Alternative methods for synthesis of renin inhibitors and intermediate compounds thereof

FIELD: chemistry.

SUBSTANCE: present invention relates to methods for synthesis of compounds of formula (A), where R1 denotes halogen, C1-C6halogenalkyl, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2 denotes halogen, C1-C4alkyl or C1-C4alkoxy; R3 and R4 independently denote a branched C3-C6alkyl; and R5 denotes C3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanoylamino(C1-C6)alkyl, HO(O)C-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl, or their pharmaceutically acceptable salts which have renin inhibiting activity, as well as to basic intermediate compounds obtained during steps for synthesis of the desired compounds and to methods for synthesis of said intermediate compounds.

EFFECT: alternative synthesis method.

43 cl, 8 dwg, 11 ex

 

The present invention relates to methods of preparation of some derivatives of 2(S),4(S)5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-allochronic or their pharmaceutically acceptable salts. The present invention also relates to novel intermediate compounds used to obtain these compounds.

More derivative 2(S),4(S)5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-allochronic, which is produced by methods of the present invention, are any of these derivatives with inhibitory activity against renin and thus, they can be used in the pharmaceutical industry, for example derivatives described in patent US 5559111.

It has been unexpectedly found that by using as a starting compound pyroglutamic acids, especially L-pyroglutamic acid, formed derivatives of 2(S),4(S)5(S),7(S)-2,7-dialkyl-4-hydroxy-5-amino-8-allochronic high diastereoisomeric and enantiomeric purity.

First of all, the present invention relates to a method for obtaining compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, R2means halogen, C1-C4and the keel or 1-C4alkoxy, R3and R4independently denote a branched C3-C6alkyl, R5means cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanolamine(C1-C6)alkyl, (O)C(C1-C6)alkyl, C1-C6alkyl-O-(O)-(C1-C6)alkyl, H2N-C(O)(C1-C6)alkyl, C1-C6alkyl-HNC(O)(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)(C1-C6)alkyl or their pharmaceutically acceptable salts, and the method includes using as the starting compound L-pyroglutamic acid (sequence of reactions shown in scheme 1A).

Scheme 1A. The method of obtaining the compounds of formula (A) from N - and O-protected 5-hydroxymethyl-3-substituted of isopropylpyrimidine (IV).

The compound (IV) is obtained from L-pyroglutamic acid, using unprotected 5-hydroxymethyl-3-substituted of isopropylpyrimidine (III), as shown in the first stages of the diagrams 1b and 1.

Thus, the present the invention also relates to a method for obtaining compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, R2means halogen, C1-C4alkyl or C1-C4alkoxy, R3and R4independently denote a branched C3-C6alkyl, R5means cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanolamine(C1-C6)alkyl, (O)C(C1-C6)alkyl, C1-C6alkyl-O-(O)C(C1-C6)alkyl, H2N-C(O)(C1-C6)alkyl, C1-C6alkyl-HNC(O)(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)(C1-C6)alkyl or their pharmaceutically acceptable salts, and the method includes using as the starting compound L-pyroglutamic acid (sequence of reactions shown in scheme 1b).

Scheme 1b. The method of obtaining the compounds of formula (A) from L-pyroglutamic acid.

the present invention also relates to a method for obtaining compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkoxy or C1-C6alkoxy(C1-C6)alkyl, R2means halogen, C1-C4alkyl or C1-C4alkoxy, R3and R4independently denote a branched C3-C6alkyl, R5means cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanolamine(C1-C6)alkyl, (O)C(C1-C6)alkyl, C1-C6alkyl-O-(O)C(C1-C6)alkyl, H2N-C(O)-C1-C6alkyl, C1-C6alkyl-HNC(O)(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)(C1-C6)alkyl or their pharmaceutically acceptable salts, and the method includes using as the starting compound L-pyroglutamic acid (sequence of reactions shown in scheme 1).

Scheme 1. The method of obtaining the compounds of formula (A) from L-pyroglutamic acid.

Each of the OI scheme, the substituents have the same values as described for compounds of formula (A) or as described below.

The compounds of formula (III), where R3shall have the meaning given for formula (A), are the primary intermediate compounds of the present invention, in which the carbon atoms in position 5 and 7 in the compound of formula (A) have the desired stereochemical configuration.

All the compounds of formula (III)shown in the diagrams 1b and 1, where R3defined in this context above, is obtained using the first stage of esterification of L-pyroglutamic acid according to the methods described in the Examples section, or by known methods, thus obtain the compounds of formula (II), where R6means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl or6-C10aryl(C1-C6)alkyl, more preferably C1-C6alkyl, even more preferably1-C4alkyl, most preferably methyl or ethyl. The compounds of formula (II) is then converted into the compounds of formula (III) according to the reactions shown below in scheme 2.

Scheme 2. The transformation of compounds of formula (II) in the compound of formula (III).

(a) In accordance with scheme 2, the compound (II), where R6defined above, recover, receive from testwuide alcohol (IIa).

Recovery is usually carried out in the presence of complex borhydride, such as LiBH4or NaBH4and LiCl in a suitable solvent, such as THF and the like, a mixture of THF and ethanol, for example, EtOH, I-D and so on, you get a compound (IIa), by a known method, see 1a) M. Moloney and others, Tetrahedron, 52, (10), 3719 (1996).

b) Compound (IIa) is subjected to acetalization in the presence of an aromatic aldehyde, thus obtain the connection formula (IIb), where the phenyl ring in the structure optionally contains one or more, for example two or three, residue, for example, selected from the group comprising From1-C7alkyl, hydroxy, C1-C7alkoxy, C2-C8alkanoyloxy, halogen, nitro, cyano and CF3. Acetalization the compounds of formula (IIa) is preferably carried out in the presence of benzaldehyde or other aromatic aldehyde, as described in the literature for compounds (IIb), see 2A) .Moloney and others, Tetrahedron, Asymmetry, 6, 337, (1995), 2b) M.Moloney and others, Tetrahedron, 52, (10), 3719 (1996).

c) the Compound (IIb) activate the carboxylation, and then alkylate using electrophile R3-X, where X is a leaving group, for example halogen or sulfonyloxy, and R3defined in this context above, you get a compound of formula (IIc), where the phenyl ring in the structure optionally contains one or more, for example two or three, about the TATKO, for example, selected from the group comprising From1-C7alkyl, hydroxy, C1-C7alkoxy, C2-C8alkanoyloxy, halogen, nitro, cyano and CF3. Preferably, the activation is carried out at carboalkoxylation, for example carbomethoxyamino or carbamaxepine, which is performed during the pre-treatment of the compound (IIb), for example, NaH in THF or in a mixture of THF/DMF and in the further processing of electrophilic agent, such as derived carbonate or phosgene, such as Cl-CO-OR6. The group R6defined in this context above and preferably means C1-C6alkyl, more preferably1-C4alkyl, most preferably methyl or ethyl. The obtained intermediate compound then deprotonated and alkylate in the presence of an electrophile, such as R3-X, where R3defined in this context above, as described, for example, article .Moloney and others, Tetrahedron, 52, (10), 3719 (1996), thus obtain the compound (IIc). Preferred alkylation is such carboalkoxylation intermediates branched secondary alkylating agents such as R-C-X-R'. Leaving group, X means halogen, sulfonyloxy etc.

d) In the compound (IIc) omelet ester group, and then decarboxylase, thus receive sedimentary (IId), where the phenyl ring in the structure optionally contains one or more, for example two or three, residue, for example, selected from the group comprising From1-C7alkyl, hydroxy, C1-C7alkoxy, C2-C8alkanoyloxy, halogen, nitro, cyano and CF3and R3defined in this context. Saponification of the ester group in the compound of formula (IIc) is preferably carried out in an aqueous solution of base (NaOH), and then acidified and decarboxylases, you get a connection (IId), which in some cases allocate, see 2b) above.

e) Compounds (IId) deacetylation or transacetalization, you get a compound of formula (III), where R3defined in this context. Deacetylases or transacetalization preferably carried out at a treatment with anhydrous acid, for example, CF3COOH, HCl in toluene or dioxane or transacetalization in the presence as catalyst of an acid and in the presence of alcohol, while having the compound (III). Cm. article 2b) above.

The compounds of formula (III), where R3defined in this context above, is transformed into the compounds of formula (IV), where R7means O-protective group, such as C1-C6alkyl, C1-C6alkoxy(C1-C6)alkoxy, C6-C10aryl(C1-C6)alkyl, C1-C6 alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl, a R8means N-protective group, such as6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl, while depending on the nature of the group R7and R8hydroxyl and amino protecting sequentially or simultaneously. Usually the protection of functional groups carried out by standard methods, as described in the literature and in the links below.

In another embodiment, the first stage (scheme 1) compound of formula (IV) are obtained from the compounds of formula (I), shown in scheme 1, according to the method shown in scheme 1C.

Scheme 1C. The method of obtaining the compounds of formula (IV) from L-pyroglutamic acid.

The esterification of the compounds of formula (I) mainly conducted according to the technique described in this context in the Examples section, or by known methods, thus obtain the compounds of formula (II), where R6defined above. In the compounds of formula (II) then protect the N atom, by the compounds of formula (IIe), where R8means N-protective group as defined above. The protection of functional groups are usually spending is by standard techniques, as described in the literature below.

At the next stage, the compound (IIe) is converted into a compound (IIf) according to the methods described in this context in the Examples section, or by well-known methods. Thus, after the formation of the anion in position 4 ester ring pyroglutamic acid in the processing of compound IIe strong base, for example a lithium base, followed by stopping the reaction with acetone in the presence of a Lewis acid, receive the intermediate tertiary alcohol. Then the alcohol group is transformed into a leaving group in the interaction with a suitable electrophile. After elimination get the desired connection IIf, where R3, R6and R8defined above. The method described in the article Hanessian S., and others, J. Org. Chem., 67, 4261 (2002).

The compound (IIf) is then converted into the compound (IIg), where R3and R8defined above, with the reduction of the ester residue to alcohol according to the methods described in this context in the Examples section, or by known methods, typically using hydrides, such as lithium borohydride.

Then, in the compounds of the formula (IIg) protect atom Oh, by the compounds of formula (IV), where R7means O-protective group, as described above, and R3and R8defined above, according to the methods described in this context in the Examples section, or by the known methods is the IKI. Usually a functional group protected by standard methods, as described in the links below.

After obtaining compounds of formula (IV), preferably one of the above methods, they are turned into compounds of the formula (V). When interacting with the ORGANOMETALLIC compound of the formula (XIIc), where R1and R2defined in the description of formula (A), and Y means, for example, lithium, or (XIIc) means the Grignard reagent, and then obtain the compounds of formula (V), where R1, R2, R3, R7and R8defined above in this context, which are also the key intermediate compounds for preparing compounds of the formula (A). The synthesis is usually carried out as described in this context in the Examples section, or by known methods, see the article in the book Houben-Weyl, volume 4/1, s-386, Reduction I. After the restoration benzyl carbonyl group by standard methods, for example, described in the book "Organicum, organisch-chemisches Grundpraktikum", 20th edition, VEB Deutscher Verlag der Wissenschaften, Berlin, (1999), and subsequent selective removal of the O-protective groups are the compounds of formula (VI), where R1, R2, R3and R8defined above in this context. These reactions are usually carried out as described in this context in the Examples section, or by known methods, see, for example, Th.W.Greene & P.G.Wuts, "Protective groups in Organic Synthesis", 2nd edition (1991), see t is the train Raney-Nickel-benzylic deoxygenation: Applied Catalysis A: General 218, c.281-289 (2001).

The compounds of formula (VI) is then oxidised to the carboxylic acid of formula (VII), where R1, R2, R3and R8defined in this context above, according to the methods described in this context in the Examples section, or by known methods, for example, by treatment with sodium hypochlorite and TEMPO in the presence of a phase transfer catalyst, such as Bu4NBr, see (a) article F.Montanari and others, J.O.C., 54, 2970 (1989) and b) overview: .Van Bekkum, etc., Synthesis, 1153 (1996).

Carboxylic acids of formula (VII) is first converted into the activated derivative of the formula (VIIIa), where R1, R2, R3and R8defined in this context above, X means, for example, halogen, such as fluorine or chlorine, R10OC(O)O-, where R10means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl or6-C10aryl(C1-C6)alkyl, Me(MeOH)N - or imidazolyl, which are also the key intermediate compounds for preparing compounds of the formula (A). Usually the reaction is conducted as described in this context in the Examples section, or by known methods, see, for example, the use of acid chlorides, see a) R.W.Saalfrank and others, Angew. Chem., 102, 292 (1990) and .Boehme etc., Chem. Ber., 99, 879 (1996), (b) Chem. Pharm. Bull., 13, 1472 (1965) and Synth. Commun., 30, 3439 (2000)

and Bull. Korean Chem. Soc., 24, 895 (2003), In) use the Finance of foramerican, see Tetrahedron Lett., 32, 10 1303 (1991), C) use imidazoline, see articles R.V.Hoffman and others, J.O.C., 62, 2292 (1997) or R.V.Hoffman and others, J.O.C., 62, 6240 (1997) or R.V.Hoffman and others, J.O.C., 67, 1045 (2002) or R.V.Hoffman and others, Tetrahedron, 53, 7119 (1997) or see J.Maibaum & D.Rich, J.O.C., 53, 869 (1998).

After condensation with chiral derivative of malonate formula (VIIIb), where R4defined in the description of formula (A), a R9means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C2-C20alkenyl or6-C10aryl(C1-C6)alkyl, preferably C1-C6alkyl or C6-C10aryl(C1-C4)alkyl, more preferably1-C4alkyl or benzyl, most preferably methyl, ethyl, tertbutyl or benzyl, get the compounds of formula (IX), where R1, R2, R3, R4, R5and R9defined in this context above. These reactions are usually carried out as described in this context in the Examples section, or by using known methods, see, for example, article Journ. Med. Chem., 41, 2461 (1998).

After removal of ester and decarboxylation of compound (IX) are obtained the compounds of formula (X), where R1, R2, R3, R4, R5and R9defined in this context above, which are also main the intermediate compounds for preparing compounds of the formula (A). Cleavage of esters is usually carried out under the conditions of hydrolysis or hydrogenation in the case of the benzyl ester by known methods. Decarboxylation is usually carried out as described in this context in the Examples section below or by using known methods, see, for example, J. Med. Chem., 41, 2461 (1998). Ester, i.e. the compound of formula (X), where R' is R9use without further purification in the next stage or, if necessary, before carrying out the next stage connection hydrolized to the corresponding acid, where R' denotes H. The hydrolysis is conducted according to known methods.

At the next stage in the compound of formula (X) stereoselective restore the carbonyl group in position C-4 and the connection cyclist when handling acid with the formation of the compounds of formula (XI), where R1, R2, R3, R4and R8defined above in this context. Stereoselective recovery is usually carried out as described in this context in the Examples section below or by using known methods, see, for example, articles R.V.Hoffman and others, JOC, 67, 1045 (2002) and cited in this article, literature, R.V.Hoffman and others, JOC, 62, 2292 (1997) and CAW and others, J.O.C., 69, 7391 (2004) and cited in this article the literature.

Chiral derivatives of malonate formula (VIIIb), where R4and R9defined in this context, the use of which has been created for the conversion of compound (VIIIa), as described above, are important synthetic fragments to obtain inhibitors of renin. Chiral derivatives of malonate formula (VIIIb) is obtained from different sources, for example, D-valine, where R4means propyl, as shown in the following scheme 3. In this case, R9preferably means methyl or ethyl. This technique is used for compounds in which R4means any branched C3-C6alkyl.

Scheme 3. Obtaining compounds (VIII'b), where R4means isopropyl, using D-valine as the source connection.

D-valine in turn D-2-hydroxyisovaleric acid by diazotization in the presence of Na nitrite in aqueous sulfuric acid solution. In another embodiment, D-2-hydroxyisovaleric acid is obtained, for example, the company Fluka or Aldrich. In accordance with a known method (Tetrahedron, 46, 6623 (1990), J. Chem. Soc.; Perk. Trans. 1, 12, 1427 (1996), J. Org. Chem., 52, 4978 (1987)) acid etherification in the presence of, for example, potassium carbonate, and R9-X, for example, Mel. At the next stage hydroxyl group in a complex ester of D-2-hydroxyisovaleric acid etherification 4-nitrobenzenesulfonamide. The reaction is preferably carried out in the presence of triethylamine and a catalytic amount of DMAR (dimethylaminopyridine), you get the R-enantiomer. For the eat ester sulfonic acid or nosrat alkylate in the presence of suitable diapir, for example a complex ester of malonic acid, you get a final triavir.

