Deuterated hepatitis c protease inhibitors

FIELD: medicine.

SUBSTANCE: invention refers to a deuterium-enriched α-ketoamide compound of formula wherein: D means a deuterium atom; the values R1-R5 are presented in cl.1 of the patent claim, and to a based pharmaceutical composition.

EFFECT: method improvement.

32 cl, 3 ex

 

Cross-reference

The present application claims the priority of provisional application U.S. serial No. 60/782778 filed March 16, 2006, provisional application U.S. serial No. 60/782976 filed March 16, 2006, and provisional application U.S. serial No. 60/844771, filed September 15, 2006.

The level of technology

Infection with hepatitis C virus ("HCV") is an urgent medical problem for a person. HCV is considered to be a causal factor in most cases of hepatitis other than hepatitis A and hepatitis B, which, as defined, is present in serum in 3% of people worldwide [A. Alberti et al., "Natural History of Hepatitis C," J. Hepatology, 31., (Suppl. 1), pp. 17-24 (1999)]. Only in the United States may be infected with about four million people [MJ. Alter et al., "The Epidemiology of Viral Hepatitis in the United States, Gastroenterol. Clin. North Am., 23, pp. 437-455 (1994); M. J. Alter, "Hepatitis C Virus Infection in the United States," J. Hepatology, 31. (Suppl. 1), pp. 88-91 (1999)].

At initial impact of HCV virus in only about 20% of infected subjects develop acute clinical hepatitis, whereas others have observed spontaneous resolution of infection. However, almost 70% of cases the virus stimulates the development of chronic infection that persists for decades [Iwarson S., "The Natural Course of Chronic Hepatitis," FEMS Microbiology Reviews, 14, pp. 201-204 (1994); D. Lavanchy, "Global Surveillance and Control of Hepatitis C," J. Viral Hepatitis, 6, pp. 35-47 (1999)]. This usually results in recurrence of the progressive complication of liver inflammation, which often leads to more serious diseases, such as cirrhosis and hepatocellular carcinoma [M.C. Kew, "Hepatitis C and Hepatocellular Carcinoma", FEMS Microbiology Reviews, 14, pp. 211-220 (1994); I. Saito et al., "Hepatitis C Virus Infection is Associated with the Development of Hepatocellular Carcinoma," Proc. Natl. Acad. Sci. USA, 87, pp. 6547-6549 (1990)]. Unfortunately, currently there is no in a broad sense, effective treatment methods to reduce the progression of chronic HCV.

The genome of HCV encodes polyprotein of 3010-3033 amino acids [Q.L. Choo, et al., "Genetic Organization and Diversity of the Hepatitis C Virus." Proc. Natl. Acad. Sci. USA, 88, pp. 2451-2455 (1991); N. Kato et al., "Molecular Cloning of the Human Hepatitis C Virus Genome From Japanese Patients with Non-A, Non-B Hepatitis," Proc. Natl. Acad. Sci. USA, 87, pp. 9524-9528 (1990); A. Takamizawa et al., Structure and Organization of the Hepatitis C Virus Genome Isolated From Human Carriers," J. Virol., 65, pp. 1105-1113 (1991)]. It is believed that non-structural (NS) proteins of HCV provide the main catalytic mechanism for replication of the virus. The NS proteins are formed as a result of proteolytic cleavage of polyprotein [R. Bartenschlager et al., "Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions," J. Virol., 67, pp. 3835-3844 (1993); A. Grakoui et. al., "Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein Cleavage Sites," J. Virol., 67, pp. 2832-2843 (1993); A. Grakoui et al., "Expression and Identification of Hepatitis C Virus Polyprotein Cleavage Products," J. Virol., 67, pp. 1385-1395 (1993); L. Tomei et al., "NS3 is a serine protease required for processing of hepatitis C virus polyprotein", J. Virol., 67, pp. 4017-4026 (1993)].

NS protein 3 (HCV NS3) has activity series is protease, which contributes to the processing of the majority of viral enzymes and, thus, is essential for viral replication and infectivity. It is known that mutations in the NS3-protease of the virus of yellow fever reduce viral infectivity [Chambers, T.J. et. al., "Evidence that the N-terminal Domain of Nonstructural Protein NS3 From Yellow Fever Virus is a Serine Protease Responsible for Site-Specific Cleavages in the Viral Polyprotein", Proc. Natl. Acad. Sci. USA, 87, pp. 8898-8902 (1990)]. It was shown that the first 181 amino acids in NS3 (residues 1027-1207 viral polyprotein) contain the domain of semipretioase NS3, which carries out the processing of all four below sites polyprotein HCV [C. Lin et al., "Hepatitis C Virus NS3 Serine Proteinase: Trans-Cleavage Requirements and Processing Kinetics", J. Virol., 68, pp. 8147-8157 (1994)].

The NS3 semipretioase HCV and its associated cofactor, NS4A, contribute to the processing of all viral enzymes and, thus, are considered to be essential for viral replication. It turned out that this processing similar to that performed espartignac the protease of human immunodeficiency virus, which is also involved in the processing of viral enzymes. The HIV protease inhibitors, which inhibit the processing of viral protein are strong antiviral agents in humans, and this suggests that interrupt this stage of the life cycle of the virus leads to a therapeutically active agents. Therefore, the NS3 semipretioase HCV also what is an attractive target for drug development.

At the present time there is no satisfactory anti-HCV or treatments. Until recently, the only accepted therapy for diseases of HCV treatment with interferon. However, interferons have significant side effects [M. A. Wlaker et al., "Hepatitis C Virus: An Overview of Current Approaches and Progress," DDT, 4, pp. 518-29 (1999); D. Moradpour et al., "Current and Evolving Therapies for Hepatitis C," Eur. J. Gastroenterol. Hepatol., 11, pp. 1199-1202 (1999); H. L. A. Janssen et al. "Suicide Associated with Alfa-Interferon Therapy for Chronic Viral Hepatitis," J. Hepatol., 21, pp. 241 to 243 (1994); P.F. Renault et al., "Side Effects of Alpha Interferon," Seminars in Liver Disease, 9, pp. 273-277. (1989)] and induce long term remission in only some (about 25%) cases [O. Weiland, "Interferon Therapy in Chronic Hepatitis C Virus Infection", FEMS Environ. Rev., 14, pp. 279-288 (1994)]. Recent pegylated forms of interferon (PEG-INTRON® and PEGASYS®) and combined therapy, including ribavirin and pegylated interferon (REBETROL®), has provided only a modest improvement in the rate of remission and only partial reduction of side effects. Moreover, the prospects for an effective vaccine against HCV, remain unclear.

Thus, there is a need for more effective therapeutic tools against HCV. Such inhibitors should have therapeutic potential as protease inhibitors, particularly as inhibitors of semipretioase, and more specifically, as the and the of gibilaro NS3 protease of HCV. Specifically, such compounds can be useful as antiviral agents, particularly as anti-HCV.

Recently it was found that the incorporation of deuterium in the compound reduces the rate of epimerization through the action of the isotope deuterium, increasing, thus, the concentration of the active isomersin vivocompared to his mediterrannee counterparts.

Brief description of the invention

The present invention relates to deuterated compounds of formula (I)

and their pharmaceutically acceptable salts, prodrugs and solvate. In the formula (I) D is a deuterium atom.

With regard to formula (I),

D is a deuterium atom;

R1represents,

where

represents an optionally substituted monocyclic azaheterocyclic or optionally substituted polycyclic azaheterocyclic, or optionally substituted polycyclic azaheterocycles, where the unsaturation is in the ring distal to the ring containing the group R21and attached to the group-C(O)-N(R2)-CDR3-C(O)-C(O)-NR4R5;

R21is a Q3-W3-Q2-W2-Q1; where

each of W2and W3independent what is a relationship -CO-, -CS-, -C(O)N(Q4)-, -CO2-, -O-, -N(Q4)-C(O)-N(Q4)-, -N(Q4)-C(S)-N(Q4)-, -OC(O)NQ4-, -S-, -SO-, -SO2-, -N(Q4)-, -N(Q4)SO2-, -N(Q4)SO2N(Q4)and hydrogen when either W2and W3represents a terminal group;

each of Q1, Q2and Q3independently represents a bond, optionally substituted aliphatic group, optionally substituted heteroaromatics group, optionally substituted cycloaliphatic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroalkyl; or hydrogen, when any of Q3, Q2or Q1represents a terminal group provided that Q2can't imagine a relationship when both W3and W2; and

each of R2, R3and R4independently, represents H or C1-6alkyl;

R5represents H, alkyl, cycloalkyl, aryl, optionally substituted with 1-4 alkyl groups, alkylaryl, aryl, amino group, optionally substituted by 1 or 2 alkyl groups; and

R21is a Q3-W3-Q2-W2-Q1; where each of W2and W3independently represents a bond, -CO-, -CS-, -C(O)N(Q4)-, -CO2 -, -O-, -N(Q4)-C(O)-N(Q4)-, N(Q4)-C(S)-N(Q4)-, -OC(O)NQ4-, -S-, -SO-, -SO2-, -N(Q4)-, -N(Q4)SO2-, -N(Q4)SO2N(Q4)and hydrogen when either W2and W3represents a terminal group; each of Q1, Q2and Q3independently represents a bond, optionally substituted aliphatic group, optionally substituted heteroaromatics group, optionally substituted cycloaliphatic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroalkyl; or hydrogen, when any of Q3, Q2or Q1represents a terminal group provided that Q2can't imagine a relationship when both W3and W2.

In some embodiments, implementation, R1represents

where

each of R6and R8independently represents a

communication; or

optionally substituted (1,1 - or 1,2-)cycloalkyl; or

optionally substituted (1,1 - or 1,2-)heterocyclyl; or

methylene or ethylene, substituted with one Deputy, selected from the group consisting of optionally substituted aliphatic group, optionally substituted cyclic group and NeoMaster is but substituted aromatic group, and where specified methylene or ethylene optionally additionally substituted by the Deputy, which represents an aliphatic group;

each of R7, R9and R11independently represents hydrogen or optionally substituted aliphatic group;

R10represents an optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;

L represents-C(O)-, -OC(O)-, -NR11C(O)-, -S(O)2-, -NR11S(O)2or communication; and

n is 0 or 1.

In some embodiments, the implementation of n is 1.

In some embodiments, the implementation of R6represents methylene substituted by one Deputy, selected from the group consisting of optionally substituted aliphatic group, optionally substituted cyclic group, and optionally substituted aromatic group.

In some embodiments, the implementation of R6represents methylene substituted by isobutyl.

In some embodiments, the implementation of R7represents hydrogen.

In some embodiments, the implementation of R8represents methylene substituted by one Deputy, selected from the group consisting of optionally substituted aliphatic group, optionally substituted cyclic g is uppy and optionally substituted aromatic group. In some other embodiments, implementation of R8represents methylene substituted by an optionally substituted cyclic group. In some embodiments, the implementation of R8represents a methylene, substituted cyclohexyl.

In some embodiments, the implementation of R9represents hydrogen.

In some embodiments, the implementation of L represents-CO-.

In some embodiments, the implementation of R10represents an optionally substituted aromatic group.

In some embodiments, the implementation of R10selected from the group

In some embodiments, the implementation of R10represents an optionally substituted pyrazinyl (for example, 2-pyrazinyl).

In some embodiments, the implementationrepresents a substituted monocyclic azaheterocyclic.

In some other embodiments, the implementationis pyrrolidinyl, substituted in position 3 carbon atoms by a group of heteroaromatic where heteroaryl optional optionally substituted by 1-4 groups of halogen.

In some embodiments, the implementationrepresents.

In some embodiments, the implementationPR is dstanley an optionally substituted polycyclic azaheterocyclic.

In another embodimentrepresentsIn some embodiments, the implementationrepresents.

