UA73170C2 - Tropan derivatives useful in therapy, method for obtaining thereof and intermediate compounds - Google Patents

Abstract

The present invention provides compounds of the formula (I): wherein R1 is C3-6 cycloalkyl optionally substituted by one or more fluorine atoms, or C1-6 alkyl optionally substituted by one or more fluorine atoms, or C3-6 cycloalkylmethyl optionally ring-substituted by one or more fluorine atoms; and R2 is phenyl optionally substituted by one or more fluorine atoms, to pharmaceutically acceptable salts and solvates thereof, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of. such compounds.

Description

Description of the invention

This invention relates to tropane derivatives useful in the treatment of various disorders, including disorders involving modulation of CSK5 receptors. More specifically, the presented invention relates to 3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|octane derivatives and methods of their preparation, intermediates compounds used in their preparation, compositions containing them, and the use of such derivatives. Disorders that can be treated or prevented by the derivatives presented are HIV and genetically determined retroviral infections (and as a result acquired immunodeficiency syndrome, AIDS), and inflammatory 710 diseases.

The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine SSK5 receptors. CSK5 receptor modulators may be useful in the treatment of various inflammatory diseases and conditions, and in the treatment of HIV-1 and genetically determined retroviruses. The name "chemokine" is an abbreviation of the term "chemotactic cytokines". Chemokines are a large family of proteins that have important structural features and that 12 have the ability to attract leukocytes. As leukocyte chemotactic factors, chemokines play an important role in the attraction of leukocytes to various body tissues, a process that is critical in both inflammation and the body's response to infection. Since chemokines and their receptors are central to the pathophysiology of inflammation and infectious diseases, agents that are active in modulating, preferably antagonizing, the activity of chemokines and their receptors are useful in the therapeutic treatment of such inflammatory and infectious diseases. 20 The chemokine SSK5 receptor is particularly important in the context of the treatment of inflammatory and infectious diseases. CSK5 is a receptor for chemokines, especially macrophage inflammatory proteins (MIRs) designated by MIR-1o and MIR-1p, and proteins that regulate the activation and expression and secretion of normal

T-cells (KAMTEZ5).

Important studies of various classes of modulators of chemokine receptor activity, especially the CSK5 c 295 chemokine receptor, for example, MUO 98/25617 concerns substituted arylpiperazines exhibiting He) chemokine receptor modulator activity.

These compounds are generally described in UUO 00/38680, but are not specifically listed here.

According to the first aspect of the present invention, a compound of formula (I) is provided

AHA Lesdchn m! -- in M district not at 35 in which KE! is C3.6 cycloalkyl, optionally substituted by one or more fluorine atoms, or C 6 - alkyl, optionally substituted by one or more fluorine atoms, or C 3.5 cycloalkylmethyl, optionally substituted on the ring by one or more fluorine atoms; and

B2 is phenyl, optionally substituted with one or more fluorine atoms; " or a pharmaceutically acceptable salt or solvate thereof. WITH

According to the second aspect of the present invention, a compound of formula (IA), c k! ts Ya. ns sn. ,» Ge) Mn X ru M z- -i ns o in which B! represents either C-C cycloalkyl, optionally substituted by one or more fluorine atoms, or C..85 alkyl, optionally substituted by one or more fluorine atoms, or its 5p pharmaceutically acceptable salt or solvate. "Ci in alkyl" is defined by KE" to include branched or unbranched groups. Examples of alkyl are methyl, 2-ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and t-butyl." The term "cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Compounds of formula (I) containing basic centers form non-toxic acid addition salts with acids.

Examples of such salts are hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrophosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate,

IF) camsylate, succinate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, co p-toluenesulfonate and pamoate. For suitable salts, see Vegde ei ai,.. Rpagt. zeii., 66, 1-19, 1977. 60 Pharmaceutically acceptable solvates of compounds of formula (I) or their salts are their hydrates.

Polymorphs of compounds of formula (I) are also included within the scope of the present invention.

The compounds of formula (I) contain one or more asymmetric carbon atoms and therefore exist in two or more of their stereoisomeric forms. The present invention relates to individual stereoisomers of compounds of formula (I) and, when possible, to their individual tautomeric forms, together with mixtures thereof. 65 Separation of diastereomers can be carried out using well-known techniques, for example, by fractional crystallization, HPLC chromatography of a stereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof. The individual enantiomers of the compound of formula (I) can also be obtained from the corresponding pure intermediate or by separation, such as by HPLC, of the corresponding racemate using suitable chiral supports, or by fractional crystallization of the diastereomeric salts obtained after the reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.

The invention also includes compounds of formula (I) labeled with isotopes.

Preferably, B is either C, 6 cycloalkyl, optionally substituted with one or two fluorine atoms, or C 1-6 alkyl, optionally substituted with one to three fluorine atoms.

Preferably, B" is either cyclobutyl, cyclopentyl, 4,4-difluorocyclohexyl, or 3,3,3-trifluoropropyl.

Mostly, V? is phenyl, optionally substituted with 1 or 2 fluorine atoms.

Mostly, V? is phenyl or monofluorophenyl.

Mostly, V? is phenyl or 3-fluorophenyl.

Preferable compounds of formula (I) are

M-415)-3-(3-13-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|oct-8-yl|- 1-phenylpropyl)cyclobutanecarboxamide;

M-415)-3-I(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|oct-8-yl |-1-phenylpropyl)cyclopentanecarboxamide;

M-415)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|oct-8-yl| -1-phenylpropyl)-4,4,4-trifluorobutanamide;

M-415)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|oct-8-yl| -1-phenylpropyl)-4,4-difluorocyclohexanecarboxamide; and

M-415)-3-I(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|oct-8-yl |-1-(3-fluorophenyl)propyl)-4,4-difluorocyclohexanecarboxamide; or any pharmaceutically acceptable salt or solvate thereof. Compounds of formula (I) can be obtained using the following general techniques, in which VK and B? are as stated above for the compound of the formula (I), CO unless otherwise indicated 1. The compound of the formula (I) can be obtained by the reaction of the compound of the formula. ns. sn, th i o r Dosyann V i M u How not - with the compound of the formula: so v'sozn (1) - under the conditions of ordinary condensation.

The reaction is preferably carried out in the presence of a suitable condensing agent (for example,

M-benzyl-M'-cyclohexylcarbodiimide (which may be attached to the polymer), or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydroxybenztriazole hydrate 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), at about room temperature, in a solvent that does not adversely affect reaction, for example, dichloromethane. The following suitable condensation conditions are described in Method 2, below. "Compounds of formula (III) are either known or obtained using generally known techniques.

Compounds of formula (II) can be prepared as shown in Scheme 1, below. 2. Compounds of formula (I) can be obtained as shown in Scheme 1. - Scheme 1 t - is "K -i m M (42) in. "Univ

Renault "Yun M." aa -0- «ek ra po p

F) track ka ' MN, M Y 60 ay

KG pknnityutnyunnnv I where P is a suitable protecting group such as t-butyloxycarbonyl, benzyl or benzyloxycarbonyl and compounds 65 of formula (II) and (MII) exist in the exo form. In a typical procedure, when P is t-butyloxycarbonyl, the amine of formula (IM) is reacted with di-tert-butyldicarbonate in the presence of a base acceptor such as aqueous sodium hydroxide and in a suitable solvent such as tetrahydrofuran.

The protected amine of formula (M) can be reduced to the aldehyde of formula (MI) using a suitable reducing agent, for example, using diisobutylaluminum hydride in dichloromethane at a temperature below 80 7T09b.

The reaction of reductive amination of an aldehyde of the formula (MI) with an amine of the formula (in the exo form): p-n

M I:

SH

(Mid) gives the compound of formula (MI). The reaction is carried out in the presence of an excess of a suitable reducing agent, such as sodium triacetoxyborohydride or sodium cyanoborohydride, in a protic solvent, such as acetic acid in either dichloromethane or 1,1,1-trichloroethane, at room temperature.

The knowledge of protection from the compound of the formula (MII) can be carried out using generally known conditions. When P is t-butyloxycarbonyl this can be accomplished using trifluoroacetic acid or an aqueous solution of hydrochloric acid in a solvent such as dichloromethane or methanol at room temperature.

A compound of the formula (II) is prepared by converting a compound of the formula (I) by reaction with a compound of the formula: 'co7 (MIV) in which 7 is a group that activates a carboxyl group such as chlorine or 1H-imidazol-1-yl, using generally known conditions , for example, using M,M'-carbonyldiimidazole, triethylamine and dichloromethane.

Preferably, the compound of the formula (MIV) is obtained directly from the compound of the formula (I) using a carbodiimide, an EM such as 3-(3-dimethylamino-1-propyl)-1-ethylcarbodiimide or M-benzyl-M"-cyclohexylcarbodiimide on a polymer, ) optionally in the presence of 1-hydroxybenztriazole hydrate and reacting with a compound of formula (II). The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran or ethyl acetate, optionally in the presence of a base such as a tertiary amine such as triethylamine or M-ethyldiisopropylamine, at about room temperature

Alternatively, the acid of formula (1) can be first activated with hexafluorophosphate Kk. benztriazol-1-yloxy-tris(dimethylamino)phosphonium (BOR), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (RUVHOR) or 2-fluoro-1-methylpyridinium p-toluenesulfonate (Mukaiyama reagent) in the presence of excess -

of M-methylmorpholine, triethylamine or M-ethyldisopropylamine in a suitable solvent such as tetrahydrofuran, dichloromethane or ethyl acetate at room temperature to give a compound of formula (MIV) and 3o which reacts with a compound of formula (II). -

Alternatively, an acid chloride of formula (MIV) wherein 2 is chlorine may be reacted with a compound of formula (I), optionally in the presence of a suitable base, for example triethylamine, M-ethyldiisopropylamine, sodium carbonate, potassium carbonate or sodium bicarbonate, and in a suitable solvent such as dichloromethane, ethyl acetate,

THF or toluene, at room temperature.

It should be understood that the conversion of a compound of formula (MI) into a compound of formula (I) via a compound of formula (II) can be carried out in a "one reactor" by deprotection/condensation using methods "similar to those previously described." Compound of formula (MIA ) can be obtained as shown in Scheme 2.

Scheme 2 " o

M

5060s (95) ry v" - in ah) -I 50 ry o and t y schich v y viya 9 0) s) o ok yuyu schu 2 t--- (MA) in 60 I (x) de R " is a suitable protecting group such as t-butyloxycarbonyl or benzyl and compounds of formulas (X), (XI) and (XII) exist in the exo form.

An oxime of formula (IX) can be prepared by condensing a ketone of formula (MI) with 65 hydroxylamine hydrochloride in the presence of a base, for example, pyridine, and in a suitable solvent, usually ethanol. The reaction is usually carried out at the boiling temperature of the solvent.

When P' is t-butyloxycarbonyl or benzyl, reduction of the oxime of formula (IX) can be carried out using sodium in the presence of an alcohol, usually pentanol, or by electrochemical reduction, resulting in an amine of formula (X).

The amide of formula (XI) can be obtained by condensing the protected amine of formula (X) with 2-methylpropanoic acid or its activated derivative. Condensation is carried out using well-known techniques for the formation of an amide bond, such as those described in Methods 1 and 2, above. Typically, the acid can first be activated using a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, optionally in the presence of 1-hydroxybenztriazole, in a suitable solvent such as dichloromethane, and in the presence of a base, such as a tertiary amine , such as triethylamine or diisopropylamine, and then react with an amine of formula (X). Alternatively, the reaction is carried out using 2-methylpropanoyl chloride in the presence of a base, such as sodium carbonate, and a suitable solvent, for example, dichloromethane.

The triazole of formula (XII) can be obtained in a "one reactor" using a two-step technique, first condensing the amide of formula (XI) with acetic acid hydrazide, followed by a cyclocondensation. 75 Typically, the amide is first activated with phosphorus oxychloride in a solvent such as chloroform and in the presence of a base such as pyridine at 02C, then treated with acetic hydrazide in a suitable solvent such as chloroform, and the reaction mixture heated to reflux. The reaction is completely completed in the presence of an acid such as p-toluenesulfonic acid and in a suitable solvent such as toluene at elevated temperature (eg 1102).