In another embodiment, the compounds of formula (XI) are obtained from compounds of formula (VI) or (VII)with compounds of formula (VI) or (VII) are obtained by any of the methods described in schemes 1, 1a, 1b, 1C or 2 separately or in combination. This method is described below in scheme 4. For this scheme to simplify the description of R4as an example, means isopropyl. However, in figure 4 the value of R4not limited to isopropyl and can mean any branched C3-C6alkyl, as defined in this context. Moreover, while in figure 4 to obtain the next phase of the corresponding aldehyde (XIV) the only method with the use of alcohol (VI), in another embodiment, it is possible to use the acid (VII), after the esterification of the acid and subsequent recovery using DIBAL-H receive the appropriate aldehyde (XIV).

Scheme 4 Alternative option for obtaining compounds of formula (XI) of the alcohol (VI):

Shown in figure 4 stages are described in detail below and in the Examples section below.

Stage A0. N-Boc-protected alcohol (VI) is selectively oxidized to the corresponding aldehyde (XIV), where R1, R2, R3and R8defined above. Usually the reaction is carried out in the processing of bleach in with outstay catalytic amounts of Tempo. Preferably the reaction is carried out under vigorous stirring, preferably in the two-phase solvent system, for example, water/toluene or water/toluene/EtOAc. Cm. article (a) F.Montanari and others, J.O.C., 54, 2970 (1989) and (b) review of: N. van Bekkum, etc., Synthesis 1153 (1996).

Stage A. To the BOC-protected aldehyde (XIV) add a suitable nucleophile, such as lithium salt of propyl ether, it acetylisoniazid formula (XV), where R1, R2, R3, R8and R9defined in this context. The reaction is usually carried out in THF at 78°C. the Desired acetylisoniazid (XV) is usually obtained as a mixture of diastereomers (S,S) and (S,R). Acetylene amerosport used without separation in a mixture of 2 epimeres.

Stage Century. Triple bond in acetaminophine (XV) hydronaut will get saturated γ-hydroxyether (XVI), where R1, R2, R3, R8and R9defined in this context. The transformation is usually carried out in a mixture of toluene and acetic acid in the presence of platinum oxide. Rich γ-hydroxy ester (XVI) is used without further purification.

Stage C. Saturated γ-hydroxyether (XVI) is subjected to lactonization, you get a γ-lactone of the formula (XVII), where R1, R2, R3and R8defined in this context. Preferably, this stage is carried out at a treatment with an acid, for example Asón, prepost is positive in the solvent at an elevated temperature of 50-150°C. for example in hot toluene for 2 h at 95-100°C.

Stage D. In the γ-lactone of the formula (XVII) remove the N-protective group, it Aminogen formula (XVIII), where R1, R2and R3defined in this context. This stage is preferably carried out in the processing of anhydrous acid such as gaseous hydrogen chloride in ethyl acetate, preferably at room temperature, while having unprotected δ-amino-γ-lactone, for example, in the form of hydrochloride.

Stage E. Aminogen formula (XVIII) is converted into the corresponding piperidine formula (XIX), where R1, R2and R3defined in this context. This stage is preferably carried out at a processing in a solvent such as methanol, for example, at room temperature, during, for example, 24 h in the presence of a base such as an amine, such as triethylamine. The base is preferably used in excess, thus receive the appropriate piperidone.

Stage F. Hydroxyl and amino groups in piperitenone formula (XIX) protect suitable protecting group by known methods, you get a bis-protected piperidine formula (XX), where R1, R2, R3, R7and R8defined in this context. Preferably piperidin obtained in stage E, is treated in a solvent such as THF, PR is the good ground, for example an amine, such as triethylamine, in the presence of a catalyst, such as N,N-dimethylaminopyridine and carbonate, such as distritbution, preferably at room temperature, thus get, for example, bis-BOC-derivative.

Stage G. piperazinone ring bis-protected piperidine formula (XX) enter branched alkyl, including tertiary hydroxyl group, you get hydroxyethylidene derived piperidine formula (XXI), where R1, R2, R3, R7and R8defined in this context. Usually bis-BOC derivative is treated with a strong base, such as LiHDMS for delivery of enolate, for example Li-enolate. The reaction is carried out in a suitable solvent, such as THF, preferably at temperatures below 0°C, preferably at -78°C. Then at the same temperature enolate preferably treated with BF3-diethyl ether, and then fit a ketone, for example acetone, after appropriate treatment, and recrystallization from hexane get adduct in the form of a crystalline residue.

Stage N. Hydroxyethylidene derived piperidine formula (XXI) in turn derived piperidine containing a double bond outside the loop, of the formula (XXII), where R1, R2, R3, R7and R8defined in this is ontext above. Preferably the tertiary alcohol is treated in a solvent, for example dichloromethane, a base, for example an amine, such as triethylamine, and methanesulfonamido, you get a mixture of isopropylidene" and "propylidene" (product XXII) depending on the nature of the group R4. The reaction is carried out preferably at a temperature of from -10 to 15°C., more preferably at -5°C.

Stage I. After isomerization of the double bond contained outside the loop, derived piperidine formula (XXII) are obtained olefin of the formula (XIII)where R1, R2, R3, R7and R8defined in this context. Preferably a solution of the compound of propenylidene (XXII) or similar compounds depending on the nature of the group R4or a mixture of both compounds obtained in stage N, is treated with a base (for example, NEt3or DBU) in ethyl acetate at room temperature for the isomerization of the double bond, thus receive the desired connection of the isopropylidene.

Stage J. Olefin of the formula (XXIII) hydronaut will get alkyl substituted derivative of piperidine formula (XXIV), where R1, R2, R3, R7and R8defined in this context. Preferably the olefin of formula (XXIII) hydronaut in a suitable solvent, such as ethyl acetate, in the presence of a small amount of base, such as AMI is a, such as triethylamine, in the presence of Pt-C. This reaction is preferably carried out at elevated temperature and pressure, or until the reaction is completed. Preferred are temperatures of 30-70°C., for example 50°C., and the pressure 2-10 bar, for example 5 bar.

Stage K. After opening cycle derived piperidine formula (XXIV) as an intermediate connection get γ-gidrokshikislotu which lactoserum, you get a compound of formula (XI), where R1, R2, R3and R8defined in this context. Preferably the compound obtained above in stage hydrogenation, is first treated with a base, for example an inorganic base, such as NaOH, thus receive the intermediate γ-gidrokshikislotu. More preferably used an aqueous solution of sodium hydroxide, for example, 2 N. the solution. Optionally the reaction is carried out in the presence of suitable co-solvents, for example THF. Preferably use interphase catalyst (for example, TEVA-Cl). The reaction is preferably carried out at 20-60°C., more preferably at 40°C. the Obtained γ-gidrokshikislotu, for example, in the form of sodium salt, is then treated with acid, such as glacial acetic acid, when lactonization. Usually use an excess of acid.

Finally, the compounds of formula (XI) in turn compounds the Oia formula (A), where R1, R2, R3, R4and R5defined in this context above, i.e. spend the remaining stages of the synthesis, using the reaction conditions described in this context in the Examples section, or known methods, see EP-A-0678503. In more detail after the treatment with the amine H2NR5where the group R5defined above in this context, there is an opening lactoovo cycle in the compound of formula (XI), thus formed amide of the formula (XIII). The reaction is usually carried out as described in this context in the Examples section below or by using known methods, see, for example, EP-A-0678503. Ultimately, the compounds of formula (XIII) is converted into the compounds of formula (A), where R1, R2, R3, R4and R5defined above in this context, using the following steps: removal of the N-protective group in the compound of formula (XIII), you get a free amine using standard protective groups and methods described in the articles listed below, and not necessarily the formation of salts, thus obtain the compounds of formula (A), as described in this context in the Examples section below. Conventional methods of obtaining salts described, for example, in patent US-A-5559111. The final stage is shown in scheme 5.

Scheme 5. The final stage of obtaining the compounds of formula (A) from compounds of formula (XI).

In another embodiment, the compounds of formula (X) are obtained using the following stages. The carboxyl group in the compound (X) interacts with the amine H2NR5where R5defined in this context above, under the conditions of condensation of peptides, thus formed amide of formula (XII) according to known methods, see, for example, Houben-Weyl, Methods der Organische Chemie, 4th edition, Synthese von Peptiden 1.

After the subsequent stereoselective recovery-4 carbonyl group in the compound of formula (XII) are obtained compound of the formula (XIII). Cm. R.V.Hoffman and other GAME, 67, 1045 (2002) and cited literature, R.V.Hoffman and others, JOC, 62, 2292 (1997), ..Reetz etc., Chem. Commun. 1474 (1989). Finally, the compounds of formula (XIII) is converted into the compounds of formula (A), where R1, R2, R3, R4and R5defined above in this context, to do this remove the N-protective group in the compound (XIII) and receive a free amine using standard protective groups described in the references cited in this context, the literature methods, and optional salt formation, thus obtain the connection formula (A), under the reaction conditions described in this context in the Examples section below. Typical methods of education salts described, for example, in patent US-A-5559111.

Other objects, features, advantages and aspects of the present invention are obvious to experts in this about the region after reading this description, the section of the Examples and the claims. It should be understood, however, that the preferred embodiments of the present invention, presented in the description and the claims, are given only to illustrate the present invention. The person skilled in the art it is obvious that various changes and modifications of the present invention without going beyond the nature and scope of the invention.

Below are definitions of various terms used in the description of the compounds of the present invention. These definitions apply to terms used in this context, unless specified otherwise in specific cases for certain term or part of a group. Each definition substituent can be combined with any other definition of another substituent, including in both cases the preferred values.

R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl. Preferred embodiments of the invention described below.

R2means halogen, C1-C4alkyl or C1-C4alkoxy.

Preferred embodiments of the invention described below.

R3and R4independently mean RA is extensive With 3-C6alkyl. Preferred embodiments of the invention described below.

R5means cycloalkyl,1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanolamine(C1-C6)alkyl, (O)C(C1-C6)alkyl, C1-C6alkyl-O-(O)C(C1-C6)alkyl, H2N-C(O)(C1-C6)alkyl, C1-C6alkyl-HNC(O)(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)(C1-C6)alkyl. Preferred embodiments of the invention described below.

R6means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl or6-C10aryl(C1-C6)alkyl. Preferred embodiments of the invention described below.

R7means suitable O-protective group known in the art. Examples of such groups include1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy, C6-C10aryl(C1-C6)alkyl, C1With 6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl. Preferred embodiments of the invention described below.

R8means suitable N-protective group known in the art, for example aminosidine group used in the chemistry of peptides (see "Protective groups in Organic Synthesis", 5th edition, Ed. .W.Greene & P.G.M.Wuts), primarily to protect pyrrolidino.

Suitable protective groups include, for example, (1) C1-C2-alkyl, mono-, di - or tizamidine by phenyl, such as benzyl (or) benzhydryl or trityl, where the phenyl ring is unsubstituted or contains as a substituent one or more, for example two or three residue, for example, selected from the group comprising From1-C7alkyl, hydroxy, C1-C7alkoxy, C2-C8alkanoyloxy, halogen, nitro, cyano and CF3, phenyl(C1-C2)alkoxycarbonyl, allyl or cinnamyl. First of all, preferred are benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), benzoyloxymethyl (CMV), pivaloyloxymethyl (RUM), trichlorocyanuric (Troc), 1-adamantanecarbonyl (Adoc), and benzyl, Cumyl, benzhydryl, trityl, allyl, alloch (allyloxycarbonyl). As the protective groups used silyl, for example trialkylsilyl, first trim ililil, tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl, trimethylsilylacetamide (SEM), and also replaced sulfonyl or substituted sulfenyl.

Examples of groups R8include6-C10aryl(C1-C6)alkyl and C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl and C6-C10aryl(C1-C6)alkoxycarbonyl. Other preferred embodiments of the invention described below.

R9means C1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C2-C20alkenyl or6-C10aryl(C1-C6)alkyl. In one embodiment, R9means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl or6-C10aryl(C1-C6)alkyl. Preferred embodiments of the invention described below.

The alkyl groups of R1and R2are linear or branched and preferably comprise from 1 to 6 carbon atoms, especially from 1 to 4 carbon atoms. Examples include methyl, ethyl, n - and isopropyl, n-, ISO - and tertbutyl, pentyl and hexyl.

Halogenated R1is a linear or did the run and preferably contains from 1 to 4 carbon atoms, first of all 1 or 2 carbon atoms. Examples include vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-triptorelin.

Alkoxy, R1and R2are linear or branched and preferably contain from 1 to 4 carbon atoms. Examples include methoxy, ethoxy, n, isopropoxy, n-, ISO - and tert-Butylochka, pentyloxy, hexyloxy.

Alkoxyalkyl R1is a linear or branched. Alkoxygroup preferably contains from 1 to 4, especially 1 or 2 carbon atoms, and the alkyl group preferably contains from 1 to 4 carbon atoms. Examples include methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxyphenyl, 6-methoxyphenyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropan, 4-ethoxymethyl, 5-ethoxyphenyl, 6-atoxigenic, propylacetate, butylacetate, 2-propylacetate and 2-butylacetyl.

C1-C6alkoxy(C1-C6)alkyloxy R1and R7are linear or branched. Alkoxygroup preferably contains from 1 to 4, especially 1 or 2 carbon atoms, alkyloxy preferably contains from 1 to 4 carbon atoms. Examples include methoxyethoxy, 2-methoxyethoxy, 3 methoxyphenoxy, 4-methoxybenzyloxy, 5-methoxybenzyloxy, 6-methoxyacetate, ethoxyethoxy, 2-ethoxyethoxy, 3-this is ciprofloxa, 4 ethoxymethylene, 5-ethoxyphenoxy, 6-ethoxyacrylate, propylacetate, butylacetate, 2-propylacetate and 2 butylacetate.

Branched alkyl, R3and R4preferably contains from 3 to 6 carbon atoms. Examples include isopropyl, ISO - and tert-butyl and branched isomers of pentile and exile.

Cycloalkyl R5preferably in the cycle contains 3 to 8 carbon atoms, especially 3 to 5. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. Cycloalkyl optionally contains one or more substituents such as alkyl, halogen, oxo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, heterocyclyl etc.

Alkyl, R5is a linear or branched alkyl and preferably contains from 1 to 6 carbon atoms. Examples of Akilov listed above. Preferred are methyl, ethyl, n - and isopropyl, n - ISO - and tert-butyl.

C1-C6hydroxyalkyl R5is linear or branched and preferably contains from 2 to 6 carbon atoms. Examples include 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-, 3 - or 4-hydroxybutyl, hydroxyphenyl and hydroxyhexyl.

C1-C6alkoxy(C1-C6)alkyl, R5is a linear or branched. Alkoxygroup pre is respectfully contains from 1 to 4 C atoms, as the alkyl group contains from 2 to 4 carbon atoms. Some examples include 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 2-, 3 - or 4-methoxybutyl, 2-ethoxyethyl, 2-ethoxypropan, 3-ethoxypropan and 2-, 3 - or 4-ethoxymethyl.

C1-C6alkanoyloxy(C1-C6)alkyl, R5is a linear or branched. Group alkanoyloxy preferably contains from 1 to 4 carbon atoms, and the alkyl group preferably contains from 2 to 4 carbon atoms. Some examples include formyloxyethyl, formyloxyethyl, acetoacetyl, propionylacetate and butyrolacetone.

C1-C6aminoalkyl R5is linear or branched and preferably contains from 2 to 4 carbon atoms. Some examples include 2-amino-ethyl, 2 - or 3-aminopropyl, and 2-, 3 - or 4-aminobutyl.

The group R5C1-C6alkylamino(C1-C6)alkyl and C1-C6dialkylamino(C1-C6)alkyl is linear or branched. Group alkylamino preferably includes With1-C4alkyl and the alkyl group preferably contains from 2 to 4 carbon atoms. Some examples include 2-methylaminomethyl, 2-dimethylaminoethyl, 2-ethylaminomethyl, 2-ethylaminomethyl, 3-methylaminopropyl, 3-dimethylaminopropyl, 4-methylaminomethyl and 4-dimethylaminomethyl.

