Polycyclic agents for treating respiratory syncytial viral infections

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new polycyclic compounds, pharmaceutically acceptable salts thereof of general formula wherein R1 -phenyl, pyridyl, optionally substituted, or C3-7-cycloalkyl; R2 -H, -CH2R3, -C(=O)R3, -C(=O)N(R4)R3, and -SO2-pyridyl, wherein R3-H, C1-6 alkyl, C2-6 alkenyl, C3-7-cycloalkyl, -(CH2)m-phenyl -(CH2)m-(5-, 6- or 9-member heterocyclyl with 1-3 heteroatoms N, O or S); m is equal to 0-6; R4 -H; X represents O or S; the alkyl, alkenyl, cycloalkyl, phenyl and heterocyclyl groups may be substituted by one or more substitutes. A together with atoms whereto attached forms phenyl or heteroaryl with 1 or 2 nitrogen atoms, optionally substituted; B-C means -CH2-(CH2)z-, wherein z is equal to 1 or 2; D represents -CRIIIRIV-, wherein RIII and RIV are identical, and mean CH3 or H; or RIII and RIV together with the atom C whereto attached form a 3-member cycloalkyl ring, a pharmaceutical composition containing them, and the use of the above compounds for treating viral RSV infections.

EFFECT: new polycyclic compounds are described.

24 cl, 4 tbl

 

The technical field to which the invention relates.

The present invention relates to antiviral compounds, methods for their preparation and their containing compositions and to the use of these compounds and compositions for treatment of viral infections. In particular, this invention relates to the use of compounds of formula I for the prevention and/or treatment of respiratory syncytial virus infections and diseases.

The level of technology

Respiratory syncytial virus (RSV) is the leading cause of acute infections of the upper respiratory tract and lower parts of the respiratory system in adults, younger children and infants. Serological confirmation indicates that in the Western world approximately 95% of all children are infected with RSV to two years and 100% of children are infected by the time of reaching puberty (see Black, C.P., 2003, Resp.Care 48: 209-31 for a review of recent advances in biology and management of RSV). In most cases of RSV infection causes only mild disease of the upper respiratory tract with symptoms that resemble the common cold. However, severe viral infection can lead to bronchitis or pneumonia, which may lead to hospitalization or death. This year approximately 91000 infants hospitalized with RSV infection in the United States. Mladen is s, they were born prematurely or has previously undergone lung disease have a significant risk of serious infections and complications. These infections are responsible for 40-50% of hospitalizations due to child bronchitis and 25% of hospitalizations due to childhood pneumonia. Because the immune response to RSV infection does not exert a protective action of RSV infection occur during puberty. For adults and older children RSV infection is associated with upper respiratory infection, tracheobronchitis and inflammation of the middle ear. However, RSV in elderly hospitalized patients may have more serious action and manifest in severe pneumonia and extent of mortality, reaching 20-78%, respectively. Adults with a previous history of heart or lung disease are at high risk of RSV infection. The infection is accompanied by the aggravation of the disease in patients with chronic obstructive pulmonary disease. Significant mortality was observed in patients with a weakened immune system, especially those who have undergone bone marrow transplantation (Evans, A.S., eds., 1989, Viral Infections of Humans. Epidemiology and Control, 3rded., Plenum Medical Book, New York, p.525-544; Falsey, A.R., 1991, Infect. Control Hosp. Epidemiol. 12:602-608; and Garvie et al, 1980, Br. Med. J. 281:1253-1254; Hertz et al, 1989, Medicine 68:269-281).

RSV is a member of the squad Mononegavirales, which includes Viru is s, containing non-segmented antisense strands of RNA, belonging to the family Paramyxoviridae, Rhahdoviridae and Filoviridae. RSV person (often also referred to as RSV or HRSV) is a member of the genus Pneumovirus subfamily Pneumovirinae, a member of the Paramyxoviridae family. On the basis of genetic or antigenic variations in the structural proteins of RSV divided into two subgroups, a and b (Mufson, M. et al., J.Gen. Virol. 66: 2111-2124). Other members of the genus Pneumovirus include viruses, like bovine RSV (BRSV), Ovine RSV (ORSV) and the virus pneumonia mice (PVM), among others. The subfamily Pneumovirinae also includes the genus Metapneumovirus, which contains the recently identified and an important human pathogen, human metapneumovirus (hMPV).

hMPV causes respiratory diseases range from mild respiratory symptoms upper respiratory tract infections to severe diseases of the lower part of the respiratory system such as bronchitis and pneumonia (van den Hoogen, et al., 2001, Nat. Med. 7:719-724). Depending on the tested patient population 5 to 15% of respiratory infections in young children can be attributed to infections caused by hMPV (van den Hoogen, B. et al., 2003, J.Infect. Dis. 188:1571-1577). 12-50% of cases of otitis of the middle ear in children is also associated with hMPV (van den Hoogen et al., 2004, Pediatr. Infect. Dis. J. 23:S25-S32). In the Netherlands 55% of the tested persons were seropositive against hMPV to 2 years, and almost all individuals in age is 5 years old and older were found to be seropositive (van den Hoogen, et al., Virology 295:119-132).

In addition to the above properties of the genome, characteristics of the family include lipid membrane containing one or more types of glycoproteins, which are considered responsible for the accession and entry into the cell host. Believe that the entry is subject to the application of the method, which consists in the fusion of the virus envelope with the membrane of the host cell. For example, the fusion of infected cells with their neighbors may also lead to the formation of a joint multi-core cells, in some cases known as a syncytium. Believe that the way the merge is mediated by glycoprotein and this property is inherent to various viruses, surrounded by a shell, in other taxonomic groups. In the case of viruses Parctmyxoviridae all kinds usually expresses merged glycoprotein (F), which mediates the fusion of membranes.

Despite the fact that licensed RSV vaccine is not yet available, some success has been achieved in preventing high risk of severe disease of the lower part of the respiratory system in infants, caused also a decrease in LRI. In particular, there are two methods of treatment based on the use of antibodies that help protect infants from high-risk from low LRI: RSV-IGIV (RSV intravenous immunoglobulin, also known as RespiGam™) and paliviumab (SYNAGIS ®). RSV-IGIV (RespiGam, Massachusetts Public Health Biological Laboratories and Medlmmune, Inc., Gaithersburg, MD) licensed by the Food and Drug Administration in January 1996 to prevent severe disease in the lower part of the respiratory system in infants and children younger than 24 months, caused by RSV suffering from CLD or having a history of premature birth (<35 weeks gestation). In June 1998 the Food and Drug Administration has licensed palivizumab (Medlmmune, Gaithersburg, MD) for introduction as a monthly intramuscular injection to prevent acute respiratory illness caused by RSV, infants and children with a history of premature birth (<35 weeks gestation), or CLD.

The only drug approved for treatment of severe disease caused by RSV, is an antiviral drug substance Mirasol (Virazole,), also known as Ribavirin (Ribavirin), currently licensed for the treatment of pneumonia and bronchitis caused by RSV (Hall et al, 1983, N.Engl. J.Med., 308: 1443; Hall et al., 1985, JAMA, 254:3047). This agent has a broad spectrum of antiviral activity together with virostatics effects and acts by inhibiting RSV replication. Unfortunately, this agent is toxic, so the introduction of the agent is limited to use in hospitals (Black, C.P., 2003, Resp. Care 48(3): 209-31). His introduction is further complicated by the need to follow strict is readername method, when the agent is administered in order to minimize the probability of some unwanted effects. The agent has a number of undesirable effects, including sudden deterioration of respiratory function (bronchospasm). The effectiveness of Virazole remains ambiguous and therefore there is a real need to find an alternative agent for the treatment of RSV infection.

Disclosure of inventions

The present invention provides compounds suitable for preventing and/or treating infection and disease caused by RSV, formula I and their salts

where:

R1selected from C1-12of alkyl, C2-12alkenyl,2-12the quinil, -(CH2)nC3-7cycloalkyl, -(CH2)nC4-7cycloalkenyl, -(CH2)naryl, -(CH2)narils1-12of alkyl, -(CH2)narils2-12alkenyl, - (CH2)narils2-12the quinil, and -(CH2)nheterocyclyl; n is 0-6 and above alkyl, alkeline, alkyline, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups optionally are substituted;

R2selected from H, Oh, -CH2R3-C(=Y)R3-C(=Y)OR3-C(=Y)N(R4R3, -C(=Y)CH2N(R4R3, -C(=Y)CH2SR3and-S(O)wR5where R3selected izvodite, C1-12of alkyl, C2-12alkenyl, C2-12the quinil, -(CH2)nC3-7cycloalkyl, -(CH2)mC4-7cycloalkenyl, -(CH2)maryl, -(CH2)marils1-12of alkyl, -(CH2)marils2-12alkenyl, - (CH2)marils2-12the quinil, and -(CH2)mheterocyclyl; and when R2represents-CH2R3or-C(=Y)R3; R3can also be selected from-S-R5and-O-R5; m is 0-6; R4is hydrogen or C1-6by alkyl; R5represents a C1-6alkyl, C2-6alkenyl,2-6quinil,3-7cycloalkyl, C4-7cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and alkyl, alkeline, alkyline, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups optionally are substituted;

X and Y independently selected from O, S and NR6where R6independently selected from hydrogen, lower Akilov, hydroxy and lower alkoxygroup;

And together with atoms to which it is attached, forms an optionally substituted aromatic ring;

In-together With the atoms to which they are attached, form an optionally substituted heterocyclic ring having from 5 to 8 atoms in the ring;

D represents a divalent linking group of the lengths of the second one to three atoms

and provided that when together with the atoms to which it is attached, form unsubstituted phenyl ring, X represents O, D represents-CH2- ,- Represents-CH2CH2-, and R1represents unsubstituted phenyl, then R2is not N.

The present invention also provides the use of compounds and their salts for the preparation of drugs for the prevention and/or treatment of RSV infections.

Although this invention is described with reference to the treatment of RSV, and, in particular, RSV person will be highly encouraged, if this invention can also be used to treat other viruses of the sub-family Pneumovirinae, more specifically family Pneumovirus and Metapneumovirus, more specifically of RSV strains of animals and humans and Metapneumovirus.

Accordingly, this invention also provides the use of compounds of the formula Ia and their salts

where:

R1selected from C1-12of alkyl, C2-12alkenyl, C2-12the quinil, -(CH2)nC3-7cycloalkyl, -(CH2)nC4-7cycloalkenyl, -(CH2)naryl, -(CH2)narils1-12of alkyl, -(CH2)narils2-12alkenyl, - (CH2)narils2-12the quinil, and -(CH2)nheterocyclyl; n is 0-6 and above lcil, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl and heterocyclic groups optionally are substituted;

R2selected from H, Oh, -CH2R3-C(=Y)R3-C(=Y)OR3, -C(=Y)N(R4R3, -C(=Y)CH2N(R4R3, -C(=Y)CH2SR3and-S(O)wR5where R3selected from hydrogen, C1-12of alkyl, C2-12alkenyl, C2-12the quinil, -(CH2)mC3-7cycloalkyl, -(CH2)mC4-7cycloalkenyl, -(CH2)maryl, -(CH2)marils1-12of alkyl, -(CH2)marils2-12alkenyl, -(CH2)marils2-12the quinil, and -(CH2)mheterocyclyl; and when R2represents-CH2R3or-C(=Y)R3; R3can also be selected from-S-R5and-O-R5; m is 0-6; R4is hydrogen or C1-6by alkyl; R5is C1-6the alkyl, C2-6alkenyl,2-6the quinil,3-7cycloalkyl, C4-7cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and alkyl, alkeline, alkyline, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups optionally are substituted;

X and Y independently selected from O, S and NR6where R6independently selected from hydrogen, lower Akilov, hydroxyl and lower alkoxygroup;

And together with atoms to which it is attached, forms an optionally substituted aromatic ring;

In-With the atoms to which they are attached, form an optionally substituted heterocyclic ring having from 5 to 8 atoms in the ring;

D represents a divalent linking group ranging in length from one to three atoms

for the preparation of drugs for the prevention and/or treatment of RSV infections.

The present invention also provides a method for the treatment of RSV infection in a subject in need of it, including the stage of introduction of the compounds of formula Ia or pharmaceutically acceptable salts of the specified entity.

The best way of carrying out the invention

The term "aromatic"as used in this context, refers to aryl cycles or cyclic systems and aromatic heterocyclic cycles or cyclic systems, known as heteroaryl or heteroaromatic cycles.

In this context, the term "aryl" refers to a carbocyclic (nheterocyclic) aromatic cycles or cyclic systems. Aromatic cycles can be mono-, bicyclic or tricyclic system. Aromatic cycles or cyclic systems usually consist of 5-10 carbon atoms. Examples of suitable aryl groups include, but are not limited to yaytsa by phenyl, the biphenyl, naphthyl, tetrahydronaphthyl etc.

Preferred aryl groups include phenyl, naphthyl, indenyl, azulene, fluorene or anthracene.

The term "heterocyclic" or "heterocyclyl"used in this context, refers to mono - or bicyclam or cyclic systems, which include one or more heteroatoms selected from N, S and O. Cycles or cyclic systems typically include in addition to the heteroatom(s) 1-9 carbon atoms and can be saturated, unsaturated or aromatic (including psevdogeometricheskie). The term "psevdogeometricheskie" refers to cyclic systems, which are not strictly aromatic, but are stabilized by delocalization of electrons and behave the same as the aromatic cycles. Aromatics includes psevdogeometricheskie cyclic system, for example foreline, thienyl and pyrrolidine cycles.

Examples of 5-membered monohierarchical include furyl, thienyl, pyrrolyl, N-pyrrolyl, pyrrolidyl, pyrrolidinyl, oxazolyl, oxadiazolyl (including, 1,2,3 - and 1,2,4-oxadiazolyl), thiazolyl, isoxazolyl, furutani, isothiazolin, pyrazolyl, pyrazolyl, pyrazolidine, imidazole, imidazoline, triazolyl (including, 1,2,3 - and 1,3,4-triazolyl), tetrazolyl, thiadiazolyl (including, 1,2,3 - and 1,3,4-tadias the Lila). Examples of 6-membered monohierarchical include pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, 1,4-dioxane, morpholine, 1,4-ditional, thiomorpholine, piperazinil, 1,3,5-tritional and triazinyl. The heterocycles may be optionally substituted by a wide range of substituents and, preferably, C1-6the alkyl, C1-6alkoxyl,2-6alkenyl,2-6the quinil, a halogen atom, hydroxy-group, mercaptopropyl, trifluoromethyl, amino, cyano or mono or di(C1-6alkyl) amino group.

The heterocycle may be condensed with carbocyclic, such as phenyl, naphthyl, indenolol, asplenia, fluorenyl or AstraZeneca.

Examples 8, 9 and 10-membered bicyclic heterocycles include 1H-thieno[2,3-C]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothiazol, benzoxazolyl, benzothiazolyl, benzisoxazole, benzisothiazole, benzimidazolyl, indazoles, ethenolysis, chinoline, honokalani, original, pyrenyl, cinnoline, phthalazine, hintline, honokalani, benzotriazines, naphthyridine, pteridine etc. These heterocycles may be optionally substituted, for example, C1-6the alkyl, C1-6alkoxyl, C2-6alkenyl,2-6the quinil, a halogen atom, hydroxy-group, mercaptopropyl, trifluoromethyl, amino, what ionography or mono - or di(C 1-6alkyl) amino group.

In one embodiment, the implementation of heterocyclic radicals include (optionally substituted) isoxazoles, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, oksazolov, thiazole, pyridine, pyridazine, pyrimidines, pyrazine, 1,2,4-triazine, 1,3,5-triazine, benzoxazole, benzothiazole, benzisoxazole, benzisothiazole, quinoline and cinoxacin. These heterocycles may be optionally substituted, for example, C1-6the alkyl, C1-6alkoxyl,2-6alkenyl, C2-6the quinil, a halogen atom, hydroxy-group, mercaptopropyl, trifluoromethyl, amino, cyano or mono or di(C1-6alkyl)amino group.

In an additional embodiment, the heterocyclic radicals include furyl, thienyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furutani, isoxazolyl, isothiazole, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo[b]furanyl, benzo[b]thiophenyl and benzisoxazoles.

Examples of the unsaturated 5-membered heterocycles include oxazole, thiazole, imidazole, 1,2,3-triazole, isoxazol, isothiazol, pyrazole, furan, thiophene and pyrrole. Examples of unsaturated 6-membered heterocycles include pyridine, pyrimidine, pyrazin, pyridazin and 1,2,4-triazine.

