Heterocycles connection method thereof and pharmaceutical composition

 

(57) Abstract:

Usage: as an inhibitor of the enzyme 5-lipoxygenase for the treatment of various inflammatory and/or allergic diseases. Product: 4/5-Bratan-2-yl/-4 - hydroxyethylamino output is 32%, so pl. 100 - 102oC 4-methoxy-4-[5-(1-methyl-2-oxo-1,2-dihydroquinoline-6 - yl-thio)Tien-2-yl] tetrahydropyran, yield 19%, so pl. 119 - 120oC. 2 C. and 7 C.p. f-crystals.

The invention relates to new heterocycles compounds, more particularly to a new heterocycles compounds which are inhibitors of the enzyme 5-lipoxygenase (5-LO). The invention also relates to methods of producing such heterocycles compounds and new pharmaceutical compositions containing these compounds. In addition, the invention enabled the use of these heterocycles compounds for the treatment of various inflammatory and/or allergic diseases, which involve direct or indirect oxidation products of arachidonic acid catalyzed by 5-LO, and also included the acquisition of new drugs intended for such treatment.

As stated above, heterocycles connection, described below, are inhibitors of 5-LO 4 farms is the process of formation of the physiologically active leukotrienes, such as: leukotrien4/FULLY4/ , peptido-lipid leukotrienes such as: leukotrien4/LTS4and leukotrien D4/LTD4/, as well as different metabolites.

Biosynthetic connectivity and physiological properties of leukotrienes summarized in the work of G. W. Taylor u S. R. Clarce, Trends in Pharmacological Sciences, 1986, 7, 100 and 103. Leukotrienes and their metabolites held responsible for the emergence and development of various inflammatory and allergic diseases such as inflammation of the joint (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel, ulcerative colitis and gastritis), skin diseases (especially psoriasis, eczema and dermatitis) and respiratory diseases (especially asthma, bronchitis and allergic rhinitis), as well as for the emergence and development of various cardiovascular disorders and disorders of the brain, such as: myocardial infarction, angina and peripheral vascular diseases. In addition leukotrienes are mediators of inflammatory diseases, due to their ability to modulate the functioning of lymphocytes and leukocytes. Other physiologically active metabolites of arachidonic acid, still is.

Discovered that certain heterocycles compounds are effective inhibitors of the enzyme 5-LO and thus of the biosynthesis of leukotrienes. I.e., these compounds are of value as therapeutic agents for the treatment of, for example: allergic symptoms, psoriasis, asthma, cardiovascular disorders and disorders of the brain and/or inflammatory and arthritic symptoms, created solely or partially by one or more leukotrienes.

In accordance with the invention are given heterocyclization the compounds of formula 1 (see below), where AG1represents phenyl or naphthyl, or 9 - or 10-membered bicyclic heterocyclic moiety containing one or two heteroatoms of nitrogen, and may contain an additional heteroatom selected from: nitrogen, oxygen and sulfur, and Ar1may possibly be substituted by up to five substituents selected from: amino, halogen, hydroxyl, cyanide, carbonyl group, tocography,1C4-alkyl, C1- C4-alkoxygroup,1C4-allylthiourea,1- C4-alkylsulfonyl,1-C4- alkylamino, di/C1C4-alkyl/amino groups, WITH2C4alkanoyl, fluoride is than phenyl, benzoline or phenyl-C1C4-alkyl substituents can be substituted by substituents selected from: halogen, C1C4-alkyl and C1C4- alkoxygroup;

where a1represents a simple bond with X1or1- C3-alkylen;

where X1is oxygraph, tigroup, sulfinil, sulfonyl or aminogroup;

Ar2represents a 5-membered heterocyclic fragment containing one heteroatom selected from: nitrogen, oxygen and sulfur, which may have one Deputy, selected from: halogen, C1C4-alkyl and C1C4-alkoxygroup;

where R1is1C4-alkyl, C3- C4alkenyl or3-C4-quinil; and

where R2and R3together form a group of the formula: -A2-X2-A3that together with the carbon atom to which attached AND2and A3forms a cycle with 5 to 7 atoms in the cycle, where a2and A3that may be the same or different, each represents C1-C3-alkylene, X2is oxygraph, tigroup, sulfinil, sulfonyl, and this cycle may have one, two or three substituent which can basegroup;

or where R1and R2form a group of the formula: -A2-X2-A3- which together with the oxygen atom attached to AND2and the carbon atom that is attached AND3form a loop with 5 to 7 atoms in the cycle, where a2and A3that may be the same or different, each represents C1- C3-alkylene and X2is oxygraph, tigroup, sulfinil or sulfonyl, and this cycle may be substituted by one, two or three1C4-alkyl substituents, and where R3is1C4-alkyl, C2C4alkenyl or2- C4-quinil, or pharmaceutically acceptable salt of these compounds.

According to another aspect of the invention provides heterocycles compound of formula 1 according to the above definition, where additional possible substituents at Ar1include:- diferensial, a-hydroxybenzyl and the a/C1C4-alkoxy/benzyl, and these substituents may be substituted by the Deputy, selected from: halogen, C1C4-alkyl and C1C4- alkoxygroup.

According to another aspect of the invention provides heterocycles compound of formulas which contains one or two heteroatoms of nitrogen, and may contain an additional heteroatom, selected from: nitrogen, oxygen and sulfur, and Ar1possibly can have up to five substituents selected from: amino, halogen, hydroxyl, cyanide, carbonyl group, tocography,1C4-alkyl, C1- C4-alkoxygroup,1C4-alkylamino, di/C1-C4- alkyl/amino group, a C2C4alkanoyl, fluorine-C1C4-alkyl, cyan-C1C4-alkyl, phenyl, benzoyl, phenyl-C1C4-alkyl, a, diferenzia, a-hydroxybenzyl and the a/C1C4-alkoxy/benzyl, and where six listed last substituent may be substituted by up to five substituents selected from: halogen, trifloromethyl,1- C4-alkyl and C1C4-alkoxygroup;

where a1represents a simple bond with X1or C1- C3-alkylen;

where X1is oxygraph, tigroup, sulfinil, sulfonyl or aminogroup;

Ar2represents a 5-membered heterocycles fragment containing one heteroatom selected from: nitrogen, oxygen and sulfur, which may possibly be substituted by one Deputy, selected from: halogen, C1- C4-alkyl, C3C4alkenyl or3- C2and A3. Forms a cycle with 5 to 7 atoms in the cycle, where a2and A3that may be the same or different, each represents C1C3-alkylene, and X2is oxygraph, tigroup, sulfinil or sulfonyl, and this cycle may have one, two or three substituent which may be the same or different, selected from: hydroxyl,1C4-alkyl and C1- C4-alkoxygroup;

where R1and R2together form a group of the formula: -A2-X2-A3- which together with the oxygen atom attached to AND2and with the carbon atom to which attached AND3forms a cycle with 5 to 7 atoms in the cycle, where a2and A3that may be the same or different, tigroup, sulfinil or sulfonyl, and this cycle may have one, two or three1C4alkenyl or2C4-quinil; or a pharmaceutically acceptable salt of these compounds.

Chemical formulas, also called Roman numerals, for facilities placed on separate pages next.

In the present description, the term "alkyl" denotes alkyl groups normal or ISO-Scrooge structure, but references to individual alkyl groups of out-buildings, such as "isopropyl" characteristic only with option isostream. The same is true for other common terms.

You must specify that because some of the compounds of formula 1, described above, can be tautomerism, and any style 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 with properties to inhibit 5-LO, and should not be limited to only one tautomeric form represented by the above mark formula.

Additionally, you must specify that because certain compounds of formula 1 described above may exist in optically active or racemic form due to the presence of one or more of the substituents at asymmetric carbon atom, the invention in its definition includes any such optical active or racemic forms, possessing properties to inhibit 5-LO. Synthesis of optically active forms can be made by standard methods of organic chemistry well known in the art, to Primerose properties against 5-LO can be identified using standard laboratory methods, below.

Acceptable values for the above General terms below.

Acceptable values for Ar1presented 9 - or 10-membered bicyclic heterocyclic fragment containing one or two heteroatoms of nitrogen, and may contain an additional heteroatom selected from: nitrogen, oxygen and sulfur, include, for example: a 9 - or 10-membered benzoannelirovannykh fragment, such as indolyl, isoindolyl, benzimidazolyl, IH-indazole, benzoxazole, benzthiazole, hinely, ethanolic, cannoli, hintline, honokalani, 4H-1,4-benzoxazine or 4H-1,4-benzothiazine or their hydrogenated derivatives, such as indolinyl, 2,3-dehydrobenzperidol, 2,3-dihydroisoxazole, 2,3-dihydrobenzofuran, 1,2-dihydrohelenalin, 1,2,3,4-tetrahydroquinolin, 1,2-dihydroisoquinolyl, 2,3-dihydro 4H-1,4-benzoxazine or 2,3-dihydro-4H-1,4-benzothiazine, or 9 - or 10-membered paedocommunion fragment such as: IH-pyrrolo/2,3-b/-pyridyl, imidazo/4,5-b/ pyridyl, 1,7-naphthyridine, 1,8-naphthyridine, pyrido/2,3-d/pyrimidinyl, pyrido/2,3-b/pyrazinyl, 4H-pyrido/3,2-b//1.4/oxazinyl and 4H-pyrido/3,2-b//1.4/triazinyl or their hydrogenated derivatives.

Heterocyclic fragment can Kochetkova fragment, including an available nitrogen atom. Heterocyclic fragment may contain an acceptable substitute, for example: C1C4-alkyl, phenyl, benzoyl or phenyl-C1- C4-alkyl in available nitrogen atom.

Suitable values for substituents which may be present in Ar1or Ar2or phenyl, benzoyl, C1- C4-alkyl, a-diferenzia, hydroxybenzyl or a--/C1- C4-alkoxy and/ or benzyl, replacement Ar1include , for example:

for halogen: fluorine, chlorine, bromine and iodine;

for C1C4-alkyl: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl;

for C1C4-alkoxygroup: methoxy, ethoxy-, propoxy -, butoxy group.

Suitable values for substituents which may be present in Ar1include , for example:

for the fluorine-C1C4-alkyl: vermeil, deformity, trifluoromethyl, 2-foretel, 2,2,2-triptorelin and pentafluoroethyl;

for C1C4-alkylamino: methylamino, ethylamino, propylamino and butylamino;

for di/C1C4-alkyl/amino: dimethylamino, diethylamino and dipropylamino;

for C1C4-allylthiourea: tilsley, ethylsulfinyl, propylsulfonyl, isopropylphenyl and butylsulfonyl;

for C1C4-alkylsulphonyl: methylsulphonyl, ethylsulfonyl, propylsulfonyl, isopropylphenyl and butylsulfonyl;

for C2C4alkanoyl: acetyl, propionyl, butyryl;

for cyano-C1C4-alkyl: cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl and 2-cyanoprop-2-yl;

for phenyl-C1C4-alkyl: benzyl, phenethyl, 3-phenylpropyl and-methylbenzyl; a-/C1C4-alkoxy/benzyl: a-methoxybenzyl and ethoxybenzyl.

Acceptable values for A1presented WITH a1- C3-alkylene include, for example: methylene, ethylene or trimethylene.

Acceptable values for Ar2presented 5-membered heterocycles fragment containing one heteroatom selected from: nitrogen, oxygen and sulfur, include, for example: pyrrole, furillen or teenren. Usually Ar2presents 2,4 - or 2,5-pyrrolidino, 2,4 - or 2,5-furjana, 2,4 - or 2,5-thienylene. You must specify that in the case of 2,4-heterocyclization derived as described above, X1can be attached in 2-position or 4-position.

Acceptable value for R1p is3C4-alkenyl include, for example: allyl, 2-butenyl or 3-butenyl, and presented WITH a3C4-quinil include, for example, 2-PROPYNYL or 2-butynyl.

When R2and R3together form a group of the formula: -A2-X2-A3- which together with the carbon atom to which is attached A2and A3forms a cycle with 5 to 7 atoms in the cycle, in this case, the acceptable values for a2and A3that may be the same or different, are represented WITH1- C3-alkylenes each are, for example: methylene, ethylene or trimethylene. Suitable values for substituents which may be present in such a 5 to 7-membered cycle, include, for example:

for C1C4-alkyl: methyl, ethyl, propyl, isopropyl, butyl and isobutyl;

for C1C4-alkoxygroup: methoxy, ethoxy-, propoxy-, isopropoxy and butoxypropan.