BUT(O)C(C1-C6)is lcil R 5is a linear or branched alkyl group preferably contains from 2 to 4 carbon atoms. Some examples include carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

C1-C6alkyl-O-(O)-(C1-C6)alkyl, R5is a linear or branched alkyl group preferably independently contains from 1 to 4 carbon atoms. Some examples include methylcarbamoylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropionyl, 4-ethoxycarbonylbutyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylphenyl and 4-ethoxycarbonylbutyl.

H2N-C(O)(C1-C6)alkyl, R5is a linear or branched alkyl group preferably contains from 2 to 6 carbon atoms. Some examples include carbamoylmethyl, 2-carbamoylethyl, 2-carbamide-2,2-dimethylethyl, 2 - or 3-carbamimidoyl, 2-, 3 - or 4-carbimidoyl, 3-urea-2-methylpropyl, 3-urea-1,2-dimethylpropyl, 3-urea-3-ethylpropyl, 3-urea-2,2-dimethylpropyl, 2-, 3-, 4 - or 5-carbamezapine, 4-carbamide-3,3 - or -2,2-dimethylbutyl.

C1-C6alkyl-NH-C(O)(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)(C1-C6)alkyl, R5is a linear or branched group NH-alkyl preferably contains 1 to 4 carbon atoms, and alkyl grouppattern contains from 2 to 6 carbon atoms. Examples include carbamidomethylated groups defined in this context above, the N atom which contains as a substituent one or two of the radicals methyl, ethyl, propyl or butyl.

Alkili R6, R7, R9and R10are linear or branched and contain from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms. First of all, preferred is a linear C1-C4alkyl. Some examples include methyl, ethyl and the isomers of propyl, butyl, penttila, hexyl, heptyl, Attila, Manila, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, Attalla and eicosyl. Most preferred are methyl and ethyl.

Cycloalkyl group R6, R9and R10preferably contain from 3 to 8 carbon atoms in the cycle, especially 5 or 6 atoms. Some examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and cyclododecyl.

Cycloalkenyl R6, R9and R10contain preferably from 4 to 8 carbon atoms in the cycle, most preferably 5 or 6 and preferably from 1 to 4 carbon atoms in the alkyl group, most preferably 1 or 2 carbon atoms. Some examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclopentylmethyl and cyclohexylmethyl or 2-cyclohexylethyl.

ALCO is dicarbonyl R 7and R8contains a linear or branched alkyl group, preferably containing from 1 to 4 carbon atoms. Examples include methoxy, ethoxy, n, isopropoxy, n-, ISO - and tert-Butylochka, pentyloxy, hexyloxy.

Arylethoxysilanes R7and R8includes linear or branched alkyl, preferably containing from 1 to 4 carbon atoms, and aryl residue, preferably phenyl. Examples include benzyloxycarbonyl.

Alkenyl R9is a linear or branched alkyl, containing a double bond, and containing preferably from 2 to 12 carbon atoms, most preferably from 2 to 8 carbon atoms. Preferred is a linear C2-C4alkenyl. Some examples of alkyl groups include ethyl and the isomers of the following groups: propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, Oktell and eicosyl, each of which contains a double bond. First of all, preferred is allyl.

Aryl R6, R9and R10preferably means phenyl or naphthyl.

Aralkyl R6, R7, R8, R9and R10preferably denote benzyl or phenethyl.

In a preferred embodiment, R1means C1-C6alkoxy(C1-C6)alkyloxy, as defined, is Elena above, most preferably methoxy or ethoxy-(C1-C4)alkyloxy.

In a preferred embodiment, R2means alkoxy as defined above, most preferably methoxy or ethoxy.

In a preferred embodiment, R1means methoxy - or ethoxy(C1-C4)alkyloxy, a R2preferably means methoxy or ethoxy. The most preferred compounds of formula (A), where R1means 3 methoxypropylamine, a R2means methoxy.

In a preferred embodiment, R3and R4in each case, the mean isopropyl.

In a preferred embodiment, R5means N2N-C(O)(C1-C6)alkyl, C1-C6alkyl-NH-C(O)(C1-C6)alkyl or (C1-C6alkyl)2N-C(O)(C1-C6)alkyl, the preferred examples described above, preferably H2N-C(O)(C1-C6)alkyl, most preferably urea-2,2-dimethylethyl.

In a preferred embodiment, R6means1-C6alkyl, more preferably1-C4alkyl, most preferably methyl or ethyl.

In a preferred embodiment, R7and R8independently mean arylethoxysilanes, alkoxycarbonyl or aralkyl, for example benzyl, tert-butoxycarbonyl or benzyloxycarbonyl.

In a preferred embodiment, R7 8independent means t-butoxy or benzyloxycarbonyl.

In a preferred embodiment, R9means C1-C6alkyl or C6-C10aryl(C1-C4)alkyl, more preferably1-C4alkyl or benzyl, most preferably methyl, ethyl, tert-butyl or benzyl.

Accordingly, preferred are the methods of the present invention, in which the compound of formula (A) is characterized by the formula

where R1means 3 methoxypropylamine, R2means methoxy, and R3and R4means isopropyl, or use its pharmaceutically acceptable salt.

More preferred are the methods of the present invention, in which the compound of formula (In) means profumata (2-carbarnoyl-2-methylpropyl)amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-(2-carbarnoyl-methoxypropane)benzyl]-8-methylnonanoic acid, known under the name aliskiren.

The present invention also includes the following intermediate compounds used to obtain the compounds of formula (A). Each of these intermediates is an important component for the synthesis of compounds of formula (a) as from the point of view of the composition of functional groups, and from the point of view of stereochemistry. Each of these sub-the face-to-face connections receive according to the stages, as indicated in schemes 1, 1a, 1b, 1c, 2, and 4, separately or in combination, any of the appropriate methods, as shown in the diagrams. In another embodiment, these intermediate compounds obtained from any other intermediate products obtained at any stage, as shown in the schemes, including pre-intermediate products, while receiving appropriate primary intermediate connection at one stage.

The following intermediate compounds can be used to obtain compounds of formula (A):

The compounds of formula

where R3means branched C3-C6alkyl, preferably isopropyl, and R6means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl or6-C10aryl(C1-C6)alkyl, preferably1-C4alkyl, most preferably methyl or ethyl;

the compounds of formula

where R3means branched C3-C6alkyl, preferably isopropyl;

the compounds of formula

where R3means branched C3-C6alkyl, preferably isopropyl, and R8means N-protective group, for example With6-C10 aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl;

the compounds of formula

where R3means3-C6alkyl, preferably isopropyl;

the compounds of formula

where R3means branched C3-C6alkyl, preferably isopropyl, R7means O-protective group, for example, C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl, R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl;

the compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, R2means halogen, C1- 4alkyl or C1-C4alkoxy, R3means branched C3-C6alkyl, R7means C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl, R8means6-C10aryl(C1-C6)alkyl, C1-C6alkalicarbonate, C6-C10arylcarbamoyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl.

Preferred compounds of formula (V), characterized by the formula

where R1means 3 methoxypropylamine, R2means methoxy, R3means isopropyl, a R11and R12independent means tert-butyl or benzyl.

Preferred are the compounds of formula (V'), where R11and R12means tert-butyl.

As intermediates for producing compounds of formula (A) can also be used:

the compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)Alki is, R2means halogen, C1-C4alkyl or C1-C4alkoxy, R3means branched C3-C6alkyl, a R8the means6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl.

Preferred are the compounds of formula (VII), characterized by the formula

where R1means 3 methoxypropylamine, R2means methoxy, R3means isopropyl, and R12means tert-butyl or benzyl.

Preferred are the compounds of formula (VII'), where R12means tert-butyl.

As intermediates for producing compounds of formula (A) can also be used:

the compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, R2means halogen, C1-C4alkyl or C1-C4alkoxy, R3and R4independently denote a branched C3-C6alkyl, R8means6-C10aryl(C1-C6)alkyl, C1-C6alkylborane is, With6-C10arylcarbamoyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl, R9means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C2-C20alkenyl or6-C10aryl(C1-C6)alkyl, preferably C1-C6alkyl or C6-C10aryl(C1-C4)alkyl, preferably1-C4alkyl or benzyl.

As intermediates for producing compounds of formula (A) can also be used:

the compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, R2means halogen, C1-C4alkyl or C1-C4alkoxy, R3and R4independently denote a branched C3-C6alkyl, R8means6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl.

Preferred are the compounds of formula (X), characterized by the formula

<>

where R1means 3 methoxypropylamine, R2means methoxy, R3means isopropyl, R4means isopropyl, a R12means tert-butyl or benzyl.

Preferred are the compounds of formula (X'), where R12means tert-butyl.

The compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkyloxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-methoxypropylamine, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3and R4independently denote a branched C3-C6alkyl, preferably every means isopropyl, R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl, C6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

The compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-methoxypropyl is lexi, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3means branched C3-C6alkyl, preferably isopropyl, R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl, R9means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C2-C20alkenyl or6-C10aryl(C1-C6)alkyl, preferably C1-C6alkyl or C6-C10aryl-C1-C4alkyl, preferably1-C4alkyl or benzyl.

The compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-methoxypropylamine, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3means branched C3-C6alkyl, preferably isopropyl, R8means N-protective the th group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl, R9means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C2-C20alkenyl or6-C10aryl(C1-C6)alkyl, preferably C1-C6alkyl or C6-C10aryl(C1-C4)alkyl, preferably1-C4alkyl or benzyl.

The compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-methoxypropylamine, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3means branched C3-C6alkyl, preferably isopropyl, a R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl,1-C6alkoxycarbonyl or6-C10aryl(C1-C6)aldoxycarb the mud.

The compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-methoxypropylamine, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3means branched C3-C6alkyl, preferably isopropyl.

The compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-methoxypropylamine, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3means branched C3-C6alkyl, preferably isopropyl.

The compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-methoxypropylamine, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3Osnach the em branched C 3-C6alkyl, preferably isopropyl, R7means O-protective group, for example, C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl, R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

The compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-methoxypropylamine, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3means branched C3-C6alkyl, preferably isopropyl, R7means O-protective group, for example, C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1 -C6)alkoxycarbonyl or (C1-C8alkyl)3silyl, R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

The compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-methoxypropylamine, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3means branched C3-C6alkyl, preferably isopropyl, R7means O-protective group, for example, C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl, R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10the Rhyl(C 1-C6)alkoxycarbonyl.

The compounds of formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-methoxypropylamine, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3means branched C3-C6alkyl, preferably isopropyl, R7means O-protective group, for example, C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl, R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

The compounds of formula:

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl, preferably 3-meth is ciprofloxa, R2means halogen, C1-C4alkyl or C1-C4alkoxy, preferably methoxy, R3means branched C3-C6alkyl, preferably isopropyl, R7means O-protective group, for example, C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl, R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

Moreover, the present invention also includes a chiral derivative of malonate formula (VIIIb), which is an important intermediate fragment for the synthesis of renin inhibitors

where R4and R9defined in this context. It is preferable chiral derivative malonate formula (VIII'b)

Preferably the substituent R9means methyl or ethyl, most preferably methyl.

As described above, in this context, the compounds according to the present invented the Yu can be converted into an acid additive salt. An acid additive salt is obtained using mineral acids, organic carboxylic acids or organic sulfonic acids, for example hydrochloric, fumaric and methanesulfonic acids, respectively.

Due to the similar structure of the free compounds and their salts at the mention of the connection in this context mean and its salt, provided that it is possible or appropriate under the circumstances.

The compounds, including their salts, are also provided in the form of hydrates or do they include other solvents used for crystallization.

The present invention also includes any of the options above methods, in which the starting compounds are used, the intermediate product obtained at any stage, for example the compound of formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), formula (IIg), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII), of the formula (XVIII), of the formula (XIX), of the formula (XX), of the formula (XXI), of the formula (XXII), of the formula (XXIII) or formula (XXIV), and then spend the rest of the stage, or in which the reagents used in the form of salts. Moreover, to obtain the compounds of formula (A) you can use a combination of any other schemes of synthesis with IP is the use of a common intermediate compounds.

If necessary to protect functional groups from unwanted interactions with components of the reaction in terms of specific chemical transformations according to the present invention uses a protective group. The use of protective groups and their choice in a particular reaction is known to specialists in this field and depends on the nature of the protected functional groups (amino, hydroxyl, thiol, etc.), structure and stability of the molecule containing the functional group, and the reaction conditions.

Known protective group that meets the desired conditions and their introduction and removal are described, for example, in the books McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, NY (1973); Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley and Sons, Inc., NY (1999).

As described, in this context, the ways activated derivatives of carboxylic acids of the formula (VIIIa) include acid chlorides, bromohydrin and foramerica, mixed anhydrides, complex (ness.)alkalemia esters and activated esters. Mixed anhydrides are preferred and include the anhydrides privalovoi acid or (ness.)alkalemia palefire of carbonic acid, such as ethyl or isobutyl counterparts. Activated esters include, for example, operations, phthalimide or 4-nitrophenolate esters. Carboxylic acids of formula (VII) in turn activated about spodnie according to the method described in this context, or by well-known methods.

The above reaction is conducted according to standard methods, in the presence or absence of a diluent, which is preferably inert in respect of reagents used, and is also a solvent, in the presence of catalysts, condensing or other agents respectively and/or in an inert atmosphere at low temperature, room temperature or elevated temperature (preferably near or equal to the boiling point of the used solvent) and at atmospheric or increased pressure.

Suitable solvents are water and organic solvents, especially polar organic solvents, which can also be used in the form of a mixture of at least two solvents. Examples of solvents include hydrocarbons (petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene, xylene), halogenated hydrocarbons (dichloromethane, chloroform, tetrachlorethane, chlorobenzene), a simple ether (diethyl ether, disutility ether, tetrahydrofuran, dioxane, dimethyl or diethyl ether of ethylene glycol), esters of carboxylic acids or lactones (methyl acetate, ethyl acetate, methylpropionate, valerolactone), N,N-substituted carboxamide and the lactams (dimethylformamide, dimethylacetamide, N-Meile religon), ketones (acetone, methyl isobutyl ketone, cyclohexanone), sulfoxidov and sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylsilane), alcohols (methanol, ethanol, n - or ISO-propanol, n-, ISO - or tert-butanol, pentanol, hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxyphenylglycol, benzyl alcohol, ethylene glycol, diethylene glycol, propandiol, butanediol, onomatology or monotropy ether of ethylene glycol, onomatology or monotropy ether of diethylene glycol, NITRILES (acetonitrile, propionitrile), tertiary amines (trimethylamine, triethylamine, Tripropylamine and tributylamine, pyridine, N-methylpyrrolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).

The above reactions are preferably carried out in an inert atmosphere, preferably under nitrogen atmosphere.

Compounds of the present invention allocate using known techniques such as extraction, crystallization and filtration, and their combination.

The following examples are provided to illustrate and not limit the scope of the present invention. If not stated otherwise, all solutions were evaporated under reduced pressure, preferably in the range of from about 5 to 50 mm Hg (20-133 mbar). The structure of final products, intermediates and starting materials a confirmation is iridessa standard methods of analysis, for example microanalysis and spectrometry, such as MS, IR and NMR.

Example 1

Obtain (S)-5-hydroxyethylpyrrolidine-2-it

A suspension of lithium borohydride (275 g) in anhydrous tetrahydrofuran (15 l) was cooled to 10°C and for 2 h was added a solution of methyl ester (S)-5-oxopyrrolidin-2-carboxylic acid (1.6 kg) in tetrahydrofuran (8 l). The resulting suspension was heated to 40°C. and was stirred for 3 h, then was added water (1.8 l) and the mixture was filtered. The obtained solid is suspended in tetrahydrofuran (7 l) and boiled under reflux for 75 min, then the mixture was cooled to 25°C. and filtered. The filtrate was slowly treated at room temperature with 1.0 M solution of oxalic acid in water (500 ml). The resulting suspension was filtered and the solid washed with tetrahydrofuran (5 l). The solvent was removed, it was obtained an oil which was re-dissolved in a mixture of ethyl acetate (6.3 liters) and ethanol (0.7 l) at elevated temperature, slightly turbid solution was filtered. The clear solution was cooled to -25°C and the resulting suspension was stirred for 2 hours, the Solid was separated by filtration, washed with ethyl acetate and dried, to receive specified in the header of the connection.

