Benzo[f]chinoline, the method of inhibiting synthesis method benzo(f)khinolinov, the way the splitting of the racemate and salt di - p-toluoyl-(d) or (l)-tartaric acid

 

(57) Abstract:

Benzo[f]chinoline formula I, where R is H, alkyl or penalcol; Z and Z' Is H, alkyl or one of Z and Z' with R5form a bond of carbon-carbon; Y Is H or methyl, or R1forms a bond of carbon-carbon; R1- N or one of Y or R3forms a bond of carbon-carbon; R2- N or C1-4alkyl; R3- N or R1forms a bond of carbon-carbon; R4- N or R5forms a bond of carbon-carbon; R5- N or one of Z or Z' forms a bond of carbon-carbon; n is 1 or 2; X Is H, halogen, NO2, cyano, CF3WITH1-6alkyl, alkoxy, carboxy, alkoxycarbonyl, amino, amido, or a group-O - R6where a - C1-6alkylen,2-6alkenyl or2-6akinyan; R6halogen, hydroxy, CF3, alkoxy, carboxy, alkoxycarbonyl, amino, alkylamino, amido, alkylamino or its pharmaceutically acceptable salt. Compounds 1 are potent selective steroidal inhibitors of 5-reductase, useful in the treatment of benign prostate, baldness in men, acne, seborrhea. 7 C. and 12 C.p. f-crystals, 1 table. (I)

This application is a partial continuation of application serial N 07/781091,

The present invention relates to hexa - and octahedrons[f]Hinayana, pharmaceutical preparations containing these compounds and their use as steroid inhibitors of 5-reductase.

It is well known that certain undesirable physiological conditions, such as benign overgrowth of the prostate gland, a common baldness of men, common acne, seborrhea, androgenic alopecia, hirsutism and prostate cancer are dictated by androgen and depend on 5-dihydrotestosterone (DHT).

The enzyme 5-reductase mediates the conversion of testosterone to more potent locally androgen DHT, that is the organ itself. It was found that the inhibitor of 5-reductase inhibitors block the formation of DHT and improve undesirable physiological condition. Recently described two isoenzyme of 5-reductase in humans (designated as type 1 and 2). Andersson et al. The OEWG. Natl. Acad. Sci U. S. A., 87. 3640-3644 (1990); Andersson et al., Nature, 354, 159-161 (1991). In addition to some structural differences, the two enzymes exhibit differences in their biochemical properties, peculiarities of expression, genetics and pharmacology, Andersson et al., Nature, 354, 159-161 (1991); Jenkius, et al., Journal of Clinical Investigation, 89, 293-300 (1992). �. the ti isoenzymes are usually described as 5-reductase 1 or 2 or 5-reductase type 1 or type 2.

Useful compounds for inhibition of 5-reductase are steroid derivatives, such as azasteroid (Rasmusson, et al., J. Med.Chem., 29 (11), 2298-2315 (1986); and derivative benzylaminopurine-butane acid, such as that described in EPO 291245.

Some compounds benzo[f]Hinayana known, See, for example, Cannon, et al. , Synthesis, 6, 494-496 (1986); Kiguchi et al., Heterocycles, 18, (Special Jssue), 217 to 220 (1982); Cannon, et al., J. Med. Chem., 22 (4), 341-347 (1979); Cannon, et al., J. Med. Chem., 23 (1), 1-5 (1980); Ninomiya, et al., J. Med. Chem. Soc. Perkin Traus 1, 12, 2911-2917 (1984); and Horri, et al. , Chem. Pharm. Bull., 16, (4), 668-671 (1968). These links are mainly related to the synthesis and dopaminergic evaluation disclosed in these compounds. References do not imply new hexa - and octahedrons[f]khinolinov of the present invention or the fact that such compounds will be useful as a steroid inhibitor of 5 - reductase.

Accordingly, one purpose of the invention to provide a new hexa - and octahedrons[f] khinolinov, which are potent selective steroidal inhibitors of 5-reductase, useful in the treatment of benign prostate, baldness in men, acne, seborrhea therapeutic composition for the treatment of these diseases.

Another objective of the invention is methods of treatment of these diseases.

Other objectives, features and advantages will be obvious to experts from the following description and claims.

The present invention provides for obtaining new hexa - and octahedrons[f]quinoline-3-ones, which are effective steroid inhibitor of 5-reductase.

More specifically, the invention relates to compounds having the formula

< / BR>
where R is hydrogen, C1-C4alkyl, unsubstituted or substituted Hairdryer(C1-C4)alkyl;

Z and Z' independently selected from hydrogen and C1-C4the alkyl or one of Z and Z' is combined with R5to form a bond of carbon-carbon;

Y is hydrogen or methyl, or is combined with R1to form a bond of carbon-carbon;

R1is hydrogen or is combined with one of Y or R to form a bond of carbon-carbon;

R2is hydrogen or C1-C4alkyl;

R3is hydrogen or is combined with R1to form a bond of carbon-carbon;

R4is hydrogen or is combined with R5to form a bond of carbon-carbon;

R5is hydrogen or is combined with one of Z or Z' to o6alkyl, C1-C6alkoxy, carboxy, C1-C6alkoxycarbonyl, amino, C1-C4alkylamino, C1-C4dialkylamino, amido, C1-C4alkylamino, C1-C4dialkylamino, mercapto, C1-C6alkylthio, C1-C6alkylsulfonyl, C1-C6alkylsulfonyl, or a group-A-R6where A - C1-C6alkylene, C2-C6albaniles or C2-C6akinyan; and R6halogen, hydroxy, CF3C1-C6alkoxy, carboxy, C1-C6alkoxycarbonyl, amino, C1-C4alkylamino, C1-C4dialkylamino, amido, C1-C4alkylamino, C1-C4dialkylamino, C1-C4alkylsulfonamides, aminosulfonyl or C1-C4alkylaminocarbonyl,

or its pharmaceutically acceptable salt; provided that

(a) at least one of R1and R5is hydrogen;

(b) if R is hydrogen, methyl, ethyl or benzyl, X is not hydrogen or methoxy; and

(c) if R is methyl, R2is not methyl.

This invention also includes pharmaceutical preparations which comprise a compound of the above formula I or its pharmaceutically acceptable salt together the b inhibition of 5 - reductase. More specifically, the proposed methods of treatment of many diseases that are associated with the activity of 5 - reductase in mammals. Among these diseases - benign conditions of the prostate, male pattern baldness, acne, seborrhea, androgenic alopecia, hirsutism and prostate cancer. These methods utilize the compound of formula I or its pharmaceutically acceptable salt. Although the compounds of the present invention inhibit the action of both isoenzymes of 5 - reductase, they demonstrate greater selectivity as an inhibitor of 5 - reductase type 1.

Another aspect of the invention is a new class of intermediate compounds useful in producing compounds of this invention and the method of obtaining sufficiently optically pure active compounds of the present invention.

Intermediate compounds have the formula

< / BR>
where X is hydrogen, halogen, NO2, cyano, CF3C1-C6alkyl, C1-C6alkoxy, carboxy, C1-C6alkoxycarbonyl, amino, C1-C4alkylamino, C1-C4dialkylamino, amido, C1-C4alkylamino, C1-C4dialkylamino, mercapto, C1-C6alkylthio,1-C6alkylsulfonyl or C2-C6akinyan; and R6halogen, hydroxy, CF3C1-C6alkoxy, carboxy, C1-C6alkoxycarbonyl, amino, C1-C4alkylamino, C1-C4dialkylamino, amido, C1-C4alkylamino, C1-C4dialkylamino, C1-C4alkylsulfonamides, aminosulfonyl or C1-C4alkylaminocarbonyl; and n is 1 or 2; or pharmaceutically acceptable salt.

Aspect of the method of the invention, which uses an intermediate compound of formula II - how to get actually optically pure active compound with the formula

< / BR>
where R is hydrogen, C1-C4alkyl, unsubstituted or substituted Hairdryer (C1-C4)alkyl;

Z and Z' independently selected from hydrogen and C1-C4of alkyl;

Y is methyl;

R2is hydrogen or C1-C4alkyl;

n is 1 or 2;

X is hydrogen, halogen, NO2, cyano, CF3C1-C6alkyl, C1-C6alkoxy, carboxy, C1-C6alkoxy-carbonyl, amino, C1-C4alkylamino, C1-C4dialkylamino, amido, C1-C4alkylamino, C1-C4dialkylamino, mercapto, C1-C6alkylthio, C1-C6UB>-C6albaniles or C2-C6akinyan; and R6halogen, hydroxy, CF3C1-C6alkoxy, carboxy, C1-C6alkoxycarbonyl, amino, C1-C4alkylamino, C1-C4dialkylamino, amido, C1-C4alkylamino, C1-C4dialkylamino, C1-C4alkylsulfonamides, aminosulfonyl or C1-C4alkylaminocarbonyl,

or its pharmaceutically acceptable salt; which includes

a) reaction of 1-methyl-2-tetralone with an optically active amine to obtain the corresponding 1-methanamine; and

b) reaction of 1-methanamine with , - unsaturated carbonylbis connection to obtain the appropriate mechanosensitivity-4-it; and

c) reaction of mechanosensitivity-4-she acidic or basic catalyst to obtain the corresponding 2,3,4,4 a, 9,10-hexahydro-4a-methyl-phenanthrene-2-it, and

d) oxidative cleavage of the specified phenanthrene-2-it to obtain the corresponding 3-[1-methyl-1-(2-keto-1,2,3,4-tetrahydronaphthyl)]propionic acid;

e) reaction of the specified propionic acid with ammonia or a primary amine to obtain the corresponding 10b-methyl-1,2,3,4,6,10 b-hexahydrobenzo[f] quinoline-3-one;

f) vosta she as specified above.

Used herein, the term "alkyl" means alkilany radical with a straight or branched chain having the specified number of carbon atoms, such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, t-butyl and, if specified, of the higher homologues and isomers, such as n-pentyl, n-hexyl, 2-methylpentyl and others.

The term "alkylene" means a divalent alkilany radical with a straight chain with the specified number of carbon atoms, such as methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentandiol, 1,6-hexandiol. In the same way "albaniles" means a divalent unsaturated hydrocarbon group with a straight chain having the specified number of carbon atoms and one double bond in the carbon-carbon bonds, such as vinile, 1-propene-1,3-diyl, 2-propylene-1,3-diyl, 2-butene-1,4-diyl, 1-butene-1,4-diyl and other. "Akinyan" means a divalent hydrocarbon group with a straight chain having the specified number of carbon atoms and one triple bond carbon-carbon bonds, such as 1,2-acetylenyl, 1-propyne-1,3-diyl, 2-Butin-1,4-diyl and others.

The term "dryer(C1-C4)alkyl" means alkilany radical with a straight or branched chain with 1 to 4 carbon odnosa is, 1-C4alkyl, C1-C4alkoxy, amino, C1-C4alkylamino or C1-C4dialkylamino. Typical dryers(C1-C4)alkyl groups include benzyl, 2-phenethyl-1-yl, 3-fanpop-1-yl, 4-pinbot-1-yl, 1-phenethyl-1-yl, 2-fanpop- -1-yl, 2-(4-halophenol)ETH-1-yl, 4-halobenzoic and so on.

The term "alkoxy" means any of methoxy, ethoxy, n-propoxy, isopropoxy and others. The term "halogen" and "halo" means any of the fluorescent, chloro, bromo and iodide. The term "alkylthio" means any of the methylthio, ethylthio, n-propylthio, isopropylthio and others.

The term "amido" means aminocarbonyl (-C(O)NH2) group. The term "alkylamino" means the group - NH(C1-C4Akil) and the term "alkylamino" means the group-C(O)NH (C1-C4alkyl). Where the specified office "C1-C4dialkylamino"[(-N) C1-C4alkyl)2] or "C1-C4dialkylamino" /C(O/N)C1-C4alkyl)2/, each alkyl group independently has 1 to 4 carbon atoms.

The term "alkylsulfonyl" means a group S(O) (alkyl) where the alkyl group has the indicated number of carbon atoms. Similarly, the term "alkylsulfonyl" refers to the group - SO2(alkyl) where the alkyl group and the alkyl). The term "aminosulfonyl" means the group - SO2NH2the term "alkylaminocarbonyl" means the group - SO2NH (C1-C4alkyl).

Octahedrons[f] hinolonami of the present invention are those compounds of formula I in which R1, R3, R4and R5- hydrogen. Accordingly, hexahydrobenzo[f]quinolones of the present invention are the compounds of formula I, having two protons less than described in the definitions for formula I.

Compounds of the present invention have at least one asymmetric carbon represented by the carbon atom marked with an asterisk in formula Ia below.

< / BR>
Compounds of the present invention also exist as individual CIS-d - Cys-l-stereoisomers, as well as TRANS-d - and TRANS-l-stereoisomers and mixtures of such isomers. Two dis and two TRANS configuration is shown below in formula 1b-1e.

< / BR>
< / BR>
< / BR>
< / BR>
Accordingly, the compounds of the present invention include not only a mixture of two or more such individual isomers, but also individual isomer.

In addition, there are other diastereomers depending on R2Z and Z' deputies. Connection Natalegawa compounds illustrate the connection covered by the scope of formula I:

CIS-dl-8-bromo-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8-bromo-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8-bromo-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8-iodide-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8,9-sodium dichloro-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8,9-sodium dichloro-4-methyl-1,2,3,4,4 a, 5,6,10 b-ocheretianko [f]quinoline-3-one;

TRANS-dl-8-chloro-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

CIS-dl-8-chloro-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-4,8-dimethyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-he;

CIS-dl-4,8-dimethyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-he;

TRANS-dl-8-fluorescent, 4-methyl-1,2,3,4,4 a, 5,6,10 b-ocheretianko[f] quinoline-3-one;

CIS-dl-8-fluorescent-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-4-methyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one;

CIS-dl-4-methyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one;

CIS-dl-1,2,3,4,4 a,5,6,10 b-ocheretianko[f]quinoline-3-one;

TRANS-dl-8-fluorescent-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8-ethoxycarbonylmethyl-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-chloro-1,2,3,4,4 a,5,6,10 b-octahedrons[f] henriettestraat[f] quinoline-3-one;

TRANS-dl-8-methyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8-ethoxycarbonylmethyl-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-methoxycarbonylmethyl-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-carboxyethyl-4-methyl-1,2,5,4,4 a, 5,6,10 b-octahedrons [f]quinoline-3-one;

TRANS-dl-8-t-butylaminoethyl-4-methyl-1,2,3,4,4 a, 5 6,10 b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-chloro-2-( -methyl)-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-chloro-2-( methyl)-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-bromo-6,6-dimethyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-bromo-4,6,6-trimethyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one;

CIS-dl-8-bromo-4,6,6-trimethyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8-t-butyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8-t-butyl-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-fluorescent-4, 10b-dimethyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one;

CIS-dl-8-fluorescent-4,10 b-dimethyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8-chloro-4,10 b-dimethyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one;

CIS-dl-8-chain-3-one;

TRANS-dl-4,10 b-dimethyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-3-chloro-10b-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one;

CIS-dl-8-chloro-10b-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one;

TRANS-dl-9-nitro-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-9-nitro-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-9-amino-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-9-chloro-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one;

TRANS-dl-8-chloro-3,4,4 a,5,6,10 b-hexahydrobenzo[f] quinoline-3-one;

dl-8-chloro-2,3,4,4 a,5,6 hexahydrobenzo[f]quinoline-3-one;

TRANS-dl-8-bromo-4-methyl-3,4,4 a,5,6,10 b-hexahydrobenzo[f] quinoline-3-one;

TRANS-dl-8-chloro, 4-methyl-3,4,4 a,5,6,10 b-hexahydrobenzo[f] quinoline-3-one;

dl-8-chloro-4-methyl-2,3,4,4 a,5,6 hexahydrobenzo[f] quinoline-3-one;

TRANS-dl-8-chloro-2-( -methyl)-4-methyl-1,2,3,4,4-a, 10b-hexahydrobenzo[f]quinoline-3-one;

TRANS-dl-8-t-butylaminoethyl-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-phenyl-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-vinyl-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one;

TRANS-dl-8-etoxycarbonyl-4-methyl-1,2,3,4,4 a, 5,6,10 b octahedrons[f] quinoline-3-one.

Preferred compounds is lkyl;

Z and Z' is independently hydrogen or methyl;

Y is hydrogen or methyl and is in the TRANS configuration relative to the hydrogen 4a provisions;

R1, R3, R4and R5is hydrogen;

R2is hydrogen or methyl;

n is 1 or 2;

X is halogen, CF3C1-C6alkyl, C1-C4alkoxy or-A-R6where A - C1-C4alkylene and R6- C1-C4alkoxycarbonyl; or its pharmaceutically acceptable salt; provided that

(b) if R is hydrogen, methyl or ethyl, X is not hydrogen or methoxy; and

(c) if R is methyl; R2is not methyl.

The most preferred compounds of the present invention are those formula I, in which

R is hydrogen or methyl;

Z and Z' are both hydrogen or methyl;

Y is hydrogen or methyl and is in the TRANS configuration relative to the hydrogen 4a provisions;

R1, R3, R4and R5is hydrogen;

R2is hydrogen or methyl;

n is 1 or 2;

X is halogen, CF3or C1-C4alkyl, or pharmaceutically acceptable salt; provided that

(c) if R is methyl, R2is not methyl.

As mentioned above, the invention includes pharmaceutically acceptable salts of the compounds, determine the residual acid, sufficiently basic, or both functional groups, and accordingly react with any of a number of non-toxic inorganic bases and non-toxic inorganic and organic acids to form pharmaceutically acceptable salt. Acids commonly used to obtain the acid salts of accession, are inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, phosphoric acid and other organic acids, such as n-toluene, sulfo, methane acid, oxalic acid, n-bromo-phenyl-acid, carbonic acid, succinic acid, citric acid, benzoic, acetic and other acids. Thus, examples of such pharmaceutically acceptable salts are sulfate, persulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, kaprilat, acrylate, format, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, Butin-1,4-diet, hexyne-1,6-diet, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, ft is Tirat, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other. Practicality pharmaceutically acceptable salts of the acid accession are those formed with mineral acids such as hydrochloric acid and Hydrobromic acid, and those formed with organic acids such as maleic acid and methansulfonate.

