Benzoxazinone and pharmaceutical composition comprising them for inhibition of reverse transcription of hiv, treatment and prevention of aids and arc, a method of inhibiting hiv reverse transcriptase, the way to prevent hiv infection, hiv treatment, and arc, in combination, a method of obtaining (-)-6-chloro - 4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2h-3,1 - benzoxa in-2-it

 

(57) Abstract:

Describes the new benzoxazinone compounds of General formula I, in which X represents halogen, X1is trihalomethyl; Z represents O; R represents a C1-8alkyl, unsubstituted or substituted with halogen, a 5-membered saturated monocyclic ring containing 1-2 heteroatoms selected from nitrogen atoms and oxygen; (b) (C2-4alkenyl, unsubstituted or substituted C1-4alkoxy, or C)2-5quinil, unsubstituted or substituted C3-6cycloalkyl, hydroxy, di(C1-2alkyl)amino, C1-4alkoxy, phenyl, unsubstituted or substituted C1-4alkoxy, nitro, CN, 5-membered saturated monocyclic ring containing 1-2 heteroatoms selected from nitrogen atoms and oxygen, or its pharmaceutically acceptable salt. The compounds I can be used for inhibition of HIV reverse transcriptase (including resistant varieties), as well as in the prevention or treatment of HIV infections and AIDS. These compounds may be used as such or in the form of their pharmaceutically acceptable salts, or as ingredients of pharmaceutical compositions to be used as the CTD is us. Also disclosed methods of treatment of AIDS and ways to prevent or treat HIV infections, the method of obtaining (-)-6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it. 10 S. and 3 C.p. f-crystals, 6 PL.

This application is related to applications firm Merck with reference 18429, I84291A and 18727. This application is a partial continuation of the application of the company "Merck" 18793, filed August 7, 1992, U. S. S. N 07/926607.

Prior art

Retrovirus called human immunodeficiency virus (HIV) is the etiological factor responsible for complex disease, manifested by progressive destruction of the immune system (acquired immune deficiency syndrome, AIDS) and degeneration of the Central and peripheral nervous system. This virus was previously known as LA, HTL-III, or R. A common feature of the replication of retroviruses is the reverse transcription of the RNA genome. carried out using a reverse transcriptase encoded by a viral genome, resulting in the synthesis of DNA copies of HIV sequences, which is a necessary stage for virus replication. It is known that some compounds are inhibi diseases, for example, azidothymidine or AZT.

By sequencing the nucleotide sequence of HIV was discovered that in one open reading frame is present in the pol gene (Rather L., and others, Nature, 313, 277 (1985)). Based on the homology of amino acid sequences was found that pol-posledovatelnosti encodes reverse transcriptase, endonuclease and HIV protease (h H., and others, EMBO J. 4, 1267 (1985). Power, M. and others, Science 231, 1567 (1966). Pearl L. H., and others, Ntu 329, 351 (1987)).

The authors of this application was demonstrated that the compounds of the present invention are inhibitors of HIV reverse transcriptase. The advantage of the compounds of the present invention is that they inhibit drug-resistant reverse transcriptase of HIV.

Brief description of the invention

In the present application are disclosed compounds of the formula I defined below. These compounds can be used for inhibition of HIV reverse transcriptase (and its resistant varieties); prevention of HIV infection; and for the treatment of HIV infections, AIDS and/or R (AIDS-associated syndrome); moreover, these compounds may be used as such or in the form of pharmaceuticalsouth alone or in combination with other antiviral agents, anti-infective agents, immunomodulators, antibiotics or vaccines. In the present application is also disclosed methods of treatment of AIDS, ways of prevention of HIV infection and methods of treating HIV infections.

Detailed description of the invention and the preferred variants of its implementation

The present invention relates to compounds of the formula I, to their compounds or their pharmaceutically acceptable salts that can be used for inhibition of HIV reverse transcriptase and its resistant varieties, as well as for the treatment of HIV infections caused by these infections acquired immunodeficiency syndrome (AIDS). The compounds of formula I have the following structure:

< / BR>
where X represents a halogen;

X1is trihalomethyl or pentaglottis;

Z represents O;

R represents:

(a)1-8-alkyl, unsubstituted or substituted by A, where a is halogen, C3-6-cycloalkyl, CN, hydroxy, C1-4-alkoxy, C2-4-quinil-C1-4-aloxi, aryloxy,1-4-alkylsulphonyl, nitro, di(C1-2-alkyl)amino, C1-4-alkylamino-C1-2-alkyl, heterocycle ILM or substituted AND,

(C)2-5-quinil, unsubstituted or substituted

(I) A, or

(II) aryl, unsubstituted go And substituted or

(d) C3-4-cycloalkyl, unsubstituted or substituted

(I) A, or

(II) aryl, unsubstituted or substituted AND,

or their pharmaceutically acceptable salts.

This connection also relates to pharmaceutical compositions intended for the inhibition of reverse transcription of the HIV genome and containing an effective amount of the compounds of formula II or its pharmaceutically acceptable salt

< / BR>
and pharmaceutically acceptable carrier,

where X represents a halogen,

X1is trihalomethyl, penthaleidae,2-5-alkyl, C2-5-quinil,3-5-cycloalkyl or aryl,

Z represents O or

R represents:

(A)1-8-alkyl, unsubstituted or substituted, And a is a halogen, WITH3-6-cycloalkyl, SP, hydroxy, C1-4-alkoxy, C2-4-quinil-C1-4-alkoxy, aryloxy,1-4-alkylsulphonyl, nitro, di(C1-2-alkyl)amino, C1-4-alkylamino-C1-2-alkyl, heterocycle or aaltio,

(in)2-4alkenyl, unsubstituted or substituted:

(I) A, BR> (I) A, or

(II)aryl, unsubstituted or substituted, And, or

(d)3-4-cycloalkyl, unsubstituted or substituted

(I) A, or

(II) aryl, unsubstituted or substituted A.

Preferred are compounds 37.2, 4, 2, 5 and 24 of table 2 (in descending order of preference).

These compounds have the following structure:

Connection 37.2

< / BR>
(-) 6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-he (the most preferred compound),

Connection 4

< / BR>
(-) 6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it,

Connection 2

< / BR>
(+/-) 6-chloro-4-(2-cyanophenyl)ethinyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-it,

Connection 5

< / BR>
(+/-) 4-(1-chloro-1,1-deformity)-4-(2-phenylethynyl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-it,

Connection 24

< / BR>
(+/-) 4-(2-dimethylaminomethylene)-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-it,

or their pharmaceutically acceptable salts.

Compounds of the present invention is illustrated in the following tables I and II.

Compounds of the present invention may have asymmetric centers and may exist (ex the Mer, or enantiomers, however, it should be noted that all isomeric forms are included in the scope of the present invention. The symbol ( + / - ) (+) optical isomers, (-) optical isomers or mixtures thereof.

If any variable (e.g., R) occurs more than one time in formula I or in any part of this formula, the definition of the specified variable in this particular case does not depend on its definition in any other case. In addition, combinations of substituents and/or variables are permissible only if such combinations can get a stable connection.

Used in the present description, the term "alkyl" (unless specified otherwise) means straight go razvetvlennye saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. The term "alkenyl" refers to a straight or branched alkyl groups having at least one carbon-carbon double bond. The term "quinil" refers to a straight or branched alkyl groups having at least one carbon-carbon triple bond. The term "halogen" or "halon" means fluorine, chlorine, bromine and iodine.