In another embodiment, R2represents hydrogen, each of R4and R5independently represents hydrogen or cyclopropyl. In another embodiment, R3represents propyl. In another embodiment, n is 0. In another embodiment, L represents a-NR11C(O)- and R11represents hydrogen. In another embodiment, R10represents an optionally substituted aliphatic group. In another embodiment, R10represents tert-butyl. In another embodiment, the compound is aor

In another embodiment, R1represents,

where

A represents -(CNH1)and-;

B represents -(CNH2)b-;

a is 0-3;

b is 0-3, provided that the sum a + b is 2 or 3;

each of X1and X2independently selected from hydrogen, optionally substituted C1-4aliphatic gr is PPI and optionally substituted aryl;

each of the Y1and Y2independently represents hydrogen, optionally substituted aliphatic group, optionally substituted aryl, an amino group or OQ4; where each Q4independently represents hydrogen or optionally substituted aliphatic group;

R22represents an optionally substituted aliphatic group, optionally substituted heteroaromatics group, optionally substituted cycloaliphatic group, optionally substituted heterocyclizations group, optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, the implementation of R21represents an optionally substituted alkylsulphonyl.

The groupincludes all stereospecific enantiomers, for example,(when A and B both represent CH2and Y1and Y2both represent H).

In some embodiments, the implementation of R21is aminoalkylsilanes, halogenoalkanes, arylalkylamines, arylalkylamines, (cycloaliphatic group)alkylaryl or (heterocyclizations group)alkylsulphonyl, each of which is optionally substituted by 1-3 substituents. In some embodiments, the implementation of R21is Soboh heteroseksualci-oxcarbazepine-alkylsulphonyl, heteroaryl-carbylamine-alkyl-carbylamine-alkyl-carbonyl, bicycloalkyl-sulfonylamino-alkylsulphonyl, aryl-alkoxy-carbylamine-alkyl-carbonyl, alkyl-carbylamine-alkyl-carbonyl, (aliphatic group), oxcarbazepine-alkyl-carbonyl, (cycloaliphatic group)alkyl-aminocarbonyl-alkyl-carbonyl, heteroaryl-carbylamine-alkyl-carbylamine-alkyl-carbonyl, alkyl-aminocarbonyl-alkyl-carbonyl or bicycloalkyl-aminocarbonyl-alkyl-carbonyl, each of which is optionally substituted by 1-3 substituents. In some embodiments, the implementation of R22represents an optionally substituted aliphatic group, optionally substituted heteroaromatics group, optionally substituted cycloaliphatic group, optionally substituted heterocyclizations group, optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, the implementation of R22represents optionally substituted phenyl, optionally substituted naphthyl, optionally substituted anthracenes, optionally substituted naphthalene or optionally substituted anthracene. In some embodiments, the implementation of each of X1X2, Y1and Y2represents hydrogen, each of a and b is equal to 1.

In some embodiments, the implementation of R 21represents an optionally substituted alkylsulphonyl.

In some embodiments, the implementation of R21is aminoalkylsilanes, halogenoalkanes, arylalkylamines, arylalkylamines, (cycloaliphatic group)alkylaryl or (heterocyclizations group)alkylsulphonyl, each of which is optionally substituted by 1-3 substituents.

In some embodiments, the implementation of R21is heteroseksualci-oxcarbazepine-alkylsulphonyl, heteroaryl-carbylamine-alkyl-carbylamine-alkyl-carbonyl, bicycloalkyl-sulfonylamino-alkylsulphonyl, aryl-alkoxy-carbylamine-alkyl-carbonyl, alkyl-carbylamine-alkyl-carbonyl, (aliphatic group), oxcarbazepine-alkyl-carbonyl, (cycloaliphatic group)alkyl-aminocarbonyl-alkyl-carbonyl, (cycloaliphatic group)alkyl-carbylamine-alkyl-carbonyl, heteroaryl-carbylamine-alkyl-carbylamine-alkyl-carbonyl, alkyl-aminocarbonyl-alkyl-carbonyl or bicycloalkyl-aminocarbonyl-alkyl-carbonyl, each of which is optionally substituted by 1-3 substituents.

In some embodiments, the implementation of R22represents an optionally substituted aliphatic group, optionally substituted heteroaromatics group, optionally substituted cycloaliphatic the group, optionally substituted heterocyclizations group, optionally substituted aryl or optionally substituted heteroaryl.

In some embodiments, the implementation of R22represents optionally substituted phenyl, optionally substituted naphthyl, optionally substituted anthracenes, optionally substituted naphthalene or optionally substituted anthracene.

In some embodiments, the implementation of each of X1X2, Y1and Y2represents hydrogen, each of a and b is equal to 1.

In some embodiments, the implementation of R22represents an optionally substituted aliphatic group, optionally substituted heteroaromatics group, optionally substituted cycloaliphatic group, optionally substituted heterocyclizations group, optionally substituted aryl or optionally substituted heteroaryl.

In one embodiment, the compound is a.

The epimerization of deuterated compounds of the present invention is slower than that of similar mediterrani compounds. As shown below, the deuterated compound1very slowly converted to mediterrannee intermediate compound, which is then converted to epimere2and3. EPI is a career 2and3then supported in equilibrium, which further slows down the epimerization of deuterated compounds 1.

As a result of their slow epimerization, deuterated compounds of the present invention can increase the concentration of active isomersin vivocompared to mediterrannee counterparts.

In some embodiments, the implementation of enrichment with deuterium is at least 50% in the compounds of the present invention. In some embodiments, the implementation of enrichment with deuterium is at least 80% in the compounds of the present invention. In some embodiments, the implementation of enrichment with deuterium is at least 90% in the compounds of the present invention. In some embodiments, the implementation of enrichment with deuterium is at least 99% in the compounds of the present invention.

The present invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a compound of formula (I) or any of its embodiments described above.

The present invention also relates to a method of increasing the concentration of the active isomer of pharmaceutical substancesin vivoinvolving the introduction of a patient in need this, deuterated isomer in pharmaceutical preparations is practical substance in a quantity sufficient to provide a pharmaceutical effect.

The present invention also relates to a method of increasing the bioavailability of the compounds, including the replacement of the hydrogen atom, which is associated with steric carbon atom in the compound atom of deuterium. In one embodiment, the deuterated compound is a compound of formula (I) or any of its embodiments described above.

The present invention also relates to a method for inhibiting HCV protease, comprising contacting the HCV protease with deuterated compound of formula (I) or any of its embodiments described above.

The present invention also relates to a method of treatment of a patient suffering from HCV infection or condition mediated by a protease of HCV, including the introduction of the patient pharmaceutically effective amount of deuterated compounds of formula (I) or any of its embodiments described above.

Also in the scope of the present invention includes a method of obtaining optically enriched compounds of formula 1, where

the carbon atoms alpha and beta relative to carboxypropyl are stereocentres;

R1independently represents H, optionally substituted aliphatic group, optionally samisen the Yu cycloaliphatic group, optionally substituted arylaliphatic group, optionally substituted heteroaromatics group or optionally substituted heteroaromatics group;

R'1represents deuterium,

R'2is an-other2or-OE;

R2represents H, optionally substituted aliphatic group, optionally substituted cycloaliphatic group, optionally substituted arylaliphatic group, optionally substituted heteroaromatics group or optionally substituted heteroaromatics group; and

E represents a C1-6alkyl or benzyl.

The method includes the following stages:

a) formation of salts of the compounds of formula 1; and

b) crystallization of the specified salt with obtaining compounds with more than 55% enantiomeric excess.

In some embodiments, the implementation of R1represents a C1-6alkyl, and R'2is an-other2where R2represents a C1-6alkyl or C1-6cycloalkyl. In some embodiments, the implementation of R1represents propyl and R2is cyclopropyl.

In some embodiments, the implementation of the method further includes amination of the compounds of formula ii

aminimum reagent with poluchenierazreshenija formula iii

In some other embodiments, the implementation miniraise reagent is an azide salt, and intermediate etidocaine restore the hydrogenation.

In some embodiments, the implementation of the method further includes the oxidation of unsaturated compounds of the formula i

where R'2is an-other2or-OE, where E represents C1-5alkyl or optionally substituted benzyl, an oxidizing reagent to obtain the compounds of formula ii.

In some other embodiments, the implementation of the oxidizing reagent comprises tert-butylhydroperoxide.

In some other embodiments, the implementation of the oxidizing reagent further includes a chiral reagent. In some other embodiments, the implementation of the oxidizing reagent is a mixture of isopropoxide samarium (III), triphenylarsine, S-(-)1,1'-bi-2-naphthol and 4 Å molecular sieves. In some other embodiments, the implementation of the oxidizing agent includes hydrogen peroxide urea-hydrogen in the presence of triperoxonane anhydride.

In some other embodiments, the implementation of the method further includes the hydrolysis of compounds of formula ii to obtain the acid, and then converting the resulting acid amide compound form of the s ii, where R'2is an-other2.

Also in the scope of the present invention is included a method of obtaining the compounds of formula 1

where

R1represents H, optionally substituted aliphatic group, optionally substituted cycloaliphatic group, optionally substituted arylaliphatic group, optionally substituted heteroaromatics group or optionally substituted heteroaromatics group;

R'1represents deuterium,

R2represents H, optionally substituted aliphatic group, optionally substituted cycloaliphatic group, optionally substituted arylaliphatic group, optionally substituted heteroaromatics group or optionally substituted heteroaromatics group; and

the compound of formula 1 has an enantiomeric excess of more than 55%. This method includes the following stages:

a) oxidation of unsaturated compounds of the formula i

obtaining the compounds of formula ii

b) interaction of the compounds of formula ii with aminimum reagent to obtain the compounds of formula iii

c) formation of salts of the compounds of formula iii with an optically active organic is coy acid; and

(d) crystallization of the specified salt with obtaining compounds with more than 55% enantiomeric excess.

In some embodiments, the implementation of the compound of formula 1 is (2S,3S)-3-amino-3-deutero-N-cyclopropyl-2-hydroxyhexanoic. In some embodiments, the implementation of the organic acid is an L-tartaric acid or desoxycholic acid.

Also in the scope of the present invention is included a method of obtaining optically enriched compounds of formula 1:

where

the carbon atoms alpha and beta relative to carboxypropyl are stereocentres;

R1independently represents H, optionally substituted aliphatic group, optionally substituted cycloaliphatic group, optionally substituted arylaliphatic group, optionally substituted heteroaromatics group or optionally substituted heteroaromatics group;

R'1represents deuterium, the deuterium enrichment is at least 50%;

R'2is an-other2or-OE;

R2represents H, optionally substituted aliphatic group, optionally substituted cycloaliphatic group, optionally substituted arylaliphatic group, optionally substituted heteroaromatic the forge group or optionally substituted heteroaromatics group; and

E represents a C1-6alkyl or benzyl.

This method includes the following stages:

a) formation of salts of the compounds of formula 1, and

b) crystallization of the specified salt with obtaining compounds with more than 55% enantiomeric excess.

In some embodiments, the implementation of R1represents a C1-C6alkyl and R'2is an-other2where R2represents a C1-6alkyl or C1-6cycloalkyl. In some embodiments, the implementation of R1represents propyl and R2is cyclopropyl.

In some embodiments, the implementation of the method further includes a step of amination of compounds of formula ii

aminimum reagent to obtain the compounds of formula iii

In some embodiments, the implementation miniraise reagent is an azide salt, and intermediate etidocaine restore the hydrogenation.

In some embodiments, the implementation of the method further includes a step of oxidation of unsaturated compounds of the formula i

where R'2is an-other2or-OE, where E represents C1-5alkyl or optionally substituted benzyl, an oxidizing reagent to obtain the compounds is of formula ii.

In some embodiments, the implementation of the oxidizing reagent comprises tert-butylhydroperoxide. In some other embodiments, the implementation of the oxidizing reagent further includes a chiral reagent. In some embodiments, the implementation of the oxidizing reagent is a mixture of isopropoxide samarium (III), triphenylarsine, S-(-)1,1'-bi-2-naphthol and 4 Å molecular sieves. In some embodiments, the implementation of the oxidizing agent includes hydrogen peroxide urea-hydrogen in the presence of triperoxonane anhydride.

