Non-nucleoside reverse transcriptase inhibitors, pharmaceutical composition comprising thereof, their using in preparing medicinal agent for treatment of hiv-1, intermediate compounds for their preparing

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

45 cl, 1 tbl, 57 ex

 

The technical field

This invention relates to a non-nucleoside reverse transcriptase inhibitor, is active against HIV-1 and which has an improved stability and pharmacokinetic profile. The invention also relates to novel intermediate compounds in the synthesis of such compounds and use of these compounds in the scan methods and compositions.

Background of the invention

Non-nucleoside reverse transcriptase inhibitors (non-nucleoside reverse transcriptase ingibitors (NNRTIS)) associated with an allosteric site on reverse transcriptase and represent an important development in the Arsenal of drugs against HIV, in particular HIV-1. International patent application WO 93/03022 reveals NNRTIS on the basis of thiourea, which were later labeled "PETT" (phenylethylenediamine) compounds in J.Med.Chem. 39 6 1329-1335 (1995) and J.Med.Chem. 39 21 4261-4274 (1996). International patent application number WO 99/47501, WO 00/39095, WO 00/56736, WO 00/78315 and WO 00/78721 describe derivatives of thiourea RHETT, who, as stated in these documents were optimized against complex RT-binding "pocket".

International patent application number WO 95/06034 and J.Med.Chem. 42 4150-4160 (1999) discloses compounds of urea, which isostere RHETT NNRTIS. International patent application number WO 99/36406 reveals NNRTIS compounds, which are compounds of urea with freedoms is about standing cyclopropyl bridge, where phenyl left wing necessarily contain functional 6-hydroxy-group, and international patent application number WO 00/47561 discloses prodrugs of such compounds.

Although NNRTIS on the basis of urea and thiourea disclosed in the above documents, active against reverse transcriptase inhibitors, especially reverse transcriptase of HIV-1, nature of the HIV virus with its excessive loss of replicative accuracy and, consequently, the tendency to rapid development of resistance, dictates the need for further development of antiretrovirals with increased antiviral action against problematic drug resistant mutants, especially on the provisions 100, 103 and/or 181 RT.

In addition, modern schemes therapeutic treatment of HIV infections identified HAART (highly active antiretroviral therapy (Highly Active Anti Retroviral Therapy)), suggest the introduction of anti-virus tools in the form of combinations of three or more anti-virus tools of different classes, such combination is administered for extended periods of time if not for life. HAART requires the patient's medication through a complex scheme, sometimes provides a daily intake of a large number of pills at different times of the day, in some cases up to, and in some cases after p is IEMA food. Thus, the necessary antiretroviral drugs, allowing greater flexibility in dosing to meet the needs of the patient.

Brief description of the invention

In accordance with the first aspect of the invention presents the compounds of formula I

where

R1represents O, S;

R2is optionally substituted, nitrogen-containing heterocycle which nitrogen is in position 2 relative to the connection with (thio)urea;

R3represents H, C1-C3alkyl;

R4-R7independently selected from H, C1-C6of alkyl, C2-C6alkenyl,2-C6the quinil, Halogens1-C6of alkyl, C1-C6alkanoyl, Halogens1-C6alkanoyl,1-C6alkoxy, Halogens1-C6alkoxy, C1-C6alkyloxy-C1-C6of alkyl, Halogens1-C6alkyloxy-C1-C6of alkyl, hydroxy-C1-C6of alkyl, amino-C1-C6of alkyl, carboxy-C1-C6of alkyl, cyano-C1-C6of alkyl, amino, carboxy, carbamoyl, cyano, halogen, hydroxy, keto and the like;

X represents -(CH2)n-D-(CH2)m-;

D is-NR8-, -O-, -S-, -S(=O)- or-S(=O)2-;

R8is H1-C3alkyl;

PI m independently represent 0 or 1,

and their pharmaceutically acceptable salts and prodrugs.

In this case, the preferred value for R1is About, i.e. the derivative of urea, although a very important option is also the case when R1is S (i.e. derived thiourea).

Presents the values for R2include thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, indolyl, triazolyl, tetrazolyl, piperidyl, piperazinil and condensed rings, such as benzothiazolyl, benzopyranyl, benzodiazepin, benzimidazolyl, hinely, purines and such, with any of these groups can be optionally substituted.

Preferred values of R2include pyrid-2-yl and thiazol-2-yl.

Optional substituents for R2can include up to three substituents, such as C1-C6alkyl, C1-C6alkoxy, C2-C6alkenyl,2-C8quinil,2-C8alkenone,1-C6alkoxyl1-C6alkyl, C1-C6alkanoyl, Halogens1-C6alkyl, C1-C4alkanoyloxy,1-C4alkylthio, amino (including C1-C3alkyl substituted an amino group), carboxy, carbarnoyl, cyano, halogen, hydroxy, aminomethyl, carboxymethyl, hydroxymethyl, nitro, aryl (such as phenyl, pyrrol-1-yl, tetrazol-5 is, triazole-4-yl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, indolyl, piperidyl, piperazinil and the like), substituted (as defined herein) aryl or-SO2Q, or-C(=O)Q, where Q represents C1-C6alkyl, halogen-substituted C1-C6alkyl, aryl (as defined herein), substituted (as defined herein) aryl or amino. Heteroatoms in the R2can be converted into derivatives, for example, With1-C6the alkyl, oxo and the like. Optional substituent R2may be in the ortho - or meta-position relative to the connection with (thio)urea functional group, but preferred is para-position.

Preferred optional substituents for R2include ethinyl, phenoxy, pyrid-1-yl, cyclopropyl, phenyl, halogen-substituted phenyl (especially para - and meta - chloro - and forfinal) and dimethylamino. The most preferred substituents R2include halogen (F, Br, Cl and I) and cyano. Preferred halogen groups include Cl.

In this case, the preferred value for R3is H.

R4preferably represents hydrogen, halogen or hydroxy, especially fluorine.

R5preferably represents halogen, C1-C3alkylsulphonyl,1-C3alkyloxy or N, especially fluorine and most predpochtitel what about N.

R6preferably represents hydrogen, halogen, C1-C3alkyloxy,1-C3alkylsulphonyl, cyano or ethinyl, especially methoxy or fluorine, and most preferably N.

R7preferably represents hydrogen, halogen, C1-C3alkyloxy or1-C3alkylsulphonyl, most preferably fluorine.

R5and R6preferably represent H, and R4andR7preferably represent halogen, most preferably both represent fluorine.

Preferably, D represents-O-, n is 0, m is 1, R1represents Oh, R2is replaced by pyrid-2-yl, and R3represents N. An alternative preferred embodiment includes compounds in which D represents-O-, n is 0, m is 1, R1is S, R2is replaced by pyrid-2-yl, and R3is N.

The compounds of formula I can be introduced in the form of a racemic mixture, but preferably the intermediate cyclopropyl fragment, (thio)urea functional group X and the phenyl ring (indicated below Y) are at least 75%, such as up to about 90%, enantiomerically pure with respect to conformation:

Preferred optical isomers of compounds of formula I show the negative value of the optical rotation. Such isomers, for example, when X is-O-CH2-as a rule, suiryudan less quickly from chiral chromatographic column, for example, chiral AGP 150 x 10 mm, 5 μm; Crom Tech LTD Colomn, flow rate 4 ml/min, the mobile phase 89%. 10 mm SPLA/NH4OAc in acetonitrile. Based on preliminary x-ray crystallographic analysis of the preferred configuration was:

In this case, the preferred value for D is-O-. The appropriate values for n and m include 1:0 and 1:1. Preferred values of n:m enable 0:2 and especially is 0:1, i.e. chromanone derived. Especially preferred compounds have the stereochemistry corresponding to (1S,1aR,7bR)-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-DRS. For the sake of clarity, it should be noted that the structure

Expression1-Cnalkyl, where n is equal to 3, 6, 7, etc., or lower alkyl includes groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, 3-methylpentyl and the like. The term halogen refers to chlorine, bromine, fluorine and iodine, especially fluorine. With1-Cnalkoxy refers to groups such as methoxy, ethoxy, propoxy, tert-butoxy and the like. With2-Cnalkenyl refers to groups such as vinyl, 1-propen-2-yl, 1-butene-4-and is, 1-penten-5-yl, 1-butene-1-yl and the like. With1-Cnalkylthio includes methylthio, ethylthio, tert-butylthio and the like. With1-Cnalkanoyloxy includes acetoxy, propionoxy, formyloxy, butyryloxy and the like. With2-Cnalkenone includes adenylate, propenyloxy, isobutoxide and the like. Halogens1-Cnalkyl (including complex substituents containing such a group, as Halogens1-Cnalkyloxy) includes alkali, as defined herein, substituted 1-3 times with halogen, including trifluoromethyl, 2-dichloroethyl, 3,3-direcrory and the like. The term amine includes groups such as the NH2, NHMe, N(Me)2which may be optionally substituted with halogen, C1-C7acyloxy,1-C6the alkyl, C1-C6alkoxy, nitro, carboxy, carbamoyl, carbamoylated, cyano, methylsulfonylamino etc. Carboxy, carboxymethyl and carbarnoyl include the corresponding pharmaceutically acceptable With1-C6alkalemia and arrowie esters.

Prodrugs of compounds of formula I are those compounds that after administration to the patient release in vivo of the compounds of formula I. Typical prodrugs are pharmaceutically acceptable ethers, and especially esters including esters of phosphoric acid), where any of R4-R7what if an optional substitute for R 2is functional hydroxy-group, pharmaceutically acceptable amides or carbamates, where any of the substituents R2or R4-R7represents a functional group amine, or pharmaceutically acceptable esters, where the substituent R2or R4-R7is functional carboxypropyl.

The compounds of formula I can form salts, which represent an additional aspect of the present invention. Suitable pharmaceutically acceptable salts of compounds of formula I include salts of organic acids, especially carboxylic acids, including, but not limited to, acetate, triptorelin, lactate, gluconate, citrate, tartrate, maleate, malate, Pantothenate, isetionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentane, glucoheptonate, glycyrrhizinate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, pivalate, comfort, undecanoate and succinate salts of organic sulfonic acids, such as methanesulfonate, aconsultant, 2-hydroxyethanesulfonic, camphorsulfonate, 2-naphthalenesulfonate, bansilalpet, p-chlorobenzenesulfonate and p-toluensulfonate; and inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, t is the cyanate, the persulfate salts of phosphoric and sulfonic acids.

Hidroxizina group, as used herein, refers to the Deputy, which protects hydroxyl groups against undesirable reactions during the synthesis process, for example, -O-protective groups disclosed in Greene, "Protective Groups in Organic Synthesis" (John Wiley & Sons, New York (1981)). Hydroxyamine groups include substituted simple methyl esters, for example, methoxymethyl, benzoyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, tert-butyl and other simple lower alkalemia esters, such as isopropyl, ethyl and especially methyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl simple esters, for example, 2,2,2-trichlorethylene; simple Silovye esters, for example, trimethylsilyloxy, tert-butyldimethylsilyloxy and tert-butyldiphenylsilyl; and esters, obtained by the interaction of the hydroxyl group with a carboxylic acid, for example, acetate, propionate, benzoate and the like.

The invention also provides pharmaceutical compositions containing the compounds of this invention and their pharmaceutically acceptable carriers or diluents. Additional aspects of the invention propose methods of inhibiting HIV, including the introduction of the compounds of formula I to a subject suffering from or Powergen the mu HIV-1. HIV-1 can include a mutant resistant to drugs, such as HIV strain comprising a mutation at 100, 103 and/or 181 provisions, especially K103N.

The invention also encompasses the use of compounds of formula I in therapy, such as making medicines for the treatment of HIV infections.

In the treatment of conditions caused by HIV, the compounds of formula I are preferably administered in amounts that are required to achieve the level of plasma of about 100-5000 nm, such as 300-2000 nm. This corresponds to the dosage, depending on the bioavailability of the composition, about 0.01-10 mg/kg/day, preferably 0.1 to 2 mg/kg/day. The usual dose to normal adult patient is about 0.05 to 5 g per day, preferably 0.1 to 2 g, for example, 500-750 mg, one to four unit doses per day. As with all pharmaceuticals, the dose will vary depending on weight and metabolism of the patient, and the severity of infection, and may be the need to adapt it to concomitant therapy.

In accordance with usual practice, the application of inhibitors of HIV is beneficial joint introduction of one to three additional antiviral drugs to obtain synergistic responses and to provide additional resistance. Such additional antiviral drugs can include AZT, dl, ddC, D4T, 3TC, DAPD, alovudine, abacavir, adefovir, adefovir dipivoxil, bis-POC-PMPA, GW420 867X, foscarnet, hydroxyurea, Hoechst-Bayer HBY 097, efavirenz, trovirdine, capravirine, nevirapine, delaviridine, tipranavir, emtricitabine, PFA, H2G (omalloor), MIV-606 (valomaciclovir stearate), TMC-126, TMC-125, TMC-120, efavirenz, DMP-450, lowered, ritonavir (including Kaletra, lopinavir, saquinavir, latinovic, indinavir, APV amprenavir, nelfinavir and the like, usually in molar ratios, reflecting their relative activity and bioavailability. Mainly, this ratio is about 25:1 to 1:25, relative to the compounds of formula I, but can be lower, for example, in the case of antagonists of cytochrome such as ritonavir.

Compounds of the invention are usually obtained in the following way:

Scheme 1

(a) DPPA, Et3N, toluene; (b) substituted 2-aminopyridine; (C) an aqueous solution of HCl, dioxane; (d) substituted 2-predilatation.

Compounds of General formula (I), where R1is O (urea) or S (thiourea), R2is, for example, 5-substituted of pyrid-2-yl, and R3represents H, obtained by the methods shown in scheme 1. Cyclopropanecarbonyl acid 1-Scheme-1 is transformed into acylated and heated to 120°to induce the rearrangement of kurzius (Curtius) and get isocyanate, 2-Scheme-1. Urea-Scheme-1 is produced by reaction of a combination of isocyanate with appropriately substituted 2-aminopyridine. Hydrolysis of the isocyanate, both at the stage (C), leading to cyclopropylamino 4-Scheme-1, followed by reaction with 2-pyridinethione gives thiourea 5-Scheme-1. Isothiocyanate can be obtained from optionally substituted on the ring of 2-aminopyridine by known methods such as treatment with thiophosgene or thiocarbonyldiimidazole. R3formula options I receive, respectively, using appropriate aminamiens amino-R2i.e. 2-(N-methylamino)pyridine, for R3in the form of bromide. Many 2-aminopyridines are commercially available, and others described in the literature, such as those shown in scheme 2. Compounds where R1=S alternative can be obtained from isothiocyanate corresponding 2-Scheme-2, or from amine 3-Scheme-2 and amino-R2in combination with RC(=S)R', both as described in No. WO 9303022. Although scheme 1 is illustrated with the use of substituted pyridyl, obviously, can be used in appropriate combinations for the other R2options, such as optionally substituted thiazolyl, pyrazinyl, benzothiazolyl, pyrimidinyl etc.

Scheme 2

(a) phenol, NaH, DMF; (b) 10% Pd/C, H21 ATM, EtOH; (C) PdCl2(PPh3)2trimethylsilylacetamide, CuI, Diisopropylamine; (d) fluoride tert-butylamine.

The substitution of bromine in 5-bromo-2-n is terpyridine phenoxypropane and subsequent reduction of the nitro group gives 2-amino-5-phenoxypyridine. The combination Sonogashira (Sonogashira) 2-amino-5-iodopyridine with limit Alcina SiMe3C≡CH in the presence of catalytic amounts dichloride bis(triphenylphosphine)palladium and copper iodide, both at the stage (C), gives 2-amino-5-(2-trimethylsilylethynyl)pyridine. Removing silyl group using TBAF leads to 2-amino-5-ethynylpyridine, which can be subjected to a reaction mix as described in scheme 1. Alternatively, the processing TBAF can be carried out with urea 3-Scheme-1 or thiourea 5-Scheme-1, where R10is- ≡CSiMe3to convert R10in≡CH.

Scheme 3

(a) ethyl diazo acetate, catalyst, CH2Cl2; (b) chromatography and then boiling under reflux with LiOH, H2O, MeOH; (C) boiling under reflux with LiOH, H2O, MeOH and then chromatography; (d) room temperature, NaOH, H2O, MeOH and then boiling under reflux with LiOH, H2O, MeOH.

Compounds of General formula (I), where R1is O (urea) or S (thiourea), R2is, for example, 5-substituted of pyrid-2-yl, R3represents H, X represents-D-CH2and where cyclopropyl fragment has a relative configuration

get the methods shown in scheme 3. Cyclopropylamine double the ligature in chromene 1-Scheme-3 ethyl diazo acetate catalyzed by copper salts or rhodium(II), such as CuI, (CuOTf)2-benzene, and Rh2(OAc)4in solvents such as dichloromethane, 1,2-dichloroethane or chloroform. The reaction gives diastereomer mixture of ethyl esters cyclopropanecarbonyl acid 2-Scheme-3 with a relative configuration for all CIS-isomers of 3-Scheme-3 for their TRANS-isomers. The separation column chromatography CIS - and TRANS-diastereomers can be performed at this stage with subsequent hydrolysis of 2-Scheme-3, for example, by boiling under reflux in an aqueous methanol solution of LiOH to obtain racemic mixture of all CIS-isomers cyclopropanecarbonyl acid 4-Scheme-3, as described in stage (b). Alternatively, diastereomer mixture of ethyl esters can be subjected to hydrolysis and separation carried out on a mixture of cyclopropanecarboxylic acids, emitting only the CIS-isomer of the product, both at the stage (C). Stage (d) includes the allocation of CIS-ethyl ether complex 2-Scheme-3, which can also be obtained by selective hydrolysis of the TRANS-compound 3-Scheme-3 at low temperatures, for example, processing water methanol solution of NaOH at ambient temperature. Selected CIS-ethyl ester can then be hydrolyzed in the usual way to cyclopropanecarbonyl acid 4-Scheme-3. Cyclopropanecarbonyl acid is subjected to a processing method and, as shown in scheme 1, to obtain a urea or thiourea 5-Scheme-3. The chromenes 1-Scheme-3 is produced by the methods shown in schemes 4, 5 and 6.

Although figure 3 illustrates the variation with D=O, it should be clear that the possible appropriate manipulation of D=S, S=O; S(=O)2and D=NR8options. When R8is N, the nitrogen is usually protected by conventional protecting group of the secondary amine, such as described in Greene &Wuts, Protective Groups in Organic Synthesis 2nded, Wiley NY (1991).

Scheme 4

(a) 3-bromopropyl, K2CO3, acetone; (b) N,N-diethylaniline or PEG-200, 225°C.

Scheme 4 describes the obtaining of chromenes, including many of the commercially available disubstituted phenols, such as those in which the substitution in the benzene ring is as follows: R4and R7represent halogen; R4and R6represent halogen; R5and R7represent halogen; R4represents halogen and R7is1-3alkylsulphonyl; and R4represents hydroxy, whereas R5is1-3alkylsulphonyl. Reaction available disubstituted phenol 1-Scheme-4 from 3-bromopropane in the presence of a base, such as2CO3in acetone or NaH in DMF leads to nucleophilic substitution of the halide with getting simple EPE is a 2-Scheme-4. Ring closure can be carried out by heating the ester in N,N-dimethylaniline or polyethylene glycol getting chromene 3-Scheme-4.

Scheme 5

(a) NaBH4, EtOH; (b) p-toluensulfonate acid, toluene, boiling under reflux.

Scheme 5 describes the obtaining of chromenes used as the starting material in scheme 3, from an appropriately substituted chromanones, which are easily accessible from commercially available chromanones, such as one of the provisions in the R4-R7substituted with halogen or1-3alkoxy. Conversion of the carbonyl group in the 4-chromanone 1A-Scheme-5 and to the corresponding alcohol using a suitable reducing agent such as sodium borohydride in ethanol gives 2-Scheme-5. Boiling under reflux alcohol with small amounts of acid, such as p-TsOH in toluene, causes dehydration of 2-Scheme-5 to the desired chromene 1-Scheme-3. Appropriate manipulations are possible for other options D. for Example, the corresponding 2H-1-benzothiophen can be easily obtained from commercially available (substituted) thiochroman-4-ones by reaction with a reducing agent, such as a metal hydride, for example, socialogical, in an organic solvent, such as ether, followed by dehydration, such as pachanee under reflux with acid, for example, acidic potassium sulfate or similar.