Used in the present description, the term "artil.

Used in the present description, the term (unless otherwise requested) "heterocycle" or "heterocyclic" means a stable 5 to 7-membered monocyclic ring or a stable 8-11 membered bicyclic heterocyclic ring which is unsaturated or partially saturated and which consists of carbon atoms and 1-4 heteroatoms selected from N, O and S, and the heteroatoms nitrogen and sulfur can be, but not necessarily, oxidized, and any bicyclic group, any of the above heterocyclic rings is fused with the benzene ring. Heterocyclic ring may be attached via any heteroatom or carbon atom that results in the formation of a stable structure. Examples of such heterocyclic elements are piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxoazetidin, azepine, pyrrolyl, 4-piperidinyl, pyrrolidinyl, pyrazolyl, pyrazolidine, imidazole, imidazoline, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidine, morpholine, thiazolyl, diazolidinyl, isothiazolin, chinuklidinyl, isothiazolinones, indolyl, chinoline, izohinolinove, tetrahydropyranyl, thienyl, benzothiazyl, thiomorpholine, themorphological, timeprimitive and oxadiazolyl.

Compounds of the present invention can be synthesized by the methods described below.

Synthesis of benzoxazines of the present invention can be realized by a method whereby the final stage represents the cyclization reaction of the benzene ring (see scheme I in the end of the description). First, the amino group para-Chloroaniline protect, for example, revalorisation, resulting in a receive connection 2. Other less preferred aminosidine groups are t-butoxycarbonyl, acetate or isovaleryl group. Then the connection 2 is subjected to reaction with alkyllithium, and preferably n-butyllithium. In this stage of metallation can also be used and other ORGANOMETALLIC compounds. Then, after the reaction with CF3SOOE and subsequent quenching of the reaction receive the connection 3.

The synthesis of the tertiary carbinol 4 is realized by using the reactions of addition of the Grignard reagent, which is subjected to the resulting ketone 3. As a Grignard reagent should be used the salt of the divalent cation, such as Mg++oWith approximately room temperature.

The reaction ring closure is performed with the use of condensing agents such as 1,1-carbonyldiimidazole, phosgene, dimethylcarbonate or di-(para-nitrophenyl)carbonate, and the result of this reaction receive connections of the present invention 5. The cyclization can be carried out with any of these agents, and other agents of a wide range.

The following scheme IA (see end of description) is a specific variant of scheme I. This scheme illustrates the synthesis of compounds L-741.211, which is a racemate compound 37.2 described below in example 6.

Scheme II (see below) illustrates one method of derivatization acetylene substituents in 4-position benzoxazinones kernel. In accordance with this scheme the connection 6 is first subjected to metallization, and then add the zinc salt. To obtain compound 7 carry out the reaction of Hake, which is used as a catalyst, tetrakis(Triveni the new group, N-containing heterocycle. The reaction manniche represents the reaction of condensation of formaldehyde with a heterocycle, such as pyrrolidino. Substitution on the end carbon atom is carried out in the presence of Si as a catalyst.

Scheme IV (see below) illustrates the separation of optical isomers of compounds of formula I or formula II. This diagram razdadim agent is (-)Campanula acid. This can be used other separating agents wide diapason, for example chloride O-methylmandelic acid or reagent Mosher. However, procedures for the separation of these isomers is well known to any specialist.

Scheme IVA (see the end of the description) was specially developed for the separation of compounds L-741.211 generated when the connection L-743.726. Scheme IVA and example 6.

Cyclopropylacetylene receive under the scheme V in accordance with known procedures, for example, S. E. Hudson, and others, J. Am.Chem. Sos. 94, 1158 (1972) and W. Schoberth, etc., Synthesis 703 (1972).

Compounds of the present invention can be used to obtain preparations for analyses in the search for antiviral compounds. For example, the compounds of the present invention can be used for ejecta compounds. In addition, the compounds of the present invention can be used to establish or identify the binding site of other antiviral agents reverse transcriptase of HIV, for example, by competitive inhibition. Thus, the compounds of the present invention are commercial products that can be supplied to the above-mentioned studies.

Compounds of the present invention can be used for inhibition of HIV reverse transcriptase, the prevention and treatment of infections caused by human immunodeficiency virus (HIV), and for treatment of pathological conditions caused by infection with the HIV virus, such as HIV. However, the present invention is not limited to the treatment or prevention of AIDS or HIV infection, in the scope of the present invention also includes the treatment of a wide range of conditions, HIV-infections, such as AIDS, ARC (AIDS-associated complex or prespic) (both symptomatic and asymptomatic), and actual or potential infection by the HIV virus. For example, the compounds of the present invention can be used to treat HIV infections p is dcosta, bites, accidental needle sticks or surgical operations.

The main advantage of the compounds of the present invention is their ability to the efficient inhibition of HIV reverse transcriptase, which is resistant against other antiviral agents, such as L-697.661 (3-(/(4,7-dichloro-1,3-benzoxazol-2-yl)methyl/amino)-5-ethyl-6-methylpyridin-2(IH)-one) or L-696.229 (3-/2-(1,3-benzoxazol-2-yl)ethyl/-5-ethyl-6-methylpyridin-2(IH)-one), or AZT.

For these purposes the compounds of the present invention can be administered orally, parenterally (subcutaneously, intravenously, intramuscularly, nutrigrain or by infusion), by inhalation, or rectally, in the form of standardized pharmaceutical preparations containing the corresponding non-toxic pharmaceutically acceptable carriers, adjuvants and fillers.

Therefore, in another embodiment, the present invention relates to a method of treatment and pharmaceutical compositions intended for the treatment of HIV infections and AIDS. This method of treatment involves the administration to a patient in need of such treatment, a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective alicestine in the form of suspensions or tablets for oral administration, preparations for inhalation through the nose, sterile injectable solutions, for example in the form of a sterile aqueous or oily suspension for injection, or suppository.

The composition in the form of oral suspensions can be obtained in accordance with well known techniques, commonly used in pharmaceutical practice for the manufacture of such drugs, and these suspensions can contain microcrystalline cellulose as a filler, alginic acid or sodium alginate as a suspending agent, methylcellulose for increasing the viscosity and sweeteners/flavoring agents well known in the art. Compositions made in the form of tablets immediate action, may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, lactose and/or other excipients, binders, carriers, disintegrators, thinners and sizing agents, well known to experts.

Compositions intended for insertion through the nose using aerosol or inhalation, can be obtained in accordance with conventional pharmaceutical practice in the form of solutions in physiological solvents using the be the accessibility), fluorocarbons and/or other solubilizing or dispersing agents, well known to experts.

Injectable solutions or suspensions can be obtained by traditional methods using suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, ringer's solution or isotonic sodium chloride solution or suitable dispersing or wetting and suspendida agents, such as sterile soft fatty oils, including synthetic mono - or diglycerides, and fatty acids such as oleic acid.

Compositions in the form of suppositories for rectal injection can be obtained by mixing the active ingredient with a suitable non-irritating carrier such as cocoa butter, synthetic esters of glycerol or polietilenglikoli, which are solid at ordinary temperature, but when introduced into the rectum melt and/or dissolve to release the drug.