In one embodiment, the implementation of the population heterocyclic ring is an aromatic ring. Heteroaryl and heteroaromatic used in this context to refer to this group of heterocycles. Heteroaryl include furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazole, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-oxadiazol-5-he, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1H thieno[2,3-C]pyrazolyl, thieno [2,3-b]furyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H- indazole, benzimidazole, tetrazolyl, original and cytosine.

In an additional embodiment, heteroaryl or heteroaromatic selected from isoxazolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isothiazoline, furazane, triazolyl, pyridyl, pyrimidinyl, furil, pyrazolyl, pyridazinyl, tanila and arylesterase condensed with aryl heteroaromatic cycles, such as benzofuranyl, benzothiophene and benzisoxazole.

In another embodiment, the heterocyclic ring is non-aromatic ring selected from the group consisting of pyrrolidine, imidazoline, 2-imidazolidone, 2-pyrrolidone, pyrrolin-2-it, tetrahydrofuran, 1,3-dioxolane, piperidine, tetrahydropyran, oxazoline, 1,3-dioxane, 1,4-piperazine, research and thiomorpholine.

Heterocyclic to lzo, containing linking group, may be selected from the above compounds, provided that the ring meets the requirement that it contains at least two nitrogen atom and excludes aromatic cyclic systems.

Unless otherwise specified, the term "optionally substituted"used in this context, means that the group can include one or more substituents, which do not reduce the binding activity of the compounds of formula I and Ia. In some cases, the Deputy can be selected for improved binding and change other properties of the molecule. The group may be substituted by one or more substituents selected from a halogen atom, a C1-6of alkyl, C2-6alkenyl,2-6the quinil, -(CH2)pC3-7cycloalkyl, -(CH2)pWith4-7cycloalkenyl, -(CH2)paryl, -(CH2)pheterocyclyl, -C6H4S(O)1C1-6of alkyl, -C(Ph)3, -(CH2)pZ, -COZ, -CN, -OR, -O-(CH2)1-6-R, -O-(CH2)1-6-OR, -OCOR, -COR, -COOR, -OCONR'R", -C(O)NR1R", -NR1R',- NRCOR', -NRCONR'R, -NRC(=S)NR'r R", -NRSO2R1, -NRCOOR', -C(=NR)R NR'r", -CRNOR, -C(=NOH)R NR'r", -CONR'R", -C(=NCN)-R NR'r", -C(=NR)R NR'r", -C(=NR')SR", -NR'r C(=NCN)SR", -CONRSO2R', -C(=S)NR1R", -S(O)1R5-SO2NR1R", -SO2NRCOR', -OS(O)2R, -PO(OR)2and-NO2; where p is equal to 0-6, t R the veins 0-2, Z represents an N-substituted amino acid selected from the group consisting of alanine,. asparagine, aspartic acid, glutamic acid, glutamine, glycine, pipecolinic acid, α-aminobutyric acid, α-aminopropionic acid and iminodiacetic acid, Z is attached at the nitrogen atom of the specified N-substituted amino acid to the carbon atom, and each of R, R' and R" are independently selected from H, C1-6of alkyl, C2-6alkenyl, C2-6the quinil,3-7cycloalkyl, C4-7cycloalkenyl, aryl, heterocyclyl, C1-6alkylaryl and C1-6alkylchlorosilanes, where the alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, C1-6alkylaryl or C1-6alkylglycerol can be optionally substituted with one to six same or different groups selected from a halogen atom, hydroxyl, lower Akilov, lower alkoxyl, -CO2H, CF3, CN, phenyl, NH2and NO2; or when R' and R" are attached to the same nitrogen atom they may together with the atom to which they are attached, form a 5-7 membered nitrogen-containing heterocyclic ring.

If the optional Deputy represents or contains an alkyl, alkenylphenol, alkenylphenol, cycloalkyl, cycloalkenyl, aryl or heterocyclyl group, the group can be neoba is consequently replaced by one six same or different halogen atom, hydroxyl group, lower alkyl group, lower CNS group, halogen-C1-6alkyl group (including, -CF3), phenyl group, benzyl group, -CN, -C(=O)-C1-6alkyl group, mercaptopropyl, -NH2mono - or di- (lower alkyl) amino group or-NO2.

With regard to nitrogen-containing heterocycles, though otherwise indicated, optionally substituted heterocycles include

pyridinium salts and N-oxides suitable nitrogen atoms of the ring.

With regard to non-aromatic carbocyclic or heterocyclic compounds, although otherwise indicated, such compounds may also be optionally substituted by one or two groups =O instead of or in addition to, the above optional substituents.

Examples of optional substituents include a halogen atom, a C1-4alkyl, C2-4alkenyl, C2-4quinil, C1-4alkoxygroup, C1-4halogenated, -CF3HE, phenyl, -NH2, -NHC1-4alkyl, -N(C1-4)2, -CN, mercaptopropyl, C1-4alkylsulphonyl and C1-4alkoxycarbonyl.

Used in this context, the term "C1-12alkyl" refers to saturated hydrocarbon groups with straight or branched chain containing 1-12 carbon atoms. The example is of such alkyl groups include methyl, ethyl, n-sawn, ISO-propyl, n-boutelou, isobutylene, second-boutelou or tert-boutelou group. Similarly, "C1-6alkyl" or "lower alkyl" refers to the same groups containing 1-6 carbon atoms.

Used in this context, the term "C3-7cycloalkyl" refers to neoromanticism saturated cyclic group containing 3-7 carbon atoms. Examples include cyclopentyloxy and tsiklogeksilnogo group.

Used in this context, the term "alkoxy" refers to alkyl groups of straight or branched chain, covalently linked through O, and the terms "C1-6CNS group" and "lower CNS group" refers to groups containing one to six carbon atoms as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy etc.

Used in this context, the term "C2-12alkenyl" refers to groups formed from C2-12straight or branched acyclic hydrocarbon containing one or more double bonds. Examples of C2-12alkenyl include allyl, 1-methylvinyl, butenyloxy, ISO-butenyloxy, 1,3-butadienyl, 3-methyl-2-butenyloxy, 1,3-butadienyl, 1,4-pentadienyl, 1-pentanediol, 1-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl and 1,3,5-hexadienyl group.

Used in this context, the term "C4-7cycloalkyl " refers to non-aromatic carbocyclic group containing 4-7 carbon atoms and having one or more double carbon bonds. Examples include cyclopentenyl, 1-methyl-cyclopentenyl, cyclohexenyl, 1,3-cyclopentadienyl, 1,3-cyclohexadienyl and 1,4-cyclohexadienyl.

Used in this context, the term "C2-12quinil" refers to hydrocarbons with straight or branched chain, containing one or more triple relations, for example one or two triple bond. Examples include 2-PROPYNYL and 2 - or 3-butynyl.

The term "aryl C1-12alkyl" refers to the above carbocyclic aromatic cycles or cyclic systems and substituted C1-12alkyl group, as described above. Similarly, the terms "aryl C2-12alkenyl" and "aryl With2-12quinil" refer to the above carbocyclic aromatic cycles or cyclic systems and substituted C2-12alkenylphenol or C2-12alkenylphenol groups described above.

Aryl group, and alkyl, Alchemilla or Alchemilla group can be optionally substituted. In one embodiment, the implementation of the aryl group is optionally substituted.

In another embodiment, alkyl, Alchemilla and the and Alchemilla group are optionally substituted. In an additional embodiment, the Deputy selected from a halogen atom, -CN, -NR1R, -COR, - COOR or-CONR'R". R, R' and R" can be independently selected from hydrogen or lower alkyl.

Used in this context, the term "halo" or "halogen" refers to fluorine atom, chlorine, bromine and iodine.

Used in this context "halogenation" group contains one or more hydrogen atoms in an alkyl group substituted by a halogen atom. The example includes-CF3.

In one of the embodiments of the compounds according to the invention include compounds in which a represents a divalent linking group consisting of 3 or 4 atoms selected from C, N, O and S. With this arrangement a and the atoms to which it is connected, together form an aromatic ring, a five or six ring atoms. When all the atoms of linking groups are carbon atoms forming the ring is a carbocyclic aromatic ring or a cyclic system. When the atoms of the linking group include one or more atoms of N, O or S, then the resulting ring is an aromatic heterocyclic ring. Examples include the structure:

represents:

or

or - or

In another embodiment, ring a represents an optionally substituted aryl or heteroaryl ring, for example phenyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl, and in an additional embodiment, selected from phenyl or pyridyl. Optional substituents include N-oxides of the nitrogen atoms of the ring.

Aromatic cycles may be optionally substituted, for example, not more than 3 substituents. In one embodiment, the implementation of the aromatic cycles can have 1-3 substituent selected from a halogen atom, lower alkyl, halogenated forms of lower alkyl, hydroxy-group, the lower alkoxygroup, nitro, amino, lower alkylamino, carboxy, carboxamido, phenyl and benzyl. Also considered N-oxides of the nitrogen atoms of the ring. When a represents a pyridyl, a nitrogen atom may be in the form of N-oxide, or the ring may be in the form of a pyridinium salt.

In one of the options, the ants implementation of the ring And represents unsubstituted phenyl.

In another embodiment, ring a is an unsubstituted pyridyl.

As for the heterocyclic ring formed by b-C, it will be understood that this ring cannot be selected from all of the heterocycles described above, due to the fact that the meaning of the term is determined by the atoms, which are attached to In-N-This ring is limited to monocyclic, non-aromatic heterocycles, which include at least two atoms of nitrogen. This ring may comprise further heteroatoms and may be partially unsaturated.

In another embodiment, In-represents a bivalent linking group of from 1-3 atoms. Linking group-together With the atoms to which it is attached, forms the non-aromatic heterocycle. Examples include the structure:

represents:

or

In an additional embodiment, In-represents-CH2-(CH )z-where z is equal to 1-4, for example 1, 2 or 3. In yet another additional embodiment, z is 1 or 2.

The atoms forming the linking group, can be optionally substituted, for example, not more than 3 substituents. Possibly a large variety of substituents, and they include a halogen atom, lower alkyl, hydroxy, lower alkoxy, phenyl and benzyl.

In another embodiment, In-represents-CH2CH2-.

In one of the embodiments of the condensed ring a and ring-containing divalent linking group, are optionally substituted by one or two substituents, independently selected from a halogen atom and C1-6the alkyl. In an additional embodiment, the condensed ring a and ring-containing divalent linking group are unsubstituted.

The divalent linking group D together with the atoms to which they are attached, may form a 6-, 7 - or 8-membered nonaromatic a heterocycle containing the remainder of the-C(=X)-N<, represented by the following structure:

where each of RIIIand RIVindependently selected from hydrogen, halogen atom, hydroxyl, C1-12of alkyl, C2-12alkenyl, C2-12the quinil, -(CH2)nC3-7cycloalkyl, -(CH2)nCsub> 4-7cycloalkenyl, -(CH2)naryl, -(CH2)narils1-12of alkyl, -(CH2)narils2-12alkenyl, -(CH2)narils2-12the quinil, and -(CH2)nheterocyclyl, or RIIIand RIVtogether with the atom to which they are attached, represent a 3-7-membered cycloalkyl or heterocyclic ring; n is 0-6 and above alkyl, Alchemilla, Alchemilla, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted;

RVselected from Oh, -CH2R3-C(=Y)R3-C(=Y)OR3, -(C=Y)N(R4R3, -C(=Y)CH2N(R4R3, -C(=Y)CH2SR3and-S(O)wR5; where R3selected from hydrogen, C1-12of alkyl, C2-12alkenyl, C2-12the quinil, -(CH2)mC3-7cycloalkyl, -(CH2)mC4-7cycloalkenyl, -(CH2)maryl, -(CH2)marils1-12of alkyl, -(CH2)marils2-12alkenyl, -(CH2)marils2-12the quinil and -(CH2)mheterocyclyl; and where RVrepresents - CH2R3or-C(=Y)R3; R3can also be selected from-S-R5and-O-R5; m is 0-6; R4represents hydrogen or C1-6alkyl; R5represents a C1-6alkyl, C2-6alkenyl, the 2-6quinil,3-7cycloalkyl, C4-7cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and alkyl, alkeline, alkyline, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; and

X and Y are not necessarily selected from O, S and NR6where R6independently selected from hydrogen, lower Akilov, hydroxyl groups and lower alkoxyl.

Will be preferred, if there is, where D is a divalent linking group,- O-CRIIIRIV-considered both of the following patterns:

and

and - and

In one embodiment, the implementation of the divalent linking group D together with the atoms to which it is attached forms a 6-membered nonaromatic a heterocycle.

In an additional embodiment, D represents-CRIIIRIV-, -O-, -NRV-, -S-, or-C(=X)-.

In yet another additional embodiment, D represents-CRIIIRIV-where:

(i) at least one of RIIIand RIVrepresents hydrogen and the other may be selected from a halogen atom, hydroxyl group, optionally substituted C1-12alkyl groups and optionally substituted aryl groups;

(ii) RIIIand RIVare the SJ are the same and represent C 1-3alkyl; or

(iii) RIIIand RIVtogether with the atoms to which they are attached, represent a 3-, 4-, 5-, 6 - or 7-membered cycloalkyl or heterocycle.

In another embodiment, D represents-CRIIIRIV-where:

(i) both RIIIand RIVare N;

(ii) both RIIIand RIVare CH3; or

(iii) RIIIand RIVtogether with the atom to which they are attached, represent a 3-membered cycloalkyl ring symmetric or 6-membered heterocyclic ring.

In another embodiment, X in the compounds of formulas I and Ia represents O.

In an additional embodiment of the present invention, all cycles: condensed ring A, the ring containing divalent linking group, and the divalent linking group D are unsubstituted.

R1may be optionally substituted by aryl, alkyl or heterocyclyl. In one embodiment, the implementation of R1represents optionally substituted aryl or heterocyclyl, for example phenyl, thienyl, pyrrolyl or pyridyl. R1may also be-C1-6alkylphenyl. Cycles R1may be optionally substituted with halogen, hydroxyl, nitro, -NR'r R" (where R' and R" are independently selected from hydrogen, lower Akilov and-C(O)R, where R represents a C1-6Ala is l, phenyl or heterocyclyl), C1-12the alkyl, phenyl and-O-Rawhere Rarepresents a C1-12alkyl, -C3-7cycloalkyl, -C1-12alkyl With3-7cycloalkyl, phenyl or-C1-12alkylphenyl; and (C1-12alkyl, phenyl, or Ramay be optionally substituted with halogen, -CN, -NR'r R"- CO2R or-CONR'R", where R, R' and R" are independently selected from hydrogen or lower Akilov. In an additional embodiment, the cycle represents a phenyl and he is optionally substituted in the para or 4-position.

R1may be phenyl, substituted alkyl chain With1-10where the alkyl chain is substituted with halogen, -CN, -NR'r R"- CO2R or-CONR'R", where R, R' and R" are independently selected from hydrogen or lower Akilov. In one embodiment, the implementation of the alkyl chain is in the 4 position of the phenyl ring and the substituents attached to the carbon of the free end of the alkyl groups.

R1may be a phenyl, optionally substituted by a Deputy selected from a halogen atom, -C1-6of alkyl, -C1-6halogenoalkane, -C1-6the CN alkyl, -OC1-6of alkyl, -O-Halogens1-6of alkyl, -OC16alkyl CO2NH2, -OC1-6alkyl, CN, -OC1-6alkyl With3-7cycloalkyl, -OC1-6alkyls6H5, -OC1-6alkyl och3, -OS6H5, -OS6H4halogen, -CF3, -OCF3, -N R" (where R' and R" are independently selected from hydrogen, -C(O)1-6of alkyl, -C(O)6H5-C(O)CH=CHCO2H, -C(O)1-6alkyls2H, -C(O)C1-6alkyl CO2CH3, -C(O)C1-6alkyl With6H5-C(O)1-6alkyl With6H4CH3, -C(O)C1-6alkyl With6H4Och3and-C(O)C1-6alkyl With6H4halogen), -CO2H, -CO2C1-6of alkyl, -NO2, -OH, -C6H5, -C6H4C1-6of alkyl, -C6H4halogen, and-OC(O)C1-6the alkyl.

In an additional embodiment, R1is optionally substituted by phenyl, in which each of the substituents independently selected from halogen atom, hydroxy - or alkoxygroup; cycloalkyl; or optionally substituted pyridium or its N-oxide, in which each of the substituents independently selected from a halogen atom.