Deprotection of the compound of formula (XII) using standard techniques gives the amine of formula (MIA)

Usually, when P' is benzyl, deprotection is carried out using catalytic hydrogenation, such as palladium(II) hydroxide as a catalyst in a suitable solvent, for example, ethanol, in the presence of ammonium formate at 709C. Alternatively, deprotection is carried out using catalytic hydrogenation using palladium on carbon as a catalyst in a suitable solvent such as methanol, optionally in the presence of a suitable acid such as p-toluenesulfonic acid. at

C. Compounds of formula (I) can be prepared as shown in Scheme 3.

Scheme З "Ж M re и "АХ о tre o web ya sha --- "KA і- (р (МА) им) 0 Me "-- -- - so where КЗ is H or С.-Се alkyl. Cha

An amide of the formula (XIM) can be prepared using well-known techniques for the formation of an amide bond, such as the activation of an acid of formula (XIII) (in which B C is H) or an acid chloride or using other techniques as described above in Method 1 and 2, followed by reaction with an amine of the formula (MIA). Alternatively, an ester of formula (XIII) (in which KZ is C-C alkyl) reacts directly with an amine or its metal salt. Thus, the acid chloride and the amine, or its salt, react in the presence of an excess of a suitable base, for example, Ma»CoOz, - with MansSoOz, K»uSoOz, triethylamine or M,M-diisopropylethylamine, and in a suitable solvent, for example, h dichloromethane, ethyl acetate, THF or toluene, with or without water as co-solvent. Alternatively, the acid can be activated with 1-N3-dimethylamino)propyl|-3-ethylcarbodiimide hydrochloride (MUSOI), KDI (1,1"-carbonyldiimidazole) or DCC (1,3-dicyclohexylcarbodiimide) and GOAT (1-hydroxy-7- azabenztriazole) or HOBT (1-hydroxybenztriazole hydrate), and react with an amine in the presence of a base, such as triethylamine, in a solvent such as THF, dichloromethane, or toluene. Also, an ester and an amine or its metal salt can be reacted in the presence of a base such as triethylamine and optionally a catalyst in a solvent such as dichloromethane, ethyl acetate, THF or toluene with or without water as a co-solvent Alternatively the ester, amine and enzyme catalyst may be reacted in a solvent such as dichloromethane, ethyl acetate, THF or toluene, with or -1 50 without water as a co-solvent. Preferably, the acid chloride, amine and Ma»CO»z are reacted in dichloromethane and water, or the acid is treated with M,M'-carbonylimidazole to form an imidazolide which then reacts with the amine in the presence of dichloromethane and triethylamine. The amide of formula (XIM) can be reduced, for example, using a nucleophilic hydride reagent or an electrophilic hydride reagent, or by catalytic hydrogenation, or using an alkyl or aryl silane with a suitable transition metal catalyst to give a compound of formula (I). Typical conditions are using Kea-Al (bis(2-methoxyethoxy)sodium aluminum hydride) in THF or toluene or borane in THF. 4. Compounds of the formula (I) can be obtained as shown in Scheme 4. Name) Scheme 4, about He) because ton yan i to high Ж mmMyu-- i in m om where ХУ is -СО2В, -СМ or -С( O)MNEA, where B" is H or C-C-C alkyl. Because the reaction giving an aldehyde of the formula (XMI) can be carried out by reduction of an ester, nitrile, amide or acid (for example, activated by a suitable reagent) of the formula (XM), by a hydride reducing agent in a suitable solvent. Alternatively, the reduction of the ester, nitrile or acid (activated by a suitable reagent) of formula (XM) can be carried out with a suitable transition metal catalyst, a source of hydrogen and in a suitable solvent. Typical conditions are the reduction of the ester, nitrile or alumo amide - either with a borohydride such as DIBAL (diisobutylaluminum hydride), Kea-Ash, GiIACO(-Vy)) with or (MegCHCH(Me))»NH in a solvent such as THF, dichloromethane or toluene, or by reducing the acid chloride using a transition metal -a catalyst, such as Ra/C or Ra/Vabzo, in a nitrogen atmosphere in the presence of a modifier, and such as 2,4-dimethylpyridine and a solvent such as THF or toluene. Preferred conditions are reduction of DIBAL ester in dichloromethane or toluene. 70 The compound of formula (I) can be obtained by reductive amination using an aldehyde of the formula (HMI) and an amine of the formula (MIA) or its salt. Usually, the reaction is carried out by reacting aldehyde with 0.8-1.5 mol of eq. amine or its salt, optionally, in the presence of 0.1-Zmol eq. of a protonic acid, with either a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, or using a transition metal as a catalyst such as palladium, platinum or rhodium and a hydrogen source such as molecular hydrogen or 7/5 ammonium formate in a suitable solvent such as such as dichloromethane, acetonitrile, toluene, ethanol or 2-propanol.

Preferably, the aldehyde reacts with the tosylate salt of the amine in the presence of sodium triacetoxyborohydride and traces of acetic acid in dichloromethane at room temperature.

An aldehyde of the formula (HMI) can also be prepared from an alcohol of the formula: "Ж in ichon mA) by standard oxidation, for example, using an oxidizing agent such as DMSO/sulfur trioxide-pyridine complex, DMSO with (SOCI)", MpO" or StOz, with or without a base, in a suitable solvent such as dichloromethane, toluene, acetone or acetonitrile; using a transition metal as a catalyst, such as KA o or Ky, with or without a base, and a hydride acceptor, such as a ketone, in a suitable solvent, such as dichloromethane, acetone, toluene or acetonitrile; or using a catalytic oxidant such as TKAR (tetrapropylammonium perutenate) or TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical), with or without a solid support, with a stoichiometric oxidant for the catalyst such as MMO (4 -methylmorpholine M-oxide), in oxygen or sodium hypochloride or sodium hypobromite, and in a suitable solvent such as dichloromethane, acetone, ditoluene or acetonitrile. Preferred conditions are the use of DMSO, a complex of sulfur trioxide-pyridine and triethylamine in dichloromethane, or TEMRO, KVg, Maosi, water and dichloromethane. -- 5. Compounds of formula (I) can be obtained by reductive amination of a compound of formula (XM), in which U is -CM, of an amine of formula (MIA) or its salt. The recovery can be carried out using a transition metal as a catalyst,

Optionally, in the presence of an acid, and a source of hydrogen, in a suitable solvent. A typical technique uses palladium on carbon or platinum oxide (PI) and a solvent such as methanol, acetic acid, or 2-propanol. b. Compounds of the formula (I) can be obtained by alkylating an amine of the formula (MIA) or its salt " (acid addition or metal salt) using a compound of the formula: - c "Xe "z ' teach a salt in which 7 is a leaving group, such as a halogen , C.-C. alkanesulfonyloxy, benzenesulfonyloxy or -I p-toluenesulfonyloxy, optionally, in the presence of a base and/or an interphase catalyst.

The reaction is usually carried out in the presence of a base such as triethylamine or M,M-diisopropylethylamine; DBU o (1,8-diazabicyclo|5,4,0)undec-7-ene; or an inorganic base, such as Ma 2CO3, MansCO3, CoCO»3 or С85CO» - optionally, in the presence of an interphase catalyst, and in a solvent such as acetonitrile, DMF (dimethylformamide), DMSO (dimethylsulfoxide), 1,4- dioxane, THF or toluene. Alternatively, the metal salt of amine 7 (ie, the deprotonated form) can be reacted with a compound of formula (CHMII) in a suitable solvent such as THF, DMF or 1,4-dioxane. Preferably, the reaction is carried out using the reaction of an amine and a compound of the formula (HMI) with either DBU in acetonitrile or CoCO" and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane) in THF. 7. Compounds of formula (I) can be prepared as shown in Scheme 5.

Scheme 5 o o o i va i Me. Me ko chn check, ptn here I lead m koma tn

The compound of the formula (XMIII) can be obtained using the Mannich reaction of the compound of the formula:

В?СОосНна вв 009 with a compound of the formula (MIA) or its salt, formaldehyde or its equivalent, with or without acid, in a suitable solvent. Typical conditions are the reaction of the amine and ketone with an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or acetic acid and paraformaldehyde in a suitable solvent such as ethanol, methanol, 2-propanol or DMF: or the reaction of the amine salt (such as hydrochloride, bulphate or tosylate) with ketone and paraformaldehyde in a suitable solvent such as ethanol, methanol, 2-propanol or DMF.

Alternatively, the compound of the formula (XMIII) can be obtained by the reaction of the compound of the formula (MIA) or its salt, with the compound of the formula: вгсОосносно2? 70 (XXI) in which 72 is a leaving group as defined for 7" using standard alkylation conditions such as those described for Method 6, above. The enamide of formula (XXI) can be prepared by reacting a compound of formula (XMIII) with an amide of the formula: v'somne (XXI) under dehydration conditions, with or without an acid catalyst, and in a suitable solvent; or by reduction of a compound of the formula (XMIII) first with hydroxylamine or its salt, and then reaction of the intermediate product with an acid anhydride of the formula: ( E'C0)2O (XXI) with a transition metal as a catalyst and an acid in a suitable solvent; or by reacting a compound of formula (XMIII) first with ammonia or its salt, and then reacting the intermediate product with an acid of formula (II) or its activated derivative , under standard conditions. Typically, a compound of formula (CHIII) is reacted with an amide of formula (XXII) in the presence of a catalytic amount of acid with azeotropic removal of water or removal of water using dehydrating agents such as molecular and sifted at

The compound of formula (I) can be obtained by asymmetric reduction of enamide of formula (XIX) using 0.001-0.1 mol eq. of a transition metal such as KI, Ky, Ra, Ri, Ig or Ti, 0.001-0.2 mol eq. chiral ligand, such as VIMAR (2,2-bis(idiphenylphosphino)-1,1'-binaphthyl), 10I-VIMAR (2,2-bis(di-p-tolylphosphino)-1,1-binaphthyl), Bi- РНОБЗ ((1,2-bis(2,5-dimethylphospholano)benzene) or Repp-Rpoz o (ReppR'-1,2-phenylenebis(endo-2,5-dimethyl-7-phosphabicyclo|2,2,1) heptane), a hydrogen donor such as molecular M hydrogen, phenylsilane, 2-propanol or ammonium formate, and a suitable solvent such as methanol, ethanol, acetonitrile, toluene, ethyl acetate, 2-propanol or THF, at a temperature of 09 to the boiling point and , -- optional, at increased pressure. 8. The compound of formula (I) can be obtained as shown in Scheme 6. yu om) mii ad) me M Z s ra khz» t: A tr . p

ЗаШ- -- - - --юй«х , 0) Me -i Ketone of the formula (HMIII) can be converted into a racemic amine of the formula (PA) by reductive amination using commonly known methods, for example, ammonia or its equivalent, and reducing agent in a suitable solvent. The racemic amine of the formula (PA) can be resolved to give the amine of the formula (II) using standard -1 50 techniques, such as classical, kinetic or dynamic separation techniques.

An amine of formula (II) can be converted into a compound of formula (I) by the routes described in Methods 1 and 2. c2 Alternatively, a racemic amine of formula (PA) can be converted into a compound of formula (I) using a compound of formula (I) or suitable activated derivatives thereof , a chiral catalyst, optionally using a catalyst to racemize the present undesired isomer, and a suitable solvent.

An amine of the formula (II) or its metal salt (i.e., deprotonated form) can also be converted into a compound of the formula (I) by reaction with an ester of the formula: v'coOjo o (XXiM) in which KE? is an ester-forming group such as C4-Cb alkyl. The reaction is usually carried out by reacting an ester and an amine or its metal salt with an excess of a base such as triethylamine and, optionally, a catalyst in a solvent such as dichloromethane, ethyl acetate, THF or toluene, with or without water as a co-solvent; or by treating the ester and amine in the presence of an enzyme catalyst in a solvent such as dichloromethane, ethyl acetate, THF or toluene, with or without water as a co-solvent.