The dose of the compounds of the present invention, intended for oral administration to man, is in the range from 1 to 100 mg/kg body weight in the form of fractional doses. Preferred is a fractional doses. In combination therapy with nucleoside analogues preferred dose of the compounds of the present invention for oral administration in fractional doses ranging from 0.1 to 20 mg/kg, and the preferred dose nucleoside analogues for oral administration in fractional dose ranges from 50 mg to 5 g/kg body weight. It should be noted that the specific dose and frequency of its introduction each particular patient may vary depending on various factors, such as activity specifically used compound, the age, body weight, General health, sex and diet of the patient, the method and time of administration, rate of release of drug, combination of drugs, the severity of the patient's condition and the body is the master, undergoing therapy.

The present invention also relates to combinations of compounds are inhibitors of HIV reverse transcriptase with one or more agents used to treat AIDS. For example, the compounds of the present invention can be successfully introduced in combination with effective amounts of agents against the virus that causes AIDS, immunomodulators, anti-infective funds or vaccines, for example, uki/or after administration of other active agents.

It should be noted that the scope of the present invention is not limited to combinations of the compounds of the present invention with means against AIDS, immunomodulators, anti-infective drugs or vaccines listed in vicepresidency Table III. In the scope of the present invention may be included, in principle any combination with any pharmaceutical composition used for treatment of AIDS. For example, the compound of formula I or formula II can be successfully introduced in combination with nucleoside analogue that has biological activity against reverse transcriptase of HIV. Suitable nucleoside analogues usually are chain terminators, such as AZT, ddC, dd1, D4T, NÖRTEN and 3'-fluoro-2',3'-dideoxythymidine.

AZT may be synthesized by methods J. P. Horwitz and others, J.Org. Chem. 29, 2076 (1964); R. P. Glinski and others, J.Org. Chem. 38, 4299 (1973); C. K. Chu and others , Tetrahedron Letters 29, 5349 (1988). Application ZT as a therapeutic agent for the treatment of AIDS is disclosed in U.S. patent 4724232.

Connection ddC can be synthesized by the methods of J. R. Horwitz and others, J. Org. hm. 32, 817 (1967); R. Marumoto, Chem.Pharm. Bull. 22, 128 (1974) and T.-S. Lin and others, J. Med. Chem. 30, 440 (1987).

D4T can be synthesized by methods Herdewijn P., and others, J. Med.Chem. 30, 1270 (1987).

Synthesis of ddC, dd1 and AZT is also described in EPO 484071.

The compound 3'-fluoro-2', 3'-dideoxythymidine can be synthesized in accordance with the procedures described Herdewijn P., and others, J. Med.Chem. 30, 1270 (1987). Connection L-735524 represents N-(2(R)-hydroxy-1(s)-indanyl)-2(R)-phenylmethyl-4-(s)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(s)-N-(t-BUTYLCARBAMATE)piperazinil))pentanone or its pharmaceutically acceptable salt. Connection L-697661 or '661' represents 3-([4,7-dichloro-1,3-benzoxazol-2-yl)methyl] amino)-5-ethyl-ethyl-6-methylpyridin-2(1H)-he; connection L-696229 is a 3-[2-(1,3-benzoxazol-2-yl)ethyl] -5-ethyl-6-methylpyridin-2(1H)-he. The synthesis of compounds L-697661 and L-696229 described in EPO 484071 and EPO 462800 (these two patents are introduced in the present description by reference).

Preferred combinations are simultaneous, periodic or alternating the introduction of L-743726 in combination with an inhibitor of HIV protease with or without him. An optional third component in this combination is a nucleoside inhibitor of HIV reverse transcriptase, such as Z, ddC or dd1. A preferred inhibitor of HIV are connection L-735524. Another preferred inhibitor reverse transcriptase HIV is L-697661. These combinations can have sinali: (1) L-743.726 with L-735.524 and not necessarily with any of the L-697.661, ZT, dd1 or ddC; (2) L-743.726 with any of the L-697.661, AZT, ddl or ddC. In the scope of the present invention also includes pharmaceutically acceptable salts of the above combinations.

EXAMPLE I.

(+/-) 4-[1,1,1-Trifluoromethyl)-4-(1-butene-4-yl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-on (compound 15).

Stage A: N-(4-chlorophenyl)-2,2-dimethylpropanamide.

A 5-liter three-neck round bottom flask, equipped with a head stirrer, was added 4-Chloroaniline (127,57 g, I, M),1200 ml of CHCl3and 1200 ml of a saturated aqueous solution of Na2CO3. An addition funnel was attached to the flask and downloaded the 2.2-dimethylpropanoate (129 ml, 1.05 M). Then to the vigorously stirred mixture over a one hour drop was added the acid chloride. Then the resulting mixture was stirred at room temperature for another 23 hours. Some of the product was separated as white crystals. These crystals were collected by filtration. The filtrate was transferred into a separating funnel and the layers were separated. Then the chloroform layer was washed with water and brine. After drying with magnesium sulfate, filtration and removal of solvent in vacuo gave additional product. Two parts of this product were combined and perekristalizovanny from a boiling mixture of EtOAc/hexane, who P CLASS="ptx2">

Stage b: 1-(2-amino-5-chlorophenyl)-2,2,2-triptoreline.

A 3-liter three-neck round bottom flask, dried in a drying Cabinet and provided with a head stirrer and a hole for the inlet of argon, and 500-ml addition funnel, dried in a drying Cabinet, was added N-(4-chlorophenyl)-2,2-dimethylpropanamide (100 g, 472 mm) and 1 l of anhydrous tetrahydrofuran. This solution was cooled in an ice bath to 0oWith, and addition funnel was loaded n-utility (387 ml of 2.5 M solution in hexane, 968 mm). Then, slowly, over hours n-utilitiy solution drop by drop) was added to the amide solution while maintaining the temperature below +5oC. the resulting solution was kept at 0oWith in an hour, and during this period of time was formed orange precipitate. To the mixture drop by drop within 1 hour was added ethyl-1,1,1-triptorelin (115 ml, 968 mm). The resulting clear solution was kept for another 30 minutes. The reaction mixture was extinguished 5% aqueous hydrochloric acid. After that, the mixture was diluted with ethyl acetate (1 l) and the layers were separated. The organic phase is washed with saline, dried with magnesium sulfate, filtered and concentrated in vacuo, resulting in a received 160 g yellow masloobraznaya refrigerator for 24 hours. Then chilled rastvor was diluted with ethyl acetate (1 l) and the resulting mixture was podslushivaet by adding concentrated NH4OH. The layers were separated and the organic phase is washed with saline and dried with magnesium sulfate, then filtered, concentrated in vacuo and was chromatographically on silica gel (1.5 kg), elwira 15% EtOAc in hexane. Chromatographically material was recrystallized from boiling hexane and was obtained 57 g (54%) of pure 1-(2-amino-5-chlorophenyl)-2,2,2-triptoreline in the form of bright yellow crystals, so pl. 9I-92oC.

IH-NMR (CDCH3): 6,46 (Shir.S., 2H), 6,69 (d, IH, J=9,2 Hz), 7,32 (DD, IH, J=2,4, 9,2 Hz), of 7.70 (d, IH, J=2.4 Hz).