Salt acid accession include those that are obtained from non-toxic inorganic bases, such as hydroxides, carbonates, bicarbonates of alkali or alkaline earth metal or ammonium, and others. Such bases useful in obtaining salts of this invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate. The most preferred salts are potassium and sodium. Compounds of the present invention is obtained using well-known specialists procedures. These compounds of the present invention where Y is hydrogen, preferably synthesized according to scheme 1 (see end of text).

If X, n and R are as defined above for formula I, R-EAA - electrophilic alkylating agent Raand Rbis independently selected from in clichesque group, which may also include an oxygen atom, provided that both Raand Rbcannot be hydrogen at the same time.

As shown in synthetic scheme 1, 4a-10bhexahydrobenzo[f]chinoline are intermediate compounds, which when restoring the double bond to give the compounds of this invention and/or compounds which are useful as intermediates for producing compounds of this invention.

Hexahydrobenzene derived from unsubstituted or substituted in the ring fenetylline. Fenetylline commercially available or is well known in the art procedures. Usually, it is suitable substituted phenylacetic acid reacts with thionyl chloride, phosphorous trichloride, oxalylamino or phosphorous pentachloride, preferably thionyl chloride, under conditions well known in the art, to obtain the corresponding fenetylline.

The reaction allazei Friedel-crafts of fenetylline with ethylene in the presence of acid catalyst of the Lewis and in an inert or nearly inert solvent or mixture of solvents is achieved by ring closure in obtaining 2-tetralone. Under the/SUB>, SnCl4, BCl3BF3, SbCl3and other, preferably AlCl3. Solvents useful for this reaction include carbon disulfide, methylene chloride, nitromethane, 1,2-dichloroethane, nitrobenzene and other, preferably methylene chloride. Activation of fenetylline with Lewis acid is carried out at temperatures from -78oC to 25oC.

Adding ethylene ectothermic by nature and when using standard procedures cooling applied temperature from -78oC to about 30oC.

Then the reaction product 2-tetralone mineralsa primary or secondary amine, preferably pyrrolidino, in an inert or nearly inert solvent or mixture of solvents to obtain the appropriate enamin. In the case of a primary amine can be accompanied by tautomerism imine. The reaction is terminated by removal of water, which can be done at elevated temperatures from 80 to 110oC using a suitable azeotrope of the solvent at room temperature using a suitable dehydrating agent such as molecular sieves or magnesium sulfate. Suitable solvents are aprotic organic solvents, such as benzene, capriatti acid and in the presence or absence of an inert or nearly inert solvent or mixture of solvents, to get hexahydro-2-(1H)-benzo[f] chinoline. The acid in this reaction include strong organic or mineral acid, preferably p-toluene acid (PTS). Although the reaction can be carried out in a solvent, it is desirable not to use it. The reaction is carried out at temperatures from 90oC to about 130oC.

Then hexahydro-2(1H)-benzo[f] chinoline can be restored to appropriate octahedrons[f] khinolinov of the present invention. Next, octahedrons[f]chinoline can N-alkylaromatic to obtain further compounds of the present invention.

Alternatively, hexahydro-2(1H)-benzo[f]chinoline beginning N-alkylaromatic, and then recover to the corresponding N-alkyl-octahedrons[f]quinoline(3)-ones of the present invention.

The recovery is carried out by reaction of hexahydrobenzo[f] Hinayana or N-alkyl-hexahydrobenzo[f] chinoline with an appropriate reducing agent in an inert or nearly inert solvent or mixture of solvents. Appropriate remedial agents include hydrogenation over a metal catalyst and reagents transfer of hydride, such as the format of ammonia over a catalyst IU is almost inert organic solvents, preferably methylene chloride. Used temperature from 0oC to 69oC, preferably about 25oC.

N-alkylation is carried out by reaction of hexahydrobenzo[f] Hinayana or octahedrons[f] chinoline with electrophilic alkylating agent R-EAA, where R is as defined above for formula 1, in the presence of a base in an inert or nearly inert solvent or mixture of solvents. For this reaction EAA preferably iodine. The base is typically a metal hydride, amide or alkoxide of metal, preferably sodium hydride. Typically, this reaction is carried out at temperatures from -30oC to the temperature of heating under reflux of the solvent.

These compounds of the present invention, where Y is methyl, preferably synthesized according to scheme 2 (see the end of the text), where X, n and R are as defined above for formula I, and Raand Rband R-EAA - as defined above for scheme 1.

As shown in scheme 2, 4a-methyl-hexahydrobenzo[f] quinoline-2(1H)-it is an intermediate compound, which is restored to obtain the compounds of the present invention and/or compounds which are useful as intermediates for producing compounds of this invention.

Next, 1-methyl-2-tetralone reacts as shown in scheme 2, using the reagents and procedures described above for scheme 1, in order to obtain the compounds of the present invention, where Y is methyl.

These compounds of the present invention, where Z, Z' or both - C1-C4alkyl, are prepared in accordance with the procedures of scheme 1 and scheme 2, except that the closure ring Friedel-crafts used reaction fenetylline corresponding alkene and not ethylene; shown in both figures 1 and 2. Examples of suitable alkenes for use in this reaction include propylene, 1-butene, ISO-butylene, 3,3-dimethyl-1-butene, 2-penten, 4-methyl-2-penten, 3-methyl-1-butene, 2-methyl-2-butene, 2,3-di-methyl-2-butene and others.

These compounds of formula I, where R2- C1-C4alkyl, he or substituted Hairdryer (C1-C4) alkyl, as shown in the following scheme 3 reactions:

< / BR>
where Y, X, n, R, and R2as described above for formula I, except that R is not hydrogen, and R2-EAA electrophilic alkylating agent, where R2is as defined above for scheme 1. R-(alkyl or penalcol) compound reacts with a base, such as metal amide or metal alkoxide, preferably hexamethyldisilazide potassium, in an inert or nearly inert solvent for the mixture of solvents at a temperature of from -78oC to about 25oC. Then, the alkylation is carried out by adding the appropriate electrophilic alkylating agent, preferably C1-C4alkylated to obtain 2-(C1-C4alkyl) compounds of formula I.

For those compounds of formula I, where R is H, a nitrogen atom at the 4 - position of first blocks of a suitable amino protecting group such as t-butoxycarbonyl or benzyloxycarbonyl, and then reacts as shown above in scheme 3. After alkylation at the 2-position of the nitrogen atom at the 4-position is not protected. The reaction protection and unlock protection are carried out under standard conditions for such reactions.

An alternative method of obtaining these compounds present the mules I.

Another aspect of this invention relates to a particular method of obtaining optically active isomers of the compounds of this invention. As shown above in scheme 4, 1-methyl-2-tetralone is reacted with a chiral amine such as 1-phenylethylamine in an inert or nearly inert solvent or mixture of solvents to obtain the corresponding enamine. If you are using chiral primary amine, enamin can be obtained by tautomer imine. The reaction is carried out by the removal of water, what can be done at elevated temperatures from 80oC to 110oC using a suitable azeotrope of the solvent at room temperature using a suitable dehydrating agent such as molecular sieves or magnesium sulfate.

Enamin then reacts with a suitable alpha, beta-unsaturated carbonylbis connection, preferably by reaction of methyl vinyl ketone are joining michael and subsequent hydrolysis mild aqueous acid to obtain 5, 6, 7, 8, 9, 10-hexahydro-8-hydroxy-5,8-dimethyl-5,9-metaevent - cycloocten-11-he. This reaction is conducted in an ethereal solvent such as THF, dioxane or other inert atmosphere, such as argon or nitrogen at a temperature of from 10oC this reaction is used from stekhiometricheskikh quantities of reactants to excess with preference given to excess. Suitable acids include organic carboxylic acid and perchloric acid, preferably acetic acid.

Mechanosensitivity-II-it is processed in an acid or basic catalyst, preferably ethoxide sodium or potassium proton solvent, preferably ethanol at reflux to obtain 2,3,4,4 a,9,10 hexahydro-4a-methyl-phenanthrene-2-it.

The phenanthrene-2-oxidative he is cleaved with a suitable oxidizing agent such as ozone, KMnO4, CrO3or preferably by tetrakis ruthenium in an inert or nearly inert solvent or mixture of solvents from -78oC to about 100oC, preferably from -10oC to about 10oC, to obtain 6-[1-methyl-1-/2-oxo-1,2,3,4-tetrahydronaphtyl/] propionic acid. Usually the solvent is inert or mixture of solvents, preferably a mixture of 2 parts of carbon tetrachloride, 3 parts of acetonitrile and 2 parts of water.

Propionic acid is reacted with ammonia or a primary amine (other, where R is as defined above for formula (I) in an inert or nearly inert solvent or solvent mixture, preferably 2-propanol at temperatures from 95oC to 200he present invention. Preferably this reaction is carried out at a relative absence of oxidizing agents such as air, in a sealed reactor or something like that.

Hexahydrobenzo[f]chinoline can be restored to the appropriate octahydronaphthalene of the present invention is almost the same procedures described above in schemes 1 and 2.

Following the procedures in scheme 4 and described above, receive almost pure optically active isomers of the compounds of this invention where Y is methyl.

Asymmetric synthesis of the individual enantiomeric compounds of the formula I or their precursors is carried out by reaction of enamine formula

Scheme 5

< / BR>
with a derivative of acryloyl formula

< / BR>
where Y, X, R2and n is as defined above for formula I; C - withdrawing group, such as chlorine, bromine, fluorine, iodine, toluensulfonate, methanesulfonate and symmetric or asymmetric anhydrides; and Rc- 1-phenethyl. 1-Phenethyl Deputy subsequently cleaved using triperoxonane acid. -COG - radical acryloyl derivative is an activated form of-COOH, which can be activated in other ways, such as active esters, mixed anhydrides, and others.

oC to 150oC and a reaction time ranging from several minutes to several hours, the maximum is sufficient. The environment of the reaction is a two-phase mixture of a suitable organic solvent and aqueous solution of a mild base. Useful solvents include, for example, haloalkane, ethers, including tetrahydrofuran, NITRILES including acetonitrile. Preferred soft bases are carbonates and bicarbonates of alkali metals; more highly basic reagents such as hydroxides of alkali and alkaline earth metals and others may be used in some cases, but the bicarbonate is preferred. If desired, the process can be carried out without reason.

The products of this synthesis are easily isolated in the usual processing steps. The use of this method provides highly pure synthesis of the forms of the reaction product with one isomer.

We must understand that the products of the present method can be used as such, in view of their biological activity, or they can be used as intermediate compounds of[f] quinoline-3-ones of the formula I, with1or 5the double bond carbon-carbon, prepared from the corresponding octahedrons[f]quinoline-3-ones by reaction of attach/detach. Octahedrons[f]quinoline-3-one is reacted with sulfur or selenium the electrophile in the presence of a base in an aprotic solvent. The base is a usually a metal hydride or amide of a metal, preferably a metal hydride such as sodium hydride. Although each equivalent of octahedrons[f]quinoline is added usually one equivalent of a base, for those compounds where R is hydrogen, is added a second equivalent of base. The temperature for this reaction from the 20oC to the temperature of heating under reflux of the solvent. The reagent attaching a is sulfur or selenium electrophile and is carried out at a temperature of from -50oC to -100oC. Suitable sulfur electrophiles such groups of sulfur used in nucelophile substitution and well-known specialists, Patai, "The Chemistry of The Thiol Group", Wiley, New York (1974); Reid, "Organic Chemistry of left-hand drive vehicles Sulfur", Chemical publishing company, New York (1958, 1963); Kharasch, "Organic Sulfur Compounds", Perganon, New York (1961).

Suitable selenium compounds include phenylsalicylate, phenylsalicylate, N -(phenylseleno)phthalimide, diphenyl of diselenide, ive, Tetrahedron, 34, 1049-1132 (1978) Aldrichimica Acta, 11, 43-49 (1978); and Miyoshi, et al., Tetrahedron Lett., 23, 4813 (1982).

The reaction removal is usually performed under oxidizing conditions in an aprotic solvent. March, "Advanced Organic Chemistry, 3 ed, pp. 912-914, Wiley-Inter-science, N. Y.(1985).

10bcompounds of the present invention are obtained by rearrangement (isomerization) of the corresponding1connections when Y is hydrogen. This reaction is carried out in an aprotic solvent in the presence of acid or basic catalyst at conditions well known to specialists.

4acompounds of the present invention are prepared as intermediate compounds by the procedures described above in scheme 4, and isolated, and not restored to their respective octahedrons[f]quinoline-3-she.

Optically active isomer of the racemate of the invention are also considered part of this invention. Such optically active isomers can be obtained from their respective optically active precursors by the procedures described above or splitting of racemic mixtures. This splitting can be carried out by chiral derivatization reagent followed by chromatography or re-crystallization. The removal of the chiral poslednee or their precursors. Further details on the splitting can be obtained from Jacques, et al., Enantiomers, Racemates and Resolutions, John Wiley & Sons, 1981.

Another aspect of the present invention and the preferred method of splitting the racemates of these compounds of formula 1, where R is hydrogen or C1-C4alkyl; Z and Z' independently selected from hydrogen and C1-C4of alkyl; Y is hydrogen; R1, R2, R3, R4and R5all hydrogen; n is 1 or 2; and X is hydrogen, halogen, NO2, CF3C1-C6alkyl, C1-C4alkoxy, amino, C1-C4alkylamino, C1-C4dialkylamino, mercapto or C1-C6-alkylthio;

on their component optical isomers, comprising the steps:

(a) contacting the solution of methanol of the racemate with a strong acid to obtain 1-(2-methoxycarbonylethyl)-2-(amino)- 1,2,3,4-tetrahydronaphthalen;

(b) contacting the specified tetrahydronaphthalene from (a) with a solution of methanol optically active di-p-toluylenediamine acid to obtain the corresponding salt of tetrahydronaphthalene; and

(c) processing the salt of (b) a base, to obtain the optically active isomer.

As another aspect of the present invention in addition to spcala tartaric acid 1-(2-methoxycarbonylethyl)-2-(amino or C1-C4alkylamino)-1,2,3,4-tetrahydronaphthalene.

This cleavage is carried out by dissolving the racemic mixture of optically active isomers, as defined above, in methanol and contacting the specified solution with a strong acid to obtain an intermediate compound 1-(2-methoxycarbonylethyl)-2-(amino or C1-C4alkylamino)-1,2,3,4-tetrahydronaphthalene. Suitable strong acids include inorganic acids such as hydrochloric acid, nitric acid, phosphoric, sulfuric, Hydrobromic, uudistoodetena acid and others, as well as organic acids such as aromatic sulfonic acids and others. Inorganic acids are preferred and most preferred sulfuric acid. Then the intermediate tetrahydronaphthalene kontaktirajte with a solution of methanol optically active di-p-toluylenediamine acid to obtain the corresponding salt of tetrahydronaphthalene. Where desirable (+) enantiomer, is (-)-di-p-toluoyl-L-tartaric acid. Accordingly, where the desired (-) isomer, is used (+)-di-p-toluoyl-D-tartaric acid.

The obtained salt can be separated from the mixture by conventional means. For example, otdering from the aqueous phase vodonasosnaya solvent. The free amine can be heated to 35-120oC for recirculation and to obtain the desired octahedrons[f] chinoline, depending on the extracting solvent.

Suitable bases for use in the above-mentioned method are usually weak base, preferably sodium carbonate or potassium bicarbonate or sodium, and preferably sodium bicarbonate. Suitable vodorazreshimye solvents include methylene chloride, toluene, ethyl acetate, tert-butyl methyl ether and diethyl ether, better methylene chloride.

The expert knows that the selective crystallization of one diastereoisomer from the organic solution is concentrated. The relatively low concentration gives the pure diastereoisomer higher purity, but with low yield and higher concentration of racemate and a decomposing agent usually gives higher yields solids is largely due to optical purity.

Compounds used as initial starting materials in the synthesis of compounds of this invention are well known and readily synthesized by standard procedures, well known to the experts.

Pharmaceutically acceptable salts of the invention Obecni or basic functionality, with equimolar or excess amount of acid or base. The reactants are typically combined in a solvent, such as diethyl ether or benzene to acid salts of accession, or water or alcohols, salts for the primary connection, and salt usually falls out of the solution for from 1 hour to 10 days, and can be isolated by filtration or other known means.

In addition, some of the compounds of the present invention may form a solvate with water or common organic solvents. Such a solvate is included as compounds of this invention.

The following examples further illustrate the compounds of the present invention and methods for their synthesis. Examples in no way limit the scope of the invention and should not be so interpreted.

Example 1

Obtaining CIS-dl and TRANS-dl-8-bromo-4-methyl-1,2,3,4, 4a,5,6,10 b-octahedrons[f]quinoline-3-it

A. 4-Bromophenylacetate

In a 250 ml flask with a round bottom, equipped with a magnetic stirrer, was added 4-bromophenylacetate acid (100.0 g; 0,465 M) and 100 ml of thionyl chloride (163.1 g; 1.37 mol). The suspension was mixed at room temperature for 22.5 hours. The excess thionyl chloride was evaporated in vacuum DL the th (-78oC; dry ice/isopropanolate bath) suspension of AlCl3(125 g; of 0.94 mol) in 1,400 ml of CH2Cl2was added the acid chloride obtained in step A (108,5 g; 0.47 mol), dissolved in 400 ml of dry CH2Cl2with stirring for 1 hour. Bath of dry ice/isopropanol was removed and the solution was warmed to -10oC. In the flask was passed bubbles ethylene with vigorous agitation. The reaction was warmed to isothermal 20oC and the addition of ethylene was stopped. The mixture is stirred at room temperature for 3 hours, then cooled to 0oC and was added to ice up until there were no ectotherm. The reaction mixture was diluted to 1 l of cold ice water and stirred to dissolve all solids. The resulting layers were separated and the organic layer was washed twice with portions in 1 l of 1 NHCl and then once with 1 l of saturated Na2HCO4. The organic layer was dried over Na2SO4and concentrated in vacuo to obtain a pale yellow crystalline substance.