Scheme 6

(a) allylbromide, K2CO3, acetone; (b) Ph3PCH3Br, NaH, THF; (C) Cl2[Pcy3]2Ru=CHPh, CH2Cl2; (d) Ph3P+CH=CH2Br-, DBU.

The chromenes for use as starting material in scheme 3 are obtained from substituted o-hydroxybenzaldehyde, as illustrated by the methods of schemes 6. The reaction of 1-Scheme 6 with allylbromide in the presence of a base, such as2CO3in acetone, results in nucleophilic substitution of the halide with simple ether 2-Scheme-6. By reaction of Witting (Witting) aldehyde group into olefin and get 3-Scheme-6. A pair of terminal double bonds can undergo intramolecular exchange by treatment with a catalyst, such as catalyst Grabba (Grubb) on the basis of a complex of ruthenium, at the stage (C) obtaining chromene. Alternative 1-Scheme 6 can be cycletour directly, as shown in stage (d) in the description of the diagram above.

Scheme 7

(a) Pd(O), DPPP, Et3N, (CH3)3SiC≡CH; (b) Pd(O), butylvinyl ether, DMF; (C) Pd(O), Zn(CN)2, DMF; (d) NaOH, H2O, MeOH. Catalyzed by Pd(O) the reaction of a combination of triflate 1-Scheme-7 leads to the replacement of cryptomaterial is philosophy and the introduction of other substituents at R 6. Thus, the circuit 7 is to obtain a synthesized intermediate compounds for use in scheme 3 to obtain a urea or thiourea 5-Scheme-3, where R6represents cyano, ethinyl or1-3alkylsulphonyl.

Scheme 8

(a) BuLi/ZnCl2, THF; Pd(OAc)2, BrCH=CHCOOEt; DIBAL

(b) TsNHN=CHCOCl; PhNMe2NEt3CH2Cl2

(c) Rh2(5-R-MEPY)4, abs. degassed dichloromethane

(d) 30% HBr, AcOH

(e) NaOH, H2O(f) NaOH; CO2; I-PrI/DMSO

(g) iPrOH, HCl; DEAD, PPh3, THF

(h) NaOH, MeOH:H2O

(i) 1. BBr3CH2Cl22. CH3CN 3. NaOH, water

(j) 1. BuLi/ZnCl2, THF; Pd(OAc) 2. connection 9-Scheme-8 3. reagent Jones (Jones) (chromic acid, sulfuric acid in acetone).

A convenient way of producing compounds in which X represents-CH2"Oh, is shown in scheme 8, where Raand Rbrepresent optional substituents R4-R7which are suitably protected, if necessary, suitable protective groups, and Rwithrepresents a complex lower alkilany ether. Optionally substituted phenol 1-Scheme-8, which is hydroxyamine protecting group, such as methyl, IOM and the like, is subjected to the interaction with the base, such as BuLi or the like, in a solvent such as TG is or similar, and turned into salt adding zinc chloride zinc or similar. A catalyst, such as Pd(OAc)2or similar, add together with activated acrylate, such as lower alkyl-CIS-3-halogencat, for example, BrCH=CHCOOEt or similar. The reaction mixture is cooled and portions add a reducing agent such as DIBAL or the like, and the reaction quenched with getting on the yield of 2-Scheme-8. Hydrazone, such as p-toluensulfonate or Glyoxylic acid, acid chloride or the like, and a base, such as N,N-dimethylaniline or the like, add in a solvent such as CH2Cl2or similar, followed by the addition of another base such as Et3N or similar, with 3-Scheme-8. The reaction product is dissolved in a solvent such as dichloromethane or the like, which is preferably degassed. Add chiral catalyst Doyle (Doyle), such as Rh2(5-R-MEPy)4(US 5175311, available from Aldrich or Johnson Matthey) or the like, to obtain 4-Scheme-8 in a large enantiomeric excess, for example, more than 80%, preferably more than 90%. Preferably, this compound is first subjected to interaction with BBr3in dichloromethane and then adding to the reaction mixture of acetonitrile and in the end add the sodium hydroxide to obtain 6-Scheme-8. Alternatively, the product of the t (4-Scheme-8) is subjected to reaction disclosure rings in the presence of the electrophile, preferably, HBr or the like, in combination with an acid, such as Asón or similar. In acidic conditions is spontaneous ring closure with the formation of chromenone 5-Scheme-8. When exposure is carried out in basic conditions such as NaOH or the like, chromene programmirovaniya education romanticloverboy acid 6-Scheme-8. Alternatively, the compound 4-Scheme-8, for example, in the case of phenolic protective group is a IOM, the interaction may be carried out in basic conditions such as NaOH in the presence of carbon dioxide and low alkylhalogenide, such as iPrI, in a solvent such as DMSO, which leads to the opening of the lactone and receiving complex Olkiluoto ether 7-Scheme-8. Substitution hydroxyamino group and ring closure free hydroxymethylene fragment takes place in acidic conditions, such as iPrOH/HCl or the like, followed by treatment of the DEAD; PPh3in an organic solvent such as THF or the like.

Alternatively, in another approach, compound 1-Scheme-8 is subjected to interaction with BuLi and transformed into a salt of zinc. This salt is subjected to interaction with cyclopropylidene, 9-Scheme 8, the reaction catalyzed by palladium, obtaining, after the reaction with the reagent Jones (Jones) compound 4-Scheme-8. This carboxylic acid, in its ocher is d', converted into isocyanate, as shown in figure 1, and then in heteroarylboronic or heteroaromatic formula I.

Another aspect of the invention offers a new intermediate compounds used in the above-described methods for obtaining the compounds of formula I. Preferred group of intermediates includes compounds of formula II:

where X and R4-R7are as defined above, and R11represents-C(O)OR12where R12represents H or carboxyamide group, such as a complex lower alkilany ether; -NCO, -NCS or amine, such as NH2. A preferred subgroup of compounds of formula II has the formula III:

where R4and R7are independently halogen, most preferably fluorine, and R11represents-COOH, its complex lower alkilany ether, isocyanate, isothiocyanate or amino.

The next group of preferred intermediates include compounds of formula IV

where R4-R7are as defined above, PG is hydroxyamino group and PG*is hydroxyamino group or together with the adjacent atom means Of functional ketogroup.

A preferred subgroup of compounds is s formula IV are compounds of the formula V:

where R4and R7independently represent halogen, most preferably fluorine, PG represents lower alkyl, such as isopropyl, ethyl and, most preferably, methyl, and PG*represents lower alkyl, such as isopropyl, ethyl and most preferably methyl, or together with an adjacent atom Of means ketogroup.

Another group of preferred intermediates include compounds of formula VI:

where R4-R7are as defined above, PG is hydroxyamino group, and R13represents H, ester or hydroxyamino group. A preferred subgroup of formula VI has the formula VII:

where R4and R7are independently halogen, preferably fluorine, PG represents lower alkyl, such as isopropyl, ethyl and most preferably methyl, and R12represents H or-C(=O)CH=N=N.

Preferred compounds of formula I include the

CIS-1-(5-cyano-2-yl)-3-(1,1a,2,7b-tetrahydrocyclopent[c|chromen-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-(6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(7-fluoro-4-methoxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-1-(5-chloropyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-1-(5-bromopyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(5-cyano-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(5-ethinyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-1-(5-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea,

CIS-1-(5-methoxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(N-acetyl-1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]quinoline-1-yl)urea,

CIS-1-(5-cyano-3-methylpyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-1-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-ethynylpyridine-2-yl)urea,

CIS-1-(5-bromopyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-1-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-phenoxypyridine-2-yl)urea,

CIS-1-(5-cyano-2-is)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)thiourea,

1-(6-chloro-5-cyanopyridine-2-yl)-3-(5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

1-(5-cyano-2-yl)-3-(5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-1-(4-bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea,

CIS-1-(4-bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(6-chloro-5-cyanopyridine-2-yl)urea,

CIS-1-(4-bromo-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea,

CIS-1-(4-bromo-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(6-chloro-5-cyanopyridine-2-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-N-[1a,6b-dihydro-1H-benzo[b]cyclopropa[d]Tien-1-yl]-N'-(5-cyano-2-pyridinyl)urea,

N-[(1S,1aR,7bR) or (1R,1aS,7bS)-1,1a,2,7b-tetrahydrocyclopent[c][1]benzothiophen-1-yl]-N'-(5-cyano-2-pyridinyl)urea,

CIS-N-(5-bromo-2-pyridinyl)-N'-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-N'-(5-chloro-2-pyridinyl)urea,

CIS-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-N'-(5-cyano-2-pyridinyl)urea,

CIS-N-(5-phenoxy-2-pyridinyl)-N'-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-N-(5-bromo-2-pyridinyl)-N'-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-N-(5-chloro-2-pyrid the Nile)-N'-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

CIS-N-(5-cyano-2-pyridinyl)-N'-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(5-fluoro-2-pyridinyl)urea,

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(5-iodine-2-pyridinyl)urea,

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(3-isoxazolyl)urea,

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]urea,

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(6-fluoro-1,3-benzothiazol-2-yl)urea,

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(4-pyrimidinyl)urea,

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(2-pyrazinyl)urea,

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(5-cyclopropyl-1H-pyrazole-3-yl)urea

and their pharmaceutically acceptable salts, especially enantiomerically enriched, for example, more than 80% by weight, preferably >90%, namely >97% EE, or pure drugs, including (-)enantiomer.

Particularly preferred compounds thus include

(-)-CIS-1-(5-cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

(-)-CIS-1-(5-chloropyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea; or

(-)-CIS-1-(5-cyano-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)thiourea;

(-)-CIS-1-(5-herperidin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea,

(-)-CIS-1-(5-herperidin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)thiourea;

and their pharmaceutically acceptable salts.

Although it is possible to introduce active agent separately, it is preferable to present as part of a pharmaceutical composition. This composition contains the above-defined active agent together with one or more acceptable carriers or excipients and optionally other therapeutic ingredients. The carrier(s) must be acceptable in terms of its compatibility with other ingredients of the composition and harmless for the recipient.

The compositions include compositions suitable for rectal, nasal, local (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, but preferably the composition is a composition for oral administration. The composition can be appropriately presented in the form of a unit dosage forms such as tablets and capsules delayed release, and can be obtained by any means known in the pharmaceutical field.

These include the stage of combining the active agent is, defined above, with a carrier. Mainly, the composition is produced by a homogeneous combining the active agent with liquid carriers or finely powdered solid carriers, or both, and then, if necessary, shaping the product. The invention also relates to methods of obtaining pharmaceutical compositions comprising combining or joining of the compounds of formula I or its pharmaceutically acceptable salt with a pharmaceutically acceptable carrier or solvent. If the manufacture of pharmaceutical compositions include a close mixture of pharmaceutical excipients and the active ingredient in the form of a salt, in this case often is the preferred use of excipients that are not basic in nature, i.e. they are either acidic or neutral. Compositions for oral administration in the present invention can be presented in the form of separate units such as capsules, sachets or tablets each containing a predetermined amount of the active agent; as powders or granules; as solution or suspension of the active substance in aqueous liquids or non-aqueous solution of the liquid; or in the form of a liquid emulsion oil-in-water or liquid emulsion, water-in-oil, or bolus, etc.

In regard to compositions for oral administration (e.g. the R, tablets and capsules), the term "suitable carrier" includes solvents, such as commonly used excipients such as binding agents, for example syrup, gum acacia, gelatin, sorbitol, tragakant, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethyl cellulose, hypromellose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; lubricants such as magnesium stearate, sodium stearate and other metallic stearates, stearic acid, glitzenstein, silicone fluid, talc waxes, oils and colloidal silicon dioxide. Can also be used for flavouring agents such as peppermint, oil of Grushenka, cherry flavouring or similar. Optionally, you can add dye to make the dosage form is easily recognizable. Tablets can also be coated by methods well known in the field. The tablet can be obtained by extrusion or molding, optionally with one or more additional ingredients. Molded tablets can be obtained by compressing in a suitable machine the active agent in free-flowing form such as powder or granules, obazatelno mixed with a binding agent, a wetting agent, inert diluent, preservative, surface-active agent or dispersant. Molded tablets can be obtained by molding in a suitable machine a mixture of the powdered compound moistened inert liquid diluent. Tablets may not necessarily be covered or marked and can be designed in such a way as to provide slow or controlled release of the active agent.

Other compositions suitable for oral administration include pellet containing the active agent in a flavored basis, usually sucrose or gum acacia or tragakant; lozenges comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and Arabian gum; and a liquid for rinsing the mouth, including an active agent in a suitable liquid carrier.

Detailed description of the invention

Various aspects of the present invention will be illustrated only with reference to the following non-limiting examples.

Example 1

(±)-CIS-1-(5-Cyano-2-yl)-3-(1,1a,2,7b-tetrahydrocyclopent[c|chromen-1-yl)urea

a) Ethyl ester (±)-CIS-1,1a,2,7b-tetrahydrocyclopent[c|chromen-1-carboxylic acid

To a mixture of 2H-chromene (4,89 g, 37 mmol) and (CuOTf)2-benzene (186 mg, and 0.37 mmol) in 1,2-dichl is retene (80 ml) at 20° With added dropwise (3 hours) a solution of ethyl diazo acetate (8,44 g, 74 mmol) in 1,2-dichloroethane (20 ml). After 15 min at 20°the reaction mixture is washed with N2O (100 ml). H2About phase was washed CH2Cl2(50 ml) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was chromatographically on column (silica gel, 20→50% EtOAc in hexane) to give a 1.96 g (24%) ethyl ester (±)-CIS-1,1a,2,7b-tetrahydrocyclopent[c|chromen-1-carboxylic acid and a 3.87 g (48%) of ethyl ether (±)-TRANS-1,1a,2,7b-tetrahydrocyclopent[c|chromen-1-carboxylic acid as a by-product.

1H-NMR (CDCl3): 7,26 (d, 1H), 7,10 (DD, 1H), 6.90 to (DD, 1H), 6,78 (d, 1H), 4,49 (DD, 1H), 4,20 (DD, 1H), of 3.97 (q, 2H), 2,44 (DD, 1H), and 2.14 (DD, 1H), 2,07-of 1.95 (m, 1H), of 1.02 (t, 3H).

b) (±)-CIS-1,1a,2,7b-Tetrahydrocyclopent[c|chromen-1-carboxylic acid

A mixture of ethyl ether (±)-CIS-1,1a,2,7b-tetrahydrocyclopent[c|chromen-1-carboxylic acid (1,96 g, 9.0 mmol), LiOH (539 mg to 22.5 mmol), N2About (10 ml) and Meon (20 ml) was boiled under reflux for 2 hours. The reaction mixture was concentrated to about 10 ml, was added dropwise 4N HCl to obtain a white precipitate. The reaction mixture was extracted with CH2Cl2(G ml) and the solvent of the combined organic phases was removed under reduced pressure. Neocidin the th product has led from a mixture of EtOAc/hexane to obtain 435 mg (25%) (± )-CIS-1,1a,2,7b-tetrahydrocyclopent[c|chromen-1-carboxylic acid in the form of a solid white color.

1H-NMR (CDCl3): 9,80 (users, 1H), 7,22 (d, 1H), 7,10 (DD, 1H), 6.89 in (DD, 1H), 6,77 (d, 1H), 4,45 (DD, 1H), 4,22 (DD, 1H), 2,45 (DD, 1H), 2,14-to 1.98 (m, 2H).

C) (±)-CIS-1-(5-Cyano-2-yl)-3-(1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

To a solution of (±)-CIS-1,1a,2,7b-tetrahydrocyclopent[c|chromen-1-carboxylic acid (285 mg, 1.5 mmol) and triethylamine (209 μl, 1.5 mmol) in toluene (1.5 ml) at 20°With added diphenylphosphoryl (413 mg, 1.5 mmol). After 30 min at 20°the reaction mixture was heated to 120°C for 15 min, then was added a solution of 2-amino-5-cyanopyridine (197 mg, of 1.65 mmol) in DMF (1 ml). After 3 hours at 120°the reaction mixture was left to reach room temperature. The reaction mixture was concentrated under reduced pressure, was added benzene (20 ml) and the reaction mixture is washed with 1N HCl (30 ml), N2O (30 ml) and saturated salt solution (30 ml). The organic solvent phase was removed under reduced pressure. The crude product was led from EtOH/CH2Cl2to obtain 133 mg (29%) (±)-CIS-1-(5-cyano-2-yl)-3-(1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea.

1H-NMR (DMSO-d6): 9,78 (s, 1H), 8,31 (d, 1H), to 7.99 (DD, 1H), 7,83 (d, 1H), 7,43 (d, 1H), 7,27 (d, 1H), to 7.09 (DD, 1H), 6.89 in (DD, 1H), 6,80 (d, 1H), 4,25 (DD,1H), to 4.14 (DD, 1H), 3.43 points (m, 1H), 2,35 (DD, 1H), 1,92 (m, 1H).

Example 2

(±)-CIS-1-(5-Cyano-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-yl)urea

a) Ethyl ester (±)-CIS-1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-carboxylic acid

Ethyl ether (±)-CIS-1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-carboxylic acid was synthesized analogously to example 1A from 1H-isochroman (3.57 g, 27 mmol) to give 910 mg (15%) ethyl ester (±)-CIS-1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-carboxylic acid.

1H-NMR (CDCl3): 7,34 (d, 1H), 7,25 (DD, 1H), 7,18 (DD, 1H), 7,03 (d, 1H), 4,81 (d, 1H), 4,51 (d, 1H), 4,28 (DD, 1H), 3,95 (kV, 2H), 2,43 (DD, 1H), 2,05 (DD, 1H), was 1.04 (t, 3H).

b) (±)-CIS-1,1a,3,7b-Tetrahydro-2-oxacyclopropane[a]naphthalene-1-carboxylic acid

(±)-CIS-1,1a,3,7b-Tetrahydro-2-oxacyclopropane[a]naphthalene-1-carboxylic acid was synthesized analogously to example 1b from ethyl ether (±)-CIS-1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-carboxylic acid (436 mg, 2 mmol) to give 86 mg (22%) (±)-CIS-1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-carboxylic acid in the form of a solid white color. The crude product was chromatographically on column (silica gel, 1→5% Meon in CH2Cl2).

1H-NMR (CDCl3): 8,50 (users, 1H), 7,39 (d, 1H), 7,30 (DD, 1H), 7,21 (the d, 1H), 7,07 (d, 1H), 4,87 (d, 1H), 4,57 (d, 1H), to 4.38 (DD, 1H), 2,59 (DD, 1H), 2,15 (DD, 1H).

C) (±)-CIS-1-(5-Cyano-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-yl)urea

(±)-CIS-1-(5-Cyano-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-yl)urea was synthesized analogously to example 1C from (±)-CIS-1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-carboxylic acid (86 mg, 0.45 mmol). The crude product was chromatographically on column (silica gel, 1→5% Meon in CH2Cl2) to obtain 21 mg (15%) (±)-CIS-1-(5-cyano-2-yl)-3-(1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-yl)urea.

1H-NMR (DMSO-d6): 9,62 (s, 1H), 8,29 (d, 1H), 7,98 (DD, 1H), 7,52-7,44 (m, 2H), 7,27-7,05 (m, 4H), 4,69 (d, 1H), 4,45 (d, 1H), of 4.05 (DD, 1H), 3.25 to 3,10 (m, 1H), 2,22 (DD, 1H).

Example 3

(±)-CIS-1-(5-Cyano-2-yl)-3-(7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

a) 1-(2-Hydroxy-4-prop-2-injectively)propane-1-he

A mixture of 2',4'-dihydroxybenzophenone (24,9 g, 0.15 mol), 3-bromopropene (24.2 g, 0.20 mol) and K2CO3(20.7 g, 0.15 mol) in acetone (500 ml) was boiled under reflux for 12 hours. The reaction mixture was left to reach room temperature and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The crude product is cleaned and column chromatography (silica gel, 0→2% Meon in N2A) obtaining 26,2 g (85%) of 1-(2-hydroxy-4-prop-2-injectively)propane-1-it.

1H-NMR (CDCl3): 12,80 (s, 1H), 7,69 (d, 1H), of 6.52 (m, 2H), 4.72 in (d, 2H), 2,96 (kV, 2H), 2,56 (t, 1H), 1,23 (t, 3H).

