ml) at 0°With add oxalicacid (3 ml) and dimethylformamide (1 drop). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour, then concentrated under reduced pressure to obtain a solid substance. The solid is dissolved in dichloromethane (10 ml) and cooled to 0°C. Portions add a solution of 1-adamantanemethylamine (2,19 g) and N,N-diisopropylethylamine (11 ml) in dichloromethane (10 ml) and the resulting solution left to stir at room temperature under nitrogen atmosphere for 2 hours, the Reaction mixture was poured into water and the organic phase is separated and washed with 2 N. hydrochloric acid, 10% aqueous sodium hydroxide and a saturated solution of salt. The organic phase is then dried over sodium sulfate, filtered and concentrated under reduced pressure and the resulting solid is recrystallized from isopropanol to obtain specified in the subtitle compound as a solid (3,52 g).

MS (APCI+ve) 349 (M+H)+

1H NMR (DMSO-d6) δ a total of 8.74 (1H, t); 7,89 (1H, m); 7,75-of 7.69 (2H, m); only 2.91 (2H, d); of 1.93 (3H, Sirs); 1,64 (6N, DD); 1,47 (6N, e)

b) 3-(4-[{1,1-Dimethylethyl}oxycarbonyl]piperazine-1-yl)-2-nitro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A mixture of 3-chloro-2-nitro-N-(tricyclo[3.3..1 3,7]Oct-1-ylmethyl)benzamide (2,80 g, example 1A) and tert-butyl methyl ether piperazine-1-carboxylic acid (7.47 g) in dry dimethyl sulfoxide (10 ml) is heated at 120°C in nitrogen atmosphere for 24 hours the Cooled reaction mixture is diluted with water and extracted three times with ethyl acetate. The combined extracts washed with water, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to obtain a solid substance. Purification by chromatography on silica gel with elution with a mixture of isohexane/ethyl acetate (2:1) gives specified in the subtitle compound as a solid (3.8 g).

MS (APCI+ve) 499 (M+H)+

1H NMR (DMSO-d6) δ 8,55 (1H, t); a 7.62 to 7.59 (2H, m); the 7.43 (1H, DD); to 3.38 (4H, shirt); 2,90-2,84 (6N, m); of 1.93 (3H, Sirs); 1,63 (6N, DD); 1,47 (6N, e); 1,41 (N, C).

C) 2-Nitro-3-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A solution of 3-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazine-1-yl)-2-nitro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,58 g, example 1b) and hydrochloric acid (6.4 ml, 4 BC in dioxane) in tetrahydrofuran (20 ml) was stirred at room temperature under nitrogen atmosphere for 18 hours, the Reaction mixture was concentrated under reduced pressure and the residue is dissolved in water, make basic with solid sodium bicarbonate and extracted with dichloromethane three times. The combined organic EXT the acts dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to obtain a solid substance. Purification by chromatography on silica gel with elution with 10% methanol in dichloromethane gives specified in the title compound in the form of solids (0,165 g).

MS (APCI+ve) 399 (M+H)+

1H NMR (DMSO-d6) δ charged 8.52 (1H, t); to 7.59 (1H, t); 7,51 (1H, d); to 7.35 (1H, d); is 2.88 (2H, d); of 2.81 (4H, m); is 2.37 (4H, m); of 1.93 (3H, Sirs); to 1.67 (3H, d)and 1.60 (3H, d); 1,47 (6N, C).

Example 2

Dihydrochloride salt of 2-amino-3-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Amino-3-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazine-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A suspension of 3-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazine-1-yl)-2-nitro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (3.8 g, example 1b), iron powder (2,13 g) and ammonium chloride (2,04 g) in a mixture of 2:1 ethanol/water (90 ml) is heated at boiling under reflux in nitrogen atmosphere for 2 h the Cooled reaction mixture is filtered and the filtrate partitioned between water and ethyl acetate. The organic layer was separated and then washed twice with water, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to obtain a residue. Purification of the residue by chromatography on silica gel with elution with 20% ethyl acetate in isohexane network indicated the data in the subtitle compound as a solid (2,27 g).

MS (APCI + ve) 469 (M+N)+.

b) Dihydrochloride salt of 2-amino-3-piperazine-1-yl-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 1C) using 2-amino-3-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazine-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.2 g, example 2A) and hydrochloric acid (5 ml 4 N. in dioxane). The reaction mixture was concentrated under reduced pressure to obtain a solid substance, which when crushed with diethyl ether gives specified in the title compound as a solid (0.2 g).

MS (APCI+ve) 369 (M-2HCl)+

1H NMR (DMSO-d6) δ 9,16 (2H, Sirs); to 8.14 (1H, t); 7,37 (1H, d); 7,07 (1H, d); only 6.64 (1H, t); with 3.27 (4H, Sirs); 2,98 (4H, Sirs); 2,95 (2H, d); of 1.93 (3H, Sirs); to 1.67 (3H, d); to 1.59 (3H, d); 1,48 (6N, C).

Example 3

2-Chloro-3-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Chloro-3-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazine-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-amino-3-(4-[{1,1-dimethylethyl}oxycarbonyl] piperazine-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (1 g, example 2A) in tetrahydrofuran (23 ml) was added 1 M aqueous hydrochloric acid (2,78 ml) and water (10 ml). The solution is cooled to 0°and portions add sodium nitrite (1,91 g) while maintaining the internal temperature the lower is 5° C. After stirring at 0-5°C for 0.5 h pre-cooled suspension of copper chloride(I) (of 10.58 g) and copper chloride(II) in water (20 ml) is added by portions to a pale yellow suspension. The mixture was stirred at 0°C for 0.5 h, then at room temperature for 0.5 hours, the Reaction mixture was poured into a mixture of water and dichloromethane and 1/1:0.88 ammonia/water up until the aqueous phase becomes homogeneous. The layers are separated and the aqueous phase extracted twice with dichloromethane. The combined organic extracts are washed with a solution of 1/1:0.88 ammonia/water up until the aqueous layer becomes colorless, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain oil. Purification by chromatography on silica gel with elution 20-35% solution in ethyl acetate/isohexane network specified in the subtitle compound as a solid (0.45 g).

MS (APCI+ve) 388 (M-BOC)+

1H NMR (DMSO-d6) δ of 8.27 (1H, t); to 7.32 (1H, t); 7,19 (1H, d);? 7.04 baby mortality (1H, d); of 3.48 (4H, m); 2,93-2.91 in (6N, m); of 1.94 (3H, Sirs); of 1.64 (3H, d); to 1.59 (3H, d); 1,52 (6N, C); 1,43 (N, C).

b) 2-Chloro-3-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-chloro-3-(4-[{1,1-dimethylethyl}oxycarbonyl] piperazine-1-yl)-2-nitro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl) benzamide (0.45 g, example 3A) in dichloromethane (10 ml) add triperoxonane acid (5 ml). After premesis the tion at room temperature in a nitrogen atmosphere, the reaction mixture was concentrated under reduced pressure to obtain resin. The resin is distributed between water and dichloromethane and make basic with solid sodium bicarbonate. The layers are separated and the aqueous layer was further extracted twice with dichloromethane. The combined organic extracts are washed twice with water, saturated salt solution, then dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to obtain foam. Foam HPLC purified with normal phase (0-20% ethanol/dichloromethane) and chromatographic on silica gel with elution with 10% methanol in dichloromethane to obtain specified in the title compound as a foam (0.05 g).

MS (APCI+ve) 388/90 (M+H)+

1H NMR (DMSO-d6) δ 8,24 (1H, t); 7,31 (1H, t); to 7.15 (1H, d); 7,00 (1H, d); 2,96-2,87 (10H, m); of 1.93 (3H, Sirs); to 1.67 (3H, d); to 1.59 (3H, d); 1,52 (6N, C).

Example 4

2-Chloro-5-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Chloro-5-nitro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-chloro-5-nitrobenzoic acid (1.22 g) in N,N-dimethylformamide (1.5 ml) add carbonyldiimidazole (1.0 g). The resulting reaction mixture is stirred for 2.5 h and then add 1-adamantanemethylamine (1.0 g). After 14 h the reaction mixture was distributed between ethyl acetate and water and the organic layer was separated, washed with water and saturated salt solution and then dried over sodium sulfate(Na 2SO4). The organic layer is concentrated under reduced pressure to obtain residue, which is purified by chromatography on silica gel (elution 3-10% methanol in dichloromethane) to obtain specified in the subtitle compound as a yellow substance (1.7 g).

MS (APCI+ve) 348/350 (M+H)+

1H NMR (CdCl3) δ 8,53 (1H, d), and 8.2 (1H, DD), and 7.6 (1H, d)and 6.2 (1H, Sirs), and 3.2 (2H, d), and 2.0 (3H, Sirs), 1,8 (N, m).

b) 5-Amino-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A solution of nitro compounds from example 4A (0.50 g) and ammonium chloride (0.5 g) dissolved in 50% aqueous ethanol. Add iron powder (0.5 g) and the mixture is stirred at a temperature of phlegmy for 3 h before cooling and the solid is removed by filtration. The mother liquor is treated with 10% sodium hydroxide solution and the product extracted with ethyl acetate. The organic solution was washed with saturated salt solution, dried over sodium sulfate (Na2SO4) and concentrated to obtain residue, which is purified by chromatography on silica gel with obtaining specified in the title compound as a white solid (0.4 g).

MS (APCI+ve) 319/21 (M+H)+

1H NMR (DMSO-d6) δ to 8.14 (1H, t); 7,03 (1H, DD); 6,56 (2H, m); are 5.36 (2H, s); 2,89 (2H, d); 1,95 (3H, s); 1,7 (N, m).

C) 2-Chloro-5-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 5-amino-2 is the PR-N-(tricyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide (1,00 g, example 4b) in xylene (20 ml) is added cleaners containing hydrochloride salt of bis-(2-chloroethyl)amine (0,620 g). The mixture is heated at 150°C for 12 h (get dark solution). The cold solution was washed with 2 M HCl, the aqueous layer washed with ethyl acetate, then alkalinized with sodium bicarbonate and extracted twice with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to obtain foam. The crude material is purified on silica gel (0-10% ethanol/dichloromethane) to obtain specified in the title compounds as white solids (0,90 g).

MS (APCI+ve) 388/90 (M+H)+

1H NMR (DMSO-d6) δ by 8.22 (1H, t); 7,22 (1H, d); of 6.96 (1H, DD); at 6.84 (1H, d); 3,50-3,20 (7H, m); 3,00-2,90 (2H, t); only 2.91 (2H, d); of 1.94 (3H, Sirs); to 1.67 (3H, d); to 1.59 (3H, d); 1,52 (6N, C).

Example 5

Cleaners containing hydrochloride salt of 2-chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 1,1-Dimethylethylene ester 4-[4-chloro-3-(etoxycarbonyl)phenyl]hexahydro-1H-1,4-diazepin-1-carboxylic acid

A mixture of ethyl ester of 5-bromo-2-chlorbenzoyl acid (0.50 g), 1,1-dimethylethylene ester hexahydro-1H-1,4-diazepin-1-carboxylic acid (0,46 g), cesium carbonate (0,86 g), palladium (II) acetate (8.5 mg) and (R)-BINAP (35 mg) in toluene (3 ml) is heated at 100°C for 14 h in the autoclave, rototom stream of hydrogen. The cooled reaction mixture was poured into water and extracted (3 times) with ethyl acetate. The combined organic extracts washed with a saturated solution of sodium chloride and then dried over magnesium sulfate. Evaporation under reduced pressure gives an oil which is purified by chromatography on silica gel with elution with 20% ethyl acetate in isohexane obtaining specified in the subtitle compound as an oil (0.21 g).

MS (APCI + ve) 282/284 (M-BOC)+.

(b) 1,1-Dimethylethylene ester 4-(3-carboxy-4-chlorophenyl)hexahydro-1H-1,4-diazepin-1-carboxylic acid

A suspension of 1,1-dimethylethylene ester 4-[4-chloro-3-(etoxycarbonyl)phenyl]hexahydro-1H-1,4-diazepin-1-carboxylic acid (example 5A, 0.21 g), monohydrate of lithium hydroxide (1,05 ml of 3 M solution in water) in a mixture of 1:1 ethanol/water (7 ml) was stirred at room temperature for 14 hours Add monohydrate of lithium hydroxide (0,55 ml of 3 M solution in water) and then tetrahydrofuran (1 ml). The resulting solution is stirred for 4 h at room temperature, then poured into water and extracted with diethyl ether. The aqueous phase is separated, acidified with 2 M hydrochloric acid and then extracted three times with dichloromethane. The combined dichloromethane layers are dried over magnesium sulfate and evaporated under reduced pressure to obtain specified in the subtitle compound in the form of art is Klah.

MS (APCI + ve) 298/300 (MtBu)+

c) 1,1-Dimethylethylene broadcast hexahydro-4-[4-methyl-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]-1H-1,4-diazepin-1-carboxylic acid

A solution of 1,1-dimethylethylene ester 4-(3-carboxy-4-chlorophenyl)hexahydro-1H-1,4-diazepin-1-carboxylic acid (example 5b, 0.10 g) and N,N'-carbonyldiimidazole (0,045 g) in dimethylformamide (3 ml) was stirred at room temperature for 2 hours Then add 1-adamantanemethylamine (0,050 ml) and stirring is continued for 14 hours, the Reaction mixture was poured into water and extracted with ethyl acetate three times. Layers of ethyl acetate are combined and washed with 2 M hydrochloric acid, 10% aqueous sodium hydroxide and saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. Purification by chromatography on silica gel with elution 20-30% ethyl acetate in isohexane network specified in the subtitle compound in the form of resin that solidifies upon standing.

MS (APCI + ve) 502/504 (M+H)+.

d) cleaners containing hydrochloride salt of 2-chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

1,1-Dimethylethylene broadcast hexahydro-4-[4-methyl-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]-1H-1,4-diazepin-1-carboxylic acid (from example 5) is dissolved in methanol (5 ml) and add chlorotoluron the acid (0.5 ml 4 N. solution in dioxane). After stirring at room temperature for 14 h the mixture was evaporated to 2/3 of the initial volume under reduced pressure. To the solution is slowly added diethyl ether and the resulting precipitate is collected by filtration, washed with diethyl ether and dried in vacuum to obtain specified in the title compound as a solid (0,027 g).

MS (APCI+ve) 402/404 (M+H)+

1H NMR (DMSO-d6) δ 9,11 (2H, Sirs); 8,18 (1H, t); from 7.24 (1H, d); for 6.81 (1H, DD); of 6.71 (1H, d); 3,71 (2H, t); 3,50 (2H, t); 3,19 (2H, Sirs); of 2.93 (2H, Sirs); 2,92 (2H, d); of 2.08 (2H, m); of 1.94 (3H, Sirs); to 1.67 (3H, d); to 1.59 (3H, Sirs); 1,52 (6N, C).

Example 6

Cleaners containing hydrochloride salt of 5-(4-amino-1-piperidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) Ethyl ester of 2-chloro-5-[4-[[(1,1-dimethylmethoxy)carbonyl]amino]-1-piperidinyl]benzoic acid

Obtaining carried out as described in example 5A), using ethyl ester 5-bromo-2-chlorbenzoyl acid (0.50 g), 1,1-dimethylethylene ether 4-piperidinylcarbonyl acid (0,46 g), cesium carbonate (0,86 g), palladium(II) acetate (8.5 mg) and (R)-BINAP (35 mg) and toluene (3 ml) to obtain specified in the subtitle compound as an oil (0.17 g).

MS (APCI + ve) 383/385 (M+N)+.

b) 2-Chloro-5-[4-[[(1,1-dimethylmethoxy)carbonyl]amino]-1-piperidinyl]benzoic acid

Getting carried out, as the description is but in example 5b), using the ethyl ester of 2-chloro-5-[4-[[(1,1-dimethylmethoxy)carbonyl]amino]-1-piperidinyl]benzoic acid (example 6A, 0.17 g), monohydrate of lithium hydroxide (0,88 ml of 3 M solution in water), a mixture of 1:1 ethanol/water (7 ml) and tetrahydrofuran (1 ml) to obtain specified in the subtitle compound as a solid (0.14 g).

MS (APCI+ve) 354/356 (M+N)+.

(C) 1,1-Dimethylethylene ether [1-[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]-4-piperidinyl]carbamino acid

Obtaining carried out as described in example 5C), using 2-chloro-5-[4-[[(1,1-dimethylmethoxy)carbonyl]amino]-1-piperidinyl]benzoic acid (example 6b, 0,065 g), N,N'-carbonyldiimidazole (0,030 g), 1-adamantanemethylamine (to 0.032 ml) and dimethylformamide (3 ml) to obtain specified in the subtitle compound as a solid substance.

MS (APCI+ve) 501/503 (M+N)+.

d) cleaners containing hydrochloride salt of 5-(4-amino-1-piperidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in the above example 5d), using 1,1-dimethylethylene ether [1-[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]-4-piperidinyl]carbamino acid (example 6C), hydrochloric acid (0.5 ml of 4 n solution in dioxane) and methanol (10 ml). The mixture is heated at the boil under reflux for 15 min to complete the Oia reaction. After evaporation of up to two thirds of the initial volume when standing crystallized solid, which is collected by filtration and dried in vacuum to obtain specified in the title compound as a solid (0.025 g).

MS (APCI+ve) 402/404 (M-HCl)+

1H NMR (DMSO-d6) δ 8,23 (1H, t); 8,11 (1H, Sirs); 7,28 (1H, d); 7,03 (1H, DD); 6,94 (1H, s); 3,74 (2H, d); 3,20 (1H, m); only 2.91 (2H, d); and 2.83 (2H, t); to 1.98 (2H, Sirs); of 1.94 (3H, Sirs); 1,69 is 1.58 (8H, m); 1,52 (6N, C).

Example 7

Cleaners containing hydrochloride salt of (+/-)-5-(3-amino-1-pyrrolidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) Ethyl ester of (+/-)-2-chloro-5-[3-[[(1,1-dimethylmethoxy)carbonyl]amino]-1-pyrrolidinyl]benzoic acid

Obtaining carried out as described in example 5A), using ethyl ester 5-bromo-2-chlorbenzoyl acid (0.50 g), 1,1-dimethylethylene ester 3-pyrrolidinylcarbonyl acid (0,42 g), cesium carbonate (0,86 g), palladium(II) acetate (21 mg) and (R)-BINAP (88 mg) and toluene (3 ml) to obtain specified in the subtitle compound as an oil (0.25 g).

MS (APCI+ve) 311/313 (M-BOC)+.

(b) (+/-)-2-Chloro-5-[3-[[(1,1-dimethylmethoxy)carbonyl]amino]-1-pyrrolidinyl]benzoic acid

Obtaining carried out as described in example 5b), using ethyl ether (+/-)-2-chloro-5-[3-[[(1,1-dimethylmethoxy)carbonyl]amino]-1-pyrrolidinyl]benzoic acid (example 7a, 0.25 g), mono is igrata of lithium hydroxide (1,36 ml of 3 M solution in water), a mixture of 1:1 ethanol/water (7 ml) and tetrahydrofuran (1 ml) to obtain specified in the subtitle compound as a solid (0,23 g).

MS (APCI+ve) 248/286 (M-BOC)+.

(C) 1,1-Dimethylethylene ether (+/-)-[1-[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]-3-pyrrolidinyl]carbamino acid

Obtaining carried out as described in example 5C), using (+/-)-2-chloro-5-[3-[[(1,1-dimethylmethoxy) carbonyl]amino]-1-pyrrolidinyl]benzoic acid (example 7b, 0,070 g), N,N'-carbonyldiimidazole (0,033 g), 1-adamantanemethylamine (0.036 ml) and dimethylformamide (3 ml) to obtain specified in the subtitle compound in the form of resin.

MS (APCI+ve) 487/489 (M+H)+.

d) cleaners containing hydrochloride salt of (+/-)-5-(3-amino-1-pyrrolidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 5d), using 1,1-dimethylethylene ether (+/-)-[1-[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]-3-pyrrolidinyl]carbamino acid (example 7C), hydrochloric acid (0.5 ml of 4 n solution in dioxane) and methanol (5 ml). Evaporation under reduced pressure gives a solid after trituration with diethyl ether. Recrystallization from methanol/diethyl ether gives specified in the title compound in the form of solids (0,030 g).

MS (APCI+ve) 388/390 (M+H)+

1H NMR (DMSO-d6/sub> ) δ 8,24 (3H, Sirs); to 8.20 (1H, t); to 7.25 (1H, d); is 6.61 (1H, DD); 6,51 (1H, d); of 3.94 (1H, m); 3,55-of 3.32 (2H, m); 3,29 (2H, m); 2,92 (2H, d); 2,37-of 2.27 (1H, m); 2,13-2,05 (1H, m); of 1.94 (3H, Sirs); by 1.68 (3H, d); to 1.59 (3H, d); 1,52 (6N, C).