When R1and R2together form a group of the formula: -A2-X2-A3- which together with the oxygen atom attached to AND2and the carbon atom that is attached AND3forms a cycle with 5 to 7 atoms in the cycle, in this case, an acceptable value for a2and A3s, for example: methylene, ethylene or trimethylene. Acceptable values for C1- C4-alkyl substituents, which may be present in such 5 - to 7-membered cycle, include, for example: methyl, ethyl, propyl, isopropyl and butyl.

Acceptable values for R3presented WITH a1- C4the alkyl include, for example: methyl, ethyl, propyl or butyl, presents WITH2C4-alkenyl include, for example: vinyl, alkyl, 2-butenyl or 3-butenyl presented WITH2C4-quinil include, for example: ethinyl, 2-PROPYNYL or 2-butynyl.

Pharmaceutically acceptable salts of the new compounds of the invention include, for example: salts formed by addition of acids to compounds of the invention which is sufficiently basic, for example, salts formed by addition of organic or inorganic acids such as hydrochloric, Hydrobromic, sulfuric, phosphoric, triperoxonane, citric and maleic acid. In addition, pharmaceutically acceptable salts of the new compounds of the invention which is sufficiently acidic, include melodramatycheskye salt, for example, sodium or potassium salt, alkaline earth salt of a metal, such as calcium or magnesium, ammatillinen, dimethylamine, trimethylamine, piperidine, morpholine or Tris/2-hydroxyethyl/ Amin.

The particular new compounds of the invention are, for example, heterocycles the compounds of formula 1 where:

/a/ Ar1represents phenyl or naphthyl which can be substituted one, two or three substituents selected from any of the above substituents for Ar1other than the carbonyl group or tocography;

/b/ Ar1represents phenyl or naphthas-2-yl, which may possibly be substituted by one or two substituents selected from: fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, metoxygroup, trifloromethyl, 2-cyanoprop-2-yl, phenyl or benzoyl, where the phenyl or benzoyl may contain a Deputy selected from: chlorine, methyl and metoxygroup, and A1X1, Ar2, R1, R2and R3take any of the above values:

/c/ Ar1represents phenyl or naphthas-2-yl, which may possibly be substituted by one or two substituents selected from: fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, metoxygroup, trifloromethyl, 2-cyanoprop-2-yl, phenyl, benzyl, benzoyl, a, diferenzia, a-methoxybenzyl, and phenyl, benzo is Atila and metoxygroup, and1X1, Ar2, R1, R2and R3can take any of the above values;

/d/ Ar1represents phenyl or naphthas-2-yl, which may possibly be substituted by one or two substituents selected from: fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tertbutyl, metoxygroup, trifloromethyl, 2-cyanoprop-2-yl, phenyl, benzoyl, benzyl, a, diferenzia, a--hydroxybenzyl and --methoxybenzyl, with six listed last Deputy can have up to five substituents selected from: fluorine, chlorine, trifloromethyl, bromide and metoxygroup, and1X1, Ar2, R1, R2and R3take any of the above values;

/e/ Ar1represents a 9 - or 10-membered benzododecinium heterocyclic fragment containing one or two heteroatoms of nitrogen, and may contain an additional heteroatom selected from: oxygen and sulfur, and such heterocyclic fragment can have one or two oxo or thioxo-substituent and up to three additional substituents selected from any of the substituents for Ar1the above and other than oxo or thioxo-Deputy, and A1m X1, Ar2, R1, R1the above and other than oxo or thioxo of deputies, AND1X1, Ar2, R1, R2and R3take any of the above values;

/g/ Ar1is chenail, 1,2-dihydrohelenalin, 1,2,3,4-tetrahydroquinolin or 2,3-dihydro-4H-1,4-benzoxazine, which may have a single oxo - or thioxo Deputy and up to three additional substituent selected from any of the substituents for Ar1the above and other than oxo or thioxo of deputies, AND1X1, Ar2, R1, R2and R3take any of the above values;

/h/ Ar1is 2-indolyl, 3-indolyl, 5-indolyl, 6-indolyl, 2-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 2-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 2-benzothiazolyl, 5-benzoylcholine, 6-honokalani, 4H-1,4-benzoxazin-6-yl or 4H-1,4-benzothiazin-6-yl, which may have one or two substituent selected from any of the above substituents for Ar1other than oxo or thioxo-Vice, and A1X1, Ar2, R1, R2and R3take any of the above values;

/i/ Ar1is 2-oxoindole, 2,3-dioxindole, 2-oxo-2-, 3-dehydrobenzperidol, 2-oxo,3-dihydrobenzofuran, 2-oxo-2,3-dihydrobenzofuran, 2-oxo-1,2-dihydroquinoline, 3-oxo-2,3-dihydro-4H-1,4 - benzoxazine or 3-oxo-2,3-dihydro-4H-1,4-benzothiazine or relevant thioxo-derivatives, which can have up to three substituents selected from any of the substituents for Ar1the above and other than oxo or thioxo of deputies, AND1X1, Ar2, R1, R2and R3take any of the above values;

/j/ Ar1represents 2-oxo-1,2-dihydrohelenalin, 2-thioxo-1,2-dihydrohelenalin, 2-oxo-1,2,3,4-tetrahydroquinoline, 2-thioxo-1,2,3,4-tetrahydroquinoline or 3-oxo-2,3-dihydro-4H-1,4-benzoxazine, which can be substituted by up to three substituents selected from any of the substituents listed above for Ar1try any of the above values for them;

/k/ Ar1is 2-oxoindole-5-yl, 2,3-dioxindole-5-yl, 2-oxo-2,3-dehydrobenzperidol-5-yl, 2-oxo-2,3-dihydroisoxazole-5-yl, 2-oxo-2,3 - dihydrobenzofuran-5-yl, 2-oxo-1,2-dihydroquinoline-3-yl, 2-oxo-1,2-dihydroquinoline-6-yl, 2-oxo-1,2-dihydroquinoline-7-yl, 3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl or 3-oxo-2,3-dihydro-4H-1,4-benzothiazol-7-yl, which may have up to three substituents selected from any of the substituents listed above for Ar1and other than oxo or thioxo-Vice, and A1X1, Ar2, R1, R2and R3take any of the above values for them;1 A1represents a simple bond with X1and X1is oxygraph, tigroup, sulfinil or sulfonyl, and Ar1, Ar2, R1, R2and R3accept whatever is given to them above values;

/m/ A1is methylene and X1is oxygraph, tigroup, sulfinil or sulfonyl, and Ar1, Ar2, R1, R2and R3accept whatever is given to them above values;

/n/ Ar2represents a 2,4 - or 2,5-furillen or 2,4 - or 2,5-Tianjin, which may have a Deputy, selected from: methyl, fluorine, chlorine and metoxygroup, and Ar1, AUP> represents a 2,4 - or 2,5-furillen or 2,4 - or 2,5-Tianjin, which may have a Deputy, selected from: methyl, fluorine, chlorine, bromine and metoxygroup, and Ar1, A1X1, R1, R2and R3take the meanings given to them above;

/p/ R1represents methyl, ethyl, allyl or 2-PROPYNYL, and Ar1, A1X1, Ar2, R2and R3take any of the above values for them;

/q/ R2and R3together form a group of the formula: -A2-X2-A3- which together with the carbon atom to which attached AND2and A3forms a cycle with 5 to 7 atoms in the cycle, where A2and A3that may be the same or different, each is methylene, ethylene and trimethylene, and X2is oxygraph, and this cycle may have one or two substituent selected from: hydroxyl, methyl, ethyl, propyl, metoxygroup and ethoxypropan, and Ar1, A1X1, Ar2and R1take any of the above values;

/r/ R1and R2together form a group of the formula: -A2-X2-A3- which together with the oxygen atom attached to A2and the carbon atom to which connected is different, each represents a methylene or ethylene and X1is oxygraph, and this cycle may have one, two or three substituent selected from: methyl, ethyl and propyl, and R3represents methyl or ethyl, and Ar1, A1X1and Ar2take any of the above values for them,

or pharmaceutically acceptable salts of these compounds.

Featured compounds of the invention include heterocycles the compounds of formula 1,

where Ar1represents phenyl or naphthas-2-yl, which may have one or two substituent selected from: fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, metoxygroup, trifloromethyl, 2-cyanoprop-2-yl, phenyl and benzoyl, and phenyl or benzoyl may be substituted by one Deputy, selected from: chlorine, methyl and metoxygroup;

A1represents a simple bond with X1or methylene;

X1is oxygraph, tigroup, sulfinil or sulfonyl;

Ar2represents a 2,4 - or 2,5-furillen or 2,4 or 2,5-tienlen;

R1represents methyl, ethyl, allyl or 2-PROPYNYL;

R2and R3together form a group of the formula: -A2-X2-A3- which together with the carbon atom, to which delivered oxygraph, and this cycle may be substituted by one or two substituents selected from: methyl and ethyl;

or R1and R2together form a group of the formula: -A2-X2-A3- which together with the oxygen atom attached to AND2and the carbon atom that is attached AND3forms a cycle with 5 atoms in the cycle, where a2is methylene, AND3is methylene and X2is oxygraph, and this cycle may have one, two or three substituent selected from: methyl and ethyl, and R3represents methyl or ethyl; or a pharmaceutically acceptable salt of these compounds.

Additional recommended compounds of the invention include heterocycles the compounds of formula 1,

where Ar1is 2-Oxendine-5-yl, 2,3-dioxindole-5-yl, 2-oxo-2,3-dehydrobenzperidol-5-yl, 2-oxo-2,3-dihydroisoxazole-5-yl, 2-oxo-2,3-dihydrobenzofuran-5-yl, 2-oxo-1,2-dihydroquinoline-3-yl, 2-oxo-1,2-dihydroquinoline-6-yl, 2-oxo-1,2-dihydroquinoline-7-yl, 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 have one, two or three substituent selected from: fluorine, chlorine, methyl, ethyl, 2-veratile, phenyl and benzyl;

A1
Ar2represents a 2,4 - or 2,5-furillen or 2,4 - or 2,5-Tianjin;

R1represents methyl, ethyl, allyl or 2-PROPYNYL;

R1and R3together form a group of the formula: -A2-X2-A3- which together with the carbon atom to which attached AND2and A3forms a cycle with 5 or 6 atoms in the cycle, where a2is oxygraph, and this cycle may have one or two substituent selected from: methyl and ethyl;

or R1and R2together form a group of the formula: -A2-X2-A3- which together with the oxygen atom attached to A2and the carbon atom that is attached AND3forms a cycle with 5 atoms in the cycle, where a2is methylene, AND3is methylene and X2is oxygraph, and this cycle may have one, two or three substituent selected from: methyl and ethyl, and R3represents methyl or ethyl;

or pharmaceutically acceptable salts of these compounds.

Additional recommended compounds of the invention include heterocycles the compounds of formula 1,

where Ar1represents phenyl which may have a Deputy, selected from: fluorine, chlorine, METI and Ar1is naphthas-2-yl, which may have a Deputy, selected from: fluorine, chlorine and methyl;

A1represents a simple bond with X1or methylene;

X1is oxygraph, tigroup, sulfinil or sulfonyl;

Ar2is a 2.5 furillen or 2.5-tienlen;

R1represents methyl, ethyl or allyl;

R2and R3together form a group of the formula: -A2-X2-A3- which together with the carbon atom to which attached AND2and A3forms a cycle with 5 or 6 atoms in the cycle, where a2is ethylene, AND3is methylene or ethylene and X2is oxygraph, and this cycle may have a Deputy, selected from: methyl and ethyl;

or pharmaceutically acceptable salts of these compounds.

Additional recommended compounds of the invention include heterocycles the compounds of formula 1,

where Ar1represents phenyl which may have a Deputy, selected from: fluorine, chlorine, methyl, tert-butyl, phenyl, benzoyl, benzyl or a-diferenzia, and phenyl, benzoyl, benzyl or a-diferensial may be substituted by fluorine or chlorine, or Ar1is naphthas-2-yl, which is or methylene;

X1is oxygraph, tigroup, sulfinil or sulfonyl;1 Ar2is a 2.5 furillen or 2.5-tienlen;

R1represents methyl, ethyl or allyl;

R2and R3together form a group of the formula: -A2-X2-A3- which together with the carbon atom to which attached AND2and A3forms a cycle with 5 or 6 atoms in the cycle, where a2is ethylene, AND3is methylene or ethylene and X2is oxygraph, and this cycle may have a Deputy, selected from: methyl and ethyl;

or pharmaceutically acceptable salts of these compounds.