The original material was prepared by the following method.

A suspension of ion exchange the second resin Dowex-H +(0.4 kg) in methanol (30 l), containing D-pyroglutamic acid (2 kg), stirred at the boiling temperature of the solvent within 72 hours the mixture was cooled to room temperature and was added an additional amount of resin Dowex-H+(0.17 kg) and methanol (30 l), then the mixture was heated to the boiling point of the solvent. The methanol was removed in vacuum, and then the reaction mixture was treated with another portion of methanol (30 l) and again evaporated. The described procedure is repeated twice, then the mixture was concentrated in vacuo to a volume of approximately 10 liters, a solid substance was separated by filtration and washed with methanol (10 l). The filtrate and washing solutions were combined and the methanol was removed in vacuo, to receive the oil. The purified methyl ester was isolated by fractional distillation at 120-132°C and 0.70 mbar, to receive the desired broadcast.

Example 2

Obtain (3S,5S)-5-hydroxymethyl-3-isopropylpyridine

A solution of (3R,6S,7aS)-6-isopropyl-3-vinyltetrahydrofuran[1,2-C]oxazol-5-she (16.5 g) in dichloromethane (175 ml) at room temperature was treated triperoxonane acid (15,35 g). The resulting solution was stirred at room temperature for 24 h, then was added an additional amount triperoxonane acid (14 g). Stirring was continued for another 24 h and rastvoritelyami in vacuum. The residue was treated with water (50 ml) and dichloromethane (100 ml), the pH of a two-phase mixture was brought to 12 by addition of conc. the sodium hydroxide solution. To the mixture was added solid sodium chloride and the mixture was stirred. The organic layer was removed under reduced pressure, was obtained (3S,5S)-5-hydroxymethyl-3-isopropylpyridine-2-it is in the form of semi-solid substances. tpl.55,9°C, [α]D=+47,9°(1% in the Meon).

The original material was prepared by the following method.

A suspension of (S)-5-hydroxyethylpyrrolidine-2-it (148,5 g) in toluene (891 ml) was treated at room temperature with benzaldehyde (172,1 ml)was added para-toluensulfonate acid (2,94 g) and the reaction mixture was stirred at the boiling temperature of the solvent for 20 h, while water was removed in the form of an azeotropic mixture. The reaction mixture was treated with sodium hydrogen carbonate solution in water (5%, 500 ml). The organic layer was separated and repeatedly washed with a solution of sodium bisulfite (40%, 500 ml)and then water (2×250 ml). The organic layer was dried over sodium sulfate, filtered and the solvent was removed, to receive the oil. After fractional distillation in vacuum has been cleared (3R,7aS)-3-vinyltetrahydrofuran [1,2-C] oxazol-5-he.

A suspension of sodium hydride (60% dispersion in mineral oil, 450 g) in tetrahydrofuran (3.3 l) was heated to 50°C. and treated Diatessaron the volume (1.8 kg), within 15 min was added to a solution of (3R,7aS)-3-vinyltetrahydrofuran[1,2-C]oxazol-5-she (800 g) in tetrahydrofuran (1.6 l) and the resulting mixture was stirred at 55°C for 180 min At 55-60°C was added a solution of Isopropylamine (1,85 kg) in dimethylformamide (1.8 kg), the temperature maintained in the specified range. Then the reaction mixture was stirred at the boiling temperature of the solvent for 20 h, cooled to room temperature and treated with a solution of citric acid in water (10%, 5 l), and was twice extracted with ethyl acetate (3 l) and the organic extracts were combined. The organic layer was twice washed with saline and dried. The solvent was removed, while received oil (1,84 kg), which was purified by chromatography on silica gel (eluent: hexane/ethyl acetate). The fractions containing the product were combined, the solvent was removed, it was obtained the desired compound in the form of oil. Crystallization from a mixture of ethyl acetate/hexane received ethyl ester (3R,6R,7aS)-6-isopropyl-5-oxo-3-vinyltetrahydrofuran[1,2-C]oxazol-6-carboxylic acid (730 g).

A solution of ethyl ester of (3R,6R,7aS)-6-isopropyl-5-oxo-3-vinyltetrahydrofuran[1,2-C]oxazol-6-carboxylic acid (960 g) in tetrahydrofuran (8 l) was treated at room temperature with a solution of sodium hydroxide (2 M, of 3.33 l). The reaction mixture was stirred for 24 h, was added toluene (5,15 l) the pH of the mixture was brought up to 2-4 by adding 10% citric acid solution. The layers were separated and the aqueous layer was saturated with sodium chloride, was washed with toluene (4 l)and the organic layers were combined and dried. Solution in toluene was boiled under reflux for 48 h, cooled to 70°C. and the toluene was removed under reduced pressure, was obtained (3R,6S,7aS)-6-isopropyl-3-vinyltetrahydrofuran[1,2-C]oxazol-5-he.

Example 3

Obtain tert-butyl ether (3S,5S)-5-tert-butoxycarbonylmethyl-3-isopropyl-2-oxopyrrolidin-1-carboxylic acid

Method And

A solution of (3S,5S)-5-hydroxymethyl-3-isopropylpyridine-2-it (20,14 g) in tetrahydrofuran (200 ml) was treated with di-tert-BUTYLCARBAMATE (39,36 g), triethylamine (17,23 g) and dimethylaminopyridine (1.04 g). The resulting mixture was stirred at room temperature for 24 h and heated at 40°C for 6 hours the Solvent was removed under reduced pressure and the residue was treated with citric acid solution (10%, 60 ml) and ethyl acetate (200 ml). The organic layer was removed, the aqueous layer was re-extracted with ethyl acetate (200 ml). The combined organic layers were concentrated to a volume of approximately 40 ml and was added hexane (50 ml). The diluted suspension was cooled to 0°C and stirred overnight. The crystalline solid was separated by filtration, washed and dried, to receive specified in the header with the Association. The absolute configuration of both stereoisomers were determined by x-ray structure analysis. tpl.111-112°C, [α]D=-60,3° (1% CH2Cl2).

1H-NMR: 4,27-4,22 (2H, osirm), 4,11-to 4.15 (1H, dd), 2,59-to 2.65 (1H, m), 2,16-of 2.21 (1H, osirm), 1,88-of 1.93 (2H, osirm), 1,50 (N, s)of 1.44 (9H, s), is 0.96 (3H, d), of 0.82 (3H, d).

Method In

A solution of tert-butyl methyl ether (3S,5S)-5-hydroxymethyl-3-isopropyl-2-oxopyrrolidin-1-carboxylic acid (12.8 g) in dichloromethane (100 ml) at room temperature was treated with dimethylaminopyridine (0.5 g) and di-tert-BUTYLCARBAMATE (7,8 g). The resulting mixture was stirred at room temperature for 4 h, then washed twice with sulfuric acid (0.5 M, 400 ml). The organic phase was separated, the solvent was removed, when it got mentioned in the title compound in the form of a semi-crystalline solid.

The original material was prepared by the following method.

A solution of L-pyroglutamic acid (387 g) in dimethylformamide (300 ml) at room temperature was treated with potassium carbonate (103,6 g), was added benzylbromide (35,6 ml) and the suspension was stirred at room temperature for 4 h, then filtered and the solid washed with acetone (300 ml). The filtrate was evaporated at 50°C, to receive the oil which was dissolved in ethyl acetate (300 ml) and washed with water (300 ml). The aqueous phase is again what was xtraceroute with ethyl acetate (150 ml). The organic layers were combined, dried, the solvent was removed, it was obtained benzyl ester (S)-5-oxopyrrolidin-2-carboxylic acid in the form of oil.

To a solution of benzyl ether (S)-5-oxopyrrolidin-2-carboxylic acid (78,9 g) in dichloromethane (400 ml) at room temperature was added dimethylaminopyridine (2.20 g) and di-tert-BUTYLCARBAMATE (78,54 g). The resulting mixture was stirred at room temperature for 4 h, then washed twice with sulfuric acid (0.5 M, 400 ml). The organic phase was separated, the solvent was removed, while received 1-tert-butyl, 2-benzyl W (S)-5-oxopyrrolidin-1,2-dicarboxylic acid in the form of a semi-crystalline solid.

The solution hexamethyldisilazide lithium in tetrahydrofuran was cooled to -78°C and treated with a solution of 1-tert-butyl, 2-benzyl of diapir (S)-5-oxopyrrolidin-1,2-dicarboxylic acid (15,95 g) in tetrahydrofuran (100 ml), maintaining the temperature of -78°C. the resulting mixture was stirred for 40 min, then for 20 min was added to a mixture of acetone (40 ml) and detragiache of boron TRIFLUORIDE (7 ml). The mixture was stirred at -78°C for 2.5 h, then was added a solution of citric acid (10%, 300 ml) and the reaction mixture was heated to room temperature. The layers were separated and the aqueous layer was re-extracted with dichloromethane (300 ml). The combined organic layers were dried, which was intervali, the solvent was removed, while received 1-tert-butyl, 2-benzyl W (S)-4-(1-hydroxy-1-methylethyl)-5-oxopyrrolidin-1,2-dicarboxylic acid in the form of oil.

A solution of 1-tert-butyl, 2-benzyl of diapir (S)-4-(1-hydroxy-1-methylethyl)-5-oxopyrrolidin-1,2-dicarboxylic acid (75,8 g) in tetrahydrofuran (200 ml) was treated with triethylamine (41.8 g) and dimethylaminopyridine (1.2 g), then was cooled to 0°C. To the resulting mixture for 60 min was added dropwise to the acid chloride methyl ester of oxalic acid (31.7 ml). The resulting mixture was stirred at room temperature for 24 h, then was added tert-butyl methyl ether (200 ml) and water (200 ml). The organic layer was separated and washed with saturated sodium bicarbonate solution (100 ml) and water (100 ml). The organic phase was dried, the solvent was removed, to receive the intermediate ester of oxalic acid (87,9 g) in the form of oil, which was re-dissolved in toluene (350 ml) and successively treated with azobisisobutyronitrile (0.6 g) and hydride tri-n-butyanova (100,7 ml). The mixture was boiled under reflux for 60 min and added an additional portion of azobisisobutyronitrile (0.6 g). This procedure was continued for 4 h (reagent was added 5 times). The reaction mixture was concentrated in vacuo, to receive the oil, which was re-dissolved in acetonitril is e (300 ml) and washed with hexane (4×400 ml). Phase of acetonitrile was concentrated in vacuo, to receive the oil, which was purified by chromatography on silica gel (eluent: ethyl acetate/hexane). The fractions containing the product were combined, the solvent was removed, while received 1-tert-butyl, 2-benzyl W (2S,4S)-4-isopropyl-5-oxopyrrolidin-1,2-dicarboxylic acid.

A suspension of lithium borohydride (27 g) in anhydrous tetrahydrofuran (15 ml) was cooled to 10°C and for 2 h the solution was added 1-tert-butyl, 2-benzyl of diapir (2S,4S)-4-isopropyl-5-oxopyrrolidin-1,2-dicarboxylic acid (15,4 g) in tetrahydrofuran (80 ml). The resulting suspension was heated to 40°C. and was stirred for 3 h, then added to water (800 ml) and the mixture was filtered. The solid is suspended in tetrahydrofuran (700 ml) and boiled under reflux for 75 min, then the mixture was cooled to 25°C. and filtered. The filtrate was slowly treated at room temperature with an aqueous solution of oxalic acid (1.0 M, 500 ml). The resulting suspension was filtered and the solid washed with tetrahydrofuran (500 ml). The filtrate was evaporated, the thus obtained oil was re-dissolved at elevated temperature in a mixture of ethyl acetate (630 ml) and ethanol (0,07 l). Received slightly opalescent solution was filtered, the clear solution was cooled to -25°C and the resulting suspension was stirred in ECENA 2 hours A solid substance was separated by filtration, washed with ethyl acetate and dried, it was obtained tert-butyl ether (3S,5S)-5-hydroxymethyl-3-isopropyl-2-oxopyrrolidin-1-carboxylic acid.

Example 4

Obtain tert-butyl, (2S,4S)-2-tert-butylcarbamoyl-4-[4-methoxy-3-(3-methoxypropane)benzoyl]-5-methylhexanoic ester of carbonic acid

A solution of 4-bromo-1-methoxy-2-(3-methoxypropane)benzene (7.9 g) in tetrahydrofuran (125 ml) was cooled to -78°C, then for 50 min, the solution was added n-utility (14,219 g, 1.6 M in hexane). The reaction mixture was stirred for 90 min at -78°C, then slowly treated with a solution of tert-butyl methyl ether (3S,5S)-5-tert-butoxycarbonylmethyl-3-isopropyl-2-oxopyrrolidin-1-carboxylic acid (8,93 g) in tetrahydrofuran (75 ml). The resulting reaction mixture was stirred at -78°C for 3 h, then the temperature was raised to -40°C and was stirred for a further 45 minutes the reaction mixture was added acetic acid (4 ml) and the solvent was removed by evaporation. The residue was dissolved in ethyl acetate (100 ml) and washed with saturated sodium bicarbonate solution (2×75 ml) and water (150 ml). The organic phase was dried, the solvent was removed, it was obtained an oil which was purified by chromatography on silica gel (eluent: hexane/ethyl acetate). The fractions containing the product, thing in common and, the solvent was removed, when it got mentioned in the title compound in the form of oil.

1H-NMR (CDCl3): 7,50 (2H, m), for 6.81 (1H, m), 4,60 (1H, d), is 4.15 (2H, t), of 4.05 (2H, m), 3,90 (3H, s), 3,55 (2H, t), 3,40 (1H, m), the 3.35 (3H, s), of 2.15 (2H, m), is 2.05 (1H, m), 1,60 (1H, m), 1,45 (N, s), 1,40-of 1.20 (9H, .s), and 1.00 (3H, d), of 0.90 (3H, d).

Example 5

Obtain tert-butyl, (2S,4S)-2-tert-butylcarbamoyl-4-[4-methoxy-3-(3-methoxypropane)benzyl]-5-methylhexanoic ester of carbonic acid

Tert-butyl (2S,4S)-2-tert-butylcarbamoyl-4-[4-methoxy-3-(3-methoxypropane)benzoyl]-5-methylhexanoic ether carboxylic acid (2.67 g) at room temperature was dissolved in a mixture of ethanol/acetic acid (2:1, 25 ml), was added metal palladium (10% on charcoal, 0.3 g) and the resulting suspension was kept in an atmosphere of hydrogen at a pressure of 5 bar. The hydrogenation was continued at 50°C for 3 days with periodic addition of additional quantities of catalyst, then the reaction mixture was filtered, the solvent was removed, it was obtained an oil which was purified by chromatography on silica gel (eluent: hexane/ethyl acetate). The fractions containing the product were combined, the solvent was removed, when it got mentioned in the title compound in the form of oil.

Example 6

Obtain tert-butyl ester {(1S,3S)-1-hydroxymethyl-3-[4-methoxy-3-(3-methoxypropane)benzyl]-4-methylpent the l}carbamino acid

Regioselective hydrolysis, as described in J. Amer. Chem. Soc., 122, 10708, (2000).

Example 7

Obtain (2S,4S)-2-tert-butoxycarbonylamino-4-[4-methoxy-3-(3-methoxypropane)benzyl]-5-methylhexanoic acid

A solution of tert-butyl ester {(1S,3S)-1-hydroxymethyl-3-[4-methoxy-3-(3-methoxypropane)benzyl]-4-methylpentyl}carbamino acid (4,39 g) in dichloromethane (50 ml) was cooled to 0°and treated With TEMPO (0.2 g), a solution of potassium bromide (2,75 M, 25 ml) and a solution of potassium bicarbonate (1.6 M, 15 ml). A two-phase system with rapid stirring, was treated with bleach (11% solution, 15 ml) and the mixture was stirred at 0°C for 60 min, then was added a solution of sodium thiosulfate (1.0 M) and the mixture was stirred at room temperature for 15 minutes the Organic layer was separated and washed twice with water (100 ml). The solvent was removed, to receive the intermediate alcohol in the form of oil, which was used in the next stage without additional purification. The oil was dissolved in tert-butanol (20 ml) was added 2-methyl-2-butene (5 ml), then for 15 min was added dropwise a solution of sodium chlorite (1.2 g, 80%) and sodium dihydrophosphate (there is a 10.03 g) in water (20 ml). The reaction mixture was stirred at room temperature for 3 h, then was diluted with saline and extraheavy and dichloromethane (3×50 ml). The combined organic layers were dried, the solvent was removed, when it got mentioned in the title compound in the form of oil.

