Bicyclic heterocyclic compound and pharmaceutical composition

 

(57) Abstract:

Usage: in medicine as a drug. The essence of the invention: bicyclic heterocyclic compounds f-ly Q-A1-X1-ArC(OR1, R3)-R2where AG - direct X or (1 - 3C) alkylene, X1- oxy, thio, sulfinil, sulfonyl, Ar is phenylene which may be substituted with halogen, hydroxy, amine, C1- C4- alkylamino, fluorine - C1- C4- alkyl, R1- C1- C4- alkyl, C3- C4alkenyl, C3- C4- quinil, R2and R3together form the group of f-crystals, A2- X2- A3that together with the carbon atom to which A2- A3attached, defines a ring containing 5 or 6 ring atoms, in which A2and A3are 1 - CS - alkylene, X - oxygraph. Reagent 1: O-A1-X1-H. Reagent 2: ZAr-C(OR1,R3R2, Z - substituted group. 2 C. and 8 C. p. F.-ly, 5 Il., table 1.

The invention relates to new bicyclic heterocyclic compounds, and especially of new bicyclic heterocyclic compounds, which are inhibitors of the enzyme 5-lipoxygenase (referred to hereafter as LO). The invention Casals is omposite, containing them. The invention also includes the use of these bicyclic heterocyclic compounds in the treatment of various inflammatory and/or allergic diseases involving the direct or indirect products catalyzed by the enzyme 5-LO oxidation of arachidonic acid and the production of new medicaments for such use.

As above described here below bicyclic heterocyclic compounds are inhibitors of 5-LO, this enzyme is known that it is due to the cascading process (including the number of reactions) causes the formation of physiologically active leukotrienes such as leukotriene4(TV4and peptido-lipid leukotrienes such as leukotriene4(CU4and leukotrien D4(DT4) and various metabolites.

Biosynthetic relationship and physiological properties of leukotrienes summarized by the authors G. W. Taylon and S. R. Clarke in "Trendsin Pharmacological Science, 1986, 7 100-103. Leukotrienes and their metabolites are involved in the process of occurrence and development of various inflammatory and allergic diseases such as inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout, inflammation as the street), disease of the skin (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the process of occurrence and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, angina and peripheral vascular disease. In addition to the above leukotrienes are mediators or mediators of inflammatory diseases due to their ability to modulate the function of lymphocytes and leukocytes. Other physiologically active metabolites of arachidonic acid such as prostaglandin and thromboxanes, arise from the action on the arachidonic enzyme cyclohexenes.

Currently I found that some of bicyclic heterocyclic compounds are effective as inhibitors of the enzyme 5-LO and thus of leukotriene biosynthesis. Thus, such compounds are of value as therapeutic agents in the treatment of, for example, allergic conditions, eczema, asthma, cardiovascular and cerebrovascular disorders and/or inflammatory and arthritic conditions, mediator, which is fully or partially one or more leukotr I

Q-A1-X1-Ar - in which Q is 4H-1.4-benzoxazine or 4H-1,4-benzothiazine, or the corresponding 2,3-dihydroergocornine, 4H-3,1-benzoxazine or 4H-3,1-benzothiazine, or its corresponding 1,2-dihydroergocornine, or 4H-pyrido[3,2-b][1,4-]oxazinyl, each of which may optionally bear one oxo or thioxo Deputy and up to four other substituents, selected from halogen, hydroxy, cyano, amino, /1-4S/alkyl, /1-4S/alkoxy, fluorine /1-4S/alkyl, /1-4S/alkylamino and di- / /1-4C/alkyl /- amino,

in which AIis a direct link to XIor a 1-3C/-alkylene,

in which XIis oxy, thio, sulfinil or sulfonium,

in which AG is phenylene which may optionally bear one or two substituent selected from halogeno, hydroxy, amino, /1-4C/ alkyl, /1-4C/ alkoxy, /1-4C/ alkylamino, di/1-4C/ /alkyl/ amino and fluoro-/1-4C/ alkyl,

in which R1is 1-4C/ alkyl, /3-4C/ alkenyl or /3-4C/ quinil, and

in which R2and R3together form a group of the formula-A2-X2-AND3- which together with the carbon atom to which AND2and3attached, defines a ring containing 5 or 6 ring atoms, in which ANDUP> is hydroxy,

moreover, the ring can Nejati one or two /1-4C/ alkyl substituent,

or is it acceptable from a pharmaceutical point of view of salt.

In this specification the generic term "alkyl" includes alkyl groups, as with the straight chain and branched chain. However references to individual alkyl groups such as "propyl" are specific only for option group with a straight chain, and references to individual alkyl groups branched chain, such as "isopropyl" are specific only for option branched chain. A similar condition applies to other General terms.

It should be understood that, insofar as certain of the compounds of formula 1 can detect the phenomenon of tautomerism, and any of the images of the formulas presented here may represent only one of the possible tautomeric forms, the invention includes in its definition any tautomeric form of the compounds of formula 1, which has the property of inhibiting 5-LO and should not be limited merely to any one tautomeric form used in the invention of formulas.

It should also be understood that because some of the compounds of formula I, defined the Fort worth, containing an asymmetric carbon atom, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting 5-LO. Synthesis of optically active forms can be carried out using standard methods of organic chemistry well known in the art, for example, by synthesis from optically active starting materials or by using the splitting of racemic forms. Similarly, inhibiting properties against 5-LO can be measured using standard laboratory techniques, referred to below.

Suitable values for the General (generic) terms mentioned above, values are presented below.

Suitable values for substituents which may be present in Q or Ar include, for example,

for halogen: fluorine, chlorine, bromine and iodine

for /1-4C/ alkyl: methyl, ethyl, propyl, isopropyl, butyl,

isobutyl, sec-butyl,

for /1-4C/ alkoxy: methoxy, ethoxy, propoxy,

isopropoxy, butoxy

for the fluoride /1-4C/ alkyl: vermeil, deformity, trifluoromethyl,

2-foretel, 2,2,2-triptorelin and pentaverate,

for /1-4C/ alkylamino: methylamino, ethylamino, propylamino chodashim value for a1when it is /1-3C/ alkylene is, for example, methylene, ethylene or trimethylene.

A suitable value for Ar when it is phenylene is, for example, 1,3-phenylene or 1,4-phenylene.

A suitable value for R1when it is /1-4C/ alkyl is, for example, methyl, ethyl, propyl or butyl, when it is /3-4C/ alkenyl, it is, for example, allyl, 2-butenyl or 3-butenyl, and when it is /3-4C/ quinil, it is for example, 2-propenyl or 2-butenyl.

When R2and R3together form a group of the formula-A2-X2-AND3- which together with the carbon atom to which attached AND2and3, defines a ring having 5-6 ring atoms then a suitable value AND2or AND3that may be the same or different, when each of them is /1-3C/ alkylene is, for example, methylene, ethylene or trimethylene. Suitable values for substituents which may be present in the specified 5 - to 7-membered ring include, for example:

for /1-4C/ alkyl: methyl, ethyl, propyl, isopropyl,

butyl, and isobutyl

A suitable pharmaceutically acceptable salt of a bicyclic heterocycle compounds of the invention, which is sufficiently basic, for example, an acid additive salt, for example, from inorganic or organic acid, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, triftoruksusnoi, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a bicyclic heterocyclic compounds of the invention which is sufficiently acidic is a salt of an alkali metal, e.g. sodium or potassium salt, salt alkaline-earth metal, e.g. calcium or magnesium salt, ammonium salt or a salt with an organic base, which gives a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or Tris-2-hydroxyethylamino.

The particular new compounds of the invention are, for example, bicyclic heterocyclic compounds of the formula I, in which

/a/ Q is 4H-1,4-benzoxazine, 4H-1,4-benzothiazine or their respective 2,3-dihydroprogesterone, which may optionally bear one oxo or taxonomical and up to four substituents having the meanings given above for additional substituent in Q, and1, 3-dihydro-4H-benzoxazine,2,3-dihydro-4H-1,4-benzo-triazinyl, 1,2-dihydro-4H-3,1-benzoxazine or 2,3-dihydro-4H-pyrido/3,2-/ /1,4/oxazinyl, which may optionally bear one oxo or thioxo Deputy and up to four substituents having the meanings defined here above for additional substituents from group Q, and1X1, Ar, R1, R2and R3have the meanings defined here above,

/c/ Q is a 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-2-yl, 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-6-yl or 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-6-yl or the corresponding 3-thioxo-derivative, or 3-oxo-2,3-dihydro-4H-benzo - thiazin-2-yl, 3-oxo-2,3-dihydro-4H-1,4-benzothiazin-6 - or 3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl or the corresponding 3-thioxo derivatives, heterocyclic fragment which may optionally have up to four substituents having the meanings given above for additional substituents from group Q; and1X1, Ar, R1, R2and R3have any of the values defined above;

/e/ Q is 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-6-yl or 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or the corresponding 3-thioxo derivatives, 3-oxo-2,3-dihydro-4H-1,4-benzothiazin-6-yl or 3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl or the corresponding the x corresponding 2-thioxo derivatives, or 3-oxo-2,3-dihydro-4H-pyrido/3,2-b/ /1.4/oxazin-6-yl or 3-oxo-2,3-dihydro-4H-pyrido /3,2-b/ /1.4/oxazin-7-yl or the corresponding 3-thioxo derivatives, heterocyclic fragment which may optionally have up to four substituents having the meanings defined here above for additional substituents from group Q; and1X1, Ar, R1, R2and R3have any of the values defined here above;

/f/ AND1is a direct link to X1and X1represents hydroxy, thio, sulfinil or sulphonyl; and Q, Ar, R1, R2and R3have any of the values defined above;

/g/ AND1is methylene, and X1represents hydroxy, thio, sulfinil or sulphonyl; and Q, Ar, R1, R2and R3have any of the values defined above;

/h/ Ar is 1,3-phenylene or 1,4-phenylene which may optionally have one or two substituent selected from fluorine, chlorine, hydroxy, amino, nitro, ureido, methyl, methoxy, methylamino, dimethylamino, trifloromethyl and acetamido; and Q, AND1X1, R1, R2and R3have any of the values defined above;

/i/ Ar is 3,5-peridinin; and Q, AND1X1, R1, R2and R31X1, Ar, R2and R3have any of the values defined above;

/k/ R2and R3together form a group of the formula-A2-X2-AND3- which together with the carbon atom to which attached AND2and3define a ring having 5-7 ring atoms, where a2and3that may be the same or different, each represents a methylene, ethylene or trimethylene, and X2represents hydroxy, and this ring may have one or two substituent selected from hydroxy, methyl, ethyl, propyl, methoxy, ethoxy; and Q, AND1X1, Ar and R1have any of the values defined above; or

/l/ R1and R2together form a group of the formula-A2-X2-AND3- which together with the oxygen atom attached to AND2and with the carbon atom to which attached AND3limit ring having 5-7 ring atoms, where a2and3that may be the same or different, each represents a methylene or ethylene and X2represents hydroxy, and this ring may have one, two or three substituent selected from methyl, ethyl and propyl, and R3represents methyl or ethyl; and Q, AND1 CLASS="ptx2">

Preferred compounds of the invention include bicyclic heterocyclic compounds of the formula I in which Q represents 4H-1,4-benzoxazine, 4H-1,4-benzothiazine or their corresponding 2,3-dihydro-derivative, which may not necessarily be one oxo or thioxo Deputy and up to four substituents selected from fluorine, chlorine, bromine, hydroxy, cyano, amino, methyl, ethyl, propyl, methoxy, trifloromethyl, 2-veratile, 2,2,2-triptoreline, 2-methylaminomethyl, 2-dimethylaminoethyl, phenyl and benzyl, and where specified phenyl or benzyl Deputy may not necessarily be the Deputy selected from chlorine, methyl and methoxy;

AND1is a direct link to X1or is methylene;

X1represents hydroxy, thio, sulfinil or sulfonyl;

Ar is 1,3-phenylene or 1,4-phenylene which may optionally have one or two substituent selected from fluorine, chlorine, hydroxy, amino, nitro, ureido, methoxy, dimethylamino, trifloromethyl and acetamido; or

Ar represents a 3,5-peridinin;

R1represents methyl, ethyl, allyl or 2-PROPYNYL; and

R2and R3together form a group of the formula-A2-X2-AND3- that instead of the atoms, where a2is ethylene, AND3is methylene or ethylene and X2represents hydroxy, and this ring may have one or two substituent selected from methyl, ethyl, propyl, methoxy, ethoxy;

or R1and R2together form a group of the formula-A2-X2-AND3- which together with the oxygen atom attached to AND2and with the carbon atom to which attached AND3, defines a ring having 5 or 6 ring atoms, where a2is methylene, AND3is methylene or ethylene and X2is oxy, and which ring /ring/ can have one, two or three substituent selected from methyl, ethyl and propyl, and R3represents methyl or ethyl; or their pharmaceutically acceptable salts.