All of the above reactions and the preparation of new starting compounds used in the above methods are generally known and acceptable reagents and reaction conditions for their implementation or preparation, as well as methods for the isolation of products will be well known to those skilled in the art with reference to previous literature and their Examples and Preparation.

A pharmaceutically acceptable salt of a compound of formula (I) can be easily prepared by mixing solutions of a compound of formula (I) and the desired acid. The salt can be precipitated out of solution and collected by filtration or can be isolated by evaporation of the solvent.

The compounds of formula (1), and their pharmaceutically acceptable salts, are useful because they have pharmacological activity in animals, including humans. More particularly, they are useful in the treatment of disorders that are modulated by CSK5 receptor engagement. Disease states that may be mentioned are HIV, a retroviral infection that 7/0 Genetically predisposes to HIV, AIDS, or an inflammatory disease. The compounds of formula (I), and their pharmaceutically acceptable salts, can be administered alone or as part of combination therapy.

The compounds of the present invention can be used in the treatment of respiratory diseases, including acute respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis. Other conditions that can be /5 Cured are diseases that are initiated, affected, or otherwise caused by T-cell traffic in various organs. It is apparent that the compounds of the present invention may be useful in the treatment of such conditions and especially, but not limited to, the following for which correlation with SSK5 or defined SSK5 chemokinesis: inflammation of internal organs, including Crohn's disease and ulcerative colitis, multiple sclerosis, rheumatoid arthritis, transplant rejection, including but not limited to kidney and lung rejection, endometriosis, type 1 diabetes, kidney disease, chronic pancreatitis, inflammatory lung conditions, or chronic heart failure. For a recent review of possible applications of chemokines and chemokine receptor blockers, see Savsiegi, M.A., and Zrgipdeg, M.5., Te spetokKipe/spetokKipe geseriog Tatu: roiepiia! apa rgodgevzz Tog (pegaretsiis ipieguepiyop". Sy. Orip. SNegii. Vio!., 4(4), 420-7 (Aidivi 2000).

The ability of the compounds of the formula (I) and their pharmaceutically acceptable salts to inhibit HIV infection can be demonstrated using one or more methods known from the literature, for example, using the HIV microculture study described by Oitig ei ai., 9. Siip. Misgobio!i., 28, 734-737 i) (1990), and the study of pseudotyped HIV reporter Soppog eii ai., Migoiodu, 206 (2) 935-44 (1995).

The ability of the compounds of formula (I) and their pharmaceutically acceptable salts to modulate the activity of the chemokine receptor is demonstrated by methods known in the field, for example, using the study of the binding of CSK5 according to the method described by Sotradiege et al., 9. Ieikkos. Vio!., 60, 147-52 (1996); and/or using intracellular calcium mobilization studies as described by the same authors. -

Cell lines of interest that express the receptor are those that express a native receptor, such as PM-1, "- or II -2 stimulated peripheral blood lymphocytes (RBI), or engineered cells that express a recombinant receptor, such as CHO, 300 ,19, 1.1,2 or NEK-293. and)

Compounds of formula (I) may be administered alone, but are usually administered in admixture with a suitable pharmaceutical carrier, diluent or carrier selected depending on the intended route of administration and standard pharmaceutical practice.

For example, the compounds of formula (I) can be administered orally, buccally or sublingually in the form of tablets, capsules, forms containing a large number of particles, gels, films, ovules, elixirs, solutions or suspensions containing flavoring or coloring agents, for immediate-, delayed-, modified-, prolonged-, pulsatile or controlled-release. Compounds of formula (I) can also be administered in the form of dosage forms with rapid dispersion or dissolution or in the form of high-energy dispersion or particles with; coating If desired, suitable formulations of compounds of formula (I) may or may not be coated.

Such solid pharmaceutical compositions, for example tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium dihydrogen phosphate, glycine and starch-I (predominantly corn, potato or tapioca starch), disintegrants such as sodium starch glycolate , croscarmellose sodium and some silicate complexes, and binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropyldelulose (HPTC), sugar, gelatin and acacia. In addition, the compositions may contain lubricating agents such as magnesium stearate, stearic acid, glycyryl behenate and talc. - General Example o A tablet formulation usually contains from 0.0 mg to 500 mg of active compound, while the weight of the tablet is in the range from 5 mg to 100 mg. An example of a recipe for a 1Omg tablet is given below:

Ingredient by weight/weight

Compound of formula (I) or salt 10.0007

GF) Lactose 64.125 k Starch 21.375

Croscarmellose sodium 3,000 in Magnesium stearate 1,500 7 The amount was set in accordance with the activity of the medicinal product.

Tablets are produced by standard techniques, for example, direct compression or wet or dry granulation. Tablet cores may be coated with an acceptable coating material. 65 Gelatin capsules or HPMC capsules can also be filled with solid compositions of this type.

Preferred excipients in this regard are lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. For example suspensions and/or elixirs, the compounds of formula (I) may be combined with various sweetening or flavoring agents, dyes or pigments, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and their combinations.

Compounds of formula () may also be administered parenterally, for example, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrinally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered 7/0 by infusion or by blunt injection. device. For such parenteral administration, it is better to use them in the form of a sterile aqueous solution, which may contain other substances, for example, a sufficient amount of salt or glucose to obtain a solution isotonic with blood. Aqueous solutions should be suitably buffered (preferably to a pH of 3 to 9) if necessary. Preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. For oral or parenteral administration to humans, the daily dose level of the compounds of formula (I) and their fPharmaceutically acceptable salts will be in the range from 0.01 to 30 mg/kg (in single or divided doses) and preferably will be in the range from 0.01 up to 15 mg/kg. Thus, the tablets will contain from 1 mg to 0.5 g of the compound to be administered once or twice or more times, depending on the circumstances. In any case, the doctor will determine the necessary dose, which will be the most acceptable for any individual patient and will depend on the age, weight and response of each patient. The above doses are an average statistical example. It is clear that in each individual case, higher or lower dose intervals are possible and such intervals fall within the scope of the present invention.

The oral route of administration is preferred. Preferably, the administration takes place immediately before the desired effect. high school

The compounds of formula (I) can also be administered intranasally or by inhalation and are readily released as a dry powder from an inhaler or aerosol spray contained in a pressurized container, pump, i) spray, nebulizer or nebulizer, with or without the use of a suitable propellant , for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (NEA 134A | trade mark) or 1,1,1,2,3,3,3-heptafluoropropane (NEA 227EA (trade o zo mark)), carbon dioxide or other suitable gases. In the case of a compressed aerosol, the dosage unit can be determined by providing a valve that releases the dosage amount. A container under pressure, a deposit, a spray, a nebulizer or a nebulizer can contain a solution or suspension of an active compound, for example, using as a solvent a mixture of ethanol and a propellant, which can additionally contain lubricating agents, for example, sorbitol trioleate. Capsules and cartridges (manufactured, for example , gelatin) for use in an inhaler or insufflator can be formulated to contain a powdered mixture of a compound of formula (I) and a suitable powder base such as lactose or starch.

Aerosol or dry powder formulations are preferably arranged so that each metered dose or "push" contains from 10 mg to 10 mg of the compound of formula (I) for administration to the patient. The total daily dose of the aerosol will be in the range from mcg to 200 mg and may be administered as a single dose or, more commonly, in divided doses throughout the day. c c Alternatively, the compounds of formula (I) may be administered in the form of a suppository or pessary, or they may

And to be used locally in the form of a gel, hydrogel, lotion, solution, cream, ointment or powder. Compounds of formula (I) can also be administered dermally or transdermally, for example, using a patch on the skin. They can also be administered by the pulmonary or rectal route.

They can also be administered intraocularly, especially in the treatment of inflammatory eye conditions. For -I ophthalmic use, the compounds may be formulated as a micronized suspension in an isotonic, pH-specified, sterile saline solution or, preferably, as solutions in an isotonic, pH-specified, sterile saline solution, optionally in combination with a preservative such as benzylalkonium chloride. Alternatively, they can be formed into an ointment based on petroleum jelly.

For topical use through the skin, the compounds of formula (I) can be formulated as an ointment containing

Ш- an active compound suspended or dissolved in, for example, a mixture of one or more of the following carriers: mineral oil, liquid petroleum jelly, white petroleum jelly, propylene glycol, polyoxyethylene, polyoxypropylene, emulsified wax and water. Alternatively, they may be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following solvents: mineral oil, sorbitol monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl wax esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

F) Compounds of formula (I) can also be used in combination with cyclodextrin. Cyclodextrins are known for forming inclusion complexes and simple complexes with drug molecules. The formation of a drug-diclodextrin complex can modify the solubility, dissolution rate, bioavailability and/or stability of the drug molecule. Drug-diclodextrin complexes are generally useful for most dosage forms and routes of administration. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary excipient, for example, as a carrier, diluent or solubilizer. Alpha-, beta- and gamma-cyclodextrins are most often used and suitable examples are described in UMO-A-91/11172, UMO-A-94/02518 and MUO-A-98/55148. 65 The compounds of formula (I), and their pharmaceutically acceptable salts, are advantageous because they are more selective, have a faster onset of action, are more active, are more stable, are more resistant to metabolism or have other more desirable properties than the compounds prior art.

The scope of the present invention includes embodiments relating to the joint use of compositions that contain, in addition to the compound of the present invention, as an active ingredient, additional therapeutic agents and active ingredients. Such multifunctional regimens, often involving combination therapy, can be used in the treatment and prevention of any diseases or conditions caused by or associated with modulation of the chemokine SSK5 receptor, in particular, in particular, human infection with the immunodeficiency virus, HIV.

The use of such combinations of therapeutic agents is particularly useful in the treatment and prevention of infection and replication of human immunodeficiency virus, HIV, and pathogenic retroviruses in patients in need of treatment or at risk for such patients. The ability of such retroviral pathogens to manifest themselves in a relatively short period of time in strains resistant to any monotherapy administered to said patient is well known from the literature.

In addition to the requirement of therapeutic efficacy, which may require the use of active agents in addition to the compounds of formula (I) and their pharmaceutically active salts, modulating the chemokine CSK5 /5 receptor, there are additional explanations that force or strongly recommend the use of drug combinations that contain active ingredients that represent adjunctive therapy, i.e., that complement and complement the function performed by the compounds of the present invention that modulate the chemokine SSK5 receptor. Such adjunctive therapeutic agents are used for adjunctive treatment purposes, including drugs that, instead of directly treating or preventing a disease mediated or caused by the chemokine CSK5 receptor, treat a disease or condition that directly results from or is indirectly accompanied by the underlying or underlying disease or condition mediated by the chemokine CSK5 receptor . For example, when the underlying chemokine SSK5 receptor-mediated disease or condition is HIV infection and replication, it may be necessary, or at least desirable, to treat opportunistic infections, neoplasms, and other conditions that occur as a secondary consequence of the immunocompromised state in the patient being treated. Other active agents can be used with the compounds of formula (I) and their pharmaceutically acceptable salts, for example, to provide immune i) stimulation or treatment of pain and inflammation, which accompanies the initial and main stage of HIV infection.