In some embodiments, the implementation of R'2represents-OE. In some embodiments, the implementation of R'2is an-other2.

In some embodiments, the implementation of the method further includes the hydrolysis of compounds of Formula ii with obtaining acid and then converting the resulting acid amide compound of the formula ii, where R'2is an-other2.

In some embodiments, the implementation of the method further includes the oxidation of the compounds of formula iv

obtaining the compounds of formula ii. In some cases, the oxidation is performed with the use of manganese dioxide.

In some embodiments, the implementation of the method further includes recovering the compounds of formula v

obtaining the compounds of formula iv. In some cases, the connection is restored using Red-Al®, and then quenched with deuterium oxide. As is known from the prior art, Red-Al®" refers to the compound [(CH3OCH2OCH2)2AlH2]Na, which is commercially available, usually in the form of a solution in toluene (for example, 70% of the mass./mass.). More detailed information regarding Red-Al®, see, for example, R.W. Bates et al., Tetrahedron, 1990, 46, 4063.

Also in the scope of the present invention is included a method of obtaining the compounds of formula 1

where

R1represents H, optionally substituted aliphatic group, optionally substituted cycloaliphatic group, optionally substituted arylaliphatic group, optionally substituted heteroaromatics group or optionally substituted heteroaromatics group;

R'1represents deuterium,

R2represents H, optionally substituted aliphatic group, optionally substituted cycloaliphatic group, optionally substituted arylaliphatic group, optionally substituted heteroaromatics group or optionally substituted heteroaromatics group; and

the compound of formula 1 has an enantiomeric excess of more than 55%.

Specified with the persons includes the following stages:

a) oxidation of unsaturated compounds of the formula i

obtaining the compounds of formula ii

b) interaction of the compounds of formula ii with aminimum reagent to obtain the compounds of formula iii

c) formation of salts of the compounds of formula iii with an optically active organic acid; and

(d) crystallization of the specified salt with obtaining compounds with more than 55% enantiomeric excess.

In some embodiments, the implementation of the compound of formula 1 is (2S,3S)-3-amino-3-deutero-N-cyclopropyl-2-hydroxyhexanoic. In some embodiments, the implementation of the organic acid is an L-tartaric acid or desoxycholic acid.

Detailed description of the invention

I. Definitions

A. Terms

Used in the present description, the term "aliphatic" includes alkyl, alkenyl and quinil.

Used in this description of the "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-8 (for example, 1-6 or 1-4) carbon atoms. The alkyl group may be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl and 2-atilgan the sludge. The alkyl group may be optionally substituted by one or more substituents, such as alkoxy, cycloalkane, heterocyclizations, aryloxy, heteroaromatic, aralkylated, heteroaromatics, amino, nitro, carboxy, cyano, halogen, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, aminocarbonyl, alkylcarboxylic, cycloalkylcarbonyl, cycloalkyl-alkylcarboxylic, arylcarboxamide, aralkylamines, heteroseksualci-carbylamine, heteroseksualci-alkylcarboxylic, heteroarylboronic, heteroarylboronic, urea, thiourea, sulfamoyl, sulphonamide, alkoxycarbonyl or alkylcarboxylic.

Used in the present description "Alchemilla" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like alkyl group, Alchemilla group can be linear or branched. Examples alkenylphenol groups include, but are not limited to, allyl, isoprenyl, 2-butenyl and 2-hexenyl. Alchemilla group may be optionally substituted by one or more substituents, such as alkoxy, cycloalkane, heterocyclizations, aryloxy, heteroaromatic, aralkylated, heteroaromatics, amino, nitro, carboxy, cyano, halogen, g is droxi, sulfo, mercapto, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, aminocarbonyl, alkylcarboxylic, cycloalkylcarbonyl, cycloalkyl-alkylcarboxylic, arylcarboxamide, aralkylamines, heteroseksualci-carbylamine, heteroseksualci-alkylcarboxylic, heteroarylboronic, heteroarylboronic, urea, thiourea, sulfamoyl, sulphonamide, alkoxycarbonyl or alkylcarboxylic.

Used in the present description "Alchemilla" group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond. Alchemilla group can be linear or branched. Examples alkenylphenol groups include, but are not limited to, propargyl and butynyl. Alchemilla group may be optionally substituted by one or more substituents, such as alkoxy, cycloalkane, heterocyclizations, aryloxy, heteroaromatic, aralkylated, heteroaromatics, amino, nitro, carboxy, cyano, halogen, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, aminocarbonyl, alkylcarboxylic, cycloalkylcarbonyl, cycloalkyl-alkylcarboxylic, arylcarboxamide, aralkylamines, heteroseksualci-carbylamine, heteroseksualci-alkylcarboxylic, heteroaryl is carbylamine, heteroarylboronic, urea, thiourea, sulfamoyl, sulphonamide, alkoxycarbonyl or alkylcarboxylic.

Used in this description of the "amino group" refers to-NRXRYwhere each of RXand RYindependently represents hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroseksualci, (heteroseksualci)alkyl, heteroaryl or heteroalkyl. When the term "amino" does not mean the end group (for example, alkylcarboxylic), it is represented by the formula-NRX-. RXhas the values defined above.

Used in this description of the "aryl" group refers to phenyl, naftilos or benzododecinium group containing 2-3 rings. For example, benzododecinium group includes phenyl condensed with one or two C4-8cycloaliphatic groups, for example, 1,2,3,4-tetrahydronaphthyl, indanyl, dihydroindol or fluorenyl. Aryl optionally substituted by one or more substituents, such as alkyl (including carboxylic, hydroxyalkyl and halogenated, such as trifluoromethyl), alkenyl, quinil, cycloalkyl, (cycloalkyl)alkyl, heteroseksualci, (heteroseksualci)alkyl, aryl, heteroaryl, alkoxy, cycloalkane, heterocyclizations, aryloxy, heteroaromatic, aralkylated, heteroarylboronic, aroyl, heteroaryl, AMI is about, nitro, carboxy, alkoxycarbonyl, alkylcarboxylic, aminocarbonyl, alkylcarboxylic, cycloalkylcarbonyl, (cycloalkyl)alkylcarboxylic, arylcarboxamide, aralkylamines, (heteroseksualci)carbylamine, (heteroseksualci)alkylcarboxylic, heteroarylboronic, heteroarylboronic, cyano, halogen, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulphonamide, oxo or carbarnoyl.

Used in the present description "kalkilya" group refers to an alkyl group (for example, C1-4alkyl group, which is substituted by an aryl group. Both "alkyl" and "aryl" as defined above. Example aranceles group is benzyl.

Used in the present description, the term cycloaliphatic covers cycloalkyl, cycloalkenyl and cycloalkyl.

Used in the present description "cycloalkyl" group refers to an aliphatic carbocyclic ring of 3 to 10 (e.g., 4 to 8) carbon atoms. Examples cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, substituted, norbornyl, Kubel, octahedrons, decahydronaphthalene, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl and bicyclo[3.2.3]nonyl. "Cycloalkenyl" group used in the present description, refers to non-aromatic carbocyclic the ring of 3-10 (for example, 4 to 8) carbon atoms having one or more double bonds. Examples cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexadienyl, cycloheptenyl, cyclooctyl, hexahydrobenzyl, octahydronaphthalene, bicyclo[2.2.2]octenyl and bicyclo[3.3.1]nonenal. Cycloalkyl or cycloalkenyl group may be optionally substituted by one or more substituents, such as alkyl (including carboxylic, hydroxyalkyl and halogenated, such as trifluoromethyl), alkenyl, quinil, cycloalkyl, (cycloalkyl)alkyl, heteroseksualci, (heteroseksualci)alkyl, aryl, heteroaryl, alkoxy, cycloalkane, heterocyclizations, aryloxy, heteroaromatic, aralkylated, heteroarylboronic, aroyl, heteroaryl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarboxylic, aminocarbonyl, alkylcarboxylic, cycloalkylcarbonyl, (cycloalkyl)alkylcarboxylic, arylcarboxamide, aralkylamines, (heteroseksualci)carbylamine, (heteroseksualci)alkylcarboxylic, heteroarylboronic, heteroarylboronic, cyano, halogen, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulphonamide, oxo or carbarnoyl.

Used in the present description, the term geterotsiklicheskikh means heteroseksualci, geteroseksualen and heteroseksualnymi. Use the controls in the present description "heterocytolysine" group refers to a 3-10-membered (e.g., 4-8-membered) saturated ring structure in which one or more ring atoms are a heteroatom, such as N, O or S. Examples geteroseksualnoe group include piperidinyl, piperazinil, tetrahydropyranyl, tetrahydrofuryl, DIOXOLANYL, oxazolidinyl, isooxazolyl, morpholinyl, activitiesfor, octahedrally, octahydrocyclopenta, octahedrally, octahydrophenanthrene, decahydroquinoline, octahedrons[b]thiophenyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl and 2,6-dioxabicyclo[3.3.1.03,7]nonyl. "Heterocyclization" group used in the present description, refers to a 3-10-membered (e.g., 4-8-membered) non-aromatic ring structure having one or more double bonds, and where one or more ring atoms are a heteroatom, such as N, O or S. Heterocytolysine or heterocyclization group may be optionally substituted by one or more substituents, such as alkyl (including carboxylic, hydroxyalkyl and halogenated, such as trifluoromethyl), alkenyl, quinil, cycloalkyl, (cycloalkyl)alkyl, heteroseksualci, (heteroseksualci)alkyl, aryl, heteroaryl, alkoxy, cycloalkane, heterocyclizations, aryloxy, heteroaromatic, aralkylated, heteroarylboronic, aroyl, heteroaryl, the Mino, nitro, carboxy, alkoxycarbonyl, alkylcarboxylic, aminocarbonyl, alkylcarboxylic, cycloalkylcarbonyl, (cycloalkyl)alkylcarboxylic, arylcarboxamide, aralkylamines, (heteroseksualci)carbylamine, (heteroseksualci)alkylcarboxylic, heteroarylboronic, heteroarylboronic, cyano, halogen, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulphonamide, oxo or carbarnoyl. In some cases, a Deputy in heteroseksualci or geterotsiklicheskie itself may be circular (which optionally contains one or more heteroatoms), and, thus, the resultant substituted heteroseksualci or geteroseksualen is spiracular system, for example,

"Heteroaryl group" used in the present description, refers to monocyclic, bicyclic or tricyclic ring structure containing 5-15 ring atoms, where one or more ring atoms are a heteroatom, such as N, O or S and where one or more rings of a bicyclic or tricyclic ring structure is aromatic. Some examples of heteroaryl are pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl 2,3-dihydroindole, chenail, 1,2-dihydrohelenalin, 1,2,3,4-tetrahydroquinolin, tetrazolyl, benzofuran, 2,3-dihydrobenzofuranyl, benzothiazolyl, Xanten, thioxanthen, phenothiazines, dihydroindol and benzo[1,3]dioxol. Heteroaryl optionally substituted by one or more substituents, such as alkyl (including carboxylic, hydroxyalkyl and halogenated, such as trifluoromethyl), alkenyl, quinil, cycloalkyl, (cycloalkyl)alkyl, heteroseksualci, (heteroseksualci)alkyl, aryl, heteroaryl, alkoxy, cycloalkane, heterocyclizations, aryloxy, heteroaromatic, aralkylated, heteroarylboronic, aroyl, heteroaryl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarboxylic, aminocarbonyl, alkylcarboxylic, cycloalkylcarbonyl, (cycloalkyl)alkylcarboxylic, arylcarboxamide, aralkylamines, (heteroseksualci)carbylamine, (heteroseksualci)alkylcarboxylic, heteroarylboronic heteroarylboronic, cyano, halogen, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulphonamide, oxo or carbarnoyl.

"Heteroalkyl" group used in the present description, refers to an alkyl group (for example, C1-4alkyl group), which substituted heteroaryl group. Both "alkyl" and "heteroaryl" defined above.

Used in the present description "cilice the Kai group" includes cycloalkyl, heteroseksualci, cycloalkenyl, geteroseksualen, aryl or heteroaryl, each of which is defined above.