Additional preferred compounds of the invention include bicyclic heterocyclic compounds of the formula I, where Q represents 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or 3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl, which may optionally have one, two or three substituent selected from fluorine, chlorine, methyl, ethyl, propyl, 2-veratile, 2-dimethylaminoethyl, phenyl and benzyl;

AND1represents a direct link with X
Ar is 3,5-peridinin;

R1represents methyl, ethyl, allyl or 2-PROPYNYL; and

R2and R3together form a group of the formula-A2-X2-AND3- which together with the carbon atom to which attached AND2and3limit ring having 5 or 6 ring atoms, where a2is ethylene, AND3methylene or ethylene, and X2oxy, and which ring /ring/ may have one or two substituent selected from methyl and ethyl;

or R1and R2together form a group of the formula-A2-X2-AND3- which together with the oxygen atom attached to AND2and with the carbon atom to which attached AND3limit ring having 5 ring atoms, where a2is methylene, AND3is methylene, and X2is oxy, and which ring /ring/ can have one, two or three substituent selected from methyl and ethyl, and R3represents methyl or ethyl;

or their pharmaceutically acceptable salts.

The following Poroi Q represents 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or 3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl, or their respective 4-methyl derivative, which may optionally have one or two substituent selected from methyl and ethyl;

AND1is a direct link to X1or is methylene;

X1represents hydroxy, thio, sulfinil or sulfonyl;

Ar is 1,3-phenylene which may optionally have one or two substituent selected from fluorine, methoxy and trifloromethyl;

R1represents methyl, ethyl or allyl; and

R2and R3together form a group of the formula-A2-X2-AND3- which together with the carbon atom to which attached AND2and3, defines a ring having 5 or 6 ring atoms, where a2is ethylene, AND3is methylene or ethylene and X2is oxy, and which may have a Deputy, selected from methyl, ethyl, propyl and methoxy;

or their pharmaceutically acceptable salts.

The following preferred group of compounds of the invention comprises a bicyclic heterocyclic compound of formula 1, in which Q is 4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin - 7-yl or 4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl, or their respective 2,2-dim the screens 1,3-phenylene or 5-fluoro-1,3-phenylene;

R1represents methylene; and R2and R3together form a group of the formula-A2-X2-AND3- which together with the carbon atom to which attached AND2and3limit ring having 6 ring atoms, where each of the A2and3is ethylene, and X2is oxy, and which may have a methyl or the ethyl substituent in the alpha position relative to the X2;

or their pharmaceutically acceptable salts.

Additionally preferred compounds of the invention include bicyclic heterocyclic compounds of the formula I, where Q represents 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-6-yl, 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl, 3-dioxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl, 2-oxo-1,2-dihydro-4h-3,1-benzoxazin-6-yl, 3-oxo-2,3-dihydro-4h-1,4-benzothiazin-7-yl or 3-oxo-2,3-dihydro-4H - pyrido/3,2-b//1.4/oxazin-7-yl or the corresponding N-methyl derivative, which may optionally have one or two substituent selected from methyl and ethyl;

AND1is a direct link to X1or is methylene;

X1represents hydroxy, thio, sulfinil or sulfonyl;

Ar is 1,3-phenylene, which may be long, the Teal, or allyl; and R2and R3together form a group of the formula-A2-X2-AND3- which together with the carbon atom that is attached TO2and3limit ring having 5 or 6 ring atoms, where a2is ethylene, AND3is methylene or ethylene and X2is oxy, and which may have a Deputy, selected from methyl, ethyl, propyl and methoxy, or their pharmaceutically acceptable salts.

The following preferred compounds of the invention include bicyclic heterocyclic compounds of the formula I in which Q is 4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin - 6-yl, 4-methyl-3-oxo-2,3-4H-1,4-benzoxazin-7-yl, 2,2,4-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl, 4-methyl - 3-thioxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl, 1-methyl-2-oxo-1,2-dihydro-4H-3,1-benzoxazin-6-yl or 4-methyl-3-oxo-2,3-dihydro - 4H-pyrido /3,2-b//1.4/oxazin-7-yl;

AND1is a direct link to X1or is methylene;

X1is oxy or thio;

Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene;

R1is methyl; and R2and R3together form a group of the formula-A2-X2-AND3- which, together with the atom AND2and3represents each ethylene, and X2is oxy, and which may have a methyl or the ethyl substituent in the alpha position relative to the X2;

or their pharmaceutically acceptable salts.

Specific features: the preferred compounds of the invention include, for example, the following bicyclic heterocyclic compounds of the formula I or their pharmaceutically acceptable salts: 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl methoxy)phenyl] -4-methoxyacridine, 4-[5-fluoro-3-(2,2,4 - trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzo - casin-7-yl methoxy)phenyl]-4-methoxyacridine and 4-[5-fluoro-3-(2,2,4-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl methoxy)phenyl]-4-methoxyacridine.

Optional features: preferred compounds of the invention include the following bicyclic heterocyclic compounds of the formula I or their pharmaceutically acceptable salts: 4-[5-fluoro-3-(4-methyl-3-thioxo-2,3-dihydro-4H - 1,4-benzoxazin-7-yl thio)phenyl-4-methoxyacridine, 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl - thio)phenyl]-4-methoxyacridine, (2S, 4R)-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro - 4H-1,4-benzoxazin-7-ylthio)phenyl] -4-me - toxi-2 methyltetrahydro-[5-fluoro-3-(2,4-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzo-casin-7-yl thio)phenyl] -4-methoxymethyl - ropean.

Compounds of the invention, including bicyclic heterocyclic compounds of the formula I or their pharmaceutically acceptable salts may be obtained using any process known in the application to obtain structurally related compounds. Such techniques are provided as a further aspect of the invention and are illustrated by the following typical examples in which, unless otherwise stated, Q, AND1X1, Ar, R1, R2and R3have any of the values defined here above.

/a/ Reaction combination, preferably in the presence of a suitable base, of a compound of the formula 0-A1-X1-H with a compound of formula II, where Z represents a substitutable group; provided that when the group Q, Ar, R2and R3there are amino, alkylamino or hydroxy group, any amino, alkylamino or hydroxy group may be protected by a conventional protecting group or alternatively any such group need not protected, then any unwanted protective group in Q, Ar, R2and R3is removed using conventional means.

Suitable substituted by a group Z is, for example, halide or sulfonyloxy group, for example, fluorine is the reaction of the combination is for example, a carbonate, (1-4C)anion, hydroxide or hydride of an alkaline or alkaline-earth metal, e.g. sodium carbonate, potassium carbonate, sodium ethylate, butyl sodium, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an ORGANOMETALLIC base such as (1-4C)alkyl-lithium, for example n-butyl lithium. The reaction mix conveniently performed in a suitable inert solvent or diluent, for example N, N-dimethyl-formamide, N, N-dimethylacetamide, N-methylpyrrolidine-2-one, dimethyl sulfoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range of, for example, 10-150aboutC, conveniently at a temperature equal to or close to 100aboutC.

The reaction can conveniently be carried out in the presence of a suitable catalyst, for example, a metal catalyst, for example palladium (0) or copper (1), such as tetrakis(triphenylphosphine) palladium, copper chloride or copper bromide.

A suitable protecting group for amino or alkylamino group is, for example, acyl group, for example, (2-4C)alcoolica group (especially acetyl), (1-4C), alkoxycarbonyl group (particularly, methoxycarbonyl, ethoxycarbonyl or tert-is and (especially benzoyl). Conditions of release or unprotect these protective groups necessarily vary depending on the choice of protective groups. So, for example, acyl group, such as alcoolica, or alkoxycarbonyl or arolina group can be removed, for example, by hydrolysis with a suitable base, such as hydroxide of alkali metal such as lithium hydroxide or sodium. Alternative arylmethylidene group such as benzyl, may be removed, for example, by hydrogenation over a catalyst such as palladium on charcoal.

Educt of the formula 0-A1-X1Mr. and formula II can be obtained using standard techniques of organic chemistry. The receipt of such starting materials is described within the accompanying non-limiting examples, which are presented only for illustration purposes.

Intermediate compounds of formula II in which Z, Ar, R1, R2and R3have the meanings given above, can be conveniently obtained using the compounds of the formula Z-Ar-Y, where Z and Ar have the meanings defined above, and Y represents, for example, halogen, formyl, alkanoyl, nitrile or alkoxycarbonyl group. So, deprecatory Y represents a halide group, in the compound of formula II (Fig.1).

It is also understood that an intermediate compound of formula II may conveniently be obtained from compounds of formula Z-Ar-Y, defined above, using the reverse order of introduction of the groups R2and R3used according to scheme I (Fig.2).

/b/ Alkylation, preferably in the presence of a suitable base, as defined above, the compounds of formula III, the compound of the formula 0-A1-Z, where Z represents a substituted group that is defined above; provided that, when the groups Q, Ar, R2or R3there are amino, alkylamino or hydroxy group, any amino, alkylamino or hydroxy group may be protected by conventional protecting group, as defined previously, or alternatively any such group is unprotected, then any unwanted protective group in the groups Q, Ar, R2or R3is removed by conventional means.

The alkylation reaction conveniently is carried out in a suitable inert solvent, defined here above, and at a temperature in the range of, for example, 10-150aboutC, conveniently at a temperature equal to or close to 100aboutC. the Reaction may conveniently be carried out in the presence of podhodjashee be obtained using standard techniques of organic chemistry. The receipt of such starting materials is described within the accompanying non-restrictive examples, which are given only for illustration purposes. Alternative necessary starting materials may be obtained using procedures similar to the procedures illustrated in scheme II (Fig.3) below, or by modifying them, which are known in the art of organic chemistry.

Suitable protective group, R4used according to scheme II, is, for example, any of the many such groups known in the art, and it includes any suitable protective group as defined above. Examples of such groups are given in scheme II. Conditions for the introduction and removal of such protective groups are described in standard reference books on organic chemistry such as, for example, Protective Groups in Organanic Synthesis authors T. W. Green, (published by J. Wiley and Sons, 1981).

/c/ Alkylation, preferably in the presence of a suitable base, as defined above, the compounds of formula IV, a compound of formula R1-Z, where R1and Z have the meanings defined above; provided that when the group Q, X1, Ar, R2or R3there are amino, imino, alkylamino or hydroxy group, any amino, imino, alkylamino or hydroxy, gray, then any unwanted protective group of the groups Q, X1, Ar, R2or R3is removed by conventional means.

A suitable protecting group for an imino groups is, for example, any of the protective groups defined above for amino or alkylamino group.

The tertiary alcohol starting material of the formula IV may be obtained using standard techniques of organic chemistry. Conveniently, and as illustrated in scheme III (Fig.4) below, the intermediate compounds of formula Q-A1-X1-Ar-Y, where Q AND1X1and Ar have the meanings defined above, and Y represents, for example, halide, formyl, alkanoyloxy, nitrile or alkoxycarbonyl group that can be used to obtain the tertiary alcohol starting material of formula IV.

/d/ To obtain those compounds of formula I in which R1and R2together form a group of the formula-A2-X2-AND3- which together with the oxygen atom attached to AND2, defines a ring having 5-7 ring atoms, and where AND2X2and3have the meanings defined above, and where R3has the values defined above; cyclization of the compounds is the compound of the formula Z-A2-Z, where Z has the values defined above; provided that when the group Q, X1or Ar is amino, imino, alkylamino or hydroxy group, any amino, imino, alkylamino or hydroxy group is protected by a conventional protecting group, then any unwanted protective group of the groups Q, X1or Ar is removed by conventional means.

Cyclization of the compounds of formula V with a suitable aldehyde or ketone or its polyacetale or acetal, conveniently carried out in the presence of a suitable acid. A suitable acid for the cyclization reaction is, for example, inorganic acid such as hydrochloric, sulfuric or phosphoric, or, for example, organic acid such as p-toluensulfonate or triperoxonane acid. The cyclization reaction is conveniently conducted in a suitable inert solvent or diluent, for example 1,2-dimethoxyethane or tetrahydrofuran. Preferably the reaction is carried out using the appropriate aldehyde or ketone, or Polyacetal or acatalog derived as a reagent, and diluent. The cyclization is carried out at a temperature in the range of, for example, 20-150aboutC, conveniently at a temperature Rav is an Association of the formula Z-A2-Z is conveniently carried out in the presence of a suitable base, as defined above.

