Tetrahydro-4n-pyrido[1,2-a]pyrimidine and related compounds, used as inhibitors of hiv-integrase

FIELD: chemistry.

SUBSTANCE: invention pertains to compounds with general formulae (I) and (II) and their pharmaceutical salts, their use as inhibitors of HIV-integrase and to pharmaceutical salts based on them. In formula (I) , R1 represents H or NR2R5; R2 represents CH3; R5 represents 1) C(O)CH2SO2CH3, 2) C(O)C(O)N(CH3)2, 3) SO2N(CH3)2 or 4) SO2R20 where R20 represents , , or ; or alternatively, R2 and R5 together with a nitrogen atom, to which they are bonded, form or , R3 represents hydrogen; R4 represents 1) n-fluorobenzyl, 2) 4-fluro-3-methylbenzyl, 3) 3-chlorobenzyl or 4) 3-chloro-4-methylbenzyl; R12 and R14 both represent H, except that, when R5 represents C(O)C(O)N(CH3)2 and R4 represents n-fluorobenzyl, and n equals 1, then R12 and R14 both represent H, or both represent CH3; and n is an integer, equal to 0, 1 or 2.

EFFECT: compounds can be used for treating HIV-infection.

12 cl, 5 dwg, 1 tbl, 8 ex

 

The present invention relates to tetrahydro-4H-pyrido[l,2-a]pyrimidines, related compounds and their pharmaceutically acceptable salts, synthesis and application of these compounds as inhibitors of the enzyme HIV-integrase. Compounds and their pharmaceutically acceptable salts according to the present invention are useful for prevention or treatment of HIV infection and to treat or delay the symptoms of AIDS.

The level of technology

Retrovirus called human immunodeficiency virus (HIV)is the etiological factor complex diseases, including progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the Central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, ARV. A common feature of replication of retroviruses is to insert DNA provirus that encodes a viral integrase into the genome of the host cell, required step in HIV replication in T-lymphocytes and monocytic human cells. It is believed that integration under the action of integrase occurs in three stages: build a stable nucleoprotein complex sequences of viral DNA; the removal of two nucleotides from the 3' ends of linear DNA provirus; covalent binding of released 3' OH ends of DNA provirus with the DNA of the host cell on the stepped arrangement is different cleavage sites. The fourth stage of the process, reparative synthesis of the resulting double-strand break can be performed by cellular enzymes.

Nucleotide sequencing of HIV indicates the presence of the pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Homology of amino acid sequence suggests that the pol sequence encodes reverse transcriptase, integrase and HIV-protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231, 1567 (1986); Pear1, L.H. et al., Nature, 329, 351 (1987)]. It is established that all three enzyme necessary for HIV replication.

It is known that some antiviral compounds acting as inhibitors of HIV replication, are very effective tools in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors, such as azidocillin (AZT) and efavirenz and protease inhibitors such as indinavir and nelfinavir. Compounds of the present invention are inhibitors of HIV integrase and inhibitors of HIV replication. Inhibition of integrase in vitro and HIV replication in cells is a direct consequence of inhibition of the reaction of the migration chain, catalyzed by recombinant integrase in vitro in cells infected with HIV. A particular advantage of the present invention is highly specific inhibition of HIV integrase and HIV replication.

With mnost inventions

The present invention relates to new pyridopyrimidines derivatives and related compounds. These compounds are useful in the inhibition of HIV integrase, the prevention of HIV and in the prevention, treatment or delay the symptoms of AIDS and/or AIDS-related complex (ARC)or in the form of their compounds, either in the form of pharmaceutically acceptable salts or hydrates (when appropriate), or as ingredients of pharmaceutical compositions, in combination with other HIV/AIDS antiviral agents, anti-infective agents, immunomodulators, antibiotics or vaccines, or in the absence of these funds. More specifically, the present invention includes compounds of formula I and their pharmaceutically acceptable salts:

R1means H or NR2R5;

R2means CH3;

R5means

1) C(O)CH2SO2CH3,

2) C(O)C(O)N(CH3)2,

3) SO2N(CH3)2or

4) SO2R20where R20means:

or alternatively, R2and R5together with the nitrogen atom to which are attached, form

or

R3means hydrogen;

R4means:

1) p-tormentil,

2) 4-fluoro-3-methylbenzyl,

3) 3-Chlorobenzyl or

4) 3-chloro-4-methylbenzyl;

R12and R14both denote H, except that when R5means C(O)C(O)N(CH3)2and R4means p-tormentil, and n is 1, R12and R14either both denote H, or both mean CH3; and

n means an integer of zero, 1 or 2.

The present invention also includes pharmaceutical compositions containing a compound according to this invention, and methods of making such pharmaceutical compositions. In addition, the present invention includes methods for the treatment of AIDS, ways to delay the symptoms of AIDS, prevention of AIDS, prevention of HIV and treatment of HIV infection.

Other embodiments of the aspects and distinctive features of the present invention or below in the above description or become apparent from the following description, examples and claims.

Detailed description of the invention

The present invention includes compounds of the above formula I and their pharmaceutically acceptable salts. These compounds and the corresponding pharmaceutically acceptable salts are inhibitors of HIV integrase.

The embodiment of the present invention is connected to the e of the formula I or its pharmaceutically acceptable salt, where R1mean NR2R5; n indicates an integer equal to 1 or 2; and all other variables take the initially specified values.

Another embodiment of the present invention is a compound of formula I or its pharmaceutically acceptable salt, where R1mean NR2R5; R2means CH3; R5means (1) C(O)C(O)N(CH3)2or 2) SO2R20where R20means

R3means hydrogen; R4means p-terbisil or 4-fluoro-3-methylbenzyl; R12and R14both denote H, except that when R5means C(O)C(O)N(CH3)2and R4means p-tormentil, and n is 1, R12and R14either both denote H, or both mean CH3; and n indicates an integer equal to 1 or 2.

The present invention also includes a compound of formula II or its pharmaceutically acceptable salt:

where R1means hydrogen, NR2R5, OR2, SR2, SOR2, SO2R2, SO2NR2R5or OC(O)NR2R5; R3means hydrogen; R4means

R2means (1) hydrogen, 2) CH3or 3)

and

R5means (1) C(O)CH3, ) C(O)CH 2SO2CH3, 3) CH3, 4) C(O)C(O)N(CH3)2, 5) SO2CH3, 6) SO2N(CH3)2, 7) C(O)CH2N(CH3)2, 8) SO2CH2SO2CH3, 9) C(O)CF3, 10)

11)

or 12)

or R2and R5together with the nitrogen atom to which are attached, form a heterocyclic ring selected from the group including

Another embodiment of the present invention is a compound or its pharmaceutically acceptable salt selected from the group comprising compounds listed in the table below.

Additional embodiments of the present invention include the following:

(a) a Pharmaceutical composition comprising a compound of formula (I) pharmaceutically acceptable carrier.

(b) a Pharmaceutical composition comprising the product obtained by combining (e.g., mixing) an effective amount of the compounds of formula (I) and a pharmaceutically acceptable carrier.

(c) the Pharmaceutical composition according to p. (a) or (b), optionally containing a therapeutically effective amount for the treatment of HIV/AIDS selected from the group comprising HIV/AIDS-anti-Christ. ironnie means, immunomodulators and anti-infective tools.

(d) the Pharmaceutical composition according to p. (C), where a cure for HIV/AIDS is an antiviral agent selected from the group comprising HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors and HIV nucleoside inhibitors of HIV reverse transcriptase.

(e) Combination, are useful for inhibiting HIV integrase, treat, cure or prevent HIV infection or the prevention, treatment or delay the symptoms of AIDS, representing a therapeutically effective amount of the compounds of formula (I) and a therapeutically effective amount for the treatment of HIV/AIDS selected from the group comprising HIV/AIDS antiviral agents, immunomodulators, and anti-infective tools.

(f) Combination in p. (e), where treatment for HIV/AIDS is an antiviral agent selected from the group comprising HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors and HIV nucleoside inhibitors of HIV reverse transcriptase.

(g) a Method of inhibiting HIV integrase in need in this patient, comprising the administration to a patient a therapeutically effective amount of the compounds of formula (I).

(h) Method of prevention or treatment of HIV infection in the needs of the people existing in this patient, includes introduction to the patient a therapeutically effective amount of the compounds of formula (I).

(i) a Method according to p. (h)where the compound of formula (I) is administered in combination with a therapeutically effective amount of at least one antiviral agents selected from the group comprising HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors and HIV nucleoside inhibitors of HIV reverse transcriptase.

(j) Method of prevention, treatment or delay the symptoms of AIDS in need thereof of a patient, comprising the administration to a patient a therapeutically effective amount of the compounds of formula (I).

(k) the Method under item (j), where the compound is administered in combination with a therapeutically effective amount of at least one antiviral agents selected from the group comprising HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors and HIV nucleoside inhibitors of HIV reverse transcriptase.

(l) a Method of inhibiting HIV integrase in need in this patient, comprising the administration to a patient the pharmaceutical composition of p. (a), (b), (c) or (d) any combination in p. (e) or (f).

(m) Method of prevention or treatment of HIV infection in need of this patient, comprising the administration to a patient the pharmaceutical composition of p. (a), (b), (c) or (d) any combination in p. (e) or (f.

(n) a Method of prevention, treatment or delay the symptoms of AIDS in need thereof of a patient, comprising the administration to a patient the pharmaceutical composition of p. (a), (b), (c) or (d) any combination in p. (e) or (f).

The present invention also includes the compound (i) to use in order, (ii) for use as a drug order, or (iii) for use in obtaining medicines used for the purpose of: (a) inhibiting HIV integrase, (b) prevention or treatment of HIV infection or (c) the prevention, treatment or delay the symptoms of AIDS. When applying for these purposes the compounds of the present invention, optional, can be used in combination with one or more means for the treatment of HIV/AIDS selected from the group comprising HIV/AIDS antiviral agents, anti-infective tools and immunomodulators.

Compounds of the present invention may have asymmetric centers and may exist, except as otherwise specified, in the form of mixtures of stereoisomers or as individual diastereomers or enantiomers, with all isomeric forms are included in the scope of the present invention.

N-substituted hydroxypyrimidinone compounds of the present invention may also exist as tautomers, such as below automar the compounds of formula I:

It goes without saying that the present invention includes all tautomers hydroxypyrimidinone compounds of formula I (or II), alone and in mixtures.

Compounds of the present invention are useful in the inhibition of HIV integrase, the prevention or treatment of infection with human immunodeficiency virus (HIV) and the prevention, treatment or delay of subsequent manifestations of pathological conditions such as AIDS. AIDS prevention, AIDS treatment, delayed manifestations of AIDS, or the prevention or treatment of HIV infection are defined as including, but not right restrictions, the treatment of a wide range of States of HIV infection: AIDS, ARC (AIDS-associated complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV infection. For example, the compounds of the present invention are useful in the treatment of HIV infection after the alleged HIV exposure, occur during the transfusion, replacement of body fluids, bites, accidental injection of contaminated needles or contact with the blood of the patient during surgery.

Typical compounds of the present invention were tested for inhibition in the research activity of integrase in the reaction of the transfer circuits. Tests carried out by the method described in WO 02/3093. The test also corresponds to the one given in Wolfe, A.L. et al., J. Virol. 1996, 70: 1424-1432 for recombinant integrase, except that: (i) for analysis using pre-assembled complexes transfer integrase-chain; (ii) reaction of the transfer circuit is carried out in the presence of inhibitor, 2.5 mm MgCl2using from 0.5 to 5 nm 3'-FITZ-labeled substrate DNA target, and (iii) the reaction products of the transfer circuit recognize, using anti-FITZ, antibody conjugated with alkaline phosphatase, and chemiluminescent substrate for alkaline phosphatase. Typical compounds of the present invention, according to this test have an inhibitory effect on the activity in the reaction of the migration chain. For example, the compounds listed in the table below, were investigated by means of analysis of the activity of integrase and give the values of the IC50about 5 mmol/l or below. Additional description of the test using the pre-assembled complexes can be found in Hazuda et al., J. Virol. 1997, 71. 7005-7011; Hazuda et al., Drug Design and Discovery 1997,15: 17-24 and Hazuda et al., Science 2000, 287: 646-650.

Some typical compounds of the present invention were also studied in the test for inhibition of acute HIV infection of T-lymphocytes, carried out according to Vacca, J.P. et al., Proc. Natl. Acad. Sci. USA 1994,91.: 4096. These connections, including connections, see the s in the table below, give the values of the IC95about 20 µmol/l or below.

Compounds of the present invention may also act as inhibitors of HIV ribonuclease H (RNase H). Reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) catalyzes the conversion of genomic RNA into double-stranded DNA provirus after penetration into the cell, using RNA - and DNA-dependent polymerase activity and the activity of RNase H. the RT of HIV-l is asymmetric dimer consisting of polypeptides p66 and p51. The catalytic activity of RT are controlled by separate sites in the p66 subunit; i.e. N-end p66 is responsible for RNA - and DNA-dependent DNA polymerase activity, and domain pl5 on the C-end is responsible for the activity of RNase H. Mcasa H is required for cleavage of the RNA chain RNA:DNA heteroduplex intermediate products of reverse transcription. Compounds of the present invention can selectively contact the domain RNase H RT HIV-1 and inhibit the activity of the specified domain. Inhibiting activity of the compounds in relation to the RNase H can be measured using appropriate tests, known from the prior art, such as the test described in Shaw-Reid et al., J. Biol. Chem. 2003, 278 (5): 2777-2780. Thus, the present invention includes a method of inhibiting HIV RNase H we need in this patient, which consists in injecting the patient E. the effective amount of the compounds according to the invention. The present invention also includes the compound (i) to apply, in order, (ii) for use as a medicinal product in order or (iii) for use in obtaining medicinal product used for the inhibition of HIV RNase H.

Compounds of the present invention can be introduced in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" means a salt with the effectiveness of the parent compound, which is not biologically or otherwise unacceptable (for example, is neither toxic nor otherwise harmful to the recipient). Suitable salts include acid additive salts which may, for example, be obtained by mixing a solution of the compound of the present invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, triperoxonane acid or benzoic acid. When the compounds according to the invention contain an acidic component, suitable pharmaceutically acceptable salts may include alkali metal salts (e.g. sodium or potassium), salts of alkaline-earth metals (e.g. calcium salts or magnesium), and salts formed with suitable organic ligands such as Quaternary ammonium salt. Also, in the presence of acid (-SON) or alcohol group, pharmaceutically acceptable esters can be used for modifying solubility or hydrolysis characteristics of the connection.

For inhibition of HIV integrase and HIV RNase H, prevention or treatment of HIV infection or prevention, treatment or delay the symptoms of AIDS compounds of the present invention can be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, epigastric injection or infusion), by aerosol inhalation, or rectally, in the form of a standard dose of a pharmaceutical composition containing a therapeutically effective amount of the compound and conventional non-toxic pharmaceutically acceptable carriers, excipients or solvents.

