Novel amide derivatives of piperidine carboxylic acid

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from a group comprising amides of peridine carboxylic acid of formula (I) , in which W denotes a phenyl ring or a six-member, non-benzocondensed aromatic ring, having one nitrogen atom, where said rings are substituted in the para-position through V; V denotes a bond; -A-(CH2)S- or -A-(CH2)v-B-; A and B independently denote -O-; U denotes mono-, di-, tri- or tetra-substituted aryl, in which substitutes are independently selected from a group consisting of halogen, alkyl and -CF3; Q denotes methylene; M denotes an aryl group, where the said group can be optionally mono- or di-substituted with substitutes independently selected from a group comprising alkyl; alkoxy; -CF3; halogen; alkyl-O-(CH2)0-4-CH2- and R'2N-(CH2)0-4-CH2-, where R' is independently selected from a group comprising hydrogen, alkyl (optionally substituted with one, two or three fluorine atoms), cyclopropyl, cyclopropylmethyl, -C(=O)-R", where R" denotes C1-C4-alkyl or -CH2-CF3; R1 denotes cycloalkyl; n equals 0 or 1; s equals 3; v equals 2; and substitutes in the ring, -CON(R1)-Q-M and -W-V-U, are in trans-position relative each other if n equals 1, and where configurations in positions 3 and 4 of the piperidine ring of formula (I) are 3R and 4R, respectively, if n equals 0; and optically pure enantiomers, mixture of enantiomers, such as racemates, diastereomers, mixture of diastereomers, diastereomer racemates, mixture of diastereomer racemates, and mesoforms, as well as to salts of such compounds. Invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having non-peptide rennin inhibiting activity.

12 cl, 27 ex, 1 tbl

 

The invention relates to new compounds of the formula (I). The invention also relates to related aspects, including methods of making the compounds, pharmaceutical compositions containing the compound of formula (I), and especially their use as renin inhibitors in cardiovascular disorders and renal failure.

In the system the renin-angiotensin (RAS) biologically active angiotensin II (Ang II) is formed by a two-step mechanism. Highly specific enzyme renin cleaves angiotensinogen to angiotensin I (Ang I), which is then further processed to Ang II less specific enzyme (ACE)converts angiotensin. It is known that Ang II acts, at least two subtypes of receptors, known as al1and al2. While al1apparently, passes the most famous functions of Ang II, the role of al2is still unknown.

Modulation of the RAS-system represents a major breakthrough in the treatment of cardiovascular diseases. ACE inhibitors and al1-blockers have been taken to treat hypertension (Waeber B.et al.“The renin-angiotensin system: role in experimental and human hypertension”, in W. H. Birkenhager, Reid J. L., (eds):Hypertension,Amsterdam, Elsevier Science Publishing Co., 1986, 489-519; Weber, M. A.,Am. J. Hypertens., 1992,5, 247S). In addition, ACE inhibitors are used to protect the kidneys (Rosenbeg M. E.et al., Kidney International, 1994,45, 403; Breyer J. A.et al., Kidney International, 1994,45, S156), for the prevention of congestive heart failure (Vaunghan D. E.et al., Cardiovasc. Res., 1994,28, 159; Fouad-Tarazi F.et al., Am. J. Med., 1988,84(Suppl. 3A), 83) and myocardial infarction (Pfeffer M. A.et al., N. Engl. J. Med., 1992,327,669).

A rational approach for the development of inhibitors of renin is the specificity of renin (Kleinert H. D.,Cardiovasc. Drugs,1995,9, 645). The only substrate, known for renin, is angiotensinogen, which can only be handled by renin (under physiological conditions). On the contrary, ACE can also cleave bradykinin in addition to Ang I and the workaround can be duplicated hemati, serinproteaza (Husain A.,J. Hypertens., 1993,11, 1155). Patients inhibition of ACE thus leads to the accumulation of bradykinin, which causes cough (5-20%) and potentially life-threatening angioedema (0.1 to 0.2%) (Israili, Z. H.et al., Annals of Internal Medicine, 1992,117, 234). Chymase is not inhibited by ACE inhibitors. Therefore, the formation of Ang II may occur in patients treated with ACE inhibitors. The blockade of al1receptor (e.g., losartan), on the other hand, excessively affects other subtypes at-receptors (e.g., al2) to Ang II, the concentration of which increases significantly the blockade of al1-receptors. Eventually inhibitors Reni is a, expected to demonstrate pharmaceutical profile different from the profile of ACE inhibitors and blockers AT1from the point of view of efficiency in blocking RAS and security aspects.

Only limited clinical experience (Azizi M.et al., J. Hypertens., 1994,12, 419; Neutel J. M.et al., Am. Heart, 1991,122, 1094) was created by renin inhibitors because of their lack of oral activity because of their coworkers peptide nature (Kleinert H. D.,Cardiovasc. Drugs, 1995,9, 645). Clinical development of several compounds was discontinued because of this problem and the high cost of products. Only one compound that contains four chiral center, has entered clinical trials (Rahuel J.et al., Chem. Biol., 2000,7, 493; Mealy N. E.,Drugs of the Future, 2001,26, 1139). Thus, the required renin inhibitors with good oral bioavailability and a prolonged period. Have been recently described the first ones renin inhibitors, which show high activityin vitro(Oefner, C.et al., Chem. Biol., 1999,6, 127; Patent Application WO 97/09311; Marki H. P.et al., Il Farmaco, 2001,56, 21). However, the development of these compounds is unknown.

This invention relates to inhibitors of renin ones nature and low molecular weight. Described orally active renin inhibitors of formula (I), which have a long period is Astia and which are active in symptoms beyond the regulation of blood pressure, where tissue system the renin/chymase can be activated, which leads to pathophysiologically modified local functions such as renal, cardiac and vascular reconstruction, atherosclerosis and possible restenosis. Thus, the present invention describes the data ones renin inhibitors of formula (I).

In particular, this invention relates to new compounds of the formula (I)

in which

W represents phenyl loop or six-membered, not benzoannelirovannykh aromatic cycle containing one to four nitrogen atoms, where these cycles are substituted in the para-position by V;

V represents a bond; -(CH2)r-; -A-(CH2)s-; -CH2-A-(CH2)t-; -(CH2)s-A-; -(CH2)2-A-(CH2)u-; -A-(CH2)v-B-; -CH2-CH2-CH2-A-CH2-; -A-CH2-CH2-B-CH2-; -CH2-A-CH2-CH2-B-; -CH2-CH2-CH2-A-CH2-CH2-; -CH2-CH2-CH2-CH2-A-CH2-; -A-CH2-CH2-B-CH2-CH2-; -CH2-A-CH2-CH2-B-CH2-; -CH2-A-CH2-CH2-CH2-B-; -CH2-CH2-A-CH2-CH2-B-; -O-CH2-CH(OCH3)-CH2-O-; -O-CH2-CH(CH3)-CH2-O-; -O-CH2-CH(CF3)-CH2-O-; -O-CH2 -C(CH3)2-CH2-O-; -O-CH2-C(CH3)2-O-; -O-C(CH3)2-CH2-O-; -O-CH2-CH(CH3)-O-; -O-CH(CH3)-CH2-O-; -O-CH2-C(CH2CH2)-O-; or-O-C(CH2CH2)-CH2-O-;

A and b independently represent-O - or-S-, preferably-O-;

U represents unsubstituted aryl; mono-, di-, tri - or Tetra-substituted aryl, where the substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and-CF3; or mono-, di-, tizamidine heteroaryl, in which the substituents are independently selected from the group consisting of halogen, alkyl, alkoxy, and-CF3;

Q represents methylene or ethylene, preferably methylene;

M represents aryl, hyalinella, athinodorou, dihydrohelenalin or tetrahydropyranyloxy group, where these groups can be optionally mono - or disubstituted by substituents independently selected from the group consisting of alkyl; alkoxy; -OCF3; -CF3; hydroxyalkyl; halogen; alkyl-O-(CH2)0-4-CH2-; alkyl-O-(CH2)2-4-O-; R'2N-(CH2)0-4-CH2-where R' is independently selected from the group consisting of hydrogen, alkyl (optionally substituted by one, two or three fluorine atoms), cyclopropyl, cyclopropylmethyl, -C(=O)O-R",- C(=O)-R", where R" on the mean With 1-C4-alkyl, -CF3, -CH2-CF3or cyclopropyl; and R"'NH-C(=O)-(O)0-1-(CH2)0-4-CH2-, where R"' is alkyl or cyclopropyl;

R1represents an alkyl or cycloalkyl, preferably cycloalkyl, namely, especially cyclopropyl;

n represents the integer 0 or 1;

r is an integer 3, 4, 5 or 6;

s is an integer 2, 3, 4 or 5;

t is an integer 1, 2, 3 or 4;

u is an integer 1, 2 or 3; and

v is an integer 2, 3 or 4;

and optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric the racemates, mixtures of diastereomeric racemates, and Metformin, as well as salts and solvate of such compounds, and morphological forms.

General terms used above and below herein, are within the scope of this disclosure the following meanings, unless expressly agreed.

Where the plural form for compounds, salts, pharmaceutical compositions, diseases and the like, it is also expected to refer to a single compound, salt or the like.

Any reference to a compound of formula (I) should be interpreted as referring also to optically pure enantiomers, mixtures or the pits of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric the racemates, mixtures of diastereomeric racemates and Metformin, as well as to the salts (especially pharmaceutically acceptable salts) and the solvate (including hydrates) of such compounds, and morphological forms, as appropriate and practical.

In the definitions of formula (I) unless otherwise stated the term alkyl, alone or in combination with other groups, means saturated, straight and branched chain groups with one to seven carbon atoms, preferably one to four carbon atoms, i.e. With1-C4-alkyl. Examples of alkyl groups are methyl, ethyl, n-propyl, ISO-propyl, n-butyl, ISO-butyl, sec-butyl,tert-butyl, pentyl, hexyl and heptyl. Prefer the methyl, ethyl and isopropyl group.

The term alkoxy, alone or in combination with other groups, refers to R-O-group, in which R means an alkyl group. Examples of alkoxygroup represent methoxy, ethoxy, propoxy, ISO-propoxy, ISO-butoxy, sec-butoxy andtert-butoxy.

The term hydroxyalkyl, by itself or in combination with other groups, refers to BUT-R group in which R means an alkyl group. Examples of hydroxyalkyl groups are BUT-CH2-BUT-CH2CH2-BUT-CH2With the 2CH2and CH3CH(OH)-.

The term halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, especially fluorine or chlorine.

The term cycloalkyl, by itself or in combination, means a saturated cyclic hydrocarbon ring system having 3-7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopropyl group is the preferred group.

The term aryl by itself or in combination, refers to phenyl, naftilos or indanernas group, preferably by phenyl group.

The term heteroaryl, by itself or in combination, means six-membered aromatic cycles containing one to four nitrogen atoms; benzododecinium six-membered aromatic cycles containing one to three nitrogen atoms; five-membered aromatic cycles containing one oxygen atom, one nitrogen atom or one sulfur atom; benzododecinium five-membered aromatic cycles containing one oxygen atom, one nitrogen atom or one sulfur atom; five-membered aromatic cycles containing two heteroatoms independently selected from oxygen, nitrogen and sulfur, and benzododecinium derivatives such loops; five-membered aromatic cycles containing three the nitrogen atom and benzododecinium derivatives; tetrazolyl the first cycle; teasingly cycle; or coumarinyl. Examples of such cyclic systems are furanyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, chinoline, ethenolysis, imidazolyl, triazinyl, thiazolyl, isothiazolin, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, benzothiazyl, hintline and honokalani.

Salts preferably are pharmaceutically acceptable salts of compounds of formula (I).

The expression pharmaceutically acceptable salts embraces salts with inorganic acids or with organic acids, such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, oxalic acid, maleic acid, lactic acid, tartaric acid, fumaric acid, benzoic acid, mandelic acid, cinnamic acid, palmitic acid, stearic acid, glutamic acid, aspartic acid, methanesulfonate acid, econsultancy acid, ethicality acid, p-toluensulfonate acid, salicylic acid, succinic acid, triperoxonane acid and the like, which are non-toxic to living organisms or, in the case of compounds of formula is (I), are acidic by nature and with an inorganic base, such as base alkaline or alkaline-earth element, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. Other examples of pharmaceutically acceptable salts is possible to make reference to “Salt selection for basic drugs”,Int. J. Pharm.(1986), 33, 201-217.

The compounds of formula (I) may contain asymmetric carbon atoms and can be prepared in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, a diastereomeric racemate, mixtures of diastereomeric racemates, or mesoform. The present invention encompasses all these forms. Divide mixture method, known for the separation of substances in pure form, for example, column chromatography, thin-layer chromatography (TLC/TLC), high performance liquid chromatography (HPLC/HPLC), or crystallization.

Compounds of the invention also include nitrosated compounds of formula (I), which were nitrotyrosine one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen. Nitrosated compounds of this invention can be prepared by conventional methods known to the person skilled in the art. For example, known FPIC who would nitrogenous compounds described in U.A. Pat. Nos. 5380758, 5703073, 5994294, 6242432 and 6218417; WO 98/19672; and Oae et al., Org. Prep. Proc. Int., 15(3): 165-198 (1983).

A group of preferred compounds of formula (I) is a group in which n represents the integer 1 and the substituents in the loop-SOP(R1)-Q-M-W-V-U, are in TRANS-position to each other.

A group of especially preferred compounds of formula (I) is a group in which n represents the integer 0 and the configuration at positions 3 and 4 piperidinol cycle of the formula (I) represent 3R and 4S, respectively.

A group of preferred compounds of formula (I) is a group, in which M represents aryl, hyalinella, athinodorou, dihydrohelenalin or tetrahydropyranyloxy group, where these groups optionally can be mono - or tizamidine substituents, independently selected from the group consisting of alkyl; alkoxy; -OCF3; -CF3; hydroxyalkyl; halogen; alkyl-O-(CH2)0-4-CH2-; alkyl-O-(CH2)2-4-O-; and R'2N-(CH2)0-4-CH2-where R' is independently selected from the group consisting of hydrogen, alkyl, cyclopropyl, and-C(=O)-R", where R" means1-C4-alkyl, -CF3, -CH2-CF3or cyclopropyl.

Another group of preferred compounds of formula (I) is a group, in which M represents aryl, predpochtitel what about the phenyl, which, in particular, optionally mono - or Disaese substituents, independently selected from the group consisting of alkyl, alkoxy, -OCF3, -CF3, hydroxyalkyl and halogen, preferably from the group consisting of alkyl, alkoxy and halogen.

Another group of especially preferred compounds of formula (I) is a group, in which M represents the following radical:

where R2means methyl or chlorine, R3means hydrogen, and R4means hydrogen, -CH2CH2-O-CH3, -CH2CH2CH2-O-CH3or R NH-(CH2)0-1-CH2-, where R' is-CH2-F2, -CH2-CF3cyclopropyl, -CO-CH3, -CO-CH2-CF3, -CO-CH2-CH3or cyclopropanecarbonyl, provided that when R4means hydrogen, R3represents methyl, methoxy, chlorine, or-och2CH2-O-CH3.

Very preferred group of compounds of formula (I) is a group, in which M represents the following radical:

where R2means chlorine, R3means hydrogen and R4means-CH2CH2-O-CH3.

Very preferred group of compounds of formula (I) is a group, in which M represents the following radical:

where R2means hydrogen, R3means methoxyethoxy and R4means-CH2CH2CH2-O-CH3.

The next group of preferred compounds of formula (I) is a group in which Q represents methylene.

The next group of preferred compounds of formula (I) is a group, in which R1is cyclopropyl.

Another group of preferred compounds of formula (I) is a group in which W represents a phenyl, substituted for V in the para-position, or the following radicals:

Another group of preferred compounds of formula (I) is a group in which W represents a phenyl, substituted for V in the para-position.

Another group of especially preferred compounds of formula (I) is a group in which W represents the following radical:

The next group of preferred compounds of formula (I) is a group, in which V represents-CH2CH2O - or-CH2CH2CH2O-, where in both cases the bivalent radical is joined to the group U of formula (I) through an oxygen atom, or-och2CH2Oh.

Very preferred group of compounds of formula (I) is a group, in which V represents-och2CH2Oh.

Another group of preferred compounds of formula (I) is a group, in which V represents-OCH2CH2O - or especially-CH2CH2CH2O- [preferably, CH2-part of the-CH2CH2CH2O-fragment attached to the group W of formula (I)].

The next group of preferred compounds of formula (I) is a group where U is a mono-, di-, tri - or Tetra-substituted aryl, preferably mono-, di-, or tizamidine phenyl, where the substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and-CF3especially from the group consisting of halogen or alkyl.

Another group of especially preferred compounds of formula (I) is a group where U represents 2,6-dichloro-4-were.

Another group of especially preferred compounds of formula (I) is a group where U represents 2-chloro-3,6-differenl.

The preferred implementation of the present invention relates to the compound of formula (I), where W represents a phenyl, substituted for V in the para-position, or the following radicals:

V represents-OCH2CH2O - or-CH2CH2CH2O, CH2-part of the-CH2CH2CH2O-fragment attached to the group W of formula (I);

U Ave dstanley tizamidine phenyl, in which the substituents independently chosen from halogen atoms (in particular, fluorine and chlorine) and alkyl (particularly methyl);

Q represents methylene;

M represents the following radical:

where R2means methyl or chlorine, R3means hydrogen, and R4means hydrogen, -CH2CH2-O-CH3, -CH2CH2CH2-O-CH3or R NH-(CH2)0-1-CH2-, where R' is alkyl (optionally substituted by one or two fluorine atoms), cyclopropyl, cyclopropylmethyl, -CO-CH3or-CO-CH2-CF3provided that when R4means hydrogen, R3represents methyl, methoxy or chlorine;

R1is cyclopropyl; and

n represents an integer of 0 or 1.

This invention also relates to compounds of formula (I)where the values of one or more substituents, or symbols defined for formula (I), or a preferred variant of the formula (I)are replaced with their preferred values defined here, namely, the values defined for vicedennich preferred groups of compounds.

Especially preferred compounds of formula (I) are compounds selected from the group including:

cyclopropyl(2,3-dichlorobenzyl)amide of (1R∗, 5∗, 6R∗, 7S∗)-7-{4-[3-(2-chloro-3,6-is ifthenelse)propyl]phenyl}-3,9-diaza-bicyclo[3.3.1]nonan-6-carboxylic acid,

cyclopropyl(3-methoxy-2-methylbenzyl)amide 4-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}piperidine-3-carboxylic acid,

cyclopropyl(3-methoxy-2-methylbenzyl)amide 4-{4-[3-(2,6-dichloro-4-methylphenoxy)propyl]phenyl}piperidine-3-carboxylic acid,

cyclopropyl(3-methoxy-2-methylbenzyl)amide 4-{4-[3-(2,3,6-tryptophanate)propyl]phenyl}piperidine-3-carboxylic acid,

cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}piperidine-3-carboxylic acid,

cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2,6-dichloro-4-methylphenoxy)propyl]phenyl}piperidine-3-carboxylic acid,

cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2-chloro-6-fluoro-3-methylphenoxy)propyl]phenyl}piperidine-3-carboxylic acid, and

cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2,3,6-tryptophanate)propyl]phenyl}piperidine-3-carboxylic acid.

The following particularly preferred compounds of formula (I) are compounds selected from the group including:

cyclopropyl(2,3-dimethylbenzyl)amide (3R∗, 4S∗)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

[2-chloro-5-(3-methoxypropyl)benzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

[2-chloro-5-(2-methoxyethyl)benzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

[Chlor-5-(3-methoxypropyl)benzyl]cyclopropylamine (3R, 4S)-6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-1',2',3',4',5',6'-hexahydro[3,4']bipyridinyl-3'-carboxylic acid, and

[2-chloro-5-(2-methoxyethyl)benzyl]cyclopropylamine (3R, 4S)-6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-1',2',3',4',5',6'-hexahydro[3,4']bipyridinyl-3'-carboxylic acid.