The tertiary alcohol starting material of the formula V may be obtained using standard techniques of organic chemistry. Conveniently, and as illustrated in accompanying scheme IV (Fig.5), the intermediate compounds of formula Q-A1-X1-Ar-Y -, in which Q AND1X1, Ar and Y have the meanings given above, can be used to obtain the tertiary alcohol starting material of the formula V.

Apply a suitable protective group, R4defined above.

/e/ To obtain the compounds of formula I, in which X1is sulfinyl or sulfonyloxy group, where R2and R3together form a group of the formula-A2-X2-AND3-, X2is sulfinyl or sulfonyloxy group, or R1and R2together form a group of the formula-A2-X2-AND3-, and R2is sulfinyl or sulfonyloxy group, the oxidation of compounds of formula I, in which X1represents thio group, where R2and R3together form a group of the formula-A2-X2-AND3-, and X2represents a thio group or the IO group.

Suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio in sulfinil and/or sulfonyl, such as hydrogen peroxide, nakilat (such as 3-chloroperoxybenzoic or peroxidasa acid), peroxosulfates alkali metal (such as peroxymonosulfate potassium, chromium trioxide or gaseous oxygen in the presence of platinum. The oxidation is usually carried out in mild conditions and using the required stoichiometric amount of oxidizing agent in order to reduce the risk of excessive oxidation and damage to other functional groups. Usually the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature of, for example, equal to or close to ambient temperature, that is, within 15-35aboutC. When you want the connection that carries sulfonyloxy group, can also be used more mildly oxidizing agent, for example, metaperiodate sodium or potassium hydroxide, conveniently in a polar solvent such as acetic acid or ethanol. When you want the connection formula I containing sulfonyloxy gruppoi connection.

/f/ To obtain the compounds of formula I where Ar is alkanolamine Deputy, the acylation of compounds of formula I in which Ar carries amino Deputy.

Suitable allermuir agent is, for example, any agent known in the art for the acylation of amino to acylamino, for example, allalone, for example, (2-6C)alcoholclone or bromide, in the presence of a suitable connection; alanovoy acid, for example, the anhydride (2-6C)alanovoy acid, or a mixed anhydride alanovoy acid, for example, the mixed anhydride formed by the reaction alanovoy acid and (1-4C)alkoxycarbonyl of halide, for example (1-4C)alkoxycarbonyl - chloride, in the presence of a suitable base. Usually the reaction is carried out in a suitable solvent or diluent such as methylene chloride, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature of, for example, equal to or near room temperature, i.e. in the range of 15-35aboutC. a Suitable base, when it is required, is, for example, pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiethanolamine, N-methylmorpholin, a carbonate of an alkali metal, e.g. potassium carbonate, or a carboxylate of an alkali metal, e.g. sodium acetate.

A suitable alkylating agent is, for example, any agent known in the art for the alkylation of available nitrogen atom, or hydroxy to alkoxy or substituted alkoxy, for example, alkyl or substituted alkylhalogenide, for example, (1-6C)alkylaryl, -bromide or-iodide or a substituted (1-4C)alkylchloride, -bromide or-iodide, in the presence of a suitable base. A suitable basis for the alkylation reaction is, for example, a carbonate of alkali or alkaline-earth metal, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. The alkylation reaction is preferably conducted in a suitable inert solvent or diluent, for example N, N-dimethylformamide, dimethyl sulfoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range of, for example, 10-150aboutC, conveniently at a temperature equal to or close to the room.

/h/ To obtain the compounds of formula I in which Q has one or two thioxo Deputy, the reaction reagent of tiliouine, to each oxazolidine turned into thioxo Deputy; provided that, when the groups Q, X1, Ar, R2or R3there is amino, imino, alkylamino or hydroxy group, any such group may be protected by conventional protecting group or alternatively any such group is not protected, then, any unnecessary protective group of the groups Q, X1, Ar, R2and R3is removed by conventional means.

A suitable agent milirovanie is, for example, any agent known in the art for the conversion of the carbonyl group in tocograph, such as, for example, 2,4-bis-/4-methoxyphenyl/-1,3-dithia-2,4-diphospha-NAT-2,4-disulfide (reagent Lawesson'a) or paternity phosphorus. The reaction milirovanie is usually performed using the required stoichiometric amount of the agent milirovanie in order to reduce the risk of affecting other functional groups. Usually the reaction is carried out in a suitable solvent or diluent such as toluene, xylene or tetrahydrofuran, and at a temperature of, for example, equal to or close to the temperature of reflux distilled solvent or diluent, i.e. in the range 65-150aboutC.

When you want pharmaceutically acceptable the Oia with a suitable acid or base using a conventional procedure. When you want optically active form of compounds of formula I, it can be obtained by carrying out one of the above procedures using an optically active starting material, or by splitting of racemic forms of the compounds using conventional procedures.

Many of the intermediates defined herein are new, for example, compounds of formulas IV and V, these compounds are available as an additional aspect of the invention.

As mentioned previously, the new compounds of formula I are inhibitors of the enzyme 5-LO. The effect of this inhibition can be demonstrated using one or more standard procedures, are presented below.

and/ enzymatic Spectrophotometric analysis system in vitro, which evaluates inhibiting properties of the test compounds in the free cell system using 5-LO, isolated from isolated Guinea-pig neutrophils and, as described by the authors D. Aharony L E. L. Stein (J. Biol Chem, 1986, 261(25) 11512-11519). This experience gives a measure of the inherent inhibitory properties of the test compounds against soluble 5-LO in the extracellular environment.

b/ System analysis introduction provocative tests calcium ionophore A, and then directly measuring inhibition of 5-LO by analyzing the number ofTB4 using specific radioimmunoassay described by the authors Carey and Forder /F. Carey L R. A. Forder, Prostaglandins, Leukotrienes Med. 1986, 22, 57; Rostaglandins, 1984, 28, 666; Brit. J. Pharmacol, 1985, 84, R/, which involves the use of protein - TV conjugate obtained using procedures Young etc. /Prostaglandins, 1983, 26 (4), 605-613/. The effect of test compounds on the enzyme cyclooxygenase (which is involved in alternative metabolic process arachidonic acid and causes prostaglandins, thromboxanes and related metabolites) can be measured at the same time using a specific radioimmunoassay for thromboxane2/T x2/, described by the authors Carey and Forder (see above). This test gives an indication of the effect of the test compounds against 5-LO and Cox in the presence of blood cells and proteins. It allows to estimate the selectivity of the inhibitory effect on 5-LO or cyclooxygenase.

c/ System analysis in vitro, which is a modification of the test b/, described above, introducing a test compound (usually orally in the form of ethylcellulose), taking blood, heparinization, the introduction of the provocative dose A and radioimmunoassay TV4and DV2. This test demonstrates the bioavailability of the test compound as an inhibitor of 5-LO or cyclooxygenase.

d/ analysis System in vitro, providing a measurement of the inhibitory properties of the test compounds against the release of CU4and GE2caused zinasanam on the example of peritoneal macrophage of mice, using the procedure described by the authors Humes and others (J. L. Humes et alia, Biochem. Pharmacol, 1983, 32, 2319-2322) and conventional systems radioimmunoassay for the measurement of CU4and PGH2. This test gives a measure of inhibitory effect on 5-LO and Cox in non-protein system.

e/ System in vivo, providing a measurement of the effect of test compounds on the inhibition of the inflammatory response to arachidonic acid on the model of rabbit skin, developed by the authors D. Aked and others (Brit. J. Pharmacol. 1986, 89, 431-438). This test gives a model in vivo for inhibitors of 5-LO entered tapicerki or orally.

f/ System in vivo, providing a measurement of the action of the test compound, prescribed orally or intravenously, of leukotr the eye previously entered antihistamine (mepyramine), -adrenergichesky blocking agent (propranolol) and inhibitor of cyclooxygenase (indomethacin), using procedures authors W. H. Andersen and others (British J. Pharmacology, 1983, 78(1), 67-574). This test gives an additional test in vivo for the detection of inhibitors of 5-LO.

g/ System in vivo, providing a measurement of the effect of the test compound, prescribed orally, against the release TV4caused zinasanam in the air bag, resulting in the subcutaneous tissue of the back of male rats. Rats anaesthetize, and form air bags by injection of sterile air (20 ml). After 3 days will be given an additional injection of air (10 ml). 6 days after the initial air injection is assigned to the test compound (usually orally in the form of a suspension obtained by adding the test compound in dimethyl sulfoxide to the hypromellose), followed vnutrimatocny injections zymosan (1 ml of 1% suspension in physiological solution). After 3 h, the rats are killed, the air bags are washed with saline, and used the above-described specific radioimmunoassay for the analysis of TV4in the wash liquid. This test gives a measure ingibirujut the E.

The connection of the patent EP 0200101:

< / BR>
Although, as expected, the pharmacological properties of the compounds of the formula I vary with structural change, usually the compounds of formula I possess the properties of inhibiting 5-LO at the following concentrations or doses in one or more of the following above tests (a) -f):

Test a): IC50in the interval, for example, from 0.01 to 30 μm,

Test b): IR50(TV4in the interval, for example, from 0.01 to 40 μm

IR50(DV2in the interval, for example, 40-100 μm

Test): oral ED50(TV) in the range of, for example, 0.1 to 100 mg/kg

Test (d): IR50( T4) in the range of, for example, 0.001 to 1 μm,

IR50(PGE2in the interval, for example, 20-1000 microns;

Test e): inhibition of inflammation in the interval, for example, 0.3 to 100 μg, intradermally;

Test (f): U50in the interval, for example, 0.5-10 mg/kg centuries

Test (g): oral ED50(TV4in the interval, for example, 0.1 to 50 mg/kg

No excessive toxicity or other side effects were not observed in the tests), e), f) and/or (g) when the compounds of formula I was administered when multiple repeated doses compared to their minimum any abscopal on oxazin-7-illcox)phenyl]-4-methoxyacridine has IR50of 0.05 μm against TV4in test b), and oral ED501.5 mg/kg versus TV4in test g); compound 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-7-yl-methoxy)phenyl] -4-me-Tox tetrahydropyran has IR50of 0.04 μm against TV4in test b), and oral ED500.4 mg/kg against TV4in test g); compound 4-[5-fluoro-3-(4-methyl-3-thioxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio) phenyl]-4-methoxyacridine has IR500.3 μm against TV4in test b), and oral ED501.5 mg/kg versus TV4in test g); compound 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin - 7-ylthio)phenyl] -4-methoxytyramine-RAS has IR50of 0.05 μm against TV4in test b),C and oral ED500.15 mg/kg versus TV4in test g). Usually those compounds of formula I which are particularly preferred are IR50less than 1 μm against TV4in test b), and oral ED50less than 100 mg/kg against TV4in the tests) and/or g).

These compounds are examples of compounds of the invention which exhibit selective inhibiting properties against 5-LO as opposed to cyclooxygenase and we should expect that these selective properties give Olufsen often associated with cyclo-oxygenase inhibitors, such as indomethacin.

According to a further aspect of the invention features a pharmaceutical composition, which comprises a bicyclic heterocyclic compound of the formula I, or a pharmaceutical acceptable salt thereof, is combined with a pharmaceutically acceptable diluent or carrier.

The compositions may be presented in a form suitable for oral use, for example in the form of tablets, capsules, aqueous or oily solutions, suspensions or emulsion; for topical use, for example, in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions; for nasal (nasal) use, for example in the form of the medicinal powder for inhalation through the nose, nasal spray or nasal drops; for vaginal (vaginal or rectal (through the rectum) use, for example in the form of medical candles; for destination via inhalation, for example, in the form of fine powder or a liquid aerosol; for use under the tongue or buccal (oral) using, for example, in the form of tablets or capsules; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular use, or which can be prepared in the usual way using common excipients.

The amount of active ingredient (i.e. bicyclic heterocyclic compounds of the formula I or its pharmaceutically acceptable salt), which is combined with one or more excipients to obtain a single dosage form will necessarily vary depending on the subject to the treatment of the patient and the particular mode of appointment. For example, preparative form intended for oral purpose people usually contains, for example, 0.5 to 2 g of active agent, combined with an appropriate and convenient amount of excipients which may vary about 5-98% by weight of the entire composition. Unit dosage forms typically contain about 1 mg to 500 mg of active ingredient.