The term "introduction" and variations of that term (for example, "accepting connection") in relation to the connection according to the invention means that the required treatment to the individual is administered a compound or prodrug of the compound. When the connection according to the invention or a prodrug is administered in combination with one or more other active agents (e.g., antiviral agents useful for the treatment of HIV infection or AIDS), it is clear that the term "introduction" and each of the options specified term include concurrent and sequential introduction of the connection is in or prodrugs, and other tools.

It is implied that the term "composition", as used here, relates to a product comprising the specified ingredients in the specified amounts, as well as any product that is formed directly or indirectly, for any combination of the specified ingredients in the specified amounts.

"Pharmaceutically acceptable" means that the ingredients of the pharmaceutical composition should be compatible with each other and not to cause harm to the recipient.

The term "subject" (alternatively referred to here as the "patient"), as used here, refers to an animal, preferably a mammal, most preferably a human, which is the object of treatment, observation or research.

The term "therapeutically effective amount", as used here, refers to an amount of active compound or pharmaceutical agent that causes a biological or pharmacological response in a tissue, system, animal or human body, which was achieved by the researcher, veterinarian, medical doctor or other Clinician, which includes the reduction or prevention of the symptoms are treatable or preventable disease or condition. The term also includes the amount of active compound sufficient to inhibit HIV integrase and/or RNase H, thereby causing the expected response. When the active connection (the. the active ingredient) is injected in the form of a salt, the amount of active ingredient refers to the connection in the form of free acid or free base.

The pharmaceutical compositions can be in the form of oral-input suspensions or tablets or capsules, nasal sprays, sterile preparations for injection, for example, in the form of a sterile aqueous or oily suspensions for injections, or suppositories. These compositions can be obtained well-known from the prior art methods and contain conventional fillers. Suitable methods and ingredients described inRemington's Pharmaceutical Sciences, 18thedition, edited by A. R. Gennaro, Mack Publishing Co., 1990, which is fully incorporated here by reference.

Compounds of the present invention can be administered orally in the range of doses from 0.001 to 1000 mg/kg of body weight of the mammal (e.g. human) per day in a single dose or multiple doses. The preferred spacing of doses is from 0.01 to 500 mg/kg body weight / day, orally in a single dose or multiple doses. Another preferred range of doses ranging from 0.1 to 100 mg/kg body weight / day, orally in a single dose or multiple doses. For oral administration the compositions may be presented in the form of tablets or capsules containing from 1.0 to 500 milligrams of the active ingredient, in particular 1, 5, 10 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400 and 500 milligrams of the active ingredient for the symptomatic recruitment dosage treatment to the patient. A particular level of doses and frequency of the dose for each individual patient can vary depending on factors including the activity of the specific compound, the metabolic stability and length of action of that compound, the age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and undergoing therapy recipient.

As indicated above, the present invention also relates to the use of inhibiting HIV integrase compounds of the present invention with one or more tools that are useful in the treatment of HIV infection or AIDS. For example, the compounds of the present invention can be effectively applied, regardless of when the preliminary exposure to and/or subsequent exposure, in combination with effective amounts of one or more HIV/AIDS antiviral agents, immunomodulators, anti-infective funds or vaccines useful for treating HIV infection or AIDS, such as the means shown in table 1 in WO 01/38332 or in the table in WO 02/30930, both documents are fully incorporated here as reference. It is obvious the bottom, that the scope of combinations of the compounds of the present invention with HIV/AIDS antiviral agents, immunomodulators, anti-infective drugs or vaccines is not limited to the list given in the above tables in WO 01/38332 and WO 02/30930, and includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS. HIV/AIDS antiviral agents, and other tools commonly used in these combinations at the level of conventional doses and according to known from the prior art schemes receive, including, for example, the dosage specified inPhysicians' Desk Reference, 57thedition, Thomson PDR, 2003. The dose range of the compounds of the present invention in such combinations is as specified above.

Abbreviations used in this description and, in particular, the schemes and the examples include the following: AIDS=acquired immunodeficiency syndrome, ARC=AIDS-associated complex, Bn=benzyl, CBZ (or Cbz)=benzyloxycarbonyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMAD=diethylazodicarboxylate, DMF=N,N-dimethylformamide, DMSO=dimethylsulfoxide, EtOAc=ethyl acetate; FIA-MS=mass spectrometry analysis method injection into the flow, h=hour(s), HIV=human immunodeficiency virus; HPLC=high performance liquid chromatography, IPA=isopropanol, LDA=sitedisability, Me=methyl, MeOH=methanol, NMP=N-metalpro is einon, NMR=nuclear magnetic resonance, Pd/C=palladium catalyst on charcoal, RP-HPLC=HPLC with reversed phase, TFA=triperoxonane acid, THF=tetrahydrofuran.

Compounds of the present invention can easily be obtained by the following reaction schemes and examples, or modifications to these techniques using readily available starting materials and reagents. The following reaction schemes may also use options, which themselves are known to the person skilled in the art, but not shown in detail. In addition, other methods of producing compounds according to the invention will become apparent to the person skilled in the art in light of the following schemes and examples. Unless otherwise noted, the variables in schemes 1, A, B, C and D, have the following meanings:

PΛmeans hydrogen or a protective group, such as ester, such as, but not in the manner restrictions, benzoate, pivalate, or a simple ester, such as, but not in the manner restrictions, benzyl ether, which is usually removed in the conditions used for the conversion of complex methyl ester to amide, or remove to another stage. The protective group commonly used for the synthesis and/or purification.

RΛmeans hydrogen or C1-6-alkyl.

Y represents hydrogen or NRsaRsb.

Rsameans C1-6 -alkyl, C(O)RscC(O)C(O)NRscRsd, SO2RSC, SO2NRscRsdC(O)CH2SO2RSCC(O)CH2NRscRsd, SO2CH2SO2RSCor CH(CH3RSCor Rsaand Rsbtogether with the nitrogen atom to which are attached, form a heterocyclic ring containing 1 or 2 heteroatoms.

Rsbmeans hydrogen, C1-6-alkyl or C(O)CF3or Rsaand Rsbtogether with the nitrogen atom to which are attached, form a heterocyclic ring containing 1 or 2 heteroatoms.

Rscmeans C1-6is alkyl, aryl, 5 - or 6-membered heteroaryl ring which is not substituted or substituted C1-6-alkyl, C(O)CH2SO2C1-6-alkyl or (CH2)1-6-aryl.

Rsdmeans C1-6-alkyl.

RS5means RscC(O)NRscRsdCH2SO2RSCCH2NRscRsd, NRscRsdor CH2SO2RSC.

Rs1means hydrogen.

Rs2means CH2Rsewhere Rsemeans unsubstituted aryl or aryl substituted by halogen.

Compounds of the present invention can be obtained by combining the corresponding amines with a suitable substituted alkyl-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (or carbon is mi acids or halides or alkyl-3-hydroxy-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-2-carboxylate (or carboxylic acids or halides), or alkyl-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-2-carboxylate (or carboxylic acids or halides, or alkyl-3-hydroxy-4-oxo-6,7,8,9,10,11-hexahydro-4H-pyrimido[1,2-a]azepin-2-carboxylate (or carboxylic acids or halides), as depicted in figure 1.

Scheme 1

The ways of combination of derivatives of carboxylic acids with amines with the formation of carboxamides well known from the prior art. Suitable methods are described, for example, in Jerry March,Advanced Organic Chemistry, 3rd edition, John Wiley & Sons, 1985, pp. 370-376. Amines of the formula1-2can be obtained using the methods described in Richard Larock,Comprehensive Organic Transformations, VCH Publishers Inc, 1989, pp 385-438 or standard variants of these methods.

Scheme A provides a General synthesis of carboxamidesA-5. Methyl etherA-4may be subjected to interaction with the amine1-2in solvents such as DMF, methanol, ethanol, toluene, NMP, at an appropriate temperature (for example, from 20 to 150° (C)that gives the target compoundA-5. Methyl etherA-4can be synthesized by one of three synthetic methods. According to the first method amidinohydrolaseA-la(sX=H; sY=H) may be subjected to interaction with dimethyl-2-(benzyloxy)-3-oxooctanoate in the presence of a base, which gives an intermediate protects the config methyl ether A-2protection which can be easily removed, resulting methyl esterA-4. According to the second method amidoxyA-lb(sX=OH; sY=H), obtained in three stages from tertbutylbenzene, may be subjected to interaction with DMAD, which gives a cyclic intermediate connectionA-3athat can be subjected to rearrangement by heating in an appropriate solvent (e.g. xylene), which leads to the formation of methyl etherA-5. According to the third method amidoximeA-1c(sX=H; sY=OH) may be subjected to interaction with DMAD in an appropriate solvent (e.g. acetonitrile), which leads to the formation of intermediate compoundsA3-bthat can be subjected to rearrangement in methyl etherA-4by heating in an appropriate solvent (e.g. xylene). All three of the above method can be applied to amidines and amidoxime containing substituents in the ring. Scheme A illustrates an example of 1.

Scheme A

Scheme B provides a method of producing compounds of the present invention containing amino, ether, simple thioester, sulfoxide or sulfonic group at position 9 of the core 3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide. Bromine-derivedB-lwhich may be obtained from the methyl ester A-4using the initial protection of the hydroxy-groupA-4a suitable protecting group (for example, becoming benzoate, or pivalate, or benzyloxy), and subsequent implementation of contact protectedA-4with brainwashin agent (e.g., NBS). Bromine-derivedB-lcan then be processed nucleophilic reagent ("Nu"; for example, an amine, a thiol or alcoholate), which gives, when the selection or no selection, the intermediate methyl esterB-2which is subjected to interaction with a given amine, which leads to the formation of the final productB-3. If the nucleophilic reagent is a thiol or contains oxidizable sulfur, the circuit can be included oxidation step with the purpose of obtaining a sulfoxide or sulfone. If the nucleophilic reagent comprises an ester, the ester can be converted into amide, using standard chemical transformations after synthesisB-3. Scheme B illustrates an example 2.

Scheme B

The scheme represents the total synthesis of derivatives ofC-3orC-4containing aliphatic ring Deputy, such as amide, sulfonamide, sulfonylurea, carbamate or urea. Bromine-derivedB-1can be processed by benzylaminoS-1and then gidrirovanie or directly subjected to vzaimodeistvie Amin C-1athat gives intermediate connectionC-2which then can be processed by Amin1-2with the selection or no selection, and then subjected to reaction in combination with a carboxylic acid or interaction with carbonylchloride (or sulphonylchloride or sulfhemoglobin) or isocyanate, which gives the final productC-3. IfC-3contains RS4=Rs3O(CO)CO,C-3may be further subjected to interaction with the nucleophilic reagent, such as amine, which leads to the formation of the productC-4. The scheme is illustrated by examples 3, 4 and 6. The last two stages can be swapped.

Scheme

1. the combination of RS4-sX,2. stages 3 and 4 can be interchanged,3. PΛ=H or a protective group,4. RS3=N or C1-6-alkyl,or=or,if=if.

Diagram D represents the synthesis of homochiral compoundsC-3,C3a,bandC-4. Perform the substitution of the bromo-derivative ofB-lchiral aminesD-lresulting mixture diastereoisomers, with subsequent or simultaneous removal of the protective group. Conduct restoration alkylation of the amino group at position 9 with aldehydes or ketonesD-2that gives intermediate connectionD-3. A mixture of diastereoisomers can be separated by crystallization Il is chromatography, which leads to individual diastereoisomersD-3a,b. Rs6can be removed by hydrogenation, which gives homochiral intermediate connectionC-2a,b. Subsequent interaction with the amine1-2and the combination with the carboxylic acid or processing carbonylchloride (or sulphonylchloride or sulfhemoglobin) or isocyanate leads to the end of homochiral productC-3a,b. As in the case of racemic compoundsC-3in scheme C, may be held an additional step to obtain homochiral compoundsC-4. Scheme D illustrates examples 5 and 7.

Scheme D

PΛ=H or a protective group

Rs6=chiral alkyl residue (for example, (S)-a-methylbenzyl)

Rsp, Rsq= N or C1-6-alkyl

Rs4=Rs5CO or Rs5SO2or Rs5(Rs6)NSO2or Rs5OCO,Rs3O(CO)CO Rs5(Rs6)NCO

sX=Cl or Br or HE

The following examples serve only to illustrate the invention and its practical implementation. The examples should not be construed as limiting the scope or the invention.

EXAMPLE 1

N-(4-Terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

Stage 1a: TertBUTYLPEROXY(4-cyanomethyl)carbamate (Bergeron,

R. J., McManis, J. S.,Tetrahedron 45 (16), 4939-4944 (1989).

To a solution of tertbutylbenzene in anhydrous dimethylformamide added 5 mol% of sodium iodide and portions of 1.36 EQ. of sodium hydride (60% dispersion in mineral oil). The mixture is stirred at room temperature for 15 min, then add to 1.05 EQ. 4-chlorovaleronitrile. The mixture is heated to 85°C and stirred for 3.5 hours After cooling to room temperature the mixture was quenched with water and extracted with diethyl ether. The combined organic phases are concentrated and washed polysystem aqueous sodium thiosulfate, water and saturated salt solution. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The oily residue is washed with petroleum ether and dried under high vacuum, receiving tertBUTYLPEROXY(4-cyanomethyl)carbamate as a pale yellow oil.

1H-NMR(400 MHz, CDCl3) δ:7.38(m, 5H), 4.84(s, 2H), 3.45(t, J=6.4 Hz, 2H), 2.34(t, J=6.8 Hz, 2H), 1.70(m, 4H), 1.52(s, N). MS m/z: 271(M+H)+.

Stage 2a: l-(Benzyloxy)piperidine-2-imagerecall

TertBUTYLPEROXY-(4-cyanomethyl)carbamate is dissolved in a solution of 4 M HCl in 1,4-dioxane and the mixture is stirred for 18 h at room temperature. The solvent is removed under reduced pressure and the residue treated with ethyl acetate and diethyl ether. The obtained solid substance, propitiation ether, filtered and dried under high vacuum, giving 1-(benzyloxy)piperidine-2-imagerecall in the form of a pale yellow solid.

1H-NMR(400 MHz, DMSO-d6) δ:9.53(s, 1H), 8.97(s, 1H), 7.57-7.41(m, 5H), 5.05(s, 2H), 3.67(t, J=6.0 Hz, 2H), 2.64(t, J=6.4 Hz, 2H), 1.90-1.84(m, 2H), 1.69-1.63(m, 2H).

MS m/z: 205(M+N)+.

Stage 3a: 2-Aminopiperidin-1-ol hydrochloride

A solution of 1-(benzyloxy)piperidine-2-Imin hydrochloride in methanol containing palladium on charcoal (10%, wt./wt.) mix in the environment of hydrogen at atmospheric pressure for 3 hours, the Catalyst was separated by filtration and the solution concentrated to dryness under reduced pressure. The residue is triturated with diethyl ether, filtered and dried under high vacuum, obtaining 2-aminopiperidin-1-ol hydrochloride in the form of a pale yellow solid.

