Substituted benzopyrano and their pharmaceutically acceptable salts and hydrates

 

(57) Abstract:

The present invention relates to compounds of the formula I

< / BR>
which is suitable, in combination with a pharmaceutical carrier as antiatherosclerotic agents. In addition, various compounds of formula I are useful inhibitors of cell proliferation. 1 9 C.p.-f-crystals, 3 tables..

The invention relates to new substituted benzopyranones that have antiatherosclerotic and antithrombotic action.

Atherosclerosis in mammals is a disease characterized by the deposition of atherosclerotic plaques on arterial walls. While atherosclerosis manifests in many different forms and consequences, the typical consequences of atherosclerotic disease include chest pectoris, myocardial infarction, stroke and transient disorders of cerebral circulation. Other forms of atherosclerotic disease include some peripheral vascular disease and other ischemia (e.g., intestinal and renal).

Medical science now recognizes that some forms of atherosclerosis can be prevented or to be reversible. Substances capable of preventing or do obecnie lipids have proven communication with atherogenesis, an important class of antiatherosclerotic agents are those that have the effects of modification of serum lipids. Serum lipids involved in atherogenesis include serum cholesterol, serum triglycerides and serum lipoproteins.

With regard to serum lipoproteins, at least three different classes of these substances are characterized in the art: high-density lipoprotein (HDL), low-density lipoproteins (LDL) and lipoprotein with a very high density (VLDL). HDL is often referred to as alphalinoleic, whereas LDL and VLDL very often referred to as betalipoprotein. Increasing levels of HDL (hyperalphalipoproteinemia activity) due to the requirement of direct antiatherosclerotic effects. Cm. Eaton R. P. , J. Chron. Dis. 31:131-135 (1978). Conversely, substances that reduce serum LDL and VLDL (hypobetalipoproteinemia agents), also associated with the anti-atherosclerotic effects. Cm. Haust, M. D. "Reaction Patterns of Intimal Mesenchyme to Injury and Repair in Atheros." Abv. Exp. Med. Biol. 43: 35-57 (1974), which postulates that the serum LDL is a factor in the formation of atherosclerotic lesions.

To assess antiatherosclerotic activity developed numerous W is ateroskleroticescoy activity in Japanese quail. For a description of the model hypobetalipoproteinemia rats should refer to known methods Schurr P. E. et al., "High Volume Screening Procedure for Lypobetalipoproteinemia Activity in Rats", Adv. Exp. Med. Biol. 67: Atherosclerotic Drug Discovery, pp. 215 - 229, Plenum Press (1975). To describe models of the Japanese quail should refer to Day C. E. et al. , "Utility of a Selected Line (SEA) of the Japanese Quail (Corturnic Corturnix japonica) for the Discovery of New Anti-Atherocslerosis Drugs, Labor. Animal Science 27: 817-821 (1977).

2-Aminopropane (4H-1-benzopyran-4-ones) are known in the literature. For example, anti-allergic activity 2-aminopropanol described in the literature Mazzei, Balbi, Ermili, Sottofattori and Roma (M. Mazzei, Ballbi A., Ermili A., Sottofattori E. and Roma G. Farmaco, Ed. Sci., (1985) 40, 895, and M. Mazzei, Ermili A. , Balbi A., Di Braccio M., Farmaco Ed. Sci., (1986), 41, 611; CA 106: 18313 w). Also described CNS-activity 2-aminopropanol (Balbi A., Roma G., Ermili A., Farmaco. Ed. Sci., (1982) 37, 582; Ermili, M. Mazzei, Roma G. , Cacciatore, Farmaco. Ed. Sci. , (1977) 32, 375 and 713). Recently described nitro-derivatives of various 2-aminopropanol (Balbi, Roma G., Mazzei m, Ermili A. , Farmaco. Ed. Sci., (1983) 38, 784) and Farmaco. Ed. Sci. 41(7), 548 - 557). 2-Amino-3-hydroxychromone described in the patent Germany 2205913 and patent UK 1389186.

U.S. patent 4092416 (see also patent Germany 2555290 and CA 87:102383 r) discloses various derivatives of benzopyrone exhibiting anti-allergic activity, including 2{ 2-[4-(2-methoxyphenyl)piperazinil-1-]-ethyl}-5-meter CLASS="ptx2">

Patent application Japan 025657 and the Japan patent 259603 disclose various 2-amino-3-carboxamidine and 3-phenyl (optional substituted)-2-aminopropiophenone as suitable annotations and immunosuppressive agents.

Pharmacomodulation-adrenergic blocking agents number of benzopyrano, including 2-(1-piperidinylmethyl)-4H-1-benzopyran-4-one, described in Eur. J. Med. Chem., 1987, 22(6), 539-44; CA 109: 92718k.

I believe that is structurally similar in the literature for 2-(4-morpholinyl)-4H-1-benzopyran-4-ONU (Conn. 2) are the analogues of 3-hydroxy, 3-methoxy and 3-atomic charges (i.e., 2-(4-morpholinyl)-3-hydroxychromone, 2-(4-morpholinyl)-3-methoxypropan and 3-(atomic charges)-2-(4-morpholinyl)chroman), see F. Eiden and Dolcher D. (F. Eiden, Dolcher D., Arch. Pharm. (Weinheim Ger.) (1975) 308, 385) and in the Federal Republic of Germany patent 2205913; and in CA 83(11): 96942w and 79(9): 115440s 6,7-Dimethoxy-2-(4-morpholinyl)chrome disclosed in J. Chem. Soc., Perkins Trans. l, (2), 173-3; CA 78(9): 58275v. 3-Acetyl-2-(4-morpholinyl)chrome disclosed in the Arch. Pharm. 316(1), 34 - 42; CA 98(15): 12915g.

3-Hydroxy-2-[4-(2-hydroxyethyl)-1-piperazinil] -4H-1-benzopyran-4-one and 3-hydroxy-2-(4-methyl-1-piperazinil)-4H-1-benzopyran-4 - one is disclosed in the Arch. Pharm. 308(5), 385 - 388; CA 83(11): 96942w. 5,8-Dimethoxy-2-(4-methyl-1-piperazinil)-4H-1-benzopyran-4-one is disclosed in J. Heterocycl. Chem. 18(4), 679-84; CA 95(17): the Suschitzky (Bantick J. R., Suschitzky J. L., J. Heterocyclic Chem., (1981) 18, 679). In this paper discloses the receipt of salts of HCl and H2SO4several 2-aminopropanol.

Antiplatelet activity of some 2-(dialkylamino)Romanov, namely 2-(diethylamino)-5,6-dimethyl-4H-1 - benzopyran-4-it, 2-(diethylamino)-6,7-dimethyl-4H-1-benzopyran-4-it, 2-(diethylamino)-7-hydroxy-5-methyl-4H-1-benzopyran-4-it, 2-(diethylamino)-5-hydroxy-7-methyl-4H-1-benzopyran-4-it, 2-(diethylamino)-6-chloro-8-isopropyl-4H-1-benzopyran-4-it, 2-(diethylamino)-5,7-methoxy-4H-1-benzopyran-4-it, 2-(ethylamino)-5 - hydroxy-4H-1-benzopyran-4-it, 2-(ethylamino)-7-hydroxy-4H-1-benzopyran-4-it, 2-(diethylamino)-7-hydroxy-6-nitro-4H-1-benzopyran-4-it, 2-(diethylamino)-4H-1-benzopyran-4-it, 2-(diethylamino)-7-methoxy-4H-1-benzopyran-4-it, 2-(diethylamino)-7-methoxy-4H-1-benzopyran-4-it, 2-(diethylamino)-7-methoxy-4H-1-benzopyran-4-it, 2-(1-pyrrolidinyl)-7-methoxy-4H-1-benzopyran-4-it, 2-(1-piperidinyl)-7-methoxy-4H-1-benzopyran-4-it, 2-(diethylamino)-7-hydroxy-4H-1-benzopyran-4-it, 2-(1-piperidinyl)-7-hydroxy-4H-1-benzopyran-4-it, 2-(ethylamino)-7-methoxy-4H-1-benzopyran-4-it, 2-(diamino)-5-hydroxy-4H-1-benzopyran-4-it, 2-(diethylamino)-5-methyl-8-isopropyl-4H-1-benzopyran-4-she 2-(diethylamino)-3-(4-morpholinomethyl)-7-methoxy-4H-1-benzopyran-4-it, programnow given Tronchet, Bachler and Bonenfant (Tronchet, J. M. J., Bachler B., A. Bonenfant, Helv. Chim. Acta (1976), 59, 941). In this work, receive 2-amino-3-glycosylation.

In the literature also known 2-amino-1,3-benzoxazin-4-ones. Specifically 2-morpholinyl-4H-1,3-benzoxazin-4-one (Conn. 98) and 8-methyl-2-(4 - morpholinyl)-4H-1,3-benzoxazin-4-one (Conn. 84) disclosed in the patent application of the Netherlands 6412966 (see also U.S. patent 3,491,092) and in the literature (E. Grigat, Putter R., K. Schneider, K. Wedemeyer, Chem. Ber., (1964) 97, 3036).

Antifungal and analgesic activity of 2-amino-1,3-benzoxazin-4-ones also stated Sankyo in Japn. Tokyo Koho 79 20504 (CA 91: 157755b) and in Japan (Kokai 72, 17, 781 (CA 77: 140107e).T These patents cover 2-(4-morpholinyl)-4H-1,3-benzoxazin-4-ones (Conn. 98) and 6,7-substituted-2-(4-morpholinyl)-analogues of the above compounds.

Synthesis of 2-dialkylamino-1,3-benzoxazin-4-ones is described Kokel et al., (see Tet. Letters (1984) 3837).

2-N-Alkyl and 2-N-aryl-1,3-benzoxazin-4-ones is described Pallazo and Giannola (Pallazo S. , Giannola L. I. Atti., Accad. Sci. Lett. Arti Palermo, Parte 1, (1976) 34(2), 83-87).

2-Benzamidine-1,3-benzoxazin-4-one is described H. Brunetti and C. E. Luthi (Helv. Chim. Acta (1972) 55, 1566).

The present invention relates to new substituted benzopyranones formula I which are suitable in combination with a pharmaceutical carrier as antiatherosclerotic wishes is egizii platelets.

Substituted benzopyrano are compounds of the formula I

< / BR>
where

X is CZ, where Z represents H, C1-C5-alkyl, amino group or halogen atom;

Y is selected from the group consisting of -(CH2)nNR9R10where R9and R10the same or different, are selected from the group consisting of

(a) a hydrogen atom, provided that R9and R10both are not hydrogen atoms;

(b) C1- C12alkyl;

(c) phenyl, optionally substituted one, two or three residues C1- C4-alkyl, C1- C4-alkoxyl, halogen, an OH group, triptorelin or-CO2(C1-C4-alkyl);

(d) (CH2)n-phenyl [where phenyl, optionally substituted one, two or three residues C1-C4-alkyl, C1-C4-alkoxyl, halogen, an OH group, triptorelin or-CO2(C1-C4-alkyl)];

(e) -(CH2)n-pyridinyl; or

(f) where R9and R10taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of

(aa) 4-the research, optionally substituted by one or two substituents, vintila,

(bb) 4-thiomorpholine, optionally substituted by one or two substituents selected from the group consisting of C1- C4-alkyl, C1-C4-alkoxyl, halogen or trifloromethyl,

(cc) 3-amino-1-pyrrolidine,

(dd) 1-pyrrolidine, optionally substituted by one or two substituents selected from the group consisting of C1- C4-alkyl, C1-C4-alkoxyl, halogen, OH, CH2OH or cryptomeria,

(ee) 1-piperidine, optionally substituted with one or two substituents selected from the group consisting of C1- C4-alkyl, C1-C4-alkoxy, halogen, trifluoromethyl, -(CH2)qOH, -COOH, -CO2CH3-, CO2CH2CH3or phenyl (where the phenyl optionally substituted with one, 2 or 3 C1-C4-alkyl, C1-C4-alkoxyl, halogen or trifluoromethyl),

(ff) 1-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (where the phenyl may be optionally substituted with one, 2 or 3 C1- C4-alkyl, C1-C4-alkoxyl, halogen or trifluoromethyl) or 4-pyridinyl-1-piperazine, optionally substituted with one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4 (gg) thiazolidin, thiazolidin-4-carboxylic acid, pipecolinate acid, p-piperazineethanol, 1-homopiperazine, 1-methylhomopiperazine, 4-phenyl-1,2,3,6-tetrahydropyridine, Proline, tetrahydrofuran, 1-(3-hydroxy)pyrrolidine, nipecotate, 1,2,3,4-tetrahydroisoquinoline or imidazole;

R5, R6, R7and R8- same or different, selected from the group consisting of a hydrogen atom, a C1-C8-alkyl, -(CH2)nphenyl [where phenyl may be optionally substituted by one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1-C4-alkyl)], -(CH2)n-naphthyl, -(CH2)n-pyridyl-, -(CH2)qNR9R10, -CH=CH-phenyl [where phenyl optionally substituted one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1- C4-alkyl)], -CH2-CH=CH2, -CH=CH-CH3, -O-CH2-CH=CH2, -C C-phenyl [where phenyl may be optionally substituted by one, two or three C1- C4-alkyl, C1- C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1- C4-alkyl)], -O(CH2)p(N-OR15, -(CH2)nC(O)-(CH2)nR9,

-(CH2)nC(O)O-(CH2)pR9, -(CH2)nC(O)O-(CH2)pNR9R10, (CH2)nC(O)(CH2)nNR9R10, NO2, -O-(CH2)nC(O)-(CH2)pR9, -O-(CH2)nC(O)O-(CH2)pR9, -O-(CH2)nC(O)-(CH2)nNR9R10, -NR9R10- N(R9)(CH2)nC(O)-(CH2)nR10, -N(R9)-(CH2)nC(O)O-(CH2)nR10N(R9(CH2)nC(O)-(CH2)nR9R10, -O-(CH2)n-phenyl [where phenyl optionally substituted one, two or three C1- C4-alkyl, C1- C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1- C4-alkyl)], -O-(CH2)n-pyridine, -O-(CH2)nC(O)-(CH2)n-pyridine, -O-(CH2)nC(O)O-(CH2)n-pyridine, -O-(CH2)nC(O)-N(R9)(CH2)n-pyridine, -O(CH2)n-khinoksalinona, -O-(CH2)n-chinoline, -O-(CH2)n-pyrazinyl, -O-(CH2)n-naphthyl, -O-(CH2)n-C(O)-(CH2)n-naphthyl, -O-(CH2)n-C(O)O-(CH2)n)q-OH, -(CH2)qOC(O)R9, -(CH2)qOC(O)-NR9R10, -(1-cyclohexyl-1H-tetrazol-5-yl)-C1- C4-alkoxyl, -[1-(C1- C5-alkyl)-1H-tetrazol-5-yl]-C1- C4-alkoxyl, -[1-(phenyl)-1H-tetrazol-5-yl]C1-C4-alkoxyl [where phenyl optionally substituted one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1-C4-alkyl)], -[1-(pyridinyl)-1H-tetrazol-4-yl] -C1-C4-alkoxyl, -[1-(1-phenylethyl)-1H-tetrazol-5-yl] -C1-C4-alkoxyl, -C1-C4-alkoxyl, a group of the formula II

< / BR>
where

R' is methyl or carboxyl;

R" is hydrogen;

R"' is selected from benzyl [optionally substituted by one, two or three groups selected from hydroxy, halogen or phenoxy (optionally substituted with one, two or three groups selected from hydroxyl or halogen)],

C1-C5-alkyl, -(CH2)nCOOH, -CH2SH, -CH2SCH3, imidazolidinethione, idolenlehre, CH3CH(OH), CH2OH, H2N(CH2)4- (optionally in protected form), or H2NC(NH)NH(CH2)3(optionally in protected form); provided, Thu the SUB>-C5is alkyl, then R7different from-O-(CH2)nC(O)O-(CH2)pR9or-O-(CH2)nC(O)-NR9R10where n has a value other than 0, and R9and R10selected from H or C1-C12-alkyl; with the overall proviso that when Y is different from (CH2)nmorpholinyl at least one of the substituents R5, R6, R7or R8is different from a hydrogen atom, a C1-C8-alkyl, NO2, OH, C1- C4-alkoxy, halogen atom, phenyl, benzyl, 4-morpholinylmethyl, NH2or dimethylaminopropyl, and yet provided that when Y is 4-morpholinyl, in the compounds of formula I do not include:

6,7-dimethoxy-2-(4-morpholinyl)4H-1-benzopyran-4-one;

7,8-(bis)-(3-trifluoromethyl)phenylmethoxy-2-(4-morpholinyl)-4H-1 - benzopyran-4-one;

N-cyclohexyl-2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran - 7-yl] oxy]-ndimethylacetamide;

2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]- N-phenylacetamide;

6-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxy] -2-(4-morpholinyl)-4H - 1-benzopyran-4-one;

2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl] oxy] -N- (1-phenylethyl)-ndimethylacetamide;

with the additional proviso that, when Y represents dimethylamino, in connection not included:

dimethyl No)-4-oxo-4H-1-benzopyran-6 - ylcarbamate acid;

dimethyl 2-(dimethylamino)-4-oxo-4H-1-benzopyran-7 - ylcarbamate acid;

methyl ether [[8-methyl-2-(4-morpholinyl)-4-hydroxy-4H-1-benzopyran-7 - ylcarbamate acid;

dimethyl ether (dimethylamino)-4-oxo-4H-1-benzopyran-6 - ylcarbamate acid;

dimethyl 2-(dimethylamino)-4-oxo-4H-1-benzopyran-7 - ylcarbamate acid;

methyl ether [[8-methyl-2-(4-morpholinyl)-4-hydroxy-4H-1-benzopyran-7 - yl] oxy]acetic acid;

lithium salt of [(8-methyl-2-(4-morpholinyl)-4-hydroxy-4H-1-benzopyran-7 - yl] exucuse acid;

R15selected from the group: C1-C5-alkyl, (CH2)n-phenyl [where phenyl optionally substituted one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1-C4)-alkyl)] , -(CH2)n-pyridin-1-yl or (CH2)p-piperidine-1-yl;

n = 0-5;

p = 2-5;

q = 1-5;

and their pharmaceutically acceptable salts and hydrates;

X preferably denotes CZ, where Z denotes H or C1-C5-alkyl, more preferably H or methyl, most preferably H.