6-Bromo-2-tetralone crystals climbed a minimal amount of ether. Carefully hexane was added at the beginning of the turbidity of the solution. The mixture was cooled for 4 hours, filtered and washed the melting point 71-73oC.

C. 2-Pyrrolidinyl-6-bromo-3,4-dihydronaphthalene

In a 250 ml flask with a round bottom was added to 5.00 g (22,21 mm) 6-bromoethylene obtained in step B; 70 ml of dry toluene and 3.1 g (3,7 ml) pyrrolidine. The flask was equipped with a trap Dean-Stark condenser, inlet tube for nitrogen and a magnetic stirrer and the reaction was conducted by heating under reflux for 4 hours. The solvent was evaporated in vacuum to obtain 6.0 g (97,4%) of the desired compound as a brown crystalline material, which was used without further purification.

D. 8-Bromo-1,2,3,4,5,6-hexahydrobenzo[f]quinoline-3-one

Enamin (2.15 g, 7,73 mm) from step C, acrylamide (1.10 g, 15,46 mm) and 100 mg of p-toluene sulfonic acids (PTSC) were thoroughly mixed in a mortar with a pestle. The mixture was transferred into a 250 ml flask with a round bottom, equipped with a magnetic stirrer and inlet for nitrogen. Using a bath of mineral oil mixture was heated to 89oC, while the stirred mixture was black and melted. The temperature was held constant at 89oC for 1.5 hours. It was further raised to 130oC and was maintained such 0.5 hour. The oil bath was removed and carefully added 60 ml of water. The obtained dark gray material carefully Pergo color. Crystals climbed in CHCl3and added activated charcoal. This mixture was mixed for 15 minutes, filtered and evaporated in vacuum. The residue was taken in minimum amount of ethyl acetate using a steam bath and transferred into Erlenmeyer flask, equipped with a magnetic stirring plate and immersed in a bath of dry ice/acetone with stirring to obtain the desired compound in the form of a crystalline substance of white color (melting point 215-217 decomposition). 1thcollection of 940 mg; 2thcollection of 175 mg (yield 55%).

E. 8-Bromo-4-methyl-1,2,3,4,5,6-hexahydrobenzo[f]chinoline-3-one

Following the procedures described above, was obtained of 5.17 g of 8-bromo-1,2,3,4,5,6-hexahydrobenzo[f] quinoline-3-one. Hexahydrobenzene (of 5.17 g, 19,6 mm) was dissolved in 60 ml of dry diethyl ether in a 250 milliliters flask with a round bottom. To the solution was added 1.2 g of sodium hydride (60% dispersion in mineral oil). The flask was adapt itself to the condenser heating under reflux with stirring plate and the mixture was heated under reflux for 2 hours. Then it was cooled to room temperature and was added to 7.35 ml methyliodide. After the addition, the reaction mixture was heated under reflux e is up in vacuum to obtain a pale crystals, who got into a mixture of ethyl acetate/water and the resulting layers were separated. The organic layer were washed twice with water and once with brine and then dried over MgSO4and was evaporated in vacuum to obtain with 5.22 g of a crystalline substance is yellow. Substances recrystallizations from acetone to obtain 3.55 g (62%) of the desired compound in the form of a substance pale yellow color. The melting point of 126-128oC.

F. 8-Bromo-4-methyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one

To a solution of hexahydrobenzene obtained above in Step E (1,17 g; 4.0 mm) in 10 ml of dry dichloromethane was added triethylsilane (1,37 g; 11.8 mm). The resulting mixture was stirred 10 minutes at room temperature. The reaction mixture was cooled in an ice bath and added triperoxonane acid (5 ml). The resulting mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated in vacuum. The oily residue was taken in CH2Cl2and were washed with saturated NaHCO3. The organic layer was dried over sodium sulfate and concentrated in vacuum to obtain orange oil. Instant chromatography on SiO2(elution with 0.5% methanol/CH2Cl2gave 1,14 g oil-dl and TRANS-dl-8-bromo-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-one

CIS and TRANS isomers were separated HPLC on SiO2(in hexane with uvelichivshimisya gradient of ethyl acetate). The TRANS isomer (example 1A) was separated first in the number of 631 mg; and CIS isomer (example 1B) the second number 192 mg of the TRANS isomer was recrystallizes from diethyl ether/hexanol to obtain 176 mg; melting point 103-104,5oC.

Elementary analysis:

TRANS (1A)

Calculated: C 57,16 H 5,48. N 4,76.

Received: C 57,57; H Of 5.53; N With 4.64.

CIS (1B)

Calculated: C 57,16; H 5,48; N 4,76.

Received: C 57,46; H 5,67; N 4,59.

Example 2

Obtaining TRANS-dl-8-bromo-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

The compound 8-bromo-1,2,3,4,5,6-hexahydrobenzo[f]quinoline-3-one was obtained in accordance with the procedures described in example 1, steps A, B, C, and D.

The desired compound was obtained in accordance with the procedure described above in example 1, stage number 84 mg of a white crystalline material (yield 29%, followed by recrystallization from ethyl acetate; melting point 252-254oC decomp.

Elementary analysis

Calculated: C 55,73; H 5,04; N 5,00.

Received: C 55,46; H 5,07; N 4,89.

Example 3

Obtaining TRANS-dl-8-iodide-4-IU is zo[f] quinoline-3-one was obtained in accordance with the procedures described in example 1, steps A, B, C, D, E, F and g

To a stirred solution of the TRANS isomer (475 mg; 1,614 mm) in 3.5 ml of dry dioxane was added hexamethylditin and 54 mg (3 mol%/ Tetra-KIS/triphenylphosphine)palladium. The reaction mixture was heated under reflux for 2.5 hours, cooled to room temperature, filtered through Celite and concentrated to obtain oil light yellow color. The material was then concentrated under high vacuum overnight at room temperature to obtain 677 mg of the corresponding 8-trimethyltin connection in the form of oil pale yellow color, which was used without further purification.

To a cold solution of compound 8-trimethyltin, obtained above, in 5.0 ml of CH2Cl2dropwise added to 1.6 ml of 1.0 M of yedinonachaliye. The reaction mixture was warmed to room temperature over 1.5 hours. The mixture was cooled and 1 ml of water, filtered, and volatiles were evaporated in vacuum to obtain an oily material black. This material was subjected to chromatography on SiO2(elution with 5% isopropanol/ CH2Cl2with a yellow crystalline substance, which was recrystallizations of etelaat is Lavinia: 103-104,5oC.

Elementary analysis:

Calculated: C 49,28; H To 4.73; N 4,11.

Received: C 49,48; H 4,72; N 3,96.

Example 4

Obtaining TRANS-dl-8,9-sodium dichloro-1,2,3,4,4 a, 5,6,10 b octahedrons[f]quinoline-3-it

The desired compound was obtained using 3,4-dichlorophenylamino acid as a starting material in the procedure described above in example 1, steps A, B, C, D, and F in the amount of 567 mg in the form of a white crystalline material. The melting point 267-268oC, decomposition.

Elementary analysis:

Calculated: C 57,80; H Is 4.85; N 5,18.

Received: C 58,22; H 5,04; N 5,18

Example 5

Obtaining TRANS-dl-8,9-sodium dichloro-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

Following the procedures described above in example 1, steps A, B, C, D, and F, followed by recrystallization from ethyl acetate there was obtained TRANS-dl-8,9-sodium dichloro-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one using 3,4-dichlorophenylamino acid as the starting material.

The desired compound was obtained from TRANS-dl-8,9-dichlorostyrene[f] Hinayana according to the procedures described in example 1, step E in the amount of 117 mg (yield 35%) as a solid beige color. The melting point of 168-169oC.

Elementchange TRANS-dl-8-chloro-4-methyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-it

The desired compound with CIS-dl-isomer (example 7) was obtained according to the procedures described in example 1, steps A, B, C, D, E and F using p-chlorophenylalanine acid as the starting material. Department in example 1, step C gave 500 mg of the desired compound. The melting point 82oC.

Elementary analysis:

Calculated: C 67,33; H 6,46; N 5,61.

Received: C 67,60; H 6,63; N 5,67.

Example 7

Obtaining CIS-dl-8-chloro-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f] quinoline-3-it

The desired connection with the TRANS-dl-isomer (example 6) was obtained according to the procedures of example 1, steps A, B, C, D, E and F using p-chlorophenylalanine acid as the starting material. Department in example 1, step C gave 200 mg of the desired compound in the form of butter.

Elementary analysis:

Calculated: C 67,33; H 6,46; N 5,61.

Received: C 67,57; H 6,82; N 5,70.

Example 8

Obtaining TRANS-dl-4,8-dimethyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

The desired compound with CIS-dl-isomer (example 9) was obtained according to the procedures of example 1, steps A, B, C, D, E and F using p-chlorophenylalanine acid as the starting material. Department in example 1, step C gave 400 mg of the desired joint is luceno: C 78,79; H 8,32; N 6,11.

Example 9

Obtaining CIS-dl-4,8-dimethyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

The desired connection with the TRANS-dl-isomer (example 8) was obtained in accordance with the procedures described in example 1, steps A, B, C, D, E and F using p-tolyloxy acid as the starting material. Department in example 1, step C gave 290 mg of the desired compound. The melting point 78oC.

Elementary analysis:

Calculated: C 78,56; H 8,35; N 6,11.

Received: C 78,26; H 8,56; N By 5.87.

Example 10

Obtaining TRANS-dl-8-fluorescent-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-it

The desired compound with CIS-dl-isomer (example 11) was obtained according to the procedures of example 1, steps A, B, C, D, E and F using p-Ferienmesse acid as the starting material. Department in example 1, step C to give 244 mg of the desired compound. The melting point of 108-109oC.

Elementary analysis:

Calculated: C 72,80; H 6,91; N 6,00.

Received: C 72,07; H 6,89; N 6,09.

Example 11

Obtaining CIS-dl-8-fluorescent-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f] quinoline-3-it

The desired connection with the TRANS-dl-isomer (example 10) was obtained according to the procedures described in example in example 1, step C gave 130 mg of the desired compound. The melting point of 136-137oC.

Elementary analysis:

Calculated: C 72,08; H 6,91; N 6,00.

Received: C 72,30; H? 7.04 Baby Mortality; N 6,06.

Example 12

Obtaining TRANS-dl-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

The desired compound with CIS-dl-isomer (example 13) was obtained according to the procedures of example 1, steps A, B, C, D, E and F using phenylacetic acid as a starting material. Department in example 1, step C gave 200 mg of the desired compound. The melting point of 128-129oC

Elementary analysis:

Calculated: C 78,10; H Of 7.96; N 6,51.

Received: C 77,87; H A 7.85; N 6,46.

Example 13

Obtaining CIS-dl-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

The desired connection with the TRANS-dl-isomer (example 12) was obtained according to the procedures described in example 1, steps A, B, C, D, E and F using phenylacetic acid as a starting material. Department in example 1, step C gave the desired compound. The melting point of 129-130oC

Elementary analysis:

Calculated: C 78,10; H Of 7.96; N 6,51.

Received: C 78,32; H? 7.04 Baby Mortality; N 6,58.

Example 14

Obtaining CIS-dl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

The connection is Itanium phenylacetic acid as the starting material.

To 94 ml of acetic acid was added 1,2,3,4,5,6-hexahydrobenzo [f]quinoline-3-one (3 g, 15 mm) and 3 g of 5% palladium on charcoal. The mixture was vestibules at room temperature for three days at an initial hydrogen pressure of 60 lb/inch2(4,21 kg/cm2). The catalyst was removed by filtration. The filtrate was diluted with ethyl acetate and made basic with saturated NaHCO3. The resulting layers were separated and the organic layer was dried over MgSO4and concentrated to obtain 1.4 g (yield 46%) of the desired compound. The melting point of 178-179oC.

Elementary analysis:

Calculated: C 77,58; H 7,51; N Of 6.96.

Received: C 77,88; H 7,52; N 7,05.

Example 15

Obtaining TRANS-dl-8-fluorescent-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

The desired compound was obtained according to the procedures of example 1, steps A, B, C, D, E, F and G using p-Ferienmesse acid as a starting material for the production of 14.2 mg of the desired compound. The melting point 262-263oC.

Elementary analysis:

Calculated: C 71,21; H 6,44; N 6,39.

Received: C 71,17; H 6,48; N 6,29.

Example 16

Obtaining TRANS-dl-8-etoxycarbonyl-ethandiyl-4-methyl - 1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-it

Connection t is 1, stages A, B, C, D, E, F and G. This compound (1.52 g, 5,17 mm) and palladium acetate (11) (12 mg, 0,052 mm), three-(o-tolyl)phosphine (64 mg, 0.28 mmol), acrylate (674 mg, 6,46 mm) and triethylamine (2.8 ml) were combined in a thick-walled tube, equipped with a magnetic plate that is coated with Teflon and mixed. The reaction mixture was heated to 100oC in a sealed tube and was kept there all night. After cooling, was added IN HCl and the solid green gently mixed with a spatula. The solids were collected by filtration and dissolved in ethanol with heating. The solution was filtered through diatomaceous earth (Celite) and were washed several times with ethanol. Volatiles were evaporated in vacuo to obtain a solid yellow residue. Recrystallization of the residue from a mixture of ethyl acetate/hexane gave 1.24 g of the desired compound in the form of loose material yellow (88% yield). The melting point of 115.5-116,5oC.

The mass spectrum with high resolution: 313,1659 C19H43NO3.

Example 17

Obtaining TRANS-dl-8-chloro-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

The desired compound was obtained in accordance with the procedures described in example 1, steps A, B, C, D, F and G using p-chlorophenols:

Calculated: C 66,24; H 5,97; N 5,94.

Received: C 66,44; H 6,17; N 6,06.

Example 18

Obtaining TRANS-dl-8-methoxy-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

The desired compound was obtained according to the procedures of example 1, steps A, B, C, D, and F, followed by recrystallization from ethyl acetate using p-methoxyphenylacetic acid as starting material to obtain 198 mg (38%) highly crystalline white material. The melting point 216-217oC.

Example 19

Obtaining TRANS-dl-8-methoxy-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

The desired compound was obtained according to the procedures described in example 1, steps A, B, C, D, F, recrystallization from ethyl acetate and then E use of p-methoxyphenylacetic acid as starting material gave 38 mg of yellow powder. The melting point of 102-103oC.

Elementary analysis:

Calculated: C 72,20; H 7,40; N 6,05.

Received: C 72,61; H To 7.59; N 5,94.

Example 20

Obtaining TRANS-dl-8-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

The desired compound was obtained according to the procedures described in example 1, steps A, B, C, D, F and G, using p-tolyloxy acid as starting material is received: C 78,39; H 8,19; N 6,27.

Example 21

Obtaining TRANS-dl-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-it

The desired compound was obtained according to the procedures described in example 1, steps A, B, C, D, and F using phenylacetic acid as a starting material to obtain 327 mg (30% yield) after four recristallization of ethyl acetate. The melting point of 227-228oC.

Elementary analysis:

Calculated: C 77,58; H 7,58; N Of 6.96.

Received: C 77,29; H 7,74; N 6,99.

Example 22

Obtaining TRANS-dl-8-ethoxycarbonylmethyl-4-methyl-1,2,3, 4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-it

The compound TRANS-dl-8-ethoxycarbonylmethyl-4-methyl - 1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-one was obtained according to the procedures described in example 16. This connection was connected (424 mg, 1,35 mm) with 50 mg of 5% palladium on charcoal in 50 ml of ethanol in a sealed reactor at room temperature and an initial pressure of 60 ft/inch2(4,21 kg/cm2). After four hours the catalyst was removed by filtration. The filtrate was concentrated in vacuum. The residue was subjected to HPLC chromatography on SiO2and elution with 5% methanol, CH2Cl2give 308 mg (72%) of the desired compound as a pale yellow oil, SUB>H25NO3.

Example 23

Obtaining TRANS-dl-8-methoxycarbonyl-ethandiyl-4-methyl-1,2,3, 4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-it

The desired compound was obtained in accordance with the procedures described in example 16, except that instead of ethyl acrylate methyl acrylate was used to obtain 1.18 g (yield 94%). Melting point 172-174oC.

Elementary analysis:

Calculated: C 72,22; H 7,07; N 4,68.

Received: C 71,97; H 7,87; N 4,72.

Example 24

Receiving, TRANS-dl-8-carboxyethyl-4-methyl-1,2,3,4,5,6, 10b-octahedrons[f]quinoline-3-it

The compound TRANS-dl-8-ethoxycarbonylmethyl-4-methyl-1, 2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one was obtained in accordance with the procedures described in example 16. To a solution of KOH (435 mg; to 7.77 mm) in a mixture of methanol and water 3:1 (V/V) was added ethyl ester (1.22 g, to 3.89 mm). The reaction mixture was heated under reflux with stirring for 1 hour. The methanol was removed in vacuo and the remaining mixture was oxidized 5N HCl. The obtained white precipitate was collected by filtration and rinsed with water. Recrystallization from ethanol gave 741 mg (yield 67%) of the desired compound as a white crystalline substance. Melting point 311oC decomp>/P>Example 25

Obtaining TRANS-dl-8-t-butylaminoethyl-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

A. TRANS-dl-8-(2-typeregelsbestand)-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one

The compound TRANS-dl-8-carboxyethyl-4-methyl-1,2,3,4, 4a,5,6,10 b-octahedrons[f]quinoline-3-one was obtained according to the procedures described in example 24. The suspension of this acid (1,99 g, 6,97 mm), triphenylphosphine (3,66 g, 13.9 mm) and 2,2'-dithiodipyridine (of 3.07 g, 13,95 mm) in 30 ml of anhydrous toluene were mixed at room temperature overnight. The reaction mixture was filtered and the precipitate was washed with 100 ml of diethyl ether and dried to obtain 2.2 g of the compound A in the form of a pale yellow substance (81%).