Used in this description of the "acyl" group refers to a formyl group or a group of alkyl-C(=O)-, where "alkyl" is defined above. Acetyl and pivaloyl are examples of acyl groups.

Used in the present description "carnemolla" group refers to a group having the structure-O-CO-NRXRYor-NRX-CO-O-RZwhere RXand RYdefined above and RZcan be an alkyl, aryl, aralkyl, heteroseksualci, heteroaryl or heteroalkyl.

Used in this description of the group "carboxy" and "sulfo" refers to-COOH and-SO3H, respectively.

Used in this description of the group "alkoxy" refers to the group alkyl-O-, where "alkyl" is defined above.

Used in this description of the group "sulfoxy" refers to-O-SO-RXor-SO-O-RXwhere RXdefined above.

Used in the present description sulfanilate group refers to-S-RXwhere RXdefined above.

Used in the present description sulfonylurea group refers to-S(O)-RXwhere RXdefined above.

Used in the present description sulfonylurea group refers to-S(O)2-RXwhere RXdefined above.

Used in infusion is eating the description of "halogen" or " the group "halo" refers to fluorine, chlorine, bromine or iodine.

Used in the present description "Altamarena" group refers to the structure-S(O)2-NRXRYor-NRX-S(O)2-RXwhere RX, RYand RZdefined above.

Used in this description of "sulfa" group refers to the structure-NRX-S(O)2-NRYRZwhere RX, RYand RZdefined above.

Used in this description of the group "urea" refers to the structure-NRX-CO-NRYRZand the group "thiourea" refers to the structure-NRX-CS-NRYRZ. RX, RYand RZdefined above.

Used in this description of the group "guanidino" refers to the structure-N=C(NRXRY)N(RXRY), where RXand RZdefined above.

Used in the present description, the term "amidinopropane" refers to the structure-C=(NRX)N(RXRY), where RXand RYdefined above.

Used in the present description, the term "oxymyoglobin" refers to the structure-C=N-ORXwhere RXdefined above.

Used in this description, an effective amount is defined as the amount needed to ensure a therapeutic effect in the patient treated, and is usually determined on the basis of age, surface area, body weight and the condition of the patient. The ratio of doses to animals and humans (based on milligrams per square meter of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). The surface area of the body can be approximately determined based on the height and weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).

Used in the present description, the term "patient" refers to mammals, including humans.

Antagonist used in the present description, is a molecule that binds to a receptor without activating this receptor. It competes with the endogenous ligand (ligands) or the substrate (substrates) for the site (sites) bind to the receptor, and thus inhibits the ability of the receptor to the intracellular signal transduction in response to the binding of the endogenous ligand.

The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." As described in this application, the compounds of the present invention can be optionally substituted by one or more substituents, such as in the General form illustrated above or illustrated with particular classes, subclasses and species of the present invention. Unless otherwise stated, each of the specific groups for the variables R1, R2, R3, R4and R in the formula (I) may be optionally substituted by one or more substituents described in this application. Each Deputy a specific group is additionally optionally substituted with one to three substituents selected from halogen, cyano, alkoxy, hydroxyl, nitro, halogenoalkane and alkyl. For example, the alkyl group may be substituted by alkylsulfonyl, and alkylsulfonyl may be optionally substituted with one to three substituents selected from halogen, oxo, cyano, alkoxy, hydroxyl, nitro, halogenoalkane and alkyl. As an additional example, the alkyl may be substituted (cycloalkyl)carbylamine and cycloalkyl part (cycloalkyl)carbylamine may be optionally substituted with one to three substituents selected from halogen, cyano, oxo, alkoxy, hydroxyl, nitro, halogenoalkane and alkyl.

As a rule, the term "substituted", regardless of whether in front of him, the term "optionally" or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Particular substituents described above in the definitions and below in the description of the compounds and their examples. Unless otherwise specified, optionally substituted group may contain a substituent at each substitutable position of the group, and when any particular structure more than one floor shall have a provision may be superseded by more than one Deputy, selected from a specified group, and these substituents may be either the same or different in each position. Annular Deputy, such as heteroseksualci, may be associated with another ring, such as cycloalkyl, with the formation of Spiro-bicyclic ring system, for example, both of the rings contain one of these ring atoms. As should be clear to experts in this field, the combination of the substituents contemplated by this invention are the combinations that provide the formation of a stable or chemically achievable connections.

The phrase "stable or chemically achievable"used in the present description, refers to compounds, which essentially do not change, being subject to conditions that make possible the obtaining, determining and, preferably, their isolation, purification and application of one or more destinations, which are disclosed in this application. In some embodiments, the implementation of a stable compound or chemically achievable connection is a connection that essentially does not change when it is maintained at a temperature of 40°C or below, in the absence of moisture or other chemically reactive conditions, for at least a week.

Unless otherwise stated, structures, presents the present application, also include all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational)) forms of these structures; for example, R and S configurations for each asymmetric center, (Z) and (E) isomers of double bonds and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) of a mixture of compounds of the present invention is included in the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the present invention is included in the scope of the present invention.

In addition, unless otherwise specified, the patterns presented in this application, also include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, compounds having the structure described in the present invention, in addition to the replacement of hydrogen by deuterium or tritium, or the replacement of carbon13C - orl4C-enriched carbon are included in the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

N-oxide derivative or pharmaceutically acceptable salt of each of the compounds of formula (I) are also included in the scope of the present invention. E.g. the measures ring nitrogen atom of imidazole or pyrazole nucleus core ring or nitrogen-containing heterocyclyl Deputy can form the oxide in the presence of a suitable oxidizing agent such as m-chloroperbenzoic acid or H2O2.

The compound of formula (I), which by its nature is an acid (for example, containing carboxyl or phenolic hydroxyl group) can form pharmaceutically acceptable salt, such as sodium, potassium, calcium or gold. Also in the scope of the present invention is enabled salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines followed, hydroxyethylamine and N-methylglucamine. The compound of formula (I) can be treated with acid to obtain the acid additive salts. Examples of such acids include hydrochloric acid, Hydrobromic acid, yodiewonderdog acid, sulfuric acid, methanesulfonate acid, phosphoric acid, p-bromophenylacetate acid, carbonic acid, succinic acid, citric acid, benzoic acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, ascorbic acid, maleic acid, acetic acid and other mineral and organic acids, are well known to specialists in this field. Acid is o-additive salts can be obtained by treating compound of formula (I) in the form of its free base sufficient amount of acid (e.g., hydrochloric acid) to obtain the acid additive salts (for example, cleaners containing hydrochloride salt). An acid additive salt can be converted to free base by treating the salt with a suitable dilute aqueous alkaline solution (for example, sodium hydroxide, sodium bicarbonate, potassium carbonate or ammonia). The compounds of formula (I) can also be, for example, in the form of achiral compounds, racemic mixtures, optically active compounds, pure diastereomers or mixtures of diastereomers.

B. Abbreviations

The following abbreviations have the following meanings. If an abbreviation is not defined, it has a common value.

=
BEMP=2-tert-Butylimino-2-diethylamino-1,3-dimethylpyridine-1,3,2-datafactory
Boc=tert-butoxycarbonyl
BOP=hexaphosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium
USD=broadened doublet
USS =broadened singlet
CDI=carbonyldiimidazole
d=doublet
DD=the doublet of doublets
DIC=diisopropylcarbodiimide
DMF=dimethylformamide
DMAP=dimethylaminopyridine
DMSO=the sulfoxide
EDCI=ethyl-1-(3-dimethylaminopropyl)carbodiimide
EQ.=equivalents
EtOAc=the ethyl acetate
g=grams
HOBT= 1-hydroxybenzotriazole
DIPEA=the basis Hunga = diisopropylethylamine
l=liter
m=multiplet
M=molar
max=max
mEq.=milliequivalent
ml=ml
mm=mm
mmol=mm
MOC=methoxycarbonyl
N.=normal
N/A=not available
ng =nanogram
nm=nm
OD=the optical density
PEPC=1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide
PP-HOBT=piperidine-piperidine-1-hydroxybenzotriazole
psi=pounds per square inch
Ph=phenyl
quart=Quartet
Quint=quintet
rpm=rpm
=the singlet
t=triplet
TFUKtriperoxonane acid
TLC=thin-layer chromatography
ál=microliter
UV=ultraviolet

II. Compounds of the present invention

Typically, the deuterated compounds of the present invention can be synthesized by methods known from the prior art as methods of their synthesis mediterrani forms, except that in the synthesis method using deuterated starting material or reagent for interaction. Examples of suitable methods include the methods described in the application U.S. No. 60/711530; WO 02/18369; WO 07/022459; Advanced Organic Chemistry, 2ndEd., p. 204, J. March, McGraw Hill, New York, NY, 1997; and A Synthesis: Elemes and Ragnarsosson, J. of Chem. Soc, Perkin 1, 1996, 537.

All publications mentioned in this application are fully incorporated by reference.

The compounds of formula I is obtained using known methods, for example, as illustrated below in scheme I.

In accordance with scheme I, the acid of formula i is subjected to interaction with deuterated amino-alcohol-amide compound of the formulaiiin risotti condensing reagent, such as, for example, EDCI and HOSu, obtaining hydroxyamide formulaiii. In some embodiments, the implementation of the percentage enrichment of deuterium (D), which is shown iniiis more than 10%. In other embodiments, the implementation of enrichment varies from 10% to 99.95%, from 40% to 99.95%, from 50% to 99.95%, from 60% to 99.95%, from 80% to 99.95%, from 90% to 99.95%, from 93% to 99.95%, from 97% to 99.95% or 99-99,95%, or at 99.95% or more. Oxidationiiisuitable oxidizing reagent gives compounds of formula I. Suitable oxidizing reagents include, for example, peridinin Dess-Martin or TEMPO and sodium hypochlorite.

Deuterated amino-alcohol-amides of the formulaiipresented in figure 1, can be obtained using known methods and, for example, as shown in the following scheme II.

In accordance with scheme II for the conversion of aminoether glycineivin the deuterated sultam formulaviicarried out in accordance with methods described previously (Y. Elemes and U. Ragnarsson, J. Chem. Soc, Perkin I, 1996, 6, p. 537). Sequential treatment of compounds of formula vii acid and base, as described previously (L. Lankiewicz, et. al., J. Chem. Soc, Perkin I, 1994, 17, p. 2503), followed by treatment of the intermediate amino acids (not shown) benzyloxycarbonylamino gives protected deuterated amino acidviii. Interactionviiiwith methoxyethylamine in the presence of densitywave reagent CDI gives amide Weinrebe formula ix. Reconnectionvifor example, diisobutylaluminium or sociallyengaged gives aldehydex. Using a technique similar to that which was described previously (see, for example, WO 02/18369), aldehydextransform in cyanohydrin xi and then the protected gidrokshikislotuxii. Acidxiiconvert protected amidexiiiwhich removes the protection from getting aminoamideii.

Alternatively, deuterated aminoamideiishown in scheme I, where R2represents H, can be obtained, for example, as shown in scheme III.