Example 8

Cleaners containing hydrochloride salt of 2-chloro-5-piperazine-1-ylmethyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 5-methyl bromide-2-chlorbenzene acid

To a stirred solution of 2-chloro-5-methylbenzoic acid (25 g) in chloroform (500 ml) at 50°add N-bromosuccinimide (27,40 g). The flask is rinsed with nitrogen and one portion add azobisisobutyronitrile (0.10 g). The solution is heated to boiling under reflux for 1 hour Add azobisisobutyronitrile (0.10 g) and the mixture is heated an additional 3 hours the Solution was concentrated in vacuo, dissolved again in diethyl ether and filtered to remove undissolved succinimide. The ether solution is washed with 2 N. aqueous solution of hydrochloric acid, then with saturated salt solution, then dried over magnesium sulfate. The solution is concentrated to a volume of 150 ml, then diluted with isohexane. After a further partial concentration crystallization starts. The mixture is left in an ice bath for 1 h the Resulting crystals filtered, washed with isohexane is dried in vacuum to obtain specified in the subtitle compound (17 g).

b) 5-methyl bromide-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a stirred solution of 5-methyl bromide-2-chlorbenzoyl acid (example 8A, 12.4 g) in dichloromethane (250 ml) and dimethylformamide (0,12 ml) at 0°With add oxalicacid (8,7 ml). The cooling bath removed and the solution allow to warm to room temperature. After cessation of gas evolution, the solution was concentrated in vacuo. The residue is again dissolved in dichloromethane (300 ml), cooled to 0°and treat diisopropylethylamine (12,4 ml) and adamantanemethylamine (7,54 ml). After 15 min at 0°the solution was poured into diethyl ether (1 l) and washed with 1 N. aqueous hydrochloric acid and then a saturated solution of salt. The organic portion is dried over magnesium sulfate and concentrated in vacuo to obtain specified in the title compound as a white powder (19 g).

MS (APCI+ve) 396/398 (M+H)+

1H NMR (DMSO-d6) δ 8,39 (1H, t); 7,50-7,40 (2H, m); 4,74 (2H, s); 2,92 (2H, d); of 2.50 (3H, s); of 1.94 (3H, Sirs); to 1.67 (3H, d); to 1.59 (3H, d); 1,52 (6N, C).

C) 2-Chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazine-1-yl)methyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A mixture of 5-methyl bromide-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 8b, 0,130 g), 1-tert-butyloxycarbonyl (0,074 g) and diisopropylethylamine (6.3 ml) in dimethylformamide (3 ml) is heated at 60&#HWS within 3 hours The mixture was diluted with water (10 ml) and extracted with ethyl acetate (3 x 10 ml). The organic layer is dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude material is purified on silica gel with elution with a mixture of dichloromethane/ethanol (gradient 0-20%) to obtain the specified title compound as a white foam (0,112 g).

MS (APCI+ve) MM 502/504 (M+H)+

1H NMR (DMSO-d6) δ of 8.28 (1H, t); 7,40 (1H, d); to 7.32 (1H, DD); 7,29 (1H, d); 3,74 (2H, s); for 3.28 (4H, t); 2,90 (2H, d); 2,31 (4H, t); of 1.92 (3H, Sirs); 1.70 to 1,50 (6N, m); 1,59 (6N, e); 1,37 (N, C).

d) cleaners containing hydrochloride salt of 2-chloro-5-piperazine-1-ylmethyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

2-Chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazine-1-yl)methyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 8C, 0,080 g) dissolved in methanol (3 ml), add 4 N. HCl in dioxane (1 ml) and the mixture is stirred at room temperature for 1.5 hours the Solvent is removed in vacuo and the resulting solid triturated with ether to obtain specified in the title compound as a white powder (0,062 g).

MS (APCI+ve) MM 402/404 (M+H)+

1H NMR (DMSO-d6) δ 8,30 (1H, t); 7,63 (2H, Sirs); at 7.55 (1H, d); 4,33 (1H, Sirs); of 4.05 (4H, m); 3,50 3.00 for (4H, m); 3,50 is 3.40 (1H, m); 2,92 (2H, d); of 1.92 (3H, Sirs); 1.70 to 1,50 (6N, m); 1.57 in (6N, Sirs).

In accordance with the procedure described in example 8, to obtain the following compounds.

P the emer 9

Cleaners containing hydrochloride salt of 2-chloro-5-[(hexahydro-1H-1,4-diazepin-1-yl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

MS (APCI+ve) MM 416/418 (M+H)+

1H NMR (DMSO-d6) δ are 11.62 (Sirs, 1H), to 9.57 (Sirs, 1H); of 9.30 (Sirs, 1H); 8.34 PER (1H, t); 7,80-of 7.60 (2H, m); to 7.59 (1H, d); 4,50-4,30 (Sirs, 2H); 3,80 is 3.00 (m, 8H); TO 2.94 (2H, d); 2,25-2,10 (m, 2H); OF 1.94 (3H, Sirs); of 1.66 (3H, d); was 1.58 (3H str); 1,54 (6N, C).

Example 10

Cleaners containing hydrochloride salt of 5-[(4-amino-1-piperidinyl)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

MS (APCI+ve) MM 416/418 (M+H)+

1H NMR (DMSO-d6) δ 8,35 (1H, t); 8,30 (2H, Sirs); 7,66 (1H, d); the 7.65 (1H, s); to 7.59 (1H, d); 4,28 (d, 2H); 3,65-3,18 (m, 4H); 3,10-2,90 (1H, m); 2,95 (2H, d); 2,15-of 2.05 (2H, m); 2,05-1,90 (1H, m); of 1.94 (3H, Sirs); 1,68 (3H d); to 1.61 (3H, d); 1,54 (6N, C).

Example 11

Cleaners containing hydrochloride salt of 5-[(3-amino-1-pyrrolidinyl)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

MS (APCI+ve) MM 402/404 (M+H)+

1H NMR (DMSO-d6) δ 8,56 (1H, Sirs); 8,42 (2H, Sirs); 8,35 (1H, t); 7,66 (2H, Sirs); to 7.59 (1H, d); 4,60-and 4.40 (m, 2H); 4,20-3,00 (m, 5H); TO 2.94 (2H, d); 2,35-of 1.95 (m, 2H); 1,95 (3H, Sirs); by 1.68 (3H, d); to 1.61 (3H, d); 1,54 (6N, ).

Example 12

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-yl is ethyl)benzamide

To a solution of 2-chloro-5-hydroxybenzoic acid (3.12 g) in N,N-dimethylformamide (50 ml) is added 1,1'-carbonyldiimidazole (3.0 g). The resulting reaction mixture is stirred for 2.5 h and then add 1-adamantanemethylamine (3.0 g). Stirring is continued for 14 hours, the Reaction mixture was distributed between ethyl acetate and water and the organic layer was separated, washed with water and saturated salt solution and then dried over sodium sulfate (Na2SO4). The organic layer is concentrated under reduced pressure to obtain residue, which is purified by chromatography on silica gel (elution 3-10% methanol in dichloromethane) to obtain specified in the subtitle compound as a white solid (0.15 g).

MS (APCI+ve) 319/321 (M+H)+

1H NMR (DMSO-d6) δ 9,85 (1H, s), of 8.25 (1H, t), from 7.24 (1H, d), 6,76-PC 6.82 (2H, m), 2,90 (2H, d), of 1.93 (3H, s)to 1.67 (3H, d), of 1.57 (3H, d)and 1.51 (6N, C).

b) cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 12A), 1,1-dimethylethylene ester 4-hydroxy-1-piperidinecarboxylic acid (0,19 g) and tributylphosphine (0,23 ml) in dry tetrahydrofuran (6 ml) was added 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g). The orange solution is heated at 60°C in an atmosphere of nitrogen at t the value of 2 hours At this point add additional 1,1-dimethylethylene ester of 4-hydroxy-1-piperidinecarboxylic acid (0,19 g), tributylphosphine (0,23 ml) and 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g). Heating is continued and the procedure described above is repeated until completion of the reaction according to LC/MS. The cooled reaction mixture is diluted with diethyl ether, then filtered. The filtrate is concentrated and purified HPLC normal phase (0-2% methanol/dichloromethane) and then by chromatography on silica gel (0-2% methanol/dichloromethane) to give tert-butyloxycarbonyl (BOC)-protected compound as a colourless foam. The foam was dissolved in methanol (5 ml) and add 4 N. hydrochloric acid in dioxane (0.25 ml). The solution was stirred at room temperature under nitrogen atmosphere until completion of the reaction according to LC/MS. Evaporation of the solvent followed by rubbing with diethyl ether gives specified in the title compound as a colourless solid (0.15 g).

MS (APCI+ve) 417/419 (M+H)+

1H NMR (DMSO-d6) δ 8,65 (2H, Sirs); 8,30 (1H, t); 7,39 (1H, d); 7,07 (1H, DD); 6,99 (1H, d); 4,72-of 4.67 (1H, m); is 3.21 (2H, SIRM); of 3.07 (2H, SIRM); 2,92 (2H, d); 2,12-2,07 (2H, m); of 1.94 (3H, Sirs); 1,88 and 1.80 (2H, m); a rate of 1.67 (3H, d); to 1.59 (3H, d); 1,52 (6N, C).

Example 13

Cleaners containing hydrochloride salt of (R)-2-chloro-5-(pyrrolidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 12A), N-tert-BOC-D-prolinol (0,19 g) and tributylphosphine (0,23 ml), dry tetrahydrofuran (6 ml) and 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g) to obtain butyloxycarbonyl(BOC)-protected compound followed by treatment of 4 N. hydrochloric acid in dioxane (0.4 ml) and methanol (5 ml) to obtain specified in the title compounds as colorless solids (0.14 g).

MS (APCI+ve) 403/405 (M+H)+

1H NMR (CD3OD) δ to 8.45 (1H, shirt); 7,46 (1H, d); 7,14-7,10 (2H, m); to 4.41 (1H, DD); 4,18 (1H, t); 4,10-Android 4.04 (1H, m); to 3.41 (2H, t); 3,10 (2H, m); 2,36-of 2.28 (1H, m); 2,25-2,08 (2H, d); 2,03 (3H, s); 2,00-1,90 (1H, m); to 1.83 (3H, m); total 1.74 (3H, d); 1,68 (6N, C).

Example 14

Cleaners containing hydrochloride salt of (S)-2-chloro-5-(2-pyrrolidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 12A), N-tert-BOC-L-prolinol (0,19 g) and tributylphosphine (0,23 ml), dry tetrahydrofuran (6 ml) and 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g) to obtain tert-butyloxycarbonyl(BOC)-protected compound and subsequent processing 4 N. of hydrochloric Kolotov dioxane (0.5 ml) and methanol (5 ml) to obtain the specified title compound as a colourless solid substances (0.07 g).

MS (APCI+ve) 403/405 (M+H)+

1H NMR (CD3OD) δ to 8.45 (1H, shirt); 7,46 (1H, d); 7,14-7,10 (2H, m); to 4.41 (1H, DD); 4,18 (1H, t); 4,10-Android 4.04 (1H, m); to 3.41 (2H, t); 3,10 (2H, m); 2,36-of 2.28 (1H, m); 2,25-2,08 (2H, d); 2,03 (3H, s); 2,00-1,90 (1H, m); to 1.83 (3H, m); total 1.74 (3H, d); 1,68 (6N, C).

Example 15

Cleaners containing hydrochloride salt of 2-chloro-5-(3-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 12A), 3-piperidinemethanol (0.20 g) and tributylphosphine (0,23 ml), dry tetrahydrofuran (6 ml) and 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g) to obtain tert-butyloxycarbonyl(BOC)-protected compound. This connection process 4 N. hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to obtain the specified title compound as a colourless solid (0.09 g).

MS (APCI+ve) 417/19 (M+H)+

1H NMR (DMSO-d6) δ a 8.34 (2H, Sirs); 8,29 (1H, t); 7,38 (1H, d); 7,01 (1H, DD); 6,93 (1H, d); 3,99-of 3.95 (1H, m); 3,91-a 3.87 (1H, m); to 3.34 (1H, m), 3,23 (1H, sird); 2,92 (2H, d); 2,82-a 2.71 (2H, m); 2,22 (1H, m); of 1.94 (3H, ); is 1.82 (2H, d); 1,72-of 1.66 (4H, m); of 1.59 (3H, d); 1,52 (6N, C); 1,39-1,32 (1H, m).

Example 16

Cleaners containing hydrochloride salt of CIS-5-[(4-aminocyclohexane)oxy]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

P is torching conduct, as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 12A), TRANS-4-aminocyclohexanol (0.20 g) and tributylphosphine (0,23 ml), dry tetrahydrofuran (6 ml) and 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g) to obtain tert-butyloxycarbonyl(BOC)-protected compound. This connection process 4 N. hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to obtain the specified title compound as a colourless solid (0,065 g).

MS (APCI+ve) 417/19 BP 417

1H NMR (DMSO-d6) δ 8,30 (1H, t); 7,97 (3H, Sirs); 7,38 (1H, d); 7,02 (1H, DD); 6,92 (1H, d); to 4.62 (1H, Sirs); 3,11 (1H, Sirs); 2,92 (2H, d); of 1.94 (5H, s); 1,76-1,58 (N, m); 1,52 (6N, C).

Example 17

Cleaners containing hydrochloride salt of 2-methyl-5-(1-piperazinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-bromo-5-(4-[{1,1-dimethylethyl}oxy carbonyl]piperazine-1-yl)methyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 65b) and tetrakis(triphenylphosphine)palladium(0) (2 mg) in dry toluene (6 ml) add tetramethylsilane (0.2 ml). The solution is heated at 130°C in a sealed tube for 18 hours. The cooled reaction mixture is evaporated and the residue is treated with 10% KF solution in acetone and stirred for 45 minutes the Mixture is concentrated and chromatographic on when likehere (isohexane, the mixture is then 60% ethyl acetate/40% isohexane) to obtain tert-butyloxycarbonyl(BOC)-protected compound as a colourless oil. The oil was dissolved in methanol (2 ml) and add 4 N. hydrochloric acid in dioxane (1 ml). The solution was stirred at room temperature under nitrogen atmosphere until completion of the reaction according to LC/MS. Evaporation of the solvent followed by rubbing with diethyl ether gives specified in the title compound as colorless solid (0.03 g).

MS (APCI+ve) 382 (M+H)+

1H NMR (CD3OD) δ to 7.61 (1H, s); of 7.55 (1H, d); 7,39 (1H, d); of 4.45 (2H, s); 3,67-of 3.46 (8H, SIRM); is 3.08 (2H, s); of 2.45 (3H, s); 1,99 (3H, s); of 1.78 (3H, d); 1,71 (3H, d); 1,62 (6N, C).

Example 18

Cleaners containing hydrochloride salt of 2-chloro-5-(1-piperazinylmethyl)-N-(2-tricyclo[3.3.1.13,7]Oct-1-retil)benzamide

a) 5-(methyl bromide)-2-chloro-N-(2-tricyclo[3.3.1.13,7]Oct-1-retil)benzamid

To a solution of 2-chloro-5-(methyl bromide)benzoic acid (1.0 g) in dichloromethane (25 ml) at 0°add dimethylformamide (0.05 ml) and then oxalicacid (0,52 ml). The reaction mixture allow to warm to room temperature and stirred for 30 minutes Volatile components are removed under vacuum and the residue is dried in high vacuum. Acylchlorides dissolved in dichloromethane (20 ml) and added to a solution of cleaners containing hydrochloride salt of 2-adamantanemethylamine (0.95 g) is dichloromethane (20 ml) and diisopropylethylamine (2 ml) at 0° C. the Reaction mixture was allow to warm to room temperature and stirred for 2 hours the Organic portion washed with water (20 ml), then saturated aqueous ammonium chloride and the organic layer is dried over magnesium sulfate, then filtered. The filtrate is concentrated under reduced pressure to obtain a solid substance. The crude material is recrystallized from a mixture of dichloromethane/hexane to obtain specified in the subtitle compound as a white solid (1.3 g).

(b) 1,1-Dimethylethylene ester 4-[[4-chloro-3-[[(2-tricyclo[3.3.1.13,7]Oct-1-retil)amino]carbonyl]phenyl]methyl]-1-piperazinecarboxamide acid

A mixture of 5-(methyl bromide)-2-chloro-N-(2-tricyclo[3.3.1.13,7]Oct-1-retil)benzamide (example 18a, 0.35 g), 1-tert-butyloxycarbonyl (0,213 g), potassium carbonate (0.20 g) and potassium iodide (10 g) in acetone (5 ml) is heated at 60°C for 2 hours, the Acetone is removed in vacuo, the residue is dissolved in dichloromethane and the solid is removed by filtration. The crude material is purified on silica gel with elution with a mixture of dichloromethane/ethanol (gradient 0-10%) to obtain specified in the subtitle compound as a white foam (0,383 g).

MS (APCI+ve) MM 516/518 (M+H)+

1H NMR (CDCl3) δ 7,63 (1H, Sirs); 7,34 (2H, Sirs); 6,09 (1H, Sirs); 3,60-3,30 (8H, m); 2.50 each-of 2.30 (4H, Sirs); of 1.97 (3H, Sirs); 1,72 (3H, d); by 1.68 (3H, d); 1,56 (6N, Sirs); 1.44MB (N, C) of 1.50 and 1.35 (2H, m).

c) cleaners containing hydrochloride salt of 2-chloro-5-(1-piperazinylmethyl)-N-(2-tricyclo[3.3.1.13,7]Oct-1-retil)benzamide

1,1-Dimethylethylene ester 4-[[4-chloro-3-[[(2-tricyclo[3.3.1.13,7]Oct-1-retil)amino]carbonyl]phenyl]methyl]-1-piperazinecarboxamide acid (example 18b, 0,270 g) dissolved in methanol (3 ml), add 4 N. HCl in dioxane (2 ml) and the mixture is stirred for 14 h at room temperature. The solvent is removed in vacuo and the resulting solid triturated with ether to obtain specified in the title compound as a white powder (0,207 g).

MS (APCI+ve) MM 416/418 (M+H)+

1H NMR (CD3OD) δ of 7.69 (1H, s); 7,66 (1H, d); of 7.60 (1H, d); a 4.86 (2H, s); 3,70-3,50 (8H, m); 3,50-to 3.35 (2H, m); to 1.98 (3H, Sirs); of 1.78 (3H, d); to 1.70 (3H, d); 1,62 (6N, Sirs); of 1.50 and 1.35 (2H, m).

Example 19

Cleaners containing hydrochloride salt of (+/-)-2-chloro-5-(3-pyrrolidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,155 g, example 12A), tributylphosphine (0,23 ml) 1,1-dimethylethylene ether (+/-)-3-hydroxy-1-pyrrolidinecarbonyl acid (0,19 g), 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g) and dry tetrahydrofuran (10 ml) to obtain tert-butyloxycarbonyl(BOC)-protected compound as a colourless foam. The connection of srabatyvayut 4 N. hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to obtain the specified title compound as a colourless solid (0.075 g).

MS (APCI+ve) 389/391 (M+H)+

1H NMR (CD3OD) δ 8,42 (1H, shirt); 7,42 (1H, d); to 7.09-7.03 is (2H, m); 5,23 (1H, SIRM); 3,59-to 3.41 (4H, m); of 3.07 (2H, d); 2,36-of 2.30 (2H, m); 1,99 (3H, Sirs); to 1.79 (3H, d); to 1.70 (3H, d); 1,63 (6N, e).

Example 20

Cleaners containing hydrochloride salt of (+/-)-2-chloro-5-(3-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.15 g, example 12A), tributylphosphine (2×of 0.18 ml), 1,1-dimethylethylene ester 3-hydroxy-1-piperidinecarboxylic acid (2×0.14 g), 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (2×0.18 g) and dry tetrahydrofuran (6 ml) to obtain tert-butyloxycarbonyl(BOC)-protected compound as a colourless foam. This connection process 4 N. hydrochloric acid in dioxane (0.25 ml) and methanol (5 ml) to obtain the specified title compound as a colourless foam (0,042 g).

MS (APCI+ve) 403/405 (M+H)+

1H NMR (CD3OD) δ 8,42 (1H, t); 7,41 (1H, d); 7,14-7,10 (2H, m); 4,82 (1H, SIRM); 3,51-3,39 (1H, m); to 3.38 (2H, m); 3,20-3,17 (1H, m); a 3.06 (2H, d); 2,10-2,04 (2H, m); 2,00 (3H, Sirs); 1,94-1,89 (1H, m); 1,84-1,68 (7H, d); 1,64 (6N, e).

Example 21

TRANS-5-[(4-Aminocyclohexane)oxy)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.15 g, example 12A), tributylphosphine (3×of 0.18 ml), 1,1-dimethylethylene ether of CIS-4-(hydroxycyclohexyl)carbamino acid (3×0.15 g), 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (3×0.18 g) and dry tetrahydrofuran (6 ml) to obtain tert-butyloxycarbonyl(BOC)-protected compound as a colourless foam. This connection process 4 N. hydrochloric acid in dioxane (0.5 ml) and methanol (3 ml) to obtain the specified title compound as a colourless foam (0,080 g).

MS (APCI+ve) 417/419 (M+H)+

1H NMR (CD3OD) δ scored 8.38 (1H, t); 7,34 (1H, d); 6,98 (1H, DD); of 6.96 (1H, d); 4,30 (1H, m); 3,17 (1H, m); 3.04 from (2H, d); 2,22 (2H, SIRM); of 2.09 (2H, m); to 1.98 (3H, Sirs); or 1.77 (3H, d); by 1.68 (3H, d); 1,62 (6N, C); of 1.55 (4H, m).

Example 22

CIS-(+/-)-5-[(3-Aminocyclopent)oxy]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 12A), tributylphosphine (0,24 ml), 1,1-dimethylethylene ester, TRANS-(+/-)-(3-hydroxycyclopent)carb is inovas acid (0,19 g), 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g) and dry tetrahydrofuran (3 ml) to give tert-butyloxycarbonyl(BOC)-protected compound as a colourless foam. This connection process 4 N. hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to obtain the specified title compound as a colourless foam (0.15 g).