When X is CZ; Y is preferably selected from the group consisting of (CH2)nNR9R
(aa) 4-the research, optionally substituted by one or two substituents selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxyl, halogen or trifloromethyl,

(bb) 4-thiomorpholine, optionally substituted by one or two substituents selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxyl, halogen or trifloromethyl,

(cc) 3-amino-1-pyrrolidine,

(dd) 1-pyrrolidine, optionally substituted by one or two substituents selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxyl, halogen, OH, CH2OH or cryptomeria,

(ee) 1-piperidine, optionally substituted with one or two substituents selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxyl, halogen, trifloromethyl, -(CH2)qOH, -CO2H, -CO2CH3-, CO2CH2CH3or phenyl (where the phenyl optionally substituted one, two or three substituents of the C1-C4-alkyl, C1-C4-alkoxyl, halogen or trifloromethyl), and

(ff) 1-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (where the phenyl optionally replaced is trifloromethyl) or 4-pyridinyl-1-piperazine, optionally substituted by one or two substituents selected from the group consisting of C1-C4-alkyl, C1-C4-alkoxyl, halogen, trifloromethyl, CH2OH, -CO2H, -CO2CH3or-CO2CH2CH3,

When X is CZ, where Z denotes H or C1-C5-alkyl (most preferably H), Y is more preferably selected from the group consisting of (CH2)nNR9R10where n is 0 or 1 (more preferably 1), and R9and R10taken together with N, form:

(aa) morpholine (preferably 4-morpholine), optionally substituted by one or two substituents selected from the group consisting of C1-C4-alkyl or phenyl (where the phenyl by selecting substituted by one or two members of C1-C4-alkyl, C1-C4-alkoxyl, halogen or trifloromethyl); and preferably at least one Deputy, selected from R5, R6, R7or R8choose from the group consisting of -(CH2)p-phenyl [where phenyl optionally substituted one, two or three substituents of the C1-C4-alkyl, C1-C4-alkoxyl, halogen, OH, trifloromethyl or-CO2(C1-C4-alkyl)] phenyl optionally substituted with one, two or three substituents of the C1-C4-alkyl, C1-C4-alkoxyl, halogen, OH, trifloromethyl or-CO2(C1-C4-alkyl)], -CH2-CH= CH2, -CH= CH-CH3, -O-CH2-CH=CH2, -C C-phenyl [where phenyl optionally substituted one, two or three substituents of the C1-C4-alkyl, C1-C4-alkoxyl, halogen, OH, trifloromethyl or-CO2(C1- C4-alkyl)], -O(CH2)p(N-methylpiperidin-3-yl), -O-(CH2)pNR9R10, -O-CH2CH(OCH3)2, -O-(CH2)pOR15[where R15selected from C1-C5of alkyl,- (CH2)n-phenyl [phenyl, optionally substituted one, two or three members of the C1-C4-alkyl, C1-C4-alkoxyl, halogen, OH, trifloromethyl or-CO2(C1-C4-alkyl)], -(CH2)n-pyridin-1-yl or (CH2)p-piperidine-1-yl, -(CH2)nC(O)-(CH2)nR9,

-(CH2)nC(O)O-(CH2)pR9, -(CH2)nC(O)O-(CH2)pNR9R10, (CH2)nC(O)(CH2)nNR9R10,

-O-(CH2)nC(O)-(CH2)pR9, -O-(CH2)nC(O)O-(CH2)pRC(O)-(CH2)nR10, -N(R9)-(CH2)nC(O)O-(CH2)nR10N(R9(CH2)nC(O)-(CH2)nR9R10, -O-(CH2)n-phenyl [where phenyl optionally substituted one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1-C4-alkyl)], -O-(CH2)n-pyridine, -O-(CH2)nC(O)-(CH2)n-pyridine, -O-(CH2)nC(O)-(CH)n-pyridine, -O-(CH2)nC(O)O-(CH2)n-pyridine, -O-(CH2)nC(O)-N(R9)(CH2)n-pyridine, -O(CH2)n-khinoksalinona, -O-(CH2)n-chinoline, -O-(CH2)n-pyrazinyl, -O-(CH2)n-naphthyl, -O-(CH2)n-C(O)-(CH2)n-naphthyl, -O-(CH2)n-C(O)O-(CH2)n-naphthyl, -O-(CH2)n-C(O)NR9-(CH2)n-naphthyl, -(CH2)q-OH, -(CH2)qOC(O)R9, -(CH2)qOC(O)-NR9R10, -(1-cyclohexyl-1H-tetrazol-5-yl)C1-C4-alkoxyl, -[1-(C1-C5-alkyl)-1H-tetrazol-5-yl] -C1-C4- alkoxyl, -[1-(phenyl)-1H-tetrazol-5-yl]C1-C4-alkoxyl [where phenyl optionally substituted one, two or tre is C4-alkyl)], -[1-(pyridinyl)-1H-tetrazol-4-yl] C1-C4-alkoxyl, -[1-(1-phenylethyl)-1H-tetrazol-5-yl]C1-C4-alkoxyl, or-C1-C4-alkoxyl;

more preferably,

(I) R5, R6, R7and R8each denotes a hydrogen atom, or

(II) R5, R6and R8each denotes a hydrogen atom and R7selected from-O-(CH2)n-phenyl (where the phenyl optionally substituted one, two or three C1-C5-alkyl, C1-C4-alkoxyl, halogen or trifluoromethyl), -C C-phenyl (where the phenyl optionally substituted one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen or trifluoromethyl), or -(CH2)n-phenyl (where the phenyl optionally substituted one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen or trifluoromethyl), or

(III) R5and R6denote hydrogen, R8denotes a hydrogen atom or halogen, or C1-C5-alkyl, and R7selected from-O-(CH2)n-phenyl (where the phenyl optionally substituted one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen or trifluoromethyl), -O-(CH2)n- the 4
-alkoxyl, halogen or trifluoromethyl), -O-(CH2)n-naphthyl, -CH2-phenyl (where the phenyl optionally substituted one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen or trifluoromethyl), -(CH2)p-pyridinyl (where pyridinyl optionally substituted one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen or trifluoromethyl), -(CH2)p(1-piperidinyl), -(CH2)p(1-pyrrolidinyl) or -[1-cyclohexyl-1H-tetrazol-5-yl]C1- C4-alkoxyl; or

(IV) R5, R7and R8each denotes a hydrogen atom and R6denotes-NH-C(O)-O-CH2is phenyl.

X most preferably represents CH.

Y most preferably represents 4-morpholinyl.

R8preferably denotes a hydrogen atom or a C1-C5-alkyl, more preferably hydrogen atom or methyl.

Accordingly, the present invention includes a new 2-amino(4H)-1-benzopyran-4-ones and 2-aminoalkyl(4H)-1-benzopyran-4-ones of formula I, when X is CZ, and antiatherosclerotic the suitability of these compounds, as well as examples of obtaining and testing antiatherosclerotic aeriana carbon of various hydrocarbon components are indicated by the prefix, denoting the minimum and maximum number of carbon atoms in the component, that is, the prefix Ci-Cjshows the content of carbon atoms of the integer i to the content of carbon atoms integer j, inclusive. So, C1-C3-alkyl refers to alkyl having from 1 to 3 carbon atoms, inclusive, or stands, ethyl, propylene and isopropyl.

Related to the above, C1-C4-alkyl represents methyl, ethyl, propyl or butyl, including isomeric forms. Similarly, C1-C6-alkyl represents methyl, ethyl, propyl, butyl, pentyl, hexyl and isomeric forms.

The term "halogen" includes fluorescent, chloro, bromo and iodo.

Examples of C1-C8-alkylthiomethyl are methylthiomethyl, ethylthiomethyl, propylthiouracil, butylthioethyl, petitioner, exitialis, getitimer, and their isomeric forms.

Examples of C1-C8-alkoxymethyl are methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, intoximeter, butoxymethyl, intoximeter, exactimate and hepoxilin, and isomeric forms.

Examples of heterocyclic amines, the corresponding heterocyclic Aminova is, ,6-dimethyl-4-morpholine, 1-pyrrolidino, 4-methyl-1-piperazine, 1-piperidine, 4-phenyl-1-piperidine, thiazolidine, 3-piperidine-methanol, 2-piperidine-methanol, pipecolinate acid, 3-piperidine-ethanol, 2-piperidine-ethanol, 1-piperidine-propanol, p-piperazineethanol, 4-phenyl-1,2,3,6-tetrahydropyridine, 4-phenylpiperidine, Proline, 1-(3-hydroxy)pyrrolidine, tetrahydrofuran, pyrrolidin-methanol, 3-pyrrolin, thiazolidin-4-carboxylic acid, thiomorpholine, nipecotate, 2-methylpiperidine, 3 methylpiperidine, 4-methylpiperidine, N-methylpiperazine, 1-methylhomopiperazine, 1-acetylpiperidine, N-carbomethoxybiphenyl, 3-methylpiperazin-2-carboxylic acid, 2-methylpiperazin, 2,3,5,6-tetramethylpyrazine, 1,4-dimethylpiperazine, 2,6-dimethylpiperazine, 2-methyl-1-phenylpiperazine, 1-(1-phenylethyl)piperazine, 1-(2-pyrazinyl)piperazine, 1-cyclopropylmethyl, 1-cyclobutylmethyl, 1,2,3,4-tetrahydroisoquinoline, imidazole, homopiperazin, as well as their pharmaceutically acceptable salts and hydrates.

Examples of-O(CH2)p(N-methylpiperidin-3-yl) [2-(N-methylpiperidin-3-yl)ethyl] hydroxy, [3-(N-methylpiperidin-3-yl)propyl]oxy, [4-(N-methylpiperidin-3-yl)butyl]oxy.

Examples of-O-(CH2)pNR9R10include [2-(1-piperidinyl)ethyl]oxy, [2-(4-Mohali is-(diethylamino)pentyl] hydroxy, [2-(4-benzylpiperazine)ethyl]oxy and [3-N,N-aminobutiramida)propyl]oxy.

Examples of-O-(CH2)pOR15include (2-methoxyethyl)oxy, (3-butoxypropyl)hydroxy, (4-phenoxybutyl)hydroxy, (2-benzyloxyethyl)hydroxy, [2-[2-(1-piperidinyl)ethoxy]hydroxy [3-(3-picolylamine)propyl]oxy.

Examples -(CH2)npyridinyl are 2-pyridyl, 3-pyridylmethyl and 4-pyridylethyl.

Examples -(CF2)npiperidinyl are 1-piperidinyl, 1-piperidinylmethyl, 2-(1-piperidinyl)ethyl and 3-(1-piperidinyl)propyl.

Examples of -(CH2)qNR9R10include (1 piperidinyl)methyl, 2-(4-morpholinyl)ethyl, 3-(1-pyrrolidinyl)propyl and 4-(1-piperazinil)butyl.

Examples -(CH2)nC(O)-(CH2)nR9is acetylethyl, methylacetylene, methylacetylene, phenylacetyl, phenylacetylene, 2-(phenylacetyl)ethyl, 2-pyridylethyl, 3-pyridylcarbonyl, 3-(tert.-butylacetyl)propyl and 4-(atlacatl)butyl.

Examples of -(CH2)nC(O)O-(CH2)pR9include carbomethoxy, carbomethoxyamino, 2-(carbomethoxy)ethyl, carbapenemase, carboranylmethyl, 2-[Carbo(3-pyridyl)methoxy] ethyl carboethoxy and 3-(turboprops) propoxy.

UB>,

-(CH2)C(O)O-(CH2)2(CH3)phenyl, -(CH2)3-C(O)O-(CH2)3(1-pyrrolidine),

-(CH2)3C(O)O-(CH2)2(1-piperidinyl), -(CH2C(O)O-(CH2)2(4-morpholinyl). Examples -(CH2)nC(O)(CH2)nNR9R10are -(CH2)C(O)(CH2)-N(ethyl)2,

-(CH2)2C(O)(CH2)2N(methyl)phenyl, -C(O)-(1-pyrrolidine), -(CH2)2C(O)(CH2)3(1-piperidine) and -(CH2)3C(O)(CH2)(4-morpholine).

Examples of-O-(CH2)nC(O)-(CH2)pR9are-O-(CH2)C(O)-(CH2)(CH3)

-O-C(O)-(CH2)2(CH)3, -O-(CH2)3C(O)-(CH2)phenyl, -O-(CH2)2C(O)-(CH2)3(2-pyridyl), -O-(CH2)C(O)-(CH2)2(3-pyridyl)- O-(CH2)4C(O)-(CH2)4(rubs. -butyl).

Examples of-O-(CH2)nC(O)O-(CH2)pR9include-O-(CH2)C(O)O-(CH2)(CH3)

-O-C(O)O-(CH2)2(CH3), -O-(CH2)2C(O)O-(CH2)3(phenyl) and-O-(CH2)3C(O)O-(CH2)2(3-pyridyl).

Examples of-O-(CH2)nC(O)-(CH2)nNR9R10include-O-(CH2)C(O)-(CH2)N(CH-N-methylpiperazin), -O-(CH2)2C(O)-(CH2)2(4-morpholine), -O-(CH2)C(O)-(CH2)3(cyclohexylamin), -O-(CH2)2C(O)-(CH2)3(rubs. -butylamine), -O-(CH2)C(O)-(CH2)2)(1-phenylethylamine), -O-(CH2)C(O)-(CH2)2(aniline), -O-(CH2)C(O)-(CH2)(1-phenylalanine, methyl ester), -O-(CH2)2C)O)-(CH2)3(3-pyridylamino).

Examples of-N(R9)(CH2)nG(O)- (CH2)nR10is-N(CH3)C(O)-(CH3), -N(H)(CH2)2C(O)-(CH2)(phenyl), -N(H)(CH2)C(O)-(CH2)2(3-pyridyl)- N(CH3(CH2)3C(O)-(CH2)(CH3).

Examples of-N(R9)(CH2)nC(O)O- (CH2)nR10are-N(H)(CH2)C(O)O-(CH3)

-N(H)-(CH2)2C(O)O-(CH2)(benzyl), -N(H)-(CH2)2C(O)O-(CH2)(3-pyridyl)- N(CH3)-(CH2)C(O)O-(CH2)2(tert.-butyl).

Examples of-N(R9)(CH2)nC(O)- (CH2)nR9R10include-N(H)(CH2)C(O)(CH2)N(CH3)2, -N(H)C(O)-(CH2)(1-pyrrolidine), -N(H)(CH2)2C(O)-(CH2)2(1-piperidine) and-N(CH3)(CH2C(O)-(CH2)2(4-morpholine).

Examples of-O-(CH2)n-f is Tyl-4-forfinal)butoxy, 2-(2-methoxyphenyl)ethoxy, 3 methoxybenzyloxy, 4-carbomethoxyamino, 2-(3,4-dichlorophenyl)ethoxy, 4-ethoxyphenylacetic, 3-(4-nitrophenyl)propoxy, 4-tert.-butylphenoxy, 4-benzyloxyaniline and 2-(3-triptoreline)ethoxy.

Examples of-O-(CH2)n-pyridines are 2-pyridyloxy, 3 pyridyloxy and 2-(4-pyridyl)ethoxy.

Examples of-O(CH2)nC(O)-(CH2)n-pyridine are-O(CH2)C(O)-(CH2(2-pyridine), -O(CH2)3C(O)-(CH2)(3-pyridine) and-0-(CH2)2C(O)-(CH2)3)(4-pyridine). Examples of-O-(CH2)nC(O)O-(CH2)n- pyridine are-O-(CH2)C(O)O-(CH2)(2-pyridine), -O(CH2)3C(O)O-(CH2)(3-pyridine) and-O(CH2)2C(O)O-(CH2)3(4-pyridine). Examples of-O-(CH2)nC(O)-N(R9) (CH2)n-pyridine are-O(CH2C(O)-N(CH3)(CH2)(2-pyridine), -O(CH2)2C(O)-N(CH3)(CH2)(3-pyridine) and-O(CH2)C(O)-N(benzyl)(CH2)2(4-pyridine).

Examples of-O-(CH2)n-khinoksalinona include 2-hinoksolinov, 2-chynoxalinilmethylen and 2-(2-honokalani)ethoxy.

Examples of-O-(CH2)n-ginalynn include 2-hyalinelike, 2-hyalinella is dimetoxy and 2-(2-pyrazinyl)ethoxy.

Examples of-O-(CH2)n-naphthyl are 1 naphthyloxy, 2-aftermatket and 2-(1-naphthyl)ethoxy.

Examples of-O-(CH2)nC(O)-(CH2)n- naphthyl include-O-(CH2)C(O)-(CH2(1-naphthyl), -O-(CH2)2C(O)-(CH2)(2-naphthyl), -O-C(O)-(CH2)(1-naphthyl)- O-(CH2)2C(O)-(CH2)2(2-naphthyl).

Examples of-O-(CH2)nC(O)O-(CH2)n- naphthyl are-O-(CH2)C(O)O-(CH2)(1-naphthyl), -O-(CH2)2C(O)O-(CH2)(2-naphthyl), -O-C(O)O-(CH2)(1-naphthyl)- O-(CH2)2C(O)O-(CH2)2(2-naphthyl).

Examples of-O-(CH2)nC(O)NR9- (CH2n)-naphthyl include-O-(CH2)C(O)N(H)(CH2(1-naphthyl), -O-(CH2)2C(O)N(CH3(CH2)2(2-naphthyl)- O-(CH2)C(O)N(benzyl)(CH2)3(1-naphthyl).

Examples -(CH2)q-OH are hydroxymethyl, hydroxyethyl and hydroxybutyl.

Examples (CH2)qOC(O)R9include (CH2)OC(O)methyl, (CH2)2-(CH2)2OC(O)ethyl,

(CH2)3OC(O)phenyl, (CH2)4OC(O)(3-pyridyl) and (CH2)-OC(O)thiophene.

Examples -(CH2)qOC(O)-NR9R10are -(CH2)OC(O)-N(CH2)2, -(CH2>OC(O)-N-benzylamine.

Examples -(1-cyclohexyl-1H-tetrazol-5-yl)C1-C4- alkoxy, -[1-(C1-C5-alkyl)-1H-tetrazol-5-yl] C1-C4-alkoxy include -(1-cyclohexyl-1H-tetrazol-5-yl)methoxy, -(1-cyclohexyl-1H-tetrazol-5-yl)ethoxy, -[1-(methyl)-1H-tetrazol-5-yl)methoxy, -[1-(cyclopropyl)-1H-tetrazol-5-yl]ethoxy, -[1-(1-tert. -butyl)-1H-tetrazol-5-yl] propoxy -[1-(cyclopentyl)-1H-tetrazol-5-yl]methoxy.

Examples -[1-(phenyl)-1H-tetrazol-5-yl]C1-C4-alkoxy (where the phenyl optionally substituted one, two or three C1-C4-alkyl, C1-C4-alkoxyl, halogen or by trifluoromethyl) are -[1-(phenyl)-1H-tetrazol-5-yl]methoxy, -[1-(phenyl)-1H-tetrazol-5-yl] ethoxy, -[1-(4-methoxyphenyl)-1H-tetrazol-5-yl] methoxy, -[1-(4-forfinal)-1H-tetrazol-5-yl]propoxy.

Examples -[1-(pyridinyl)-1H-tetrazol-5-yl] C1-C4- alkoxy or -[1-(1-phenylethyl)-1H-tetrazol-5-yl] C1-C4-alkoxy are -[1-(2-pyridinyl)-1H-tetrazol-5-yl]methoxy, -[1-(3-pyridinyl)-1H-tetrazol-5-yl]ethoxy, -[1-(4-pyridinyl)-1H-tetrazol-5-yl] propoxy, -[1-(1-phenetyl)-1H-tetrazol-5-yl]methoxy, -[1-(1-phenetyl)-1H-tetrazol-5-yl]ethoxy.

Tertiary amines and aromatic heterocyclic amines in accordance with this and what edenia compounds of the present invention, and include hydrochloride, bromohydrin, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate, and the like. These salts may be in hydrated form.

The compounds of formula I differ expressed antiatherogenic activity, which makes these compounds useful in the treatment and prevention of atherosclerosis.

Because of the known similar compounds described in Mazzei, Farmaco, Ed. Sci, 41: 611 (1986) possess anti-allergic activity, it was amazing, that the compounds of formula I have anti-atherosclerotic effect or are inhibitors of platelet aggregation or cell proliferation.

A strong step 2-morpholinylcarbonyl formula I of this application against ADP-induced platelet aggregation (at a concentration of 8.0 µm) clearly show given in tables I - III data. Please note that a number of compounds have the IC50less [all values are average SD (n = 3)].

2-Morpholinopropan has IC50equal to 154 μm, effective against ADP-induced platelet aggregation (ADP = 8.0 µm). Please note that not all 2-morpholinopropan have IC50< 154 μm against ADP-induced aggregation TTL. Many of the compounds of formula I are inhibitors of cell proliferation (it was not yet known 2-aminopropanol). The 1:1 ratio exists between the inhibition of ADP-induced platelets and inhibition of cell proliferation.

Publication Mazzei et al. [Document D6; Eur. J. Med. Chem. 23, 237-242 (May-June 1988)] does not disclose and does not offer any 12-morpholinopropan. Moreover, Mazzei reported in table II (page 240) IC50= 200-750 μm for most compounds at a concentration of ADP (5.0 µm). Mazzei indicates that the highest activity was found in the test of Romanov containing the 2-amino substituent of diethylamino group. Indeed, 2-(diethylamino)-7-hydroxychromone (Compound 5q) had IC50equal 250160 at a concentration of ADP (5.0 µm). According to Mazzei et al acetylsalicylic acid has the IC50= 1000 μm at a concentration of ADP (5.0 µm).

With regard to toxicity, it was fully tested one of the compounds (Y = morpholinyl, X = CH, R5and R6= H, R7= -O(CH)2-4-methyl-piperazine, R8= methyl). 8-Methyl-7-(2-(4-methyl-1-piperazinil)ethoxy)-2-(4-morpholinyl)-4H-1 - benzopyran-4-one with the introduction of in vitro in rats during 14 days not shown any toxicity. Based on this you can Dellosa 2-(4-morpholinyl)-4H-benzopyran-4-one (N 2), 2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one (98 N), 8-methyl-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one (N 84), 2-(1-(4-thiomorpholine)-4H-1,3-benzoxazin-4-one (N 95) and 2-(4-methyl-1-piperazinil)-4H-1,3-benzoxazin-4-one (N 96), reduce blood cholesterol accumulation in the model SEA of Japanese quail. Reduction of blood cholesterol is accompanied by low levels of serum cholesterol when using compounds N 84 and 95, but not with the compounds N 2, 98 and 96. Normal cholesterinspiegel Japanese quail SEA there is a decrease in serum cholesterol when using connection N 84. Ref description model Japanese partridges see Day C. E. et al., "Utility of a Selected Line (SEA) of the Japanese Quail (Coturnic Coturnix japonica) for the Discovery of New Anti-Atherosclerotic Drugs, Laboratory Animal Science 27: 817-821 (1977).

Preferred antiatherosclerotic compounds include compounds N 2, 3, 19, 51, 72, 76, 84, 95, 96, 98, 112, 139, 163, 164, 171 and 204.

In addition, various compounds of formula I are also strong inhibitors of cell proliferation and is suitable in the treatment of proliferative diseases such as cancer, rheumatoid arthritis, psoriasis, pulmonary fibrosis, scleroderma, cirrhosis, and for advanced usage of artificial prosthetic devices, t is prohodymosty or restenosis of the arteries by the subsequent introduction of the drug in such cases, as bypass surgery, coronary bypass surgery, plastic surgery on the blood vessels (and other techniques aimed at re-restoring capacity in occluded or partially occluded vessels, i.e. atherectomy, laser or ultrasonic techniques), grafts and post restenosis.