3b) 1-(5-Hydroxy-2H-chromen-6-yl)propan-1-he

A mixture of 1-(2-hydroxy-4-prop-2-injectively)propane-1-it (19,8 g, 97 mmol) and N,N-diethylaniline (100 ml) was boiled under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified column chromatography (silica gel, 5→10% EtOAc in hexane) and then recrystallized from a mixture of EtOAc/hexane to obtain 8,91 g (45%) of 1-(5-hydroxy-2H-chromen-6-yl)propan-1-it.

1H-NMR (CDCl3): 13,00 (s, 1H), 7,49 (d, 1H), 6.75 in (dt, 1H), 6,27 (d, 1H), 5,67 (dt, 1H), a 4.86 (DD, 2H), 2,90 (kV, 2H), 1,19 (t, 3H).

3C) Ethyl ester of 7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

To a mixture of 1-(5-hydroxy-2H-chromen-6-yl)propan-1-it (511 mg, 2.5 mmol) and Rh(II)Ac2)2(11 mg, of 0.025 mmol) in 1,2-dichloroethane (8 ml) at 20°With added dropwise (3 hours) a solution of ethyl diazo acetate (571 mg, 5 mmol) in 1,2-dichloroethane (2 ml). After 20 min at 20°the reaction mixture is washed with N2About (10 ml). H2About phase was washed CH2Cl2(10 ml) and the solvent of the combined organic phases was removed under reduced Yes the tion. The crude product was purified column chromatography (silica gel, 1→5% Meon in CH2Cl2) to obtain 300 mg (41%) of ethyl ester of 7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (mixture 33/64 CIS - and TRANS-isomers).

1H-NMR (CDCl3): 13,13-13,07 (m, 1H), EUR 7.57-7,49 (m, 1H), 6,41-6,38 (m, 1H), 4,65-to 3.92 (m, 4H), 3,01-of 1.95 (m, 5H), 1,29-a 1.08 (m, 6H).

3d) (±)-CIS-7-Hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

(±)-CIS-7-Hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid was synthesized analogously to example 2b from the ethyl ester of 7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (299 mg, 1,03 mmol, mixture 33/64 CIS - and TRANS-isomers) with getting to 39.3 mg (15%) (±)-CIS-7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid in the form of a solid white color and (±)-TRANS-7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid as a byproduct. The crude product was purified column chromatography (silica gel, 1→5% Meon in CH2Cl2).

1H-NMR (DMSO-d6): to 7.67 (d, 1H), 6.35mm (d, 1H), 4,57 (DD, 1H), 4,36 (DD, 1H), 2,98 (kV, 2H), 2,55 is 2.46 (m, 1H), 2,18 is 2.00 (m, 2H), 1,10 (t, 3H).

3E) (±)-CIS-1-(5-Cyano-2-yl)-3-(7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydro what ecoprobe[c]chromen-1-yl)urea

(±)-CIS-1-(5-Cyano-2-yl)-3-(7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was synthesized analogously to example 1C from (±)-CIS-7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (39,3 mg, 0.15 mmol). The crude product was purified HPLC (C18, 5→95% acetonitrile in H2A) obtaining a 2.9 mg (5,1%) (±)-CIS-1-(5-cyano-2-yl)-3-(7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea.

1H-NMR (DMSO-d6): 13,15 (s, 1H), 9,71 (s, 1H), 8.30 to (d, 1H), 8,01 (DD, 1H), 7,73 (d, 1H), EUR 7.57 (d, 1H), 7,50 (d, 1H), gold 6.43 (d, 1H), 4,42 (DD, 1H), 4,13 (DD, 1H), 3.45 points-of 3.32 (m, 1H), 3,01 (kV, 2H), 2,49-to 2.42 (m, 1H), 1,97-1,86 (m, 1H), 1,12 (t, 3H).

Example 4

(±)-CIS-1-(6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea

4A) 1-(2-Hydroxy-4-prop-2-injectively)alanon

1-(2-Hydroxy-4-prop-2-injectively)Etalon synthesized analogously to example 3A from 1-(2,4-dihydroxyphenyl)ethanone (20 g, 131 mmol) to give 22 g (88%) of 1-(2-hydroxy-4-prop-2-injectively)ethanone.

1H-NMR (CDCl3): 12,70 (s, 1H), 7,66 (d, 1H), of 6.52 (m, 2H), 4.72 in (d, 2H), 2,58 is 2.55 (m, 4H).

4b) 1-(5-Hydroxy-2H-chromen-6-yl)alanon

1-(5-Hydroxy-2H-chromen-6-yl)Etalon synthesized analogously to example 3b from 1-(2-hydroxy-4-prop-2-injectively)this is it (17 g, 89 mmol) to give 6.0 g (35%) of 1-(5-hydroxy-2H-chromen-6-yl)ethanone.

1H-NMR (CDCl3): 12,92 (s, 1H), 7,51 (d, 1H), 6,79 (dt, 1H), 6,32 (d, 1H), 5,71 (dt, 1H), 4,89 (DD, 2H), by 2.55 (s, 3H).

4C) Ethyl ester of 6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Ethyl ester of 6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (40/60 mixture of CIS - and TRANS-isomers) was synthesized analogously to example 3 from 1-(5-hydroxy-2H-chromen-6-yl)ethanone.

1H-NMR (CDCl3): of 13.05-12,97 (m, 1H), 7,54-7,47 (m, 1H), to 6.43-6,33 (m, 1H), 4.63 to-3,94 (m, 4H), 3,02 is 1.96 (m, 6H), 1,31-1,08 (m, 3H).

4d) 6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid was synthesized analogously to example 1b from the ethyl ester of 6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (2 g, 8.1 mmol, 40/60 mixture of CIS - and TRANS-isomers) to obtain 300 mg (17%) of 6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (40/60 mixture of CIS - and TRANS-isomers). The crude product was purified column chromatography (silica gel, 1→5% Meon in CH2Cl2).

1H-NMR (CDCl3): 7,55 was 7.45 (m, 1H), 6,45-6,30 (m, 1H), 4,65-4,00 (m, 2H), 3,05-of 1.95 (m, 6H).

4E) (±)-CIS-1-(6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydro is coprop[c]chromen-1-yl)-3-(5-cyano-2-yl)urea

(±)-CIS-1-(6-Acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea was synthesized analogously to example 1C from 6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (300 mg, to 1.21 mmol, 40/60 mixture of CIS - and TRANS-isomers). The crude product was purified HPLC (C18, 5→95% acetonitrile in H2A) obtaining 7.7 mg (17%) (±)-CIS-1-(6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea and 9.0 mg (20%) (±)-TRANS-1-(6-acetyl-7-hydroxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea as a by-product.

1H-NMR (CDCl3+CD3OD): 7,98 (d, 1H), 7,74 (DD, 1H), 7,60 (d, 1H), 7,01 (d, 1H), 6,40 (d, 1H), 4,43 (DD, 1H), 4,29 (DD, 1H), only 3.57 (DD, 1H), 2,69 (m, 1H), 2,61 (s, 3H), 2.00 in to 1.86 (m, 1H).

Example 5

(±)-CIS-1-(5-Cyano-2-yl)-3-(7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

5A) 1-(4-fluoro-2-prop-2-injectively)propane-1-he

To a mixture of NaH (95%, 278 mg, 11 mmol) in DMF (20 ml) at 0°C was added 1-(4-fluoro-2-hydroxyphenyl)propane-1-he (1.68 g, 10 mmol) in DMF (5 ml). After 15 min at 0°to the reaction mixture were added 3-bromopropene (to 3.02 g, 20 mmol). After 1 hour at 0°the reaction mixture was left to reach room temperature. The reaction mixture was extracted with N2/sub> O (100 ml). H2About phase washed with Et2O (g ml) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was purified column chromatography (silica gel, CH2Cl2) to obtain 1.40 g (68%) of 1-(4-fluoro-2-prop-2-injectively)propane-1-it.

1H-NMR (CDCl3): to 7.64 (DD, 1H), 6,69 (DD, 1H), 6,60 (DDD, 1H), and 4.68 (d, 2H), 2,85 (kV, 2H), 2,58 (t, 1H), of 1.03 (t, 3H).

5b) 1-(5-fluoro-2H-chromen-8-yl)propane-1-he

1-(5-fluoro-2H-chromen-8-yl)propane-1-he synthesized analogously to example 3b from 1-(4-fluoro-2-prop-2-injectively)propane-1-it (1,34 g, 6.5 mmol) to give 619 mg (46%) of 1-(5-fluoro-2H-chromen-8-yl)propane-1-it.

1H-NMR (CDCl3): 7,60 (DD, 1H), 6,67 return of 6.58 (m, 2H), 5,86 (dt, 1H), amounts to 4.76 (DD, 2H), 2,93 (kV, 2H), of 1.23 (t, 3H).

5C) Ethyl ester (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Ethyl ether (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid was synthesized according to method 3C) of 1-(5-fluoro-2H-chromen-8-yl)propane-1-she (619 mg, 3 mmol) to give 142 mg (16%) ethyl ester (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid ethyl ester (±)-TRANS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid as a by-product is the same.

1H-NMR (CDCl3): to 7.59 (DD, 1H), 6,65 (m, 1H), 4,50-to 4.46 (m, 2H), 3,95 (kV, 2H), 2,89 (kV, 2H), 2.57 m (DD, 1H), measuring 2.20 (DD, 1H), 1,13-of 1.03 (m, 1H), 1,12-a 1.01 (m, 6H).

5d) (±)-CIS-7-Fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

(±)-CIS-7-Fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid was synthesized analogously to example 1b from ethyl ether (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (140,3 mg, 0.48 mmol) to give 83 mg (65%) (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid in the form of a solid white color. The crude product was purified column chromatography (silica gel, 1→5% Meon in CH2Cl2).

1H-NMR (DMSO-d6): 12,15 (users, 1H), 7,46 (DD, 1H), 6,78 (DD, 1H), 4,57 (DD, 1H), 4,43 (DD, 1H), 2.93 which is 2.80 (m, 2H), by 2.55 (DD, 1H), 2,24 (DD, 1H), 2,20-2,10 (m, 1H), of 1.02 (t, 3H).

5e) (±)-CIS-1-(5-Cyano-2-yl)-3-(7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-1-(5-Cyano-2-yl)-3-(7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was synthesized analogously to example 1C from (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (81,9 mg, 0.31 mmol). The crude product was purified HPLC (C18, 5→95% acetone is trila in N 2About) to obtain 12 mg (10%) (±)-CIS-1-(5-cyano-2-yl)-3-(7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea.

1H-NMR (DMSO-d6): 9,81 (s, 1H), with 8.33 (d, 1H), 8,04 (DD, 1H), 7,83 (users, 1H), 7,49-7,40 (m, 2H), 6.89 in (DD, 1H), to 4.41 (DD, 1H), 4,34 (DD, 1H), 3.46 in-to 3.38 (m, 1H), was 2.76 (q, 2H), 2,56 is 2.46 (m, 1H), 2,09-to 1.98 (m, 1H), of 0.93 (t, 3H).

Example 6

(±)-CIS-1-(5-Cyano-2-yl)-3-(7-fluoro-4-methoxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

6A) 6-fluoro-2-hydroxy-3-methoxybenzaldehyde

1M Trichloride boron in dichloromethane (25 ml, 25 mol) was added to a solution of 6-fluoro-2,3-dimethoxybenzaldehyde [Cantrell, Amanda S.; Engelhardt, Per; Hoegberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; et al.; J.Med.Chem.; 39; 21; 1996; 4261-4274] (4.26 deaths g, 23 mmol) in dichloromethane (30 ml), maintaining the reaction temperature at -70°C. the Reaction mixture was stirred at room temperature overnight and hydrolyzed in water. The organic phase was separated, washed with water and evaporated in vacuum. The residue was chromatographically (silica gel, EA:Hex, 5:1) obtaining and 3.72 g (94%) of 6-fluoro-2-hydroxy-3-methoxybenzaldehyde in the form of yellow crystals.

1H-NMR (CDCl3): of 11.61 (s, 1H), 10,23 (s, 1H), 7,02 (DD, 1H), 6,55 (problt, 1H), a 3.87 (s, 3H).

6b) 5-fluoro-8-methoxy-2H-chromen

6-fluoro-2-hydroxy-3-methoxybenzaldehyde (of 3.32 g, 19 mmol) was dissolved in acetonitrile (20 ml) was added DBU (2,97 ml, 19 mol) followed by the addition of vinyltrimethylsilane (7.2 g, 19 mmol)Reaktsionnuyu the mixture was boiled under reflux for 48 hours, was diluted with water and was extracted with ether (CH ml). The organic phase is washed with water, 10% sodium hydroxide, water and saturated salt solution and evaporated in vacuum. The residue was subjected to column chromatography (silica gel, EA:Hex, 1:20) to give 1.2 g of 5-fluoro-8-methoxy-2H-chromene (34%).

1H-NMR (CDCl3): of 6.65 (m, 2H), is 6.54 (t, 1H), of 5.83 (dt, 1H), 4,88 (DD, 2H), 3,83 (s, 3H).

6C) Ethyl ester (±)-CIS-7-fluoro-4-methoxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Specified in the title compound was synthesized analogously to example 3C from 5-fluoro-8-methoxy-2H-chromene.

1H-NMR (CDCl3): of 6.7 to 6.5 (m, 2H), 4,48 (m, 2H), 3,99 (m, 2H), 3,80 (s, 3H), 2.57 m (problt, 1H), 2,20 (problt, 1H), 2.05 is (m, 1H), only 1.08 (t, 3H).

6d) (±)-CIS-7-Fluoro-4-methoxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Specified in the title compound was synthesized analogously to example 1b from ethyl ether (±)-CIS-7-fluoro-4-methoxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

1H-NMR (CDCl3): of 6.7 to 6.5 (m, 2H), 4,48 (m, 2H), 3,80 (s, 3H), 2,61 (problt, 1H), 2,17 (problt, 1H), 2.06 to (m, 1H).

6E) (±)-CIS-1-(5-Cyano-2-yl)-3-(7-fluoro-4-methoxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

Specified in the title compound was synthesized analogously to example 1C from (±)-CIS-7-fluoro-4-methoxy-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (62 mg, 0,17 mmol). Vyhod mg (40%).

1H-NMR (CDCl3): 10,06 (users, 1H), 9,40 (userd, 1H), 8,11 (d, 1H), of 7.70 (DD, 1H), 6,91 (d, 1H), of 6.68 (m, 2H), 4,48 (DD, 1H), 4,28 (DD, 1H), 3,90-and 3.72 (m, 4H), 2,64 (problt, 1H), 1,96 (m, 1H).

Example 7

(±)CIS-1-(5-Cyano-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

7a) 1-Chloro-4-fluoro-2-prop-2-enlacement

Specified in the title compound was synthesized analogously to example 15A) of 2-chloro-5-terfenol (2.5 g). Yield 2.8 g (90%).

1H-NMR (CDCl3): to 7.32 (DD, 1H), 6,85 (DD, 1H), of 6.68 (m, 1H), 4,77 (d, 2H), 2,58 (t, 1H).

7b) 5-fluoro-8-chloro-2H-chromen

Specified in the title compound was synthesized analogously to example 15b) of 1-chloro-4-fluoro-2-prop-2-ineloquently (2.8 g). Yield 0.97 g (35%).

1H-NMR (CDCl3): to 7.09 (DD, 1H), 6,63 (dt, 1H), 6,56 (t, 1H), of 5.84 (dt, 1H), 4.95 points (DD, 2H).

7C) Ethyl ester (±)-CIS-7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Specified in the title compound was synthesized analogously to example 15C) of 5-fluoro-8-chloro-2H-chromene.

1H-NMR (CDCl3): 7,14 (DD, 1H), 6,60 (t, 1H), 4,51 (m, 2H), 4,01 (m, 2H), 2,60 (problt, 1H), 2,23 (t, 1H), 2,09 (m, 1H), only 1.08 (t, 3H).

7d) (±)-CIS-7-Fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Specified in the title compound was synthesized analogously to example 15d) of the ethyl ester (±)-CIS-7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (850 mg). Yield 43 mg (96%).

1/sup> H-NMR (CDCl3): 8,86 (users, 1H), 7,13 (DD, 1H), 6,59 (t, 1H), 4,50 (m, 2H), 2.63 in (t, 1H), 2,23-2,05 (m, 2H).

7E) (±)-CIS-1-(5-Cyano-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

Specified in the title compound was synthesized analogously to example 1C from (±)-CIS-7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (63 mg). Yield 52 mg (56%).

1H-NMR (CDCl3): 9,79 (users, 1H), 9,34 (users, 1H), they were 8.22 (d, 1H), 7,72 (DD, 1H), 7,17 (DD, 1H), 6.87 in (d, 1H), to 6.67 (t, 1H), 4,54 (DD, 1H), 4,33 (DD, 1H), 3,84 (pribik, 1H), 2,68 (DD, 1H), 2,00 (m, 1H).

Example 8

(±)-CIS-1-(5-Chloropyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-1-(5-Chloropyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea (15 mg, 24%) was obtained in accordance with the method described in example 1C from (±)-CIS-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chrome)-1-carboxylic acid (40 mg, 0.16 mmol) and 2-amino-5-chloropyridine (76 mg, or 0.57 mmol).

1H-NMR (400 MHz, CDCl3) δ ppm: 9,29 (users, 1H), 9,26 (users 1H), to 7.84 (d, 1H), 7,47 (DD, 1H), 7,16 (DD, 1H), 6,76 (d, 1H), to 6.67 (DD, 1H)and 4.65 (DD, 1H), 4,34 (DD, 1H), 3,82 (DD, 1H), 2,62 (DD, 1H), 1,96 (m, 1H).

Example 9

(±)-CIS-1-(5-Bromopyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-1-(5-Bromopyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea (13 mg, 19%) was obtained in the fit is accordance with the methodology described in example 1C from (±)-CIS-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen)-1-carboxylic acid (40 mg, 0.16 mmol) and 2-amino-5-bromopyridine (99 mg, or 0.57 mmol).

1H-NMR (400 MHz, CDCl3) δ ppm: 9,27 (users, 1H), 9,02 (users, 1H), 7,95 (d, 1H), 7,60 (DD, 1H), 7,16 (DD, 1H), 6,70 (d, 1H), to 6.67 (DD, 1H), 4,50 (DD, 1H), 4,35 (DD, 1H), 3,81 (DD, 1H), 2.63 in (DD, 1H), 1,97 (m, 1H).

Example 10

(±)-CIS-1-(5-Cyano-2-yl)-3-(5-cyano-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

10A) 4-Formyl-3-hydroxyphenylethyl ether triftormetilfullerenov acid

A solution of anhydride triftormetilfullerenov acid (1.77 ml, 10.5 mmol) in dichloromethane (10 ml) was added to a mixture of 2,4-dihydroxybenzaldehyde (1,38 g, 10 mmol) and pyridine (of 0.85 ml, 10.5 mmol) in dichloromethane (30 ml) at -70°C. Bath with dry ice was removed and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with dichloromethane, washed with water, saturated salt solution and evaporated in vacuum. The crude product was purified column chromatography (silica gel, EA:Hex, 1:6) to obtain 1.55 g of 4-formyl-3-hydroxyphenylazo ether triftormetilfullerenov acid (57%).

1H-NMR (CDCl3): to 11.28 (s, 1H), to 9.93 (s, 1H), to 7.67 (d, 1H), 6,95 (m, 2H).

10b) 3 Allyloxy-4-formylphenyl ether triftormetilfullerenov acid

Potassium carbonate (1.6 g, 11.5 mmol) and allylbromide (1 ml, 11.5 mmol) was added the solution of 4-formyl-3-hydroxyphenylazo ether triftormetilfullerenov acid (1.55 g, 5.7 mmol) in acetone (50 ml). The reaction mixture was stirred at 55°C for 2 h, filtered and evaporated in vacuum. The residue was chromatographically (silica gel, EA:Hex, 1:20) to obtain 1.3 g (73%) of 3-allyloxy-4-formylphenyl ether triftormetilfullerenov acid.

1H-NMR (CDCl3): of 10.47 (s, 1H), to 7.93 (d, 1H), 6,95 (d, 1H), 6.90 to (s, 1H), equal to 6.05 (m, 1H), vs. 5.47 (d, 1H), of 5.40 (d, 1H), 4,69 (d, 2H).

10C) 3 Allyloxy-4-finalfantasy ether triftormetilfullerenov acid.