Another group of especially preferred compounds of formula (I) is a compound selected from the group including:

{2-chloro-5-[(2,2-diferentiating)methyl]benzyl}cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

{2-chloro-5-[(3,3,3-triphosphopyridine)methyl]benzyl}cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

{2-chloro-5-[(cyclopropylamino)methyl]benzyl}cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

[5-(acetamidomethyl)-2-Chlorobenzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

[2-chloro-5-(2-methylaminomethyl)benzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

(2-chloro-5-methylaminoethanol)cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

{2-chloro-5-[2-(3,3,3-triphosphopyridine)ethyl]benzyl}cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-METHYLPHENOL and)ethoxy]phenyl}piperidine-3-carboxylic acid,

[2-chloro-5-(2-ethylaminomethyl)benzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

[5-(2-acetylamino)-2-Chlorobenzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

{2-chloro-5-[(2-foretelling)methyl]benzyl}cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

(2-chloro-5-ethylaminomethyl)cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,

(2-chloro-5-cyclopropanecarbonyl)cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid, and

[2-chloro-5-(2-cyclopropylamino)benzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid.

The compounds of formula (I) applicable for treatment and/or prevention of diseases, such as (or related) hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal decompensation, kidney fibrosis, cardiac insufficiency, cardiac hypertrophy, fibrosis of the heart, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications derived from diabetes, namely, nephropathy, vasculopathies and neuropathy, glaucoma, increases the TES intraocular pressure, atherosclerosis, restenosis after plastic surgery on vessels, complications after surgery on the heart and vessels, erectile dysfunction, giperaldosteronizm, pneumovirus, scleroderma, fear, disorder cognitive abilities, complications from treatment with immunosuppressants, and other diseases, which are known as associated with the system renin-angiotensin.

The compounds of formula (I) is particularly applicable for the treatment and/or prevention of diseases, such as (or related) hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, renal decompensation, kidney fibrosis, cardiac insufficiency, cardiac hypertrophy, fibrosis of the heart, myocardial ischemia, cardiomyopathy, complications derived from diabetes, namely, nephropathy, vasculopathies and neuropathy.

In one embodiment, the invention relates to a method for the treatment or prevention of diseases that are associated with impaired regulation of the renin-angiotensin, in particular, to a method of treatment or prophylaxis of the aforementioned diseases, with the specified method comprises administration to a patient a pharmacologically active amount of the compounds of formula (I).

Another aspect of this invention relates to pharmaceutical compositions containing with the unity of formula (I) and pharmaceutically acceptable material as a carrier. Data pharmaceutical compositions can be used for the treatment and/or prophylaxis of the aforementioned diseases. The pharmaceutical compositions can be used for enteral, parenteral or local administration. They can be administered, e.g. orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of solutions for injection or solution for infusion, or locally, for example, in the form of ointments, creams or oils.

The invention also relates to the use of compounds of formula (I) for the preparation of pharmaceutical compositions for the treatment or prophylaxis of the aforementioned diseases.

The manufacture of pharmaceutical compositions can be carried out in a manner that will be familiar to any person skilled in the art (see, for example, Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IS Health Group, Englewood, CO, USA, 2001; Remington,The Science and Practice of Pharmacy, 20thEdition, Philadelphia College of Pharmacy and Science), making the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically useful substances in herbal form for injection together with suitable, non-toxic, inert, therapeutically compatible solid or liquid is held and, if desirable, useful pharmaceutical adjuvants.

The compounds of formula (I) or the above-mentioned pharmaceutical compositions are also applicable in combination with other pharmacologically active compounds, such as ACE inhibitors, inhibitors of neutral endopeptidase, aldosterone antagonists, receptor antagonists angiotensin II receptor antagonists endothelin, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholytic, beta-adrenergic antagonists, alpha-adrenergic antagonists and/or other drugs useful for the prevention or treatment of the aforementioned diseases, such as inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1 and activators of soluble guanylate cyclase.

This invention also relates to prodrugs of the compounds of formula (I), which becomein vivoin the compound of formula (I) as such. Any reference to a compound of formula (I) should therefore be interpreted as referring also to the corresponding prodrugs of the compounds of formula (I), as appropriate and practical.

The compounds of formula (I) can be prepared from compounds of the form A (WO 03/093267; WO 04/002957)as described in scheme 1, where W, V, U and n take the values defined for formula (I). PG means a suitable protective group. Rbwho appoints suitable ester, which then can be decomposed, for example, by saponification or by hydrogenation. During the saponification connection type And connection is formed species with 20-100% yield, depending on the conditions in which the double bond is partially shifted to deconjugating position. This compound can be separated or can not be separated from the corresponding analogue of the double still conjugated bond, and then, for example, amide condensation leads to the connection type S, where R1, Q and M take the values defined for formula (I). During the amide condensation by optimizing conditions of the double bond can be displaced almost completely. The connection view is then restored in the connection type D. Finally, remove protection leads to the compound of formula (I). Of course, recovery can also occur with the connection type, which in this case is separated from its regioisomer with more conjugated double bonds. In this case, we have the connection type E, which is transformed into a compound of the D after amide condensation. If n=0 then conjugated connection type a or b can be restored to the corresponding saturated compound with magnesium in methanol. After equilibrium is allocated TRANS-spatial situated stereoisomer. Saponification (if necessary) leads to the connection type that is

The specialist is this area it will be obvious the sequence data of stages may be changed or modified in most cases. The shift of the double bond in compound form In his recovery in the compounds D and E lead to mixtures of stereoisomers. These stereoisomers may be isolated by standard methods, such as flash column chromatography, HPLC or chiral HPLC.

Scheme 1

Otherwise the connection type F can be used as described in scheme 2, where Rbmeans suitable ester Deputy, and Rameans predecessor Deputy V, defined for formula (I). This connection type F is transformed into a compound of the form G, which, in turn, is transformed into a compound type N, using conditions amide condensation, which contribute to the shift of the double bond. The restoration of the double bond leads to the connection type J, which is then transformed into a compound of formula (I). Also the connection type F can recover in the connection type K. U-V-W-chain is completed with the formation of compounds of type L, then the ester is hydrolyzed to the connection type that is

Scheme 2

Examples

Reduction(used in this document):

acetyl
AU
Asónacetic acid
Angangiotensin
water.water
9-BBN9-borabicyclo[3.3.1]nonan
Vostert-butyloxycarbonyl
BSAbovine serum albumin
VIbutyl
BuLin-utility
conc.concentrated
Cycyclohexyl
DIPEAdiisopropylethylamine
DMAP4-N,N-dimethylaminopyridine
DMFN,N-dimethylformamide
DMSOthe sulfoxide
EDC.HClethyl-N,N-dimethylaminopropylamine hydrochloride
EIA enzyme-linked immunosorbent assay
ELSDdetection of light scattering pair
EQ.equivalent(s)
ESelectrospray
Etethyl
EtOActhe ethyl acetate
EtOHethanol
FCflash chromatography
hhour(s)
Hexhexane
HOBthydroxybenzotriazole
HPLChigh performance liquid chromatography
LC-MSliquid chromatography-mass spectroscopy
IUmethyl
MeOHmethanol
minminute(s)
MSthe mass spectrum is scopy/MS
NMON-methylmorpholine
SLAacetate
ODthe optical density
Org.organic
PBSphosphate-saline buffer solution
PGprotective group
Phphenyl
Rfthe rate of retention (TLC)
K.T.room temperature/K.T.
us.rich
Rast.solution
TWAStetrabutylammonium chloride
TBAFtetrabutylammonium fluoride trihydrate
TBDMStert-butyldimethylsilyl
BTUO-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetraphobia the
tButert-butyl
TfTrifloromethyl
TFAtriperoxonane acid
THFtetrahydrofuran
TLCthin-layer chromatography
tRretention time
UVUltraviolet
type.visible

HPLC or LC-MS-conditions (unless otherwise stated)

Analytical: Bond 59 SB Aqua column of 4.6 × 50 mm) from Agilent Technologies. Eluent: A: acetonitrile; B: N2ABOUT A + 0.5% TFA. Gradient: 90% → 5% b for 2 min Flow rate: 1 ml/min Detection: UV/view. + MS.

Preparative: Bond SB Aqua column, 20 × 500 mm) from Agilent Technologies. Eluent: A: acetonitrile; B: N2O + 0.05% ammonium hydroxide (25% aqueous). Gradient: 80% → 10% b for 6 min Flow: 40 ml/min Detection: UV + MS or UV + ELSD.

Chiral analytical: Regis Whelk column of 4.6 × 250 mm, 10 μm. Eluent: EtOH + 0,05% Et3N. Eluent: hexane. Isocratic conditions, 1 ml/min Isocratic mixture may vary in the depending on the connection.

Chiral formulation: such as analytical conditions, but Regis Whelk 01 column, 50 × 250 mm, flow at 100 ml/min

A General method forMitsunobucondensation and removal of the BOC-protection

The desired phenol (2 EQ.) placed in the reaction flask. Add connection J3 or J4 (about 80 mg, 1 EQ.), dissolved in toluene (1 ml), followed by the addition of dipiperidide azodicarboxylic acid (2 equiv.) dissolved in toluene (1 ml). The reaction mixture Tegaserod with N2and at the end add Rvi3(3 EQ.). The reaction mixture is heated at 90°C (preheated) for 1 hour, then cooled again to K.T. Add Et2O (5 ml), the mixture is filtered, and the solvent is evaporated under reduced pressure. The crude intermediate product was then purified HPLC with reversed phase. The purified product is dissolved in dioxane (1 ml) and added HCl in dioxane (4 m, 1 ml). The mixture was stirred at K.T. within 2 hours. The solvents are removed under reduced pressure, obtaining cleaners containing hydrochloride salt of the final compounds of formula (I).

General conditions for amide condensation

HOBt (to 16.9 mg, 0.125 mmol), DMAP (3,05 mg of 0.025 mmol), DIPEA (0,068 ml, 0.40 mmol) and EDC.HCl (28.8 mg, 0,150 mmol) was added to a mixture of carboxylic acid (0,100 mmol) and amine (0,100 mmol) in CH2Cl2(1,00 ml). The mixture was stirred for 4 days at K.T. Mixture was filtered the via Isolute® (0.6 g sorbent, prepared with 1 ml of aqueous 1 M Hcl). The organic layer was evaporated under reduced pressure. The crude product is used without purification.

General conditions for removal of the BOC-protection

The original product was dissolved in CH2Cl2(1 ml)and the solution was cooled to 0°C. HCl (4 M in dioxane, 0.5 ml)and the mixture was stirred for 1 hour while the mixture was heated to K.T.) was Added aqueous 1 M NaOH, and the mixture was stirred for 5 min, the Layers were separated, and the organic layer was evaporated under reduced pressure. Purification by HPLC (acetonitrile with 0.05% of water concentrated NH3/water 10:90→90:10 for all X-bridge column) gave specified in the header of the connection.

General conditions for amide condensation via the acid chloride acid

The original carboxylic acid (1.00 equiv.) was dissolved in toluene (14 ml/mmol of carboxylic acid) was added DMF (catalytic amount). Added oxalicacid (1,30 equiv.) and the mixture was stirred for 1 hour at K.T. Solvents were removed under reduced pressure and the crude acid chloride acid was divided into 0,100 mmol-portions for subsequent amide condensations. Such portion of the carboxylic acid (0,100 mmol) was dissolved in CH2Cl2(1,00 ml)and to this solution was added Et3N (of 0.014 ml, 0.10 mmol) and a solution of the target amine (0,100 mmol) in CH2CL2(0,50 ml). mesh was stirred for 1 hour at K.T. and filtered through an Isolute®, pre-washed with aqueous 1 M Hcl. After elution with CH2CL2the organic layer was evaporated under reduced pressure and the residue used in the next stage without purification.

3-tert-Butyl ester 6-ethyl ester (rat.)-(1R∗, 5S∗)-9-methyl-7-tripterocalyx-3,9-diazabicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid

3-tert-Butyl ester 6-ethyl ester (rat.)-(1R∗, 5S∗)-9-methyl-7-oxo-3,9-diazabicyclo[3.3.1]nonan-3,6-dicarboxylic acid (WO 2003/093267, 99,58 g, 305 mmol) dissolved in dry THF (1450 ml) under nitrogen atmosphere and the mixture cooled to 0°C. NaH (16,64 g; 55% dispersion in mineral oil, 381 mmol) is added in portions of 2 g for 35 min, maintaining the temperature in the interval from 0 to 4°C. is Allocated N2gas. After adding the mixture becomes yellow-green and is a weak suspension. The reaction mixture is stirred for 75 minutes at a temperature of from 0 to 4°C. Then add Tf2NPh (of 128.6 g, 360 mmol) in the form of solids within 5 minutes, the Reaction mixture becomes brown. The cooling bath removed and the reaction mixture was stirred over the weekend at K.T. Reaction mixture is poured into 1 l of a mixture of ice/water and the solvents removed under reduced pressure. The remaining aqueous phase extracted with EtOAc (3 × 500 ml). Obyedinennaya layers washed with water (500 ml) and saturated brine (500 ml). The organic phase is then dried over MgSO4, filtered and evaporated under reduced pressure. To the crude brown residue (174 g) add 50 ml of pentane and the mixture was stirred at 4°C over night. The crystals are filtered and washed with cold hexane (70 ml) and cold hexane/Et2O (4:1, 100 ml). This leads to 84 g of product containing some number TfNPh. This product is filtered through silica gel (75 g). TfNPh wash with CH2CL2. This product is then washed with EtOAc (3 x 1 l), receiving specified in the title compound after evaporation under reduced pressure. Specified in the header of the connection get in three fractions: a) 44,45 g of off-white crystals, b) 27,98 g of a slightly brown crystals and (C) 15 g of yellow oil containing the product and TfNPh. After 2 days TfNPh contained in the fraction), crystallizes. It is filtered, getting 9,43 g of the product as a brown oil.

Treatment of uterine solutions

United uterine solutions obtained above was concentrated in vacuo. The brown oily residue (75 g) is treated with FC (1500 g of silica gel)using a gradient elution (EtOAc/heptane 1-9 → EtOAc). The column is then washed with a mixture of EtOAc/MeOH 9:1. Specified in the title compound is isolated in the form of 25,44 g not quite white solid as the pure product. LC-MS: tR = 0,87 min; ES+: 459,24.

1-Allyl-4-Brabanthal

Mg (8,76 g, 360 mmol) suspended in THF (90 ml) under nitrogen atmosphere in a three-neck flask, equipped with a refrigerator and an addition funnel. Addition funnel fill 1,4-dibromobenzene (77,3 g, 327 mmol) in THF (40 ml). Approximately 5% solution of 1,4-dibromobenzene with carefully added to a suspension of Mg and the reaction run using the heat of the gun. When the reaction starts, add a solution of 1,4-dibromobenzene with such a rate that the reaction mixture is weakly boiled under reflux (about 20 min). The mixture is stirred for another 30 min and cooled to 0°C. Add THF (100 ml) and addition funnel filled with a solution of allylbromide (30,5 ml, 360 mmol) in THF (50 ml). Allylbromide added slowly, maintaining the temperature of the reaction mixture below 20°C. When the addition is complete, the mixture is stirred for another 30 min, while cooling to 0°C. Add water 1 M Hcl. The mixture was diluted with Et2O and washed with aqueous 1 M Hcl and saturated salt solution. The combined aqueous extracts again extracted with Et2O. the combined organic extracts dried over MgSO4, filtered and the solvents removed under reduced pressure. Distillation of the residue (11 mbar, 88-92°C) allows specified in the header connection (39,3 g, approximately 61%) together with other unidentified impurity

3-(4-Bromophenyl)propan-1-ol

NR3(1 M in THF, 412 ml, 412 mmol) are added to a solution of 1-allyl-4-bromine benzol (204 g of 1.03 mmol) in THF (1,00 l) under nitrogen atmosphere at 0°C. the Mixture is stirred overnight while it is heated to K.T. Added aqueous NaOH (2.5 M, 1,65 l, 4,12 mol) and the mixture cooled to 0°C. Carefully added dropwise N2About2(35%, 480 ml, 5,15 mol)and the mixture is stirred for 3 hours. Add Et2O and the phases are separated. The organic layer was washed with water (1×) and saturated brine (1×). The organic layer is dried over MgSO4, filtered and the solvents removed under reduced pressure. Purification by FC (Et2O/petroleum ether 1:1 → Et2O) gives specified in the header connection (97,4 g, 44%).

[3-(4-Bromophenyl)propoxy]tert-butyldimethylsilyl

A solution of 3-(4-bromophenyl)propan-1-ol (49,4 g, 230 mmol) in DMF (500 ml) cooled to 0°C and added imidazole (23,77 g, 349 mmol) and TBDMS-Cl (52,6 g, 349 mmol). The mixture is stirred overnight while it is heated to K.T. Mixture is diluted with heptane (1.0 l) and aqueous saturated NH4Cl (800 ml)and the mixture shaken. The layers are separated. The aqueous layer was extracted with heptane and the combined organic extracts washed with saturated saline solution. The organic extracts dried over MgSO4, filtered and the solvents removed under reduced pressure is I. Purification by FC (Et2O/heptane 1:99 → 1:19) gives specified in the header connection (68,1 g, 90%). LC-MS: tR= 1,24 minutes

2-(2,6-Dichloro-4-methylphenoxy)ethanol

In a three-neck flask, equipped with a gas drip counter and efficient cooling system, heated mixture of 2,6-dichloro-p-cresol (20,0 g, 113 mmol), [1,3]dioxolane-2-it (9.95 g, 113 mmol) and imidazole (115 mg, 1.70 mmol) at 160°C for 25 hours. The mixture was allowed to cool to K.T. Cleaning with FC (Et2O/heptane 1:1) gave specified in the title compound (18.7 g, 75%). LC-MS: tR= 0,88 minutes

5-Bromo-2-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]pyridine

A solution of 2-(2,6-dichloro-4-methylphenoxy)ethanol (18.6 g, 84 mmol) in THF (360 ml) was cooled to 0°C. NaH (55% in oil, 6.60 g, approximately 153 mmol) was added in portions and the mixture was stirred at K.T. within 30 minutes a Solution of 2,5-dibromopyridine (18.0 g, to 76.3 mmol) in THF (60 ml) was added dropwise, and the mixture was heated at the boil under reflux for 90 minutes the Mixture was allowed to cool to K.T. and was carefully added to ice. The solvents were partially removed under reduced pressure, and the residue was diluted with EtOAc. This mixture was washed with aqueous saturated NH4Cl. The aqueous layer was extracted again with EtOAc (2×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4the filter is the Wali and the solvents were removed under reduced pressure. Purification of the crude product by FC (Et/heptane 3:97) gave specified in the title compound (22.7 g, 79%). LC-MS: tR= 1,13 min; ES+: 378,08.

5-Bromo-2-chloro-N-cyclopropylbenzene

To a suspension of 5-bromo-2-chlorbenzoyl acid (17.6 g, 75 mmol) in CH2CL2(180 ml) was added oxalicacid (7,0 ml, 83 mmol). Was added DMF (8 drops)and the mixture was stirred for 2 hours at K.T. (gas evolution). The mixture was concentrated under reduced pressure and the crude residue was diluted with CH2CL2(530 ml). The mixture was cooled to 0°C., and a solution of cyclopropylamine (5.8 ml, 83 mmol) in CH2CL2(45 ml) was added dropwise. The mixture was stirred for 10 min at 0°C and allowed to warm to K.T.) was Added DIPEA (14,3 ml, 84 mmol)and the mixture was stirred for 2 hours at K.T. Mixture was diluted by a large number of CH2CL2and washed with aqueous 10% HCl, water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. The residue is triturated in hexane, filtered and dried in a high vacuum, getting mentioned in the title compound (19.3 g, 94%). LC-MS: tR= 0,84 min; ES+: 316,89.

2-Chloro-N-cyclopropyl-5-(3-methoxypropyl)benzamide

5-Bromo-2-chloro-N-cyclopropylbenzene (19.3 g, 70.5 mmol) was dissolved in a mixture of DMF (350 ml) and 1-propanol (210 ml). Was added Pd(OAc)2 (PPh3)3(2.64 g, of 3.53 mmol). Was added via syringe (E)-2-(3-methoxypropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (15 ml, 70.5 mmol) was added aqueous 2 M Na2CO3(123 ml). The mixture was stirred for 2 hours at 80°C, and she was allowed to warm to K.T. Aqueous 10% Hcl was carefully added to until the pH does not become equal to 2. The solvents were partially removed under reduced pressure, and the residue was extracted with Et2O (3H). The combined organic extracts were washed with water and saturated saline solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (Et/heptane 1:2 → 1:1 → EtOAc) gave specified in the title compound (12.7 g, 68%). LC-MS: tR= 0,82 min; ES+: 266,17.