The compounds of formula I, which are inhibitors of cell proliferation are those that are active in the test method described Pledger, W. J., C. D. Stiles , Antniades H. N. and C. D. Scher Proc. Natl. Acad. Sci. (USA) (1977). Examples of inhibitors of cell proliferation are compounds N 1-14, 16-17, 19-23, 25 and 26, 30-34, 36-39, 42, 46-48, 51, 52, 54-46, 58-76, 81, 100-103, 105-112, 120-122, 125-133, 135-145, 149, 155 and 156, 158-160, 163, 166, 171, 173-180, 183-190, 193, 204 and 207.

In addition, various compounds of formula I are inhibitors of platelet aggregation induced by adenosine 5'-diphosphate (ADP), and are useful in the prevention or treatment of thrombotic diseases and related complications, for example, by inhibition or treatment of platelet aggregation or adhesion of platelets or blood clotting.

The compounds of formula I are inhibitors of platelet aggregation, those that are active in the method ispytyvaut connection N 2-3, 5-6, 9-11, 13, 20-22, 25-26, 28, 31-32, 34, 36-38, 51-53, 56, 58-59, 63, 65, 72-76, 80, 100, 102, 104, 106-107, 109-113, 115, 116, 118, 120-123, 125-131, 133, 136-140, 147, 149, 154-160, 162-167, 169, 171, 172, 178, 181-188, 192-198 and 207.

Accordingly, when using the compounds of formula I for the prevention or treatment of atherosclerotic disease or thrombotic diseases of the oral route of administration, or traditional oral dosage form or mixed with food are the preferred method of system administration. Alternatively, these compounds can be entered in other ways, which lead to the achievement of system activity. These routes of administration include rectal, vaginal, subcutaneous, intramuscular, intravenous, and others.

When using compounds of formula I for the plastic surgery on the blood vessels oral route of administration is the preferred method of system administration. Alternative these compounds may be introduced in other traditional ways, which can lead to system activity.

People and animals should receive periodic dose of the medication in amounts effective for reducing serum and/or blood cholesterol, and to reduce the size armeniangenocide or treatment of platelet aggregation adhesion of platelets or blood clotting, or to prevent blockage of blood vessels or vascular injury associated with techniques such as bypass grafts, coronary bypass grafts, angioplasty, restenosis post and grafts.

Such effective dose is easily determined by known methods. For example, a small daily dose of the drug (for example, from 0.01 to 200 mg/kg) can be entered initially with higher subsequent doses. Thus, the compound of formula I initially administered at a dosage of about 0.01 mg/kg weight of the patient per day, with the consequent increase of the dose up to 200 mg/kg of body weight of the patient per day. In that case, if the response of the patient receiving 200 mg/kg / day medications, insufficient, use a higher dose depending on the stamina of the patient.

Despite the fact that the regimen of medicines based on the introduction of single doses, to obtain a more uniform serum levels of drugs preferred multiple doses per day (for example, up to 4-6 times daily). Accordingly, with the introduction of four daily doses of medicines each dose should contain about 50 mg/described for mammals animals for example, from 0.01 to 200 mg/kg/day.

Schemes A-I disclose various methods for obtaining the compounds of formula I In these graphs X, Y, R5, R6, R7, R8,R9and R10have the above values.

Scheme A: compounds of formula I are obtained by mixing a complex ester of salicylic acid with pure morpholine-enamino or in an organic solvent under stirring. After a few minutes add the tertiary amine base, such as tea (triethylamine), and the reaction mixture is stirred for a certain time. The product can be distinguished by recrystallization or column chromatography.

Scheme B: the compounds of formula I are obtained by interaction of orthokeratology with amidamaru, for example, N,N-dimethylformamidine, obtaining winlogonexe amide. The processing of this amide halogen (Br, Cl, I or F) in an organic solvent, such as CHCl3or CHCN, then lets get a 3-holochrome. Processing of this alohamora amines, either pure or in the presence of organic solvents, allows you to get the required 2-aminopropane.

Scheme C: the compounds of formula I are obtained by processing orthokeratology serogonin. Processing the received mercaptan corresponding amine allows to obtain 2-aminochrome.

Scheme D: compounds of formula I is produced by hydrogenation of the corresponding analogs of benzilate, which is produced by the methods described in schedules A, B and C, followed by alkylation of the resulting phenol.

Scheme E: these compounds can be obtained by treatment of o-hydroxyacetophenone iminium salt, such as morpholine 4-phosgene-imini chloride, in the presence of epirate boron TRIFLUORIDE. Subsequent hydrolysis and alkylation allows you to get the required connections.

Scheme F: the above compounds of formula I can be obtained by treating o-hydroxyacetophenone containing sulphonate group trifloromethyl, iminium salt, such as 4-morpholine-dichloromaleimide chloride, in the presence of epirate boron TRIFLUORIDE. Subsequent hydrolysis and alkylation allow to obtain 2-aminochrome. Treatment 2-aminopropane acetylene in the presence of a palladium catalyst, such as dichloride (bis)triphenylphosphine palladium, and copper iodide allows to obtain 2-aminopropan with a substituted acetylene. Hydrogenation of acetylene results in the desired derivative.

the folin-dichloromaleimide, in the presence of epirate boron TRIFLUORIDE, followed by hydrolysis and alkylation of intermediate compounds allows to obtain 2-aminochrome. Treatment 2-aminopropane reagent tetraalkyllead in the presence of a palladium catalyst, such as dichloride (bis)triphenylphosphine, and salt, such as lithium chloride, yields a 2-aminopropane, substituted alkyl Deputy.

Scheme H: compounds of formula I can be obtained by treating 4-benzyloxy-2-hydroxy-3-methylacetophenone sodium hydride, then ethyl-methylthiourea and finally acid to obtain 7-benzyloxy-8-methyl-2-methylthiomethyl-4H-[1] -benzopyran-4-it. Treatment of this compound with methyliodide leads to the corresponding 7-benzyloxy-8-methyl-2-iodomethyl-4H-[1] -benzopyran-4-it. Treatment of this compound corresponding amine allows to obtain the compounds of formula I. the compounds of formula I are also obtained by treatment of compounds of formula I, such as 7-benzyloxy-8-methyl-2-(4-morpholinylmethyl)-4H-[1] -benzopyran-4-one, a catalyst based on a metal of the transition series in hydrogen atmosphere, which allows to obtain 7-hydroxy-8-methyl-2-(4-morpholinylmethyl)-4H-[1] -benzopyran-4-one. Alkylation Dunn is the compounds of formula I can also be obtained by hydrogenation of R5-8benzyloxy 2-amino-4H-1-benzopyran-4-she with subsequent alkylation of the resulting phenol, as shown in figure 1.

Obtaining the compounds of the present invention is illustrated in detail by the following examples:

Procedure 1: Getting 1-ethynylnaphthalene

Part a: Getting trichloroacetaldehyde

Morpholine (4.0 ml, 45 mm) was dissolved in EtOAc (50 ml) was added saturated K2CO3(40 ml). The mixture was besieged in an ice bath, then drop by drop added trichloroethylene (5.0 ml, 45 mm). The reaction mixture was stirred for 20 min, and then diluted with EtOAc (200 ml) and washed with water K2CO3(20 ml), water (I ml) and brine (30 ml). The organic layer was dried with magnesium sulfate. After evaporation using a rotary evaporator received trichloroacetimidates. So pl. 80-81oC.

1H-Yarm (300 MHz, DCl C3) 3,81-3,76 m

UV EtOH 224 (4,520)

IR (mull) 2955, 2926, 2859, 1657, 1431, 1270, 1239, 1116, 962, 852, 848, 842, 810, 777.

MS(m/e (relative intensity) 233 (12), 231 (12), 115 (8). 114(100), 86(10), 70(67), 56(26), 42(20), 28(18), 27(8).

VRMS (high resolution mass spectroscopy) for C6H8NO2C13:

Calculated: 230,9621; found: 230,9629.

Elementary analysis for C6<="ptx2">

Part B: Getting trichlorovinylsilane

Trichloroacetimidate (8,3 g, 36 mm) was dissolved in toluene, and then was added triphenylphosphine (9,44 g, 36 mm). The mixture was heated under reflux for 1.5 h, and then cooled, and the solvent was removed in vacuum. The residue was subjected to fractional distillation under reduced pressure and resulted trichlorovinylsilane. So Kip. 85-87oC, 20 mm RT.article.

Part C. Obtaining turtleninja

Trichlorovinylsilane (5.50 g, 24,5 mm) was dissolved in anhydrous simple ether (30 ml) under nitrogen atmosphere. The mixture was cooled to -30oC and slowly added utility (50 ml, 1.5 M, 75 mm), after which the mixture was heated to a temperature of 23oC for 2 hours Then the mixture was cooled to -30oC and poured into cold 20% ammonium hydroxide (20 ml), was added a simple ether (50 ml) and the solution was quickly divided. The organic layer was filtered through anhydrous K2CO3(5 cm) and concentrated in vacuo, resulting in the obtained oily substance yellow-orange color, which was subjected to fractional distillation (0.9 mm RT.art., So Kip. 53oC) and received inamin, 1-tinymotion in the form of colorless product (1.1 g, 40%).

IR (film) 2970, 2940, 2870, 2137, 1647, 1458, 1382, 6-chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-it

Connection 1.

Methyl ester 5-chlorosalicylic acid (2.00 g, 10,7 mm) drop was mixed with tinymotion (clean 1,00 g, 9,00 mm). This reaction is exothermic. After cooling, the mixture was added triethylamine (TEA, 1 drop) and the liquid mixture immediately crystallized. The resulting mixture was chromatographically (a thin layer of SiO2CH2Cl2/EtOH, 95:5) was obtained 6-chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one(1.07 g, 45%). So pl. 194-195oC.

IR (mull) 2949, 2946, 2855, 1640, 1615, 1566, 1464, 1450, 1437, 1345, 1246, 1118, 822, 787 cm-1;

1H-NMR (CDCl3, 200 MHz) 8,11-(d,J=2.5 Hz, 1H); 7,49 (dd, J=8,7, 2.5 Hz, 1H); 7.23 percent (d,J=8.7 Hz, 1H); 5,49 (s, 1H); 3,85-3,82 (m, 4H); 3,53-to 3.50 (m, 4H);

UV (EtOH)max() 217 (31,360), 230 (24,900), 245 DM (12,100), 290 MD(11,170), 301 (15,810), 315 (16,070);

MS; ions at m/e (relative intensity) 267 (35), 265 (100), 210 (24), 209 (22), 208 (74), 207 (31), 180 (47), 154 (27), 126 (19), 52 (21);

VRMS for C13H12NO3Cl: calculated 265,0506; found 265,0512

Elementary analysis for C13H14NO3Cl

Calculated: C 58,77; H 4,55; N 5,27; Cl 13,34,

Found: C 58,52; H Of 4.66; N 5,11; Cl Of 13.58.

Repeating the procedure of example 1, but instead of the methyl ester 5-chlorosalicylic acid used appropriate on-gidroksikislotny methyl ester, which hung in the resulting received the following connections:

Conn. 2: 2-(4-morpholinyl)-4H-1-benzopyran-4-one,

So pl. 160-161oC;

Conn.4: 7-chloro-2-(4-morpholinyl(4-H-1-benzopyran-4-one,

So pl. 160-161oC (CH2Cl/EtOH);

Conn.5: 8-chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one,

So pl. 190-191oC (CH2Cl2/Et2O);

Conn.6; 6-bromo-2-(4-morpholinyl)-4H-1-benzopyran-4-one,

So pl. 164-165oC (CH2Cl2/Et2O);

Conn.7: 6-fluorescent-2-(4-morpholinyl)-4-H-benzopyran-4-one,

So pl. 198-199oC (CH2Cl/Et2O);

Conn.8: 6-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one,

So pl. 166-167oC (CH2Cl2/Et2O);

Conn.9: 7-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one,

So pl. 163-164oC(CH2Cl2/Et2O);

Conn.10: 8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one,

So pl. 169-170oC (from EtOAc/hexane);

Conn. 11: 6-methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 148-149oC (from EtOH/CH2Cl2);

Conn. 12: 7-methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 173-174oC (from EtOH/hexane);

Conn. 13: 6-(phenylmethoxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 210-212oC;

Conn. 14: 8-(phenylmethoxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 192-194oC;

Conn. 15: [2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-6-yl]-1,1 - dimethylethyl is S="ptx2">

Example 17. Getting 2-(morpholinyl)-6-nitro-4H-1-1-benzopyran-4 - it. The connection 17:

Ethyl ester of 5-nitrosalicylic acid (634 mg, 3.0 mm) was dissolved in tea (2.0 ml) was added morpholinium. The mixture is stirred for 48 hours. Then the reaction mixture was diluted with EtOAc (200 ml) and washed with water (5 x 25 ml), brine (30 ml) and was dried with magnesium sulfate. After evaporation of the solvent the product was chromatographically on silica gel (50 g, 4% EtOH/CH2Cl2), resulting in a received 182 mg (22%) of the desired product. So pl. 258-259oC.

1H-NMR (CDCl3, 300 MHz) 9,05 (d,J=2,9 Hz, 1H) 8,44 (dd,J=8,7, 2,9 Hz, 1H); 7,46 (d, J=9,3 Hz, 1H); 5,69 (s, 1H); 3,91-3,86 (m, 4H); 3,61 of 3.56 (m, 4H); UV (EtOH) 226 (23,700), 234 MD. (19,000), 282 (17,600), 316 (15,000);

VRMS (m/e) (relates. intens.) 277 (28), 276 (100), 261 (38), 219 (80), 218 (53), 191 (38), 172 (19), 55 (30), 53 (35), 41 (31);

IR (mull) 2954, 2924, 2856, 1637, 1627, 1604, 1565, 1447, 1422, 1347, 1253, 1126, 740, 638;

VRMS for C13H12N2O5calculated 276,0746; found 276,0742.

Elemental analysis for C13H12N2O5< / BR>
Calculated: C 56,52; H to 4.38; N 10,14,

Found: C 56,32; H To 4.52; N, 10,16.

Example 18. Obtaining 2-(4-morpholinyl)-4H-pyrano[2,3 b]pyridine-4-it. The connection 18:

Methyl ester of 2-hydroxy-3-carboxamidine (300 mg, 1.9 mm) was dissolved in tocci was heated to 10oC for 24 h the Mixture was cooled and purified using flash chromatography (CH2Cl/EtOH, 95: 5) and received chrome in the form of pale yellow crystals (270 mg, 63%). So pl. 190-191oC;

IR (mull) 2924, 2868, 2855, 1652, 1639, 1611, 1590, 1557, 1453, 1405, 1250, 1120, 788, 602 cm-1;

1H-NMR (CDCl3, 200 MHz) : at 8.60 (s, 1H); to 8.57 (dd,J=3.2, and 2.4 Hz, 1H); 7,45 (m, 1H); to 5.56 (s, 1H); 3,92-a 3.87 (m, 4H); 3,68 2.63 in (m, 4H);

UV (EtOH) max() 215 (16,740), 243 (10,250), 281 DM. (8,330), 289 (10,500), 320 (15,320);

MS: ions at m/e (relates.intens.) 233 (14), 232 (100), 217 (17), 175 (37), 174 (39), 146 (15), 122 (17), 79 (34), 53 (15), 42 (14);

Elemental analysis for C12H12N2O3< / BR>
Calculated: C 62,06; H to 5.21; N 12,06,

Found: C 68,85; H 5,18; N 11,88.

Example 19. Obtain 6-[[(phenylmethoxy)carbonyl]amino]-2- (4-morpholinyl)-4H-1-benzopyran-4-it.

The connection 19:

Methyl ester of 2-hydroxy-5-[[phenylmethoxy)carbonyl] amino]benzoic acid (1.0 g, 3.3 mm) was added to the CH2Cl2(1 ml) and cooled to 0oC. To the specified solution was added inamin (366 mg, net), and then one drop was added a few drops of tea. The reaction solution became yellow, and after stirring at room temperature for 18 hours the solution was heated in an oil bath for 6 hours at 80oC. the Solid product image is Tate 350 mg (19.4%) of the target product. An analytical sample was obtained by recrystallization from CH3CN. So pl. 245-250oC.

IR (mull) 3263, 2947, 2925, 2921, 2867, 2854, 1716, 1638, 1623, 1577, 1564, 1558, 1464, 1456, 1453, 1404, 1246, 1231, 1121, 731 cm-1;

1H-NMR (CDCl3) : 8,15 (d, 1H, J=2 Hz); of 7.95 (s, 1H); 7,87 (s, 1H); and 7.3 (m, 7H); 5,42 (s, 1H, vinyl); and 5.2 (s, 2H); 3,7 m, 4H);

UV (EtOH)max() 231 (27,520), 246 (34,960), 300 DM. (16,300), 307 (17,830), 320 SD. (12,800);

MS: ions at m/e (relative. intens.) 380 (17), 335 (12), 272 (100), 215 (69), 187 (44), 161 (32), 108 (79), 91 (87), 79 (99), 53 (32), 44 (50);

Elemental analysis for C21H20N2O5< / BR>
Calculated: C 66,31; H 5,26; N OF 7.36,

Found: C 66,40; H 5,28; N 7,30.

Example 20. Getting 8-methoxy-2-(4-morpholinyl)-4H-1 - benzopyran-4-it. The connection 20:

Method a: Methoxysalicylaldehyde (750 mg, 4 mm) was dissolved in THF (4 ml) and cooled to 0oC. Morpholinium (445 mg, 4.0 mm) was dissolved in THF (4 ml), and then one drop was added to the cooled solution of the acid chloride. Immediately after adding the formed white precipitate, and after stirring for 20 min was added TEA (of 0.60 ml, 4.5 mm), and then the reaction temperature was raised to 23oC. After heating in a flask under reflux for 20 min, the reaction mixture was cooled to room temperature and THF was removed in vacuum. The crude reaction mixture of peristaltically received 115 mg (12%) of the desired product. So pl. 184-186oC.

IR 2952, 2925, 2870, 2855, 1642, 1625, 1618, 1581, 1575, 1463, 1455, 1410, 1350, 1250, 1244, 1116, 773 cm-1;

UV (EtOH)max() 212 SD. (20,710), 236 (25,000), 250 DM. (12,000), 301 (17,800);

1H-NMR (CDCl3) 7,74 (dd, 1H, J=2 and 8 Hz); 7,27 (t, 1H, J=8 Hz); 7,10 (dd, 1H, J= 2 and 8 Hz); 5,52 (s, 1H); of 3.96 (s, 3H); 3,88 (m, 4H); 3,55 (m, 4H);

MC: (ions at m/e (relative. intens.) 261 (100), 204 (63), 203 (19), 176 (27), 122 (33), 77 (26), 55 (26), 57 (32), 43 (37);

Elemental analysis for C14H15NO4:

Calculated: C 64,35; H 5,76; N ARE 5.36,

Found: C 64,39; H Of 5.83; N 5,74.

Method B: 3-methoxyethylamine (547 mg, 3.0 mm) was dissolved in tea (4.0 ml) was added morpholinium (400 mg, 3.7 mm). The mixture is stirred for 48 h, then diluted with EtOAc (200 ml) and washed with water (5 to 20 ml), brine (30 ml) and dried MgSO4. After evaporation in vacuo received 690 mg of crude product. The product was chromatographically on silica gel (50 g, 4% EtOH/CH2Cl2) and received the desired product (160 ml, 20%).

Example 21. Obtain 3-amino-2-(4-morpholinyl)-4H-1-benzopyran-4-it

The connection 21:

Part A. 2-(4-Morpholinyl)-4H-benzopyran-4-one (2.00 g, 8,00 mm) was dissolved in CH2Cl2and stirring at 23oC, one drop was added nitric acid. After 2 h the mixture was heated to 60oC and added three drops Serneus material was consumed, as evidenced by TCX (EtOAc/CH3OH, 9/1). Then the reaction mixture was poured on ice (30 ml), resulting in almost immediately began to precipitate crystals. These crystals were filtered off and washed with cold water. The crude product was dissolved in ethyl acetate (200 ml) and the remaining precipitate was removed by filtration. The EtOAc layer was washed with saturated NaHCO3(2 30 ml) and brine (50 ml) and then dried with magnesium sulfate. After rotary evaporation was obtained 1.44 g (60%) of 2-(4-morpholinyl)-3-nitro-4H-1-benzopyran-4-it. Then this compound was purified by column chromatography on silica gel (EtOAc) to obtain the analytical material. So pl. 206-208oC.

IR (mull) 2954, 2925, 2869, 2856, 1646, 1620, 1599, 1575, 1487, 1467, 1445, 1435, 1422, 1379, 1341, 1325, 1116 cm-1;

1H-NMR (CDCl3) : 8,23 (dd, J=1,9, a 8.9 Hz, 1H); the 7.65 (ddd, J=2,1, 7,3, 10,2 Hz, 1H); 7,39 (m, 2H); 3,90 (m, 4H); 3,62 (m, 4H);

MC (m/e) (skidding. intens.) 276 (78), 201 (36), 187 (38), 121 (100), 120 (56), 92 (30), 79 (23), 77 (21), 73 (22), 42 (25);

UV (EtOH)max() 230 (15,730), 286 (17,000), 295 SD. (14,760), 360 MD. (1,840);

Elemental analysis for C13H12N2O5:

Calculated: C 56,52; H to 4.38; N 10,14,

Found: C 56,53; H 4,56; N 9,79.