Thus, the treatment methods and pharmaceutical compositions of the present invention can use the compounds of formula (I) and their pharmaceutically acceptable salts, in the form of monotherapy, but the aforementioned methods and compositions can also be used in the form of multicomponent therapy in which one or more compounds of the formula (I) or their pharmaceutically acceptable salts is prescribed in combination with one or more therapeutic agents described in more detail below. "-

Preferred combinations of the present invention are the simultaneous or sequential administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more HIV protease inhibitors or HIV reverse transcriptase inhibitors, preferably selected from the class of non-nucleoside reverse transcriptase inhibitors (MMACTIs), including but not limited to nevirapine, delavirdine and efavirenz; from nucleoside/nucleotide inhibitors including but not limited to zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adnfovir and dipivoxil and from protease inhibitors including but not limited to indinavir, ritonavir, saquinavir, nelfinavir, lopinavir and amprenavir. Other agents are useful in the described "

The above preferred embodiments of the combinations of the present invention are widely distributed and researched and developed drugs from any of the above-mentioned classes of inhibitors, including but not limited to

ETS, PMRA, fosivudine tidoxyl, talviralin, 5-1153, MKOSM42, M5OS-204, M5N-372, OMRAB5O, RMO-140690, ;" AVT-378 and KMI-764. Also within the scope of the preferred embodiments of the present invention are included combinations of the compound of formula (I) or its pharmaceutically acceptable salt together with additional therapeutic agents that

Used for the purposes of additional treatment, in which said additional therapeutic agents are -And one or more members independently selected from the group containing proliferation inhibitors, for example, hydroxyurea; immunomodulators, for example, sargramostin, and various forms of interferon or derivatives of interferon; fusion inhibitors, for example, AMOZ3100, T-20, RMKO-542, A-349, BB-10010 and others - chemokine receptor agonists/antagonists; tachykinin receptor modulators, for example MK antagonists; integrase inhibitors, for example, AK177; RNazinH inhibitors; inhibitors of viral transcription and replication

Sh-RNA; and other agents that inhibit viral infection or improve the condition or consequences of HIV infection in individuals through various mechanisms.

Preferred methods of treatment of the present invention for preventing HIV infection, or treating aviremic and asymptomatic subjects potentially or actually infected with HIV, including but not limited to the administration of a member independently selected from the group consisting of: (iii) a compound within the formula ( I), as described here; (ii) one MMCTI in addition to compound (It); (iii) two MKTIs in addition to compound (Her); (him)

F) one MKTI in addition to the combination (ii, and (m)) a compound selected from the class of protease inhibitors that are used instead of MKTI in combinations (iii) and (im).

Preferred methods of the present invention for the treatment of HIV-infected individuals with established viremia or abnormally low CO4 further include a member selected from: (mi) treatment according to (Her), above, in addition to the standard recommended initial treatment regimens of established HIV infections, for example, see per://pimaiz.ogoLgidaIpv.yiti. Such standard regimens include, but are not limited to, agents from the protease inhibitor class in combination with two MCTIs; and (my) standard recommended initial regimens for the treatment of established HIV infections, e.g., zee PNEr://pPimaiv.ogoLgdapv.yit!, in which either a 65 protease inhibitor or one or both MKTIs are replaced by a compound of formula (I) as herein described

Preferred methods of the present invention for the treatment of HIV-infected individuals with subsequent failure of antiviral therapy include a member selected from: (my) treatment according to (i), above, in addition to standard recommended treatment regimens for such patients, for example, see per:/ pimayiv.ogoaypidaipv.yiti; and (their standard recommended initial treatment regimens for patients who have failed antiviral therapy, for example, zee PEr://pimayiv.ogalhydapv.yiti, where either one protease inhibitor component or one or both MKTIs are replaced by a compound within compound (I) , as described here.

In the above-described preferred embodiments of the combinations of the present invention, the compound of formula (1) and other therapeutic agents can be administered based on dosage forms either separately or in combination with each other, and based on their time of administration, or in series or simultaneously. Thus, the introduction of one component may be 7/0 priority, competitive, or later introduction of the other component(s).

It should be noted that all references to treatment given here refer to curative, mitigating and preventive treatment. Thus, the invention provides: a compound of formula (I) or its pharmaceutically acceptable salt or solvate; a method of obtaining the compound of formula (I) or its pharmaceutically acceptable salt or solvate; a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier, a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a medicament; a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for the treatment of a disorder in which modulation of SSK5 receptors is involved; a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for the treatment of HIV, a retroviral infection genetically predisposing to HIV, AIDS or an inflammatory disease; a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for the treatment of a respiratory disorder including acute respiratory distress syndrome (ARDS5), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis or chronic o sinusitis; a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for the treatment of inflammation of internal organs, including Crohn's disease or ulcerative colitis, multiple sclerosis, rheumatoid arthritis, transplant rejection, including kidney or lung rejection, endometriosis, type I diabetes, disease at

From the kidneys, chronic pancreatitis, lung inflammation or chronic heart failure; the use of a compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition, for - the manufacture of a medicament for the treatment of a disorder in which the modulation of CSK5 receptors is involved; "- use of the compound of formula (I) or its pharmaceutically acceptable salt, solvate or composition, for the manufacture of a medication for the treatment of HIV, retroviral infection that genetically causes HIV, AIDS or me) z5 inflammatory disease; the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of a respiratory disorder including acute respiratory distress syndrome (AKO5), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis or chronic sinusitis; "use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of inflammation of internal organs, including Crohn's disease or

Ulcerative colitis, multiple sclerosis, rheumatoid arthritis, transplant rejection, including kidney or lung rejection, endometriosis, type I diabetes, kidney disease, chronic pancreatitis, lung inflammation, or chronic heart failure; a method of treating a disorder in a mammal involving the modulation of CSK5 receptors, which consists in administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof; o a method of treating a mammal for HIV, a retroviral infection that genetically causes HIV, AIDS, or an inflammatory disease, which consists in administering to said mammal an effective amount of a compound of formula (I) or its 5p pharmaceutically acceptable salt, solvate, or composition; ш- a method of treating a respiratory disorder in a mammal, including acute respiratory distress syndrome o (AKOZ5), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis or chronic sinusitis, which consists in administering to said mammal an effective amount of a compound of the formula ( I) or its pharmaceutically acceptable salt, solvate or composition; method of treating inflammation of internal organs in a mammal, including Crohn's disease or ulcerative colitis, multiple sclerosis, rheumatoid arthritis, transplant rejection, including kidney or (F, lung, endometriosis, type I diabetes, kidney disease, chronic pancreatitis, lung inflammation conditions, or ca chronic heart failure, which consists in administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof; and intermediate compounds of formulas (II), (PA), (MI), (MIA), (XII ), (KHIM), (XM) and (XIX).

The invention is illustrated by Examples, in which the following abbreviations can be used: 0.88 ammonia - concentrated ammonium hydroxide solution, 0.88 VS g hour min - minute 65 IU - mass spectrum

NMR - nuclear magnetic resonance

Me - methyl

Example 1

M-415)-3-I(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo/|3.2.1|oct-8- yl-1-phenylpropyl)cyclobutancarboxamide

In NK base o mn Lya T with mm in SY no -

M-Benzyl-M'-cyclohexylcarbodiimide on the polymer (1.15g, 0.88mmol) was added to a solution of the compound indicated in the title Preparation 11 (25µg, 0.68mmol) and cyclobutanecarboxylic acid (13µl, 1.37mmol) in dichloromethane (1µl) and the mixture was stirred at room temperature for 16 hours. The mixture was filtered 75 Through Celite? (filtering material and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of dichloromethane:methanol:0.88 ammonia (1:0:0 to 95:5:0.5, by volume) as eluent) yielding the title compound as a white foam, 20Omg.

Found C, 69.98; N, 8.67; M, 14.8995

C27NzeM5O; 0.2 of the CIS"; C, 70.01 is required; H, 8.51; M, 15.0190 7TN-NMR (400MHz, SOSIv): 5 |m.ch.Y 1.40 (Е6Н, d), 1.63 (4Н, m), 1.85-2.45 (14Н, m ), 2.52 (ЗН, с), 3.00 (2Н,

M), 3.39 (2Н, m), 4.30 (1Н, m), 5.15 (1Н, m), 6.35 (1Н, m), 7.15-7.40 (5Н, m ).

NRMS: t/z 450.3 (MH) (cMo-34.02 (s - 0.10, MeonH)

Example 2 with 29 M-415)-3-I(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|oct -8-yl|-1-phenylpropyl)c He)cyclopentanecarboxamide

Vya ry | "c) plural su r te also --

Cyclopentanecarboxylic acid (115 μl, 1.0 mmol) was added to a solution of the preparation indicated in the heading (9 11 compounds (30 mg, 0.82 mmol), hydroxybenztriazole hydrate (1 mg, 74 μmol) and methyl iodide of 1-"3-dimethylaminopropyl)-3-ethylcarbodiimide (30mg, 1.07mmol) in dichloromethane (10ml) and the mixture was stirred at room temperature for 3 hours. To the mixture was added a saturated aqueous solution of sodium carbonate (50ml) and the product was extracted with dichloromethane (2x). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried (MazO,), filtered and evaporated under reduced pressure. The residue was purified " 70 by means of column chromatography on silica gel using as eluent a gradient of c dichloromethane:methanol:0.88 ammonia (1:0:0 to 96:4 :0.4, by volume) to give the title compound as a white foam, 3ZOmg. :z» Found C, 69.73; H, 9.00; M, 14.0995

Sovna MBO; 0.25 СНоСИ"; C, 69.98 is required; H, 8.63; M, 144490. "H-NMR (400 MHz, SOSIv): 5 (m.ch.1) 1.35 (6Н, d), 1.51-2.04 (16Н, m), 2.17 (2Н, m), 2.39 (2H, m), 2.45 (4H, -i m), 2.95 (1H, m), 3.36 (2H, s), 4.25 (1H, m), 5.09 (1Н, m), 6.12 (1Н, m), 7.20-7.33 (5Н, m). с НРМС: t/z 464.8 (МН") (сЧо-29.21е (c - 0.10, MeOH) - Melting point (es): 68-70 - 20 Example C

M-413)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo/3.2.1|oct-8-yl| -1-phenylpropyl)- (ze) 4,4,4-trifluorobutanamide ba

EGO: o c r (F; Dol B ne 60 M-Benzyl-M'-cyclohexylcarbodiimide on polymer (37Omg, 0.336 mmol) was added to a solution of the title Preparation 11 compound (10Omg, 0.27mmol) and 4,4,4 -trifluorobutanecarboxylic acid (45 mg, 0.32 mmol) in dichloromethane (4 mL) and the mixture was stirred at room temperature for 1.5 h. The mixture was filtered through Celite® and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using gradient eluent dichloromethane:methanol:0.88 ammonia (1:0:0 to 65 95:5:0.5, by volume) to give the title compound as a white foam, 7 mg.

Found C, 61.55; N, 7.46; M, 13.6290

SovNzeM5O55; 0.25 SNSI"; C, 61.48 is required; H, 7.17; M, 13.6690 "H-NMR (400 MHz SOSIv): 5 (m.h.) 1.39 (6Н, d), 1.65 (5Н, m), 1.98 (2Н, m) 2, 07 (2H, m), 2.15-2.29 (2H,

М), 2.43 (B5Н, m), 2.52 (ЗН, s), 3.00 (1ИН, m), 3.40 (2Н, s), 4.30 (1Н, m), 5, 15 (IN, m), 6.94 (1Н, m), 7.28 (ЗН, m), 7.36 (2Н, m)

NRMS: t/: 492.3 (MN")

Is9Cho-32.412 (s - 0.10, MeOOnH)

Example 4

M-415)-3-I(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo/3.2.1|oct-8-yl) -i-phenylpropyl)- 70. 4,4-difluorocyclohexanecarboxamide bo. oh nyu osn, y Lolchyah,

You are not

M-Benzyl-M'-cyclohexylcarbodiimide on the polymer (30mg, 0.545mmol) was added to a solution of compound 11 (100mg, 0.27mmol) and 4,4-difluorocyclohexanecarboxylic acid (5mg, 00.3mmol) in dichloromethane ( 4 ml) and the mixture was stirred at room temperature for 1.5 hours. Was the mixture filtered through Celite? and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of dichloromethane:methanol:0.88 ammonia (1:0:0 to 95:5:0.5, by volume) as eluent to give the title compound as a white foam, b7mg . high school

Found C, 64.68; H, 7.88; M, 12.6590

Sena MBO 2; 1.36 H2O; you need C, 64.72; H, 8.19; M, 13.01965 o 7TN-NMR (400 MHz, SOSIa): 5 |m.h.| 1.39 (6Н, d), 1.61-2.18 (19Н, m), 2.28 (2Н, m), 2.48 (ЗН, с), 2.85 (1

H, m), 3.36 (2H, w d), 4.28 (1H, m), 5.15 (1H, m), 6.48-6.61 (1H, w m), 7.23 (ЗН, m), 7.36 (2Н, m).