In an additional embodiment, R1is optionally substituted by phenyl, in which each of the substituents independently selected from a chlorine atom, hydroxy - or metoxygroup, lower cycloalkyl or optionally substituted pyridyl or its N-oxide, in which each of the substituents independently selected from a chlorine atom.

In yet another additional embodiment, R1is phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 5-chloro-2-pyridium, 4-pyridium or 4-pyridi is-N-oxide.

In another embodiment, R1is unsubstituted phenyl or halogenfree. In an additional embodiment, R1is 4-chlorophenyl.

In an additional embodiment, R2is not hydrogen.

In yet another additional embodiment, the presented compounds of formula Ia.

In another embodiment, when R2represents-CH2-R3, R3represents -(CH2)maryl or -(CH2)mheterocyclyl, where m is 0-3. R3may be a benzyl (m=1). The ring atoms may optionally be replaced by a wide range of different substituents. Preferred substituents selected from halogen atom, lower Akilov, hydroxyl groups, lower alkoxyl and phenyl.

In another embodiment, when R2represents-C(=Y)CH2N(R4R3or-C(=Y)CH2SR3, R3represents -(CH2)maryl or -(CH2)mheterocyclyl, where m is 0-3. Himself heterocyclyl can be replaced by exography, hydroxy-group or lower alkyl.

In yet another embodiment, when R2represents-CON(R4R3, R4represents hydrogen and R3represents -(CH2)maryl or -(CH2)mheteroaryl. In another embodiment, m is 0-2, preferably 0 or 1. The atoms of the aryl and heteroaryl rings may be optionally substituted by a wide range of different substituents. In the above embodiment, the substituents may include halogen, lower alkali, a hydroxyl group, a lower alkoxy and phenyl.

In another embodiment, R2represents-C(=Y)-R3where Y is O. In another embodiment, R3represents - (CH2)maryl or -(CH2)mheteroaryl, where m is 0-3. In another embodiment, R3represents optionally substituted aryl or optionally substituted heterocycle (m=0), and more preferably optionally substituted 5 - or 6-membered monomaterial or optionally substituted 9 - or 10-membered bicyclic a heterocycle or optionally substituted aryl group.

In the above embodiment, the substituents R3can be a phenyl, naphthyl, furyl, thienyl, pyrrolyl, N-pyrrolyl, pyrrolidyl, pyrrolidinyl, oxazolyl, oxadiazolyl (including, 1,2,3 - and 1,2,4-oxadiazolyl), thiazolyl, isoxazolyl, furutani, isothiazolin, pyrazolyl, pyrazolyl, pyrazolidine, imidazole, imidazoline, triazolyl (including, 1,2,3 - and 1,3,4-triazolyl), tetrazol is l, thiadiazolyl (including, 1,2,3 - and 1,3,4-thiadiazolyl), pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, 1,4-dioxane, morpholine, 1,4-ditional, thiomorpholine, piperazinil, 1,3,5-tritional, triazinyl, 1H thieno[2,3-C]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothiazol, benzoxazolyl, benzothiazolyl, benzisoxazole, benzisothiazole, benzimidazolyl, indazoles, ethenolysis, chinoline, honokalani, original, purinol, cinnoline, phthalazine, hintline, honokalani benzotriazines, naphthyridine or pteridinyl.

Heterocyclic ring may be condensed with a carbocyclic ring, for example phenyl, naphthyl, indenolol, asplenia, fluorenyl or AstraZeneca.

Aryl or heterocyclic group can be optionally substituted by a wide range of different substituents, and preferably, C1-6the alkyl, C1-6alkoxyl, alkenyl,2-6alkenyl,2-6the quinil, halogen, hydroxyl, mercapto, trifluoromethyl, amino, nitro, cyano or mono or di(C1-6alkyl)amino group. These substituents include phenyl, benzyl and heterocyclyl.

In one embodiment, the implementation of R3selected from phenyl, furil, teinila, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furazane, isoxazolyl, isothiazole, 1,2,3-triazolyl, 1,,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo[b]furanyl, benzo[b]thiophenyl and benzisoxazole (which can be optionally substituted).

In one embodiment, the implementation of R2represents-CH2R3-C(=O)R3, -C=O)N(R4R5or-SO2R6; where

A. R3is optionally substituted by alkyl, where the substituents independently selected from-COOH, -SCH2CONH aryl, -NHSO2aryl, heteroaryl and aryl, each of which is independently substituted with halogen or alkoxygroup; optionally substituted phenyl, where the substituents independently selected from halogen; optionally substituted 5 - or 6-membered heteroaryl, where the substituents independently selected from halogen, alkyl, halogenoalkane, cycloalkyl, aryl, heteroaromatic and heteroaryl, optionally substituted alkyl or halogenation; or optionally substituted alkenyl, in which the substituents are independently selected from heteroaryl;

b. R4represents N;

C. R5is cycloalkyl, heteroalkyl, alkyl or aralkyl; and

d. R6is heteroaryl.

In an additional embodiment, R2represents-CH2R3-C(=O)R3, -C(=O)N(R4R5or-SO2R6; where

A. R3one is camping optionally substituted stands, the ethyl or propylene, in which the substituents are independently selected from-COOH, -SCH2CONH-3,4-acid, -NHSO2-4-ftoheia, pyridyloxy, benzisoxazole, pyridyl, furil, 4-ftoheia or 4-methoxyphenyl; optionally substituted phenyl, where the substituents independently selected from methoxypropyl, F and Cl; optionally substituted thiazolium, pyridium, fullam, teinila, isoxazolyl, isothiazolines, 1,2,3-thiadiazolyl or pyrazolyl, in which the substituents are independently selected from pyridyloxy, cyclopropyl, Me, CF3, phenyl, teinila, pyridyl, F, Cl, Br, 5-CF3-3-methyl-1-pyrazolyl; or 2-fulleren-1-yl;

b. R4represents N;

C. R5is a 2-fenet-1-yl, benzyl, cyclohexyl, 2-furylmethyl, methyl or 4-methylbenzyl; and

d. R6represents pyridyl.

In another embodiment, R2represents-COR3condensed ring a represents an optionally substituted phenyl or optionally substituted pyridyl (including its N-oxides and pyridinium salts), and D represents-CRIIIRIV-.

In another embodiment where the present invention relates to compounds of formula I or formula Ia per se, R1represents optionally substituted phenyl, X represents O And together with atoms to which which it is attached, forms an optionally substituted phenyl or optionally substituted peregrinae ring (including its N-oxides and pyridinium salts),-represents-CH2CH2-, D represents - CH2and R2represents-C(O), optionally substituted aryl, or-C(O), optionally substituted by heterocyclyl.

Will be highly encouraged, when the compounds of formula I or formula Ia and some of their derivatives may contain at least one asymmetric center and therefore able to be in more than one stereoisomeric form. The present invention extends to each of these forms separately and mixtures thereof, including racemates. The isomers can be separated by conventional chromatographic methods or by using a agent for optical breakdown. Alternatively, the individual isomers can be obtained by asymmetric synthesis using chiral intermediates.

For example, it will be considered that the compounds of the present invention are chiral due to non-uniform arrangement of the substituents at the carbon atom connected to the substituent R1. Accordingly, the compounds of the present invention can be in the form of mixtures of enantiomers, for example, enantiomerically enriched mixtures, or racemizes the mixtures thereof. However, it is preferable that the compounds of the present invention have been "enantiomerically pure".

In this context, when referring to the enantiomer, the term "enantiomerically pure" means that the enantiomer essentially contains no enantiomeric pairs. The enantiomeric purity is usually expressed in terms of the enantiomeric excess or % E.E. For the pair of enantiomers [(+) and (-)]when a mixture of two isomers, expressed as the molar or mass fraction F(+)and F(-)(where F(+)+F(-)=1), the enantiomeric excess is defined as |F(+)-F(-)|. Accordingly, the percentage of E.E. expressed as 100×|F(+)-F(-)|. In this context, the term "enantiomerically pure" refers to the enantiomer having the % E.E. greater than 70%. Preferably enantiomerically pure enantiomer has % E.E. greater than 80%, more preferably more than 90%, and most preferably more than 95%.

The preferred stereoisomer of the compounds of formula I, which contains an asymmetric center at the point of connection R1represented by the structure below.

Specialists in the art will recognize that the establishment of the absolute configuration (R or S) depends on the seniority of the sequence of each group connected to the asymmetric center in accordance with rule Cana-Ingold the-Priloga.

When the connection has at least one carbon-carbon double bond, it may be in Z - and E-forms, and all isomeric forms of the compounds included in the present invention.

Salts of compounds of formulas I and Ia are preferably pharmaceutically acceptable, but take into account that non-pharmaceutical acceptable salts are also included in the scope of the present invention, since they are used as intermediates in the preparation of pharmaceutically acceptable salts.

Will be taken into account that the pharmaceutically acceptable derivatives of compounds of formulas I and Ia and their salts are also included within the scope and essence of the present invention. Such derivatives include pharmaceutically acceptable ester, prodrug, solvate, and hydrates of the compounds or their salts. Pharmaceutically acceptable derivatives may include any solvate, hydrate or any other compound or prodrug, which when administered to a subject capable of providing (directly or indirectly) a compound of formula I, or a metabolite, which has antiviral activity or rest.

Pharmaceutically acceptable salts include additive salt of the acid additive salts of bases, salts, pharmaceutically acceptable esters and salts of Quaternary ammonium and pyridinium bases. Additi the basic salts of the acids formed from the compounds of the present invention and a pharmaceutically acceptable inorganic or organic acid, but not limited to hydrochloric, Hydrobromic, sulfuric, phosphoric, methylsulfonate, toluensulfonate, benzosulfimide, acetic, propionic, ascorbic, citric, malonic, fumaric, maleic, lactic, salicylic acid, sulfamic or tartaric acids. The counterion of the Quaternary ammonium and pyridinium bases include chloride, bromide, iodide, sulfate, phosphate, methylsulfonate, citrate, acetate, malonate, fumarate, sulpham and tartrate. Additive salts of bases include, but are not limited to salts, such as sodium, potassium, calcium, lithium, magnesium, ammonium and alkylammonium. Additionally, basic nitrogen-containing groups can be quaternity such agents as lower alkylhalogenide, for example methyl-, ethyl-, propyl - and butylchloride, bromides and iodides; diallylsulfide, such as dimethyl - and diethylsulfate; and others. Salts can be obtained in a known manner, for example by treating compound corresponding acid or base in the presence of a suitable solvent.

Compounds of the present invention may be in crystalline form or in the form of the free compounds, or solvate (e.g. hydrate) and have in mind that both forms are included in the scope of the present invention. Methods of solvation is usually known in this technical field.

Those who min "MES" refers to a complex of variable stoichiometry, the resulting soluble substance (in this invention the compound of the present invention and a solvent. Such solvents preferably do not interfere with the manifestation of biological activity of soluble substances. As an example, the solvent can be water, ethanol or acetic acid. Methods of solvation is usually known in this technical field.

The term "prodrug" is used in its broadest sense and covers such derivatives, which are converted in vivo into compounds of the present invention. Such derivatives are often specialists in the art and include, for example, compounds in which free hydroxyl groups are converted to ester derivative or a ring nitrogen atom is converted to N-oxide. Examples of ester derivatives include alkalemia esters, esters of phosphoric acid, and those formed from the amino acid, preferably valine. Any compound which is a prodrug compounds of the present invention, included in the scope and essence of the present invention. The usual procedure for obtaining the appropriate prodrugs according to the present invention is described in textbooks, for example, "Design of Prodrugs" Ed.H.Bundgaard, Elsevier, 1985. The term "pharmaceutically acceptable ester" includes biologically acceptable is false esters of the compounds of the present invention, for example, derivatives of sulfonic, phosphonic and carboxylic acids.

Thus, another aspect of the present invention provides a prodrug or pharmaceutically acceptable esters of the compounds of formulas I and Ia. In another embodiment, the present invention provides a pharmaceutical composition that contains a therapeutically effective amount of one or more of the above-described anti-viral (RSV) compounds of formulas I and Ia, including their pharmaceutically acceptable derivatives, and optionally a pharmaceutically acceptable carrier or solvent.

If not given another definition, the terms "treatment" or "cure" in the context of this method or application of the present invention include both therapeutic and prophylactic treatment.

In an additional embodiment provides for the use of compounds of formulas I and Ia, or their salts for the treatment (therapeutic or prophylactic) of RSV infections.

Without going into theory, suggest that the compounds of the present invention are suitable anti-RSV activity through inhibition of way merge, due to the RSV virus.

In an additional embodiment provides a method of obtaining compounds of formulas I and Ia. These compounds can be obtained by the use of procedures, described in the following ways.

Scheme 1 depicts the General method of preparing compounds of formula III. The compounds of formula III are included in the scope of compounds of formula Ia, where R2represents H, and act as useful synthetic intermediates. The compounds of formula III can be obtained from the corresponding starting materials of the formula II.

Scheme 1

Usually one equivalent of the corresponding keto-acid of formula II interacts with about 3 equivalents of the appropriate diamine of the General formula H2N-B-C-NH2. The mixture is heated at the boiling inert solvent, for example 1,2-dichloroethane, toluene or xylene in a flask equipped with a unit Dean-stark within 3-24 hours. Can be used catalyst toluensulfonate. After the reaction mixture is allowed to cool and the product is filtered and recrystallized from a suitable solvent. If the precipitate is not formed, the solvent evaporated and the residue is recrystallized or purified using flash chromatography or preparative HPLC.

Methods of obtaining 2-(2'-hydroxy-2'-aryl)benzoic acids of the formula II described Guion .S. et al., 1996, Synthetic Communications, 26:1753-1762, Epsztajn, J. et al., Synth. Communications, 1992, 22:1239-1247, A. Bruggink et al., Tetrahedron, 1975, 31:2607-2619 and Ames, D.E. et al., 1976, J.Chem. Soc. Perkin Trans. 1,1073-1078.

In the l is an additional aspect of the present invention developed new ways of obtaining some of the compounds of the formula II is described in this context. Scheme 2 illustrates an example sequence of reactions applicable to obtain the ketoacid of formula II (where X=O and D represents-CH2-). Usually, the appropriate aromatic o-halogenecarbonate acid are suspended in tert-butanol or other suitable solvent approximately together with 1.5 equivalents of a suitable β-diketone. To this mixture is added about 0.25 equivalents of copper, copper bromide (I) or copper iodide (I), or both components. Then, the suspension is treated with about 1.6 equivalents of tert-butoxide potassium or ethoxide sodium, sealed in resistant pressure vessel and heated in a microwave reactor under stirring at approximately 180°C for approximately 1 hour. Alternatively can be used a solvent with high boiling point (for example, N,N-dimethylacetamide and the mixture is heated at boiling in an open vessel until then, until virtually complete conversion of the substrate. The resulting mixture is diluted with water, neutralized aqueous NH4Cl and extracted with a suitable organic solvent. The organic extracts are dried and concentrated and the residue purified flash chromatography. The lactone intermediate compound is then hydrolized by treatment with diluted aqueous alkali solution using ACET the nitrile as a co-solvent.

Scheme 2

Other compounds of formula II can be obtained by substitution of α-meilensteine. Fit the ketoacid of formula II (where X=O and D is -[CH2]n-) and a catalytic amount of 18-crown-6-ether suspended in THF and cooled to -78°C. Add the selected alkylhalogenide or dihalogenide (about 3 equivalents), and then tert-piperonyl potassium. The mixture is stirred and allowed to warm to room temperature. When the reaction completed, the mixture is again cooled and quenched with a saturated solution of ameriglide and diluted with a small amount of water. The organic layer is separated and washed with saturated salt solution, dried over MgSO4and concentrate. The residue may be purified by recrystallization or flash chromatography. This method is a modification of the procedure described in J.Org.Chem. 1991, 56:7188-7190.

Other compounds of formula I can be obtained by acylation of compounds of formula III as shown in Scheme 3.

Scheme 3

In one of two ways equivalent diisopropylethylamine or triethylamine is added to one equivalent of the compounds of formula III in THF at 0°C. the acid chloride or other allerease agent added to the mixture and then the reaction is controlled by using HPLC. When the reaction ends, the reactionary see the camping quenched with water and the product extracted into a suitable organic solvent and treated with standard methods. This acylation may also be carried out in the interaction of one equivalent of the compound of formula III with one equivalent of the appropriate acid chloride in xylene at 120°C for 1-24 hours. Then the reaction is allowed to cool and the product isolated. Alternatively, the compounds of formula III can be treated approximately 2.2 equivalents of the appropriate acid chloride or anhydride in pyridine at approximately -5°C. the Mixture is allowed to warm to room temperature and after stirring for a period of 2-24 hours product produce by standard methods. The acylation can also be carried out by treatment of the corresponding compounds of formula III to the corresponding carboxylic acid (3 equivalents), TFFH (3,3 equivalents) and DIEA (3,3 equivalents) in DMF and heated to 45°C for approximately 14 days. After that, the product emit standard methods.