Part B. 2-(4-Morpholinyl)-3-nitro-4H-1-benzopyran-4-one (500 mg) was dissolved in EtOAc (30 ml). In an atmosphere of nitrogen was added to the PA) for 4 h, then was filtered (celite, 1 cm), and the solution was removed in vacuum. The product was purified using flash-chromatography (EtOAc) and was obtained 3-amino-2-(morpholinyl)-4H-1-benzopyran-4-one (419 mg, 94%). So pl. 140-141oC.

IR (mull) 2954, 2925, 2856, 1621, 1607, 1551, 1466, 1423, 1382, 1277, 1271, 1240, 1115, 952, 762 cm-1;

1H-NMR (CDCl3) : 8,24 (dd, J=7,8, 2.0 Hz, 1H); 7,60 (ddd, J=6,8, 6,7, 1.8 Hz, 1H); 7,38 (br.d., J=7.8 Hz, 2H); 3,91 is 3.76 (m, 4H); 3,52-3,47 (m, 4H); 3.43 points (br.s., 2H);

UV (EtOH)max() 212 (19,150), 233 (15,180), 255 DM. (9,900), 300 (3,000); 356 (12,000);

MC: ions at m/e (relative. intens.) 262 (21), 246 (100), 201 (21), 188 (18), 187 (40), 148 (88), 121 (52), 114 (21), 70 (36), 42 (17);

Elemental analysis for C13H14N2O3:

Calculated: C 63,40; H 5,73; N 11,38;

Found: C 63,48; H Of 5.84; N 11,46.

Example 22. Obtain 3-chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-it.

The connection 22:

2-(4-Morpholinyl)-4H-benzopyran-4-one (2.0 g, 8.0 mm) was dissolved in CH1Cl2(20 ml). Then drop by drop) was added tert.-butylhypochlorite (1.0 ml, 8.5 mm) at 23oC. the Reaction mixture was slowly heated and almost instantly stopped. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (200 ml). The organic layer was washed with water (2 50 ml) and brine (80 ml) and then dried with magnesium sulfate. The solution was concentrated in vacuume%). So pl. 127-128oC.

IR (mull) 2962, 2923, 2856, 1635, 1612, 1597, 1562, 1555, 1466, 1457, 1325, 1233, 1119, 872, 762 cm-1;

1H-NMR (200 MHz, CDCl3) : to 8.20 (br.d., J=7.5 Hz); 7,60 (ddd, J=9,1, 6,7, 1.7 Hz, 1H); of 7.36 (m, 2H); 3,88 (m, 4H); 3,74 (m, 4H);

MC (m/e) (skidding. the intensity.) 267 (33), 266 (15), 265 (100), 231 (15), 230 (98), 209 (16), 207 (45), 120 (27), 110 (19), 41 (16);

UV (EtOH)max() 214 (18,900), 238 (18,160), 300 SD. (11,530);

Elemental analysis for C13H12N3Cl:

Calculated: C 58,76; H 4,55; N 5,27;

Found: C 58,82; H 4,58; N Lower Than The 5.37.

Example 23. Obtain 3-bromo-2-(4-morpholinyl)-4H-1-benzopyran-4-it.

The connection 23:

2-(4-Morpholinyl)-4H-1-benzopyran-4-one (2.0 g, 8.0 mm) was dissolved with CH2Cl2(20 ml). Then was added N-bromosuccinimide (1.6 g, 8.2 mm) and the reaction mixture was slowly heated, and the source material quickly disappeared, as was shown by TCX. The solvent was removed in vacuo and the colorless residue was dissolved in EtOAc (200 ml) and washed with water (4 30 ml), brine (50 ml) and was dried with magnesium sulfate. After evaporation in a rotary evaporator received target product of 2.27 g, 92%) as colorless crystals. So pl. 145-146oC.

IR (mull) 3337, 3016, 2922, 2871, 2855, 1698, 1609, 1585, 1502, 1462, 1378, 1367, 1341, 1303, 1295, 1260, 1234, 996, 812 cm-1;

1H-NMR (CDCl3) : by 8.22 (dd, J = 7,9, 1.8 Hz, 1H); 7,63 (ddd, J = 8,2 7,4,;

UV (EtOH)max() 216 (18,400), 238 (18,600), 317 (17,040);

BPMC: calculated C13H12NO3Br 309,0001; found 308,9990.

Elemental analysis for C13H12NO3Br:

Calculated: C 50,34; H 3,90; N TO 4.52;

Nagano: C 50,40; H Of 4.05; N, 4,46.

About the scheme B:

Example 24. Getting 8-methyl-2-(4-morpholinyl)-7-phenylmethoxy-4H-1-benzopyran-4-it.

Compound 24:

Part A. 3-(Dimethylamino)-1-(2-hydroxy-3-methyl-4-benzyloxyphenyl)-propen-1-it.

2-Hydroxy-3-methyl-4-(phenylmethoxy)-acetophenone (25 g, 98 mm) and DMF-DMA (17.9 g, 150 mm) was heated at 95-100oC for 2,75 hours the Reaction was cooled to room temperature and the excess reagent and CH3OH was removed in vacuo, resulting received a dark solid. This substance was pereirae with simple ether at 0oC and after filtering received 19,64 g (64,4%) of yellow solid product. The mother liquor also contained the product, but this product has not been allocated. An analytical sample was obtained by recrystallization from EtOAc/Skelly-B.

Part B. 3-Bromo-8-methyl-7-(phenylmethoxy)-[4H]-1-benzopyran-4-one

Vinyl amide part of A (19,0 g, 61 mm) was dissolved in CHCl3and was cooled to 0oC. and Then for 5 min on a drop of added Br3
was separated, dried with magnesium sulfate, the solvent was evaporated in vacuum and resulted 23.1 g of crude product. After recrystallization from EtOAc was obtained 15.2 g (66%) of analytically pure product.

Part C: 8-Methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one.

3-Bromopropane part B (1.0 g, 2.9 mm) was dissolved in acetonitrile (35 ml). Then was added anhydrous potassium carbonate (371 mg, 2.9 mm) followed by the addition of a drop of the research (0,252 mg, 2.9 mm). Then the mixture was stirred and heated in a vessel under reflux for 36 hours. The acetonitrile was removed in vacuo, and the organic material was dissolved in ethyl acetate. The organic phase is washed with water and brine, and then dried with magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographically on silica gel (CH2Cl2/Et2O; 2/1), which received two main factions. The first fraction contained 3-amino-substituted product.

The second fraction contained the product with a reduced cycle and the target 2-morpholinopropan. This mixture again was chromatographically (EtOAc/CH3OH; 95/5) and received two factions, more fast-moving and containing a product with a reduced ring (211 is-NMR (200 MHz, CDCl3) : to 7.64 (dd, J = 8,57, of 1.27 Hz, 1H); 7,49-7,41 (m, 5H); 6.89 in (s, vinyl, 1H), 8,84 (d, J = to 8.57 Hz, 1H); 5,22 (s, 2H); 3,89-a-3.84 (m, 4H); 3,79 is 3.76 (m, 4H); 2,30 (s, 3H);

UV (EtOH)max() 204 (25,300), 205 DM. (24,500), 252 (8,550), 258 (6,670), 321 (18,900), 377 (33,100), 391 (29,300);

BPMC: for C21H21NO4calculated 351,1470; found 351,1470.

Elemental analysis for C21H21NO4:

Calculated: C 71,78; H of 6.02; N 3,99;

Nagano: C 71,60; H X 6.15; N 3,96.

Then, continuing the elution of received target 2-morpholinopropan (Compound 24) (127 mg, 12%). So pl. 181,5-182,5oC.

IR (mull) 2953, 2925, 2864, 2857, 1637, 1612, 1592, 1675, 1413, 1274, 1272, 1251, 1240, 1119, 782 cm-1;

1H-NMR (200 MHz, CDCl3) : 8,00 (d, J = 9.1 Hz, 1H); 7,47-7,38 (m, 5H); 6,98 (d, J = 9.1 Hz, 1H); 7,47-7,38 (m, 5H); 6,98 (d, J = 9.1 Hz, 1H); 5,44 (s, 1H); 5,19 (s, 2H); 3,89-a-3.84 (m, 4H); 3,54-to 3.49 (m, 4H); of 2.33 (s, 3H);

UV (EtOH)max() 217 (33,610), 239 (23,600), 291 DM. (13,980), 312 (26,160), 376 (509);

BPMC: for C21H21NO4calculated 351,1470; found 351,1464.

Elemental analysis for C21H21NO4:

Calculated: C 71,78; H of 6.02; N 3,99;

Found: C 71,79; H Of 5.99; N 3,98.

Example 25. Obtaining 2-(4-morpholinyl)-5-(phenylmethoxy)-4H-1-benzopyran-4-it.

Compound 25:

Part a: 6-Benzyloxy-2-hydroxyacetophenone

2,6-Dihydroxyacetophenone (84,48 g, 0.55 M), benzylbromide (95 g, 0.55 M) and K< is in the atmosphere of nitrogen, vigorously stirring in a vertical mixer for 18 hours Then the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated in vacuum and received an oily semi-solid product. This product was dissolved in CH2Cl2and washed 1H. HCl. CH2Cl2the solution was dried with magnesium sulfate, the solvent was removed and received an oily light substance. This material was chromatographically on silica gel (400 g), elwira CH2Cl2in the result of which was received by 72.8 g (54,5%) of product. An analytical sample was obtained by recrystallization from EtOAc/Stelly-B.

Part B: 3-(Dimethylamino)-1-(2-hydroxy-6-benzyloxyphenyl)-propen-1-it.

A mixture of 6-benzyloxy-2-hydroxyacetophenone (15.0 g, 62 mm) and N,N-dimethylformamidine (DMF-DMA; 10,71 g, 90 mm) was heated in a nitrogen atmosphere for 2 h at 100-110oC. for several minutes to find the reaction mixture in an oil bath already at 100oC source heterogeneous mixture became homogeneous and dark in color. After another few minutes, the solid began to separate, and at the end of the reaction time, the flask was filled yellow solid substance. The reaction was cooled to room temperature, and excess DMF and drained the air, resulting received 15,41 g (83,7%) of pure product. An analytical sample prepared by recrystallization from EtOAc.

Part C: 5-Benzyloxy-3-bromo-[4H]-1-benzopyran-4-one

Vinyl amide part B (10.0 g, 33,6 mm) was dissolved in CHCl3(150 ml) and cooled to 0oC. To the resulting solution for 10 minutes drop added Br2(5,38 g, 33,6 mm) in CHCl3(50 ml). After complete addition, the reaction was diluted with water and vigorously stirred 5 minutes the Organic layer was separated, washed with brine, dried with magnesium sulfate, evaporated and was given a dark red substance. This substance was chromatographically on silica gel (400 g), elwira 1% CH3OH/CH2Cl2and after recrystallization from EtOAc/Skelly-B received a score of 4.75 g (42,8%) of product.

5-Benzyloxyresorufin part B (of 3.31 g, 10.0 mm) was dissolved in acetonitrile (50 ml). Added anhydrous potassium carbonate (1,38 g, 10.0 mm) and then was added morpholine (of 1.02 ml, 110 mm). The mixture was heated under reflux, 72 h, the Solvent was removed in vacuo, and the residue was dissolved in EtOAc (400 ml) and washed with water (3 50 ml) and brine (100 ml), then were dried with magnesium sulfate. The solvent was removed in vacuo and the residue was purified using flash chromatograph (0,92 g, 51%). So pl. of 122.5-124oC.

IR (mull) 2956, 2924, 2856, 1641, 1604, 1464, 1459, 1269, 1235, 1180, 1115, 1070, 1064, 772, 699 cm-1;

1H-NMR (200 MHz, CDCl3) : to 7.61 (dd, J = 6,7, 1.5 Hz, 1H); to 7.59-7,29 (m, 5H); 6,98 (dd, J = 8,2, 1.5 Hz, 1H); 6,77 (dd, J = 8,2, 1.5 Hz, 1H); 5,31 (s, 2H); 3,94-3,90 (m, 4H); is 3.08-3.04 from (m, 4H);

UV (EtOH)max() 244 (22,700), 249 (21,500), 336 (6,270);

Elemental analysis for C20H19NO4:

Calculated: C 71,20; H of 5.68; N 4,15

Found: C 70,84; H Of 5.75; N 4,05.

The second fraction contained the product with a reduced ring (0,60 g, 33%). So pl. 179-181oC.

The third fraction contained the target 2-morpholinopropan (Compound 25) (0,29 g, 16%). So pl. 139-140oC.

IR (mull) 2954, 2926, 2870, 2855, 1640, 1623, 1615, 1600, 1470, 1449, 1407, 1239, 1122, 745, 740 cm-1;

1H-NMR (CDCl3, 200 MHz) : the 7.65 (br.d.., J = 7.2 Hz, 2H); 7,47-7,30 (m, 4H); 6,92 (dd, J = 8,1, 0.9 Hz, 1H); 6,85 (br.d., J = 8,1 Hz, 1H); of 5.45 (s, 1H); 5,32 (s, 2H); 3,89-of 3.85 (m, 4H); 3,52-3,47 (m, 4H);

UV (EtOH)max() 210 (32,900), 238 (23,500), 252 SD. (8,040), 260 SD. (5,650), 313 (18,460);

MC: ions at m/e (Rel. intens.) 91 (100), 337 (66), 231 (36), 174 (33), 173 (16), 338 (16), 336 (15), 218 (15), 65 (14), 146 (12);

BPMC: for C20H19NO4calculated 337,1314; found 337,1312.

Elemental analysis for C20H19NO4:

Calculated: C 71,20; H 5,58; N 4,16;

Found: C 71,05; H 5,56; N 4,17.

Example 26. Getting 7,8-dimethoxy-2-esis (1979) / 901], (3.42 g, 12.0 mm) was dissolved in acetonitrile (100 ml) was added anhydrous potassium carbonate (1.66 g, 12.0 mm). Then drop by drop) was added morpholine (1,10 ml, 12.5 mm) and the reaction mixture was heated under reflux for 24 h (bath temperature 82oC). The acetonitrile was removed in vacuo, and the mixture was dissolved in ethyl acetate (400 ml). The solution was washed with water (2 50 ml) and brine (100 ml), dried with magnesium sulfate, concentrated in vacuo and the resulted solid product is yellow. This product has chromatographically with pleskrestore on silica gel (EtOAc/MeOH, 95/5) and received 3-morpholinium (2,77 g, 79%), the product of the reduction cycle (0.24 g, 6.9 per cent) and 0.23 g of a mixture of the product of the reduction cycle and 2-substituted product (79%). So pl. 168-169oC.

IR (mull) 2952, 2924, 2866, 2854, 1639, 1619, 1509, 1456, 1441, 1433, 1322, 1291, 1200, 1171 cm-1;

1H-NMR (200 MHz, CDCl3) : 8,0 (d, 1H); 7,56 (c, 1H, =C(H)OAr), 7,02 (d, 1H, J=8,9 Hz), 4,0 (s, 3H, OCH3), 3,98 (s, 3H, OCH3), 3,91 (m, 4H), is 3.08 (m, 4H);

UV (EtOH)max() 247 (30,060), 303 (7,490), 326 (3,990);

BPMC: for C15H17NO5: calculated 291,1107; found 291,1110.

Elemental analysis for C15H17NO5:

Calculated: C 61,85; H 5,88; N 4,81;

Found: C 61,79; H 5,86; N 4,74.

Part B: a Mixture of the product) Product with a reduced ring recrystallized from EtOH and was obtained as pale-yellow crystals. So pl. 180-181oC.

2-Morpholinopropan recrystallized from EtOH and got the desired product (Compound 26) as colorless crystals. So pl. 194,5-195,55oC.

1H-NMR (CDCl3) : 7,88 (d, J = 8,8 Hz, 1H); 6,97 (d, J = 8,8 Hz, 1H); 5,43 (s, 1H); 3,98 (s, 3H); of 3.94 (s, 3H); 3,86 (m, 4H); 3,55 (m, 4H);

UV (EtOH)max() 217 (27,140), 239 (23,530), 270 (6,700), 311 (23,530);

BPMC for C15H17NO5: calculated 291,1107; found 291,1093.

Elemental analysis for C15H17NO5:

Calculated: C 61,85; H 5,88; N 4,81;

Found: C 61,85; H Of 5.83; N 4,78.

Example 27. Obtaining 2-(4-methyl-1-piperazinil)-4H-1-benzopyran-4-it.

Compound 27:

The procedure of this example, in General terms, is illustrated in scheme B, and as a result of implementation of this procedure has been the target connection.

Regarding schema C:

Example 28. Getting 8-methyl-7-(phenylmethoxy)-2-[4-(2- pyridinyl)-1-piperazinil]-4H-benzopyran-4-it.

Compound 28:

Part a: Getting 8-methyl-7-(phenylmethoxy)-2-mercapto-4H-1-benzopyran-4-it

Tert.-piperonyl potassium (65,5 g) was covered with 500 ml of benzene in a nitrogen atmosphere and the solution was placed in a water bath. 4'-Benzyloxy-2'-hydroxy-3'-methylacetophenone (50.0 g) and carbon disulphide (14,82 g) was dissolved in 500 ml of Bo-red paste is stirred over night at room temperature, and then diluted with 1 l of water. This mixture was poured into a separating funnel and the organic layer is discarded. The aqueous solution was diluted with 300 ml of 20% H2SO4and the solid substance was collected by filtration, dried by air and received 31.0 g of yellow powder. So pl. 245oC.

[D] 2954, 2869, 2855, 1619, 1602, 1542, 1499, 1462, 1455, 1377, 1305, 1280, 1113, 1076, 822 cm-1;

UV (EtOH)max() 208 (34260), 231 (24940), 252 (15070), 263 DM. (9470), 285 (5030), 299 (4930), 353 (18200), 392 (6840);

1H-NMR (DMSO-d6) :/ 7,73 (d, 1H, J = 8,9 Hz); was 7.45 (m, 5H, arene.); from 7.24 (d, 1H, J = 8,9 Hz); to 6.58 (s, 1H, vinyl at C-3); of 5.29 (s, 2H); to 2.29 (s, 3H, -CH3);

MC (ions at m/e (Rel. online.) 298 (12), 207 (1), 179 (1), 149 (1), 121 (1), 91 (100), 65 (6), 43 (1). [see Bantick J. R. and Suschitzky, J. L., J. Chem Heterocyclie., 18, 679 (1981)].

Part B: 8-Methyl-7-(phenylmethoxy)-2-mercapto-4H-1-benzopyran-4-one (2.0 g, 6.7 mm), 1-(2-pyridyl)piperazine (1.19 g, 7,3 mm) and TsOH (25 mg) was added to toluene and heated under reflux for 20 hours

The reaction temperature was lowered to room temperature and the toluene was removed in vacuum. The obtained dark oily product was diluted with EtOAc, and the precipitated crystals were collected on a filter, resulting in a received 2,42 g of the product. So pl. 148 - 149oC.

Following the basic procedure described in example 28, but using the corresponding amine instead of 1 is benzopyran-4-one, So pl. 165 - 170oC;

Conn. 30: 8-methyl-7-(phenylmethoxy)-2-(1-pyrrolidinyl)-4H - benzopyran-4-one, So pl. 190 - 193oC;

Conn. 31: 8-methyl-7-(phenylmethoxy)-2-(1-piperidinyl)-4H-benzopyran-4-one, So pl. 172 and 174oC;

Conn. 32: 8-methyl-2-(4-methyl-1-piperazinil)-7-(phenylmethoxy)-4H - benzopyran-4-one, So pl. 180 - 181oC;

Conn. 33: 8-methyl-7-(phenylmethoxy)-2-(2,6-dimethyl-4-morpholinyl)- 4H-benzopyran-4-one, So pl. 166 - 168oC;

Conn. 34: 2-[4-(hydroxyethyl)-1-piperazinil]-8-methyl-7- (phenylmethoxy)-4H-benzopyran-4-one, monohydrochloride, So pl. 235 - 255oC;

Conn. 35: 2-[4-(diphenylmethyl)-1-piperazinil]-8-methyl-7- (phenylmethoxy)-4H-benzopyran-4-one, So pl. 90 - 95oC;

Conn. 36: 8-methyl-7-(phenylmethoxy)-2-(4-phenyl-1-piperidinyl)- 4H-benzopyran-4-one, So pl. 193 - 194oC;

Conn. 37: 8-methyl-7-(phenylmethoxy)-2-(4-phenyl-1-piperazinil)- 4H-benzopyran-4-one, So pl. 153 - 154oC;

Conn. 38: 2-(4-hydroxy-1-piperidinyl)-8-methyl-7-(phenylmethoxy)- 4H-benzopyran-4-one.

Relatively schemes D and E:

Example 39. Obtain 7-hydroxy-2-(4-morpholinyl)-8-methyl-4H-1 - benzopyran-4-it.