MS (APCI+ve) 403/405 (M+H)+

1H NMR (CD3OD) δ of 7.36 (1H, d); 7,02-6,98 (2H, m); 4,94-of 4.90 (1H, m); 3.75 to 3,68 (1H, m); 3.04 from (2N, C); to 2.55 (1H, m); 2,24-2,17 (1H, m); 2,09-2,03 (2H, m); 1,98 is 1.86 (5H, m); of 1.76 (3H, d); by 1.68 (3H, d); 1,62 (6N, D.).

Example 23

Cleaners containing hydrochloride salt of (S,S)-2-chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 5-Bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Get as in example 1A, from 5-bromo-2-chlorbenzoyl acid (7,17 g), oxalicacid (5,3 ml), dichloromethane (150 ml), dimethylformamide (0.05 ml), diisopropylethylamine (6 ml) and adamantanemethylamine (5 ml) to obtain specified in the subtitle compound as white colorless needles (7,3 g).

MS (APCI-ve) 382/384 (M-N)+

b) cleaners containing hydrochloride salt of (S,S)-2-chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A mixture of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (1.70 g, example 23a), 1,1-dimethylethylene ether 2,5-diazabicyclo[2.2,a]heptane-2-carboxylic acid (1.06 g), of cesium carbonate (2.20 g), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl((R)-(+)-BINAP, 0.20 g) and palladium(II) acetate (0,050 g) in dry toluene (10 ml) is heated at 100°C in nitrogen atmosphere for 24 hours the Cooled reaction mixture is filtered, washing the residue with ethyl acetate. The filtrate is washed with water and saturated salt solution, dried (MgSO4) and evaporated under reduced pressure to obtain an orange oil. The oil is purified by chromatography on silica gel with elution with a solution of 0.5% methanol/dichloromethane to obtain tert-butyloxycarbonyl(BOC)-protected compound as a colourless foam. The foam was dissolved in methanol (20 ml) and add 4 N. hydrochloric acid in dioxane (2.5 ml). The solution was stirred at room temperature until completion of the reaction (LC/MS). The solution is then evaporated under reduced pressure and the residue triturated with diethyl ether to obtain specified in the connection header in the form of not-quite-white solid (0,92 g).

MS (APCI+ve) 400/402 (M+H)+

1H NMR (CD3OD) δ 8,32 (1H, t); 7,30 (1H, d); 6,77-3,70 (2H, m); 4,69 (1H, s); 4,50 (1H, s); of 3.73 (1H, DD); to 3.67 (2H, s); a 3.06 (2H, d); 2,30 (1H, sird); to 2.06 (1H, sird); 1,99 (3H, Sirs); of 1.78 (3H, d); to 1.70 (3H, d); 1,64 (3H, s); of 1.55 (4H, m). Peak methanol screens other1H-signal.

Example 24

Cleaners containing hydrochloride salt of 2-chloro-5-(2-methyl-1-piperazinil)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in the above example 23, from 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,30 g, example 23a), 1,1-dimethylethylene ester 3-methyl-1-piperazinecarboxamide acid (0.20 g), cesium carbonate (0.36 g), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ((R)-(+)-BINAP, 0.036 g), palladium(II) acetate (0,009 g) and dry toluene (10 ml) to obtain tert-butyloxycarbonyl(BOC)-protected compound. This connection process 4 N. hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to obtain the specified title compound as a solid (0.025 g).

MS (APCI+ve) 402/404 (M-HCl)+

1H NMR (CD3OD) δ to 8.40 (1H, t); 7,37 (1H, d); 7,11 (1H, DD); 7,07 (1H, d); 4,00-of 3.96 (1H, m); 3,43-3,39 (3H, m); 3,28-3,19 (3H, m); a 3.06 (2H, d); to 1.98 (3H, Sirs); or 1.77 (3H, d); to 1.70 (3H, d); 1,63 (6N, C); 1,10 (3H, d).

Example 25

Cleaners containing hydrochloride salt of (+/-)-2-chloro-5-(3-pyrrolidinyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in the above example 23, from 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,30 g, example 23a), 1,1-dimethylethylene ester 3-amino-1-pyrrolidinecarbonyl acid (0.18 g), cesium carbonate (0.36 g), (R)-BINAP (0.036 g), anhydrous toluene (3 ml) and palladium(II) acetate (0,009 g); the mixture is heated for 14 h in an autoclave, purged with nitrogen. Add more the positive quantity (R)-BINAP (0.036 g) and palladium(II) acetate (0,009 g) and heating continued for an additional 24 h The cooled reaction mixture was poured into water and extracted three times with ethyl acetate. The organic fractions are combined and washed with water, then with saturated salt solution and dried (MgSO4). Evaporation under reduced pressure gives an oil which is purified HPLC normal phase (0-5% methanol/dichloromethane) to give tert-butyloxycarbonyl(BOC)-protected compound as a colourless foam. The foam will dissolve in methanol (5 ml) and add 4 N. hydrochloric acid in dioxane (0.5 ml). The solution was stirred at room temperature under nitrogen atmosphere until completion of the reaction according to LC/MS. Evaporation followed by rubbing with diethyl ether and methanol gives specified in the title compound in the form of not quite white solid/foam (0,040 g).

MS (APCI+ve) 388/390 (M-HCl)+

1H NMR (CD3OD) δ to 8.20 (1H, shirt); for 7.12 (1H, d); 6,63-6,60 (2H, m); 4,76-4,08 (1H, m); 3.43 points-to 3.38 (2H, m); 3,35 of 3.28 (1H, m); of 3.25 (1H, m); 2,94 (2H, s); 2,31-2,22 (1H, m); 2,01-of 1.94 (1H, m); 1,89 (3H, Sirs); to 1.67 (3H, d)and 1.60 (3H, d); 1,53 (6N, C).

Example 26

(+/-)-5-(3-Amino-1-piperidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in the above example 23, from 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 23a), 1,1-dimethylethylene ester 3-piperidinylcarbonyl acid (0.12 g), carbon is the cesium (0.24 g), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ((R)-(+)-BINAP, 0,024 g), palladium(II) acetate (0,006 g) and dry toluene (3 ml) to give tert-butoxycarbonyl(BOC)-protected compound. tert-Butoxycarbonyl(BOC)-protected compound was dissolved in methanol (5 ml) and hydrochloric acid (0.5 ml of 4 n solution in dioxane). After stirring at room temperature for 24 h the mixture was evaporated and the residue distributed between ethyl acetate and saturated sodium bicarbonate. The layers are separated and the aqueous phase is acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then evaporated under reduced pressure to obtain resin. Purification by chromatography on silica gel with elution 4-10% methanol in a mixture of dichloromethane/aqueous ammonia gives specified in the title compound as a solid (0.036 g).

MS (APCI+ve) 402/404 (M+H)+

1H NMR (CD3OD) δ to 7.25 (1H, d); 7,00 (1H, DD); of 6.96 (1H, d); 3,59 (1H, DD); 3,48 is-3.45 (1H, m); 3.04 from (2H, d); 2,91-to 2.85 (1H, m); 2,82 is 2.75 (1H, m), 2,58 (1H, DD); 1,98-of 1.93 (4H, m); 1.85 to about 1.75 (3H, m); 1.70 to 1,62 (10H, m); 1,34-1,25 (1H, d).

Example 27

(+/-)-2-Chloro-5-(3-piperidinylidene)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in the above example 23, from 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,30 g, example 23 is), 1,1-dimethylethylene ester 3-amino-1-piperidinecarboxylic acid (0,19 g), cesium carbonate (0.36 g), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ((R)-(+)-BINAP, 0.036 g), palladium(II) acetate (0.008 g) and dry toluene (3 ml) to give tert-butyloxycarbonyl(BOC)-protected compound. This compound is treated with methanol (5 ml) and hydrochloric acid (0.5 ml of 4 M solution in dioxane) followed by treatment with an acid/base. Purification by chromatography on silica gel with elution 4-10% methanol in a mixture of dichloromethane/aqueous ammonia gives specified in the title compound as a solid (0.008 g).

MS (APCI+ve) 402/404 (M+H)+

1H NMR (CD3OD) δ 7,14 (1H, d); 6,68-of 6.65 (2H, m); 3,47 is 3.40 (1H, m); of 3.25 (1H, m); 3,05-to 3.02 (3H, m); 2,72-to 2.65 (1H, m); 2,52-2,47 (1H, m); 2,08-2,04 (1H, m); of 1.97 (3H, Sirs); 1,89-to 1.82 (1H, m); 1.77 in (3H, m); 1.70 to 1,62 (10H, m); 1,50-of 1.40 (1H, m).

Example 28

2-Chloro-5-[hexahydrofuro[3,4-c]pyrrol-2(1H)-yl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in the above example 23, from 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.15 g, example 23a), 1,1-dimethylethylene ether hexahydrofuro[3,4-c]pyrrol-2(1H)-carboxylic acid (0.17 g), cesium carbonate (0.33 g), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl ((R)-(+)-BINAP, 0,018 g), palladium(II) acetate (0.004 g) and dry toluene (2 ml) to give tert-b is tiroxinebond(BOC)-protected compound. This compound is treated with methanol (5 ml) and hydrochloric acid (0.5 ml of 4 M solution in dioxane) followed by treatment with an acid/base. Rubbing the residue with dichloromethane gives specified in the title compound in the form of solids (0,020 g).

MS (APCI+ve) 414/416 (M+H)+

1H NMR (CD3OD) δ 8,17 (1H, t); then 7.20 (1H, d); 6,63 (1H, DD); is 6.54 (1H, d); to 3.36 (2H, m); to 3.02 (2H, DD); 2,95-2,90 (4H, m); 2,80 (2H, m); 2,60 (2H, DD); of 1.94 (3H, Sirs); to 1.67 (3H, d); to 1.59 (3H, d); 1,52 (6N, e).

Example 29

Cleaners containing hydrochloride salt of N-[2-methyl-5-(4-piperidinyloxy)phenyl]tricyclo[3.3.1.13,7]decane-1-ndimethylacetamide

Obtaining carried out as described in example 12b, using N-(5-hydroxy-2-were)tricyclo[3.3.1.13,7]decane-1-ndimethylacetamide (0.51 g, example 12, WO 99/29660), tributylphosphine (0,64 ml), 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.65 g), 1,1-dimethylethylene ester 4-hydroxy-1-piperidinecarboxylic acid (0.52 g) and dry tetrahydrofuran (10 ml) to obtain tert-butoxycarbonyl(BOC)-protected compound as a colourless solid. This connection process 4 N. hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to obtain the specified title compound as a colourless solid (0,13 g).

MS (APCI+ve) 383 (M-HCl)+

1H NMR (CD3OD) δ 7,19 (1H, d); for 7.12 (1H, d); 6,83 (1H, d is); 4,71-of 4.66 (1H, m); 3.46 in is 3.40 (2H, m); 3,28-up 3.22 (2H, m); of 2.25 (3H, s); of 2.21 (1H, s); 2.21 are to 2.14 (2H, m); 2,11-2,04 (5H, m); 1,84-1,73 (N, m).

Example 30

Cleaners containing hydrochloride salt of N-[2-chloro-5-(4-piperidinyloxy)phenyl]tricyclo[3.3.1.13,7]decane-1-ndimethylacetamide

Obtaining carried out as described in example 12b, using N-(2-chloro-5-hydroxyphenyl)tricyclo[3.3.1.13,7]decane-1-ndimethylacetamide (0.25 g, example 28, WO 99/29660), tributylphosphine (0,29 ml), 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0,30 g), 1,1-dimethylethylene ester 4-hydroxy-1-piperidinecarboxylic acid (0.24 g) and dry tetrahydrofuran (10 ml) to obtain tert-butyloxycarbonyl(BOC)-protected compound as a colourless solid. This connection process 4 N. hydrochloric acid in dioxane (1 ml) and methanol (20 ml) to obtain the specified title compound as colorless solid (0.08 g).

MS (APCI+ve) 375/377 (M-HCl)+

1H NMR (CD3OD) δ at 7.55 (1H, d); 7,41 (1H, d); to 6.88 (1H, DD); 4,76-4,70 (1H, m); 3,48-3,39 (2H, m); 3,30-up 3.22 (2H, m); of 2.25 (2H, s); 2,22-of 2.16 (2H, m); 2,14-2,03 (2H, m); 1,84-1,72 (N, m).

Example 31

Dihydrochloride salt of 2-chloro-5-[(4-piperidinyl-amino)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Chloro-5-formyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Dec-ylmethyl)benzamide (3.25 g, example 23a) in anhydrous tetrahydrofuran (150 ml) cooled to -78°C in nitrogen atmosphere. For 2 minutes and add a solution metallyte (1.4 M in diethyl ether, 6,1 ml). The mixture was stirred at -78°C for 10 min, then added dropwise a solution of tert-utility (1.7 M in pentane, 10.0 ml). The mixture was stirred at -78°C for an additional 10 min, then add dimethylformamide (1.0 ml). The resulting solution was stirred at -78°C for 30 min, quenched with saturated aqueous ammonium chloride (100 ml) and extracted with ethyl acetate. The combined extracts dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to obtain specified in the subtitle compound as a solid (2.76 g).

MS (APCI+ve) 332 (M+H)+

1H NMR (DMSO-d6) δ 10,04 (1H, s); 8,49 (1H, t); of 7.96-to $ 7.91 (2H, m); 7,74 (1H, d); 2,96 (2H, d); 1,95 (3H, s); 1,64 (6N, AB); 1,53 (6N, e).

(b) 1,1-Dimethylethylene ester 4-[[[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]-1-piperidinecarboxylic acid

2-Chloro-5-formyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,270 g, example 31A) and 1,1-dimethylethylene ester 3-amino-1-pyrrolidinecarbonyl acid (0,325 g, Journal of Medicinal Chemistry, 1998, 41(22), 4273-4278) dissolved in 1,2-dichloroethane (30 ml) under nitrogen atmosphere. Add triacetoxyborohydride sodium (0.24 g) and see what camping is stirred for 14 h at room temperature. Add water and dichloromethane and the layers separated. The organic extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified HPLC with elution with a gradient of 0-10% ethanol in dichloromethane, followed by chromatography on silica gel with elution with a mixture of ethyl acetate:isohexane (1:1), then a mixture of ethyl acetate:ethanol (98:2) to obtain specified in the subtitle compound as a colourless oil (0,158 g).

MS (APCI+ve) 516 (M+N)+

C) Dihydrochloride salt of 2-chloro-5-[(4-piperidylamine)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Getting hold of the 1.1-dimethylammonio ester 4-[[[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl] methyl]amino]-1-piperidinecarboxylic acid (0,158 g, example 31b), methanol (3 ml) and 4 n hydrochloric acid in dioxane (2 ml). The solvents are removed under reduced pressure and the residue triturated with ethyl acetate, isohexane and diethyl ether to obtain specified in the title compound as a white solid (0.126 g).

MS (APCI+ve) 416 (M+H-2HCl)+

1H NMR (CD3OD) δ of 8.47 (1H, t); a 7.62-7,56 (3H, m); 4,33 (2H, s); to 3.58-3,55 (3H, m); of 3.12 (2H, t); of 3.07 (2H, d); 2,44 (2H, d); 2,03-of 1.92 (5H, m); 1,73 (6N, kV); 1,63 (6N, e).

Example 32

Dihydrochloride salt of 5-[[[4-(aminomethyl)cyclohexyl]amino]methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-ylmethyl)benzamide

a) 1,1-Dimethylethylene ether [[4-[[[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]methyl] amino]cyclohexyl]methyl]carbamino acid

Obtaining carried out according to the method described in example 31b, from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,30 g, example 31A) and 1,1-dimethylethylene ether [(4-aminocyclohexane)methyl]carbamino acid (0,207 g, WO 97/32882), triacetoxyborohydride sodium is 0.135 g) and 1,2-dichloroethane (10 ml). The residue is purified by chromatography on silica gel with elution with a mixture of ethyl acetate:isohexane (1:1), then ethyl acetate:ethanol (9:1) to obtain specified in the subtitle compound as a colourless oil (0.26 g).

MS (APCI+ve) 544 (M+H)+

b) Dihydrochloride salt of 5-[[[4-aminomethyl)cyclohexyl]amino]methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Getting hold of the 1.1-dimethylammonio ether [[4-[[[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]cyclohexyl]methyl]carbamino acid (0.26 g, example 32A), methanol (5 ml) and 4 n hydrochloric acid in dioxane (2 ml). The solvents are removed under reduced pressure and the residue triturated with diethyl ether to obtain specified in the title compound as a white powder (0,191 g).

MS (APCI+ve) 444 (M+H-2HCl)+

1H NMR (CD3 OD) δ 7,60-7,58 (3H, m); the 4.29 (2H, s); 3,28-of 3.12 (1H, m); 3,09 (2H, s); 2,84 (2H, d); 2,31 (2H, sird); 2,00 (5H, Sirs); 1,75 (6N, kV); 1,65 (6N, e); 1,71-of 1.65 (1H, m); 1,63-of 1.44 (2H, m); 1,31 by 1.12 (2H, m).

Example 33

Dihydrochloride salt of 5-[[(4-aminocyclohexane)amino]methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 1,1-Dimethylethylene ester [4-[[[4-chloro-3-[[(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]methyl] amino]cyclohexyl]carbamino acid

Obtaining carried out according to the method described in example 31b, from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,30 g, example 31A) and 1,1-dimethylethylene ether (4-aminocyclohexane)carbamino acid (0,194 g, Journal of Organic Chemistry, 1996, 61(25), 8811-8818), triacetoxyborohydride sodium is 0.135 g) and 1,2-dichloroethane (10 ml). The residue is purified by chromatography on silica gel with elution with a mixture of ethyl acetate:isohexane (1:1), then ethyl acetate:ethanol (95:5) to obtain specified in the subtitle compound as a colourless oil (0.24 g).

MS (APCI+ve) 530 (M+H)+.

b) Dihydrochloride salt of 5-[[(4-aminocyclohexane)amino]methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Getting hold of the 1.1-dimethylammonio ester [4-[[[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]methyl]amino]cyclohexyl]carbamino acid (0.26 g, example 33a), methanol (5 ml) and a solution of 4 is. hydrochloric acid in dioxane (1 ml). The solvents are removed under reduced pressure and the residue triturated with diethyl ether to obtain specified in the title compound as a white powder (0,190 g).

MS (APCI+ve) 430 (M+H-2HCl)+

1H NMR (CD3OD) δ to 7.61-to 7.59 (3H, m); 4,30 (2H, s); 3,28-3,11 (2H, m); is 3.08 (2H, s); 2.40 a of-2.32 (2H, m); 2.21 are 2,17 (2H, m); 2,00 (3H, s); 1,74 (6N, kV); 1,64 (6N, e); 1,63 is 1.48 (4H, m).

Example 34

5-[(1-Azabicyclo[2.2.2]Oct-3-ylamino)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example 31b of 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,30 g, example 31A), dihydrochloride salt 1-azabicyclo[2.2.2]Octan-3-amine (0.18 g), triacetoxyborohydride sodium is 0.135 g) and 1,2-dichloroethane (10 ml). The residue is purified by chromatography on silica gel with elution with a mixture of ethyl acetate:isohexane (1:1), then a mixture of ethyl acetate:ethanol (95:5). Repeated purification by chromatography on silica gel with elution with a mixture of dichloromethane:methanol (95:5), then (9:1) gives specified in the title compound as a white resin (0,013 g).

MS (APCI+ve) 442 (M+H)+

1H NMR (CDCl3) δ to 7.68 (1H, d); 7,39 (1H, d); 7,31 (1H, DD); 6,41 (1H, t); of 3.75 (2H, s); 3,42-and 3.31 (2H, m); 3.25 to 3,09 (6N, m); 2,94 (1H, d); 2,38-of 2.23 (2H, m); 2,22 with 2.14 (1H, m); for 2.01 (3H, s); 1,92 of-1.83 (2H, m); 1,69 (6N, kV); 1,59 (6N, e).

Example 35

Dihydrochloride Sol is N-[4-(3-aminopyrrolidine-1-yl)-2-were]-2-(tricyclo[3.3.1.1 3,7]Oct-1-yl)ndimethylacetamide

a) tert-Butyl ether [1-(3-methyl-4-nitrophenyl)pyrrolidin-3-yl]carbamino acid

4-fluoro-2-methyl-1-nitrobenzene (1 g), tert-butyl methyl ether pyrrolidin-3-ylcarbamate acid (1.2 g), potassium carbonate (1,79 g) and dimethyl sulfoxide (10 ml) are heated together at 80°C in nitrogen atmosphere for 15 h the Mixture was then cooled, diluted with ethyl acetate (200 ml), washed with 2 N. aqueous hydrochloric acid (200 ml), dried (MgSO4), then concentrated. Purification of the residue by chromatography on silica gel (elution with 20% ethyl acetate in isohexane) gives specified in the subtitle compound (1,744 g).

1H NMR (DMSO-d6) δ 8,03-of 8.00 (1H, d), 7,28-7,21 (1H, sird), 6,51-6,47 (2H, m), 4,20-4,12 (1H, SIRM), 3,61-and 3.16 (4H, m), of 2.56 (3H, s), 2,20-of 2.08 (1H, m), 1,98-of 1.85 (1H, m), 1.39 in (N, C).

b) tert-Butyl ether [1-(4-amino-3-were)pyrrolidin-3-yl]carbamino acid

tert-Butyl ether [1-(3-methyl-4-nitrophenyl)pyrrolidin-3-yl]carbamino acid (1,744 g, example 35A), iron powder (1.52 g), ammonium chloride (1.45 g), ethanol (50 ml) and water (50 ml) is boiled together under reflux in nitrogen atmosphere for 2 hours the Mixture is cooled and the iron is separated by filtration. To the residue add water (200 ml) and the product extracted into ethyl acetate (3×200 ml), dried (MgSO4) and concentrate to obtain specified in podzagolovke the compound (1.56 g).