Additional recommended compounds of the invention include heterocycles the compounds of formula 1,

where Ar1represents phenyl which may have a Deputy, selected from: fluorine, chlorine, methyl, tert-butyl, phenyl, benzoyl, benzyl, a-diferencia or a--hydroxybenzyl, and five listed last substituents can have up to five substituents selected from: fluorine, chlorine or trifloromethyl, or Ar1is naphthas-2-yl, which may have a Deputy, selected from: fluorine, chlorine and methyl;

A1is simple with>Ar2is a 2.5 furillen or 2.5-tienlen;

R1represents methyl, ethyl or allyl;

R2and R3together form a group of the formula: -A2-X2-A3- which together with the carbon atom to which attached AND2and A3forms a cycle with 5 or 6 atoms in the cycle, where a2is ethylene, AND3is methylene or ethylene and X2is oxygraph, and this cycle may have a Deputy selected from methyl and ethyl;

or pharmaceutically acceptable salts of these compounds.

Additional recommended compounds of the invention include heterocycles the compounds of formula 1,

where AG1is 1,3 .3m-trimethyl-2-oxoiron-yl, 1,3-dimethyl-2-oxo-2,3-dehydrobenzperidol-5-yl, 3-methyl-2-oxo-2,3-dihydrobenzofuran-6-yl, 1-methyl-2-oxo-1,2-dihydroquinoline-6-yl, 1-ethyl-2-oxo-1,2-dihydroquinoline-6-yl, 4-methyl-3-oxo,3-dihydro-4H-1,4-benzoxazin-7-yl or 2,2,4-trimethyl-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl;

A1is oxygraph, tigroup, sulfinil or sulfonyl;

Ar2is a 2.5 furillen or 2.5-tienlen;

R1represents methyl, ethyl or allyl;

R2and R3together form groix3forms a cycle with 5 or 6 atoms in the cycle, where a2is ethylene, AND3is methylene or ethylene and X2is oxygraph, and this cycle may have a Deputy, selected from: methyl and ethyl;

or pharmaceutically acceptable salts of these compounds.

Additional recommended compounds of the invention include heterocycles the compounds of formula 1, where Ar1represents 1-methyl-2-oxo-1,2-dihydroquinoline-6-yl, 1-ethyl-2-oxo-1,2-dihydroquinoline-6-yl, 1-methyl-2-oxo,2,3,4-tetrahydroquinolin-6-yl, 1-ethyl-2-oxo,2,3,4-tetrahydroquinolin-6-yl or the corresponding 2-thioxo-derivative, or Ar1is 4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl;

A1represents a simple bond with X1;

X1is oxygraph, tigroup, sulfinyl or sulfonyl;

Ar2is 2.5-tienlen;

R1represents methyl, ethyl or allyl;

R2and R3together form a group of the formula: -A2-X2-A3- which together with the carbon atom to which attached AND2and A3forms a cycle with 5 or 6 atoms in the cycle, where A2represent ethylene, AND3is methylene or ethylene and X2efticiency acceptable salts of these compounds.

Especially recommended compounds of the invention include heterocycles the compounds of formula 1,

where Ar1is 4-tert-butylphenyl or naphthas-2-yl;

A1represents a simple bond with X1;

X1is tigroup;

Ar2is 2.5-tienlen;

R1is methyl;

R2and R3together form a group of the formula: -A2-X2-A3- which together with the carbon atom to which attached AND2and A3forms a cycle with 5 or 6 atoms in the cycle, where a2is ethylene, AND3is methylene or ethylene and X2is oxygraph, and this cycle may be the methyl substituent in the alpha-position to X2;

or pharmaceutically acceptable salts of these compounds.

Especially recommended compounds of the invention include heterocycles the compounds of formula 1, where Ar1represents 1-methyl-2-oxo-1,2-dihydroquinoline-6-yl, 1-methyl-2-thioxo-1,2-dihydroquinoline-6-yl, 1-methyl-2-oxo,2,3,4-tetrahydroquinolin-6-yl, 1-methyl-2-thioxo,2,3,4-tetrahydroquinolin-6-yl or 4-methyl-3-oxo-2,3 - dihydro-4H-1,4-benzoxazin-7-yl;

A1represents a simple bond with X1;

X1pre>and R3together form a group of the formula: -A2-X2-A3- which together with the carbon atom to which attached AND2and A3forms a cycle with 6 atoms in the cycle, where a2is ethylene, AND3is ethylene and X2is oxygraph, and this cycle may be the methyl substituent in the alpha-position to X2;

or pharmaceutically acceptable salts of these compounds.

Typical recommended connection of the invention is the following heterocycles compound of formula 1 or its pharmaceutically acceptable salt:

4-/5-(4-tert-butylphenyl)Tien-2-yl/-4 - methoxyacridine.

More particularly, the recommended connection of the invention can be any of the following heterocycles compounds of formula 1 or their pharmaceutically acceptable salts:

4-methoxy-4-/5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl-thio) Tien-2-yl/tetrahydropyran,

4-methoxy-4/5-(1-methyl-2-oxo-1,2-dihydroquinoline-6-yl-thio)- Tien-2-yl/tetrahydropyran,

4-methoxy-4-/5-(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-yl-thio) Tien-2-yl/tetrahydropyran,

4-methoxy-4-/5-(4-methyl-3-oxo-2,3-dihydro-4H-1,4 - benzoxazin-7-yl-thio)Tien-2-yl/ASS="ptx2">

More particularly, the recommended connection of the invention is the following heterocycles compound of formula 1 or its pharmaceutically acceptable salt:

4-/5-(4-(alpha-hydroxybenzyl)penalty)Tien-2-yl/-4 - methoxy-tetrahydropyran.

Compounds of the invention, including heterocycles the compounds of formula 1 or their pharmaceutically acceptable salts can be obtained by any known method, applicable to obtain the similar structure of the compounds. Such techniques are provided as an additional characteristic of the invention and are illustrated by the following representative examples in which, unless otherwise specified, Ar1, A1X1, Ar2, R1, R2and R3take any specified for them above values.

/a/ Attaching, preferably in the presence of reasonable grounds, the compounds of formula: Ar1-A1-X1-H to the compound of formula II, where Z is a replaceable group, provided that when Ar1, R2or R3there is an amino group, alkylamino or hydroxyl, then they can be protected by a conventional protecting group or these groups do not require protection, but in subsequent unwanted protective group in A is, for example, a halogen or sulfonyloxy, such as fluorine, chlorine, bromine, iodine, methanesulfonate - or toluene-n-sulfonyloxy.

Examples of acceptable reasons for the reaction of compounds include, for example: a carbonate of alkali or alkaline earth metal, WITH1- C4-alkoxide, hydroxide or hydride of an alkaline or alkaline-earth metal, e.g. sodium carbonate, potassium hydroxide, sodium hydride or potassium hydride, or an ORGANOMETALLIC base such as: C1- C4-alcolici, for example: n-utillity. The reaction of the compound is usually carried out in acceptable inert solvent or diluent, for example: N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidine-2-one, dimethyl sulfoxide, acetone, 1,2-dimethoxyethane and tetrahydrofuran and in the temperature range 10 150oC, usually under 100oC or so.

Generally, the reaction can be carried out in the presence of an appropriate catalyst, for example, a metal catalyst such as palladium /0/ or copper /1/, for example: tetrakis - triphenylphosphine/palladium, copper chloride /1/ or copper bromide /1/.

Acceptable protective group for amino or alkylamino group is, for example, the acyl hrxtuanal, etoxycarbonyl or tert-butoxycarbonyl/ arylethoxysilanes /especially benzyloxycarbonyl/ or aroyl /especially benzoyl/. Conditions of removal of the above protective groups, of course, vary depending on the selected protection group. So, for example, acyl, such as alkanoyl, alkoxycarbonyl or aroyl may be removed, for example, by hydrolysis in the presence of an acceptable base, such as hydroxide of alkali metal such as lithium hydroxide or sodium. Or acyl, such as tert-butoxycarbonyl may be removed, for example, processing acceptable acid, such as hydrochloric, sulfuric, phosphoric or triperoxonane acid, and arylethoxysilanes, such as benzyloxycarbonyl may be removed, for example, by hydrogenation over a catalyst such as palladium on coal.

Acceptable protective group for hydroxyl is, for example, acyl, such as: C2C4-alkanoyl /especially acetyl, aroyl /especially benzoyl/ or arylmethyl /especially benzyl/. Conditions of removal of the above protective groups will vary depending on the selected protection group. So, for example, acyl, such as alkanoyl or aroyl may be removed, for example, by hydrolysis acceptable bases of the benzyl may be removed, for example, by hydrogenation over a catalyst such as palladium on coal.

The initial compounds of the formula: Ar1-A1-X1-H and 11 can be obtained by standard methods of organic chemistry. So, for example, if you want the original compound of the formula: Ar1-SH, it can be obtained, for example, by reaction of the heterocyclic fragment of the formula: Ar1-H, according to the above definition, with haloalkaliphilic means, such as, for example, chlorosulfonic acid in an acceptable solvent or diluent, such as dichloromethane or pyridine in the temperature range, for example 40 150oC, usually under 100oC or so. The resulting intermediate compound of the formula: Ar1-SO2-Cl can be restored in the compound of the formula: Ar1-SH using conventional reducing agents, such as, for example, acceptable healing metal salt such as the halide of the metal, such as tin halide, usually the chloride of tin /IV/ acceptable solvent or diluent, such as2- C4-albanova acid, for example acetic acid, for example, in the temperature range 40 to 150oC, typically at 80 to 100oC. Or reducing agent can serve as the reception is native, sulfuric and phosphoric acid, in a temperature range of, for example, 10 to 150oC, usually under 100oC or so. Or reducing agent may serve three /C1C4-alkyl/ silicalite, usually trimethylsilylmethyl in an acceptable solvent or diluent such as methylene chloride at room temperature or thereabouts.

Typically, the intermediate compound of formula 11, where Z, Ar2, R1, R2and R3take the above values can be obtained from compounds of the formula: Z-Ar2-Y, where Z and Ar2take the above meanings and Y represents, for example: halogen, formyl, alkanoyl, nitrile or alkoxycarbonyl that shown in the accompanying diagram 1 ( see below)

You must also specify that an intermediate compound of formula 11 can be obtained from compounds of formula Z-Ar2-Y, defined above, by changing the order of introduction of the groups R2and R3used according to scheme 1.

/b/ the Compound of the formula Ar1-A1-X1-Z, where Z represents tigroup, Z can represent a group of the formula: Ar1-A1- X1- with ORGANOMETALLIC reagent of formula III, where M represents an alkali metal or alkaline-earth metal, tcto, if Ar1, R2and R3there is amino or alkylamino, or hydroxyl, then these groups may be protected by conventional protective groups according to the definition above, or such groups do not require protection, then any unwanted group in Ar1, R2or R3remove by conventional methods.

The reaction of the compound is usually carried out in acceptable inert solvent as described above, in the temperature range, for example, from -80 to +50oC, usually in the range of from -80oC to room temperature.

Synthesis of starting compounds of the formula: Ar1-A1- X1-Z and III are shown in the attached non-limiting the invention to the examples given only for the purpose of illustration. Or such parent compound can be derived by standard methods of organic chemistry.

/c/ Compound preferably in the presence of acceptable reasons described above the compounds of formula IV with the compound of the formula: Ar1-A1-Z, where Z is vysokorentabelnoy replaceable group, provided that, if Ar1, R2or R3there is an amino group, alkylamino or hydroxyl, these groups can the donkey which all sorts of junk protective group in Ar1, R2or R3remove by conventional methods.

The reaction accession is usually carried out in acceptable inert solvent as described above, in the temperature interval, for example 10 150oC, usually under 100oC or so. The reaction can be carried out in the presence of acceptable vysokoreaktsionnogo catalyst.

Starting compound of the formula Ar1-A1-Z and of the formula IV can be obtained by standard methods of organic chemistry. The initial compounds of formula IV can be obtained by methods similar to the methods shown in the accompanying diagram II (see below) or by modification of these methods, it is quite within the competence of the ordinary organic chemist.

Acceptable protective group R4shown in scheme II may be any known group used for these purposes, including appropriate protective group as described above. Examples of such groups is shown in scheme II. Conditions for the introduction and removal of protective groups are given in the standard manuals on organic chemistry such as, for example, "Protective groups in organic synthesis", T. w. Green /J. Willy and sons, 1981/.

/d/ Alkylation, preferably in
-Z, where R1and Z take values above, provided that if Ar1X1, R2or R3there is an amino group, aminogroup, alkylamino or hydroxyl, then such group may be protected by conventional protective groups, or such groups do not require protection, then all sorts of junk protective group in Ar1X1, R2or R3can be removed by conventional methods.

Acceptable protective group for aminogroup may be any protective group, as listed above to protect the amino - or alkylamino.