2-Chloro-N-cyclopropyl-5-(3-methoxypropyl)benzamide

2-Chloro-N-cyclopropyl-5-(3-methoxypropyl)benzamide (12,6 g, or 47.6 mmol) was dissolved in dry toluene (650 ml). Was added dry DMF (70 ml) and the mixture was heated to 110°C. Benzosulfimide (24.5 g, 143 mmol) was added in three portions over 3 hours. The mixture was heated for a total period of time of 3 hours, and she was allowed to cool to K.T. Solvents were removed under reduced pressure and the residue was diluted with Et2O. the Mixture was washed with water and the aqueous phase was extracted again Et2O (3×). The combined organic extracts washed is whether water and saturated salt solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (Et/heptane 1:9 → 1:4 → 1:3 → 1:1) gave specified in the title compound (10.0 g, 78%). LC-MS: tR= 0,83 min; ES+: 268,19.

[2-Chloro-5-(3-methoxypropyl)benzyl]cyclopropylamine

LiAlH4(5,70 g, 151 mmol) was added in portions to a solution of 2-chloro-N-cyclopropyl-5-(3-methoxypropyl)benzamide (10 g, of 37.7 mmol) in THF (230 ml) at 0°C. the Ice bath was removed, and the mixture was heated at the boil under reflux for 4 hours. The mixture was allowed to cool to K.T., and cool it to 0°C. was Carefully added water (7.5 ml), aqueous 15% NaOH (17 ml) and water (5.7 ml). The mixture was filtered and the precipitate washed with EtOAc. The filtrate was evaporated under reduced pressure. The residue was diluted with EtOAc, and the resulting mixture was washed with water and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (Et/heptane 1:4 → 1:3 → 1:2) gave specified in the header of the connection (the ceiling of 5.60 g, 59%). LC-MS: tR= 0,86 min; ES+: 254,19.

A General method for reductive amination of the substituted benzaldehydes with cyclopropylamino:

X = halogen, in particular Br

A solution of the substituted benzaldehyde (17.8 mmol, 1.0 EQ.), cyclopropylamine (3,13 ml of 44.5 mmol, 25 EQ.) and cyanoborohydride sodium (1,34 g, 21,4 mmol, 1.2 EQ.) in the Meon (100 ml) was treated with drip by adding glacial acetic acid (3,06 ml, with 53.4 mmol, 3.0 EQ.). The resulting solution was stirred at K.T. for 16 hours during the night. The reaction mixture was extinguished drip the addition of saturated aqueous NaHCO3and concentrated under reduced pressure to remove the Meon. The crude residue was poured into a 250 ml separating funnel containing saturated aqueous solution of NaHCO3(150 ml)and was extracted with EtOAc (3×50 ml). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. Cleaning with FC gave benjaminov product.

The General procedure for BOC-protection of cyclopropylbenzene:

X = halogen, in particular Br

The solution cyclopropylbenzene (43,7 mmol, 1.0 EQ.) in bi-phase mixture of CH2CL2(50 ml) and 1 M aqueous NaOH (50 ml) was treated with BOC2(15.1 ml, 65,6 mmol, 1.5 EQ.). The mixture was intensively stirred at K.T. for 16 hours. The mixture was poured into 500 ml separating funnel containing H2O (300 ml)and was extracted with CH2Cl2(3×100 ml). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. The sight of the TKA using FC gave Amin, the protected BOC-group.

A General method for Allilueva the BOC-protected cyclopropylbenzene:

X = halogen, in particular Br

In a round bottom flask and dried by the fire, or vessel Slanka, in an atmosphere of N2was added Pd[PCy3]2(of 0.05 equiv.) CsF (2.0 EQ.) and the corresponding arylboronic (1.0 EQ.). If used areshared as the original product, was used (Pd[PtBu3]Br)2dimer (0,025 EQ.) instead of Pd[PCy3]2of the catalyst. The flask was pumped under reduced pressure (0.1 mm Hg) and again filled the N2(repeated 3 times). The obtained solid substance was dissolved in anhydrous THF or dioxane (0.15 M solution), and to this solution was added tri-n-butylalcohol (1.5 equiv.) then the resulting mixture was boiled under reflux for 8-16 hours until TLC showed complete consumption of the original product. The reaction mixture was cooled to K.T. and filtered through a pad of silica gel on the funnel with sintered glass, rinsing with Et2O. the Filtrate was concentrated and was purified by means of FC, receiving the relevant allylbenzene derived.

A General method for hydroporinae/oxidation of allylbenzene:

In a flame dried round bottom flask, equipped with a magnetic stirrer, was added alivans the min (1.0 EQ.) and anhydrous THF (0.3 M solution). The solution was cooled to 0°C and porandamaterjalides complex (1.1 EQ.) was added dropwise within 20 minutes the Solution was stirred at 0°C for 1 hour, and then he was allowed to warm to K.T., and was stirred for additional 2 hours. The solution was cooled to 0°C., and thereto was added dropwise a 1 M aqueous NaOH (CAUTION - EXOTHERMIC REACTION), followed by adding dropwise a 30% aqueous H2About2. The mixture was allowed to warm to K.T. and stirred for 2 hours. The mixture was poured into a separating funnel containing H2O and was extracted with Et2O (3 times). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. Cleaning with FC gave the target liquid product.

General procedure for the oxidative cleavage/restoreallevantamento:

The solution allylbenzene (1.0 EQ.) in CH2Cl2(a 0.4 M solution) was cooled to -78°C and introduced into a solution of O3gas, using a pipe for gas distribution. Ozone gas was introduced until then, until he was spent for the original product, as determined by TLC, and the reaction mixture was kept weak blue staining. The reaction mixture was stirred at -78°C for 20 min, then EXT is ulali EtOH (0.5 M solution) and NaBH 4(2.5 EQ.). The mixture was allowed to warm up during K.T. over night (16 h). The reaction mixture was extinguished drip the addition of saturated aqueous NH4Cl (5 ml) and poured into a separating funnel containing saturated aqueous NH4Cl. The mixture was extracted with Et2O (3 times). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. Cleaning with FC gave the target alcohol.

General procedure for the esterification of an aromatic primary alcohols with methyliodide:

The suspension of the primary alcohol (1.0 EQ.) in THF (0.25 M solution) was cooled to 0°C. and treated with NaH (60% in oil, 2.0 EQ.). The resulting mixture was stirred at 0°C for 30 min and then at K.T. within 30 minutes, the Suspension was again cooled to 0°C and then MeI (8.0 EQ.) was added in one portion. The reaction mixture was stirred at 0°C for 30 min, K.T. for 30 min, and then heated at the boil under reflux for 4 hours until, until he was spent for the original product, as determined by TLC. The cooled reaction mixture is extinguished drip the addition of saturated aqueous NH4Cl and was poured into a separating funnel containing saturated aqueous NH4Cl, and extracted with SIP is utilized EtO (3 times). The combined organic layers were washed with saturated salt solution, dried over MgSO4, filtered and concentrated under reduced pressure. Cleaning with FC gave methyl ether.

A General method for removing protection from cyclopropylbenzene protected BOC-group:

To a solution of cyclopropylbenzene (1.0 EQ.), the protected BOC-group, CH2Cl2(0.1-0.5 M solution) was added 4 M HCl in dioxane (5.0 EQ.). The reaction mixture was stirred at K.T. within 8-16 hours up until TLC showed full conversion of the original product. The reaction mixture was poured into a separating funnel containing 1 M aqueous NaOH, and was extracted with CH2Cl2(3 times). Cleaning with FC gave the corresponding free amine.

(5-Bromo-2-chlorobenzoyloxy)tert-butyldimethylsilyl

TBDMS-Cl (10.6 g, from 66.7 mmol) was added to a solution of (5-bromo-2-chlorophenyl)methanol (12.8 g, at 55.6 mmol) and imidazole (9,42 g, 138 mmol) in DMF (190 ml) at 0°C. the Mixture was stirred for 2 hours at 0°C., and thereto was added aqueous saturated NH4Cl. The mixture was extracted with heptane (2×). The combined organic extracts were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane → EtOAc/heptane 1:49) gave specified in the header of the giving (18.0 g, 96%). LC-MS: tR= 1,22 minutes

3-(tert-Butyldimethylsilyloxy)-4-chlorobenzaldehyde

BuLi (of 1.6 M in hexane, 46.6 ml, 74,6 mmol) are added to a solution of (5-bromo-2-chlorobenzoyloxy)tertbutyldimethylsilyl (16.7 g, 49.7 mmol) in THF (500 ml). The mixture was stirred for 30 min at -78°C., and thereto was added DMF (19.2 ml, 249 mmol) at such a speed that the temperature did not rise above -70°C. the Mixture was stirred for 30 min at -78°C, and she was allowed to warm to K.T. Mixture was poured into aqueous saturated NH4Cl. The resulting mixture was extracted several times with EtO. The combined organic extracts were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:4) gave specified in the title compound (11.2 g, 79%). LC-MS: tR= 1,15 minutes

tert-Butyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]-(2,2-dottorati)carbamino acid

2.2-Deperately (660 mg, of 7.90 mmol) was added to a solution of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzaldehyde (1.50 g, at 5.27 mmol) in Meon (53 ml). The mixture was heated at the boil under reflux for 4 hours, and allowed it to cool down to a temperature below K.T. portions To the mixture was carefully added NaBH4(300 mg, of 7.90 mmol)and the mixture was stirred for 1 hour. Dissolve Italy was removed under reduced pressure, and the remaining oil was diluted with EtOAc. The mixture is washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure, obtaining [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]-(2,2-dottorati)Amin (1.86 g) in the form of a light crude oil that is then used directly. The crude product was dissolved in CH2CL2(53 ml), and to the solution was added DIPEA (2.7 ml, 15.6 mmol), then Vos2(1.70 g, of 7.90 mmol). The mixture was stirred at K.T. within 1 hour. The mixture was diluted with CH2CL2(50 ml) and washed with aqueous 1 M HCl, water, saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 5:95) gave specified in the header of the connection of 2.27 g, 96%). LC-MS: tR= 1,22 minutes

tert-Butyl ester (4-chloro-3-hydroxymethylene)-(2,2-dottorati)carbamino acid

TBAF (1 M in THF, to 9.57 ml, to 9.57 mmol) was added dropwise to a solution oftertbutyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]-(2,2-dottorati)carbamino acid (2.15 g, 4,78 mmol) in THF (48 ml) at 0°C. the Mixture was stirred for 1 hour, while it was heated dont The mixture was diluted with EtOAc and the resulting mixture was washed with aqueous saturated NH4Cl (×2) and saturated brine (1×). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 30:70) gave specified in the header connection (591 mg, 37%). LC-MS: tR= 0,97 min; ES+: 336,09.

tert-Butyl ester (4-chloro-3-formylmethyl)-(2,2-dottorati)carbamino acid

MnO2(830 mg, 8,59 mmol) was added to a solution oftert-butyl ester (4-chloro-3-hydroxymethylene)-(2,2-dottorati)carbamino acid (577 mg, 1,72 mmol) in CH3CN (35 ml). The mixture was stirred at K.T. within 4.5 hours, and it was again added to MnO2(830 mg, 8,59 mmol). The mixture was stirred for 1 hour. The mixture was filtered through celite, and the precipitate was washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure to give crude specified in the title compound (563 mg, 98%), which is then used without purification. LC-MS: tR= 1,03 min

tert-Butyl ester (4-chloro-3-cyclopropanecarbonyl)-(2,2-dottorati)carbamino acid

The mixture oftert-butyl ester (4-chloro-3-formylmethyl)-(2,2-dottorati)carbamino acid (563 mg, was 1.69 mmol) and cyclopropylamine (0,180 ml, 2,52 mmol) in Meon (18 ml) was heated at pile the AI under reflux for 4 hours. The mixture was allowed to cool to K.T.) was Added in portions NaBH4(96 mg, of 2.53 mmol)and the reaction mixture was stirred for 1 hour. The solvents were removed under reduced pressure and the resulting oil was diluted with EtOAc.

The mixture is washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2Cl2/MeOH 95:5) gave specified in the title compound (558 mg, 88%). LC-MS: tR= 0,76 min; ES+: 375,17.

The oxime of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzaldehyde

3-(tert-Butyldimethylsilyloxy)-4-chlorobenzaldehyde (12.7 g and 44.6 mmol) was dissolved in CH3CN (53 ml). To this solution was added NaHCO3(11.2 g, 134 mmol)and the mixture was stirred intensively for 5 minutes was Added water (96 ml) and the mixture was stirred for 10 min. NH2OH.HCl (6.20 g, of 89.2 mmol) was added dropwise, then add TBAC (622 mg, 2,24 mmol). The mixture was stirred at K.T. within 1 hour, and thereto was added dropwise Asón (4,00 ml) to pH 6-7. The mixture was diluted with water (100 ml)and this mixture was extracted with Et2O (×3). The combined organic extracts were dried over MgSO4was filtered and the solvents were removed under reduced pressure. Drying of the residue in high vacuum Dawa is and untreated specified in the title compound (15.1 g, 98%), which is then used without purification. LC-MS: tR= 1,09 min; ES+: 341,13.

3-(tert-Butyldimethylsilyloxy)-4-chlorobenzylamino

LiAlH4(4.11 g, 108 mmol) was added in portions to a solution of oxime of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzaldehyde (13,0 g, a 43.4 mmol) in Et2O (433 ml). The mixture was stirred at K.T. within 1 hour. Aqueous saturated solution of potassium tartrate sodium (400 ml) was carefully added to the mixture. The mixture was stirred for 3 h and was extracted with Et2O (3×). The combined organic extracts were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum gave the crude specified in the title compound (12.4 g, quantitative yield), which is then used without purification. LC-MS: tR= 0,84 min; ES+: 327,37.

N-[3-(tert-Butyldimethylsilyloxy)-4-Chlorobenzyl]-3,3,3-triptocaine

TBTU (3,37 g, 10.5 mmol) was added to a solution of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzylamino (2.00 g, 7,00 mmol), DIPEA (4,80 ml of 28.0 mmol) and 3,3,3-triptocaine acid (0,927 ml, 10.5 mmol) in CH2Cl2(70 ml). The mixture was stirred at K.T. within 1 hour. CH2Cl2(30 ml) was added, and the mixture is washed with aqueous saturated NH4Cl (2×), aqueous 1 M NaOH (1×) and saturated brine (1×). Organically the layer was dried over MgSO 4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 40:60) gave specified in the title compound (1.80 g, 65%). LC-MS: tR= 1,10 min; ES+: 396,15.

N-(4-chloro-3-hydroxymethylene)-3,3,3-triptocaine

TBAF (1 M in THF, 9,10 ml, 9,10 mmol) was added to a solution of N-[3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]-3,3,3-triptocaine (1.80 g, 4,55 mmol) in THF (45 ml) at 0°C. the Mixture was stirred for 1 hour, while it was heated to K.T. EtOAc (100 ml) was added, and the mixture is washed with aqueous saturated NH4Cl (3×) and water (4×). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 70:30) gave specified in the title compound (835 mg, 65%). LC-MS: tR= 0,76 min; ES+: 323,02.

N-(4-chloro-3-formylmethyl)-3,3,3-triptocaine

MnO2(1.44 g, 14.9 mmol) was added to a solution of N-(4-chloro-3-hydroxymethylene)-3,3,3-triptocaine (841 mg, 2,99 mmol) in CH3CN (60 ml). The mixture was stirred at K.T. within 3 hours. Again added MnO2(1.44 g, 14.9 mmol)and the mixture was stirred for 90 minutes the Mixture was filtered through celite, and the precipitate was washed with CH3CN and CH2Cl2. The solvents were removed under reduced pressure, and the residue was dried in high vacuum, receive the raw I mentioned in the title compound (840 mg, quantitative yield)which was used without purification. LC-MS: tR= 0,84 min; ES+: 341,21.

N-(4-Chloro-3-cyclopropanecarbonyl)-3,3,3-triptocaine

A mixture of N-(4-chloro-3-formylmethyl)-3,3,3-triptocaine (840 mg, 3.00 mmol) and cyclopropylamine (0,320 ml, 4,51 mmol) in Meon (30 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T.) was Added in portions NaBH4(170 mg, 4,51 mmol). The mixture was stirred for 1 hour, and the solvent was removed under reduced pressure. The residue was diluted with EtOAc, and the resulting mixture was washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2Cl2/MeOH 90:10) gave specified in the header connection (929 mg, 96%). LC-MS: tR= 0,64 min; ES+: 321,05.

tert-Butyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]cyclopropylmethanol acid

A mixture of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzylamino (2.00 g, 7,00 mmol) and cyclopropanecarboxaldehyde (0,784 ml, 10.5 mmol) in Meon (70 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T. To the mixture portion was added NaBH4(397 mg, 10.5 mmol), and MES was stirred for 1 hour at K.T. The solvents were removed under reduced pressure and the resulting oil was diluted with EtOAc. The resulting mixture was washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure to give crude product [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]cyclopropanemethylamine. This crude product was dissolved in CH2CL2(70 ml). To the solution was added DIPEA (of 3.60 ml, or 21.0 mmol) and Vos2(2.30 g, 10.5 mmol). The mixture was stirred at K.T. within 2 hours, and the mixture was diluted with CH2CL2(30 ml). The resulting mixture was washed with aqueous 1 M HCl, water, saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by FC (heptane → EtOAc/heptane 10:90) gave specified in the title compound mixed with Vos2(Of 3.60 g, quantitative yield). LC-MS: tR= 1,25 min; ES+: 440,80.

tert-Butyl ester (4-chloro-3-hydroxymethylene)cyclopropylmethanol acid

TBAF (1 M in THF, of 14.0 ml, 14.0 mmol) was added to a solution oftertbutyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]cyclopropylmethanol acid (is 3.08 g, 7,00 mmol) in THF (68 ml) at 0 the S. The mixture was stirred for 1 hour, while it was heated to K.T. was added EtOAc, and the mixture is washed with aqueous saturated NH4Cl and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2CL2→ CH2Cl2/MeOH 9:1) gave specified in the header connection (1,00 g, 44%). LC-MS: tR= 0,99 min; ES+: 326,10.

tert-Butyl ester (4-chloro-3-formylmethyl)cyclopropylmethanol acid

MnO2(1.48 g, and 15.3 mmol) was added to a solution oftert-butyl ester (4-chloro-3-hydroxymethylene)cyclopropylmethanol acid (1,00 g of 3.07 mmol) in CH3JV (61 ml). The mixture was stirred at K.T. within 4 hours, and it was again added to MnO2(1.48 g, and 15.3 mmol). The mixture was stirred for 1 hour and filtered through celite. The precipitate was washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure. Drying the residue under high vacuum gave crude specified in the header connection (1,00 g, quantitative yield), which is then used without purification. LC-MS: tR= 1,06 minutes

tert-Butyl ester (4-chloro-3-cyclopropanecarbonyl)cyclopropylmethanol acid

The mixture oftert-butyl ester (4-chloro-3-formylmethyl)C is chlorophenethylamine acid (1,00 g, to 3.09 mmol), Et3N (0,646 ml, with 4.64 mmol) and cyclopropylamine (0,325 ml, with 4.64 mmol) in Meon (10.5 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and to it was added NaBH4(292 mg, 7,71 mmol). The mixture was stirred for 1 hour, and thereto was added aqueous saturated NaHCO3. The mixture was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (Meon/CH2Cl21:49) gave specified in the title compound (535 mg, 48%). LC-MS: tR= 0,81 min; ES+: 406,20.