Stage C: (+/-) 2-(2-amino-5-chlorophenyl)-1,1,1-Cryptor-5-hexane-2-ol.

In a 300-ml three-neck round bottom flask, dried in a drying Cabinet and provided with a rod for mixing, a hole for the argon inlet, addition funnel and condenser hot irrigation, was added magnesium turnings (3.03 g, 125 mm) and 75 ml of anhydrous tetrahydrofuran. This thoroughly stirred mixture was added 4-bromo-1-butene (12.0 ml, 118,21 mm) so that has been a mild reflux. After complete addition, the mixture was left at Apple solution was added 1-(2-amino-5-chlorophenyl)-2,2,2-triptoreline (5,00 g, in tetrahydrofuran, 35 ml). The cooling bath was left to evaporate and the mixture was stirred for 20 hours at room temperature. Then the reaction mixture was diluted with ethyl acetate and 10% aqueous citric acid solution. After that, the mixture was stirred for 4 hours. The layers were separated and the organic phase was washed with an aqueous solution of sodium bicarbonate and saline. After drying with magnesium sulfate, filtration, removal of solvent in vacuo and chromatographicaliy on silica gel (300 g) (eluent: 15% EtOAc in hexane) received 4,80 g(+/-) 2-(2-amino-5-chlorophenyl)-1,1,1-Cryptor-5-hexane-2-ol as a yellow solid.

Stage D: (+/-) 4-(1,1,1-trifluoromethyl)-4-(1-butene-4-yl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-it.

In a 200-ml round-bottom flask equipped with a rod for mixing, the intake of argon and partial condenser hot irrigation was added(+/-) 2-(2-amino-5-chlorophenyl)-1,1,1-Cryptor-5-hexane-2-ol (4,80 g, 17,16 mm), 1,1'-carbonyldiimidazole (13,91 g, 85,81 mm) and anhydrous tetrahydrofuran (75 ml). Then this mixture was heated at 60oC for 18 hours. The cooled reaction mixture was diluted with ethyl acetate, and then washed with water (3 x 200 ml) and brine (asego EtOAc/hexane received 3,22 g(+/-) 4-(1,1,1-trifluoromethyl)-4-(1-butene-4-yl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-it is in the form of a white crystalline solid, so pl. 165-166oC.

IH-NMR (CDCL3): 1,99 (m, IH), 2,09-to 2.40 (m,3H), 5,00 (d, IH, J=1.4 Hz), to 5.03 (DD, IH, J=1,4, 7,9), 5,78 (m, IH), 6,85 (d, IH, J=8.6 Hz), 7,21 (Shir.S., IH), 7,35 (DD, J=2,2, 8.6 Hz), 9,63 (Shir.S., IH).

EXAMPLE 2.

(+/-) 6-Chloro-4-ethinyl-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-on (compound 26).

Stage A: 2-(2-amino-5-chlorophenyl)-1,1,1-Cryptor-3-butyn-2-ol.

500-ml three-neck round bottom flask equipped with addition funnel, a hole for the inlet of argon, a rod for mixing and digital thermometer, was loaded with ethnicminorities (0.5 M in hexane, 268 ml, 134 mm), and then was cooled to -78oC. Then drop by drop in for 15 minutes was added a solution of 1-(2-amino-5-chlorophenyl)-2,2,2-triptoreline (6.0 g, 26,8 mm) in 50 ml of THF while maintaining the temperature -55oC. After the reaction mixture was stirred for 16 hours and then slowly heated to room temperature. Dark red reaction solution was suppressed with -5oWith by adding one drop of a saturated aqueous solution of ammonium chloride (60 ml). After extraction with ethyl acetate, the solution washed with 10% citric acid, saturated sodium bicarbonate, water and brine. The result of this procedure was obtained 8.5 g Lesh-chromatography (eluent: 15-20% ethyl acetate/hexane) was obtained pure 2-(2-amino-5-chlorophenyl)-1,1,1-Cryptor-3-butyn-2-ol (5 g light brown oily substance, yield 75%).

Stage b: (+/-) 6-chloro-4-ethinyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-it.

Tertrahydrofuran ring solution of 2-(2-amino-5-chlorophenyl)-1,1,1-Cryptor-3-butyn-2-ol (5.0 g, 20.0 mm 225 mm tetrahydrofuran (THF) was treated with 1,1'-carbonyl diimidazol (13,0 g, 80,0 mm) and heated in an oil bath for 17 hours lying 60oC. After removal of the tetrahydrofuran in vacuo, the residue was dissolved in ethyl acetate, and then washed with 10% citric acid, sodium bicarbonate, water and brine. After drying with sodium sulfate, filtration and evaporation in vacuo, the resulting crude product was isolated (3.6 g) and recrystallized from ethyl acetate/hexane. Thus received (+/-) 6-chloro-4-ethinyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-it is in the form of a white crystalline solid (3,22 g, yield 58,4%), so pl. 226-227 of theoC.

IH-NMR (CDCL3+trace amounts of DMSO): 3,16 (s, 1H), 6,98 (d, J=3.3 Hz, 1H), 7,35 (m, 1H), 7,51 (c, 1H), 10,66 (c, 1H).

EXAMPLE 3.

(+/-) 6-Chloro-4-(1,1,1-trifluoromethyl)-4-/(3-(1-pyrrolidinyl))-1-PROPYNYL/-1,4-dihydro-2H-3,1-benzoxazin-2-on (compound 7).

Dioxane solution (+/-) 6-chloro-4-ethinyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-she (150 mg, 0,544 mm), PI is mg, 0,207 mm in 3.5 ml of dioxane) was heated to 50oC in an oil bath for approximately 2 hours. Then the reaction mixture was extinguished at 2 N. hydrochloric acid and was extracted with ethyl acetate. Then the aqueous layer was neutralized by adding solid potassium carbonate and three times were extracted with ethyl acetate. The combined extracts were washed with water and brine, then dried with sodium sulfate and received 140 mg of the crude product. This crude product was purified by chromatography on silica gel and recrystallized from ethyl acetate/hexane, resulting in the obtained crystalline (+/-) 6-chloro-4-(1,1,1-trifluoromethyl)-4-/(3-(1-pyrrolidinyl))-1-PROPYNYL/-1,4-dihydro-2H-3,1-benzoxazin-2-he (89 mg, yield 46%), so pl. 160-161o(When Razlog.).

IH-NMR (CDCL3): 1,85-1,89 (m, 4H), 2,68-a 2.71 (m, 4H), to 3.67 (s, 1H), to 6.88 (d, J=8,55 Hz, 1H), 7,40 (DD, J=2,19, 8,54 Hz, 1H), 7,55 (c, 1H), 9,45 (c, 1H).

(+/-) 6-Chloro-4-(2-cyanophenyl)ethinyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-on (compound 2).