1H-NMR(400 MHz, DMSO-d6) δ:11.76(s, 1H), 8.82(s, 1H), 8.49(s, 1H), 3.63(t, J=6.0 Hz, 2H), 2.63(t, J=6.0 Hz, 2H), 1.87(m, 2H), 1.66(m, 2H).13C-NMR (150 MHz, DMSO-d6) δ:159.06, at 50.92, at 25.76, 22.01, 17.22.

MS m/z: 115(M+H)+.

Stage 4a: Methyl-2-(2-methoxy-2-oxoethyl)-5,6,7,8-tetrahydro-2H-

[1,2,4]oxadiazole[2,3-a]pyridine-2-carboxylate

To a solution of 2-aminopiperidin-1-ol hydrochloride in chloroform add triethylamine. The mixture is stirred for 5 min at room temperature, then cooled to 0°C and added dropwise with stirring, 1.2 EQ. dimethylethylenediamine elata. The cooling bath is removed and the mixture is stirred at room temperature for one hour. The solvent is removed under reduced pressure and the solution is distributed between ethyl acetate and polysystem aqueous ammonium chloride. The aqueous phase is additionally extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered through silica gel. The solvent is removed in vacuum, obtaining methyl-2-(2-methoxy-2-oxoethyl)-5,6,7,8-tetrahydro-2H-[1,2,4]oxadiazole[2,3-a]pyridine-2-carboxylate as a pale yellow oil.

1H-NMR(400 MHz, CDCl3) δ:3.82(s, 3H), 3.70(s, 3H), 3.51(m, 1H), 3.36(m, 1H) 3.31 (d, J=16.6 Hz, 1H), 2.98(d, J=16.6 Hz, 1H), 2.53(m, 2H), 1.94(m, 2H), 1.74(m, 2H).13C-NMR (100 MHz, CDCl3) δ:169.15, 168.88, 164.97, 103.27, 55.71, 52.97, 51.84, 42.26, 26.06, 23.49, 22.83.

MS m/z: 257(M+N)+.

Stage 5a: Methyl-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-

pyrido[1,2-a]pyrimidine-2-carboxylate

A solution of methyl 2-(2-methoxy-2-oxoethyl)-5,6,7,8-tetrahydro-2H-[1,2,4]oxadiazole[2,3-a]pyridine-2-carboxylate in anhydrous o-xylene are placed in a two-neck round bottom flask. Flask provided with a thermometer, and close by the membrane. The mixture is heated to 148-150°C for 5 h Heating bath is removed and the mixture is left to stand at room temperature for 16 hours To a mixture containing the precipitate, add diethyl ether. After 5 min the precipitate was separated by filtration, about what to see diethyl ether and dried in vacuum. The product, methyl-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate, obtained as pale brown solid.

1H-NMR(400 MHz, DMSO-d6) δ:10.03(s, 1H), 3.86(t, J=6.0 Hz, 2H), 3.80 (s, 3H), 2.75(t, J=6.8 Hz, 2H), 1.90-1.70(m, 4H).13C-NMR (150 MHz, DMSO-d6) δ:165.81, 158.65, 148.60, 143.10, 127.07, 51.98, 42.87, 30.32, 20.91, 18.40.

MS m/z: 115(M+H)+.

The following method is an alternative method for the synthesis of methyl-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate.

Stage 1b: Dimethyl-2-(benzyloxy)-3-accountant

A solution of methyl(benzyloxy)acetate (1 EQ.) and dimethyloxalate (1.2 EQ.) in dry THF cooled to -78°C and added dropwise LDA (2M in a mixture of THF-heptane, 1.2 EQ). After stirring for one hour the cooling bath is removed and stirring is continued for another hour. The reaction is quenched at 0°C, pouring into a chilled 1 N. aqueous HCl, and the aqueous phase extracted with EtOAc; the organic layer was washed with saturated salt solution, dried and concentrated, giving the crude product which is used without further purification.

Stage 2b: Methyl-3-(benzyloxy)-4-oxo-6,7,8,9-tetrahydro-4H-

pyrido[1,2-a]pyrimidine-2-carboxylate

Industrial output 2-aminopiperidine (1.5 EQ.) added at room temperature to a solution of oxooctanoate obtained at the stage of lb, (1 EQ.) in MeOH. After the dropwise adding the net DBU (4.5 EQ.) the reaction mixture is stirred for 2 days. Evaporation of solvent gives a residue, which absorb EtOAc and washed with 1 N. hydrochloric acid and saturated salt solution; the organic layer is dried over Na2SO4and the solvent is removed. The crude product is used without further purification.

An analytical sample of this product was then purified flash chromatography (mixture of petroleum ether/EtOAc 1:2-1:5), the following spectroscopic data:

1H-NMR(400 MHz, CDCl3) δ:7.49-7.30(m, 5H), 5.25(s, 2H), 4.00(t, J=6.2 Hz, 2H), 3.86 (s, 3H), 2.94(t, J=6.6 Hz, 2H), 2.01-1.95(m, 2H), 1.92-1.87(m, 2H).13C-NMR (75 MHz, CDCl3) δ:164.1, 159.3, 154.1, 141.1, 140.6, 136.0, 128.1, 127.8, 127.7, 73.8, 52.2, 42.7, 30.9, 21.0, 18.4.

MS m/z: 315(M+H)+.

Stage 3b: Methyl-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-

pyrido[1,2-a]pyrimidine-2-carboxylate

The intermediate methyl-3-(benzyloxy)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate, obtained in stage 2b, dissolved in MeOH and added dropwise at room temperature catalytic 10% Pd/C. the Mixture is stirred in an atmosphere of H2within 3.5 hours Filtration of the catalyst and evaporation of methanol gives a residue, to which is added diethyl ether, filtering leads to the production of methyl-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate as a pale brown solid with spectral characteristics identical to the characteristics of the connection, opican the th stage 5a.

Stage 6: N-(4-Terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-

4H-pyrido[1,2-a]pyrimidine-2-carboxamide

A solution of methyl-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate, obtained in stage 3b or stage 5a and 4-fluoro-benzylamine (2 EQ.) in methanol is stirred and heated to 65°C for 22 hours the Solvent is removed under reduced pressure and specified in the header of the product is obtained preparative RP-HPLC, using water (0.1% of TFA) and acetonitrile (with 0.1% TFA) as eluents (column: C18). Containing product combined fractions lyophilized, getting mentioned in the title compound in the form of friable white material.

1H-NMR(400 MHz, DMSO-d6) δ:12,12(s, 1H), 9.35(m, 1H) of 7.36 (m, 2H), 7.15(m, 2H), 4.44 (m, 2H), 3.84(t, J=6.4 Hz, 2H), 2.80 (t, J=6.8 Hz, 2H), 1.90-1.73(m, 4H).

MS m/z: 318(M+N)+.

EXAMPLE 2

N-(4-Terbisil)-3-hydroxy-9-morpholine-4-yl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide hydrochloride

Stage 1: Methyl 3-(benzoyloxy)-4-oxo-6,7,8,9-tetrahydro-4H-

pyrido[1,2-a]pyrimidine-2-carboxylate

To a solution of methyl-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (obtained according to example 1) in pyridine added benzoic anhydride (1.55 EQ.). The mixture is stirred at room temperature for 16 hours the Solvent is removed under reduced pressure and the residue R is opredelyaut between ethyl acetate and 0.5 M aqueous HCl. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with 0.5 M aqueous HCl, water and saturated salt solution. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness in vacuo. Specified in the title compound is obtained after flash chromatography (eluent is a mixture of petroleum ether/ethyl acetate, 1:2) as unpainted solid.

1H-NMR(400 MHz, DMSO-d6) δ:8.07(m, 2H), 7.78(m, 1H), 7.62(m, 2H), 3.86 (t, J=6.0 Hz, 2H), 3.74 (s, 3H), 2.92 (t, J=6.4 Hz, 2H), 1.93-1.81(m, 4H).

MS m/z: 329(M+N)+.

Stage 2: Methyl 3-(benzoyloxy)-9-bromo-4-oxo-6,7,8,9-

tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate

A mixture of methyl 3-(benzoyloxy)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate, N-bromosuccinimide (1.2 EQ.) and dibenzoylperoxide (70%, 0.13 EQ.) in carbon tetrachloride is stirred while heating to the boiling temperature under reflux for one hour. The mixture is cooled to room temperature, succinimide separated by filtration and the solvent is removed under reduced pressure. Methyl-3-(benzoyloxy)-9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate obtained after flash chromatography (eluent a mixture of petroleum ether/ethyl acetate, 1:1) as pale yellow oil.

1H-NMR(400 MHz, DMSO-d6) δ:8.08(m, 2H), 7.79 (m, 1H), 7.63(m, 2H), 5.58 (m, 1H), 4.24 (m,1H), 3.77 (s, 3H), and 3.72(m, 1H), 2.43-2.35 (m, 1H), 2.30-2.05 (m, 3H).

MS m/z: 409/407(M+N)+.

Stage 3: N-(4-Terbisil)-3-hydroxy-9-morpholine-4-yl-4-oxo-

6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-

carboxamid.

To a solution of methyl 3-(benzoyloxy)-9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate in DMF added morpholine (3 EQ.) and the mixture is stirred at room temperature for 1 h the Solvent is removed under reduced pressure and the residue triturated with diethyl ether. The crude product is dissolved in methanol, add 4-forbindelsen (3 EQ.) and the mixture is stirred for 1.5 h at 65°C. the Solvent is removed under reduced pressure and the product purified preparative RP-HPLC, using water (0.1% of TFA) and acetonitrile (with 0.1% TFA) as eluents (column: C18). Containing product combined fractions lyophilized and re-dissolved in 1 N. HCl. The solvent is removed under reduced pressure and the residue lyophilized of a mixture of water/acetonitrile, getting hydrochloride N-(4-terbisil)-3-hydroxy-9-morpholine-4-yl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide in the form of a slightly pinkish loose material.

1H-NMR(400 MHz, DMSO-d6) δ:12.34(s, 1H), 10.99(s, 1H), 10.47(s, 1H), 7.44 (m, 2H), 7.16(m, 2H), 4.85(m, 1H), 4.60-4.40(m, 3H), 4.10-3.85(m, 4H), 3.60-3.05(m, 5H masked by the signal of water), 2.35-2.15(m, 2H), 2.03-1.80(m, 2H).

MS m/z: 403(M+N)+.

The USE of the 3

(+/-)-9-[[(dimethylamino)sulfonyl](methyl)amino]-N-(4-terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide C-3

Stage 1: Methyl-9-[benzyl(methyl)amino]-3-hydroxy-4-oxo-6,7,8,9

-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate

hydrochloride

To a stirred solution of bromo-derivative, methyl-3-(benzoyloxy)-9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (obtained according to example 2, stage 2), in anhydrous dimethylformamide added N-benzyl-N-methylamine (3 EQ.). The mixture is stirred for 1.5 h at room temperature, then add diethyl ether and 2 M HCl in diethyl ether. The mixture is stirred for 5 min, the resulting precipitate was separated by filtration and washed with diethyl ether. The residue is dissolved in anhydrous methanol and the solution is concentrated to dryness under reduced pressure. Specified in the header of the crude product, obtained as a pale yellow oil containing an excess of N-benzyl-N-methylaminopropane use without additional purification.

MS m/z: 344 (M+H)+.

Stage 2: Methyl-3-hydroxy-9-(methylamino)-4-oxo-6,7,8,9-

tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate

Obtained in stage 1 the solution of crude product in methanol containing palladium on charcoal (10% wt./wt.) mix in the environment of hydrogen at ATM the sphere pressure for 3 hours The catalyst is separated by filtration and the solution concentrated to dryness under reduced pressure. The residue is triturated with diethyl ether, filtered and dried under high vacuum to give crude product as yellow solid, which is used in the next stage without additional purification.

MS m/z: 254 (M+H)+.

Stage 3: N-(4-Terbisil)-3-hydroxy-9-(methylamino)-4-oxo-6,7,

8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

To the solution obtained in stage 2 of the crude product in dry methanol is added an excess of triethylamine. The solvent is removed under reduced pressure and then under high vacuum. The oily residue is dissolved in anhydrous methanol and add 4-forbindelsen (3.1 equiv., theoretical.). The mixture is stirred and heated to 60°C during the night. After cooling to room temperature the solvent is removed under reduced pressure. The residue is triturated with diethyl ether and left under high vacuum for 15 minutes Specified in the header of crude product is obtained as a yellow solid, which contains an excess of 4-forbindelsen (about 3.5 equiv.) and used without further purification.

MS m/z: 347 (M+H)+.

Stage 4: (+/-)-9-[[(dimethylamino)sulfonyl](methyl)amino]-N-

(4-terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-

4H-pyrido[1,2-a]pyrimidine-2-carboxamide

To rest the ru obtained in stage 3 of the crude compound in a mixture of 2:1 tetrahydrofuran (THF) and 2 M aqueous sodium hydroxide added N,N-dimethylsulphamoyl (4.6 EQ.). The mixture is stirred at room temperature for 16 hours the Mixture is concentrated under reduced pressure and the product emit preparative RP-HPLC, using water (0.1% of TFA) and acetonitrile (with 0.1% TFA) as eluents (column: C18). Containing product combined fractions lyophilized, getting mentioned in the title compound in the form of friable, slightly pinkish substance.

1H-NMR(300 MHz, CDCl3) δ:11.95(s, 1H). 9.13(m, 1H), 7.38(m, 2H), 7.04(m, 2H), 4.98 (m, 1H), 4.56(m, 2H), 4.36(m, 1H), 3.62(m, 1H), 2.84(s, 6N), 2.57(s, 3H), 2.38-1.85(m, 4H).13C-NMR (100 MHz, CDCl3) δ:167.53, 162.55, 160.11, 157.74, 145.76, 144.11, 132.70, 128.89, 128.81, 124.82, 114.60, 114.39, 58.06, 42.93, 41.53, 37.00, 29.03, 23.89, 20.09.

MS m/z: 454(M+H)+.

EXAMPLE 4

(+/-)-N1-(2-{[(4-Terbisil)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N1N2N2-trimethylenediamine

Stage 1: (+/-)-N1-(2-{[(4-Terbisil)amino]carbonyl}-3-

hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]

pyrimidine-9-yl)-N1N2N2-trimethylenediamine

To a stirred solution of crude N-(4-terbisil)-3-hydroxy-9-(methylamino)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide (synthesized as described in example 3, stage 3) in dichloromethane add 6 EQ. of triethylamine and 6 EQ. METHYLCHLOROSILANE. The mixture is stirred at room temperature for 2 hours, dissolve the al is removed under reduced pressure and the residue is dissolved in a solution of dimethylamine (2 M in tetrahydrofuran. The mixture was stirred at 57°C during the night. After cooling to room temperature the solvent is removed under reduced pressure and the product emit preparative RP-HPLC, using water (0.1% of TFA) and acetonitrile (with 0.1% TFA) as eluents (column: C18). Containing product combined fractions lyophilized, getting mentioned in the title compound in the form of friable, slightly pinkish substance. According to NMR the product is a mixture of rotamers.