In accordance with scheme III propargilovyh alcoholxivrestore bis(2-methoxyethoxy)aluminohydrides sodium with subsequent quenching of the reaction with deuterium oxide to obtain deuterated allyl alcoholxv. Oxidation connectionxvthe manganese dioxide gives the aldehydexvithat must undergo further oxidation to acidxviithe sodium chlorite (NaClO2in the presence of sodium phosphate and 2-methyl-2-butene. Interaction acidxviiwith isobutylphthalate (ICBF) in the presence of N-methylmorpholine with subsequent interaction of the intermediate mixed anhydride with the amine HNR4R5gives amidexviii. Epoxidation connectionxviiiobtaining epoxide you can use peroxide urea-hydrogen (UHP) in the presence of triperoxonane acid and p-toluensulfonate acid. Interaction connectionxixwith sodium azide gives intermediate etidocainexxthat then restore with obtaining racemic amerosportxxicatalytic hydrogenation in the presence of palladium on carbon. The racemic amerosportxxiyou can split using known methods, such as chiral chromatography, obtaining optically active derivatives or the formation of salts with optically active acid HA, followed by crystallization from an organic solvent. Suitable optically active organic acid to obtain the salt include, for example, L-tartaric acid, L-malic acid, (S)-almond acid, (1S)-(+)-10-camphorsulfonic acid, hydrate (-)2,2:4,6-di-O-isopropylidene-2-keto-L-gulonovoy acid, N-acetyl-L-leucine, desoxycholic acid, (+)-O,O'-Dibenzoyl-D-tartaric acid, O,O'-di-(4-toluoyl)-D-tartaric acid, S-(+)1,1-binaphthyl-2-2-phosphoric acid, L-lactic acid, D-gluconic acid, lactobionic acid, dipivoxil-L-tartaric acid, S-(+)-O-acetylindole acid and S-(-)2-(phenylcarbamoyloxy)propionic acid. Examples of suitable organic solvents for recrystallization include dimethylacetamide is, the ethyl acetate and acetone.

Deuterated compounds, thus obtained, can be identified by traditional analytical methods, such as NMR and mass spectroscopy. NMR can be used to determine the structure of the compounds, whereas mass spectroscopy can be used to determine the number of deuterium atoms in the compound compared to its mediterranei form.

Deuterated compounds of the present invention, generally, are more stable and less prone to epimerization compared to their mediterrannee counterparts. Thus, they can be used for such purposes, where desirable specific spatial configuration in the compounds of the present invention. For example, deuterated compounds of formula (I) can be used to treat or prevent infections caused by HCV virus, or other mediated by the HCV protease States, because they have the ability of inhibiting HCV protease. Their inhibitory activity can be measured by traditional tests of inhibition of enzymes, some of which are described in the publications mentioned above. See, for example, Perni, R.B. et al., Antimicrobial Agents and Chemotherapy, 2006 (march), 50 (3): 899-909.

In addition, deuterated compounds of formula (I) can be used as a biological tool is enta for the study of the pharmacological properties of their mediterrani analogues. Accordingly, such applications are also included in the scope of the present invention.

Example 1. Obtain (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazin-2-carboxamido)acetamido)-3,3-dimethylbutyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxo-3-deutero-hexane-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

Stage a: Getting

Deuterated to sultam (i.e. the connectionvipresented on the diagram below) received by known methods such as methods described in Y. Elemes and U. Ragnarsson, J. of Chem. Soc., Perkin 1, 1996, 6, 537; W.Oppolzer, et al., Helv. Chim. Acta., 1994, 25: 2363, using the corresponding unsubstituted of Sultana and propyliodide.

17,32 g connectionvi(by 45.8 mmol) and 229 ml of THF was then loaded into a round bottom flask of 500 ml with a magnetic stir bar and enter for N2. The resulting solution was cooled to -78°C was added n-BuLi (31.5 ml of 1.6 M solution in hexane, 50.3 mmol) via syringe pump over one hour. The obtained yellow solution was kept for 30 minutes, and then thereto was added a solution of HPMA (56 ml) and n-PrI (13.4 ml, 137 mmol) for 30 minutes. The mixture was allowed to warm to room temperature for 8 hours and then cooled to -20°C before adding to a mixture of D2O (50 ml). The reaction mixture then was extracted with EtOAc (400ml) and the organic layer was dried over MgSO 4and concentrated with getting to 61.3 g of crude oil. Chromatography on 500 g of silica gel with elution with a mixture of 2:1 heptane/EtOAc, followed by concentration of the enriched fractions gave 20,35 g of a white solid. This white solid is then recrystallized from EtOH (210 ml) to obtain the 15,39 g connectionviiin the form of a white crystalline solid. The incorporation of deuterium was 93%, as determined by the method1H-NMR.

Stage b: Obtaining (S)-2-(benzyloxycarbonylamino)-2-deuteromethane acid, viii

Connectionvii(15,39 g, 32.1 mmol) withstage adownloaded in THF (100 ml) and 1 n HCl solution (50 ml). The resulting emulsion was stirred over night at room temperature and then concentrated in vacuum to obtain a viscous oil. The resulting oil was then dissolved in THF (100 ml) and to the solution was added water (25 ml) and LiOH (is 3.08 g, 128 mmol). The resulting solution was again stirred overnight at room temperature and then concentrated to remove THF. Remained turbid light yellow emulsion. This emulsion was diluted with water (25 ml) and was extracted with CH2Cl2(three times, each time 50 ml). The aqueous phase was diluted with THF (200 ml) and cooled to 0°C with rapid stirring and added dropwise CBZ-Cl (7,6 ml, 54 mmol) for 15 minutes. After stirring within the underwater hours at 0°C the solvent THF was removed in vacuum and the obtained residue was acidified by adding 1 to N. HCl solution (50 ml). The solution was extracted with EtOAc (3 times, each time 100 ml) and the organic phase was dried over Na2SO4and concentrated to obtain oil. The obtained residue was dissolved in EtOAc (25 ml) and heptane (150 ml), was made the seed crystal and was stirred over night at room temperature. The solids were collected on a Frit, washed with heptane (30 ml) and dried in air to obtain the 5.65 g (70%) of compoundviiipresented in the diagram above. The incorporation of deuterium was 93%, as determined by the method1H-NMR.

Stage c: Receive (S)-benzyl 1-(methoxy(methyl)amino)-1-oxo-2-dataromance-2-ylcarbamate

Into a flask containing 1.0 g of (S)-2-(benzyloxycarbonylamino)-2-deuteromethane acid (of 3.97 mmol) in 20 ml of dichloromethane, supported at 0°C, was added 3.0 EQ. N-methylmorpholine (700 μl), 1.5 equiv. the hydrochloride of N,O-dimethylhydroxylamine (581 mg) and 1.5 EQ. EDCI (1,14 g). The reaction mixture was stirred overnight at a temperature from 0°C to room temperature. The reaction mixture was then diluted in dichloromethane and washed with HCl (1 BC) and a saturated solution of salt. The organic layer was dried over MgSO4. The crude mixture was purified flash chromatography (ethyl acetate 15-75% in hexane) to obtain 814 mg of pure amide (specified in the header of the connection). ES+=296,1, ES-=295,2. Art is ucture confirmed data range 1H-NMR.

Stage d: Obtaining (S)-benzyl 1-oxo-2-dataromance-2-ylcarbamate

Using the methodology described in WO 02/18369, Cbz-protected amino acid withstage cconvert specified in the header connection. Specifically, in a flask containing 1.0 in EQ. (S)-benzyl 1-(methoxy(methyl)amino)-1-oxo-2-dataromance-2-ylcarbamate (810 mg, of 2.75 mmol) in 10 ml of anhydrous THF, supported at 0°C (ice bath)was slowly added 1.7 EQ. solution of lithium borohydride (1,0M) (4,67 ml). After about 10 minutes the ice bath was removed and the reaction was continued for one hour. The reaction was suppressed at 0°C by adding 5 ml of a solution of KHSO4(10%). The solution is then diluted by adding 10 ml of HCl (1 BC). The mixture was stirred for 30 minutes, then was extracted 3 times with dichloromethane. The organic phases were combined and washed with HCl solution (1 ad), water and saturated salt solution. The organic phase is then dried over MgSO4and volatiles evaporated. The aldehyde used as such in the next stage. ES+=237,1, ES-=235,2.

Stage e: Obtain benzyl (3S)-1-(cyclopropylamino)-2-hydroxy-1-oxo-3-dateregex-3-ylcarbamate

Cyclopropylethanol received in accordance with the scheme below.

Cyclopropylethanol the ATEM was subjected to combination with the aldehyde product stage dobtaining specified in the connection header, as described by J. E. Semple et al., Org. Lett., 2000, 2(18), p.2769; Lumma, W., J. Org. Chem., 1981, 46, 3668". ES+=322,1.

Stage f: Obtain (3S)-3-amino-N-cyclopropyl-3-deutero-2-hydroxyhexanoic

Hydrogenolysis of Cbz connection withstage ecarried out using a catalyst of palladium on carbon in presence of hydrogen with obtaining specified in the connection header. In the diagrams belowstage c, d, eandf.

Stage g: Obtain (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazin-2-carboxamido)acetamido)-3,3-dimethylbutyl)-N-((3S)-1-(cyclopropylamino)-3-deutero-2-hydroxy-1-oxohexyl-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

Specified in the title compound was obtained from hydroxyquinolines productstage fby condensation with a suitable acid in the presence of reagent combinations, such as, for example, EDCI and HOSu. Specifically, in a flask containing 1,2 EQ. (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazin-2-carboxamido)acetamido)-3,3-dimethylbutanol)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (1,59 g) in 20 ml of DMF, was added 2.5 EQ. Diisopropylamine (980 μl), 1.2 equiv. hydrate, N-hydroxybenzotriazole (411 mg) and 1,3 EQ. EDCI (558 mg). After 15 minutes stirring at room temperature the e to the mixture was added 1.0 EQ. hydrochloride (3S)-3-amino-N-cyclopropyl-3-deutero-2-hydroxyhexanoate (500 mg). After another 24 hours the reaction mixture was diluted with 400 ml ethyl acetate. The organic phase mixture was washed with HCl (1 ad), water, saturated sodium bicarbonate solution, saturated salt solution and then dried over MgSO4. The crude product was purified by chromatography on silica (ethyl acetate 70-100% in hexane) to give 1.31 g specified in the title compounds as white solids. ES+=683,6, ES-=682,2. The structure was confirmed by data range1H-NMR.

Stage h: Obtain (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazin-2-carboxamido)acetamido)-3,3-dimethylbutyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxo-3-deutero-hexane-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

Specified in the title compound was obtained by oxidation of the productstage gsuitable oxidizing reagent, such as peridinin Dess Martin or TEMPO and sodium hypochlorite. Specifically, in a flask containing 1.31 g of (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazin-2-carboxamido)acetamido)-3,3-dimethylbutyl)-N-((3S)-1-(cyclopropylamino)-3-deutero-2-hydroxy-1-oxohexyl-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide in 40 ml of dichloromethane was added at room temperature 1.06 g periodinane Dess Martin. After 2 hours stirring was added 50 ml of bisulfite intothree the (1 H.) and the mixture was stirred for 30 minutes. 2, the phases were separated, the organic phase is washed twice with water, saturated salt solution and dried over Na2SO4. The crude product was purified by chromatography on silica (ethyl acetate 20-100% in hexane) to give 1.07 g specified in the title compounds as white solids. ES+=681,5, ES-=TO 680.0. The structure was confirmed by data range1H-NMR.

The incorporation of deuterium, a certain MS method was 93%. Diastereoisomeric ratio was determined by chiral HPLC, normal phase, and it was more than 99% CI (diastereoisomeric excess).

The diagram below presents the responsestages gandh.

Example 2. Obtaining hydrochloride (2S,3S)-3-amino-3-deutero-N-cyclopropyl-2-hydroxyhexanoic

The schematic above illustrates the General synthesis specified in the connection header. Each stage is described in detail below.

Stage 1:Obtaining 3-deutero-(E)-Gex-2-EN-1-ol

In a three-neck round bottom flask of 250 ml, equipped with a mechanical stirrer and reflux condenser was loaded 2-hexyne-1-ol (10 g, 0.1 mol) and THF (100 ml, 10 vol). The resulting mixture was cooled to 0±5°C and then slowly added Red-Al (65% in toluene, 32 ml, 1.6 EQ.) in nitrogen atmosphere at a temperature in the range from 0°C to 20°C. the resulting mixture was given on retsa to 25°C and was stirred for 5 hours. The reaction mixture was cooled to a temperature of -5±5°C and added dropwise D2O (8,2 g, 4 EQ.) at a temperature in the range from 0°C to 15°C. To the mixture was added IPAC (50 ml, 5 vol.) and a saturated solution of NH4Cl (50 ml, 5 vol.). After stirring the mixture for 10 minutes the resulting white solid was filtered. The organic layer was separated from the filtrate and the aqueous layer was extracted with IPAC (30 ml, 3 vol). The organic layers were combined and washed with water (30 ml, 3 vol., dried over MgSO4and concentrated to obtain 9.8 g of the product (compound2) as a colourless oil. The crude product2used in the next stage without additional purification.