Methyltriphenylphosphonium (1,95 g, the 5.45 mmol) was added to a suspension of sodium hydride (60% in oil) (0.25 g, 6.3 mmol) in THF (35 ml) at 0°and the mixture was stirred for 30 min at room temperature. To the above solution was added a solution of 3-allyloxy-4-formylphenyl ether triftormetilfullerenov acid (1.3 g, 4.2 mmol) in THF (15 ml) and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with hexane and extracted with water. The organic phase is washed with saturated salt solution and evaporated. Column chromatography with silica gel (EA:Hex, 1:20) gave 3-allyloxy-4-finalfantasy ether triftormetilfullerenov acid (0.68 g, 53%).

1H-NMR (CDCl3): 7,51 (d, 1H), 7,02 (DD, 1H), 6,85 (DD, 1H), 6,77 (d, 1H), equal to 6.05 (m, 1H), USD 5.76 (DD, 1H), 5,43 (m, 1H), 5,32 (m, 2H), 4,58 (dt, 2H).

10d) 2N-Chromen-7-silt ether triftormetilfullerenov acid

To a solution of 3-allyloxy the-4-vinylgroover ether triftormetilfullerenov acid (0.68 g, 2.2 mmol) in dichloromethane (5 ml) was added Ru catalyst (catalyst Grabba) (36 mg, 2 mol.%) and the reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction (gas chromatography (GC)), the reaction mixture was used in the next stage without additional processing. After removal of the solvent column chromatography on silica gel (EA:Hex, 1:20) received analytical sample.

1H-NMR (CDCl3): 6,97 (d, 1H), 6,76 (DD, 1H), of 6.68 (d, 1H), 6,39 (dt, 1H), of 5.81 (dt, 1H), to 4.98 (DD, 2H).

10E) Ethyl ester (±)-CIS-5-tripterocalyx-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Rh(OAc)2(19 mg, 2 mol.%) was added to a solution of the compound obtained in 10d, and was added a solution of EDA (of 0.44 ml, 4.4 mmol) in 1 ml dichloromethane syringe pump over 5 h at room temperature. After completion of the reaction (GC) dichloromethane is evaporated, the residue was dissolved in ethyl acetate and washed with a saturated solution of ammonium chloride and a saturated solution of salt. The organic phase is evaporated and the crude mixture of CIS - and TRANS-isomers (1:1,3) were divided by column chromatography (silica gel, EA:Hex, 1:6) to obtain 0.4 g (50%) ethyl ester (±)-CIS-5-tripterocalyx-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

1H-NMR (CDCl3): 7,29 (d, 1H), PC 6.82 (DD, 1H), 6.73 x (d, 1H), 4,51 (DD, 1H), 4.2V (DD, 1H), 3,98 (m, 2H), 2,45 (t, 1H), 2,19 (t, 1H), 2.05 is (m, 1H), of 1.03 (t, 3H).

10f) Ethyl ester (±)-CIS-5-cyano-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Ethyl ether (±)-CIS-5-tripterocalyx-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (154 mg, 0.42 mmol), Pd(OAc)2(9 mg, 10 mol.%) and PPh3(44 mg, 40 mol.%) mixed in DMF (4 ml) and through the reaction mixture for 10 minutes let in a weak stream of nitrogen. Was added Zn(CN)2(74 mg, to 0.63 mmol), the container was sealed and the reaction mixture was stirred at 120°With during the night. The reaction mixture was diluted with ethyl acetate and was extracted with saturated ammonium chloride. The organic phase is evaporated and the residue was chromatographically (silica gel, EA:Hex, 1:5) to give 53 g (52%) of ethyl ether (±)-CIS-5-cyano-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

1H-NMR (CDCl3): 7,33 (d, 1H), 7,19 (DD, 1H), 7,05 (d, 1H), 4,50 (DD, 1H), 4,25 (DD, 1H), 3,99 (kV, 2H), 2,46 (t, 1H, in), 2.25 (t, 1H), 2,11 (m, 1H), 1.06 a (t, 3H).

10g) (±)-CIS-5-Cyano-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Ethyl ether (±)-CIS-5-cyano-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (53 mg, 0.22 mmol) and NaOH (35 mg, 0.88 mmol) was dissolved in a mixture of methanol and water (1:1) (5 ml). The reaction mixture was stirred for 30 min at 60°C. the Methanol is evaporated in vacuo and added 20 ml of water. The resulting solution uh what was strayaway ether. The aqueous phase was concentrated, acidified using 1M HCl to pH˜2 and was extracted with ether. The organic phase is washed with saturated salt solution and evaporated to obtain 42 mg (90%) (±)-CIS-5-cyano-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

1H-NMR (CDCl3): 7,33 (d, 1H), 7,19 (DD, 1H), 7,06 (d, 1H), 4,51 (DD, 1H), or 4.31 (DD, 1H), 2,53 (problt, 1H), 2,27 (problt, 1H), 2,16 (m, 1H).

10h) (±)-CIS-1-(5-Cyano-2-yl)-3-(5-cyano-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-5-Cyano-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (42 mg, 0,19 mmol) and tea (to 0.032 ml, 0.21 mmol) was dissolved in 3 ml of toluene. Added DPPA (0,046 ml, 0.21 mmol) and 2-amino-5-cyanopyridine (25 mg, 0.21 mmol). The reaction mixture is boiled under reflux with stirring for 3 hours. The precipitate was filtered and washed with hot ethanol (3 ml) to give 41 mg (63%) (±)-CIS-1-(5-cyano-2-yl)-3-(5-cyano-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea.

1H-NMR (DMSO-d6): 9,86 (s, 1H), 8,48 (d, 1H), 8,07 (DD, 1H), 7,97 (users, 1H), 7,51 (d, 1H), 7,43 (d, 1H), 7,37 (d, 1H), 7,34 (DD, 1H), 4,39 (DD, 1H), 4,19 (DD, 1H), 3,57 (pribik, 1H), 2,54 (problt, 1H), 2,09 (m, 1H).

Example 11

(±)-CIS-1-(5-Cyano-2-yl)-3-(5-ethinyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

11a) Ethyl ester (±)-CIS-5-trimethylsilylethynyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

E. the silt ether (± )-CIS-5-tripterocalyx-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (152 mg, 0.41 mmol), DPPP (38 mg, 20 mol.%), PD(dba)2(24 mg, 10 mol.%), CuI (3 mg, 4 mol.%) mixed in 3 ml of triethylamine and through the reaction mixture for 10 minutes let in a weak stream of nitrogen. Added trimethylsilylacetamide (0,088 ml of 0.62 mmol), the container was sealed and the reaction mixture was stirred at 120°With during the night. The reaction mixture was diluted with ethyl acetate, washed with water, saturated salt solution and evaporated. The residue was purified column chromatography on silica gel (EA:Hex, 1:15) to give 0.1 g (77%) of ethyl ether (±)-CIS-5-trimethylsilylethynyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

1H-NMR (CDCl3): to 7.15 (d, 1H), 7,01 (DD, 1H), to 6.88 (d, 1H), 4,47 (DD, 1H), 4,16 (DD, 1H), 3.96 points (q, 2H), 2,38 (t, 1H), 2.13 in (t, 1H), 2,01 (m, 1H), was 1.04 (t, 3H)and 0.22 (s, 9H).

11b) (±)-CIS-5-Ethinyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Ethyl ether (±)-CIS-5-trimethylsilylethynyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (0.1 g, 0.32 mmol) and sodium hydroxide (0,076 g, 1.9 mmol) was dissolved in a mixture of methanol:water (1:1) (5 ml). The reaction mixture was heated for 5 hours at 60°With, then it was acidified using 1M HCl to pH˜2 and was extracted with ether. The organic phase is washed with saturated salt solution and evaporated to obtain 66 mg (97%) (±)-the IP-5-ethinyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

1H-NMR (CDCl3): 7,17 (d, 1H), 7,03 (DD, 1H), 6,91 (d, 1H), 4,45 (DD, 1H), 4,23 (DD, 1H), 3,02 (s, 1H), 2,46 (t, 1H), 2.13 in (t, 1H), 2,07 (m, 1H).

11C) (±)-CIS-1-(5-Cyano-2-yl)-3-(5-ethinyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

Specified in the title compound was synthesized analogously to example 10h (±)-CIS-5-ethinyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (66 mg, 31 mmol). Yield 53 mg (52%).

1H-NMR (DMSO-d6): 9,88 (s, 1H), to 8.41 (d, 1H), of 8.06 (DD, 1H), 7,86 (users, 1H), 7,46 (d, 1H), 7,32 (d, 1H), 7,02 (DD, 1H), 6,93 (d, 1H), or 4.31 (DD, 1H), 4,16 (DD, 1H), 4,12 (s, 1H), 3,47 (kV, 1H), 2,43 (problt, 1H), 2,00 (m, 1H).

Example 12

(±)-CIS-1-(5-Acetyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea

12A) Ethyl ester (±)-CIS-5-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Ethyl ether (±)-CIS-5-tripterocalyx-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (117 mg, 0.32 mmol), DPPP (7,3 mg, 50 mol.%), PD(SLA)2(2 mg, 25 mol.%) and triethylamine (and 0.09 ml, 0.64 mmol) were mixed in DMF (3 ml) and through the reaction mixture for 10 minutes let in a weak stream of nitrogen. Added butylvinyl ether (of 0.21 ml, 1.6 mmol), the container was sealed and the reaction mixture was stirred at 100°C for 2 hours. Was added 5% HCl (5 ml) and the reaction mixture was stirred at room temperature for 30 minutes the mixture was extracted with atilas what tatom. The organic phase was washed with saturated ammonium chloride and evaporated. The residue was purified column chromatography on silica gel (EA:Hex, 1:5) to give 76 mg (91%) of ethyl ether (±)-CIS-5-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

1H-NMR (CDCl3): 7,52 (DD, 1H), was 7.36 (d, 1H), 7,34 (d, 1H), 4,51 (DD, 1H), 4,21 (DD, 1H), 3,98 (kV, 2H), 2,53 (s, 3H), 2,47 (t, 1H), 2,23 (t, 1H), 2,08 (m, 1H), of 1.05 (t, 3H).

12b) (±)-CIS-5-Acetyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Specified in the title compound was synthesized analogously to example 10g of ethyl ether (±)-CIS-5-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (76 mg, 29 mmol). Yield 66 mg (97%).

1H-NMR (CDCl3): 7,52 (DD, 1H), 7,37 (d, 1H), 7,34 (d, 1H), to 4.52 (DD, 1H), 4.26 deaths (DD, 1H), to 2.55 (s, 3H), 2,53 (t, 1H, in), 2.25 (t, 1H), 2,13 (m, 1H).

12C) (±)-CIS-1-(5-Cyano-2-yl)-3-(5-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

Specified in the title compound was synthesized analogously to example 10h (±)-CIS-5-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (66 mg, 28 mmol). Yield 58 mg (59%).

1H-NMR (DMSO-d6): 9,87 (s, 1H), 8,42 (d, 1H), with 8.05 (DD, 1H), 7,88 (users, 1H), 7,52 (DD, 1H), 7,49-7,44 (m, 2H), 7,37 (d, 1H), 4,39 (DD, 1H), 4,18 (DD, 1H), 3,55 (kV, 1H), 2,55-of 2.50 (m, 4H, peak svirneliene on residual DMSO-d6), 2,07 (m, 1H).

Example 13

(±)-CIS-1-(5-Methoxy-1,1a,2,7b-tetrahydrocyclopent[c]chromium is-1-yl)-3-(5-cyano-2-yl)urea

Specified in the title compound was synthesized analogously to example 10 from 2-hydroxy-4-methoxybenzaldehyde.

1H-NMR (CDCl3): 8,44 (users, 1H), of 8.06 (d, 1H), of 7.70 (DD, 1H), 7,18 (d, 1H), 6,82 (userd, 1H), 6,55 (DD, 1H), 6,36 (d, 1H), 4,32 (DD, 1H), 4,24 (DD, 1H), 3,76 (s, 3H), to 3.58 (q, 1H), 2,36 (DD, 1H), to 1.86 (m, 1H).

Example 14

(±)-CIS-1-(5-Cyano-2-yl)-3-(N-acetyl-1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]quinoline-1-yl)urea

a) N-Acetyl-1,2-dihydroquinoline

The quinoline (19,37 g, 150 mmol) was dissolved in anhydrous diethyl ether (500 ml) and cooled to 0°in an inert atmosphere. Was added dropwise DIBAL, 1.5 M in toluene (100 ml, 150 mmol) for 2 h and the reaction mixture was stirred at 0°C for 30 minutes was added dropwise acetic anhydride (500 ml) for 30 min and the reaction mixture was stirred at 0°C for 30 minutes was Carefully added N2O. the Reaction mixture was extracted with diethyl ether and concentrated to obtain N-acetyl-1,2-dihydroquinoline (11,5 g, 44%).

b) Ethyl ester (±)-CIS-(N-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]quinoline)-1-carboxylic acid

Ethyl ether (±)-CIS-(N-acetyl-1,1a,2,7b-tetrahydrocyclopent[C]quinoline)-1-carboxylic acid was obtained in accordance with the procedure described in example 1A, from N-acetyl-1,2-dihydroquinoline (10 g, 58 mmol). The product was purified column chromatography on silica gel (EtOAc/hexane 5%→50%) from the floor is the group of ethyl ether (± )-CIS-(N-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]quinoline-1-carboxylic acid (2.0 g, 13%).

C) (±)-CIS-(N-Acetyl-1,1a,2,7b-tetrahydrocyclopent[c]quinoline-1-carboxylic acid

(±)-CIS-(N-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]quinoline)-1-carboxylic acid (425 mg, 24%) was obtained in accordance with the method described in example 1b, from ethyl ether (±)-CIS-(N-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]quinoline-1-carboxylic acid (2.0 mg, 7.7 mmol).

d) (±)-CIS-1-(5-Cyano-2-yl)-3-(N-acetyl-1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]quinoline-1-yl)urea

(±)-CIS-1-(5-Cyano-2-yl)-3-(N-acetyl-1,1a,3,7b-tetrahydro-2-oxacyclopropane[a]quinoline-1-yl)urea (250 mg, 40%) was obtained in accordance with the method described in example 1C from (±)-CIS-(N-acetyl-1,1a,2,7b-tetrahydrocyclopent[c]quinoline-1-carboxylic acid (416 mg, 1.8 mmol)

1H-NMR (250 MHz, DMSO-d6) δ ppm: 9,51 (users, 1H), 8.30 to (d 1H), 8,01 (DD, 1H), 7,54 (DD, 1H), 7,44, (DD, 1H), was 7.36 (d, 1H), 7.23 percent-to 7.18 (m, 3H), 4,10 (d, 1H), 3,60 (DD, 1H), 3,12 was 3.05 (m, 1H), 2,37 (t, 1H), 2,0-of 1.92 (m, 4H).

Example 15

(+/-)-CIS-1-(5-Cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

15A) 2,4-Debtor-2-propionylacetate

Commercially available 2,5-diferena (20 g, 0.15 mol), K2CO3(53 g, 0.38 mol) and commercially available 3-bromopropene (45 g, 0.38 mol), R is was storyli in acetone (300 ml), boiled under reflux overnight, cooled and filtered. The solvent was removed, the crude product was dissolved in ether and washed with water and saturated salt solution. The organic phase was evaporated and the crude product was re-dissolved in a small amount of ether and filtered through a column of basic Al2O3. Evaporation and drying gave 20 g (80%) 2,4-debtor-2-propenylbenzene.

15b) 5.8 Debtor-2H-chromen

2,4-Debtor-2-propionylacetate (20 g, 0.12 mol) was dissolved in N,N-diethylaniline (100 ml) and heated in an argon atmosphere at 225°C in oil bath for 6-8 hours. Added ether (150 ml) and aniline was removed by extraction using 2M HCl(aq.). Purification by chromatography (silica gel, n-hexane) gave the 5.8 debtor-2H-chromen 5.8 g (29%).

15C) Ethyl ester of (+/-)-CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

5.8 Debtor-2H-chromen (5 g, 0.03 mol), Rh(II)Ac2)2(0.39 g, 0,00089 mol) was dissolved in 1,2-dichloroethane (60 ml) or chloroform containing no ethanol. Was added dropwise the ethyl diazo acetate (9.4 ml, 0,0089 mol) in the same solvent over a period of time of approximately 5 hours, in an atmosphere of N2. Then the solvent was removed in vacuum and the mixture was transferred into ethyl acetate, washed with NaHCO3(aq.), water is a saturated solution of salt and the solvent was removed. The product (33% CIS, 66% TRANS) was purified by chromatography (0→10% ethyl acetate in n-hexane) to obtain 2.2 g specified in the connection header (30%).

15d) CIS-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Ethyl ester of CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (2 g, 0,008 mmol) was heated in 1M LiOH in a mixture of methanol-water (25%) at 80°C for 2 hours. The volume was reduced by half and acidified. Extraction with ether followed by chromatography (silica gel, ether) gave specified in the title compound (35%).

15th) (+/-)-CIS-1-(5-Cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(+/-)-CIS-1-(5-Cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was obtained analogously to example 1C, but using CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (0.2 g, 0,00088 mol), with 0,130 g (42%) of the net specified in the connection header. The crude product was purified by extraction between 0,01M HCl (aq.) and ethyl acetate and chromatography (silica gel, 0→1% Meon in the air). The solvent is evaporated and the solid is washed with a cold solution of 50% acetone in n-hexane.

1H-NMR (CDCl3-MeOD): 8,16 (d, 1H), 7,72 (DD, 1H), 6,97-6,86 (m, 2H), 6,69-of 6.61 (m, 1H), 4,47 (DD, 1H), or 4.31 (DD, 1H, in), 3.75 (m, 1H),2,65 (t, 1H), 2.05 is is 1.96 (m, 1H).

Example 16

(±)-CIS-1-(5-Cyano-3-methylpyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-1-(5-Cyano-3-methylpyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was obtained analogously to example 1C, but using CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (168 mg, of 0.74 mmol) and 6-amino-5-methylnicotinamide (109 mg, 0.82 mmol), obtaining (±)-CIS-1-(5-cyano-3-methylpyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea, 52 mg (20%). The crude product was purified by extraction between 0,01M HCl (aq.) and ethyl acetate and chromatography (silica gel, 0→25% Meon in the air). The solvent is evaporated and the solid is washed with 25% acetone in n-hexane.

1H-NMR (CDCl3-MeOD): 8,02 (d, 1H), to 7.61 (DD, 1H), 6,97-6,87 (m, 1H), 6,70-6,62 (m, 1H), 4,48 (DD, 1H), 4,30 (DD, 1H), 3,78 (t, 1H), 3,37 (s, 3H), of 2.66 (t, 1H), 2,03(m, 1H).

Example 17

(±)-CIS-1-(5-Chloropyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-1-(5-Chloropyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was obtained analogously to example 1C, but using CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (90 mg, 0.4 mmol) and 6-amino-5-chloropyridin (51 mg, 0.44 mmol)pick (�B1; )-CIS-1-(5-chloropyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea (50 mg, 35%). The crude product was purified by extraction between 0,01M HCl (aq.) and a mixture of ethyl acetate:ether (1:1) and chromatography (silica gel, ether).

1H-NMR (CDCl3): 9,2 (users, NH), 8,6 (users, NH), 7,81 (DD, 1H), of 7.48 (DD, 1H), 6.89 in (m, 1H), 6.75 in (d, 1H), 6,69 (m, 1H), 4,45 (DD, 1H), 4,33 (DD, 1H, in), 3.75 (m, 1H), 2,61 (m, 1H), 1,97 (m, 1H).

Example 18

(±)-CIS-1-(4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-ethynylpyridine-2-yl)urea

(±)-CIS-1-(4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-ethynylpyridine-2-yl)urea was obtained analogously to example 1C), but using CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (100 mg, 0.44 mmol) and 5-trimethylsilylethynyl-2-ylamine (93 mg, 0.49 mmol), which gave 25 mg (17 %) of the desired product. The crude product was purified by extraction between 0,01M HCl (aq.) and a mixture of ethyl acetate:ether (1:1) and chromatography (silica gel, ether). The resulting mixture (containing specified in the header connection together with similarbank compound) was mixed with Bu4N+F-25% water in THF for 30 min and re-chromatographically with getting clean (±)-CIS-1-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-ethynylpyridine-2-yl)urea.