1H NMR (CDCl3) δ of 6.65 (1H, Sirs), 6,38 (2H, SIRM), 4,80 (1H, m)to 4.33 (2H, SIRM), 3,60 is 2.80 (5H, m), 2,31-2,17 (4H, m), 1,92-to 1.82 (1H, m), 1,45 (N, Sirs).

c) tert-Butyl ether ({1-[4-(2-(tricyclo[3.3.1.13,7]Oct-1-yl)acetylamino)-3-were]pyrrolidin-3-yl}carbamino acid

To a solution of adamantane-1-luxusni acid and 0.46 g) in dichloromethane (10 ml) at 0°add dimethylformamide (0.1 ml), then oxalicacid (2,50 ml). The reaction mixture allow to warm to room temperature and stirred for 30 minutes Volatile components are removed under vacuum and the residue is dried in high vacuum. The residue is dissolved in dichloromethane (10 ml) and added to a solution of tert-butyl methyl ether [1-(4-amino-3-were)pyrrolidin-3-yl]carbamino acid (0,70 g, example 35b) in dichloromethane (10 ml) and triethylamine (0.8 ml) at 0°C. the Reaction mixture allow to warm to room temperature and stirred for 3 hours the Solution was washed with 2 N. aqueous hydrochloric acid (20 ml), then saturated salt solution (20 ml) and the organic layer dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure. The crude material is purified by chromatography on silica gel (elution with 1% methanol in dichloromethane) to obtain specified in the subtitle compound (1.1 g).

MS (APCI+ve) MM 468 (M+H)+

1H NMR (DMSO-d6) δ 8,86 (1H, s); 7,01-6,98 (1H, d); 7.18 in-7,14 (1H, sird); 6,33-6,27 (3H, m); 4,15-Android 4.04 (1H, m); 3,42 is 3.15 (3H, m); 3,00-of 2.97 (1H, m); a 2.12 (3H, s); 2,00 (2H, s); 1,99 and 1.80 (5H, m); 1.70 to 1,61 (N, m); 1,39 (IN with).

d) Dihydrochloride salt of N-[4-(3-aminopyrrolidine-1-yl)-2-were]-2-(tricyclo[3.3.1.13,7]Oct-1-yl)ndimethylacetamide

tert-Butyl ether ({1-[4-(2-(tricyclo[3.3.1.13,7]Oct-1-yl)acetylamino)-3-were]pyrrolidin-3-yl}carbamino acid (0.20 g, example 35C) is dissolved in methanol (5 ml) and add hydrochloric acid (0.5 ml of 4 n solution in dioxane). After stirring at room temperature for 14 h the mixture was evaporated to 2/3 of the initial volume under reduced pressure. To the solution is slowly added diethyl ether and the resulting precipitate is collected by filtration, washed with diethyl ether and dried in vacuum to obtain specified in the title compound as a solid (0.15 g).

MS (APCI+ve) 368 (M+H)+

1H NMR (DMSO-d6) δ of 8.92 (1H, s); 8,21 (2H, Sirs); 7,07? 7.04 baby mortality (1H, d); 6,41 to 6.35 (2H, m); 3,91 (1H, SIRM); 3,50-3,39 (2H, m); 3,29-3,20 (2H, m); 2,37-of 2.27 (2H, m); and 2.14 (3H, s); 2,02 (2H, s); of 1.94 (3H, s); 1.70 to 1,58 (N, m).

Example 36

Dihydrochloride salt of N-(2-methyl-4-piperazine-1-ylphenyl)-2-(tricyclo[3.3.1.13,7]Oct-1-yl)ndimethylacetamide

a) tert-Butyl ether 4-(3-methyl-4-nitrophenyl)piperazine-1-carboxylic acid

4-fluoro-2-methyl-1-nitrobenzene (2 g), tert-butyl methyl ether piperaz the n-1-carboxylic acid (4.8 g), potassium carbonate (3.57 g) and dimethyl sulfoxide (20 ml) are heated together at 80°C in nitrogen atmosphere for 15 h the Mixture was then cooled, diluted with ethyl acetate (200 ml) washed with 2 N. aqueous hydrochloric acid (200 ml), dried (MgSO4) and concentrate to obtain specified in the subtitle compound (4,10 g).

MS (APCI+ve) 321 (M)+

1H NMR (DMSO-d6) δ 8,02-7,98 (1H, d), 6.89 in-6,86 (2H, m), of 3.45 (8H, s)to 2.55 (3H, s), 1,42 (N, C).

b) tert-Butyl ether 4-(4-amino-3-were)piperazine-1-carboxylic acid

tert-Butyl ester 4-(3-methyl-4-nitrophenyl)piperazine-1-carboxylic acid (2 g, example 36A), iron powder (1,74 g), ammonium chloride (1,67 g), ethanol (50 ml) and water (50 ml) is boiled together under reflux in nitrogen atmosphere for 2 hours the Mixture is cooled and the iron is separated by filtration. To the residue add water (200 ml) and the product extracted into ethyl acetate (3×200 ml), dried (MgSO4) and concentrate to obtain specified in the subtitle compound (1.22 g).

1H NMR (DMSO-d6) δ 6,62-6,52 (3H, m), to 4.38 (2H, s)to 3.41 (4H, Sirs), and 2.83 (4H, Sirs), 2,02 (3H, s), 1,41 (N, C).

C) tert-Butyl ether 4-[4-(2-(tricyclo[3.3.1.13,7]Oct-1-yl)acetylamino)-3-were]piperazine-1-carboxylic acid

To a solution of adamantane-1-luxusni acid (0.40 g) in dichloromethane (10 ml) at 0°add dimethylformamide (0.1 ml), then oxalicacid 2,00 ml). The reaction mixture allow to warm to room temperature and stirred for 30 minutes Volatile components are removed under vacuum and the residue is dried in high vacuum. The residue is dissolved in dichloromethane (10 ml) and added to a solution of tert-butyl ester 4-(4-amino-3-were)piperazine-1-carboxylic acid (0,60 g, example 36b) in dichloromethane (10 ml) and triethylamine (0.7 ml) at 0°C. the Reaction mixture allow to warm to room temperature and stirred for 3 hours the Solution was washed with 2 N. aqueous hydrochloric acid (20 ml), then saturated salt solution (20 ml) and the organic layer is dried over magnesium sulfate, then filtered. The filtrate is concentrated under reduced pressure. The crude material is purified by chromatography on silica gel (elution with 1% methanol in dichloromethane) to obtain specified in the subtitle compound (0,42 g).

MS (APCI+ve) MM 468 (M+H)+

1H NMR (DMSO-d6) δ 8,96 (1H, s); 7,14-7,11 (1H, d); 6,79-6,72 (2H, m); 3,47 is 3.40 (4H, m); 3,20-of 3.00 (4H, m), and 2.14 (3H, s); 2,03 (2H, s); of 1.94 (3H, Sirs); 1.70 to 1,56 (N, m); 1,42 (N, C).

d) Dihydrochloride salt of N-(2-methyl-4-piperazine-1-ylphenyl)-2-(tricyclo[3.3.1.13,7]Oct-1-yl)ndimethylacetamide

tert-Butyl ether 4-[4-(2-(tricyclo[3.3.1.13,7]Oct-1-yl)acetylamino)-3-were]piperazine-1-carboxylic acid (0.05 g, example 36C) is dissolved in methanol (2 ml) and add floristware the strong acid (0.5 ml 4 N. solution in dioxane). After stirring at room temperature for 14 h the mixture was evaporated to 2/3 of the initial volume under reduced pressure. To the solution is slowly added diethyl ether and the resulting precipitate is collected by filtration, washed with diethyl ether and dried in vacuum to obtain specified in the title compound as a solid (0,043 g).

MS (APCI+ve) 368 (M+H)+

1H NMR (DMSO-d6) δ 9,01 (3H, Sirs); 7,18-to 7.15 (1H, d); 6,84-PC 6.82 (1H, d); 6,79-6,76 (1H, DD); 3,31 be 3.29 (4H, m); 3,28-and 3.16 (4H, m); of 2.16 (3H, s); 2,04 (2H, s); of 1.94 (3H, Sirs); 1,69-1,58 (N, m).

Example 37

Cleaners containing hydrochloride salt of CIS-4-(3-aminocyclopentane)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Chloro-4-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-chloro-4-hydroxybenzoic acid (3,30 g) in dimethylformamide (20 ml) is added 1,1'-carbonyldiimidazole (3,30 g). The reaction mixture was stirred for 2.5 h and then add 1-adamantanemethylamine (3.4 ml). After 14 h the reaction mixture was distributed between ethyl acetate and 2 N. aqueous hydrochloric acid and the organic layer was separated, washed with water, then with saturated salt solution and dried (MgSO4). The organic layer is concentrated under reduced pressure to obtain residue, which is purified by chromatography on silica the Le (elution 10-70% ethyl acetate in dichloromethane) to give white solids, which is triturated with ethyl acetate to obtain specified in the subtitle compound as a white solid (3.6 g).

MS (APCI+ve) 320/322 (M+H)+

1H NMR (DMSO-d6) δ 10,12 (1H, s), 8,10-of 8.06 (1H, t), 7,27-7,24 (1H, d), for 6.81 (1H, d), 6,77-of 6.73 (1H, DD), 2.91 in-2,88 (2H, d), of 1.93 (3H, Sirs), 1,69-1,56 (6N, shirk), 1,50 (6N, Sirs).

b) cleaners containing hydrochloride salt of CIS-4-(3-aminocyclopentane)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-chloro-4-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 37A), tert-butyl ether TRANS-(3-hydroxycyclopent)carbamino acid (0,19 g) and tributylphosphine (0,23 ml) in dry tetrahydrofuran (6 ml) was added 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g). The orange solution is heated at 60°C in an atmosphere of nitrogen for 2 hours Add additional tert-butyl ether TRANS-(3-hydroxycyclopent)carbamino acid (0,19 g), tributylphosphine (0,23 ml) and 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g). The heat and continue the above procedure is repeated until completion of the reaction according to LC/MS. The cooled reaction mixture is diluted with diethyl ether, then filtered. The filtrate is concentrated and purified by chromatography on silica gel (25-33% ethyl acetate/hexane) to give tert-butyloxycarbonyl(BOC)-protected compound as a colourless foam. Foam is dissolved in methanol (5 ml) and add 4 N. hydrochloric acid in dioxane (0.25 ml). The solution was stirred at room temperature under nitrogen atmosphere until completion of the reaction according to LC/MS. Evaporation of the solvent followed by rubbing with diethyl ether gives specified in the title compound as a colourless solid (0.24 g).

MS (APCI+ve) 403/405 (M+H)+

1H NMR (DMSO-d6) δ 8,18 (1H, t); of 7.96 (2H, Sirs); 7,37-7,34 (1H, d); 7,05 (1H, m); 6,97-6,94 (1H, m); 4,87 (1H, SIRM); 3,72 is 3.40 (2H, m); 2,93-2,90 (2H, d); 2,04-1,51 (N, m); 1,22 (2H, m).

Example 38

Cleaners containing hydrochloride salt of 2-chloro-4-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-chloro-4-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 37A), 1,1-dimethylethylene ester 4-hydroxy-1-piperidinecarboxylic acid (0,19 g) and tributylphosphine (0.25 ml) in dry tetrahydrofuran (6 ml) was added 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g). The orange solution is heated at 50°C in an atmosphere of nitrogen for 2 hours Add an additional amount of 1,1-dimethylethylene ester 4-hydroxy-1-piperidinecarboxylic acid (0,19 g), tributylphosphine (0.25 ml) and 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g). The heat and continue the above procedure is repeated until completion of the reaction according to LC/MS. The cooled reaction speciesbased diethyl ether, then filtered. The filtrate is concentrated and purified by chromatography on silica gel (isohexane/ethyl acetate, 3:1) to give tert-butyloxycarbonyl(BOC)-protected compound as a colourless foam. The foam was dissolved in methanol (10 ml) and add 4 N. hydrochloric acid in dioxane (10 ml). The solution was stirred at room temperature under nitrogen atmosphere until completion of the reaction according to LC/MS. Evaporation of the solvent followed by rubbing with diethyl ether gives specified in the title compound as a colourless solid (0,165 g).

MS (APCI+ve) 403 (M+H)+

1H NMR (DMSO-d6) δ 8,80 (2H, Sirs); 8,21-8,16 (1H, t); 7,37-7,34 (1H, d); 7,16 (1H, m); 7.03 is-6,99 (1H, m); 4.80 to and 4.68 (1H, m); 3.25 to 3,18 (2H, m); 3,17-a 3.01 (2H, m); 2,93-2,90 (2H, d); 2,17-2,02 (2H, m); of 1.93 (3H, Sirs); 1,87-of 1.73 (2H, m); 1,69-1,57 (6N, AB); 1,51 (6N, C).

Example 39

(+/-)-2-Chloro-4-(pyrrolidin-3-yloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 38, from 2-chloro-4-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 37A), 1,1-dimethylethylene ether (+/-)-3-hydroxy-1-pyrrolidinecarbonyl acid (0.18 g), tributylphosphine (0.25 ml), dry tetrahydrofuran (6 ml) and 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g) to obtain tert-butyloxycarbonyl(BOC)-protected compound. The connection clicks the functioning 4 N. hydrochloric acid in dioxane (10 ml) and methanol (10 ml) to obtain the specified title compound as a colourless solid (0,165 g).

MS (APCI+ve) 389 (M+H)+

1H NMR (DMSO-d6) δ 8,19-of 8.15 (1H, t); 7,35-to 7.32 (1H, d); 6,99 (1H, m); 6,93-of 6.90 (1H, m); 4,94-4,89 (1H, m), 3,24 (1H, s); is 3.08-to 3.02 (1H, DD); 2,92-2,90 (2H, d); 2,88-of 2.72 (3H, m); 2,08-to 1.98 (1H, m); of 1.93 (3H, s); 1,76-1,57 (7H, m); 1,51 (6N, C).

Example 40

Cleaners containing hydrochloride salt of 2-chloro-4-(piperidine-3-yloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-chloro-4-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 37A), tert-butyl ester 3-hydroxypiperidine-1-carboxylic acid (0,189 g) and tributylphosphine (0,23 ml) in dry tetrahydrofuran (6 ml) was added 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g). The orange solution is heated at 60°C in an atmosphere of nitrogen for 2 hours Add an additional amount tert-butyl ester 3-hydroxypiperidine-1-carboxylic acid (0,19 g), tributylphosphine (0,23 ml) and 1-[[(1-piperidinylcarbonyl)azo]carbonyl]piperidine (0.24 g). The heat and continue the above procedure is repeated until completion of the reaction according to LC/MS. The cooled reaction mixture is diluted with diethyl ether, then filtered. The filtrate is concentrated and purified by chromatography on silica gel (25% ethyl acetate:from exon), then HPLC normal phase (0-1% ethanol in dichloromethane) to give tert-butyloxycarbonyl(BOC)-protected compound as a colourless foam. The foam was dissolved in methanol (5 ml) and add 4 N. hydrochloric acid in dioxane (0.25 ml). The solution was stirred at room temperature under nitrogen atmosphere until completion of the reaction according to LC/MS. Evaporation of the solvent followed by rubbing with diethyl ether gives specified in the title compound as a colourless solid (0,006 g).

MS (APCI+ve) 403/405 (M+H)+

1H NMR (DMSO-d6) δ 8,84 (2H, Sirs), 8,21 (1H, t); 7,38 (1H, d); to 7.18 (1H, s); 7,05 (1H, DD); 4,82 (1H, Sirs); 3,24 (1H, d); 3,20 (1H, DD); to 3.06 (2H, Sirs); 2,92 (2H, d); 1,94-1,51 (N, m).

Example 41

Cleaners containing hydrochloride salt of 2-chloro-4-(4-piperazine-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 4-Bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a suspension of 4-bromo-2-chlorbenzoyl acid (5,00 g) in dichloromethane (25 ml) at 0°With add oxalicacid (3,7 ml) and dimethylformamide (5 drops). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour, then concentrated under reduced pressure to obtain a solid substance. The solid is dissolved in dichloromethane (20 ml) and added dropwise to a solution of 1-adamantanemethylamine to 3.36 g) and N,N-diisopropylethylamine (5,55 ml) in dichloromethane (20 ml). The resulting solution left to stir at room temperature under nitrogen atmosphere for 20 hours, the Reaction mixture was diluted with dichloromethane and washed with water, 10% aqueous potassium carbonate, 10% aqueous potassium hydrosulfate and saturated salt solution. The organic phase is then dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain specified in the title compound as a solid (4,28 g).

MS (APCI+ve) 382/384 (M+H)+

1H NMR (DMSO-d6) δ 8,39-to 8.34 (1H, t); for 7.78 (1H, m); a 7.62 to 7.59 (1H, m); 7,37-7,34 (1H, d); 2,94 of 2.92 (2H, d); of 1.94 (3H, Sirs); 1,69-1,57 (6N, Shir. AB); 1,52 (6N, C).

b) cleaners containing hydrochloride salt of 2-chloro-4-(4-piperazine-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a suspension of 4-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 41A, of 0.30 g), 1,1-dimethylethylene ether piperazine-1-carboxylic acid (0.18 g), cesium carbonate (0.36 g) and (R)-BINAP (0.036 g) in anhydrous toluene (3 ml) is added palladium acetate(II) (0,009 g) and the mixture is heated at 100°C for 14 h in an autoclave, purged with nitrogen. The cooled reaction mixture is evaporated under reduced pressure to obtain oil, which is purified by chromatography on silica gel (isohexane:ethyl acetate, 2:1) to give tert-butyloxycarbonyl(BOC)-protected compound as a colourless foam. The foam was dissolved in methanol (15 ml) and DOB is given in 4 B.C. hydrochloric acid in dioxane (15 ml). The solution was stirred at room temperature under nitrogen atmosphere until completion of the reaction according to LC/MS. Evaporation followed by rubbing with diethyl ether and methanol gives specified in the title compound in the form of not quite white solid/foam (0,161 g).

MS (APCI+ve) 388/390 (M+H)+

1H NMR (DMSO-d6) δ 8,98 (2H, Sirs); 8,11-8,07 (1H, t); 7,33-7,31 (1H, d); 7,05 (1H, m); 6,99-to 6.95 (1H, m); 3.46 in-of 3.43 (4H, m); 3,20 (4H, Sirs); of 1.94 (3H, Sirs); 1,69-1,57 (6N, Shirov); 1,51 (6N, Sirs).

Example 42

Cleaners containing hydrochloride salt of 2-chloro-4-(3-pyrrolidinyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example 41b, from 4-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.25 g, example 41A), 1,1-dimethylethylene ester 3-amino-1-pyrrolidinecarbonyl acid (of 0.182 g, Journal of Medicinal Chemistry, 1998, 41(22), 4273-4278), cesium carbonate (0,347 g), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.036 g), palladium(II) acetate (0,009 g) and anhydrous toluene (3 ml). The residue is purified HPLC with gradient elution 0-5% ethanol in dichloromethane. The product is dissolved in methanol and stirred at room temperature for 3 h in the presence of 4 n hydrochloric acid in dioxane (2 ml). The solution is concentrated under reduced pressure and triturated with IER the silt ether to obtain specified in the title compound as a white powder (0,057 g).

MS (APCI+ve) 388 (M+H-HCl)+

1H NMR (CD3OD) δ 7,33 (1H, d); of 6.71 (1H, d); 6,63 (1H, DD); 4,27-is 4.21 (1H, m); 3,57 is 3.40 (3H, m), 3,23 (1H, DD); 3,05 (2H, s); 2,43 is 2.33 (1H, m); 2,33 is 2.01 (1H, m); 1,99 (3H, Sirs); 1,73 (6N, kV); 1,62 (6N, e).

Example 43

Cleaners containing hydrochloride salt of 2-chloro-4-(hexahydro-1H-1,4-diazepin-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example 41b, from 4-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.25 g, example 41A), 1,1-dimethylethylene ester hexahydro-1H-1,4-diazepin-1-carboxylic acid (of 0.182 g), cesium carbonate (0,347 g), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.036 g), palladium (II) acetate (0,009 g) and anhydrous toluene (3 ml). The residue is purified HPLC with gradient elution 0-5% ethanol in dichloromethane. The product is dissolved in methanol and stirred at room temperature for 3 h in the presence of 4 n hydrochloric acid in dioxane (2 ml). The solution is concentrated under reduced pressure and triturated with diethyl ether to obtain specified in the title compound as a white powder (0.17 g).

MS (APCI+ve) 402 (M+H-HCl)+

1H NMR (CD3OD) δ 7,41 (1H, d); to 6.88 (1H, d); for 6.81 (1H, DD); a 3.83 (2H, t); 3,63 (2H, t); 3,40 (2H, t); 3,30 (2H, t); a 3.06 (2H, s); 2,24-of 2.16 (2H, m); 1,99 (3H, Sirs); 1,74 (6N, kV); 1,63 (6N, e).