Used as the source connection of the tertiary alcohol of the formula Y can be obtained by standard methods of organic chemistry. The synthesis of these starting compounds are shown in the attached not limiting the invention to the examples which are given merely to illustrate the invention. Typically, as shown in the accompanying diagram III (see the end of the description), to obtain the source of the tertiary alcohol of the formula Y can be used in the intermediate compounds of the formula: Ar1-A1-X1-Ar2-Y, where Ar1, A1X1and Ar2take the above meanings and Y represents, for example halogen, Faure>
together form a group of the formula: -A2-X2-A3- which together with the oxygen atom attached to AND2forms a cycle c of 5-7 atoms in the cycle, where A2X2and A3take the above values and where R3accept above values, carry out the cyclization of the compounds of formula VI with an appropriate aldehyde or ketone, or their polyacetylene and acetals, or with the compound of the formula: Z-A2-X, where Z takes values above, provided that, if Ar2or X1there is an amino group, aminogroup, alkylamino or hydroxyl, the group protects customary protective groups, after which all sorts of junk protective group in Ar1or X1remove by conventional methods.

The cyclization of the compounds of formula VI with an appropriate aldehyde or ketone or their polyacetylene or acetals usually carried out in the presence of acceptable acids. Examples of acceptable for the reaction of cyclization of the acid include inorganic acids such as hydrochloric, sulfuric or phosphoric acid or organic acids, such as n-toluensulfonate or triperoxonane acid. The cyclization reaction is usually not. It is recommended to carry out the reaction of the appropriate aldehyde or ketone, or their polyacetale or acetals and as a diluent, and as a reagent. The cyclization is carried out in a temperature range of, for example, 20 to 150oC, usually at the boiling point of the diluent or solvent or so.

The cyclization of the compounds of formula VI with the compound of the formula Z-A2-Z is usually carried out in the presence of an acceptable reason as described above.

Used as the source of the product is a tertiary alcohol of the formula VI can be obtained by standard methods of organic chemistry. Typically, and as shown in the accompanying diagram IV (see below), in obtaining the source of the tertiary alcohol of the formula VI can be used in the intermediate compounds of the formula: Ar1- A1-X1-Ar2-Y, where Ar1, A1X1, Ar2and Y agree to the above values.

Use acceptable protective group, R4above.

/f/ To obtain the compounds of formula 1, where X1is sulfinil or sulfonyl and where R2and R3together form a group of the formula: -A2-X2- A3and X2is UP>2is sulfinil or sulfonyl, carry out the oxidation of the compounds of formula 1 where X1is tigroup, where R2and R3together form a group of the formula-A2-X2- A3and X2is tigroup or, where R1and R2together form a group of the formula-A2-X2-A3-, and X2is tigroup.

As oxidant accept any oxidizer, known for the ability to oxidize tigroup in sulfinil and/or sulfonyl, such as hydrogen peroxide, nagkalat /such as 3-chlormadinone or peracetic acid/ peroxosulfates alkali metal such as peroxymonosulfate potassium, chromium trioxide or gaseous oxygen in the presence of platinum. To reduce the risk of pereokislenie and damage to other functional groups, oxidation, as a rule, carried out in may mild conditions by applying the necessary stoichiometric amount of oxidant. Usually the reaction is carried out in an acceptable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tertBUTYLPEROXY ether, at a temperature of, for example, close to the room temperature, i.e. in the range of 15 to 35oC. If primer, metaperiodate sodium or potassium hydroxide in a polar solvent such as acetic acid or ethanol. It must be emphasized that to obtain the compounds of formula 1 with sulfonyloxy group can oxidize appropriate alvinlee derived, as well as the corresponding diprosone.

/g/ To obtain the compounds of formula 1, where Ar1has an available nitrogen atom alkyl or substituted alkyl substituent, or Ar2is alkoxy, Deputy, in this case, carry out the alkylation of the compounds of formula 1, where Ar1has hydrogen in available nitrogen atom, or where Ar2has as a substituent a hydroxyl.

For alkylation can be used any alkylating agent used, for example, alkylation of available nitrogen atom, or for the conversion of the hydroxyl to alkoxygroup, for example, alkyl or substituted alkylamide, such as C1C4-alkylchloride, -bromide or iodide or a substituted C1C4-alkylchloride, -bromide or-iodide in the presence of reasonable grounds. Acceptable grounds for alkylation reaction is, for example, a carbonate of alkali or alkaline earth metal, sodium hydroxide, potassium hydroxide, hydride nutrovita, for example N,N-dimethylformamide, dimethyl sulfoxide, acetone, 1,2 - dimethoxyethane or tetrahydrofuran, in a temperature range of 10 to 150oC, typically at room temperature or thereabouts.

/h/ To obtain the compounds of formula 1, in which Ar1has one or more thioxo-deputies carry out the reaction heterocyclization the compounds of formula 1, in which Ar1has one or more oxo-substituents, with the reagent datirovaniya, resulting in each oxo-Deputy turns into thioxo Deputy, provided that, if Ar1X1, Ar2, R2or R3there is an amino group, aminogroup, alkylamino or hydroxyl, then these groups may be protected by conventional protective groups, or these groups do not require protection, then unwanted protective group in Ar1X1, Ar2, R2or R3can be removed by conventional methods.

As a reagent datirovaniya accept any reagent known for the ability to turn oxo-group in thioxo group, such as, for example 2,4-bis/4-methoxyphenyl/- 1,3-dithia-2,4-diphosphate-2,4-disulfide /reagent Lassana/ or pentasulfide phosphorus. The reaction datirovaniya usually Denia other functional groups. Typically, the reaction is carried out in an acceptable solvent or diluent, such as toluene, xylene or tetrahydrofuran, for example, at the boiling temperature of the solvent or diluent or so, i.e. in the range of 65 to 150oC.

/i/ To obtain the compounds of formula 1, in which Ar1has one or more possibly substituted-hydroxybenzyl deputies carry out the reaction heterocyclization the compounds of formula 1, in which Ar1has as substituents one or more halogen atoms, with a metal, such as magnesium or WITH1C4-alkyllithium reagent, such as n-utility with the formation of the ORGANOMETALLIC reagent, which enter into reaction with possibly substituted benzaldehyde, provided that if Ar1X1, Ar2, R2or R3there is an amino group, aminogroup, alkylamino or hydroxyl, the group protects customary protective groups, or these groups do not require protection, then all sorts of junk protective group in Ar1X1, Ar2, R2and R3remove by conventional methods.

/j/ To obtain the compounds of formula 1, in which Ar1has one or more possibly substituted neskolko possibly substituted a-hydroxybenzyl deputies.

As oxidant is acceptable, for example, any oxidizing agent, which is known for the ability to oxidize a secondary alcohol to a ketone, for example, chromium reagent such as chlorproma pyridinium/. Generally, the oxidation is carried out in an acceptable solvent or diluent such as methylene chloride or chloroform, for example, at room temperature or thereabouts, i.e. in the range of 15 to 35oC.

To obtain pharmaceutically acceptable salts of the new compounds of formula 1 carry out the reaction of this compound with acceptable bases or acids in the usual manner. If you want to obtain optically active form of compounds of formula 1, then hold one of the above reactions using optically active starting products or divide in the usual manner racemic form of the compound of formula 1.

Many described here intermediates are novel, for example, compounds of formulas V and VI, and these connections are provided as an additional characteristic of the invention.

As mentioned previously, the new compounds of formula 1 are inhibitors of the enzyme 5-LO. The effect of such inhibition can be demonstrated using one or more of trophotometric system test im enzymes vitro, which identifies inhibiting properties of the test compound in a cell-free system using 5-LO, isolated from neutrophils of Guinea pigs. In this test get the measure inherent to the subject the compound inhibiting properties with respect to soluble 5-LO in extratone environment.

b/ System testing in vitro, comprising the incubation of test compounds with humanitariannet human blood before the reaction with iodoform A calcium with subsequent indirect measurement of the inhibitory effect on 5-LO by identifying the number of fully4the use of specific radioimmunoassay described Carey u Forder (F. Carey u R. A. Forder, Prostaglandins, Zeukotrienes Med. 1986, 22, 57 Prostaglandins, 1984, 28, 666; Brit. J. Phormacol. 1985, 84, 34P/, which includes the use of a conjugate protein-fully4obtained by the method of Joung and other Prostaglandins, 1983. 26/4/, 605-613/. The effect of the test compound on the enzyme cyclooxygenase (which is involved in the alternative pathway of arachidonic acid metabolism with the formation of prostaglandins, thromboxanes and related metabolites) can be measured at the same time, the use of specific radioimmunoassay on the thromboxane2/TXV2/ described Carey u Forder (see above). outstay blood cells and proteins. The test allows to detect the selective inhibitory effect on 5-LO or cyclooxygenase.

c/ System tests in vivo, which is a modification of the test of/ that include the introduction of the test compound (usually administered orally in the form of a suspension obtained by adding a solution of the test compound in dimethyl sulfoxide to the carboxymethyl cellulose), blood collection, heparinization, the reaction with A and radioimmunoassay fully4and TXV2. This test provides an indication of the bioavailability of the test compound as an inhibitor of 5-LO or cyclooxygenase.

d/ System in vitro tests, including the measurement of inhibiting properties of the test compounds in relation to the selection LTS4and PIUS2induced simhasanam on peritoneal resident macrophages of the mouse according to the method Humes (J. Z/ Humes and others Biochem Pharmacol 1983, 32, 2319-2322) and conventional systems radioimmunoassay for measuring LTS4and PIUS2. This test provides an indication of the inhibitory effect on 5-LO and cyclooxygenase in non-protein system.

e/ System in vivo, including the definition of the action of the test compounds on the inhibition of inflammatory reactions of arachidonic kislota inhibitors of 5-LO, input into the eyes or mouth.

f/ System in vivo, including the definition of the action of the test compound, administered orally or intravenously, dependent on the leukotriene bronchostenosis caused by the presence of antigen in Guinea pigs previously received a dose of antihistamine (mepyramine), b-adrenergic blocking agents (propranolol) and inhibitor of cyclooxygenase (indomethacin), by the method of W. H. Anolerson and others (British J. Pharmacology, 1983, 78/1/, 67-574/. This test provides additional in vivo test for the detection of inhibitors of 5-LO.

g/ System in vivo, including the definition of the action of the test compound, administered orally, allocation is fully4caused simhasanam inside the air pocket created within the subcutaneous tissue on the back of male rats. Rats anaesthetize and air pockets formed by the injection of sterile air (20 ml). After 3 days performed similarly additional injection of air (10 ml). 6 days after the initial injection of air injected with the test compound (usually administered orally in the form of a suspension obtained by adding a solution of the test compound in dimethyl sulfoxide to the hypromellose) and then injects, air pockets are washed with physiological saline solution and to identify in the wash solutions is fully4carry out the above-described specific radioimmunoassay. This test provides an indication of the inhibitory activity against 5-LO in the inflamed environment.

Although, as expected, the pharmacological properties of the compounds of formula 1 are changed depending on changes in their structure, however in General, the compounds of formula 1 possess inhibitory against 5-LO activity in the following concentrations or doses in one or more tests a/-/:

Test a/: IR50in the interval, for example, 0.01 to 30 microns;

Test b/ IR50/FULLY4/ in the interval, e.g. 0.01 to 40 μm; IR50/TXV2/ in the interval, e.g. 40 200 microns;

Test/: oral ED50/FULLY4/ in the interval, for example, 0.1 to 100 mg/kg;

Test d/ IR50>/LTS4/ in the interval, e.g. 0.001 to 1 μm, IR50/PGE2/ in the interval, e.g. 20 to 1000 microns;

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

Test f/: ED50in the interval, for example, 0.5 to 10 mg/kg centuries

Test g/: oral ED50in the interval, for example, cal/, e/ f/ and/g/ with the introduction of compounds of formula 1 in quantities that exceed the minimum inhibiting dosage or concentration.

So, as an example, the compound 4-/5-(4-tert-butylphenyl)Tien-2-yl/-methoxyethylamine is set IR50of 0.15 μm with respect to fully4in test b/ and the value of oral ED501.5 mg/kg compared to fully4in test g/, and the compound 4-methoxy-4-/5- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl-thio)Tien-Il/tetrahydro - operon is set IR500,04 µm in relation to fully4in test b/ and the value of oral ED50< 1.5 mg/kg compared to fully4in test g/. In General especially recommended compounds of formula 1 have values IR50< 1 μm against fully4in test b/ and the values of the oral ED50< 100 mg/kg on fully4in tests/ and/or / g/.