1H-NMR (CDCl3): 9,2 (users, NH), 795 (d, 1H), to 7.59 (DD, 1H), of 7.48 (users, 1H), 6.89 in (TD, 1H), only 6.64 (dt, 1H), to 6.57 (d, 1H), 4,46 (DD, 1H), 4,33 (DD, 1H), 3,78 (kV, 1H), 3,11 (s, 1H), 2,62 (t, 1H), 1,99-of 1.97 (m, 1H).

Example 19

(±)-CIS-1-(5-Bromopyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-1-(5-Bromopyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was obtained analogously to example 1C, but using CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (50 mg, 0.22 mmol) and 6-amino-5-bromopyridin (42 mg, 0.24 mmol)pick (±)-CIS-1-(5-bromopyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea (50 mg, 35%). The crude product was purified by extraction between 0.01 M HCl (aq.) and ethyl acetate and chromatography (silica gel, ether).

1H-NMR (CDCl3): 9,2 (users, NH), 7,88 (d, 1H), 7,75 (users, 1H), 7,60 (DD, 1H), 6.89 in (m, 1H), 6,63 (TD, 1H), 6,59 (d, 1H), 4,45 (DD, 1H), 4,33 (DD, 1H), 3,78 (kV, 1H), 2,62 (t, 1H), up to 1.98 (m, 1H).

Example 20

(±)-CIS-1-(4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-phenoxypyridine-2-yl)urea

(±)-CIS-1-(4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-phenoxypyridine-2-yl)urea was obtained analogously to example 1C), but using CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (60 mg, 0.26 mmol) and 6-amino-5-phenoxypyridine (56 mg, 0.29 mmol), with 32 mg, 30%) specified in the connection header. The crude product was purified by extraction between 0,01M HCl (aq.) and ethyl acetate and chromatography (silica gel, 20% ether in n-hexane).

1H-NMR (CDCl3): of 7.60 (d, 1H), 7,45 (users, 1H), 7,37-7,34 (m, 2H), 7,27-7,24 (m, 2H), 7,14-7,11 (m, 1H), 6,94-9,92 (m, 2H), 6,79-7,74 (m, 1H), 6,63 (d, 1H), 6,59-6,55 (m, 1H), 4,43 (DD, 1H), 4,36 (DD, 1H, in), 3.75 (q, 1H), 2,59 (t, 1H), 1,98-of 1.94 (m, 1H).

Example 21

(±)-CIS-1-(5-Cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)thiourea

CIS-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (113 mg, 0.5 mmol), DPPA (118,6 μl, 055 mmol) and tea (70,7 μl, 0.55 mmol) was boiled under reflux in toluene (2 ml) for 1 hour. Then was added dioxane (3 ml) and HCl(aq.)(1.5 ml, 6M) and the reaction mixture was left at 50°With 1 hour. Then was added ether and water and the layers were separated. The aqueous phase was washed with ether and then was podslushivaet ammonia(aq.). Extraction with dichloromethane and drying gave the intermediate compound 4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-ylamine, which was immediately treated with 6-isothiocyanateconjugated (34 mg, 0.55 mmol) in acetonitrile (4 ml) at room temperature over night. Precipitated crystals were filtered and washed with cold acetonitrile to obtain 30 mg (17%) of pure (±)-CIS-1-(5-cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-yl)thiourea. LC-MS:m/z 358,9.

Example 22

1-(6-Chloro-5-cyanopyridine-2-yl)-3-(5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

1-(6-Chloro-5-cyanopyridine-2-yl)-3-(5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was obtained analogously to example 1C), but using CIS-5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (280 mg, to 1.21 mmol) and 6-amino-2-chloro-3-cyanopyridine (203 mg, of 1.33 mmol)with obtaining specified in the connection header in a small amount. The crude product was purified by extraction between 0.01 M HCl (aq.) and ether and chromatography (silica gel, ether), then washed with a mixture of acetone-ether.

1H-NMR (DMSO-d6): 10 (users, NH), to 8.20 (d, 1H), of 7.70 (d, 1H), 6,9 (users, NH), 6,8 (m, 1H), 6,6 (m, 1H), 4,4 (DD, 1H), 4.2V (DD, 1H), 3,2 (m, 1H), 2,4 (t, 1H), and 1.9 (m, 1H).

Example 23

1-(5-Cyano-2-yl)-3-(5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

1-(5-Cyano-2-yl)-3-(5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was obtained analogously to example 1C), but using CIS-5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (390 mg, 1,72 mmol) and 2-amino-5-cyanopyridine (226 mg, 1,89 mmol). The crude product was purified by extraction between 0.01 M HCl (aq.) and ether, recrystallization, several washings with acetone and acetonitrile and chromatogra the Oia (silica gel, 1% EtOAc in ether) to give 28 mg specified in the connection header.

1H-NMR (CDCl3-MeOD): 8,16 (t, 1H), 7,78 (DD, 1H), to 7.09 (d, 1H), 6,56-6,34 (m, 2H), 4,34 (m, 2H), 3,54 (t, 1H), 2.57 m (DD, 1H), 2.00 in 1,90 (m, 1H).

Example 24

CIS-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea

CIS-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea was obtained analogously to example 1C), but using CIS-4-bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (178 mg, of 0.62 mmol) and 2-amino-5-cyanopyridine (0,81 mg, of 0.68 mmol). The crude product was chromatographically (silica gel, ether and washed with acetone to obtain 40 mg (16%) of CIS-1-(4-bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea.

1H-NMR (CDCl3): 9,85 (s, 1H), and 9.3 (s, 1H), of 7.75 (DD, 1H), 7,33 (DD, 1H), 6,95 (d, 1H), 6,65 (t, 1H), of 4.05 (DD, 1H), 4,32 (DD, 1H), 3,35 (t, H)to 2.65 (t, 1H), 2,05-of 1.95 (m, 1H).

Example 25

CIS-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(6-chloro-5-cyanopyridine-2-yl)urea

CIS-1-(4-Bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(6-chloro-5-cyanopyridine-2-yl)urea was obtained analogously to example 1C, but using CIS-4-bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (178 mg, of 0.62 mmol) and 2-amino-6-chloro-5-canopied is on (105 mg, of 0.68 mmol). The crude product was chromatographically (silica gel, 0→1% Meon in ether and washed with a mixture of acetone-hexane to obtain 40 mg (13%) of CIS-1-(4-bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(6-chloro-5-cyanopyridine-2-yl)urea.

1H-NMR (CDCl3): 9,90 (s, 1H), 8.30 to (s, 1H), of 7.75 (d, 1H), 7,25 (d, 1H), 6,60 (t, 1H), 4,5 (DD, 1H), 4,35 (DD, 1H), 3,5 (m, 1H), 2,65 (m, 1H), 2,1-of 1.95 (m, 1H).

Example 26

CIS-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea

CIS-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea was obtained analogously to example 1C, but using CIS-4-bromo-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (177 mg, of 0.62 mmol) and 2-amino-5-cyanopyridine (81 mg, 0,68 mmol). The crude product was extracted between ether and 0.02 M HCl(aq.)was chromatographically (silica gel, 0→1% Meon in ether and washed with a mixture of acetone-hexane to obtain 42 mg (17%) of CIS-1-(4-bromo-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(5-cyano-2-yl)urea.

1H-NMR (CDCl3-MeOD): of 8.37 (m, 1H), of 7.75 (DD, 1H), 7,14 (DD, 1H), 7,05 (DD, 1H), 6,93 (d, 1H), 4,56 (DD, 1H), 4,21 (DD, 1H), of 3.77 (t, 1H), 2,42 (DD, 1H), 2,00 (m, 1H).

Example 27

CIS-1-(4-Bromo-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(6-chloro-5-cyanopyridine-2-yl)urea

CIS-1-(4-Bromo-6-ft is R-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(6-chloro-5-cyanopyridine-2-yl)urea was obtained analogously to example 1C), but using CIS-4-bromo-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (177 mg, of 0.62 mmol) and 2-amino-6-chloro-5-cyanopyridine (105 mg, of 0.68 mmol). The crude product was extracted between ether and 0.01 M HCl(aq.)was chromatographically (silica gel, 0→1% Meon in ether and washed with a mixture of acetone-hexane to obtain 46 mg (17%) of CIS-1-(4-bromo-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-3-(6-chloro-5-cyanopyridine-2-yl)urea.

1H-NMR (CDCl3): 9,41 (s, 1H,), of 8.28 (DD, 1H),? 7.04 baby mortality (DD, 1H), 4,54 (DD, 1H), 4,25 (DD, 1H), 3,50 (m, 1H), 2,41 (DD, 1H), 2.06 to to 1.98 (m, 1H).

Example 28

CIS-1-(5-Cyano-2-yl)-3-(6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

CIS-1-(5-Cyano-2-yl)-3-(6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was obtained analogously to example 1C), but using CIS-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (168 mg, 0.8 mmol) and 2-amino-5-cyanopyridine (105 mg, 0.88 mmol). The crude product was extracted between ether and 0.01 M HCl(aq.)was chromatographically (silica gel, 0→1% Meon in ether and washed with a mixture of acetone-hexane to obtain only 10 mg (4%) of CIS-1-(5-cyano-2-yl)-3-(6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea.

1H-NMR (CDCl3-MeOD): 8,16 (d, 1H), 7,73 (DD, 1H), 7,05 (DD, 1H), of 6.96 (d, 1H), at 6.84 (TD,1H), 6,76 (DD, 1H), 4,39 (DD, 1H), 4,17 (DD, 1H), to 3.67 (t, 1H), 2,39 (DD, H), 1,96-of 1.92 (m, 1H).

Example 29

Intermediate compounds

29A) 6-Ferroman-4-ol

6-Ferroman-4-one (10 g, 61 mmol) was dissolved in ethanol (100 ml). Added NaBH4(excess) and cooled in an ice bath. The mixture was then left at room temperature for 2 hours, followed by boiling under reflux for 4 hours. Purification by chromatography (silica gel, ether-hexane, 1:5) gave 8 g (80%) of pure 6-ferroman-4-ol.

29b) 6-Fluoro-2H-chromen

6-Ferroman-4-ol (8 g, 48 mmol) and toluene-4-sulfonic acid (1 g) was dissolved in toluene and heated under reflux overnight with gradual removal of water. The mixture was then cooled and washed with NaHCO3(aq.) and purified by chromatography (silica gel, n-hexane) to obtain 4,2 g (52%) of pure 6-fluoro-2H-chromene.

29s) Ethyl ester (±)-CIS-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

This compound was obtained analogously to obtain ethyl ester CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid, but using 6-fluoro-2H-chromen, with the receipt of 1.9 g (29%) specified in the connection header.

29d) CIS-6-Fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

This compound p which were given similarly to obtain CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid, but using the ethyl ester of CIS-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (1.9 g, 8 mmol), to obtain 350 mg (21%) of pure CIS-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

E) 1-Bromo-4-fluoro-2-prop-2-enlacement

This compound was obtained analogously to obtain 2,4-debtor-2-propenylbenzene, but using 2-bromo-5-terfenol (15 g, 78 mmol), to obtain 1-bromo-4-fluoro-2-prop-2-ineloquently 15.6 g (87%).

29f), 2-Bromo-4-fluoro-1-prop-2-enlacement

This compound was obtained analogously to obtain 2,4-debtor-2-propenylbenzene, but using 2-bromo-4-terfenol (15 g, 78 mmol), to obtain 2-bromo-4-fluoro-1-prop-2-ineloquently, 15 g (84%).

29g) 1,3-Debtor-5-prop-2-enlacement

This compound was obtained analogously to obtain 2,4-debtor-2-propenylbenzene, but using 3,5-diferena (14 g, 107 mmol), to obtain 12 g (67%) 1,3-debtor-5-prop-2-ineloquently.

29h) 8-Bromo-6-fluoro-2H-chromen

This compound was obtained analogously to receive the 5.8 debtor-2H-chromene, but using (15 g, 65 mmol) of 2-bromo-4-fluoro-1-prop-2-enlacement, to obtain 7 g (46%) specified in the connection header.

29i) 8-Bromo-5-fluoro-2H-chromen

the data connection was obtained similarly to obtain 5.8 debtor-2H-chromene, but using (15 g, 65 mmol) 1-bromo-4-fluoro-2-prop-2-enlacement, to obtain (3.7 g, 25%) specified in the connection header.

29j) 5,7-Debtor-2H-chromen

This compound was obtained analogously to receive the 5.8 debtor-2H-chromene, but using (18 g, 107 mmol) 1,3-debtor-5-prop-2-ineloquent and PEG-200 as a solvent, to obtain 4 g (23%) specified in the connection header.

29k) Ethyl ester (±)-CIS-4-bromo-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

This compound was obtained analogously to obtain ethyl ester (±)-CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid, but using 5 g (22 mmol) of 8-bromo-6-fluoro-2H-chromene, with the receipt of 1.9 g (30%) of the ethyl ester of CIS-6-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

29l) Ethyl ester (±)-CIS-4-bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

This compound was obtained analogously to obtain ethyl ester (±)-CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid, but using 3.5 g of 15.3 mmol) 8-bromo-5-fluoro-2H-chromene, to obtain 1.6 g (33%) ethyl ester (±)-CIS-4-bromo-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

29m) Ethyl ester (±)-C is C-5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

This compound was obtained analogously to obtain ethyl ester (±)-CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid, but using 2 g (12 mmol) of 5,7-debtor-2H-chromene, to obtain 0.9 g (29%) ethyl ester (±)-CIS-5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

Example 30

Optical isomers of CIS-1-(5-cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

Racemic (±)-CIS-1-(5-cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea (see example 15) were divided into optically active compounds using chiral AGP column 150 x 10 mm, 5 μm; Crom Tech LTD. The flow rate reached 4 ml/min Mobile phase was 89% vol. 10mm SPLA/NH4OAc in acetonitrile. Observed two peaks of elution. Isomer, eluruumist second, usually showing a negative rotation, is particularly active.

Not wishing in any way to be bound by this observation, I believe that the most slowly eluruumist isomer carries absolute configuration, shown below, which was determined on the basis of the received x-ray crystallography coordinates unsubstituted analogue of example 1, the bound ligand in the enzyme reverse transcriptase. The configuration shown is who, clearly visible in the divided structure, while the other enantiomer is not present.

Example 31

(-)CIS-1-(5-Chloropyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

Racemic (±)-CIS-1-(5-chloropyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea (see example 17) was divided into optically active compounds using chiral AGP column 150 x 10 mm, 5 μm; Crom Tech LTD. The flow rate reached 4 ml/min Mobile phase was 89% vol. 10mm SPLA/NH4OAc in acetonitrile. Observed two peaks of elution 27.7 min and 33.2 minutes Specified in the header isomer was elyuirovaniya when 33,2 min, usually by showing a negative rotation, and was especially active.

Example 32

(-)CIS-1-(5-Cyano-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

a) Separation of racemic CIS-7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

0.32 g (1,32 mmol) of racemic CIS-7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid was dissolved in hot acetonitrile (50 ml) was added (1R,2R)-2-benzyloxycarbonylamino (0.25 g, of 1.32 mmol). The resulting solution was left for crystallization. After a few hours the mother liquid decantation and the crystals were washed with acetonitrile. The second crystallization is C acetonitrile gave 92 mg of pure diastereomeric salt. Salt was treated with 1 M HCl and the resulting mixture was extracted with ethyl acetate. The organic phase is washed with water, saturated salt solution and evaporated to obtain 0.05 g enantiomeric CIS-7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid.

b) (-)CIS-1-(5-Cyano-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

Specified in the title compound was synthesized analogously to example 1C) from enantiomeric CIS-7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (50 mg). The output of 60.2 mg (84%). [α]D=-0,388 (c=0.5, CHCl3).

Example 33

(±)-CIS-N-(5-cyano-2-pyridinyl)-N-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

a) 1,4-Dichloro-2-(2-propenyloxy)benzene

2.5-Dichlorphenol (8 g, 49 mmol) was mixed with potassium carbonate (13,6 g, 98 mmol) and 80% solution of propargylamine in toluene (11 ml, 98 mmol) in acetone (100 ml) and was stirred over night at room temperature. The precipitate was removed by filtration and washed with acetone. The obtained acetone solution was concentrated by rotary evaporation and was kept in vacuum for 5 hours. Received the product as a yellow oil in quantitative yield. It was used for further transformation without further purification.

b) 5,8-Dichloro-2H-chromen

1,4-Dichloro-2-(2-propenyloxy)benzene was degirolami and was heated with stirring in an argon atmosphere for 4 h at 224°C. the Reaction mixture was then subjected to distillation in a Kugelrohr apparatus (150-175°C/4,1x10-2mbar) to give 3.58 g of the desired product as a solid white color. Exit 36% of the original dichlorphenol.

C) (±)-CIS-Ethyl 4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylate

5,8-Dichloro-2H-chromen (3,15 g, 16 mmol), Rh(II)Ac2)2(30 mg, 0,1 mol.%) was dissolved in degassed dry methylene chloride (3 ml). Added ethyl diazo acetate (3 ml, 2 EQ.) in the same solvent using a syringe at a flow rate of 0.4 ml/hour, for about 5 hours in an atmosphere of N2. The reaction mixture was then washed with NH4Cl (aq.), water and saturated salt solution and the solvent was removed. The product (45% of the CIS and 55% TRANS) was purified by chromatography on silica gel (200 g, ethyl acetate/n-hexane 1:15) to obtain 0.9 g of pure CIS-product (racemate). A yield of 20%. M+=287.

1H-NMR (CDCl3): to 7.15 (d, 1H, J=8.5 Hz), 6,91 (d, 1H, J=8,8 Hz), 4,59 (DD, 1H, J1=12,02, J2=7,03), 4,48 (DD, 1H, J1=12,02, J2=4,10), 4,07-of 3.94 (m, 3H), 2,62 (t, 1H, J=8,8 Hz), and 2.27 (t, 1H, J=at 8.36 Hz), 2,20-2,12 (m, 1H), 1,1 (t, 3H).

d) (±)-CIS-4,7-Dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

(±)-CIS-Ethyl 4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylate was mixed with methanol (3 ml) and aqueous solution of NaOH (1.5 EQ., 3 ml) and was heated with stirring for 1.5 hours at 60°C. Extraction of the primary reaction mixture in hexane showed the absence of starting material. The reaction mixture was acidified with an excess of 3 M HCl solution (pH 1). The precipitate was collected by suction and washed with water. The obtained solid white color was dried in high vacuum (yield 80%).

(e) (±)-CIS-N-(5-Cyano-2-pyridinyl)-N-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-4,7-Dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (100 mg, 0,39 mmol) was mixed with toluene (3 ml), triethylamine (1.1 EQ.), DPPA (1.1 EQ.) and barbotirovany with argon for about 5 minutes, the Reaction mixture was then heated with stirring at 115°C for 3 h in argon atmosphere. The reaction mixture was concentrated by evaporation on a rotary evaporator and mixed with a small amount of dry ethanol. The precipitate was collected by suction and washed with ethanol (2 × 2 ml). The desired product (+/-)-CIS-isomer) was obtained in the form of a beige-white powder (65 mg, yield 45%).

1H-NMR (DMSO-d6): 9,83 (s, 1H), 8.34 per (d, 1H), 8,03 (DD, 1H), 7,75 (users, 1H), 7,44 (d, 1H), 7,30 (d, 1H), 7,0 (d, 1H), 4,43 (DD, 1H), 4,18 (DD, 1H), 3,55 is-3.45 (m, ˜1H, overlapped with a signal of H2O)to 2.54 (DD, 1H), 2,10-2,02 (m, 1H).

Example 34

(±)-CIS-N-(5-Chloro-2-pyridinyl)-N-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-N-(5-Chloro-2-pyridinyl)-N-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was synthesized analogously to example 33 from (±)-CIS-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (100 mg, 0,39 mmol) and 2-amino-5-chloropyridine (1,1 EQ.) to obtain 66 mg of product as a white powder. Yield 44%.

1H-NMR (DMSO-d6): for 9.47 (s, 1H), 7,98 (d, 1H), 7,86 (users, ˜1H), 7,83 (DD, 1H), 7,30 (d, 1H), 7.23 percent (d, 1H), 7,10 (d, 1H), of 4.44 (DD, 1H), 4,18 (DD, 1H), 3,55-of 3.48 (m, 1H), 2,54 (DD, 1H), 2,10-2,02 (m, 1H).