N-alkylated and N-sulfonylamine the compounds of formula I are best obtained by using the appropriate N-substituted diamines. They can be obtained by known methods, for example, described Kruse L. l, et al., J.Med. Chem. 1990, 33, 781-789. The corresponding ketoacid (2 equivalent) and N-substituted diamine (1 equivalent) in chlorobenzene, toluene or xylene are placed in a flask equipped with stirrer and water separator Dean-stark, and heated at Kip the treatment until until you can see the separation of new portions of water (1-8 hours) (Scheme 4). The solvent is then removed, and the residue can be purified using standard methods.

Scheme 4

Upon receipt of the compounds of formula I, where R2is a urea or thiourea, one equivalent of the corresponding compounds of formula III interacts with one equivalent of the appropriate isocyanate or isothiocyanate in an inert solvent, for example THF or xylene at a temperature in the range of 20-120°C for 1-24 hours. Then cool the reaction mixture, and the product is filtered, washed or recrystallized from an appropriate solvent or purified using chromatography.

Other compounds of formula I can be obtained by attaching, removing or modifying existing deputies. This can be achieved using standard methods of interconversion of functional groups are well known in the industry, such as that described in "Comprehensive organic transformations: a guide to functional group preparations", Larock, R. C5New York, VCH Publishers, Inc. 1989.

Examples of the interconversion of functional groups are-C(O)NRR of CO2CH3by heating in the presence of catalytically active metal cyanide, for example, NaCN, and HNRR in CH3HE; -OC(O)R of the N, or without it, in the presence of, e.g., ClC(O)R in pyridine; -NC(S)NR'r R" with other allylisothiocyanate or titanoboa acid; -NRC(O)OR' other with alkylchlorosilanes; -NRC(O)NR'r R" from other treatment with isocyanate, for example, HN=C=O or RN=C=O; -NRC(O)R' from other processing ClC(O)R' in pyridine; - C(=NR)R NR'r"- C(NR'r R)SR processing H3NR+OAc-by heating in alcohol; -C(NR'r R")SR-C(S)R NR'r" with R-I in an inert solvent, for example acetone; -C(S)R NR'r" (where R' or R" is not hydrogen) from C(S)NH2with HNR'R';- C(=NCN)-NR'r R"- C(=NR'r R")-SR with NH2CN by heating in anhydrous alcohol, alternatively from-C(=NH)-NR'r R" processing Enrichment and NaOEt in EtOH; -NR-C(=NCN)from SR-other' processing (RS)2C=NCN; -NR"SO2R from other' processing ClSO2R by heating in pyridine; -NR'r C(S)R-NR'r C(O)R by treatment with a reagent of Losona [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide]; -NRSO2CF3from other processing anhydride of triftoratsetata and base, -CH(NH2)From CHO-CH(NH2)C(O)OR' processing Na(Hg) and HCl/EtOH; CH2(O)HE's from-C(O)HE treatment SOCl2then CH2N2then H2O/Ag2O; -C(O)OH of CH2C(O)och3processing PhMgX/HX, then acetic anhydride, then CrO3; R-OC(O)R' from RC(O)R' processing R"CO3N; -CCH2OH-C(O)OR' processing Na/R OH; -SSN2of CH2CH2OH by the reaction tchugaev; -NH2from-C(O)HE reaction kurzius; -NH2from-C(O)NHOH processing TsCl/base, for the eat H 2O; -CHC(O)CHR-CHCHOHCHR using reagent dessa-Martin or CrO3/aq. H2SO4/acetone; -C6H5SNO-From6H5CH3when processing CrO2Cl2; -SNO from CN when processing SnCl2/HCl; -CN,- C(O)other during processing PCl5; -CH2R-C(O)R in the processing of N2H4/KOH.

When carrying out the reactions of some groups should be protected. Suitable protective groups are well known in this field and have been described in many references, for example, Protective Groups in Organic Synthesis, Greene, T.W. and Wuts, P.G.M., Wiley-biterscience, New York, 1999 or Protecting Groups, Kocienski, PJ., Thieme, Stuttgart, 1994.

Abbreviations that may be used in this context included in Schemes 1-4 and in the experimental section, are as follows, unless otherwise specified:

DCM: dichloromethane

DIEA: diisopropylethylamine

DMF: dimethylformamide (DMF)

Et: ethyl

EtOAc: ethyl acetate

Me: methyl

Meon: methyl alcohol

MS: mass spectrometry

NMR: nuclear magnetic resonance (NMR)

Ph: phenyl

HPLC: high performance liquid chromatography (HPLC)

TEA: triethylamine

TFA: triperoxonane acid (TFU)

TFFH: fluoro-N,N,N",N"-tetramethylguanidine hexaphosphate

TNR: tetrahydrofuran (THF)

TsCl: taillored

TsOH: toluensulfonate

The present invention also relates to therapeutic compositions for before the rotation and/or treatment of RSV, containing at least one compound of formula I or Ia, including pharmaceutically acceptable salts or prodrugs.

Assume that the composition of the present invention may also contain or to be entered into one or more other compounds with antiviral activity against RSV, such as Mirasol or other agents, for example RespiGam™ or Synagis®.

Assume that the composition of the present invention may also contain, or be introduced in combination with other medicines to treat symptoms of the disease, such as anti-inflammatory drugs such as diclofenac, diflunisal, etodolac, fenoprofen, flubiprofen, ibuprofen, indomethacin, Ketoprofen, Ketorolac, meganova acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin.

Assume that the composition of the present invention may also contain or be introduced together with other medicines to treat symptoms of the disease, such as steroids, such as beta-antagonists: albuterol, levalbuterol, bitolterol, pirbuterol, terbutaline, ipratropium, prednisone, prednisolone, and methylprednisolone; beta-antagonists with prolonged action, such as salmeterol or formoterol; the modifier is leukotriene, such as monologist, zafirlukast and zileuton; theophylline; nedocromil and chromaline.

The term "composition" is intended to include the formulation of the active ingredient with conventional carriers and excipients, as well as encapsulating materials, such as the media, in order to obtain a capsule in which the active ingredient (along with other media or without them) surrounded by encapsulating the media.

How easily identify experts in the art, the method of administration and the nature of the pharmaceutically acceptable carrier depends on the nature of the disease and the animal undergoing treatment. Assume that the choice of the particular carrier or delivery system and method of administration can be readily determined by a person skilled in the art. When preparing any dosage forms containing the compound of the present invention, it is necessary to ensure that the potency of the compound was reduced when cooked, and that the connection was able to reach the point of application of actions without destruction. In some circumstances it is necessary to protect the connection means known in the art, such as microencapsulation. Similarly, the selected route of administration should be such that the connection has reached its place is prilojeniya.

The pharmaceutical compositions or dosage forms include those suitable for oral, rectal, nasal, local (including oral and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. It is envisaged that the compositions can be provided in a form suitable for oral or nasal injection or inhalation or insufflation.

Compounds of the present invention together with a conventional adjuvant, carrier, or diluent, may thus be in the form of a pharmaceutical composition and its disposable dosage forms, and in this form can be used in the form of solids, such as tablets or hydraulic capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with these liquids, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.

Such pharmaceutical compositions and their disposable dosage forms may contain conventional ingredients in conventional proportions, together with additional active compounds or action is appropriate at the beginning, or without them, such disposable dosage forms may contain any suitable effective amount of the active ingredient, comparable to the planned daily dose range that should be used. Dosage forms containing ten (10) milligrams may contain any suitable effective amount or, more generally, from 0.1 up to one hundred (100) milligrams, per tablet, respectively, are suitable typical disposable medical forms.

Compounds of the present invention can be introduced into a wide variety of oral and parenteral dosage forms. Specialists in the art will understand that the following dosage forms may contain as a component or a connection of the present invention, or pharmaceutically acceptable salt of the compound of the present invention.

To obtain pharmaceutical compositions of the compounds of the present invention, pharmaceutically acceptable carriers can be solids or liquids. Drugs in solid form may include powders, tablets, pills, capsules, starch capsules, candles and single granules. A solid carrier can include one or more substances which may also act as solvents, aromatic substances, solubilization is, lubricants, suspendida agents, binders, preservatives and additives, agents, disintegrating tablets, or encapsulating material.

For example, in powders, the carrier is a finely powdered solid substance in a mixture with finely ground active component.

For example, in tablets, the active ingredient is mixed with carrier having the necessary binding capacity in suitable proportions and compact form and the right amount.

The powders and tablets preferably contain from five or ten to about seventy percent of the active component. Suitable carriers can be magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragant, methylcellulose, sodium carboxymethyl cellulose, viscoplastic wax, cocoa butter, etc. mean that the term "drug" includes pharmaceutical form active compounds containing the encapsulating material as carrier providing a capsule in which the active ingredient together with a carrier, or without it is surrounded by carrier, which is thus associated with him. Similarly, enabled and starch capsules and lozenges. Tablets, powders, pills, capsules, starch capsules and lozenges can be the used as solid dosage forms, suitable for oral administration.

For making candles, viscoplastic wax, for example, a mixture of glycerides of fatty acids or cocoa butter is first melted and the active component is homogeneous dispersed therein under stirring. The molten homogeneous mixture is then poured into forms convenient size, is allowed to cool and thereby solidify.

Dosage forms suitable for vaginal insertion, can be represented in the form of tubal rings, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art, are suitable.

Liquid form preparations include solutions, suspensions and emulsions, such as water or solutions of water-propylene glycol. For example, parenteral injection, liquid preparations can be prepared in the form of solutions in water solution of polyethylene glycol.

Sterile compositions are liquid forms include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both components.

Compositions according to the present invention can thus be prepared for parenteralnogo introduction (for example, by injection, for example by injection of a test dose of the substance or continuous infusion) and may be presented in the form of single-dose ampoules, syringes, pens, injection of small volumes or packaging of drugs for multiple reception together with preservative chemicals or without them. The compositions can be used such forms as suspensions, solutions or emulsions in oily or aqueous vesicles and may contain agents for the preparation of dosage forms, for example suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic selection of sterile solid or by lyophilization from solution, for inclusion in a suitable environment, for example sterile, containing no pyrogen water, before use.

The pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions and sterile powders for extemporanea preparation of sterile injectable solutions. They can be stable in the conditions of preparation and storage, and can be protected from oxidation and contaminating action of microorganisms, such as bacteria or fungi.

Specialists in the art can easily make a decision from is Oseni suitable drugs for the compounds of the present invention using conventional approaches. Setting the preferred range of pH and suitable excipients, such as antioxidants, is routine in the art. Buffer systems are typically used to provide values for pH in the desired range and include buffers based on carboxylic acids, such as acetate, citrate, lactate and succinate. For those medicines available in various antioxidants, including phenolic compounds such as BHT or vitamin E, regenerating agents, such as methionine or sulfite, and chelating metals, such as EDTA.

The solvent or dispersion medium for injection solutions that can contain any of the usual solvents or systems-carriers for compounds and may contain, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures and vegetable oil. Proper fluidity can be achieved, for example, by using a protective layer, such as lecithin, by the maintenance of the desired particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be achieved, if necessary, the inclusion of various antibacterial antifungal agents such as parabens, chlorobutanol, phenol, sorbic what islote, thimerosol, etc. In many cases it will be preferable to include agents for leveling the osmolality, for example, sugars or sodium chloride. Preferably, medicines for injection were isotonic to the blood. Prolonged absorption of the injected compositions may be caused by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. The pharmaceutical forms suitable for injectable use may be introduced by any suitable means, including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.

Sterile injectable solutions are prepared by introduction of active compounds in the required amount of the appropriate solvent with various other ingredients, for example, above, if necessary, with subsequent filtration sterilization. Generally, dispersions are prepared by introduction of various sterilized active ingredients into a sterile medium containing the original dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injection solutions, the preferred methods of preparation is vacuum drying or lyophilization pre is varicella sterile filtered solution of the active ingredient plus any additional desired ingredients.

When the active ingredients are suitably protected, they can be administered orally, for example, with an inert diluent or with an assimilable usable in food carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be subjected to compression into tablets, or they can be entered directly with the food of the diet. For oral therapeutic injection of the active compound can be introduced with the excipients to be used in the form taken orally tablets, tablets for slow dissolution in the buccal pocket, pastilles, capsules, elixirs, suspensions, syrups, cakes, etc. Such compositions and preparations preferably contain at least about 1 wt.% active compounds. The percentage of the compositions and preparations may, of course vary and may be suitable in the range of from about 5 to about 80 wt.% units. The number of active compounds in therapeutically useful compositions may be sufficient to obtain a suitable dose.

Tablets, lozenges, pills, capsules and the like may also contain the components listed below: a binder, such as glue, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; dezintegriruetsja agents, for example to kurosky starch, potato starch, alginic acid and the like; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose or saccharin, which can be added, or flavoring substances such as peppermint oil, oil Wintergreen or cherry flavor. When disposable dosage form is a capsule, it is in addition to the materials described above may contain a liquid carrier.

Various other materials can be presented in the form of coatings or those that modify the physical form of disposable medicinal substances. For example, tablets, pills or capsules can be coated with shellac, sugar or both substances. A syrup or elixir may contain the active compound, sucrose or sweetener, methyl - and propylparaben as preservatives, a dye and flavoring agents, such as cherry or orange flavor. Any material that is used for any one-time dosage forms may be pharmaceutically pure and substantially non-toxic in the quantities used. In addition, the active compound(I) can be included in the drugs and dosage forms with delayed release, including those that allow for targeted delivery of the active peptide to specific regions of the intestine.

adnie solutions suitable for oral use can be obtained by dissolving the active component in water and adding suitable colorants, flavoring, stabilizing and thickening agents, if necessary.

Aqueous suspensions suitable for oral use can be obtained by dispersing finely ground active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium salt of carboxymethyl cellulose or other well-known suspendresume agents.

Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and agents and agents that slow down the absorption, etc. the Use of such media and agents for pharmaceutically active substances is well known in the art. Along with the fact that any conventional medium or agent is incompatible with the active ingredient, its use in therapeutic compositions should seriously consider. The composition can be also introduced additional components.

Also include solid forms of drugs that are suppose to turn shortly before use, to liquid form preparations for oral introduction the deposits. Such liquid form preparations include solutions, suspensions and emulsions. These preparations may contain in addition to the active component, colorants, flavouring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents, etc.

For local injection into the upper skin layer connection according to the present invention can be prepared in the form of ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be prepared in an aqueous or oily base with the addition of suitable thickeners and/or gelling agents. Lotions can be prepared in water or oil based and will generally also contain one or more emulsifying agents, solubilizing agents, dispersing agents, suspendida agents, thickeners or dyes.

Dosage forms intended for local injection in the mouth include lozenges containing the active agent to a flavored base, usually sucrose and acacia or tragant; tablets containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and liquid mouth rinse containing the active ingredient in a suitable liquid carrier.

Rast is ora or suspension is used directly by the introduction into the nasal cavity by conventional means, for example, using a dropper, pipette or spray. The dosage form can be applied in single or multiple form. In the latter case, when using droppers or pipettes this can be achieved by the introduction of the patient is appropriate, predetermined volume of solution or suspension. In the case of the sprayer this can be achieved, for example, when using the measuring spray pump. To improve nasal delivery and preservation of the compounds according to the present invention can be encapsulated with cyclodextrins or cooked with other agents that presumably enhance the delivery and retention in the nasal mucosa.

Introduction to the respiratory system can also be achieved through the preparation of an aerosol dosage form in which the active ingredient provide sealed with a suitable spray substance, such as a chlorofluorocarbon (CFC), such as DICHLORODIFLUOROMETHANE, trichloromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Conveniently, if the aerosol may also contain a surface-active substance, such as lecithin. The dose of medicinal substance can be controlled by a device with a measuring valve.

Alternatively, the active ing eventy can be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives, for example hydroxymethylcellulose and polyvinylpyrrolidone (PVP). Usually powder carrier forms a gel in the nasal cavity. The powder composition may be presented in the form of a single dose, for example, capsules or cartridges, for example, gelatin or blister packaging, from which the powder may be introduced using an inhaler.