These compounds are examples of compounds of the invention, showing a selective inhibiting effect on 5-LO, but not for cyclooxygenase, and such selective properties are expected to give the compounds of improved therapeutic quality, for example, the reduction or elimination of gastro-kylechristie with another characteristic of the invention provides the pharmaceutical composition, including heterocycles compound of formula 1 or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable diluent or carrier.

This composition may be in the form acceptable for oral administration such as tablets, capsules, aqueous or oily solution, suspension or emulsion; for use locally, for example: cream, ointment, gel or aqueous or oily solution or suspension; for use through the nose, such as dowani, sosalnyh sprays or sosalnyh drops; for use vaginally or rectally, for example, suppository; for administration by inhalation, for example, in the form of fine powder or a liquid aerosol; for use sublingual or transbukkalno, such as tablets or capsules; for parenteral use (including intravenous, subcutaneous, intramuscular, vnutrisosudisto or infusion/, for example, sterile aqueous or oily solution or suspension. Generally, the above compositions can be prepared in the usual way using conventional fillers.

The number of active component (i.e. heterocyclization the compounds of formula 1 or its pharmaceutically acceptable salt), which are mixed by depending on a subject to treatment of the patient and the particular route of administration to a person, as a rule contain from 0.5 mg to 2 g of active funds, mixed with the corresponding normal amount of fillers that can be 5 to 98% of the mass. from the whole composition. Dosage unit form usually contains 1 to 500 mg of the active component.

In accordance with another characteristic of the invention is given heterocycles compound of formula 1 or its pharmaceutically acceptable salt, intended for the treatment of human or animal by his treatment.

The invention also includes a method of treatment of a disease or medical condition that is generated wholly or partly by one or more leukotrienes, the method consists in the introduction of a warm-blooded animal in need of such treatment, an effective amount vysokoreaktsionnogo active component. The invention also provides the use of such active ingredient in getting new drugs intended for use in the event created leukotrienes diseases or medical symptoms.

The size of the dose of the compounds of formula 1 for therapeutic or prophylactic purposes, of course, will vary depending on the nature and severity of symptoms, age and PoE, the compounds of formula 1 are applicable for the treatment of allergic and inflammatory symptoms that arise solely or partially due to the effects of metabolites of arachidonic acid arising by the linear (catalyzed by 5-LO) scheme, in particular, leukotrienes, which promotes the formation of 5-LO. As mentioned earlier, such symptoms include, for example, asthma symptoms, allergic reactions, allergic rhinitis, allergic shock, atopic dermatitis, psoriasis, cardiovascular disorders and abnormalities in the blood vessels of the brain inflammatory disorders, arthritic and inflammatory joint diseases and inflammatory bowel disease.

When using the compounds of formula 1 for therapeutic or prophylactic purposes it is usually injected in such quantities that the daily dose is in the range of 0.5 to 75 mg per kg of body weight, if necessary, this dose is administered single doses. Generally, parenteral requires a smaller dose. For example, when administered intravenously is usually used dose 0.5

30 mg per kg of body weight. Likewise, when the introduction of inhalation use a dose in the range of 0.5 to 25 mg per kg of body weight.

Although the connection fnih (including humans), these same compounds are used in all those cases when it is necessary to inhibit the enzyme 5-LO. Thus, these compounds applicable as pharmacological standards required for the creation of new biological tests and the search for new pharmacological agents.

Due to its ability to influence the formation of leukotrienes compounds of formula 1 possess some cytotoxity action, for example, they are applicable to reduce or suppress certain undesirable gastrointestinal effects created any abscopal cyclooxygenase nesteroidnymi anti-inflammatory drugs (ICDPS), such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin, piroxicam. In addition, co-administration of an inhibitor of 5-LO formula 1, ACNPS can reduce the number required to create a therapeutic effect, and thus to decrease the likelihood of unwanted side effects. In accordance with another characteristic of the invention provides a pharmaceutical composition comprising heterocycles compound of formula 1 or its pharmaceutically acceptable salt as described above, in combination or mixed with armaceuticals acceptable diluent or carrier.

Chitosamine action of the compounds of formula 1 can be shown, for example, in standard laboratory test, which revealed protection caused by indometacinum or ethanol ulceration in the gastrointestinal tract of rats.

Compositions of the invention can optionally include one or more therapeutic or prophylactic agents, obviously valuable for the treatment of this disease. For example, a known inhibitor of platelet aggregation, lipid-lowering agent, remedy for high blood pressure, beta-adrenergic blocker or vasodilator can be successfully used in the compositions of the invention intended for the treatment of cardiac or vascular diseases or symptoms. Similarly, in the example, antihistamine, steroid (such as the dipropionate of beclometasone), sodium cromoglycate, a phosphodiesterase inhibitor or a beta adrenergic stimulator with success can be entered in the pharmaceutical composition of the invention intended for the treatment of lung diseases or symptoms.

The invention is further illustrated by the following not limiting examples in which, unless otherwise specified:

/1/ IP is s solids by filtration;

/II/ operation is carried out at room temperature, i.e. at 18 - 25oC and in an atmosphere of inert gas, such as argon;

/III/ column chromatography /pressurization method/ and liquid chromatography medium pressure /RHSD/ carry on Markowski Kiselevoy oxide /silicon Art. 9385/ or on MicroPrep RP-18 /Art. 9303/ oxide silicon inverted phases, manufactured by E. Merck, Darmstadt, Germany;

/IV/ output is given only for the purpose of illustration, and are not necessarily the maximum attainable;

/V/ final products of formula 1 are satisfactory microanalysis, and their structure confirmed by NMR and mass spectral techniques;

/VI/ intermediate compounds is not always completely characterized, and their purity reveal thin-layer chromatography, infrared /IR/ or NMR analysis;

/VII/ the melting temperature was not adjusted and was determined at the device by Mettler SP62 automatic melting point or device with an oil bath; the melting point of the final products of formula 1 were determined after crystallisation from a conventional organic solvent, such as ethanol, methanol, acetone, ether or hexane in pure form or in mixture shall lipoxin;

DMF N,N-dimethylformamide;

DMA N,N-dimethylacetamide.

EXAMPLE 1. To a solution of 4-/5-(4-tert-butylphenyl)Tien-2-yl/- 4-hydroxymitragynine /0,285 g/ THF /10 ml/ portions add sodium hydride /60% wt./ mass. in mineral oil, 0,065 g/ and the mixture is stirred for 30 min at room temperature. Add methyliodide /0,213 g/ and the mixture was stirred for 12 h at room temperature. The mixture is transferred into a cold saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase is dried /MgSO4/ and evaporated. The residue is purified by column chromatography using as eluent a mixture of methylene chloride-diethyl ether /19:1. /about. / The result is the 4-/5-(4-tert-butylphenyl)-Tien-2-yl/-4-methoxyacridine /0,275 g, 95%/ in the form of butter.

NMR spectrum /CDCl3values d/:1.3M /s, 9H/, 1,9 2,15 /m, 4H/, 3,05 /c, 3H/, 3,7 3,9 /m, 4H/, 6,8 7,4 /m, 6N/.

Used as the source of the product 4-/5-(4-tert-butylphenyl)Tien-2-yl)-4-hydroxyethylamino obtained as follows.

A mixture of copper /1/ salts 4-tert-butylaniline /2.5 g, obtained by heating a mixture of copper oxide /1/ /4.3 g/, 4-tert-butylaniline /5 g/ ethanol /25 ml/ to the boil for 3 hours and filtering/, 2-idioten /2.3 g/, pyrid elaut between 6 N. aqueous hydrochloric acid and ethyl acetate. The organic layer is dried /MgSO4/ and evaporated. The residue is purified by column chromatography using as eluent a mixture of chloride methylamphetamine ether /so Kip. 40 60oC/ /19:1.about./. The result is 4-tert-butylphenyl-2-thienylmethyl /1,15 g, 43% of/ in the form of butter.

To a solution of the obtained product /0.5 g/ THF /10 ml, cooled to -30oC, are added dropwise n-utility /1.6 M in hexane, 1.25 ml/ and the mixture is stirred for 1 h at -20oC. the mixture is Then cooled to -78oC and added dropwise tetrahydropyran-4-one /0.2 g/. The mixture is stirred 58 h and allowed to warm to room temperature. The mixture is partitioned between cold saturated aqueous ammonium chloride and ethyl acetate. The organic layer is dried /MgSO4/ and evaporated. The residue is purified by column chromatography using as eluent a mixture of methylene chloride-diethyl ether /9:1 vol. /about. /. The result is the target source connection /0,305 g, 44%/, so pl. 112oC.

EXAMPLE 2. According to the method described in example 1, the reaction of 4 - hydroxy-4-/5-(naphthas-2-yl-thio)Tien-2-yl/tetrahydropyrane with methyliodide with the release of 81% is obtained 4-methoxy-4-/5- (naphthas-2-yl-thio)-Tien-2-yl/tet the l-thio)Tien-2-yl/tetrahydropyran obtained as follows.

Reproduced by the method of example 1 shown in that part of it which relates to the receipt of the original product, but using 2-naphthalenethiol instead of 4-tert-butylaniline and 2-bromothiophene instead of 2-idioten.

The result: a 2-naphthyl-2-thienylmethyl, yield 45% so pl. 77 - 79oC source and target product, yield 67% so pl. 130oC.

EXAMPLE 3. According to the method of example 1 by reaction of 4-hydroxy-4-/5- (naphthas-2-yl-thio)FSD-2-yl/tetrahydropyrane with methyliodide with the release of 92% is obtained in the form of oil 4-methoxy-4-/(5-(naphthas-2-yl-thio)FSD-2-yl/ tetrahydropyran.

NMR spectrum (CD3OCD3values d/: 1,9 2,3 /m, 4H/, 3,05 /C, 3N/, 3,45 3,9 /m, 4H/, 6,6 /d, IH/, 6,9 /d, IH/, 7,25 8 /m, 7H/.

Used as the source of the product 4-hydroxy-4 -/5-(naphthas-2-yl-thio)FSD-2-yl/tetrahydropyran obtained as follows.

A mixture of copper /1/ salt 2-naphthalenethiol /2.1 g, obtained by heating a mixture of copper oxide /1/ /0.71 g/, 2-naphthalenethiol /1.6 g/ ethanol /10 ml/ boiling 3 hours and filtering/, 2-bromofuran /1.47 g, Getrahedron b 41, 1919/, pyridine /0.5 ml/ and quinoline /7 ml/ heated 3 h at 200oC. the mixture is Then transferred into a mixture of crushed ice and 6 N. aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase promem as eluent a mixture of petroleum ether /T. the TRC. 40 -60oC/-methylene chloride /19: 1.about./. As a result, yield 52% in oil are 2-furyl-2-aftercooled.

To a solution of part /0,68 g/ resulting product is cooled in a bath with ice to 0oC, are added dropwise utility /1.6 M in hexane, 1.9 ml/. The mixture is stirred for 2.5 h at 0oC, and then added dropwise tetrahydropyran-4-one /0.3 g/. The mixture with stirring, leave to rise slowly to room temperature /20oC/ and stirred at room temperature for 12 hours the Mixture was partitioned between cold saturated aqueous ammonium chloride and ethyl acetate. The organic layer is dried /MgSO4/ and evaporated. The residue is purified column chromatography using as eluent a mixture of methylene chloride-diethyl ether /9:1 vol./about./. The result is the target source connection /0.5 g, 51%/, so pl. 120 122oC.

EXAMPLE 4. According to the method of example 1 reaction /2RS, 3RS/-3 - hydroxy-2-methyl-3-/5-(naphthas-2-yl-thio)Tien-2-yl/tetrahydrofuran with methyliodide with 75% yield in the form of oils obtained /2RS, 3RS/- 3-methoxy-2-methyl-3-/5-(naphthas-2-yl-thio)Tien-2-yl/tetrahydrofuran. NMR spectrum /CDCl3values d/: 1,29 /d, 3H/, 2,29 2,6 /m, 2N/, 3,23 /C, 3N/, 3,7 4,2 /m, 3H/, 6,93 7,78 /m, N/.

Used as what atom.

To a cooled to -78oC to a solution of 2-naphthyl-2 - tailslide /0,31 g/ THF /8 ml/ added dropwise n-utility /2.5 M in hexane, 0,512 ml/. The mixture is left to warm to 0oC and stirred at the same temperature for 1 h Then the mixture is cooled to -60oC and added dropwise 2-methyltetrahydrofuran-3-one. The mixture is left to warm to room temperature and stirred for 12 hours the mixture is Then partitioned between cold saturated aqueous ammonium chloride and ethyl acetate. The organic layer is dried /MgSO4/ and evaporated. The residue is purified column chromatography using as eluent a mixture of methylene chloride with diethyl ether /23:2 vol./about./. The result is the target source connection /a 0.23 g, 52%/, so pl. 105 107oC with CIS-configuration 2-methyl and 3-hydroxyl substituents.