Example 35

(±)-CIS-N-(5-Bromo-2-pyridinyl)-N'-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-N-(5-Bromo-2-pyridinyl)-N'-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was synthesized analogously to example 33 from (±)-CIS-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (100 mg, 0,39 mmol) and 2-amino-5-bromopyridine (1.1 EQ.) to obtain 35 mg of the product as a gray powder. The output of 21%.

1H-NMR (DMSO-d6): for 9.47 (s, 1H), of 7.97 (d, 1H), 7,86 (users, ˜1H), 7,83 (DD, 1H), 7,30 (d, 1H), 7.23 percent (d, 1H), 7,10 (d, 1H), 4,43 (DD, 1H), 4,18 (DD, 1H), 3,55-of 3.48 (m, 1H), 2,54 (DD, ˜1H, Perek is Ivashina with a signal of DMSO), 2,08 is 2.01 (m, 1H).

Example 36

(±)-CIS-N-(5-Phenoxy-2-pyridinyl)-N'-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-N-(5-Phenoxy-2-pyridinyl)-N'-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was synthesized analogously to example 33 from (±)-CIS-4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (58 mg, 0.22 mmol) and 2-amino-5-phenoxypyridine (1.1 EQ.) to obtain 49 mg of the product as a slightly brown powder. Yield 49%.

1H-NMR (CDCl3): of 9.30 (users, 1H), compared to 8.26 (s, 1H), 7,53 (d, 1H), 7,35 (m, 2H), 7,25 (DD, 1H), 7,16-7,10 (DD, ˜1H, overlapped with a signal CHCl3), 7,05 (d, 1H), 6,97-of 6.90 (m, 3H), 6,72 (d, 1H), 4,46 (DD, 1H), 4,30 (DD, 1H), 2,73 (m, 1H), 2.63 in (DD, 1H), 2,05-of 1.95 (m, 1H).

Example 37

(±)-CIS-N-(7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-N'-(5-cyano-2-pyridinyl)urea

a) 5-Chloro-2-terfenol

5-Chloro-2-ftoranila (10 g, 68 mmol) was dissolved in 6 M sulfuric acid and cooled in a bath of ice/saturated salt solution to -5°C. a Solution of NaNO2(5,2 g, 76 mmol) in minimum amount of water was added dropwise to the stirred suspension at a temperature not higher than -2°C. After the addition the resulting clear yellow solution was left to mix for an additional 30 min while cooling. CuSO4dissolved water (80 ml) and the MCA is ivali with sulfuric acid (32 ml). Salt the page was added dropwise to a pre-heated (160°and (C) copper sulphate solution and the product was removed from the reaction flask by distillation with steam. To complete the reaction time was about 2 hours. A solution of water/phenol was extracted into ether, washed with saturated salt solution and dried over Na2SO4. Concentration gave 4 g of the crude phenol (40%).

b) 4-Chloro-1-fluoro-2-(2-propenyloxy)benzene

4-Chloro-1-fluoro-2-(2-propenyloxy)benzene was synthesized analogously to example 33a (4 g, 27 mmol) 4-chloro-1-terfenol obtaining 4.6 g of product (purified column chromatography on silica gel, ethyl acetate/n-hexane 1:15) as a yellow oil. Output 90%.

C) 5-Chloro-8-fluoro-2H-chromen

5-Chloro-8-fluoro-2H-chromen synthesized analogously to example 33b) of 4-chloro-1-fluoro-2-(2-propenyloxy)benzene (4.6 g, 25 mmol) to give 1 g of the product (purified column chromatography on alumina, ethyl acetate/n-hexane 1:15) as a colourless oil. Yield 22%.

d) Ethyl (±)-CIS-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylate

Ethyl (±)-CIS-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylate was synthesized analogously to example 33 5-chloro-8-fluoro-2H-chromene (1 g, 5.4 mmol) to obtain 360 mg (+-)-CIS-product (purified column chromatography on silica gel, the ethyl acetate/n-hexane 1:20) in the form of a white solid. The output 25%.

(e) (±)-CIS-7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

(±)-CIS-7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid was synthesized analogously to example 33d of ethyl (±)-CIS-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylate (360 mg, 1.3 mmol) to obtain 259 mg (+/-)-CIS-acid (80%).

f) (±)-CIS-N-(7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-N'-(5-cyano-2-pyridinyl)urea

(±)-CIS-N-(7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-N'-(5-cyano-2-pyridinyl)urea was synthesized analogously to example e of (±)-CIS-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (60 mg, 0.25 mmol) and 2-amino-5-chloropyridine (1.1 EQ.) to obtain 59 mg of product as a white powder. Yield 66%.

1H-NMR (DMSO-d6): for 9.47 (users, 1H), 7,89 (d, 1H), 7,80 (users, 1H), 7,74 (DD, 1H), 7,32 (d, 1H), 7,16-7,05 (m, 2H), 4,39 (DD, 1H), 4,16 (DD, 1H), 3,55-of 3.48 (m, 1H), of 2.51 (DD, ˜1H, overlapped with a signal of DMSO), 2,08 is 2.01 (m, 1H).

Example 38

(±)-CIS-N-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-N'-(5-chloro-2-pyridinyl)urea

(±)-CIS-N-(7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-N'-(5-chloro-2-pyrid the Nile)urea was synthesized analogously to example 5 from (± )-CIS-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (60 mg, 0.25 mmol) and 2-amino-5-chloropyridine (1.1 EQ.) to obtain 59 mg of product as a white powder. Yield 65%.

1H-NMR (DMSO-d6): for 9.47 (users, 1H), 7,89 (d, 1H), 7,80 (users, 1H), 7,74 (DD, 1H), 7,32 (d, 1H), 7,16? 7.04 baby mortality (m, 2H), 4,39 (DD, 1H), 4,16 (DD, 1H), 3,55-of 3.48 (m, 1H), of 2.51 (DD, ˜1H, overlapped with a signal of DMSO), 2.06 to a 2.01 (m, 1H).

Example 39

(±)-CIS-N-(5-Bromo-2-pyridinyl)-N'-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(±)-CIS-N-(5-Bromo-2-pyridinyl)-N'-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea was synthesized analogously to example e of (±)-CIS-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (60 mg, 0.25 mmol) and 2-amino-5-bromopyridine (1.1 EQ.) to obtain 56 mg of the product as a white powder. Yield 55%.

1H-NMR (DMSO-d6): 9,46 (users, 1H), of 7.96 (d, 1H), 7,83 (DD, 1H), 7,81 (users, 1H), 7,27(d, 1H), 7,16? 7.04 baby mortality (m, 2H), to 4.38 (DD, 1H), 4,17 (DD, 1H), 3,55-of 3.48 (m, 1H), of 2.51 (DD, ˜1H, overlapped with a signal of DMSO), 2,07 is 2.00 (m, 1H).

Example 40

(±)-CIS-N-(7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-N'-(5-phenoxy-2-pyridinyl)urea

(±)-CIS-N-(7-Chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)-N'-(5-phenoxy-2-pyridinyl)urea was synthesized analogously to example e of (±)-qi is-7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (60 mg, 0.25 mmol) and 2-amino-5-phenoxypyridine (1.1 EQ.) to obtain 76 mg of the product as a slightly brown powder. The yield was 73%.

1H-NMR (CDCl3): was 9.33 (users, 1H), to 7.93 (s, 1H), 7,51 (d, 1H), 7,38-to 7.32 (m, 2H), 7,25 (DD, ˜1H, overlapped with a signal CHCl3), 7,16-7,10 (m, 1H), of 6.96-to 6.88 (m, 3H), 6,79 (DD, 1H), of 6.68 (d, 1H), 4,45 (DD, 1H), 4,25 (DD, 1H), 3.75 to 3,70 (m, 1H), 2,61 (DD, 1H), 2,05-of 1.95 (m, 1H).

Example 41

N-[(1S,1aR,7bR) or (1R,1aS,7bS)-1,1a,2,7b-tetrahydrocyclopent[c][1]benzothiophen-1-yl]-N'-(5-cyano-2-pyridinyl)urea

a) 3,4-Dihydro-2H-1-benzothiophen-4-ol

The solution thiochroman-4-it (9 g) in ether (27 ml) was slowly added to a mixture of socialogical (0,53 g) in ether (54 ml). After complete addition, the mixture was boiled under reflux for 2 hours. The reaction mixture was cooled and added to ice and then adding water and a 20% solution of N2SO4. The aqueous phase was twice washed with ether. The ether phase is twice washed with 2N NaOH, once with water, dried over MgSO4and evaporated. Clean oil in (8.9 g) was led in a few hours. Rdt=97%.

b) 2N-1-Benzothiophen and 4H-1-benzothiophen

4-Thiochroman in (8.9 g) and acidic potassium sulfate (0,89 g) was placed in a flask and created a vacuum of 1 mm. the Flask was placed in a bath heated at 90°up until the alcohol has melted. Included magnetic stirrer and the temperature is Anna slowly brought up to 120° C. Dehydration was quick, the mixture of product and water were released and collected in a cooled ice tank. The product was transferred into the ether and dried. The crude product (7 g, Rdt=88%) were not purified. An NMR spectrum showed the presence of 10% 4H-1-benzothiophene.

(C) Ethyl ester of (1S,1aR,7bR) or (1R,1aS,7bS)-1,1a,2,7b-tetrahydrocyclopent[c][1]benzothiophen-1-carboxylic acid

The ethyl diazo acetate was slowly added to 500 mg of thiochroman at 140°C. the Reaction was monitored by gas chromatography and stopped when all of the source materials were consumed (about 7 hours). The residue was purified flash chromatography (5% ether in hexane). CIS-isomer (46,5 mg, Rdt=6%) identified using NMR spectroscopy.

d) (1S,1aR,7bR) or (1R,1aS,7bS)-1,1a,2,7b-tetrahydrocyclopent[c][1]-benzothiophen-1-carboxylic acid

A mixture of the CIS isomer (46,5 mg), LiOH (4 EQ., 19 mg) in 5 ml of methanol/25% water boiled under reflux for 1 hour. After evaporation of the solvent in vacuo the residue was dissolved in water and washed with ether. The aqueous phase was acidified with concentrated HCl and was extracted twice with dichloromethane. After drying the organic phase is evaporated to obtain the desired acid (30 mg). Rdt=73%.

e) N-[(1S,1aR,7bR) or (1R,1aS,7bS)-1,1a,2,7b-Tetrahydrocyclopent[c][1]benzothiophen-1-yl]-N'-(5-cyano-2-pyridinyl)the urine is in

CIS-acid (30 mg) was boiled under reflux for 4 hours in toluene (2 ml) in the presence of Et3N (0,02 ml), diphenylphosphinite (0,03 ml) and 2-amino-6-cyanopyridine (19.5 mg). After cooling, the toluene phase was washed with water, then with a solution of HCl (0.01 M). The organic phase was dried and evaporated. The residue was purified flash chromatography (EtOAc 2/hexane 1) and received 10 mg of the desired compound. Rdt=22%.

1H-NMR (DMSO-d6): a 1.96 (1H, m); 2,30 (1H, t, 8,6); a 2.71 (1H, DDT, 13,65, 6,24); 3,24 (2H, m); 7,19 (3H, m); 7,37 (1H, DD, 7,4, 1,56); 7,42 (1H, DD, 9,0, 3,1); 7,60 (1H, NH); 8,02 (1H, DD, 9,0, 2,3); 8,15 (1H, s); of 9.89 (1H, NH)

Mass: 322 (M+), 321 (M-H).

Example 42

(1S,1aR,7bS)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

a) (2Z)-3-(3,6-Debtor-2-methoxyphenyl)-2-propen-1-ol

A solution of BuLi (2.5 m) in hexane (9.6 ml, 0,024 mol) was added to a stirred solution of 2,5-diferente (2,88 g, 0.02 mol) in dry THF (30 ml) at -70°then add 2 hours of a solution of zinc chloride (3.6 g, was 0.026 mol) in dry THF (50 ml). The reaction temperature was brought to room temperature and then stirring was maintained at room temperature for 30 minutes was Added Pd(OAc)2(8 mg, 0.2 mol.%), then ethyl CIS-3-bromoacrylic (3.58 g, 0.02 mol). The reaction mixture was placed in a preheated oil bath and boiled fix refrigerator for 1 hour. The reaction mixture was cooled to -78°and added dropwise 60 ml (0.06 mol) of DIBAL (1M solution in hexane). Stirring was continued at -78°C for 2 hours and for 1 hour at room temperature. The reaction mixture is extinguished by water, and all solids were dissolved by addition of HCl. The organic phase was diluted with ether, separated, washed with 5N HCl, saturated salt solution and evaporated in vacuum. The rest drove in a Kugelrohr apparatus (1,5x10-2mbar, 150° (C) to obtain 3.7 g (92%) of crude (2Z)-3-(3,6-debtor-2-methoxyphenyl)-2-propen-1-ol, solariega ˜6% other regioisomers. The crude product was used in the next stage without additional purification.

1H-NMR (CDCl3): 7,00 (m, 1H); 6,77 (m, 1H); of 6.31 (pribid, 1H); 6,12 (pribid, 1H); 4,08 (ushort, 2H); to 3.89 (d, 3H); 1,80 (ushort, 1H).

b) (2Z)-3-(3,6-Debtor-2-methoxyphenyl)prop-2-initiatiated

p-Toluensulfonate Glyoxylic acid chloride of acid (5,16 g, 0.02 mol) was added to a solution of (2Z)-3-(3,6-debtor-2-methoxyphenyl)-2-propen-1-ol (3.6 g, 0.018 mol) in dry CH2Cl2(50 ml) at -5°and was slowly added N,N-dimethylaniline (2.5 ml, 0.02 mol). After stirring for 30 min at -5°slowly added With Et3N (12 ml, 0.09 mol). The resulting mixture was stirred for 15 min at -5°and then for 30 min at room temp is the temperature, after this was added water (˜50 ml). The organic phase was separated by washing with water, saturated salt solution and concentrated in vacuum. Flash chromatography (silica gel, EA:Hex; 1:15) gave 3,86 g (80%) of product as a solid yellow color.

1H-NMR (CDCl3): 7,00 (m, 1H); 6,76 (m, 1H); 6,41 (pribid, J=12,2 Hz; 1H); 6,00 (pribid, J=12,2; 6,10 Hz; 1H); 4,71 (users, 1H); of 4.67 (dt, 2H); to 3.89 (d, 3H).

C) (1S,5R,6S)-6-(3,6-Debtor-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2-he

(2Z)-3-(3,6-Debtor-2-methoxyphenyl)prop-2-initiatiated (of 3.45 g of 0.013 mol) was dissolved in 100 ml of dry degassed dichloromethane and added dropwise to a solution of chiral catalyst Doyle (Doyle) (Aldrich, also available from Johnsson Matthey, 10 mg, with 0.1 mol.%) in 50 ml of dichloromethane in an argon atmosphere at ambient temperature during the period ˜6 hours. By the end of the input blue color goes in olive. The reaction mixture was concentrated in vacuum and the crude product was purified flash chromatography (silica gel, EA:Hex, 1:5→1:1) obtaining of 2.72 g (88%) of (1S,5R,6S)-6-(3,6-debtor-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2-it is in the form of a colorless solid. The enantiomeric purity can be checked at this stage by using column Chiracel OD, 10% IPA in hexane - 94% EE.

1H-NMR (CDCl3): 7,00 (m, 1H); 6,72 (m, 1H); to 4.33 (DD, 1H); 4,10 (d, 1H); was 4.02 (d, 3H); 2,6 (m, 2H); is 2.37 (t, 1H).

d) (1S,1aR,7bS)-1-(methyl bromide)-4,7-debtor-1a,7b-dihydrocyclopenta[c]chromen-2(1H)-he

(1S,5R,6S)-6-(3,6-Debtor-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2-he (130 mg, 0.55 mmol) was mixed with 1.2 ml of 30% HBr/AcOH (6 mmol) and heated in a sealed vessel under stirring for about 4 h at 90°C. the Reaction mixture was then cooled, mixed with water and was extracted into diethyl ether (3h20 ml). The ether extract was washed with a saturated solution of sodium bicarbonate and a saturated solution of salt. Was dried over magnesium sulfate. Concentration gave 160 mg of white solid. Exit 98%.

1H-NMR (CDCl3): was 7.08 (m, 1H); to 6.88 (m, 1H); 3,44 (DD, 1H); to 3.06 (t, 1H); 2,96 (DD, 1H); of 2.64 (DD, 1H); to 2.46 (m, 1H).

(e) (1S,1aR,7bS)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

(1S,1aR,7bS)-1-(methyl bromide)-4,7-debtor-1a,7b-dihydrocyclopenta[c]chromen-2(1H)-he (360 mg, 1.2 mmol) was mixed with NaOH solution (0.1 g, 2.5 mmol) in 5 ml of water and heated with stirring for 1 hour at 90°C. After completion of the reaction the mixture was cooled and was extracted into diethyl ether (2x20 ml). The aqueous phase was acidified using conc. HCl. The precipitate was collected by filtration to obtain 180 mg of the pure product. The mother liquor was extracted into ether and washed with saturated salt solution, dried over alpacamania. Concentration gave an additional 70 mg of product (containing up to 15% impurities). The total yield of about 92%.

1H-NMR (CDCl3): 6,86 (m, 1H); is 6.54 (m, 1H); 4,48 (m, 2H); 2,62 (t, 1H); 2,20 (t, 1H); 2,11 (m, 1H).

Example 43

(+/-)-CIS-N-[1a,6b-Dihydro-1H-benzo[b]cyclopropa[d]Tien-1-yl]-N'-(5-cyano-2-pyridinyl)urea

a) Ethyl ester of (1S,1aS,6bR) or (1R,1aR,6bS)-CIS-1a,6b-dihydro-1H-benzo[b]cyclopropa[d]thiophene-1-carboxylic acid

The ethyl diazo acetate was slowly added to 10 g of thiophene at 140°C. the Reaction was monitored by gas chromatography and stopped after 7 hours. The residue was purified flash chromatography (5% ether in hexane). CIS-isomer (917 mg, Rdt=6%) was identified by NMR spectroscopy.

Reference: G.M. Badger et al, J. Chem. Soc., 1958, 1179-1184.

Badger G.M. et al, J. Chem. Soc., 1958, 4777-4779.

b) (1S,1aS,6bR) or (1R,1aR,6bS)-CIS-1a,6b-Dihydro-1H-benzo[b]cyclopropa[d]thiophene-1-carboxylic acid

A mixture of the CIS isomer (443 mg), LiOH (193 mg) in 15 ml of methanol/25% N2About boiled under reflux for 1 hour. After evaporation of the solvent in vacuo the residue was dissolved in water and washed with ether. The aqueous phase was acidified with concentrated HCl and was extracted twice with dichloromethane. After drying the organic phase is evaporated and got the desired acid (313,6 mg). Rdt=81%.

C) (+/-)-CIS-N-[1a,6b-Dihydro-1H-b is the site, located between[b]cyclopropa[d]Tien-1-yl]-N'-(5-cyano-2-pyridinyl)urea

CIS-acid (313 mg) was boiled under reflux for 4 hours in toluene (20 ml) in the presence of Et3N(0.25 ml), diphenylphosphinite (0.3 ml) and 2-amino-6-cyanopyridine (220 mg). After cooling, the toluene phase was washed with water, then with a solution of HCl (0.01 M). The organic phase was dried and evaporated. The residue was purified flash chromatography (EtOAc 2/hexane 1) and received 10 mg of the desired compound. Rdt=2%.

1H-NMR (DMSO-d6): of 3.32 (1H, m); 3,39 (1H, TD, 8,05, 7,69); to 3.52 (1H, DD, 7,69, 6,22); was 7.08 (1H, dt, 7,32, 1,1); to 7.15 (1H, TD, 7,32, 1,1); 7,22 (1H, DD, and 8.4, 0,8); 7,39 (2H, m); 7,50 (1H, NH); 8,00 (1H, DD, 8,79, 2,2); 8,23 (1H, d, 2,2); 9,76 (1H, NH)

13C-NMR (DMSO-d6): 25,6 (CH)and 29.5 (CH), 33,7 (CH), 101,5 (C), 112,1 (CH), 118,0 (C), 122,1 (CH), was 124.9 (CH), RUB 127.3 (CH), USD 128.0 (CH), 136,3 (C), 141,7 (CH), 143,7 (C), USD 151.6 (CH), 155, 1mm (C), 156,1 (C)

Mass: 310 (M+2), 309 (M+H).