In accordance with the procedure described in example 8, receive the following connections:

Example 44

Cleaners containing hydrochloride salt (±)-5-[(3-amino-1-piperidinyl)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

MS (APCI+ve) MM 416/418 (M+H)+

1H NMR (CD3OD) δ of 7.70 (1H, Sirs); to 7.67 (1H, DD); of 7.60 (1H, d); of 4.49 (1H, d); of 4.45 (1H, d); to 3.73-to 3.58 (2H, m); 3,57 is-3.45 (1H, m); 3,14-2,95 (4H, m); 2,25-2,04 (2H, m); to 1.98 (4H, Sirs); to 1.76 (3H, d); 1,73 is 1.58 (1H, m); to 1.70 (3H, d); 1,63 (6N, Sirs).

Example 45

Cleaners containing hydrochloride salt of 2-chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

MS (APCI+ve) MM 414/416 (M+H)+

1H NMR (CD3OD) δ 7,74 (1H, d); 7,72 (1H, DD); of 7.60 (1H, d); 4,70-4,55 (3H, m); of 4.45 (1H, d); 4,00 (1H, d); to 3.73 (1H, d); 3,60-3,50 (2H, m); of 3.07 (2H, s); a 2.71 (1H, d); and 2.27 (1H, d); to 1.98 (3H, Sirs); or 1.77 (3H, d); was 1.69 (3H, d); 1,63 (6N, Sirs).

Example 46

Cleaners containing hydrochloride salt of 2-chloro-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

MS (APCI+ve) MM 442/446 (M+H)+

1H NMR (CD3OD) δ 7,60-7,40 (3H, m); 4.25 in-4,00 (2H, m); 3,70 is 3.40 (2H, m); 3.46 in (4H, m); of 3.07 (2H, s); 3,15-2,90 (2H, m); 2,80-of 2.50 (2H, m); 2,00 (3H, Sirs); of 1.78 (3H, d); 1,71 (3H, d); 1,63 (6N, Sirs).

Example 47

Cleaners containing hydrochloride salt of 2-chloro-5-(3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

MS (APCI+ve) MM 442/444 (M+H)+

1H NMR (CD 3OD) δ to $ 7.91 (1H, s); for 7.78 (1H, d); 7,56 (1H, d); 7,46 (1H, Sirs); of 4.44 (2H, Sirs); 3,65 of 3.28 (8H, m); is 3.08 (2H, Sirs); 2,48 (2H, Sirs); 2,05-1,90 (5H, m); 1.77 in (3H, d); 1,71 (3H, d); 1,64 (6N, Sirs).

Example 48

Cleaners containing hydrochloride salt of TRANS-2-chloro-5-[[8-(methylamino)-3-azabicyclo[3.2.1]Oct-3-yl]methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

MS (APCI+ve) MM 456/458 (M+H)+

1H NMR (CD3OD) δ 7,79 (1H, d); to 7.77 (1H, DD); 7,58 (1H, d); 4,71 (2H, Sirs); of 3.80 (2H, d); 3,40 (1H, t); of 3.25 (2H, DD); of 3.07 (2H, s); of 2.86 (3H, s); 2,70 (2H, Sirs); 2,10-1,90 (7H, m); 1.77 in (3H, d); to 1.70 (3H, d); 1,63 (6N, Sirs).

Example 49

Cleaners containing hydrochloride salt of CIS-2-chloro-5-[(hexahydrofuro[3,4-c]pyrrol-2(1H)-yl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

MS (APCI+ve) MM 428/430 (M+H)+

1H NMR (DMSO-d6) δ 8,00 (1H, t); the 7.65 (1H, s); 7,63 (1H, d); 7,52 (1H, d); 4,34 (2H, Sirs); 3,60-3,05 (10H, m); 2,97 (2H, d); 1,95 (3H, Sirs); to 1.70 (3H, d); and 1.63 (3H, d); 1,57 (6N, C).

Example 50

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinylidene)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) Dimethyl [[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]methyl]phosphonic acid

5-methyl bromide-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (5,70 g, example 8b) in 100 ml of trimethylphosphite heated to boiling under reflux in techenie PM The solvent is removed by azeotropic distillation with toluene under high vacuum to obtain specified in the subtitle compound as a yellow solid.

MS (APCI+ve) MM 426/428 (M+H)+

1H NMR (DMSO-d6) δ a 8.34 (1H, t); 7,42 (1H, d); 7,35-7,27 (2H, m), 3,63 (3H, s); to 3.58 (3H, s); 3,42 (2H, d); 2,92 (2H, d); of 1.94 (3H, Sirs); to 1.67 (3H, d); to 1.59 (3H, d); 1,52 (6N, Sirs).

(b) 1,1-Dimethylethylene ester 4-[[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]methylene]-1-piperidinecarboxylic acid

To a solution of crude dimethyl ether [[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]methyl] phosphonic acid (2.50 g, example 50A) in tetrahydrofuran (50 ml) at -78°add a solution of diisopropylamide lithium (7,30 ml, 2 M in tetrahydrofuran). The reaction mixture allow to warm to room temperature and stirred for 15 minutes Then add N-tert-butoxycarbonylamino-4-one (1.52 g) in tetrahydrofuran (5 ml) and the mixture stirred for 24 h, the Reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over magnesium sulfate. The crude material is purified on silica gel (0 to 5% methanol in dichloromethane) to obtain specified in the subtitle compound as a white foam.

MS (APCI+ve) MM 443/445 (M+H)+

1H NMR (DMSO-d6) ´ 7,52 (1H, d); 7,34 (1H, d); 7,16 (1H, DD); 6,30 (1H, s); of 6.25 (t, 1H); OF 3.48 (2H, t); 3,40 (2H, t); 3,40 (2H, t); 3,18 (2H, d); to 2.42 (t, 2H); 2,32 (t, 2H); IS 2.05 (3H, Sirs); at 1.73 (3H, d); of 1.64 (d, 3H); 1,59 (6N, C); 1,47 (N, Sirs).

(C) cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinylidene)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A solution of 1,1-dimethylethylene ester 4-[[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]methylene]-1-piperidinecarboxylic acid (0.10 g, example 50b) in methanol (3 ml) is treated with 4 N. a solution of hydrochloric acid in dioxane (1 ml) and stirred for 14 h at room temperature. The reaction mixture was concentrated in vacuo and the residue is recrystallized from a mixture of isopropanol/ether to obtain specified in the title compounds as white solids (0,071 g).

MS (APCI+ve) MM 399/401 (M+H)+

1H NMR (DMSO-d6) δ 7,52 (1H, d); 7,34 (1H, d); 7,16 (1H, DD); 6,30 (1H, s); of 6.25 (t, 1H); OF 3.48 (2H, t); 3,40 (2H, t); 3,40 (2H, t); 3,18 (2H, d); to 2.42 (t, 2H); 2,32 (t, 2H); IS 2.05 (3H, Sirs); at 1.73 (3H, d); 1,64 (d, 3H); 1,59 (6N, C); 1,47 (N, Sirs).

Example 51

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinylidene)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.10 g, example 50C) in ethanol (10 ml) is added platinum oxide (2 mg). The vessel put in at the ospero hydrogen at a pressure of 3 bar for 3 hours. The catalyst was removed by filtration through a pillow celite, washed with ethanol and the solution was concentrated in vacuo. The crude material is recrystallized from isopropanol to obtain white solids. tert-Butoxycarbonylamino compound is dissolved in methanol (10 ml) and treated with 4 N. a solution of HCl in dioxane (2 ml). The reaction mixture is stirred for 14 hours at room temperature, the volatile components are removed under vacuum and the residue is recrystallized from a mixture of isopropanol/ether to obtain cleaners containing hydrochloride salt as a white powder (0,065 g).

MS (APCI+ve) MM 402/404 (M+H)+

1H NMR (CD3OD) δ scored 8.38 (1H, t); 7,38 (1H, d); 7,30-7,20 (2H, m); at 3.35 (2H, d); 3,05 (2H, d); 2,92 (2H, TD); 2,63 (2H, d); to 1.98 (3H, Sirs); 1,95 and 1.80 (1H, m); of 1.85 (2H, d); or 1.77 (3H, d); by 1.68 (3H, d); 1,62 (6N, (C); of 1.40 (2H, HF).

Example 52

Cleaners containing hydrochloride salt of 2-chloro-5-(4-hydroxypiperidine-4-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,30 g, example 23a) in anhydrous tetrahydrofuran (10 ml) at -78°With added dropwise a solution of n-utility in hexano (2.5 M to 0.72 ml). After 10 min add a solution of tert-butoxycarbonyl-4-piperidone (0.21 g) in tetrahydrofuran (2 ml). The solution is stirred for additional 20 min, then treated with a saturated aqueous solution of floridaone. The mixture allow to warm to room temperature, and then distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic extracts are dried over magnesium sulfate and concentrated in vacuo. The remainder chromatographic on silica (ethyl acetate:isohexane, gradient from 1:4 to 1:2) to obtain tert-butoxycarbonylamino product (0,153 g). This product is again dissolved in methanol (4 ml) and treated for 14 h 4 N. HCl in dioxane (1 ml). The solution is partially concentrated in vacuo and the product precipitated in diethyl ether. The solution is filtered and the white solid washed with diethyl ether to obtain specified in the connection header (0,091 g).

MS (APCI+ve) MM 403 (M+H)+

1H NMR (CD3OD) δ 8,43 (1H, m, width); to 7.59 (1H, m); at 7.55 (1H, d); 7,49 (1H, d); 3,52-3,30 (4H, m); to 3.09 (2H, d); of 2.23 (2H, m); 2,04-of 1.88 (5H, m); 1,95 and 1.80 (1H, m); 1,84-1,66 (6N, m); 1,65 (6N, e).

Example 53

Cleaners containing hydrochloride salt of 2-chloro-5-(1,2,3,6-tetrahydropyridine-4-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Grout cleaners containing hydrochloride salt of 2-chloro-5-(4-hydroxypiperidine-4-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.25 g, example 52) in concentrated hydrochloric acid (10 ml) is heated at 100°C for 5 hours the Solution is allowed the opportunity to slowly cool down. Highlights colorless Krista the crystals. The crystals are separated by filtration, washed with diethyl ether, then with acetonitrile and dried to obtain specified in the connection header (0,031 g).

MS (APCI+ve) MM 385 (M+H)+

1H NMR (CD3OD) δ 8,44 (1H, m, width); 7,55 was 7.45 (3H, m); 6,23 (1H, m); of 3.85 (2H, m); 3,47 (2H, t); of 3.07 (2H, d); and 2.79 (2H, m); to 1.98 (3H, m); 1.77 in (3H, m); 1,69 (3H, m); 1,63 (6N, s, W).

Example 54

Cleaners containing hydrochloride salt of 2-ethyl-5-piperazine-1-ylmethyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

2-Bromo-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazine-1-yl)methyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 65b, 0,89 g) dissolved in dry tetrahydrofuran. Add sodium hydride (60% dispersion, 0.07 g) and the mixture is stirred at room temperature for 5 minutes the Mixture is cooled to -70°C in nitrogen atmosphere and add tert-utility (1.9 ml, 1.7 M solution). After 5 min add ethyliodide (0.5 ml) and the mixture was stirred at -70°C for 30 minutes Add the aqueous solution of ammonium chloride and the product extracted with diethyl ether, dried (MgSO4) and concentrated in vacuo. Chromatography on silica gel gives tert-butyloxycarbonyl(BOC)-protected compound in the form of foam. The foam was dissolved in methanol (5 ml) and add 4 N. HCl in dioxane (1 ml). The mixture is stirred at room temperature for 14 hours, the Solution is partially concentrated in vacuo the product precipitated in diethyl ether. The formed solid is filtered and washed with ether to obtain specified in the title compound as a white powder (0,040 g).

1H NMR (DMSO) δ 9,59 (2H, s, W); of 8.15 (1H, t); 7,58 (2H, s, W); to 7.35 (1H, d); 4,37 (2H, s, W); 3,49 (m)of 3.25 (2H, m, W); 2,95 (2H, d); a rating of 2.72 (2H, kV)was 1.94 (3H, s, W); 1,69-1,59 (6N, m); 1,52 (6N, C); 1,165 (3H, t).

Example 55

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) tert-Butyl ether 4-(toluene-4-sulfonylmethane)piperidine-1-carboxylic acid

tert-Butyl ether 4-idependent-1-carboxylic acid (1.3 g) and toluene-4-thiosulfonic potassium (1.0 g) are mixed in ethanol (10 ml) with CIS-dicyclohexano-18-crown-6 (10 mg) and heated to boiling under reflux for 12 hours After cooling, the reaction mixture is distributed between ethyl acetate and water, the organic layer separated, washed with water and saturated salt solution, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica gel (elution with a mixture of isohexane/ethyl acetate, 4:1 to 7:3) to obtain specified in the subtitle compound as an oil (0.65 g).

MS (APCI+ve) 315 (M+H-tBu)+

1H NMR (CDCl3) δ 7,80-a 7.85 (2H, m), 7,30-7,40 (2H, m), 3.95 to-4,10 (1H, m), 3.75 to of 3.85 (1H, m), 3,40-3,50 (1/2H, m), of 3.10-3.20 (1/2H, m), 2.95 and was 3.05 (1H, m), 2,802,90 (1H, m)to 2.46 (3H, s), 1,90-2,10 (2H, m), 1,50-1,70 (2H, m), USD 1.43 and 1,45 (S, pair).

b) 2-Chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,30 g, example 23a) in anhydrous tetrahydrofuran (10 ml) at -78°With added dropwise a solution of n-utility in hexano (2.5 M to 0.72 ml). After 10 min add a solution of tert-butyl ester 4-(toluene-4-sulfonylmethane)piperidine-1-carboxylic acid (0,38 g, example 55A) in tetrahydrofuran (7 ml). After maturing in the next 1 hour at -78°the reaction mixture is heated to ambient temperature and quenched by addition of water (5 ml). The reaction mixture was diluted with ethyl acetate and washed twice with saturated aqueous sodium hydrogen carbonate solution, then with saturated salt solution and dried over magnesium sulfate. The organic layer is concentrated under reduced pressure to obtain residue, which is purified by chromatography on silica gel (elution 0-5% ethanol in dichloromethane) to obtain specified in the subtitle compound (0.20 g).

MS (APCI+ve) 419/21 (M+H-BOC)+

(C) cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

2-Chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]de the-1-ylmethyl)benzamide (0.20 g, example 55b) is dissolved in methanol (15 ml) and add hydrochloric acid (1.0 ml of a 4 n solution in dioxane). After stirring at room temperature for 14 h, the reaction mixture was doing basic with a saturated solution of sodium bicarbonate and extracted twice with dichloromethane. The organic layer is concentrated under reduced pressure to obtain residue, which is purified by chromatography on silica gel (elution 0-100% methanol in dichloromethane). The residue is dissolved in dichloromethane (5 ml) and add hydrochloric acid (1 N. in diethyl ether, 2 ml). Evaporation to dryness gives specified in the title compound in the form of cleaners containing hydrochloride salt (0,050 g).

MS (APCI+ve) 419/21 (M+H)+

1H NMR (DMSO-d6) δ is 8.75 (2H, sird), scored 8.38 (1H, t), of 7.48 (2H, s), 7,37 (1H, s), 3,50-3,60 (1H, m), 3,30 (2H, sird), 2,92 was 3.05 (4H, m)to 2.06 (2H, sird), was 1.94 (3H, s), 1,57 is 1.75 (8H, m), 1,52 (6N, C).

Example 56

2-Chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

m-Chloroperoxybenzoic acid (166 mg) are added to a solution of 2-chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.35 g, example 55C) in dichloromethane (5 ml). After 2 h, add calcium hydroxide (0.20 g) and after 30 min of salt removed by filtration. The filtrate is concentrated under reduced pressure to obtain residue, which is first purified by chromatography on silica gel (elution 0-25% ethanol in dichloromethane). The residue is dissolved in methanol (5 ml) and add hydrochloric acid (0.5 ml of 4 n solution in dioxane). After stirring at room temperature for 14 h, the solution concentrated under reduced pressure and triturated with diethyl ether to obtain specified in the connection header in the form of cleaners containing hydrochloride salt (0,030 g).

MS (APCI+ve) 435/37 (M+H)+

1H NMR (DMSO-d6) δ 8,88 (1H, Sirs), of 8.47 (2H, shirt), 7,76 (1H, d), to 7.67 (1H, DD), to 7.61 (1H, d), 3,30 is 3.40 (2H, m), 3,13 (N, t), 2,98 (2H, d), 2,80-2,90 (2H, m)to 2.15 (1H, d), of 1.95 (3H, m), 1,50-1,85 (15 NM, m).

Example 57

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

m-Chloroperoxybenzoic acid (0,30 g) are added to a solution of 2-chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,30 g) in dichloromethane (10 ml). After 2 h, add calcium hydroxide (170 mg) and after 30 min of salt removed by filtration. The filtrate is concentrated under reduced pressure to obtain residue, which is purified by chromatography on silica gel (elution 0-2% ethanol in dichloromethane). The residue is dissolved in methanol (5 ml) and add hydrochloric acid (0.25 ml of a 4 n solution in dioxane). After stirring at room temperature for 14 h, the solution concentrated under reduced pressure and RUB the diethyl ether obtaining specified in the title compound (0.03 g).

MS (APCI+ve) 451/53 (M+H)+

1H NMR (DMSO-d6) δ 8,89 (1H, Sirs), to 8.57 (1H, t), and 8.50 (1H, Sirs), 7,87 (2H, Avcv), of 7.75 (1H, d), 3,71 (1H, TD), 3,40 (2H, d), of 3.00 (2H, d), 2,80-2,90 (2H, m), 1,95-2,05 (5H, m), 1,50-1,90 (14N, m).

Example 58

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-elmersolver)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperidine-4-elmersolver)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Anhydride triperoxonane acid (2 ml) are added to a solution of 2-chloro-5-methylsulfinyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,53 g, example 58A, WO 99/29661) in dichloromethane (10 ml) and heated to boiling under reflux for 1.5 h, cooled and concentrated. The resulting residue is dissolved in methanol (30 ml), allowed to stand for 1 hour, then concentrated. The resulting residue is dissolved in acetone (10 ml) and add potassium carbonate (0,60 g) and tert-butyl ether 4-iodothyrin-1-carboxylic acid (0,94 g). The reaction mixture is heated at the boil under reflux for 3 h, cooled and concentrated. The resulting residue is dissolved in ethyl acetate, washed with twice 10 wt.%/wt. a solution of KHSO4twice with a saturated solution of sodium bicarbonate, once with saturated salt solution and dried over sulfate is magnesium. The organic layer is concentrated under reduced pressure to obtain residue, which is purified by chromatography on silica gel (elution 0-2% ethanol in dichloromethane) to obtain specified in the subtitle compound (0,46 g).

MS (APCI+ve) 433/35 (M+H-BOC)+

1H NMR (CDCl-d3) δ to 7.61 (1H, d), 7,25-7,31 (2H, m), 6,27 (1H, shirt), 4.09 to (2N, sird), 3,17 (2H, d), of 2.86 (2H, d), of 2.66 (2H, t), a 2.01 (3H, s), 1.60-to 1,90 (15 NM, m), 1,45 (N, C)of 1.18 (2H, DQC).

b) cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-elmersolver)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Hydrochloric acid (4 BC in dioxane, 0.5 ml) are added to a solution of 2-chloro-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperidine-4-elmersolver)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,235 g, example 58A) in methanol (10 ml). After 24 h the reaction mixture was concentrated, then triturated with ether to obtain specified in the title compound (0.20 g).

MS (APCI+ve) 433/35 (M+H)+

1H NMR (DMSO-d6) δ 8,76 (1H, Sirs), 8,48 (1H, Sirs), 8,35 (1H, t), 7,40 (2H, Avcv), 7,28 (1H, d), 3,24 (2H, d), of 3.00 (2H, d), of 2.92 (2H, d), 2,84 (2H, HF), was 1.94 (5H, Sirs), a 1.75-to 1.82 (1H, m), 1,65 (6N, kV)1,52 (6N, (C), 1,40 (2H, HF).

Example 59

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-elmersolver)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

m-Chloroperoxybenzoic acid (0,19 g) are added to a solution of 2-chloro-5-(4-[{1,1-DIMET later)oxycarbonyl]piperidine-4-elmersolver)-N-(tricyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide (0,165 g, example 58A) in chloroform (10 ml). After 5 h add calcium hydroxide (120 mg) and after 30 min of salt removed by filtration. The reaction mixture was concentrated, then dissolved in methanol (10 ml) and add hydrochloric acid (1.0 ml of a 4 n solution in dioxane). After stirring at room temperature for 14 h concentration under reduced pressure gives specified in the title compound (0.075 g).

MS (APCI+ve) 465/67 (M+H)+

1H NMR (DMSO-d6) δ to 8.70 (1H, Sirs), 8,55 (1H, t), 8,48 (1H, Sirs), 7,95 (1H, DD), 7,88 (1H, d), of 7.82 (1H, d), 3,47 (2H, d), 3,21 (2H, d), of 2.97 (2H, d), 2,89 (2H, d), 2,10-of 2.25 (1H, m), of 1.95 (5H, Sirs), of 1.40 and 1.80 (14N, m).

Example 60

Cleaners containing hydrochloride salt of 2-chloro-5-(piperazine-1-carbonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 4-Chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)izofluranova acid

n-Utility (3 ml, 2 M in hexano) is added at -78°to a solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (1.0 g, example 23a) in tetrahydrofuran (20 ml). After 10 min the reaction mixture was decanted on a dry solid carbon dioxide and allow to warm to ambient temperature. The reaction mixture is acidified with concentrated hydrochloric acid and extracted with ether. The organic portion is separated, dried over what Ulfat magnesium and concentrated under reduced pressure to obtain a residue, which is purified by chromatography on silica gel (elution with a mixture of isohexane/ethyl acetate, 3:1 to 1:1, + 1% Asón) obtaining specified in the subtitle compound as a solid (0.45 g).