In dosage forms intended for introduction into the respiratory system, including intranasal formulations, the connection usually has a small particle size, for example of the order of 5-10 microns or less. This particle size can be obtained by methods known in the art, for example a very thin grinding.

If desired, can be used in dosage forms suitable for slow release of the active ingredient.

Pharmaceutically preparations are preferably in a disposable form. In this form, the drug preparation is crushed at a single dose containing appropriate quantities of the active component. Disposable dosage form can be a packaged preparation, the package containing a certain amount of the drug, such as packaged tablets, capsules and Oreshkov in vials or ampoules. In addition, the single dosage form can be a capsule, a pill, a starch capsule or tablet dispersible, or it may consist of an appropriate number of any of these packaged forms.

Especially, it is preferable to prepare parenteral compositions in the form of a single dosage form for ease of administration and uniformity of dosage. Disposable dosage form used in this context, refers to physically fragmented units corresponding to single doses intended for subjects undergoing treatment, with each unit contains a predetermined quantity of active material calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. Feature disposable dosage forms of the present invention is determined by and directly dependent on (a) the individual properties of the active material and the particular therapeutic effect to be achieved, and (b) by the limitations of the field of preparation of such an active material for the treatment of disease in living subjects in the pathological condition in which physical health is weakened.

The present invention also includes compounds of formulas I, Ia, II is the absence of the carrier, when these connections are in one-time dosage form.

The amount of injected compounds of formula I may be in the range from about 10 mg to 2000 mg per day depending on the activity of the connection and the disease to be treated.

The preferred compositions are liquids or powders for intranasal, tablets or capsules for oral administration and a liquid for intravenous injection.

Specialists in the art will appreciate that the invention described in this context, subject to changes and modifications other than those specifically described. It should be understood that the present invention includes all such changes and modifications are consistent with the essence and scope of the invention. The present invention also includes all stages, features, compositions and compounds related to or indicated in this specification, individually or collectively, and any and all combinations of any two or more stages or signs.

Reference in this specification to any prior publication (or derived from it), or any material that is known, is not considered and should not be construed as a confirmation or acknowledgement or any form assumptions that the previous publication the situation (or derived from it) or known material forms part of a widespread basic knowledge in science, belongs to this specification.

Throughout this specification and the following the following claims, unless it follows otherwise from the context, the word "contain" and such variations as "includes" and "including"implies the inclusion of a received single integer or step or group of the whole or stages, and no allocation of any other single integer or step or group of the whole or stages.

Experimental part

Synthetic procedures

1H NMR spectra were taken either on a Bruker Avance DRX 400, AC 200 or spectrometer AM 300. Spectra were recorded in CDCl3d6-acetone, CD3OD or d6-DMSO using the residual solvent peak as reference. Chemical shifts were represented on the δ scale in parts per million (ppm), using the following legend distribution of multiplicities: s (singlet), d (doublet), t (triplet), q (Quartet), m (multiplet) and set the prefix b (broad). Mass spectra (ESI) were recorded on a Flimigan LCQ Advantage spectrometer. Flash chromatography was carried out on 40-63 μm silica gel 60 (Merck No. 9385). Preparative HPLC was performed using a Gilson 322 pump from Gilson 215 liquid manipulator and the detector HPI PDA 100. If not specified, the system HPLC using column Phenomenex C8(2) using water containing 0.1% TFU and either acetonitrile or acetonitrile is, containing 0.06% of the TFU.

Method And

One equivalent of the corresponding keto-acid of formula II or its ether complex interacts with about 3 equivalents of the appropriate diamine of the General formula H2N-B-C-NH2. The mixture is heated at the boiling inert solvent, for example 1,2-dichloroethane, toluene or xylene, in a flask that can be equipped by the unit Dean-stark within 1-24 hours, or until until the trap will not cease to gather water. Can be used catalyst, such as toluensulfonate. After the reaction mixture is allowed to cool and the product is filtered and recrystallized from a suitable solvent. If the precipitate is not formed, the solvent is evaporated in vacuum and the residue is recrystallized or purified using flash chromatography or preparative HPLC.

The methods for obtaining the compounds of formula III are modifications of the procedures described in US 4,058,529, Sulkowski, T.S., et al., 1967, J.Org. Chem., 32:2180-2184 and Houlihan, W.J., et al., 1975, J.Med. Chem., 18:182-185.

10A-(4-Chlorophenyl)-2,3,10,10A-tetrahydro-1H-imidazo[1,2-b]isoquinoline-5-he

The above derived isoquinoline get in the Way And using Ethylenediamine and 2-(benzoylmethyl)benzoic acid.

Data1H NMR: (300 MHz, d6-acetone) δ of 2.58-2.70 (m, 1H), 3.27 to to 3.36 (m, 1H), 3.43 points-to 3.52 (m, 1H), 3.46 in (d, 1H, J 154 Hz), of 3.53 (d, 1H, J 15.3 Hz), 3,68-with 3.79 (m, 1H), 7,05-7,10 (m, 1H), 7,24 (d, 2H, J is 8.8 Hz), 7,29-7,34 (m, 2H), 7,32 (d, 2H, J 8.8 Hz). 7,93-of 7.97 (m, 1H).

Data electrospray mass spectrometry (ESI-MS) m/z: calculated for [M+H]+: 299,0; defined: to 298.9.

9a-(4-Chlorophenyl)-2,3,9,9a-tetrahydro-1H-1,3A,8-triazacyclohexane[b]naphthalene-4-one

Derived above polyesterification get in the Way And using Ethylenediamine and 2-[2-(4-chlorophenyl-2-oxyethyl]-nicotinic acid.

Data1H NMR: (300 MHz, d6-acetone) δ 3,33-with 3.79 (m, 6N), 7,26 and 7.36 (m, 5H), 8,21 (DD, 1H), 8,48 (DD, 1H).

Data ESI-MS m/z: calculated for [M+H]+: 300.0; defined: 299.9.

Method In

Two equivalent diisopropylethylamine or triethylamine is added to one equivalent of the compounds of formula III in THF or other suitable inert solvent at 0°C. To the mixture of isocyanate, isothiocyanate, acid chloride or other allerease agent and reaction control using HPLC. After completion of the reaction is quenched with water and the product extracted with EtOAc. EtOAc successively washed with solutions of 1:1 saturated NH4Cl(water)/water, 1:1 saturated Na2CO3(water)/water and saturated Na2CO(water). EtOAc is dried (Na2SO4or MgSO4), the solvent evaporated in vacuum and the residue is either recrystallized or purified with use the of flash chromatography or preparative HPLC.

N-{2-[10A-(4-Chlorophenyl)-5-oxo-2,3,10,10A-tetrahydro-5H-imidazo[2-b]isoquinoline-1-yl]-2-oxyethyl}-4-forbindelsesfaneblad

The above amide get Method using 4-(permentantly)acetylchloride and triethylamine in dichloromethane and purified using flash chromatography.

Data1H NMR: (300 MHz, CDCl3) δ 3,39 (d, 1H, J 15 Hz), 3,54-3,62 (m, 1H), 3,66-to 3.89 (m, 4H), of 4.44 (d, 1H, J 16 Hz), of 4.44-4.53-in (m, 1H), 5,48-the 5.51 (m, 1H), 7,13-7,33 (m, 8H), 7,37-7.42 (m, 1H), 7,86-to $ 7.91 (m, 2H), of 7.97 (DD, H, J 7.5 Hz, 1.3 Hz).

Data ESI-MS m/z: calculated for [M+H]+: 514,0; defined: 514,0.

Way

One equivalent of the corresponding compounds of formula III to give interact with one equivalent of the appropriate acid chloride or other Alliluyeva agent in a suitable inert solvent, for example toluene, in the presence of dinucleophiles base, such as triethylamine, at elevated temperatures up until reaction is basically will not be completed. Allerease reagent, for example N,N-dimethyl-4-aminopyridine, can also be added to the reaction mixture. The mixture is allowed to cool and the product is filtered and recrystallized from a suitable solvent. If the precipitate is not formed, the solvent is evaporated in vacuum and the residue is recrystallized or purified using flash chromatography and or preparative HPLC.

4-[10A-(4-Chlorophenyl)-5-oxo-2,3,10,10A-tetrahydro-5H-imidazo[1,2-b]isoquinoline-1-yl]-4-oxomalonate acid

The above amide get Way With using succinic anhydride and triethylamine with the addition of N,N-dimethyl-4-aminopyridine in toluene at boiling for 3 days and purified using flash chromatography.

Data1H NMR: (300 MHz, CDCl3) δ 2.57 m-2,60 (m, 2H), 2,64-to 2.67 (m, 2H), 3,55 (d, 1H, J 16 Hz), 3,76-a-3.84 (m, 2H), 3.96 points-4,06 (m, 1H), 4,43-to 4.52 (m, 1H), 4,60 (d, 1H, J 16 Hz), 7,12-7,20 (m, 3H), 7,28-7,0 (m, 4H), of 7.96 (DD, 1H, J 1.6 Hz, 1.2 Hz).

Data ESI-MS m/z: calculated for [M+H]+: 399,0; defined: 399,0.

Method D

N-substituted diamines can be obtained by methods which are well known to specialists in this field of technology. One such procedure is described Kruse L.I., et al., 1990, J.Med. Chem., 33:781-789.

The corresponding compound of formula II (2 equivalent) and N-substituted diamine of the formula H2N-B-C-other3(1 equivalent) in toluene, xylene or other suitable inert solvents are placed in a flask equipped with stirrer and the office of the Dean-stark. The mixture is heated at boiling until, while in the trap will not cease to separate water (usually 1-24 h). The solvent is then distilled off and the residue is cooled. The residue is purified using flash chromatography or preparative HPLC.

10A'-(4'-Chlorophenyl)-1'-(4'-terbisil)-2'3'10'10a'-t is trihydro-1 N-Spiro[cyclopropane-(1,10'-imidazo[1,2-b]isoquinoline[5]he)]

The above amide prepared as in Method D using N-(4-terbisil)Ethylenediamine in xylenes boiling for 21 h and purified flash chromatography.

Data1H NMR: (300 MHz, CDCl3) δ 0,42-0,49 (m, 1H), 1.56 to of 1.64 (m, 1H), 1.76-to 1.82 (m, 1H), 1,92 of 1.99 (m, 1H), 2,36 (d, 1H, J 14 Hz), 2,55-to 2.65 (m, 1H), 3,19-of 3.25 (m, 1H), 3,71 (d, 1H, J 14 Hz), 3,83-3,93 (m, 1H), 4,12-4,19 (m, 1H), 6,97-7,05 (m, 3H), 7,13-7,21 (m, 5H), 7,25-7,35 (m, 3H), to 7.84 (DD, 1H, J 7,6 Hz, 1.3 Hz).

Data ESI-MS m/z: calculated for [M+H]+: 433,0; defined: 433,1.

Method E

One equivalent of the corresponding compounds of formula III interacts with one equivalent of the appropriate isocyanate or isothiocyanate in THF or xylene at a temperature in the range of 20-120°C. for 1-48 hours Then the reaction is allowed to cool, and the product filtered, washed and recrystallized from a suitable solvent. If the precipitate is not formed, the product can be purified using flash chromatography or preparative HPLC.

Method F

The appropriate isocyanate, isothiocyanate, sulphonylchloride, acid chloride, anhydride or other allerease agent (2.2 equivalents) is added directly, if they are liquids or in solution in pyridine (~1 M), if they are solids, the solution of the corresponding compounds of formula III (0.1 mmol) in pyridine (500 ml) at -5°C. the Reaction p is remediat and allowed to warm to room temperature for 2-24 hours The reaction sequentially diluted with water and three times extracted with CH2Cl2or other suitable organic solvent. The combined organic extracts washed with 1 N NaOH (3×) and 10% HCl (3×). In the case of basic products omit the washing acid and in the case of acidic foods to omit the washing base. For neutral and basic products rough cleaning stage can be improved by stirring the combined extracts in CH2Cl2in the presence of an immobilized on the polymer base (for example, MP-carbonate resin. Argonaut Technologies Inc.) for 0.5-12 h of Extract in CH2Cl2dried (MgSO4), and the solvent evaporated in vacuum. The crude products consistently clean flash chromatography.

10A-(4-Chlorophenyl)-1-(pyridine-3-carbonyl)-2,3,10,10A-tetrahydro-1H-imidazo[1,2-b]isoquinoline-5-he

The above acylated derivative of isoquinoline is produced by Method F using nicotinamide and 10A-(4-chlorophenyl)-2,3,10,10A-tetrahydro-1H-imidazo[1,2-b]isoquinoline-5-it.

Data1H NMR: (300 MHz, d6-acetone) δ 3,78-3,88 (m, 3H), of 3.97-4.09 to (m, 1H), 4,28-to 4.38 (m, 1H), 4.72 in (d, 1H, J 16.0 Hz), 7,29 (d, 2H, J a 8.9 Hz), 7,31-7,38 (m, 1H), 7,41-7,52 (m, 3H), 7,58 (d, 2H, J a 8.9 Hz), 7,87-to $ 7.91 (m, 1H), 7,92 (DDD, 1H, J 1.7 Hz, J 2.2 Hz, J 7.9 Hz), 8,67 (DD, 1H, J 1.7 Hz, J 4.9 Hz), 8,73 (DD, 1H, J 0.9 Hz, J 2.2 Hz).

Data ESI-MS m/z: calculated for [M+is] +: 404,0; defined: 404,1.

10A-(4-Chlorophenyl)-1-(2-pyridin-2-yl-acetyl)-2,3,10,10A-tetrahydro-1H-imidazo[1,2-b]isoquinoline-5-he

The above acylated derivative of isoquinoline is produced by Method F. Pyridine-2-yl-acetic acid pre-activated by treatment with one equivalent of O-benzotriazole-N,N,N',N'-tetramethylethylenediamine in a solution of DMF/pyridine. After 10 minutes this solution is added to 10A-(4-chlorophenyl)-2,3,10,10A-tetrahydro-1H-imidazo[1,2-b]isoquinoline-5-ONU.

Data1H NMR: (300 MHz, CD2Cl2) δ 3,57 (d, 1H, J 16.0 Hz), to 3.73-of 3.96 (m, 4H), 4.04 the-4,12 (m, 1H), 4,37 is 4.45 (m, 1H), 4,63 (d, 1H, J 16.0 Hz), 7,16-7,46 (m, N), to 7.68 (DDD, 1H, J 7.7 Hz, 7.7 Hz, 1.8 Hz), 7,92 (DD, 1H, J 7.7 Hz, 1.8 Hz), charged 8.52 (d, 1H, J 4.9 Hz).

Data ESI-MS m/z: calculated for [M+H]+: 418,0; defined: 418,0.

Method G

This method is a modification of the method described Coperet, .et al., J. Org. Chem., 1998, 63, 1740-1741. 30% hydrogen Peroxide (10 EQ.) add to the solution or the corresponding compounds of formula I or formula III (1 EQ.) and rhenium trioxide to 2.5 mol.% in CH2Cl2(4× volume of hydrogen peroxide solution) at ambient temperature. The mixture is stirred overnight, after which the mixture is diluted with water and stirred for 30 minutes. Then separate the CH2Cl2and the aqueous layer was extracted with additional CH2Cl2 (2×). The combined extracts are dried and the solvent evaporated in vacuum, resulting in the desired product can be purified by crystallization or by chromatography, if necessary.

9a-(4-Chlorophenyl)-1-(furan-3-carbonyl)-8-hydroxy-2,3,9,9a-tetrahydro-1H-1,3A,8-triaza-cyclopent[b]naphthalene-4-one

The above oxidized derivative obtained by method G of 10A-(4-chlorophenyl)-2,3,10,10A-tetrahydro-1H-imidazo[1,2-b]isoquinoline-5-it.

Data1H NMR: (300 MHz, d6-acetone) δ 3,38 (d, 1H, J of 17.8 Hz), 3,93-was 4.02 (m, 1H), 4,24 is 4.35 (m, 2H), 4,37-4,56 (m, 1H), 5,46 (d, 1H, J of 17.8 Hz), 6,76-6,77 (m, 1H), 7,26 (d, 2H, J 8.7 Hz), 7,35-7,39 (m, 1H), 7,41 (d, 2H, J 8.7 Hz), to 7.59-to 7.61 (m, 1H), to 7.64 (d, 1H, J 7.9 Hz), 8.07-a 8,08 (m, 1H), with 8.33 (d, 1H, J 6.5 Hz).

Data ESI-MS m/z: calculated for [M+H]+: 410,0; defined: 410,0.