N-[3-(tert-Butyldimethylsilyloxy)-4-Chlorobenzyl]ndimethylacetamide

AcCl (0,547 ml of 7.70 mmol) was added to a solution of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzylamino (2.00 g, 7,00 mmol) and DIPEA (4,80 ml of 28.0 mmol) in CH2Cl2(70 ml) at 0°C. the Mixture was stirred for 1 hour, while it was heated to K.T. CH2Cl2(30 ml) was added, and the mixture is washed with aqueous saturated NH4Cl (2×), aqueous 1 M NaOH (1×) and saturated brine (1×). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 60:40) gave specified in the title compound (2.10 g, 91%). LC-MS: tR= 1,07 min; ES+: 369,19.

N-(4-Chloro-3-hydroxymethylene)ndimethylacetamide

TBAF (1 M in THF, 12.0 ml of 12.0 mmol) was added to a solution of N-[3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]ndimethylacetamide (2,05 g, 6,00 mmol) in THF (60 ml) at 0°C. the Mixture was stirred for 2 hours, while it was heated to K.T. EtOAc (100 ml) was added, and the mixture is washed with aqueous saturated NH4Cl (1×) and water (4×1). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2CL2/MeOH 90:10) gave specified in the title compound (750 mg, 59%). LC-MS: tR= 0,63 min; ES+: 237,09.

N-(4-Chloro-3-formylmethyl)ndimethylacetamide

NMO (1,15 g, compared to 8.26 mmol) was added to a solution of N-(4-chloro-3-hydroxymethylene)ndimethylacetamide (588 mg, of 2.75 mmol) in CH3CN (27 ml). The mixture was stirred at K.T. within 30 minutes, and thereto was added perruthenate of tetrapropylammonium (97 mg, 0.28 mmol). The mixture was stirred for 1 hour at K.T. and filtered through celite. The precipitate was washed with CH3CN. The filtrate was evaporated under reduced pressure. Purification of the crude product by FC (CH2CL2/MeOH 95:5) gave specified in the title compound (382 mg, 66%). LC-MS: tR= 0,71 min; ES+: 253,07.

N-(4-Chloro-3-cyclopropanecarbonyl)ndimethylacetamide

A mixture of N-(4-chloro-3-formylmethyl)ndimethylacetamide (382 mg, is 1.81 mmol) and cyclopropylamine (0,194 ml, a 2.71 mmol) in Meon (18 ml) was heated at boiling with inverse x is Hladilnika within 4 hours. The mixture was allowed to cool to K.T., and to it was added by portions NaBH4(102 mg, a 2.71 mmol). The mixture was stirred for 1 hour, and the solvent was removed under reduced pressure. Added EtOAc (50 ml)and the resulting mixture was washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2Cl2/MeOH 95:5) gave specified in the title compound (371 mg, 81%). LC-MS: tR= 0,53 min; ES+: 253,11.

tert-Butyl-[2-chloro-5-(2-nitrovinyl)benzyloxy]dimethylsilane

A mixture of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzaldehyde (14.0 g, 49,1 mmol) and ammonium acetate (3,79 g, 49,1 mmol) in nitromethane (8,19 ml, 152 mmol) and Asón (39 ml) was heated at the boil under reflux for 3 hours. The mixture was allowed to cool to K.T., and the mixture was poured into water. The resulting mixture was extracted several times with EtOAc. The combined organic extracts were washed with water and aqueous saturated NaHCO3several times. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. The residue was dried in high vacuum overnight and dissolved in DMF (217 ml). The solution was cooled to 0°C., and thereto was added imidazole (at 8.36 g, 123 mmol) and TBDMS-Cl (8,84 g, 58,6 mm is eh). The mixture was stirred for 2 hours at 0°C and was poured into aqueous saturated NH4Cl. The resulting mixture was extracted several times with EtOAc. The combined organic extracts were washed with water and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 2:8) gave specified in the header of the connection (of 9.50 g, 59%). LC-MS: tR= 1,18 minutes

2-[3-(tert-Butyldimethylsilyloxy)-4-chlorophenyl]ethylamine

LiAlH4(1,09 g, 28.7 mmol) was added to a solution oftert-butyl-[2-chloro-5-(2-nitrovinyl)benzyloxy]dimethylsilane (3,95 g, 11.5 mmol) in Et2O (115 ml). The mixture was stirred at K.T. within 1 hour, and thereto was added an aqueous saturated solution of potassium tartrate sodium. The mixture was stirred for 1 hour, and the layers were separated. The aqueous layer was extracted several times with Et2O. the combined organic extracts were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum gave the crude specified in the header connection (3,20 g, 93%), which is then used without purification. LC-MS: tRor = 0.90 min; ES+: 341,18.

tert-Butyl ether {2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}methylcarbamate sour is s

To2CO3(728 mg, at 5.27 mmol) and methylchloroform (0,405 ml, at 5.27 mmol) was added to a solution of 2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl] - ethylamine (1,05 g, 3,51 mmol) in CH2CL2(36 ml). The mixture was stirred at K.T. within 1 hour and again added methylchloroform (0,304 ml, 3.95 mmol). The mixture was stirred at K.T. within 1 hour and again added methylchloroform (0,304 ml, 3.95 mmol). The mixture was stirred at K.T. for 1 hour and added CH2Cl2(30 ml). The resulting mixture was washed with aqueous saturated NH4Cl (2×), aqueous 10% To2CO3(1×) and saturated brine (1×). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure to give crude methyl ether {2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}carbamino acid. The crude product was dissolved in THF (36 ml). The solution was cooled to 0°C., and to it carefully portions was added LiAlH4(400 mg, 10.5 mmol). The mixture was allowed to warm to K.T., and mixed it with K.T. during the night. The mixture was poured into aqueous saturated potassium tartrate sodium (50 ml)and the mixture was stirred at K.T. within 2 hours. The mixture was extracted with Et2O (3×). The combined organic extracts were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure to give crude {2-3-( tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}methylamine. This crude product was dissolved in CH2CL2(36 ml). To the solution was added DIPEA (1.80 ml, 10.5 mmol), then Vos2(2.30 g, 10.5 mmol). The mixture was stirred at K.T. within 1 hour, and thereto was added CH2CL2(50 ml). The mixture is washed with aqueous 1 M HCl, saturated salt solution, aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 4:1) gave specified in the header connection (1,00 g, 91%). LC-MS: tR= 0,84 min; ES+: 355,23.

tert-Butyl ether [2-(4-chloro-3-hydroxymethylene)ethyl]methylcarbamate acid

TBAF (1 M in THF, 2,90 ml, 2,90 mmol) was added to a solution oftert-butyl ether {2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}methylcarbamate acid (600 mg, 1,45 mmol) in THF (of 14.2 ml) at 0°C. the Mixture was stirred for 1 hour, while it was heated to K.T. EtOAc was added and the mixture washed with aqueous saturated NH4Cl and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2CL2/MeOH 19:1) gave specified in the header connect the tion (435 mg, quantitative yield). LC-MS: tR= 0,93 minutes

tert-Butyl ether [2-(4-chloro-3-formylphenyl)ethyl]methylcarbamate acid

NMO (607 mg, 4.35 mmol) was added to a solution oftert-butyl ether [2-(4-chloro-3-hydroxymethylene)ethyl]methylcarbamate acid (435 mg, 1,45 mmol) in CH2Cl2(30 ml). The mixture was stirred for 30 minutes, and thereto was added perruthenate of tetrapropylammonium (51,0 mg, 0,145 mmol). The mixture was stirred for 1 hour and filtered through celite. The filtrate was evaporated under reduced pressure. Purification of the crude product by FC (CH2CL2/MeOH 19:1) gave specified in the title compound (330 mg, 76%). LC-MS: tR= 1,00 minutes

tert-Butyl ether [2-(4-chloro-3-cyclopropylmethyl)ethyl]methylcarbamate acid

The mixture oftert-butyl ether [2-(4-chloro-3-formylphenyl)ethyl]methylcarbamate acid (325 mg, of 1.09 mmol), Et3N (0,228 ml of 1.64 mmol) and cyclopropylamine (0,115 ml of 1.64 mmol) in Meon (3,66 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and to it was added NaBH4(103 mg, 2,73 mmol). The mixture was stirred for 1 hour at K.T., and to it was added aqueous saturated NaHCO3. The mixture was extracted with EtOAc several times. The combined organic extracts were dried over MgSO4, filtered, and dissolve Italy was removed under reduced pressure. Purification of the crude product by FC gave specified in the title compound (186 mg, 50%). LC-MS: tR= 0,79 min; ES+: 339,39.

tert-Butyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]methylcarbamate acid

To2CO3(363 mg, 2,63 mmol) and methylchloroform (0,202 ml, 2,63 mmol) was added to a solution of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzylamino (500 mg, of 1.76 mmol) in CH2CL2(18 ml). The mixture was stirred at K.T. within 1 hour, and thereto was again added methylchloroform (0,151 ml, 1.97 mmol). The mixture was stirred at K.T. within 1 hour, and thereto was added CH2CL2(30 ml). The resulting mixture was washed with aqueous saturated NH4Cl (2×), aqueous 10% To2CO3(1×) and saturated brine (1×). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure to give crude methyl ester [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]carbamino acid. This crude product was dissolved in THF (18 ml). The solution was cooled to 0°C., and to it carefully portions was added LiAlH4(200 mg, at 5.27 mmol). The mixture was allowed to warm to K.T., and mixed it with K.T. during the night. The mixture was poured into aqueous saturated potassium tartrate sodium (50 ml)and the mixture was stirred at K.T. within 2 hours. The mixture was extracted with the aid of the d Et 2O (3×). The combined organic extracts were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure to give crude [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]methylamine. This crude product was dissolved in CH2CL2(18 ml). To the solution was added DIPEA (to 0.900 ml of 5.26 mmol), then Vos2On (1,15 g, at 5.27 mmol). The mixture was stirred at K.T. during the night, and to it was added CH2CL2(50 ml). The mixture is washed with aqueous 1 M HCl, water, saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 50:50) gave a mixture (to 0.900 g) specified in the title compound, Boc2O andtert-butyl ester of [3-(tert-butyldimethylsilyloxy)benzyl]methylcarbamate acid. This crude mixture, which is specified in the header connection had 439 mg (83%), used without purification. LC-MS: tR= 1,10 min; ES+: 344,13.

tert-Butyl ester (4-chloro-3-hydroxymethylene)methylcarbamate acid

TBAF (1 M in THF, 2.25 ml, 2.25 mmol) was added to a solution oftertbutyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]methylcarbamate acid (450 mg, 1.13 mmol) in THF (11 ml) at 0°C. the Mixture was stirred t the value of 1 hour, while it was heated to K.T. EtOAc (50 ml) was added, and the mixture was washed with aqueous saturated NH4Cl (2×) and saturated brine (1×). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 40:60) gave specified in the title compound (110 mg, 34%). LC-MS: tR= 0,91 min; ES+: 271,10.

tert-Butyl ester (4-chloro-3-formylmethyl)methylcarbamate acid

MnO2(372 mg, of 3.85 mmol) was added to a solution oftert-butyl ester (4-chloro-3-hydroxymethylene)methylcarbamate acid (110 mg, 0,385 mmol) in CH3JV (7,70 ml). The mixture was stirred at K.T. within 4.5 hours, and it was again added to MnO2(186 mg, of 1.93 mmol). The mixture was stirred for 1 hour, and the mixture was filtered through celite. The precipitate was washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure. Drying the residue under high vacuum gave crude specified in the title compound (95 mg, 87%), which is then used without purification. LC-MS: tR= 0,99 minutes

tert-Butyl ester (4-chloro-3-cyclopropanecarbonyl)methylcarbamate acid

The mixture oftert-butyl ester (4-chloro-3-formylmethyl)methylcarbamate acid (95 mg, 0,335 mmol) and cyclopropylamine (0.036 ml, 0.50 mmol) in Meon (3,30ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and to it was added by portions NaBH4(19 mg, 0.50 mmol). The mixture was stirred for 1 hour, and the solvent was removed under reduced pressure. The resulting oil was diluted with EtOAc (20 ml)and this mixture is washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2CL2/Meon 90:10) gave specified in the title compound (81 mg, 75%). LC-MS: tR= 0,73 min; ES+: 366,20.

N-{2-[3-(tert-Butyldimethylsilyloxy)-4-chlorophenyl]ethyl}-3,3,3-triptocaine

TBTU (2,09 g of 6.50 mmol) was added to a solution of 2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl] - ethylamine (1.30 grams, to 4.33 mmol), 3,3,3-triptocaine acid (0,574 ml, 6.5 mmol) and DIPEA (2,97 ml, 17.3 mmol) in CH2Cl2(43 ml). The mixture was stirred for 1 hour, and thereto was added CH2Cl2. The mixture is washed with aqueous saturated NH4Cl, water 10% Na2CO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 60:40) gave specified in the title compound (500 mg, 28%). LC-MS: tR= 1,12 min; ES+: 410,14.

N-[2-(4-Chloro-3-hydroxymethylene)ethyl]-3,3,3-trip acrophonic

TBAF (1 M in THF, 2,46 ml of 2.46 mmol) was added to a solution of N-{2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}-3,3,3-triptocaine (500 mg, 1,22 mmol) in THF (15,8 ml) at 0°C. the Mixture was stirred for 1 hour at 0°C, and added to her water saturated NH4Cl. The mixture was extracted with EtOAc (3×). The combined organic extracts were washed with water (4H), dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 19:1) gave specified in the title compound (230 mg, 64%). LC-MS: tR= 0,79 minutes

N-[2-(4-Chloro-3-formylphenyl)ethyl]-3,3,3-triptocaine

NMO (318 mg, 2.28 mmol) was added to a solution of N-[2-(4-Chloro-3-hydroxymethylene)ethyl]-3,3,3-triptocaine (225 mg, 0,761 mmol) in CH2Cl2(16 ml). The mixture was stirred for 30 minutes, and thereto was added perruthenate of tetrapropylammonium (26,7 mg, 0,076 mmol). The mixture was stirred for 1 hour at K.T. and filtered through celite. The filtrate was evaporated under reduced pressure. Purification of the crude product by FC (CH2CL2/MeOH 19:1) gave specified in the title compound (180 mg, 81%). LC-MS: tR= 0,88 min; ES+: 335,28.

N-[2-(4-Chloro-3-cyclopropylmethyl)ethyl]-3,3,3-triptocaine

A mixture of N-[2-(4-chloro-3-formylphenyl)ethyl]-3,3,3-triptocaine (175 mg, 0,596 mmol), Et3N (0,125 ml, 0.89 mmol) and cyclopropylamine (0,063 ml, 0.90 mmol) in Meon (2.00 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and to it was added by portions NaBH4(of 56.4 mg, 1,49 mmol). The mixture was stirred for 1 hour and was added aqueous saturated Panso3. The mixture was extracted with EtOAc several times, and the combined organic extracts were washed with saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 95:5) gave specified in the title compound (130 mg, 65%). LC-MS: tR= 0,65 min; ES+: 335,12.

{2-[3-(tert-Butyldimethylsilyloxy)-4-chlorophenyl]ethyl}ethylamine

A mixture of 2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl] - ethylamine (1,05 g, 3.50 mmol) and acetaldehyde (1,19 ml, or 21.0 mmol) in Meon (35 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and portions were added NaBH4(198 mg, the 5.25 mmol). The mixture was stirred at K.T. within 1 hour, and the solvent was removed under reduced pressure. The resulting oil was diluted with EtOAc, and the mixture washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. The sight of the TKA crude product by FC (CH 2CL2/Meon 19:1 → 9:1) gave specified in the title compound (320 mg, 28%). LC-MS: tRor = 0.90 min; ES+: 369,22.

tert-Butyl ether {2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}ethylcarbamate acid

A mixture of {2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl} - ethylamine (320 mg, 0,976 mmol), DIPEA (0,501 ml of 2.93 mmol) and Vos2On (320 mg, about 1.47 mmol) in CH2CL2(10 ml) was stirred at K.T. within 2 hours. Added CH2CL2(30 ml)and the mixture is washed with aqueous 1 M Hcl, water, saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 20:80) gave specified in the title compound (298 mg, 71%). LC-MS: tR= 1,25 min; ES+: 428,19.

tert-Butyl ether [2-(4-chloro-3-hydroxymethylene)ethyl]ethylcarbamate acid

TBAF (1 M in THF, 1.39 ml of 1.39 mmol) was added to a solution oftert-butyl ether {2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}ethylcarbamate acid (298 mg, 0,696 mmol) in THF (6,82 ml) at 0°C. the Mixture was stirred for 1 hour, while it was heated to K.T. EtOAc was added and the mixture washed with aqueous saturated NH4Cl and saturated salt solution. The organic layer was dried over MgSO4 , was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2CL2/MeOH 19:1) gave specified in the title compound (110 mg, 50%). LC-MS: tR= 0,97 min; ES+: 314,11.

tert-Butyl ether [2-(4-chloro-3-formylphenyl)ethyl]ethylcarbamate acid

NMO (133 mg, 0,956 mmol) was added to a solution oftert-butyl ether [2-(4-chloro-3-hydroxymethylene)ethyl]ethylcarbamate acid (110 mg, 0,319 mmol) in CH2Cl2(7.0 ml). The mixture was stirred for 30 minutes, and thereto was added perruthenate of tetrapropylammonium (11.2 mg, to 0.032 mmol). The mixture was stirred for 1 hour and filtered through celite. The filtrate was evaporated under reduced pressure. Purification of the crude product by FC (CH2CL2/MeOH 49:1) gave specified in the title compound (80 mg, 80%). LC-MS: tR= 1,07 minutes

tert-Butyl ether [2-(4-chloro-3-cyclopropylmethyl)ethyl]ethylcarbamate acid

The mixture oftert-butyl ether [2-(4-chloro-3-formylphenyl)ethyl]ethylcarbamate acid (80,1 mg, 0,257 mmol), Et3N (0,054 ml, 0,386 mmol) and cyclopropylamine (0,027 ml, 0,386 mmol) in Meon (0,86 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and to it was added by portions NaBH4(and 24.2 mg, 0,642 mmol). The mixture was stirred for 1 hour, and thereto dobavlyayutsya saturated NaHCO 3. The mixture was extracted with EtOAc several times, and the combined organic extracts were washed with saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2CL2/MeOH 95:5) gave specified in the title compound (40 mg, 44%). LC-MS: tR= 0,81 min; ES+: 353,22.

N-{2-[3-(tert-Butyldimethylsilyloxy)-4-chlorophenyl]ethyl}ndimethylacetamide

AcCl (0,063 ml, 0.88 mmol) was added to a solution of 2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl] - ethylamine (252 mg, 0,840 mmol) and DIPEA (0,575 ml, to 3.36 mmol) in CH2Cl2(8,4 ml). The mixture was stirred at K.T. within 30 minutes, and thereto was added aqueous saturated NH4Cl. The layers were separated, and the organic layer washed with aqueous 1 M NaOH, dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2Cl2/MeOH 19:1) gave specified in the title compound (190 g, 66%). LC-MS: tR= 1,09 min; ES+: 342,19.

N-[2-(4-Chloro-3-hydroxymethylene)ethyl]ndimethylacetamide

TBAF (1 M in THF, of 1.12 ml, 1.12 mmol) was added to a solution of N-{2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}ndimethylacetamide (190 mg, 0,555 mmol) in THF (7,10 ml) at 0°C. the Mixture was stirred for 1 hour, while it was heated to K.T. Aqueous saturated NH Cl was added, and the mixture was extracted with EtOAc (3×). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2CL2/MeOH 19:1) gave specified in the title compound (100 mg, 79%). LC-MS: tR= 0,67 min; ES+: 284,11.

N-[2-(4-Chloro-3-formylphenyl)ethyl]ndimethylacetamide

NMO (184 mg, of 1.32 mmol) was added to a solution of N-[2-(4-chloro-3-hydroxymethylene)ethyl]ndimethylacetamide (100 mg, 0,439 mmol) in CH2Cl2(which 9.22 ml). The mixture was stirred for 30 minutes, and thereto was added perruthenate of tetrapropylammonium (15,5 mg, 0,044 mmol). The mixture was stirred for 1 hour at K.T. and filtered through celite. The filtrate was evaporated under reduced pressure. Purification of the crude product by FC (CH2CL2/MeOH 49:1) gave specified in the title compound (50 mg, 50%). LC-MS: tR= 0,75 min; ES+: 267,10.