B. TRANS-dl-8-t-butylaminoethyl-4-methyl-1, 2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-one

To a stirred suspension of dipyridyl-ester obtained in step A above (440 mg, 1,13 mm) in dry THF (11,0 ml) was added tert-butylamine (95 ml, 9,04 mm). The reaction mixture was stirred at room temperature for 24 hours. The mixture was filtered and the solids were washed with hexane to obtain 256 mg (yield 66,5%) of the desired compound. Melting point 243-245oC decomposition.

Elementary analysis:

Rasch( s )- methyl-4-methyl-1, 2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-one

The compound TRANS-dl-8-chloro-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f] quinoline-3-one was obtained in accordance with the procedures described in example 6.

To a cold (-78oC; dry ice/isopropanol) mixed solution of TRANS-dl-8-chloro-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one (759 mg, 2,88 mm) in 45 ml of dry THF was added 17.6 ml of 0.5 M hexamethyldisilazide potassium (1.1 equivalent, 8,81 mm) in toluene dropwise. After the addition, the reaction mixture was stirred in the cold for another 45 minutes. Excess (5,0 equiv/methyliodide (2.5 ml) was added to the reaction mixture. The cooling bath was removed and the reaction mixture was vestibules to room temperature for 2 hours. The reaction was cooled cautious addition of water and the mixture is transferred into a separating funnel. To the mixture was added ethyl acetate and 1N HCl and the layers were separated. The organic layer was washed 1N HCl, once with saturated NaHCO3and then brine. The organic material was dried over magnesium sulfate and evaporated in vacuum to obtain 2,11 desired compound in the form of a yellow substance.

and the isomers were separated HPLC on silica gel using 0-75% ethyl acetate/toluene (V/V) gradient to obtain 414 mg(example 26B, the melting point of 82-83oC) as a colourless solid.

Elementary analysis:

- isomer

Calculated: C 68,30; H 6,88; N 5,31.

Received: C 68,09; H 6,93; N 5,20.

- isomer

Calculated: C 68,30; H 6,88; N 5,31.

Received: C 68,05; H Of 6.68; N 5,55.

Example 27

Obtaining TRANS-dl-8-bromo-6,6-dimethyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

4,4-Dimethyl-6-bromo-2-tetralone was obtained in accordance with the procedures described in example 1, steps A and B, except that in step B instead of ethylene was used isobutylene and that the resulting 1:1 mixture of 4,4-dimethyl and 3,3-dimethyl regioisomerism of tetralones were separated on silica gel using a 7.5% ethyl acetate/hexane gradient (V/V) to obtain the desired 4,4-dimethyl-6-bromo-2-tetralone. The desired compound was obtained from this tetralone by the procedure described in example 1, steps C, D and F and then recrystallization from ethyl acetate gave to 109.3 mg substance of white color. Melting point 281-282oC.

Elementary analysis:

Calculated: C 58,45; H Of 5.89; N 4,54.

Received: C 58,68; H 5,77; N Of 4.44.

Example 28

Obtaining TRANS-dl-8-bromo-4,6,6-trimethyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

Stratov of recristallization in ethyl acetate of TRANS-dl - 8-bromo-6,6-dimethyl-1,2,3,4,4 a,5,8,10 b-octahedrons[f] quinoline-3-one (example 27). The desired compound was prepared from this material together with CIS-dl-isomer (example 29) using the procedures described in example 1, steps E and C to obtain 67.2 per mg solid white. Melting point 133-136oC.

Elementary analysis:

Calculated: C 59,64; H Of 6.26; N 4,35.

Received: C 59,50; H 6,21; N 4,55.

Example 29

Obtaining CIS-dl-8-bromo-4,6,6-trimethyl-1,2,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

A mixture of TRANS - and CIS-dl-8-bromo-6,6-trimethyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-one was obtained by concentration of the filtrates of recristallization in ethyl acetate of TRANS-dl-8 - bromo-6,6-dimethyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one (example 27). The desired compound was obtained from this material, together with TRANS-dl-isomer (example 28) using the procedures described in example 1, steps E and C to obtain 67.2 per mg solid white. Melting point 177-180oC.

Elementary analysis:

Calculated: C 59,64; H Of 6.26; N 4,35.

Received: C 59,85; H 6,16; N 4,28.

Example 30

Obtaining TRANS-dl-8-t-butyl-1,2,3,4,4 a, 5,6,10 b - octahedrons[f]quinoline-3-it

A. 6-tert-butyl-2-naphthol

2 - liter flask with a round bottom loaded svezheraspilennaya hee t-butyl chloride (150,0 g, of 1.62 mol) dropwise over 30 minutes. When the reaction mixture was gradually heated under reflux, the solution was not obtained. The reaction mixture was cooled to room temperature and added to 100 ml of CH2Cl2. The reaction mixture was heated under reflux overnight, cooled and concentrated in vacuo to obtain the substance of white color. The solid was heated under reflux with 1800 ml of 10% NaOH was filtered, and was vestibules before cooling. The precipitated sodium salt white were collected by filtration. Substance, collected by filtration, stirred with an excess of 5.0 M HCl and the resulting phenol was collected by filtration and were washed with 2 l of water. Recrystallization from heptane gave 30,67 g of compound A in the form of a solid white color.

B. 6-t-butyl-2-methoxynaphthalene

A 2-liter flask with a round bottom was added 6-t-butyl-2-naphthol (30,67 g, 0,153 mm) and 550 ml of 15% KOH in water. The solution is stirred while adding dropwise within 30 minutes of dimethylsulfate (6,0 equiv.). After complete addition, the mixture was mixed for 2 hours. The solids were collected on the filtrate was washed with water to obtain 28,97 g (yield 88%) of compound B.

C. 6-t-butyl-2-tetralone
balls sodium (36 g, 11,5 equiv. ) 2 hours with a rate as to maintain the reflux. The viscous reaction mixture was mixed until until the sodium is not dissolved. The mixture was cooled and carefully added 140 ml of water. Was added concentrated HCl and the reaction mixture was heated under reflux for 30 minutes. After cooling, the reaction mixture was filtered and the aqueous layer was extracted three times with toluene. Evaporation of volatiles in vacuo gave to 28.1 g of a red viscous oil. The oil is extracted by 300 ml of diethyl ether was mixed with 50 ml of saturated aqueous NaHCO3the whole night. The obtained white precipitate was collected by filtration and were washed several times with hexane. This material was partially dissolved in 500 ml of H2Oh was added 200 ml of diethyl ether. The mixture is vigorously stirred and added to 300 ml of saturated aqueous Na2CO3. The mixture was mixed for 1 hour, the layers were separated and the aqueous layer was extracted three times with diethyl ether. The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuum to obtain a grade of 5.74 g of compound C as an orange oil which slowly crystallized upon maturation.

E. 8-t-butyl-1,2,3,4,5,6-hexahydrobenzo[f]quinoline-3-one

6-t-butyl-2-pyrrolidinyl-3,4-dihydronaphthalene (7,25 g, 28,37 mm) was added to 3.0 equiv. acrylamide (6,05 g; 85,11 mm). The reaction mixture was mixed with 89oC all night. Then the temperature was increased to 130oC and was maintained such 20 minutes. Caution was added water (100 ml) and the reaction mixture was cooled to room temperature. The obtained solid substance was pulverized with water in the powder was collected on a filter to obtain a brown substance. The solid was recrystallization twice from dimethylformamide (DMF) H2O to obtain a desired compound. Melting point 265-268oC decomp.

F. TRANS-dl-8-t-butyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one

To a cold (0oC) stirred solution of 8-t-butyl-1, 2,3,4,5,6-hexahydrobenzo[f]quinoline-3-one (4,00 g, 15,66 mm) and triethylsilane (7,29 g, 62,66 mm) in 90 ml) was added 24 hours. The reaction mixture was carefully poured into saturated NaHCO3, was shaken and the layers were separated. The organic layer was washed once NaHCO3were dried over sodium sulfate and concentrated in vacuum to obtain 5,86 g solid brown color. Recrystallization from ethyl acetate gave the desired compound (2.5 g, yield 62%) as a crystalline material beige color. The melting temperature of more than 280oC.

Elementary analysis:

Calculated: C 79,00; H 9,01; N, 5,44.

Received: C 79,36; H 9,16; N 5,49.

Example 31

Obtaining TRANS-dl-8-t-butyl-4-methyl-1,2,3,4,5,6 - 10b-octahedrons[f] quinoline-3-it

The desired compound was obtained in accordance with the procedures described in example 30, steps A, B, C, D, E and F and then N-methylated in accordance with the procedures described in example 1, step E, using 1,2-dimethoxyethane as solvent in the amount of 1.14 (yield 73%) solids. Melting point 183-184oC.

Elementary analysis:

Calculated: C 79,66; N 9,29; N 5,16.

Received: C 80,08; H 9,31; N 4,99.

Example 32

Obtaining TRANS-dl-8-fluorescent-4,10 b-dimethyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-it

A. 6-fluorescent-2-pyrrolidinyl-3,4-di is re 1, stages A, B and C, using as starting material p-florfenicol acid.

B. 6-fluorescent-1-methyl-2-pyrrolidinyl-3,4-dihydronaphthalene

At 6-fluorescent-2-pyrrolidinyl-3,4-dihydronaphthalene (13 g, 60,8 mm) in 200 ml dry tetrahydrofuran (THF) was added methyliodide (30 ml, 482 mm), and the mixture was heated under reflux for 2 hours. The reaction mixture was vestibules to cool with stirring, and at this time crystallization occurred. The solids were collected by filtration to obtain compound B.

C. To 6-fluorescent-1-methyl-2-pyrrolidinyl-3,4-dihydronaphthalene obtained above in step B, in 1700 ml of ethyl acetate, was added sodium acetate (10.2 g, to 124.4 mm), acetic acid (10,2 ml, 178,2 mm) and 102 ml of water. The reaction mixture was stirred at room temperature for 4 hours. The layers were separated, and the organic layer was washed successively with brine, 5% NaHCO3and again with brine. The organic layer was dried over MgSO4and concentrated to obtain 7.9 g of compound C as a dark oil orange-red color (yield 60%),

D. 8-fluorescent-10b-methyl-1,2,3,4,6, 10b-hexahydrobenzo[f]quinoline-3-one

At 6-fluorescent-3-methyl-2-tetralone (7,06 g, 39,6 mm) in a round bottom flask was added p-toluensulfonate (1,23 g, 6,5 Mona the mixture was heated up to 88-90oC in nitrogen for three days. The mixture was diluted with ethyl acetate and water, and stirred at room temperature for 1 hour. The resulting layers were separated. The organic layer were washed three times with water, dried over MgSO4and concentrated to obtain a viscous oil. The crude product is crystallized from ethyl acetate to obtain of 1.59 g (yield 17%) of compound D. the melting point of 202oC.

Elementary analysis:

Calculated: C 72,71; H 6,10; N 6,06.

Received: C 72,45; H 6,14; N 6,03.

E. 8-fluorescent-4,10 b-dimethyl-1,2,3,4,6, 10b-hexahydrobenzo[f]quinoline-3-one

8-fluorescent-10b-methyl-1,2,3,4,6, 10b-hexahydrobenzo[f]quinoline-3-one (1,38 g, 6 mm) was added to a suspension of NaH (475 mg; 20 mm) in glyme (glyme) (15 ml). The mixture was heated under reflux for 1.5 hours and rapidly cooled to room temperature. Added methyliodide (15 ml) and the mixture was heated under reflux for 4 hours, then was vestibules to cool to room temperature. After adding water, the mixture was subjected to concentration almost dry. The residue was separated between ethyl acetate and water. The organic layer were washed three times with water, dried over MgSO4and concentrated under vacuum. Recrystallization from hexane gave 737 mg (C 73,45; H TO 6.57; N 5,71.

Received: C 73,72; H 6,84; N 5,86.

F. 8-fluorescent-4,10 b-dimethyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one

Tretinoin (1 ml; 6,12 mm) was added to 8-fluorescent-4,10 b - dimethyl-1,2,3,4,6,10 b-hexahydrobenzo[f]quinoline-3-ONU (500 mg; 2,04 mm) in CH2Cl2(15 ml) at room temperature. The reaction mixture was cooled to 0oC, and to it was added triperoxonane acid (2.6 ml). After stirring at room temperature for 4 days, the reaction mixture was diluted CH2Cl2and was treated with a saturated NaHCO3. The resulting layers were separated, and the organic layer was washed with saturated NaHCO3were dried over MgSO4and concentrated under vacuum to obtain a yellow oil.

G. of TRANS-dl-8-fluorescent-4,10 b-dimethyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-one

The mixture obtained above in step F, was separated by column chromatography on SiO2(elution ethyl acetate/hexane 9:1 (: about)). The appropriate fractions containing the desired product were evaporated almost to dryness and diluted with hexane. The obtained crystals were collected by filtration to obtain 190 kg connection G. melting point 130-131oC.

Elementary analysis:

Russ-dimethyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

The desired compound was obtained along with the TRANS-dl-isomer in accordance with the procedures described in example 32, steps A-F.

The mixture obtained in example 32, step F, divided column chromatography on SiO2(elution with ethyl acetate/hexane 9:1 (about:about:)). The appropriate fractions containing the desired product were evaporated almost to dryness and diluted with hexane. The obtained crystals were collected by filtration to obtain the desired compound.

Example 34

Obtaining TRANS-dl-8-chloro-4,10 b-dimethyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

The desired compound was obtained along with the CIS-dl-isomer (example 35) in accordance with the procedures described in example 32, steps A, B, C, D, E and F using p-chlorophenylalanine acid as the starting material. Column chromatography in accordance with example 32, step G, give 523 mg of the desired compound. Melting point 94oC.

Elementary analysis:

Calculated: C 68,30; H 6,88; N 5,31.

Received: C 68,51; H 6,67; N Are 5.36.

Example 35

Obtaining CIS-dl-8-chloro-4,10 b-dimethyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-it

The desired compound was obtained together what Itanium p-chlorophenylalanine acid as the starting material. Column chromatography in accordance with example 32, step G, to give 145 mg of the desired compound.

Elementary analysis:

Calculated: C 68,30; H 6,88; N 5,31.

Received: C 68,09; H 6,76; N 5,11.

Example 36

Obtaining TRANS-dl-10b-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

A. 10b-methyl-1,2,3,4,6, 10b-hexahydrobenzo[f]quinoline-3-one

Following the procedures described in example 32, steps A, B, C and D, except using phenylacetic acid as a starting material and by using column chromatography on SiO2instead recrystallization from ethyl acetate, there was obtained the desired compound in the form of white crystalline substance. Melting point 123-124oC.

Elementary analysis:

Calculated: C 78,84; H To 7.09; N 6,57.

Received: C 78,82; H 6,95; N 6,58.

B. TRANS-dl-10b-methyl-1,2,3,4,6, 10b-octahedrons[f]quinoline-3-one

To a solution of 10b-methyl-1,2,3,4,6, 10b-hexahydrobenzo[f]quinoline-3-one (500 mg, 2.3 mm) in 50 ml of acetic acid was added 500 mg of 5% palladium on carbon. The reaction mixture is stirred overnight at room temperature under an initial hydrogen pressure of 60 pounds per square inch (4,22 kg/sq. cm). The reaction mixture was filtered and koncentrirovalisb the HCO3and water, and then dried over MgSO4and concentrated under vacuum. The residue was pulverized into powder with ether to obtain 180 mg (yield 36%) of compound B. the melting point of 178-179oC.

Elementary analysis:

Calculated: C 78,00; H Of 7.96; N 6,51.

Received: C 78,38; H 8,02; N 6,36.

Example 37

Obtaining TRANS-dl-4,10 b-dimethyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f] quinoline-3-one

Following the procedures described in example 36, was obtained TRANS - dl-10b-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one. To 4 ml of glima was added NaH (31 mg; 1,26 mm) and TRANS-dl-10b-methyl - 1,2,3,4,4 a,5,6,10 b-octahedrons[f] quinoline-3-one (130 mg, 0.6 mm). The reaction mixture was heated under reflux for 1.5 hours. After cooling to room temperature was added 10 mloC methyliodide, and the reaction mixture was heated under reflux for 3 hours. Water was added, and the mixture was concentrated almost to dryness. The residue was distributed between ethyl acetate/water. The organic layer were washed three times with water, dried over MgSO4and concentrated under vacuum. The residue was pulverized with petroleum ether to obtain 60 mg (yield 44%) of the desired compound. Melting point 93oC.

Elementary analysis:

PPO-10b-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

Following the procedures described in example 32, steps A, B, C, D, E and F, except for using p-chlorophenylalanine acid as starting material, was obtained the compound 8-chloro-10b-methyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f]quinoline-3-one as a mixture of CIS - and TRANS-isomers.

The mixture was purified HPLC (reverse phase, CN) elution THF: isooctane (48% THF by volume) to obtain 32 mg of the desired compound.

Elementary analysis:

Calculated: C 67,33; H 6,46; N 5,61.

Received: C 67,53; H 6,35; N 5,73.

Example 39

Obtaining CIS-dl-8-chloro-10b-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-it

The desired compound was obtained along with the TRANS-dl-isomer (example 38) in accordance with the procedures described in example 38. CIS-dl-isomer was obtained by purification by HPLC using the procedure described in example 38, followed by rubbing with diethyl ether.

Example 40

Obtaining TRANS - and CIS - R(-) 8-chloro-10b-methyl-1,2,3,4,4 a,5, 6,10 b-octahedrons[f]quinoline-3-it

A. 6-chloro-1-methyl-2-tetralone

Following the procedures described in example 32, steps A, B and C, except using p-chlorophenylalanine acid as ishrin

To 500 ml of toluene was added 6-chloromethyl-2-tetralone (50.0 g, 0,256 M) and (R)-(+)-1-phenylethylamine (35 ml, 0.27 M). The mixture was heated under reflux for 4 hours with azeotropic removal of water. The solvent was removed under vacuum to obtain 79 g of compound B along with its iminobis tautomerism in the form of a yellow oil which was used without further purification.