Example 8

Obtaining the ethyl ester of (2S,5S,7S)-5-tert-butoxycarbonylamino-3-etoxycarbonyl-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)benzyl]-8-methyl-4-oxo-3-propoxycarbazone acid

A solution of (2S,4S)-2-tert-butoxycarbonylamino-4-[4-methoxy-3-(3-methoxypropane)benzyl]-5-methylhexanoic acid (a 4.53 g) in toluene (25 ml) was boiled under reflux was added oxalicacid (1.75 g). The resulting mixture was stirred at room temperature, then the solvent was removed in vacuo and added another portion of toluene (25 ml). The distillation was repeated and added another portion of toluene (25 ml). The distillation was repeated, it was obtained acid chloride in the form of oil, which was re-dissolved in tetrahydrofuran, cooled to 0°C and added to a solution of sodium salt of ethyl ester of (R)-2-(bis-ethoxycarbonylmethyl)-3-methylmalonic acid (11 mmol) in tetrahydrofuran (obtained by treating ethyl ester (R)-2-(bis-ethoxycarbonylmethyl)-3-methylmalonic acid, sodium hydride). The resulting mixture was stirred at room temperature for 2 h, then was added a solution of citric acid (10%, 20 ml). The organic layer was separated, dried, the solvent was removed is in vacuum, if this has been mentioned in the title compound in the form of a semi-crystalline solid.

Example 9

Obtain (2S,5S,7S)-5-tert-butoxycarbonylamino-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)benzyl]-8-methyl-4-oksanalove acid

A solution of ethyl ester of (2S,5S,7S)-5-tert-butoxycarbonylamino-3-etoxycarbonyl-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)benzyl]-8-methyl-4-oxo-3-propoxycarbazone acid (10.0 g) in ethanol (20 ml) at room temperature was treated with sodium hydroxide solution (37%, 25 ml). The resulting mixture was stirred at room temperature for 24 hours, then the ethanol was removed in vacuum. The residue was extracted with dichloromethane (2×25 ml), the pH of the aqueous layer was carefully brought to 2.5 by the addition of hydrochloric acid (2 BC) at 0°C., then the reaction mixture was stirred for 16 h and was extracted with dichloromethane (4×50 ml). The organic layer was dried, the solvent was removed in vacuum, thus received is listed in the title compound in the form of oil.

Example 10

Obtain tert-butyl ester {[1S,3S)-1-((2S,4S)-4-isopropyl-5-oxitetraciclina-2-yl)-3-[4-methoxy-3-(3-methoxypropane)benzyl]-4-methylpentyl}carbamino acid

A solution of (2S,5S,7S)-5-tert-butoxycarbonylamino-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)Ben who yl]-8-methyl-4-oksanalove acid (5,51 g) in tetrahydrofuran (25 ml) was cooled to -30°C and for 30 min was added dropwise a solution of selenide To in tetrahydrofuran (1.0 M, 10 ml). The mixture was stirred at -30°C for 2 h, warmed up to 0°C and was stirred for 16 hours the Reaction was stopped by adding hydrochloric acid (1.0 M, 50 ml) and the mixture was extracted with dichloromethane (3×100 ml). The organic layer was dried, the solvent was removed in vacuum, thus received is listed in the title compound in the form of semi-solid substances.

Example 11

Getting aliskiren from tert-butyl ether ((1S,2S,4S)-4-(2-carbarnoyl-2-methylpropionyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropane)benzyl]-3-methylbutyl}-5-etylhexyl)carbamino acid

Method And

A solution of compound (XIa), 3-amino-2,2-dimethylpropanamide and 2-hydroxypyridine in tert-butylmethylether ether containing triethylamine, stirred at 83°C for 18 h, then the reaction mixture was cooled to room temperature, diluted with toluene and washed with aqueous 10% solution of sodium hydrosulphate. The organic phase was separated and washed with water, the solvent was removed in vacuum, to receive the oil that is suspended in hexane and stirred. A solid substance was separated by filtration, hexane was removed under vacuum, it was obtained tert-butyl ester ((1S,2S,4S)-4-(2-carbarnoyl-2-methylpropionyl)-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxypropane)benzyl]-3-methylbutyl}-5-etylhexyl)carbamino sour is you, the compound (XIb), in the form of foam.

The compound of formula (XIb) was dissolved in a solution triperoxonane acid at room temperature in methylene chloride, and the mixture was stirred for 2 h, then the pH is brought to 10 by addition of 37% solution of sodium hydroxide. The aqueous phase was extracted (g ml), dichloromethane (see, for example, in EP 0678503, example 137).

Profumata specified in the title compound was obtained from the free compound or its hydrochloride, as described, for example, in US 6730798, example J1 (including mixing with fumaric acid, dissolved in ethanol, filtering, evaporation of the resulting solution, re-dissolving the residue in acetonitrile, adding a small amount of profumata specified in the title compound as a seed and separating precipitated in the sediment material). The referenced patent is incorporated in this description by reference.

Method In

Receiving from the compounds of formula (Ha) using tert-butyl ester ((1S,2S)-4-(2-carbarnoyl-2-methylpropionyl)-1-{(S)-2-[4-methoxy-3-(3-methoxypropane)benzyl]-5-metal-2-oxohexyl}carbamino acid

The compound of formula (Ha) was converted into amide (Xb) is a standard way of condensing peptides. The restoration was performed as described above. The method is described in detail in the book Houben-Weyl, Methods der Organische Cheie, 4-eed., Synthese von Peptiden 1.

An alternative method of preparing compounds of the formula (XI) is shown in scheme 4.

Stage A0)

Tert-butyl ester {(1S,3S)-1-formyl-3-[4-methoxy-3-(3-methoxypropane)benzyl]-4-methylpentyl}carbamino acid (XIVa)

N-Boc-protected alcohol (VIa) is selectively oxidized to the corresponding aldehyde (XIVa) according to the method described in the following activities: a) F.Montanari and others, J.O.C., 54, 2970 (1989) or b) Review: H. van Bekkum, etc., Synthesis 1153 (1996).

Stage And

Ethyl ester of (4S,5S,7S)-5-tert-butoxycarbonylamino-4-hydroxy-7-[4-methoxy-3-(3-methoxypropane)benzyl]-8-methylnon-2-inaaway acid (XVa)

In the solution of the lithium salt of ethyl ester of propionic acid in tetrahydrofuran (110 ml) (obtained by treatment of ethylpropyl (12,27 g) molar equivalent of LDA and stirring for 30 min to complete the transformation) at -78°C was slowly added a solution of aldehyde (31 g, 70,8 mmole) in tetrahydrofuran (60 ml). The reaction mixture was stirred for 60 min and the reaction was stopped by slow addition of glacial acetic acid. The solvent was removed, the residue was dissolved in methylene chloride and the resulting solution washed with water (2×200 ml). The aqueous phase re-extracted with methylene chloride (200 ml), the organic phases were combined and the solvent was removed. The residue was re-dissolved in ethyl acetate and fil is listed through a layer of silica gel (eluent: ethyl acetate). The fractions containing the product were combined, the solvent was removed in vacuum, when it received an acetylene alcohol (of 31.4 g) in the form of oil red.

1H-NMR (CDCl3): 6,8-of 6.65 (3H, m, Ph), 4,71 (1H, .d, HE), 4,42 (1H, .d, CHNH), 4,30-of 4.05 (4H, m, 2×CH2), 3,81 (3H, s, MeO), 3,70 (1H, m, SNON), OF 3.57 (2H, m, CH2O)to 3.35 (3H, s, MeO), 2,50 (1,5H, m, CHPh and part of the signal SN), 2,10 (2,5H, CH2and part of the signal SN), 1,80-1,20 (N, m), 1.85 to (6N, d, iPr).

B) Ethyl ester of (4S,5S,7S)-5-tert-butoxycarbonylamino-4-hydroxy-7-[4-methoxy-3-(3-methoxypropane)benzyl]-8-methylnonanoic acid (XVIa)

In solution acetylene (14 g) in tetrahydrofuran (350 ml) was added platinum oxide (1.7 g). The resulting suspension was kept in an atmosphere of hydrogen and stirred for 2 h 20 min under normal pressure, then the suspension was filtered, the solvent was removed, it was obtained a colorless oil (31 g)which was used in the next stage without additional purification (see below).

C) Tert-butyl ether [(1S,3S)-3-[4-methoxy-3-(3-methoxypropane)benzyl]-4-methyl-1-((S)-5-oxitetraciclina-2-yl)pentyl]carbamino acid (XVIIa)

The hydrogenation product (31 g)obtained at the previous step, was dissolved in toluene (50 ml) was added glacial acetic acid (16 ml). The resulting mixture was heated at 95-100°C for 2 h, then cooled and the solvent UDA the Yali in vacuum. The residue was dissolved in toluene (200 ml), diluted with water (100 ml) and saturated aqueous sodium bicarbonate (100 ml). The mixture was extracted and the organic phase was separated. The organic phase is again washed with water (100 ml). The aqueous phase was separated and combined with the previous aqueous phases. The combined aqueous phase was extracted again with toluene (200 ml), the organic phase was separated and combined with the previous organic phase. The solvent was removed in vacuum, when it received a yellow oil (27.4 g). The residue is triturated in isopropanol (100 ml), and the product began to crystallize, and then slowly added hexane (200 ml) and the resulting suspension was stirred at room temperature for 1 h, the Suspension was filtered, the product washed with hexane and dried in vacuum, to receive the lactone in the form of a crystalline solid, white (14 g). tpl.110°C, [α]D=-10,8° (1% in the Meon).

1H-NMR (DMSO, 120°C): 6,85-6,79 (2H, m, Ph)6,70 (1H, m, Ph), and 6.25 (1H, .d, NH), and 4.40 (1H, m, lactone CH), was 4.02 (2H, t, CH2O in), 3.75 (3H, s, MeO), 3,62 (1H, m, CHN), 3,30 (2H, t, CH2O)of 3.25 (3H, s, MeO), 2,60-of 2.30 (4H, m, CH2CO-lactone and PhCH2), to 2.15 (1H, m, CH lactone), 1,95 and 1.80 (3H, m, CH2+CH lactone), of 1.65 (2H, m, 2×CH), 1,50 (1H, m, CH), 1,40 (N, s, tBu), 1,20 (1H, m, CH), of 1.80 (6H, d, 2×iPr).

D) (S)-5-{(1S,3S)-1-Amino-3-[4-methoxy-3-(3-methoxypropane)benzyl]-4-methylpentyl}dihydrofuran-2-he (XVIIIa)

The lactone hydrochloride

A solution of lactone (2,96 g)obtained at the previous step, was dissolved in ethyl acetate (10 ml) and treated 1,55 M solution of gaseous hydrogen chloride in ethyl acetate. The resulting mixture was stirred at room temperature for 3 h, the solvent was removed in vacuo, the residue was re-dissolved 1.55 M solution of gaseous hydrogen chloride in ethyl acetate (16 ml) and the mixture was stirred at room temperature for a further 16 hours the Solvent was removed in vacuum, thus obtained amine hydrochloride in the form of a yellow foam (2.5 g).

(E) (5S,6S)-5-Hydroxy-6-{(S)-2-[4-methoxy-3-(3-methoxypropane)benzyl]-3-methylbutyl}piperidine-2-he (XIXa)

Amin (13,0 g)obtained at the previous step, was dissolved in methanol (40 ml) and at room temperature was added triethylamine (5,69 g). The resulting mixture was stirred at room temperature for 24 h, the solvent was removed in vacuo, the residue was re-dissolved in methylene chloride (100 ml) and the solution was washed with water (100 ml). The organic phase was dried over sodium sulfate, the solvent was removed in vacuum, it was received piperidine-2-he (12,08 g) as a yellow foam, which was used in the next stage without additional purification.

1H-NMR (CDCl3): 7,29 (1H, .s, NH), 6,85-of 6.65 (3H, m, Ph), the 5.45 (1H, .s, HE), 4,10 (2 is, t, CH2O)a 3.83 (4H, m, MeO+NIT), TO 3.58 (2H, t, CH2O)to 3.35 (3H, s, MeO), up 3.22 (1H, users, CHNH), 2.71 to 1,25 (12H, m), 0,90 (6N, m, 2×iPr).

F) Tert-butyl ether (2S,3S)-3-tert-butoxycarbonylamino-2-{(S)-2-[4-methoxy-3-(3-methoxypropane)benzyl]-3-methylbutyl}-6-oxopiperidin-1-carboxylic acid (HHA)

Piperidine-2-he (12,08 g)obtained in the previous phase at room temperature was dissolved in tetrahydrofuran (20 ml) was added N,N-dimethylaminopyridine (0,63 g), triethylamine (5,98 g) and di-tert-BUTYLCARBAMATE (12,89 g). The resulting mixture was stirred at room temperature for 24 h, the solvent was removed in vacuo, the residue was dissolved in ethyl acetate (150 ml) and the solution was washed with an aqueous solution of citric acid (5%, 100 ml). The aqueous phase is re-extracted with ethyl acetate (100 ml), the combined organic phases were washed with water (2×100 ml). The solvent was removed in vacuum, when it received a yellow oil (16,95 g). After purification by chromatography on silica gel (eluent: toluene/ethyl acetate, 1:1) were purified bis-BOC-derivative, which crystallized upon storage at room temperature. tpl.89-90°C, after recrystallization from EtOAc/cyclohexane. [α]D=13,0° (1% in the Meon).

1H-NMR (CDCl3): 6,85-6,70 (3H, m, Ph), is 4.93 (1H, m, CHOBoc), 4,70 (1H, m, CHNHBoc), 4,11 (2H, t, CH2O)a 3.83 (3H, s, MeO), to 3.58 (2H, t, CH2O)3,37 (3H, s, MeO), 2,652,30 (3H, m), 2,18-of 1.40 (6H, m), of 1.52 (9H, s, tBu), to 1.48 (9H, s, tBu), of 0.82 (6H, m, 2×iPr).

G) Tert-butyl ether (2S,3S)-3-tert-butoxycarbonylamino-5-(1-hydroxy-1-methylethyl)-2-{(S)-2-[4-methoxy-3-(3-methoxypropane)benzyl]-3-methylbutyl}-6-oxopiperidin-1-carboxylic acid (XXIa)

A solution of bis-BOC-derivative (2,46 g) in tetrahydrofuran (10 ml) was cooled to

-78°C and for 10 min was added dropwise a solution of hexamethyldisilazide lithium (5,19 g) in tetrahydrofuran (3 ml). The resulting solution was stirred at

-78°C for 2 h, was added diethylether of boron TRIFLUORIDE (0,705 g), then acetone (1,93 g) in tetrahydrofuran (3 ml). The mixture was stirred at -78°C for 1 h, was added another portion of titlefirst of boron TRIFLUORIDE (0.12 g), then stirred at -78°C for 24 h In the mixture was quickly added to the buffer solution, pH 7.0 (100 ml), the temperature was raised to 0°C, the mixture was diluted with buffer solution pH 7.0 (60 ml) and ethyl acetate (200 ml). The aqueous phase was extracted and the organic phase was separated, then the aqueous phase is re-extracted with ethyl acetate (100 ml) and the organic phase was separated. The organic phases were combined, the solvent was removed in vacuo, the residue was led. The solid is suspended in hexane (25 ml) and stirred at 0°C during the night. A solid substance was separated by filtration and washed with hexane, if e is ω was obtained the desired compound (2.37 g). tpl.118-119°C, after recrystallization from EtOAc/hexane. [α]D=to 34.8° (1% in the Meon).