MS (APCI+ve) 348/350 (M+H)+

1H NMR (DMSO-d6) δ 13,33 (1H, s), 8,44 (1H, t), 7,94 (1H, DD), 7,87 (1H, d), 7,63 (1H, d), 2,95 (2H, d), of 1.95 (3H, s), and 1.63 (6N, kV)1,53 (6N, C).

b) cleaners containing hydrochloride salt of 2-chloro-5-(piperazine-1-carbonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Ethyldiethanolamine (0.3 ml) is added at ambient temperature to a solution of 4-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)isophthalamide acid (0.15 g, example 60A), tert-butyl methyl ether piperazine-1-carboxylic acid (0.16 g) and PyBrOP (0.40 g) in N-methylpyrrolidinone (10 ml). After 5 h the reaction mixture was diluted with ethyl acetate and washed twice with water, twice with 10% solution of KHSO4twice with saturated solution of NaHCO3and once with saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica gel (elution with ethanol (0-5%) in dichloromethane), and then dissolved again in methanol (10 ml) and treated with hydrochloric acid (4 n solution in dioxane, 1 ml). After 48 h, the reaction mixture was concentrated under reduced pressure and recrystallized from a mixture of isohexane/propan-2-ol with getting at asanoha the title compound as a solid (0.10 g).

MS (APCI+ve) 416/418 (M+H)+

1H NMR (DMSO-d6) δ 9,18 (1H, t), 8,42 (1H, t), to 7.59 (1H, d), 7,47-7,52 (2H, m), 3,50-3,90 (4H, Sirs), 3,05-of 3.25 (4H, Sirs), to 2.94 (2H, d), of 1.95 (3H, s), and 1.63 (6N, kV)1,52 (6N, C).

In a similar way we obtain the following connections.

Example 61

Cleaners containing hydrochloride salt of 2-chloro-5-([1,4]diazepan-1-carbonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

MS (APCI+ve) 430/432 (M+H)+

1H NMR (DMSO-d6) δ 9,10 (2H, Sirs), of 8.06 (1H, Sirs), 7,53 (1H, d), 7,45-of 7.48 (2H, m), of 3.78 (2H, Sirs), of 3.54 (2H, Sirs), 3,20-of 3.25 (4H, m), 2,97 (2H, d), from 2.00 (2H, m), of 1.95 (3H, s), 1,65 (6N, kV), 1.55V (6N, C).

Example 62

Cleaners containing hydrochloride salt of 4-chloro-N1-(piperidine-4-yl)-N2-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)isophthalamide

MS (APCI+ve) 430/432 (M+H)+

1H NMR (DMSO-d6) δ 8,66-8,76 (3H, m), 8,42 (1H, t), 7,89-to 7.93 (2H, m), 7,60 (1H, d), to 4.01-4.09 to (1H, m), 3,29 (2H, d), 2.95 and was 3.05 (4H, m), of 1.95 (5H, Sirs), 1,47-1,82 (14N, m).

Example 63

Cleaners containing hydrochloride salt of 2-chloro-5-(hydroxy-4-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Chloro-5-[4-[[{1,1-dimethylethyl}oxycarbonyl]piperidinyl] hydroxymethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (1.5 g, example 23a) in anhydrous tetrahydrofuran (50 ml) in the atmosphere is zhota at -78° With added dropwise a solution of n-utility (2.5 M in hexano, 3.4 ml). The mixture is stirred for 10 min at -78°then added dropwise a solution of 1,1-dimethylethylene ether 4-formyl-1-piperidinecarboxylic acid (1,09 g, Journal of Medicinal Chemistry, 1999, 42(12), 2180-2190) in anhydrous tetrahydrofuran (10 ml). The reaction mixture was stirred at -78°C for 30 min, then quenched with saturated aqueous ammonium chloride (100 ml). The product is extracted twice with ethyl acetate (2×100 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on silica gel with elution with a mixture of isohexane:ethyl acetate (2:1), then (1:2), then purified further HPLC with elution with a gradient of 0-5% ethanol in dichloromethane to obtain specified in the subtitle compound as a white foam (0,61 g).

MS (APCI+ve) 517 (M+H)+

1H NMR (DMSO-d6) δ of 8.28 (1H, t); 7,40 (1H, d); 7,33-7,27 (2H, m); 5,33 (1H, d); 4,34 (1H, t); 3,93 (3H, Sirs), with 2.93 (2H, d); 2,61 (2H, Sirs); of 1.94 (3H, Sirs); 1,63 (6N, kV); 1,53 (6N, e); 1,37 (N, C); 1,34 is 1.23 (2H, m); 1,09 (2H, dt).

b) cleaners containing hydrochloride salt of 2-chloro-5-(hydroxy-4-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A solution of 2-chloro-5-[4-[[{1,1-dimethylethyl}oxycarbonyl] piperidinyl]hydroxymethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.10 g, example 63A) in meta is OLE (3 ml) is treated with 4 N. a solution of hydrochloric acid in dioxane (1 ml). After 14 h, the solvent removed under reduced pressure and the residue triturated with diethyl ether to obtain specified in the title compound as a white powder (0,062 g).

MS (APCI+ve) 417 (M+H-HCl)+

1H NMR (DMSO-d6) δ to 8.70 (1H, Sirs); 8,29 (2H, shirt); 7,44 (1H, d); 7,33 (2H, dt); of 5.53 (1H, d); however, 4.40 (1H, t); 3,23 (2H, Sirs); of 2.93 (2H, d); was 2.76 (2H, sird); of 1.94 (3H, Sirs); 1,77-of 1.36 (1H, m); 1,53 (6N, C).

Example 64

Cleaners containing hydrochloride salt (±)-2-chloro-5-(hydroxy-3-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out in a manner analogous to example 63, using 1,1-dimethylethylene ester 3-formyl-1-piperidinecarboxylic acid.

MS (APCI+ve) MM 417/419 (M+H)+

1H NMR (CD3OD) δ to 8.41 (1H, t); 7,46 (1H, d); 7,41 (1H, d); 7,39 (1H, s); 4,65 (0,5H, d); 4,50 (0,5H, d); 3,74 (0,5H, TD); 3,66 (1H, HF); 3,57 (0,5H, t); 3,44 (0,5H, sird); 3,18 (0,5H, sird); a 3.06 (2H, d); of 2.86 (2H, arc); 2,10-to 1.87 (m, 2H); TO 1.98 (3H, Sirs); or 1.77 (3H, d); by 1.68 (3H, sird); 1,63 (6N, s), 1.60-to 1,50 (m, 1H); 1,50-of 1.36 (m, 1H).

Example 65

Cleaners containing hydrochloride salt of 2-bromo-5-piperazine-1-ylmethyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Bromo-5-methyl bromide-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-bromo-5-bromomethylphenyl acid (6,1 g) in dichloromethane (100 ml) at 0°With EXT the keys dimethylformamide (0.2 ml), then oxalicacid (3 ml). The reaction mixture was stirred at room temperature for 0.5 hour and concentrated in vacuo. Acylchlorides again dissolved in dichloromethane (100 ml) and at 0°With add diisopropylethylamine (6 ml), then adamantanemethylamine (3.5 ml). The mixture was stirred at 0°C for 10 min, then partitioned between diethyl ether and 1 N. aqueous hydrochloric acid. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by recrystallization from a mixture of dichloromethane/ethyl acetate/isohexane obtaining specified in the title compound as a white solid (6.5 g) (sample contains a number of relevant benzylchloride).

b) 2-Bromo-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazine-1-yl)methyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A mixture of 2-bromo-5-methyl bromide-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 65A, 5.0 g), 1-tert-butyloxycarbonyl (2.3 g), potassium carbonate (3.2 g), potassium iodide (0,30 g) and acetone (75 ml) is refluxed in the dark for 14 h the Mixture was concentrated in vacuo, distributed between ethyl acetate and water, then washed with a saturated solution of salt. The organic layer is dried over magnesium sulfate and concentrated in vacuo. Recrystallization from a mixture of ethyl acetate:isohexane on the et is indicated in the subtitle compound as a colourless solid (4.7 g).

MS (APCI+ve) MM 546 (M+N)+.

(C) cleaners containing hydrochloride salt of 2-bromo-5-piperazine-1-ylmethyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

2-Bromo-5-(4-[{1,1-dimethylethyl}oxycarbonyl]piperazine-1-yl)methyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 65b, 0.40 g) was dissolved in methanol (15 ml) and add 4 N. HCl in dioxane (3 ml). The mixture is stirred at room temperature for 14 hours, the Solvent is removed in vacuo and the resulting solid triturated with ether to obtain specified in the title compound as a white powder (0,23 g).

MS (APCI+ve) MM 447 (M+H)+

1H NMR (DMSO-d6) δ at 9.53 (1H, s, W); 8,31 (1H, t); 7,72 (1H, d); 7,60 (1H, m)to 4.33 (1H, m); 3,50 3.00 for (4H, m); 3,50 is 3.40 (1H, m); 2,94 (2H, d); of 1.94 (3H, Sirs); 1,71-1,58 (6N, m); 1,54 (6N, Sirs).

Example 66

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(1-piperazinil)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Chloro-5-(2-hydroxyethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (3.0 g, example 23a) in anhydrous tetrahydrofuran (100 ml) cooled to -78°C in nitrogen atmosphere. For 2 minutes and add a solution metallyte (1.4 M in diethyl ether, 4,9 ml). The mixture was stirred at -78°C for 10 min, then added dropwise a solution of tert-utility (1.7 M in pentane, and 9.3 ml). See the camping stirred at -78° C for an additional 10 min, then add the ethylene oxide (1.0 ml). The resulting solution was stirred at -78°C for 30 min, then warmed to 0°C and stirred for additional 6 hours, the Reaction mixture was quenched with saturated aqueous ammonium chloride (70 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue is purified by chromatography on silica gel with elution with a mixture of dichloromethane:ethanol (98:2) to obtain specified in the subtitle compound as a pale yellow solid (0,89 g).

MS (APCI+ve) 348 (M+H)+

1H NMR (DMSO-d6) δ of 8.27 (1H, t), of 7.36 (1H, d); 7,28-of 7.23 (2H, m); the 4.65 (1H, t); of 3.60 (2H, q); 2,92 (2H, d); by 2.73 (2H, t); of 1.94 (3H, Sirs); 1,63 (6N, kV); 1,52 (6N, e).

b) 2-Chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-chloro-5-(2-hydroxyethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (1.07 g, example 66A) in anhydrous dichloromethane (20 ml) add reagent Dess-Martin periodinan (1,95 g) and the mixture is stirred at room temperature for 1 h sodium Thiosulfate (3,43 g) dissolved in aqueous sodium bicarbonate solution (28 ml) and added dropwise to the reaction mixture. Then add diethyl ether (50 ml) and the mixture is stirred for 10 minutes, the Layers separated and the organic is the third layer is washed with water, then a saturated solution of salt. The organic extracts are then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain specified in the subtitle compound as a white solid (1.06 g).

MS (APCI+ve) 346 (M+H)+

1H NMR (DMSO-d6) δ RS 9.69 (1H, s); 8,32 (1H, t); was 7.45 (1H, d); 7,30-7,24 (2H, m); a-3.84 (2H, s); 2,92 (2H, d); of 1.94 (3H, Sirs); 1,63 (6N, kV); 1,52 (6N, e).

(C) cleaners containing hydrochloride salt of 2-chloro-5-[2-(1-piperazinil)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,101 g, example 66b) in anhydrous 1,2-dichloroethane (5 ml) is added 1,1-dimethylethylene ether 1-piperazinecarboxamide acid (to 0.108 g), then triacetoxyborohydride sodium (0,086 g). The reaction mixture is stirred for 14 h at room temperature. Add water (10 ml) and dichloromethane (10 ml) and the layers separated. The organic extract is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified HPLC with c elution with a gradient of 0-5% ethanol in dichloromethane, followed by chromatography on silica gel with elution by ethyl acetate. The obtained white powder was dissolved in methanol (5 ml) and add a solution of hydrochloric acid in dioxane (4 ad, 1 ml). The mixture is stirred for 14 h at room temperature. Rest ritali then removed under reduced pressure and the product triturated with diethyl ether to obtain specified in the title compound as a white powder (0,047 g).

MS (APCI+ve) 416 (M+H)+

1H NMR (CD3OD) δ 8,42 (1H, t); 7,46 (1H, d); 7,41-7,38 (2H, m); 3,63-to 3.49 (8H, m); 3,48 is-3.45 (2H, m); 3,19-3,14 (2H, m); a 3.06 (2H, s); 1,99 (3H, Sirs); 1,73 (6N, kV); 1,63 (6N, e).

Example 67

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example C, from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,094 g, example 66b), 1,1-dimethylethylene ether 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (to 0.108 g), triacetoxyborohydride sodium (of 0.081 g) and 1,2-dichloroethane (2 ml). After processing, the residue is purified HPLC with elution with a gradient of 0-5% ethanol in dichloromethane. The obtained white powder was dissolved in methanol (2 ml) and add a solution of hydrochloric acid in dioxane (4 ad, 1 ml). The mixture is stirred for 14 h at room temperature. The solvents are then removed under reduced pressure and the product triturated with diethyl ether to obtain specified in the title compound as a white powder (0,067 g).

MS (APCI+ve) 428 (M+H)+

1H NMR (CD3OD) δ 7,49-7,40 (3H, m); with 4.64 (2H, d); to 3.92 (2H, d); of 3.77-of 3.48 (4H, m); 3,18 (2H, t); is 3.08 (2H, s); 2,61 (1H, sird); 2,28 (1H, sird); 2,00 (3H, Sirs); 1,75 (6N, kV); 1,64 (6N, e).

Example 68

Cleaners containing hydrochloride salt of 5-[2-(4-amino-1-piperidinyl)ethyl]-2-chlorine is-N-(tricyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example C, from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,094 g, example 66b), 1,1-dimethylethylene ether 4-piperidinylcarbonyl acid (0,109 g), triacetoxyborohydride sodium (of 0.081 g) and 1,2-dichloroethane (2 ml). After processing, the residue is purified HPLC with elution with a gradient of 0-5% ethanol in dichloromethane. The obtained white powder was dissolved in methanol (2 ml) and add a solution of hydrochloric acid in dioxane (4 ad, 1 ml). The mixture is stirred for 14 h at room temperature. The solvents are then removed under reduced pressure and the product triturated with diethyl ether to obtain specified in the title compound as a white powder (0,065 g).

MS (APCI+ve) 430 (M+H)+

1H NMR (CD3OD) δ 8,43 (1H, t); 7,49-7,38 (3H, m); of 3.78 (2H, sird); 3,64-of 3.42 (2H, m); 3,41-to 3.35 (2H, m); 3,23-3,14 (3H, m); is 3.08 (2H, s); 2,33-to 2.29 (2H, m); 2,13-2,04 (2H, m); 2,00 (3H, Sirs); 1,75 (6N, kV); 1,64 (6N, D.).

Example 69

Dihydrochloride salt of 2-chloro-5-[2-(3-piperidylamine)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example C, from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,094 g, example 66b), 1,1-dimethylethylene ether-amino-1-piperidinecarboxylic acid (0,109 g), triacetoxyborohydride sodium (of 0.081 g) and 1,2-dichloroethane (2 ml). After processing, the residue is purified HPLC with elution with a gradient of 0-5% ethanol in dichloromethane. The obtained white powder was dissolved in methanol (2 ml) and add a solution of hydrochloric acid in dioxane (4 ad, 1 ml). The mixture is stirred for 14 h at room temperature. The solvents are then removed under reduced pressure and the product triturated with diethyl ether to obtain specified in the title compound as a white powder (0,065 g).

MS (APCI+ve) 430 (M+H)+

1H NMR (CD3OD) δ 7,49-7,46 (1H, m); 7,42-7,38 (2H, m); 3,76 (1H, sird); 3,64-of 3.54 (1H, m); 3,44-to 3.34 (3H, m); 3,19 are 2.98 (4H, m); is 3.08 (2H, s); 2,34 (1H, sird); 2,18-2,12 (1H, m); 2,00 (3H, Sirs); 1,89-of 1.78 (2H, m); 1,74 (6N, kV); 1,64 (6N, e).

Example 70

Cleaners containing hydrochloride salt of 5-[2-(3-amino-1-piperidinyl)ethyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example C, from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,094 g, example 66b), 1,1-dimethylethylene ester 3-piperidinylcarbonyl acid (0,109 g), triacetoxyborohydride sodium (of 0.081 g) and 1,2-dichloroethane (2 ml). After processing, the residue is purified HPLC with elution with a gradient of 0-5% ethanol in dichloromethane, then HPLC with elution with a gradient of 0-2% ethanol in dichloromethane. Receiving the hydrated white powder was dissolved in methanol (2 ml) and add a solution of hydrochloric acid in dioxane (4 N., 1 ml). The mixture is stirred for 14 h at room temperature. The solvents are then removed under reduced pressure and the product triturated with diethyl ether to obtain specified in the title compound as a white powder (to 0.032 g).

MS (APCI+ve) 430 (M+H)+

1H NMR (CD3OD) δ 7,49-7,46 (1H, m); 7,42-7,39 (2H, m); 3,80-to 3.67 (3H, m); of 3.46 (2H, t); 3,19 (2H, t); is 3.08 (2H, s); 3,09 totaling 3.04 (1H, m); and 2.14 (1H, shirt); 2,00 (3H, Sirs); 1,74 (6N, kV); 1,77 by 1.68 (2H, m); 1,64 (6N, D.).

Example 71

Dihydrochloride salt of 2-chloro-5-[2-(3-pyrrolidinyl)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example C, from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,094 g, example 66b), 1,1-dimethylethylene ester 3-amino-1-pyrrolidinecarbonyl acid (0,101 g), triacetoxyborohydride sodium (of 0.081 g) and 1,2-dichloroethane (2 ml). After processing, the residue is purified HPLC with elution with a gradient of 0-5% ethanol in dichloromethane. The obtained pale-orange powder was dissolved in methanol (2 ml) and add a solution of hydrochloric acid in dioxane (4 ad, 1 ml). The mixture is stirred for 14 h at room temperature. The solvents are then removed under reduced pressure and the product triturated with diethyl ether to obtain specified in the connection header in view of the pale orange powder (0,033 g).

MS (APCI+ve) 416 (M+H)+

1H NMR (CD3OD) δ 7,46-7,39 (3H, m); 4,12 (1H, Sirs); 3,78-3,71 (1H, m); 3,69 is 3.57 (2H, m); 3.43 points-of 3.42 (4H, m); of 3.13 (2H, shirt); a 3.06 (2H, s); 2,62 is 2.51 (1H, m); 2,38-to 2.29 (1H, m); to 1.98 (3H, s); 1,73 (6N, kV); 1,63 (6N, ).

Example 72

Cleaners containing hydrochloride salt of 5-[2-[(3R)-3-aminopyrrolidine]ethyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example C, from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,094 g, example 66b), 1,1-dimethylethylene ether (3R)-pyrrolidinylcarbonyl acid (0,101 g), triacetoxyborohydride sodium (of 0.081 g) and 1,2-dichloroethane (2 ml). After processing, the residue is purified HPLC with elution with a gradient of 0-5% ethanol in dichloromethane. The obtained white powder was dissolved in methanol (2 ml) and add a solution of hydrochloric acid in dioxane (4 ad, 1 ml). The mixture is stirred for 14 h at room temperature. The solvents are then removed under reduced pressure and the product triturated with diethyl ether to obtain specified in the title compound as a white powder (to 0.060 g).

MS (APCI+ve) 416 (M+H)+

1H NMR (CD3OD) δ 7,49-7,41 (3H, m); a 4.86 (1H, Sirs); 4,05-of 3.80 (2H, m); to 3.58 (4H, Sirs); 3,17 (2H, t); is 3.08 (2H, s); of 2.66 (1H, Sirs); 2,28 (1H, Sirs); 2,00 (3H, s); 1,74 (6N, kV); 1,64 (6N, C).

Example 73

Cleaners containing hydrochloride salt of 2-chloro-5-[2-[2-(gidron imethyl)-1-piperazinil]ethyl]-N-(tricyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example C, from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,094 g, example 66b), 1,1-dimethylethylene ester 3-(hydroxymethyl)-1-piperazinecarboxamide acid (0,117 g), triacetoxyborohydride sodium (of 0.081 g) and 1,2-dichloroethane (2 ml). After processing, the residue is purified HPLC with elution with a gradient of 0-5% ethanol in dichloromethane, followed by chromatography with elution by ethyl acetate, then with a mixture of ethyl acetate:ethanol (95:5). The obtained white powder was dissolved in methanol (2 ml) and add a solution of hydrochloric acid in dioxane (4 ad, 1 ml). The mixture is stirred for 14 h at room temperature. The solvents are then removed under reduced pressure and the product triturated with diethyl ether to obtain specified in the title compound as a white powder (0,016 g).