C. (5S)-5,6,7,8,9,10-hexahydro-8-hydroxy-2-chloro-5,8 - dimethyl-5,9-mechanosensation-11-he

To a stirred solution of 1-methyl-2-(- methylbenzylamino)- 6-chloro-1,2-didehydrothymidine (79 g, 0.25 M) in 500 ml of THF was added methyl vinyl ketone are (23 ml; 0,28 M). The solution was mixed at ambient temperature in an argon atmosphere in the dark for 96 hours. Was added aqueous acetic acid (20%, 500 ml) and the mixture stirred a further 2 hours. The reaction mixture is then distributed between ethyl acetate and water. The organic phase was washed with saturated NaCO3and were dried over Na2SO4. The solvent was removed under vacuum to obtain 82 g of compound C in the form of a brown oil, which was used without further purification.

D. (R) (+(8-chloro-10b-methyl-1,2,3,5,6,10 b-hexahydro-phenanthrene-3-one

To a stirred solution of ethoxide sodium poly 50oC for 3 hours in nitrogen atmosphere. The solution was cooled to ambient temperature and distributed between diethyl ether and water. The organic phase was washed with brine and dried over Na2SO4and concentrated under vacuum. The residue was purified by chromatography on SiO2(elution 25% ethyl acetate in hexane) to obtain 34 g of compound as a brown oil, zatverdevanie over time.

E. (R) 3-[1-(1-methyl-6-chloro-2-tetralone)]propanoic acid

To a stirred mixture of RuCl3nH2O (620 mg, 2,99 mm) in solvent mixture (200 ml) of 2 parts of 4-chloride of carbon, 3 parts of acetonitrile and 2 parts of water was added iodine acid (20,45 g of 89.7 mm). The mixture was cooled to 0oC, and stirred for 15 minutes. To the mixture was slowly added the desired compound from step D (3.7 g, 14,95 mm) in acetonitrile, and the mixture is stirred at 0oC for 3 hours, was added 2-propanol (20 ml) and the mixture stirred for 1 hour. Then the reaction mixture was distributed between ethyl acetate and water, and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were filtered through diatomaceous earth and the filter cake was rinsed with ethyl acetate. The solution was concentrated in vacuum and n the,3,4,6, 10b-hexahydrobenzo[f]quinoline-3-one

To a stirred solution of the desired compound from step E (1,74 g 6,457 mm) in 15 ml of 2-propanol was added ammonia (1 ml), and the tubular reactor was gerotziafas. The reaction mixture was heated to 180oC for 15 minutes. The mixture was cooled to room temperature and concentrated under vacuum to obtain a glassy solid brown color. The solid was placed in etelaat, filtered through SiO2was loirevalley with ethyl acetate to obtain compound as a light solid. A sample crystallized from diethyl ether/hexane to obtain 219 mg of compound F. the melting point 61-63oC.

Elementary analysis:

Calculated: C 67,88; H 5,70; N 5,65.

Received: C 67,54; H The 5.65; N, 5,44.

Optical rotation: 589 nm = - 40,32o/C=1, methanol 365 nm = -185,48o.

G. of 8-Chloro-10b-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one

To a stirred solution of the desired compound from step F (776 mg, 3.1 mm) and triethylsilane (of 4.95 ml, 31 mm) in CH2Cl2at 0oC was added triperoxonane acid (4,82 ml; 6,26 mm). The solution was slowly heated to room temperature and stirred for 48 hours. The reaction was Sesrovires under vacuum to obtain 790 mg of the crude product, including a connection G.

H. TRANS-8-chloro-10b-methyl-1,2,3,4,4 a, 5,6, 10-octahedrons[f]quinoline-3-one

Chromatography on SiO2(ethyl acetate as eluent) of the crude product on stage G give 341 mg of compound H. the melting point of 135-137oC.

Elementary analysis:

Calculated: C 67,33; H 6,46; N 5,61.

Received: C 67,41; H 6,55; N Are 5.36.

Optical rotation: 589 nm = +113,86o. (C = 1, CHCl3) 365 nm = +371,29o.

Example 41

Obtaining CIS-8-chloro-10b-methyl-1,2,3,4,4 a, 5,6, 10-octahedrons[f] quinoline-3-one

The desired compound was obtained along with TRANS-isomer (example 40) using the procedures described in example 40, steps A-G. Chromatography on SiO2(ethyl acetate as eluent) of the crude product from example 40, step G, gave 91 mg of the desired compound. Melting point 178 - 181oC.

Elementary analysis:

Calculated: C 67,33; H 6,46; N 5,61.

Received: C 66,73; H Of 6.73; N Are 5.36.

Optical rotation: 589 nm = +199,10o< / BR>
(C = 1, CHCl3) 365 nm = +660,63o.

Example 42

Obtain TRANS-4-ethyl-10b-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f] quinoline-3-it

Following the procedures described in example 40, steps A, B, C, D, E and F, use them instead of ethylene glycol in step 7, was the compound obtained 4-ethyl-10b-methyl-1,2,3,4,6,10 b-hexahydrobenzo[f] quinoline-3-one. This hexahydrobenzo[f]quinoline-3-one was subjected to hydrogenation using procedures described in example 22, except that the reaction was conducted at 70oC over 7 hours to obtain a crude reaction mixture. The reaction mixture was filtered, and the solvents were evaporated under vacuum to obtain a glassy solid residue. The crude product was purified by chromatography on SiO2/gradient elution from 100% hexanol to 100% CHCl3/ to obtain 92 mg of the desired compound as a colourless oil.

Elementary analysis:

Calculated: C 78,97; H To 8.70; N 5,76.

Received: C 79,07; H 8,90; N 5,56.

Example 43

Obtain TRANS-4-n-butyl-10b-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

Following the procedures described in example 40, steps A, B, C, D, E and F, using phenylacetic acid as a starting material and in step F using n-butylamine instead of ammonia and dimethoxyethane instead of ethylene glycol, there was obtained compound 4-n-butyl-10b-methyl-1,2,3,4, 6,10 b-hexahydrobenzo[f] quinoline-3-one. This hexahydrobenzo[f]quinoline-3-one was subjected to hydrogenation using procedures apicontext with the procedures described in example 42 to obtain 61 mg of the desired compound as a colourless oil.

Elementary analysis:

Calculated: C 77,10; H 9,35; N 5,00.

Received: C 77,44; H 9.28 Are; N 4,95.

Example 44

Obtain TRANS-4-(4-methoxybenzyl-8-chloro-10b-methyl-1,2, 3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-it

A. (R) 3-[1-(1-methyl-6-chloro-2-tetralone)]propanoic acid

Following the procedures described in example 40, steps A, B, C, D, E, using n-chlorophenylacetic acid as starting material, was obtained the compound 3-[(methyl-6-chloro-2-tetralone)]-propanoic acid.

B. 4-(4-methoxybenzyl)-8-chloro-10b-methyl-1,2,3,4,6, 10b-hexahydrobenzo[f]quinoline-3-one

To 40 ml of dimethoxyethane was added 3-[1-(1-methyl-6 - chloro-2-tetralone)] -propanoic acid (2 g) and p-methoxybenzylamine (5 ml) in a tightly closed tubular reactor. The solution was heated at 120oC during the night. After maturation of the reaction mixture to cool to room temperature, the solvent was removed under vacuum. The residue was dissolved in CHCl3were washed successively 1N HCl, water, saturated NaHCO3and brine. The organic base was dried over Na2SO4and concentrated under vacuum. The rest of podvergalssya B in the form of butter.

C. TRANS-4-(4-methoxybenzyl)-8-chloro-10b-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-one

To a stirred solution of the desired compound from step B (693 mg) in CH2Cl2(2.5 ml) under nitrogen atmosphere was added triethylsilane (1,4 ml). The reaction mixture is stirred for 15 minutes. To the solution was added 1.5 ml triperoxonane acid, and the reaction mixture stirred at room temperature overnight. The reaction mixture was distributed between CHCl3and saturated NaHCO3. The organic phase was dried over NaSO4, and the solvent was removed in vacuum. The residue was purified by chromatography on SiO2, (25% ethyl acetate in hexane as eluent). Productstream fractions were evaporated under vacuum to obtain compound C in the form of foam (459 mg). Melting point 55-60oC.

Elementary analysis:

Calculated: (+1/2 M H2O) C 69,74; H OF 6.65; N 3,70.

Received: C 70,27; H Of 6.49; N 3,68.

Example 45

Obtain TRANS-4-methyl-10b-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-it

Following the procedures described in example 40, steps A, B, C, D, E and F, using phenylacetic acid as a starting material and in step F, using methylamine instead of ammonia and diglyme hexahydrobenzo[f]quinoline-3-one was subjected to hydrogenation using procedures described in example 22, except that the reaction was conducted at 60oC over 7 hours. The reaction mixture was filtered, and the solvent was evaporated under vacuum. The residue was purified by chromatography on SiO2(CHCl3as eluent) followed by recrystallization from ethyl acetate/hexanol to obtain 154 mg of the desired compound. Temperature 111 - 113oC.

Elementary analysis:

Calculated: C 78,56; H 8,56; N 6,11.

Received: C 78,33; H 8,62; N 6,14.

Example 46

Obtaining TRANS-dl-9-nitro-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

The compound TRANS-dl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one was obtained in accordance with the procedures described in example 21. To this compound (8.0 g; 39,75 mm) in 320 ml of a mixture 1:1 (about:) glacial acetic acid and concentrated sulfuric acid at 0oC was added 1.4 equivalent of 90% fuming nitric acid in amounts that would not allow the temperature to rise above 10oC. the Mixture is stirred for 30 minutes at 0oC and then poured on ice. The obtained solid substance was collected by filtration and was recrystallizations from a mixture of DMF/water to yield of 5.40 g (55%) of the desired compound in the form of a solid yellow color. Those/P> Received: C 63,61; H 5,97; N Is 11.39.

Example 47

Obtaining TRANS-dl-9-nitro-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-it

The compound TRANS-dl-4-methyl-1,2,3,4,4 a, 5,6,10 b - octahedrons[f]quinoline-3-one was obtained in accordance with the procedures described in example 12. The desired compound was obtained in accordance with the procedure described in example 46 using TRANS-dl-4-methyl-1,2,3,4,4 a,5,6,10 b-octahedrons[f]quinoline-3-one as starting material, except that the reaction was cooled with water and the product was recrystallizes from ethyl acetate/hexanol. The melting point 172-172,5oC.

Elementary analysis:

Calculated: C 64,60; H 6,20; N 10,76.

Received: C 64,80; H 6,34; N 10,85.

Example 48

Obtaining TRANS-dl-9-amino-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-it

The compound TRANS-dl-9-nitro-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f] quinoline-3-one was obtained according to the procedure described in example 47. This compound (700 mg, 2,69 mmol) was dissolved in 100 ml of ethanol was added 100 mg of 10% palladium on coal. The reaction mixture was first made for 1 hour under hydrogen pressure 2.95 kg/cm (42 l/square inch). The mixture was filtered and the filtrate was concentrated in vacuum to obtain Svenja 308 mg of the target compound as white solid. Melting point 213-214,5oC.

Elementary analysis:

Calculated: C 73,01; H 7,88; N 12,16.

Received: C 73,22; H 8,02; N 12,20.

Example 49

Obtaining TRANS-dl-9-chloro-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-it

The compound TRANS-dl-9-amino-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f] quinoline-3-one was obtained in accordance with the procedures described in example 48. At 0oC to a solution of this compound (74 mg; 0,321 mm) in 0.3 ml of concentrated HCl was added sodium nitrite (23 mg; 0,324 mm) in 0.15 ml of water. The reaction mixture was stirred at 0oC in 30 minutes and was then added at a temperature of 0oC to a solution of chloride of copper (1) (35 mg; 0,353 mm) in 0.2 ml of concentrated HCl. The reaction mixture was vestibules to warming to room temperature over 2.5 hours, then 30 minutes was heated to 60oC. After cooling, the mixture was distributed between CHCl3and saturated NaCl. The organic layer was dried over Na2SO4and concentrated in vacuo to obtain 65 mg of solid material. The desired compound was obtained as a solid white color after instant chromatography on SiO2(10% isopropanol/ethyl acetate). Melting point 228-230oC.

E is
Obtaining TRANS-dl-8-chloro-3,4,4 a, 5,6, 10b-hexahydrobenzo[f]quinoline-3-one and TRANS-dl-8-chloro-2,3,4,4 a,5,6 hexahydrobenzo[f]quinoline-3-it

A. TRANS-dl-4-t-butyloxycarbonyl-3-chloro-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one

The compound TRANS-dl-3-chloro-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one was obtained in accordance with the procedures described in example 17. To this compound (1.56 g; 6,62 mm) in 40 ml of anhydrous 1,2-dimethoxyethane (1,2-DME) was added 380 mg of sodium hydride as a 60% dispersion in mineral oil. The mixture was heated under reflux for 1 hour in nitrogen atmosphere, then cooled to room temperature. Was added a solution of di-t-butyl dicarbonate (1,74 g; 7,94 mm) in 10 ml of anhydrous 1,2-DME, and the mixture was heated under reflux for another 1 hour. The mixture then was cooled, and to it was carefully added water and then diethyl ether. The layers were separated, and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with saturated NaCl, dried over Na2SO4and concentrated to obtain a semi-solid substances orange color, which was purified column chromatography (SiO21:1 ethyl acetate/hexane) to yield 1.2 g (54%) of compound A in the form of a solid white flowe
Protective lactam obtained in step A (1.2 g; to 3.58 mm) in 20 ml of anhydrous THF at - 78oC was added dropwise a 0.5 M solution hexamethyldisilazide (14,3 ml, 7,16 mm) in toluene. After maturation for 1 hour at -78oC was added a solution of fenilcetonuria (755 mg; 3,94 mm) in 5 ml of anhydrous THF. The reaction mixture was vestibules before warming up to room temperature and stirred for 2 hours, then cooled and 5 ml of saturated NH4Cl. The mixture was distributed between saturated NH4Cl and ethyl acetate. The organic layers were dried over PA2SO4and concentrated in vacuo to obtain 2,197 g of compound B in the form of an orange oil.

C. TRANS-dl-4-t-butyloxycarbonyl-8-chloro-3,4,4 a, 5,6,10 b-hexahydrobenzo[f] quinoline-3-one and TRANS-dl-4-t-butyloxycarbonyl-8-chloro-2,3,4,4 a,5, 6 hexahydrobenzo[f]quinoline-3-one

To a solution of selenide obtained above in step B (2,197 g, 4,48 mm) in 20 ml THF at 0oC and buffer containing excess solid NaHCO3, was added 1.2 equivalent of 30% hydrogen peroxide (610 mg) in 4 ml of THF. After 30 minutes the reaction mixture was distributed between water and ethyl acetate. The organic layer was washed with saturated NaHCO3were dried over PA2SO4and conc is the axis using column chromatography over with a mixture of 2:1 hexanol/ethyl acetate. Olefin1,2was obtained in the form of 293 mg solid white color (example 50A). The more polar isomer of olefin10B,1was obtained in the form of 149 mg solid white color (example 50B).

D. TRANS-dl-8-chloro-3,4,4 a, 5,6, 10b-hexahydrobenzo[f] quinoline-3-one and dl-8-chloro-2,3,4,4 a,5,6 hexahydrobenzo[f]quinoline-3-one

To a solution of protective olefin1,2obtained in stage C (290 mg, 0,869 mm) in 20 ml of CH2Cl2added triperoxonane acid (0,14 ml of 1.74 mm). The reaction mixture was stirred at room temperature for one hour and is then distributed between CH2Cl2and saturated NaHCO3. The organic layer was dried over Na2SO4and concentrated in vacuum. The resulting crude product was recrystallizes from ethyl acetate to obtain 142 mg (70%) of white crystalline TRANS-dl-8-chloro-3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one (example 50A). Melting point 227-228oC.

Elementary analysis:

Calculated: C, 66.81; H, 5.18; N, 5.99.

Obtained: C, 67.09; H, 5.18; N, 6.22.

Protective olefin 1,10 B(149 mg, 0.446 mm) were processed as described above for the protective olefin1,2with the exception that the crude product was purified column chromatography on SiOAgogo substance of white color.

Melting point 241 to 243oC.

Elementary analysis:

Calculated: C, 66.81; H, 5.18; N, 5.99.

The Obtained C, 67.06; H, 5.35; N, 5.93.

Example 51

Obtaining TRANS-dl-8-bromo-4-methyl-3,4,4 a,5,6, 10b-hexahydrobenzo[f]quinoline-3-it

TRANS-dl-8-bromo-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one was obtained in accordance with the procedures described in example 1. This compound was converted into the desired compound in accordance with the procedures described in example 50, stages B and C, followed by recrystallization from ethyl acetate/hexanol. The melting point of 136-138oC.

Elementary analysis:

Calculated: C 57,55; H A 4.83; N 4,79.

Received: C 57,81; H 4,74; N 4,81.

Example 52

Obtaining TRANS-dl-8-chloro-4-methyl-3,4,4 a, 5,6, 10b-hexahydrobenzo[f] quinoline-3-it

TRANS-dl-8-chloro-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one was obtained in accordance with the procedures described in example 6. This compound was converted into the desired compound in accordance with the procedures described in example 50, step B, and C, followed by column chromatography on SiO2(ethyl acetate). Melting point 124-125oC.

Elementary analysis:

Calculated: C 67,88; H 5,70; N is ebenso[f]quinoline-3-it

TRANS-dl-8-chloro-4-methyl-3,4,4 a, 5,6, 10b-hexahydrobenzo[f]quinoline-3-one was obtained in accordance with the procedures described in example 52. To this compound (250 mg, 1 mm) in 30 ml anhydrous THF was added 800 mg (6.8 mm) pyridine hydrochloride. The reaction mixture was stirred at room temperature for 7 days and then was distributed between ethyl acetate and 1N HCl. The organic layer was washed 1N HCl, water, then dried over MgSO4and concentrated in vacuo to a volume of 10 ml of the Desired compound was crystallized from this solution and was collected by filtration. Melting point 99oC.

Elementary analysis:

Calculated: C 68,16; H 5,31; N 5,67.

Received: C 67,95; H 4,48; N 5,64.