According to further aspect of the invention features a bicyclic heterocyclic compound of the formula I or its pharmaceutically acceptable salt for use in the method of treatment of the human or animal therapy.

The invention also includes a method of treating diseases or medical conditions, the cause of which is fully or partially one or more leukotrienes which provides for the appointment of a warm-blooded animal, needs the same offers the use of such an active ingredient for new medicines for use in the treatment of diseases or medical conditions, the intermediary which are leukotrienes.

The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary depending on the nature and severity of the condition, age and sex of the animal or patient and the method of appointment, in accordance with well known principles or foundations of medicine. As mentioned above, the compounds of formula I are useful in treating those allergic and inflammatory conditions which are due solely or in part the action of metabolites of arachidonic acid arising by direct steps, catalyzed by 5-LO and, in particular leukotrienes, which are caused by the action of 5-LO. As mentioned above, such conditions include, for example, asthmatic conditions, allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopic dermatitis, cardiovascular and cerebrovascular disorders, inflammatory disorders, arthritis and inflammatory joint diseases, and inflammatory diseases of the digestive tract.

When using compounds of formula I for therapeutic or prophylactic purposes of a compound is usually administered that the de separate doses. Usually, when applied parenteral way, are assigned a lower dose. For example, for intravenous destination is commonly used dose in the range, for example from 0.5 mg to 30 mg per kg of body weight. Similarly, for purposes through inhalation will be used dose in the range, for example, from 0.5 mg to 25 mg per kg of body weight.

Although the compounds of formula I above all are of value as therapeutic agents for use in relation to warm-blooded animals (including humans), they are also useful, however, when this is required for inhibition of the enzyme 5-LO. So they are useful as pharmacological standards for use in the development of new biological tests and studies in the search for new pharmacological agents.

Due to their action on receipt of leukotrienes, compounds of formula I have some cytotoxicity effects, for example they are useful in the reduction or suppression of some negative gastrointestinal actions caused by nonsteroidal anti-inflammatory agents (NSAIA), any abscopal cyclooxygenase, such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and pirineu number of the last agent, required to achieve a therapeutic effect, through, which decreases the likelihood of negative side effects. According to further aspect of the invention features a pharmaceutical composition, which comprises a bicyclic heterocyclic compound of the formula I or its pharmaceutically acceptable salt as defined above, in combination or in a mixture with non-steroidal anti-inflammatory agent, inhibiting cyclooxygenase (as mentioned above) and a pharmaceutically acceptable diluent or carrier.

Chitosamine action of the compounds of formula I can be demonstrated, for example, using a standard laboratory model, which allows evaluation of protective action from caused by indomethacin or ethanol expressing the gastrointestinal tract of rats.

Compositions of the invention may in addition contain one or more therapeutic or prophylactic agents that are known as valuable in the case of the disease under treatment. For example, for use in the treatment of cardiac or vascular diseases or conditions in the pharmaceutical compositions of the invention mogulones agents, betaadrenergic blockers or vasodilatory. Similarly, for use in the treatment of lung diseases in the pharmaceutical compositions of the invention can usefully also be present, for example, antihistamines, steroids (such as beclomethasone), sodium cromoglycate, a phosphodiesterase inhibitor or beta-adrenergichesky stimulating agent.

The invention will now be illustrated using the following non-limiting examples, in which the following symbols are used:

/I/ evaporation was carried out using rotary evaporation under vacuum, and handling procedures were carried out after removal of residual solids by filtration;

(II) operations were carried out at room temperature, i.e. in the range of 18-25aboutWith, and in the atmosphere of inert gas, such as argon;

/III/ chromatography on a column (with the help of instant admission) and liquid chromatography medium pressure (LC) was performed on silica Merck Kieselgel (Art. 9385) or the Merck MicroPrep RP-18 (Art. 9303) back-phase silica, leave the firm E. Merck, Darmstadt, Zap. Germany;

/IV/ outputs are given for illustration only and for long the microanalysis, and their structure was confirmed by NMR data and spectrometries analysis;

/VI/ intermediate products are usually not fully characterised and purity was assessed according to thin-layer chromatographic, infra-red (IR) or NMR analysis;

/VII/ melting points are uncorrected and were determined using an automatic device determining the melting point by Mettler R or device using an oil bath; the melting point of the final products of the formula I were determined after crystallisation from a conventional organic solvent, such as ethanol, methanol, acetone, simple ether or hexane, used singly or in mixture; and

/VIII/ used the following abbreviations:

THF tetrahydrofuran

DMSO dimethyl sulfoxide

DMF dimethylformamide

DMA N,N-dimethylacetamide.

P R I m e R 1. 7-methyl bromide-4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin (to 0.127 g) was added to a mixture of 4-(5-fluoro-3-hydroxyphenyl)-4-methoxyacridine (0,113 g), potassium carbonate (0.083 g) and DMF (1 ml). The mixture was stirred at room temperature for 24 h the Mixture was distributed between diethyl ether and water. The organic phase was washed with water, dried (magnesium sulfate) and vol is the volume mixture of methylene chloride and diethyl ether. Thus was obtained 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin - 7-yl-methoxy)phenyl] -4-methoxytyramine - Piran (0,132 g, 68%), melting point 87-89aboutC (recrystallized from hexane).

NMR Spectrum (l3, value) 1,75-2,0 (m, 4H), 2,98 (C. 3H),

3,37 (C. 3H), 3,65 to-3.9 (m, 4H),

4,62 (C. 2H), 4,98 (S. 2N),

6.5 to 7.2 (m 6N).

7-methyl bromide-4-methyl-3-oxo-2,3-dihyd - ro-4H-1,4-benzoxazin used as starting material was obtained as follows.

Ethylbromoacetate (20 g) was added to a mixture of 5-methyl-2-NITROPHENOL (17 g), potassium carbonate (17 g) and acetone (170 ml) and the mixture was heated to 60aboutC for 90 minutes the Mixture was cooled to room temperature and distributed between diethyl ether and water. The organic phase was washed in turn 1 N. aqueous sodium hydroxide solution, water and saline, dried (magnesium sulfate) and was evaporated. The residue was precrystallization from a mixture of diethyl ether and hexane. Thus was obtained ethyl 2,5-methyl-2-nitrophenoxy(acetate) (21,5 g, 82%), melting point 67aboutC.

The mixture thus obtained product, the catalyst of palladium on charcoal (10 wt./wt. 0.6 g) and ethanol (300 ml) were mixed wale, and the solution was heated to 50aboutC for 30 minutes the Mixture was evaporated. The residue was pulverized in diethyl ether, giving 7-methyl-3-oxo-4H-1,4-benzoxazin (14 g, 95%), melting point 197aboutC.

Portion (11.4 g) thus obtained product was added to a stirred suspension of sodium hydride (60 wt./wt. the dispersion in mineral oil, 3,36 g; oil was removed by washing with petroleum ether in DMF (70 ml) and the mixture stirred at room temperature for 1 h was Added methyliodide (14.9 g) and the mixture stirred at room temperature for 1 h the Mixture was distributed between water and 1:1 volume/volume mixture of diethyl ether and ethyl acetate. The organic phase was washed saturated aqueous sodium thiosulfate and brine, dried (magnesium sulfate) and was evaporated. Thus was obtained 4,7-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin in (11.5 g, 92%), melting point 107aboutC.

N-Bromosuccinimide (4,27 g) and benzoyl peroxide (0.1 g) were added successively to the mixture thus obtained product (3,54 g) and carbon tetrachloride (50 ml) and the mixture was heated to the temperature of reflux distilled for 15 minutes the Mixture was cooled to room temperature, Fe first eluent mixture of methylene chloride and petroleum ether (so the TRC. 40-60aboutWith), and then methylene chloride. Thus was obtained an oil, which was crystallizability after trituration with diethyl ether, giving the desired starting material (0.27 g, 5%).

4-(5-fluoro-3-hydroxyphenyl)-4-methoxy - tetrahydropyran used as starting material was obtained as follows.

Sodium hydride (50 wt./wt. the dispersion in mineral oil, 12.4 g) was added in portions to a mixture of benzyl alcohol (26,7 ml) and DMA (500 ml) and the mixture stirred at room temperature for 1 h was Carefully added 1-bromo-3,5-differental (50 g) for regulating the degree of completion of the exothermic reaction. The mixture is stirred at room temperature for 2 h, and the solvent was evaporated. The residue was distributed between methylene chloride and water and the organic phase was washed with water (4 x 50 ml), dried with magnesium sulfate and evaporated. The residue was purified by distillation, yielding 3-benzyloxy-1-bromo-5-torbenson (41.8 g, 57%) as a colourless liquid (so Kip. 124-130aboutC/ 0.3 mm RT.cent.).

The solution of a portion (9.7 g) of this product in THF (150 ml) was cooled to -75aboutWith, and dropwise added n-butyl lithium (1.6 M in hexane, 22 ml). The mixture is stirred at -75aboutWITH THE 75aboutC for 1 h, and then remained to be heated up to 0aboutC. was Added a saturated aqueous solution of ammonium chloride (60 ml) and the organic phase was separated, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using as eluent a 1:1 volume/volume mixture of toluene and ethyl acetate. Was thus 4-(3-benzyloxy-5-forfinal)-4-hydroxy-tetrahydropyran (7,4 g, 71%) as oil.

After appropriate repetition of the above-mentioned reaction of the thus obtained product (12.1 g) was dissolved in THF (150 ml), and the portions was added sodium hydride (50 wt./wt. the dispersion in mineral oil, 2,11 g). The mixture is stirred at room temperature for 1 h, cooled in an ice bath, was added dropwise mutilated (3.75 ml). The mixture is stirred at room temperature for 18 h, was added 2 N. hydrochloric acid (3 drops), and the organic solvent was evaporated. The residue was distributed between ethyl acetate and water. The organic phase was separated, washed with water and brine, dried (magnesium sulfate) and was evaporated. Was thus 4-(3-benzyloxy-5-forfinal)-4-methoxyacridine (12.5 g, 99% ) as a pale Zheltov is that in ethanol (100 ml) was gidrirovaniya in the presence of 10% palladium catalyst on charcoal for 3 hours The mixture was filtered and the filtrate was evaporated. Thus was obtained 4-(5-fluoro-3-hydroxyphenyl)-4-methoxyacridine (7.7 g, 86%), melting point 123-124aboutC.

P R I m m e R 2. The procedure described in example 1 was repeated except that instead of 7-methyl bromide-4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazine used 7-methyl bromide-2,2,4-trimethyl-3-oxo-2, 3-dihydro-4H-1,4-benzoxazin. Thus was obtained 4-[5-fluoro-3-(2,2,4-trimethyl-3-oxo-2,3-di - hydro-4H-1,4-benzoxazin-7-ylethoxy)Fe - Neil]-4-methoxyacridine with the release of 35% of melting point 118aboutC.

NMR Spectrum (l3, value) 1,50 (C. 6N), 1,75-2,0 (m, 4H),

2,98 (C. 3H), 3,36 (C. 3H),

the 3.65-3,95 (m, 4H), 4.98 (S. 2N),

6,95-7,25 (m 6N).

7-methyl bromide-2,2,4-trimethyl-3-oxo-2,3 - dihydro-4H-1,4-benzoxazin used as starting material was obtained as follows.

Methyl 2-bromo-2-methylpropionate (5,43 g) was added to a mixture of 5-methyl-2-NITROPHENOL (4.59 g), potassium carbonate (4,14 g) and acetone (50 ml) and the mixture was heated to the temperature of reflux distilled within 90 minutes because the reaction rate was slow, the mass of the acetone was evaporated, was added DMF (25 ml) and the mixture was heated to 100aboutC for 3 h, and then 50aboutWith those what LOTOS and 1:1 volume/volume mixture of diethyl ether and ethyl acetate. The organic phase was washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using as elution solvent of methylene chloride. Thus was obtained 2-methyl-2-5-methyl-2-nitrophenoxy/propionate (1.2 g, 16%), melting point 60-61aboutC (recrystallized from hexane).

Using the procedures described in the paragraphs from the second to the fourth section of example 1 which is concerned with the obtaining 7-methyl bromide-4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazine, thus obtained product was transformed into the desired starting material with 29%

P R I m e R 3. The procedure described in example 1 was repeated except that instead of 7-methyl bromide-4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazine used 7-methyl bromide-2,2,4-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin. Thus was obtained 4-[5-FTIR-3-(2,2,4-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-Ilmatar si)phenyl] -4-labels - literalization 51% yield melting point 141-142aboutC.