1H-NMR (500 MHz, CDCl3) δ to 5.66 (t, 1H, J=5.0 Hz), 4,12 (d, 2H, J=5.0 Hz), 2,04 (t, 2H, J=5.0 Hz), 1,38~of 1.46 (m, 2H), of 0.93 (t, 3H, J=5.0 Hz)

Stage 2:Obtaining 3-deutero-(E)-Gex-2-anale

In a three-neck round bottom flask of 250 ml, equipped with a mechanical stirrer, containing 3-deutero-2-hexanol (10 g, 0.1 mol) in CH2Cl2(150 ml, 15 vol.), downloaded activated MnO2(87 g, 10 EQ.) at room temperature. After intensive stirring for 1 hour was added another portion of MnO2(16 g, 2 EQ.) and the shaking was continued for 4 hours. The reaction solution was filtered through a layer of celite. The solvent was removed in vacuo (25°C, 100 mm Hg) to give 8.8 g is not the shelled aldehyde product (compound 3) as a pale yellowish oil. The crude product was used in the next stage without additional purification.

1H-NMR (500 MHz, CDCl3) δ 9,54 (d, 1H, J=10.0 Hz), 6,14(s, 1H), 2,34 (m, 2H), 1,55~1,60 (m, 2H), and 1.00 (t, 3H, J=5.0 Hz)

Stage 3:Obtaining 3-deutero-(E)-Gex-2-ene acid

In a three-neck round bottom flask of 500 ml, equipped with a mechanical stirrer and reflux condenser was loaded with 3-deutero-2-HEXEN-1-al (10 g, 0.1 mol), tert-BuOH (90 ml, about 9.) and 2-methyl-2-butene (30 ml, 3 vol). To the resulting solution was added a freshly prepared aqueous solution of NaClO2(27.4 g, 3 EQ.) and NaH2PO4(62,9 g, 4 EQ.) in water (200 ml) for 30 minutes. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was cooled to 0°C was added a saturated aqueous solution of Na2SO3up until the reaction mixture became colorless. The stirring was stopped, the organic layer was separated and the aqueous layer was extracted with EtOAc (3 vol. × 3). The organic layers were combined and concentrated in vacuo to until the total volume was about 3. The resulting solution was extracted with 1 N. NaOH solution (3 vol. × 3) and the remaining organic layer was decanted. The combined aqueous solution was acidified using 6 N. HCl solution up until the pH reached a value of 1.0. The solution was extracted with CH2Cl2( vol. × 5). The combined organic layers were dried over MgSO4and concentrated to obtain 8.7 g of the product (compound4in the form of a white solid.

1H-NMR (500 MHz, CDCl3) δ of 5.84 (s, 1H), 2,23 (t, 2H, J=5.0 Hz), 1,51~of 1.55 (m, 2H), and 0.98 (t, 3H, J=5.0 Hz)

Stage 4:Obtaining 3-deutero-(E)-N-cyclopropylamino-2-enamide

In a three-neck round bottom flask of 250 ml, equipped with a mechanical stirrer and reflux condenser was loaded 2-hexenoic acid-3d (10 g, 0.09 mol), IBCF (13 g, 1.1 EQ.) in CH2Cl2(100 ml, 10 vol). The resulting solution was cooled to 0°C and slowly added NMM (13,2 g, 1.5 EQ.), adjust the temperature in the range from 0 to 20°C. Then the mixture was allowed to warm to room temperature and was stirred for 1 hour. To the resulting solution was added cyclopropylamine (5.9 g, 1.2 EQ.) and the solution was stirred for 2 hours. The reaction mixture was washed with 1 N. NaOH solution (3 vol. × 2), 1 N. HCl solution (3 vol. × 2) and saturated salt solution (3 vol.) and water (3 vol.). The organic layer was dried over MgSO4and concentrated to obtain the crude product as oil. The crude product was dissolved heptane (5 vol.) and was cooled to -78°C under stirring. The precipitated solid was filtered and dried to obtain 8.7 g of the product (compound5in the form of a white solid.

1H-NMR (500 MHz, DMSO) δ a 7.92 (s, 1H), 5,78 with, 1H), 2,66~of 2.68 (m, 1H), 2,08 (t, 2H, J=5.0 Hz), 1,38~of 1.42 (m, 2H), of 0.87 (t, 3H, J=5.0 Hz), 0,63 (t, 2H, J=3.0 Hz), and 0.40 (t, 2H, J=3.0 Hz)

Stage 5:Obtaining 3-deutero-N-cyclopropyl-3-prophylaxie-2-carboxamide

In a three-neck round bottom flask of 250 ml, equipped with a mechanical stirrer and containing (E)-N-cyclopropylamino-2-ename-3d (i.e. the product from step4) (10 g, 0.06 mol), urea peroxide, hydrogen (25 g, 4 EQ.) and p-TsOH (12.3 g, 1 EQ.) in CH2Cl2(100 ml, 10 vol.), at 0°C was added triperoxonane anhydride (40,9 g, 3 EQ.) in CH2Cl2(50 ml, 5 vol.) within 30 minutes. The reaction mixture was heated to a temperature of 40±5°C and was stirred for 3 hours. After cooling to 0°C the reaction mixture was suppressed by slow addition of 6 n NaOH solution (100 ml, 10 vol.) and was stirred for 30 minutes. The organic layer was separated and washed with saturated salt solution (5 vol.) and water (5 vol.). The washed organic layer was dried over MgSO4and the solvent evaporated to obtain 9.7 g of epoxide product (i.e. compound 6) as a pale yellow oil. The crude product was used in the next stage without additional purification.

1H-NMR (500 MHz, DMSO) δ 8,01 (s, 1H), 3,09 (s, 1H), 2.63 in~to 2.65 (m, 1H), 1,39~and 1.54 (m, 4H), of 0.91 (t, 3H, J=5.0 Hz), 0,60 (t, 2H, J=3.0 Hz), 0,45 (t, 2H, J=3.0 Hz)

Stage 6:Obtaining 3-azido-3-deutero-N-cyclopropyl-2-hydroxyhexanoic

In a three-neck round bottom flask, 250 ml, with agenoy with a mechanical stirrer and reflux condenser, containing epoxide-3d6(10 g, 0.06 mol) and anhydrous magnesium sulfate (14.1 g, 2.0 EQ.) in MeOH (100 ml, 10 vol.), was added sodium azide (15.3 g, 4.0 EQ.) one portion. The resulting mixture was heated to a temperature of 65±5°C and was stirred for 5 hours. The reaction mixture was cooled to room temperature, was added IPAC (100 ml, 10 vol.) and the mixture was stirred for another 10 minutes. The mixture was filtered through a layer of celite® to remove insoluble salts and the resulting clear solution was concentrated to about 3. To the resulting solution was added IPAC (170 ml, about 17.) and the mixture was stirred for another 10 minutes. Again the solution was filtered through a layer of celite® product, azide-3d (connection7), in the form of a transparent solution in IPAC (approximately 200 ml), which was used in the next stage without additional purification.

1H-NMR (500 MHz, DMSO) δ to $ 7.91 (s, 1H), 6,00 (d, 1H, J=5.0 Hz), a 4.03 (d, 1H, J=5.0 Hz), 2,66~to 2.67 (m, 1H), 1,30~1,58 (m, 4H), to 0.88 (t, 3H, J=5.0 Hz), 0,60 (t, 2H, J=3.0 Hz), 0,48 (t, 2H, J=3.0 Hz)

Stage 7:Obtain 3-amino-3-deutero-N-cyclopropyl-2-hydroxyhexanoic

In a reactor for the hydrogenation of 500 ml, which represents an autoclave, equipped with a mechanical stirrer, containing azide-3d7(200 ml, 0.05 mol) in IPAC obtained in the previous phase were loaded Pd/C (10% Pd, the water content is 50%, 0.8 g). The solution was injected into the nitrogen (1.0 ATM) and then released three times, then typed hydrogen (3.0 a is m) and released three times. In the resulting solution was injected hydrogen (3 ATM) and stirred for 5 hours. After the release of gaseous hydrogen, the solution was purged with nitrogen for 5 minutes. To the resulting solution was added MeOH (30 ml, 3 vol.) and the reaction mixture was heated to a temperature of 50±5°C. the Reaction mixture was filtered through a layer of celite with obtaining a clear solution. The product was isolated by concentration of the solution at a temperature of 20±5°C as long as there was about 3. solution. The solid is collected by filtration, washed (IPAC, 3 vol.) and dried to obtain 7.7 g is specified in the header connection (connection8in the form of a white crystalline solid.

1H-NMR (500 MHz, DMSO) δ of 7.70 (s, 1H), 5,31 (s, 2H), 3,68 (s, 1H), 2,64~of 2.66 (m, 1H), 1,10~1,50 (m, 4H), of 0.82 (t, 3H, J=5.0 Hz), 0,59 (t, 3H, J=3.0 Hz), 0,45 (t, 3H, J=3.0 Hz)

Stage 8:Getting desoxycholate (2S,3S)-3-amino-3-deutero-N-cyclopropyl-2-hydroxyhexanoic

Desoxycholic acid (15.7 g, 0.75 EQ.) loaded in a three-neck round bottom flask of 250 ml, equipped with a mechanical stirrer and containing racemic (2S,3S)-3-amino-3-deutero-N-cyclopropyl-2-hydroxyhexanoic withstage 7(10 g, 0.05 mol) in THF (100 ml, 10 vol). The reaction mixture was heated to a temperature of 65±5°C and was stirred for 1 hour. The obtained homogeneous mixture was cooled to a temperature of 23±2°C for 1 hour and left at ambient temperature the re within the specified limits within 1 hour. Precipitated solids were collected by filtration, washed with THF (50 ml, 5 vol.) and dried to obtain 12.4 g of the compound in the form of salt (compound9in the form of a white solid. The product had an enantiomeric ratio (ER) 2:98.

Stage 9:Obtaining hydrochloride (2S,3S)-3-amino-3-deutero-N-cyclopropyl-2-hydroxyhexanoic

In a three-neck round bottom flask of 250 ml, equipped with a mechanical stirrer, was loaded dihydrofolate salt (stage8) and 2-propanol (62 ml, 5 vol.). The solution was heated to a temperature of 75±5°C and slowly added 5-6 n HCl in IPA (12 ml, 3 EQ.) under vigorous stirring. The resulting solution was stirred at the same temperature for 1 hour and then cooled to a temperature of 23±2°C. the Reaction mixture was maintained at the same temperature for 1 hour. Precipitated solids were collected by filtration, washed with 2-propanol (36 ml, 3 vol., dried to obtain 3.0 g specified in the connection header (enantiomeric ratio =0:100) as a white solid. The incorporation of deuterium was more than 99%, as determined by the method MS and1H-NMR.

1H-NMR (500 MHz, DMSO) δ 8,07 (s, 1H), 7,97 (s, 3H), and 6.25 (d, 1H, J=5.0 Hz), 4,16 (d, 1H, J=5.0 Hz), 2,67~2,70 (m, 1H), 1,33~of 1.46 (m, 4H), from 0.84 (t, 3H, J=5.0 Hz), and 0.61 (t, 3H, J=3.0 Hz), 0,53 (t, 3H, J=3.0 Hz).