NRMS: t/» 514.4 (MN") (av)

DRVP analysis showed that the product is a mixture of polymorphs designated as "Form A" and "Form B". Separate crystals of pure Form A and Form B were isolated and identified from the mixture. The DRVP data for Forms A and B are given in -

Appendix 1. ch

Example 5

M-415)-3-(3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicycloi|3.2.1|oct-8-yl| -1-(3-fluorophenyl) o propyl)-4,4-difluorocyclohexanecarboxamide h-

E E I re ns. SN, ch un Lolchei, - with Mi ne

And" "

The title compound was prepared from the title compound Preparation 13 (200mg, 0.52mmol) and 4,4-difluorocyclohexanecarboxylic acid (128mg, 0.79mmol) using a technique similar to that described in Example 4 and 16bOmg. oo Found C, 64.25; N, 7.67; M, 12.5390

SooNao MBO from; 0.7 H2O; C, 64.00 is required; H, 7.67; M, 12.8790 - "H-NMR (400 MHz, SOSIv): 5 parts.) 1.39 (6Н, d), 1.60-2.35 (19Н, m), 2.42-2, 60 (2H, m), 2.55 (ZH, s), 2.98 - | 50 (IN, m), 3.40 (2H, w d), 4.32 (1H, m), 5.14 (1H, m), 6.79 (1H, w m), 6.97 (2H, m), 7.05 (1H, m), 7.31 (1H, m). o NRMS: t/ 532 ( MN).

Example 6

M-415)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|oct-8-yl| -1-phenylpropyl)-4,4-difluorocyclohexanecarboxamide

IS

E m o d i s. historical

Seya

Mch chh

And su Z not

The compound indicated in the title of Preparation 20 (176 mg, 0.48 mol) was dissolved in dichloromethane (1.7 ml). A solution of saturated aqueous sodium carbonate (1.7bl) and water (1.7bl) was added. The release of heat was observed and the mixture was cooled to 1592. A solution of the compound specified in the heading Preparation 14 (191 g, 0.72 mol) in toluene (50 Oml) was added to the reaction mixture and the release of heat was observed. The resulting mixture was stirred for 12 h at room temperature. HPLC analysis of the reaction mixture showed that the reaction was complete. Water (1 L) and dichloromethane (1 L) were added to facilitate phase separation. The phases were separated and the pH of the aqueous phase was pH-11. The aqueous phase was washed with dichloromethane (1.7 ml). The combined organic phases were washed with 0.5M aqueous sodium hydroxide (1.7bl) and then with water (1.7bl). The organic phase was concentrated and ethyl acetate (/OO0ml) was added. The mixture was left for granulation at room temperature overnight. The white solid was filtered and the product washed with ethyl acetate (bOml) and dried in vacuo for 12g at 402C to give the title compound as a white solid 146g (5995). "H-NMR was identical to that of the title compound in Example 4. 70 DRVP analysis showed the product to be an individual polymorphic form designated "Form B". DRVP data for Form B are provided in Appendix 1.

The melting point of Form B was determined to be 197 C (peak temperature) using the T. A. device.

Ipvigitepiv 2100 Yu5S. Scanning was performed at a rate of 202C/minute (up to 3002) in a nitrogen stream.

Example 7

M-((15)-3-(3-(3-isopropyl-5-methyl)-4H-1,2,4-triazol-4-yl)-exo-8-azabicycloil|3.2. Zoct-8-yl |-1-phenylpropyl)-4,4-difluorocyclohexanecarboxamide

Esh re not sleep, g AY

M -

You are, no.

The compound indicated in the title of Preparation 9 was suspended in dichloromethane (dhml) and a solution of the compound indicated in the title of Preparation 17 (1.58g, 5.35mmol) in toluene (3.2ml) was added to the reaction mixture, followed by the addition of acetic acid (0. Zml). Sodium triacetoxyborohydride (1.36 g, 6.24 mmol) was added to the resulting solution in portions. The resulting suspension was stirred at room temperature for 30 minutes. The sample was analyzed by HPLC and TLC and the reaction was complete. Water (1Oml) was added, after which a 2M aqueous solution of potassium hydroxide (1Oml) was added and the layers were separated. The aqueous phase was washed with dichloromethane (1Oml) and (a) the combined organic layers were washed with 1M aqueous potassium hydroxide solution (1Oml). The organic layer was concentrated under reduced pressure to give a pale brown foam, which was suspended in ethyl acetate (1 mL) for 12 hours at room temperature. The white solid was filtered off and dried under reduced pressure and at 40°C for 4 hours to give the title compound, which was identified as the title compound of Example 4, 2.05g, yield 7590.

The following preparations illustrate the preparation of some intermediate compounds used in the above. above Examples.

Preparation 1

Methyl (35)-3-amino-3-phenylpropanoate « n o. " What" - c 2" A solution of tert-butyl (35)-3-amino-3-phenylpropanoate (5.04 g, 22.9 mmol) in 2.25 M methanolic hydrogen chloride (10 Oml) was heated under reflux for 2 1/2 hours . The mixture was cooled to room temperature, basified with a saturated aqueous solution of sodium carbonate to pH 8 and the phases were separated. The aqueous layer I was extracted with dichloromethane (4x). The combined organic solutions were washed with a saturated aqueous solution of sodium chloride, dried (MaSO)), filtered and evaporated under reduced pressure to obtain the title compound, 3.97 g. -H-NMR (400 MHz, SOSIS): 5 (m.p. 11.70 (2H, s), 2.66 (2H, d) .

Preparation of 2 Methyl me, (35)-3-Ct-butoxycarbonyl)amino|-3-phenylpropanoate as sn, NM o. sleep, oh oh name)

A mixture of the compound indicated in the title Preparation 1 (5.38g, ZOmmol), di-tert-butyl dicarbonate (8.72g, ZOmmol), tetrahydrofuran (50ml) and 2M aqueous sodium hydroxide solution (25ml) was stirred at room temperature for 2 hours . The reaction mixture was diluted with ethyl acetate, the layers were separated and the aqueous phase was extracted with ethyl acetate (2x). The combined organic solutions were washed with water, saturated aqueous sodium chloride solution, dried (NaCl), filtered and evaporated under reduced pressure to give the title compound as a white solid, 8.39 g. 65 TN NMR (400MHz, SOSIv): 85 (m.h.) 1.41 (9H, s), 2.84 (2H, m), 3.61 (ZN, s), 5.10 (IN, w s), 541 (1H, w s), 7.22-7.36 (5H, m).

NRMS: t/» 279.7 (MN)

Preparation With tert-Butyl (15)-3-oxo-1-phenylpropylcarbamate on o. n in di

Diisobutylaluminum hydride (1M in dichloromethane, bOml, bOmmol) was cooled to -782C and 70 was added dropwise to a solution of the compound indicated in the title Preparation 2 (8.39g, ZOmmol) in dichloromethane (15Oml) at -78260.

The reaction mixture was stirred for 90 minutes, then methanol (cooled to -782C, 4 Oml) was added.

The mixture was allowed to warm to room temperature and poured into a 2M aqueous solution of hydrochloric acid (200 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (2x). The combined organic layers were dried (MA50), filtered and evaporated under reduced pressure to give the title compound as a white solid, 6.72g.

TN NMR (400 MHz, SOSIZ): 85 |m.h. 1.42 (9H, s), 2.86-3.00 (2H, m), 5.06 (IN, w s), 5.20 (IN, w s), 7.22-7.38 ( 5H, m), 9.75 (1H, s).

NRMS: t/: 250.1 (MN).

Preparation of 4 8-Benzyl-8-azabicycloi|3.2.P|octan-3-one

Same about

A solution of 2,5-dimethoxytetrahydrofuran (50g, 378mmol) in a 0.025M aqueous solution of hydrochloric acid (16b0ml) was cooled to 02 and stirred for 16 hours. Benzylamine hydrochloride (b5g, o) 453mmol), ketomalonic acid (55g, 377mmol) and aqueous sodium acetate solution (300ml, 0.69M) were added and the reaction mixture was stirred at room temperature for 1 hour. The mixture was heated at 502C for another 90 minutes, then cooled in an ice bath and alkalized to pH 12 with a 2M aqueous solution of sodium hydroxide. Ha")

The layers were separated and the aqueous phase was extracted with ethyl acetate (III). The combined organic solutions were washed with water, dried (Ma95O), filtered and evaporated under reduced pressure. The remaining brown oil was distilled under reduced pressure (1262C/0.4kPa) to give the title compound as an off-white solid, 37.81g.

TN nMR (400 MHz, SOSIv): 5 (m.h) 1.64 (2Н, m), 2.06-2.14 (2Н, m), 2.18 (IN, s), 2.23 (1Н , s), 2.68 (1Н, о m), 2.72 (1Н, m), 3.48 (2Н, s), 3.73 (2Н, s), 7.20-7.29 (1Н , m), 7.32 (2H, m), 7.42 (2H, d). and -

NRMS: t/z: 216.3 (MN).

Preparation of 5 8-Benzyl-8-azabicyclo|3.2.1|octan-3-one oxime « c | A mixture of the title compound of Preparation 4 (17.72g, 82mmol), hydroxylamine hydrochloride (5.72g, 82mmol) and pyridine (7.2ml, 89mmol) was heated under reflux in ethanol (5000ml) for 20 hours. The reaction mixture was allowed to cool to room temperature and diluted with a saturated aqueous solution of sodium carbonate. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was partitioned between dichloromethane and water, the layers were separated and the aqueous layer was extracted with dichloromethane (2x). oo The combined organic extracts were washed with a saturated aqueous solution of sodium chloride, dried (MgSO), filtered and evaporated under reduced pressure to give the title compound as a pale brown solid, 18.10 g. -I 20 TN nNMR (400MHz SOSIv): 5 (m.h1) 1.45-1.56 (1H, m), 1.60-1.67 (IN, m), 1.96-2.07 (2H, w m), 2.12 (IN, m), 2.21 (IN, m), 2.57 (1IN, m), 2.97 (IN, m), 3.32 (2H, m ), 3.64 (2H, s), 7.06 (1H, s), 7.21-7.28 (1H, m), s 7.32 (2H, m), 7.38 (2H, d ).

NRMS: t/: 231.2 (MN")

Preparation of 6 8-Benzyl-8-azabicycloi|3.2. Zoctane-3-exo-amine Preparation A solution of the title compound (18.10 g, 7 mmol) in pentanol (50 mmol) was heated under reflux. Sodium (22.0 g, 957 mmol) was added in portions over 2.5 hours. The reaction mixture was heated under reflux for 2 hours, then cooled to 02C in an ice bath. Water was added until no more hydrogen was released. The mixture was acidified using a 6 mM aqueous solution of hydrochloric acid and the phases were separated. The organic layer was extracted with a 6M aqueous solution of hydrochloric acid (3x), the combined aqueous extracts were alkalized to pH 12 with sodium hydroxide tablets (400g) and the aqueous solution was extracted with ethyl acetate (3x). The combined organic solutions were dried (MASO), filtered and evaporated under reduced pressure to give the title compound, 15.65 g. "YAN NMR (400 MHz, SOSIv): 5 (m.h.) 1.20-1.40 (2H, w m), 1.48 (2H, m), 1.58 (2H, d), 1, 64-1.76 (2H, w m), 2.00 (2H, w m), 2.95 (1H, m), 3.19 (2H, w s), 3.57 (2H, s), 7.18-7.26 (1H, m), 7.30 (2H, m), 7.37 (2H, d).

NRMSO- t/2 217.3 (MN).