A solution of 6-chloro-4-ethinyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-she (138 mg, 0.5 mm) in 3 ml of anhydrous tetrahydrofuran was stirred at -78oC. Then, to this solution was added 0.4 ml (1.0 mm) n-utility (2.5 M in hexane). Agenoy the reaction mixture was left for stirring at -78oWith 15 minutes, after which the ice bath was removed and the mixture was slowly heated to 0oC for 30 minutes. Then to this reaction mixture was added a solution of 2-iodobenzonitrile (149 mg, 0.65 mm) in 2 ml of THF, and then added 56 mg (0.06 mmol) of tetrakis(triphenylphosphine) palladium (0). The resulting reaction mixture was left to warm to room temperature and continued stirring for 15 hours. Then this reaction mixture was suppressed by adding 10 ml of 2 N. hydrochloric acid, was extracted with ethyl acetate (2 x ml) and the combined extracts were washed with water, brine and dried with magnesium sulfate. The solvent was removed and received 195 mg of the oily substance, which was purified using flash chromatography on silica gel (eluent: 20% EtOAc in hexane). The result of this procedure were given 60 mg of unreacted starting material and 35 mg of the combined product. This combined product is triturated with ether and received 25 mg (+/-) 6-chloro-4-(2-cyanophenyl)ethinyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-it, so pl. 245-246oC. FAB-MS (M + +): 377 m/E.

IH-NMR (CDCL3): 6,82-6,85 (d, J= 8.5 Hz, 1H), 7,40-7,44 (DD, J=2,1, 8.5 Hz, 1H), 7,56-7,79 (m, 5H), of 8.00 (s, 1H).

EXAMPLE 4.

(+/-) 4-(1-Chloro-1,1-deformity)-4-(2-dryer is 2-defloration.

In a 300-ml three-neck round bottom flask, dried in a drying Cabinet, equipped with a magnetic rod for mixing, the intake of nitrogen, and 100-ml addition funnel, dried in a drying Cabinet, was added N-(4-chlorophenyl)-2,2-dimethylpropanamide (10 g, 47,2 mm) and 100 ml of anhydrous tetrahydrofuran. This solution was cooled in an ice bath to 0oWith, and addition funnel was loaded n-utility (38,7 ml of 2.5 M solution in hexane, to 96.8 mm). Then n-utilitiy the solution slowly, drop by drop, and within 1 hour was added to the amide solution, maintaining the temperature below +5oC. the resulting solution

kept for one hour at 0oC. during this time formed an orange precipitate. Then to the mixture, drop by drop within 15 minutes was added ethyl-1-chloro-1,1-deflorated (10,2 ml, 96,8 mm). The obtained clear solution was kept for 30 minutes. The reaction was completed by adding 5% aqueous solution of hydrochloric acid. The mixture was diluted with ethyl acetate (1 l) and the layers were separated. The organic phase is washed with saline, dried with magnesium sulfate, filtered and concentrated in vacuum to obtain 160 g of a yellow oily substance. This substance suspen the hours. The cooled solution was diluted with 500 milliliters of ethyl acetate and the mixture was podslushivaet by adding concentrated NH4OH. Then the layers were separated and the organic phase is washed with saline, dried with magnesium sulfate, filtered, concentrated in vacuo and was chromatographically on silica gel (350 g, eluent: 15% t in hexane). Chromatographically material was recrystallized from boiling hexane, resulting in received 5.5 g of pure 1-(2-amino-5-chlorophenyl)-2-chloro-2,2-deperately in the form of bright yellow crystals, so pl. 55-56oC.

IH-NMR (CDCl3): to 6.43 (Shir.S., 2H), 6,69 (d, 1H, J= 9.0 Hz), 7,31 (DD, 1H, J=2,4, and 9.0 Hz), 7,80 (d, 1H, J=2.4 Hz).

Stage: (+/-) 2-(2-amino-5-chlorophenyl)-4-phenyl-1-chloro-1,1-debtor-3-butyn-2-ol.

In a 100-ml three-neck round bottom flask, dried in a drying Cabinet and provided with a rod for mixing, intake argon partial condenser hot irrigation and membrane, was added ethynylbenzene (2,13 g, 20,83 mm), anhydrous tetrahydrofuran (50 ml) and ethylmagnesium (6,94 ml of 3.0 M solution in ether). The resulting mixture was stirred for 2 hours at room temperature, and then with a syringe was added a solution of 1-(2-amino-6-chlorophenyl and at room temperature for 21.5 hours. The reaction was completed by addition of 1 N. hydrochloric acid (50 ml), and then the mixture was diluted with ethyl acetate. The resulting solution was podslushivaet by adding concentrated NH4HE, and the layers were separated. The organic phase is washed with water and brine. After drying with magnesium sulfate, filtration, removal of solvent in vacuo and chromatography was carried out on silica gel (eluent: 20% EtOAc in hexane) was received(+/-) 2-(2-amino-5-chlorophenyl)-4-phenyl-1-chloro-1,1-debtor-3-butyn-3-ol (1,02 g) in the form of a whitish solid.

IH-NMR (CDCl3): 4,42 (Shir.S., 2H), 5,10 (Shir.S., 1H), 6,65 (d, 1H, J= 8.5 Hz), to 7.15 (DD, 1H, J=2,4, 8.5 Hz), 7,38 (m, 3H), 7,55 (m, 2H), of 7.70 (d, J=2,4 Hz).

Stage With: (+/-) 4-(1-chloro-1,1-differenl)-4-(2-phenylethynyl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-it.

In a 100-ml round-bottom flask equipped with a rod for mixing, partial condenser hot irrigation and intake of argon, was added(+/-) 2-(2-amino-5-chlorophenyl)-4-phenyl-1-chloro-1,1-debtor-3-butyn-2-ol (0,81 g, 2,37 mm), anhydrous tetrahydrofuran (25 ml) and 1,1-carbonyldiimidazole (1,919 g, 11,84 mm). This solution was heated for 20 hours at 60oC. the Cooled reaction mixture was diluted with ethyl acetate, and then washed with 0.5 G. hydrochloric acid, wodli 890 mg of the oily substance. This substance was chromatographically on 80 g of silica gel (eluent: 20% ethyl acetate in hexane). Programirovanii material was recrystallized from boiling ethyl acetate/hexane, resulting in received 507 mg(58%) (+/-) 4-(1-chloro-1,1-deformity)-4-(2-phenylethynyl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-it is in the form of white needle-shaped crystals, so pl. 154-155oC.

IH-NMR (CDCl3): 6.89 in(d, 1H, J=8,4 Hz), 7,35-of 7.48 (m, 4H), 7,56(m, 2H), to 7.64(Shir.S., 1H), 9,19 (Shir.s, 1H).

EXAMPLE 5.

(-)6-Chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-on (compound 4).

Stage A: 2-(2-amino-5-chlorophenyl)-4-phenyl-1,1,1-Cryptor-3-butyn-2-ol.

The solution lithogenicity obtained from a 4.83 ml phenylacetylene (0,044 M) and 17.2 ml of 2.5 n solution of n-utility in hexane (0,043 M) in 50 ml THF at -78oWith and within 5 minutes we were treated to 11.4 grams (0,044 M) of iterate of minibrain. The resulting mixture was left to warm to -20oC, and then stirred in an argon atmosphere for 30 minutes. After that, the mixture was cooled to -60oWith and added to a solution containing 2.5 g (0,011 M) 1-(2-amino-5-chloro)-2,2,2-triftoratsetofenona, pre-integrated with equivalent (2.8 g, to 0.011 M) of iterate of minibrain in 25 ml of THF. Proceduracivila drop of a mixture of a saturated aqueous solution of ammonium chloride (30 ml) and water (30 ml). The resulting mixture was extracted with two portions of ethyl ether, and the combined organic phases are washed with brine (100 ml) and was dried with magnesium sulfate. Removing ossaudio agent and solvent remained 6 g of the oily substance, which was chromatographically using flash chromatography on silica gel (eluent: 20% Et in hexane). Thus obtained 2-(2-amino-6-chlorophenyl)-4-phenyl-1,1,1-Cryptor-3-butyn-2-ol.