EXAMPLE 5. To a cooled to -78oC n-butyllithium /1.5 M in hexane, 1 ml/ added dropwise a solution of 4-/5-Bratan-2-yl/-4 - methoxyacridine /0,415 g/ THF /1.5 ml and the mixture is stirred 2 h at -78oC. Then add a solution of di/4-bromo-phenyl)disulfide /0,564 g/ THF /1.5 ml and the mixture is stirred for 3 h at -78oC. the Mixture is left to warm to room temperature and stirred for 16 the economic phase is washed with water, dried /MgSO4/ and evaporated. The residue is purified by column chromatography using as eluent first mixture petroleum ether /so Kip. 40 60oC/-ethyl acetate /9:1 vol./about./ and then a mixture of petroleum ether-ethyl acetate /4: 1/. The result is a 4-/5-(4-pampanito)Tien-2-yl/-4-methoxyacridine /0,217 g, 38%/, so pl. 62 -63oC.

NMR spectrum /CDCl3values d/: 2 2,4 /m, 4H/, 3,06 /c, 3H/, 3,6 3,85 /m, 4H/, 7,05 7,6 /m, 6H/.

Used as the source of the product 4-(5-Bratan-2-yl)-4-methoxyacridine obtained as follows.

To a cooled to -40oC and stirred solution of 2,5-dibromothiophene /12,1 g/ THF /40 ml/ added dropwise n-utility /1.6 M in hexane, 31 ml/, after which the mixture is left to warm to -20oC and stirred at this temperature for 1 hour. The mixture is cooled to -78oC and added dropwise tetrahydropyran-4-one /5 g/. The mixture is left to warm to room temperature and stirred for 12 hours the mixture is Then transferred into a cold aqueous solution of ammonium chloride /15% wt./about./ and extracted with ethyl acetate. The organic phase is washed with water, dried /MgSO4/ and evaporated. The residue is purified column chromatography using as eluent a mixture of chlorine,16 g, 32%/, so pl. 100 - 102oC.

Part /2,48 g/ obtained product by the procedure of example 1 is introduced into the reaction methyliodide target and get the original connection /2.1 g, 80%/, so pl. 57 59oC.

NMR spectrum /CDCl3values d/: 1,9 2,2 /m, 4H/, 3,06 /C, 3N/, 3,6 3,85 /m, 4H/, 6,87 /d, IH/, 7,03 /d, IH/.

Used as a source of product di/4-bromophenyl/disulfide based methods J. Org. Chem. 1963, 28, 3246, as follows.

A solution of 4-potenitial /2 g/ heated in DMSO /5 ml/ 16 hours at 100oC. the mixture is Then transferred into ice water, the precipitate is separated and dried. The result is the target source connection /1,9 g, 95%/.

EXAMPLE 6 TO a cooled to -78oC and stir the solution Diisopropylamine /0,275 ml/ THF /2 ml/ added dropwise n-utility /1.6 M in hexane, to 1.35 ml), and the mixture is stirred for 20 min, then added dropwise a solution of 4-methoxy-4- (3-thienyl/tetrahydropyrane /0,37 g/ THF /1.5 ml/. The resulting mixture was left to slowly warm to -30oC for about 2 hours Then the mixture is again cooled to -70oC and added dropwise di-(4-tert-butylphenyl)disulfide /0,595 g/ THF / 2 ml/. The mixture is left to warm to room temperature and stirred for 12 hours Then slices phase is washed with water, dried /MgSO4/ and evaporated. The residue is purified by column chromatography using as eluent by increasing polarity mixtures of methylene chloride with diethyl ether. As a result, in the form of oil get 4-/2-(4-tert-butylphenyl) Tien-4-yl/-4-methoxyacridine /of 0.133 g, 20%/.

NMR spectrum /CDCl3values d/: 1,28 /s, N/, 1,9 2,15 /m, 4H/, 3,03 /C, 3N/, 3,7 3,95 /m, 4H/, 7 7,45 /m, 6N/.

Used as the source of the product 4-methoxy-4- (Tien-3-yl)tetrahydropyran obtained as follows.

According to the method described in Bull. Soc. Chem. Hub 1955, 84, 424, boiling mixture of magnesium /4,45 g/, 3-bromothiophene /10 g/, ethylbromide /14 ml and diethyl ether /200 ml for 1 h the resulting Grignard reagent. The mixture is cooled to room temperature and added dropwise tetrahydropyran-4-one /1.2 ml/. The resulting mixture was stirred for 12 h at room temperature, and then transferred into a cold aqueous solution of ammonium chloride /15% wt./about./ and extracted with ethyl acetate. The organic phase is washed with water, dried /MgSO4/ and evaporated. The residue is purified column chromatography using as eluent a mixture of chloride metrodetroit ether /9:1 vol./about./. The result is 4-hydroxy-4-(3-thienyl)then it is carbonated is 0.45 in/g/ of the obtained product by the procedure of example 1 is introduced into the reaction methyliodide target and get the original connection /0,468 g, 98%/, so pl. 44oC.

Used as a source of product di/4-tertbutylphenyl)disulfide obtained by the method of example 5 is shown in that part of it which relates to the production of di(4-bromophenyl) disulfide. The result with the output 96% of the target disulfide, so pl. 90oC /recrystallized from ethanol/.

EXAMPLE 7. According to the method of example 5 by reaction of 4-(5-Bratan-2-yl)-4 - methoxyacridine with di(1-methyl-2-oxo-1,2,3,4 - tetrahydroquinolin-6-yl)disulphide with the release of 55% receive 4-methoxy-4-/5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-yl-thio)Tien- -2-yl/tetrahydropyran, so pl. 84 86oC.

NMR spectrum /CDCoCD3values d/: 1,95 2,2 /m, 4H/, 2,4 3 /m, 4H/, 3,06 /C, 3N/, 3,27 /C, 3N/, 3,65 3,8 /m, 4H/, 7 7,3 /m, 5H/.

Used as a source of product di(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)disulphide obtained as follows.

A mixture of 1-methyl-1,2-dihydroquinoline-2-it /3 g/, 10% palladium on coal /2 g catalyst/ ethanol /60 ml/ stirred for 24 hours under the hydrogen pressure of 3.5 atmospheres. The mixture is then filtered and evaporated. The residue is purified column chromatography using as eluent a mixture of methylene chloride-diethyl ether /9:1 vol./about./. As a result, in the form of oil get 1-IU alsultanova acid /8 ml and the resulting mixture is heated for 2.5 hours at 80oC. the mixture is Then cooled to room temperature, transferred into ice water and extracted with ethyl acetate. The organic phase is washed with water, dried /MgSO4/ and after evaporation receive 1-methyl-2-oxo,2,3,4-tetrahydroquinolin-6-yl-sulphonylchloride /1,97 g, 76%/, so pl. 137 139oC.

NMR spectrum /CDCl3values d/: 2,7 3,25 /m, 4H/, 3,41 /C, 3N/, 7,13 /d, IH/, 7,8 8,1 /m, 2N/.

Part /1.2 g/ received product in methylene chloride /40 ml/ added dropwise trimethylsilylmethyl /5 g/ and the mixture is stirred for 16 h at room temperature. The mixture is then washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium sulfite, dried /MgSO4/ and evaporated. The residue is purified by column chromatography using as eluent a mixture of chloride metrodetroit ether /9:1 vol./about./. The result is the target disulfide /0,418 g, 43% of T. pl. 130oC.

NMR spectrum /CDCOCD3/: 2,4 3 /m, 4H/, 3,26 /c, 3H/, 6,84 /d, IH/, 7,15 7,4 /m, 2N/.

EXAMPLE 8. According to the method of example 5 carry out the reaction of di(1-methyl-oxo-1,2-dihydroquinoline-6-yl)disulfide, 4-(5-Bratan-2 - yl)-4-methoxyacridine to obtain 4-methoxy-4-/5- (1-methyl-2-oxo-1,2-dihydroquinoline-6-yl-thio)Tien-2-yl/ tetrahydropyrane, exit 19% so what, H/ 7,27 /d, IH/, 7,5 7,7 /m, 3H/, 7,75 /d, IH/.

Used as a source of product di(1-methyl-oxo-1,2-dihydroquinoline-6-yl)disulphide obtained from 2-methyl-1,2 - dihydroquinoline-2 on the methodology described in the portion of example 7, which relates to the production of di(1-methyl-2-oxo-1,2,3,4 - tetrahydroquinolin-6-yl)disulfide, except that in this case the stage of hydrogenation is not required. As a result, yield 83% receive target source connection, so pl. 222 223oC.

EXAMPLE 9. According to the method of example 5 by reaction of 4-(5-Bratan-2-yl)-4 - methoxyacridine with di(1-methyl-2-thioxo,2,3,4-tetrahydroquinolin-6-yl)disulphide exit 62% receive 4-methoxy-4-/5-(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6 - yl-Titan-2-yl/tetrahydropyran, so pl. 100 102oC.

The NMR spectrum of /CD3COCD3values d/: 2 2,2 /m, 4H/, 2,7 - 3,3 /m, 4H/, 3,07 /c, 3H/, 3,65 3,85 /m, 4H/, a 3.87 /c, 3H/,? 7.04 baby mortality of 7.3 /m, 5H/.

Used as a source of product di(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-yl)disulphide obtained as follows.

A mixture of di(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6 - yl)disulphide /1 g/, 2,4-bis(4-methoxyphenyl-1,3-dithia-2,4 - diphosphate-2,4-disulfide /reagent Lassana 0.5 g/ and toluene /10 ml/ boiled for 1 h the Mixture was evaporated, and the mod is hodom 79% /0,86 g/ get the target source connection, so pl. 180 182oC.

EXAMPLE 10. According to the method of example 5 by reaction of 4-(5-Bratan-2-yl)-4 - methoxyacridine with di(4-methyl-3-oxo-2,3-dihydro-4H1,4-benzoxazin-7-yl) - disulfide with the release of 28% receive 4-methoxy-4-/5-(4-methyl-3-oxo-2,3-dihydro-4H-1,4 - benzoxazin-7-yl-thio)Tien-2-yl/tetrahydropyran, so pl. 65 69oC.

The NMR spectrum of /CD3COCD3values d/: 1,95 2,15 /m, 4H/, 3,07 /C, 3N/, 3,31 /c, 3H/, 3,6 3,85 /m, 4H/, 4,58 /c, 2H/, 6,8 7,3 /m, 5H/.

Used as a source of product di(4-methyl-oxo-4H-1,4-benzoxazin-7-yl)disulphide obtained as follows.

A mixture of 5-fluoro-2-NITROPHENOL /of 10.05 g/, potassium carbonate /10.6 g/ and acetone /125 ml/ boil for 10 minutes the Mixture is cooled to room temperature and added dropwise to ethylbromoacetate /7,8/ ml in acetone /10 ml/. The resulting mixture was boiled for 2.5 h, then evaporated and the residue partitioned between diethyl ether and water. The organic phase is washed with water, dried /MgSO4/ and evaporated. The result is the ethyl ester of 2-(5-fluoro-2-nitrophenoxy)acetic acid /of 14.28 g, 92%/, so pl. 44 46oC.

A mixture of ethyl ester of 2-(5-fluoro-2-nitrophenoxy)acetic acid /11 g/, benzylmercaptan /5,2 g/, triethylamine /5,08 g/ and DMF /50 ml/ stirred for 7 h at 80oC. the Mixture is cooled, transferred EOM. The organic phase is washed with water and brine, dried /MgSO4/ and after evaporation receive the ethyl ester of 2-(5-benzylthio-2-nitrophenoxy)acetic acid /10.6 g, 68%/ in the form of a solid substance.

A mixture of part /8,68 d/ received product, chloride dihydrate tin /11/ Tet. Zett. 1984, 839; of 28.1 g/, ethyl acetate /5 ml/ ethanol /50 ml/ boil for 30 minutes the Mixture is transferred to the ice where add saturated aqueous sodium bicarbonate solution. The formed precipitate is filtered off and the filtrate is extracted with ethyl acetate. The organic phase is washed with water and brine, dried and after evaporation receive 7 benzylthio-3-oxo-2,3-dihydro-4H1,4-benzoxazin /3,32 g, 49%/, so pl. 153 154oC.