Compound 39: (in accordance with scheme 1) part a: 8-Methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4 - one (8,59 g, 24,4 mm) suspended in 250 ml of ethyl acetate. Then was added to 9.9 ml of C is rinicom within 18 PM After that, the reaction was cooled and filtered, the solid residue was dissolved in methanol, decanted and filtered. The methanol is evaporated and received 4.71 g (74%) phenol; so pl. > 250oC.

Alternative part a: 2',4'-dihydroxy-3'-methyl-acetophenone (with a purity of 90%, 1,108 g, 6 mm) suspended in 25 ml of 1,2-dichloroethane and the resulting mixture was treated with triploidization boron (1,48 ml, 12 mm), stirring in 50 ml of odnogolosy round bottom flask under nitrogen atmosphere. The mixture is stirred 30 min at room temperature and then was treated with morpholine-4-pogenemine chloride (2.70 g, 13.2 mm). Then the reaction mixture was heated to 70oC for 3 h then the reaction was cooled to room temperature, and nerastvorim solid orange product was collected by filtration; the filter cake was thoroughly washed with titilation. The solid product was dissolved in 25 ml of acetonitrile in a 50 ml odnogolosy round bottom flask in the presence of nitrogen, and the resulting solution was cooled to 0oC. the Mixture was treated with 2.5 ml water and the reaction mixture stirred 48 h, until the cooling bath. The acetonitrile was removed in vacuo, and the residue was carefully diluted with 75 ml of a mixture of saturated sodium bicarbonate and sodium chloride (2:1). Stuck in a vacuum and got a solid amber color. This product is then washed with ethyl acetate and titilation and resulted 980 mg [8-methyl-2-(4-morpholine)-4-oxo-4H-benzopyran-7-yl]- 4-morpholinyl-carboxylic acid of ester (Compound 100), So pl. 232 - 234oC. Carbamate (945 mg , of 2.51 mm) suspended in 9 ml of a mixture of methanol and water (2:1) in 25-ml of odnogolosy round bottom flask in the presence of nitrogen. The suspension was treated with lithium hydroxide (236 mg, 5,62 mm) and the reaction mixture was stirred 48 h at room temperature. The methanol was removed in vacuo, and the pH of the aqueous residue was brought to pH of 4.9 by addition of 5% HCl. Precipitated material was collected by filtration and dried in vacuum at 25oC, resulting in a received 569 mg (87%), phenol (39), (So pl. > 250oC) in the form of grayish milabrega substances.

The second alternative part a: 2',4'-Dihydroxy-3'-methyl-acetophenone (90% purity, 18,46 g, 100 mm) suspended in 50 ml of diethyl ether, 100 ml of odnogolosy round bottom flask under nitrogen atmosphere. The mixture was treated with triploidization boron (of 18.45 ml, 150 mm) and the reaction mixture stirred over night at room temperature. The precipitate was collected by filtration and washed with fresh titilation. The filtrate was dried by air and received 10,45 g (47%) diversional the Olin-4-povenmire (21.2 g, 104 mm) in 125 ml of 1,2-dichloroethane in a 250 ml odnogolosy round bottom flask in the presence of argon. The reaction mixture was heated to 70oC for 3 h and cooled to room temperature. Orange-yellow precipitate was collected by filtration and washed with 1,2-dichloroethane, and then titilation, resulting received 25,3 solid orange color. This substance is suspended in 200 ml of acetonitrile in a 500-ml odnogolosy round bottom flask and the mixture was cooled to 0oC. the Cooled mixture was treated with 20 ml of water, and then stirred 20 min at 0oC and overnight at room temperature. After that, the mixture was cooled to -33oC for 2 h, and cooled cleaners containing hydrochloride salt was collected by filtration and washed with 125 ml ice acetonitrile. The precipitate on the filter was dried and got 13,25 g (69%) carbamate hydrochloride-chromone in the form of a white solid product. The filtrate was concentrated in vacuo to obtain a syrup amber color. This syrup was diluted with 100 ml saturated sodium bicarbonate, and the mixture was extracted with dichloromethane (4 50 ml). The combined organic layers were dried with magnesium sulfate and concentrated in vacuo to obtain an oily reddish substance, after crystallization that is in the method B, received target phenol. Part B: 7-Hydroxy-8-methyl-2-(4-morpholinyl)-1H-1-benzopyran-4-one (0.50 g, 1,91 mm) suspended in 15 ml of acetonitrile. Then was added 1.3 g of potassium carbonate, and then 0.39 g (2.1 mm) alfaromeo-p-xylene. The mixture was heated under reflux 5 hours Then added 0.04 g of additional alkylation agent and the mixture was heated under reflux for another 2 C. the Cooled mixture was diluted with 5 ml of water and filtered. A white precipitate was washed with water and dried. After recrystallization from ethyl acetate received 0,59 g (84%) (compound 48); so pl. 167,5 - 168oC.

Following the basic procedure of example 39, but using the appropriate fenilmetilketenom instead of (7 phenylmethoxy)-8 - methyl-2-(4-morpholinyl)-4H-benzopyran-4-she received the following connections:

Conn. 40: 6-hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 290 - 292oC;

Conn. 41: 7-hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one;

Conn. 42: 5-hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 295 - 297oC;

Conn. 43: 8-hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 300oC;

Conn. 44: 7-methoxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran - 4-one, So pl. of 224.5 - 225,5oC;

Conn. 45: [[8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-7 - yl]oxy]acetic acid is milovy ether, So pl. 181 - 182oC;

Conn. 47: 7-[(4-methoxyphenyl)methoxy]-8-methyl-2-(4-morpholinyl)- 4H-1-benzopyran-4-one, So pl. 171 - 172oC;

Conn. 48: 8-methyl-7-[(4-were)methoxy] -2-(4-morpholinyl)- 4H-1-benzopyran-4-one, So pl. 167,5 - 167,8oC;

Conn. 49: 7-[)4-chlorophenyl)methoxy]-8-methyl-2-(4-morpholinyl)- 4H-1-benzopyran-4-one, So pl. 226 - 227oC;

Conn. 50: 7-[(4,5-dichlorophenyl)methoxy]-8-methyl-2-(4 - morpholinyl)-2H-1-benzopyran-4-one, So pl. 243 - 244oC;

Conn. 51: 8-methyl-2-(4-morpholinyl)-7-(2-pyridinylmethyl)- 4H-1-benzopyran-4-one, So pl. 174 - 175,5oC;

Conn. 52: 8-methyl-7-[[(phenyl)carbonyl] oxy] -2-(4 - morpholinyl)-4H-1-benzopyran-4-one, So pl. 223,5 - 223,25oC;

Conn. 53: 8-methyl-7-[2-[4-methyl(1-piperazinyl)]ethyl]oxy-2- (4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 159,0 - 159,5oC;

Conn. 54: 7-[[4-1,1-dimethylethyl)phenyl]methoxy]-8 - methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 218,5 - 220oC;

Conn. 55: 8-methyl-2-(4-morpholinyl)-7-[[(4-phenylmethoxy)phenyl]methoxy]- 4H-1-benzopyran-4-one, So pl. 110 - 111oC;

Conn. 56: 7-[(3-methoxyphenyl)methoxy]-8-methyl-2-(4 - morpholinyl)-4H-1-benzopyran-4-one, So pl. 153,5 - 155,5oC;

Conn. 57: 7-[(4-nitrophenyl)methoxy] -8-methyl-2-(4 - morpholinyl)-4H-1-benzopyran-4-one, So pl. 285oC decomp.;

Conn. 58: 7-[(2-phenylethyl)methoxy]-8-methyl-2-(4 - morpholinyl)-4H-1-benzopyran-4-one, So pl. 202 - 203oC;

Conn. 60: 7-[(4-ethoxyphenyl)methoxy] -8-methyl-2-(4 - morpholinyl)-4H-1-benzopyran-4-one, So pl. 186 - 188oC;

Conn. 61: 8-(4-ethoxybenzyl)-2-(4-morpholinyl)-4H-1 - benzopyran-4-one, So pl. of 149.5 - 151,5oC;

Conn. 62: 2-(4-morpholinyl(-8-(4-nitrobenzyloxy)-4H-1 - benzopyrene-4-one, So pl. 240 - 241oC;

Conn. 63: 8-(2-methoxybenzyloxy)-2-(4-morpholinyl)-4H-1 - benzopyran-4-one, So pl. 149 - 150oC;

Conn. 64: 2-(4-morpholinyl)-8-(2-phenylethane)-4H-1 - benzopyran-4-one, So pl. 131 - 132oC;

Conn. 65: 2-(4-morpholinyl)-(2-oxo-2-phenylethane)-4H-1 - benzopyran-4-one, So pl. 200 - 201,5oC;

Conn. 66: 8-(4-benzyloxybenzyl)-2-(4-morpholinyl)-4H - benzopyran-4-one, So pl. 143,5 - 145oC;

Conn. 67: 8-(4-chlorobenzoyloxy)-2-(4-morpholinyl)-4H-1 - benzopyran-4-one, So pl. 208 - 209oC;

Conn. 68: 8-(4-tert. -butylbenzyl)-2-(4-morpholinyl)-4H-1 - benzopyran-4-one, So pl. 165,5 - KZT 166.5oC;

Conn. 69: 8-(3-methoxybenzyloxy)-2-(4-morpholinyl)-4H-1 - benzopyran-4-one, So pl. 177 - 178oC;

Conn. 70: 8-(3,4-dichlorobenzoate)-2-(4-morpholinyl)-4H-1- -benzopyran-4-one, So pl. 207 - 208oC;

Conn. 71: 8-(4-methoxybenzyloxy)-2-(4-morpholinyl)-4H-1 - benzopyran-4-one, So pl. 177 - 178oC;

Conn. 72: 8-(4-methoxybenzyloxy)-2-(4-morpholinyl)-4H-1 - benzopyran-4-one, So pl. 173.5 metric - of 174.5oC;

Neil)-8-(naphthyl-1-metiloksi)-4H-1 - benzopyran-4-one, So pl. 192.5 kg - of 193.5oC;

Conn. 75: 8-methyl-2-(4-morpholinyl)-7-(naphthyl-2-metiloksi)- 4H-1-benzopyran-4-one, So pl. 158,5 - 159,5oC;

Conn. 76: 8-methyl-2-(4-morpholinyl)-7-(naphthyl-1-metiloksi)- 4H-1-benzopyran-4-one, So pl. 205,5 - 207oC;

Conn. 77: 2-(dimethylamino)-8-methyl-4-oxo-4H-1-benzopyran-7 - from carbamino acid complex dimethyl ether;

Conn. 78: 2-(dimethylamino)-4-oxo-4H-1-benzopyran-6-yl his carbamino acid-dimethyl ether complex, So pl. 179,5 - 180oC;

Conn. 79; 2-(dimethylamino)-4-oxo-4H-1-benzopyran-7-yl his carbamino acid-dimethyl ether complex, So pl. 158 - 159oC;

Conn. 80: 2-(dimethylamino)-4H-1-benzopyran-4-one, So pl. 122 - 123,5oC;

Conn. 81: 2-(dimethylamino)-8-methyl-7-(phenylmethoxy)-4H-1 - benzopyran-4-one, So pl. 165 - 166oC;

Conn. 102: 8-methyl-2-(4-morpholinyl)-7-(2-oxo-2-phenylethane)- 4H-1-benzopyran-4-one, So pl. 226,5 - 227,5oC;

Conn. 103: 6-chloro-8-methyl-2-(4-morpholinyl)-7 - phenylmethoxy)-4H-1-benzopyran-4-one, So pl. 207 - 209oC;

Conn. 104: [[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]- oxy]acetic acid methyl ester, T. pl. 192.5 kg - 193oC;

Conn. 105: 4-[[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1 - benzopyran-7-yl] oxy]methyl]benzoic acid methyl ester, T. pl. 226 - 228oC;

Conn. 106: 4-[[[2- C;

Conn. 107: 8-methyl-2-(4-morpholinyl)-7-[[3 - trifluoromethyl)phenyl]methoxy] -4H-1-benzopyran-4-one, So pl. 194,5 - 195,5oC;

Conn. 108: 2-(4-morpholinyl)-8-[[3-(trifluoromethyl)phenyl]methoxy]- 4H-1-benzopyran-4-one, So pl. 204 - 204,5oC;

Conn. 109: 7-(cyclohexylmethoxy)-8-methyl-2-(4-morpholinyl)- 4H-1-benzopyran-4-one, So pl. 184,5 - 185,5oC;

Conn. 110: 8-methyl-2-(4-morpholinyl)-7-(2-propenyloxy)-4H-1 - benzopyran-4-one, So pl. 191 - 192oC;

Conn. 111: 2-(4-morpholinyl)-7-(1-naphthalenyloxy)-4H-1 - benzopyran-4-one, So pl. 195,2 - 195,8oC;

Conn. 112: 8-methyl-2-(4-morpholinyl)-7-(3-pyridinylmethyl)-4H - 1-benzopyran-4-one, So pl. 182,5 - 184oC;

Conn. 113: 8-methyl-2-(4-morpholinyl)-7-(4-pyridinylmethyl)-4H - 1-benzopyran-4-one, So pl. 253,5 - 255,5oC;

Conn. 115: 8-methyl-2-(4-morpholinyl)-7-(2-chynoxalinilmethylen)- 4H-1-benzopyran-4-one, So pl. 250,5 - 252,5oC;

Conn. 116: 8-methyl-2-(4-morpholinyl)-7-(personalitati)-4H-1 - benzopyran-4-one, So pl. 236 - 237oC;

Conn. 117: 8-methyl-2-(4-morpholinyl)-7-(2-pyridinylmethyl)-4H - 1-benzopyran-4-one, N-oxide, So pl. 248 - 249,5oC;

Conn. 118: 8-methyl-2-(4-morpholinyl)-7-(3-pyridinylmethyl)-4H - 1-benzopyran-4-one, N-oxide, So pl. 233,5 - 234oC;

Conn. 119: 8-iodo-2-(4-morpholinyl)-7-(3-pyridinylmethyl)-4H - 1-benzopyran-4-, So pl. 214 - 215oC;

Conn. 120: 3,8-methyl-2-(4-morpholinyl)-4-oxo-4H-1 - benzopyran-7-yl] oxy]propan-2-it, So pl. 206,5oC;

Conn. 122: 1-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1 - benzopyran-7-yl] oxy]butane-2-it, So pl. 183 - 184oC;

Conn. 123: 8-methyl-2-(4-morpholinyl)-7-(2-oxo-2-(2-naphthyl)- ethoxy)-4H-1-benzopyran-4-one, So pl. 214,5 - 215,5oC;

Conn. 125: 2-(4-morpholinyl)-7-(2-pyridinylmethyl)-4H-1 - benzopyran-4-one, So pl. 274 - 276oC;

Conn. 126: 2-(4-morpholinyl)-7-(3-pyridinylmethyl)-4H-1 - benzopyran-4-one, So pl. 193 - 194oC;

Conn. 127: 2-(4-morpholinyl)-8-(2-pyridinylmethyl)-4H-1 - benzopyran-4-one, So pl. 199 - 200oC;

Conn. 128: 2-(4-morpholinyl)-8-(3-pyridinylmethyl)-4H-1 - benzopyran-4-one, So pl. 160 - 161oC;

Conn. 129: 8-methyl-2-(4-morpholinyl)-7-(2-hyalinella)-4H - 1-benzopyran-4-one, So pl. 223,5 - 224,5oC;

Conn. 130: 7,8-(bis)-phenylmethoxy-2-(4-morpholinyl)-4H-1 - benzopyran-4-one, So pl. 165,5 - 167oC;

Conn. 131: 7,8-(bis)-the atomic charges-2-(4-morpholinyl)-44H-1 - benzopyran-4-one, So pl. 231,5 - 233oC;

Conn. 132: 7,8-(bis)-hydroxy-2-(4-morpholinyl)-4H-1 - benzopyran-4-one, So pl. > 300oC;

Conn. 133: 7-hydroxy-2-(4-morellini)-8-phenylmethoxy-4H-1 - benzopyran-4-one, So pl. 198 - 199oC;

Conn. 134: 7,8-(bis)-(3-trifluoromethyl)phenylmethoxy-2-(4 - morpholinyl)-4H-1-benzopyran-4-one, So pl. 178,5 - 179,5oC;

Conn. 135: 8-hydroxy-2-(4-morpholinyl)-7-(3 - trifluoromethyl)phenylmethoxy-4H-1-benzopyran-1-it, So pl. 236 - 237oC;

Conn. 137: 7-[3-(1-cyclohexyl-1H-tetrazol-5-yl)-propoxy - 8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 228 - 230oC;

Conn. 138: 8-[3-(1-cyclohexyl-1H-tetrazol-5-yl)propoxy]- 2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 185 - 186oC;

Conn. 139: 7-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxy]-8 - methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 228oC;

Conn. 140: 8-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxy]-5 - yl-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 218oC;

Conn. 141: 2-(4-morpholinyl)-8-[(1-phenyl-1H-tetrazol-5 - yl)oxy]-4H-1-benzopyran-4-one, So pl. 214 - 215oC;

Conn. 142: N-cyclohexyl-2-[[2-(4-morpholinyl)-4-oxo-4H-1 - benzopyran-8-yl]oxy]acetamide", she So pl. 238 - 241oC;

Conn. 143: N-(1,1-dimethylethyl)-2-[[2-(4-morpholinyl)-4 - oxo-4H-1-benzopyran-8-yl]oxy]acetamide", she T.. pl. 219 - 220oC;

Conn. 144: 2-[[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8 - yl]-N-phenylacetamide, So pl. 225 - 228oC;

Conn. 145: 2-[[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl]- oxy]-N-(1-phenylethyl)-ndimethylacetamide, So pl. 178 - 180oC;

Conn. 146: N-cyclohexyl-2-[[8-methyl-2-(4-morpholinyl)-4 - oxo-4H-1-benzopyran-7-yl]oxy]acetamide", she So pl. 255 - 256oC;

Conn. 147: N-[[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1 - benzopyran-7-yl] oxy]acetyl]-phenylalanine, complex ethyl ester, So pl. 173 >C;

Conn. 149: 8-methyl-2-(4-morpholinyl)-7-[(1-phenyl-1H-tetrazol-5 - yl)oxy] -4H-1-benzopyran-4-one, So pl. 209 - 211oC;

Conn. 150: 6-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxy]-2- (4-morpholinyl)-4H-benzopyran-4-one, So pl. 215 - 217oC;

Conn. 151: 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl] oxy]- N-(1-phenylethyl)-ndimethylacetamide, So pl. 203 - 205oC;

Conn. 152: 2-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1 - benzopyran-7-yl] oxy]-N-3-pyridylacetate, So pl. 243 - 245oC;

Conn. 153: N-[[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1 - benzopyran-7-yl] oxy]acetyl]-phenylalanine, So pl. 259 - 262oC;

Conn. 154: 7-(2,2-dimethoxyethoxy)-8-methyl-2-(4-morpholinyl)- 4H-1-benzopyran-4-one, So pl. 168 - 169oC;

Conn. 155: 2-(4-morpholinyl)-8-(2-propenyl)-4H-1-benzopyran-4 - one, So pl. 145,5 - 146,5oC;

Conn. 156: 2-(4-morpholinyl)-8-(1-propenyl)-4H-1-benzopyran-4 - one, So pl. 163 - 164oC;

Conn. 157: 8-formyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one, So pl. 209 - of 209.5oC;

Conn. 158: 2-(4-morpholinyl)-8-(phenylamino)methyl)-4H-1 - benzopyran-4-one, So pl. 226 - 227oC;

Conn. 159: 2-(4-morpholinyl)-8-(2E-phenyl)ethyl-4H-1-benzopyran - 4 he, So pl. 209 - of 209.5oC;

Conn. 160: 8-hydroxymethyl-2-(4-morpholinyl)-4H-1-benzopyran-4 - one, So pl. 243 - 243,5oC;

Conn. 162: 8-methyl-7-[(1-methyl-3-piperidinyl)methoxy] -2- (4-Mor is-4H-1-benzopyran-4-one, So pl. 154 - 156oC;

Conn. 164: 8-methyl-2-(4-morpholinyl)-7-[2-(1- pyrrolidinyl)ethyl]oxy-4H-1-benzopyran-4-one, So pl. 136 - 138oC;

Conn. 165: 8-methyl-2-(4-morpholinyl)-7-[2-(4- morpholinyl)ethyl]oxy-4H-1-benzopyran-4-one, So pl. 170,5 - 172,5oC;

Conn. 166: 8-methyl-2-(4-morpholinyl)-7-[3-(1- piperidino)propyl[hydroxy-4H-1-benzopyran-4-one, So pl. 144 - 145oC;

Conn. 167: 7-(2-diethylaminoethyl)hydroxy-8-methyl-2-(4-morpholinyl)- 4H-1-benzopyran-4-one, So pl. 162 - 162,5oC;

Conn. 168: 7-[2-(ethylvanillin)ethoxy]-8-methyl-2-)4 - morpholinyl)-4H-1-benzopyran-4-one, So pl. 146 - 147oC;

Conn. 169: 7-[2-diisopropylaminoethyl)hydroxy-8-methyl-2- (4-morpholinyl)-4H-1-benzopyran-4-one, So to 136.5 square - 138,5oC;

Conn. 170: 7-hydroxy-8-methyl-2-(1-piperidine)-4H-1-benzopyran - 4-one, So pl. 278 - 284oC;

Conn. 171: 8-methyl-2-(1-piperidinyl)-7-(3-pyridinylmethyl)-4H - 1-benzopyran-4-one, So pl. 144 - 158oC;

Conn. 172: 7-[2-[4-benzyl-(1-piperidinyl)ethyl]oxy]-8-methyl-2- (4-morpholinyl)-4H-1-benzopyran-4-one, So square 138 - 139oC.