Preparation 7

M-(8-Benzyl-8-azabicycloi|3.2. Zoct-3-yl-oxo)-2-methylpropanamide 70 FI n

Triethylamine (duml, 6b6, 1mmol) was added to a solution of compound b (13Hg, 60, mmol), isobutyric acid (5.bml, 60.5mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 11.6 g, 60 4 mmol) in dichloromethane (150 ml). The reaction mixture was stirred at room temperature for 75 hours, after which isobutyric acid (1.4 mL, 15 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.9 g, 15.1 mmol) were added. The reaction mixture was stirred at room temperature. temperature for 2 days, after which isobutyric acid (2.6 mL, 28 mmol), 1-"3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5 g, 2 mmol) and triethylamine (3 mL, 22.3 mmol) were added. The reaction mixture was stirred for 24 hours. A saturated aqueous solution of sodium carbonate (ZOOml) was added to the mixture and the product was extracted with dichloromethane (2x). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (M9504), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a dichloromethane:methanol:0.88 ammonia gradient (1:0:0 to 97 3:0.3, by volume) obtaining the title compound as a white powder, 9.2 g. family

Found C, 75.43, H, 9.30; M, 9.8290 o

SivNovMoO needs C, 75.48; H, 9.15, M, 9.7895 7TN-NMR (400MHz, SOSI): 5 Im.h.) 1.10 (6H, d), 1.47 (2H, tr), 1.60 (2H, c), 1.70 (2Н, m), 1.80 (2Н, m), 2.02 (2Н, m), 2.27 (1Н, m), 3.20 (2Н, с), 4, 10 (1H, m), 5.15 (1H, m), 7.20-7.40 (5H, m).

NRMS: t/z 287.4 (MN") o

Melting point (es): 138-140 h-

Preparation 8 8-Benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicycloi|3.2.Zoctane - . pr" so sutu y; i- ne

Phosphorus oxychloride (U9ml, 96.9mmol) was added to a solution of compound 7 (9.2g, 32mmol) and pyridine (1bml, 19bmmol) in chloroform (200ml) at 09C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 5 hours. The mixture - c was evaporated under reduced pressure. The residue was dissolved in chloroform (40 ml) and acetic hydrazide (3.6 g, 48.6 mmol) was added. The mixture was heated under reflux for 3 hours. A saturated aqueous solution of sodium carbonate (25 Oml) was added to the mixture and the product was extracted with dichloromethane (2x). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried (M9503), filtered and evaporated under reduced pressure. Toluene (200 ml) and p-toluenesulfonic acid monohydrate (100 mg, 0.5 mmol) were added to the residue. The reaction mixture was heated under reflux for 2 hours. The reaction mixture was then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of dichloromethane:methanol:0.88 ammonia (1:0:0 to 95:5:0.5, by volume) as an eluent to give the crude product. The crude material was suspended in an EM aqueous solution of hydrochloric acid (40 ml) and -1 50 was heated under reflux for 12 hours, after which a 12 M aqueous solution of hydrochloric acid (4 ml) was added. The reaction mixture was heated under reflux for 2 hours. The mixture was evaporated under reduced pressure. The residue was alkalized by adding a saturated aqueous solution of potassium carbonate (200 ml) and the product was extracted with dichloromethane (3). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried (MaSO), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of dichloromethane:methanol:0.88 ammonia (1:0:0 to 96:4:0.4, by volume) as eluent to give the title compound as a white powder, Z, 12 years. o "H-NMR (Z0O0MGCz, SOSI): 5 (m.h.) 1.40 (6Н, d), 1.70 (4Н, m), 2.15-2.40 (4Н, m), 2 .60 (ZH, s), 3.07 (1H, m), 3.37 (2H, s), 3.60 (2H, s), 4.30 (1H, m), 7.25-7, 40 (BN, m). 60 NRMS: t/» 325.3 (MN)

Preparation 9 3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.Zoctane b5

. three

M

"Mich pe

Ammonium formate (bg, 9U2mmol) was added to a solution of the compound indicated in the title Preparation 8 (3.12g, 9.bmmol) and palladium (II) hydroxide (50mg) in ethanol (400ml). The mixture was heated under reflux for 2 hours, after which 0.88 ammonia solution (2 ml) was added. The mixture was refluxed for 1 hour and the reaction mixture was allowed to cool to room temperature and filtered through 70 Arboceltm (filter material). The solvent was evaporated under reduced pressure to give the title compound as a white solid, 1.91 g. "H-NMR (Z0OMHCts, SOSIV): 5 (m.ch.1) 1.37 (6Н, d), 1.70-2.25 (ВН, m), 2.50 (ЗН, с), 3 .05 (1H, m), 3.70 (2H,

M), 4.32 (1Н, m).

NRMS: t/: 235.0 (MN")

Melting point (Si: 150-154

Preparation 10 tert-Butyl (15)-3-I3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|oct-8 -yl|-1-phenylpropylcarbamate

AH oeK sn» r

We

Su Mr en sch ne

Sodium triacetoxyborohydride (1.7g, 8.02mmol) and glacial acetic acid (1ml, 17.50mmol) were added to a solution of the compound indicated in the heading Preparation 9 (1.6bg, b6.84mmol) and the compound indicated in the heading Preparation C (2g , 8.03 mmol) in dichloromethane (40 ml) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was basified with a 1095 wt/w aqueous solution of potassium carbonate and extracted (av) with dichloromethane (2x). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride, dried (M950), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of dichloromethane:methanol:0.88 ammonia (1:0:0 to 97.5:2.5:0.25, by volume) as an eluent, obtaining the indicated in the title compound in the form of white foam, 2.5 g. c 7"H-NMR (300 MHz, SOSIv): 5 Im.h.) 1.40 (15Н, m), 1.70 (4Н, m), 1.80-2.15 (4Н, m), 2 ,30 (2H, m), 2.40 (2H,

Зо m), 2.58 (ЗН, с), 3.00 (1Н, m), 3.40 (2Н, m), 4.30 (1Н, m), 4.85 (1Н, m), 6 .20 (1N, m), 7.20-7.40 (5N, m). in.

NRMS: t/z 468.4 (MN")

Preparation of 11 (15)-3-(3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicycloi|3.2. Zoct-8-yl|- 1-phenyl-1-propanamine " ne. chn, " t" -o s sut M pev) ;" what

A mixture of the compound indicated in the title Preparation 10 (2.5g, 5.35mmol), 2.25M aqueous solution of hydrogen chloride

Acids and methanol (7 Oml) were heated under reflux for 5 minutes and stirred at room temperature for 1.5 hours. The reaction mixture was allowed to cool to room temperature and evaporated under reduced pressure. The residue was basified by adding a saturated aqueous solution of sodium carbonate (150 ml) and extracted with dichloromethane (2x). The combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried (MASO), filtered and evaporated under reduced pressure to obtain the title compound indicated in 5p as a white foam, 1.80 g. - "H-NMR (400MHz, SOSIV): 5 (m.h1) 1.37 (6Н, m), 1.42 (4Н, m), 1.85 (2Н, m), 2.05 (2Н, m), 2.20 (2Н, m), 62 2.42 (5Н, m), 3.00 (1Н, m), 3.37 (2Н, m), 4.10 (1Н, m). 4 .30 (1Н, m), 7.30 (5Н, m). (сЧо 15.02 (с - 0.10, MeOH)

Preparation of 12 tert-Butyl o (15)-3-(3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicycloi/3.2.1|oct -8-yl|-1-"Z-fluorophenyl) propyl arbamate ko Her in the eye of the dream: ni. -sn, n Lya S

65 The title compound was obtained from the title Preparation of compound 9 (1.0 g, 4.27 mmol) and tert-butyl (15)-3-oxo-1-(3-fluorophenyl)propylcarbamate (ER- A-1013276) (2.2g, 8.2Zmmol) using a method similar to that described in Preparation 10, 0.76g.

NRMS: t/2486 (MN).

Preparation of 13 (15)-3-(3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicycloil|3.2. Zoct-8-yl-1 -(3-fluorophenyl)-1-propanamine er and stu 10. no

IS

The title compound was prepared from the title compound of Preparation 12 (7bOmg, 1.57mmol) using a technique similar to that described in Preparation 11, 20Omg.

NRMS: t/ 386.2 (MN). t Preparation 14 4,4-Difluorocyclohexanecarbonyl chloride

IS

AND

4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (29 bml). Thionyl chloride (261 mL, 3.bmol) was added to the clear solution and the resulting solution was heated under reflux for 1.5 hours. A sample was collected and concentrated and H-NMR indicated completion of the reaction to form the title compound. The reaction mixture was cooled to room temperature and the thionyl chloride was removed with H under reduced pressure and replaced with toluene to give the title compound as a concentrate in toluene with a total volume of 591 mL . i) "H-NMR (300 MHz, SOSIZ): 5 (m.p. 12.29 (1N, m), 2.20-1.70 (8N, m).

Preparation 15

Ethyl (35)-3-1(4,4-difluorocyclohexyl)carbonyl|amino)-3-phenylpropanoate (ав)

E E them "-

And so o) chn o m

Su

Ethyl (35)-3-amino-3-phenylpropanoate hydrochloride (10 g, 43.6 mmol) was suspended in dichloromethane (100 mL) and a saturated aqueous solution of sodium carbonate (100 mL) and water (100 mL) were added. The mixture was cooled to 09C and a solution of compound 14 (7.96g, 43.bmol) in toluene (Zvml) indicated in the heading Preparation was added to the reaction mixture. The resulting mixture was stirred for 1 hour at room temperature. HPLC analysis of the reaction mixture showed that the reaction was complete. The layers were separated. The pH of the aqueous phase was set to pH-9. The aqueous layer was washed with dichloromethane (100 ml). The combined organic layers were washed with water (100 ml) and then with TM aqueous solution of hydrochloric acid (100 ml) then washed with water (100 mL). The organic layer was concentrated to a brown oil and the oil was granulated in ethyl acetate:heptane 1:2, by volume, (5 mL) for 4 h. The white solid was filtered off and dried under reduced pressure for 12 hours at 402C, giving the title compound as a white solid, 10.9g, yield 6690. - TN-NMR (SOOMHC, SOSIv): 85 (mch) 7.30 (B5H, m), 6.76 (IN, w d), 540 (IN, m), 4.08 (2Н, ю, 2.95-2.75 -1 20 (2Н, m), 2.30-165 (ОН, m), 1.15 ( ZN, t).

NRMS: t/: - 338 (M") m Preparation of 16 (15)-4,4-Difluoro-M-(3-hydroxy-1-phenylpropyl)cyclohexanecarboxamide

(35)-3-Amino-3-phenylpropanol (30.9g, 0.200mol) was dissolved in dichloromethane (300ml) and a saturated aqueous solution of sodium carbonate (300ml) was added. The resulting biphasic mixture was cooled to 59C and 65 toluene concentrate of the title Preparation 14 compound (37.3g, 0.20mol, 224ml) was added, maintaining the temperature below 102. The resulting suspension was stirred for 15 minutes at 520. HPLC analysis of the sample showed that the reaction ended Water (31 Oml) was added and a biphasic mixture was obtained. The layers were separated, the aqueous layer was washed with dichloromethane (3000ml) and the combined organic layers were washed with 1M aqueous sodium hydroxide solution (3000ml). The combined organic layers were concentrated under reduced pressure to a brown solid

The solid was suspended in toluene (120 ml) to obtain a finely dispersed white suspension. Methyl tert-butyl ether (240 ml) was added to give a mobile white suspension. The suspension was stirred at 0°C for 1 hour and a white solid was filtered off. The solid was dried under reduced pressure for 12 hours at 40°C to give the title compound, 53.9g, yield 89905. 7"H-NMR (SO00MHCc, SOSIv): 5 |m.h.| 7.30 (5H, m) , 6.18 (IN, w d), 5.20 (1H, m), 3.75-3.50 (2H, m), 3.05 (1 70. H, sh), 2.18 (4H , m), 2.00-1.62 (7Н, m).

NRMS ti/z - 297 (M")

Preparation of 17 (15)-4,4-Difluoro-M-(3-oxo-1-phenylpropyl)cyclohexanecarboxamide

E E in o MN

Su

The sulfur trioxide:pyridine complex (80.3 g, 0.500 mol) was suspended in dichloromethane (175 ml) under a nitrogen atmosphere.