Example 44

(-)-CIS-1-(5-Chloropyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

This compound was obtained analogously to example 1C, but using chiral (+)-CIS-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (see example a) (1.3 g, of 5.75 mmol). The product is purified on silica gel, recrystallized from acetonitrile to obtain 0.95 g (47%) specified in the header of the product. The absolute stereochemical configuration is defined as for example 30.

1H-NMR (CDCl3): 9,25 (Sirs, 1H), 8,67 (s, 1H), 7,79 (d, 1H), of 7.48 (DD, 1H), 6,92-6,86 (m, 1H), of 6.71 (d, 1H), 6,65-6,60 (m, 1H), 4,45 (DD, 1H), 4,34 (DD, 1H), 3,80 (kV, 1H), 2,61 (t, 1H), 2.00 in to 1.98 (m, 1H).

Example 45

(-)-CIS-1-(5-Cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

(+)-CIS-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (see example e) (1.18 g, 5.2 mmol), diphenylphosphoryl [1340 μl, 6.3 mmol (d=amounted to -1,277)], triethylamine (870 μl, 6.3 mmol) and 2-amino-5-cyanopyridine (740 mg, 6.3 mmol) was dissolved in toluene (15 ml) and boiled under reflux for 4 hours. The solvent was then removed in vacuo, the crude product was dissolved in ether, washed (CH ml of 0.01 M HCl) and was purified by chromatography (silica gel, 0→1% Meon in ether) to give pure (-)-CIS-1-(5-cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea (1.1 g, 64%). The enantiomeric excess of 92%, as determined by HPLC on a Chiral column AGP, eluent 11% acetonitrile in sodium-phosphate buffer, flow rate 0.9 ml/min Absolute stereochemical configuration is defined as for example 30.

1H-NMR (CDCl3): 9 (s, NH), 8,42 (s, NH), 8,16 (d, 1H), 7,72 (DD, 1H), 6,97-6,76 (m, 2H), 6,69-of 6.61 (m, 1H), 4,47 (DD, 1H), or 4.31 (DD, 1H, in), 3.75 (m, 1H), 2,65 (t, 1H), 2.05 is is 1.96 (m, 1H).

Example 46

(-)-CIS-1-(5-Cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)thiourea

(+)-CIS-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (2.2 g, 9.7 mmol), DPPA [2380 µl of 10.7 mmol 97% (d=amounted to -1,277)] and TEM (1510 μl, 11.7 mmol) was boiled under reflux for 2 hours in toluene (20 ml). Then was added dioxane (26 ml) and HCl(aq.)(26 ml, 6M) and the reaction mixture was left for 1-2 hours at 50°C. was Added water (50 ml), the aqueous phase was washed with ether (2 x 25 ml) and then was podslushivaet ammonia(aq.). Extraction with dichloromethane and drying gave the intermediate compound 4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-ylamine (1,37 g, 71%)which was immediately treated with 6-isothiocyanateconjugated (1,25 g, 7.7 mmol) in acetonitrile (2 ml) at room temperature over the weekend. Precipitated crystals were filtered off, the solvent was removed in vacuum and chromatographically (silica gel, 20% ether in pentane). The obtained product was combined with the crystals and the crude product (900 mg) was subjected to recrystallization (ethanol-acetone) to give pure (-)-CIS-1-(5-cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)thiourea (590 mg, 18%). The absolute stereochemical configuration is defined as for example 30.

1H-NMR (CDCl3-MeOD): 8,1 (d, 1H), to 7.77 (DD, 1H), 6,99-6,91 (m, 1H), 6,74 (DD, 1H) 6.73 x of 6.66 (m, 1H), 4,48 (DD, 1H), 4,33 (DD, 1H), 4,20 (DD, 1H), 2,78 (t, 1H), 2,16-2,1 (m, 1H).

Example 47

(+/-)-CIS-1-(5-Bromopyridin-2-yl)-3-(7-fluoro-propionyl-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

a) 1-(4-fluoro-2-prop-2-injectively)propane-1-he

To a mixture of NaH (95%, 278 mg, 11 mmol) in DMF (20 ml) at 0°C was added 1-(4-fluoro-2-hydroxyphenyl)propane-1-he (1.68 g, 10 mmol) in DMF (5 ml). After 15 min at 0°to the reaction mixture were added 3-bromopropene (to 3.02 g, 20 mmol). After 1 hour at 0°the reaction mixture was left to reach room temperature. The reaction mixture was extracted with N2O (100 ml). H2About phase washed with Et2O (g ml) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was purified column chromatography (silica gel, CH2Cl2) to obtain 1.40 g (68%) of 1-(4-fluoro-2-prop-2-injectively)propane-1-it.

1H-NMR (CDCl3): to 7.64 (DD, 1H), 6,69 (DD, 1H), 6,60 (DDD, 1H), and 4.68 (d, 2H), 2,85 (kV, 2H), 2,58 (t, 1H), of 1.03 (t, 3H).

b) 1-(5-fluoro-2H-chromen-8-yl)propane-1-he

1-(5-fluoro-2H-chromen-8-yl)propane-1-he synthesized analogously to example 3b from 1-(4-fluoro-2-prop-2-injectively)propane-1-it (1,34 g, 6.5 mmol) to give 619 mg (46%) of 1-(5-fluoro-2H-chromen-8-yl)propane-1-it.

1H-NMR (CDCl3): 7,60 (DD, 1H), 6,67 return of 6.58 (m, 2H), 5,86 (dt, 1H), amounts to 4.76 (DD, 2H), 2,93 (kV, 2H), of 1.23 (t, 3H).

(C) Ethyl ester (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

Ethyl ether (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid Synthe is Aravali in accordance with the method of example 3C) of 1-(5-fluoro-2H-chromen-8-yl)propane-1-she (619 mg, 3 mmol) to give 142 mg (16%) ethyl ester (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid ethyl ester (±)-TRANS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid as a by-product.

1H-NMR (CDCl3): to 7.59 (DD, 1H), 6,65 (m, 1H), 4,50-to 4.46 (m, 2H), 3,95 (kV, 2H), 2,89 (kV, 2H), 2.57 m (DD, 1H), measuring 2.20 (DD, 1H), 1,13-of 1.03 (m, 1H), 1,12-a 1.01 (m, 6H).

d) (±)-CIS-7-Fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

(±)-CIS-7-Fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid was synthesized analogously to example 1b from ethyl ether (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (140,3 mg, 0.48 mmol) to give 83 mg (65%) (±)-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid in the form of a solid white color. The crude product was purified column chromatography (silica gel, 1→5% Meon in CH2Cl2).

1H-NMR (DMSO-d6): 12,15 (users, 1H), 7,46 (DD, 1H), 6,78 (DD, 1H), 4,57 (DD, 1H), 4,43 (DD, 1H), 2.93 which is 2.80 (m, 2H), by 2.55 (DD, 1H), 2,24 (DD, 1H), 2,20-2,10 (m, 1H), of 1.02 (t, 3H).

(e) (±)-CIS-1-(5-Bromopyridin-2-yl)-3-(7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl)urea

Specified in the title compound was synthesized analogously to example 1C) by the interaction of 1 equivalent (± )-CIS-7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid and 1 EQ. of triethylamine in toluene with 1 EQ. diphenylphosphinite for 30 min at room temperature. The reaction mixture was heated to 120°and added approximately equimolar solution of 2-amino-5-bromopyridine. After 3 hours the solution was left to reach room temperature and is listed in the title compound was extracted, as shown above.

Example 48

(1S,5R,6S)-6-(3,6-Debtor-2-methoxyphenyl)-2-methoxy-3-oxabicyclo[3.1.0]hexane

a) Iodine-3-oxabicyclo[3.1.0]hexane-2-he

Specified in the title compound was synthesized in the specified stereochemistry, as described Doyle J Amer Chem Soc 117 (21) 5763-5775 (1993).

b) Iodine-2-methoxy-3-oxabicyclo[3.1.0]hexane

Specified in the title compound was synthesized in the specified stereochemistry, as described by Martin et al Tett Lett 39 1521-1524 (1998).

C) (1S,5R,6S)-6-(3,6-Debtor-2-methoxyphenyl)-2-methoxy-3-oxabicyclo[3.1.0]hexane

2,4-Differenital (90 mg, of 0.62 mmol) was dissolved in anhydrous, degassed THF (7 ml) and cooled to -78°C in an atmosphere of N2. Added nBuLi, 2.5 M in hexane (0,30 ml, 0.77 mmol) and the reaction mixture was stirred at -78°C for 2 hours. Added ZnCl2(150 mg, 1.1 mmol) is a solution of anhydrous THF (7 ml) and the reaction mixture was left to warm to ambient temperature over 2 hours. Iodine-2-methoxy-3-oxabicyclo (150 mg, was 0.63 mmol), Pd(OAc)2(1.5 mg, 6.2 mmol) and the ligand Tris(2,4-di-tert-butylphenyl)fosfat (40 mg, 62 μmol) were mixed in anhydrous THF (7 ml) and was added to the reaction mixture. The reaction mixture is boiled under reflux for 3 days and extinguished H2The acting was Added diethyl ether and the layers were separated, the organic layer washed with N2About water and saturated NaCl, dried over MgSO4, filtered and concentrated to obtain specified in the connection header, otherwise known as 2,4-debtor-5-(cyclopropylmethyl)anisole. Column chromatography on silica gel (EtOAc/hexane 1:3) gave (4) 50 mg, 31%.

1H-NMR (CDCl3): 6,88-6,94 (m, 1H, ArH), of 6.68-6.73 x (m, 1H, ArH), 4,82 (s, 1H, CHOCH3), 3,97-3,98 (m, 1H, CHOCH), of 3.94 (s, 3H, OCH3), 3,79-3,81 (m, 1H, CHOCH), 3,30 (s, 3H, OCH3), 2,13-2,19 (m, 2H, 2x CH-cyclopropyl), 1,89 (Tr, J=7,Hz, 1H, CH-cyclopropyl).

Example 49

CIS-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid

1M Solution of BBr3in CH2Cl2(5.8 ml, 5.8 mmol, 2.1 EQ.) added to the original lactone (1S,5R,6S)-6-(3,6-debtor-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2-ONU example 42s) (0.66 g, a 2.75 mmol) at 0°C. the Reaction mixture was stirred at 0°C for 1 hour. Added acetonitrile (5.8 ml) and stirring was continued for 3 h at 0°C. the Reaction mixture Gus is whether the addition of water and the organic phase was separated. The aqueous phase was extracted with CH2Cl2and the combined organic phases are evaporated. To the obtained precipitate was added NaOH (0.33 g, 8.25 mmol, 3 EQ.) in water (˜5 ml) and stirred at 80°C for 45 minutes, the Reaction mixture was extracted with ether to remove non-acidic impurities. Remaining in the aqueous phase of the ether evaporated in vacuo and added conc. HCl to pH˜3. Through ˜1 hour the solid was filtered to obtain at the output 0,497 g (80%) of the crude final acid as a brownish solid. The crude acid was dissolved in 6 ml of EtOH/H2On (40/60 V/V) and treated with activated charcoal. The hot solution was filtered and left for crystallization. Yield 0.4 g (64%).

Example 50

N-[(1S,1aR,7bR)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N-(5-fluoro-2-pyridinyl)urea

(1S,1aR,7bS)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (50 mg, 0.22 mmol, its ˜90%) was mixed with toluene (1 ml), triethylamine (0,034 ml, 1.1 equiv.) 2-amino-5-herperidin (28 mg, 1.1 equiv.) DPPA (0,054 ml, 1.1 EQ.). The reaction mixture was then heated under stirring at 110°C for 3 hours. The reaction mixture was concentrated by evaporation on a rotary evaporator and purified column chromatography on silica gel (50 g, ethyl acetate/hexane 1:1) to give 30 mg of the product VI is e solid white color.

1H-NMR (DMSO-d6): 9,34 (users, ˜1H), 7,85 (userd, 2H), 7,6 (dt, 1H), 7,33 (DD, 1H), 7,06 (m, 1H), 6,77 (dt, 1H), 4,29 (m, 2H), 3,48 (m, 1H), 2,48 (m, 1H/overlapped with a signal of DMSO), 2,00 (m, 1H). LC-MS: M+336.

Example 51

N-[(1S,1aR,7bR)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N-(5-iodine-2-pyridinyl)urea

(1S,1aR,7bS)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (50 mg, 0.22 mmol, its ˜90%) was mixed with toluene (1 ml), triethylamine (0,034 ml, 1.1 equiv.) 2-amino-5-iodopyridine (54 mg, 1.1 equiv.) DPPA (0,054 ml, 1.1 EQ.). The reaction mixture was then heated under stirring at 110°C for 3 hours. The reaction mixture was concentrated by evaporation on a rotary evaporator and purified column chromatography on silica gel (50 g, ethyl acetate/hexane 1:1) to give 35 mg of the product as a solid white color.

1H-NMR (DMSO-d6): 9,4 (users, ˜1H), 8,07 (d, 1H), 8,02 (users, ˜1H), to $ 7.91 (DD, 1H), 7,11 (d, 1H), 7,06 (m, 1H), 6,77 (dt, 1H), 4,29 (userd, 2H), 3,5 (m, 1H), 2,46 (m, 1H/overlapped with a signal of DMSO), 2,00 (m, 1H), LC-MS: M+444.

Example 52

N-[(1S,1aR,7bR)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N-(3-isoxazolyl)urea

(1S,1aR,7bS)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (50 mg, 0.22 mmol, its ˜90%) was mixed with toluene (1 ml), triethylamine (0,034 ml, 1,1 is square), 3-aminoisoquinoline (0,018 ml, 1.1 equiv.) DPPA (0,054 ml, 1.1 EQ.). The reaction mixture was then heated under stirring at 110°C for 3 hours. The reaction mixture was concentrated by evaporation on a rotary evaporator and purified column chromatography on silica gel (50 g, ethyl acetate/hexane 1:1) to obtain 10 mg of the product as a solid white color.

1H-NMR (DMSO-d6): 9,45 (users, ˜1H), and 8.6 (d, 1H), 7,06 (m, 1H), 6.75 in (dt, 1H), 6,63 (d, 1H), 6,33 (users, ˜1H), 4,29 (m, 2H), 3,37 (overlapped with water signal), 2,43 (m, 1H), up to 1.98 (m, 1H), LC-MS: M+308.

Example 53

N-[(1S,1aR,7bR)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]urea

(1S,1aR,7bS)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (50 mg, 0.22 mmol, its ˜90%) was mixed with toluene (1 ml), triethylamine (0,034 ml, 1.1 equiv.) 2-amino-4-(4-chlorophenyl)-1,3-thiazole (52 mg, 1.1 equiv.) DPPA (0,054 ml, 1.1 EQ.). The reaction mixture was then heated under stirring at 110°C for 3 hours. The reaction mixture was concentrated by evaporation on a rotary evaporator, the product was led from ethanol and collected by filtration to obtain 50 mg of the product as a solid white color.

1H-NMR (CDCl3): 10,32 (users, ˜1H), 7,68 (d, 2H), 7,37 (s, 1H), 7,32 (d, 2H), of 6.96 (s, 1H), 6.87 in (m, 1H), 6,62 (dt, 1H), of 4.44 (DD, 1H), 4,33 (DD, 1H), 3,53 (m, 1H), 2,56 (m, DC; 1H), a 1.96 (m, 1H), LC-MS: M+434.

Example 54

N-[(1S,1aR,7bR)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(6-fluoro-1,3-benzothiazol-2-yl)urea

(1S,1aR,7bS)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (50 mg, 0.22 mmol, its ˜90%) was mixed with toluene (1 ml), triethylamine (0,034 ml, 1.1 equiv.) 2-amino-6-fluoro-1,3-benzothiazole (41 mg, 1.1 equiv.) DPPA (0,054 ml, 1.1 EQ.). The reaction mixture was then heated under stirring at 110°C for 3 hours. The reaction mixture was concentrated by evaporation on a rotary evaporator, the product was led from ethanol and collected by filtration to obtain 20 mg of the product as a solid white color.

1H-NMR (CDCl3): of 10.58 (users, ˜1H), 7,78 (userd, 1H), 7,52 (DD, 1H), 7,45 (DD, 1H), 7,05 (dt, 1H), 6,94 (m, 1H), 6,65 (dt, 1H), of 4.44 (DD, 1H), 4,33 (DD, 1H), 3,53 (m, 1H), 2,58 (m, ˜1H), 2,03 (m, 1H), LC-MS: M+434.

Example 55

N-[(1S,1aR,7bR)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(4-pyrimidinyl)urea

(1S,1aR,7bS)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (50 mg, 0.22 mmol, its ˜90%) was mixed with toluene (1 ml), triethylamine (0,034 ml, 1.1 equiv.) 4-aminopyrimidine (25 mg, 1.1 equiv.) DPPA (0,054 ml, 1.1 EQ.). The reaction mixture was then heated under stirring at 110°C for 3 hours. The reaction mixture was concentrated issue of ywaniem on a rotary evaporator, the product was led from ethanol and collected by filtration to obtain 20 mg of the product as a solid white color.

1H-NMR (DMSO-d6): 9,71 (users, 1H), 8.4V (users, 1H), 8,39 (d, 1H), 7,86 (users, 1H), 7,31 (d, 1H), was 7.08 (m, 1H), 6,77 (dt, 1H), or 4.31 (m, 2H), 3,48 (m, 1H), 2,48 (m, ˜1H, overlapped with a signal of DMSO), 2,02 (m, 1H).

Example 56

N-[(1S,1aR,7bR)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(2-pyrazinyl)urea

(1S,1aR,7bS)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-carboxylic acid (50 mg, 0.22 mmol, its ˜90%) was mixed with toluene (1 ml), triethylamine (0,034 ml, 1.1 equiv.) 4-aminopyrazine (25 mg, 1.1 equiv.) DPPA (0,054 ml, 1.1 EQ.). The reaction mixture was then heated under stirring at 110°C for 3 hours. The reaction mixture was concentrated by evaporation on a rotary evaporator, the product was led from ethanol and collected by filtration to obtain 5 mg of the product as a solid white color.

1H-NMR (DMSO-d6): to 9.57 (users, 1H), 8,67 (users, 1H), 8,10 (d, 1H), 7,95 (users, 1H), to 7.64 (users, 1H), 7,05 (m, 1H), 6,77 (dt, 1H), or 4.31 (m, 2H), 3,49 (m, 1H), 2,48 (m, ˜1H, overlapped with a signal of DMSO), 2,02 (m, 1H).

Example 57

N-[(1S,1aR,7bR)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(5-cyclopropyl-1H-pyrazole-3-yl)urea

(1S,1aR,7bS)-4,7-Debtor-1,1a,2,7b-tetrahydrocyclopent[c]XP is Myung-1-carboxylic acid (50 mg, 0.22 mmol, its ˜90%) was mixed with toluene (1 ml), triethylamine (0,034 ml, 1.1 equiv.) 3-amino-5-cyclopropyl-1H-pyrazole (30 mg, 1.1 EQ.), DPPA (0,054 ml, 1.1 EQ.). The reaction mixture was then heated under stirring at 110°C for 3 hours. The reaction mixture was concentrated by evaporation on a rotary evaporator and two compounds were divided by column chromatography on silica gel (50 g, ethyl acetate/hexane 1:3) to give 3 mg specified in the header of the product. The structure was confirmed by experiments13With, gHMBC, gHMQC and NOESY NMR.

1H-NMR (CDCl3): 7,05 (userd, ˜1H), to 6.88 (m, 1H), only 6.64 (dt, 1H), 5,24 (d, 1H), 4,49 (DD, 1H), 4,33 (DD, 1H), 3,63 (m, 1H), 2,61 (m, ˜2H), 1,99 (m, 1H), 0,99 (m, 2H), EUR 0.58 (m, 2H).

The results of biological tests

A detailed guide to the study of the tested compounds on the enzymatic level and in cell culture, including the selection and/or selection of mutant strains of HIV and mutant RT, can be found in DAIDS Virology Manual for HIV Laboratories complied by Division of AIDS, NIAID USA 1997. Studies of resistance, including the right for the various mutants that are resistant to medicines that are described in HIV Resistance Collaborative Group Data Analysis Plan for Resistance Studies, revised 31 August 1999.