MS (APCI+ve) 446 (M+H)+

1H NMR (CD3OD) δ 8,43 (1H, t); of 7.48-7,40 (3H, m), 4,14 (1H, sird); 3,93 (1H, sird); 3,81 is 3.76 (2H, m); 3,74-to 3.58 (5H, m); 3,57 is-3.45 (2H, m); 3,28-3,19 (1H, m); 3,17-3,11 (1H, m); of 3.07 (2H, s); 1,99 (3H, Sirs); 1,73 (6N, kV); 1,64 (6N, C).

Example 74

Cleaners containing hydrochloride salt of 2-chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(2-tricyclo[3.3.1.13,7]Oct-1-retil)benzamide

a) 1,1-Dimethylethylene ester 4-[4-chloro-3-[[(2-tricyclo[3.3.1.13,7 ]Oct-1-retil)amino]carbonyl]phenyl]hexahydro-1H-1,4-diazepin-1-carboxylic acid

A solution of 1,1-dimethylethylene ester 4-(3-carboxy-4-chlorophenyl)hexahydro-1H-1,4-diazepin-1-carboxylic acid (0.075 g, example 5b) and 1,1'-carbonyldiimidazole (0,034 g) in dimethylformamide (3 ml) was stirred at room temperature for 2.5 hours Then add cleaners containing hydrochloride salt tricyclo[3.3.1.13,7]decane-1-ethanamine (0,045 g) and N,N-diisopropylethylamine (0.037 ml) and stirring is continued for 14 hours, the Reaction mixture was poured into water and extracted three times with ethyl acetate. Layers of ethyl acetate are combined and washed with 2 M hydrochloric acid, 10% aqueous sodium hydroxide and saturated salt solution, then dried over magnesium sulfate and concentrate under reduced pressure. Purification by chromatography on silica gel with elution with 20% ethyl acetate in isohexane network specified in the subtitle compound as a yellow oil (0,053 g).

MS (APCI+ve) 460/462 (MtBu)-.

b) cleaners containing hydrochloride salt of 2-chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(2-tricyclo[3.3.1.13,7]Oct-1-retil)benzamide

1,1-Dimethylethylene ester 4-[4-chloro-3-[[(2-tricyclo[3.3.1.13,7]Oct-1-retil)amino]carbonyl]phenyl]hexahydro-1H-1,4-diazepin-1-carboxylic acid (0,053 g, example a) dissolved in methanol (5 ml) and add hydrochloric acid (0.5 ml of 4 n solution in dioxane). After peremeci the project at room temperature for 14 h the mixture was evaporated to 3/4 of the initial volume under reduced pressure. To the solution is slowly added diethyl ether and the resulting precipitate is collected by filtration, washed with diethyl ether and dried in vacuum to obtain specified in the connection header in the form of a cream solid color (0,017 g).

MS (APCI+ve) 416/418 (M-HCl)+

1H NMR (DMSO-d6) δ 9,07 (2H, Sirs); 8,18 (1H, t); 7,22 (1H, d); to 6.80 (1H, DD); of 6.71 (1H, d); 3,70 (2H, m); 3,50 (2H, t); 3,25-3,17 (4H, m); of 3.07 (2H, m); 2,09 e 2.06 (2H, m); of 1.93 (3H, Sirs); by 1.68 (3H, d); to 1.61 (3H, d); 1,51 (6N, C); 1,34 of 1.28 (2H, m).

Example 75

Cleaners containing hydrochloride salt of (+/-)-5-(3-amino-1-pyrrolidinyl)-2-chloro-N-(2-tricyclo[3.3.1.13,7]Oct-1-retil)benzamide

Obtaining carried out as described in example 74, using (+/-)-2-chloro-5-[3-[[(1,1-dimethylmethoxy)carbonyl]amino]-1-pyrrolidinyl]benzoic acid (0,090 g), 1,1'-carbonyldiimidazole (0,043 g), cleaners containing hydrochloride salt tricyclo[3.3.1.13,7]decane-1-ethanamine (0,057 g), N,N-diisopropylethylamine (0,046 ml) and dimethylformamide (3 ml). This connection process 4 N. hydrochloric acid in dioxane (0.5 ml) and methanol (5 ml) to obtain the specified title compound (0.025 g).

MS (APCI+ve) 402/404 (M-HCl)+

1H NMR (DMSO-d6) δ 8,24 (3H, Sirs); 8,18 (1H, t); from 7.24 (1H, d); 6,60 (1H, DD); of 6.49 (1H, d); 3,93 (1H, m); 3,54-3,37 (2H, m); 3,31-3,17 (4H, m); 2,37-of 2.28 (1H, m); 2,07 (1H, m); of 1.93 (3H, Sirs); by 1.68 (3H, d); to 1.61 (3H, d); 1,51 (6N, C); 1,34 of 1.28 (2H, m).

Example 76

Hydro is Lorena salt of 2-chloro-5-(4-piperidinylcarbonyl)-N-(tricyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide

a) 1,1-Dimethylethylene ester 4-[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]benzoyl]-1-piperidinecarboxylic acid

To dimethylsulfoxide (0,155 ml) in anhydrous dichloromethane (11 ml) at -78°With add oxalicacid (0,086 ml) and the mixture stirred for 5 min at -78°C. added dropwise a solution of 1,1-dimethylethylene ester 4-[[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]hydroxymethyl]-1-piperidinecarboxylic acid (0,47 g, example 64) in anhydrous dichloromethane (3 ml) and the mixture stirred for 15 min at -78°C. Then add triethylamine (0,633 ml) and the solution warmed to room temperature. After 45 min the reaction mixture at room temperature, poured into water and the layers separated. The organic extract is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified HPLC with elution with a gradient of 0-5% ethanol in dichloromethane to obtain specified in the subtitle compound as a white foam (0.31 g).

MS (APCI+ve) 415 (M+H)+

1H NMR (DMSO-d6) δ 8,46 (1H, t); 8,06 shed 8.01 (1H, m); 7.95 is-a 7.92 (1H, m); 7,70-the 7.65 (1H, m); of 3.97 (2H, sird); 3,72-3,61 (1H, m); of 2.97 (2H, t); 2,92 (2H, Sirs); a 1.96 (3H, Sirs); or 1.77 (2H, d); 1,65 (6N, kV); 1.55V (6N, C); 1,41 (N with); to 1.48 and 1.33 (2H, m).

b) cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidin the carbonyl)-N-(tricyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide

A solution of 1,1-dimethylethylene ester 4-[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]benzoyl]-1-piperidinecarboxylic acid (0.07 g, example 76A) in methanol (3 ml) is treated with 4 N. a solution of hydrochloric acid in dioxane (1 ml). After 14 h, the solvent removed under reduced pressure and the residue triturated with diethyl ether to obtain specified in the title compound as a white powder (0.025 g).

MS (APCI+ve) 415 (M+H-HCl)+

1H NMR (DMSO-d6) δ of 8.90 (1H, Sirs); 8,64 (1H, Sirs); 8,46 (1H, t); 8,03 (1H, d); of 7.95 (1H, s); of 7.69 (1H, d); 3,81 (1H, t); 3,24-3,18 (2H, m); 3,09-to 2.99 (2H, m); 2,96 (2H, d); for 2.01 (2H, DD); 1,95 (3H, s); to 1.79 (2H, t); 1,64 (6N, kV); 1,45 (6N, C).

Example 77

Cleaners containing hydrochloride salt of 2-chloro-5-[1-hydroxy-1-(4-piperidinyl)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 1,1-Dimethylethylene ester 4-[1-[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]phenyl]-1-hydroxyethyl]-1-piperidinecarboxylic acid

To methylacrylamide (3 M solution in diethyl ether, 0,225 ml) in anhydrous diethyl ether (7 ml) under nitrogen atmosphere is added slowly 1,1-dimethylethylene ester 4-[4-chloro-3-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]benzoyl]-1-piperidinecarboxylic acid (0,23 g, example 76A) in anhydrous diethyl ether (7 ml). The reaction mixture was stirred in t the exercises 14 h at room temperature, then poured on crushed ice. Add a 10% aqueous solution of potassium hydrosulfate to maintain the solution pH >4. The layers are separated and the aqueous layer was extracted with ethyl acetate (4×25 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in methanol (3 ml) and hydrochloric acid (4 n solution in dioxane, 2 ml) and stirred for 14 h at room temperature. The solvents are then removed under reduced pressure and the product (0.11 g) dissolved again in dichloromethane (3 ml). Add triethylamine (of 0.066 ml), then di-tert-BUTYLCARBAMATE (by 0.055 g) and the reaction mixture is stirred for 1 hour at room temperature. Add water and the layers separated. The organic extract is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified HPLC with elution with a gradient of 0-5% ethanol in dichloromethane, then RP-HPLC with elution with a gradient 75-5% 0.1% aqueous ammonium acetate in acetonitrile to obtain specified in the subtitle compound as a white foam (0.06 g).

MS (APCI+ve) 431 (M+H-BOC)+.

b) cleaners containing hydrochloride salt of 2-chloro-5-[1-hydroxy-1-(4-piperidinyl)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 1,1-dimethylethylene ester 4-[1-[4-chloro-3-[[(tricyclo[3.3.1.13,7/sup> ]Oct-1-ylmethyl)amino]carbonyl]phenyl]-1-hydroxyethyl]-1-piperidinecarboxylic acid (0.07 g, example 77A) in methanol (3 ml) is added 4 n hydrochloric acid in dioxane (1 ml). After 14 h, the solvent removed under reduced pressure and the residue triturated with diethyl ether to obtain specified in the title compound as a white powder (0,038 g).

MS (APCI+ve) 431 (M+H-HCl)+

1H NMR (DMSO-d6) δ 8,78 (1H, Sirs); 8,28 (1H, t); 7,44-7,40 (3H, m); a total of 5.21 (1H, s); of 3.25 (1H, d); and 3.16 (1H, d); 2,98-2,89 (2H, m); 2,79-to 2.67 (2H, m); of 1.94 (3H, Sirs); of 1.84 and 1.75 (2H, m); 1,63 (6N, kV); 1,53 (6N, C); of 1.42 (3H with); 1,53 to 1.31 (3H, m).

Example 78

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(1-piperazinil)ethoxy]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 12A) and 1,1-dimethylethylene ester 4-(2-hydroxyethyl)-1-piperazinecarboxamide acid.

MS (APCI+ve) 432 (M+H)+

1H NMR (CD3OD) δ to 8.40 (1H, t); 7,41 (1H, d); 7,14-7,06 (2H, m); of 4.45 (2H, t); 3,76-to 3.58 (10H, m); 3,07-3,03 (2H, m); to 1.98 (3H, s); or 1.77 (3H, d); was 1.69 (3H, d); 1,62 (6N, C).

Example 79

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(4-piperidinyl)ethoxy]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-PI is R-5-hydroxy-N-(tricyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide (example 12A) and 1,1-dimethylethylene ester 4-(2-hydroxyethyl)-1-piperidinecarboxylic acid.

MS (APCI+ve) 431 (M+H)+

1H NMR (DMSO-d6) δ is 8.75 (1H, Sirs); 8,49 (1H, Sirs); of 8.27 (1H, t); 7,37 (1H, d); 6,99 (1H, DD); 6,91 (1H, d); a 4.03 (2H, t); 3,22 (2H, d); 2,92 (2H, d); 2,82 (2H, t); of 1.94 (3H, s); is 1.82 (2H, d); 1,79 is 1.70 (1H, m); 1,69-of 1.64 (5H, m); of 1.59 (3H, d); 1,53 (6N, C); 1,43-of 1.30 (2H, m).

Example 80

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(4-piperidinyloxy)ethoxy]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 12A) and 1,1-dimethylethylene ester 4-(2-hydroxyethoxy)-1-piperidinecarboxylic acid.

MS (APCI+ve) 447 (M+H)+

1H NMR (CD3OD) δ 8,39 (1H, shirt); 7,38-7,33 (1H, m); 7,06-6,98 (2H, m); 4,22-4,16 (2H, m); 3,88-3,82 (2H, m); 3,80-3,71 (1H, m); 3,36-3,24 (2H, m); 3,16 totaling 3.04 (4H, m); 1,99 (3H, s); 2,08 is 1.86 (4H, m); of 1.78 (3H, d); 1,69 (3H, d); 1,62 (6N, C).

Example 81

Cleaners containing hydrochloride salt of 2-chloro-5-[2-[2-(1-piperazinil)ethoxy]ethoxy]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out as described in example 12b, using 2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.20 g, example 12A) and 1,1-dimethylethylene ester 4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinecarboxamide acid(0.26 g).

MS (APCI+ve) 476 (M+H)+

1H NMR (CD3OD) δ and 7.7 (1H, DD);? 7.04 baby mortality-7,01 (2H, m); 4.25 in-4,18 (2H, m); of 3.94 (2H, t); 3,91-a 3.87 (2H, m); 3,80-3,43 (10H, m); a 3.06 (2H, s); 1,99 (3H, s); a 1.75 (3H, d); rate of 1.67 (3H, d); 1,62 (6N, C).

Example 82

2-Chloro-5-[(5,6-dihydro-1(4H)-pyrimidinyl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining carried out according to the method described in example 8, from 5-methyl bromide-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 8b) and 1,4,5,6-tetrahydropyrimidine.

MS (APCI+ve) 400/402 (M+H)+

1H NMR (CDCl3) δ to 7.84 (1H, s); of 7.60 (1H, d); the 7.43 (1H, d); 7,29 (1H, DD); 6,51 (1H, t); 4,39 (2H, s); 3.40 in-3,10 (3H, m); 3,17 (2H, d); 3,14 (1H, t); a 2.01 (3H, s); at 1.91 (q, 2H); OF 1.74 (3H, d); of 1.64 (3H, d); 1,59 (6N, Sirs).

Example 83

Cleaners containing hydrochloride salt of 2-chloro-5-[[4-[(2-hydroxyethyl)amino]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Chloro-5-[(4-oxo-1-piperidinyl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining performed according to the method described in example 8C, 5-methyl bromide-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 8b) and 4-piperidine.

MS (APCI+ve) 456/458 (M+H)+.

b) cleaners containing hydrochloride salt of 2-chloro-5-[[4-[(2-hydroxyethyl)amino]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To a solution of 2-chloro-5-[(4-oxo-1-piperidinyl)methyl]-N-(tricyclo[3.3.1.13,7]Dec-ylmethyl)benzamide (0,150 g, example 83A) in methanol (3 ml) at room temperature add ethanolamine (0,11 ml) and cyanoborohydride sodium (0,068 g). pH adjust up to 6 by addition of 4 n solution of hydrogen chloride in dioxane and the reaction mixture is stirred for 48 hours the Reaction mixture is acidified with concentrated hydrochloric acid until gas evolution stops. The precipitate is removed by filtration and the filtrate concentrated in vacuo. The residue is distributed between ethyl acetate and water. The aqueous layer was alkalinized with 5% aqueous sodium hydroxide and extracted with dichloromethane. The organic portion was washed with saturated salt solution and dried over magnesium sulfate. The crude material is purified on silica gel (5% 7 n ammonia in methanol/95% dichloromethane) to give a white foam which was dissolved in a mixture of ether/methanol and treated with 4 N. solution of hydrogen chloride in dioxane to obtain specified in the connection header (is 0.135 g).

MS (APCI+ve) 460/462 (M+H)+

1H NMR (CD3OD) δ of 8.47 (1H, t); to 7.67 (1H, d); to 7.64 (1H, DD); of 7.60 (1H, d); 4,39 (2H, s); 3,81 (2H, t); 3,62 (2H, sird); to 3.52 (1H, t); 3,23-3,10 (4H, m); to 3.09 (2H, d); 2,39 (2H, d); 2,07 (2H, kV)to 1.99 (s, 3H); 1.77 in (3H, d); to 1.70 (3H, d); 1,64 (6N, e).

Example 84

2-Chloro-5-[[4-hydroxy-4-[[(1-methylethyl)amino]methyl]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

a) 2-Chloro-5-(1-oxa-6-azaspiro[2.5]Oct-6-ylmethyl)-N-(t is icicle[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide

To dimethylsulfoxide (2 ml) is added sodium hydride (0,033 g, 60% in oil) at room temperature. The mixture is stirred for 5 min at this temperature and add a solution of iodide trimethylsulfoxonium (0,178 g) in dimethyl sulfoxide (2 ml). After 30 minutes add 2-chloro-5-[(4-oxo-1-piperidinyl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.28 g, example 83A) in dimethyl sulfoxide (2 ml) and the reaction mixture was stirred at room temperature for 3 h before quenching with a mixture of ice/water (20 ml). The mixture is extracted three times with ethyl acetate, the combined organic layers washed with saturated salt solution and dried over magnesium sulfate. The crude material is purified on silica gel with elution by ethyl acetate to obtain specified in the subtitle compound as a white foam (0.25 g).

MS (APCI+ve) 429/431 (M+H)+

1H NMR (CDCl3) δ to 7.68 (1H, s); 7,40-7,30 (2H, m); 6,27 (1H, t); of 3.54 (2H, s); 3,18 (2H, d); 2,70-2,50 (6N, m); 2,00 (s, 3H); 1,90 IS 1.75 (2H, m); total 1.74 (3H, d); of 1.66 (3H, d); 1,59 (6N, Sirs); 1,80 of 1.50 (m, 2H).

b) 2-Chloro-5-[[4-hydroxy-4-[[(1-methylethyl)amino]methyl]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

In a sealed tube 2-chloro-5-(1-oxa-6-azaspiro[2.5]Oct-6-ylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example a, 0.15 g) dissolved in a mixture of ethanol (4 ml) and Diisopropylamine (1 ml) and heated at 65°in ECENA 14 PM Volatile components are removed in vacuo and the residue purified on silica gel (5% 7 n ammonia in methanol/95% dichloromethane) to obtain specified in the title compounds as white solids (0,115 g).

MS (APCI+ve) 488/490 (M+H)+

1H NMR (CD3OD) δ 7,45-to 7.35 (3H, m); 3,55 (2H, s); a 3.06 (2H, s); was 2.76 (1H, HF); 2,70 is 2.55 (2H, m); figure 2.54 (2H, s); 2,50 to 2.35 (2H, m); 1,99 (s, 3H); 1.77 IN (3H, d); to 1.70 (3H, d); and 1.63 (10H, Sirs); of 1.07 (m, 2H).

Example 85

Cleaners containing hydrochloride salt of 2-chloro-5-[(1,2,3,6-tetrahydro-3-pyridinyl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

To pyridine (6 ml) at 0°add portions sociallyengaged (0.24 g). The mixture allow to warm to room temperature and stirred for 24 h Added lithium iodide (0,220 g) and pyridine (1 ml) and the reaction mixture was stirred for another 1 hour To the solution at room temperature add 5-methyl bromide-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,30 g, example 8b) in dry pyridine (2 ml). After 2 h the mixture was quenched at 0°With cold 15% aqueous solution of acetic acid, stirred for one hour and concentrated in vacuo. The residue is dissolved in 1 N. the sodium hydroxide, extracted with dichloromethane and the organic layers dried over magnesium sulfate. The crude material is purified on silica gel (2-10% 7 n ammonia in methanol/dichloromethane, then treated with a 4 n solution of hydrogen chloride in dioxane and methanol to obtain specified in the title compound (0.20 g).

MS (APCI+ve) 399/401 (M+H)+

1H NMR (CD3OD) δ 8,42 (1H, t); the 7.43 (1H, DD); to 7.32 (1H, DD); 7,30 (d, 1H); OF 5.89 (1H, d); 5,80 (1H, d); of 3.64 (2H, s); 3.40 in-3,30 (1H, m); a 3.06 (4H, d); 1,99 (s, 3H); OF 1.78 (3H, d); by 1.68 (3H, d); 1,63 (6N, e).

Example 86

The acetate salt of 2-chloro-5-(3-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

(a) Acetate salt of 2-chloro-5-(3-pyridinylmethyl)-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)benzamide

To pyridine (12 ml) at 0°add portions sociallyengaged (0,46 g). The mixture allow to warm to room temperature and stirred for 24 h Added lithium iodide (0,44 g) and pyridine (5 ml) and the reaction mixture is stirred for a further 1 h the Solution is cooled to -10°and add 5-methyl bromide-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 8b, 0.5 g) in dry pyridine (5 ml). After 1 hour the mixture was quenched at -10 degrees cold water, then 1 N. sodium hydroxide. The solution is stirred for 1 h, then concentrated in vacuo. The residue is dissolved in water, extracted with dichloromethane and the organic layers dried over magnesium sulfate. The crude material is purified on silica gel (ethyl acetate:isohexane, 4:1) to obtain specified in the subtitle compound as a white foam (0,355 g).

b) the Acetate salt of 2-chloro-5-(3-piperidinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

p> 2-Chloro-5-(3-pyridinylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.10 g, example 86a) is dissolved in methanol and treated with 4 N. solution of hydrogen chloride in dioxane. Cleaners containing hydrochloride salt is isolated and hydronaut in ethanol over platinum oxide, followed by the procedure described in example 51, obtaining specified in the title compound as the acetate salt after purification HPLC with reversed-phase (0.1% aqueous ammonium acetate/acetonitrile) (0,053 g).

MS (APCI+ve) 401/403 (M+H)+

1H NMR (CD3OD) δ 7,42 (1H, d); 7,31-of 7.25 (2H, m); 3,38 of 3.28 (1H, m); 3,28-3,18 (1H, 2m)of 3.07 (2H, s); 2,86 (1H, dt); 2,72-2,61 (1H, m); to 2.65 (1H, d); 2,13-2,05 (1H, m); for 2.01 (3H, s); of 1.94 (3H, s); 1,90-of 1.85 (1H, m,); 1.85 to to 1.60 (2H, m); of 1.80 (3H, d); 1,71 (3H, d); 1,64 (6N, e); 1,29 (1H, CHP).