1H-NMR(400 MHz, DMSO-d6) δ:12.05(s, 0,2N), 11.89(s, 0,8H), 9.21(m, 0,8H), 8.74(m, 0,2H), 7.40-7.28(m, 2H), 7.20-7.10(m, 2H), 5.17(m, 0,8H), 4.63-4.35 (m, 2,2H), 4.13-4.00(m, 1H), 3.65-3.53(m, overlap signal of water), 2.95-2.75(m, N), 2.15-1.80(m, 4H).13C-NMR (100 MHz, DMSO-d6) δ:167.87, 167.73, 165.92, 165.46, 164.51, 164.30, 162.42, 160.01, 157.50, 157.41, 146.27, 146.18, 145.76, 145.49, 134.44, 129.43, 129.35, 129.08, 129.00, 125.17, 125.05, 115.07, 114.85, 57.47, 53.60, at 43.14, 41.37, 36.49, 35.95, 32.92, 32.64, 32.36, 28.19, at 23.88, 22.12, 19.67, 19.35.

MS m/z: 115(M+H)+.

EXAMPLE 5

(+)-N1-(2-{[(4-Terbisil)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N1N2N2-trimethylenediamine

Stage 1: (+)3-Hydroxy-2-(methoxycarbonyl)-N-methyl-4-oxo-N-

[(1S)-1-phenylethyl]-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-ammonium triptorelin

To a mixture of 7:3 (V/V) of methanol and water at -30°C containing (1S)-1-phenylethylamine (4.5 equiv.) add the bromo-derivative, methyl-3-(benzoyloxy)-9-bromo-4-ox is -6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (synthesized, as indicated in example 2, step 2) (1.0 EQ.). The mixture is vigorously stirred for 1.5 h at -30°C. the Cooling bath is removed and stirring is continued for 1 h at room temperature. The PH was adjusted to approximately 5 with acetic acid, then add 37% aqueous formaldehyde (11.5 EQ.) and cyanoborohydride sodium (3.25 equiv.). After stirring at room temperature for 20 min, the volume reduced to approximately 1/4 under reduced pressure. The formed white precipitate was separated by filtration and the filtrate podkalyvayut to pH 2-3 using triperoxonane acid. The solution is applied on the cartridges with a cation exchange resin (Varian MEGA BOND ELUTE SCX), cartrigde washed with methanol and the crude product washed with 2 M ammonia in methanol. United eluent concentrated to dryness under reduced pressure, the oily residue is dissolved in methanol and neutralized triperoxonane acid. After removal of the solvent to obtain an oily residue. Obtained in a ratio of 1:3 diastereoisomer share by purification preparative RP-HPLC (column: C18), eluent: water (with 0.1% TFA), acetonitrile (with 0.1% TFA). The main diastereoisomer out the second peak, and after lyophilization specified in the title compound obtained as a slightly pink solid.

1H-NMR(500 MHz, pyridine-d5) δ:7.53(m, 2H), 7.39(m, 2 is), 7.29(m, 1H), 4.45(m, 1H), 4.38(m, 1H), 4.14(m, 1H), 3.91(s, 3H), 3.80(m, 1H), 2.13(s, 3H), 1.95-1.82(m, 3H), 1.70-1.60(m, 1H), 1.49(d, J=6.4 Hz, 3H).

MS m/z: 358(M+N)+.

Stage 2: (-)3-Hydroxy-2-(methoxycarbonyl)-N-methyl-4-oxo-

6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-

ammonium triptorelin

A solution of (+)-3-hydroxy-2-(methoxycarbonyl)-N-methyl-4-oxo-N-[(1S)-1-phenylethyl]-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-ammonium trifenatate in methanol containing palladium on charcoal (10%, wt./wt.) mix in the environment of hydrogen at atmospheric pressure for 1.5 hours, the Catalyst was separated by filtration and the solution concentrated to dryness under reduced pressure, obtaining mentioned in the title compound as a slightly pink oil.

1H-NMR(400 MHz, CD3OD) δ:to 4.41(m, 1H), 4,14(m, 1H), 3,99(s, 3H), 3,91(m, 1H), 2,86(s, 3H), of 2.50(m, 1H), and 2.26(m, 1H), 2,08(m, 1H), to 1.86(m, 1H). MS m/z: 254(M+N)+.

Stage 3: (+)-N1-(2-{[(4-Terbisil)amino]carbonyl}-3-

hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]

pyrimidine-9-yl)-N1N2N2-trimethylenediamine

A solution of (-)-3-hydroxy-2-(methoxycarbonyl)-N-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-ammonium triptoreline, p-forbindelsen (2.2 EQ.) and triethylamine (1.3 EQ.) in methanol is stirred and heated to 65°C for 3 hours the Solvent is removed in vacuum and the residue is dissolved in anhydrous dichloromethane Add methylchlorosilanes (5 EQ.) and triethylamine (5 EQ.) and the mixture is stirred at room temperature for 50 minutes The solvent is removed under reduced pressure and the residue is dissolved in 2 M solution of dimethylamine in tetrahydrofuran. The mixture was stirred at 57°C during the night. After cooling to room temperature the solvent is removed under reduced pressure, and the product emit preparative RP-HPLC, using water (0.1% of TFA) and acetonitrile (with 0.1% TFA) as eluents (column: C18). Containing product combined fractions lyophilized, getting listed in title product in the form of loose white material (enantiomeric excess ee 94,4%).

The compound is dissolved in a mixture of ethyl acetate/heptane (mixture 3:2,5 (about./about.)) and leave to stand at room temperature for four days. Remove the supernatant from the resulting precipitate, concentrated under reduced pressure and the residue lyophilized of a mixture of water/acetonitrile, receiving specified in the header of the enantiomerically pure product e.e. 100% (e.e. determined by Chiral HPLC Chiralpak AS the mobile phase a mixture of 0.2% TFA-n-Gex./IPA), spectroscopic characteristics of which are identical to the corresponding characteristics of the compound described in example 4, stage 1.

[a]20D=+36,5+2,5° (C=0.63 in ethanol).

EXAMPLE 6

(+/-)-N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene

Specified in the header of the connection of the floor is up according to the synthetic sequence, shown in EXAMPLE 4, with the following changes:

Stage 1: l-(Benzyloxy)azepin-2-Imin

Tertbutyl(benzyloxy)-(5-cyanophenyl)carbamate (synthesized according to the method described in EXAMPLE 1 -stage 1aon the basis of 6-bromoxynil) is dissolved in a saturated solution of HCl in EtOH and the mixture is stirred for 45 minutes. Through the solution bubbled nitrogen to remove excess HCl. The solvent is removed under reduced pressure and the residue dissolved in 1,4-dioxane, treated with triethylamine, bringing the pH to 10. The ethanol is removed and listed in the title compound containing an excess of triethylammonium and ethyl-6-[(benzyloxy)amino]hexanoate use without additional purification. An analytical sample purified preparative RP-HPLC, using water (0.1% of TFA) and acetonitrile (with 0.1% TFA) as eluents (column:18). Containing product combined fractions lyophilized.

1H-NMR(400 MHz, DMSO-d6, 300K) δ:9.39(s, 1H), 8.81(s, 1H), 7.61-7.52(m, 2H), 7.48-7.38(m, 3H), 5.03 (s, 2H), 4.02-3.93(m, 2H), 2.70-2.59(m, 2H), 1.69-1.54(m, 6N).

MS m/z: 219(M+N)+.

Stage 2: (+/-)-N-(2-{[(4-Terbisil)amino]carbonyl}-3-hydroxy-

4-oxo-4-6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene

To a stirred solution of crude N-(4-terbisil)-3-hydroxy-10-(methylamino)-4-oxo-4,6,7,8,9,10-hexahydropyrazino[l,2-]azepin-2-carboxamide (synthesized, and the walking of 1-(benzyloxy)azepin-2-imine according to the method used in a similar 6-membered series (EXAMPLE 3 - stage 3)) in dichloromethane, add 3 EQ. of triethylamine, 2 EQ. potassium(dimethylamino)(oxo)acetate, 2.2 EQ. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 2.2 EQ. 1-hydroxybenzotriazole. The mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the residue distributed between ethyl acetate and 1 M aqueous HCl. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness in vacuo. Specified in the header of the product emit preparative RP-HPLC, using water (0.1% of TFA) and acetonitrile (with 0.1% TFA) as eluents (column: C18). Containing product combined fractions lyophilized, getting mentioned in the title compound in the form of loose, white material. According to1H-NMR of the product is a mixture of rotamers.

1H-NMR(400 MHz, DMSO-d6, 300K) δ:12.29(USS, N), 11.95(USS, N), of 9.30(USS, 0,N), 8.45(Ust, N), 7.38(DD, J=8.33, 5.5 Hz, D), 7.33(DD, J=8.33, 5.5 Hz, D), 7.15(t, J=9.0 Hz, 2H), 5.45-5.25(m, N), 4.94(DD, J=14, 5.7 Hz, N), 4.84-4.79(m, N), 4.57-4.43(m, 2H), 3.54(DD, J=14,11 Hz, M), 3.28-3.18(m, N), 3.05(s, N), 2.92(s, N), 2.90(s, N), 2.81(s, N), 2.76(s, N), 2.19-1.78(m, 5H), 1.41-1.27(m, 1H).

MS m/z: 460(M+N)+.

EXAMPLE 7

(-)-N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydrofuro the IDO[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene

Stage 1: Dimethyl-(2E)-2-[(azepin-2-ylideneamino)oxy]but-2-

entiat and dimethyl-(2Z)-2-[(azepin-2-ylideneamino)oxy]

but-2-entiat

To a suspension azepin-2-noxema in acetonitrile is added dropwise with stirring, 1.1 EQ. diethylazodicarboxylate. The mixture is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure, obtaining a mixture 8/1 dimethyl-(2E)-2-[(azepin-2-ylideneamino)oxy]but-2-indioate and dimethyl-(2Z)-2-[(azepin-2-ylideneamino)oxy]but-2-indioate in the form of a yellow oil. For better identification specified in the title compounds, a small amount of crude product was then purified preparative RP-HPLC, using water (0.1% of TFA) and acetonitrile (with 0.1% TFA) as eluents (column:18). Containing product combined fractions lyophilized. Isomer E:

1H-NMR(400 MHz, DMSO-d6, 300K) δ:7.08(USS, 1H), 5,63(s, 1H), 3.77(s, 3H), 3.59(s, 3H), 3.19-3.11(m, 2H), 2.29-2.21(m, 2H), 1.66-1.42(m, 6N).

13C-NMR (125 SMC, DMSO-d6, 300K) δ:166.20, 162.81, 161.90, 161.61, 92.38, 52.42, at 50.92, 42.28, 29.84, 29.32, 28.81, 25.40.

MS m/z: 271(M+N)+.

The Z isomer:1H-NMR(400 MHz, DMSO-d6, 300K) δ:6.66(USS, 1H), 5,63(s, 1H), 3.74(s, 3H), 3.61(s, 3H), 3.24-3.16(m, 2H), 2.20-2.12(m, 2H), 1.65-1.44(m, 6N).

13C-NMR (125 MHz, DMSO-d6, 300K) δ:165.01, 163.01, 161.45, 154.11, 101.09, 52.32, 51,05, 42.24, 29.93, 29.31, 28.45, 25.14.

MS m/z: 271(M+N)+.

Stage 2: Methyl-3-hydroxy-4-oxo-4,6,7,8,9,10-

GE is shitzopherenia[1,2-a]azepin-2-carboxylate

A mixture of dimethyl-(2E)-2-[(azepin-2-ylideneamino)oxy]but-2-indioate and dimethyl-(2Z)-2-[(azepin-2-ylideneamino)oxy]but-2-indioate in the ratio of 8/1 dissolved in o-xylene and heated to the boiling temperature under reflux. After 16 h the solvent is removed under reduced pressure and the residue dissolved in ethyl acetate, extracted with saturated solution of NaHCO3in the water. The PH of the aqueous phase was adjusted to approximately 3 by addition of 6 M aqueous HCl and the solution extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrate.

1H-NMR(400 MHz, DMSO-d6, 300K) δ:10.12(s, 1H), 4.29-4.16(m, 2H), 3.80(s, 3H), 2.95-2.78(m, 2H), 1.79-1.41(m, 6N).

13C-NMR (100 MHz, DMSO-d6, 300K) δ:165.79, 158.54, 153.41, 143.55, 126.61, at 52.04, 43.02, 35.75, 28.76, 26.94, 24.58.

MS m/z: 239(M+N)+.

Stage 3: Methyl 3-(benzoyloxy)-4-oxo-4,6,7,8,9,10-

hexahydropyrazino[1,2-a]azepin-2-carboxylate

To a solution of methyl-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-2-carboxylate in pyridine added benzoic anhydride (1.1 EQ.) and a catalytic amount of dimethylaminopyridine. The mixture is stirred at room temperature for 3 hours the Solvent is removed under reduced pressure and the residue partitioned between dichloromethane and 1 M aq. HC1. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 1 M aqueous HCl and saturated the salt solution. The organic phase is dried over sodium sulfate, filtered and concentrated to dryness in vacuo. Specified in the title compound is obtained after flash chromatography (eluent petroleum ether/ethyl acetate mixture 6:4) as a brown solid.

1H-NMR(400 MHz, DMSO-d6, 300K) δ:8.07(DD, J=8.6, 1.3 Hz, 2H), 7.78(t, J=7.5 Hz, 1H), 7.62(t, J=7.9 Hz, 2H), 4.31-4.29(m, 2H), 3.74(s, 3H), 3.06-3.04(m, 2H), 1.82-1.65(m, 6N).

13C-NMR (75 MHz, DMSO-d6, 300K) δ:162.78, 162.65, 162.43, 157.01, 140.29, 135.23, 134.18, 129.63, 128.86, 127.59, 52.46, 43.13, 36.07, 28.47, 26.12, 23.68.

MS m/z: 343(M+N)+.

Stage 4: Methyl 3-(benzoyloxy)-10-bromo-4-oxo-4,6,7,8,9,10-

hexahydropyrazino[1,2-a]azepin-2-carboxylate

A mixture of methyl 3-(benzoyloxy)-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-2-carboxylate, N-bromosuccinimide (2 EQ.) and a,a'-azoisobutyronitrile (of 0.45 EQ.) in carbon tetrachloride is stirred while heating to the boiling temperature under reflux for 14 hours the Mixture is cooled to room temperature, succinimide separated by filtration and the solvent is removed under reduced pressure. Methyl-3-(benzoyloxy)-10-bromo-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-2-carboxylate obtained after flash chromatography (eluent petroleum ether/ethyl acetate mixture 8:2) as a pale yellow solid.

1H-NMR(400 MHz, DMSO-d6, 300K) δ:8.07,(DD, J=8.3, 0.9 Hz, 2H), 7.79(t, J=7.5 Hz, 1 is), 7.63(t, J=7.9 Hz, 2H),5.63(DD,J=5.9,2.2 Hz, 1H),4.98(DD,J=14.3), 6.1 Hz, 1H), 3.97(DD, J=14.3, 11.0 Hz, 1H), 3.76(s, 3H), 2.31-2.13(m, 2H), 2.10-1.79(m, 3H), 1.-1.61-1.48(m, 1H).