N-[2-(4-Chloro-3-cyclopropylmethyl)ethyl]ndimethylacetamide

A mixture of N-[2-(4-chloro-3-formylphenyl)ethyl]ndimethylacetamide (50,1 mg, 0,222 mmol), Et3N (0,046 ml of 0.332 mmol) and cyclopropylamine (0,023 ml of 0.332 mmol) in Meon (0,50 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and to it was added by portions NaBH4(21,0 mg, 0,554 mmol). The mixture was stirred for 1 hour and was added aqueous saturated NaHCO3. The mixture was extracted with EtOAc several the AZ, and the combined organic extracts were washed with saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 95:5) gave specified in the title compound (35 mg, 59%). LC-MS: tR= 0,59 min; ES+: 267,17.

tert-Butyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]-(2-foradil)carbamino acid

A mixture of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzaldehyde (1.50 g, at 5.27 mmol), DIPEA (1.80 ml, 10.5 mmol) and hydrochloride of 2-foretelling (873 mg, of 7.90 mmol) in Meon (53 ml) was heated at boiling under reflux for 4 hours. The reaction mixture was allowed to cool to K.T. and gently portions was added NaBH4(300 mg, to $ 7.91 mmol). The mixture was stirred for 1 hour, and the solvent was removed under reduced pressure. To the residue was added EtOAc (100 ml)and the mixture is washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure to give crude [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]-(2-foradil)amine. This crude product was dissolved in CH2CL2(70 ml). To the solution was added DIPEA (2,70 ml, 15.8 mmol), then Vos2(1.70 g, to $ 7.91 mmol). The mixture is PE is amasyali when K.T. within 1 hour. The mixture was diluted with CH2CL2(50 ml) and washed with aqueous 1 M HCl, water, saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 10:90) gave specified in the title compound (1.92 g, 85%). LC-MS: tR= 1,22 min; ES+: 417,17.

tert-Butyl ester (4-chloro-3-hydroxymethylene)-(2-foradil)carbamino acid

TBAF (1 M in THF, 8,84 ml, 8,84 mmol) was added to a solution oftertbutyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]-(2-foradil)carbamino acid (1,91 g, was 4.42 mmol) in THF (44,2 ml) at 0°C. the Mixture was stirred for 1 hour, while it was heated to K.T. was Added EtOAc (100 ml)and the resulting mixture was washed with aqueous saturated NH4Cl (2×) and saturated brine (1×). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 30:70) gave specified in the header connection (901 mg, 64%). LC-MS: tR= 0,64 min; ES+: 318,07.

tert-Butyl ester (4-chloro-3-formylmethyl)-(2-foradil)carbamino acid

MnO2(1.22 g, 12.6 mmol) was added to a solution oftert-butyl ester (4-chloro-3-hydroxymethylene who yl)-(2-foradil)carbamino acid (801 mg, 2,52 mmol) in CH3JV (50 ml). The mixture was stirred at K.T. within 4.5 hours, and it was again added to MnO2(1.22 g, 12.6 mmol). The mixture was stirred for 1 hour and filtered through celite. The precipitate was washed with CH3CN and CH2Cl2. The filtrate was evaporated under reduced pressure. Drying the residue under high vacuum gave crude specified in the title compound (800 mg, quantitative yield), which is then used without purification. LC-MS: tR= 1,01 minutes

tert-Butyl ester (4-chloro-3-cyclopropanecarbonyl)-(2-foradil)carbamino acid

The mixture oftert-butyl ester (4-chloro-3-formylmethyl)-(2-foradil)carbamino acid (850 mg, 2,69 mmol) and cyclopropylamine (0,290 ml of 4.05 mmol) in Meon (27 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and to it was added by portions NaBH4(153 mg, 4.40 mmol). The mixture was stirred for 1 hour. The solvents were removed under reduced pressure and to the residue was added EtOAc. The resulting mixture was washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2Cl2/MeOH 95:5) gave specified in the title compound (845 mg, 88%). LC-MS: tR= 0,76 min; ES+: 35,19.

tert-Butyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]ethylcarbamate acid

Acetaldehyde (2.4 ml, 42 mmol) was added to a solution of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzylamino (2.00 g, 7,00 mmol) in Meon (70 ml). The mixture was heated at the boil under reflux for 4 hours, and she was allowed to cool to K.T. To the mixture carefully portions was added NaBH4(397 mg, 10.5 mmol) for 1 hour. The solvents were removed under reduced pressure. The residue was diluted with EtOAc (100 ml)and the resulting mixture was washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure to give crude [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]ethylamine (of 3.07 g). This crude product was dissolved in CH2CL2(70 ml). To this solution was added DIPEA (of 3.60 ml, or 21.0 mmol), then Vos2About (to 2.29 g, 10.5 mmol). The mixture was stirred at K.T. within 2 hours. The mixture was diluted with CH2CL2(30 ml) and washed with aqueous 1 M HCl, water, saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 5:95) gave specified in the header is VCE compound (850 mg, 29%). LC-MS: tR= 1,23 min; ES+: 414,23.

tert-Butyl ester (4-chloro-3-hydroxymethylene)ethylcarbamate acid

TBAF (1 M in THF, 3,03 ml, 3.03 mmol) was added dropwise to a solution oftertbutyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]ethylcarbamate acid (628 mg, of 1.52 mmol) in THF (14.9 ml) at 0°C. the Mixture was stirred for 1 hour, while it was heated to K.T. was Added EtOAc, and the mixture is washed with aqueous saturated NH4Cl and saturated salt solution). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (Meon/CH2Cl219:1) gave specified in the title compound (300 mg, 66%). LC-MS: tR= 0,98 min; ES+: 300,28.

tert-Butyl ester (4-chloro-3-formylmethyl)ethylcarbamate acid

MnO2(475 mg, to 4.92 mmol) was added to a solution oftert-butyl ester (4-chloro-3-hydroxymethylene)ethylcarbamate acid (295 mg, 0,984 mmol) in CH3SP (20 ml). The mixture was stirred at K.T. within 5 hours, and it was again added to MnO2(475 mg, 0,984 mmol). The mixture was stirred for 1 hour, and the mixture was filtered through celite and washed with CH3CN and CH2Cl2. Evaporation of the solvents under reduced pressure gave crude specified in the header connection 240 mg, 82%), which is then used without purification. LC-MS: tR= 1,02 minutes

tert-Butyl ester (4-chloro-3-cyclopropanecarbonyl)ethylcarbamate acid

The mixture oftert-butyl ester (4-chloro-3-formylmethyl)ethylcarbamate acid (240 mg, 0,806 mmol), cyclopropylamine (of 0.085 ml, 1.2 mmol) and Et3N (0,169 ml of 1.21 mmol) in Meon (2.7 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and to it was added NaBH4(76,2 mg, a 2.01 mmol). The mixture was stirred for 1 hour at K.T., and to it was added aqueous saturated NaHCO3. The mixture was extracted several times with EtOAc. The combined organic extracts were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (Meon/CH2Cl21:49) gave specified in the title compound (125 mg, 46%). LC-MS: tR= 0,78 min; ES+: 380,20.

tert-Butyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]cyclopropylamino acid

A mixture of 3-(tert-butyldimethylsilyloxy)-4-chlorobenzaldehyde (1.73 g, the 6.06 mmol) and cyclopropylamine (of 0.64 ml, 9.1 mmol) in Meon (60 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and portions were added NaBH4(344 mg, 9.09 mmol). With the ect was stirred, and to it was added water (20 ml). The solvents were partially removed under reduced pressure. The resulting aqueous suspension was diluted with water (50 ml) and was extracted with EtOAc. The organic extracts washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure to give crude [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]cyclopropylamine (1.54 g). This crude product was dissolved in CH2CL2(60 ml). To the solution was added DIPEA (3.1 ml, 18 mmol), then Vos2On (1.98 g, 9.09 mmol). The mixture was stirred at K.T. within 2 hours. Added CH2CL2(40 ml)and the mixture is washed with aqueous 1 M HCl, water, saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by FC (heptane →EtOAc/heptane 5:95) gave specified in the title compound (1.54 g, 78%). LC-MS: tR= 1,26 min; ES+: 426,14.

tert-Butyl ester (4-chloro-3-hydroxymethylene)cyclopropylamino acid

Aqueous 1 M NaOH (16 ml) was added to a solution oftertbutyl ester of [3-(tert-butyldimethylsilyloxy)-4-Chlorobenzyl]cyclopropylamino acid (700 mg, of 1.64 mmol) in Meon (32 ml). The mixture was heated the ri boiling under reflux for 2 hours, and allowed it to cool to K.T. Solvents were partially removed under reduced pressure and the resulting aqueous layer was diluted with water (100 ml). The mixture was extracted with Et2O (3×). The combined organic layers were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (Et/heptane 40:60) gave specified in the title compound (550 mg, quantitative yield). LC-MS: tR= 0,98 min; ES+: 312,04.

tert-Butyl ester (4-chloro-3-formylmethyl)cyclopropylamino acid

MnO2(815 mg, 8,44 mmol) was added to a solution oftert-butyl ester (4-chloro-3-hydroxymethylene)cyclopropylamino acid (526 mg, was 1.69 mmol) in CH3JV (34 ml). The mixture was stirred at K.T. for 3 h, filtered through celite and washed with CH3CN and CH2Cl2. Evaporation of the solvents under reduced pressure gave crude specified in the title compound (563 mg, quantitative yield), which is then used without purification. LC-MS: tR= 1,05 min; ES+: 310,04.

tert-Butyl ester (4-chloro-3-cyclopropanecarbonyl)cyclopropylamino acid

The mixture oftert-butyl ester (4-chloro-3-formylmethyl)cyclopropylamino acid (563 mg, 1.82 mmol) and cyclopropylamine (of € 0.195 ml, 2,73 mmol) in Meon (18 ml) load the Wali at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and to it was added by portions NaBH4(103 mg, 2,73 mmol). The mixture was stirred for 1 hour, and the solvent was removed under reduced pressure. The resulting oil was diluted with EtOAc (100 ml)and the resulting mixture was washed with aqueous saturated NaHCO3and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2Cl2/Meon 95:5) gave specified in the title compound (343 mg, 54%). LC-MS: tR= 0,78 min; ES+: 351,39.

tert-Butyl-(2-chloro-5-vinylbenzoate)dimethylsilane

Pd(PPh3)4(173 mg, 0,149 mmol) was added to a solution of (5-bromo-2-chlorobenzoyloxy)tertbutyldimethylsilyl (1,00 g, 2,98 mmol) in dimethoxyethane (30 ml). The mixture was stirred at K.T. for 20 minutes, and thereto were added To a2CO3(411 mg, 2,98 mmol), water (10 ml) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolan (of 0.53 ml, 2,98 mmol). The mixture was quickly heated to boiling under reflux and stirred at the boil under reflux for 2 hours. The mixture was allowed to cool to K.T., and diluted it with Et2O (100 ml). The mixture was washed with water, and the aqueous layer was extracted again with Et2O (3×). The combined organic extracts were dried over MgSO4, filtered, and Rast is oriali was removed under reduced pressure. Purification of the crude product by FC (Et/heptane 5:95) gave specified in the header connection (822 mg, 98%). LC-MS: tR= 1,22 minutes

2-[3-(tert-Butyldimethylsilyloxy)-4-chlorophenyl]ethanol

9-BBN (0.5 M in THF, 34,0 ml of 17.0 mmol) was added dropwise over 30 min to a solution oftert-butyl-(2-chloro-5-vinylbenzoate)dimethylsilane (800 mg, and 2.83 mmol) in THF (28 ml) at 0°C. the Mixture was stirred for 30 min at 0°C and for 4 hours at K.T. Mixture was again cooled to 0°C., and thereto was added dropwise aqueous 1 M NaOH (39,0 ml) and N2About2(33%, and 9.8 ml, 113 mmol). The mixture was stirred for 2 hours, while it was heated to K.T., and was cooled to 0°C. was Carefully added water saturated Na2S2O3(100 ml)and the mixture was allowed to gently heat up when K.T. during the night. The solvents were partially removed under reduced pressure and the aqueous residue was extracted with EtOAc (3×). The combined organic extracts were washed with saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (Et/heptane 40:60) gave specified in the title compound (677 mg, 80%). LC-MS: tR= 1,10 min; ES+: 301,08.

2-[3-(tert-Butyldimethylsilyloxy)-4-chlorophenyl]ethyl ester methanesulfonic acid

It is astory 2-[3-( tert-butyldimethylsilyloxy)-4-chlorophenyl]ethanol (2.00 g, of 6.65 mmol) in CH2CL2(66 ml) at 0°C was added dropwise Et3N (of 1.02 ml, 7,31 mmol) and methanesulfonamide (or 0.57 ml, 7,31 mmol). The reaction mixture was stirred at 0°C for 1 hour and was diluted with CH2CL2(40 ml). The resulting mixture was washed with aqueous saturated NH4Cl (2×). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure to give crude specified in the title compound (2.55 g, quantitative yield), which is then used without purification. LC-MS: tR= 1,13 min; ES+: 379,29.

{2-[3-(tert-Butyldimethylsilyloxy)-4-chlorophenyl]ethyl}cyclopropylamine

Cyclopropylamine (1,14 ml, 16.3 mmol) was added to a solution of 2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl ester methanesulfonic acid (1,76 g and 4.65 mmol) in EtOH (46 ml). The mixture was heated at the boil under reflux for 2 h and again added cyclopropylamine (or 0.57 ml, 8.2 mmol). The mixture was heated at boiling under reflux in the continuation of the night, and she was allowed to cool to K.T. Solvents were removed under reduced pressure, and the residue was purified by means of FC (Et/heptane 50:50 → 7 M NH3/MeOH), getting mentioned in the title compound (865 mg, 68%). LC-MS: tR= 0,92 min; ES+: 340,39.

tert -Butyl ether {2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}cyclopropylamino acid

DIPEA (2,61 ml, the ceiling of 5.60 mmol) and Vos2(1.22 g, the ceiling of 5.60 mmol) was added to a solution of {2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}cyclopropylamine (1.73 g, 5,09 mmol) in CH2Cl2(50 ml). The mixture was stirred at K.T. within 4 hours. The mixture was diluted with CH2Cl2(50 ml), washed with aqueous saturated NaHCO3water saturated NH4Cl and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by FC (Et/heptane 10:90) gave specified in the title compound (2.14 g, 96%). LC-MS: tR= 1,26 minutes

tert-Butyl ether [2-(4-chloro-3-hydroxymethylene)ethyl]cyclopropylamino acid

Aqueous 1 M NaOH (48 ml) was added to a suspension oftert-butyl ether {2-[3-(tert-butyldimethylsilyloxy)-4-chlorophenyl]ethyl}cyclopropylamino acid (2.10 g, 4.77 mmol) in Meon (96 ml). The mixture was heated at the boil under reflux for 90 minutes the Mixture was allowed to cool to K.T., and the solvents were partially removed under reduced pressure. The resulting aqueous mixture was diluted with water (100 ml) and was extracted with Et2O (3×). The combined organic extract is dried over MgSO 4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by FC (Et/heptane 40:60) gave specified in the header connection (1,34 g, 86%). LC-MS: tR= 0,98 min; ES+: 326,30.

tert-Butyl ether [2-(4-chloro-3-formylphenyl)ethyl]cyclopropylamino acid

MnO2(1.97 g, of 20.4 mmol) was added to a solution oftert-butyl ether [2-(4-chloro-3-hydroxymethylene)ethyl]cyclopropylamino acid (1,33 g, 4,08 mmol) in CH3JV (41 ml). The mixture was stirred at K.T. during the night. The mixture was filtered through celite and washed with CH3CN and CH2Cl2. Evaporation of the filtrate under reduced pressure gave crude specified in the header connection (1,32 g, quantitative yield), which is then used without purification. LC-MS: tR= 1,05 minutes

tert-Butyl ether [2-(4-chloro-3-cyclopropylmethyl)ethyl]cyclopropylamino acid

The mixture oftert-butyl ether [2-(4-chloro-3-formylphenyl)ethyl]cyclopropylamino acid (1,32 g, 4,08 mmol) and cyclopropylamine (0,438 ml, 6.1 mmol) in Meon (41 ml) was heated at boiling under reflux for 4 hours. The mixture was allowed to cool to K.T., and to it was added by portions NaBH4(232 mg). The mixture was stirred for 1 hour, and the solvent was removed under reduced pressure. Added EtOAc (100 ml)and the mixture is washed with aqueous saturated NaHCO 3and saturated salt solution. The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2Cl2/Meon 95:5) gave specified in the header connection (883 mg, 59%). LC-MS: tR= 0,82 min; ES+: 365,38.

3,9-Di-tert-butyl ester 6-ethyl ester (rat.)-(1R∗, 5S∗)-7-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (A1)

A mixture of compound F3 (56,0 g, 106 mmol), 2-chloro-3,6-differenoe (34.8 g, 211 mmol), dipiperidide azodicarbonamide acid (53,4 g, 211 mmol) and Rvi3(85%, 83 ml, 317 mmol) in toluene (1,20 l) is heated at boiling under reflux in nitrogen atmosphere for 1 hour. Allow the mixture to cool to K.T. Mixture was diluted with EtOAc (2.00 l), and the mixture is washed with aqueous 1 M NaOH (2×900 ml). The organic extracts dried over MgSO4, filtered, and the solvents removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:19 → 1:1) is specified in the header connection (67,5 g, 94%). LC-MS: tR= 1,24 min; ES+: 617,25.

1'-tert-Butyl ether 3'-methyl ester 6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-5',6'-dihydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (A2)

BuLi (1.6 M in hexane, to 39.3 ml of 45.2 mmol) was added to a solution of 5-bromo-2-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]pyridine (13,0 g, 34.5 mmol) in the GF (700 ml) at -78°C. The mixture was stirred for 1 hour at -78°C., and thereto was added ZnCl2(0,72 M in THF, 78,6 ml of 56.5 mmol). The mixture was allowed to warm to K.T. To the mixture was added 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (WO 2004/002957, 11,0 g, 28.3 mmol) and Pd(PPh3)4(813 mg, 0,704 mmol). The mixture was stirred for 30 min at 70°C, then overnight at K.T. To the mixture was added aqueous saturated NH4Cl, and the mixture was extracted with EtOAc (2×). The organic extracts were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (heptane/EtOAc 9:1 → 5:5) gave specified in the title compound (10.7 g, 70%). LC-MS: tR= 1,16 min; ES+: 537,33.

3,9-Di-tert-butyl ether (rat.)-(1R∗, 5S∗)-7-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}-3,9-diazabicyclo[3.3.1]non-7-ene-3,6,9-tricarboxylic acid (B1)

In a 250 ml round bottom flask equipped with a magnetic stir bar, dissolve the compound A1 (4.72 in) 6,97 mmol) in EtOH (100 ml). To this mixture is added aqueous 1 M NaOH (50 ml)and the resulting colorless solution is heated at 80°C for 14 hours. Received light pink solution allow to cool before K.T., and the solution is carefully acidified to a pH of 1.5. Volatile components are removed under vacuum and the resulting residue partitioned between EtOAc (300 ml) and water (300ml). The aqueous phase is separated and again extracted with EtOAc (3×300 ml). The combined organic extracts are then washed with saturated brine (500 ml), discolor activated charcoal and dried over MgSO4. Filtration through a layer of celite and concentration colorless filtrate in vacuo gives a white foamy substance. Division 3,9-di-tert-butyl ether (rat.)-(1R∗, 5S∗)-7-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid [1.01 g, 22%; Rf = 0.55 and (hexane:EtOAc + 1% Asón)] and specified in the connection header (2,77 g, 61%) can be achieved using FC (SiO2, 2:1 hexane: EtOAc + 1% Asón). Residual Asón can be removed quantitatively first azeotropic distillation with heptane and then with toluene. Rf = 0.50 in (1:1 hexane: EtOAc + 1% Asón); ES = 646,8.