NMR Spectrum (l3, value) 1,43 (C. 6N), 1,8-2,1 (m, 4H),

2,98 (C. 3H), 3.46 in (C. 3H), 3.75 to 3,95 (m, 4H), 4,99 (C. 2H), 6,5-7,5 (m 6N).

7-methyl bromide-2,2,4-trimethyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin used the I to a mixture of 3-fluoro-4-nitrotoluene (4,65 g), sodium bicarbonate (3 g) and methanol (46 ml) and the mixture was heated to 70aboutC for 5 h the Mixture was cooled to room temperature and distributed between diethyl ether and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution and saline, dried (magnesium sulfate) and was evaporated. The residue was precrystallization from a mixture of diethyl ether and hexane, yielding methyl 2-(5-methyl-2-nitrophenylthio)acetate (6.5 g, 90%), melting point 74-75aboutC.

The mixture portions (4 g) thus obtained product, palladium on charcoal (10% 0.4 g) and methanol stirred under hydrogen pressure of 4 atmospheres for 5 hours the Mixture was filtered, and the filtrate was evaporated. The residue was dissolved in toluene and the solution was heated to the temperature of reflux distilled within 3.5 hours the Mixture was evaporated, and the residual solid was washed with diethyl ether. Thus was obtained 7-methyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin (2.1 g, 70%), melting point 207aboutC.

Thus obtained product was dissolved in DMF (5 ml) and added dropwise to a stirred suspension of sodium hydride (60 wt./wt. in oil, 0.64 g), washed with petroleum ether in DMF (10 ml what about the drops were added methyliodide (1,15 ml), and the mixture is stirred for 30 minutes and the Mixture was distributed between diethyl ether and water. The organic phase was washed with water and brine, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using as eluent 9:1 volume/volume mixture of methylene chloride and diethyl ether. Thus was obtained 4,7-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzothiazin (2,07 g, 88%), the melting point of 84-86aboutC.

Portion (1.35 g) of the product thus obtained was dissolved in DMF (15 ml). Portions were added sodium hydride (60 wt./wt. dispersion in oil, 0.84 g) and the mixture stirred at room temperature for 30 minutes was added dropwise methyliodide (0,69 ml) and the mixture stirred at room temperature for 16 hours were Alternately added an additional portion of a dispersion of sodium hydride (0.28 g) and under the conditions (1,38 ml) and the mixture was heated to 45aboutC for 1 h the Mixture was distributed between water and 1:1 volume/volume mixture of diethyl ether and ethyl acetate. The organic phase was washed with water and brine, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using kachestve - 1,4-benzothiazin (1,02 g, 66%).

Benzoyl peroxide (5 mg) was added to a mixture of a portion (0,22 g) of the product, thus obtained, N-brooklynite (0,242 g) and carbon tetrachloride (5 ml). The mixture was irradiated with light from the lamp 250 watts and was heated to 40aboutC for 90 minutes the Mixture was cooled to room temperature, was added diethyl ether (5 ml) and the mixture was filtered. The filtrate was evaporated, giving the required starting material (0.33 g, 78% (70% pure according to NMR) in the form of oil, which was used without further purification.

P R I m e R 4. A mixture of 6-chloromethyl-4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin (0,106 g), 4-(5-fluoro-3-hydroxyphenyl)-4-methoxyacridine (0,113 g), potassium carbonate (0.083 g) and DMF (1 ml) was heated to 80aboutC for 3 h and up to 60aboutEven for an additional hour. The mixture was cooled to room temperature and distributed between ethyl acetate and water. The organic phase was washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using as eluent 93:7 volume/volume (V/o) mixture of methylene chloride and acetone. Thus was obtained 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-6-ylethoxy)phenyl-4-methoxytyramine (C. 3H), 3,38 (C. 3H), 3,68-3,90 (m, 4H), 5,62 (C. 2H) 5,0 (C. 2H), measuring 6.5 to 7.25 (m 6N).

6-Chloromethyl-4-methyl-3-oxo-2,3-dihyd - ro-4H-1,4-benzoxazin used as starting material was obtained as follows.

The solution chloroacetanilide (31,2 g) in chloroform (100 ml) was added dropwise to a mixture of 2-aminophenol (25 g), benzylmethylamine (52,4 g), sodium bicarbonate (77 g) and chloroform (500 ml) which was cooled in an ice bath. The mixture was mixed for 1 h and left to warmed to room temperature. The mixture was heated to 55aboutC for 5 h and then stirred at room temperature for 16 hours the Mixture was evaporated, and the residue was distributed between ethyl acetate and aqueous potassium carbonate solution. The organic phase was washed with diluted aqueous hydrochloric acid and water, dried (magnesium sulfate) and was evaporated. The residue was washed with a mixture of hexane and diethyl ether, leaving 3-oxo-2,3-dihydro-4H-1,4-benzoxazin (11 g, 32%), melting point 172-173aboutC.

Portion (5,2 g) of the product, thus obtained, was added in portions to a stirred suspension of sodium hydride (60 wt./wt. the dispersion in mineral oil, 1.66 g), the oil was removed by washing the solid the offer was cooled in an ice bath, and dropwise added (methyliodide (2.3 ml). The mixture was mixed for 1 h and left to warmed to room temperature. The mixture was poured into water, padillas by adding dilute aqueous acid and was extracted with ethyl acetate. The organic phase was washed with water, dried (magnesium sulfate) and was evaporated. The resulting oil crystallized after trituration in a mixture of 1:9/diethyl ether and hexane. Thus was obtained 4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzo-casin (4 g, 70%), melting point 57-58aboutC.

A mixture of a portion (0,489 g) of the product, thus obtained, paraformaldehyde (is 0.135 g), glacial acetic acid (3 ml) and conc. hydrochloric acid (3 ml) was heated to 60aboutC for 90 minutes the Mixture was cooled to room temperature and distributed between ethyl acetate and water. The organic phase was washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using methylene chloride as eluent. Thus was obtained the required starting material (0,368 g, 58%) as a solid.

P R I m e R 5. Butyl lithium (1.6 M in hexane, 1 ml) were added capl is on (0,342 g) and N-methylpyrrolidine-2-she (3.75 ml), pre-cooled in an ice bath. The mixture was mixed and left to warmed to room temperature. The mixture was heated to 145aboutC for 90 min, and hexane were distilled from the reaction mixture. The mixture was cooled to room temperature and distributed between ethyl acetate and water. The organic phase was rinsed with water and an aqueous solution of sodium hydroxide, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 15:1/mixtures of methylene chloride and diethyl ether as eluent. Thus was obtained 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl] -4 - labels-literalization (0,202 g, 33% ), melting point 131-133aboutC.

ESR Range (l3, value) 1,8-2,1 (m, 4H), 2,98 (C. 3H), 3,37 (C. 3H), 3.75 to 3,95 (m, 4H), 4,63 (C. 2H), 6,76-7,25 (m 6N).

7-Mercapto-4-methyl-3-oxo-2,3-dihydro - 4H-1,4-benzoxazin used as starting material was obtained as follows.

A mixture of 5-fluoro-2-nitrophenyl (of 10.05 g), potassium carbonate (10.6 g) and acetone (125 ml) was heated to the temperature of reflux distilled within 10 minutes the Mixture was cooled to room temperature and was added dropwise a solution of ethylbromoacetate between diethyl ether and water. The organic phase was washed with water, dried (magnesium sulfate) and was evaporated. Thus was obtained ethyl 2-(5-fluoro-2-nitrophenoxy/acetate (of 14.28 g, 92%), melting point 44-46aboutC.

A mixture of ethyl 2-(5-fluoro-2-nitrophenoxy) acetate (11 g), benzyl mercaptan (5,2 g), triethylamine (5,08 g) and DMF (50 ml) was stirred and heated to 80aboutWith over 7 hours the Mixture was cooled, poured into water and padillas the addition of dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether. The organic phase was washed with water and brine, dried (magnesium sulfate) and was evaporated, yielding ethyl(5-benzylthio-2-nitrophenoxy) acetate (10.6 g, 68%) as a solid.

A mixture of a portion (of 6.68 g of the product obtained in this way, chloride dihydrate tin (Tet. Let. 1984, 839, 28.1 g), ethyl acetate (5 ml) and ethanol (50 ml) was heated to reflux distilled for 30 minutes the Mixture was poured into ice, and added a saturated aqueous solution of sodium bicarbonate. The resulting precipitate was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (magnesium sulfate) and was evaporated, yielding 7-benzyl-thio-3-oxo-2,3 - 4H-1,4-benzoxazin (3,32 of vslas to a stirred suspension of sodium hydride (60 wt./wt. the dispersion in mineral oil, 0.52 g of the oil was removed by washing the dispersion of the solid with petroleum ether) in DMF (10 ml) and the mixture stirred at room temperature for 30 minutes was Added methyliodide (2,13 g) and the mixture stirred at room temperature for 30 minutes the Mixture was distributed between diethyl ether and water. The organic phase was washed with water and brine, dried (magnesium sulfate) and was evaporated, yielding 7-benzylthio-4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin (2.6 g, 91%) as a solid.

A solution of 3-chlormadinone acid (1,72 g) in chloroform (10 ml) was added dropwise to a solution of a portion (2 g) benzoxazine, thus obtained, in chloroform (15 ml) which was cooled to 0aboutC, and the mixture is stirred at 0aboutC for 4 h was Added calcium hydroxide (0.74 g) and the mixture stirred at room temperature for 15 minutes the Mixture was filtered, and the filtrate was evaporated, yielding 7-benzylmethyl-4-methyl-3-oxo-2,3-di - hydro-4H-1,4-benzoxazin (2.1 g) as a solid, which was used without further purification.

Triperoxonane acid (4,2 g) was added dropwise to a stirred suspension portion (1.5 g) benzo at room temperature for 30 min, and then was heated to reflux distilled for 30 minutes the Mixture was evaporated and the residue was distributed between ethyl acetate and water. The organic phase was washed with water and saturated aqueous sodium bicarbonate, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using parastatals polar mixtures of methylene chloride and diethyl ether as eluent. Thus was obtained di-(4-methyl-3-oxo-2, 3-dihydro-4H-1,4-benzoxazin-7-yl)disulfide (0,69 g, 60%), the melting point of 133-135aboutC.

After repeating the previous step was added triphenylphosphine (0,576 g) to a suspension disulfide (0,776 g) in 1,4-dioxane (9 ml). Alternately, water was added (2.5 ml) and concentrated hydrochloric acid (1 drop) and the mixture was heated to 50aboutC for 1 h the Mixture was cooled to room temperature and distributed between ethyl acetate and 0.5 N. aqueous solution of sodium hydroxide. The organic phase was washed with water and brine, dried (magnesium sulfate) and was evaporated. Thus was obtained the required starting material (0,425 g, 55%), melting point 95-96aboutC.

4-(3,5-Differenl)-4-otoxicity - gidropony used in cachestoreprivate (38,6 g) and magnesium (4,88 g) in a mixture of toluene (100 ml) and THF (50 ml) using the following method. 3,5-Deferrement was dissolved in toluene (50 ml), and a portion (approximately 5%) solution was added to a stirred suspension of magnesium in a mixture of toluene (50 ml) and THF (50 ml). The mixture is stirred at room temperature for about 40 min until then, until he observed the beginning of the exothermic formation of the Grignard reagent. The mixture was cooled in an ice bath to a temperature in the range of 15-20aboutWith, when this was added to the remaining solution of 3,5-diversamente. The mixture is stirred at room temperature for 2 h

Tetrahydropyran-4-one (10,69 g) was added over 1 h to a portion (100 ml) of the Grignard reagent thus obtained, which was cooled to a temperature in the range of 15-20aboutC. the Mixture is stirred at room temperature for 2 hours the Mixture was cooled in an ice bath, and in turn was added aqueous hydrochloric acid solution (50 wt./about 25 ml) and saline solution (30 wt./Oh, 52 ml). Toluene layer was separated and the aqueous layer was extracted with toluene (32 ml). The organic solutions were combined and were washed with water (4 x 32 ml). The solution was evaporated under reduced pressure to a volume of 16.3 ml of Thus obtained concentrated (90 wt./a) a solution of 4-(3,5-differenl)-4-hydrom temperature was maintained at 60aboutC. the Mixture was allowed to cool to room temperature, and then it was cooled in an ice bath to a temperature in the range of 0-5aboutC. the Precipitate was separated and was washed with hexane (2 x 10 ml). Thus was obtained 4-(3,5-differenl)-4-hydroxycitrate - Piran (12.2 g).