Way N

The corresponding aromatic o-halogenecarbonate acid are suspended in tert-butanol or other suitable solvent together with about 1.5 equivalents of the corresponding β-diketone. To this mixture is added about 0.25 equivalents of copper, copper bromide (I) or copper iodide (I). Then, the suspension is treated with about 1.6 equivalents of tert-butoxide potassium or ethoxide sodium, sealed in resistant pressure vessel and heated in a microwave reactor under stirring at approximately 180°C for approximately 1 hour is. Alternatively can be used a solvent with high boiling point (for example, N,N-dimethylacetamide and the mixture is heated at boiling in an open vessel until then, until complete conversion of the substrate. The resulting mixture is diluted with water, neutralized aqueous NH4Cl and extracted with a suitable organic solvent. The organic extracts are dried and concentrated and the residue purified flash chromatography. The lactone intermediate compound is then hydrolized by treatment with diluted aqueous alkali solution using acetonitrile as co-solvent.

3-[2-(4-Chlorophenyl)-2-oxoethyl]isonicotinoyl acid

The above 3-[2-(4-Chlorophenyl)-2-oxyethyl]isonicotinoyl acid is obtained according to the Method N using 3-chloro-isonicotinic acid and 1,3-bis-(4-chlorophenyl)-propane-1,3-dione.

Data1H NMR: (300 MHz, d6-DMSO) δ 4,74 (s, 2H), a 7.62 (d, 2H, J 8.7 Hz), 7,72 (d, 1H, J 5.0 Hz), of 8.06 (d, 2H, J 8.7 Hz), 8,51 (s, 1H), to 8.57 (d, 1H, J 5.0 Hz).

Data ESI-MS m/z: calculated for [M+H]+: 276,0; defined: 276,1.

The way I

The corresponding derivative of the aromatic carboxylic acid is treated with aluminofluoride (1-3 equivalents) and an excess of a suitable aromatic nucleophile. The mixture is cooled or heated (usually up to 0-90°C) at high q is on and subject interaction as long while the carboxylic acid derivative to a significant degree will not be spent. The reaction mixture was poured into ice water and diluted HCl. If a solid substance is deposited, it is possible to filter and wash. If the solid is not precipitated, the mixture is extracted with ethyl acetate or dichloromethane, dried over MgSO4and concentrate. The product can be further purified by recrystallization from a suitable solvent or by chromatography. In some cases, the product cyclized with the formation of the lactone, which can be subjected to hydrolysis treatment with dilute hydroxide solution using acetonitrile as co-solvent.

2-[2-(4-Chlorophenyl)-2-oxoethyl]benzoic acid

The above 2-[2-(4-chlorophenyl)-2-oxyethyl]benzoic acid was obtained according to Method I, using homophthalic anhydride and chlorobenzene. In this case, it was shown that it is preferable to heat the reaction mixture to 85°C for 4 hours. The product was isolated by flash chromatography.

Data1H NMR: (300 MHz, CDCl3) 4.66 (s, 2H), 7,26 (d, 1H, J 7,1 Hz), 7,41 (DD, 1H, J 7,6 Hz, J and 7.6 Hz), was 7.45 (d, 2H, J 8.5 Hz), 7,55 (DD, 1H, J 7.4 Hz, J 7.5 Hz), of 7.96 (d, 2H, J 8.5 Hz), to 8.12(d, 2H, J 7.8 Hz).

Method J

A mixture of the corresponding 2-methylamino aromatic carboxylic acid in THF is treated with approximately 2-4 equiv the ribbons sitedisability at a temperature of from -78°C to 0°C. The mixture is stirred for about 1 hour, while the temperature rises to 0°C. the mixture is Then cooled to -78°C and then add approximately 1.2 equivalent of the corresponding complex ester, amide, amide Weinrebe or other suitable electrophilic agent. The reaction mixture is allowed to warm to 0°C under stirring for 2-4 hours and then allowed to warm to room temperature before pouring into dilute aqueous HCl. The crude product is collected by filtration and purified by recrystallization or flash chromatography. If the precipitate is not formed, the solution is extracted with a suitable organic solvent and the organic extract is dried and concentrated. The residue may be purified by recrystallization or flash chromatography.

This method is a modification of procedures described Guion, .S., et al., 1996, Synth. Communications, 26:1753-1762 and Epsztajn, J., et al., 1992, Synth. Communications, 22:1239-1247.

2-[2-(4-Chlorophenyl)-2-oxoethyl]-3-Formentera acid

Above the ketoacid get Method J using 3-fluoro-2-methylbenzoic acid and methyl-4-chlorobenzoate.

Data1H NMR: (300 MHz, d6-acetone) δ value of 4.76 (s, 2H), 7,33 (m, 1H), 7,43 (m, 1H), 7,47 (d, 2H, J 8.5 Hz), to 7.93 (d, 1H, J 7.7 Hz), 7,98 (d, 2H, J 8.5 Hz).

The way To

The compound of formula II (where X=O and D is -[CH2]n-and rolled the practical amount of 18-crown-6-ether suspended in THF and cooled to -78°C. Add selected alkylhalogenide or dihalogenide (about 3 equivalents) and then tert-piperonyl potassium. The mixture is stirred and allowed to warm to room temperature. After completion of the reaction the mixture is cooled again and quenched with a saturated solution of ameriglide and diluted with a small amount of water. The organic layer was separated and water and washed with a saturated saline solution, dried over MgSO4and concentrate. The residue may be purified by recrystallization or flash chromatography.

This method is a modification of procedures described in J.Org. Chem. 1991, 56:7188-7190.

Methyl ester 2-[2-(4-chlorophenyl)-1,1-dimethyl-2-oxoethyl]benzoic acid

Above ketoester get on the Way To from 2-[2-(4-chlorophenyl)-2-oxyethyl]benzoic acid and 3.1 equivalents under the conditions.

Data ESI-MS m/z: calculated for [M+H]+: 317,0; defined: 317,0.

Method L

The corresponding 2-formylamino aromatic carboxylic acid and the corresponding α-melancton dissolved or suspended in ethanol. The mixture is cooled to 0°C and the temperature is kept lower than 5°C, while added dropwise an aqueous solution containing about 1.2 equivalent of 1M sodium hydroxide. Stir the solution is allowed to warm to ambient temperature. The solution is acidified with H2/sub> SO4, heated to 60°C for 30 minutes and then filtered. Thus obtained betalaktam suspended in ethanol and hydrolyzing using aqueous sodium hydroxide. Then a solution of the crude kenana subjected to interaction with hydrogen in the presence of palladium or activated charcoal to until alkene is completely exhausted. The reaction mixture is acidified, extracted with ethyl acetate, dried over MgSO4and concentrate.

2-[3-(4-Chlorophenyl)-3-oxopropyl]benzoic acid

Above the ketoacid get in the Way L of 2-formylbenzoate acid and 1-(4-chlorophenyl)ethanone.

Data1H NMR (300 MHz, CDCl3): 3,15-to 3.50 (M, 4H), 7,15 to 7.62 (m, 5H, overlaps with CHCl3), 7,74-7,83 (m, 1H), 7,87-7,98 (m, 2H)/

Data ESI-MS m/z: calculated for [M+H]+: 289,0; defined: 288,9/

Method M

The corresponding compound of formula I, which contains oxidizable alkylenes group, is dissolved or suspended in dichloromethane and treated with potassium permanganate (5 equivalents) and a catalytic amount of 18-crown-6-ether in dichloromethane and the mixture was stirred at ambient temperature. After giving time (usually 2-48 hours) for the reaction, the mixture was washed with an equal volume of water is approximately six times. Then the organic layer is dried (MgSO4) is concentrating. The residue may be purified flash chromatography. Alternatively, the substrate is dissolved or suspended in acetic acid and treated with chromium oxide (VI). After giving time (usually 2-48 hours) for the reaction, the mixture is diluted with ethyl acetate and washed several times with water. Then the organic layer is dried (MgSO4) and concentrate. The crude product can be purified flash chromatography.

10A'-(4'-Chlorophenyl)-1'-(4'-methoxybenzoyl)-2',3',10',10A'-tetrahydro-1 N-Spiro[cyclopropane-(1,10'-imidazo[1,2-b]isoquinoline[5]he)]

Above isoquinoline derivative gain according to the Method M from 10A'-(4'-chlorophenyl)-1'-(4'-methoxybenzyl)-2',3',10',10A'-tetrahydro-1 N-Spiro[cyclopropane-(1,10'-imidazo[1,2-b]isoquinoline[5]she) using potassium permanganate in dichloromethane and purified flash chromatography.

Data1H NMR: (300 MHz, d6-acetone) δ 0,62 (DDD, 1H, J 10,1, 7,4, and 4.5 Hz), 1.61 of (DDD, IH, J 10,1, 6,6, 4,5), 2,10-2,19 (m, 2H), 3,85 (s, 3H), 3,94-to 4.14 (m, 3H), 4,36-to 4.41 (m, 1H), 6,97 (d, 2H, J is 8.8 Hz), to 7.15 (d, 2H, J is 8.8 Hz), 7,26 (TD, 1H, J of 7.7, 1.1 Hz)that was 7.36 (d, 1H, J 7.7 Hz), 7,41 (d, 2H, J is 8.8 Hz), 7,53 (t, 1H, J 7.7 Hz), to 7.59 (d, 2H, J is 8.8 Hz), to 7.77 (DD, 1H, J of 7.7, 1.1 Hz).

Data ESI-MS: m/z calculated for [M+H]+: 459,0; defined: 459,0.

10A-(4-Chlorophenyl)-10,10A-dihydro-1H-imidazo[1,2-b]isoquinoline-2,3,5-Trion

Above isoquinoline derivative gain is about the Way M from 10A-(4-chlorophenyl)-2,3,10,10A-tetrahydro-1H-imidazo[1,2-b] isoquinoline-5-it is when using chromium oxide (VI) in acetic acid.

Data1H NMR: (300 MHz, d6-acetone) δ Android 4.04 (d, 1H, J 15.7 Hz), or 4.31 (d, 1H, J 15.7 Hz), 7,37 (d, 2H, J a 8.9 Hz), 7,39-7,44 (m, 1H), of 7.48-7,53 (m, 1H), 7,51 (d, 2H, J is 8.8 Hz), 7,60 (DDD, 1H, J 7.5 Hz, 7.4 Hz, 1.1 Hz), 7,98 (DD, 1H, J of 7.8, 1.1 Hz).

Data ESI-MS: m/z calculated for [M+H]+: 327,0; defined: 326,9.

Way N

Selected carbonyl compound is dissolved in toluene or a suitable inert organic solvent and treated with a reagent Losson (about 1.1 equivalent). The mixture is heated at boiling within 24-72 hours Then cooled mixture is washed several times with water and the organic phase is dried (MgSO4) and concentrate. The residue may be purified flash chromatography.

10A-(4-Chlorophenyl)-2,3,10,10a-tetrahydro-1H-imidazo[1,2-b]isoquinoline-5-tion

The above tioned get in the Way N of 10A-(4-chlorophenyl)-2,3,10,10A-tetrahydro-1H-imidazo[1,2-b]isoquinoline-5-it.

Data1H NMR (300 MHz, d6-acetone) δ 2,68 is 2.75 (m, 1H), 3,38-of 3.42 (m, 1H), 3,55 (wide s, 2H), 3,71 (wide s, 1H), a 3.87 (DD, 1H, J 13,5, 7,7 Hz), of 4.05 (DDD, 1H, J 13,5, 9,7, 8,3 Hz),? 7.04 baby mortality (d, 1H, J 7,l Hz), 7,22-7,33 (m, 6N), 8,42 (d, 1H, J 7.5 Hz).

Data ESI-MS: m/z calculated for [M+H]+: 315,0; defined: 315,0.

How About

Selected compounds of the present invention can be separated into individual stereoisomers HPLC using chromatographic columns with chiral stationary phase. Nab is emer, these racemic compounds were separated into the enantiomers in the conditions, described in detail below.

Column: Chiralcel OD-H Column 250×4.6 mm

Wavelength detector: 254 nm

Separation connections 1-019

Mobile phase: Ethanol

The flow rate: 0.7 ml/min

Isocratic elution: 100% Mobile Phase And

The duration of the experiment: 30 min

The column temperature: 30°C

Injected volume: 20 ál

Separation of compounds 1-008,1-036 & 1-043

Mobile phase A: Hexane

Mobile phase b: Ethanol

The flow rate: 0.7 ml/min

Working time: 42 min

Time after work column: 5 min

The column temperature: 30°C

Injected volume: 20 ál

Gradient Graph:

time (min)% mobile phase
02
3098
4098
422

Separation of compounds 1-006, 1-005, 1-029, 1-031, 1-032, 2-02 & 2-06

Mobile phase A: Hexane

Mobile phase b: Ethanol

The flow rate: 0.7 ml/min

Isocratic elution: 70% Mobile phase a, 30% Mobile phase

Working time:33 min

The column temperature: 30°C

Injected volume: 20 ál

Table 1: Separation of enantiomers using column Chiralcel OD-H (elution conditions described above)

The connection numberThe retention time of enantiomer A (min)The retention time of enantiomer B (min)
1-0199.312.66
1-00830.434.5
1-00615.718.0
1-00513.417.9
2-028.213.4
1-02913.019.7
1-03120.623.9
1-03213.215.4
1-03624.928.0
1-04322.625.3
2-067.110.3

It is clear that the compounds of formula I, obtained by the methods described above when necessary, can be converted into further compounds of formula I using methods known in the art. The above methods are used for producing compounds below in Table 2 and Table 3. All the compounds were obtained. These compounds are characterized by mass spectrometry and certain masses of the molecular ions are given in tables.

td align="left"> 1-004
Table 2: compounds of formula I
The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-001387.0H, A, F
1-002453.1H, A, F
Nearby 1-003370.1H, A, F
359.1H, A, F
1-005421.1I, A, F
1-006393.1I, A, F
1-007422.1I, A, F
1-008404.1I, A, F
1-009422.1H, A, F
1-010394.1H, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-011 423.1H, A, F
1-012405.2H, A, F
1-013422.1H, A, F
1-014405.2H, A, F
1-015447.1H, A, F
1-016359.1I, A, F
1-017419.0I, A, F
1-018438.0I, A, F
1-019443.0I, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-020438.0I, A, F
1-021487.0I, A, F
1-022422.0I, A, F
1-023438.0I, A, F
1-024419.0I, A, F
1-025394.1I, A, F
1-026438.0I, A, F
1-027558.0 I, A, F
1-028411.0I, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-029475.0I, A, F
1-030422.0I, A, F
1-031409.0I, A, F
1-032393.0I, A, F
1-033487.0I, A, F
1-034424.0I, A, F
1-035 475.0I, A, F
1-036424,9I, A, F
1-037421.0I, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-038486.0I, A, F
1-039484.0I, A, F
1-040492.0I, A, F
1-041407.1I, A, F
1-042 418.1I, A, F
1-043394.1H, A, F
1-044438.0I, A, F
1-045477.9I, A, F
1-046417.1I, A, F

1-050
The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-047389.0I, A, F
1-048410.0H, A, F, G
1-049400.2I, A, F
428.0I, A, F
1-051446.0I, A, F
1-052432.0I, A, F
1-053405.1I, K, D
1-054416.1I, K, D
1-055416.1I, K, D

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-056433.1I, K, D
1-057 445.0I, K, D
1-058447.0I, K, D, M
1-059430.0I, K, D, M
1-060430.0I, K, D, M
1-061459.0I, K, D, M
1-062390.0J, A, F
1-063419.0J, A, F
1-064418.0J, A, F

The connection numberStructureA certain m/z ([M+H]+) The method of synthesis(s)
1-065443.0J, A, F
1-066418.0I, A, F
1-067418.1I, A, F
1-068435.1I, A, F
1-069447.0I, A, F
1-070436.9I, A, N, F
1-071411.0J, A, F
1-072440.1J, A, F
1-073 439.1J, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-074422.1J, A, F
1-075464.0J, A, F
1-076450.0J, A, F
1-077355.0I, A, F
1-078440.0I, A, F
1-079514.0I, A, B
1-080458.0I, A, B
1-081341.0I, A, F
1-082440.1J, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-083422.0J, A, F
1-084439.1J, A, F
1-085411.0J, A, F
1-086412.0J, A, F
1-087493.0J, A, F
1-088 412.0J, A, F
1-089399.0I, A, C
1-090369.0I, A, F
1-091566.0I, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-092486.0I, A, F
1-093335.1J, A, F
1-094429.1J, A, F
1-095464.0 J, A, F
1-096450.0J, A, F
1-097447.0J, A, F
1-098433.3J, A, F
1-099505.0J, A, F
1-100395.0H, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-101410.0H, A, F
1-102394.0H, A, F
1-103 444.0H, A, F
1-104487.9H, A, F
1-105439.0H, A, F
1-106425.0H, A, F
1-107394.0J, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-108405.0J, A, F
1-109422.0J, A, F
1-110 423.0J, A, F
1-111395.0J, A, F
1-112406-0J, A, F
1-113423.0J, A, F