Example 54

Obtaining TRANS-dl-8-chloro-2-(a-methyl-4-methyl-1,2,3,4,4-a, 10b-hexahydrobenzo[f]quinoline-3-it

A mixture of TRANS-dl-8-chloro-2-(a and b)-methyl-4-methyl-1,2,3, 4,4 a,5,6,10 b-octahedrons[f] quinoline-3-ones were obtained in accordance with the procedure described in example 26. To a solution of this mixture (759 mg, 2,88 mm) at -78oC in 15 ml of anhydrous THF in the presence of 2.0 equivalents hexamethylphosphorotriamide (HMPA) was added to 11.6 ml of 0.5 M solution hexamethyldisilazide potassium (5,76 mm) in toluene. The reaction mixture was stirred at-what was taiwanse to warm to room temperature over 2 hours, cooled saturated solution of NH4Cl, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated NH4Cl, dried over Na2SO4and concentrated in vacuo to obtain 1.42 g of brown oil. The crude product was purified column chromatography on SiO2(ethyl acetate) to obtain 252 mg of 6-fenilalanina. To a solution of selenide in 10 ml of THF was added 100 mg NaHCO3and about 1.1 equivalent of 3-chloroperoxybenzoic acid (m-HPBC) (142 mg of 80-85% m-HPBC, 658-700 mm). After 15 minutes the reaction mixture was distributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated solution of NaHCO3were dried over Na2SO4and concentrated in vacuum. The crude oil thus obtained was purified instant chromatography on SiO2(70% ethyl acetate/hexane) to yield 114 mg of the desired compound in the form of a solid white color.

1N-Yarm analysis showed that there were5,6olefin and that the 2-methyl group is in the alpha position. Melting point 130-132oC.

Elementary analysis:

RAS is aminocarbonylmethyl - 4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

The compound TRANS-dl-8-t-butylaminoethyl-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one was obtained in accordance with the procedures described in example 25. To a solution of this compound (122 mg, 0,358 mm) in 150 ml of anhydrous ethanol was added 15 mg of 10% palladium on carbon. The mixture was subjected to hydrogenation at room temperature for 6 hours under an initial hydrogen pressure of 40 ft/sq. inch (2,81 kg/sq. cm). The catalyst was removed by filtration through diatomaceous earth (Celite), and the filtrate was concentrated to obtain a solid white color. Proton NMR spectroscopy showed that the reaction had not yet been completed and therefore, the material was again placed in the same reaction conditions for an additional 6 hours. Purification of the obtained solid substance was performed using column chromatography on SiO2(20% isopropanol/ethyl acetate) to obtain the desired compound in the form of a solid white color. The melting point of 178-179oC.

Elementary analysis:

Calculated: C To 73.65; H 8,83; N 8,18.

Received: C 73,21; H 8,69; N 8,32.

Example 56

Obtaining TRANS-dl-8-phenyl-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-it

what abrami, described in example 1. To a mixture of this compound (160 mg, 0,54 mm) and tetranitroaniline palladium (0) (19 mg, 0.02 mm) in 1.2 ml of toluene in a nitrogen atmosphere was added 0.6 ml of 2 M aqueous solution of Na2CO3and then phenylboric acid (80 mg, 0,653 mm). The reaction mixture was heated for 18 hours at 80oC. the Mixture was vestibules to cool and is then distributed between 75 ml of CH2Cl2(75 ml) and 25 ml of 2 M aqueous Na2CO3add 2 ml of concentrated NH4OH. The organic layer was dried over MgSO4and concentrated to obtain a solid substance. The desired compound (106 mg, 67%) as a crystalline solid white color was obtained after carrying out the instant chromatography on SiO2(5% isopropanol/ CHCl3) and trituration of the product with hexane. Melting point 186,5-137,5oC.

Elementary analysis:

Calculated: C 82,44; H 7,26; N 4,81.

Received: C 82,38; H 7,12; N 5,08.

Example 57

Obtaining TRANS-dl-8-vinyl-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-it

The compound TRANS-dl-8-bromo-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f] quinoline-3-one was obtained in accordance with the procedures described in example 1. The tube with the stopper phoneslimited (1,24 ml, 4,25 mm) and 5 ml of anhydrous dioxane. Within 15 minutes through a mixture of argon was passed. The reaction tube was backed up and was heated with stirring at 100oC 18 hours. The reaction mixture was cooled and filtered through diatomaceous earth (Celite) . The filtrate was concentrated in vacuo, and the resulting material was analyzed by capillary gas-chromatography (G. H.), who found in him a mixture of 4.7 to 1 of the desired product to the original material. Column chromatography of this mixture on SiO2(7% methanol/CHCl3) gave the desired compound in the form of 212 mg solid white. Melting point 89-90oC.

Elementary analysis:

Calculated: C 79,63; H 7,94; N 5,80.

Received: C 79,39; H 7,98; N 5,56.

Example 58

Obtaining TRANS-dl-8-etoxycarbonyl-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

The compound TRANS-dl-8-iodide-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-one was obtained in accordance with the procedures described in example 3. To a solution of iodide (1,0034 g, 2,94 mm) in 280 ml of ethanol was added tetranitroaniline palladium (11) chloride (160 mg) and 1.0 ml of triethylamine. A mixture of 30 minutes was flushed with nitrogen, and then carbon monoxide. The reaction mixture was sybaseserver (Celite), the filtrate was concentrated in vacuo to obtain a viscous orange oil. Proton NMR spectroscopy showed that the reaction was not completed. The oil was placed in the conditions described above for an additional 48 hours. Capillary gas chromatography showed that the reaction was completed by 85%. The resulting material was purified column chromatography on SiO2, (10% methanol/CHCl3), and then HPLC on a CN column reverse phase to obtain 122 mg of the desired compound. Melting point 140-140.5oC.

Elementary analysis:

Calculated: C 71,06; H 7,37; N 4,87.

Received: C 70,97; H 7,17; N 4,60.

Example 59

Receive (R) (+)-TRANS-4-methyl-3-chloro-10b-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-it

Following the procedures described in example 40, steps A, B, C, D, E and F using p-chlorophenylalanine acid as starting material in step F, using methylamine instead of ammonia and 2-propanol instead of ethylene glycol, there was obtained compound (R) - (+)- 4-methyl-8-chloro-10b-methyl-1,2,3,4,6, 10b-hexahydrobenzo[f] quinoline-3-one. This hexahydrobenzo[f]quinoline was restored in accordance with the procedure described in example 40. step G. the Crude product was purified by chromatography n is devusheka over time. The melting point of 60-61oC.

Elementary analysis:

Calculated: C 68,30; H 6,88; N 5,31.

Received: C 68,14; H 6,94; N 5,27.

Optical rotation: 589 nm= +76,16o< / BR>
(C = 1, CHCl3)

Example 60

Receive (R) (+)-TRANS-4-methyl-8-chloro-10b-methyl-3,4,4 a,5,6, 10b-hexahydrobenzo[f]quinoline-3-it

Following the procedures described in example 59 was obtained compound (R) - (+)- TRANS-4-methyl-8-chloro-10b-methyl-1,2,3,4, 4a, 5,6,10 b-octahedrons[f] quinoline-3-one in the form of a mixture (4:1 TRANS:CIS) the CIS-isomer. Stirred, cooled (-78oC) a solution of 1.4 g (5.56mm) this mixture in THF (25 ml) was treated with hexamethyldisilazide potassium (12,2 ml; 6,12 mm), its solution in toluene. The solution was mixed for 30 minutes and treated with a solution of fenilcetonuria (1,17 g 6,117 mm) in 5 ml of THF. The solution was warmed to ambient temperature over 1 hour and then cooled to 20 ml of a saturated solution of NH4Cl. The mixture was distributed between ethyl acetate and water, and the aqueous phase was dried over Na2SO4and concentrated to obtain diastereomeric mixture of phenylseleno. Untreated phenylsilane was dissolved in 10 ml of ethyl acetate and cooled to 0oC. To the solution was added a saturated solution of NaHCO3(was 2 hours. The mixture was extracted with ethyl acetate, and the residue was subjected to chromatography on SiO2(ethyl acetate as eluent) to obtain 611 mg of the desired compound in the form of a solid waxy substance. Melting point 45-48oC.

Elementary analysis:

Calculated: C 68,83; H 6,16; N 5,35.

Received: C 69,26; H 6,48; N 5,08.

Optical rotation: 589 nm = +87,38o< / BR>
(C = 1, CHCl3)

Example 61

Receive (R) (+)-TRANS-8-chloro-10b-methyl-3,4,4 a, 5,6, 10b-hexahydrobenzo[f]quinoline-3-it

Using the procedures described in example 40, steps A, B, C, D, E, F and G, was obtained the compound (R) - (+)- 8-chloro-10b-methyl-1,2,3,4,4 a,5,6, 10 octahedrons[f] quinoline-3-one in the form of a mixture (4:1) TRANS - and CIS-isomers. A mixture of 1.02 g; 4,07 mm) was dissolved in 15 ml Dilana and processed by dichlorodicyanoquinone (1,02 g; 4,45 mm), followed by bis (trimethylsilyl)trifurcation (4.8 ml; 17,9 mm). The solution was mixed at ambient temperature for 4 hours and then was heated to 100oC for 14 hours. The reaction mixture was cooled to ambient temperature and was distributed between ethyl acetate and water. The organic phase was concentrated in vacuo, and the residue was subjected to chromatography on SiO2(ethyl acetate in cachemira to obtain 60 mg of the desired compound as a light solid. Melting point 151-154oC.

Elementary analysis:

Calculated: +1/2 M H2O C 65,50; H OF 5.89; N 5,46.

Received: C 65,67; H The 6.06; N 5,40.

Optical rotation: 589 nm = +51,33o< / BR>
(C = 1, CHCl3) 365 nm = -85,55o< / BR>
Example 62

Obtaining TRANS-dl-8-trifluromethyl-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-it

TRANS-dl-8-bromo-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one was obtained in accordance with the procedures described in example 1. A mixture of bromide (1.2 g, 4.1 mm), triptoreline sodium (2,22 g of 16.3 mm) and copper iodide (1.55 g, 8,1 mm) in 25 ml of N-methyl-2-pyrrolidinone was heated at 180oC 18 hours in an argon atmosphere. After cooling, the mixture was filtered through silica gel, and silikagelevye tube was rinsed with ethyl acetate. The combined organic layers twice rinsed with water and once with brine, dried over MgSO4and evaporated in vacuo to obtain 1,14 g of dark oil, crystallized in time. The crude product was purified using instant chromatography on silica gel (ethyl acetate), followed by reverse-phase chromatography (1:1 water/acetonitrile) to obtain 312 mg solid white (yield 27%).

The mass spectrum with high Ronnie (+)-(4aR)-(10bR)-8-chloro-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-it

A. (S)-(-)-8-chloro-4-( -methylbenzyl)-1,2,3,4,5,6-hexahydrobenzo[f] quinoline-3-one

< / BR>
To a stirred solution of 6-chloro-2-tetralone (1.0 EQ., 100,0 mm, 18,06 g) in toluene (300 ml) was added (S) - ( -) - methylbenzylamine (1.0 EQ., 100,0 mm, 12.9 ml). The mixture was heated under reflux for 3 hours with azeotropic removal of water (Dean-Stark). The cooled reaction mixture was concentrated in vacuo to obtain enamine, (S)-6-chloro-2-(-methylbenzyl)-3,4 - dihydronaphthalene in the form of oil Magenta. The oil was placed in chloroform (150 ml) and thereto was added saturated aqueous sodium bicarbonate. Thoroughly mixed and the mixture was treated with akriloilkhlorida (of 1.05 EQ; 105,0 mm, 8.5 ml) added dropwise over 5 minutes. The reaction mixture was pomescyalas at ambient temperature for 20 minutes, then was diluted with chloroform, and the layers were separated. The aqueous layer was extracted with chloroform (1x). The combined organic layers were washed with brine (1x), dried (Na2SO4) and concentrated in vacuo to obtain of 37.9 g of a dark oil. The crude oil was subjected to HPLC on silica gel (gradient elution with hexane increased to 25% ethyl acetate/hexanol) for receipt of 19.03 g butter purple CEE what Etat/hexane) to obtain 17,96 g /53% output/ desired compound as a brown glassy substance, which was homogeneous according to HPLC (reverse phase, C18mobile phase: 60% acetonitrile/ 0.5% aqueous buffer of ammonium acetate), thin-layer chromatography (silica gel, Rf= of ~ 0.5, with 40% ethyl acetate/hexane), and 300 MHz

1H NMR analysis. FDMS: m/e = 337.[D]589 = - 24,75 (C=1,0, CHCl3).

B. (-)-(4aR)-(10bR)-8-chloro-4-(S-- methylbenzyl)- 1,2,3,4,4 a,5,6,10 b-octahedrons[f]quinoline-3-one

< / BR>
Mixed solution (12.0 g; 35.4 mm) of the product from stage And in 96% formic acid (175 ml) was treated with solid cyanoborohydride sodium (2.0 EQ. , 70,98 mm, 4,46 g) every hour for 5 hours (a total of 10.EQ., 354,9 mm, 22,3 g). The mixture is stirred overnight (14 hours) at ambient temperature. The reaction mixture was concentrated to a paste light yellow color, which was placed in dichloromethane and was washed 1N sodium hydroxide (1x). The aqueous layer was back extracted with dichloromethane (2x). The combined organic layers were washed with brine (1x), dried (Na2SO4) and concentrated in vacuo to obtain 12.0 g of colorless foam. Preliminary HPLC of the residue on silica gel (gradient elution with dichloromethane - 1% ethyl acetate/dichloromethane) and the United factions that were more than 90% Diaz is brata phase, C18, 230 nm, the mobile phase; 60% acetonitrile /40% 0,5% buffer ammonium acetate). Recrystallization of the solid substance from ethyl acetate gave the desired compound in diastereomeric pure form in the form of colorless needles (more than 99: 1 diastereomeric purity according to HPLC analysis). Fractions enriched in the desired compound were combined and concentrated in vacuo to obtain 3.0 g of colorless foam. Fractionally crystallization of this material from ethyl acetate (3 crystallization) gave additional 370 mg of pure desired compound, 2.50 g, yield 21%. Melting point 176-177oC. FDMS: me = 339. [D]589= -126,63 (C = 1,0, CHCl3). The complete configuration of the desired compound was identified

Theoretical C 74,21; H Of 6.52; N 4,12.

Obtained 74,07; N 6,59; N Of 4.04.

C. (+)-(4aR)-(10bR)-8-chloro-1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-one

< / BR>
A mixture of the product from step B (1.0 EQ., 4.09 to mm, 1.39 g) and triperoxonane acid (35 ml) was placed in a round bottom flask. The stirred mixture was heated under reflux for 2 hours. The cooled reaction mixture was concentrated in vacuo, was placed in dichloromethane and washed with saturated aqueous sodium bicarbonate solution (1x). The layers were separated, and the aqueous layer was back extragear>
) and concentrated in vacuo to obtain a solid white color. Recrystallization from ethyl acetate gave 0,81 g, yield 84% of the desired compound as colorless needles. Melting point 241,5-242oC. FDMS: me = 235. [D]589= 32,61 (C = 1,0, THF)

Theoretical C 66,24; H Of 5.99; N 5,94.

Obtained 66,35; N 6,10; N Of 5.83.

Example 64

(-)-(4AR)-(10bR)-8-chloro-1-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f] quinoline-3-one

< / BR>
To a stirred solution of the product from step C of example 63 (1.0 EQ., in 0.288 mm, 98 mg) in dry 1,2-dimethoxyethane (5 ml) was added 60% (weight/weight) dispersion of sodium hydride (26 mg) in oil. The mixture was heated under reflux in a nitrogen atmosphere with stirring for 1 hour, cooled and treated with methyliodide (5.0 EQ., 1,44 mm, and 0.09 ml). The mixture was heated under reflux for another 1.5 hours. The cooled reaction mixture was cooled water (1 ml) and was extracted with dichloromethane (3x). The combined organic layers were washed with brine (1x), dried (Na2SO4) and concentrated in vacuo to obtain orange oil. Preliminary thin layer chromatography on silica gel (2 mm plate, ethyl acetate) gave 50 mg, yield 69% colorless solid. The temperature of the melt is.0999.

Example 65

Obtain (+)-(4aS)-(10bS)-8-chloro-4-(methyl)-1,2,3,4,4 a, 5, 6,10 b-octahedrons[f]quinoline-3-it

A. (+)-(4aS)-(10bS)-8-chloro-4-(S-- methylbenzyl)- 1,2,3,4,4 a,5,6,10 b-octahedrons[f]quinoline-3-one

< / BR>
The mixed solution of the product from step A, example 63, 96% formic acid (20 ml) was treated with cyanoborohydride sodium in portions over 8 hours (30 EQ. , 88,8 mm, of 6.68 g) at ambient temperature. The mixture then was heated at 50oC for 2 hours. The cooled reaction mixture was concentrated in vacuo to obtain a colorless foam. The residue was placed in dichloromethane and was washed with water (1x). The aqueous layer was back extracted with dichloromethane (2x). The combined organic extracts were washed 1N sodium hydroxide (1x), brine (1x), dried (Na2SO4) and concentrated in vacuo to obtain a colorless foam. Liquid chromatography (medium pressure silica gel (elution) with 10% ethyl acetate/dichloromethane) gave 201 mg of the product from step B of example 63. Further elution gave 129 mg of the desired compound as a colourless solid, yield 13%. HPLC analysis of this material (reverse phase, C18, 230 nm, 60% acetonitrile/ 40% 0.5% aqueous buffer of ammonium acetate) revealed that the material was more than 99% Diaz is/BR> The mixed solution of the product from step A (1.0 EQ., 0,359 mm, 122 mg) in triperoxonane acid (6 ml) was heated under reflux for 1.5 hours. The cooled reaction mixture was concentrated in vacuo to yield solid yellow color, which was placed in dichloromethane and was washed with a saturated solution of sodium carbonate (1x). The aqueous layer was back extracted with dichloromethane (1x). The combined organic extracts were washed with brine (1x), dried (Na2SO4) and concentrated in vacuo to obtain (-)-(4aS)-(10bS)-8-chloro-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one as a pale yellow solid. The residue was dissolved in dry 1,2-dimethoxyethane (5 ml) and treated with sodium hydride (19 mg, 60% dispersion in mineral oil, washed 3x with pentane). The mixture was heated under reflux for 1.5 hours, cooled and treated with methyliodide (5.0 EQ., 1,80 mm, 0.2 ml). The reaction mixture was heated for another 1.5 hours. The cooled reaction mixture was cooled with water and extracted with dichloromethane (3x). The combined organic extracts were washed with brine (1x), dried (Na2SO4) and concentrated in vacuo to obtain orange oil. Preliminary thin layer chromatography the matter. The melting temperature for 71.5-73oC. [D]589= = + 79,00 (C = 1.0 in CHCl3). HRMS(FAB+): Calculated for C14H17NOCl: 250,0999. Received 250,1002.