13C-NMR (75 MHz, DMSO-d6, 300K) δ:162.65, 162.14, 157.22, 157.10, 139.45, 136.59, 134.37, 129.72, 128.94, 127.36, 53.56, 52.67, 42.37, 31.52, 25.78, 24.40.

MS m/z: 423/421(M+N)+.

Stage 5: Methyl-3-hydroxy-4-oxo-10-{[(1R)-1-phenylethyl]amino}

-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-2-

carboxylate

Methyl-3-(benzoyloxy)-10-bromo-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-2-carboxylate (1.0 equiv.) added to a solution of (1R)-1-phenethylamine (2.2 EQ.) triethylamine (1 EQ)dissolved in N,N-dimethylformamide. The mixture is vigorously stirred for 2 hours at room temperature and then at 50°C for 30 minutes. The solvent is removed under reduced pressure, and specified in the header of the crude product (a mixture of diastereoisomers 1:1) suitable for use without additional purification. According to an alternative method (stage 5A) solid methyl-3-(benzoyloxy)-10-bromo-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-2-carboxylate (1.0 equiv.) added to a solution of (1R)-1-phenethylamine (4.5 equiv.) dissolved in a mixture of 7:3 methanol/water at -30°C. the Interaction is carried out for the night, the temperature was then raised to room temperature and the solvent concentrated, getting a white solid, which was separated by filtration and discarded. is shown in the header of the connection (in the form of a mixture of diastereoisomers 7:3) and extracted with dichloromethane from the mother liquor for use in the next stage without additional purification.

MS m/z: 358 (M+H)+.

Stage 6: N-(4-terbisil)-3-hydroxy-4-oxo-10-{[(1R)-1-

phenylethyl]amino}-4,6,7,8,9,10-hexahydropyridine

[1,2-a]azepin-2-carboxamide

p-Forbindelsen (3 EQ.) add to methyl-3-hydroxy-4-oxo-10-{[(1R)-1-phenylethyl]amino}-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-2-carboxylate (obtained as described in stage 5 or stage 5A), dissolved in methanol. The mixture was stirred at 70°C overnight, then cooled to room temperature for immediate use on stage 7. According to an alternative method (stage 6A) the solvent is removed and the crude product is crystallized several times from acetonitrile, resulting in an individual diastereoisomer specified in the connection header in 4-farbensymposium salt d.e.>95%.

Stage 7: (+)N-(4-terbisil)-3-hydroxy-10-{methyl-[(1R)-1-

phenylethyl]amino}-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-2-carboxamide

N-(4-terbisil)-3-hydroxy-4-oxo-10-{[(1R)-1-phenylethyl]amino}-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-2-carboxamide obtained at stage 6, is dissolved in methanol and the pH adjusted to approximately 5 with acetic acid, then add 37% aqueous formaldehyde (6 EQ.) and cyanoborohydride sodium (6.25 equiv.). The mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure ostatok, dissolved in minimum quantity of methanol, podkalyvayut to pH 2-3 using triperoxonane acid. The solution is applied on the cartridges with a cation exchange resin (Varian MEGA BOND ELUTE SCX), the cartridge was washed with methanol and the crude product washed with 2 M ammonia in methanol. United eluent concentrated to dryness under reduced pressure, obtaining an oily residue. The product, a mixture of diastereoisomers, divided by purification preparative RP-HPLC (column: C18), eluent: water (with 0.1% TFA), acetonitrile (with 0.1% TFA). Specified in the header diastereoisomer comes the first peak, and after lyophilization specified in the title compound obtained as a white solid (TFA salt).

According to an alternative method (stage 7A) product stage 6A is subjected to interaction in the same way as the product from step 6 when receiving a single diastereoisomer without purification by HPLC method.

1H-NMR(300 MHz, DMSO-d6-TFA, 300K) δ:9.42(t, J=6.2 Hz, 1H), 9.20(USS, 1H), 7.60(USD, J=7.3 Hz, 2H), 7.51-7.29(m, 5H), 7.21(t, J=8.9 Hz, 2H), 4.98-4.75(m, 3H), 4.69(DD, J=15.5, 6.9 Hz, 1H), 4.47(DD, J=15.5, 5.5 Hz, 1H), 3.66(t, J=12.8 Hz, 1H), 2.94-2.81(m, 3H), 1.97-1.81(USM, 2H), 1.79-1.33(m, 7H).

MS m/z: 465(M+N)+.

[a]20D=+62±2(C=0.1 in chloroform).

Stage 8: (-)2-{[(4-Terbisil)amino]carbonyl}-3-hydroxy-N-

methyl-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]

azepin-10-ammoniumnitrate

RA is creative TFA-salt of the product from step 7 (or 7A) in methanol, containing palladium on charcoal (10%, wt./wt.) mix in the environment of hydrogen at atmospheric pressure for 4 hours, the Catalyst was separated by filtration and the solution concentrated to dryness under reduced pressure, obtaining specified in the header of the connection.

1H-NMR(300 MHz, DMSO-d6-TFA, 300K) δ:9.88(USS, 1H), 9.56(USS, 1H), 9.14(USS, 1H), 7.41(DD, J=8.6, 5.7 Hz, 2H), 7.17(t, J=8.8 Hz, 2H), 4.92(DD, J=14.6, 4.6 Hz, 1H), 4.72(USM, 1H), 4.58-4.44(m, 2H), 3.51(DD, J=13.9, 11.7 Hz, 1H), 2.66(t, J=4.9 Hz, 3H), 2.29(d, J=13.3 Hz, 1H), 2.02-1.57(m, 4H), 1.45-1.27(m, 1H).

MS m/z: 361(M+N)+.

[a]20D=-4±2(C=0.4 in methanol).

Stage 9: (-)-N-(2-{[(4-Terbisil)amino]carbonyl}-3-hydroxy-

4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]

azepin-10-yl)-N,N',N'-trimethylethylene

Methylchlorosilanes (2-6 EQ.) and N-ethyldiethanolamine (4 equiv.) add to the solution ammoniumnitrate connection with the stage 8 in chloroform. The mixture is stirred at room temperature for 1 h the Solvent is removed under reduced pressure and the residue dissolved in a 2 M solution of dimethylamine in methanol, stirred at room temperature for 6 hours the Solvent is removed under reduced pressure and the residue dissolved in dichloromethane, washed with 1 M HCl in water. The organic phase is dried over anhydrous Na2SO4and the solvent is removed under reduced pressure. Specified in the title is information the product emit preparative RP-HPLC, using water with 0.1% TFA) and acetonitrile (with 0.1% TFA) as eluents (column: C18). Containing product combined fractions lyophilized, receiving specified in the header of the product enantiomeric excess of 99.5% (e.e. determined by Chiral HPLC Chiralpak AD, mobile phase a mixture of 0.2% TFA - n-Gex./of 0.2% TFA - ethanol with 3% methanol). Amorphous potassium salt specified in the title compound is obtained by treating compound, dissolved in acetonitrile, aqueous KOH and subsequent freeze drying.

Range1H-NMR identical to the corresponding spectrum of the compound described in example 6.

13C-NMR(100 MHz, DMSO-d6, 300K) δ:168.01, 165.80, 165.03, 161.30(l, JC-F=243 Hz), 157.68, 149.67, 145.94, 134.59, 129.56(l, JC-F=8.5 Hz), 124.72, 115.10(l, JC-F=21 Hz), 55.88, at 42.42, at 41.56, 36.24, 32.79, 32.34, 28.83, 27.10, 26.15.

MS m/z: 460(M+N)+.

[a]20D=-72±2(C=0.1 in chloroform).

EXAMPLE 8

Racemic N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene

Stage 1: Getting ω-hydroxy-N-methylaminomethyl 3

MaterialsMmassEquiv.MolWt.(g)About.(ml)Density
DHP84,12 10,250021,1022,930,92
5% H2SO498,080,1220,030560 ml
40% MeNH231,060,2440,06104,745,30,902
MeNH2.HCl67,5151,25084,4
NaCN49,0110,250012,25
IPAc900

To 5% aqueous solution of H2SO4add 3,4-dihydro-2H-Piran (DHP; 21.1 g) at 20-35°C. the resulting solution was maintained at 20-35°C for 1 h, the Reaction mixture is cooled to 0-5°C and neutralized to pH 6-7 by means of 40% aqueous methylamine. To the reaction mixture, in that order, methylaminopropane and sodium cyanide. The resulting solution incubated at room temperature for 36 h, the Reaction mixture was extracted with IPAc (6x150 ml). The combined organic layers are concentrated to a total volume of about 150 ml (yield in the experiment is of the order of 91%) ispolzuut at the next stage.

1H-NMR(CDCl3, 400 MHz) δ:3.81(m, 1H), 3.45(m, 2H), 2.47(s, 3H), 1.90-1.40(m, 6N).

Stage 2: Getting ω-hydroxy-N-methyl-N-Boc-aminonitriles 4

MaterialsMmassEquiv.MolWt.(g)About.(ml)
Aminonitriles3142,2010,210629,95
(Boc)2°218,251,050,221148,3
5% NH2OH/35
10% NH4Cl
IPAc80

To a solution ω-hydroxy-N-methylaminomethyl3(0,2106 mol) in IPAc (stage 1) is added (Boc)2O (48,3 g) at room temperature. The resulting solution was incubated at 30-35°C for 2 h (100% conversion by1H-NMR). The reaction mixture is cooled to 0-5°C and add a mixture of 5% NH2OH/10% NH4Cl (35 ml). The resulting mixture vyderjivaut 10-20° C for 3 hours After separation of the phases the aqueous layer was extracted with IPAc (80 ml), the combined organic layers washed with saturated salt solution (50 ml) and then concentrated and the solvent replaced with IPA (total volume of 230 ml), which is used in the next stage.

1H-NMR(CDCl3, 400 MHz) δ:5.18(m, 1H), 3.64(q, J=5.7 Hz, 2H), 2.88(s, 3H), 1.88-1.75(m, 3H), 1.65-1.61(m, 2H), 1.49-1.46(m, 1H), 1.18(s, N).

Stage 3: Getting hydroxyamide 5

MaterialsMmassEquiv.MolWt.(g)About.(ml)Density
N-Boc-amino

nitrile4
242,3110,210651,03
50% of NH2OH33,031,250,263317,4016,201,078
IPA180
MeOH600

To a solution of N-Boc-aminonitriles4(0,2106 mol) in IPA (total volume of 230 ml) is added 50% hydroxylamine (16.2 ml) is ri ambient temperature. The resulting solution was incubated at 60°C for 3 hours the Reaction mixture was then concentrated and the solvent substitute, receiving a methanol solution (total volume of 230 ml), which is used in the next stage.

1H-NMR(CDCl3, 400 MHz) δ:7.53(USS, 1H), 4.84(USS, 2H), 4.84(t, J=7.1 Hz, 1H), 3.71-3.62(m, 2H), 2.72(s, 3H), 2.00(USS, 1H), 1.92-1.82(m, 1H), 1.76(1.55(m, 3H), 1.49(s, N), 1.42-1.23(m, 2H).

The HPLC conditions: column: Bond, Rx C8 250x4,6 mm; temperature: 30°C; detection at 210 nm; mobile phase: a mixture of 0.1% aq. H3PO4(A)/MeCN (B); gradient: 90:10 mixture of (A)/(B) to 10:90 within 15 min, 10:90 maintained for 5 min, 10:90 to 90:10 mixture of (A)/(B) for 10 seconds; flow rate: 1 ml/min retention Time: amidoxime - 6,152 minutes and 6,256 minutes (two isomers).

Stage 4: Getting O-alkeneamine 6

MaterialsMmassEquiv.MolWt.(g)About.(ml)Density
Hydroxyamide5275,3510,210657,93
DMAD142,111,050,221131,4227,101,16
MeOH
The cumene500

To a solution of hydroxyamide5(about 0,2106 mol) in methanol (total volume of 230 ml) add diethylazodicarboxylate (27,10 ml) at room temperature. The resulting solution was incubated at room temperature for 16 hours, the Reaction mixture was concentrated and the solvent replaced with cumene at 40-60°C (total volume of 430 ml). The solution is used in the next stage.

1H-NMR(CDCl3, 400 MHz) δ:5.82(s, N), 5.73(s, N), 5.44(USS, N), 5.25(USS, N), 4.61(m, 1H), 3.89(s, N), 3.84(s, N), 3.72(s, N), 3.68(s, N), 3.65-3.58(m, 2H), 2.73(s, N), 2.71(s, N), 1.90-1.52(m, 4H), 1.47(s, N), 1.43-1.30(m, 2H).

The HPLC conditions: column: Bond, Rx C8 250x4,6 mm; temperature: 30°C; detection at 210 nm; mobile phase: a mixture of 0.1% aq. H3PO4(A)/MeCN (B); gradient: 90:10 mixture of (A)/(B) to 10:90 within 15 min, 10:90 maintained for 5 min, 10:90 to 90:10 mixture of (A)/(B) for 10 seconds; flow rate: 1 ml/min retention Time: amidoxime6-12,051, 12,315 minutes, a ratio of about 3.6:1.

Stage 5: Getting pyrimidine 7

MaterialsMmassEquiv. MolWt.(g)About.(ml)Tight.
O-Altenmedingen6417,4510,210687,91
The cumene430(sum.)
5% NaHCO384,1the 1.440,3032510
EtOAc750
Us. aq salt150
THF

A solution of O-alkeneamine6(about 0,2106 mol) in cumene (total volume of 430 ml) is heated to 120°C (internal temperature) for 12 h, the Reaction mixture is then cooled to about 60°C, concentrated to a total volume of 250 ml, then diluted with EtOAc (250 ml) and cooled to 25-35°C. Then slowly add 5% sodium bicarbonate (330 ml, about 1 equiv.) and the resulting solution was maintained at 25-35°C for 0.5 is. After phase separation the organic layer is again extracted with 5% sodium bicarbonate (180 ml). The combined aqueous extracts podkalyvayut using 5 N. HCl to pH 2-3 and extracted by EtOAc (3x250 ml). The combined organic layers washed with saturated salt solution (150 ml). The organic solution is concentrated and the solvent replaced with THF (about 30-40% of the total output, KF is of the order of 100-150 ppm).

1H-NMR(CDCl3, 400 MHz) δ:10.66(USS, 2H), 4.77(m, 1H), 4.01(s, 3H), 3.72-3.67(m, 2H), 2.77(s, 3H), 2.20-1.55(m, 5H), 1.48(s, N), 1.43-1.35(m, 1H).

The HPLC conditions: column: Bond, Rx C8 250x4,6 mm; temperature: 30°C; detection at 210 nm; mobile phase: a mixture of 0.1% aq. H3PO4(A)/MeCN (B); gradient: 90:10 mixture of (A)/(B) to 10:90 within 15 min, 10:90 maintained for 5 min, 10:90 to 90:10 mixture of (A)/(B) for 10 seconds; flow rate: 1 ml/min retention Time: pyrimidine7- 9,905 minutes.