To a stirred suspension of sodium hydride /60% wt./ mass. the dispersion in mineral oil, 0.52 g; oil is removed by washing the solids dispersion petroleum ether/ DMF add part /2.7 g/ of the resulting product and the mixture is stirred for 30 min at room temperature. Then add methyliodide /2,13 g/ and the mixture is stirred for 30 min at room temperature. The mixture is partitioned between diethyl ether and water. The organic phase is washed with water and brine, dried /MgSO4/ and after evaporation receive 7 benzylthio-4 - methyl-3-oxo-2,3-dihydro-4H-1,4-b is forme /15 ml/, cooled to 0oC added dropwise a solution of 3-chlormadinone acid /1,72 g/ chloroform /10 ml and the mixture is stirred for 4 h at 0oC. Then add the calcium hydroxide /0.74 g/ and stirred for 15 min at room temperature. The mixture is filtered and evaporation of the filtrate obtained as solids 7-benzylmethyl-4 - methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin /2.1 g/ used without further purification.

To a stirred suspension parts /1.5 g/ received benzoxazine in methylene chloride /45 ml/ added dropwise triperoxonane acid /4,2 g/ and the resulting solution was stirred for 30 min at room temperature and then boiled for 30 minutes the mixture is evaporated and the residue is distributed between ethyl acetate and water. The organic phase is washed with water and saturated aqueous sodium bicarbonate, dried /MgSO4/ and evaporated. The residue is purified column chromatography using increasing polarity mixtures of methylene chloride-diethyl ether as eluent. The result is di(4-methyl-3-oxo-2,3-dihydro-4H1,4-benzoxazin-7-yl)disulphide /0.68 g, 60%/, so pl. 133 135oC.

EXAMPLE 11. According to the method of example 5 reaction /2S, 4R/-4-(5-Bratan-yl)-4-methoxy-2-methylthio)Tien-2-yl/-4-methoxy-2 - methyl-tetrahydropyran.

Used as the source of the product /2S, 4R/- 4-(5-Bratan-2-yl)4-methoxy-2-methyltetrahydrofuran obtained as follows.

To a stirred suspension of magnesium /0,29 g/ diethyl ether /3 ml/ added dropwise a solution of a mixture of 2,5-dibromothiophene /1,9 g/ and ethylbromide /2,56 g/ THF /6/ ml and the mixture was gently heated for promotion of education of the Grignard reagent. Then the mixture is heated 1 h at 40oC, cooled in a bath with ice, and thereto are added dropwise a solution /2S/-2-methyltetrahydrofuran-4-one /an Application for a European patent 0385662 /example 20 in the application/; 0,61 g in THF /5 ml/. The mixture is left to warm to room temperature and then stirred for 16 hours the mixture is transferred into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed with water and brine, dried /MgSO4/ and evaporated. The residue is purified column chromatography using as eluent methylene chloride, and then mixtures of increasing polarity methylene chloride-diethyl ether. The result is obtained as the less polar isomer /2S, 4R/-4-(5-Bratan-2-yl)-4-hydroxy-methyltetrahydrofuran /0,248 g, 19%/ oil transconfiguration 2-methyl and 4-hydroxyl for the. the reaction with a yield of 82% gain in the form of oil target source connection.

EXAMPLE 12. According to the method of example 5 by reaction of (2S, 4R)-4-(5 - Bratan-2-yl)-4-methoxy-2-methyltetrahydrofuran with di(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-yl)disulphide with the release of 55% gain in the form of oil (2S, 4R)-4-methoxy-2 - methyl-4-/5-(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-yl-thio)- Tien-2-yl/tetrahydropyran.

The NMR spectrum of /CD3COCD3values d/: 1,15 /d, 3H/, 1,25 - 2,25 /m, 4H/, 2,7 3,25 /m, 4H/, 3-08 /c, 3H/, 3,6 3,9 /m, 3H/, 3,85 /c, 3H/, 7,35 7 /m, 5H/.

EXAMPLE 13. According to the method of example 1 treatment 4-/5-(4-(altacebuvillagegardenresort)phenylthio)Tien-2-yl/- 4-hydroxymitragynine methyliodide exit 66% gain in the form of oil 4-/5-(4-(alpha-tert-butyldimethylsilyloxy)- phenylthio)Tien-2-yl/-4-methoxyacridine.

A mixture of the obtained product /0,58 g/, tetrabutylammonium /0.1 M in THF, 0.4 ml/ and THF /1 ml/ stirred for 16 hours at room temperature, then evaporated, and the residue is distributed between etilatsetatom and water. The organic phase is washed with water, dried /MgSO4and evaporated. The residue is purified column chromatography using as eluent a mixture of methylene chloride-diethyl ether /47:3 about pl. 109 110oC.

Used as the source of the product 4-/5- (4-(alpha-tert-butyldimethylsilyloxy)phenylthio)Thien-Il/-4-hydro - sitetracker obtained as follows.

A mixture of copper /1/ salt 4-bromperidol /of 2.51 g, obtained by boiling for 3 hours a mixture of copper oxide /1/ /1.86 g/, 4-bromo-fenistil /5 g/ ethanol /30 ml/ s followed by filtration/, 2-bromothiophene /1.2 ml/ pyridine /0.5 ml/ and quinoline /8 ml/ heated 3 h at 200oC. the mixture is Then cooled to room temperature and partitioned between 6 N. aqueous hydrochloric acid and diethyl ether. The organic phase is dried /MgSO4/ and evaporated. The residue is purified by column chromatography using as eluent a mixture of petroleum ether /so Kip. 40 60oC/-methylene chloride /19:1.about./. As a result, in the form of oil get 4-bromophenyl-2 - thienylmethyl /0,926 g, 34%/.

To gently heated to initiate the reaction of a suspension of magnesium /0,09 g/ THF /2.5 ml/ added dropwise a solution of 4-bromophenyl-2-tailslide /1.2 g/ THF /2 ml/ obtaining Grignard reagent. You must ensure that the reaction began before adding to the main quantity of 4-bromophenyl-tailslide, otherwise it may happen intensive exotic is this magnesium. Then added dropwise benzaldehyde /0,38/ ml and the mixture is stirred for 16 h at room temperature. The mixture is transferred into a mixture of ice with an aqueous solution of ammonium chloride /15% wt./about./ and extracted with ethyl acetate. The organic phase is washed with water, dried /MgSO4/ and evaporated. The residue is purified by column chromatography using as eluent a mixture of petroleum ether /so Kip. 40 - 60oC/-diethyl ether /10:1/about./. As a result, in the form of oil get 4-(alpha-hydroxybenzyl)phenyl-2 - thienylmethyl /0.25 g, 23%/.

After repeating the above stages a mixture of the obtained product /0,413 g/, tert-butyldimethylsilyloxy /0,521 g/, imidazole /0,472 g/ and DMF /1.5 ml/ stirred for 3 h at room temperature. The mixture is then partitioned between diethyl ether and cold water, dried /MgSO4/ and evaporated. The residue is purified by column chromatography using as eluent petroleum ether /so Kip. 40 60oC. as a result, In the form of oil get 4-(alpha-tributyltinoxide) phenyl-2-thienylmethyl /0,227 g, 40% /.

To a cooled to -78oC to a solution of the obtained product /0,225 g/ THF /2 ml/ added dropwise utility /1.5 M in hexane, 0.35 ml, and the mixture is stirred 2 h at -784/ and evaporated. The residue is purified column chromatography using as eluent a mixture of chloride metrodetroit ether. The result is the target source connection /0.09 g, 32%/, so pl. 118 120oC.

EXAMPLE 14. To a cooled to -110oC to a solution of 4-/5-(4 - pampanito)Tien-2-yl/-4-methoxyacridine /1,58 g/ THF /16 ml/ added dropwise n-utility /1.6 M in hexane, 2.6 ml, and the mixture is stirred for 2 h at the same temperature. Then added dropwise 4-forbindelse. The mixture is stirred and left to slowly warm to room temperature. The mixture is then transferred into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated. The residue is purified column chromatography using as eluent a mixture of petroleum ether /so Kip. 40 60oC/-diethyl ether /2:3.about./. As a result, in the form of oil receive a 4-/5-(4-fluoro-alpha-hydroxybenzyl)phenylthio)- Tien-2-yl/-4-methoxyacridine /1.29 g, 73%/.

The NMR spectrum of /CD3COCD3values d/: 1,85 is 14, but using 2,4-diferentialglea instead of 4-forventelige exit 33% gain in the form of oil 4-/5-(4-(2,4-debtor-alpha hypoxanthin)phenylthio)Tien-2-yl/-4-methox - tetrahydropyran.

The NMR spectrum of /CD3COCD3values d/: 1,85 2,15 /m, 4H/, 3,05 /c, 3H/, 3,6 3,8 /m, 4H/, 6,7 7,5 /m, N/.

EXAMPLE 16. Playback method of example 14, but using pentafluorobenzaldehyde exit 49% gain in the form of oil 4-/5-(4-(2,3,4,5,6-pendaftar-alpha hydroxybenzyl) phenylthio)Tien-2-yl/4-methoxyacridine.

The NMR spectrum of /CD3COCD3values d/: 1,8 2,15 /m, 4H/, 3,05 /c, 3H/, 3,6 3,8 /m, 4H/, 6,25 /c, IH/, 7 7,05 /m, 6H/.

EXAMPLE 17. Playback method of example 14, but using 4-triftormetilfullerenov instead of 4-forventelige exit 79% gain in the form of oil 4-/5-(4-alpha-hydroxy-4 - trifloromethyl)phenylthio)Tien-2-yl/-4 - methoxyacridine.

The NMR spectrum of /CD3COCD3values d/: 1,8 2,1 /m, 4H/, of 5.05 /m, 4H/, of 5.05 /d, IH/, 5,8 /d, IH/, 7 7,75 /m, 10H/.

EXAMPLE 18. To a stirred solution of 4-/5-(4-fluoro-alpha-hydroxybenzyl)phenylthio)Tien-2-yl/-4-methoxymethyl - itaperuna /0.95 g/ methylene chloride /20 ml portions add pyridine-chlorproma /1.19 g/ and the resulting mixture stirred for 12 h at th using as eluent a mixture of petroleum ether /T. the TRC. 40 60oC/-diethyl ether /3: 2 vol./about/. The result 4-/5-(4-(4-perbenzoic)-phenylthio)Tien-2-yl/-4 - methoxyacridine /0,683 g, 72%/, so pl. 81oC.

EXAMPLE 19. Using the method of example 18 treatment 4/-5-(4-(2,4-debtor-alpha hydroxybenzyl)phenylthio)Tien-2-yl/- 4-methoxyacridine pyridine-chlorbromuron with 71% yield in the form of oil get 4-/5-(4-(2,4-differentail)phenylthio)- Tien-2-yl/-4-methoxyacridine.

The NMR spectrum of /CD3COCD3values d/: 1,9 2,15 /m, 4H/, 3,1 /c, 3H/, 3,6 3,8 /m, 4H/, 7 7,8 /m, 9H/.

EXAMPLE 20. According to the method of example 18 treatment 4-/5-(2,3,4,5,6 - pendaftar-alpha hydroxybenzyl)phenylthio)Tien-2-yl/-4 - methoxyacridine pyridine-chlorbromuron with a yield of 75% receive 4-/5-(4-(2,3,4,5,6-pentafluorobenzoyl)phenylthio) Tien-2-yl/-4-methoxyacridine, so pl. 83 94oC.

EXAMPLE 21. Processing according to the method of example 18 4-/5-(4-(alphahydroxy-4-trifloromethyl)phenylthio)Tien-2-yl/-4 - methoxyacridine pyridine-chlorbromuron with a yield of 75% receive 4-/5-(4-(4-trifloromethyl)phenylthio=Tien-2 - yl/-4-methoxyacridine, so pl. 86 87oC.

EXAMPLE 22. Add to cooled to -78oC solution Diisopropylamine /0,394 g/ THF /5 ml/ h-utility /1.6 M in g the 5oC. is added dropwise a solution of 4-(5-Bratan-2 - yl/-4-methoxyacridine /1 g/ THF /15 ml and the mixture is stirred for 2 h at -85oC. and Then added dropwise a solution of di(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)disulphide /1.5 g/ THF /3 ml, stirred for 4 h and allowed to warm to room temperature. The resulting mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic phase is washed with water, dried /MgSO4/ and evaporated. Purification of the residue column chromatography using as eluent diethyl ether get foam 4-in/4-Brom-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl-thio) Tien-Il/-4-methoxyacridine /0,43 g, 26%/.

The NMR spectrum of /CD3COCD3values d/: 1,9 2,2 /m, 4H/, 2,5 3,05 /m, 4H/, 3,1 /c, 3H/, 3,3 /c, 3H/, 3,7 3,65 /m, 4H/, 7,35 7 /m, 4H/.