Example 3. Analysis measuring the rate of epimerization

Deuterated soy is inane of the present invention were slow epimerization as follows:

The rate of epimerization was measured in accordance with the following analysis. Specifically, 100 μl of medium (buffer, plasma rat plasma dog or human plasma) were added to 96-well deep plate. The plasma was then added 10 μl of a solution of acetonitrile containing the test compound (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazin-2-carboxamido)acetamido)-3,3-dimethylbutyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxo-3-deutero-hexane-3-yl)octahydrocyclopenta[c]pyrrol-1-carboxamide (at a concentration of 1 µm or 10 µm) and 1200 ál of ethyl acetate in 96-well plate with deep holes (2 ml), using the installation for liquids TomTec (Hamden, CT, USA). The tablet is then tightly closed and shaken for mixing by turbulence within 20 minutes, and then centrifuged at 3000 rpm for 10 minutes. After centrifugation 900 ál of supernatant was transferred into a new 96-well plate with V-shaped deep holes using a TomTec, and then dried in an atmosphere of nitrogen gas (flow rate 60 l/min) at 25°C for about 30 minutes. The obtained residue restructured 100 ál of ethyl acetate and the solution again was transferred to a glass insert in a 96-well plate. 20 μl of the restructured solution was injected into the device for analysis by LC-MS/MS to determine the number of epimeres. For LC-MS/MS is pectrometry used column ChiralPak AD (a 4.6×150 mm, 10 μm), a mixture of isopropanol and n-heptane (10:90, 50:50 or 90:10) as mobile phase and isopropanol as a solvent for cleaning. Also in MS spectrometer used deuterated analogue of the tested compounds containing 11 deuterium atoms tsiklogeksilnogo group (C36H42D11N7O6MM 690,47).

The test compound had a mass (M+H, m/z) 681,36, while his mediterrannee counterparts (with the same or different chiral configurations in deuterated carbon center) had a mass (M+H, m/z) 680,36. Their spectra LC-MS/MS showed the fragment 323,30 (deuterium) and 322,30 (Mediterranee).

At both concentrations (1 μm and 10 μm) and in the same environment (i.e. buffer, plasma rat plasma dog and human plasma) test deuterated compound of formula (I) showed a slower rate of epimerization than his Mediterranea form in the buffer, plasma rat plasma and dogs; and a much slower rate of epimerization in plasma. For example, in the plasma of man and at 1 μm or 10 μm deuterated compound was subjected to epimerization by about 30% within 180 minutes, whereas Mediterranea form was subjected to epimerization by almost 40%. In addition, plasma deuterated compound was subjected to epimerization with a linear speed for 180 minutes, then ka is mediterranena form showed an exponential rate of epimerization during the first 60 minutes, then the speed was leveled.

Example 4. Analysis definition IR50in cells with HCV replicon

This analysis used (1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazin-2-carboxamido)acetamido)-3,3-dimethylbutyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxo-3-dateregex-3-yl)octahydrocyclopenta[c]pyrrol-1-carboxamide and (5S,8S)-3-(5-chloro-2,4-acid)-7-((S)-2-(2-cyclohexylacetate)-3,3-dimethylbutyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxo-3-dateregex-3-yl)-1-oxa-2,7-diazaspiro[4.4]non-2-EN-8-carboxamide, as described in Lin, C. et al., J. Biol. Chem., 2004, 279: 17508-17514; Lin, K. et al., Antimicrob. Agents Chemother., 2004, 48:4784-4792.

Cells Huh-7, including an independent replicate, subgenomic the HCV replicon Con1 strain, maintained in the modified Dulbecco environment Needle (DMEM)containing 10% thermoinactivation fetal bovine serum (FBS), 2 mm L-glutamine and non-essential amino acids (JRH Biosciences, Lenexa, KS), plus 0.25 mg/ml G418 (Invitrogen, Carlsbad, CA). Subgenomic the HCV replicon encodes also neomycinphosphotransferase that makes possible the selective growth HCV replicon-containing Huh-7 cells compared with the HCV replicon-negative Huh-7 cells in the presence of G418. The concentration of the test compounds, in which the level of HCV RNA in cells with replicon is reduced by 50% (IC50) or 90% (IR90) or cell viability is reduced by 50% (CC50), was determined in the cell is x with HCV Conl abgenommen the replicon (19) using the curve with 4 parameters (SoftMax Pro). Containing the replicon cells were incubated with the test compound, diluted in DMEM containing 2% FBS and 0.5% DMSO (without G418), at 37°C. Total cellular RNA was extracted using RNeasy kit-96 (QIAGEN, Valencia, CA) and the number of copies of HCV RNA was determined by quantitative, real-time, multiple analysis of reverse transcription-PCR (QRT-PCR or Taqman). Cytotoxicity of compounds in cells with the HCV replicon was measured in the same experimental conditions using tetrazolium analysis of the viability of the cells.

The results show that both of the tested compounds had Ki less than 50 nm and IR50(within 5 days) less than 10.0 microns.

Other embodiments of

It should be understood that although the present invention has been disclosed in connection with the detailed description, the above description is intended for illustration and does not limit the scope of the present invention, which is defined by the scope of the attached claims. Other aspects, advantages, and modifications are covered by the following claims.

1. Enriched with deuterium α-catholicisation formulas(1)

where D is a deuterium atom;
R1representswhere
represents a C 4-C8, monocyclic azaheterocyclic, or C3-C10polycyclic azaheterocyclic, or C3-C10polycyclic azaheterocycles, where the unsaturation is in the ring distal to the ring containing the group R21and attached to the group-C(O)-N(R2)-CDR3-C(O)-C(O)-NR4R5where each azaheterocyclic or azaheterocycles optionally substituted phenyl, optionally substituted by one or more substituents selected from alkoxy and halogen;
R21representswhere
each R6and R8represents independently C1-C4alkyl, substituted C1-C4the alkyl or C3-C10cycloalkyl;
each R7, R9and R11represents independently hydrogen or C1-C4alkyl;
R10is pyrazin or C1-C4alkyl, optionally substituted C3-C10cycloalkyl;
L represents-C(O) -, or-NR11C(O)-;
n is 0 or 1; and
each of R2, R3and R4independently, represents H or C1-6alkyl; and
R5represents N or C3-C10cycloalkyl,
where "hetero" atoms in heteroaryl or heterocyclizations groups represent N or O,
and the connection:

2. The compound according to claim 1, where n is equal to 1.

3. The compound according to claim 1, where R6represents methylene substituted by isobutyl.

4. The compound according to claim 1, where R7represents hydrogen.

5. The compound according to claim 1, where R8represents a methylene, substituted C3-C10cycloalkyl.

6. The compound according to claim 5, where R8represents a methylene, substituted cyclohexyl.

7. The compound according to claim 1, where R9represents hydrogen.

8. The compound according to claim 1, where L represents-C(O)-.

9. The compound according to claim 1, where R10is pyrazin.

10. The connection according to claim 9, where R10is a 2-pyrazin.

11. The compound according to claim 1, whererepresents a C4-C8monocyclic azaheterocyclic.

12. The compound according to claim 1, whererepresents a C6-C10polycyclic azaheterocyclic or C6-C10polycyclic azaheterocyclic, optionally substituted phenyl, optionally substituted by one or more substituents selected from alkoxy and halogen.

13. The connection section 12, whererepresents a

14. The connection indicated in paragraph 13, whererepresents a

15. The compound according to claim 1, R 2represents hydrogen, R4represents hydrogen, and R5independently represents hydrogen or cyclopropyl.

16. The compound according to claim 1, where R3is a drunk.

17. The compound according to claim 1, where n is equal to 0.

18. The compound according to claim 1, where L represents-NR11C(O)- and R11represents hydrogen.

19. The compound according to claim 1, where R10represents a C1-C4alkyl, optionally substituted C3-C10cycloalkyl.

20. The connection according to claim 19, where R10represents tert-butyl.

21. The compound according to claim 1, where the connection is a

22. The connection section 12, whererepresents a
where
A represents a-CH2-;
Represents a-CH2-;
each of the Y1and Y2represents hydrogen;
R22represents phenyl, optionally substituted by one or more substituents selected from alkoxy and halogen.

23. Connection p.22, where R22represents phenyl substituted by one or more substituents selected from alkoxy and halogen.

24. Connection p.22, where
represents

25. The connection point 24 where the compound has the structure:
img src="https://img.russianpatents.com/1121/11210226-s.jpg" height="63" width="78" />

26. The compound according to claim 1, where the enrichment of deuterium in the compound is at least 50%.

27. Connection p, where the enrichment of deuterium is at least 80%.

28. Connection item 27, where the enrichment of deuterium is at least 90%.

29. Connection p, where the enrichment of deuterium is at least 99%.

30. Pharmaceutical composition having activity against HCV containing a pharmaceutically acceptable carrier and a compound according to any one of claims 1, 21, 25, 28 or 29.

31. The method of increasing the bioavailability of the compounds, including the replacement of the hydrogen atom, which is associated with steric carbon atom in the compound, a deuterium atom, where the resulting deuterated compound is a compound according to any one of claims 1, 21, 25, 28 or 29.

32. Method of inhibiting HCV protease, comprising contacting the HCV protease with the compound according to any one of claims 1, 21, 25, 28 or 29.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a quinazoline derivative of general formula [1], or a pharmaceutically acceptable salt thereof [1], where R1-R6 assume values given claim 1, except compounds in which R5 is hydrogen and R6 is -NH2. The invention also relates to a pharmaceutical composition having the activity of an antipruritic agent, containing as an active ingredient said quinazoline derivative or pharmaceutically acceptable salt thereof.

EFFECT: obtaining a novel quinazoline derivative with low irritant action on skin and excellent action of significant suppression of scratching behaviour, as well as an antipruritic agent containing such a quinazoline derivative as an active ingredient.

9 cl, 250 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives having PGDS inhibiting properties. In formula (I): (I), R1 denotes phenyl or a 5- or 6-member heteroaryl containing 1-3 heteroatoms selected from N, O and S, each optionally having one or more of the following independent substitutes: halogen, (C1-C6)-alkyl, or (C1-C4)-haloalkyl; R2 denotes hydrogen or (C1-C6)-alkyl, which is optionally substituted with one or more halogens; R3 denotes hydrogen, (C1-C6)-alkyl or phenyl; R4 denotes C6-cycloalkyl, phenyl, a 6-member heterocyclyl containing one N heteroatom, a 6-member heteroaryl containing one N heteroatom, -C(=O)-NY1Y2, -C(=S)-NY1Y2, or -C(=O)-R5, where the phenyl, 6-member heteroaryl or 6-member heterocyclyl group optionally has one or more independent substitutes R6, or R3 and R4 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclyl containing one or two heteroatoms selected from N, O and S, a 6-member heterocyclenyl containing two or three N heteroatoms, a 5-member monocyclic or 9-member bicyclic heteroaryl containing one to three N heteroatoms, phenylheterocyclyl, where the heterocyclyl is 5- or 6-membered and contains one or two heteroatoms selected from N and O, each optionally having one or more independent substitutes R6. Values of R5, R6, Y1, Y2 are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds.

EFFECT: improved method.

15 cl, 227 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts possessing the properties of a MMP12 inhibitor, a method for preparing them, an intermediate compound of formula (III), a pharmaceutical composition, a method for preparing it, using the compounds of formula (I) and versions of methods of treating with the use of the compounds of formula (I). The compounds may be used for treating the MMP12-mediated diseases, such as chronic obstructive pulmonary disease. In formula (I) and (III) R1 represents H, CH3, CH3CH2, CF3 or cyclopropyl; and R2 represents H or CH3.

EFFECT: higher clinical effectiveness.

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SUBSTANCE: invention refers to new 1,3-disubstituted 4-methyl-1H-pyrrol-2-carboxamides of formula I: wherein the values R1, R2, R3, R4 are presented in cl.1 of the patent claim.

EFFECT: preparing the compounds found to be serotonin-5-HT reuptake inhibitors that enables using them in medicine.

14 cl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to substituted sulphamide derivatives of formula I: , in which n, m, R1, R2a-c, R3, R4, R5 and R6 are as described in claim 1, in form of a racemate, enantiomers, diastereomers, mixtures of enantiomers or diastereomers or a separate enantiomer or diastereomer, bases and/or salts of physiologically compatible acids. The invention also relates to a method of producing said compounds, a medicinal agent having antagonist action on bradykinin receptor 1 (B1R), containing such compounds, use of such compounds to produce medicinal agents, as well as sulphamide-substituted derivatives selected from a group of compounds given in claim 8.