Example 82. Obtaining 2-(4-morpholinyl)-4H-1-benzopyran-4-it.

Connection 2:

Part A: Tert.-piperonyl potassium (134 g, 1.2 M) was poured benzene (1 l) in a round bottom flask, drained flame and equipped with a stirrer, additional funnel, thermometer and inlet is R o-hydroxyacetophenone (54,4 g, of 48.1 ml, 0.4 M) and hydrogen sulfide (30,4, 24 ml, 0.4 M) in benzene (700 ml), periodically replenishing ice bath to maintain the temperature of the 18oC. the resulting suspension stirred at ambient temperature for 1 day. After the reaction mixture was transferred into a separating funnel containing water (4 l) and was extracted with ether (4 250 ml) and EtOAc (3 250 ml). The aqueous layer was acidified with 10% H2SO4(1 l) and stirred over night at room temperature. The resulting solid was filtered and dried at 50oC during the night, getting 22,07 g 2-mercapto-4H-benzopyran-4-it. So pl. 207 - 208oC.

Part B: Tsiavou acid (0.4 g, 2 mm) was added to a solution of 2-mercapto-4H-1-benzopyran-4-it (of 3.56 g, 20 mm) and research (2,44 g, 2,44 ml, 28 mm) in benzene (400 ml). After 4 hours of heating in a flask with reflux condenser, the reaction mixture was transferred into a separating funnel containing EtOAc and water. Then the mixture was extracted with EtOAc (2x), washed with combined organic layers with water and brine, filtered through sodium sulfate and received 4,56 g of crude product after evaporation of the solvent. In the flash-chromatography on silica gel (300 g, and 2.5% MeOH/CHCl3, 50-ml RDF 83. Getting 6-methyl-2-(4-morpholinyl)-4H-1,3 - benzoxazin-4-it.

Compound 83:

Methyl ester 5-methylsalicylic acid (2,73 g, 16.4 mm) was dissolved in acetone (50 ml), then was added methyl cyanide and the solution was cooled to 0oC. Triethylamine (1.73 g, 18.2 mm) was dissolved in acetone (5 ml) and one drop was added to the solution. Quickly loose residue and a solid substance was removed by filtration. The filtrate was concentrated in vacuum and got to 3.41 g of the intermediate compound canoeiro. This cyanoethyl was dissolved in acetonitrile (50,1), was added morpholine (1,43 g, 16.4 mm) in acetonitrile (5 ml) and the reaction mixture is 2 hours and stirred at room temperature. The resulting crystals and the reaction mixture was cooled to 0oC, washed with cold acetonitrile and received 1,65 g (40,8%) of product. Royal solutions recrystallized from acetonitrile and received 0,54 g (13,4%) of product. So pl. 197-197,9oC.

IR (mull) 2955, 2923, 2858, 1674, 1619, 1576, 1466, 1453, 1433, 1424, 1333, 1325, 1315, 1112, 817 cm-1;

1H-NMR (CDCl3) : to $ 7.91 (d, J = 1.4 Hz, 1H, arene.); 7,40 (dd, J = 8,3, 1.9 Hz, 1H, arene.); to 7.09 (d, J = 8,4 Hz, 1H, arene.); 3,81 (br.s., 8H, morpholinothio); 2.40 a (s, 3H, methyl);

UVmax() 217 MD. (26,550), 223 MD. (26,350), 259 (15,100), 296 (4,250), 304 SD. (3,550);

MC: ions at m/e (relative. intens.) 246 (Max., 293:

Calculated: C 63,40; H 5,73; N 11,38;

Found: C 63,29; H Of 5.92; N 11,31.

Following the basic procedure of example 83, but using the appropriate methyl ester o-gidroksistearinovoj acid instead of methyl ester 5-methylsalicylic acid, there were obtained the following compounds:

Conn. 84: 8-methyl-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, So pl. 229-231oC;

Conn. 85: 6-bromo-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, So pl. 207-214oC;

Conn. 86: 7-chloro-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, So pl. 207-214oC;

Conn. 87: 6,8-bis(1-methylethyl)-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, So pl. 120-120,5oC;

Conn. 88: 6-fluorescent-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, So pl. 220-231oC;

Conn. 89: 6-dimethoxymethyl-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, So pl. 101-108oC;

Conn. 90: 7-methoxy-2-(4-morpholinyl)-4H-1,3-benzoxazin-4-one, So pl. 197-200oC;

Conn. 91: 6-(morpholinyl-1-yl)-pyrido[2,3-e] -1,3-oxazin-4-one, So pl. 181-184oC;

Following the basic procedure of example 83, but using the appropriate methyl ester o-gidroksistearinovoj acid instead of complicated methyl ester 5-methylsalicylic acid and the corresponding heterocyclic compounds instead of the research provided the following sedimentological)-4H-1,3-benzoxazin-4-one, So pl. 199,5-200,5oC;

Conn. 94: 2-(1-pyrrolidinyl)-4H-1,3-benzoxazin-4-one, So pl. 163-164oC;

Conn. 95: 2-[1-(4-thiomorpholine)]-4H-1,3-benzoxazin-4-one, So pl. 179-180oC;

Conn. 96: 2-(4-methyl-1-piperazinil)-4H-1,3-benzoxazin-4-one.

Example 98. Obtaining 2-(4-morpholinyl)-4H-1,3-benzoxazin-4-it.

Compound 98 (Method A):

Methyl salicylate (25 g, 0,164 M) and Enrichment (18,08 g, 0,172 M) was added to dry weight acetone (500 ml) and cooled to 0oC. Then the mixture was treated with TEA (17,37 g, 0,172 M) in acetone (50 ml) for 20 min on a drop. From the solution stood out white precipitate. After stirring for 1 h, the acetone was decanted, and the precipitate was washed with acetone. The filtrate was concentrated in vacuo and used without further purification. The above cyanoethyl (29.0 g, 0,164 M) was added to acetonitrile (300 ml) under nitrogen atmosphere. Then for 30 min on a drop added (14,26 g, 0,164 M) the combined acetonitrile solution of the research. During the addition the reaction mixture was heated. After stirring for 3 hours the solvent was removed in vacuum and received a reddish-brown solid product, after washing which ether was obtained 22 g (58%) of pure product. An analytical sample was obtained by recrystallization from EtOAc. So pl. 184,5-of 186.0oC (tiora. So pl. 1UP>H-NMR (CDCl3) of 8.25 (dd, 1H, J = 1,5 m 6.0 Hz); 7,8-to 7.2 (m, 3H, aromatic. ); of 3.80 (s, 8H);

MC: ions at m/e (Rel. online.) 232 (47), 215 (13), 204 (20), 189 (11), 176 (14), 175 (56), 121 (35), 120 (100), 92 (46), 64 (14);

UV (EtOH) max() 210 (24,000), 218 (24,200), 240 DM. (11,200), 258 (14,750), 286 (4,850), 295 (3,900);

Elemental analysis for C12H12N2O3:

Calculated: C 62,06; H 5,17; N 12,06

Found: C 61,70; H 5,22; N 11,99.

Example 99. Obtaining 2-(4-morpholinyl)-4H-1,3-benzoxazin-4-it.

Compound 98 (Method B):

Tsiavou acid (0.4 g, 2 mm) was added to a solution of 2-mercapto-4H-1-benzopyran-4-it (of 3.56 g, 20 mm) and piperidine (2.38 g, 2,77 ml, 28 mm) in benzene (400 ml). Then the solution was heated in a flask under reflux for 5 h and evaporated in vacuum. The residue was transferred into a separating column with methylene chloride and water. After extraction with methylene chloride the organic layer was twice washed with water, filtered through sodium sulfate and received 2,80 g of crude product after evaporation of the solvent). In the flash-chromatography on silica gel (300 g, 7% MeOH/CH2Cl2) received 0.39 g of 2-(4-morpholinyl)-4H-1,3-benzoxazin-4-it.

Example 101. 2-(4-Morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one.

Compound 101:

The compound was obtained by way proillyustrirovali scheme E).

Part a: 2',4'-Dihydroxy-3'-methyl-propiophenone (7,21 g, 40 mm) suspended in 200 ml of dichloromethane in a 500 ml odnogolosy round bottom flask in the presence of nitrogen. The suspension was treated with diisopropylethylamine (6,97 ml, 40 mm) and the solution was cooled to 0oC. Then the reaction mixture at 0oC slowly drop by drop (within 1 h) was added acetylchloride (3,26 ml, 46 mm) in 80 ml of dichloromethane. After that, the mixture was heated to room temperature and stirred for 20 minutes, the Reaction mixture was washed with 5% hydrochloric acid (1 150 ml) and the organic layers were dried with magnesium sulfate. The mixture was concentrated in vacuum and received a yellow oily substance, which was then led and recrystallized from ethanol, resulting in a received 7.2 g (81%) of acetate in the form of a white solid product. So pl. 59-61oC.

Part B: Getting 7-acetoxy-3,8-dimethyl-2-(4-morpholinyl)-4H-1-benzopyran-4-she (Compound 173).

4'-Acetoxy-2'-hydroxy-3'-methyl-propiophenone (6.2 g, 27,9 mm) was dissolved in 60 ml of diethyl ether in a 100-ml odnogolosy round bottom flask in the presence of nitrogen. The solution was treated with triploidization boron and the reaction mixture stirred over night at room temperature. The precipitate was collected by filtration is th solids. This complex of diferida boron (1,05 g, 5,13 mm) and chloride-4-morpholinosydnonimine (1,25 g, 4,63 mm) were combined in 12 ml of 1,2-dichloroethane in 25-ml odnogolosy flask in the presence of nitrogen. The reaction mixture was heated to 60oC for 3 hours Then the mixture was cooled to room temperature, and dichloromethane was removed in vacuum. The oily residue was dissolved in 12 ml of acetonitrile in a 25 ml odnogolosy round-bottom flask, and the mixture was heated to 60oC, diluted with 10 ml of water, stirred 5 minutes, the Reaction mixture was immediately neutralized with 25 ml of saturated sodium bicarbonate and acetonitrile was removed in vacuum. The aqueous residue was extracted with dichloromethane (4 x 25 ml). The combined organic layers were dried with magnesium sulfate and concentrated in vacuo, resulting in a received 750 mg (51%) of compound 173 in the form of a solid product of orange color. So pl. 142,5 - 144,5oC.

Part C. Receiving 3,8-dimethyl-7-hydroxy-2-(4-morpholinyl)-4H-1 - benzopyran-4-she (compound 174).

Complex diferida boron (obtained in part A, 3.0 g, 11,1 mm) was combined with chloride 4-morpholinosydnonimine (2.5 g, 12.2 mm) in 29 ml of 1,2-dichloroethane in a 50 ml odnogolosy round bottom flask in the presence of nitrogen. The reaction mixture was heated to 60oC for 3 to 5 h, and then cooled to the 00-ml odnogolosy round bottom flask in the presence of nitrogen. The solution was heated to 60oC, diluted with 25 ml water and stirred 5 minutes, the Reaction mixture was rapidly cooled to 30 ml saturated sodium bicarbonate and acetonitrile was removed in vacuum. The aqueous residue was extracted with dichloromethane (4 x 25 ml) and the combined organic layers were dried with magnesium sulfate. The dried organic layers were concentrated in vacuo, resulting in the yellow solid (2,82 g) which was dissolved in 30 ml of methanol in a 100-ml odnogolosy round bottom flask in the presence of nitrogen. The solution was diluted with 15 ml water and the mixture was treated with lithium hydroxide (8) (mg, 19,1 mm). The reaction mixture was stirred for 1 h at room temperature. The methanol was removed in vacuo, and the pH of the aqueous residue was brought to 5 with 5% hydrochloric acid (pH meter). Precipitated phenol was collected by filtration, dried off and got 1.2 g (40%) of compound 174. So pl. > 300oC.

Part D. Getting 7-benzyloxy-3,8-dimethyl-2-(4-morpholinyl)-4H - 1-benzopyran-4-it, the connection 175.

3,8-Dimethyl-7-hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one (355 mg, 1,29 mm) suspended in 9 ml of dry acetonitrile in a 25 ml odnogolosy round bottom flask in the presence of nitrogen. The suspension was treated successively with potassium carbonate (1.1 g, 8.0 mm) and antiversary. Volatiles were removed in vacuum and the residue is washed with 25 ml dichloromethane. Nerastvorim material was removed by filtration and the filtrate was concentrated to obtain a light oily substance. After crystallization of the substance of diethyl ether was received 323 mg (69%) of compound 175 in the form of a white solid product. So pl. 136 - 137,5oC.

Following the basic procedure of example 173, but using as starting compound 2'-hydroxypropiophenone received the following connections:

Conn. 176: 3,8-dimethyl-2-(4-morpholinyl)-7-(naphthyl-1-metiloksi)- 4H-1-benzopyran-4-one, So pl. 204 - 206oC;

Conn. 177: 3,8-dimethyl-7-(4-methoxy-benzyloxy)-2-(4-morpholinyl) -4H-1-benzopyran-4-one, So pl. 141 - 142oC;

Conn. 178: 3,8-dimethyl-2-(4-morpholinyl)-7-(2-phenylethylene)-4H - 1-benzopyran-4-one, So pl. 160 - 161,5oC;

Conn. 179: 3,8-dimethyl-7-(4-chlorobenzoyloxy)-2-(4-morpholinyl)-4H - 1-benzopyran-4-one, So pl. 166 - 167,5oC;

Conn. 180: 3,8-dimethyl-2-(4-morpholinyl)-7-(3 - triftormetilfosfinov)-4H-1-benzopyran-4-one, So pl. 158,5 - 160oC;

Conn. 181: 7-(carbomethoxyamino)-3,8-dimethyl-2-(4-morpholinyl) -4H-1-benzopyran-4-one, So pl. 174 - 175oC;

Conn. 182: 8-hydroxy-3-methyl-2-(4-morpholinyl)-4H-1-benzopyran - 4-one, So pl. 239 - 240oC;

Conn. 183: 8 antivirmailservice) -4H-1-benzopyran-4-one, So pl. 160,5 - 161oC.

Example 185. Getting C-7-alilovic, alkenilovyh and alkylaryl deputies. (Scheme F)

Part A. Obtaining 2'-hydroxy-3'-methyl-4'- tripterocalyx-acetophenone.

2', 4'-Dihydroxy-3'-methyl-acetophenone (11 g, 60,2 mm) suspended in 300 ml of dichloromethane in a 1000 ml odnogolosy round bottom flask in the presence of nitrogen. The resulting suspension was sequentially treated with pyridine (4.4 ml, 54 mm) and N, N-dimethylaminopyridine (730 mg, 6 mm) and cooled the solution to 0oC. the reaction mixture was slowly (30 min) was added drop angelic triperoxonane acid (11 ml, 66,2 mm) in dichloromethane (1 x 100 ml). The reaction mixture was stirred 1 h at room temperature, and then washed with 5% HCl (2 x 200 ml). The organic layers were dried with magnesium sulfate and concentrated in vacuo, resulting in a yellow oily residue. This residue was distilled using a cylindrical apparatus under high vacuum (165oC) received a 16.4 g (91%) of the triflate as a white solid product. So pl. 60 - 64oC.

Part B. Getting 8-methyl-2-(4-morpholinyl)-7 - tripterocalyx-4H-1-benzopyran-4-it.

2'-Hydroxy-3'-methyl-4'-triftoratsetilatsetonom (1.5 g, 5,03 mm) p is the Wali triploidization boron (0.9 ml, 7.5 mm) and the reaction mixture is stirred for 6 hours at room temperature. Approximately 1/2 of the ether was removed in vacuo, and the residue was collected by filtration. The light yellow solid was washed with cold diethyl ether and was obtained 1.1 g (63%) of diversionary. Complex diferida boron (1.1 g, 3.2 mm) was combined with chloride 4-morpholinosydnonimine (to 0.72 g, 3.5 mm) in 12 ml of 1,2-dichloroethane in a 50 ml odnogolosy round bottom flask in the presence of nitrogen. The reaction mixture was heated to 65oC for 3 h, and then cooled to room temperature. The precipitate was removed by filtration and washed with diethyl ether, resulting in the received 1.35 g of product. The solid product is suspended in 12 ml of acetonitrile in a 25 ml odnogolosy round bottom flask in the presence of nitrogen. The suspension is stirred 48 hours with 1.2 ml of water. The colorless solution was diluted with 10 ml saturated sodium bicarbonate and acetonitrile was removed in vacuo.

The aqueous residue was extracted with dichloromethane (4 x 25 ml). The combined organic layers were dried with sodium sulfate and concentrated in vacuo, resulting in the obtained red solid product. After recrystallization of this product from ethyl acetate received 566 mg (45%) of bromotrifluoro in the form of a whitish solid fuel is supiran-4-she (compound 185).

8-Methyl-7-(tripterocalyx)-2-(4-morpholinyl)-4H-1 - benzopyran-4-one (190 mg, 0.48 mm) suspended in 6 ml of a mixture of benzene and triethylamine (1:1) in 15-ml tube with pressure screw head. The suspension was treated sequentially with phenylacetate (100 μl, of 0.91 mm) dichloride bis(triphenylphosphine)palladium (14 mg, 0.02 mm) and copper iodide (2 mg, 0.01 mm). The reaction mixture was heated overnight to 100 - 110oC. Then the mixture was cooled to room temperature and again was treated sequentially with phenylacetylene (100 μl, of 0.91 mm), bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 M) and copper iodide (2 mg, 0.01 mm). The reaction mixture was heated to 110oC for 4 h and cooled to room temperature. Volatiles were removed in vacuo to obtain a black residue. This residue was chromatographically on silica gel (12 g, 230 - 400 mesh), elwira 1% methanol/dichloromethane, and collected 3 ml for 48 fractions. After elution with 2% methanol/dichloromethane were collecting 5 ml fractions. Fractions 55 - 72 were combined, concentrated and received 153 mg of a dark brown solid product. After recrystallization of this product from ethyl acetate received 94 mg (56%) of compound 185 as a light grey solid product. So pl. 228,5 - of 229.5oC.

When the Il-2-(4-morpholinyl)-7-(2-phenylethyl)-4H-1-benzopyran-4-one (90 mg, 0,261 mm) was dissolved in 90 ml of a mixture of methanol and acetone (8:1) in the mixer Parra. The solution was treated with 18 mg of 10% palladium charcoal and the reaction mixture was hydrogenosomal for 2 hours at a pressure of 40 pounds/inch2(275,76 kPa). The catalyst was removed by filtration through a 1" (25.4 mm) layer of zeolite, and the residue was washed with methanol. The filtrate was concentrated in vacuo, the obtained yellow oily product was led from the hexane and received 70 mg (77%) of compound 186 as a yellow-brown solid product. So pl. 162 - 163oC.

Following the basic procedure of example 185, but using as starting compound corresponding 2'-hydroxyacetophenone received the following connections:

Conn. 187: 2-(4-morpholinyl)-8-(2-phenyl)ethinyl-4H-1-benzopyran-4 - one, So pl. 196 - 197oC;

Conn. 188: 2-(4-morpholinyl)-8-(2-phenyl)ethyl-4H-1-benzopyran-4 - one, T square 110 - 112oC;

Conn. 189: 2-(4-morpholinyl)-8-[2-(3-trifluoromethyl)phenyl] ethinyl - 4H-1-benzopyran-4-one, So pl. 157,5 - 158,5oC;

Conn. 190: 2-(4-morpholinyl)-8-[2-(3-trifluoromethyl)phenyl]ethyl-4H - 1-benzopyran-4-one, So pl. 130 - 131oC;

Conn. 192: 8-methyl-2-(4-morpholinyl)-7-[2-(1-naphthyl)] ethyl-4H-1 - benzopyran-4-one, So pl. 188,5 - 189,5 C;

Conn. 193: 8-methyl-2-(4-morpholinyl)-7-phenyl-4H-1-benzopyran-4 - one, So pl. 194,5 is Nona.

2', 4'-Dihydroxy-3'-iodoacetate (55,6 g of 0.2 M) suspended in 600 ml of methylene chloride. Then was added triethylamine (27.8 ml, 0.2 M) and cooled mixture (0oC) drop were treated with acetylchloride (16,35 ml of 0.23 M). The mixture is stirred 1 hour at 0oC and 2 h at room temperature. The mixture is then washed with 5% HCl, dried with magnesium sulfate and evaporated. The solid residue was recrystallized from ethanol and obtained 48,39 g of the product.