Portion (7,15 g) of the material so obtained was dissolved in N-methylpyrrolidine-2-Ohe (25 ml) and added to a suspension of sodium hydride (60 wt. /Mac. the dispersion in mineral oil, 3,34 g) in N-methylpyrrolidine-2-Ohe (32 ml) which was cooled in an ice bath to approximately 20aboutC. the Mixture is stirred at this temperature for 30 min Methyliodide (5,22 g) was dissolved in N-methylpyrrolidine-2-Ohe (2 ml) and was added to the mixture. The resulting mixture was heated to 30aboutC and stirred for 2 h the Mixture was evaporated. Thus was obtained 4-(3,5-differenl)-4-methoxyacridine, which was used without further purification.

P R I m e R 6. The solution peroxymonosulfate potassium (0,115 g) in water (1 ml) was added to a solution of 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl] 4-methoxyacridine (is 0.102 g) in a mixture of methylene chloride (1 ml) and chloroform (1 ml) and the resulting mixture Peremena phase was washed with water, aqueous solution of sodium bisulfate and brine, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using as eluent parastatals polar mixtures of methylene chloride and diethyl ether. Thus was obtained 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxa - Zin-7-ylsulphonyl)phenyl] -4-otoxicity - gidropony (of 0.066 g), melting point 190-191aboutC.

An NMR spectrum (l3, size) of 1.85 and 2.1 (m, 4H), 2,89 (C. 3H), 3,37 (C. 3H), 3,8-3,95 (m, 4H), 4,66 (C. 2H), 7,0-7,8 (m 6N).

P R I m e R 7. 2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (reagent Lawesson'a, 0,121 g) was added in portions to a solution of 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl - thio)phenyl]-4-methoxyacridine (0.12 g) in toluene (10 ml), and the mixture is stirred and heated to reflux distilled for 15 minutes the Mixture was evaporated and the residue was purified using chromatography on a column using 19:1/mixtures of methylene chloride and diethyl ether as eluent. Thus was obtained 4-[5-fluoro-3-(4-methyl-3-thioxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl]- 4-me - oxitetraciclina (0,089 g, 70%), melting point is 125-127aboutC.

An NMR spectrum (l31,2-dihydro-4H-3,1-benzoxazine (0,289 g), 4-(3-mercaptophenyl)-4-methoxyacridine (0,324 mg), potassium carbonate (0,225 g), copper chloride (0.03 g) and DMF (3 ml) was heated to 140aboutC for 3 hours the Mixture was cooled to room temperature and distributed between ethyl acetate and water. The organic phase was washed with water and brine, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 1:1 o/a mixture of toluene and ethyl acetate as eluent. Thus was obtained 4-methoxy-4-(3-(1-methyl-2-oxo-1,2-dihydro-4H-3,1-benzoxazin-6-ylthio)phenyl) tetrahydropyran (0,164 g, 43%) as oil.

An NMR spectrum (l3, value) 1,85-2,05 (m, 4H), 2.95 and (C. 3H), 3,4 (C. 3H), 3.75 to 3,90 (m, 4H), 5,15 (C. 2H), 6,9 (D. 1H), and 7.1 to 7.4 (m 6N).

6-Iodine-1-methyl-2-oxo-1,2-dihydro-4H-3,1 - benzoxazin used as starting material was obtained as follows.

Phosgene (20 wt./about in toluene, 54 ml) was added dropwise to a stirred mixture of 2-aminobenzamide alcohol (12,32 g), triethylamine (27.9 ml) and toluene (500 ml), which was deposited in an ice bath to approximately 15aboutC. the Mixture is stirred at room temperature for 2 h, and then was heated to 85aboutC for 2 h the Mixture was poured into water (500 ml) lifecom magnesium) and was evaporated. The residue and a solid substance, which is pre-filtered, purified via chromatography on a column using a 7:3 o/a mixture of toluene and ethyl acetate as eluent. Thus was obtained 2-oxo-1,2-dihydro-4H-3,1-benzoxazin (7,8 g, 52%), melting point 115-116aboutC.

Hydric sodium (55 wt./wt. the dispersion in mineral oil, 0.32 g) was added to a mixture of a portion (1 g) benzoxazine, thus obtained, in DMF (25 ml) pre-cooled to approximately 3aboutC, and the mixture is stirred at room temperature for 1 h was Added methyliodide (1 ml) and the mixture stirred at room temperature for 16 hours the Mixture was distributed between ethyl acetate and water. The organic phase was washed with water and brine, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column and used as eluent 7:3 o/a mixture of toluene and ethyl acetate. Thus it turns out-methyl-2-oxo-1,2-dihydro-4H-3,1-benzoxazin (0.8 g, 73% ) as oil.

An NMR spectrum (l3, value) 3,38 (C. 3H), 5,20 (C. 2H), 6,92-7,39 (m, 4H).

A mixture of a portion (0,77 g) benzoxazine, thus obtained, concentrated chamois is vialis iodata acid (0,276 g) and iodine (0.6 g). The resulting mixture was heated to 95-100aboutC for 2 h the Mixture was cooled to room temperature, was added methylene chloride (10 ml) and the mixture was kind of balanced out by the addition of saturated aqueous sodium bicarbonate solution. The mixture was washed with a saturated aqueous solution of sodium sulfite and brine, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 4:1 o/a mixture of toluene and ethyl acetate as eluent. Thus was obtained the required starting material (0.45 g, 33%) as a solid.

An NMR spectrum (l3, value) 3,35 (C. 3H), 5,15 (C. 2H), 6,7 (D. 1H), 7,45 (D. 1H), 7,65 (m, 1H).

4-(3-Mercaptophenyl)-4-methoxytyramine - Piran, used as the starting material, was obtained as follows.

A solution of 1,3-dibromobenzene with (23,8 g) in THF (120 ml) was cooled to -78aboutC in an atmosphere of argon, was added dropwise n-utility (1.6 M in hexane, 62.5 ml). The mixture is stirred at -78aboutC for 30 min, and was added to the solution tetrahydropyran-4-it (10 g) in THF (40 ml). The resulting suspension stirred at -78aboutC for 1 h, was left to warmed to room temperature, the second ether. The organic phase was dried (magnesium sulfate) and was evaporated. The residue was pulverized with hexane and the resulting solid (16,8 g) was filtered off.

The solution thus obtained product in DMF (100 ml) was added dropwise to a suspension of sodium hydride (60 wt./wt. the dispersion in mineral oil; the 5.25 g) in DMF (10 ml) and the mixture stirred at room temperature for 90 minutes was Added mutilated (36.5 g) and the mixture stirred at room temperature for 16 hours were Alternately added ethanol (2 ml) and water (500 ml) and the mixture was extracted with diethyl ether (3 x 200 ml). The combined extracts were washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using nerastas polar mixtures of hexane and ethyl acetate as eluent. Thus was obtained 4-(3-bromophenyl)-4-methoxyacridine (12 g, 44%) as a solid.

An NMR spectrum (l3, value) 1,88-2,1 (m, 4H), 3.0 a (C. 3H), 3,78-3,95 (m, 4H), 7,2-7,35 (m, 2H), 7,42 (m, 1H), 7,55 (m, 1H).

The solution of a portion (1 g) of the product thus obtained, in THF (4 ml) was cooled to -80aboutC in an atmosphere of argon, was added dropwise n-utility (1.6 M in hexane -80aboutEven for 30 minutes, water was Added (10 ml) and the mixture was allowed to warmed to room temperature. The mixture was extracted with diethyl ether (10 ml). The aqueous phase was padillas to pH 4 by addition of dilute aqueous hydrochloric acid solution and was extracted with diethyl ether (2 x 10 ml). The combined organic extracts were dried (magnesium sulfate) and was evaporated. Thus was obtained the required starting material as an oil (0.5 g), which crystallized upon standing, and used without further purification.

P R I m e R 9. the procedure described in example 5 was repeated except that instead of 4-(3,5-differenl)-4-tamoxifenhydromorphone was used (2RS, 4SR)- 4-(3,5-differenl)-4-methoxy-2-METALTECH - rehydration. Thus was obtained (2RS, 4SR)-4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihyd - ro-4H-1,4-benzoxazin-7-ylthio)phenyl]-4 - methoxy-2-methyltetrahydrofuran with a yield of 20% melting point 110-112aboutC.

NMR Spectrum (l3values) of 1.20 (3H D.), 1,5-of 2.15 (m, 4H), 2,98 (C. 3H), 3,37 (C. 3H), 3.75 to 4,10 (m, 3H), 3,63 (C. 2H), 's 6.75 to 7.25 (m 6N).

(2RS, 4SR)-2(3,5-differenl)-4-methoxy-2-methylentetrahydrofolate used as starting material was obtained as follows.

aboutC for 15 minutes the Mixture gave the opportunity to re-cool to room temperature and was added dropwise a solution of 2-methyltetrahydrofuran-4-it (J. Amer. Chemical Soc. 1982, 104, 4666) in THF (1 ml). The mixture is stirred at room temperature for 1 h the Mixture was poured into dilute aqueous hydrochloric acid and was extracted with diethyl ether. The organic phase was washed with saline, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 9:1/mixtures of methylene chloride and diethyl ether as eluent. Thus was obtained the less polar isomer, (2RS, 4SR)-4-(3,5-differenl)-4-hydroxy-2-methylether-gidropony (0.25 g), 36% with 2-methyl and 4-hydroxy substituents in a TRANS-relationship.

Sodium hydride (50 wt. /Mac. the dispersion in mineral oil, 0,053 g) was added to a mixture of the product thus obtained, under the conditions (0,233 g) and DMF (3 ml). The mixture is stirred at room temperature for 30 minutes and the Mixture was padillas to pH 3 by adding hydrochloric acid and was extracted with diethyl ether. Organic fat chromatography on a column using 19:1/mixtures of methylene chloride and diethyl ether as eluent. Thus was obtained the required starting material (0,23 g, 87%) as oil.

P R I m e R 10. The procedure described in example 5 was repeated with the exception that instead of 4-(3,5-differenl)-4-methoxyethylamine was used (2S, 4R)-4-(3,5-differenl)-4-methoxy-2-methyltetra - hydroporn. Thus was obtained (2S, 4R)-4-(5-fluoro-3-)4-methyl-3-oxo-2,3-dihydro - 4H-1,4-benzoxazin-7-yl-thio(phenyl)-4-methoxy-2-methyltetrahydrofuran exit 16% melting point 115-117aboutC.

(2S, 4R)-4-(3,5-differenl)-4-methoxy-2-methyltetrahydrofuran used as the starting material, was obtained using procedures described in example 9, which relates to the receipt of the initial substances, except that instead of the racemic compounds, i.e., (2SR)-2-methyltetrahydrofuran-4-it was used (2S)-2-methyltetrahydrofuran-4-one (European patent application N 0385663) example 20 applications). Thus was obtained the required starting material with a yield of 18% in the form of butter.

P R I m e R 11. A mixture of 7-bromo-4-methyl-2,3-dihydro-4H-pyrido(3,2-b)(1,4)-oxazin-3 - one (0,244 g), 4-(3-mercaptophenyl)-4-methoxyacridine (0,224 g), potassium carbonate (0,223 g), copper chloride (0,029 g) and DMF (1.1 ml) was heated to 140aboutC for 5 h was Speculas water and salt solution, were dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 1: 1/hexane and ethyl acetate as eluent. Thus was obtained 4-methoxy-4-[3-(4-methyl-3-oxo-2,3-dihydro-4H-pyrido(3,2-b)(1,4)oxa - Zin-7-eltigani]tetrahydropyran (0.1 g, 26%), melting point 118-120aboutC.

7-Bromo-4-methyl-2,3-dihydro-4H-pyrido- (3,2-b)(1,4)oxazin-3-one used as starting material was obtained as follows.

2,3-Dihydro-4H-pyrido(3,2-b)(1,4)-oxa - Zin-3-one (U.S. patent N 3854926, 1.5 g) was added in portions to a stirred suspension of sodium hydride (60 wt. /Mac. the dispersion in mineral oil, 0.4 g) in DMF (30 ml), which was pre-cooled in an ice bath. The mixture was allowed to warmed to 30 minutes was Added methyliodide (0.65 g) and the mixture stirred at room temperature for 16 hours the Mixture was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic phase was washed with water and brine, dried (magnesium sulfate) and was evaporated, yielding 4-methyl-2,3-dihydro-4H-pyrido (3,2-b)(1,4)oxazin-3-one (1,58 g), which was used without further purification.