Dimethyl sulfoxide (175 ml) was added and the resulting solution was cooled to 092C. Slowly maintaining the temperature below 102C, a solution of the compound of Preparation 16, triethylamine (7Oml, about 0O.5Omol) and dimethylsulfoxide (88ml) in dichloromethane (88ml) was added to the reaction mixture. The resulting yellow solution was stirred at 02 for 2 hours until TLC of the sample showed that all the starting materials had been used. Water (750 ml) was added and a biphasic mixture was obtained. The mixture was diluted with toluene (750 Oml) and the layers were separated. The organic layer was washed with a 0.5M aqueous solution of hydrochloric acid (750 ml) and a saturated aqueous solution of sodium chloride (750 ml). The organic layer was concentrated under reduced pressure to a brown solid, which was used in Example 7 without further purification. The solid sample was purified by granulation in ethyl acetate: methyl tert-butyl ether (1:5, 4 ml/g). -- "H-NMR (300 MHz, SOSIV): 5 Im.h.) 9.78 (1H, s) 7.30 (BN, m), 6.15 (IN, w d), 5.50 (1H , m), 3.05 (2Н, m), so 2.18 (ЗН, m), 2.00-1.55 (6Н, m).

NRMO: down -295 (MU) he preparation 18

Benzyl (15)-3-oxo-1-phenylpropylcarbamate o "

Su - ;" 15 The sulfur trioxide:pyridine complex (965 g, b,imol) was suspended in dichloromethane (2 L) under a nitrogen atmosphere. - Dimethyl sulfoxide (2 l) was added and the resulting solution was cooled to 09C. Slowly maintaining the temperature below 102C, a solution of benzyl (15)-3-hydroxy-1-phenylpropylcarbamate (577g, 2.Omol), triethylamine (845ml, 6b, 1mol) and dimethylsulfoxide (Tl) in dichloromethane (1ml) was added to the reaction mixture. The resulting yellow solution was stirred at 02C for 2.5 hours. The sample was analyzed by TLC, which showed that all the starting materials were used. Water (8.bl) was added and a biphasic mixture was obtained. The mixture was diluted

Sh-toluene (8.bl) and the layers were separated. The organic layer was concentrated under reduced pressure to give a brown foam, which was used in Preparation 19 without further purification. 7TH-NMR (ZO0MHZc, SOSIZ): 5 |m.h.) 9.78(1 N, s) 7.30 (BN, m), 6.15 (1IN, w d), 5.50 (1N, m), 3.05 (2Н, m), 2.18 (ЗН, m), 2.00-1.55 (6Н, m).

NRMS: t/:2 283

Preparation 19 o Benzyl ko (15)-3-I3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo/|3.2.1|oct- 8-yl|-1-phenylpropyl carbamate o Me- Me sh on , Ve vashikh

Me 65 The compound indicated in the title Preparation 9 (13.5 g, 32 mmol) was suspended in dichloromethane (27 ml) and a solution of the compound Preparation 18 (9.93 g, 5 mmol) in toluene (5 O ml) and dichloromethane was added to the reaction mixture

(BOml) and then acetic acid (2./7ml) was added. Sodium triacetoxyborohydride (8.1 g, Zvmmol) was added to the resulting solution in portions. The resulting suspension was stirred at room temperature for 1.5 hours. The sample was analyzed by HPLC and TLC and the completion of the reaction was determined. Water (27ml) was added, followed by a 2M aqueous solution of sodium hydroxide (27ml). The aqueous layer was alkalized to pH 11-12 by adding a 10M aqueous solution of sodium hydroxide and the layers were separated. The organic layer was washed with 1M aqueous sodium hydroxide (27ml) and a saturated aqueous solution of sodium chloride (27ml). The organic layer was concentrated under reduced pressure to obtain a pale brown foam, 13.3 g, 76 95. "H-NMR (30 OMHCc, SOCIv): 5 (m. part. 1) 1.39 (6H, d), 1.55- 1.75 (4H, m), 1.84 (2H, m), 2.05 (2H, m), 2.15-2.45 70. (BN, m), 2.97 (1H, m) , 3.36 (1H, w s), 3.45 (1H, w s), 4.25 (1H, m), 4.93 (1H, w s), 5.10 (2H, m), 7 ,10-7,40 (1OH, m).

NRMS: t/:2 502

Preparation of 20 (15)-3-I3-(3-Isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo/3.2.1oct-8-yl|-1 -phenyl-1-propanamine t Me Me ev U su Uran

Me

The compound indicated in the heading Preparation 19 (309g, 0.62 mol) was dissolved in methanol (3.11). Palladium(II) hydroxide (3g) was added and the resulting suspension was stirred in a hydrogen atmosphere at 345 kPa (50 psi) for 12 hours. A sample was taken and analyzed by TLC and HPLC and the completion of the reaction was determined. The reaction mixture was filtered through Arboceltm (filter material) and the filter was washed with methanol (500 ml).

The methanol solution was concentrated to obtain the title compound as a white foam, 176 g, 78965. p 29 "H-NMR identical to the title Preparation 11 compound. Ge)

Preparation of 21 8-Benzyl-8-azabicyclo|3.2.1|octan-3-one oxime

M ich-

The mixture indicated in the heading Preparation 4 of the compound (50g, 0.23mol) was dissolved in industrially methylated alcohol (2500ml). A solution of hydroxylamine hydrochloride (17.8 g, 0.2 bmol) in water (250 ml) was added exothermically to the resulting solution. Sodium bicarbonate (23.4 g, 0.28 mol) was added with a small endothermy and foaming was observed. The resulting solution was stirred for 12 h. The resulting white solid was collected by vacuum filtration and dried in an oven under reduced pressure for 4 hours at 5023 to give the title compound as a white solid, 43.1g, yield 81905.

Preparation 22

Benzyl-8-azabicyclo!/3.2.1|octane-3-exo-amine «

Pure sodium (24.3g, 1.0bmol) was added piecewise to toluene (300ml) at room temperature and the mixture was heated under reflux. DVOZhCHIN of the title Preparation 5 compound (20.0g, 8/mmol) in toluene (200ml) and pentanol (120ml) was added slowly over 15 minutes to the boiling reaction mixture. -I During this time, the release of gas was observed. The resulting mixture was refluxed for 2 hours to ensure complete sodium utilization. A finely dispersed white suspension was formed. and The reaction mixture was cooled to 809C and isopropyl alcohol (200ml) was added. The reaction mixture was left to cool to room temperature and water was added (100 ml). The aqueous layer was adjusted to pH 1 by adding 5 g of concentrated hydrochloric acid (140 ml), (emission of heat was observed). The reaction mixture was stirred. for 15 minutes and the layers were separated. Ethyl acetate (7/000 ml) was added to the aqueous layer with a pH of 12, which was made by adding a 10 M aqueous solution of sodium hydroxide (40 ml). The layers were separated and the organic layer was concentrated under reduced pressure to give a pale yellow oil. The pentanol retained in the oil was removed by azeotropic distillation with water (200ml) and the remaining water was removed by azeotropic distillation with toluene brine (200ml) to give the title compound as a pale yellow oil containing traces of toluene, 18.0g, yield 9590 .

Preparation 23

F) Exo-M-(8-benzyl-8-azabicycloyl3,2-octyl-3-yl)-2-methylpropanamide

Lola" because S M N ke

Dichloromethane (5 L), sodium carbonate (900 g), water (8.7 L) and the compound specified in the heading Preparation 6 (1200 g, 5.5 bmol) were loaded into a 20 L fixed reactor. The resulting mixture was cooled to 02C. Isobutyric acid chloride (7/0Oml, 6.b7mol) was added for 30 minutes while maintaining the temperature below 109.

The resulting mixture was stirred at a temperature of 09 to room temperature for 2 hours. The reaction was complete after 2 hours, as determined by HPLC analysis. The layers were separated and the aqueous layer was washed with dichloromethane (1.5 L). The aqueous layer had a pH of 8. The combined organic layers were washed with 1 M aqueous sodium hydroxide solution (1.5 L) and the dichloromethane was distilled off and ethyl acetate was added to give a final volume of 7. The resulting mixture was refluxed to give a clear brown solution.

The solution was cooled to 252 for 1.5 hours and then to 22C for 1 hour and kept at this temperature for 30 minutes. The white solid that formed was separated by filtration and the filtrate was added to the reactor with a dent in the bottom. The temperature was maintained at about 22C. The resulting suspension was added to the filtrate. Ethyl acetate (0O,bl) was added to the reactor, separating the remaining solid, and the suspension was added to the filtrate. The solid was dried in an oven under reduced pressure to give the title compound, 9Zbg, yield 5996. The liquid was evaporated under reduced pressure to a total volume of 1.5 L and the resulting brown solution was cooled to 102 to give a suspension. The white solid was filtered off and dried in an oven under reduced pressure to give the second part of the title compound, 144g, 995. Total yield: 1080g, 68905. Preparation 24 8-Benzyl-3-(3-isopropyl-5-methyl-4H-1 ,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.|octane

LA

La language

Me

Dichloromethane (7 L) and PSI5 (719 g, 345 mol) were loaded into the fixed reactor. The resulting suspension was cooled to 02С. During 30 minutes, maintaining the temperature below 102, a solution of the compound specified in the title Preparation 7 (7b0g, 2.6bmol) in dichloromethane (2.5l) was added. The resulting solution was stirred at a temperature of 29°C from 02°C to room temperature for 2 hours. The resulting pale yellow solution was cooled to 020. Slowly maintaining the temperature below 102, a solution of acetic hydrazide (315 g, 4.27 mol) in 2-methyl-2-butanol (pr. 1.5 L) was added (obtained by dissolving acetic hydrazide in acetonitrile ( Tl) and 2-methyl-2-butanol (2 l) and distillation of acetonitrile and 500 ml of 2-methyl-2-butanol). The resulting solution was stirred at room temperature for 15 hours. The completion of the reaction was determined by HPLC analysis through o

30 minutes after it started, but they left it just in case. The mixture was cooled to 02C and a 2M aqueous solution of sodium hydroxide (7.5 L) was added, maintaining the temperature below 202C. The aqueous layer was adjusted to pH 9 - using a 10 M aqueous solution of sodium hydroxide (pro. O,bl). The layers were separated and the aqueous layer was washed with dichloromethane (1 L). The combined organic layers were evaporated under reduced pressure to obtain CO 2-methyl-2-butanol concentrate (pr. 2, B5l). Ethyl acetate (1.5 L) and acetic acid (200 mL) were added. The obtained solution M was heated at 802C for 30 minutes. The solution was cooled to room temperature overnight. The solution was cooled to 09C and the mixture was alkalized to pH 12 with a 2M aqueous solution of sodium hydroxide (2 l). The layers were separated and the aqueous layer was washed with ethyl acetate (IL). The combined organic layers were concentrated to 2L under reduced pressure and heptane (2L) was added and the mixture was evaporated to 3L under reduced pressure. Heptane was added

10 ml of ethyl acetate (100 ml) and the mixture was heated under reflux. The solution was cooled to 2090 (F) s for 1 hour and to 02C for 2 hours. The white solid that formed was filtered off and dried in a vacuum oven at 402 overnight to give the title compound, 622g, yield 7290. "» Preparation 25 para-Toluenesulfone salt 3-(3-isopropyl-5--methyl -4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2. Zoctane

Me. Me mm me-4 U--v(ohon (65) NM y-- - Me

The compound indicated in the heading Preparation 8 (6O00g, 1.85mol) and para-toluenesulfonic acid monohydrate

Sh- (351g, 1.8B5mol) was dissolved in methanol (Zl). 1095 wt/w of palladium on coal (b0g) was added. The mixture was stirred under a hydrogen atmosphere at 345kPa (5Opsi) and room temperature for 12 hours. A sample was collected and HPLC analysis showed that the reaction was complete. The reaction mixture was filtered through Arboceltm (filter material) and the residue was washed with methanol (500 mL). The methanol was evaporated under reduced pressure and the resulting brown oil was dissolved in hot isopropyl alcohol (1.8 L). The solution was left for granulation at room temperature for 12 hours and then at 09C for 2 hours. The white solid was filtered off and dried in

F, in a vacuum oven for 12 hours, obtaining the title compound, 623 g, yield 8390. ko Biological activity

The compounds of Examples 1-5 were tested using the CSK5 binding assay described by Sotbradiege et al., U. Geikos. Vioi 60, 1147-52 (1996) (cited above). All tested compounds were found to have IC values less than TONM.