EXAMPLE 23. Using the method of example 5 reaction /2RS, 4SR/-4- (5-Bratan-2-yl)-4-methoxy-2-methyltetrahydrofuran with di-(4-tert-butylphenyl)sulfide with exit 77% gain in the form of oil (2RS, 4SR)-4-/5-(4-tert-butylphenyl)Tien-2 - yl/-4-methoxy-2-methyltetrahydrofuran.

The NMR spectrum of /CD3COCD3values d/: 1,2 /d, 3H/, 1,3 /c, 9H/, 1,3 2,3 /m, 4H/, 3,1 /c, 3H/, 3,6 3,9 /m, 3H/, 7 7,05 /m, 6H/.

Used as and>/P>Reproduced technique that part of example 11, which deals with the synthesis of the starting materials, but instead of (2S)-2 - methyltetrahydrofuran-4-it is used (2RS)-2-methyltetrahydrofuran-4-one/ J. Am. Chem. Soc. 1982, 104, 4666/. As a result, in the form of the less polar isomer get /2RS, 4SR/-4-/5-Bratan-2-yl/-4 - hydroxy-2-methyltetrahydrofuran, a yield of 20% oil.

The resulting product is treated according to the method of example 1 methyliodide and 74% receive in the form of oil target source connection.

EXAMPLE 24. According to the method of example 5 by reaction of (2RS, 4SR)-4-(5 - Bratan-2-yl)-4-methoxy-2-methyltetrahydrofuran with di(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-yl)disulphide with the release of 72% gain in the form of oil (2RS, 4SR)-4-methoxy-2 - methyl-4-/5-(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6 - yl-thio)-Tien-2-yl/tetrahydropyran.

The NMR spectrum of /CD3COCD3values d/: 1,15 /d, 3H/, 1,25 - 2,25 /m, 4H/, 2,7 3,25 /m, 4H/, is 3.08 /c, 3H/, 3,6 3,9 /m, 3H/, 3,85 /c, 3H/, 7,35 7 /m, 5H/.

EXAMPLE 25. According to the method of example 6 by reaction of 4-methoxy-4-(3 - thienyl)-tetrahydropyrane with di(1-methyl-2-oxo,2,3,4-tetrahydroquinolin-6-yl)disulphide with the release of 26% receive 4-methoxy-4-/2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-yl-thio)-tie - n-2-yl/tetrahydropyran, so pl. 106 108oC.

EXAMPLE 26. Below the purpose and the or its pharmaceutically acceptable salt (hereinafter referred to as compound X/, intended for therapeutic or prophylactic use in humans.

/a/ Tablet 1 mg tablet

Compound X 100

Lactose Ph. Eur 182,75

Croscarmellose sodium 12

Pasta corn starch /5% wt./about.pasta/ 2,25

Magnesium stearate 3

/b/ Tablets II mg/tablet

Compound X 50

Lactose Ph. Eur. 223,75

Croscarmellose sodium 6

Corn starch 15

Polyvinylpyrrolidone /5% wt./about. pasta/ 2,25

Magnesium stearate 3

/c/ Tablet III mg/tablet

Connection X 1

Lactose Ph. Eur 93,25

Croscarmellose sodium 4

Pasta corn starch /5% wt./about.pasta/ 0,75

Magnesium stearate 1

/d/ Capsule mg/capsule

Compound X 10

Lactose Ph. Eur. 488,5

Magnesium stearate 1.5 to

/e/ Injection 1 /50 mg/ml/

Compound X 5.0% wt./about.

IM a sodium hydroxide solution 15.0% wt./about

0.1 M hydrochloric acid to establish a pH of 7.6/

The polyethylene glycol 400 4.5% wt./about.

Water for injection to 100%

/f/ Injection 11 /10 mg/ml/

Compound X 1.0% wt./about.

Sodium phosphate BP 3.6% wt./about.

0,1 M sodium hydroxide solution 15.0% wt./about.

Water for injection to 100%

/g/ Injection III /1 mg/ml, buffered to pH 6/

The polyethylene glycol 400 3.5 wt./about.

Water for injection to 100%

/h/ Aerosol I mg/ml

Compound X 10

Trioleate sorbitol 13,5

Trichlorofluoromethane 910

DICHLORODIFLUOROMETHANE 490

/i/ II Aerosol mg/ml

Compound X 0,2

Trioleate sorbitol 0,2

Trichlorofluoromethane 70

DICHLORODIFLUOROMETHANE 280

Diclorhidrato 1094

/j/ III Aerosol mg/ml

Compound X 2,5

Trioleate sorbitol 3,38

Trichlorofluoromethane 67,5

DICHLORODIFLUOROMETHANE 1086

Dichlorotetrafluoroethane to 191.6

// Spray IV mg/ml

Compound X 2,5

Soy lecithin 2,7

Trichlorofluoromethane 67,5

DICHLORODIFLUOROMETHANE 1086

Dichlorotetrafluoroethane to 191.6.

The above compounds may be prepared by conventional methods, well known to pharmacists. Tablets /a/ /c/ can be covered by conventional means small bowel coating, for example, with coverage from azettftalat cellulose. Aerosol formulations /h/ /K/ can be used in combination with standard dosing aerosol spray, and such suspendresume means as trioleate sorbitol and soya lecithin may be replaced by alternative dispendious means, such as: monooleate sorbitol, p the>BR>
< / BR>
< / BR>
< / BR>
< / BR>
Scheme I

Scheme II

Scheme III

Scheme IV

-

1. Heterocycles compound of the formula I

< / BR>
where Ar1phenyl, or naphthyl, or 10-membered benzododecinium heterocyclic fragment containing heterocyclic ring one or two nitrogen heteroatom and optionally containing an additional heteroatom of oxygen, and Ar1optionally can contain up to three substituents selected from halogen, carbonyl group, tocography, C1- C4-alkyl, benzoyl, phenyl-C1C4-alkyl and-hydroxybenzoyl, and bentely, phenyl-C1- C4-and alkyl-hydroxybenzamide the optional substituents can have up to five substituents selected from halogen, trifloromethyl and C1-C4-alkyl;

Ar25-membered heterocycles fragment containing one heteroatom selected from oxygen and sulfur, which may not necessarily have one Deputy, selected from halogen and C1C4-alkyl;

R1C1C4-alkyl;

R2and R3together form a group of the formula-A2-O-A3- which together with the carbon atom to which is attached A2B> - C3-alkylen, and this cycle may have one or two C1- C4is an alkyl substituent,

or pharmaceutically acceptable salt of this compound.

2. Connection on p. 1, characterized in that Ar1phenyl, or naphthyl, or 10-membered benzododecinium heterocyclic fragment containing heterocyclic ring one or two heteroatoms of nitrogen, and possibly containing one additional heteroatom of oxygen, Ar1possibly can have up to three substituents selected from halogen, carbonyl group, tocography, C1C4-alkyl, benzoyl, phenyl-C1C4-alkyl, where two of these last Deputy may have substituents selected from halogen and C1C4-alkyl, and Ar25-membered heterocycles fragment containing one heteroatom selected from oxygen and sulfur, which may contain one Deputy, selected from halogen and C1C4-alkyl; R1C1- C4-alkyl; R2and R3work together to form the formula-A2-O-A3- which together with the carbon atom to which is attached A2and A3forms a cycle with 5 to 6 atoms in the cycle, where A2and A3the same or rasleela, or their pharmaceutically acceptable salts.

3. Connection on p. 1, characterized in that Ar1phenyl, or naphthyl, or 10-membered benzododecinium heterocyclic fragment containing heterocyclic ring one or two nitrogen heteroatom and optionally containing one additional heteroatom of oxygen, and Ar1optional may have up to three--hydroxybenzyl substituents, and the substituents may optionally be Deputy selected from halogen and C1C4-alkyl, Ar25-membered heterocycles fragment containing one heteroatom selected from oxygen and sulfur, which can optionally contain one Deputy, selected from halogen and C1C4-alkyl, R1represents C1-C4alkyl, R2and R3together form a group of the formula-A2-O-A3- which together with the carbon atom to which is attached A2and A3forms a cycle with 5 to 6 atoms in the cycle, where A2and A3the same or different, each C1- C3-alkylen, and this cycle may have one or two C1- C4is an alkyl substituent, or a pharmaceutically acceptable salt of these compounds.

4.P> methyl, R2and R3together form a group of the formula-A2-O-A3- which together with the carbon atom to which is attached A2and A3form a cycle with 5 or 6 atoms in the cycle, where A2ethylene, A3is methylene or ethylene, and this cycle may have a Deputy, methyl b-position with respect to oxygen, or a pharmaceutically acceptable salt of these compounds.

5. Connection on p. 1, characterized in that Ar1- 1-methyl-2-oxo-1,2-dihydroquinoline-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl, 1-methyl-2-thioxo-1,2,3,4 - tetrahydroquinolin-6-yl or 4-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-yl, Ar22.5-tienlen, R1methyl, R2and R3together form a group of the formula-A2-O-A3- which together with the carbon atom to which is attached A2and A3forms a cycle with 6 atoms in the cycle, where A2ethylene, A3ethylene, and this cycle may have a Deputy selected from bromide in a-position to the oxygen, or a pharmaceutically acceptable salt of these compounds.

6. The compound of formula I or its pharmaceutically acceptable salt p. 1, wherein selected from the group comprising 4-methoxy-4-[5-(1-methyl-2-oxo-1,2,3,4 - tetrahydroquinolin-6-ylthio is hydroxy-4-[5-(1-methyl-2-thioxo-1,2,3,4 - tetrahydroquinolin-6-ylthio)Tien-2-yl] tetrahydropyran, 4-methoxy-4-[5-(4-methyl-3-oxo-2,3-dihydro-4H-1,4 - benzoxazin-7-ylthio)Tien-2-yl] tetrahydropyran, (2S, 4R)-4-methoxy-2-methyl-4-[5-(1-methyl-2 - thioxo-1,2,3,4-tetrahydroquinolin-6-ylthio)Tien-2-yl]tetrahydropyran.

7. The method of obtaining heterocyclization the compounds of formula I or its farmatsevticheskii acceptable salt p. 1, wherein combining the compound of the formula

Ar1-S-Z

where Z replaceable group, or a group of the formula

Ar1-S-,

with an ORGANOMETALLIC reagent of formula III

< / BR>
where M is alkali metal or alkaline earth metal or M - mangalitsa part of a normal Grignard reagent,

and where to obtain those compounds of formula I where Ar1has one or more possibly substituted-hydroxybenzyl deputies conduct the reaction heterocyclization the compounds of formula I where Ar1has one or more halogen substituents, with metal or with C1- C4-alkyllithium reagent with the formation of the ORGANOMETALLIC reagent, which enter into reaction with possibly substituted benzaldehyde; or to obtain those compounds of formula I where Ar1has one or more possibly substituted benzoline deputies, oxidize heterocycles SOEDINENIYa pharmaceutically acceptable salt of the new compounds of formula I, it can be obtained by reaction with the appropriate acid or base.

8. The method of obtaining heterocyclization the compounds of formula I or its pharmaceutically acceptable salt according to p. 1, characterized in that carry out the alkylation of the compounds of formula V

< / BR>
where Ar1, Ar2, R2and R3have the specified values,

the compound of the formula

P1-Z

where P1and Z have the above values,

and to obtain those compounds of formula I where Ar1has one or more possibly substituted-hydroxybenzyl deputies conduct the reaction heterocyclization the compounds of formula I where Ar1has one or more halogen substituents, with metal or C1- C4-alkyllithium reagent with the formation of the ORGANOMETALLIC reagent, which enter into reaction with possibly substituted benzaldehyde; to obtain those compounds of formula I where Ar1has one or more possibly substituted benzoline deputies, oxidize heterocycles compound of formula I where Ar1has one or more possibly substituted a-hydroxybenzyl deputies, and if you want pharmaceutically acceptable salt of the new connected the mini-composition, inhibiting 5-lipoxygenase, comprising an active ingredient and a pharmaceutically acceptable diluent or carrier, wherein the active ingredient contains heterocycles compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs. 1 6 5 98%

Priority points:

21.06.90 on p. 2;

15.01.91 on p. 1.

 

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1 tbl, 4 ex

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3 dwg, 1 tbl

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EFFECT: improved preparing method.

3 tbl, 4 ex

FIELD: pharmaceutical industry.

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6 cl, 1 ex

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1 dwg, 2 ex

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2 ex, 1 tbl

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18 cl, 5 ex, 11 tbl

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