The mixture portions (0.9 g) obtained is 24 hours Water was added (6 ml) and the mixture was cooled in an ice bath. The residue (0.3 g) was separated and dried. The filtrate was distributed between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was washed with water, aqueous sodium thiosulfate solution and brine, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using as eluent 19:1 o/a mixture of toluene and ethyl acetate. The product thus obtained was combined with the selected sediment, giving the required starting material (0,46 g, 34%) as a solid.

P R I m e R 12. Sodium hydride (60 wt./wt. the dispersion in mineral oil, 0,021 g) was added in portions to a stirred mixture of 4-[5-fluoro-3-(3-oxo-2,3 - dihydro-4H-1,4-benzoxazin-7-yloxy)Fe-Neil]-4-methoxyacridine (0,19 g), under the conditions (0,109 g) and N-methylpyrrolidine-2-she (2 ml) and the mixture stirred at room temperature for 1 h the Mixture was distributed between ethyl acetate and water. The organic phase was washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 9:1/mixtures of methylene chloride and diethyl ether as eluent. Thus the, 7% ) in the form of oil, which crystallized upon rubbing with a mixture of hexane and diethyl ether, the melting point of 108-109aboutC.

4-[5-fluoro-3-(3-oxo-2,3-dihydro-4H-1,4 - benzoxazin-7-yloxy)phenyl]-4-methoxy-tetrahydropyran used as starting material was obtained as follows.

Sodium hydride (60 wt./wt. the dispersion in mineral oil, 0,088 g) was added in portions to a stirred mixture of ethyl 2-(5-fluoro-2-nitrophenoxy)acetate (0,486 g) 4-(5-fluoro-3-hydroxyphenyl)-4-methoxyacridine (0,452 g) and N-methylpyrrolidine-2-it (10 ml) and the mixture stirred at room temperature for 5 h and then was heated to 60aboutC for 10 h, the Mixture was cooled to room temperature and distributed between diethyl ether and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution and water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 9: 1/mixtures of methylene chloride and diethyl ether as eluent. Thus was obtained 4-[5-fluoro-3-(3-ethoxycarbonylmethoxy-4-nitrophenoxy)phenyl] -4-methoxymethyl RAPIRA (0.32 g, 35%) as oil.

The mixture thus obtained is was peremeshivaesh at room temperature under a pressure of hydrogen gas in four of the atmosphere for 3 hours The mixture was filtered and the filter was evaporated. Thus was obtained the required starting material (0,19 g, 73%) as a solid, which was used without further purification.

P R I m e p 13. Using the procedure described in example 12, 4-[5-fluoro-3-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl] -4-metoxi tetrahydropyran (was subjected to reaction with methyliodide, giving 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-benzothiazin-7-ylthio)phenyl] -4-methods-to - literalization exit 41% melting point 131-133aboutC.

4-[5-fluoro-3-oxo,3-dihydro-4H-1,4 - benzothiazin-7-ylthio)phenyl] -4-otoxicity-gidropony used as starting material was obtained as follows.

The solution ethyldiglycol (13,2 g) in bis(2-methoxyethyl)-ether (50 ml) was added dropwise to a mixture of 2,4-deformirovannoe (15.9 g), monohydrate of lithium hydroxide (4.83 g) and N-methylpyrrolidine-2-she (150 ml) which was cooled in a water bath. The mixture is stirred at room temperature for 45 minutes, water was Added (200 ml) and the mixture was pagkilala at pH 5 by adding dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether (3 x 150 ml). The combined extracts were washed with water and saline

Ispolzovaniem 1:1 o/a mixture of petroleum ether (so Kip. 40-60aboutC) and diethyl ether as eluent. Thus was obtained ethyl 2-(5-fluoro-2-nitrophenylthio)acetate (8,9 g, 29%) as oil, which crystallized upon rubbing with a mixture of hexane and diethyl ether.

The monohydrate of lithium hydroxide (0,063 g) was added in portions to a stirred mixture of ethyl 2-(5-fluoro-2-nitrophenylthio)acetate (0,401 g), 4-(5-fluoro-3-mercaptophenyl)-4-methoxyacridine (European patent application N 04205110 example 4 it 0,363 g) and N-methylpyrrolidine-2-she (4 ml). The mixture is stirred at ambient temperature for 2 hours the Mixture was distributed between diethyl ether and water. The organic phase was washed with water and brine, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 19:1 o/o of a mixture of methylene chloride and diethyl ether as eluent. Thus was obtained 4-[5-fluoro-3(3-etoxycarbonyl-methylthio-4-nitrophenylthio)phenyl] -4-methoxymethyl ID RAPIRA (0,61 g, 87%) as oil, which crystallized upon rubbing with a mixture of hexane and diethyl ether.

Zinc (0,715 g) was added in portions to the mixture thus obtained product (0,529 g), water (1.5 ml) and acetic acid (14 ml) and the mixture of nagrevatelnyh on column using 1:1 o/o of a mixture of methylene chloride and diethyl ether as eluent. Thus was obtained the required starting material in the form of oil, which crystallized when grinding with diethyl ether, giving a solid (0.3 g, 67%), melting point 151-152aboutC.

P R I m e R 14. Using the procedure described in example 11, 7-bromo-4-methyl-2,3-dihydro-4H-pyrido(3,2-b)(1,4-oxa-Zin-3-one was subjected to reaction with 4-(5-fluoro-3-mercaptophenyl)-4-ethoxymethylene - ran, giving 4-[5-fluoro-3-(4-methyl-3-oxo-2,3-dihydro-4H-pyrido(3,2-b)(1,4)oxazin-7-ylthio )phenyl]-4-methoxyacridine with 4% melting point 127-128aboutC.

P R I m e R 15. A solution of 4-[5-fluoro-3-(2,3-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzo-casin-7-ITIL)FeNi l] -4-methoxymethyl - apirana (0.21 g) in DMF (2 ml) was added dropwise to a stirred suspension of sodium hydride (50 wt./wt. the dispersion in mineral oil, 0.03 g) in DMF (0.3 ml) and the mixture stirred at room temperature for 20 minutes was Added methyliodide (0.4 ml) and the mixture stirred for 1 h, the Mixture was distributed between diethyl ether and water. The organic phase was washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 1:1/mixtures of hexane and ethyl acetate as a researcher who is methoxymethyl-ropean (0.15 g, 70%), melting point 116-118aboutC.

4-[5-fluoro-3-(2,2-dimethyl-3-oxo-2,3-di - hydro-4H-1,4-benzoxazin-7-ylthio)phenyl] -4-methoxyacridine used as starting material was obtained as follows.

A mixture of 5-fluoro-2-NITROPHENOL (3,14 g), methyl 2-bromo-2-methyl-propionate (3.6 g), potassium carbonate (4.1 g) and DMF (20 ml) was heated to 120aboutC for 2 h the Mixture was distributed between diethyl ether and water. The organic layer was washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified by chromatography on a column using 19:1 o/o of a mixture of hexane and ethyl acetate as eluent. Thus was obtained methyl 2-methyl-2-(5-fluoro-2-nitrophenoxy)propionate (1.5 g, 28%) as oil.

A mixture of a portion (1,33 g) thus obtained product, potassium carbonate (1.3 g), 4-(5-fluoro-3-mercaptophenyl)-4-methoxyacridine (1.2 g) and DMF (10 ml) was stirred and heated to 80aboutC for 1.5 h the Mixture was cooled to room temperature and distributed between diethyl ether and water. The organic phase was washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 3: 1/mixtures of hexane and tilateral]-4-meth oxitetraciclina (2.4 g, 89%) as oil.

A mixture of a portion (0,48 g) thus obtained product, 30% palladium on coal (0.4 g) and ethyl acetate (10 ml) were mixed in an atmosphere of hydrogen for 16 hours the Mixture was filtered and the filtrate was evaporated. the residue was purified using chromatography on a column using 1:1 o/o of a mixture of hexane and ethyl acetate as eluent. Thus was obtained the required starting material (0.24 g, 57%), melting point 130-133aboutC.

P R I m e R 16. Solution (S)-(+)-4-[5-fluoro-3-(2-methyl-3-oxo-2,3-dihydro-4H-1,4-Ben-oxazin-7-ylthio) phenyl]-4-otoxicity - hydroprene (0.18 g) in DMF (5 ml) was added dropwise to a stirred suspension of sodium hydride (60 wt./wt. the dispersion in mineral oil, 0,018 g) in DMF (2 ml), which was pre-cooled to 10aboutC. the Mixture is stirred at room temperature for 30 minutes was Added methyliodide (0,077 g), the mixture was mixed at room temperature for 1 h the Mixture was distributed between water and ethyl acetate. The organic phase was washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 1:1/mixtures of hexane and ethyl acetate as eluent. Thus was obtained (S)-temperature melting point 104-106aboutC.

Specific rotation: (alpha)D+39about(methylene chloride, 1 g/100 ml temp. 25aboutC).

(S)-(+)-4-[5-fluoro-3-(2-methyl-3-oxo-2,3-di - hydro-4H-1,4-benzoxazin-7-ylthio)phenyl] 4-methoxyacridine used as starting material was obtained as follows.

A mixture of 5-fluoro-2-nitrophenyl (0,47 g), (R)-(+)-methyl 2-chloropropionate (0,37 g), potassium carbonate (0,621 g) and DMF (10 ml) was heated to 60aboutC for 18 hours the Mixture was distributed between ethyl acetate and water. The organic layer was washed with water, dried (magnesium sulfate) and was evaporated. Thus was obtained (S)-(+)-methyl 2-(5-fluoro-2-nitrophenoxy)propionate (0,453 g, 62%), melting point 50-52aboutC.

Specific rotation: (alpha)D+40,2about(methylene chloride, 1 g/100 ml).

A mixture of a portion (0.4 g) thus obtained product, potassium carbonate (0.33 g), 4-(5-fluoro-3-mercaptophenyl)-4-meloxicam-rehydration (0.39 g) and DMF (5 ml) were mixed and heated to 85aboutC for 3 hours the Mixture was cooled to room temperature and distributed between ethyl acetate and water. The organic phase was washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column shall-(1-methoxycarbonyl)ethoxy)-4-nitrophenylthio)phenyl]-4-labels literalization (0,558 g, 75%) as oil.

A mixture of a portion (0,314 g) thus obtained product, iron filings (1,135 g), iron sulfate heptahydrate (0,192 g) and methanol (25 ml), stirred vigorously and heated to the temperature of reflux distilled for 4 hours the Mixture was cooled to room temperature and filtered. The residue was rinsed with methylene chloride. The combined filtrates were washed with water, dried (magnesium sulfate) and was evaporated. The residue was purified using chromatography on a column using 1: a mixture of hexane and ethyl acetate as eluent. Thus was obtained the required starting material (0,238 g, 84%) as an oily solid.

NMR Spectrum (l3, value) 1,59 (doctor 3H), 1,89 (m, 4H), 2.98 (C. 3H), and 3.8 (m, 4H), 4,7 (square 1H), 6,8-7,1 (m 6N), and 8.4 (broad peak, 1H).

P R I m e R 17. Using a similar procedure described in example 16, (R)-(-)-4-[5-FTIR-3-(2-methyl-3-oxo-2,3-di - hydro-4H,1,4-benzoxazin-7-ylthio)phenyl]-4-methoxyethylamine was subjected to reaction with methyliodide, giving (R)-(-)-4-[5-fluoro-3-(2,4-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-IO tli)phenyl] -4-labels-literalization with the release of 42% melting point 107-109aboutC.

Specific rotation: (alpha)D36,8aboutaboutC.