1H-NMR (CDCl3): 6,80-of 6.65 (3H, m, Ph), 4,95-4,80 (2H, m, HE+CHOBoc), 4,50 (1H, m, CHNHBoc), 4,11 (2H, t, CH2O)a 3.83 (3H, s, MeO), of 3.56 (2H, t, CH2O)to 3.35 (3H, s, MeO), 2,70-of 2.38 (3H, m), 2,20-to 1.60 (6H, m), of 1.52 (9H, s, tBu), a 1.45 (9H, s, tBu), 1,25 (3H, s, Me), of 1.18 (3H, s, Me)to 0.85 (6H, m, 2×iPr).

H) Tert-butyl ether (2S,3S)-3-tert-butoxycarbonylamino-5-Isopropenyl-2-{(S)-2-[4-methoxy-3-(3-methoxypropane)benzyl]-3-methylbutyl}-6-oxopiperidin-1-carboxylic acid (XXIIa)

The solution of the tertiary alcohol (2,786 g)obtained at the previous step, in methylene chloride (30 ml) was cooled to -5°C. at this temperature was added triethylamine (4,33 g) and added dropwise over 20 min a solution of methanesulfonamide (2,45 g) in methylene chloride (7 ml). The reaction mixture was stirred at -5°C for 60 min, the reaction was stopped by adding buffer solution, pH 3.0 (20 ml), aqueous citric acid (10%, 30 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The organic phase was separated and washed with water (2×100 ml). The combined aqueous washing solutions are re-extracted with methylene chloride (100 ml) and the organic phases were combined. The solvent was removed in vacuum, to receive the crude product as oil (3,41 g)which was purified by chromatography (eluent: toluene/ethyl acetate, 9:1) and, if e is ω has received cleared the desired product (of 2.26 g).

1H-NMR (CDCl3): 6,85-of 6.65 (3H, m, Ph), 5,10-4,88 (2H, m, CH2=With+CHOBoc), with 4.64 (1H, m, CHNHBoc), 4,11 (2H, t, CH2O)a 3.83 (3H, s, MeO), to 3.58 (2H, t, CH2O)to 3.35 (3H, s, MeO), and 3.2 (1H, t, CH), 2,60-of 2.30 (2H, m, PhCH2), 2,10 (2H, m), of 1.80 (3H, s, Me), 1,79 is 1.60 (3H, m), of 1.52 (9H, s, tBu), to 1.48 (9H, s, tBu), 0,81 (6H, m, 2×iPr).

I) Tert-butyl ether (2S,3S)-3-tert-butoxycarbonylamino-5-isopropylidene-2-{(S)-2-[4-methoxy-3-(3-methoxypropane)benzyl]-3-methylbutyl}-6-oxopiperidin-1-carboxylic acid (XXIIIa)

Solution connection with ekzoticheskoy double bond (1,95 g) in ethyl acetate (25 ml) was treated with activated charcoal (1 g) and triethylamine (0.3 g). The mixture was stirred at room temperature for 2 h and filtered. The solid is washed with ethyl acetate (10 ml), the solvent was removed in vacuum, while the received semi-solid substance (1,90 g), which was led from hexane, to receive the purified product (1,257 g).

1H-NMR (CDCl3): 6,80-of 6.65 (3H, m, Ph), of 4.95 (2H, m, CHOBoc), and 4.75 (1H, m, CHNHBoc), 4,10 (2H, t, CH2O)a 3.83 (3H, s, MeO), to 3.58 (2H, t, CH2O)to 3.35 (3H, s, MeO), 2,85 is 2.55 (2H, m, PhCH2), a 2.45-of 2.30 (2H, m), 2,10 (5H, m), 1,73-1,40 (23H, m), 0,81 (3H, d, iPr), of 0.71 (3H, d, iPr).

J) Tert-butyl ether (2S,3S,5S)-3-tert-butoxycarbonylamino-5-isopropyl-2-{(S)-2-[4-methoxy-3-(3-methoxypropane)benzyl]-3-methylbutyl}-6-oxopiperidin-1-carboxylic acid (XXIVa)

A solution of olefin (0,38 g)obtained in the previous the stage, in ethyl acetate (10 ml) was treated with Pt/C (5%, 0.3 g), was added triethylamine (0,086 g) and the suspension was kept in an atmosphere of hydrogen. The temperature was raised to 50°C and pressure up to 5 bar. The reaction mixture was stirred under these conditions for 24 h, cooled to room temperature and the catalyst was removed by filtration. The solvent was removed in vacuo, the residue was purified by chromatography on silica gel (eluent: toluene/ethyl acetate, 3:1). The fractions containing the product were combined and the solvent was removed, it was obtained the desired compound (0.3 g) as oil.

1H-NMR (CDCl3): 6,85-6,70 (3H, m, Ph)to 5.00 (1H, m, CHOBoc)and 4.65 (1H, m, CHNHBoc), is 4.15 (2H, t, CH2O)a 3.83 (3H, s, MeO), to 3.58 (2H, t, CH2O)to 3.35 (3H, s, MeO), 2,60-to 2.40 (2H, m, PhCH2), 2,10 (2H, m, CH2), 2,00-of 1.65 (4H, m), 1,58-of 1.30 (20H, m)to 0.85 (6H, m, 2×Me), 0,75 (6N, m, 2×Me).

C) Tert-butyl ester {(1S,3S)-1-((2S,4S)-4-isopropyl-5-oxitetraciclina-2-yl)-3-[4-methoxy-3-(3-methoxypropane)benzyl]-4-methylpentyl}carbamino acid (XIa)

The solution piperidine (0.28 g) in tetrahydrofuran (3 ml) at room temperature was treated with an aqueous solution of sodium hydroxide (2.0 M, 1 ml)was added to chloride of benzyltriethylammonium (2 mg) and the mixture was stirred at 40°C for 5 h, then was added ethanol (1 ml) and stirred at 40°C for another 24 h the mixture was cooled to room temperature and added to ice MC usnow acid (2 ml). The acidic mixture was extracted with a mixture of toluene/water and the organic phase was separated. The solvent was removed in vacuum, to receive the oil, which was re-dissolved in glacial acetic acid (5 ml) and stirred at 100°C for 24 h Acetic acid was removed in vacuo, the residue was purified preparative thin-layer chromatography (eluent: ethyl acetate/hexane, 1:1), it was obtained the desired product (0,0476 g). [α]D=-6,1° (C=3 in CH2Cl2).

1H-NMR (CDCl3): for 6.81-6,70 (3H, m, Ph), and 4.40 (1H, m cyclic, SNO-lactone), 4,10 (2H, t, CH2O), 3,85-with 3.79 (4H, m, MeO+CHNBoc), to 3.58 (2H, t, CH2O)to 3.35 (3H, s, MeO), 2,85 is 2.55 (2H, m, PhCH2), to 2.65 (1H, dd, PhCH), to 2.55 (1H, m, lactone-SNA), is 2.40 (1H, dd, PhCH), 2,12-2,05 (5H, m), 1.70 to 1,30 (13H, m), of 1.05 (3H, d, Me)of 0.95 (3H, d, Me)to 0.85 (6H, d, iPr).

Examples of obtaining compound (VIIIb)

Obtain methyl ester of 2-(R)-(4-nonyloxy)isovalerianic acid (R4means isopropyl, R9means methyl)

Methyl ester of 2-(R)-hydroxyisovaleric acid (43,6 g, 330 mmol), obtained according to the method described in these papers (see references: 1A-1C), was dissolved in dichloromethane (50 ml), was added triethylamine (38,4 g, 379,4 mmole) and dimethylaminopyridine (4.0 g, 33 mmole). After cooling the solution to 0°C. slowly over 45 min under stirring was added 4-nitrobenzenesulfonamide (80,42, 362,9 mmole) in dichlormid is not (250 ml). The resulting mixture was stirred overnight, cooled to 0°C and acidified to pH 3.5 by the addition of hydrochloric acid (2 N., 25 ml). The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were washed with water (100 ml). The organic phase was evaporated in vacuo, the resulting orange oil was re-dissolved in toluene (200 ml) and was extracted with hydrochloric acid (1 N., 30 ml), brine (50 ml), saturated sodium bicarbonate solution (50 ml) and again with saline. The organic phase was filtered through a layer of silica gel and the product was suirable toluene (approximately 2 liters). The fractions obtained product was evaporated in vacuum, thus obtained orange oil (91,5 g), which crystallized after addition of the seed and cooling in the refrigerator. The obtained crystals are triturated in pentane, filtered and washed with pentane (2×50 ml)after drying was obtained crystalline product (84,3 g). tpl.46-48°C. [α]D=+6,5° (1% in CHCl3).

1H-NMR (CDCl3): a 8.34 (2H, d), 8,08 (2H, d), of 4.77 (1H, d), 3,61 (3H, s), 2,17-of 2.24 (1H, m), of 0.91 (3H, d)0,86 (3H, d).

References: 1a) Tetrahedron, 46, 6623, (1990)

b) J. Chem. Soc.; Perk. Trans. 1 (12), 1427 (1996)

1C) J. Org. Chem. 52, 4978 (1987).

Getting dimethyl ether (R)-2-isopropyl-3-methoxycarbonyl-succinic acid (R4means isopropyl, all R9mean is ethyl)

In a three-neck flask with a volume of 500 ml was placed sodium hydride (16,8 g, 420 mmol, 60% in mineral oil)NaH was washed with portions of hexane (3×20 ml) in a stream of argon and then was added n-dipropionyl ether (150 ml). The reaction mixture was cooled to 0°C and slowly under stirring was added diethylmalonate (59,45 g, 450 mmol), dissolved in n-DIPROPYLENE ether (50 ml). While there has been an evolution of hydrogen and the temperature rise, adding the reagent, the temperature of the mixture was maintained at 15°C, while formed white viscous suspension. To dilute the heterogeneous mixture was added another portion of n-dipropylamino ether (50 ml). The reaction temperature was raised to 50°C. and the mixture was stirred for 2 h to complete deprotonation. At the same temperature in the heterogeneous mixture was added a solution of noselite" (47,58 g, 150 mmol) in n-DIPROPYLENE ether (120 ml). A very viscous brown suspension was heated at an internal temperature of 85°C for 24 h, while there was complete conversion of noselite (GC). The reaction mixture was cooled to room temperature, the reaction was stopped by the careful addition of toluene (150 ml) and water (150 ml). The aqueous phase was extracted with toluene (2×50 ml), the organic phases were combined and washed with sodium bicarbonate (2×50 ml), hydrochloric what Isletas (2 ad, 2×50 ml) and water (3×50 ml), the solvent was evaporated in vacuum, thus obtained yellow oil (48,2). The resulting oil is triturated in hexane (150 ml) under stirring, was evaporated, the thus obtained oil is light yellow (28 g)which was filtered through a layer of silica gel, the product was suirable a mixture of toluene/ethyl acetate (9:1). The fractions containing pure product were combined, purified by chromatography, the solvent was evaporated in vacuum, thus received almost colorless oil, which crystallized in the refrigerator over night. The obtained crystals were washed in cold pentane, filtered and washed with a small amount of pentane, after drying in vacuo received the product almost white (9.5 g), tpl.45-48°C. [α]D=+62,5° (1% in the Meon).

1H-NMR (CDCl3): a 3.87 (1H, d), 3,74 (3H, s), 3,70 (3H, s), 3,68 (3H, s), of 3.12 (1H, dd), 1,78-of 1.85 (1H, m), a 1.01 (3H, d)to 0.88 (3H, d).

1. The method of obtaining the compounds of formula (A)

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3and R4independently denote a branched C3-C6alkyl; and R5means3-C12cycloalkyl, Csub> 1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanolamine(C1-C6)alkyl, (O)-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl; or (C1-C6alkyl)2N-C(O)-(C1-C6)alkyl; or pharmaceutically acceptable salts, comprising the following stages:
disclosure laktamovogo ring in N - and O-protected 5-hydroxymethyl-3-substituted pyrrolidinone formula (IV)

where a value of R3defined above, R7means O-protective group, a R8means N-protective group;
in the presence of ORGANOMETALLIC compounds of the formula (XIIc)

obtaining substituted benzoylpropionic formula (V)

where the values of R1, R2, R3, R7and R8defined above;
recovery benzylcarbamoyl group in the compound of formula (V) with subsequent selective removal of the O-protective group receiving the receiving the compounds of formula (VI), containing free hydroxyl group

where the values of R1, R2, R3and R8defined above;
oxidation of the hydroxyl group in the compound of formula (VI) to carboxyl group in a compound of formula (VII)

where the values of R1, R2, R3and R8defined above;
activation of the carboxyl group in the compound of formula (VII) to obtain the corresponding activated derivative of the formula (VIIIa)

where the values of R1, R2, R3, R7and R8defined above and X is halogen, R10OC(O)O-, where R10means C1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl or6-C10aryl(C1-C6)alkyl, Me(MeOH)N - or imidazolyl;
condensation of an activated derivative of the formula (VIIIa) and chiral derivative malonate (VIIIb)

where a value of R4defined above, E means C(O)OR9and R9means C1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C2-C20alkenyl or6-C10aryl(C1-C6)alkyl, predpochtite is the super C 1-C6alkyl or C6-C10aryl(C1-C4)alkyl;
obtaining the compounds of formula (IX)

where the values of R1, R2, R3, R4, R8, R9and E defined above;
decarboxylation of the ester (carboxyl) groups E and simultaneous hydrolysis of the ester group to obtain carboxylic acid of formula (X)

where the values of R1, R2, R3, R4and R8defined above, a R/means hydrogen or R9;
the transformation of the carboxylic acid of formula (X) in the compound of formula (A);
and, if necessary, conversion of the compounds of formula (A) into its pharmaceutically acceptable salt.

2. The method according to claim 1, in which the starting compound used is N - and O-protected 5-hydroxymethyl-3-substituted, pyrrolidine (IV), and the sequence of stages corresponds to the diagram 1A

where the values of R1, R2, R3, R4, R5, R7, R8and R9defined in claim 1.

3. The method according to claim 2, in which the starting compound used L-pyroglutamic acid (I), and the sequence of stages corresponds to the diagram 1b

where the values of R1, R2, R3, R4, R5, R7, R8and 9defined in claim 2, and R6means C1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl or6-C10aryl(C1-C6)alkyl.

4. The method according to claim 2 or 3, in which the starting compound used L-pyroglutamic acid (I), and the sequence of stages corresponds to the diagram 1

where the values of R1, R2, R3, R4, R5, R6, R7, R8and R9defined in claim 2 or 3, respectively.

5. The method according to claim 1, wherein the compound of formula (IV) is obtained from L-pyroglutamic acid as shown in scheme 1 with

where the values of R3, R6and R8defined in claim 1 respectively.

6. The method according to any of PP and 4, in which the compound of formula (II) into a compound of formula (III) as shown in scheme 2

where the values of R3and R6defined in claim 3 or 4, respectively.

7. The method of obtaining the N - and O-protected 5-hydroxymethyl-3-substituted of pyrrolidinone formula (IV), comprising the following stages:
the esterification of L-pyroglutamic acid of the formula (I)

to obtain the corresponding complex ester of the formula (II)

PR is the rotation of the compounds of formula (II), 5-hydroxymethyl-3-substituted, pyrrolidine formula (III)

protection of the hydroxyl group O-protecting group, R7and protection of the amino group of the N-protecting group R8obtaining N - and O-protected 5-hydroxymethyl-3-substituted of pyrrolidinone formula (IV)

where the values of R3, R6, R7and R8defined in claim 1.

8. The method of obtaining the N - and O-protected 5-hydroxymethyl-3-substituted of pyrrolidinone formula (IV), comprising the following stages:
the esterification of L-pyroglutamic acid of the formula (I)

to obtain the corresponding complex ester of the formula (II)

protection of the amino group in the compound of formula (II) an N-protecting group R8to obtain N-protected pyrrolidinone formula (IIe)

the transformation of compounds of formula (IIe) in the compound of formula (IIf)

by introducing a hydroxyalkyl substituent in pyrrolidino with subsequent conversion of the hydroxyl group into a leaving group and elimination,
the transformation of compounds of formula (IIf) in the compound of formula (IIg)

by restoring the ester residue to alcohol, and
protection of the hydroxyl group in the compound of formula (IIg) O-protecting group, R7obtaining N - and O-protected 5-hydroxymethyl-3-umestnogo of pyrrolidinone formula (IV)

where the values of R3, R6, R7and R8defined in claim 1.