Part B. Obtaining 7 atomic charges-8-iodo-2-(4-morpholinyl)-4H-1 - benzopyran-4-she (compound 194). 4'-Acetoxy-3'-iodo-2'-hydroxy-propiophenone (48,4 g, 0.15 M) suspended in 750 ml of simple ether and treated with triploidization boron (27.9 ml, 0.22 M). The mixture is stirred over night at room temperature, was filtered, and the solid residue was washed with ether, which was received and 47.0 g of a complex of diferida boron. This complex was combined with chloride 4-morpholinylcarbonyl in 400 ml of ethylene dichloride and heated for 5 h at 70oC and 16 h at 50oC. Then the reaction mixture was cooled to 0oC, and the solid residue was filtered and thoroughly washed with ether (45 g). The solid residue suspended in 400 ml of acetonitrile, was then added 40 ml of water and the resulting mixture was stirred over night at rastvoritel evaporated, and the residue was dissolved in a mixture of methylene chloride and saturated sodium bicarbonate. The aqueous layer was extracted twice with methylene chloride and the organic layers were dried with magnesium sulfide. After evaporation of the solvent and recrystallization from methanol was obtained from 20.8 g (39%) chromone. Royal solutions contained 5.8 g of the crude product, after the second recrystallization which was obtained 0.7 g of product. So pl. 201,5 - 202,5oC.

Part C. Getting 8-ethyl-7-hydroxy-2-(4-morpholinyl)-4H-1 - benzopyran-4-it.

7 atomic charges-8-iodo-2-(4-morpholinyl)-4H-1-benzopyran-4-one (2,07 g, 5.0 mm) were combined with lithium chloride (0.64 g, 15 mm), tetraethyllead (1,04 ml, 5.25 mm) and dichloride(bis)triphenylphosphine (70 mg, 0.10 mm) in 20 ml of dimethylformamide. The resulting mixture was heated for 40 min at 100oC, was poured into Polynesians solution of sodium chloride and was extracted twice with methylene chloride. The organic layers were washed twice polysystem solution of sodium chloride, dried with magnesium sulfate and evaporated. The residue was dissolved in 20 ml of methanol and 10 ml of water and treated 0,63 g (15 mm) of lithium hydroxide. The mixture is stirred 30 min at room temperature. The solvent is evaporated, the mixture was diluted with water and extracted with ethyl acetate. Water who has Ssali and received 0,98 g (71%) of product.

Part D. Getting 8-ethyl-2-(4-morpholinyl)-7-(3 - pyridinylmethyl)-4H-1-benzopyran-4-she (compound 195).

8-Ethyl-7-hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one (0,176 g, 0.64 mm) and sodium hydride (0,105 g, 60%, 2.6 mm) were combined in 4 ml of dimethylformamide and heated to 60oC for 20 minutes. Then was added the hydrochloride of 3-pikillacta (0,321 g, 1,76 mm) and the mixture was heated at 60oC for 1 h, the Cooled mixture was poured into 2n. sodium hydroxide and ice. The solid residue was filtered, thoroughly washed with water and ether and recrystallization from ethyl acetate received 0.156 g of product. So pl. 178 - 179oC.

Following the basic procedure of example 194, but using as starting compound 2'-hydroxyacetophenone received the following connections:

Conn. 196: 8-ethyl-2-(4-morpholinyl)-7-phenylmethoxy-4H-1 - benzopyran-4-one, So pl. 153 - 154,5oC;

Conn. 197: 8-iodo-2-(4-morpholinyl)-7-phenylmethoxy-4H-1 - benzopyran-4-one, So pl. 155 - 157oC;

Conn. 198: 8-ethyl-2-(4-morpholinyl)-7-[2-(1-piperidinyl-4 - one, So pl. 151 - 152oC;

Conn. 199: 8-iodo-2-(4-morpholinyl)-7-(3-pyridinylmethyl)-4H - 1-benzopyran-4-one, So pl. 214 - 215oC;

Conn. 200: 8-iodo-7-hydroxy-2-(4-morpholinyl)-4H-1 - benzopyran-4-one, So pl. 224 - 225oC.

Example 201 (Scheme H).< To a solution of benzyl ether Conn. 31 (1,00 g of 2.86 mm) and EtOAc (80 ml) was added palladium carbon (225 mg). After stirring at hydrogenator Parra at hydrogen pressure of 50 pounds/inch2(344,7 kPa) for 2 days, the catalyst was filtered through a glass funnel, washed with EtOAc and MeOH. After evaporation of solvent received 0,99 g crude material. This material was subjected to flash chromatography (60 g silica gel, 10% MeOH/CH2Cl2) and received 0,83 g of phenol. As a result of recrystallization of the MtOH/EtOAc at 4oC was obtained 0.65 g (88%) of the desired product as white crystals. So pl. 278 - 284oC.

Part B: Obtain 7-(3-pyridinylmethyl)-2-(1-piperidinyl)-8 - methyl-4H-1-benzopyran-4-it, the connection 202.

Suspension of a phenolic compound 170 (130 mg, 0.5 mm), 3-picolinate-HCl (161 mg, 1.0 mm), potassium carbonate (277 mg, 2.0 mm) in dimethylformamide (5 ml) was stirred at 90oC. After 7 days the reaction mixture was evaporated and added CHCl3. The solid product was filtered, and the filtrate evaporated. After flash chromatography of the residue (15 g silica gel, 2% MeOH-CH2Cl2, 6 ml fractions) received 18 mg (10%), fraction 37 - 52 connection 202. So pl. 144 - 158oC.

Example 203. Getting 7 phenylmethoxy-2-methylthiomethyl-8-methyl - 4H-1-benzopyran-4-she (the) stirred in THF (185 ml) in the presence of nitrogen in a 2 l three-neck round bottom flask, drained flame and equipped with an additional funnel and reflux condenser. A solution of 2-hydroxyacetophenone (25 g, which is 97.6 mm) and ethyl- -- dimethylacetate (130,4 g, 123 ml, 0.9 M) in THF (164 ml) slowly, drop by drop, was added to a suspension of sodium hydride. After you've added about half of the solution, the reaction mass was heated by means of the apparatus for heating with hot air before reflux distilled. After that, when the stirring was slowly added to the remaining half of the solution. Then 10 min the solution was kept at room temperature and 1 h 40 min at the temperature of reflux distilled, and the solution was evaporated in vacuum. Then the solution was transferred into a separating funnel with a mixture of methylene chloride and 2n HCl and shaken for about 10 minutes After extraction with methylene chloride (2x) and dried with magnesium sulfate, received raw - diketone, not subjected to further purification.

Two-phase solution of the diketone in the 6N. HCl (250 ml) stirred over night at room temperature. After extraction with methylene chloride and drying the magnesium sulfate was obtained 127,13 g crude material (after solvent evaporation). This material was subjected to flash chromatography (700 g of silica gel, 30 to 50% EtOAc/hexane) and received 122 g of a mixture of shadnagar recrystallized from ether/hexane and obtained the desired product as white crystals. So pl. 110 - 114oC.

Part B. Obtaining 7-phenylmethoxy-2-iodomethyl-8-methyl-4H-1 - benzopyran-4-it.

A solution of compound 203 (4.0 g, 12.3 mm) methyliodide (12.5 ml) and CH2Cl2(8 ml) stirred under irrigation. After 3 days the solution was cooled to 0oC, the yellow precipitate was filtered. The filtrate is evaporated, and the residue was subjected to flash chromatography on silica gel (100 g, 40% EtOAc/hexane), which was obtained 1.48 g 7 phenylmethoxy-2-iodomethyl-8-methyl-4H-1-benzopyran-4-it (30%). An analytical sample was obtained by recrystallization from CH2Cl2/EtOAc/hexane in the form of a crystal of the target product in white. So pl. 144 - 147oC.

Part C. Getting 8-methyl-2-(4-morpholinylmethyl)-7-(phenylmethoxy)-4H-1-benzopyran-4 - it, the connection 204.

Morpholine (0.21 g, 2.5 mm) was added to a stirred solution of 7-phenylmethoxy-2-iodomethyl-8-methyl-4H-4-it (1.0 g, 2.5 mm) and triethylamine (0.25 ml, 2.5 mm) in CHCl3(12 ml). After stirring at room temperature for 2.4 h the solvent is evaporated in vacuum. The residue was subjected to flash chromatogram (100 g silica gel, 50 to 100% EtOAc/CH2Cl2, 45-ml fractions) and got to 0.72 g (79%) of product. After recrystallization from ether there was obtained a white solid target n-4-it, connection 205.

Palladium carbon (140 mg) was added to a solution of benzyl ester compounds 204 (0.65 g, 1,78 mm) in EtOAc (50 ml). The mixture was which in hydrogenator Parra for 23 h under hydrogen pressure of 50 pounds/inch2(344,7 kPa), after which the catalyst was filtered through a funnel sintered glass, washed with EtOAc and MeOH. After evaporation of solvent received 0,49 g crude product. This product was subjected to flash chromatography on silica gel [(100 g), 4% MeOH/CH2Cl2, 50-ml fractions] and received 35 mg (5%, fractions 6 and 7) of the source material and 0.33 g (68%) fractions 11 - 16) phenol. An analytical sample prepared by recrystallization from EtOAc/ether/hexane at 4oC, which was received in the form of a white crystal of the target product. So pl. 144 - 146oC.

Part E. Obtaining 7-[(cyclohexyl-1H-tetrazol-5-yl)methoxy - 8-methyl-2-(4-morpholinylmethyl)-4H-1-benzopyran-4-it, the connection 206.

A suspension of compound 205 (100 mg, 0.36 mm), 5-(4-chloromethyl)-1 - cyclohexylmethanol [see, for example, Chem. Phatm. Bull. 31, 1151 (1983)] (146 mg, 0,73 mm) and potassium carbonate (201 mg, 1,45 mm) in acetonitrile (3 ml) was stirred at 60oC. After 17 h, the reaction mixture was evaporated and added CHCl3. The solid residue was filtered and focali 134 mg (85%, fractions 5 and 6) of a white crystal of the target product. So pl. 193 - 195oC.

Part F. Getting 8-methyl-2-(4-morpholinylmethyl)-7- (3-pyridinylmethyl)-4H-1-benzopyran-4-it, the connection 207.

A suspension of compound 205 (50 mg, 0.18 mm), 3-picolinate-HCl (58 mg, 0.36 mm) and potassium carbonate (100 mg, 0,72 mm) in acetonitrile (2 ml) was stirred at 60oC. After 2 days the reaction mixture was evaporated and added INSTRUMENTS3. The solid residue was filtered and the filtrate evaporated. After flash chromatography of the residue (20 g silica gel, 3% MeOH/CH2Cl210 ml fractions) received 45 mg (68%, fraction 17 - 25) of a white crystal of the desired product, which was recrystallized from ether. So pl. 105 - 108oC.