IH-NMR (CDCl3): 4,63(Shir.S., 3H), 6,69(d, J=8.5 Hz, 1H), 7,15(d, J=2 Hz, 1H), 7,17(d, J=2 Hz, 1H), 7,35-7,44(m, 3H), 7.5 (C-7,56(m, 2H), 7,66(d, J= 2 Hz, 1H).

F-MS: M+H=326 m/E.

Stage b: (+/-) 6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-on (compound 12).

A solution of 2-(2-amino-5-chlorophenyl)-4-phenyl-1,1,1-Cryptor-3-butyn-2-ol (2.0 g, 6.1 mm) and 11.0 g (12.0 mm) 1,1-carbonyldiimidazole in 300 ml of anhydrous tetrahydrofuran was stirred in argon atmosphere at 55oWith in 24 hours. The solvent was removed on a rotary evaporator and the resulting residue was distributed between ether (200 ml) and water (400 ml). The layers were separated, and the aqueous layer was extracted again with ether. Then the combined ether extracts were washed with 10% citric acid (2 x 200 ml), then brine and the CSOs connection in the form of an oily substance. In the trituration with ether/hexane received 875 mg (+/-) 6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it is in the form of a white solid, which melts at 137oWith and becomes transparent at 147oC.

IH-NMR (CDCl3): 6,92 (d, J=8 Hz, 1H), 7,30-7,49 (m, 4H), 7,58-the 7.65 (m, 3H), 8,99 (s, 1H).

Stage C: 6-chloro-1-(1S)-campanil-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it.

To the solution, stirred in an argon atmosphere in an ice bath and containing (+/-) 6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-he (2.24 g, 6,37 mm), 4-dimethylaminopyridine (0.10 g, 0.8 mm) and chloride (-)-campanulas acid (2,07 g of 9.55 mm) in 60 ml of anhydrous dichloromethane, was added triethylamine (2,22 ml, 15,3 mm). Refrigerated bath was removed and the reaction mixture was left at room temperature to continue the reaction. After the reaction was completed, as evidenced by thin layer chromatography (Si02, 4% EtOAc in CHCl3), the solution was diluted with 200 ml of CHCl3and then washed with 10% citric acid (twice) and brine. After drying with magnesium sulfate the solvent is evaporated on a rotary evaporator and the resulting foamy estato Amphenol-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it is in the form of oily substance.

IH-NMR (CDCl3): 0,85 (s, 3H), of 1.08(s, 3H), 1,22(s, 3H), 1,73-of 1.85(m, 1H), 1,92-of 2.08 (m, 1H), 2,50-to 2.67 (m, 2H), 7,30-of 7.69 (m, 8H).

Then received of 1.52 g of mixed fractions (diastereomers I and II). Then continued elution and got 680 mg more slowly moving diastereoisomer II target compounds that triturated with ether/hexane, and received comcourse substance in the form of white needle-shaped crystals, so pl. 177-178,5oC.

IH-NMR (CDCl3): or 0.83 (s, 3H), of 1.12 (s, 3H), 1,23 (c, 3H), 1,73 is 1.86 (m, 1H), 1.93 and e 2.06 (m, 1H), 2,50 2.63 in (m, 2H), 7,38-7,51 (m, 4H), 7,49 to 7.62 (m, 2H), 7,72(d, J=9 Hz, 1H), 7,76(d, J=2 Hz, 1H).

1.52 g of the isomeric mixture obtained by flash-chromatography was dissolved in 75 ml of ether and the resulting solution was diluted with 50 milliliters of hexane, and then this solution as a seed crystal was added a crystal of isomer II. After a slow crystallization was given to 385 mg of isomer II, which was recrystallized from ether/hexane and obtained diastereomeric material with a purity of >96% (IHVR analysis).

Stage D: (-) 6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it.

Crystalline diastereoisomer (II) 6-chloro-1-(1S)-campanil-4-phenylethynyl-4-trifluoromethyl-1,2-dihydro-4H-3,1-benzoxazin-2-she (53 mg, 0.10 mm) races is on the solution TO2CO3. After 10 minutes of stirring the starting material was completely consumed as evidenced by TLC (SiO2, 4% Et in l3). The resulting solution was concentrated in vacuo, and the residue was dissolved in ether. After washing with 0.1 N. hydrochloric acid and a salt solution of the ether solution was dried with magnesium sulfate, filtered and evaporated in vacuum to obtain an oily solid, which was purified by chromatography on silica (eluent: 5% 2-propanol in hexane). After trituration with ether/hexane received (-) 6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it is in the form of white needle-shaped crystals with so pl. 178-179oC. []D20 = -92,5o(CHCl3c=0,0012 g ml-1).

IH-NMR (CDCl3): 6,87 (d, J=8.5 Hz, 1H), 7,37-to 7.50 (m, 4H), 7,56-7,63 (m, 3H), at 8.60 (s, 1H).

Stage E: (+) 6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-on (compound 3).

In accordance with the method described in stage D, (+)-6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-he received from a non-crystalline product of stage C (diastereoisomer I). The melting point of the obtained product was 178-179oC. []D20 = +87,6o

EXAMPLE 6.

(-) 6-Chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it (L-743.726, the connection 37.2) and (+) 6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it (L-743.725).

Stage A: 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-Cryptor-3-butyn-2-ol.

The solution bromosalicylaldehyde received from 23 g of cyclopropylacetylene (0,348 M) in 240 ml of tetrahydrofuran by adding drop by drop within hours 116 ml of 3.0 M solution ethylacetamide in ether (0,348 M). The resulting solution was maintained at 0oWith in an hour, and then the solution was maintained at 40oC for 3 hours. To the resulting solution was cooled to 0oWith, portions during 5 minutes was added 15,66 g of solid 1-(2-amino-5-chlorophenyl)-2,2,2-cryptomaterial (0,0696 M). Then the reaction mixture was left for stirring at 0oWith over one and a half hours. The reaction was completed at 0oWith by adding one drop of a saturated aqueous solution of ammonium chloride (700 ml). The resulting mixture was twice extracted with ethyl acetate (400 ml) and the combined organic phases are washed with saline and dried with magnesium sulfate. After removal of drying agent and solvent were formed Gcal 14,67 g 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-Cryptor-3-butyn-2-ol, so pl. 153-154oC. a Second collection (2.1 g) of product was obtained from the concentrated mother solutions.

IH-NMR (CDCl3): 0,84 (m, 2H), 0,90 (m, 2H), 1,38 (m, 1H), 4,50 (Shir.c. , 3H), 6,63 (d, J=8.5 Hz, 1H), 7,13 (DD, J=2.5 and 8.5 Hz, 1H), 7,55 (d, J=2.5 Hz, 1H).

Stage B: (+/-) 6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it (L-741.211).