EFFECT: providing novel compounds which are suitable as pharmacologically active substances in medicinal agents for treating disorders or diseases which are at least partially transmitted through B1R receptors.

13 cl, 581 ex

FIELD: chemistry.

SUBSTANCE: described are novel 1,2,4-triazolones of general formula (I):

, where A denotes N and values of other radicals are given in the claim, which are vasopressin receptor inhibitors, synthesis method thereof and use thereof to prepare medicinal agents for treating and/or preventing diseases, particularly for treating and/or preventing cardiovascular diseases.

EFFECT: high efficiency of using said derivatives.

6 cl, 512 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula (I), where R1 represents C1-6 alkyl, optionally substituted with hydroxy, monocyclic C3-8 cycloaliphatic radical, optionally substituted with hydroxy, or phenyl; R2 represents H, C1-6 alkyl, optionally substituted with hydroxy or morpholine, monocyclic C3-8 cycloaliphatic radical, optionally substituted with a hydroxy group or a heterocycloaliphatic radical, where the heterocycloaliphatic radical is piperidine, pyrrolidine or morpholine; each of a, a', b and c independently represents N or C(R3); each of R3, R5 and R6 independently represents H, halogen, phenyl, substituted with one substitute selected from methoxy methyl, amino, methoxy or trifluoromethoxy, or heteroaryl substituted with alkyl, hydroxy or alkoxy; R4 represents H; K represents -N(RX')-; J represents a bond, -O, alkylene, -C(O)-, -C(O)-O-, or -C(O)-N(Rx')-; RX' represents H; n equals 0; and under the condition that if R1 represents an unsubstituted alkyl, J represents -O-, then R2 represents H. The invention also relates to a pharmaceutical composition based on a compound of formula (I).

EFFECT: obtaining novel heterocyclic compounds, useful as modulators of interleukin receptor-associated kinase IRAK.

20 cl, 18 ex

New compounds // 2458920

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or to its pharmaceutically acceptable salts wherein -A-(R1)a means a group; -B-(R2)b means a group specified in the patent claim 1, R3 means hydrogen; X means CH2 or O; and Y means CH2. Also, the invention refers to a pharmaceutical composition exhibiting FGFR inhibitor activity on the basis of the declared compound.

EFFECT: there are produced new compounds and based pharmaceutical composition which can find application in medicine for preparing a cancer drug.

8 cl, 1 tbl, 180 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, possessing properties of inhibiting activity of receptor of kinase insertion domain (KDR), or their pharmaceutically acceptable salts. In formula (1): each of X and Y independently represent O, NR, where R represents H; Z represents CR', where R' represents H or halogen; V, U and T together represent or each of R1, R2, R3, R4 and R6 independently represent H, halogen, cyano, C1-10alkyl; R5 values are given in the invention formula; R7 represents C1-10alkyl.

EFFECT: invention also relates to method of treating angiogenesis-associated disorder such as cancer or age-related macular degeneration.

16 cl, 318 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula l , where a and b are independently equal to 0-5; R1 and R2 independently denote -C1-4alkyl, CN, halogen, -ORa, -CH2OH, Ra independently denotes H, C1-4alkyl; R3 denotes -C(O)NR3aR3b, -CN; R3a and R3b denote H; R5 denotes -C1-6alkyl; Q denotes -C0-5-alkylene-Q'-C0-1alkylene-, Q' denotes -CH2-, -CH=CH-, -C≡C-, -O-, -S-, -S(O)-, -SO2-, -C(O)-, -OC(O)-, -C(O)O-, -NRQ1C(O)-, -C(O)NRQ1-, -NRQ2-C(O)-NRQ3-, -C=N-O-, -S-S- and -C(=N-O-RQ4)-, RQ1 denotes H; RQ2 and RQ3 denote H; RQ4 denotes -C1-4alkyl, benzyl; e equals 0-5; R6 independently denotes halogen, -C1-4alkyl, -C0-4alkylene-OH, CN, -C (O)O-C1-4alkyl, -O-C1-4alkyl, -S-C1-4alkyl, -NH-C(O)-C1-4alkyl, -N (C1-4alkyl)2 and -N+(O)O; where the alkyl group in R6 is optionally substituted with 1-5 F atoms; one -CH2- group in Q is optionally substituted with one -OH; or a pharmaceutically acceptable salt or zwitterion form thereof.

EFFECT: compounds exhibit antagonistic activity towards muscarinic receptors, which enables their use to produce pharmaceutical compositions for treating lung diseases such as chronic obstructive pulmonary disease and asthma.

32 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of novel 4-(azacycloalkyl)phthalonitriles. Novel 4-(azacycloalkyl)phthalonitriles of general formula

are obtained. The method of obtaining said compounds involves nucleophilic substitution of the bromine atom in 4-bromophthalonitrile (BPN) with N,N-cycloalkyleneamines.

.

The reaction takes place in the presence of a deprotonation agent K2CO3 and a catalytic complex Cul/dipyridyl formed in situ at temperature 90-95°C for 12 hours. Molar ratio of reactants BPN: amine: Cul: dipyridyl: K2CO3=1:1.2:0.1:0.1:1.5. After the reaction, the mixture is cooled and filtered. The filtered residue is washed with water and recrystallised.

EFFECT: obtaining novel 4-(azacycloalkyl)phthalonitriles using a method which is safe for this class of compounds.

2 cl, 4 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 3,4-substituted pyrrolidine derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is an acyl selected from values given paragraph 1 of the formula of invention; R2 is unsubstituted C1-C4-alkyl or C3-C7-cycloalkyl; R3 is a fragment selected from a group of fragments of formulae: (a), (b),

(c) and (f), where any of the fragments of formulae given above (a), (b) and (f), the star (*) indicates a bond of the corresponding fragment R3 with the molecule residue in formula I; Ra denotes N-C1-C4-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl- C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(C3-C7-cycloalkyl-C1-C4-alkyl)aminocarbonyl, N,N-di-(C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl)aminocarbonyl or hydrogen; Rb and Rc are independently selected from a group comprising unsubstituted C1-C4-alkyl, unsubstituted monocyclic aryl, unsubstituted monocyclic heterocyclyl, unsubstituted or substituted monocyclic C3-C7-cycloalkyl, unsubstituted aryl- C1-C4-alkyl, usubstituted monocyclic C3-C7-cycloalkyl- C1-C4-alkyl, hydrogen or acyl, where the acyl is selected from values given in paragraph 1 of the formula of invention; or Rb and Rc together may form a 6-member nitrogen-containing ring which may be unsubstituted or disubstituted with =O; Rd in the fragment of formula (c) denotes a phenyl or phenyl-C1-C4-alkyl; Re denotes hydrogen or C1-C4-alkyl; and m equals 2; each of R4 and R5 denotes hydrogen; and T denotes methylene. The invention also relates to the pharmaceutical composition based on the compound of formula I and a method of treating hypertension using the compound of formula I.

EFFECT: novel pyrrolidine derivatives having renin inhibiting activity are obtained.

7 cl, 19 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of ethylenediamine derivatives (4), having a halogenated carbamate group and an acyl group, involving catalytic hydrogenation of aminonitrile with a halogen-substituted carbamate group in the presence of an acid and then acylation of the formed amino derivative. The initial aminonitrile may be obtained with high output by reacting an amino acid amide with a halogen-substituted carbamating agent in the presence of water and then reacting the formed amide, which has a halogen-substituted carbamate group, with a reducing agent such as a Wilsmeyer reagent.

EFFECT: high yield.

22 cl, 45 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): where: n equals 1 or 3; R1 denotes H, straight or branched (C1-C7)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl; X denotes H, either one or more substitutes selected from halogen atoms and the following groups: CF3, straight or branched (C1-C6)alkyl, (C1-C6)alkoxy; R2 denotes H, one or more substitutes selected from halogen atoms, CF3, straight or branched (C1-C6)alkyls, (C1-C6)alkoxy, -NR3R4, -SO2NR3R4, -CONR3R4, where R3 and R4 each independently denotes H, straight or branched (C1-C6)alkyl, in form of a base or additive salt with an acid.

EFFECT: formula I compounds are inhibitors of glycine glyt 1 and/or glyt 2 carriers, which enables their use in preparing a pharmaceutical composition and a medicinal agent.

1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and their acid-additive and basic salts as FAAH enzyme inhibitors, method of producing said compounds, a pharmaceutical composition based on said compounds and their use, as well as to intermediate compounds of formula (IIa). In general formula (I) , m is an integer ranging from 1 to 4; n is equal to 1 or 2; o is equal to 1 or 2; A is selected from one or several groups X, Y; X denotes a methylene group optionally substituted with one group which is C1-6-alkyl; Y denotes a C2-alkynylene group; B denotes a covalent bond or C1-6-alkylene group; G denotes a covalent bond, an oxygen atom; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes a group selected from oxazolyl, isoxazolyl, thiazolyl, phenyl, pyridinyl, naphthyl, quinolinyl, isoquinolinyl; R5 denotes a halogen atom, a cyano group, C1-6-alkyl, C1-6-alkoxy, C1-6-fluoroalkyl, C1-6-fluroalkoxy, NR7R8; R6 denotes a phenyl group, phenyloxy or pyrimidinyloxy; where R6 group(s) can be substituted with one or two R5 groups which are identical or different from each other; R7 and R8 independently denote a C1-6-alkyl group; R2 denotes a hydrogen atom; R3 denotes a hydrogen atom or C1-C6-alkyl group. In general formula (IIa) , m is an integer ranging from 1 to 2; n equals 2, o equals 2; A denotes X, X denotes a methylene group; B denotes a C1-6-alkylene group; G denotes a covalent bond; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes phenyl; R5 denotes a halogen atom, C1-6alkoxy; R6 denotes a phenyl group; R2 denotes a hydrogen atom.

EFFECT: compounds can be used for treating and preventing diseases mediated by FAAH enzyme activity, such as acute and chronic pain, dizziness, vomiting, nausea, disrupted eating behaviour, neurologic and psychiatric pathologies, acute and chronic neurodegenerative diseases etc.

The invention relates to derivatives of cyclic amines and their use as pharmaceuticals, particularly to a compound represented by the General formula (I), its pharmaceutically acceptable acid additive salts or its pharmaceutically acceptable C1-C6alcaldicios salt, R1-phenyl, C3-8-cycloalkyl, aromatic heterocycle with 1-3 heteroatoms selected from O, S, N, or combinations thereof, and these groups may be condensed with benzene ring or an aromatic heterocyclic group with heteroatoms, selected from O, S or N, or combinations thereof, and may also have different substituents

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new β-cyclodextrine clathrate complex (an inclusion compound) with 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylindole derivative: β-cyclodextrine 1:1 to 1:5, preferentially at the relation of 1:1 to 1:3 of general formula (I): wherein X means - hydrogen, chlorine, iodine, n=1 or 2, R3-C1-C3 alkyl, ALK means C1-C6 alkyl group, R1, R2 are independently specified in C1-C4-alkyl, preferentially methyl, or R1 and R2 together with a nitrogen atom (i.e. group - NR1R2) means the groups described by formulas: wherein Bn is benzyl, a Ph is phenyl with the molar ratio of 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylindole derivative: β-cyclodextrine 1:1 to 1:5, preferentially 1:1 to 1:3, especially preferentially in the relation of 1:2. The clathrate complex may represent nanoparticles of size not less than 100 nm. There are preferential clathrate complexes wherein 5-hydroxy-4-aminomethyl-1-cyclohexyl(or cycloheptyl)-3-alkoxycarbonylindole derivative represents 1-cyclohexyl-4-aminomethyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester. The new clathrate complexes possess antiviral action and exhibit high activity versus influenza viruses. The invention also involves a pharmaceutical composition and a drug based on the clathrate complexes. Besides, the invention refers to liquid-phase and solid-phase synthesis of the clathrate complexes.

EFFECT: preparing the compounds which possess antiviral action and exhibit high activity versus influenza viruses.

20 cl, 2 ex, 2 tbl, 8 dwg

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