A mixture of the four possible diastereoisomers 3,9-di-tert-butyl ester 7-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}-3,9-diazabicyclo[3.3.1]nonan-3,6,9-tricarboxylic acid (E1)

In a 250 ml round bottom flask, equipped with magnetic stirrer, suspended connection B1 (1,17 g of 1.80 mmol) and Pd/C (10% wt./wt., 1.20 g) in the Meon (100 ml). The resulting suspension toxigenic and then passed through the H2gas for 15 minutes Finally, the reaction mixture is now stirred at K.T. in a static atmosphere of H2regulated by the container. After 2 h the with can be marked quantitative consumption of compound B1. Then the reaction vessel is effectively rinsed with N2and the suspension is filtered through a layer of celite and SiO2. After washing the insoluble substances with copious quantities of CH2CL2and EtOAc, the filtrate was concentrated in vacuo to obtain specified in the title compounds as a mixture of four diastereomers (1,116 g, 95% crude yield, ES- = 648,9). This product is used then without purification.

Di-tert-butyl ether (rat.)-(1R∗, 5∗, 6R∗, 7S∗)-7-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}-6-[cyclopropyl-(2,3-dichlorobenzyl)carbarnoyl]-3,9-diazabicyclo[3.3.1]nonan-3,9-dicarboxylic acid (D2) and di-tert-butyl ether (rat.)-(1R∗, 5∗, 6R∗, 7R∗)-7-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}-6-[cyclopropyl-(2,3-dichlorobenzyl)carbarnoyl]-3,9-diazabicyclo[3.3.1]nonan-3,9-dicarboxylic acid (D1).

In a 100 ml round bottom flask, equipped with magnetic stirrer, mix the compound E1 (905 mg, of 1.39 mmol), cyclopropyl-(2,3-dichlorobenzyl)amine (obtained from 2,3-dichlorobenzaldehyde and cyclopropylamine by reductive amination, 600 mg, 2,78 mmol), HOBt (282 mg, of 2.08 mmol) and DMAP (509 mg, of 4.17 mmol) in DMF (10 ml). Then added EDC.HCl (400 mg, of 2.08 mmol)and the resulting yellow solution stirred at K.T., and the course of the reaction is followed by means of LC-MS. After the reaction was fully completed in 56 hours with 86% conversion, the reaction mixture rasb the keys 150 ml Et 2O and quenched with cold 10% aqueous HCl (150 ml). The organic fraction is separated, and the aqueous fraction is again extracted with Et2O (3×100 ml). The combined organic extracts are successively washed with aqueous 1 M NaOH (100 ml), water (150 ml) and saturated brine (150 ml). Drying over MgSO4, filtration and concentration of the filtrate in vacuo gives a white foamy product. Further purification by the method of column chromatography (SiO2of 1.5:1 hexane: Et2O) gives specified in the header connection (0,8591 g, 73%) as 16:80:4 mixture of diastereomers. 200 mg of the mixture, thus obtained, is then dissolved in a mixture of 10 ml of 95% SN3SP + 4,9% N2O + 0.1% of formic acid. This solution is then injected with 500 µl samples on the HPLC equipped with a Phenomenex Synes 4 MK max RP 80 angstroms 100 × 21,20 mm column. Elution at a speed of 20 ml/min isocratic mixture of 95% SN3SP + 4,9% N2O + 0.1% of formic acid gives two major diastereoisomer:

connection D1: tR= 5,04 min, ES- = 848,1, white foamy substance of 40.0 mg (highlighted with a yield of 20%);

connection D2: tR= 6,64 min, ES- = 848,1, white foamy substance, 140,4 mg (with a yield 70%).

tert-Butyl ether (rat.)-(3R∗, 4S∗)-3-[cyclopropyl-(2,3-dimethylbenzyl)carbarnoyl]-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D3)

A solution of compound E2 (90 mg, 0,17 shall mol), (2,3-dimethylbenzyl)cyclopropylamine (prepared by reductive amination of 2,3-dimethylbenzaldehyde and cyclopropylamine, 90 mg, 0.51 mmol), DMAP (5 mg, 0.04 mmol), DIPEA (amount of 0.118 ml, 0.69 mmol), HOBt (29 mg, 0.21 mmol) and EDC.HCl (49 mg, 0.26 mmol) in CH2CL2(3 ml) was stirred for 18 hours. The mixture was diluted with EtOAc, washed with aqueous 1 M HCl and saturated salt solution. The organic phase was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Specified in the header of the connection has not been further purified. LC-MS: tR= 1,25 min, ES+: = 681,37.

tert-Butyl ether (3R, 4S)-3-{[5-chloro-2-(3-methoxypropyl)benzyl]cyclopropanecarbonyl}-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D4)

A solution of compound E3 (0,052 g, 0.10 mmol), [5-chloro-2-(3-methoxypropyl)benzyl]cyclopropylamine (0,073 g, 0.30 mmol), DMAP (0.003 g, 0.03 mmol), DIPEA (0,068 ml, 0.40 mmol), HOBt (of 0.017 g, 0.13 mmol) and EDC.HCl (0,029 g, 0.15 mmol) in CH2CL2(2 ml) was stirred for 48 hours. The mixture was diluted with EtOAc, washed with aqueous 1 M HCl and saturated salt solution. The organic phase was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Specified in the header of the connection has not been further purified. LC-MS: tR= 1,27 min, ES+: = 761,44.

tert-Butyl ether (3R, 4S)-3-{[2-chloro-5-(2-methoxyethyl)benzyl]CEC is propellerblades}-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D5)

A mixture of compound 3 (200 mg, 0,383 mmol), [2-chloro-5-(2-methoxyethyl)benzyl]cyclopropylamine (120 mg, 0,473 mmol), HOBt (64,7 mg, 0,479 mmol), DMAP (11.7 mg, 0,096 mmol), DIPEA (0,262 ml, 1.53 mmol) and EDC.HCl (110 mg, 0,574 mmol) in CH2CL2(4 ml) was stirred for 48 h at K.T. Mixture was filtered through an Isolute®, pre-washed with aqueous 1 M HCl. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification by FC (EtOAc) gave specified in the title compound (280 mg, 98%). LC-MS: tR= 1,26 min, ES+: = 747,54.

tert-Butyl ether (rat.)-(3R∗, 4S∗)-3'-{[2-chloro-5-(3-methoxypropyl)benzyl]cyclopropanecarbonyl}-6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-3',4',5',6'-tetrahydro-2 N-[3,4']bipyridinyl-1'-carboxylic acid (D6)

A mixture of compound E4 (1,00 g, 1,90 mmol), [5-chloro-2-(3-methoxypropyl)benzyl]cyclopropylamine (531 mg, of 2.09 mmol), DIPEA (1,30 ml, to 7.61 mmol), DMAP (58,1 mg, 0,476 mmol), HOBt (321 mg, of 2.38 mmol) and EDC.HCl (547 mg, of 2.86 mmol) in CH2CL2(4 ml) was stirred for 4 days at K.T. EDC.HCl (100 mg, 0,506 mmol) was added again and the mixture was stirred for 24 hours. Added CH2CL2and the mixture is washed with aqueous 1 M HCl (1×), water (1×) and saturated brine (1×). The organic layer was dried over MgSO4was filtered and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2CL2/sub> → SN2CL2/Meon 97:3) gave specified in the header connection (1,14 g, 79%). LC-MS: tR= 1,26 min, ES+: = 762,50.

tert-Butyl ether (rat.)-(3R∗, 4S∗)-3'-{[2-chloro-5-(2-methoxyethyl)benzyl]cyclopropanecarbonyl}-6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-3',4',5',6'-tetrahydro-2 N-[3,4']bipyridinyl-1'-carboxylic acid (D7)

A mixture of compound E4 (1,00 g, 1,90 mmol), [5-chloro-2-(3-methoxyethyl)benzyl]cyclopropylamine (533 mg, of 2.09 mmol), DIPEA (1,30 ml, to 7.61 mmol), DMAP (58,1 mg, 0,476 mmol), HOBt (321 mg, of 2.38 mmol) and EDC.HCl (547 mg, of 2.86 mmol) in CH2CL2(4 ml) was stirred for 5 days at K.T. EDC.HCl (100 mg, 0,506 mmol) was added again and the mixture was stirred for 24 hours. Added CH2CL2and the mixture is washed with aqueous 1 M HCl (1×), water (1×) and saturated brine (1×). The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (CH2CL2→ SN2CL2/Meon 97:3) gave specified in the title compound (1.12 g, 79%). LC-MS: tR= 1,24 min, ES+: = 746,16.

tert-Butyl ether (3R, 4S)-3-[(5-{[tert-butoxycarbonyl-(2,2-dottorati)amino]methyl}-2-Chlorobenzyl)cyclopropanecarbonyl]-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D8)

Received, following the General conditions And, from compound E3, andtert-butyl ether (4 the PRS-3-cyclopropanecarbonyl)-(2,2-dottorati)carbamino acid. LC-MS: tR= 1,28 min, ES+: = 880,26.

tert-Butyl ether (3R, 4S)-3-({2-chloro-5-[(3,3,3-triphosphopyridine)methyl]benzyl}cyclopropanecarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D9)

Received, following the General conditions And, from compound E3 and N-(4-chloro-3-cyclopropanecarbonyl)-3,3,3-triptocaine. LC-MS: tR= 1,21 min, ES+: = 828,20.

tert-Butyl ether (3R, 4S)-3-({5-[(tert-butoxycarbonylmethylene)methyl]-2-Chlorobenzyl}cyclopropanecarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D10)

Received, following the General conditions And, from compound E3, andtert-butyl ester (4-chloro-3-cyclopropanecarbonyl)cyclopropylmethanol acid. LC-MS: tR= 1,31 min, ES+: = 872,31.

tert-Butyl ether (3R, 4S)-3-{[5-(acetamidomethyl)-2-Chlorobenzyl]cyclopropanecarbonyl}-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D11)

Received, following the General conditions And, from compound E3 and N-(4-chloro-3-cyclopropanecarbonyl)ndimethylacetamide. LC-MS: tR= 1,19 min, ES+: = 758,22.

tert-Butyl ether (3R, 4S)-3-({5-[2-(tert-butoxycarbonylmethylene)ethyl]-2-Chlorobenzyl}cyclopropanecarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D12)

was Received, following the General terms And, from compound E3, andtert-butyl ether [2-(4-chloro-3-cyclopropylmethyl)ethyl]methylcarbamate acid. LC-MS: tR= 1,29 min, ES+: = 844,33.

tert-Butyl ether (3R, 4S)-3-({5-[(tert-butoxycarbonylmethylene)methyl]-2-Chlorobenzyl}cyclopropanecarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D13)

Received, following the General conditions And, from compound E3, andtert-butyl ester (4-chloro-3-cyclopropanecarbonyl)methylcarbamate acid. LC-MS: tR= 1,28 min, ES+: = 832,31.

tert-Butyl ether (3R, 4S)-3-({2-chloro-5-[2-(3,3,3-triphosphopyridine)ethyl]benzyl}cyclopropanecarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D14)

Received, following the General conditions And, from compound E3 and N-[2-(4-chloro-3-cyclopropylmethyl)ethyl]-3,3,3-triptocaine. LC-MS: tR= 1,22 min, ES+: = 840,25.

tert-Butyl ether (3R, 4S)-3-({5-[2-(tert-butoxycarbonylamino)ethyl]-2-Chlorobenzyl}cyclopropanecarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D15)

Received, following the General conditions And, from compound E3, andtert-butyl ether [2-(4-chloro-3-cyclopropylmethyl)ethyl]ethylcarbamate acid. LC-MS: tR= 1,30 minutes

tert-B is tilby ether (3R, 4S)-3-{[5-(2-acetylamino)-2-Chlorobenzyl]cyclopropanecarbonyl}-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D16)

Received, following the General conditions And, from compound E3 and N-[2-(4-chloro-3-cyclopropylmethyl)ethyl]ndimethylacetamide. LC-MS: tR= 1,22 min, ES+: = 774,29.

tert-Butyl ether (3R, 4S)-3-[(5-{[tert-butoxycarbonyl-(2-foradil)amino]methyl}-2-Chlorobenzyl)cyclopropanecarbonyl]-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D17)

Received, following the General conditions And, from compound E3, andtert-butyl ester (4-chloro-3-cyclopropanecarbonyl)-(2-foradil)carbamino acid. LC-MS: tR= 1,28 min, ES+: = 864,27.

tert-Butyl ether (3R, 4S)-3-({5-[(tert-butoxycarbonylamino)methyl]-2-Chlorobenzyl}cyclopropanecarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D18)

Received, following the General conditions of connection E3 andtert-butyl ester (4-chloro-3-cyclopropanecarbonyl)ethylcarbamate acid. LC-MS: tR= 1,30 min, ES+: = 846,32.

tert-Butyl ether (3R, 4S)-3-({5-[(tert-butoxycarbonylamino)methyl]-2-Chlorobenzyl}cyclopropanecarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D19)

Received following General conditions is, from compound E3, andtert-butyl ester (4-chloro-3-cyclopropanecarbonyl)cyclopropylamino acid. LC-MS: tR= 1,31 min, ES+: = 856,37.

tert-Butyl ether (3R, 4S)-3-({5-[2-(tert-butoxycarbonylamino)ethyl]-2-Chlorobenzyl}cyclopropanecarbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylic acid (D20)

Received, following the General conditions of connection E3 andtert-butyl ether [2-(4-chloro-3-cyclopropylmethyl)ethyl]cyclopropylamino acid. LC-MS: tR= 1,31 min, ES+: = 872,35.

1-tert-Butyl ether (rat.)-(3R∗, 4S∗)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid (E2)

To a solution of compound L2 (0.15 g, 0.27 mmol) in Meon (1 ml) was added aqueous 1 M NaOH (1 ml). The mixture was stirred at 70°C for 2 hours. Was added water, and the mixture was extracted with EtOAc. The organic phase was washed with saturated saline solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. The crude residue was purified on Pade silica gel, getting mentioned in the title compound (93 mg, 65%). LC-MS: tR= 1,12 min, ES+: = 524,24.

1-tert-Butyl ether (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid (E3)

Compound E2 (4,46 g, 8.5 mmol) was separated using preparative the Yu HPLC, equipped with a chiral column, described herein above. Used isocratic eluent consisting of 97% hexane, 3% ethanol and 0.1% THF. Got mentioned in the title compound (1.35 g, 30%). Analytical chiral HPLC (eluent, identical preparative): tR= 29,00 minutes

1'-tert-Butyl ether (rat.)-(3R∗, 4S∗)-6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (E4)

The mixture of compounds L4 (4,92 g, 9,12 mmol) in aqueous 1 M NaOH (75 ml) and Meon (75 ml) was stirred at 70°C for 4.5 hours. Was added aqueous 1 M HCl up until the pH reached 4. The mixture was extracted with EtOAc (3×). The combined organic extracts were washed with saturated salt solution, dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum gave crude specified in the header connection (4,63 g, 97%), which is then used without purification. LC-MS: tR= 1,08 min, ES+: = 525,40.

1-tert-Butyl ester 3-methyl ester 4-{4-[2-(tert-butyldimethylsilyloxy)ethoxy]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (F1)

To a solution of 4-[2-(tert-butyldimethylsilyloxy)ethoxy]bromine benzol (WO 03/093267, of 7.95 g, 24 mmol) in THF (200 ml) at -78°C. was added BuLi (1.6 M in hexane, 17,12 ml, a 27.4 mmol). The solution was stirred at -78°C for 30 min then added ZnCl 2(1 M in THF, 30 ml, 30 mmol). The resulting solution was allowed to cool to K.T., and to it was added 1-tert-butyl ester 3-methyl ester 4-tripterocalyx-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (WO 2004/002957, 7,79 g, 20 mmol) in THF (20 ml) and Pd(PPh3)4(0,69 g to 0.60 mmol). The reaction mixture was heated at 50°C for 1 hour and was stirred 16 h at K.T. Mixture was cooled to 0°C. and to it was added aqueous saturated NH4Cl. Added EtOAc, and the organic phase was washed with saturated saline solution, dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 2:8 → 1:0) gave specified in the title compound (8.1 g, 82%). LC-MS: tR= 1,23 min, ES+: = 506,47.

3-tert-Butyl ester 6-ethyl ester (rat.)-(1R∗, 5S∗)-7-{4-[3-(tert-butyldimethylsilyloxy)propyl]phenyl}-9-methyl-3,9-diazabicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid (F2)

A solution of [3-(4-bromophenyl)propoxy]tertbutyldimethylsilyl (102,1 g, 310 mmol) in THF (1.50 l) under nitrogen atmosphere cooled to -78°C. Add BuLi (1.5 M in hexane, 212 ml, 318 mmol). After 30 minutes add ZnCl2(1 M in THF, 465 ml, 465 mmol). Mixture was allowed to warm to K.T. To it was added 3-tert-butyl ester 6-ethyl ester (rat.)-(1R∗, 5S∗)-9-methyl-7-tripterocalyx-3,9-diazabicyclo[3.3.1]non-6-ene-3,6-dicarboxylic KIS is the notes (of 83.6 g, 155 mmol) in THF (100 ml) and then Pd(PPh3)4(4,48 g, a 3.87 mmol). The mixture is heated at the boil under reflux for 30 min, and allow it to cool to K.T. Mixture is diluted with EtOAc and washed with aqueous 1 M NaOH (1×). The organic extracts dried over MgSO4, filtered, and the solvents removed under reduced pressure. Purification of the residue by FC (Meon/CH2Cl21:49 → 1:24 → 3:47 → 2:23) gives the specified header connection (88,6 g, virtually quantitative yield). LC-MS: tR= 0,98 min, ES+: = 559,24.

3,9-Di-tert-butyl ester 6-ethyl ester (rat.)-(1R∗, 5S∗)-7-[4-(3-hydroxypropyl)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid (F3)

Compound F2 (32,0 g of 57.3 mmol) dissolved in dry 1,2-dichloroethane (590 ml). To this solution was added NaHCO3(48,2 g, 573 mmol) and 1-chloroethylphosphonic (62.5 ml, 573 mmol), and the suspension is heated at 80°C. After 3 h the reaction mixture was allowed to cool to K.T. the Mixture is filtered, and the filtrate evaporated under reduced pressure. The residue is dried for 15 minutes in a high vacuum. The product is diluted with Meon (400 ml), and the mixture is heated at 50°C for 20 minutes the Reaction mixture was allowed to cool to K.T., and the solvents removed under reduced pressure. The yellow solid is dried in high vacuum for 1 hour. The solid is dissolved in CH2CL2 (190 ml)and the solution cooled to 0°C. Add DIPEA (49,1 ml, 287 mmol) and Vos2On (37,5 g, 172 mmol). The mixture is stirred overnight while it heats up K.T., the Reaction mixture was diluted with CH2CL2(110 ml). The organic layer was washed with aqueous 1 M Hcl (2×300 ml) and aqueous saturated NaHCO3(300 ml). The organic layer is dried over MgSO4, filtered, and the solvents removed under reduced pressure. Purification of the residue by FC (CH2Cl2/Meon 100:0 → 2:98 → 5:95) gives the specified header connection (26,2 g, 86%). LC-MS: tR= 1,05 min, ES+: = 531,33.

1-tert-Butyl ester 4-{4-[3-(tert-butyldimethylsilyloxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (G1)

1-tert-Butyl ester 3-methyl ester 4-{4-[3-(tert-butyldimethylsilyloxy)propyl]phenyl}-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid (WO 2004/002957, 17.1 g of 35.0 mmol) dissolved in a mixture of DMSO (300 ml) and THF (100 ml). Add aqueous NaOH (1 M, 70 ml) and 2 M, 50 ml). The mixture is heated at 50°C for 7 h, then cooled to 0°C. and add water (100 ml). the pH was adjusted to 2 by addition of aqueous HCl (1 M, 100 ml)and the reaction mixture extracted with EtOAc (2×250 ml). The combined organic layers dried over MgSO4, filtered, and the solvents removed under reduced pressure. Light brown oil is dried in a high vacuum (18 g). LC-MS: tR/sub> = 0,86 min, [M+H]+: = 362,05.