Example 87

2-Bromo-5-[[4-[(2-hydroxyethyl)amino]-1-piperidinyl]methyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Obtaining performed according to the methods described in example 83a and 83b, from 2-bromo-5-methyl bromide-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (example 65A), 4-piperidone and ethanolamine.

MS (APCI+ve) MM 505/506 (M+H)+

1H NMR (CDCl3) δ 7,53 (1H, d); 7,52 (1H, d); 7,26 (1H, DD); 6,05 (1H, t); the 3.65 (2H, t); of 3.46 (2H, s); 3,17 (2H, d); 2,82 (2H, t); 2,60 at 2.45 (1H, m); 2,20-of 1.95 (7H, m); 1,95-1,82 (2H, sird); a 1.75 (3H, d); of 1.66 (3H, d); 1,61 (6N, e); of 1.50 and 1.35 (2H, arc).

Example 88

2-Chloro-5-[(E)-3-piperidinylidene]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)is ansamed

a) 2-Chloro-5-[(E)-(5,6-dihydro-3(4H)-pyridinoline)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

2-Chloro-5-formyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0.152 g, example 31A) and the trimer 2,3,4,5-tetrahydropyridine (Org. Synth., 1977, Vol. 56, 118-122, 0,038 g) dissolved in methanol (3 ml) and heated to boiling under reflux for 4 hours the Mixture is evaporated under reduced pressure, then purified HPLC with elution with a gradient of 0-5% ethanol in dichloromethane to obtain specified in the subtitle compound as a white foam (0,046 g).

MS (APCI+ve) 397 (M+H)+

1H NMR (CD3OD) δ 7,98 (1H, s); 7,51 (3H, s); 6,83 (1H, s); 3,66-3,62 (2H, m); of 3.07 (2H, s); 2,78-by 2.73 (2H, m); 1,99 (3H, Sirs); 1,73 (6N, kV); 1,77 was 1.69 (2H, m); 1,64 (6N, C).

b) 2-Chloro-5-[(E)-3-piperidinylidene]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide

Borohydride sodium (0,009 g) in methanol (0.5 ml) are added to a solution of 2-chloro-5-[(E)-(5,6-dihydro-3(4H)-pyridinoline)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide (0,046 g, example a) in methanol (1.5 ml). The reaction mixture was stirred for 4 h under nitrogen atmosphere at room temperature. Add concentrated hydrochloric acid (0.01 ml) and the mixture is evaporated under reduced pressure. To re-alkalizing the residue is added an aqueous solution of sodium hydroxide (2 M, 2 ml), then water (10 ml) and dichlo is methane (10 ml). The layers are separated and the aqueous layer was extracted with further dichloromethane (2×10 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain specified in the title compound as a white powder (0,024 g).

MS (APCI+ve) 399 (M+H)+

1H NMR (CD3OD) δ the 7.43 (1H, d); 7,29-7,26 (2H, m); 6,38 (1H, s); of 3.45 (2H, s); of 3.07 (2H, s); 2,96 (2H, t); to 2.55 (2H, t); 2,00 (3H, Sirs); 1,75 (6N, kV); 1,81-of 1.64 (2H, m); 1,64 (6N, C).

Pharmacological analysis

It is known that some compounds, such as benzoylmethylecgonine (BATF)are agonists RH7receptors influencing the formation of pores in the plasma membrane (Drug Development Research (1996), 37(3), R. 126). Therefore, when the receptor is activated using bath in the presence of ethidium bromide (fluorescent probe DNA), see the increase in fluorescence associated with intracellular DNA ethidium bromide. The increase in fluorescence can be used to measure activation RH7-receptor and, consequently, to quantify the impact of connections on RH7the receptor.

In this way each of the above title compounds of examples 1-88 tested for antagonistic activity against RH7-receptor. Thus, the test was performed in 96-well titration microplate is, having a hole with a flat bottom, and the wells were filled with 250 μl of the test solution, containing 200 μl of the suspension TNR-1 cells (2,5×106cells/ml)containing 10-4M ethidium bromide, 25 μl of buffer solution with a high content of potassium, containing 10-5M BATF and 25 μl of buffer with a high content of potassium, containing 3×10-5M of the test compound. The tablet is covered with a plastic plate and incubated at 37°C for one hour. The tablet data is then read in fluorescent tablet reader Perkin-Elmer, excitation 520 nm, emission 595 nm, slit width: Ex 15 nm, Eat 20 nm. In order to compare bath (agonist RH7-receptor) and pyridoxal-5-phosphate (antagonist RH7-receptor) were used separately in the test as controls. From the obtained evidence is pIC50was calculated for each test compound, and this value is the negative logarithm of the concentration of test compound required to reduce agonistic activity BATF 50%. Each of the compounds of examples 1-88 showed antagonistic activity, with a value pic50>4,50.

Obtaining a pharmaceutical composition according to the invention in tablet form for oral administration.

The original components.

Active ingredient (a derivative of adamantane PR)60 wt.%
Lactose14 wt.%
Microcrystalline cellulose15 wt.%
Magnesium stearate1 wt.%
Sodium crosscarmellose5 wt.%
The starch pre-gelatinizing5 wt.%
Only100 wt.%

The ingredients included in the composition is thoroughly mixed and tabletirujut in teletrauma machine in accordance with known methods.

1. Adamantane derivatives of General formula

where m is 1 or 2;

each R1independently represents a hydrogen atom;

A represents C(O)NH or NHC(O);

Ar represents a group

X represents a bond, an oxygen atom or a group CO, (CH2)1-6CH=, O(CH2)1-6, O(CH2)2-6Oh, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2CH2S(O)n;

n is 0, 1 or 2;

R' represents a hydrogen atom;

one of R2and R3represents halogen, nitro, C1-C6-alkyl, and others is another of R 2and R3represents a hydrogen atom or halogen;

or R4is 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atom and optionally an oxygen atom, and the heterocyclic ring system optionally substituted by one or more substituents, independently selected from atoms of hydroxyl, C1-C6-alkyl, C1-C6-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7,

or R4represents a 3-8-membered saturated carbocyclic ring system, substituted with one or more substituents independently selected from-NR6R7, -(CH2)rNR6R7, r is 1;

R5represents a hydrogen atom;

R6and R7each independently represents a hydrogen atom or a C1-C6-alkyl or C2-C6-hydroxyalkyl group;

provided that

(a) when a represents C(O)NH and R4is unsubstituted 3-8-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, then X is other than a bond, and

(b) when a represents C(O)NH, and X represents a group (CH2)1-6or O(CH2)1-6then R4not a Ki is unsubstituted imidazolines, unsubstituted morpholinyl, unsubstituted piperidinyl or unsubstituted pyrrolidinyl group, and

(c) when a represents NHC(O) and R4is unsubstituted 3-8-membered saturated aliphatic heterocyclic ring system containing one nitrogen atom, then X is other than a bond, and

(d) when a represents NHC(O) and X represents O(CH2)1-6or SCH2then R4is not unsubstituted 1-piperidinyl or unsubstituted 1-pyrrolidinyl group, and

or its pharmaceutically acceptable salt or MES.

2. The compound according to claim 1, where a represents NHC(O).

3. The compound according to claim 1 or 2, where Ar represents a group

4. The compound according to any one of claims 1 to 3, where X represents a bond, an oxygen atom or a group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6Oh, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)nor S(O)nCH2.

5. The compound according to any one of claims 1 to 4, where R4is 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atom and optionally an oxygen atom, and the heterocyclic ring system optionally substituted by one or the two substituents, independently selected from hydroxyl, C1-C6-alkyl, C1-C6-hydroxyalkyl, -NR6R7and -(CH2)rNR6R7.

6. The compound according to any one of claims 1 to 4, where R4represents a group selected from the

7. The compound of formula (I) or its pharmaceutically acceptable salt or MES, according to claim 1 which is:

2-Nitro-3-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Dihydrochloride salt of 2-amino-3-piperazine-1-yl-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)benzamide,

2-Chloro-3-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

2-Chloro-5-piperazine-1-yl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 5-(4-amino-1-piperidinyl)-2-chloro-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of (+/-)-5-(3-amino-1-pyrrolidinyl)-2-chloro-N-(tricyclo [3.3.1. 13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-piperazine-1-ylmethyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[(GE is sagita-1H-1,4-diazepin-1-yl)methyl]-N-(tricyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 5-[(4-amino-1-piperidinyl)methyl]-2-chloro-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 5-[(3-amino-1-pyrrolidinyl)methyl]-2-chloro-N-(tricyclo [3.3.1.I3,7]Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinyloxy)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of (R)-2-chloro-5-(2-pyrrolidinyloxy)-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of (S)-2-chloro-5-(2-pyrrolidinyloxy)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(3-piperidinyloxy)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of CIS-5-[(4-aminocyclohexane)oxy]-2-chloro-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-methyl-5-(1-piperazinylmethyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(1-piperazinylmethyl)-N-(2-tricyclo[3. 3.1.13'7] Oct-1-retil) benzamide,

Cleaners containing hydrochloride salt of (+/-)-2-chloro-5-(3-pyrrolidinyloxy)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of (+/-)-2-chloro-5-(3-piperidinyloxy)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

TRANS-5-[(4-Aminocyclohexane)ACS is]-2-chloro-N-(tricyclo[3.3.1.1 3,7] Oct-1-ylmethyl)benzamide,

CIS-(+/-)-5-[(3-Aminocyclopent)oxy]-2-chloro-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of (S,S)-2-chloro-5-(2,5-diazabicyclo[2.2.1] hept-2-yl)-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(2-methyl-1-piperazinil)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of (+/-)-2-chloro-5-(3-pyrrolidinyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

(+/-)-5-(Z-Amino-1-piperidinyl)-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-metil) benzamid,

(+/-)-2-Chloro-5-(3-piperidinylidene)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl) benzamide,

2-Chloro-5-[hexahydrofuro[3,4-C]pyrrol-2(1H)-yl]-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of N-[2-methyl-5-(4-piperidinyl-hydroxy)phenyl]tricyclo [3.3.1.13,7] decane-1-acetamide", she

Cleaners containing hydrochloride salt of N-[2-chloro-5-(4-piperidinyl-hydroxy)phenyl]tricyclo [3.3.1.13,7] decane-1-acetamide", she

Dihydrochloride salt of 2-chloro-5-[(4-piperidinyl-amino)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Dihydrochloride salt of 5-[[[4-(aminomethyl)cyclo-hexyl]amino]methyl]-2-chloro-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Dihydrochloride salt of 5-[[(4-amino-cyclohexyl)amino]methyl]-2-chloro-N-(tricyclo [3.3.1.13,7] d is C-1-ylmethyl)benzamide,

5-[(1-Azabicyclo[2.2.2]Oct-3-ylamino)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Dihydrochloride salt of N-[4-(3-aminopyrrolidine-1-yl)-2-were]-2-(tricyclo [3.3.1.13,7] Oct-1-yl) acetamide", she

Dihydrochloride salt of N-(2-methyl-4-piperazine-1-ylphenyl)-2-(tricyclo [3.3.1.13,7] Oct-1-yl)acetamide", she

Cleaners containing hydrochloride salt of CIS-4-(3-aminocyclopentane)-2-chloro-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-4-(4-piperidinyloxy)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

(+/-)-2-Chloro-4-(pyrrolidin-3-yloxy)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-4-(piperidine-3-yloxy)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-4-(4-piperazine-1-yl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-4-(3-pyrrolidinyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-4-(hexahydro-1H-l,4-diazepin-1-yl)-N-(tricyclo [3.3.1.13'7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of (±)-5-[(3-amino-1-piperidinyl)methyl]-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(2,5-diazabicyclo[2.2.1]hept-2-ylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl) b is samida,

Cleaners containing hydrochloride salt of 2-chloro-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(3,7-diazabicyclo[3.3.1]non-3-ylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of TRANS-2-chloro-5-[[8-(methylamino)-3-azabicyclo [3.2.1] Oct-3-yl]methyl]-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of CIS-2-chloro-5-[(hexahydrofuro[3,4-C]pyrrol-2(1H)-yl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinylidene)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinylmethyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(4-hydroxypiperidine-4-yl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(1,2,3,6-tetrahydropyridine-4-yl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-ethyl-5-piperazine-1-ylmethyl-1-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl) benzamide,

2-Chloro-5-(piperidine-4-ylsulphonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-x is the PR-5-(piperidine-4-ylsulphonyl)-N-(tricyclo [3.3.1.1 3,7]Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-ylmethyl-sulfanyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(piperidine-4-Ilmatar-sulfonyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(piperazine-1-carbonyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-([1,4]diazepan-1-carbonyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 4-chloro-N1-(piperidine-4-yl)-N2-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) isophthalamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(hydroxy-4-piperidinyl-methyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of (±)-2-chloro-5-(hydroxy-3-piperidinyl-methyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-bromo-5-piperazine-1-ylmethyl-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(1-piperazinil)ethyl]-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(2,5-diazabicyclo[2.2.1]hept-2-yl) ethyl]-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 5-[2-(4-amino-1-piperidinyl)ethyl]-2-chloro-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Dihydrochloride salt of 2-chloro-5-[2-(3-piperidinyl-amino)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 5-[2-(3-amino-1-piperidinyl)ethyl]-2-chloro-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Dihydrochloride salt of 2-chloro-5-[2-(3-pyrrolidinyl-amino)ethyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 5-[2-[(3R)-3-aminopyrrolidine)ethyl]-2-chloro-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-[2-(hydroxymethyl)-1-piperazinil] ethyl]-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(hexahydro-1H-1,4-diazepin-1-yl)-N-(2-tricyclo [3.3.1.13,7] Oct-1-retil) benzamide,

Cleaners containing hydrochloride salt of (+/-)-5-(3-amino-1-pyrrolidinyl)-2-chloro-N-(2-tricyclo [3.3.1.13,7] Oct-1-retil) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-(4-piperidinylcarbonyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[1-hydroxy-1-(4-piperidinyl) ethyl]-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(1-piperazinil)ethoxy]-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(4-piperidinyl)ethoxy]-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl) benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-(4-shall piperidinyl-hydroxy)ethoxy]-N-(tricyclo[3.3.1.1 3,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[2-[2-(1-piperazinil)ethoxy]ethoxy]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

2-Chloro-5-[(5,6-dihydro-1(4H)-pyrimidinyl)methyl]-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[[4-[(2-hydroxyethyl)amino]-1-piperidinyl]methyl]-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)benzamide,

2-Chloro-5-[[4-hydroxy-4-[[(1-methylethyl)amino]methyl]-1-piperidinyl]methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

Cleaners containing hydrochloride salt of 2-chloro-5-[(1,2,3,6-tetrahydro-3-pyridinyl)methyl]-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,

The acetate salt of 2-chloro-5-(3-piperidinylmethyl)-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl)benzamide,

2-Bromo-5-[[4-[(2-hydroxyethyl)amino]-1-piperidinyl] methyl]-N-(tricyclo [3.3.1.13,7]Oct-1-ylmethyl)benzamide and

2-Chloro-5-[(E)-3-piperidinylidene]-N-(tricyclo [3.3.1.13,7] Oct-1-ylmethyl)benzamide.

8. The compound of formula (I) or its pharmaceutically acceptable salt or MES according to any one of claims 1 to 7, which has antagonistic activity against R2X7-receptor.

9. The method of obtaining the compounds of formula (I)as defined in claim 1, which includes:

when X is CH2group, R4is 3-9-membered saturated or unsaturated Alif the political heterocyclic ring system, containing one or two nitrogen atom and optionally an oxygen atom, and the heterocyclic ring system optionally substituted by one or more substituents, independently selected from atoms of hydroxyl, C1-C6-alkyl, C1-C6-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7and R4linked to X via a nitrogen atom, the interaction of the compounds of General formula

where one of R10and R11represents a hydrogen atom and the other of R10and R11represents a group-CH2L1in which L1represents a leaving group, and m, A, R1, R2and R3have the meanings indicated in the formula (I), with the compound of General formula

R4'-H (III)

in the presence of a base, where R4'is 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system containing one or two nitrogen atom and optionally an oxygen atom, and the heterocyclic ring system optionally substituted by one or more substituents, independently selected from atoms of hydroxyl, C1-C6-alkyl, C1-C6-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7and where R6and R7have the meanings indicated in the formula (I).

p> 10. Pharmaceutical composition having an antagonistic action against R27receptor, comprising the compound of formula (I) or its pharmaceutically acceptable salt or MES according to any one of claims 1 to 7, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. The method of obtaining the pharmaceutical composition of claim 10, which comprises mixing the compounds of formula (I) or its pharmaceutically acceptable salt or MES as defined in any one of claims 1 to 7, with a pharmaceutically acceptable adjuvant, diluent or carrier.

12. A method of treating rheumatoid arthritis which comprises the administration to a patient a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or MES according to any one of claims 1 to 7.

13. A method for the treatment of obstructive diseases of the respiratory tract, which includes the introduction to the patient a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or MES according to any one of items 1 to 7.

Priority signs of PCP. 1-11 and 15 claims (original version) installed from 09.04.1999 and from 01.02.2000 according to the correspondence of the applicant from 28.04.2004.



 

Same patents:

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to N-(indolcarbonyl)piperazine derivatives of general formula I

, wherein R1 is optionally substituted phenyl or naphthyl; R2 and R3 are independently Hal or Het1, A, OA, CN; R4 is H, CN, acyl, Hal, CONH2, CONHA or CONA; R1 is H; or R4 and R5 together form C3-C5-group; Het1 is aromatic heterocyclic ring, optionally substituted with one or two halogen atoms and containing 1-3 similar or different heteroatoms such as nitrogen, sulfur and oxygen, A-(C1-C6)-alkyl; Hal is F, Cl,Br, and J; and indole ring may be substituted with isatin, except for (1H-indole-5-yl)-(4-phenethylpiperazine-1-yl)-methanone and 1-((5-methoxy-1H-indole-7-yl)-carbonyl)-4-(2-phenethyl)-piperazine. Claimed compounds are potent 5-HT2A antagonists and are useful in treatment of psychosis, schizophrenia, depression, neurological diseases, dismepodia, Parlinson's disease, Alzheimer's disease, Hungtington's disease, amyotrophic lateral sclerosis, bulimia or anorexia, premenstrual syndrome, and/or in alleviation of hypomania.

EFFECT: new pharmaceutical agents.

9 cl, 10 ex, 1 tbl

FIELD: organic synthesis.

SUBSTANCE: invention provides substituted methyl-N-amidooxamoyl-N-phenyl-D,L-alaninates having general formula I:

where R1 and R2 represent C1-C4-alkyl, R3 and R4 either represent H, C1-C6-alkyl or form together group -(CH3)2-X-(CH2)2- wherein X is O or CH2. Compounds exhibit fungicide activity and can be used to prevent and treat plant diseases.

EFFECT: increased choice of fungicides.

5 cl, 1 tbl, 11 ex

The invention relates to derivatives of piperazine or piperidine derivatives of General formula I, in which G represents a carbon atom or nitrogen; And selected from (i) phenyl substituted by a group-COOH, CONH2-SOON3, -CN, NH2or-PINES3; (ii) naphthyl, benzofuranyl and hineline; or a group of the formula (iii), R1selected from hydrogen; branched or straight C1-C6of alkyl, C1-C6alkenyl - (C1-C6alkyl); each of R9, R10, R13, R14, R17and R18independently has the meanings indicated above for R1; Represents a substituted or unsubstituted aromatic, optionally substituted C5-C10hydroaromatics balance

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to new thiazole derivative of the formula I, where R1denotes a group of formula (a), (b), (C), R2denotes a group of formula (d), where Het represents a five - or six-membered heterocyclic group which is substituted by9and in the loop which, in addition to the nitrogen atom, can optionally contain an oxygen atom, R3denotes hydrogen, alkyl, cycloalkyl, phenyl, R4denotes hydrogen, phenyl, R5- R8independently of one another denotes hydrogen, R9denotes a group of formula (e) and (f), R10denotes phenyl, a-i denotes 0 or a positive integer, i.e
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< / BR>
the method of production of these compounds, their use as levogyrate and programalso, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -piperazine

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to a method of preventing loss of whiteness (brightness) and increase resistance to yellowing in the pulp and paper

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds

The invention relates to new naphtylpropionate F.-ly (I), where R1and R2- N, -HE or-O(C1-C4-alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholinyl, dialkylamino - or 1-hexamethylen-aminogroup; n = 2 or 3, or pharmaceutically acceptable salts

The invention relates to the derivatives of pyrrolidine formula (I) in which either R is methylene, ethyleneglycol, >SO, >SO2group or a sulfur atom; R1means pyridinyl, furyl, thienyl, optionally substituted by one or more alkyl groups, naphthyl, indolyl or phenyl, optionally substituted by one or more substituents selected from halogen atoms, alkyl-, alkoxy-, hydroxy - and dialkylamino; R5means a hydrogen atom; or R is methylene, R1is a hydrogen atom and R5means phenyl; or R is a group > CHR6, R1and R5mean a hydrogen atom; R2means alkoxycarbonyl, cycloalkyl-alkyloxy-carbonyl -, etc., R3means indolyl - or phenylaminopropyl, the phenyl nucleus of which is substituted by one or more substituents selected from a range that contains the halogen atom, the alkyl-, alkoxy-, alkylthio group and others; R4means a hydrogen atom and alkylaryl; R6means phenyl radical in the form of iamiceli mixture or enantiomers and their salts

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds
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