Appendix 1

DRVP data for Form A and Form B polymorphs selected in Examples 4 and 6

M-415)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|oct-8-yl| -1-phenylpropyl)- 65 4,4-difluorocyclohexanecarboxamide was obtained according to the methods of Examples 4 and 6, and it was established that it exists in 2 polymorphic forms designated Form A and Form B. DRVP (X-ray powder diffraction) modeling analysis includes α-distance and relative intensity calculated on a separate crystal structure using Segiiz? Oiygassiop-Stuvia! Fashionista The modulation parameters were as follows:

The wavelength is 1.54178 A.

The polarization factor is 0.5

The dimensions of the crystal are 5x00x500x500 A

Lorentzian shape of the peaks

The main peaks (in degrees of 2-theta) obtained in the DRVP radiograph are given in the following tables.

It should be understood by one of ordinary skill in the art that the relative intensity of the various peaks 70 shown in the tables may vary depending on a number of factors, including the orientational effects of the crystals in the X-ray beam, the purity of the sample being examined, or the degree of crystallinity of the sample, the location of the peak will be remain as indicated in the tables.

A person skilled in the art should also understand that measurements using x-rays of different wavelengths will produce different shifts in the peak positions relative to the Bragg equation. Such 75 DRVP radiographs obtained using different wavelengths are considered as an alternative to the presented DRVP radiographs of crystalline materials of the present invention and thus fall within the scope of the present invention.

List of peaks of Form A » 2-theta | 2-theta o 2-theta o 2-theta | 9 and cm o pyaava| soya oto tyao0ovlvv 52003? 655 was called 5200 EV; by will) 45 half| blo ten zva ozobiv| cart? 38 o z zaliv ovo obi p25 sob 5eyayuo 26 m -

Fo zv cha theses!) zve o ZBovo! then aya 42

List of peaks of Form B «

WITH

Angle Intensity |Angle Intensity |Angle Intensity | Angle Intensity p

And" tega) 14 ba! eat (voi! ve zbem vo zve? 433 tgyaoe saya zolu b500left 25 5 i: o pavvyatya 0 ozvzh4400vilavi 8e00zaomo 5 - - sz sv pvoi| bb5 ovbev 032 zBiz 800 zalzh 34 o yu osv lobo Zovdevi olovo zabayu| 40111

Claims (1)

The formula of the invention 1. The tropane derivative of the formula: b5 IS ' A. not Sn. (8) MN re y Zhe Lya m e M y ne 70 in which KE! is C3.6 cycloalkyl, optionally substituted by one or more fluorine atoms, or C4.6 alkyl, optionally substituted by one or more fluorine atoms, or C3.5 cycloalkylmethyl, optionally substituted on the ring by one or more fluorine atoms; and B2 is phenyl, optionally substituted with one or more fluorine atoms; or a pharmaceutically acceptable salt or solvate thereof. 2. Derivative of tropane according to clause 1 of the formula: c" ; H. not SN. IF) MN Y I bu Asya i: I IA M - chi not in which KE! is either C3-6 cycloalkyl, optionally substituted with one or more fluorine atoms, or cm С..в6 alkyl, optionally substituted by one or more fluorine atoms, or its pharmaceutically (o) acceptable salt or solvate. C. A tropane derivative according to item 1, where B is either C. 6 cycloalkyl, optionally substituted with one or two fluorine atoms, or C. 4 alkyl, optionally substituted with one to three fluorine atoms. at 4. A tropane derivative according to point 3, where KE" is cyclobutyl, cyclopentyl, 4,4-difluorocyclohexyl or 33,3,3-trifluoropropyl. - 5. A tropane derivative according to item 1, C or 4, where B: is phenyl, optionally substituted with 1 or 2 fluorine atoms. co 6. The tropane derivative according to point 5, where KE? is phenyl or monofluorophenyl. From 7. Derivative of tropane according to point 6, where B? is phenyl or 3-fluorophenyl. uh- 8. Tropane derivative according to point 1, which is selected from the group including: M-415)-3-I(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl )-exo-8-azabicyclo|3.2.1|oct-8-yl|-1-phenylpropyl)cyclobutanecarboxamide; « IM-(15)-3-I3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1)oct-8-yl |-1-phenylpropyl)cyclopentanecarboxamide; o) c M-415)-3-I3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo/3.2.1|oct-8- yl|-1-phenylpropyl)- "» 4,4,4-trifluorobutanamide; " M-415)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4- yl)-exo-8-azabicyclo|3.2.1|oct-8-yl|-1-phenylpropyl)-4,4-difluorocyclohexanecarboxamide and M-415)-3-I(3-(3-isopropyl-5-methyl -4H-1,2,4-triazol-4-yl)-exo-8-azabicyclo|3.2.1|oct-8-yl s- -1-(3-fluorophenyl)propyl)-4,4-difluorocyclohexanecarboxamide; oo or any pharmaceutically acceptable salt or solvate thereof. 9. A pharmaceutical composition containing a tropane derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof, as specified in any of the preceding clauses, together with a pharmaceutically acceptable excipient, diluent or carrier. 10. A tropane derivative of formula (I) or its pharmaceutically acceptable salt, solvate or composition, as specified in one of items 1 - 8 and 9, respectively, for use as a medicinal product. 11. A tropane derivative of formula (I) or its pharmaceutically acceptable salt, solvate or composition, as specified in one of items 1 - 8 and 9, respectively, for the treatment of a disorder that is associated with the modulation of 22 SSV5 receptors. GF) 12. A tropane derivative of formula (I) or its pharmaceutically acceptable salt, solvate or composition, as specified in one of items 1 - 8 and 9, respectively, for the treatment of HIV, retroviral infection that genetically causes HIV, AIDS or inflammatory disease. 13. A tropane derivative of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, as specified in one of items 1 - 8 and 9, respectively, for the treatment of a respiratory disorder, including acute respiratory distress syndrome (ARDS5), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis or chronic sinusitis. 14. A tropane derivative of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, as specified in one of items 1 - 8 and 9, respectively, for the treatment of inflammation of internal organs, including Crohn's disease or ulcerative colitis, multiple sclerosis, rheumatoid arthritis, transplant rejection, including kidney or lung rejection, endometriosis, type I diabetes, kidney disease, chronic pancreatitis, lung inflammation, or chronic heart failure. 15. The method of treating a disorder in a mammal, which is associated with the modulation of SSK5 receptors, which consists in introducing to said mammal an effective amount of a tropane derivative of formula (I) or its pharmaceutically acceptable salt, solvate or composition, as specified in one of items 1 - 8 and 9, respectively. 16. The method of treating a mammal with HIV, a retroviral infection that genetically causes HIV, AIDS, or an inflammatory disease, which consists in administering to said mammal an effective amount of a tropane derivative of formula (I) or its pharmaceutically acceptable salt, solvate, or composition, as specified in one of the points 70 1-8 and 9, respectively. 17. A method of treating a respiratory disorder in a mammal, including acute respiratory distress syndrome (ARDS5), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis or chronic sinusitis, comprising administering to said mammal an effective amount of a derivative tropane of formula (I) or its pharmaceutically acceptable salt, solvate or composition, as specified in one of items 1 - 8 and 9, respectively. 18. Method of treatment in a mammal for inflammation of internal organs, including Crohn's disease or ulcerative colitis, multiple sclerosis, rheumatoid arthritis, transplant rejection, including kidney or lung rejection, endometriosis, type I diabetes, kidney disease, chronic pancreatitis, lung inflammation or chronic heart conditions inadequacy, consisting in the introduction to the mentioned mammal of an effective amount of the 2oTtropane derivative of formula (1) or its pharmaceutically acceptable salt, solvate or composition, as specified in one of items 1 - 8 and 9, respectively. 19. Tropan derivative according to one of the formulas: not SNU! AD SN ! I: І with І 0 o ЖА To m (1) Zhom Di M (PA) in M -M in M -kfi no no o no SN. , them P p- МН - АХА Mom) с E -- M i - ns in which K2 is as defined in point 1, and P is a protective group. " 20. A tropane derivative according to claim 19, wherein He is phenyl. 21. A tropane derivative according to claim 19 or 20, wherein P is t-butyloxycarbonyl or benzyloxycarbonyl. - p 22. The derivative of tropane according to one of the formulas: "z va ; a ,; p An M (MA) Yyachya SCHO Os R (95) and not - . in which P" is a protecting group, or a salt of a compound of the formula (MIA), preferably a p-toluenesulfonate salt. -i 23. A tropane derivative according to item 22, where P" is benzyl. o 24. The derivative of the tropane of the formula: v ry NS. .sOn 59 MN with Her " (F. ZD M (khm) he) e -ki vo ne in which B and 22 are as defined in clause 1. 25. A tropane derivative of the formula: b5 not СНа , Mem och i-m (SMP) not in which B2 is as defined in clause 1. 70 26. A tropane derivative according to clause 25, where B is phenyl. 27. Derivative of the tropane of the formula: Е" , Ж not sn. 6) МН re ЖоАДшя МОm (their ХюЮ is з- not in which В1 and В2 are as defined in point 1. 28. A tropane derivative according to claim 27, wherein He is phenyl. 29. The method of obtaining a tropane derivative of the formula (I) according to point 1, according to which: (a) compounds of the formula are subjected to condensation: NS isNa sch MN. re (o) The same Thanks to what (1) in y and ns o ich- with the compound of the formula: В'СОН, (II) - in which В and В? are as defined for the tropane derivative of formula (I); or co (b) carry out the reaction of the compound of the formula (II) with the compound of the formula: BC, (MIV) i- in which 2 is a group that activates a carboxyl group; or (c) conduct a reaction of a compound of the formula (II) or its metal salt with a compound of the formula: v'Sov, (XXM) " in which B is as defined for the tropane derivative of formula (I), and E? is an ester-forming group; or with 70 (g) conduct the reaction of the compound of the formula: with NIS. Osn;" and Mn. Alya T v ra MOM (PA) - e -k g ns - or with the compound of formula (I) under condensation conditions, or with the compound of formula (MIV), in the presence of - 20 chiral catalyst; at the same time, any of the mentioned processes is not necessarily completed by the conversion of the tropane derivative (ze) of formula (I) into its pharmaceutically acceptable salt. 30. The method of obtaining a tropane derivative of the formula (I) according to point 1, in accordance with which: (a) compounds of the formula: EE" are reduced; o ry not Sn. her and XX Asya I MOm khm dv M - OM) not in which B and 22 are as defined for the tropane derivative of formula (1); (b) carry out asymmetric reduction of the compound of formula: b5 IS ' A. not a dream. (8) МН их -- М МОм (their Р is not 70 in which В and 22 are as defined for the derivative tropane of formula (1); at the same time, any of the mentioned processes is not necessarily completed by the transformation of the derivative tropane of the formula (I) in its pharmaceutically acceptable salt. 31. The method of obtaining a tropane derivative of the formula (I) according to point 1, according to which: (a) reductive amination is carried out with a compound of the formula: are as defined for the tropane derivative of the formula (I), compounds of the formula: ne sno , І с Іє Ан ще (MA) о и о or its salts; or (b) carry out reductive amination with a compound of the formula: - c! ' - A. o (o) МН Ж and - Кі (ихм) Е in which M is CM and 27 and B are as defined for the tropane derivative of the formula (I), the compound of the formula (MIA) or its salt; - at the same time, any of the mentioned processes are optionally completed by the conversion of the tropane derivative of formula (I) into its pharmaceutically acceptable salt. :z» 32. The method of obtaining a tropane derivative of the formula (I) according to clause 1, in accordance with which: alkylation of the compound of the formula (MIA) or its salt with the compound of the formula: E' is carried out t A. s ato mn - Ж 1 (ХМ) e Е -I in which 7 is a leaving group, and В and ВЕ? are as defined for the tropane derivative of formula (1); with this, the process is optionally completed by converting the tropane derivative of formula (I) into its pharmaceutically acceptable salt. pharmac rynyatnu si Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated GF) microcircuits", 2005, M 6, 15.06.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 60 b5