This crude compound (17,98 g) dissolved in DMF (300 ml) followed by addition of imidazole (6,84 g of 97.7 mmol) and TBDMS-Cl (11.1 g, 73.8 mmol). The mixture was stirred at K.T. within 14 hours. Add saturated aqueous NH4Cl (250 ml) and water (250 ml)and the mixture extracted with Et2O (2×250 ml). The combined organic layers dried over MgSO4, filtered, and the solvent is evaporated under reduced pressure. The residue is dissolved in THF (300 ml) and add Meon (125 ml), water (125 ml) and K2CO3(3.00 g). The mixture was stirred at K.T. within 10 minutes Add saturated aqueous NH4Cl (250 ml) and water (25 ml)and the mixture is extracted with Et (2×250 ml). The combined organic layers dried over MgSO4, filtered, and the solvent is evaporated under reduced pressure. Purification of the residue by means of FC (hexane/EtOAc = 4/1-1/1) gives specified in the title compound (5.1 g, 32%). LC-MS: tR= 1,16 min; ES+: = 476,35.

tert-Butyl ester 4-{4-[3-(tert-butyldimethylsilyloxy)propyl]phenyl}-3-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbarnoyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid (N1)

Connection G1 (2 g, is 4.21 mmol) dissolved in CH2CL2(30 ml), and to the solution was added (1-chloro-2-methylpropenyl)dimethylamine (618 mg, 4,63 mmol). The mixture was stirred at K.T. for 5 min, and added to it cyclopropyl(3-methods the si-2-methylbenzyl)amine (obtained by reductive amination of 3-methoxy-2-methylbenzaldehyde, omins, D. L.; Brown, J. D.,J. Org. Chem., 1989,54, 3730, and cyclopropylamine, 844 mg, was 4.42 mmol) and DIPEA (815 mg, 6,32 mmol). The mixture was stirred at K.T. for 15 min, diluted with CH2CL2(100 ml) and extracted with aqueous 10% citric acid (100 ml). The aqueous layer was washed with CH2CL2(50 ml). The combined organic layers dried over MgSO4, filtered, and the solvent is evaporated under reduced pressure. Purification of the crude product by FC (CH2CL2/Meon 19/1) gives specified in the header connection (3,36 g, quantitative yield). LC-MS: tR= 1,28 min; ES+: = 649,42.

tert-Butyl ester 4-{4-[3-(tert-butyldimethylsilyloxy)propyl]phenyl}-3-[cyclopropyl-(2,3-dimethylbenzyl)carbarnoyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid (H2)

Following the procedure for compound N1, but using cyclopropyl-(2,3-dimethylbenzyl)amine (obtained by reductive amination of 2,3-dimethylbenzaldehyde and cyclopropylamine) instead of cyclopropyl-(3-methoxy-2-methylbenzyl)amine, compound H2 (2,84 g, quantitative yield) was obtained from G1 (2.00 g). LC-MS: tR= 1,30 min; ES+: = 633,45.

tert-Butyl ester 4-{4-[3-(tert-butyldimethylsilyloxy)propyl]phenyl}-3-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbarnoyl]piperidine-1-carboxylic acid (J1)

Pd/C (10%; 340 mg) suspended in the atmosphere of nitrogen in tOH (25 ml). Add a solution of compound H1 (3,36 g, 5,19 mmol) in EtOH (25 ml). The mixture was kept in an atmosphere of H2(3 bar) for 3 h, filtered through celite and concentrated in vacuo. The residue is dried in high vacuum, giving specified in the title compound (2.20 g, 65%), which is then used without purification. LC-MS: tR= 1,31 min; ES+: = 651,46.

tert-Butyl ester 4-{4-[3-(tert-butyldimethylsilyloxy)propyl]phenyl}-3-[cyclopropyl-(2,3-dimethylbenzyl)carbarnoyl]piperidine-1-carboxylic acid (J2)

Following the method for connecting J1 receive specified in the header connection (2,42 g, 85%) of compound H2 (2,84 g, 4,47 mmol). LC-MS: tR= 1,32 min; ES+: = 635,47.

tert-Butyl ester 3-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbarnoyl]-4-[4-(3-hydroxypropyl)phenyl]piperidine-1-carboxylic acid (J3)

Connection J1 (2.20 g, to 3.38 mmol) dissolved in THF (50 ml) followed by addition of TBAF (1,21 g of 3.84 mmol). The reaction mixture was stirred at K.T. for 2.5 h, diluted with EtOAc (250 ml) and washed with water (200 ml). The organic layer is dried over MgSO4, filtered and concentrated in vacuo. Purification of the residue by means of FC (hexane/EtOAc 1/1) gives the specified header connection (0,91 g, 50%). LC-MS: tR= 1,07 min; ES+: = 537,37.

tert-Butyl ester 3-[cyclopropyl-(2,3-dimethylbenzyl)carbarnoyl]-4-[4-(3-hydroxypropyl)phenyl]piperid the n-1-carboxylic acid (J4)

Following the method for connecting J3, get mentioned in the title compound (0,91 g, 46%) from compound J2 (2,42 g). LC-MS: tR= 1,08 min; ES+: = 521,36.

1-tert-Butyl ester 3-methyl ester 4-{4-[2-(tert-butyldimethylsilyloxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid (K1)

Mg (1.40 g, 58 mmol) was added to a solution of compound F1 (8,10 g, 17 mmol) in Meon (40 ml) in an atmosphere of Ar. The mixture was stirred for 1 hour while the temperature was maintained below 30°C. was Added dropwise aqueous 1 M Hcl (115 ml, 115 mmol)and the mixture was stirred for 1 hour. This mixture was extracted with EtOAc (2×). The combined organic layers were washed with water, saturated salt solution, dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 2:1) gave 2:3TRANS/CISthe mixture specified in the title compound (7.6 g, 93%). LC-MS: tR= 1,23 min; ES+: = 508,47.

1-tert-Butyl ester 3-methyl ester 4-[4-(2-(hydroxyethoxy)phenyl]piperidine-1,3-dicarboxylic acid (K2)

To a solution of compound K1 (7,60 g of 15.4 mmol) in THF (150 ml) at 0°C and in an atmosphere of Ar was added TBAF (a 4.86 g of 15.4 mmol). After stirring the mixture for 1 hour was added aqueous saturated NH4Cl (100 ml)and the reaction mixture was extracted with EtOAc (2×). The organic layer was washed with water, feast upon the authorized saline, dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 2:1 → 1:0) gave specified in the header of the connection (of 5.06 g, 87%). LC-MS: tR= 0,91 min; ES+: = 380,30.

1-tert-Butyl ester 3-methyl ester 4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid (L1)

A mixture of compound K2 (5.50 g, 15 mmol), 2,6-dichloro-p-cresol (is 3.08 g, 18 mmol), dipiperidide azodicarboxylic acid (7,31 g, 29 mmol) and Rvi3(14 ml, 58 mmol) in toluene (150 ml) was heated at 50°C for 16 hours. The mixture was allowed to cool to K.T., filtered, and the precipitate was washed with toluene. The filtrate was diluted with EtOAc, washed with water (2×) and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the crude product by FC (EtOAc/heptane 0:1 → 1:9 → 2:8) gave specified in the title compound as a colourless oil (7,3 g, 90%). LC-MS: tR= 1,18 min; ES+: = 538,34.

1-tert-Butyl ester 3-methyl ester (rat.)-(3R∗, 4S∗)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1,3-dicarboxylic acid (L2)

To a solution of compound L1 (0.21 g, 0.38 mmol) in Meon (2 ml) in an atmosphere of Ar was added NaOMe (6 mg, 0.11 mmol). The mixture was stirred for 3 days at 70°C. was Added water, and the mixture was extracted with EtOAc. the content of inorganic fillers phase was washed with saturated saline solution, dried over MgSO4was filtered and the solvents were removed under reduced pressure. Specified in the title compound (150 mg, 72%) not further purified. LC-MS: tR= 1,18 min; ES+: = 538,32.

The mixture of all possible stereoisomers of 1'-tert-butyl ether 3'-methyl ester 6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (L3)

Compound A2 (7,00 g, 13,0 mmol) was dissolved in Meon (130 ml). To this solution was slowly added Mg (500 mg, of 20.6 mmol). The mixture was stirred for 1 hour, and thereto was again added Mg (608 mg, 25,0 mmol). The mixture was stirred 3 hours. Was slowly added aqueous 1 M Hcl, and the mixture was stirred for 1 hour at K.T. Solvents evaporated under reduced pressure, and the mixture was extracted with EtOAc. The organic extracts were dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Drying under high vacuum gave crude specified in the header connection (4,92 mg, 70%). LC-MS: tR= 1,16 min; ES+: = 539,43.

1'-tert-Butyl ether 3'-methyl ether (rat.)-(3R∗, 4S∗)-6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridinyl-1',3'-dicarboxylic acid (L4)

A mixture of compound L3 (5,40 g, 10.0 mmol) and MeONa (540 mg, 10.0 mmol) in Meon (250 ml) was stirred overnight at 70°C. MeONa (54 mg, 1.00 mmol) was added again and the mixture was stirred during the s 5 h at 70°C. MeONa (54 mg, 1.00 mmol) was added again and the mixture was stirred overnight at 70°C. Water 1 M Hcl was added to establish a pH of 6-7. The solvents are evaporated under reduced pressure, and the mixture was extracted with EtOAc. The combined organic extracts were washed with water and saturated salt solution. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 8:2 with 1% Et3N) gave specified in the header connection (4,92 g, 91%). LC-MS: tR= 1,16 min; ES+: = 539,43.

Example 1

Cyclopropyl-(2,3-dichlorobenzyl)amide (rat.)-(1R∗, 5∗, 6R∗, 7R∗)-7-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}-3,9-diazabicyclo[3.3.1]nonan-6-carboxylic acid

A 25 ml round bottom flask equipped with a magnetic stir bar, dissolve the compound D1 (31 mg, 0,037 mmol) in CH2CL2(1 ml). At 0°C is added dropwise 4 M Hcl (dioxane, 0,36 ml)and the resulting solution heated under K.T. within 2 hours, and then stirred at K.T. over the next 8 hours. Volatile components are removed under vacuum and the resulting residue partitioned between CH2CL2(10 ml) and aqueous 1 M NaOH (10 ml). The organic layer is separated and the aqueous rinse again extracted with CH2CL2(3×10 ml). The combined organic extracts washed with saturated brine (10 ml), su is at over MgSO 4, filtered, and the filtrate was concentrated in vacuo. Thus obtained product is then purified column chromatography (SiO2, 95:5 CH2Cl2:2 M NH3in the Meon), highlighting specified in the title compound (15.2 mg, 63%). tR= 2,0 min Agilent Bond RX-C18 of 4.6 × 150 mm HPLC column (isocratic mixture of 49.8% CH3SP + 49.9% OF N2O + 0,1% formic acid); ES+: = 648,1.

Example 2

Cyclopropyl-(2,3-dichlorobenzyl)amide (rat.)-(1R∗, 5∗, 6R∗, 7S∗)-7-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}-3,9-diazabicyclo[3.3.1]nonan-6-carboxylic acid

A 25 ml round bottom flask equipped with a magnetic stir bar, dissolve the compound D2 (54 mg, 0,064 mmol) in CH2CL2(1 ml). At 0°C is added dropwise 4 M Hcl (dioxane, to 0.47 ml)and the resulting solution heated under K.T. within 2 hours, and then stirred at K.T. over the next 8 hours. Volatile components are removed under vacuum and the resulting residue partitioned between CH2CL2(10 ml) and aqueous 1 M NaOH (10 ml). The organic layer is separated, and the aqueous rinse again extracted with CH2CL2(3×10 ml). The combined organic extracts washed with saturated brine (10 ml), dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude product is then purified column chromatography (SiO2, 95:5 CH2Cl2:2 M NH3in M IS HE), getting listed in the title compound (36,1 mg, 87%). tR= 3,1 min Agilent Bond RX-C18 of 4.6 × 150 mm HPLC column (isocratic mixture of 49.8% CH3SP + 49.9% OF N2O + 0,1% formic acid); ES+: 648,1.

Example 3

Cyclopropyl(3-methoxy-2-methylbenzyl)amide 4-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}piperidine-3-carboxylic acid

Specified in the header connection get the General procedure described above from compound J3 and 2-chloro-3,6-differenoe. LC-MS: tR= 0,99 min; ES+: 583,23.

Example 4

Cyclopropyl(3-methoxy-2-methylbenzyl)amide 4-{4-[3-(2,6-dichloro-4-methylphenoxy)propyl]phenyl}piperidine-3-carboxylic acid

Specified in the header connection get the General procedure described above from compound J3 and 2,6-dichloro-p-cresol. LC-MS: tR= 1,02 min; ES+: 595,43.

Example 5

Cyclopropyl(3-methoxy-2-methylbenzyl)amide 4-{4-[3-(2,3,6-tryptophanate)propyl]phenyl}piperidine-3-carboxylic acid

Specified in the header connection get the General procedure described above from compound J3 and 2,3,6-tryptophanol. LC-MS: tR= 0,98 min; ES+: 567,48.

Example 6

Cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}piperidine-3-carboxylic acid

Specified in the header connection get the General procedure described above from compound J4 and 2-chloro-3-differenoe. LC-MS: tR= 1,00 min; ES+: 567,26.

Example 7

Cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2,6-dichloro-4-methylphenoxy)propyl]phenyl}piperidine-3-carboxylic acid

Specified in the header connection get the General procedure described above from compound J4 and 2,6-dichloro-p-cresol. LC-MS: tR= 1,04 min; ES+: 579,44.

Example 8

Cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2-chloro-6-fluoro-3-methylphenoxy)propyl]phenyl}piperidine-3-carboxylic acid

Specified in the header connection get the General procedure described above from compound J4 and 2-chloro-6-fluoro-3-METHYLPHENOL. LC-MS: tR= 1,04 min; ES+: 563,47.

Example 9

Cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2,3,6-tryptophanate)propyl]phenyl}piperidine-3-carboxylic acid

Specified in the header connection get the General procedure described above from compound J4 and 2,3,6-tryptophanol. LC-MS: tR= 1,00 min; ES+: 551,48.

Example 10

Cyclopropyl(2,3-dimethylbenzyl)amide (rat.)-(3R∗, 4S∗)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Compound D3 (0,068 g, 0.10 mmol) was dissolved in CH2CL2(1 ml)and the solution was cooled to 0°C. was Added 4 M Hcl in dioxane (1 ml)and the reaction mixture was stirred for 1 hour at K.T. Solvents evaporated under reduced pressure. Cleaning ostad is using HPLC gave specified in the title compound (37 mg, 63%). LC-MS: tR= 0,95 min; ES+: 581,44.

Example 11

[2-Chloro-5-(3-methoxypropyl)benzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Compound D4 (0,076 g, 0.10 mmol) was dissolved in CH2CL2(1 ml)and the solution was cooled to 0°C. was Added 4 M Hcl in dioxane (1 ml)and the reaction mixture was stirred for 1 hour at K.T. Solvents evaporated under reduced pressure. Purification of the residue by HPLC gave specified in the title compound (44 mg, 67%). LC-MS: tR= 0,99 min; ES+: 661,41.

Example 12

[2-Chloro-5-(2-methoxyethyl)benzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Compound D5 (279 mg, the 0.375 mmol) was dissolved in CH2CL2(3 ml). This solution was cooled to 0°C., and thereto was added Hcl (4 M in dioxane, and 1.00 ml). The mixture was stirred at 0°C for 1 hour. Again was added Hcl (4 M in dioxane, and 1.00 ml)and the mixture was stirred at K.T. within 2 hours. Again was added Hcl (4 M in dioxane, and 1.00 ml)and the mixture was stirred at K.T. within 3 hours. Aqueous 1 M NaOH was added until, until the mixture became slightly alkaline. The mixture was filtered through an Isolute®. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by means of FC (MeOH/CH2Cl2 1:19) gave specified in the title compound (120 mg, 50%). LC-MS: tR= 0,96 min; ES+: 645,49.

Example 13

[2-Chloro-5-(3-methoxypropyl)benzyl]cyclopropylamine (3R, 4S)-6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-1',2',3',4',5',6'-hexahydro[3,4']bipyridinyl-3'-carboxylic acid

A solution of compound D6 (1,14 g, 1.50 mmol) in CH2CL2(4,13 ml) was cooled to 0°C., and thereto was added Hcl (4 M in dioxane, 3,75 ml). The mixture was stirred at K.T. within 3 hours, and the solvents were removed under reduced pressure. Added CH2CL2and the mixture is washed with aqueous 1 M NaOH. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave racemic specified in the title compound (621 mg, 63%). This racemate was separated by HPLC (Regis Whelk, eluent 75% → 30% for 30 min, then isocratic mixture). Got mentioned in the title compound (167 mg, 27%). LC-MS: tR= 0,95 min; ES+: 684,49. Chiral HPLC column: tR= 17,0 minutes

Example 14

[2-Chloro-5-(2-methoxyethyl)benzyl]cyclopropylamine (3R, 4S)-6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-1',2',3',4',5',6'-hexahydro[3,4']bipyridinyl-3'-carboxylic acid

A solution of compound D7 (1.12 g, 1.50 mmol) in CH2CL2(4,13 ml) was cooled to 0°C., and thereto was added Hcl (4 M in dioxane, 3,75 ml). The mixture was stirred at K.T. during the course the e 3 h, and the solvents were removed under reduced pressure. Added CH2CL2and the mixture is washed with aqueous 1 M NaOH. The organic layer was dried over MgSO4, was filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave racemic specified in the title compound (392 mg, 40%). This racemate was separated by HPLC (Regis Whelk, eluent 75% → 30% for 30 min, then isocratic mixture). Got mentioned in the title compound (167 mg, 27%). LC-MS: tR= 0,94 min; ES+: 646,50. Chiral HPLC column: tR= 17,4 minutes

Example 15

{2-Chloro-5-[(2,2-diferentiating)methyl]benzyl}cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D8 has been specified in the header connection (17,8 mg, 26% two steps). LC-MS: tR= 0,83 min; ES+: 682,21.

Example 16

{2-Chloro-5-[(3,3,3-triphosphopyridine)methyl]benzyl}cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D9 has been specified in the title compound (30.0 mg, 42% of the two stages). LC-MS: tR= 0,95 min; ES+: 727,81.

Example 17

{2-Chloro-5-[(cyclopropylamino)methyl]benzyl}cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}PIP is ridin-3-carboxylic acid

Following the General conditions of connection D10 has been specified in the header connection (20,3 mg, 30% two steps). LC-MS: tR= 0,84 min; ES+: 672,30.

Example 18

[5-(acetamidomethyl)-2-Chlorobenzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D11 got mentioned in the title compound (30 mg, 46% of the two stages). LC-MS: tR= 0,91 min; ES+: 658,25.

Example 19

[2-Chloro-5-(2-methylaminomethyl)benzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D12 has been specified in the header connection (to 34.3 mg, 53% of the two stages). LC-MS: tR= 0,82 min; ES+: 646,25.

Example 20

(2-Chloro-5-methylaminoethanol)cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D13 has been specified in the header connection (24,1 mg, 38% two steps). LC-MS: tR= 0,81 min; ES+: 630,26.

Example 21

{2-Chloro-5-[2-(3,3,3-triphosphopyridine)ethyl]benzyl}cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D14 has been specified in the header of the compounds is their (30.0 mg, 40% two steps). LC-MS: tR= 0,96 min; ES+: 742,24.

Example 22

[2-Chloro-5-(2-ethylaminomethyl)benzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D15 got mentioned in the title compound (11.8 mg, 18% two steps). LC-MS: tR= 0,83 min; ES+: 660,28.

Example 23

[5-(2-acetylamino)-2-Chlorobenzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D16 got mentioned in the title compound (11.8 mg, 18% two steps). LC-MS: tR= 0,93 min; ES+: 672,27.

Example 24

{2-Chloro-5-[(2-foretelling)methyl]benzyl}cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D17 got mentioned in the title compound (21.2 mg, 32% two steps). LC-MS: tR= 0,82 min; ES+: 682,21.

Example 25

(2-Chloro-5-ethylaminomethyl)cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D18 has been specified in the header of the connection (of 38.7 mg, 60% in two stages). LC-MS: tR= 0,81 min; ES+: 644,20.

Example 26

(2-Chloro-5-cyclopropyl aminomethylbenzoic)cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D19 has been specified in the header connection (41,1 mg, 63% of the two stages). LC-MS: tR= 0,81 min; ES+: 656,24.