Stage 6: Getting bisneseliitin 8

MaterialsMmassEQ.MolWt.(g)About.(ml)Tight.
The pyrimidine7385,4110,0902943,5(80%)
TEA101,193 0,270927,4of 37.80,726
MsCl114,5530,270931,021,01,480
THF575
K2CO3138,2110,0902912,5
MeOH200
EtOAc400

To a solution of pyrimidine7(43,5 g, 80% purity, 0,09029 mol) in THF (275 ml) is slowly added TEA (37,8 ml) and MsCl (21,0 ml), at 0-5°C for 1 h the resulting solution was incubated at the same temperature for 4 hours, the Solid is separated by filtration, washed with THF (3x100 ml). The combined filtrates are concentrated and the solvent replaced with methanol (total volume 200 ml). To a solution of trimethylpyridine in methanol added potassium carbonate (12.5 g, 0,09029 mol) at 10-20°C. the resulting solution was incubated at the same temperature for 6-10 h (monitored by HPLC). The reaction mixture was neutraliz the Ute to pH 6-7 with 5 N. HCl and concentrated to a total volume of about 100 ml. Add 16% salt solution (100 ml) and the resulting solution extracted with EtOAc (3x100 ml). The combined organic layers washed with saturated salt solution (50 ml), concentrated and the solvent replaced with DMF. By-product (MeSO3Me), resulting in a quantity of 1 equiv. when the selective hydrolysis of trimethylpyridine, is removed by azeotropic distillation with DMF at 60-65°C (monitoring method1H-NMR to <10 mol%). The concentration of bisneseliitin8in DMF 0.3 M (total volume 300 ml).

1H-NMR(CDCl3, 400 MHz) δ:11.00(USS, 1H), 4.78(d, J=7.8 Hz, 1H), 4.24-4.15(m, 2H), 3.95(s, 3H), 3.50(s, 3H), 2.99(s, 3H), 2.81(s, 3H), 2.12-2.11(m, 1H), 1.90-1.76(m, 2H), 1.46(s, N), 1.43-1.35(m, 2H).

The HPLC conditions: column: Bond, Rx C8 250x4,6 mm; temperature: 30°C; detection at 210 nm; mobile phase: a mixture of 0.1% aq. H3PO4(A)/MeCN (B); gradient: 90:10 mixture of (A)/(B) to 10:90 within 15 min, 10:90 maintained for 5 min, 10:90 to 90:10 mixture of (A)/(B) for 10 seconds; flow rate: 1 ml/min retention Time: trimethylpyridine 14,140 minutes; bismesylate 12,760 minutes.

Stage 7: Getting pyrimidinedione with semiclean cycle 9

MaterialsMmassEquiv.MolWt.(g) About.(ml)
Bismesylate8541,5910,0902948,90
Cs2CO3325,821,20,108335,30
DMF

To a solution of bisneseliitin8(0,09029 mol) in DMF (total volume 300 ml) is added cesium carbonate (35,30 g) at room temperature. The obtained suspension is incubated at 55°C for 2-3 h (76% conversion by HPLC). After neutralization to pH 7, the mixture is diluted with 250 ml of water, extracted with IPAc (2x250 ml). The combined organic layers washed with saturated salt solution (2x200 ml). The organic layer is concentrated, give crude product. Half of the crude product is purified by passing through a short column (silica gel, hexane:EtOAc 2:1), resulting in the desired product9(6,00 g, 98A% purity) and9a(2.3 g, 40% purity). The overall yield of the cyclic product per DHP is, with amendments, of about 13%.

1H-NMR(CDCl3, 400 MHz) For compounds9: δ:5.34(m, 1H), 5.22(m, 1H), 3.93(s, 3H), 3.51(s, 3H), 2.97(s, 3H), 2.20-2.05(m, 3H), 1.90-1.65(m, 2H), 1.44(s, N), 1.24(m, 1H). To connect9a: 11.86(USS, 1H), 7.907.55(USS, 1H), 7.31(DD, J=8.5, 5.4 Hz, 2H), 7.06(t, J=8.5 Hz, 2H), 5.40-4.90(m, 2H), 4.53-4.40(m, 2H), 3.45-3.23(m, 1H), 2.23-2.05(m, 3H), 1.86-1.76(m, 1H); 1.74-1.64(m, 1H), 1.47-1.37(m, 1H), 1.30(s, N). The HPLC conditions: column: Bond, Rx C8 250x4,6 mm; temperature: 30°C; detection at 210 nm; mobile phase: a mixture of 0.1% aq. H3PO4(A)/MeCN (B); gradient: 90:10 mixture of (A)/(B) to 10:90 within 15 min, 10:90 maintained for 5 min, 10:90 to 90:10 mixture of (A)/(B) for 10 seconds; flow rate: 1 ml/min retention Time: pyrimidinemethanol with semiclean cycle913,969 minutes; the pyrimidine with semiclean cycle9a13,141 minutes.

Also used an alternative method using LiH: to a solution of bisneseliitin8(65 mg) in dioxane (1 ml) is added LiH powder at room temperature. The mixture was incubated at 65°C for 4 h Then the reaction mixture is cooled to room temperature and add 1 N. HCl to repay the excess LiH. The solution is extracted with EtOAc (2x5 ml). The combined organic layer was washed with saturated salt solution and then concentrated. The residue is purified flash chromatography (silica gel, hexane: EtOAc=2:1), getting pyrimidinemethanol with semiclean cycle9(of 45.6 mg, 85%).

1H-NMR(CDCl3, 400 MHz) δ:5.34(m, 1H), 5.22(m, 1H), 3.93(s, 3H), 3.51(s, 3H), 3.47(m, 1H), 2.97(s, 3H), 2.20-2.05(m, 3H), 1.90-1.65(m, 2H), 1.44(s, N), 1.24(m, 1H).

Stage 8: Getting pyrimidinamine with semiclean the m cycle 10

MaterialsMmassEQ.MolWt.(g)About.(ml)Tight.
The pyrimidine with semicell.9445,4910,013476,000
4-forbindelsen125,1530,040415,0605,221,09
EtOH80

To a solution of pyrimidinethione with semiclean cycle9(6 g) in EtOH (80 ml) is added 4-forbindelsen (5,060 g). The resulting solution was refluxed for 8 h (100% conversion by HPLC). The reaction mixture was concentrated to a total volume of approximately 20 ml and add 80 ml of EtOAc. To the resulting solution was added a 20% salt solution (15 ml), 4 N. HCl (15 ml) and water (10 ml). After phase separation the aqueous layer was again extracted with EtOAc (25 ml). The combined organic layers washed with a mixture of 4 N. HCl:20% salt solution (1:1, 3x15 ml), saturated salt solution (15 ml). The organic solution concentrated to a total volume of about 30 ml To the solution for 1 h, slowly add the hexane (70 ml). The obtained suspension was kept at 0-5°C for 1 h Crystalline solid is separated by filtration, washed with hexane:EtOAc (4:1, 50 ml), dried in vacuum at blowing with nitrogen and receive pyrimidinone with semiclean cycle10(5.30 g, 86%, HPLC>97A%).

1H-NMR(CDCl3, 400 MHz) δ:11.85(USS, 1H), 7.84(USS, N), 7.68(USS, N), 7.31(m, 2H), 7.04(m, 2H), 5.40-4.90(m, 2H), 4.53(m, 2H), 3.38(m, 1H), 2.87(s, 3H), 2.20-2.15(m, 3H), 1.90-1.40(m, 3H), 1.37(s, N).

The HPLC conditions: column: Bond, Rx C8 250x4,6 mm; temperature: 30°C; detection at 210 nm; mobile phase: a mixture of 0.1% aq. H3PO4(A)/MeCN (B); gradient: 90:10 mixture of (A)/(B) to 10:90 within 15 min, 10:90 maintained for 5 min, 10:90 to 90:10 mixture of (A)/(B) for 10 seconds; flow rate: 1 ml/min retention Time: pyrimidine with semiclean cycle10-15,467 minutes.

Stage 9: Obtaining hydrochloride pyrimidinamine with semiclean11

MaterialsMmassEquiv.MolgmlTight.
Pyrimidinone with semicell.10460,5010,0018460,8500
HCl (gas)36,468to 0.0478 0,5389
EtOAc3,5

Through a solution of ethyl acetate (3.5 ml) bubbled gaseous HCl (0,5389 g)at a temperature of from -30 to -20°C. In HCl-EtOAc solution contribute at a temperature of from -30 to -20°C pyrimidinone with N-Boc-semiclean cycle10(crystalline solid). The resulting solution was slowly warmed to room temperature for 2.5 h and incubated at room temperature for 0.5 h (100% conversion by HPLC). The reaction mixture was diluted with EtOAc (7 ml). The obtained suspension was kept at 0-5°C for 1 h Crystalline solid is separated by filtration, washed with EtOAc, hexane, dried in a vacuum injecting nitrogen and receive the desired product11(98% isolated yield, >97A% purity).

1H-NMR(CDCl3, 400 MHz) δ:12.35(s, 1H), 9.96(t, J=6.3 Hz, 1H), 9.51(USS, 1H), 9.19(USS, 1H), 7.42(DD, J=8.5, 5.6 Hz, 2H), 7.19(t, J=8.5 Hz, 2H), 4.92(DD, J=14.5, 5.1 Hz, 1H), 4.71(m, 1H), 4.57-4.45(m, 2H), 3.52(t, J=14.5 Hz), 2.65(t, J=5.0 Hz, 3H), 2.30 (USD, J=12.6 Hz, 1H), 1.99-1.92(m, 1H), 1.90-of 1.75(m, 2H), 1.68-1.60(m, 1H), 1.41-1.33(m, 1H).

The HPLC conditions: column: Bond, Rx C8 250x4,6 mm; temperature: 30°C; detection at 210 nm; mobile phase: a mixture of 0.1% aq. H3PO4(A)/MeCN (B); gradient: 90:10 mixture of (A)/(B) to 10:90 within 15 min, 10:90 p is derivat for 5 min, from 10:90 to 90:10 mixture of (A)/(B) for 10 seconds; flow rate: 1 ml/min retention Time: hydrochloride pyrimidinamine with semiclean cycle 8,118 minutes.

Stage 10: Obtaining racemic N-(2-{[(4-terbisil)amino]

the carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-

pyrimido[1,2-a]azepin-10-yl)-N,N',N'-trimethyl-

Academica 14

MaterialsMmassEQ.mmolWt.(g)About.(ml)Tight.
Acid12(96% purity)117,1051,0000,122
Ethylchloride125,154,80,9600.104 g0,0921,135
4-NMM101,154,80,9600,09710,1060,9200
THF3
the pyrimidine hydrochloride11396,8410,2000,0794
40% dimethylamine45,07 6,251,2500,1410,1580,8900
2N HCl

To a solution of acid12(122 mg) in THF (3 ml) add ethylchloride (92 ml) at 0-5°C. Then the reaction mixture is added slowly at 0-5°C 4-NMM (106 μl). The reaction mixture was kept at the same temperature for 2 hours To the solution of mixed anhydride is added in the form of a solid substance at 0-5°C pyrimidine hydrochloride11(79,4 mg) and incubated at the same temperature for 5 h and then at 5-10°C for another 2 h (100% conversion by HPLC).

To the reaction mixture is added aqueous dimethylamine (40%, 158 μl) and the mixture was kept at 10-15°C for 1 h, after which monitor the reaction by HPLC to confirm the completeness of the transformation. The reaction mixture podkalyvayut 2 N. HCl to pH 3-4 with 5-15°C. Add, in this order, EtOAc (6 ml) and saturated salt solution (2 ml). After phase separation the organic layer was washed with 1 N. HCl (2 ml), saturated salt solution (2x2 ml). The organic layer is concentrated to a total volume of 1 ml. Slowly over 0.5 h add hexane (5 ml). The obtained suspension was kept at 0-5°C for 1 h Crystalline solid separated Aut filtering washed with hexane/EtOAc (5:1), MTBE, and dried in a vacuum injecting nitrogen and receive specified in the header of the connection14(75,6 mg, 82%).

1H-NMR(CDCl3, 400 MHz) δ:12.13(s, 1H), 9.41(USS, 1H), 7.38(DD, J=8.5, 5.4 Hz, 2H), 7.00(t, J=8.5 Hz, 2H), 5.40(USS, 1H), 5.29(DD, J=14.5, 6.0 Hz, 1H), 4.60(DD, J=14.5, 6.6 Hz, 1H), 4.52(DD, J=14.5, 6.3 Hz, 1H), 3.35(DD, J=14.5, 11.6 Hz, 1H), 3.04(s, 3H), 3.01(s, 3H), 2.98(s, 3H), 2.23-2.12(m, 3H), 1.95-1.81(m, 2H), 1.58-1.49(m, 1H).

The HPLC conditions: column: Bond, Rx C8 250x4,6 mm; temperature: 30°C; detection at 210 nm; mobile phase: a mixture of 0.1% aq. H3PO4(A)/MeCN (B); gradient: 90:10 mixture of (A)/(B) to 10:90 within 15 min, 10:90 maintained for 5 min, 10:90 to 90:10 mixture of (A)/(B) for 10 seconds; flow rate: 1

ml/min retention Time: specified in the header connection 14-12, 191 minutes.

The following table provides a list of the compounds obtained according to the present invention. The table below presents the structure and name of each compound, the mass of the molecular ion plus 1 (M+)set by FIA-MS, and the synthetic scheme used to obtain each connection.

Table 1
StructureNameM+Scheme
N-(4-terbisil)-3-hydroxy-4-oxo-6,7,8,9-those whom rehydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide 318And

(App.1)
N-(4-terbisil)-3-hydroxy-9-morpholine-4-yl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide403In

(PR)
9-[[(dimethylamino)sulfonyl](methyl)amino]-N-(4-terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide454With

(PR)
(+/-)-N1-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N1N2N2-trimethylenediamine446With

(PR)

(+)-N1-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N1N2N2-trimethylenediamine446D

(PR)
(-)-N-(4-terbisil)-3-hydroxy-9-{methyl[(methylsulphonyl)acetyl]

amino}-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide
467D
N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N,N',N'-trimethylethylene460
N-(2-{[(3-chloro-4-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N,N',N'-trimethylethylene476
N-(2-{[(3-Chlorobenzyl)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N,N',N'-trimethylethylene462
N-(4-terbisil)-3-hydroxy-9-(6-methyl-1,1-dioxido-1,2,6-thiadiazine-2-yl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine--2-carboxamide466In
(-)-N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N,N',N'-trimethylethylene460D
(+)-N-(4-terbisil)-3-hydroxy-9-(6-methyl-1,1-dioxido-1,2,6-thiadiazine-2-yl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide466D
/td> N-(4-terbisil)-3-hydroxy-9-[methyl(pyrrolidin-1-ylsulphonyl)amino]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide480
9-[(azetidin-1-ylsulphonyl)(methyl)amino]-N-(4-terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide466
(-)-N-(4-terbisil)-3-hydroxy-9-[methyl - (morpholine-4-ylsulphonyl)amino]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide496D
(+)-N-(4-terbisil)-3-hydroxy-9-[methyl - (morpholine-4-ylsulphonyl)amino]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide496D
(+)-9-[(azetidin-1-ylsulphonyl)(methyl)amino]-N-(4-terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide466D
(-)-9-[{[(dimethylamino)

sulfanyl]-acetyl}(methyl)amino]-N-(4-fluoro-3-methylbenzyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide
510D
(-)-N-(4-terbisil)-3-hydroxy-9-{methyl[(4-methylpiperazin-1-yl)sulfonyl]amino}-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide509D
(+)-N-(4-terbisil)-3-hydroxy-9-{methyl[(4-methylpiperazin-1-yl)sulfonyl]amino}-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide509D
N-(4-terbisil)-3-hydroxy-9-{methyl[(4-methylpiperazin-1-yl)

sulfonyl]amino}-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide
509D
N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene460With

(PR. 6)
(-)-N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene460D (PR. 7)
(+)-N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene460D
N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene474
(+)-N-(2-{[(4-fluoro-3-methylbenzyl) amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene474D
(-)-N-(2-{[(4-fluoro-3-methylbenzyl) amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene474D
N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-8,8-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N,N',N'-trimethylethylene474

Although the above description sets out the basic principles of the present invention and illustrative examples are presented to illustrate the practical implementation of the invention covers all possible changes, additions and/or modifications that are covered under the scope of the attached items.