A solution of 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-Cryptor-3-butyn-2-ol (15,00 g, 0,0518 M) and 41,98 g (0,259 M) 1,1'-carbonyldiimidazole in 250 ml of anhydrous tetrahydrofuran was stirred in an argon atmosphere for 24 hours at 55oC. the Solvent was removed on a rotary evaporator and the resulting residue was distributed between 500 ml of ethyl acetate and 400 ml of water. Then the layers were separated, and the aqueous phase is once again extracted with ethyl acetate. United an ethyl acetate extracts were washed with 2% aqueous solution of hydrochloric acid (2 x 200 ml), saturated aqueous sodium bicarbonate and saline. After drying with magnesium sulfate, filtration and removal of solvent in vacuo received 16,42 g of target compound in the form of solids. This substance was recrystallized from etelaat/hexane, which was obtained analytically pure (+/-) 6-chloro-4-cyclopropylamino-4-SUB>3): 0,85 (m, 2H), were 0.94 (m, 2H), 1,40 (m, 1H), for 6.81 (d, J= 8.5 Hz, 1H), 7,37 (DD, J=2.5 and 8.5 Hz, 1H), 7,49 (d, J=2.5 HZ, 1H), 8,87 (Shir.S.,1H).

Stage C: 6-chloro-1-(1S)-campanil-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it.

To the solution, stirred in an argon atmosphere in an ice bath and containing (+/-) 6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-he (12,97 g 0,041 M), 4-dimethylaminopyridine (1,02 g, 0,0083 M) and (-)-chloride(-)-campanulas acid (14,22 g, 0,06556 M) in 360 ml of anhydrous dichloromethane, was added triethylamine (22.84 to ml, 0,164 M). The cooling bath was removed, the reaction mixture was left at room temperature to continue the reaction. After 75 minutes the reaction was completed, as evidenced by thin layer chromatography (SiO2, 4% Etc in CHCl3). After that, the solution was diluted with 500 milliliters of chloroform, and then washed 2 times with 10% citric acid, once with water and once with brine. After drying with magnesium sulfate, filter and remove solvent under vacuum formed colorless foam. This foamy substance is triturated with 200 ml of boiling hexane. After cooling to room temperature deposited to the desired connection, namely diastereomeric imide campan is the query result which was obtained 6-chloro-1-(1S)-campanil-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-he (7,79 g) as white crystals, so pl. 164-165oC.

GHUR-purity: 99.2% of at 254 nm.

IH-NMR (DI3): of 0.77 (s, 3H), 0,86-to 0.96 (m, 4H), of 1.08 (s, 3H), 1,19 (s, 3H), of 1.44 (m, 1H), 1,76 (m, 1H), 1,95 (M, 1H), of 2.51 (m, 2H), 7,42 (DD, J=2,4, and 9.0 Hz, 1H), 7,63 (m, 2H).

Stage D: (-) 6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it (L-743.726) (connection 37.2).

In an argon atmosphere 6-chloro-1-(1S)-campanil-4-cyclopropylamino-4-trifluoromethyl-1,2-dihydro-4(H)-3,1-benzoxazin-2-he (7.50 g, 0,01512 M) was dissolved in 150 ml of n-butanol at 60oC. To this solution was added 10 ml of 1 N. hydrochloric acid. After this, the solution was kept at 60oC for 72 hours, then the mixture is neutralized by adding an aqueous solution of sodium bicarbonate and n-butanol was removed in vacuum. The resulting residue was dissolved in 150 ml of tetrahydrofuran and treated at room temperature for 3 hours and 50 milliliters of 2 N. Li. The resulting mixture was diluted with ethyl acetate and washed with two portions of water and one portion of brine. After drying with magnesium sulfate, filtration and removal of solvent in vacuo received a white solid. This substance was recrystallized from hot hexane and received (-) 6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1 l3, C = 0.005 g ml-I).

IH-NMR (CDCl3): 0,85 (m, 2H), were 0.94 (m, 2H), 1,40 (m, 1H), for 6.81 (d, J= 8.5 Hz, 1H). 7,37 (DD, J=2.5 and 8.5 Hz, 1H), 7,49 (d, J=2.5 Hz, 1H), 8,87 (Shir.S.,N).

Stage E: (+) 6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it (L-743.725).

Royal solutions obtained in the above stage, was purified by column chromatography on silica gel (eluent: 10% ethyl acetate in hexane). Clean, undesired diastereoisomer (colorless foam) hydrolyzed as described above in stage D. Thus was obtained the enantiomeric benzoxazinone, (+) 6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it is in the form of white crystals, so pl. 131-132oC.

[]20D= +84,4o(CHCl3, C=0.005 g ml-I).

IH-NMR (CDCl3) : 0,85 (m, 2H), were 0.94 (m, 2H), 1,40 (m, 1H), for 6.81 (d, J= 8.5 Hz, 1H), 7,37 (DD, J=2.5 and 8.5 Hz, 1H), 7,49 (d, J=2.5 Hz, 1H), 8,87 (Shir.S., 1H).

Analysis of reverse transcriptase

In this analysis, we measured the incorporation using recombinant reverse transcriptase HIV (HIV-RTR) (or other RT) of tritium-labeled deoxyguanosine-monophosphate in the besieged acid cDNA at specific values of KmdG and rough(C) d(G)12-18. This Is N 8,2), 30 mm KS1, 30 mm MgCL2I mm dithiothreitol, 20 mg/g: dG12-18(Pharmacia)/ml, 8 mm /3H/dGTP (New England Nuclear) in 0.01% Triton X-100, 50 mm ethylene glycol-bis (-aminoethylamino)-N, N, N, N-tetraoxane acid (G), 1 mg of bovine serum albumin/ml After 60-minute incubation at 37oC, acid precipitable material was collected on glass fiber filters using a semi-automated harvester cells. Bacterial cell extracts containing RT, diluted to concentrations within the linear range of the assay, after which activities were determined in the presence or absence of inhibitor. As control served also cleaned heterodimer HIV-I RT, produced in E. coli. The analysis results were expressed as the concentration of inhibitor (IC50, nanomoles/liter), giving 50% inhibition.

In this analysis to estimate the double mutant (dm) used AI7-RT. AI7-RT is resistant to various aminopyridines as described Nunberg, J. H. and others, J. Virol 65, 4887 (1991). The results were expressed as IC50dm in nm/L.

Analysis of cell proliferation.

Inhibition propagated in cell culture of the HIV virus was evaluated in accordance with the description Nunberg, J. H., and others, J. Virol 65, 4887 (1991). In this analysis of the MT-4-T-Limpo determenirovana inoculum, then the cultures were incubated for 24 hours. After this time, 1% of cells were analyzed by indirect immunofluorescence assay showed a positive reaction. The cells are then thoroughly washed, and distributed on 96-well plates. After that, the wells were added in serial two-fold dilution of the inhibitor and continued to cultivate another 3 days. 4 days after infection in the control cultures were infected 100% of the cells. Accumulation of HIV (after 24 hours) directly correlated with the replication of the virus. Inhibitory concentration was defined as the concentration of inhibitor (nanomole per liter), reducing the spread of infection, at least 95% or CIC95and presented in table IV.

Energeticheskie action.

A. Receiving HIV-infected MT-4 cell suspension.

MT cells were infected (Day 0) at a concentration of 250000 cells/ml stock of strain V HIV-I at a dilution of 1:1000 (the final. conc. after 24 hours 125 PG/ml, sufficient to infect 1% of the cells on day 1 and 25-100% on day 4). Cells were infected and cultured in the following medium: PPMI 1640 (Whittaker BioProducts), 10% inactivated amniotic bovine serum, 2 m is P>o
C in an atmosphere of 5% CO2.