The compounds of this invention was investigated on HIV activity, for example, by the use of multiple definitions with HTT in cells MT-4 (Weislow et al, J Nat Cancer Inst 1989, vol 81 no 8, 577 et seq), preferably the including definitions in the presence of 40-50% of human serum, to establish the contribution from the binding protein. Briefly, XTT analysis using MT-4 line of T-cells, grown in RPMI medium, supplemented with 10% fetal calf serum (or 40-50% human serum as appropriate), penicillin and streptomycin, seeded in 96-well microplates (2·104cells/well), infected 10-20 TCID50the hole HIV-1IIIB(wild type) or mutant virus, such as a virus, carrying the RT mutation Ile 100, Cys 181 or Asn 103. Serially diluted test compounds were added into the appropriate wells, the culture incubated at 37°in the atmosphere, enriched in CO2and cell viability was determined on the fifth or sixth day with the vital dye XTT. The results are usually in the form of the ED50um.

The compounds of this invention were analyzed in the above XTT analysis using HIV-1IIIB(wild-type), as shown in the table below:

Table
ExampleED50(nm)
Example 77
Example 166
Example 186
Example 1910
Example 207
Example 237
Example 2420
Example 303
Example 312,5
Example 339
Example 432

The compounds are preferably active against the virus wild-type and mutant HIV virus, particularly a virus containing mutations that are resistant to medicines. Mutations that are resistant to medicines, are those that occur in patients due to the selective action of an antiviral medication prior art and which reported enhanced resistance to such antiviral drug. Data Analysis Plan, to which reference was made above, briefly identifies important mutants that are resistant to medicines, for each class of antiviral drugs that are currently coming to market. Clones that are resistant to medicines, easily distinguish among HIV-patients who are not amenable to specific antiviral therapy. Alternatively, the receiving RT-known genetic mutations on the basis shown in No. WO 97/27319, WO 99/61658 and WO 00/73511, which also shows the use of such mutants in the analysis of the sensitivity profile.

K N is particularly relevant mutant resistant to medicines in the context of NNRTIS therapy, and the program of the present invention preferably have a low ED 50against this mutant, especially in tests simulating the presence of human serum. The compounds of this invention, such as shown in the examples above demonstrate in such research activity at micromolar concentrations.

1. The compound of the formula I

where R1represents O, S;

R2is optionally substituted, nitrogen-containing heterocycle which nitrogen is in position 2 relative to the connection with (thio)urea;

R3represents H, C1-C3alkyl,

R4-R7independently selected from H, C1-C6of alkyl, C2-C6alkenyl,2-C6the quinil, Halogens1-C6of alkyl, C1-C6alkanoyl, Halogens1-C6alkanoyl, C1-C6alkoxy, Halogens1-C6alkoxy, hydroxy-C1-C6of alkyl, cyano, halogen, hydroxy;

X is -(CHR8)n-D-(CHR8)m-;

D represents-O - or-S-;

R8is N;

n and m are independently 0, 1 or 2;

and its pharmaceutically acceptable salts.

2. The compound according to claim 1, in which R1represents O.

3. The compound according to claim 1, in which R2is optionally substituted Piri is Il, isoxazolyl, benzothiazolyl, pyrimidinyl, pyrazinyl or thiazolyl.

4. The compound according to claim 3 in which R2represents a 5-substituted of pyrid-2-yl.

5. The compound according to claim 4, in which the substituent in position 5 represents halogen, cyano, phenoxy or ethinyl.

6. The compound according to claim 5, in which the substituent in position 5 represents a cyano or chlorine.

7. The compound according to claim 1, in which R3is N.

8. The compound according to claim 1, in which cyclopropyl fragment has an enantiomeric excess of conformation, shown in partial formulas:

or

where X is as defined, Y is the bridge to the (substituted) phenyl ring depicted in formula I and Z represents a bond with (thiourea)-R2depicted in formula I.

9. The compound according to claim 1 in which the compound of formula I contains the enantiomeric excess isomer showing a negative optical activity.

10. The compound according to claim 1, in which D represents-O-.

11. The compound according to claim 1, in which n is 0 and m is 1.

12. Connection by claim 11, in which D represents-O-.

13. The compound according to claim 1, in which R4represents hydrogen, halogen or hydroxy.

14. The connection 13, in which R4is fluorine.

15. The compound according to claim 1, in which R5predstavljaet hydrogen, halogen, C1-C3alkylaryl or C1-C3alkyloxy.

16. The connection indicated in paragraph 15, in which R5represents hydrogen or fluorine.

17. The compound according to claim 1, in which R6represents hydrogen, halogen, C1-C3alkyloxy, C1-C3alkylsulphonyl, cyano or ethinyl.

18. The connection 17 in which R6represents hydrogen, methoxy or fluorine.

19. The compound according to claim 1, in which R7represents hydrogen, halogen, C1-C3alkyloxy or1-C3alkylsulphonyl.

20. The connection according to claim 19, in which R7is fluorine.

21. The compound according to claim 1, in which R5and R6represent N and R4and R7represent halogen.

22. Connection item 21, in which R4and R7represent fluorine.

23. Connection p.22, in which D represents-O-, n is 0, m is 1, R1represents Oh, R2is replaced by pyrid-2-yl, and R3is N.

24. Connection p.22, in which D represents-O-, n is 0, m is 1, R1is S, R2is replaced by pyrid-2-yl, and R3is N.

25. Connection item 23, in which R2represents 5-chloropyridin or 5-cyanopyridyl.

26. The connection point 24, in which R2represents 5-chloropyridin or 5-cyanopyridyl.

27. The compound according to claim 1, selected and the

CIS-1-(5-cyano-2-yl)-3-(1,1A,2,7b-tetrahydrocyclopent [|chromen-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(1,1A,3,7b-tetrahydro-2-oxacyclopropane[a]naphthalene-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(7-hydroxy-6-propionyl 1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(6-acetyl-7-hydroxy-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-3-(5-cyano-2-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(7-fluoro-4-propionyl 1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(7-fluoro-4-methoxy-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(7-fluoro-4-chloro-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(5-chloropyridin-2-yl)-3-(4-chloro-7-fluoro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(5-bromopyridin-2-yl)-3-(4-chloro-7-fluoro-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(5-cyano-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(5-ethinyl-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(5-acetyl-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-3-(5-cyano-2-yl)urea,

CIS-1-(5-methoxy-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-3-(5-cyano-2-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(N-and ethyl-1,1A,3,7b-tetrahydro-2-oxacyclopropane[and]quinoline-1-yl)urea,

CIS-1-(5-cyano-3-methylpyridin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(4,7-debtor-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-3-(5-ethynylpyridine-2-yl)urea,

CIS-1-(5-bromopyridin-2-yl)-3-(4,7-debtor-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(4,7-debtor-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-3-(5-phenoxypyridine-2-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(4,7-debtor-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)thiourea,

1-(6-chloro-5-cyanopyridine-2-yl)-3-(5,7-debtor-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

1-(5-cyano-2-yl)-3-(5,7-debtor-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-1-(4-bromo-7-fluoro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-3-(5-cyano-2-yl)urea,

CIS-1-(4-bromo-7-fluoro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-3-(6-chloro-5-cyanopyridine-2-yl)urea,

CIS-1-(4-bromo-6-fluoro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-3-(5-cyano-2-yl)urea,

CIS-1-(4-bromo-6-fluoro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-3-(6-chloro-5-cyanopyridine-2-yl)urea,

CIS-1-(5-cyano-2-yl)-3-(6-fluoro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-N-[1A,6b-dihydro-1H-benzo[b]cyclopropa[d]Tien-1-yl]-N'-(5-cyano-2-pyridinyl)urea

N-[(1S,1aR,7bR) or (1R,1aS,7bS)-1,1A,2,7b-tetr is hydrocyclone[I][1]benzothiophen-1-yl]-N'-(5-cyano-2-pyridinyl)urea

CIS-N-(5-bromo-2-pyridinyl)-N'-(7-chloro-4-fluoro-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-N-(7-chloro-4-fluoro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-N'-(5-chloro-2-pyridinyl)urea

CIS-N-(7-chloro-4-fluoro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)-N'-(5-cyano-2-pyridinyl)urea

CIS-N-(5-phenoxy-2-pyridinyl)-N'-(4,7-dichloro-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-N-(5-bromo-2-pyridinyl)-N'-(4,7-dichloro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-N-(5-chloro-2-pyridinyl)-N'-(4,7-dichloro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

CIS-N-(5-cyano-2-pyridinyl)-N'-(4,7-dichloro-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

N-[(1S,1R,7bR)-4,7-debtor-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl]-N'-(5-fluoro-2-pyridinyl)urea

N-[(1S,1R,7bR)-4,7-debtor-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl]-N'-(5-iodine-2-pyridinyl)urea

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(3-isoxazolyl)urea

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-[c]chromen-1-yl]-N'-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]urea

N-[(1S,1R,7bR)-4,7-debtor-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl]-N'-(6-fluoro-1,3-benzothiazol-2-yl)urea,

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[c]chromen-1-yl]-N'-(4-pyrimidinyl)urea

N-[(1S,1aR,7bR)-4,7-debtor-1,1a,2,7b-tetrahydrocyclopent the[c]chromen-1-yl]-N'-(2-pyrazinyl)urea

N-[(1S,1R,7bR)-4,7-debtor-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl]-N'-(5-cyclopropyl-1H-pyrazole-3-yl)urea

and its pharmaceutically acceptable salts.

28. Connection item 27, selected from

(-)-CIS-1-(5-cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

(-)-CIS-1-(5-chloropyridin-2-yl)-3-(4,7-debtor-1,1A,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea; or

(-)-CIS-1-(5-cyano-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)thiourea;

and its pharmaceutically acceptable salts.

29. The compound according to claim 1, selected from

(-)-CIS-1-(5-herperidin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)urea,

(-)-CIS-1-(5-herperidin-2-yl)-3-(4,7-debtor-1,1a,2,7b-tetrahydrocyclopent[with]chromen-1-yl)thiourea;

and its pharmaceutically acceptable salts.

30. Pharmaceutical composition having inhibitory activity against reverse transcriptase of HIV-1 containing the compound as defined in any one of claims 1 to 29, and its pharmaceutically acceptable carrier or diluent.

31. The use of compounds as defined in any one of claims 1 to 29, in the manufacture of medicinal products for the treatment of a patient infected with or exposed to HIV-1.

32. Use p, in which HIV-1 is a mutant resistant to Lakers the governmental funds.

33. Use p, in which the mutant resistant to medicines, includes K103N mutation.

34. The compound of formula II:

where X and R4-R7are as defined in claim 1,

R11represents-C(O)OR12where R12represents H or carboxyamide group, such as lower alkilany ester.

35. The connection 34, having the formula III:

where R4and R7represent independently a halogen and R11represents-COOH or lower alkilany ester.

36. Connection p, in which R4and R7represent fluorine.

37. The compound of formula IV:

where R4-R7are as defined in claim 1, PG is hydroxyamino group and PG*is hydroxyamino group or together with the neighboring atom On denotes ketogroup.

38. The connection clause 37, having the formula V:

where R4and R7are independently halogen, PG represents lower alkyl, PG,* represents lower alkyl or together with the neighboring atom On denotes ketogroup.

39. Connection § 38, in which R4and R7represent fluorine.

40. Connected the e in § 38, where the protective group is isopropyl, ethyl or, preferably, methyl.

41. Connection § 38, in which PG together with the neighboring atom On denotes ketogroup.

42. The compound of formula VI:

where R4-R7are as defined in claim 1, PG is hydroxyamino group, and R13is N, its ester or hydroxyamino group.

43. Connection § 42, having the formula VII:

where R4and R7are independently halogen, PG represents lower alkyl and R13represents H or-C(=O)CH=N=N.

44. Connection p.43, in which R4and R7represent fluorine.

45. Connection p.43, in which PG represents isopropyl, ethyl or, preferably, methyl.



 

Same patents:

FIELD: organic chemistry, medicine, cosmetics, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means radical of the following formulae: (a) or (b) wherein R2 and R3 are similar or different and mean hydrogen atom, alkyl with 10-12 carbon atoms, aryl, radical -OR7; X means a binding fragment of the following formula: -(CH2)m-(Z)n-(CO)p-(W)q- wherein a binding fragment can be read from the left to the right or inversely; R4 means alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl; Y means radical -CH2 or sulfur atom; R5 means hydroxyl, alkoxyl with 1-6 carbon atoms, radical -NH-OH or radical -N(R8)(R9); R6 means alkyl with 1-12 carbon atoms, radical -OR10 or radical -(CH2)r-COR11; R7 means hydrogen tom or aralkyl; Z means oxygen atom or radical -NR12; W means oxygen atom, radical -NR13 or radical -CH2; m, n, p and q are similar or different and can mean 0 or 1 under condition that the sum (m + n + p + q) = 2 or above, and when p = 0 then n or q = 0; R8 means hydrogen atom; R9 means hydrogen atom or aryl; r means 0 or 1; R10 means alkyl with 1-12 carbon atoms; R11 means hydroxyl or radical -OR14; R12 means hydrogen atom or alkyl with 1-12 carbon atoms; R13 means hydrogen atom or alkyl with 1-12 carbon atoms; R14 means alkyl with 1-12 carbon atoms; and optical and geometric isomers of abovementioned compounds of the formula (I), and their salts also. These compounds are useful as activating agents of receptors of type PPAR-γ in pharmaceutical compositions designated for using in medicine, in particular, in dermatology, in treatment of cardiovascular diseases and related to immunity of diseases and/or diseases associated with lipid metabolism, and in cosmetic compositions also.

EFFECT: valuable properties of compounds and compositions.

19 cl, 1 tbl, 2 dwg, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine that are partial agonists of D2 receptors and can be used in treatment of the central nervous system disorders, in particular, Parkinson's disease. Invention describes derivatives of benzoxazolone of the formula (1): wherein R means group of the formula (a) or (b) , and their salts. Also, invention describes a method for preparing compounds of the formula (1), pharmaceutical composition based on compounds of the formula (1), method for treatment of Parkinson's disease and method for treatment of the central nervous system disorders, such as schizophrenia, anxiety state and depression based on compounds of the formula 91). Invention provides preparing new compounds possessing the useful biological properties.

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

5 cl, 1 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means phenyl or naphthyl comprising the following substitutes: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl (-CF3), phenyl or heteroaryl representing aromatic 5-membered ring that comprises sulfur atom; each among R2, R3, R4 and R6 and independently of one another means hydrogen atom, hydroxy-group, (lower)-alkenyl, halogen atom, (lower)-alkyl or (lower)-alkoxy-group wherein at least one radical among R2, R3, R4 and R6 doesn't mean hydrogen atom, or R3 and R4 are bound and also bound with carbon atoms to which they are bound and form ring, and R3 and R4 mean in common -CH=CH-S-, -S-CH=CH-, -CH=CH-O-, -O-CH=CH-, -CH=CH-CH=CH-, -(CH2)3-5-, -O-(CH2)2-3 or -(CH2)2-3-O- wherein R2 and R6 have above given values; R5 means (lower)-alkoxy-, (lower)-alkenyloxy-group, or ; R7 means hydrogen atom or (lower)-alkyl; R8 means (lower)-alkyl; R9 means hydrogen atom; R10 means phenyl or naphthyl that can be mono- or poly-substituted with -CF3; n means 1, 2 or 3, and wherein the bond between Ca carbon atom and Cb carbon atom represents carbon-carbon single or double bond, and to their pharmaceutically acceptable salts and esters also. Indicated compounds can be used as therapeutically active substances in treatment and/or prophylaxis of diseases mediated by agonists of PPAR-α and/or PPAR-γ receptors, for example, in treatment of diabetes.

EFFECT: valuable medicinal properties of compounds.

24 cl, 167 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted glutarimides of the general formula (I): wherein X means group of the formula -(CH2)n-(CR8R9)p-Z-(CR8R)m wherein Z means sulfur (S) or oxygen (O) atom, SO- or SO2-group, residue -NR8 (optionally as N-oxide) or the group -CR8R9; m and p mean 0 or 1; n means 0, 1, 2 or 3, and m, n and p can't mean 0 simultaneously; R1 and R2 mean carboxyl, ester or acyl group and others; R3 means hydrogen atom, hydroxyl group and others; R4 means hydrogen atom, (C1-C3)-alkyl group, fluorine atom, trifluoromethyl group; R8 and R9 means hydrogen atom, benzyl, alkyl and others, and to their physiologically acceptable salts also. Compounds of the formula (I) possess immunomodulating effect and can be used in treatment of angiopathy and/or oncohematological diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

15 cl, 1 tbl, 20 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new sulfonamide derivatives possessing anti-tumor activity, namely to compounds of the formula (I): wherein R6 means hydroxyl; R7 means methyl, isopropyl, isobutyl, benzyl or indole-3-ylmethyl; R8 means hydrogen atom; R9 means phenylene; R10 means thienyl, furyl or pyridyl optionally substituted with lower alkyl or halogen atom. Also, invention relates to their derivatives or pharmaceutically acceptable salts or solvates. Invention describes medicinal agents used in treatment or prophylaxis of cancer and for prophylaxis of metastasis. Also, invention describes a case for treatment of cancer in mammal.

EFFECT: improved treatment method, valuable medicinal properties of agent.

5 cl, 17 tbl, 112 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active ortho-substituted nitrogen-containing bis-aryl compounds. Invention describes compounds of the formula (I): wherein A1, A2, A3, A4, A5, A6, A7 and A8 mean independently of one another nitrogen atom or -CH and wherein at least one or two (not above) these groups mean nitrogen atom; R(1) means -C(O)OR(9) or -COR(11) wherein R(9) and R(11) mean independently of one another CxH2x-R(14) wherein x has a value 0, 1, 2, 3 or 4 and R(14) means alkyl c 1, 3, 4, 5 or 6 carbon atoms, phenyl or isoxazolyl wherein phenyl and isoxazolyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J, CF3, OCF3, alkyl with 1, 2, 3 or 4 carbon atoms and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(2) means hydrogen atom; R(3) means CyH2y-R(16) wherein y has a value 0, 1, 2, 3 or 4but y can't mean 0 if R(16) means -OR(17), and R(16) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkyl with 3 carbon atoms, -OR(17), phenyl or pyridyl wherein phenyl and pyridyl are not substituted or substituted with 1, 2 or 3 substitutes chosen from the group consisting of F, Cl, Br, J and alkoxy-group with 1, 2, 3 or 4 carbon atoms; R(17) means hydrogen atom; or R(3) means -CHR(18)R(19) wherein R(18) means alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms and R(19) means -CONH2; R(4) means hydrogen atom; R(30) and R(31) mean hydrogen atom, and their pharmaceutically acceptable salts also. Also, invention describes a pharmaceutical composition showing effect that inhibits K+-channel and comprising the effective amount of at least compound of the formula (I) and using compounds of the formula (I). Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 8 tbl, 35 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-aminomethylquinolone-2 of the general formula (1)

(2)

or (3) wherein R1 means hydrogen atom (H) or Alk; R2 is taken among Alk; -OAlk, -SCH3, -Hal, -CF3, 3,4-OCH2CH2O-, 3,4-OCH2O-, 4-OCF3, 2-Ph, -OPh, -NHCOR, 2-OCH3, 5-Ph, 4-Obzk, 3-NO2, 2-CH3, 5-iPr, di-OAlk, di-Hal; or R2 represents halogen atom and alkyl group, or halogen atom and alkoxy-group taken simultaneously and independently of one another; or R2 represents the group -CONR4R5 wherein each R4 and R5 means independently of one another the group Alk, or they form the group -(CH2)n- wherein n = 2-6. R means -CH3; R3 means hydrogen atom (H); X is taken among hydrogen atom (H), 6-(C1-C3)-Alk, 6-iPr, 6-iBu; 7-(C1-C2)-Alk, 8-(C1-C2)-Alk, 6-(C1-C2)-OAlk, 6-OCF3, 7-(C1-C2)-Alk, 7-SCH3, 6,7-OCH2O-, 6,7-OCH2CH2O-, 5,6,7-OCH3, 6-F; X and Y are similar or different and taken among 7,8-CH3, 6,8-CH3, 5,8-CH3, 5,7-CH3, 6,7-CH3, 6,7-OCH3, 6-CH3, 7-Cl. Also, invention relates to a method for preparing indicated compounds and to pharmaceutical composition inhibiting activity of NO-synthetase based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims preparing medicinal agents for treatment diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

19 cl, 1 tbl, 95 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

Up!