1-118
The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-114378.1J, A, F
1-115389.1J, A, F
1-116407.1J, A, F
1-117406.2J, A, F
423.1J, A, F
1-119476.1J, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-120493.0J, A, F
1-121481.0J, A, F
1-122448.1J, A, F
1-123559.1J, A, F
1-124476.1J, A, F
1-125 487.1J, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-126424.1J, A, F
1-127487.1J, A, F
1-128448.1J, A, F
1-129459.1J, A, F
1-130420.1J, A, F
1-131420.1J, A, F

The connection numberThe structure is ur A certain m/z ([M+H]+)The method of synthesis(s)
1-132419.1J, A, F
1-133435.1J, A, F
1-134425.0J, A, F
1-135423.0J, A, F
1-136357.0J, A, F
1-137447.1J, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-138 413.0J, A, C
1-139422.1J, A, F, G
1-140419.1J, A, F
1-141434.1I, A, F
1-142449.0H, A, F
1-143465.0H, A, F

1-146
The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-144451.0H, A, F
1-145447.0H, A, F
433.0H, A, F
1-147488.0H, A, F
1-148476.1H, A, F
1-149485.1H, A, F

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
1-150487.0H, A, F
1-151501.1H, A, F
1-152426.0H, A, F
1-153 567.1H, A, F
1-154356.0H, A, F

Table 3:
The compounds of formula III
The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
2-01265.0N, And
2-02298.9I, A
2-03300.0N, And
2-04300.0N, And
2-05300.0N, And
2-06325.0I, K, And
2-07295.9J, A
2-08314.8I, A, N
2-09317.0J, A
2-10317.0J, A

The connection numberStructureA certain m/z ([M+H]+)The method of synthesis(s)
2-11327.0I, K, A
2-12295.0I, A
2-13 300.1J, A
2-14272.0J, A
2-15301.0J, A
2-16284.1J, A
2-17294.0J, A
2-18313.0L, A
2-19326.9L, A, M
2-20300.9J, A

Biological data

Method P: Protocol RSV antiviral activity

Tested compounds of the present invention for their antiviral activity against respiratory syncytial virus. Identify the population cytopathic effect (CPE) is conducted, mainly, as described in the literature (see, for example, Watanabe et al, 1994, J.Virological Methods, 48:257). Serial dilutions of control samples is carried out in 96-well pad. Cells ner2(1,0×104cells/well) infect RSV at a low multiplicity of infection (e.g., RSV A2 at a multiplicity of infection equal to ~0.01) and add to the plates in order to evaluate the antiviral activity. Uninfected cells ner2used to assess the cytotoxicity of this compound. Samples are incubated for 5 days at 37°C in air containing 5% CO2. The degree of CPE determine the metabolism of the vital dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT). MTT (1 mg/ml) added to each well and tablets incubated for 2 hours incubation at 37°C. the wells to remove the liquid, add ISO-propanol (200 μl) and determine the absorption at 540/690 nm. The concentration of compound that inhibited CPE by 50% (EC50and exhibit cytotoxicity (SS50), determined using nonlinear regression analysis.

Typical data for compounds of the present invention, which has antiviral activity against RSV A2, are presented in Tables 4 and 5, where the values of the EU50are the intervals: <0.25 μm, In: 0,25-1,0 µm, With: 1,0-5,0 µm and D: >5.0 µm.

p>
Table 4:
The results of the determination of antiviral activity against RSV A2 shown by the compounds of Table 2
The connection numberThe range of activityThe connection numberThe range of activity
1-001In1-029In
1-002In1-043And
Nearby 1-003In1-066
1-005D1-069In
1-006And1-071And
1-0071-073In
1-0081-077
1-010 1-079In
1-014C1-083B
1-015B1-087And
1-019B1-101And
1-025C1-109

Table 5:
The results of the determination of antiviral activity against RSV A2 shown by the compounds of table 1
The connection numberThe range of activityThe connection numberThe range of activity
1-aD1-019bIn
1-aD1-008b
1-aD1-006b And
1-aD1-029bIn
1-aD1-031bIn
1-aD1-036bAnd
1-aD1-043bAnd

Method Q: the Definition of merge RSV

Selected compounds of the present invention can be tested for their ability to inhibit important processes merge respiratory syncytial virus.

The formation of structures RSV-F

Oligonucleotides are single-stranded synthetic DNA encoding parts of the glycoprotein RSV A2 F containing optimal codons and without potential poly (A) joining or splicing sites, are formed by synthetic means (Mason et al, W00242326). Membrane-bound primary product of translation of F is generally formed according to the method described in this context and in Morton et al.

Determination of the formation of syncytium

The activity of the fusion constructs RSV-F determined in 293 cells, mainly in the manner described Morton et al, 2003, Virology, 311:275. For example: six wells at approximately 80%of lianyi transferout the addition of plasmid DNA (2 µg/well), support we are interested in the design solution CaPO4within 4 hours. After glycerol shock and washing transfetsirovannyh cells are trypsinolysis and add to 1.5×104cells/well in 96-well tablet containing subjects substances with semi-log serial dilution. The formation of syncytium find visual observation and quantitatively determined by 48 hours post-transfection by adding 20 μl of CellTiter 96 One Solution (Promega) followed by incubation for 4 hours at 37°C. Then, the color reaction is stopped by adding 25 µl of 10%VAT (SDS) to each well and determine the absorption at 540/690 nm. The concentration of compound that reduces the value of the absorption relative to untreated control cultures by 50% (EC50), calculated using nonlinear regression analysis.

Method R: Model using RSV cotton hamster

Model using cotton hamster used mainly as described in the literature (Wyde et al, 2003, Antiviral Res., 60:221). Briefly, cotton hamsters weighing 50-100 g slightly anaesthetize soporano and give the dose that matches the introduction of 100 mg/kg/day compound or placebo control. Viral infection occurs within 2 hours after exposure in mice, shot in a similar way, when intransa enom introduction dropwise at approximately 1000 TCID 50RSV A2 at the animal. Four days after infection with the virus each cotton hamster kill and remove the light and determine the titers of RSV reaction rosethorne.

Method S: Model using RSV Balb/c mice

Model using mice used mainly as described Cianci et al., 2004, Antimicrobial Agents and Chemotherapy, 48:413). In short, eight-week old female Balb/c mice are weighed, anaesthetize Avertin intraperitoneally™ connection or placebo, administered orally for 6 hours prior to infection. Mice infect vnutripuzarno approximately 10,000 TCID50RSV A2 at the animal. Three days after infection, each mouse kill, remove her lungs and determine the titers of RSV reaction rosethorne.

1. The compound of formula I or its pharmaceutically acceptable salt

where R1selected from phenyl, optionally substituted with halogen, hydroxy or C1-6-alkoxygroup; C3-7-cycloalkyl; pyridyl, optionally substituted with halogen, or N-oxide pyridyl;
R2selected from H, -CH2R3-C(=O)R3-C(=O)N(R4R3and-SO2-pyridyl, where R3selected from hydrogen, C1-6of alkyl, C3-6alkenyl,3-7-cycloalkyl, -(CH2)m-phenyl and -(CH2)mTo(5-, 6 - or 9-membered heterocyclyl with 1-3 heteroatoms and, independently selected from N, O or S; m is 0-6;
R4is hydrogen; and alkyl, alkeline, cycloalkyl, phenyl and heterocyclyl groups optionally are substituted by one or more substituents independently selected from-COOH, -SCH2CONHea, -NSO2phenyl, heteroaryl, phenyl, halogen, C1-6of alkyl, C1-6alkoxy, Gialos1-6of alkyl, C3-7-cycloalkyl, heteroaromatic, where each phenyl or heteroaryl may be optionally additionally substituted by one or more Deputy, independently selected from halogen, Gialos1-6of alkyl, C1-6the alkyl and C1-6alkoxy; and where the specified heteroaryl represents an aromatic heterocyclyl with 1-3 heteroatoms independently selected from N, O or S;
X represents O or S;
And together with atoms to which it is attached forms a phenyl, optionally substituted with halogen, or heteroaryl with 1 or 2 ashtami, optionally substituted with halogen, or its N-oxide form;
-Represents-CH2-(CH2)z-where z is 1 or 2;
D represents-CRIIIRIV-where RIIIand RIVare the same and represent CH3or N; or RIIIand RIVtogether with the atom to which they are attached, form a 3-membered cycloalkyl ring, and provided that to the Yes And together with atoms, to which it is attached, form unsubstituted phenyl ring, X represents O, D represents-CH2- ,- Represents-CH2CH2-, and R1represents unsubstituted phenyl, then R2is not N.

2. The compound according to claim 1 in which the ring a is optionally halogenated phenyl.

3. The compound according to claim 1, where the cycle And is optionally halogenated pyridium.

4. The compound according to claim 1, where-represents-CH2CH2-.

5. The compound according to claim 1, where D represents-CRIIIRIV-where both groups of RIIIand RIVrepresent N or CH3.

6. The compound according to claim 1, where D represents-CH2-.

7. The compound according to claim 1, where R1selected from phenyl, optionally substituted by chlorine, hydroxy or methoxy group; C3-7-cycloalkyl; pyridyl, optionally substituted by chlorine; or N-oxide pyridyl.

8. The compound according to claim 1, where R1represents phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 5-chloro-2-pyridyl, 4-pyridyl or 4-pyridyl N-oxide.

9. The compound according to claim 1, where R2represents-CH2-R3where R3represents -(CH2)m-(optionally substituted phenyl) or -(CH2)m-(optionally substituted 5-, 6 - or 9-membered heterocyclyl with 1-3 heteroatoms, independently researched the performance of selected from N, O or S and m is 0-3, and where the optional substituents defined in claim 1.

10. The compound according to claim 1, where R2represents-CON(R4R3where R3represents -(CH2)m-(optionally substituted phenyl) or -(CH2)m-(optionally substituted 5-, 6 - or 9-membered heteroaryl where specified heteroaryl is aromatic heterocyclyl with 1-3 heteroatoms independently selected from N, O or S, and m is 0-2, and where the optional substituents defined in claim 1.

11. The compound according to claim 1, where R2represents-C(=O)R3where R3represents -(CH2)m-(optionally substituted phenyl) or -(CH2)m-(optionally substituted 5-, 6 - or 9-membered heteroaryl where specified heteroaryl is aromatic heterocyclyl with 1-3 heteroatoms independently selected from N, O or S), and m is 0-3, and where the optional substituents defined in claim 1.

12. Connection to item 11, where m is 0, and R3represents an optionally substituted 5 - or 6-membered monomaterial with 1-3 heteroatoms independently selected from N, O or S, optionally substituted 9-membered ring of the bicyclic heterocycle with 1-3 heteroatoms independently selected from N, O or S, or an optionally substituted phenyl group, where the optional substituents defined in claim 1.

13. The compound according to claim 1, the de
A. R2represents a
-CH2R3-C(=O)R3,
where R3selected from optionally substituted C1-6-alkyl, where the substituents independently chosen from-COOH, -SCH2CONH-phenyl, -NHSO2-phenyl, 5-or 6-membered heteroaryl where specified heteroaryl is aromatic heterocyclyl with 1-3 heteroatoms independently selected from N, O or S, and phenyl, each of which is optionally independently substituted by a halogen atom or C1-6-alkoxyl; optionally substituted phenyl, where the substituents independently selected from halogen; optionally substituted 5 - or 6-membered heteroaryl where specified heteroaryl is aromatic heterocyclyl with 1-3 heteroatoms independently selected from N, O or S, where the substituents independently chosen from halogen, C1-6-alkyl, C1-6-halogenoalkane,3-7-cycloalkyl, phenyl, 5 - or 6-membered heteroepitaxial and 5 - or 6-membered heteroaryl where specified heteroaryl is aromatic heterocyclyl with 1-3 heteroatoms independently selected from N, O or S, and optionally substituted C1-6-alkyl or C1-6-halogenation; or optionally substituted C2-6-alkenyl, in which the substituents are independently selected from 5 - or 6-membered heteroaryl where specified heteroaryl is aromatic heterocyclyl is 1 to 3 heteroatoms, independently selected from N, O or S; or
b. R2represents-C(=O)N(R4)-C3-7-cycloalkyl, -C(=O)N(R4-heteroalkyl, -C(=O)N(R4)-C1-6-alkyl, -C(=O)N(R4- phenylalkyl, where R4represents hydrogen; or
C. R2represents-SO2-pyridyl.

14. The compound according to claim 1, where
a. R3represents-CH2R3-C(=O)R3,
where R3is optionally substituted with stands, ethyl or propylene, in which the substituents are independently chosen from-COOH, -SCH2CONH-3,4-acid, NHSO2-4-ftoheia, pyridyloxy, benzisoxazole, pyridyl, furil, 4-ftoheia or 4-methoxyphenyl; optionally substituted phenyl in which the substituents are independently selected from groups: methoxy, F and Cl; optionally substituted thiazolyl, pyridyl, furil, teinila, isoxazolyl, isothiazole, 1,2,3-thiadiazolyl or pyrazolyl, in which the substituents are independently selected from pyridyloxy, cyclopropyl, Me, CF3, phenyl, teinila, pyridyl, F, Cl, Br, 5-CF3-3-methyl-1-pyrazolyl; or 2-fulleren-1-yl; or
b. R2represents-C(=O)N(R4)-2-fenet-1-yl, -C(=O)N(R4)-benzyl, -C(=O)N(R4)-cyclohexyl, -C(=O)N(R4)-2-furylmethyl, -C(=O)N(R4)-methyl or-C(=O)N(R4)-4-methylbenzyl,
R4represents N; or
C. R2is the Oh or-SO 2-pyridyl.

15. The connection indicated in paragraph 13, where R3is optionally substituted and selected from phenyl, furil, teinila, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furazane, isoxazolyl, isothiazole, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo[b]furanyl, benzo[b]thiophenyl and benzisoxazole.

16. The compound according to claim 1, where R2represents-C(=O)R3condensed ring a represents a phenyl, optionally substituted with halogen, or pyridyl; D represents-CRIIIRIV-, R3is optionally substituted and selected from phenyl, furil, teinila, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furazane, isoxazolyl, isothiazole, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo[b]furanyl, benzo[b]thiophenyl and benzisoxazole; and both of RIIIand RIVrepresent N or CH3or RIIIand RIVtogether with the atom to which they are attached, form a 3-membered cycloalkyl ring.

17. The compound according to claim 1, where X represents O.

18. The compound according to claim 1, where R1represents phenyl, optionally substituted with halogen, hydroxy or With the1-6-alkoxy, X represents O And together with atoms to which o is attached, forms a phenyl, optionally substituted with halogen, or pyridyl,-represents-CH2CH2-, D represents-CH2and R2represents-C(O)-(optionally substituted phenyl) or-C(O)-(optionally substituted 5 - or 6-membered heterocyclyl with 1-3 heteroatoms independently selected from N, O or S), and where the optional substituents defined in claim 1.

19. The compound according to claim 1 in which the ring a is an unsubstituted phenyl.

20. The compound according to claim 5 in which the ring a is an unsubstituted pyridyl.

21. The compound according to claim 1, which contains an asymmetric center at the point of connection R1as shown in the structure

22. Pharmaceutical composition for the treatment of RSV infections with RSV antiviral activity containing a compound of the formula I according to claim 1 or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable adjuvant, carrier or solvent.

23. The use of the compounds of formula I according to claim 1 or its pharmaceutically acceptable salts for the preparation of drugs for the treatment of RSV infections.

24. The compound of formula I, as defined according to claim 1, for use in the treatment of RSV infection.

25. The compound or its pharmaceutically acceptable salt selected from the group consisting of













































































and



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new N-aryl-2,3-diaroyl-8,10-dimethylpyrido[2',3':3,4]pyrazolo[1,5-α]pyrimidine-4-carboxamides of formula I possessing analgesic activity, and to a method for preparing them. In formula I Ar1=Ph, C6H4Me-4, C6H4OMe-4; Ar2-Ph, C6H4Me-4, C6H3(Me)2-2,5. The method for preparing said compounds consists in a reaction of 1-aryl-4,5-diaroyl-1H-pyrrol-2,3-diones with 3-amino-4,6-dimethyl-2H-pyrazolo[3,4-6]pyridine at temperature 108-110°C in an absolute toluene medium.