P R I m e R 18. The following examples illustrate typical pharmaceutical dosage forms, containing a compound of formula I, or its pharmaceutically acceptable salt (here below compound X), for therapeutic or prophylactic use in humans: (a) Tablet I mg/tablet Compound X 100 Lactose Pharm. Heb. 182,75 Crosscarmellose sodium 12,9 Corn krahmal - Naya pasta (52 wt./O. paste) 2.25 magnesium Stearate 3.0 a (b) Tablet II mg/tablet Compound X 50 Lactose Pharm. Heb. 223,75 Crosscarmellose sodium 6,0 Corn starch 15.0 Polyvinylpyrrolidone (5 wt./about paste) 2.25 magnesium Stearate, and 3.0 (C) Tablet III mg/tablet Compound X 1.0 Lactose Pharm. Heb. 93,25 Croscarmellose - sodium 4,0 Corn krahmal - Naya pasta (5 wt./about pasta) 0.75 Stearate and 1.0 (d) Capsule mg/capsule Compound X 10 Lactose Pharm. Heb. 488,5 magnesium Stearate and 1.5 (e) Injection Is,6) polyethylene Glycol 400 4.5 wt./about Water for injection to 100% (f) Injection II (10 mg/ml) Compound X 1.0 wt./about sodium Phosphate BP 3.6 wt./about 0.1 M solution of sodium hydroxide 15,0 about. Water for injection to 100% (g) Injection III (1 mg/ml, Boo

ferroan-

tion to pH 6) Compound X 0.1 wt./about sodium Phosphate BP 2.26 wt./of Citric acid to 0.38 wt./about polyethylene Glycol 400 3.5 wt./about Water for injection to 100% (h) Aerosol I mg/ml Compound X 10.0 Sarbatorile of 13.5 Trichlorofluoromethane 910,0 DICHLORODIFLUOROMETHANE 490,0 (i) Aerosol II mg/ml Compound X 0.2 Sarbatorile 0,27 Trichlorofluoromethane 70,0 DICHLORODIFLUOROMETHANE 280,0 Dichlorotetrafluoroethane 1094,0 (j) Aerosol III mg/ml Compound X 2.5 Sarbatorile 3,38 Trichlorofluoromethane 67,5 DICHLORODIFLUOROMETHANE 1086,0 Dichlorotetrafluoroethane to 191.6 (k) Aerosol IV mg/ml Compound X 2.5 Soy lecithin 2,7 Trichlorofluoromethane 67,5 DICHLORODIFLUOROMETHANE 1086,0 Dichlorotetrafluoroethane to 191.6

Note.

The above formulation can be obtained using standard procedures well known in the pharmaceutical industry equipment. The tablets (a)-(C) can be enterococci coating applied by conventional means, for example, to obtain a coating azettftalat cellulose. Aerosol formulations of (h) to(k) may be used in combination with standard dosing of aerosol spray cans, and suspendresume agents sarbatorile and soya lecithin may be replaced of enterpriselearn or oleic acid.

1. Bicyclic heterocyclic compound of General formula

< / BR>
where Q 4H-1,4-benzoxazine, or 4H-1,4-benzothiazine, or the corresponding 2,3-dihydroprogesterone, 4H-3,1-benzoxazine, or 4H-3,1-benzothiazines, or its corresponding 1,2-dihydroprogesterone, or 4H-pyrido-[3,2-b] [1,4] -oxazinyl, each of which may optionally bear one oxo or taxonomical and up to four other substituents, selected from halogen, hydroxy, cyano, amino, C1WITH4-alkyl, C1- C4-alkoxy, fluorine-C1WITH4-alkyl, C1- C4-alkylamino and di-(C1WITH4-alkyl)-amino;

AND1direct X1or1WITH3-alkylen;

X1hydroxy, thio, sulfinil or sulfonyl;

Ah phenylene which may optionally bear one or two substituent selected from halogeno, hydroxy, amino, C1WITH4of alkyl, C1- C4-alkoxy, C1WITH4-alkylamino, di-(C1- C4-alkyl)-amino and fluoro-(C1WITH4)-alkyl;

R1WITH1WITH4-alkyl, C3WITH4alkenyl or3WITH4-quinil;

R2and R3together form a group of the formula-A2-X2-A3- which, together with the atom uglee2and a3the same or different, each WITH1WITH3-alkylene, X2-oxy, and the ring may bear one or two1WITH4is an alkyl substituent,

or is it acceptable from a pharmaceutical point of view of salt.

2. Bicyclic heterocyclic compound of the formula under item 1, characterized in that Q is 4H-1,4-benzoxazine, 4H-1,4-benzothiazine or their respective 2,3-dihydroergocornine, which may bear one oxo or taxonomical and up to four substituents selected from fluorine, chlorine, bromine, hydroxy, cyano, amino, methyl, ethyl, propyl, methoxy, cryptomeria, 2-veratile and 2,2,2-triptoreline AND1direct X1or methylene, X1hydroxy, thio, sulfinil or sulfonyl, Ar is 1,3-phenylene or 1,4-phenylene, which may bear one or two substituent selected from fluorine, chlorine, hydroxy, amino, methoxy, dimethylamino and trifloromethyl, R1methyl, ethyl, allyl or 2-PROPYNYL and R2and R3together form a group of the formula-A2-X2-A3- which together with the carbon atom to which AND2and a3attached, defines a ring containing 5 or 6 ring atoms, in which A2is ethylene, AND3the methylene or E. the sludge, or is it acceptable from a pharmaceutical point of view of salt.

3. Bicyclic heterocyclic compound of the formula under item 1, wherein Q is 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or 3-oxo-2,3-dihydro-4H-1,4 - benzothiazin-7-yl which may bear one, two or three substituent selected from fluorine, chlorine, methyl, ethyl, propyl or veratile AND1direct X1or methylene, X1hydroxy, Teal, sulfinil or sulfonyl, Ar is 1,3-phenylene or 1,4-phenylene, which may bear one or two substituent selected from fluorine, hydroxy, amino, methoxy, dimethylamino or trifloromethyl, R1methyl, ethyl, allyl or 2-PROPYNYL, R2and R3together form a group of the formula-A2-X2-A3- which together with the carbon atom to which AND2and a3attached, defines a ring having 5 or 6 ring atoms, where a2ethylene AND3methylene or ethylene and X2- oxy, and the ring may bear one or two substituent selected from methyl and ethyl, or acceptable from a pharmaceutical point of view of salt.

4. Bicyclic heterocyclic compound of the formula under item 1, wherein Q is 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl, inesti one or two substituent, selected from methyl and ethyl, AND1direct X1or methylene, X1-oxy, thio, sulfinil or sulfonyl, Ar is 1,3-phenylene which may bear one or two substituent selected from fluorine, methoxy and trifloromethyl, R1methyl, ethyl or allyl, R2and R3together form a group of the formula-A2-X2-A3- which together with the carbon atom to which AND1and a3attached, defines a ring containing 5 or 6 ring atoms, where a2ethylene AND3methylene or ethylene and X2hydroxy, and where this ring may carry Deputy selected from methyl, ethyl and propyl, or acceptable from a pharmaceutical point of view of salt.

5. Bicyclic heterocyclic compound of the formula under item 1, wherein Q is 4-methyl-3-oxo-2,3-dihydro-4H-1,4 - benzoxazin-7-yl, or 4-methyl-3-oxo-2,3-dihydro-4H-1,4 - benzothiazin-7-yl, or their respective 2,2-DIMETHYLPROPANE AND1methylene, X1hydroxy, AG-1,3-phenylene or 5-fluoro-1,3-phenylene, R1is methyl, R2and R3together form a group of the formula-A1-X2-A3- which together with the carbon atom to which AND2and a3attached, defines a ring containing 6 kolotilova or ethyl Deputy alpha relative to the X2or it acceptable from a pharmaceutical point of view of salt.

6. Bicyclic heterocyclic compound of the formula under item 1, wherein Q is 3-oxo-2,3-dihydro-4H-1,4 - benzoxazin-6-yl, 3-oxo-2,3-dihydro-4H-1,4 - benzoxazin-7-yl, 3-dioxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl, 2-oxo-1,2-dihydro-4H-3,1 - benzoxazin-6-yl, 3-oxo-2,3-dihydro-4H-1,4-benzothiazin-7-yl or 3-oxo-2,3-dihydro-4H-pyrido- [3,2-b] [1,4] -oxazin-7-yl or their respective 11-methyl derivative, which may bear one or two substituent selected from methyl or ethyl, AND1direct X1or methylene, X1hydroxy, thio, sulfinil or sulfonyl, Ar is 1,3-phenylene which may bear one or two substituent selected from fluorine, methoxy and trifloromethyl, R1is methyl, ethyl or allyl, and R2and R3together form a group of the formula-A2-X2-A3- which together with the carbon atom to which AND2and a3attached, defines a ring containing 5 or 6 ring atoms, where a2ethylene AND3methylene or ethylene and X2hydroxy, and the ring may carry Deputy selected from methyl, ethyl and propyl, or acceptable from a pharmaceutical point of view of salt.

the-2,3-dihydro-4H - 1,4-benzoxazin-6-yl, 4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl, 2,2,4-trimethyl-3-oxo-2,3 - dihydro-4H-1,4-benzoxazin-7-yl, 4-methyl-3-thioxo-2,3-dihydro - 4H-1,4-benzoxazin-7-yl, 1-methyl-2-oxo-1,2-dihydro-4H-3,1 - benzoxazin-6-yl or 4-methyl-3-oxo-2,3-dihydro-4H - pyrido [3,2-b][1,4]oxazin-7-yl, AND1-direct X1or methylene, X1hydroxy or thio, Ar is 1,3-phenylene or 5-fluoro-1,3-phenylene, R1is methyl, and R2and R3together form a group of the formula-A2X2-A3- which together with the carbon atom to which AND2and a3attached define a ring containing 6 ring atoms, in which each of A2and a3is ethylene, and X2hydroxy, and this ring carries a methyl or ethyl Deputy alpha relative to the X2or it acceptable from a pharmaceutical point of view of salt.

8. Bicyclic heterocyclic compound of the formula or its acceptable from a pharmaceutical point of view of salt under item 1, characterized in that they are chosen from the group, 4-[5-fluoro-3(4-methyl-3-oxo-2,3-dihydro - 4H-1,4-benzoxazin-7-yl-methoxy) -4-methoxyacridine, 4-[5-fluoro-3-(2,2,4-trimethyl-3 - oxo-2,3-dihydro-4H-1,4-benzoxazin - 7-ylethoxy)phenyl] -4-methoxyacridine and 4-[5-fluoro-3-(2,2,4-trimethyl-3-oxo-2,3 - the systematic connection of the formula or its acceptable from a pharmaceutical standpoint salt p. 1, wherein they are selected from 4-[5-fluoro-3-(4-methyl-3-thioxo-2,3-dihydro - 4H-1,4-benzoxazin-7-ylthio)phenyl] -4 - methoxyacridine, 4-[5-fluoro-3-(4-phenyl-3-oxo-2,3-dihydro - 4H-1,4-benzoxazin-7-ylthio)phenyl]-4 - methoxyacridine, (2S, 4R)-4-[5-fluoro-3-(4-methyl-3 - oxo-2,3-dihydro-4H-1,4-benzoxazin-7 - ylthio)phenyl] -4-methoxy-2 - methyltetrahydrofuran, (S)-(+)-4-[5-fluoro-3-(2,4-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl] -4-methoxyacridine and (R)-(-)-4-[5-fluoro-3-(2,4-dimethyl - 3-oxo-2,3-dihydro-4H-1,4 - benzoxazin-7-ylthio)phenyl]-4 - methoxyacridine.

10. The pharmaceutical composition exhibiting inhibitory activity against 5-lipoxygenase and leukotriene comprising the active ingredient in combination with pharmaceutically acceptable diluent or carrier, wherein as the active ingredient it contains a bicyclic heterocyclic compound of the formula or its pharmaceutically acceptable salt under item 1 in the amount of from 0.5 mg to 2 g per unit dose.

 

Same patents:

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to new aminoven derivatives, processes for their production and insecticide containing as selective compounds listed derivatives

Derivative amide // 2037493

The invention relates to new derivatives substituted benzoylbenzene-, biphenyl - 2-oxazolidinone acid, which has inhibitory activity against lipoxygenase, phospholipase A2and which are leukotriene antagonists; derivatives, which are suitable for use as anti-inflammatory, antiallergic agents, but also as protectors

The invention relates to new chemical compounds derived benzothiazine responsible of General formula I

where R1lower alkyl WITH1-C4

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to new derivatives substituted benzoylbenzene-, biphenyl - 2-oxazolidinone acid, which has inhibitory activity against lipoxygenase, phospholipase A2and which are leukotriene antagonists; derivatives, which are suitable for use as anti-inflammatory, antiallergic agents, but also as protectors

Derivative oxazole // 2032677
The invention relates to heterocyclic carbon compounds that have medicinal and biosdecode properties and to their preparation and use

The invention relates to benzoxazolinone, more specifically to certain benzoxazolinone, substituted not only in position 6 amine side chain, but also in the provisions of 4,5 or 7 of the benzene ring

The invention relates to antimicrobial compound used as a drug for humans and animals, and fish

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
Up!