In the examples 66-69 uses the following abbreviations "A HPLC": 40% acetonitrile in water and 0.5% ammonium acetate on a Waters Nova-pak C-8at 220 nm, in a 2.00 ml/min, 25oC. the HPLC System B": 50% acetonitrile in water and 0.5% ammonium acetate in Dupont BondC-18 at 220 nm, in a 2.00 ml/min, 25oC. System C HPLC": 10% isopropyl alcohol in hexane at Chiralel ODat 254 nm, at 1,00 ml/min and 25oC.

"HPLC system D": 10% isopropyl alcohol in hexane at Chiralel ODat 220 nm, in a 2.00 ml/min and 40oC.

Example 66.

Obtain (+)-(4aR)-(10bR)-4-methyl-8-chloro-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

< / BR>
A. salt of di-p-toluylene acid 1-(2-methoxycarbonylethyl)- 2-(methylamino-6-chloro)-1,2,3,4-tetrahydronaphthalene.

A solution of TRANS - (d, l)-4-methyl-8-chloro-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-one (1.5 g) obtained mainly from example 6 in methanol (30 ml) with concentrated sulfuric acid (3.5 g) was heated under reflux 144 hours. The solution was concentrated to approximately 20 ml and was diluted with ether (50 ml), water (100 ml) (100 ml) and methylene chloride (100 ml). The combined organic phases were dried with 4 A molecular sieves was added to a solution of the monohydrate of (-)-p-toluoyl-L-tartaric acid (DTC) (2.00 g) in methanol (10 ml). All volatile compounds were removed under vacuum, and the resulting foam was dissolved in approximately 40 ml of methanol. The solids were filtered and dried to obtain 1.01 g (theoretically 50%) of salt, mixed with 6.3% of non-hydrolyzed TRANS-dl-8-chloro-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one. Melting point 126-130oC.

TLC (silica gel with toluene-ethyl acetate-acetic acid - methanol 7: 4:1:4: Rf= 0,34)

HPLC (system A): tr (min): 0,48 (43% DTC), tr = 1,33 (53% free aminoester), tr = 3,36 (3,15%, racemate).

HPLC (system B): tr (min) 1,06 (48,1%, DTC), 2,77 (1,2%, unknown), to 3.73 (46,1% free aminoester), 5,54 (4.5 per cent (required connection).

1H NMR (CDCl3): 5,43 (s, 2H), only 3.57 (s, 3H), of 2.38 (s, 6H), UV (methanol): (): 276 (30,100).

IR (CHCl3): 1723 cm-1.

B. (+)-(4aR)-(10bR)-4-methyl-8-chloro-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-one

A solution of the above salt DTC (100 mg) was mixed with toluene (5 ml), water (10 ml) and sodium bicarbonate (50 ml) for 20 minutes at 25oC. the Toluene layer was separated, vysushila the tx2">

1H NMR (benzene - d6): 6,99 (dxd, 1H), 6,83 (d, 1H), to 6.57 (d, 1H), to 2.67 (3H, s), 2.40 a (dxt, 2H).

1H NMR (benzene - d6with 2 copies of R-(-)-2,2,2-triflora-1-(9-antrel)ethanol (TFAE): d and 2.14 (3H, s), methyl singlet in the upper part by 2.10 for 5-6% (-) enantiomer.

HPLC (system A): tr (min) to 3.36 (required connection).

HPLC (system B): tr (min) 5,68 (required connection).

HPLC (system D): tr (min) 13,85 (92%, the desired connection), 15,8 (8%, (-) enantiomer).

1H NMR (CDCl3): of 3.07 (3H, s).

Example 67

Obtain (+)-(4aR)-(10bR)-4-methyl-8-chloro-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one

< / BR>
A. Di-p-toluylenediamine salt of 1-(2-methoxycarbonylethyl)- 2-(methylamino)-6-chloro-1,2,3,4-tetrahydronaphthalene

A solution of TRANS-d,l-8-chloro-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-one (2.3 g) in a 0.85 N hydrochloric acid in methanol was heated for 168 hours, after which was added concentrated sulfuric acid (to 3.00 ml) and an additional amount of methanol (100 ml). After 96 hours the mixture was concentrated and treated with solid sodium bicarbonate (20 g). A mixture containing 1-(2-methoxycarbonylethyl)-2- (methylamino)-6-chloro-1,2,3,4-tetrahydronaphthalen, was distributed between ethyl acetate (100 ml) and water (100 ml). The phases were separated, and vodarny sieves (15 g) in a solution of 5.9 g of (-)-p-toluene-L-tartaric acid (monohydrate) in methanol. All volatile components were removed under vacuum, and the white foam was dried in vacuum for 30 hours to obtain stereometrical salt (6,1 g, 99%; containing 5.0% non-hydrolyzed TRANS-dl-8-chloro-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-one, melting point 126-130oC.

The above foam (salt DTBK) (5,69 g) were produced in methanol (43oC, 32 ml) and the resulting solution was cooled to 25oC. the Mixture was filtered and dried in vacuum, obtaining of 2.92 g of salt DTBK. Recrystallization of this salt from 30 ml of methanol gave 2,12 g of pure structure of salt (47%, 94% theoretical). HPLC (system A): 0,48 (46%, DTBK), 1.28 (in 54%, aminoester), other foreign substances are not detected.

B (+)-(4aR)-(10bR)-4-methyl-8-chloro-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-one

The above salt (1.50 g) was mixed (25oC, 10 minutes) with toluene (30 ml), saturated aqueous sodium bicarbonate (10 ml) and water (40 ml). The phases were separated and the toluene layer was dried (3-A molecular sieves). The resulting solution was heated (16 hours, 92oC) and was evaporated to obtain 0.55 g of (+)-(4aR)-(10bR)- 4-methyl-8-chloro-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it is mixed with 5-7% of the enantiomer (-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f]quinoline-3-she.

HPLC (Sistema C): 93% of the desired connection, and 7% (-) enantiomer.

UV (methanol) 204 (24100).

Example 68

Obtaining (-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4 a, 5,6, 10b-octahedrons[f]quinoline-3-it

< / BR>
A. Di-p-towarnicka salt of 1-(2-methoxycarbonylethyl-2-(methylamino)-6-chloro-1,2,3,4 - tetrahydronaphthalene

A solution of 90.0 g of TRANS-dl-8-chloro-4-methyl-1,2,3,4,4 a,5,6, 10b-octahedrons[f] quinoline-3-she (approximately 95% purity according to HPLC analysis), which was prepared generally in accordance with the procedures of example 6 were mixed while heating under reflux in nitrogen in anhydrous methanol (4 l) and sulfuric acid (98%, 200 ml) for 160 hours (as long as there was < 1.5% of TRANS-dl-8-chloro-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one, according to HPLC). The solution was concentrated in vacuo and extracted with 10-15oC using methylene chloride, sodium bicarbonate (700 g) and water (2 l). Treatment with organic extracts of (+)-p-toluoyl-L-tartaric acid (DTBK) (monohydrate) (derived from unnatural tartaric acid/ S,S isomer), 132,9 g in methanol (700 ml) and three crystallization gave 48,2 g of purified salt (melting point 125-130oC, suitable for analytical standard).

HPLC (system A): 0.48 (DTBK), 1.28 (in aminoester).

UV (methanol): 204 (51200), 239 (31400), 270 (2500).o
C). The aqueous layer was separated and again extracted with toluene (5 ml). The combined toluene extracts were washed once with saturated sodium bicarbonate (5 ml), dried (4-A molecular sieves) was heated at 95-105oC (18 hours). The toluene was removed in a stream of nitrogen at 40oC, and the oil obtained was pulverized with hexane-ether to obtain compound B.

TLC (silica gel with toluene-ethyl acetate-acetic acid, 7:4:1): Rf= 0,68.

HPLC (system A): 3,25 min (> 99%, the desired connection).

HPLC (system C): 31,12 min (> 99% of the desired compounds), 28 min (< 1%) + (enantiomer).

1H NMR (CDCl3): 3,22 (dxd).

IR (CHCl3): 1620 cm-1.

UV (methanol): 205 (20800).

Example 69

Obtaining di-p-towarnicki salt of 1-(2-methoxycarbonylethyl)-2-(methylamine)-6-chloro-1,2,3, 4-tetrahydronaphthalene

< / BR>
The initial filtrate dissolution, separation and uterine fluid from the first recrystallization from example 68, described above, were combined and evaporated at 25oC in vacuum to obtain a white foam (190,4 g). This salt (180,4 g) was Astragalus cold methylene chloride, water, bicarbonate (450 ml) and three crystallization gave pure salt DTBK (57,0 g). Melting point 126-130oC.

HPLC (system A): 0,48 min (47%, DTBK), 1.28 (in 53%, aminoether).

IR (CHCl3): 1720 cm-1.

UV (methanol): 204 (46200), 239 (28000), 270 (4200).

Following the procedures described above, to obtain the compounds of formula I.

As mentioned previously, the compounds of the present invention are useful in the inhibition of the conversion of testosterone into 5 - dihydro testosterone (DHT), and more specifically, of the type 1 isoenzyme. Therefore, another option of the present invention is a method for inhibition of 5 - reductase appointment to a mammal in need of inhibition of 5 - reductase, dose (effective amount) of a compound according to formula I or its pharmaceutically acceptable salt. Compounds of the present invention is useful in its pure form or in combination with other inhibitors of 5 - reductase inhibitors, in particular inhibitors of the enzyme type 2, such as finasteride, 3-carboxylamide described in Holt et al., J. Med. Chem. 33, 943-950 (1990), and shown here as a reference, and compounds described in EP 0291245, data here as a link.

The term "effective amount", as used here, means the amount of compound of the present invention, which is able to inhibit the conversion is Oset 5 - reductase; more specifically, the isoenzyme type 1. Inhibition of 5 - reductase of the present method includes both medical therapeutic and/or prophylactic treatment. A certain dose of a compound appointed in accordance with this invention to achieve therapeutic and/or prophylactic effects will, of course be determined by the specific circumstances of the case, including, for example, a self-join, type of assignment and state of the body. A typical daily dose contains non-toxic dose level of 0.01 mg/kg to 50 mg/kg of body weight of active compound of this invention. Preferred dosages range from 0.05 to 20 mg/kg and is from 0.1 to 10 mg/kg

Many physiological functions associated with excessive secretion of 5 - dihydrotestosterone. As such, the compounds of this invention have the ability to treat in mammals many disorders associated with 5 - dihydrotestosterone, including benign growths of the prostate (or hypertrophy), male pattern baldness, acne, seborrhea, androgenic alopecia, hirsutism and prostate cancer. Therefore, the present invention also provides methods of treatment for these disorders doses . is soedineniya of the present invention are used alone or in combination with other inhibitors of 5 - reductase, such as finasteri, 3-carboxylamide and compounds in EP 0291245, in such methods of treatment.

The compounds can be administered in various applications, including oral, rectal, cutaneous, subcutaneous, intravenous, intramuscular, through the nose and external use if baldness in men, acne and hirsutism. Usually these compounds are formed in the preparations for the destination. Therefore, another aspect of the invention is to obtain a pharmaceutical preparation comprising an effective amount of the compounds of formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent or excipient. The active ingredient in these preparations contain from 0.1% to 99.9% by weight of the preparation. "Pharmaceutically acceptable" means a carrier, diluent or excipient that is compatible with other ingredients of the product and is not harmful to the recipient. These pharmaceutical preparations are prepared by known procedures with known ingredients. In the preparation of compositions of the present invention the active ingredient is usually mixed with a carrier, or resbala the container. When the carrier serves as a diluent, it may be solid, semi-solid or liquid material acting as a carrier, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), soft and hard gelatin capsules, balls, sterile injectable solutions, sterile packaged powders, wafers, cakes and so on. Typical preparations for topical application are ointments, creams, gels and lotions containing, for example, up to 10 wt.% active compounds.

The following examples of drugs are only illustrative and do not limit the scope of the invention in any way. "Active ingredient" means a compound according to formula I or its pharmaceutically acceptable salt.

The drug 1

Hard gelatin capsules are prepared using the following ingredients:

Ingredients Quantity (mg/capsule)

Active ingredient: 250

Starch, dried 200

Magnesium stearate - 10

Only 460 mg

Drug 2

Preparing the tablet using the following ingredients:

Ingredients - the Number is molten 10

Stearic acid - 5

Just - 665 mg

The components are mixed and compression molded tablets, each weighing 665 mg

Drug 3

Preparing a spray solution containing the following components:

Ingredients - Weight

Active ingredient - 0,25

Ethanol - 25,75

Reactive substance 22

(Chlorodifluoromethane) - 70,00

Just 100,00

The active compound is mixed with methanol and the mixture is added to part reactive substances 22, cooled to -30oC and transferred to a filling device. The required quantity is then fed into a stainless steel container and diluted with a small amount of reactive substances. Next to the container is attached to the valve.

The drug 4

Tablets, each containing 60 mg of active ingredient, are prepared as follows:

The active ingredient 60 mg

Starch - 45 ml

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone (as 10% solution in water) 4 mg

The sodium carboxymethyl starch 4.5 mg

Magnesium stearate 0.5 mg

Talc 1 mg

150 mg

The active ingredient, starch and cellulose are passed through a sieve of 45 mesh U.S. and thoroughly mixed. Water N 14 mesh U. S. Poluchenie granules are dried at 50oC and passed through a sieve and 18 mesh U. S. Sodium carboxymethyl starch, magnesium stearate and talc, previously passed through sieve # 60 U. S., then added to the granules which, after mixing, are compressed on teletrauma machine to obtain tablets weighing 150 mg each.

The drug 5

Capsules, each containing 80 mg of the active ingredient, are prepared as follows:

The active ingredient 80 mg

Starch - 59 mg

Microcrystalline cellulose - 59 mg

Magnesium stearate 2 mg

Only 200 mg

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a sieve N 45 U. S. and filled into hard gelatin capsules in the amount of 200 mg.

The drug 6

Balls, each containing 225 mg of active ingredient, are prepared as follows:

Active ingredient - 225 mg

Glycerides of saturated fatty acid 2,000 mg

Just 2,225 mg

The active ingredient is passed through U.S. sieve # 60 and is suspended in the glycerides of saturated fatty acids, previously melted with minimum heat. Then the mixture is poured in the form of balls with a capacity of 2 g and cools.


Active ingredient: 50 mg

The sodium carboxymethyl cellulose 50 mg

The syrup 1.25 mg

A solution of benzoic acid 0.10 ml

Odorant - q.v.

Dye - q.v.

Purified water to total 5 ml

The active ingredient is passed through U.S. sieve No. 45 mesh and mixed with the sodium carboxymethyl cellulose and syrup to make a smooth paste. A solution of benzoic acid, perfume and dye diluted part water and added to the paste with stirring. Then added enough water to get the desired volume.

Preparation 8

Preparation for intravenous administration can be prepared as follows:

Active ingredient: 100 mg

Isotonic saline solution to 1,000 ml

The solution of the above ingredients is usually administered intravenously with the rate of infusion of 1 ml per minute.

Ointments are usually prepared using either (1) an oil base, i.e. consisting of oils or hydrocarbons, such as white petrolot or mineral oil, or (2) absorbent grounds, i.e. consisting of anhydrous substances or substances that can absorb water, such as anhydrous lanolin. Usually polimom to the desired concentration.

Creams are oil/water emulsions. They consist of an oil phase (internal phase), comprising normally fixed oils, hydrocarbons, and others, such as waxes, perolat, mineral oil and other substances, and the aqueous phase (continuous phase) comprising water and any water-soluble substances, such as added salt. Two phases are stabilized by the use of emulsifying agent, for example, surfactants such as sodium laurylsulfate; hydrophilic colloids, such as the Arabian colloidal clay and others. When forming the emulsion, the active ingredient is usually added in amounts to achieve the desired concentration.

Gels include a base selected from an oil base, water or emulsion-suspension base, such as described above. To the base is added a gelling agent that forms a matrix in the basis, increasing its viscosity. Examples of gelling agents are hydroxypropylcellulose, polymers of acrylic acid, and others. Usually the active ingredient is added to the drug to the desired concentration prior to adding the gelling agent.

The amount of the active ingredient included in the product of this invention is not critical; the concentration of Dol number, providing the right amount of the active ingredient.

To demonstrate the ability of compounds of the present invention in the inhibition of 5 - reductase was carried out the following experiments.

Cell culture: the activity of 5 - reductase was measured using Hs 68 fibroblasts of the skin of the genital organs, which were originally obtained from American Type Culture Collection (Rockvill, MD). Cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) plus 10% purified amniotic bovine serum, which was supplemented with amphotericin b (0.25 mg/ml) and gentamicin (25.0 mg/ml) (Gldco, Grand Island, NY).

Serum was purified from endogenous steroids by incubation with coal, the dextran-coated before it is added to the environment. Cells were maintained at 37oC in an atmosphere of 95% air, 5% CO2and every 7-10 days were subjected to contact with a solution of trypsin-EDTA (edtc) (0.025% trypsin, 0,265 mm EDTA). Before analysis HS 68 cells were collected and placed in a Cup Falcon with 6 capillaries (Becton Dickinson Labware, Lincoln, ragc) with a density of 6104cells in the capillary. Cells were grown for 4-5 days until, until they reached approximately 80% confluence.