EFFECT: there are prepared the compounds possessing analgesic activity.

4 cl, 1 dwg, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) where values of the substitutes are disclosed in the patent claim.

EFFECT: compounds can be applied for treating the infections caused by Pneumovirinae subfamily viruses (RSV, PCB).

53 cl, 502 ex, 11 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - 7-[2-[4-(6-fluoro-3-methyl-1,2-benzioxazol-5-yl)-1-piperazinyl]ethyl]-2-(propynyl)-7H-pyrazolo-[4, 3-e]-[1, 2, 4]-triazolo-[1, 5-c]pyrimidine-5-amine or pharmaceutically acceptable salt thereof, having A2a receptor selective antagonist properties, a pharmaceutical composition based on said compound and use thereof in preparing a medicinal agent for treating central nervous system diseases.

EFFECT: enhanced efficiency of composition and treatment method.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel derivatives of benzo[7,8]azonino[5,4-b]indoles, 7,9-etheno-azecino[5,4-b]indoles and 7,9-ethano-azecino[5,4-b]indoles with general structural formulae: , , , I, IV, VII X=H,Y=CO2Me; II, V, VIII X=H, Y=COMe; III, VI, IX X=Y=CO2Me, which have proved to be cytostatic and cytotoxic compounds. The method involves dissolving 3,8,13,13b-tetrahydro-5H-benzo[1,2]indolysino[8,7-b]indole, ethyl eburnamenine-14-carboxylate or methyl (3-α, 14-β, 16α)-14-hydroxy-14,15-dihydro eburnamenine -14-carboxylate in methanol and then reaction with excess dimethyl acetylenedicarboxylate (ADCX) or methyl propiolate or acetyl acetylene, while stirring at +40-+50°C, with subsequent removal of the solvent and grinding the residue in hexane or a mixture of hexane with ethylacetate (ether) or purified using column chromatography on aluminium oxide.

EFFECT: design of an efficient method of obtaining hazardous compounds.

9 ex

FIELD: chemistry.

SUBSTANCE: described are novel imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine derivatives of formula , where R1 is hydrogen, halogen, lower alkyl or lower alkoxy, possibly substituted with a halogen, nitro group, C3-6cycloalkyl, -O(CH2)mO(CH2)mOH or -C≡C-R'; R2 is hydrogen or methyl; R3 is lower alkyl, lower alkenyl, lower alkynyl, possibly substituted with a halogen, -(CH2)n-C3-6cycloalkyl, -(CR'R'')m-CH3, phenyl, possibly substituted with a halogen, pyridinyl substituted with a lower alkyl, -(CH2)n- NH-C3-6cycloalkyl, lower alkenyl-C3-6cycloalkyl, lower alkynyl- (CR'R")m-OH, lower alkynyl-phenyl, where the phenyl ring is possibly substituted with a halogen, CF3, lower alkyl or lower alkoxy; R' is hydrogen or lower alkyl; R" is hydrogen, hydroxy or lower alkyl; n is equal to 0, 1, or 2, m is equal to 1, 2 or 3, o is equal to 1 or 2, or their pharmaceutically acceptable acid addition salts.

EFFECT: obtaining compounds which can be used as a cognitive enhancer or for treating cognitive disorders similar to Alzheimer's disease.

22 cl, 60 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds with affinity to MC4 receptors, of the general formula (I): , where A is -CH2- or -C(O)-; R1 is (C1-C8)alkyl; R2 is (C1-C8)alkyl; R3 is radical of the formula -(CH2)s-R'3; R'3 is 5-6-member heterocycloalkyl containing one or two nitrogen atoms and possibly one oxygen atom possibly substituted with (C1-C6)alkyl or benzyl; or radical of the formula -NW3W'3; W3 is hydrogen atom or (C1-C8)alkyl; W'3 is radical of the formula -(CH2)s'-Z3; Z3 is hydrogen atom, (C1-C8)alkyl; s and s' are independently an integer within 0 to 6; B is 5-6-member monocyclic unsaturated, aromatic or non-aromatic radical which can be condensed with 5-6-member unsaturated, aromatic or non-aromatic radical forming bicyclic condensed system, and B is possibly containing one or more equal or different heteroatoms selected out of O, S and N, and possibly substituted with one or more equal or different radicals selected out of halogen atom, nitro group, cyano group, oxy group, -XB-YB and phenyl possibly substituted with one substitute selected out of halogen atom and (C1-C6)alkyl; XB is a covalent bond, -O-, -S-, -C(O)-, -C(O)-O-; YB is (C1-C6)alkyl; or pharmaceutically acceptable salt of claimed compounds.

EFFECT: improved obtainment and application efficiency of compounds for production of drug for treatment of diseases related to MC4 receptor activation.

20 cl, 4 dwg, 2 tbl, 81 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula (I) and their pharmaceutically acceptable salts with antagonistic properties towards adenosine A2A receptor, which can be used for treating central nervous system diseases such as Parkinson's disease. In general formula (I) , R is ,, R1, R2, R3, R4 and R5 is independently selected from a group which consists of hydrogen; R6 is hydrogen, (C1-C6)alkyl or -CH2F; R7, R8 and R9 are independently selected from a group which consists of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, haloid and -CF3; Z is R10-phenyl, R10-5-6-member heteroaryl, which contains 1 or 2 hetwroatoms, selected from nitrogen or from nitrogen and oxygen, possibly condensed with a benzene ring, or ; R10 represents 1 to 3 substitutes, independently selected from a group which consists of hydrogen, (C1-C6)-alkyl, hydroxy, (C1-C6)-alkoxy, hydroxy-(C1-C6)-alkyl, hydroxy-(C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkoxy, (C1-C6)-alkoxy-(C1-C6)-alkoxy-(C1-C6)-alkyl, (di-(C1-C6)-alkoxy)-(C1-C6)-alkyl, (hydroxy)-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C6)-cycloalkyloxy, (C3-C6)-cycloalkyl-O-(C3-C6)-alkoxy, (C1-C6)-alkyl-SO2-, (C1-C6)-alkyl-SO-, haloid, -CN, cyano-(C1-C6)-alkyl, -CHF2, -CF3, -C(O)R13, -C(O)O-(C1-C6)-alkyl, -N(R11)(R12), N(R11)(R12)- (C1-C6)-alkyl, - C(O)N(R13)(R16), R11-5-6-member nitrogen-containing heteroaryl, possibly condensed with a benzene ring, R15-5-6-member heterocycoalkyl, with 1 or 2 heteroatoms selected from nitrogen and oxygen, R15-5-6-member heterocycloalkyl-(C1-C6)-alkyl, with 1 or 2 heteroatoms selected from nitrogen and oxygen, R15-5-6-member heterocycloalkyl-(C1-C6)-alkoxy, with 1 or 2 heteroatoms selected from nitrogen and oxygen, R15-5-6-member heterocycloalkyl-oxy, with 1 or 2 heteroatoms in a heterocyclic ring selected from nitrogen and oxygen, CF3-(C1-C4)alkylene-O-(C1-C6)alkyl, CF3-hydroxy(C1-C6)alkyl, cyano-(C1-C6)-alkoxy, (C1-C4)alkylene-C(O)-O-(C1-C6)alkyl, -SO2-N((C1-C4)alkyl)2, ((C3-C4)cycloalkyl)hydroxy(C1-C6)alkyl, (hydroxy(C1-C6)alkyl)-(C1-C4)alkoxy, (dihydroxy)-(C1-C6)-alkyl, (dihydroxy)(C1-C6)alkoxy, -C(=NOR17)- (C1-C6)alkyl and -C(=NOR17)-CF3; or two R10 groups, on neighbouring carbon atoms of the ring, together form -O-CH2-O-, -O-(CH2)2-O-, -CH2-O(CH2)2-O-, -O-(CH2)2-, -(CH2)3-O-, -O-(CH2)3-O, -(CH2)3-, where the ring, formed by two R10 substitutes and ring carbon atoms with which they are bonded, is substituted with R16; or two R10 groups on neighbouring ring carbon atoms, together form -O(CH2)3CH((OR18)-, each R11 is independently selected from a group which consists of hydrogen and (C1-C6)alkyl; each R12 is independently selected from a group which consists of (C1-C6)alkyl, hydroxy(C1-C6)alkyl, -C(O)-(C1-C6)alkyl, -C(O)O-(C1-C6)alkyl, ((C1-C6)alkoxy)hydroxy(C1-C6)alkyl, (C1-C6)alkoxy (C1-C6)alkyl-C(O)-, -SO2(C1-C6)alkyl; R13 is hydrogen, (C1-C6)alkyl or -CF3; R14 is (C1-C6)alkoxy-C(O)-; R15 represents 1 to 3 substitutes, independently selected from a group which consists of (C1-C6)alkoxy, hydroxy-(C1-C6)alkyl; or two R15 substitutes, taken together with the carbon atom with which they are bonded, form a -C(=O)- group; R16 is (C1-C6)alkoxy(C1-C6)alkyl, hydroxy or hydroxy(C1-C6)alkyl; R17 is hydrogen or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds.

EFFECT: increased effectiveness of composition and method of treatment.

17 cl, 23 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel derivatives of 5-aminopyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine of the general formula: wherein R means furanyl, possibly substituted pyrrolyl, possibly substituted pyridyl, possibly substituted phenyl or (C4-C6)-cycloalkenyl; X means (C2-C6)-alkylene or -C(O)CH2-; Y means the following groups: -N(R2)CH2CH2N(R3)-, -OCH2CH2N(R2)- wherein R2 and R3 mean hydrogen atom or (C1-C6)-alkyl, -O-, -S-, -CH2S-, -(CH2)2-NH- or compound of the formula: wherein Q means or R4 means hydrogen atom or (C1-C6)-alkyl, or two R at one carbon atom form group =O; Z means phenyl comprising from 1 to 5 of different substitutes, phenylalkyl or heteroaryl, diphenylmethyl and other values; or Z and Y in common can form substituted piperidinyl or substituted phenyl also possessing activity of antagonist of A2a adenosine receptors. Also, invention relates to a pharmaceutical composition based on these compounds, using novel compounds for preparing medicinal agents in treatment, for example, Parkinson's disease, and two methods for synthesis of intermediate compounds of formulae (II) and (IIIa) .

EFFECT: improved methods of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 17 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (I) where values of substituents are given in description, possessing inhibiting activity with respect to cathepsin K as well as to pharmaceutical compositions for treating diseases, associated with cysteine protease activity and to methods of inhibiting cathepsin K in mammals, requiring such treatment by introduction of efficient amount of compound to mammal.

EFFECT: claimed is application of formula (I) compound or its pharmaceutically acceptable salt in manufacturing medication for application in cathepsin K inhibition in a warm-blooded animal.

10 cl, 45 ex, 5 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, in which: one of A, B, C and D denotes N, and the rest independently denote CH and C(R1); m equals a whole number from 1 to 4; n equals a whole number from 0 to 4; R1 denotes halogen; R2 and R3 denote hydrogen; R4 is selected from H, C1-6alkyl; Ar denotes aryl, optionally substituted with one or more halogen atoms; X denotes -C(Ra)(Rb)-, where Ra and Rb denote H; Y denotes -S(O)2-. The invention also relates to a pharmaceutical composition having CRTH2 receptor antagonist properties and containing a compound of formula I, to use of a compound of formula I when producing a drug for treating or preventing CRTH2 mediated diseases and a method for antagonistic action on CRTH2 receptor in mammals.

EFFECT: novel compound, which can be useful as a CRTH2 receptor antagonist, is obtained and described.

16 cl, 6 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) where values of the substitutes are disclosed in the patent claim.

EFFECT: compounds can be applied for treating the infections caused by Pneumovirinae subfamily viruses (RSV, PCB).

53 cl, 502 ex, 11 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to novel compounds with affinity to MC4 receptors, of the general formula (I): , where A is -CH2- or -C(O)-; R1 is (C1-C8)alkyl; R2 is (C1-C8)alkyl; R3 is radical of the formula -(CH2)s-R'3; R'3 is 5-6-member heterocycloalkyl containing one or two nitrogen atoms and possibly one oxygen atom possibly substituted with (C1-C6)alkyl or benzyl; or radical of the formula -NW3W'3; W3 is hydrogen atom or (C1-C8)alkyl; W'3 is radical of the formula -(CH2)s'-Z3; Z3 is hydrogen atom, (C1-C8)alkyl; s and s' are independently an integer within 0 to 6; B is 5-6-member monocyclic unsaturated, aromatic or non-aromatic radical which can be condensed with 5-6-member unsaturated, aromatic or non-aromatic radical forming bicyclic condensed system, and B is possibly containing one or more equal or different heteroatoms selected out of O, S and N, and possibly substituted with one or more equal or different radicals selected out of halogen atom, nitro group, cyano group, oxy group, -XB-YB and phenyl possibly substituted with one substitute selected out of halogen atom and (C1-C6)alkyl; XB is a covalent bond, -O-, -S-, -C(O)-, -C(O)-O-; YB is (C1-C6)alkyl; or pharmaceutically acceptable salt of claimed compounds.

EFFECT: improved obtainment and application efficiency of compounds for production of drug for treatment of diseases related to MC4 receptor activation.

20 cl, 4 dwg, 2 tbl, 81 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to serotonin 5-HT6 receptor antagonists - new substituted 3-sulphonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-e]pyrimidines of formula and substituted 3-sulphonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-c1]pyrimidines of general formula 2, a medicinal base and pharmaceutical compositions containing the medicinal base in form of the said compounds, as well as to a method of treating and preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals. In formulae and Ar is phenyl which is optionally substituted with halogen atoms, or a 6-member heteroaryl which contains a nitrogen atom in the ring; R1 is a hydrogen atom, C1-C3alkyl, hydroxy C1-C3alkyloxy group, C1-C3alkylsulphanyl group; R2 is a hydrogen atom or C1-C3alkyl, R3 is a hydrogen atom optionally substituted C1-C3alkyl or tert-butyloxycarbonyl.

EFFECT: obtaining compounds for preventing development of different conditions and diseases of the central nervous system of humans and warm-blooded animals.

16 cl, 3 tbl, 1 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel antagonists of serotonin 5-HT6 receptors - substituted 2-amino-3-sulfonyl-6,7,8,9-tetrahydro-pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines of general formula 1 and substituted 2-amino-3-sulfonyl-5,6,7,8-tetrahydro-pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines of general formula 2 or their pharmaceutically acceptable salts and/or hydrates, method of producing said compounds and pharmaceutical compositions, medicinal agents and treatment method. In compounds of formula 1 and general formula 2 , Ar is phenyl which is possibly substituted with halogen atoms, or a 6-member nitrogen-containing heteroaryl; R1 is a hydrogen atom, C1-C3alkyl which is possibly substituted with phenyl, C1-C5alkoxycarbonyl; R2 is a hydrogen atom, halogen or C1-C3alkyl; R13 and R23 are optionally identical substitutes selected from a hydrogen atom, optionally substituted C1-C3alkyl or R13 and R23 together with the nitrogen atom with which they are bonded form a nitrogen-containing 6-member saturated heteroaryl optionally substituted with C1-C5alkoxycarbonyl, where the said heteroaryl has 1-2 heteroatoms selected from nitrogen.

EFFECT: compounds can be used to prevent and treat diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors for enhancing mental capacity.

14 cl, 3 tbl, 19 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: invention refers to method for prevention of mirtazapin sublimation from a pharmaceutical preparative form containing solid enantiomer pure form of mirtazapin, by making the preparative forms by addition of at least one pharmaceutically acceptable adjuvant to the solid form of mirtazapin enantiomer. The enantiomer pure form is pharmaceutically acceptable, nonsublumating and solid salt of S- or R-mirtazapin. There are also described nonsublumating salts of S-mirtazapin and the pharmaceutical preparative form of the latter.

EFFECT: higher efficiency of the composition.

4 cl, 4 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaindole-indole derivatives and pharmaceutically acceptable salts thereof of general formula: Y=Z (G), wherein Y means a group of azaindole of formula (Yl) Z means a group of indole of formula (Z1) or (Z2) wherein the values "=", R, R1, R1', R2, R3, R4, R2', R3, R4', R5' are presented in cl. 1 of the patent claim.

EFFECT: compounds inhibit cycline-dependent kinase that enables using them in a pharmaceutical composition.

6 cl, 3 dwg, 9 tbl, 8 ex

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