1 1. Substituted benzopyrano formula I 6 1 where X - CZ, where Z is H, C1- C5-alkyl, amino group or halogen atom; 4 Y is selected from the group consisting of -(CH2)nNR9R10where R9and R10- same or different, are selected from the group consisting of 2 (a) hydrogen, provided that R9and R10both together are not hydrogens; 2 (b) C1- C12-alkyl; 2 (c) phenyl, optionally substituted one, two or three residues C1- C4-alkyl, C1- C4 phenyl, where phenyl, optionally substituted one, two or three residues C1- C4-alkyl, C1- C4-alkoxyl, halogen, an OH group, triptorelin or-CO2(C1- C4-alkyl); 2 (e) -(CH2)npyridinyl or 2 (f) where R9and R10taken together with N, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of 2 (aa) 4-the research, optionally substituted by one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxyl, halogen or trifloromethyl; 2 (bb) 4-thiomorpholine, optionally substituted by one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxyl; halogen or trifloromethyl; 2 (cc) 3-amino-1-pyrrolidin; 2 (dd) 1-pyrrolidine, optionally substituted by one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxyl, halogen, OH, -CH2OH or trifloromethyl; 2 (ee) 1-piperidine, optionally substituted with one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxyl, halogenation substituted by one, 2 or 3 C1- C4-alkyl, C1- C4-alkoxyl, halogen or trifluoromethyl; 2 (ff) 1-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (where the phenyl may be optionally substituted with one, 2 or 3 C1- C4-alkyl, C1- C4-alkoxyl, halogen or trifluoromethyl) or 4-pyridinyl-1-piperazine, optionally substituted with one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxyl, halogen, trifloromethyl, -COOH, -CH2OH, -CO2CH3or-CO2CH2CH3and 2 (gg) thiazolidin, thiazolidin-4-carboxylic acid, pipecolinate acid, p-piperazineethanol, 1-homopiperazine, 1-methylhomopiperazine, 4-phenyl-1, 2, 3, 6-tetrahydropyridine, Proline, tetrahydrofuran, 1-(3-hydroxy)pyrrolidine, nipecotate, 1, 2, 3, 4-tetrahydroisoquinoline or imidazole, 1 a R5, R6, R7and R8the same or different, selected from the group consisting of hydrogen, C1- C8-alkyl, -(CH2)nphenyl (where the phenyl may be optionally substituted with one, 2 or 3 C1- C4-alkyl, C1- C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1- C4-alkyl)], -(CH2)is but substituted one, 2 or 3 C1- C4-alkyl, C1- C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1- C4-alkyl)], -CH2-CH= CH2, -CH= CH-CH3, -O-CH2-CH= CH2, -CC-phenyl [where phenyl may be optionally substituted with one, 2 or 3 C1- C4-alkyl, C1- C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1- C4-alkyl)], -O-(CH2)p(N-methylpiperidin-3-yl), -O-(CH2)pNR9R10, -O-CH2CH(OCH3)2, -O-(CH2)pOR15, -(CH2)nC(O)-(CH2)nR9, -(CH2)nC(O)0-(CH2)pR9, -(CH2)nC(O)O-(CH2)pNR9R10, -(CH2)nC(O)(CH2)nNR9R10, NO2, -O-(CH2)nC(O)-(CH2)pR9, -O-(CH2)nC (O)O-(CH2)pR9, -O-(CH2)nC(O)-(CH2)nNR9R10, - NR9R10,-N(R9)(CH2)nC(O)-(CH2)nR10, -N(R9)-(CH2)nC(O)O-(CH2)nR10, -N(R9)(CH2)nC(O)-(CH2)nNR9R10, -O-(CH2)nphenyl where phenyl optionally substituted with one, 2 or 3 C1- C42)npyridine, -O(CH2)nC(O)-(CH2)npyridine, -O-(CH2)nC (O)0-(CH2)npyridine, -O(CH2)n-C(O) -N(R9) (CH2)npyridine, -O(CH2)nhonokalani, -O-(CH2)nchinoline, -O-(CH2)npyrazinyl, -O-(CH2)nnaphthyl, -O-(CH2)n-C(O)-(CH2)nnaphthyl, -O-(CH2)n-C(O)O-(CH2)nnaphthyl, -O-(CH2)nC(O)NR9- (CH2)nnaphthyl, halogen (fluorine, chlorine, bromine, iodine), OH, -(CH2)q-OH,-(CH2)qOC(O)R9, -(CH2)qOC(O) - NR9R10, -(1-cyclohexyl-1H-tetrazol-5-yl)-C1- C4-alkoxy, - [1-(C1- C5-alkyl)-1H-tetrazol-5-yl)- C1- C4-alkoxyl, -(1-(phenyl)-1H-tetrazol-5-yl)-C1- C4-alkoxyl [where phenyl optionally substituted with one, 2 or 3 C1- C4-alkyl, C1- C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1- C4-alkyl)] , -[1-(pyridinyl)-1H-tetrazol-5-yl] C1- C4-alkoxyl, -[1-(1-phenylethyl)-1H-tetrazol-5-yl] C1- C4-alkoxy, C1- C4-alkoxyl, a group of the formula II 6 1 where RIis methyl or carboxyl; 4 RII- hydrogen and 4 RIIIselected from benzyl [which certainly substituted by one, two or three groups selected from hydroxyl Lee halogen)]; C1- C5-alkyl, ((CH2)nCOOH, -CH2SH, -CH2SCH3imidazolidinethione, idolenlehre, -CH3CH(OH), -CH2OH, H2N(CH2)4-(optionally in protected form), or H2NC(NH) NH(CH2)3(optionally in protected form), provided that, when R5, R6and R8selected from: H, C1- C8-alkyl, or halogen, and Z is H or C1- C5is alkyl, then R7different from-O-(CH2)nC(O)O-(CH2)pR9or-O-(CH2)nC(O) - NR9R10where n has a value other than 0, and R9and R10selected from H or C1- C12-alkyl; with the overall proviso that when Y is distinct from -(CH2)nmorpholinyl at least one of the substituents R5, R6, R7or R8different from hydrogen, C1- C8-alkyl, NO2, OH, C1- C4-alkoxy, halogen atom, phenyl, benzyl, 4-morpholinylmethyl, NH2or dimethylaminopropyl, and yet provided that when Y is 4-morpholinyl, in the compounds of formula I do not include: 2 6,7-dimethoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 7,8-(bis)-(3-trifluoromethyl)phenylmethoxy-2-(4-morpholinyl)-4H-is l-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl] oxy] -N-phenylacetamide; 2 6- [(1-cyclohexyl-1H-tetrazol-5-yl)methoxy] -2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 2- [[8-methyl-2-(4)morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]] oxy] -N -(1-phenylethyl)-ndimethylacetamide; 1 with the additional condition that, when Y represents dimethylamino, in connection not included: 2 dimethyl ester 2-(dimethylamino)-8-methyl-4-oxo-4H-1-benzopyran-7-yl-carbamino acid; 2 dimethyl ether (dimethylamino)-4-oxo-4H-1-benzopyran-6-Il-carbamino acid; 2 dimethyl ester 2-(dimethylamino)-4-oxo-4H-1-benzopyran-7-yl - carbamino acid; 2 methyl ether [[8-methyl-2-(4-morpholinyl)-4-hydroxy-4-H]-benzopyran-7-yl-carbamino acid; 2 dimethyl ester 2-(dimethylamino)-4-oxo-4H-1-benzopyran-6-Il - carbamino acid; 2 dimethyl ester 2-(dimethylamino)-4-oxo-4H-1-benzopyran-7-yl his carbamino acid; 2 methyl ether [[8-methyl-2-(4-morpholinyl)-4-oxo-4H-benzopyran-7-yl] oxy] acetic acid; 2 lithium salt of [(8-methyl-2-(4-morpholinyl)-4-hydroxy-4H-1 - benzopyran-7-yl) exucuse acid; 4 R15selected from the group: C1- C5-alkyl, -(CH2)nphenyl where phenyl optionally substituted with one, 2 or 3 C1- C4-alkyl, C1- C4-alkoxyl, halogen, OH, trifluoromethyl or-CO2(C1- C4-alkyl)] -(CH2)plemya salts and hydrates. 2 2. Substituted benzopyrano formula I under item 1, in which Y is selected from the group consisting of -(CH2)nR9R10where R9and R10taken together with the N atom, form a saturated or unsaturated heterocyclic amine ring selected from the group consisting of: 2 (aa) 4-the research, optionally substituted by one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxyl, halogen or trifloromethyl, 2 (bb) 4-thiomorpholine, optionally substituted by one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxyl, halogen or trifloromethyl; 2 (cc) 3-amino-1-pyrrolidine; 2 (dd) 1-pyrrolidine, optionally substituted by one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxyl, halogen, OH,-CH2OH or trifloromethyl; 2 (ee) 1-piperidine, optionally substituted with one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxyl, halogen, trifloromethyl, -(CH2)qOH, -COOH, -CO2CH3, -CO2CH2CH3or phenyl (where the phenyl nabali reformation; 2 (ff) 1-piperazine, 4-methyl-1-piperazine, 4-phenyl-1-piperazine (where the phenyl may be optionally substituted by one, two or three C1- C4-alkilani, C1- C4-alkoxylate, halogen or triptorelin) or 4-pyridinyl-1-piperazine, optionally substituted with one or two substituents selected from the group consisting of C1- C4-alkyl, C1- C4-alkoxyl, halogen, trifloromethyl, -COOH, -CH2OH, -CO2CH3or-CO2CH2CH3. 2 3. Substituted benzopyrano formula 1 p. 1, wherein Z is H or C1- C5-alkyl. 2 4. Substituted benzopyrano formula 1 on p. 3, in which Y is chosen from the group consisting of -(CH2)nNR9R10where R9and R10together with N form a 4-morpholine, and n = 0. 2 5. Substituted benzopyrano formula I on p. 4, in which Z - H. 2 6. Substituted benzopyrano formula I under item 5, in which n = 0. 2 7. Substituted benzopyrano formula I on p. 2, in which at least one Deputy from R5, R6, R7or R8selected from the group consisting of - (CH2)nphenyl [ where phenyl may be optionally substituted by one, two or three substituents of the C1- C4-alkyl, C1- C2)npyridinyl, -(CH2)qNR9R10-CH= CH-phenyl [where phenyl optionally substituted one, two or three substituents from the group of C1- C4-alkyl, C1- C4-alkoxyl, halogen, OH, trifloromethyl or-CO2(C1- C4-alkyl)] , -CH2-CH= CH2, -CH= CH-CH3, -O-CH2-CH= CH2. 2 8. Substituted benzopyrano formula I on PP. 2, 3, 4, or 6, where R5, R6, R7and R8choose from groups: R5, R6, R7and R8each is hydrogen, R5, R6and R8each is hydrogen, and R7selected from-O(CH2)nphenyl, where phenyl may be optionally substituted by one, two or three substituents of the C1- C4-alkyl, C1- C4-alkoxyl, halogen or trifloromethyl) or -(CH2)nphenyl (where the phenyl may be optionally substituted by one, two or three substituents of the C1- C4-alkyl, C1- C4-alkoxyl, halogen or trifloromethyl; 2 R5and R6mean hydrogen; 4 R8is hydrogen, halogen or C1- C5-alkyl and R7selected from-O(CH2)nphenyl (where the phenyl may be substituted by one, two or three substituents of the C1- C1- C4-alkyl, C1- C4-alkoxyl, halogen or trifloromethyl), -O-(CH2)nnaphthyl, -(CH2)nphenyl (where the phenyl may be substituted by one, two or three substituents of the C1- C4-alkyl, C1- C4-alkoxyl, halogen or trifloromethyl), -(CH2)npyridinyl (where the pyridinyl may be substituted by one, two or three substituents of the C1- C4-alkyl, C1- C4-alkoxyl, halogen or trifloromethyl). 2 9. Substituted benzopyrano formula I on p. 1, selected from the group: 2 1. 6-Chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 2. 2-(4-Morpholinyl)-4H-1-benzopyran-4-one; 2 3. 8-Methyl-2-(4-morpholinyl)-(7 phenylmethoxy)-4H-1-benzopyran-4-one; 2 4. 7-Chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 5. 8-Chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 6. 6-Bromo-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 7. 6-Fluorescent-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 8. 6-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 9. 7-Methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 10. 8-Methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 11. 6-Methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 12. 7-Methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 13. 6-(Phenylmethoxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 14. 8-(the dryer is an ester of carbamino acid; 2 16. 6-(3-Pyridinecarboxamide) -2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 17. 2-(4-Morpholinyl)-6-nitro-4H-1-benzopyran-4-one; 2 18. 6-([[Phenylmethoxy]carbonyl]amino) -2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 19. 8-Methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 20. 3-Amino-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 21. 3-Chloro-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 22. 3-Bromo-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 23. 8-Methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one; 2 24. 2-(4-Morpholinyl)-5-(phenylmethoxy)-4H-1-benzopyran-4-one; 2 25. 7,8-Dimethoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 26. 8-Methyl-7-(phenylmethoxy)-2-[4-(2-pyridinyl)-1-piperazinil] -4H-benzopyran-4-one; 2 27. 8-methyl-7-(phenylmethoxy)-2-(1-piperazinil)-4H-benzopyran-4-one; 2 28. 8-Methyl-7-(phenylmethoxy)-2-(1-pyrrolidinyl)-4H-benzopyran-4-one; 2 29. 8-Methyl-7-(phenylmethoxy)-2-(1-piperidinyl)-4H-benzopyran-4-one; 2 30. 8-Methyl-2-(4-methyl-1-piperazinil)-7-(phenylmethoxy)-4H-benzopyran-4-one; 2 31. 8-Methyl-7-(phenylmethoxy)-2-(2,6-dimethyl-4-morpholinyl) -4H-benzopyran-4-one; 2 32. 8-Methyl-7-(phenylmethoxy)-2-(4-phenyl-1 - piperidinyl)-4H-benzopyran-4-one; 2 33. 8-Methyl-7-(phenylmethoxy)-2- (4-phenyl-1-piperazinil)-4H-benzopyran-4-one; 2 34. 7-Hydroxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 35. 6-Hydroxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 36. 7-Hydroxy-2-(4-morpholine the Iran-4-one; 2 39. 7-Methoxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 40. 7-[(4-Methoxyphenyl)methoxy] -8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 41. 8-Methyl-7-[(4-were)methoxy] -2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 42. 7-[(4-Chlorophenyl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 43. 7-[(4,5-Dichlorophenyl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 44. 8-Methyl-2-(4-morpholinyl) -7-(2-pyridinylmethyl)-4H-1-benzopyran-4-one; 2 45. 8-Methyl-7-[[(phenyl)carbonyl]oxy] -2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 46. 7-Methoxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 47. 7-[[4-1,1-Dimethylethyl)phenyl]methoxy-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 48. 7-[(3-Methoxyphenyl)methoxy] -8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 49. 7 -[(2-Phenylethyl)methoxy] -8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 50.7-[(2-Methoxyphenyl)methoxy] -8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 51. 7-[(4-Ethoxyphenyl)methoxy]-8-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 52. 8-(4-Ethoxybenzyl) -2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 53. 8-(2-Methoxybenzyloxy) -2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 54. 2-(4-Morpholinyl)-8-(2-phenylethane)-4H-1-benzopyran-4-one; 2 55. 2-(4-Morpholinyl)-(2-oxo-2-phenylethane)-4H-1-benzopyran-4-one; 2 56. 8-(4-Chlorobenzoyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 57. 8-(4-so-n; 2 59. 8-(3,4-Dichlorobenzoate)-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 60. 8-(4-Methylbenzylamino)-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 61. 8-(4-Methoxybenzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 62. 2-(4-Morpholinyl)-8-(naphthyl-2-metiloksi)-4H-1-benzopyran-4-one; 2 63. 2-(4-Morpholinyl)-8-(naphthyl-1-metiloksi)-4H-1-benzopyran-4-one; 2 64. 8-Methyl-2-(4-morpholinyl)-7-(naphthyl-2-metiloksi)-4H-1-benzopyran-4-one; 2 65. 8-Methyl-2-(4-morpholinyl)-7-(naphthyl-1-metiloksi)-4H-1-benzopyran-4-one; 2 66. 2-(Dimethylamino)-8-methyl-7-(phenylmethoxy)-4H-1-benzopyran-4-one; 2 67. Ester [8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]-4-morpholinylcarbonyl acid; 2 68. 2-(4-Morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one; 2 69. 8-Methyl-2-(4-morpholinyl)-7-(2-oxo-2-phenylethane)-4H-1-benzopyran-4-one; 2 70. 6-Chloro-8-methyl-2-(4-morpholinyl)-7-(phenylmethoxy)-4H-1-benzopyran-4-one; 2 71. Methyl ester [[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl] oxy] acetic acid; 2 72. Methyl ester 4-[[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl] oxy] methyl]benzoic acid; 2 73. Methyl ester 4-[[[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl] oxy] methyl] benzoic acid; 2 74. 8-Methyl-2-(4-morpholinyl)-7-[[3-(trifluoromethyl)phenyl]methoxy] -4H-1-benzopyran-4-one; 2 75. 2-(4-Morpholinyl)-8-[[3-(trifluoromethyl)til-2-(4-morpholinyl)-7-(2-propenyloxy)-4H-1-benzopyran-4-one; 2 78. 2-(4-Morpholinyl)-7-(1-naphthalenyloxy)-4H-1-benzopyran-4-one; 2 79. 8-Methyl-2-(4-morpholinyl)-7-(3-pyridinylmethyl)-4H-1-benzopyran-4-one; 2 80. 8-Methyl-2-(4-morpholinyl)-7-(4-pyridinylmethyl)-4H-1-benzopyran-4-one; 2 81. 8-Methyl-2-(4-morpholinyl)-7-(2-chynoxalinilmethylen)-4H-1-benzopyran-4-one; 2 82. 8-Methyl-2-(4-morpholinyl)-7-(personalitati)-4H-1-benzopyran-4-it; 2 83. N-Oxide-8-methyl-2-(4-morpholinyl)-7-(2-pyridinylmethyl)-4H-1-benzopyran-4-one; 2 84. N-Oxide-8-methyl-2-(4-morpholinyl)-7-(3-pyridinylmethyl)-4H-1-benzopyran-4-it; 2 85. 8-Iodo-2-(4-morpholinyl)-7-(3-pyridinylmethyl)-4H-1-benzopyran-4-one; 2 86. 3,3-Dimethyl-1-[[8-methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl] - oxy]butane-2-it; 2 87. 1-[[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl] oxy]propan-2-it; 2 88. 1-[[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl]oxy]butane-2-he; 2 89. 8-Methyl-2-(4-morpholinyl)-7-(2-oxo-2-(2-naphthyl)ethoxy)-4H-1-benzopyran-4-one; 2 90. 2-(4-Morpholinyl)-7-(2-pyridinylmethyl)-4H-1-benzopyran-4-one; 2 91. 2-(4-Morpholinyl)-7-(3-pyridinylmethyl)-4H-1-benzopyran-4-one; 2 92. 2-(4-Morpholinyl)-8-(2-pyridinylmethyl)-4H-1-benzopyran-4-one; 2 93. 2-(4-Morpholinyl)-8-(3-pyridinylmethyl)-4H-1-benzopyran-4-one; 2 94. 8-Methyl-2-(4-Morpholinyl)-7-(2-hyalinella)-4H-1-benzopyran-4-one; 2 95. 7,8-(Bis)-phenylmethoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one; is n; 2 98. 7-Hydroxy-2-(4-morpholinyl)-8-phenylmethoxy-4H-1-benzopyran-4-one; 2 99. 8-Hydroxy-2-(4-morpholinyl)-7-(3-trifluoromethyl)phenylmethoxy-4H-1 - benzopyran-4-one; 2 100. 7-Hydroxy-2-(4-morpholinyl)-8-(3-trifluoromethyl)phenylmethoxy-4H-1-benzopyran-4-one; 2 101. 7-[3-(1-Cyclohexyl-1H-tetrazol-5-yl)propoxy]-8-methyl-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 102. 8-[3-(1-Cyclohexyl-1H-tetrazol-5-yl)propoxy]-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 103. 7-[(1-Cyclohexyl-1H-tetrazol-5-yl)methoxy] -8-methyl-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 104. 8-[(1-Cyclohexyl-1H-tetrazol-5-yl)methoxy]-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 105. 2-(4-Morpholinyl)-8-[(1-phenyl-1H-tetrazol-5-yl)oxy] -4H-1-benzopyran-4-one; 2 106. N-cyclohexyl-2-[[2-(4-morpholinyl)-4-oxo- -4H-1-benzopyran-8-yl] oxy]ndimethylacetamide; 2 107. N-(1,1-Dimethylethyl)-2-[[2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-8-yl] oxy] ndimethylacetamide; 2 108. 2-[[2-(4-Morpholinyl)-4-oxo-4H-1-benzopyran-8-yl] -N] -phenylacetamide; 2 109. 2-[[2-(4-Morpholinyl)-4-oxo-4H-1-benzopyran-8-yl] oxy] - N-(1 - phenylethyl)ndimethylacetamide; 2 110. 8-Methyl-2-(4-morpholinyl)-7-[(1-phenyl-1H-tetrazol-5-yl)oxy] -4H-1-benzopyran 4-one; 2 111. 2-[[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl] oxy] -N-3-pyridylacetate; 2 112. N-[[[8-Methyl-2-(4-morpholinyl)-4-oxo-4H-1-benzopyran-7-yl] oxy]-N-3-pyridylacetate; 2 113. 7-(2,2-Dimethoxyethoxy)-8-methyl-2-(4-starved)-4H-1-benzopyran-4-one; 2 116. 8-Formyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 117. 2-(4-Morpholinyl)-8-(phenylamino)methyl-4H-1-benzopyran-4-one; 2 118. 2-(4-Morpholinyl)-8-(2E-phenyl)ethinyl-4H-1-benzopyran-4-one; 2 119. 8-Hydroxymethyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 120. 8-Methyl-7-[(1-methyl-3-piperidinyl)methoxy]-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 121. 8-Methyl-2-(4-morpholinyl)-7-(2-(1-piperidinyl)ethyl)oxy-4H-1-benzopyran-4-one; 2 122. 8-Methyl-2-(4-morpholinyl)-7-(2-(1-pyrrolidinyl)ethyl)oxy-4H-1-benzopyran-4-one; 2 123. 8-Methyl-2-(4-morpholinyl)-7-(2-(4-morpholinyl)ethyl)oxy-4H-1-benzopyran-4-one; 2 124. 8-Methyl-2-(4-morpholinyl)-7-(3-(1-piperidino)propyl)oxy-4H-1-benzopyran-4-one; 2 125. 7-(2-Diethylaminoethyl)hydroxy-8-methyl-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 126. 7-[2-(Ethylvanillin)ethoxy]-8-methyl-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 127. 7-(2-Diisopropylaminoethyl)hydroxy-8-methyl-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 128. 7-Hydroxy-8-methyl-2-(1-piperidinyl) -4H-1-benzopyran-4-one; 2 129. 8-Methyl-2-(1-piperidinyl)-7-(3-pyridinylmethyl) -4H-1-benzopyran-4-one; 2 130. 7-Acetoxy-3,8-dimethyl-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 131. 3,8-Dimethyl-7-hydroxy-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 132. 7-Benzyloxy-3,8-dimethyl-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 133. 3,8-Dimethyl-2-(4-morpholinyl)-7-(naphthyl-1-metiloksi) -4H-1-benzopyran-4-one; 2 134. 3,8-D is-4H-1-benzopyran-4-one; 2 136. 3,8-Dimethyl-7-(chlorobenzoyloxy)-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 137. 3,8-Dimethyl-2-(4-morpholinyl)-7-(3-triftormetilfosfinov) -4H-1-benzopyran-4-one; 2 138. 7-(Carbomethoxyamino)-3,8-dimethyl-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 139. 8-Hydroxy-3-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 140. 8-Benzyloxy-3-methyl-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 141. 3-Methyl-2-(4-morpholinyl)-8-(m-triftormetilfosfinov) -4H-1-benzopyran-4-one; 2 142. 8-Methyl-7-(2-phenylethenyl)-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 143. 8-Methyl-2-(4-morpholinyl)-7-(2-phenyl)ethyl-4H-1-benzopyran-4-one; 2 144. 2-(4-Morpholinyl)-8-(2-phenyl)ethinyl-4H-1-benzopyran-4-one; 2 145. 2-(4-Morpholinyl)-8-(2-phenyl)ethyl-4H-1-benzopyran-4-one; 2 146. 2-(4-Morpholinyl)-8-(2-(3-trifluoromethyl)phenyl)ethinyl-4H-1-benzopyran-4-one; 2 147. 2-(4-Morpholinyl)-8-(2-(3-trifluoromethyl)phenyl)ethyl-4H-1-benzopyran-4-one; 2 148. 8-Methyl-2-(4-morpholinyl)-7-(2-(1-naphthyl)ethyl-4H-1-benzopyran-4-one; 2 149. 8-Methyl-2-(4-morpholinyl)-7-phenyl-4H-1-benzopyran-4-one; 2 150. 7 atomic charges-8-iodo-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 151. 8-Ethyl-2-(4-morpholinyl)-7-(3-pyridinylmethyl) -4H-1-benzopyran-4-one; 2 152. 8-Ethyl-2-(4-morpholinyl)-7-phenylmethoxy-4H-1-benzopyran-4-one; 2 153. 8-Iodo-2-(4-morpholinyl)-7-phenylmethoxy-4H-1-benzopyran-4-one; 2 154. 8-Ethyl-2-(4-morpholinyl)-7-[2-(1-piperidinyl)ethyl)-11-hydroxy-4H-1-berenil)-4H-1-benzopyran-4-one; 2 157. 7-(3-Pyridinylmethyl)-2-(1-piperidinyl)-8-methyl-4H-1-benzopyran-4-one; 2 158. 8-Methyl-2-(4-morpholinylmethyl)-7-(phenylmethoxy) -4H-1-benzopyran-4-one; 2 159. 7-Hydroxy-2-(4-morpholinylmethyl)-8-methyl-4H-1-benzopyran-4-one; 2 160. 7-[(1-Cyclohexyl-1H-tetrazol-5-yl)metiloksi] -8-methyl-2- (4-morpholinylmethyl)-4H-1-benzopyran-4-one; 2 161. 8-Methyl-2-(4-morpholinylmethyl)-7-(3-pyridinylmethyl) -4H-1-benzopyran-4-one, 1 or its pharmaceutically acceptable salt, or hydrate, 2 10. replaced by benzopyrano formula 1, p. 1, selected from the group: 2 1. 2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 2. 8-methyl-2-(4-morpholinyl)-(7 phenylmethoxy)-4H-1-benzopyran-4-one; 2 3. 6-[[phenylmethoxy]carbonyl]amino)-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 4. 8-methyl-2-(4-morpholinyl)-7-(2-pyridinylmethyl) -4H-1-benzopyran-4-one; 2 5. 8-(4-methoxybenzyloxy)-2-(4-morpholinyl)-4H-1-benzopyran-4-one; 2 6. 8-methyl-2-(4-morpholinyl)-7-(naphthyl-1-metiloksi) -4H-1-benzopyran-4-one; 2 7. 8-methyl-2-(4-morpholinyl)-7-(3-pyridinylmethyl) -4H-1-benzopyran-4-one; 2 8. 7-[(1-cyclohexyl-1H-tetrazol-5-yl)methoxy]-8-methyl-2-(4-morpholinyl) -4H-1-benzopyran-4-one; 2 9. 8-methyl-2-(4-morpholinyl)-7-(2-(1-piperidinyl)ethyl)oxy-4H-1-benzopyran-4-one; 2 10. 8-methyl-2-(4-morpholinyl)-7-(2-(1-pyrrolidinyl)ethyl)oxy-4H-1-benzopyran-4-one; 2 11. 8-methyl-2-(1-piperidinyl)-7-(3-pyridinylmethyl) -4H-

 

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The invention relates to branched amino-thiazole, methods for their preparation and the pharmaceutical compositions

The invention relates to new chemical compound, namely 3-(4-methyl-2-thiazolyl)-6-proper-7-(1-methyl-1-etoxycarbonyl)metaxia - Mona, of the formula I

< / BR>
which has analepticheskih, hypoglycemic and hypolipidemic effect

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to the field of organic chemistry, in particular to the synthesis of medicinal substances

The invention relates to novel 4,5-dihydro-1H-2,4-allowin the benzodiazepines and benzodiazipine appropriate diamines and aminoamides, to methods for their preparation and to methods and compositions for treating arrhythmia in mammals with said 4,5-dihydro-1H-2,4-ariovich of benzodiazepines and benzodiazipines

The invention relates to new benzothiophen-2-carboxamide-S,S-dioxides having valuable properties, in particular to derive benzothiophen-2-carboxamide - S,S-dioxide of the General formula I

< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

The invention relates to a new alkylenediamine derivative, a method for obtaining and drug treatment for dysuria containing the specified new alkylenediamine derivative or its pharmaceutically acceptable salt as an active ingredient

The invention relates to the field of organic chemistry and relates to a method of obtaining new derivatives of imidazole

The invention relates to organic chemistry, specifically to new chemical compounds, of General formula:

< / BR>
in particular 1,3-bis(2'-hydroxy-3'-morpholinopropan)-6-methyluracil(a); 1,3-bis(2'-hydroxy-3'-piperidinoethyl)-6-stands-rallu (b); 3-bis(2'-hydroxy-3'-morpholinopropan)-5-hydroxy-6-methyluracil (); 1,3-bis(2'-hydroxy-3'-piperidinoethyl)- 5-hydroxy-6-methyluracil (g); 1,3-bis(2'-hydroxy-3'-morpholinopropan)-5-(2'-hydro - XI-3'-morpholinoethoxy)-6 - methyluracil (d) and 1,3-bis(2'-hydroxy-3'-piperidinoethyl)-5-(2'-hydroxy-3'-piperidino - poxy)- 6-methyluracil (E), showing immunotropic and anti-inflammatory activity

- aminoacyl)-5,10-dihydro-11h-dibenzo[b, e] [1,4]- diazepin-11-ons or their salts, possess antiarrhythmic activity" target="_blank">

The invention relates to the field of chemistry, particularly to the new series of compounds - 5-(-aminoacyl)-5,10-dihydro-11N - dibenzo [b,e]-[1,4]-diazepin-11-Onam General formula

where R1is a hydrogen atom or chlorine;

R2is a hydrogen atom or a C1-C2-alkyl;

R3- C1-C2-alkyl or cyclohexyl, or R2and R3together with the nitrogen atom can be morpholinyl or N-methylpiperazine balance; provided that, if R2is a hydrogen atom, R3can be1-C3-alkyl or cyclohexyl,

n=3-6;

m = 0-1; X=Cl or Br

The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

The invention relates to new chemical compounds with valuable properties, in particular to piperidinylmethyl derived chromane General formula (I)

< / BR>
where A is hydrogen or lower alkoxy,

E is hydrogen, hydroxyl, phenyl or piperidyl,

G phenyl not substituted or substituted with halogen and/or trifluoromethyl, fenoxaprop substituted by trifluoromethyl, benzyl, substituted phenylcarbinol, aminocarbonyl,

provided that E does not mean hydrogen or hydroxide, when G is phenyl, and their salts with inorganic acids
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