9. The method according to claim 7, in which the stage of transformation of compounds of formula (II), 5-hydroxymethyl-3-substituted, pyrrolidine formula (III) is conducted as shown in scheme 2

where the values of R3and R6defined in claim 1.

10. The method according to claim 7, in which the phase transformation of compounds of formula (II), 5-hydroxymethyl-3-substituted, pyrrolidine formula (III) includes the following stages:
the reduction of the ester group in the compound of formula (II)

with the formation of alcohol (IIa)

acetalization the compounds of formula (IIa) in the presence of an aromatic aldehyde with the formation of the compounds of formula (IIb)

activation of the compounds of formula (IIb) in terms of carboalkoxylation with subsequent alkylation of the electrophile R3-X, where X means halogen or sulfonyloxy with obtaining the compounds of formula (IIc)

saponification of compounds of formula (IIc) ether group, followed by decarboxylation to obtain the compounds of formula (IId), and

deacetylase or peracetylated the compounds of formula (IId) with the formation of the compounds of formula (III)

where the values of R3and R6defined in claim 1.

11. The method according to claims 1 and 2, in which the phase transformation of the carboxylic acid of formula (X) in the compound of formula (A) includes the following stages:
stereoselective recovery4-the carbonyl group in the compound of formula (X)

and subsequent cyclization to obtain a lactone of the formula (XI)

disclosure lactoovo cycle in the compound of formula (XI) by treatment with the amine H2NR5to obtain the amide of formula (XIII), and

removal of the N-protective group in the compound of formula (XIII) with the formation of free amine and optional salt to obtain the compounds of formula (A)

where the values of R1, R2, R3, R4, R5, R8and R/defined in claim 1.

12. The method according to claims 1 and 2, in which the phase transformation of the carboxylic acid of formula (X) in the compound of formula (A) includes the following stages:
the formation of amide carboxylic acid compound of formula (X)

in terms of condensing peptides with obtaining the compounds of formula (XII)

stereoselective recovery4-the carbonyl group in the compound of formula (XII) with a compound of the formula (XIII)

removal of the N-protective group in the compound of formula (XIII) with the formation of free amine and optional salt to obtain the compounds of formula (A)

where the values of R1, R2, R3, R4, R5, R8and R/defined in claim 1.

13. The method of obtaining the compounds of formula (A)

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3and R4independently denote a branched C3-C6alkyl; and R5means3-C12cycloalkyl, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6alkoxy(C1-C6)alkyl, C1-C6alkanoyloxy(C1-C6)alkyl, C1-C6aminoalkyl, C1-C6alkylamino(C1-C6)alkyl, C1-C6dialkylamino(C1-C6)alkyl, C1-C6alkanolamine(C1-C6)alkyl, (O)-(C1-C6)alkyl, C1-C6alkyl-O-(O)C-(C1-C6)alkyl, H2N-C(O)-(C1-C6)alkyl, C1-C6alkyl-HNC(O)-(C1-C6)alkyl; or (C1-C6alkyl)2N-C(O)-(C1 -C6)alkyl; or pharmaceutically acceptable salts, comprising the following stages:
disclosure laktamovogo ring in N - and O-protected 5-hydroxymethyl-3-substituted pyrrolidinone formula (IV)

where the values of R3defined above, R7means O-protective group, a R8means N-protective group;
in the presence of ORGANOMETALLIC compounds of the formula (XIIc)

obtaining substituted benzoylpropionic formula (V)

where the values of R1, R2, R3, R7and R8defined above;
recovery benzylcarbamoyl group in the compound of formula (V) with subsequent selective removal of the O-protective group to obtain the compounds of formula (VI)containing a free hydroxyl group

where the values of R1, R2, R3and R8defined above;
selective oxidation of N-protected alcohol of formula (VI) to the corresponding aldehyde of formula (XIV)

where the values of R1, R2, R3and R8defined above;
nucleophilic attach to N-protected aldehyde of formula (XIV) with the formation of acetaminophine formula (XV)

where the values of R1, R2, R3and R8about the defined above, a R9means C1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C2-C20alkenyl or6-C10aryl(C1-C6)alkyl;
hydrogenation of acetaminophine formula (XV) with the formation of saturated γ-hydroxyether of the formula (XVI)

where the values of R1, R2, R3, R8and R9defined above;
circuit lactoovo cycle in a saturated γ-hydroxyether of the formula (XVI) with the formation of the γ-lactone of the formula (XVII)

where the values of R1, R2, R3and R8defined above;
the release of the nitrogen atom in the γ-lactone of the formula (XVII) with the formation of aminoethane formula (XVIII)

where the values of R1, R2and R3defined above;
turning aminoethane formula (XVIII) in the appropriate piperidine formula (XIX)

where the values of R1, R2and R3defined above;
protection of both hydroxyl and amino groups, in piperitenone formula (XIX), with the formation of the bis-protected piperidine formula (XX)

where the values of R1, R2, R3, R7and R8defined above;
the introduction of branched alkyl groups, soda is containing a tertiary hydroxyl, in piperidinoethyl cycle in the structure of bis-protected piperidine formula (XX) with the formation of hydroxyalkylated derivative of the formula (XXI)

where the values of R1, R2, R3, R7and R8defined above;
turning hydroxyalkylated derived piperidine formula (XXI) in derived piperidine containing ekzoticheskuyu double bond of the formula (XXII)

where the values of R1, R2, R3, R7and R8defined above;
isomerisation of the double bond (ekzoticheskoy double bond) in the derived piperidine formula (XXII) with the formation of the olefin of formula (XXIII)

where the values of R1, R2, R3, R7and R8defined above;
hydrogenation of the olefin of formula (XXIII) with the formation of alkyl substituted derivative of piperidine formula (XXIV)

where the values of R1, R2, R3, R7and R8defined above; and
disclosure cycle derived piperidine formula (XXIV) with formation of an intermediate derived γ-hydroxy acid, which is subjected to lactonization with obtaining the compounds of formula (XI)

the transformation of compounds of formula (XI) in the compound of formula (A);
and, if necessary, to build the group of the compounds of formula (A) into its pharmaceutically acceptable salt.

14. The method of obtaining the compounds of formula (A) in item 13, in which the compound of formula (VI) into a compound of formula (XI) according to the method comprising the following stages:
selective oxidation of N-Boc-protected alcohol of formula (VI) to the corresponding aldehyde of formula (XIV);
nucleophilic attach to the BOC-protected aldehyde of formula (XIV) with the formation of acetaminophine formula (XV);
hydrogenation of acetaminophine formula (XV) with the formation of saturated γ-hydroxyether of the formula (XVI);
circuit lactoovo cycle in a saturated γ-hydroxyether of the formula (XVI) with the formation of the γ-lactone of the formula (XVII);
the release of the nitrogen atom in the γ-lactone of the formula (XVII) with the formation of aminoethane formula (XVIII);
turning aminoethane formula (XVIII) in the appropriate piperidine formula (XIX);
protection of both hydroxyl and amino groups in piperitenone formula (XIX) with the formation of bis-protected piperidine formula (XX);
introduction branched alkyl group containing a tertiary hydroxyl, piperidinoethyl cycle in the structure of bis-protected piperidine formula (XX) with the formation of hydroxyalkylated derivative of the formula (XXI);
turning hydroxyalkylated derived piperidine formula (XXI) in derived piperidine containing ekzoticheskuyu double bond of the formula (XXII);
isomerization of the active ingredient is Inoi communication (ekzoticheskoy double bond) in the derived piperidine formula (XXII) with the formation of the olefin of formula (XXIII);
hydrogenation of the olefin of formula (XXIII) with the formation of alkyl substituted derivative of piperidine formula (XXIV); and
disclosure cycle derived piperidine formula (XXIV) with formation of an intermediate derived γ-hydroxy acid, which is subjected to lactonization with obtaining the compounds of formula (XI).

15. The method according to any of the preceding paragraphs, in which the compound of formula (A) is characterized by the formula

where R1means 3 methoxypropylamine, R3means methoxy, and R3and R4means isopropyl, or its pharmaceutically acceptable salt.

16. The method according to item 15, in which the compound of formula (In) means profumata (2-carbarnoyl-2-methylpropyl)amide (2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropane)benzyl]-8-methylnonanoic acid.

17. The compound of the formula

where R3means branched C3-C6alkyl; R6means C1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl or6-C10aryl(C1-C6)alkyl.

18. The compound of the formula

where R3means branched C3-C6alkyl.

19. The compound of the formula

where R 3means branched C3-C6alkyl, a R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

20. The compound of the formula

where R3means branched C3-C6alkyl.

21. The compound of the formula

where R3means branched C3-C6alkyl; R7means O-protective group, for example, C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl; a R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

22. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or1-C6/sub> alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3means branched C3-C6alkyl; R7means C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl; and R8means6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl.

23. Connection p.22 characterized by the formula

where R1means 3 methoxypropylamine, R2means methoxy, R3means isopropyl, a R11and R12independent means tert-butyl or benzyl.

24. Connection item 22 or 23, in which R11and R12means tert-butyl.

25. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4 alkoxy; R3means branched C3-C6alkyl; R8means6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl,1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl.

26. Connection A.25 characterized by the formula

where R1means 3 methoxypropylamine, R2means methoxy, R3means isopropyl, a R12means tert-butyl or benzyl.

27. Connection on p. 25 or 26, where R12means tert-butyl.

28. The compound of the formula

where R1means halogen, C1-C6halogenated,1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3and R4independently denote a branched C3-C6alkyl; R8means6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl; and R9means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1 -C6)alkyl, C6-C10aryl, C2-C20alkenyl or6-C10aryl(C1-C6)alkyl.

29. Connection p formula

where R1means 3 methoxypropylamine, R2means methoxy, R3means isopropyl, R4means isopropyl, and R12means tert-butyl or benzyl.

30. Connection p or 29, where R12means tert-butyl.

31. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3means branched C3-C6alkyl; R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl; and R9means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C2-C20alkenyl or6-C10aryl(C1-C6)alkyl.

32. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3means branched C3-C6alkyl; R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl; and R9means C1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C2-C20alkenyl or C6-C10aryl(C1-C6)alkyl.

33. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3means branched C3-C6alkyl; and R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10 arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

34. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3means branched C3-C6alkyl.

35. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3means branched C3-C6alkyl.

36. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3means branched C3-C6alkyl; R7means O-protective group, for example, C1-C6alkyl, C1-C6alcox is(C 1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl; and R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

37. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3means branched C3-C6alkyl; R7means O-protective group, for example, C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl; and R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1With 6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

38. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3means branched C3-C6alkyl; R7means O-protective group, for example, C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl, and R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

39. The compound of the formula

where R1means halogen, C1-C6halogenated, C1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C 4alkoxy; R3means branched C3-C6alkyl; R7means O-protective group, for example, C1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3silyl; and R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

40. The compound of the formula:

where R1means halogen, C1-C6halogenated,1-C6alkoxy(C1-C6)alkyloxy or C1-C6alkoxy(C1-C6)alkyl; R2means halogen, C1-C4alkyl or C1-C4alkoxy; R3means branched C3-C6alkyl; R7means O-protective group, for example With1-C6alkyl, C1-C6alkoxy(C1-C6)alkyloxy,6-C10aryl(C1-C6)alkyl, C1-C6alkoxycarbonyl,6-C10aryl(C1-C6)alkoxycarbonyl or (C1-C8alkyl)3Seeley is; and R8means N-protective group, for example With6-C10aryl(C1-C6)alkyl, C1-C6alkylsulphonyl,6-C10arylcarbamoyl, C1-C6alkoxycarbonyl or6-C10aryl(C1-C6)alkoxycarbonyl.

41. Derived malonate formula (VIII'b)

where R9means C1-C20alkyl or C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C3-C20alkenyl or6-C10aryl(C1-C6)alkyl.

42. The method of obtaining the compounds of formula (VIIIb)

where R4means branched C3-C6alkyl, and R9means1-C20alkyl, C3-C12cycloalkyl,3-C12cycloalkyl(C1-C6)alkyl, C6-C10aryl, C2-C20alkenyl or6-C10aryl(C1-C6)alkyl, including
the transformation of D-valine or its derivative in D-2-hydroxyisovaleric acid by diazotization;
the esterification of D-2-hydroxyvalerenic acid in the presence of R9-X, where R9has the values defined above, and X denotes a leaving group, for example halogen or-HE;
etherification of the hydroxy-group in the structure of the ether D-2-isovalerianic the acid in the presence of 4-nitrobenzenesulfonamide getting nosilca; and
alkylation of noselite in the presence of an ester of malonic acid to obtain the compounds of formula (VIIIb).

43. The method according to § 42, in which the original connection using D-valine or its derivative, and the sequence of stages corresponds to the diagram 3

where the values of R9defined in § 42.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula pharmaceutically acceptable salts thereof, where ---- independently denotes a single or double bond; ring Q is imidazole, triazole (for example 1,2,3-triazole or 1,3,4-triazole), tetrazole or oxadiazole; B denotes C(R7)(R8) or C(R7), where if the bond between B and Y is a single bond, B denotes C(R7)(R8), and when the bond between B and Y is a double bond, B denotes C(R7); Y denotes C(R7), C(R7)(R8) or O, where if the bond between B and Y is a single bond, Y denotes C(R7)(R8) or O, and when the bond between B and Y is a double bond, B denotes C(R7); Z1 denotes -CH2-, -(CH2)2-, -CH2CH-CH3-, where Z1 is bonded on the left side to a nitrogen atom or -(CH2)3-; X denotes C(R1) or N; A denotes quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substitutes, which can be identical or different and are selected from a group comprising halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C(O)N(R3)(R4), 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; when R is present, each independently denotes halogen, C1-6-alkyl; each R1 denotes hydrogen or methyl; each R2 denotes cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5)R6, -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; R3 and R4 independently denote hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3 and R4 are bonded to the same nitrogen atom, they, together with the nitrogen atom, they form a 4-, 5- or 6-member ring which optionally contains one extra O atom in the ring; R5 denotes C1-4-alkyl; R6 denotes C3-7-cycloalkyl or C1-6-alkyl; R7 and R8 independently denote hydrogen or C1-6-alkyl; p equals 0, 1 or 2; r equals 0, 1, 2 or 3; s equals 0, 1, 2 or 3. The invention also relates to 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide, 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide, dihydrochloride 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide, 7-methyl-6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide, to use of the compound in any of claims 1-16, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 5-HT1 receptor mediated activity.

23 cl, 195 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of a compound of formula , where R1 is an alkyl or aryl group, or a pharmaceutically acceptable salt or solvate thereof, including hydrate, involving reaction of a compound of formula with a Grignard reagent of formula , where X is a halogen selected from Cl, Br and I, and R1 is an alkyl or aryl group; and optional conversion of the obtained free base compound of formula (I) to a pharmaceutically acceptable salt. The invention also relates to a compound of formula II; a compound of formula , where X is a halogen selected from O, Br and I and to use of formula II and IIIA compounds in synthesis of delmopinol and a derivative of the formula I compound.

EFFECT: novel method for synthesis of a compound of formula I using novel intermediate compounds of formulae II and IIIA.

18 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I or its pharmaceutically acceptable salt , where R, R9, Z, X, Q and Y are defined in the formula of invention. The compounds are chemokine receptor 2 and chemokine receptor 5 antagonists and can be used as a medicinal agent for preventing, relieving or treating autoimmune or inflammatory diseases or conditions.

EFFECT: obtaining a formula (I) compound, a pharmaceutical composition based on the formula (I) compound, use of the compound in paragraph 1 to prepare a medicinal agent for treating an autoimmune or inflammatory disease or condition, as well as use of the compound in paragraph 1 to prepare a medicinal agent for treating HIV infection or AIDS.

11 cl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are derivatives of 5H-pyrazolo[1,5-c][1,3]benzoxasin-5-yl)phenylmethanon of formula , possessing ability to inhibit HIV replication, where values of R1, R2, R3 substitutes are given in invention formula. Also describes is pharmaceutical preparation and application of compound for obtaining medication applied for treatment of conditions associated with HIV infection.

EFFECT: claimed compounds are applicable for prevention or treatment of HIV-produced infection and for AIDS treatment.