The method I analysis. The substrate was prepared by dissolving unlabelled testosterone (Sigmaucler, Boston. The solution of the steroid was brought to dryness under a stream of nitrogen and then rebuilt in the environment.

Method II analysis. The substrate used for this method was [14C]-testosterone (50 MCI/mmol), New England Nucleer. An aliquot of the substrate was brought to dryness under a stream of nitrogen. After adding 30 l of ethanol testosterone was dissolved in the appropriate volume of medium.

The sample preparation. Compound were placed in absolute ethanol to achieve the desired concentration. Subsequent dilutions of the tested compounds in the environment was carried out Biomek100 Automated Laboratory Workstation (Beckman Instruments, polo Alto, CA). The existing environment in the capillaries of the sample was missives and filled with fresh medium. The test compound was then added to the capillaries and then adding 0.5 ml of substrate. The volume of the incubation mixture was maintained at 2.0 ml Final concentration of substrate was 12 mm. The concentration of the tested compounds ranged from 0.001 to 150 mm. An additional three capillary (background) containing medium and the substrate, but not cells, were also included in the calculation of the non-enzymatic metabolism of the substrate. Cups were returned to the incubator and incubated for 4 hours.

At the end of the incubation the medium was collected and the case is armirovannykh steroids (estriol, estradiol, estrone, 5-androstane-3, 17-diol, 5-androstane-3, 17-diol, 4-androsten-3,17-dione, 5 - androstane-3,17-dione, testosterone and 5 - dihydrotestosterone Steraloids, Inc., Wieton, NH). In the case of method I analysis of the extraction tube also contained 1,000 and 10,000 dpm [4-14C]-dihydrotestosterone (50-60 MCI /mmol) [4-14C] -testosterone (50 MCI/mmol) (New England Nuclear, Boston, Ma), respectively. [14C] -steroids were included as recovery standards to fill procedural losses. A small amount of NaCl was also added to the extraction tube to prevent pricing. The samples were subjected to rotation for 30 seconds and then tsentrifugirovanie 10 minutes at 500 x g Organic phase was collected and the samples were dried, re-dissolved in dichloromethane-methanol (9:1) and analyzed by thin-layer chromatography using one of the methods described below.

Chromatography Method I (duchessina).

Extracted samples were submitted to silikagelevye 60F254thickness of 0.25 mm thin-layer chromatography plates (EM Science, Cincinnatl, OH). The plate was increased in the first amount of the solvent system containing dichloromethane-ethyl acetate-metanalyses acid (160:38:1,5:0,5, Mallinckrodt Inc. , Paris, KY). Tarel the residents, containing dichloromethane-methanol-ammonium hydroxide (180:19:1, Mallinckrodt Inc., Paris, KY).

Chromatography Method II (one dimensional).

Extracted samples were submitted to silikagelevye 60F254thickness of 0.25 mm thin-layer chromatography plates (EM Science, Cincinnati, OH). The plate was increased in the solvent system containing either cyclohexane-ethyl acetate (1: 1, Mallinckrodt Inc., Paris, KY) or chloroform-ethyl acetate (3: 1, Mallinckrodt Inc. , Paris, KY). Both these systems solvent gave adequate separation and allowed the best results when compared with dvukhyadernoj system described above.

Plates were first viewed under 254 mm UV light was observed visible spots. Then they sprayed primulin Aldrich Chemical Co., Milwaukee, WI) (0,001% in acetone-water (4:1) in accordance with the method of Wright, R. S.,"A reagent for the non-olestructive localization of steroids and some other lopophilic materials on silica gel thin-layer chromatograms," J. Chramatogr., 59; 220-221 (1971), which allowed the identification of additional steroids at 365 mm UV light. Samples obtained using method II analysis were analyzed directly using the Ambis Radioanalitic Jmaging System (Ambis Systems, Inc., San Diego., CA). In the case of the samples according to the method I analysis spots were socialis from the plate by a Pasteur pipette with glass wool, zalojeno the ml dichloromethane, followed by two premiume 2.0 ml of methanol. The organic solvent was evaporated and added 10.0 ml of scintillation fluid (Ready Organic, Beckman Instments, Inc. , Fullerton, CA). The samples were analyzed by spectrometry liquid scintillation.

After removing the medium from the extraction cells were washed with phosphate buffer solution (FBI, pH 7,4) and then harvested in trypsin-EDTK solution (0.025% trypsin, 0,265 mm EDTK). Cells were collected and tsentrifugirovanie at 1400 x g for 5 minutes. Pop-up stickiness was decentralise and cells re-suspendibility in PBS. An aliquot of cell suspension was calculated in Coulter Electronics, Ltd., Luton Beds, England. The remaining cells were treated with sound and protein was determined in accordance with the method of Bradford, M. M., "A rapid and sensitive method for protein quantitation of microgvaam guantities of protein utilizing the principle of protein-dye bibing", Anal. Biohem., 72; 248-254 (1976). Made correction for procedural losses and the data was expressed as percentage inhibition, based either on the concentration of steroid in picomoles per mg/protein, or picomoles/105cells.

The results of the evaluation are given in the table. The percentage inhibition is used on a scale of 0-100%, where 0 is equal to zero activity and 100 equals complete inhibition.

Note that the description and examples set forth herein, daudai spirit and scope of the present invention, certain accompanying formula.

1. Benzo[f]chinoline formula I

< / BR>
where R is hydrogen, C1- C4alkyl, unsubstituted or substituted Hairdryer(C1-C4)alkyl;

Z and Z1is independently selected from hydrogen and C1-C4the alkyl or one of Z and Z1with R5form a bond of carbon-carbon;

Y is hydrogen or methyl, or R1forms a bond of carbon-carbon;

R1is hydrogen or one of Y or R3forms a bond of carbon-carbon;

R2is hydrogen or C1- C4alkyl;

R3is hydrogen or R1forms a bond of carbon-carbon;

R4is hydrogen or R5forms a bond of carbon-carbon;

R5is hydrogen or one of Z or Z1forms a bond of carbon-carbon;

n is 1 or 2;

X is hydrogen, halogen, NO2, cyano, CF3C1- C6alkyl, C1- C6alkoxy, carboxy, C1- C6alkoxycarbonyl, amino, amido, C1- C4alkylamino, or group And R6where A - C1- C6alkylene, C2- C6albaniles or C2- C6akinyan; R6halogen, hydroxy, CF3C1- C6alkoxy, carboxy, C1- C6alkoxycarbonyl salt; provided that at least one of R1and5is hydrogen; when R is hydrogen, methyl, ethyl or benzyl, X is not hydrogen or methoxy, and, if R is methyl, R2is not methyl.

2. Connection on p. 1, wherein R is hydrogen or C1- C4alkyl; Z and Z1is independently hydrogen or methyl; Y is hydrogen or methyl and is in the TRANS configuration relative to the hydrogen at the 4-position; R1, R3, R4and R5is hydrogen; R2is hydrogen or methyl; n is 1 or 2; X is halogen, CF3C1- C6alkyl, C1- C4alkoxy or-A - R6where A-C1- C4alkylene and R6- C1- C4alkoxycarbonyl, or its pharmaceutically acceptable salt, provided that when R is hydrogen, methyl or ethyl, X is not hydrogen or methoxy, and, if R is methyl, R2is not methyl.

3. Connection on p. 2, wherein R is hydrogen or methyl; Z and Z1is hydrogen or methyl; Y is hydrogen or methyl and is in the TRANS configuration relative to the hydrogen at the 4-position; R1, R3, R4and R5is hydrogen; R2is hydrogen or methyl; n is 1 or 2; X is halogen, CF3or C1- C4alkyl, or its pharmaceutically acceptable salt, provided that if R - mahoro-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one or its pharmaceutically acceptable salt.

5. Connection on p. 3, characterized in that it is a TRANS-d1-4,8-dimethyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one or its pharmaceutically acceptable salt.

6. Connection on p. 3, characterized in that it is a TRANS-d1-8-bromo-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one or its pharmaceutically acceptable salt.

7. Connection on p. 3, characterized in that it is a (-)-(4R)-(10bR)-8-chloro-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f]quinoline-3-one or its pharmaceutically acceptable salt.

8. Connection on p. 3, characterized in that it is a (+)-(4aS)-(10bS)-8-chloro-4-methyl-1,2,3,4,4 a, 5,6,10 b-octahedrons[f] quinoline-3-one or its pharmaceutically acceptable salt.

9. The pharmaceutical composition inhibiting 5 alpha-reductase in a mammal, characterized in that it includes, along with one or more pharmaceutically acceptable carriers, diluents or fillers effective amount of a compound claimed in any of paragraphs.1 - 8, as an active ingredient.

10. The method of inhibition of 5-reductase in mammals, different Tiesto connection declared in one of the paragraphs.1 - 8.

11. The method according to p. 10, characterized in that prescribe an effective dose of a compound, as claimed in one of the paragraphs.1 - 8, in the treatment of benign prostate, baldness in men, acne, hirsutism, or prostate cancer in mammals.

12. The method according to p. 10, characterized in that prescribe an effective dose of a compound, as claimed in one of the paragraphs.1 - 8, in the treatment of androgenic alopecia or seborrhea.

13. The method according to p. 10, characterized in that prescribe an effective dose of a compound, as claimed in one of the paragraphs.1 - 8, for cosmetic treatment of androgenic alopecia, baldness in men or hirsutism adults.

14. The compound of formula II

< / BR>
where X is hydrogen, halogen, NO2, cyano, CF3C1- C6alkyl, C1- C6alkoxy, carboxy, C1- C6alkoxycarbonyl, amino, amido, C1- C4alkylamino, or the group-A-R6where A - C1- C6alkylene, C2- C6albaniles or C2- C6akinyan;

R6halogen, hydroxy, CF3C1- C6alkoxy, carboxy, C1- C6alkoxycarbonyl, amino, C1- C4alkilani the>

15. Connection on p. 14, in which X is halogen, CF3or C1- C6alkyl, C1- C4alkoxy or-A-R6where A - C1- C4alkylene, R6- C1- C4alkoxycarbonyl n is 1 or 2; or its pharmaceutically acceptable salt.

16. Connection on p. 15 in which X is halogen, CF3or C1- C4alkyl; n is 1 or 2; or its pharmaceutically acceptable salt.

17. The method of obtaining the compounds of formula

< / BR>
where R is hydrogen, C1- C4alkyl, unsubstituted or substituted Hairdryer(C1- C4)alkyl;

Z and Z1is independently selected from hydrogen and C1- C4of alkyl;

Y is hydrogen or methyl;

R2is hydrogen or C1- C4alkyl;

n is 1 or 2;

X is hydrogen, halogen, NO2, cyano, CF3C1- C6alkyl, C1- C6alkoxy, carboxy, C1- C6alkoxycarbonyl, amino, amido, C1- C4alkylamino or group-A-R6where A - C1- C6alkylene or C2- C6albaniles or C2- C6akinyan; and R6halogen, hydroxy, CF3C1- C6alkoxy, carboxy, C1- C6alkoxycarbonyl, amino, C1- C4alkylamino, amido,make

reaction of 1-methyl-2-tetralone with an optically active amine to obtain the corresponding 1-methanamine;

the reaction of 1-methanamine with , -unsaturated carbonyl compound to obtain the corresponding mechanosensitivity-4-it;

the reaction mechanosensitivity-4-it alkoxide of an alkali metal to obtain the corresponding 2,3,4,4 a,9,10 hexahydro-4-methyl-phenanthrene-2-it;

oxidative cleavage of the specified Fenatran-2-it to obtain the corresponding 3-[1-methyl-1(2-keto 1,2,3,4-tetrahydronaphthyl)]propionic acid;

the specified reaction of propionic acid with ammonia or a primary amine to obtain the corresponding 10b-methyl-1,2,3,4,6,10 b-hexahydrobenzo[f] quinoline-3-one;

restore the specified hexahydrobenzo[f]quinoline-3-one to obtain the corresponding octahedrons[f]quinoline-3-she.

18. The way the splitting of the racemates of compounds of the formula I

< / BR>
where R is hydrogen or C1- C4alkyl,

Z and Z1is independently selected from hydrogen and C1- C4of alkyl;

Y is hydrogen;

R1, R2, R3, R4and R5is hydrogen;

n is 1 or 2;

X is hydrogen, halogen, NO2, CF3C1- C6alkyl, C1- C is Aut stage:

the contacting of the solution of methanol of the racemate with a strong acid to obtain 1-(2-methoxycarbonylethyl)-2-(amino)-1,2,3,4-tetrahydronaphthalene;

the contacting of the specified tetrahydronaphthalene with a solution of methanol optically active di-p-toluylene acid to obtain the corresponding salt of tetrahydronaphthalene and processing said salt is the basis for obtaining a single optically active isomer.

19. Sol di-p-toluoyl-(D) or (L)-tartaric acid and TRANS-isomers of compounds with formula

< / BR>
in which R is hydrogen or C1- C4alkyl;

Z or Z1is independently selected from hydrogen and C1- C4of alkyl;

n is 1 or 2;

X is hydrogen, halogen, NO2, CF3C1- C6alkyl, C1- C4alkoxy or amino.

Priority signs.

21.08.91 - on the basis of "X is hydrogen, halogen, NO2, CYANOGEN, CF3C1- C6alkyl, C1- C6alkoxy, carboxy, C1- C6alkoxycarbonyl, amino, amido, C1- C4alkylamino, or A group-R6where A - C1- C6alkylene, C2- C6albaniles or C2- C6akinyan; and R6halogen, hydroxy, CF3C1- C6AB>4alkylamino";

21.10.91 - on the grounds of: a) At least one of R1and R5- hydrogen; (b) If R is hydrogen, methyl, ethyl or benzyl, X is not methoxy; (c) If R is methyl, R2is not methyl.

10.08.92 - on the basis of "If R is hydrogen, methyl, ethyl or benzyl, X is not hydrogen or methoxy."

 

Same patents:

The invention relates to new carboxamides f-ly 1, where E-N, G-H, lower alkyl, lower alkylene COOH, COO-lower alkyl, lower alkanoyl, lower alkanoyloxy, lower alkoxy, aryl-lower alkoxy, СОNH2and others, M-H, lower alkyl, lower alkenyl, aryl, heteroaryl, cycloalkyl, L-H, lower alkyl, aryl, cycloalkyl, or M and L together with the atoms to which they are linked, form a group - N (het), or E and G spot form a methylene or carbonyl group, and M represents H, lower alkyl, lower alkenyl, aryl, heteroaryl, cycloalkyl, L-H, lower alkyl, aryl , cycloalkyl, A-H, alkyl, aralkyl, Q represents a group of formula Q1or Q2T-CH2or Oh, R6and R7- H, cerboneschi alkoxy, HE

The invention relates to novel 2,6-dimethylaniline N - cyclopropylmethyl-2-carboxylic acid f-ly I, where R is cyclopropyl or methylcyclopropyl in the form of a racemic mixture or the individual enantiomers or their salts, which exhibit increased antiarrhythmic and local anestesiologia properties and can find application in medicine

The invention relates to new derivatives of pyridone F.-ly (I'), where R1- C1- C4-alkyl, R2is hydrogen, R3- SC6H5, R4- CH2OR13where R13is hydrogen, benzyl, R'- tetrazolyl, which have high antagonistic activity against receptor antiotensin II and can find application in medicine

The invention relates to the derivatives of pyrrolidine formula (I) in which either R is methylene, ethyleneglycol, >SO, >SO2group or a sulfur atom; R1means pyridinyl, furyl, thienyl, optionally substituted by one or more alkyl groups, naphthyl, indolyl or phenyl, optionally substituted by one or more substituents selected from halogen atoms, alkyl-, alkoxy-, hydroxy - and dialkylamino; R5means a hydrogen atom; or R is methylene, R1is a hydrogen atom and R5means phenyl; or R is a group > CHR6, R1and R5mean a hydrogen atom; R2means alkoxycarbonyl, cycloalkyl-alkyloxy-carbonyl -, etc., R3means indolyl - or phenylaminopropyl, the phenyl nucleus of which is substituted by one or more substituents selected from a range that contains the halogen atom, the alkyl-, alkoxy-, alkylthio group and others; R4means a hydrogen atom and alkylaryl; R6means phenyl radical in the form of iamiceli mixture or enantiomers and their salts

The invention relates to new biologically active chemical compound exhibiting the properties of activator germination of seeds of agricultural crops

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to medicine and veterinary medicine, particularly to drugs, causing an increase in the target cells of the level of progesterone receptor and estrogen in the treatment of tumors of the uterus, the mammary glands of mammals, overcoming and preventing the development of gormonorezistentnost these tumors

The invention relates to new antimicrobial 5-(N-heterosomata amino) quinolone compounds of General formula I

< / BR>
where R1, R2and R3form any of a variety of quinolones and friends heterocyclic structures similar to those known socialists as having antimicrobial activity, and (2) (a) R4and R5are, independently, hydrogen, lower alkyl, cycloalkyl, heteroalkyl, or-C(=O)-X-R8where X is a covalent bond, N, O or S and R8is lower alkyl, lower alkenyl, arylalkyl, carbocyclic ring, heterocyclic ring, or (b) R4and R5together form a heterocyclic ring that includes the nitrogen to which they are attached, and their pharmaceutically acceptable salts and biokerosene esters and solvate

The invention relates to a new method of treatment of patients, such as people with benign prostatic hyperplasia (BPH), which includes treatment by assigning a therapeutically effective amount of an inhibitor 5- reductase in combination with blocker1- adrenergic receptor

The invention relates to pharmaceutical compounds, their preparation and use

The invention relates to new N-quinoline derivative, to a method of obtaining them, to the new obtained intermediate products for their use as medicaments and to their containing pharmaceutical compounds

The invention relates to new derivatives aminoquinolone

The invention relates to novel condensed derivative indana formula I

< / BR>
in which A represents an optionally substituted benzene ring, naphthalene ring or benzene ring condensed with the lowest alkylenedioxy; ring B represents an optionally substituted benzene, Y = -N= CR or CR=N-
The invention relates to medicine, for treatment of allergic and diatopically diseases of the eyes and nose

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

Up!