C. Processing inhibitors.

Got the matrix (at nanomolar concentrations) for paired combinations (see table 5). On day I, aliquots of 125 μl of inhibitors were added to equal volumes of HIV-infected MT-4 cells (50000 cells per well) in 96-well tablet for micrometrology. Incubation was continued for 3 days at 37oWith 5% CO2-the atmosphere.

C. evaluation of the propagation of the virus.

Using a multichannel pipette precipitated cells resuspendable and 125 μl was collected in a separate tablet for micrometrology. The supernatant was analyzed for HIV-P24 antigen (after 24 hours).

The concentration of HIV-P24 antigen was measured using immunoassay described below. Aliquots P24 antigen, intended to measure, added to microwells coated with a monoclonal antibody specific to the antigen, HIV-kernel. At this stage, the wells were washed (and other subsequent relevant stages). After this was added biotinidase HIV-specific antibody, and then conjugate with streptavidin horseradish peroxidase. After adding hydrogen peroxide and tetramethylbenzidine substrate was observed cwie degree of synergism.

It was found that paired combinations of inhibitors (see table V) inhibit the replication of the virus in a higher degree than each inhibitor, taken separately or in comparison with total inhibition observed for each inhibitor. For example, it was found that pair combination 726 and AZT is more effective inhibition of the spread of the virus than one connection 726 or AZT, or than total inhibition of connection 726 and AZT.

These data were processed as follows: the relationship of fractional ingebirah concentrations (FI) was calculated by the method described Eop etc., J. WO. hem. , 208, 477 (1954). For different pairs of combinations was determined minimum amount of FICS, which represents the maximum synergies. Alternatively, the calculated average amount FIS, which represents the average of synergies. Cm. table V. These results illustrate a significant degree of synergy in the inhibition of the spread of the virus. The smaller the number, the higher synergies.

Although the above invention is illustrated by specific examples, however, it should be borne in mind that it can be made various changes or modifications not beyond following formul:

AIDS: acquired immunodeficiency Syndrome

HIV: Human Immunodeficiency Virus

ARC: - Complex associated with AIDS

AZT: - zidovudine

ZTS: - lamivudine

ddI: - dideoxyinosine

ddC: - dideoxycytidine

L-735524: indinavir, having the following structure:

< / BR>
L-697661: 3-([(4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino)-5-ethyl-6-methylpyridin-2(1H)-he,

L-743726: efavirenz (a.k.a. connection 37.2).

It should be noted that the claims directed to the combinational treatment methods are a very important aspect of the present invention, because the most common method of treatment is the use of combinations of drugs against AIDS. The Addendum provides several articles/annotation demonstrating the effectiveness of efavirenz (a.k.a. connection 37.2) and one in combination with indinavir (compound L-735524) and other drugs against AIDS, including zidovudine (AZT) and lamivudine (ZTS). These reference sources provide data on the doses used in these combinations, and should be recognized as supporting the petitioners ' allegation that the invention claims a useful medication.

The pharmaceutical composition n the AI.

1. Benzoxazinone formula

< / BR>
in which X represents halogen;

X1is trihalomethyl;

Z represents O;

R represents (a)1-8alkyl, unsubstituted or substituted with halogen, a 5-membered saturated monocyclic ring containing 1-2 heteroatoms selected from nitrogen atoms and oxygen; (b) (C2-4alkenyl, unsubstituted or substituted C1-4alkoxy or c2-5quinil, unsubstituted or substituted C3-6cycloalkyl, hydroxy, di(C1-2alkyl)amino, C1-4alkoxy, phenyl, unsubstituted or substituted C1-4alkoxy, nitro, CN, 5-membered saturated monocyclic ring containing 1-2 heteroatoms selected from nitrogen atoms and oxygen

or its pharmaceutically acceptable salt.

2. Connection on p. 1, which is

(-)-6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-he;

(-)-6-chloro-4-phenylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-he;

(+/-)-6-chloro-4-(2-cyanophenyl)ethinyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-he;

(+/-)-4-(1-chloro-1,1-deformity)-4-(2-phenylethynyl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-he;

(+/-)-4-(2-[dimethylaminomethyl] ethinyl)-4-trifluoromethyl-6-chloro-1,4-vtoroe is (-)-6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one or its pharmaceutically acceptable salt.

4. Pharmaceutical composition suitable for inhibiting reverse transcription of HIV, comprising an effective amount of the compounds of formula I

< / BR>
and pharmaceutically acceptable carrier,

in which X represents halogen;

X1is trihalomethyl;

Z represents O;

R represents (a)1-8alkyl, unsubstituted or substituted with halogen, a 5-membered saturated monocyclic ring containing 1-2 heteroatoms selected from nitrogen atoms and oxygen (b) (C2-4alkenyl, unsubstituted or substituted WITH1-4alkoxy, or c2-5quinil, unsubstituted or substituted C3-6cycloalkyl, hydroxy, di(C1-2alkyl)amino, C1-4alkoxy, phenyl, unsubstituted or substituted C1-4alkoxy, nitro, CN, 5-membered saturated monocyclic ring containing 1-2 heteroatoms selected from nitrogen atoms and oxygen or its pharmaceutically acceptable salt.

5. Method of inhibiting HIV reverse transcriptase, comprising the administration to a mammal an effective amount of (-)-6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it.

6. The way to prevent HIV infection, or treatment of HIV infection or Leche is tormentil-1,4-dihydro-2H-3,1-benzoxazin-2-it.

7. Pharmaceutical composition useful for inhibiting HIV reverse transcriptase comprising an effective amount of (-)-6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-she pharmaceutically acceptable carrier.

8. Pharmaceutical composition useful for the prevention or treatment of HIV infection, or treating AIDS or ARC, comprising an effective amount of (-)-6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-she pharmaceutically acceptable carrier.

9. The combination of (-)-6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-she nucleoside analogue that has biological activity against HIV reverse transcriptase.

10. The combination of AIDS antiviral compounds, which is (-)-6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it, N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-pyridylmethyl)-2(S)-N'-(tributylstannyl)-piperazinil))-pentanolide and one or more HIV inhibitors selected from the group consisting of 3-([4, 7-dichloro-1,3-benzoxazol-2-yl)methyl] amino)-5-ethyl-6-methylpyridin-2(1H)-she's, azidothymidine, dideoxyinosine or dideoxycytidine.

11. the ro-2H-3,1-benzoxazin-2-it, and one or more HIV inhibitors selected from the group consisting of 3- ([4,7-dichloro-1,3-benzoxazol-2-yl)methyl]amino)-5-ethyl-6-methylpyridin-2-(1H)-she's, azidothymidine, dideoxyinosine or dideoxycytidine.

12. The method of obtaining (-)-6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-it includes the following stages: (a) the condensation of (+/-)-6-chloro-4-cyclopropylamino-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one with a separating agent; (b) separation of the resulting diastereomers and (C) removing the modification of the separating agent to obtain the target compounds.

13. The method according to p. 12, in which a separating agent is (-) campanularia).

Priority points:

07.08.92 - PP.1 and 4-8;

27.04.93 - PP.2, 3 and 9-13.

 

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