15 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I with anti-HIV activity , where R1 represents C1-6(Ar1)alkyl or C1-6(Ar1)oxyalkyl; R2 represents hydrogen or OR14; R3 represents hydrogen, halogen, hydroxyl, cyano, C1-6alkyl, C5-7cycloalkenyl, C1-6halogenalkyl, C1-6alkoxy, C1-6alkylthio, N(R8)(R9), NHAr2, N(R6)COR7, OCON(R8)(R9), OCH2CON(R9)(R9), CO2R6, CON(R8)(R9), SOR7, S(=N)R7, SO2R7, SO2N(R6)(R6), PO(OR6)2, C2-4(R12)alkynyl, R13, Ar2 or Ar3; R4 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R5 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy; R6 represents hydrogen or C1-6alkyl; R7 represents C1-7alkyl; R8 represents hydrogen or C1-6alkyl; R9 represents hydrogen, C1-6alkyl, C1-6hydroxyalkyl or C1-6(C1-6dialkylamino)alkyl; or N(R8)(R9) taken together represent azetidinyl, pyrrolydinyl, (R10)-piperidinyl, N-(R11)-piperazinyl, morpholinyl or dioxothiazinyl; R10 represents hydrogen; R11 represents hydrogen, C1-6alkyl, COR6 or CO2R6 ; R12 represents hydrogen, hydroxyl, N(R6)(R6), OSO2R7 or dioxothiazinyl; R13 represents dioxothiazinyl; R4 represents hydrogen or C1-6alkyl; Ar1 represents ,,,,,,,,; or Ar2 represents tetrazolyl, triazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl or indolyl, and is substituted with 0-2 substitutes selected from a group consisting of halogen, benzyl, C1-6alkyl, C1-6alkoxy, N((R8)(R9), CON(R8)(R9) and CO2R8; Ar3 represents phenyl substituted with 0-2 substitutes selected from a group consisting of halogen, cyano, hydroxy, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)methyl, C1-6halogenalkoxy, N(R8)(R9), CON(R6)(R6) and CH2N(R8)(R9), or represents dioxolanylphenyl; and X-Y-Z represents C(R14)2OC(R14)2C(R14)2, C(R14)2OC(R14)2C(R14)2C(R14)2; or pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition.

EFFECT: bicyclic heterocycles are disclosed, as well as their use HIV integrase inhibitors.

21 cl, 38 dwg, 8 tbl, 282 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R1 and R2 independently represent a hydrogen atom or a C1-6alkyl group, R3 is a hydroxyl group, R4 is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR7R8 or NR9, R5 is a hydrogen atom, R6 is a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group, C3-8cycloalkenyl group, amino group, C1-6alkylamino group, C6-14aryl group, C2-9heteroaryl group or C2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on HsEg5. In formula (I) A is C=O or CH2; B is optionally substituted C1-6alkyl, D is O or N, where O is substituted with one R8, and where N is substituted with one or more R8, R1 and R2 together with the carbon atoms with which they are bonded form optionally substituted isothiazole or isoxazole, condensed with a pyrimidine ring, optionally substituted with a substitute which is C1-6 alkyl. Values of the rest of the radicals are given in the formula of invention.

EFFECT: invention relates to use of disclosed compounds in making medicinal agents with inhibitory effect on HsEg5, to a method of obtaining inhibitory effect on HsEg5, to a pharmaceutical composition which contains the disclosed compound as an active ingredient.

22 cl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 2,3-dihydro-6-nitroimidazo[2,1-b]oxazol of general formula (1), as well as to their optically active forms and pharmacologically acceptable salts: where values of R1, R2 and n are given in i.1 of invention formula.

EFFECT: development of compounds, which have bactericidal action against Mycobacterium tuberculosis, polyresistant Mycobacterium tuberculosis and can be applied as antituberculosis medication.

3 cl, 16 ex, 183 tbl, 1515 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new derivatives of piperidine of formula I: , in which: R1 and R2 are selected from group, including alkyl, halogenalkyl, alkyl substituted with one or more hydroxy groups, -CN, alkynyl, -N(R6)2, - N(R6)-S(O2)-alkyl, -N(R6)-C(O)-N(R9)2, -alkylene-CN, -cycloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR5)-alkyl, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R9)2 and group , , , ,

provided that at least one of R1 and R2 stands for -CN or group , , , ,

W stands for =C(R8)- or =N-; X stands for -C(O)- or -S(O2)-; Y is selected from group, including -CH2-, -O- and -N(R6)-C(O)-, provided that: (a) atom of nitrogen of group -N(R6)-C(O)- is linked with X, and (b) if R1 and/or R2 stands for and Y stands for -O-, then X does not stand for -S(O2)-; Z stands for -C(R7)2-, -N(R6)-, or -O-; R3 is selected from group, including H and non-substituted alkyl; R4 stands for H; R5 stands for H or alkyl; R6 is selected from group, including H, alkyl, cycloalkyl and aryl; each R7 independently stands for H or alkyl; or each R7 together with circular atom of carbon, to which they are linked, as indicated, forms cycloalkylene ring; R8 is selected from group including H, alkyl, alkyl substituted with one or large number of hydroxygroups, -N(R6)2, -N(R6)-S(O2)- alkyl, -N(R6)-S(O2)-aryl, -N(R6)-C(O)-alkyl, -N(R6)-C(O)-aryl, alkylene-O-alkyl and -CN; R9 is selected from group including H, alkyl and aryl, or each R9 jointly with atom of nitrogen, to which, as indicated, they are linked, forms heterocycloalkyl ring; Ar1 stands for non-substituted phenyl; Ar2 stands for phenyll substituted with 0-3 substituents, selected from group including halogenalkyl; n equals 0, 1 or 2; and m equals 1, 2 or 3, and to their pharmaceutically acceptance salts and hydrates.

EFFECT: production of new biologically active compounds, having properties of antagonist of neurokinin receptor NK1.

35 cl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I and to its pharmaceutically acceptable salts. In formula I R1 is selected from C1-6alkyl, C3-12cycloalkyl, phenyl, furanyl, thienyl, pyridyl, where phenyl of radical R1, is optionally substituted with radical, which is selected from halogen, nitro, C1-6alkyl, C1-6alkoxy, substituted with halogen of C1-6alkyl and -XC(O)YR5; where X represents C1-4alkylene, Y represents O, and R5 represents hydrogen; R2 represents -C(O)NR4XOR5, where X represents C1-4alkylene; R4 is selected from hydrogen and C1-6alkyl; R5 represents phenyl; where any phenyl of radical R2, is optionally substituted with two radicals, which are independently selected from halogen, nitro and halogen-substituted C1-6alkyl; R3 represents phenyl, which is optionally substituted with radicals in number from 1 to 2, which are independently selected from halogen, C1-6alkyl, C1-6alkoxy, -XOXC(O)OR5, -XC(O)OR5, where X is independently selected from simple link and C1-4alkylene; and R5 is selected from hydrogen and C1-6alkyl. Invention also relates to compounds selected from 2-(2-nitro-4-trifluoromethylphenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 2-(2,4-dichlorophenoxy)ethyl ester 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carbonic acid, 3-(2,6-dichlorophenyl)-5-methyl-4-[2-(2-nitro-4-trifluoromethylphenoxy)ethoxymethyl]isoxazole, other compounds are specified in invention formula.

EFFECT: compounds of present invention may find application as medicinal agent that modulates activity of receptors activated by PPARδ.

7 cl, 2 tbl, 65 ex

FIELD: chemistry.

SUBSTANCE: in compounds of formula:

, A and B denote a pair of condensed saturated or unsaturated 5- or 6-member rings, where the said system of condensed rings A/B contains 0-2 nitrogen atoms, and said rings are further substituted with 0-4 substitutes independently selected from halogen, lower alkyl or oxo; and a and b are bonding positions for residues Y and D, respectively, and these positions a and b are in the peri-position relative each other on the said condensed ring system A/B; d and e are condensed positions between ring A and ring B in the said condensed ring system A/B; D is an aryl or heteroaryl cyclic system which denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S; which can be further substituted with 0-4 substitutes independently selected from lower alkyl and amine; Y is selected from -CH2 and -O-; M is selected from aryl, aryl substituted with a halogen or alkoxy; R1 is selected from aryl, aryl substituted with a halogen, heteroaryl, heteroaryl substituted with a halogen, where heteraryl denotes a 5- or 6-member aromatic ring containing 0-3 heteroatoms selected from O, N or S, and CF3; and if Y denotes -CH2- or -O-, then R1 further denotes a lower alkyl. The invention also pertains to use of compounds in claim 1, a pharmaceutical composition, a screening method on selective ligands of prostanoid receptors, as well as compounds of the formula.

EFFECT: obtaining novel biologically active compounds for inhibiting binding of prostanoid E2 with EP3 receptor.

25 cl, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula [I]: where A cycle represents a benzene cycle optionally having substitute(s) different from R1, R1 represents a group of formula RaSO2NH-, RaSO2NH-CH2- or (Rb)(Rc)NSO2-, Ra represents C1-C6 alkyl group, C3-C10cycloalkyl group, an amino group, 6-10-member monocyclic or bicyclic aryl group or 5-10-member monocyclic or bicyclic heteroaryl group containing 1-2 heteroatoms, chosen from oxygen, sulphur and nitrogen atoms, Rb and Rc are identical or different, and each represents hydrogen atom, C1-C6alkyl group or C3-C10cycloalkyl group, one of R2 and R3 represents hydrogen atom, halogen atom or C1-C6alkyl group, and the other represents hydrogen atom, C1-C6alkyl group, C1-C6alkoxycarbonyl group or phenyl group, or both are combined with each other together with the neighbouring carbon atom to form C3-C10cycloalkyl group, X represents oxygen atom, sulphur atom, or formula group of -NR4-; Y represents a group of formula -C(=O)-, -C(=S)- or CH(R5)-; Ar represents optionally substituted 6-10-member monocyclic or bicyclic aryl group or 5-10-member monocyclic or bicyclic group; Q represents a simple bond, C1-C6alkylene group or C2-C6alkenylene group, or its pharmaceutically acceptable salts There are described specific compounds of formula [I], and also intermediate compounds.

EFFECT: presented compounds exhibit affinity to mineralocorticoid receptor (MR) and are applicable for prevention or treatment of various diseases or diseased states associated with such receptor.

11 cl, 54 tbl, 410 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where X is C(R8R9), NR10, O, S; R1 is phenyl which is substituted with 1-3 substitutes selected from a group which includes halogen, hydroxy group, lower alkyl, hydroxy-lower alkyl and CN; R2 is hydrogenor lower alkyl; R3 and R4 are hydrogen; R5 and R6 are hydrogen; R7 is oxadiazolyl or triazolyl, where oxadiazolyl or triazolyl is substituted with R11; R8 and R9 denote hydrogen; R10 denotes hydrogen, lower alkyl, lower alkyl-carbonyl or lower alkyl-sulfonyl, R11 denotes aryl or hetearyl, selected from a group comprising pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl-2-one, oxadiazolyl, indazolyl, 1,3-dihydrobenzimidazol-2-one, 1,3-dihydroindol-2-one, benzotriazolyl, imidazopyridinyl, triazolepyridinyl, tetrazolepyridinyl, benzimidazolyl, 2-oxo-2,3-dihydro-1H-indol-5-yl, pyrimidin-4-one, furanyl, thiadiazolyl, pyrazolyl, isoxazolyl, pyrimidin-2,4-one, benzoxazin-3-one, 1,4-dihydrobenzoxazin-2-one, indolyl, thiophenyl, oxazolyl, benzooxazin-2-one; 3,4-dihydroquinazolin-2-one, pyridazinyl, quinoxalinyl, benzothiazolyl, benzothiadiazolyl, naphthyridinyl, cinnolinyl, 1,4-dihydroquinoxalin-2,3-dione and 1,2-dihydroindazol-3-one, where the aryl or heteroaryl is optionally substituted with 1-3 substitutes selected from a group which includes lower alkyl, hydroxy group, B(OH)2, carboxy-lower alkoxy group, carbamoyl-lower alkoxy group, cyano group, hydroxy-lower alkyl, fluoro-lower alkyl, lower alkoxy group, halogen, S(O2)R13, C(O)R14, NO2, NR15R16, phenyl-lower alkoxy group, [1,3,4]oxadiazol-2-one, oxadiazolyl, triazolyl and isoxazolyl, imidazolyl, pyrazolyl, tetrazolyl, pyrrolyl, where imidazolyl is optionally substituted with lower alkyl, and where isoxazolyl is substituted with lower alkyl; R12 denotes hydrogen or lower alkyl; R13 denotes lower alkyl, NR17R18 or fluoro-lower alkyl; R14 denotes NR19 R20, lower alkoxy group, lower alkenyl-oxy group or lower alkyl; R15 and R16 independently denote hydrogen, lower alkyl, lower alkyl-carbonyl, lower alkyl-SO2, lower alkenyl-oxycarbonyl and lower alkyl-NH-carbonyl; or NR15R16 denotes heterocyclyl selected from a group which includes morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperidin-2-one, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, pyrrolidinyl, 1,1-dioxoisothiazolidinyl, pyrrolidin-2-one, imidazolidine-1,4-dione, 2,4-dihydro[1.2.4]triazol-3-one, pyrrolidine-2,5-dione, azetidin-2-one and 1,3-dihydroimidazol-2-one, where the heterocycle is optionally substituted with hydroxy-lower alkyl or lower alkyl-carbonyl; R17 and R18 independently denote hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl; or NR17 R18 denotes morpholinyl; R19 and R20 independently denote hydrogen, lower alkyl, cycloalkyl, hydroxy-lower alkyl, lower alkoxy group-lower alkyl or cyano-lower alkyl; or NR19 R20 denotes heterocyclyl selected from a group which includes morpholinyl, pyrrolidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperidinyl, piperazinyl, piperazin-2-one, thiazolidinyl, thiomorpholinyl, 1,3,8-triaza-spiro[4.5]decane-2,4-dione and spiro(1- phthalan)piperidin-4-yl, where the heterocyclyl is optionally substituted with a hydroxy group, lower alkyl-(SO2), lower alkyl, lower alkyl-carbonyl or lower alkoxy group, carboxyl group, carbamoyl, cyano group and phenyl; and to their pharmaceutically acceptable salts. Invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which inhibit hepatic carnitine palmitoyltransferase 1 (L-CPT1).

35 cl, 565 ex, 10 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel salt form of 5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]piridine-2-amine (I): , and specifically to 5-[2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridine-2-amine di-(1S)-camphorsulphonate (di-S-camsylate), to a pharmaceutical composition having effect on dopamine D3 receptor, as well use of the given compound in preparing a medicinal agent for treating sexual dysfunction and neuropsychiatric disorders and a method of obtaining the said compound and an intermediate compound.

EFFECT: novel salt form of a dopamine agonist which has advantages, specifically is not hygroscopic, has a crystalline form and has high melting point is obtained and described.

11 cl, 9 ex, 2 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: claimed is method of obtaining derivative of 2,2-difluorine-2-dezoxi-1-oxoribose (I), , where R is , R1 - methyl or ethyl, R2 - C1-3 alkyl, R3 - benzoyl or R4 - phenyl; and M - sodium or potassium, including stages: (i) of interaction of compound (V) with derivative of biphenylcarbonyl obtaining compound (IV) , which has 3-hydroxygroup, protected with biphenylcarbonyl group; (ii) of interaction of compound (IV) with base (sodium carbonate or potassium carbonate) in mixed solvent, which mainly includes water (mixture of water, tetrahydrofurane and methanol), obtaining mixture of 3R-enanthiomer of carboxylate (III) with 3S-enenthiomer of carboxylate (III) and isolation from mixture of 3R-enanthiomer of carboxylate (III)(also claimed as novel compound); (iii) of interaction of compound (III) with 12N HCl obtaining derivative of 5-hydroxy-1-oxoribose (II) ; and (iv) introduction of protection R3 on 5-hydroxygroup of compound (II). Invention method is characterised by possibility of selective production of 3R-enanthiomer of carboxylate (III) by protection of 3-hydroxyl group of formula (V) compound with biphenylcarbonyl group and obtaining derivative of 2,2-difluorine-2-dezoxy-1-oxoribose of formula (I), which has required erythrostructure and is important intermediate compound, used in production of gemcitabine of formula (A) , agent for treatment of non-small cell lung cancer.

EFFECT: elaboration of efficient method of obtaining derivative which can be used in pharmacology.

6 cl, 4 ex

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