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

1means N or NR2R5;

R2means of CH3;

R5means

1) C(O)CH2SO2CH3,

2) C(O)C(O)N(CH3)2,

3) SO2N(CH3)2or

4) SO2R20where R20means

or

or, alternatively, R2and R5together with the nitrogen atom to which are attached, form

or

R3means hydrogen;

R4means:

1) p-tormentil,

2) 4-fluoro-3-methylbenzyl,

3) 3-Chlorobenzyl or

4) 3-chloro-4-methylbenzyl;

R12and R14both denote H, except that when R5means C(O)C(O)N(CH3)2and R4means p-tormentil, and n is 1, R12and R14either both denote H, or both means of CH3; and

n means an integer of zero, 1 or 2.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where R1mean NR2R5and n is 1 or 2.

3. The compound according to claim 1 or its pharmaceutically acceptable salt, where

R1mean NR2R5;

R2 means of CH3;

R5means C(O)C(O)N(CH3)2or SO2R20where R20means

R3means hydrogen;

R4means p-terbisil or 4-fluoro-3-methylbenzyl;

R12and R14both denote H, except that when R5means C(O)C(O)N(CH3)2and R4means p-tormentil, and n is 1, R12and R14either both denote H, or both means of CH3; and

n means an integer equal to 1 or 2.

4. The compound of formula II or its pharmaceutically acceptable salt

where R1means hydrogen, NR2R5, OR2, SR2, SOR2, SO2R2, SO2NR2R5or OC(O)NR2R5;

R3means hydrogen;

R4means

R2means

1)hydrogen,

2) CH3or

3)

and R5means

1) C(O)CH3,

2) C(O)CH2SO2CH3,

3)CH3,

4) C(O)C(O)N(CH3)2,

5) SO2CH3,

6) SO2N(CH3)2,

7) C(O)CH2N(CH3)2,

8) SO 2CH2SO2CH3,

9)S(O)CF3,

10)

11)

or

12)

or R2and R5together with the nitrogen atom to which they are attached, form a heterocyclic cycle selected from the group including

and

5. The compound according to claim 1, or its pharmaceutically acceptable salt selected from the group including:

N-(4-terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-(4-terbisil)-3-hydroxy-9-morpholine-4-yl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

9-[[(dimethylamino)sulfonyl](methyl)amino]N-(4-terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N1-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N1N2N2-trimethylenediamine;

(+)-N1-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N1N2N2-trimethylenediamine;

(-)-N-(4-terbisil)-3-hydroxy-9-{methyl[(methylsulphonyl)acetyl]amino}-4-oxo-6,7,8,9-is tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N,N',N'-trimethylethylene;

N-(2-{[(3-chloro-4-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N,N',N'-trimethylethylene;

N-(2-{[(3-Chlorobenzyl)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N,N',N'-trimethylethylene;

N-(4-terbisil)-3-hydroxy-9-(6-methyl-1,1-dioxido-1,2,6-thiadiazine-2-yl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

(-)-N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N,N',N'-trimethylethylene;

(+)-N-(4-terbisil)-3-hydroxy-9-(6-methyl-1,1-dioxido-1,2,6-thiadiazine-2-yl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N(4-terbisil)-3-hydroxy-9-[methyl(pyrrolidin-1-ylsulphonyl)amino]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

9-[(azetidin-1-ylsulphonyl)(methyl)amino]-N-(4-terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

(-)-N-(4-terbisil)-3-hydroxy-9-[methyl - (morpholine-4-ylsulphonyl)amino]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

(+)-N-(4-terbisil)-3-hydroxy-9-[methyl - (morpholine-4-ylsulphonyl)amino]-4-oxo-6,7,8,9-tetrahydro-4H-pyrid is[1,2-a]pyrimidine-2-carboxamide;

(+)-9-[(azetidin-1-ylsulphonyl)(methyl)amino]-N-(4-terbisil)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

(-)-9-[{[(dimethylamino)sulfonyl]acetyl}(methyl)amino]-N-(4-fluoro-3-methylbenzyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

(-)-N-(4-terbisil)-3-hydroxy-9-{methyl[(4-methylpiperazin-1-yl)sulfonyl]amino}-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

(+)-N-(4-terbisil)-3-hydroxy-9-{methyl[(4-methylpiperazin-1-yl)sulfonyl]amino}-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-(4-terbisil)-3-hydroxy-9-{methyl[(4-methylpiperazin-1-yl)sulfonyl]amino}-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

(-)N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

(+)-N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

(+)-N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-Gex is hydroperiod[1,2-a]azepin-10-yl)-N,N,N'-trimethylethylene;

(-)-N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-8,8-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-N,N',N'-trimethylethylene.

6. The compound according to claim 5, or its pharmaceutically acceptable salt selected from the group including:

N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

(+)-N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

(-)-N-(2-{[(4-fluoro-3-methylbenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

(-)-N-(4-terbisil)-3-hydroxy-9-{methyl[(4-methylpiperazin-1-yl)sulfonyl]amino}-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

(+)-N-(4-terbisil)-3-hydroxy-9-{methyl[(4-methylpiperazin-1-yl)sulfonyl]amino}-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-(4-terbisil)-3-hydroxy-9-{methyl[(4-methylpiperazin-1-yl)sulfonyl]amino}-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-8,8-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimi the in-9-yl)-N,N',N'-trimethylethylene;

N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

(-)N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

(+)-N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene.

7. The connection according to claim 6, or its pharmaceutically acceptable salt selected from the group including

N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene;

(-)N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene; and

(+)N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-N,N',N'-trimethylethylene.

8. The connection according to claim 7, representing (-)N-(2-{[(4-terbisil)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrazino[1,2-a]azepin-10-yl)-]-N,N',N'-trimethylethylene or its pharmaceutically acceptable salt.

9. Pharmaceutical composition having the property inhibitor of HIV integrase containing a therapeutically effective amount of a compound according to any one of claims 1 to 8, or its pharmaceutically acceptable salts, and pharmaceutically acceptable the th media.

10. The use of compounds according to any one of claims 1 to 8, or its pharmaceutically acceptable salts for inhibiting HIV integrase.

11. The compound according to any one of claims 1 to 8, or its pharmaceutically acceptable salt for use in obtaining drugs for the inhibition of HIV integrase.

12. The compound according to any one of claims 1 to 8, or its pharmaceutically acceptable salt for use in obtaining medicines to treat HIV infection.

Priorities from 12.12.2003 and 27.12.2002 apply equally to claims 1 to 12 claims.



 

Same patents:

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to application as ligands of 5-NT6 receptor azaheterocyclic compositions of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates , where R2 and R3 independently represent substitute of amides chosen from hydrogen; substituted carbonyl; substituted aminocarbonyl; substituted aminothiocarbonyl; substituted sulphonyl; C1-C5-alkyl, optionally substituted with C6-C10-aryl, optionally substituted with heterocyclil, C6-C10-arylaminocarbonyl, C6-C10- arylaminothiocarbonyl, C5-C10-azaheteroaryl, optionally substituted with carboxyl, nitrile group; optionally substituted with aryl; R1k are 1 to 3 independent substitutes to cyclic system chosen from hydrogen, optionally substituted C1-C5-alkyl, C1-C5-alkyloxy, C1-C5-alkenyl, C1-C5- alkenyl, halogen, trifluoromathyl, nitrile, carboxyl, optionally substituted heterocyclil, substituted sulphonyl, optionally substituted carboxyl; dashed line with accompanying continuous line () corresponds to single or double bond; n=1.2 or 3. Invention also concerns a pharmaceutical formulation, production method and tabletted, capsulated or injection medical product in pharmaceutically acceptable package.

EFFECT: agent has improved efficiency.

17 cl, 8 tbl, 5 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to producing the novel compounds with dipeptidyl peptidase IV (DPP-IV) inhibiting activity and particularly, it relates to the compounds with the condensed 1,3-dihydroimidazole cycle. The invention relates to the compounds represented by the common formula (II), or their pharmaceutically acceptable salts, where, Z3a means nitrogen atom or the group with formula -CR2a=; X3a means oxygen atom or sulfur atom; T1a means piperazine-1-yl group, 3-amino-piperidine-1-yl group, 3-methylamino-piperidine-1-yl group; X1a means oxygen atom hydrogen, C2-6-alkenyl group, C2-6-alkynyl group or benzyl group; each of R1a and R2a independently means hydrogen atom, halogenatom, C1-6-alkyl group, cyanogroup or group, represented with formula-A0a-A1a; A0a means oxygen atom, sulfur atom or group, represented with formula-NA2a-; Ala means hydrogen atom, C1-6-alkyl group, C1-6-alkenyl group, C2-6-alkynyl group, phenyl group, cyanophenyl group, carbamoylphenyl group, benzyl group; A2a means hydrogen atom or C1-6-alkyl group; X2a means hydrogen atom, C2-6-alkenyl group, C2-6-alkynyl group, 1H-piridine-2-onyl group, 1-methyl-1H-piridine-2-onyl group, C1-6-alkyl group, which can have a group, selected from the substitutes group specified below B, phenyl group, which can have a group, selected from the substitutes group specified below B, 5- or 6-membered heteroarylgroup, containing one or two nitrogen atoms, oxygen or sulfur, which can have a group, selected from the substitutes group specified below B, phenylC1-6-alkyl group, which can have a group, selected from the substitutes group specified below B: <Substitutes group B> substitutes group B is group, including chlorine atom, bromine atom; cyanogroup, C1-b-alkyl group, C2-b-alkenyl group, C2-6-alkynyl group, C3-8-cycloalkyl group, C1-6alcoxigroup, carbamoyl groupcarboxyl group and C1-6-alcoxicarbonyl group.

EFFECT: research and revealing compounds with DPP-IV inhibiting activity, useful as pharmaceutical agents which can be used as therapeutic and preventing medicines in such diseases as diabetes, obesity and hyperlipidemia.

12 cl, 84 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the formula (I) or their pharmaceutically or veterinary-acceptable salts: where: R1 and R3 independently represent H; F; Cl; Br; C1-C6alkyl; R2 represents H or C3-C7cycloalkyl; Y represents -S- or -N(R5)-, where R5 represents H; X represents the bind; R4 represents -C(=O)NR6R7, where R6 represents H or radical of formula -(Alk)b-Q, where b is equal to 0 or 1, and Alk is not necessarily substituted with C1-C6alkyl, C1-C6alkoxi, F, Cl, Br, oxo, COOH, bivalent C1-C12alkylen, C2-C12alkenylen with direct or ramified chain, which can be disconnected with one ore several non-adjacent -O-, -S- or -N(R8)-, where R8 represents H or C1-C4alkyl, C3-C4alkenyl or C3-C6cycloalkyl, and Q represents H; -SH; -NR8R8, where each R8 can be similar or different; the complex ether group; or not necessarily substituted with C1-C6alkyl, C1-C6alkoxi, phenyl, benzyl, phenoxy, C3-C8cycloalkyl, amino, fluor, bromine, oxo, -COOH, -CORA, -COORA, NHRA, -NRARB, where RA and RB are independent (C1-C6)alkyl group, phenyl, C3-C7cycloalkyl, C5-C7cycloalkenyl or heterocyclilc ring containing 5 to 8 ring atoms; and R7 represents H or C1-C6alkyl; or, taken together with atom or atoms, they are bound with, R6 and R7 form not necessarily substituted with (C1-C6)alkyl, COORA, where RA is the (C1-C6)alkyl group, phenyl, not necessarily substituted with F, Cl, Br, heterocyclilc ring containing 5 to 8 ring atoms. The invention also relates to N-(3-dimethylaminopropyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydropirazol[4,3-c]quinoline-2-il]benzamide; to application of the compounds; to the immunomodulation method and to the pharmaceutical and veterinary composition.

EFFECT: production of novel immunobiologic compounds.

14 cl, 173 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the novel substituted indoline phemylsulfamide derivatives with the common formula , where A means C-R11 group or nitrogen, and R11 means hydrogen or alkyl with 1-4 carbon atoms, X means oxygen, R1 means aryl with 6-10 carbon atoms, unsubstituted or once-triple substituted with the similar or different substitutes, selected from the group which includes halogen, zyano, alkyl with 1-6 carbon atoms, alkoxi with 1-6 carbon atoms, phenoxi, benziloxi, trifluoromethyl, trifluorometoxi, alkenil with 2-6 carbon atoms, phenyl, alkylthio with 1-6 carbon atoms, mono- and dialkylamino with 1-6 carbon atoms in each alkyl group, or means the group with formula , R2 and R3 similar or different and independently from each other mean hydrogen or alkyl with 1-6 carbon atoms, or with the carbon atom they are bound to form the 3-7-membered spiro-compound cycloalkylic ring, R4 means hydrogen or alkyl with 1-6 carbon atoms, R5 R4 means hydrogen or alkyl with 1-6 carbon atoms, R6 means hydrogen or alkyl with 1-6 carbon atoms, R7 means hydrogen, alkyl with 1-6 carbon atoms, R8 - R10 mean hydrogen; as well as to their pharmaceutically compatible salts.

EFFECT: compounds are designated for prevention and/or treatment of cardio-vascular diseases, particularly dislipidemia and ischemic heart disease.

4 cl, 1 dwg, 96 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention pertains to derivatives of 7-phenylpyrazolopyridine with formula (I) ,where R1, R5, R6, R40, R41 and R42 represent different hydrocarbon substitutes or functional groups, its salts or hydrates, and especially to salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine. The compound with formula (I), especially salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine, act as antagonists of the receptor of corticotrophin release factor and can be used in medicine for treating various diseases of the nervous system and the gastrointestinal tract.

EFFECT: obtaining of new biologically active substances.