Example 27

[2-Chloro-5-(2-cyclopropylamino)benzyl]cyclopropylamine (3R, 4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid

Following the General conditions of connection D20 has been specified in the header of the connection (of 45.7 mg, 68% of the two stages). LC-MS: tR= 0,82 min; ES+: 670,24.

Biological tests

1. Enzyme-linked immunosorbent assay (EA) to assess AngI accumulation and inhibition of renin

1.1. Preparation AngI-BSA conjugate

1.3 mg (1 mmol) AngI [1-10 (Bachem, H-1680)] and 17 mg (0.26 mmol) of BSA (Fluka, 05475) was dissolved in 4 ml of 0.1 M phosphate buffer, pH 7.4, and then was added dropwise 2 ml of glutaraldehyde in N2About when diluted 1:100 (Sigma G-5882). The mixture is incubated over night at 4°C, then deliberately on the background of 2 liters of 0.9% NaCl, twice for 4 hours at K.T., followed by dialysis against the background of 2 liters of 1X PBS overnight at K.T. Solution is then filtered through Syringe filter, 0.45 µm (Nalgene, Cat. No. 194-2545). The conjugate can be stored in plastic tubes in 0.05% sodium azide at 4°C for at least 12 months.

1.2. Preparation of materials coated with BSA-AngI

Microtiter plates (MRT, MaxiSorp™, Nunc) were incubated over night at 4°C With 80 ál of AngI (1-10)/BSA conjugate, diluted 1:100,000 in PBS IX, in a Teflon beaker (the exact dilution depending on the load of the conjugate), drained, filled 90 µl of blocking solution [0.5% of BSA (Sigma A-2153) in 1X PBS, 0.02% of NaN3], were incubated for at least 2 hours at K.T., or over night at 4°C. 96-well MTP (MaxiSorp™, Nunc) were coated with 200 µl conjugate and blocked with 250 μl of blocking solution, above, except that the blocking solution contained 3% BSA. The tablets can be stored in the blocking solution at 4°C for 1 month.

1.3. AngI-EIA in 384-well MTP

Materials covered with AngI (1-10)/BSA, washed 3 times proryvnym buffer (1X PBS, 0.01% tween-20) and was filled with 75 μl of a solution of primary antibody (anti-AngI anticavity, pre-diluted 1:10 in serum of horses), diluted to a final concentration of 1:100,000 in estimated buffer (1X PBS, 1 mM EDTA, 0,1% BSA, pH 7,4). 5 ál of the mixture from the interaction of renin (or standards in the evaluation buffer) (see below) was added to a solution of primary antibody and the plates were incubated overnight at 4°C. After incubation the tablets were washed 3 times proryvnym buffer and incubated with secondary antibody [anti-rabbit IgG linked to horseradish peroxidase (Amersham Bioscience, NA 934V), rasb the run of 1:2000 in the washing buffer] for 2 h at K.T. The tablets were washed 3 times proryvnym buffer and then incubated for 1 hour at K.T. with substrate solution [1,89 mM ABTS (2,2'-Azino-di(3-ethylbenzthiazolinesulfonic))] (Roche Diagnostics, 102 946) and 2.36-mm H2About2[30%, (Fluka, 95300)] in substrate buffer (0.1 M sodium acetate, 0.05 M sodium dihydrophosphate, pH 4.2). OD tablet was read at 405 nm using a reader for microplates (FLUOStar Optima from BMG). Education AngI during the interaction of renin quantitatively determined by comparing the OD of the sample with a standard curve OD AngI(1-10), measured in parallel.

2. Analysis of primary inhibition of renin: IC50in the buffer hole 384 MTP

Analysis of renin was adapted from the analysis, as described previously (W. Fischliet al., Hypertension, 1991, 18:22-31), and consists of two stages: the first stage, recombinant human renin incubated with its substrate (commercial human tetradecapeptide rezinovy substrate) to form the product of angiotensin I (AngI). In the second stage accumulated AngI measured by immunoassay (enzyme-linked immunosorbent assay, EIA). A detailed description of this analysis is below. EIA is a very sensitive and well suited for the measurement of renin activity in the buffer or in plasma. Due to the low concentration of renin used in this analysis (2 fmol on the analyzed provincail 10 PM), it is possible to measure the affinity of the inhibitors in this initial test lower PM concentration.

2.1 Methodology

Recombinant human renin (3 PG/ml) in the evaluation buffer (1X PBS, 1 mM EDTA, 0,1% BSA, pH 7,4), human tetradecapeptide (1-14) substrate (Bachem, M-1120) [5 μm in 10 mm HCl], hydroxyanisole (Fluka, 55100) [30 mm in H2On] and the estimated buffer was pre-mixed at 4°C in the ratio of 100:30:10:145. of 47.5 μl per well of pre-prepared mixture was transferred into a polypropylene plates (MTR, Nunc). Test compounds were dissolved and diluted in 100% DMSO and 2.5 μl was added to the previously prepared mixture, and then incubated at 37°C for 3 hours. At the end of the incubation period, 5 ál content innovage interaction (or standards in the evaluation buffer) was transferred into EIA tests (as described above) and quantitatively determined AngI produced by renin. The percentage of inhibition of renin (decrease AngI) was calculated for each concentration of the compound and determine the concentration of inhibiting renin, which inhibited enzyme activity by 50% (IC50). The compounds of formula (I) have the IC50values from 0.1 nm to 300 nm, especially from 1 nm to 30 nm.

Examples of inhibition:

Compound of example No.IC50[The m] Compound of example No.IC50[nm]
10,65160,23
20,19210,50
100,31240,38
130,17

1. A compound selected from the group consisting of amides piperidinecarboxylic acid of the formula (I)

in which W represents a phenyl loop or six-membered, dibenzothiophenes aromatic cycle containing one nitrogen atom, where these cycles are substituted in paraprotein through V;
V is a bond, -A-(CH2)s- or-A-(CH2)v-B-;
A and b independently represent-O-;
U is a mono-, di-, tri - or Tetra-substituted aryl, where the substituents independently selected from the group consisting of halogen, alkyl, and-CF3;
Q represents methylene;
M represents an aryl group, where this group may be the long is the super mono - or disubstituted by substituents, independently selected from the group consisting of alkyl; alkoxy; -CF3; halogen; alkyl-O-(CH2)0-4-CH2and R'2N-(CH2)0-4-CH2-where R' is independently selected from the group consisting of hydrogen, alkyl (optionally substituted by one, two or three fluorine atoms), cyclopropyl, cyclopropylmethyl, -C(=O)-R", where R" means1-C4-alkyl or-CH2-CF3;
R1is cycloalkyl;
n represents the integer 0 or 1;
s is an integer 3;
v represents an integer 2;
and the substituents in the cycle, -CON(R1)-Q-M-W-V-U, are in TRANS-position is obtained to each other, if n represents the integer 1, and where the configuration at positions 3 and 4 piperidinol cycle of the formula (I) represent the 3R and 4R, respectively, if n represents the integer 0;
and optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric of the racemates, mixtures of diastereomeric racemates and Metformin, as well as salts of such compounds.

2. The compound according to claim 1, in which M represents an aryl group, where the group may be optionally mono - or disubstituted by substituents independently selected from the group consisting of alkyl; alkoxy; -CF3; halogen; alkyl-O-(CH2)0-4 -CH2and R'2N-(CH2)0-4-CH2-where R' is independently selected from the group consisting of hydrogen, alkyl, cyclopropyl, and-C(=O)O-R", where R" means1-C4-alkyl or-CH2-CF3; or a salt of such compounds.

3. The compound according to claim 1, in which M represents the following radical:

where R2means methyl or chlorine, R3means hydrogen and R4means hydrogen, -CH2CH2-O-CH3, -CH2CH2CH2-O-CH3or R NH-(CH2)0-1-CH2-, where R' is-CH2-CHF2, -CH2-CF3cyclopropyl, -CO-CH3, -CO-CH2-CF3or-CO-CH2-CH3provided that when R4means hydrogen, R3represents methyl, methoxy, chlorine;
or a salt of such compounds.

4. The compound according to any one of claims 1 to 3, in which W represents a phenyl, substituted for V in paraprotein, or the following radicals:

or a salt of such compounds.

5. The compound according to any one of claims 1 to 3, in which V represents-CH2CH2CH2O-, where in both cases the bivalent radical is joined to the group U of formula (I) through an oxygen atom, or-OCH2CH2O-; or its salt.

6. The compound according to any one of claims 1 to 3, in which U represents sobelman-, di - or tizamidine phenyl, where the substituents independently selected from the group consisting of halogen, alkyl, alkoxy, and-CF3; or its salt.

7. The compound according to any one of claims 1 to 3, in which R' represents cyclopropyl or its salt.

8. The compound according to claim 1, selected from the group including:
cyclopropyl(2,3-dichlorobenzyl)amide of (1R*,5S*,6R*,7S*)-7-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}-3,9-diaza-bicyclo[3.3.1]nonan-6-carboxylic acid,
cyclopropyl(3-methoxy-2-methylbenzyl)amide 4-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}piperidine-3-carboxylic acid,
cyclopropyl(3-methoxy-2-methylbenzyl)amide 4-{4-[3-(2,6-dichloro-4-methylphenoxy)propyl]phenyl}piperidine-3-carboxylic acid,
cyclopropyl(3-methoxy-2-methylbenzyl)amide 4-{4-[3-(2,3,6-tryptophanate)propyl]phenyl}piperidine-3-carboxylic acid,
cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2-chloro-3,6-divergence)propyl]phenyl}piperidine-3-carboxylic acid,
cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2,6-dichloro-4-methylphenoxy)propyl]phenyl}piperidine-3-carboxylic acid,
cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2-chloro-6-fluoro-3-methylphenoxy)propyl]phenyl}piperidine-3-carboxylic acid, and
cyclopropyl(2,3-dimethylbenzyl)amide 4-{4-[3-(2,3,6-tryptophanate)propyl]phenyl}piperidine-3-carboxylic acid,
or its salt.

9. The compound according to claim 1, selected from the group including:
cyclopropyl(2,3-DIMET Ventil)amide(3R*,4S*)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
[2-chloro-5-(3-methoxypropyl)benzyl]cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
[2-chloro-5-(2-methoxyethyl)benzyl]cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
[2-chloro-5-(3-methoxypropyl)benzyl]cyclopropylamine(3R,4S)-6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-1',2',3',4',5',6'-hexahydro[3,4']bipyridinyl-3'-carboxylic acid, and
[2-chloro-5-(2-methoxyethyl)benzyl]cyclopropylamine(3R,4S)-6-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-1',2',3',4',5',6'-hexahydro[3,4']bipyridinyl-3'-carboxylic acid, or its salt.

10. The compound according to claim 1, selected from the group including:
{2-chloro-5-[(2,2-diferentiating)methyl]benzyl}cyclopropylamine (3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl)piperidine-3-carboxylic acid,
{2-chloro-5-[(3,3,3-triphosphopyridine)methyl]benzyl}cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
{2-chloro-5-[(cyclopropylamino)methyl]benzyl}cyclopropylamine (3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
[5-(acetamidomethyl)-2-Chlorobenzyl]cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
[2-chloro-5-(2-methylaminomethyl)benzyl]cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
(2 is the PR-5-methylaminoethanol)cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
{2-chloro-5-[2-(3,3,3-triphosphopyridine)ethyl]benzyl}cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
[2-chloro-5-(2-ethylaminomethyl)benzyl]cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
[5-(2-acetylamino)-2-Chlorobenzyl]cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
{2-chloro-5-[(2-foretelling)methyl]benzyl}cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
(2-chloro-5-ethylaminomethyl)cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid,
(2-chloro-5-cyclopropanecarbonyl)cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid, and
[2-chloro-5-(2-cyclopropylamino)benzyl]cyclopropylamine(3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-3-carboxylic acid, or its salt.

11. Pharmaceutical composition, which has activity ones renin inhibitors containing the compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt and pharmaceutically acceptable product in the form of media.

12. The compound according to claims 1-10, or its pharmaceutically acceptable salt, or a composition according to claim 11 for use as l is drug money, which has the active ones of renin inhibitors.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described is a compound selected from formulae , , , , and , where X1 denotes CH; X2-X5 each independently denotes CH or C-, where -C represents the point where group B is bonded and where one of X2-X5 denotes -C; X7-X10 each independently denotes CH or CR2; X18-X21 each independently denotes CH or CR5; X22 and X23 each independently denotes CH or CR12, where at least one of X22 and X23 denotes CR12; X24 denotes CH; B denotes CH2 or C=O; B1 denotes CH; Y denotes oxygen or sulphur; Z denotes O; m equals 2; R denotes hydrogen or R denotes each indendently (C1-C6)alkyl, (C3-C8)cycloalkyl, halogen, imidazolyl substituted with (C1-C6)alkyl and/or an oxo group or OR9; R9 denotes hydrogen, (C1-C6)alkyl which is unsubstituted or substituted with once or several times with fluorine, or (C4-C8)cycloalkylalkyl; R12 denotes a (C1-C6)alkoxy group which is substituted once or several times with fluorine, unsubstituted thiazolyl, thiazolyl which is substituted with (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyranyl, tetrahydropyranyl or tetrahydropyranyloxy, and pharmaceutically acceptable salts of the said compounds. Described also are pharmaceutical compositions containing the said compounds.

EFFECT: invention relates to ligands of nicotinic acetylcholine receptors (nAChR), activation of nAChRs and treatment of diseases associated with defective or with functional disorders of nicotinic acetylcholine receptors, especially in the brain.

69 cl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.

EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes with general formula: The method involves reacting aliphatic aldehyde (acetic, propionic, butyric, valerianic, caproic) saturated with hydrogen sulphide with 1,2-diaminoethane in molar ratio diamine:aldehyde:hydrogen sulphide equal to 1:3:2, at 0°C for 3 hours. 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3.2.1]octanes can be used as selective sorbents and extraction agents of precious metals, as antibacterial, antiviral, fungicidal and acaricidal agents.

EFFECT: stereoselective synthesis of one conformationally pure 2,4-cis-8-anti-trialkyl-3-thia-1,5-diazabicyclo[3,2,1]octane isomer; the method is also distinguished by simplicity of carrying experiments and availability of initial reagents.

1 cl, 1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there described are diazabicyclic aryl derivatives of general formula I , their enantiomers or any mixture of those enantiomers, or their pharmaceutically acceptable salts, where radical values A, L, B and n are given in the description, and pharmaceutical composition containing the above diazabicyclic aryl derivatives.

EFFECT: new compounds represent cholinergic ligands of nicotinic receptors of acetylcholine and modulators of receptors and carrying agents of monoamines, and can be used for treatment of diseases and illnesses related to cholinergic system of central nervous system and periphery nervous system, which are related to activity of muscles, endocrine diseases, inflammatory diseases, and neurodegenerative diseases.

12 cl, 2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I), where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: invention claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: chemistry.

SUBSTANCE: description is given of new diazabicyclic aryl derivatives, with general formula I: its enantiomers, or mixture of enantiomers, or its adjoining pharmaceutical salt, where X and Y independently represent CR2, CR3 or N, where R2 is hydrogen, C1-6alkyl or halogen; and R3 is hydrogen or halogen; and R1 is hydrogen or halogen, CF3, NO2 or phenyl, possibly substituted, group with formula phenyl-Z-(C1-6alkyl)m-, phenyl -C≡C- or pyridyl -Z-(C1-6alkyl)m-, where m equals 0 or 1; Z - O or S, where phenyl and pyridyl are possibly substituted, or R1 and R3 , together with carbon atoms to which they are bonded, form a benzocondensed aromatic carbocyclic ring, which can be substituted. The new compounds are cholinergic ligands of nicotinic acetylcholine receptors.

EFFECT: compounds can be useful for treating such diseases or disorders related to the cholinergic system of the central nervous system, peripheral nervous system etc.

11 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, tautomers, or N-oxides, for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases. In formula (Ia) X stands for group R1-A-NR4; A stands for link, C=O, or NRg(C=O, where R8 stands for hydrogen or C1-3 alkyl; Y stands for link or alkylene chain, made of 1, 2 or 3 atoms of carbon; R1 stands for carbocyclic or heterocyclic group, containing from 3 to 12 circular units; or saturated C1-8hydrocarbyl group, optionally substituted with one or more substituents selected from halogen (for instance, fluorine), hydroxygroups, C1.4alkoxygroups, and carbocyclic or heterocyclic groups, and where 1 or 2 atoms of hydrocarbyl group carbon may be optionally substituted with atom or group selected from O, S, NH, SO, SO2; R2 stands for hydrogen or methyl; R3 is selected from hydrogen and carbocyclic or heterocyclic groups, containing from 3 to 6 circular units; and R4 stands for hydrogen or methyl. Specified carbocyclic and heterocyclic groups are determined in formula of invention and may be optionally substituted with groups specified in invention formula. Objects of invention are also a pharmaceutical composition based on proposed compounds, their application to produce medicinal agents and methods of their application.

EFFECT: production of pharmaceutical composition based on proposed compounds for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases.

48 cl, 6 tbl, 254 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazine-2-carboxamide derivatives of general

formula , where R1 denote a 5- or 6-member ring, having a formula given in claim 1, R2 denotes H or C1-C7-alkyl; R3 denotes phenyl, pyridinyl or pyrimidinyl, possibly substituted with the following substitutes: Cl, F or Br; R4 denotes H, CI, F, Br, CF3 or C1-C7-alkyl; R5 denotes C1-C7-alkyl; as well as pharmaceutically acceptable salts thereof. Disclosed compounds are metabotropic glutamate receptor (mGLUR 5) antagonists. The invention also pertains to a medicinal agent based on disclosed compounds.

EFFECT: improved method.

17 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (III): , in which D is a benzene ring, 2-pyridone ring, pyridine ring, benzoxalone ring, benzoxadinone ring or benzimidazole ring; R1 denotes carboxy or hydroxy; R2 independently denotes a halogen atom; alkyl optionally substituted with a halogen atom, aryl or alkylamine; alkynyl, optionally substituted alkoxy; hydroxy; carboxy; alkoxy optionally substituted with phenyl, aromatic heterocyclic ring which denotes a 5-6-member aromatic monocyclic carbocyclic ring containing one or two heteroatoms, independently selected from oxygen and nitrogen atoms; alkylsulphonyl; aryloxy; amino optionally substituted with alkyl; acyl optionally substituted with alkyl or alkyloxy; alkyloxycarbonyl; alkanesulphonyl; arylsulphonyl or alkylcarbamoyl; carbamoyl optionally substituted with alkyl, phenyl, cycloalkyl, acetyl, alkanesulphonyl, heteroarylalkyl, cycloalkylalkyl, heteroaryl which denotes a 5-6-member aromatic monocyclic ring containing one or three heteroatoms independently selected from oxygen and nitrogen atoms, and which is optionally substituted with alkyl or cycloalkyl; acylcyano; nitro, aryl; heteroaryl which denotes a 5-6-member aromatic ring containing one or more heteroatoms independently selected from oxygen, sulphur and nitrogen atoms, and which is optionally substituted with alkyl; alkylsulphonyl; morpholinylsulphonyl; non-aromatic heterocyclic group which denotes a 5-6-member non-aromatic heterocyclic ring containing one or more nitrogen atoms and optionally an oxygen and/or sulphur atom; R3 denotes C1-C6alkyloxy, C1-C6alkylthio; R4 denotes a halogen atom or alkyloxy; R5 denotes alkyl; M denotes sulphonyl; L3 independently denotes alkylene optionally containing one oxygen or nitrogen atom, alkenylene, or -N(R7)-; R7 independently denotes a hydrogen atom, alkyl; Y denotes a single bond or CO; Z denotes CH or N; n equals 0 or 1; p equals 0, 1, or 2; q equals 0 or 1; provided that R1 does not denote carboxy when ring D is a benzene ring, -L3- denotes -(O-alkylene)- and the substitution position of L3 and Y is an ortho-position in ring D; to pharmaceutically acceptable salts thereof. The invention also relates to compounds of formula (IV), a pharmaceutical composition, a method of treating diseases associated with the DP receptor, use of compounds in any of the claims 1-17, as well as compounds of general formula (V).

EFFECT: obtaining novel biologically active compounds having DP receptor antagonist activity.

30 cl, 8 ex, 62 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

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