162 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of indole with general formula 1: where R is unsubstituted or substituted quinolyl, pyridopyrazinyl, indazolyl or pyridyl and which is directly bonded to nitrogen of the amide group; R1 is unsubstituted or substituted alkly-aryl; R2 represents hydrogen; R3-R6 represent hydrogen, R7 represents (C1-C6)-alkylcarbonyl or (C1-C6)- alkoxycarbonyl, and X, Y represent oxygen or sulphur, under the condition that, when R is an unsubstituted or substituted 2-, 3-, 4-, 5- and 6-pyridyl group and R1-R6 have the above mentioned values, R7 is not an acetyl radical or tert-butyloxycarbonyl group. The invention also relates to physiologically tolerant salts of the indole derivatives, as well as to pharmaceutical compositions based on them and their use in obtaining medicinal preparations.

EFFECT: obtaining of medicinal preparations, used as medicines for curing tumorous diseases, especially in case of resistance to other drugs and metastasising carcinomas.

14 cl, 7 tbl, 6 dwg, 25 ex

Asaindoles // 2326880

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmaceutical formulation inhibiting protein kinase, containing inhibiting selective kinase compound amount of general formula (I): , where: R means aryl or indolyl, and the latter is optionally substituted with one or more groups selected from R4, -C(=O)-R, -C(=O)-OR5, -C(=O)-NY1Y2 and -Z2R; R2 means H; R3 means H; R4 means C1-C6 alkyl, optionally substituted with one substitute -C(=O)-NY1Y2; R5 means H; R7 means C1-C6 alkyl; R means C1-C6 alkyl; X1 means C-aryl, C-heteroaryl, such as pyridile or isoxasolyl, and the latter is optionally substituted with one or two C1-C6 alkyls, C-heterocycloalkyl, such as morpholinile or peperidynil, C-halogen, C-CN, C-OH, C-Z2R, C-C(=O)-OR5, C-NYlY2, C-C(=O)-NY1Y2; Y1 and Y2 means redardless H, aryl, C3-C6 cycloaryl, C1-C6 alkyl, optionally substituted with one group selected from phenyl, halogen, heterocyclil, such as morpholinile, phurile, hydroxyl, -C(=O)-OR5, OR7; or group-NY1Y2 can form morpholinile, peperidynil, optionally substituted with one or two substitutes selected from OH, C1-C6 alkyl; Z means O; where aryl as group or part of group means optionally substituted with one or two substitutes monocyclic aromatic C6carbocyclic fragment, where substitute is selected from halogen or C1-C6 alkoxy, C(=O)-OR5; except compounds: 4-chlorine-2-(4-tert-butylphenyl)-1H-pyrrole[2,3-b]pyridine, 2-(5-methoxy-1 -methyl-1 H-indole-3-il)-4-phenyl-1H- pyrrole[2,3-b]pyridine, 2-(5- methoxy-1 -methyl-1 H-indole-3-il)-1H- pyrrole[2,3-b] pyridine-4-carbonitrile, 4-chlorine-2-(5- methoxy-1 -methyl-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine, or 2-(5- methoxy-1H-indole-3-il)-1H- pyrrole[2,3-b]pyridine -4- carbonitrile.

EFFECT: application of compound for production of medicinal agent for inflammatory disease.

51 cl, 9 tbl, 148 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compounds of and formula: I II those developing antiviral activity allowing application in pharmaceutical formulations and for antiviral medicines production.

EFFECT: new compounds have useful biological properties.

5 cl, 3 dwg, 6 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the formula I compounds or its pharmaceutically acceptable salt or hydrate where Z means N; X1 means O or S, R1 means alkyl containing one to six carbon atoms; R2 designates hydrogen or alkyl containing one to six carbon atoms; and R3 designates hydrogen or alkyl containing one to six carbon atoms substituted with the -ORa group where Ra means alkyl containing one to six carbon atoms; saturated nonaromatic cyclic radical containing 3 to 8 atoms in a cycle where one atom in a cycle is a heteroatom selected from N or O, whereas the rest of the atoms in the cycle are carbon atoms, one or two of these carbon atoms being not necessarily substituted by nitrogen atom with the groups -C(O)(C1-C6alcoxy) or -SO2-C1C6alkyl. Invention also relates to pharmaceutical composition.

EFFECT: compounds possess inhibiting activity.

13 cl, 1 tbl, 8 ex

FIELD: CHEMISTRY.

SUBSTANCE: invention relates to novel method for preparation of compounds of formula IX or IXа, which implies reaction of compound of formula Va, in solvent, with compound of formula VII or formula VIIa, in the presence of palladium catalyst and phospho ligand, in the presence of amine base, resulting in compound of formula VIII or VIIIa. The method also implies reaction of compound of formula VIII or VIIIa, in solvent, with cyclopropylamine, not necessarily in the presence of catalyst. Also, invention relates to method for purification of compound of formula IX or IXa.

Va - R1 may be either С1-8alkyl, aryl or heteroaryl, not necessarily aryl- and/or С1-8alkyl-substituted; and

.

EFFECT: method for preparation of biologically useful compounds is described.

17 cl, 3 tbl, 77 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns combination for HIV-infection treatment, containing (a) therapeutically effective amount of HIV-protease inhibitor by formula or its pharmaceutically accepted salt or ester and (b) effective amount of rhytonavir or its pharmaceutically accepted salt or ester. Besides, method of improved pharmacokinetics of HIV-protease inhibitor by formula (4) or its pharmaceutically accepted salt or ester, including introduction to an individual requiring such treatment, therapeutically effective amount of rhytonavir or its pharmaceutically accepted salt or ester with therapeutically effective amount of specified HIV-protease inhibitor by formula (4) is described.

EFFECT: offered combination has synergetic action if taken in any molar ratios.

33 cl, 6 dwg, 9 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new compounds of and formula: I II those developing antiviral activity allowing application in pharmaceutical formulations and for antiviral medicines production.

EFFECT: new compounds have useful biological properties.

5 cl, 3 dwg, 6 tbl, 3 ex

FIELD: medicine, molecular biology, antibodies.

SUBSTANCE: invention relates to an antibody raised against CCR5 and comprising: (i) two light chains wherein each light chain comprises product of plasmid expression and designated as pVK:HuPRO140-VK (ATCC - PTA-4097), and (ii) two heavy chains wherein each heavy chain comprises product of plasmid expression and designated as pVg4:HuPRO140 HG2-VH (ATCC - PTA-4098), or plasmid designated as pVg4:HuPRO140 (mut B+D+I)-VH (ATCC - PTA-4099), or fragment of such antibody binding with CCR5 on a human cell surface. Invention relates to nucleic acid encoding light and heavy chains of antibody, expression vector, cell-host transformed with at least one vector, and a method for preparing antibody. Antibody is used as an active component in composition used for inhibition of infection of cells CD4 + HIV-1, and to a pharmaceutical composition used in treatment of a patient with HIV-1 infection. Also, invention relates to antibody conjugate against CCR5 and its using. Use of antibodies provides enhancing effectiveness of prophylaxis and treatment of HIV-1 infection.

EFFECT: valuable medicinal properties of antibody.

31 cl, 23 dwg, 3 ex

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 5'-phosphonates of 3`-azido-3`-deoxythymidine of the general formula (I) possessing anti-HIV activity, and to using 5'-phosphonates of 3`-azido-3`-deoxythymidine as an active component for preparing drugs possessing anti-HIV activity. In compound of the general formula (I): at n = 0-2; R1 means (wherein X means -CH2, -NH, O); R2 means -NH-C(O)- (wherein R2 means H, (C1-C6)-alkyl, (C5-C7)-cycloalkyl), -HO(CH2)k- (wherein k = 2-4); at n = 0 R1 means -Cl3C; at n = 1-6 R1 means Cl-, Br-, J-, and at n = 2-6 R3 means -C(O)O- (wherein R3 means (C1-C6)-alkyl) at n = 2-6.

EFFECT: valuable medicinal properties of compounds.

3 cl, 2 tbl, 10 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: pharmaceutical composition comprises abacavir and alovudin taken in the ratio = (1-10):(200-800) and a pharmaceutical carrier for them. Package designated for a patient for treatment of poly resistant HIV comprises alovudin and abacavir and information instruction for using both alovudin and abacavir in combination. Use of abacavir in common with alovudin for treatment of polyresistant HIV wherein use involves simultaneous, combined or successive administration of alovudin and abacavir. Invention provides more inhibition of virus, suppression of virus for longer period, limiting safety for arising mutations and development of polyresistant HIV, and decreasing toxicity of drugs.

EFFECT: valuable properties and enhanced effectiveness of drugs.

10 cl, 1 tbl, 3 dwg, 2 ex

FIELD: medicine, polymers.

SUBSTANCE: invention relates to conjugates consisting of a water-soluble polymer of molecular mass from 200 to 20000 Da and representing polyethylene glycol or alkyl chain to which two molecules of synthetic peptides, not less, are bound by reactive functional group and wherein each peptide comprises amino acid sequence originating from region HR1 or HR2 of human immunodeficiency virus (HIV) gp41. Invention relates to methods for using these conjugates for delivery inhibition of to HIV target-cell by addition of indicated conjugates in the amount providing effective inhibition of cell infection with indicated virus. Also, invention relates to methods for preparing conjugates by functional adding of each molecule of synthetic peptide to polymer through reactive functional group.

EFFECT: valuable biological properties of conjugates.

27 cl, 2 dwg, 6 tbl, 6 ex

FIELD: organic chemistry of natural compounds.

SUBSTANCE: invention relates to novel compounds, namely, to N'-{N-[3-oxo-lupan-28-oyl]-9-aminononanoyl}-3-amino-3-phenylpropionic acid and its salts of the formula (I) given in the invention description. This compound shows antiviral activity, in particular, anti-HIV activity, and immunostimulating activity. Compounds of the formula (I) are nontoxic and can be obtained from betulin isolated from birch bark as available raw with the high yield.

EFFECT: valuable medicinal properties of compound.

4 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts or isomers wherein Q means nitrogen atom (N); X and Z are chosen independently from group consisting of -CH and N under condition that one or both groups among Q and Z mean N; R, R4, R5, R and R are chosen independently from group consisting of hydrogen atom (H) and (C1-C6)-alkyl; R1 means H, (C1-C6)-alkyl, R9-aryl-(C1-C6)-alkyl-, (C1-C6)-alkyl-SO2-, (C3-C6)-cycloalkyl-SO2-, fluoro-(C1-C6)-alkyl-SO2-, R9-aryl-SO2-, R9-heteroaryl-SO2-, -N(R22)(R23)-SO2-, (C1-C6)-alkyl-C(O)-, (C3-C6)-cycloalkyl-C(O)-, fluoro-(C1-C6)-alkyl-C(O)-, R9-aryl-C(O)-, CH3CH2-NH-C(O)- or R9-aryl-NH-C(O)-; R2 means H or (C1-C6)-alkyl, and R3 means H, (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl-, (C3-C10)-cycloalkyl-, (C3-C10)-cycloalkyl-(C1-C6)-alkyl-, R9-aryl, R9-aryl-(C1-C6)-alkyl- or R9-heteroaryl under condition that each X and X doesn't mean N, or R2 and R3 in common mean =NOR10. Proposed compounds can be used as selective CCR5 antagonists. Compounds are useful in HIV treatment. Also, invention describes a pharmaceutical composition based on compounds thereof and combination with antiviral or anti-inflammatory agent.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 4 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to method for reducing of LDL-cholesterol and/or triglyceride level increased due to therapy by HIV protease inhibitors in HIV-infected subjects. According to invention Atazanavir is administered in combination with other HIV protease inhibitor, metabolized cytochrom P450 monooxygenase in therapeutically effective amounts.

EFFECT: effective treatment due to Atazanavir ability to cytochrom P450 monooxygenase inhibition; increased concentration of HIV protease inhibitors without preparation dose.

3 cl

FIELD: medicine, biology, virology.

SUBSTANCE: invention involves creature of complex of membranotropic compounds providing target delivery of antiviral preparation to HIV-1/2 damaged focus and suppression of viral infection at initial and later steps of its development. Invention provides effect on more expanded targets of human immunodeficiency virus and blocking HIV-infection at the early steps of interaction virus/cell based on synergism of components in the proposed complex. Modifying agents of polyanionic matrix - norbornene or adamantine and peptide-simulators of HIV-1/2 co-receptor bind with different sites of gp120 of HIV-1 that excludes the competition possibility and reciprocal steric hindering in virus-specific pharmacophore-modifying agents. Invention can be used for prophylaxis of HIV-infection and AIDS treatment, and in research works for study of ligand-receptor interaction (of type surface viral proteins - cellular receptors).

EFFECT: valuable biological and medicinal properties of complex.

3 cl, 5 tbl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with formula I or their pharmaceutically acceptable salts and based on them pharmaceutics with the CRF (corticotrophin releasing factor) related activity. In the common formula I , X1 means (CH2)n, where n equal to 0-2, R1 means (1)C1-C10alkyl or C1-C10alkenyl, not necesserily substituted with substitute, selected from the group, including hydroxy, cyano, (C1-C3alkyl)arylamino and phenyl, and said phenyl not necesserily substituted with one-three substitutes, independently selected from the group including C1-C6alkyl, C1-C6alkoxi, halogen, (2) C3-C7cycloalkyl, not necesserily substituted with hydroxy,(3) C3-C7cycloalkyl(C1-C3)alkyl or C3-C7cycloalkenyl(C1-C3)alkyl,(4) C4-C12tricyclic alkyl,(5)C3-C7heterocycloalkyl or C3-C7heterocycloalkyl(C1-C3)alkyl, where each of the heterocyclic rings contains in the ring 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, and not necesserily can be substituted with the group C1-C3alkyl, phenyl or phenyl(C1-C6)alkyl, or the CH2 group in the heterocycloalkyl residue is substituted with C=O,(6) benzo-condensed (C5-C7)cycloalkyl,(7) phenyl, and said phenyl is not necesserily substituted with one-three substitutes, independently selected from the group including C1-C6alkyl, C1-C6alkoxi, methylendioxy, halogen, (8) naftyl, (9) heteroaryl(C1-C6)alkyl, and said heteroaryl(C1-C6)alkyl has 5-6 atoms in the ring and contains 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, can be condensed with the benzene ring and not necesserily substituted with one-three substitutes, selected from the group, including C1-C6alkyl, (10) 1,2-diphenylethyl,(12) C1-C3alkoxi(C1-C6)alkyl or (13) aryloxy(C1-C6)alkyl, R2 means C1-C6alkyl, R3 means (1) hydrogen,(2) C1-C6alkyl, not necesserily substituted with the group C1-C3acyloxy,(3) C3-C6alkenyl,(8) benzene, and R4 means phenyl, not necesserily substituted with one-three substitutes, independently selected from the group including C1-C6alkyl, halogen.

EFFECT: compounds can be used in treatment of phobias, stress dependent disorders, mental disorders, gastro-intestine disfunctions, neurodegenerative and other psychoneurologic disease.

19 cl, 2 dwg, 2 tbl, 8 ex

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