RU2058306C1 - Heterocyclic compounds and pharmaceutical composition on their base having inhibiting action on 5-lipoxygenase - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: heterocyclic compounds having formula which is given in specification are used for production of pharmaceutical composition. Said composition has inhibiting action on 5-lipoxygenase. EFFECT: improves quality of desired product. 10 cl

Description

The invention relates to new heterocycles, and more particularly to new heterocycles that are inhibitors of the 5-lipoxygenase enzyme (hereinafter referred to as 5-LO). The invention also relates to methods for producing said heterocycles and to new pharmaceutical compositions containing said heterocycles that can be used in the treatment of various inflammatory and / or allergic diseases, which involve direct and by-products of the oxidation of arachidonic acid catalyzed by 5-LO. The heterocycles described hereinafter are inhibitors for 5-LO, the enzyme of which must be involved in catalyzing the oxidation of arachidonic acid in order to lead through physiological active leukotrienes, such as leukotriene B ₄ (LTB ₄ ), and peptide-lipid leukotrienes, such as leukotriene C ₄ (STS ₄ ), m to various metabolites (metabolic products).

 The biosynthetic dependence and physiological properties of leukotrienes are known. Leukotrienes and their metabolites are involved in the production and development of a variety of inflammatory and allergic diseases, such as gouty diseases, asthma, allergic rhinitis, atopic dermatitis, psoriasis, cardiovascular and central vascular disorders and inflammatory bowel disease. In addition, leukotrienes are mediators (intermediaries) of inflammatory diseases due to their ability to modulate lymphocytic and leukocyte function. Other physiologically active metabolites of arachidonic acid, such as prostaglandins and thromboxanes, arise from the action of the cyclooxygenase enzyme on arachidonic acid.

 Currently, the inventors have discovered that some heterocycles are effective as inhibitors of the 5-LO enzyme and thereby leukotriene biosynthesis. Thus, such compounds are valuable as therapeutic agents in the treatment of, for example, allergic conditions, psoriasis, asthma, cardiovascular and central vascular disorders, and / or inflammatory and gouty (arthritic) conditions that are intermediate, exclusively or partially actions of one or more leukotrienes.

A heterocycle of formula I is provided (presented below), in which Q is a 6-membered monocyclic or 10-membered biocyclic heterocyclic residue containing one or two nitrogen atoms, which optionally may have one, two or three substituents selected from halogen, hydroxy, carboxy, cyano, amino, (1-4C) alkyl, (1-4C) alkoxy, fluoro (1-4C) alkyl, (1-4C) alkylamino, di - [(1 -4C) -alkyl] -amino, hydroxy- (1-4C) -alkyl, amino (1-4C) -alkyl, (1-4C) -alkylamino (1-4C) -alkyl, di - [( 1-4C) alkyl] amino (1-4C) alkyl, amino (2-4C) alkoxy, (1-4C) alkylamino (2-4C) alkoxy, di [(1-4C) alkyl] amino (2-4C) alkoxy and phenyl (1-C) alkyl, and wherein the phenyl group in said phenyl (1-4C) alkyl substituent may optionally wear a substituent selected from halogen, (1-4C) alkyl and (1-4C) alkoxy; in which A is (1-6C) alkenyl, (3-6C) alkenylene, (3-6C) alkylene or cyclo (3-6C) alkylene; in which X is an oxy, thio, sulfinyl, sulfonyl or imino group in which Ar is phenylene, which may bear one or two substituents selected from halogen, hydroxy, amino, nitro, cyano, ureido groups, carbamoyl, (1-4C) alkyl, (3-4C) alkenyloxy, (1-4C) alkoxy, (1-4C) alkylthio, (1-4C) alkylsulfinyl (thionyl ), (1-4C) -alkylsulfonyl, (1-4C) -alkylamino, di - [(1-4C) -alkyl] amino, fluoro- (1-4C) -alkyl, (1- 4C) -alkoxycarbonyl, N - [(1-4C) -alkyl] -carbamoyl, N, N-di [(1-4C) -alkyl] -carbamoyl, (2-4C) -alkanoylamino-, cyano- ( 1-4C) -alkoxy-, carbamoyl- (1-4C) -alko xy-, amino- (2-4C) -alkoxy-, (1-4C) -alkylamino- (2-4C) -alkoxy, di - [(1-4C) -alkyl] amino- (2-4C) - (2-4C) alkoxy and (1-4C) alkoxycarbonyl- (1-4C) alkoxy groups; or
Ar is a 6-membered heterocyclene residue containing up to three nitrogen atoms, which can carry one or two substituents selected from halogen, selected from halogen, hydroxy, amino-cyano groups, (1-4C) -alkyl, (1 -4C) alkoxy, (1-4C) -alkyl-amino and di - [(1-4C) -alkyl] amino groups;
R ¹ is hydrogen, (1-6C) -alkyl, (3-6C) -alkenyl, (3-6C) -alkynyl, cyano- (1-4C) -alkyl or (2-4C) -alkanyl, or R ¹ is benzoyl, which may be a substituent selected from halogen, (1-4C) -alkyl (1-4C) -alkoxy-;
and R ² and R ³ together form a group of the formula -A ^2- X ² -A ³ -, which, together with the carbon atom to which A ² and A ³ are attached, defines a ring having from 4 to 7 atoms in the ring, which A ² and A ^{3 are the} same or different, each is (1-4C) alkylene, and X ² is an oxy, thio group, sulfinyl, sulfonyl or imino group, and the cycle of which may have one or two substituents, which may be the same or different, selected from hydroxy (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylthio, (1-4C) alkylthionyl and (1-4C) -alkylsulfonyl, or the cycle of which can em is a (1-4C) alkylenedioxy substituent;
or a pharmaceutically acceptable salt thereof (heterocycle):
According to an additional feature of the present invention, there is provided a heterocycle of formula I in which Q is a 6-membered monocyclic or 10-membered bicyclic heterocyclic radical containing one or two nitrogen atoms, which optionally may bear one or two substituents selected from halogen, hydroxy, oxo -, carboxy, cyano, amino, (1-4C) -alkyl, (1-4C) -alkoxy, fluoro- (1-4C) -alkyl, (1-4C) -alkylamino, di - [(1 -4C) -alkyl] -amino, hydroxy- (1-4C) -alkyl, amino (1-4C) -alkyl, (1-4C) -alkylamino (1-4C) -alkyl, di - [( 1-4C) -alkyl] -amino (1-4C) -alkyl, amino (2-4C) -a alkoxy, (1-4C) alkylamino (2-4C) alkoxy and di - [(1-4C) alkyl] amino (2-4C) alkoxy groups;
A is (1-6C) alkylene, (3-6C) alkenylene, (3-4C) alkynylene or cyclo- (3-6C) alkylene;
X is oxo, thio, sulfinyl, sulfonyl or imino;
Ar is phenylene, which may have one or two substituents selected from halogen, hydroxy, amino, nitro, cyano, carbamoyl, (1-4C) alkyl, (3-4C) alkenyloxy, (1- 4C) -alkoxy, (1-4C) -alkylthio-, (1-4C) -alkylthionyl, (1-4C) -alkylsulfonyl, (1-4C) -alkylamino, di - [(1-4C) -alkyl] - amino, fluoro- (1-4C) -alkyl, (1-4C) -alkoxycarbonyl, N - [(1-4C) -alkyl] -carbonyl, N, N-di - [(1-4C) -alkyl] - carbamiol, (2-4C) -alkanoylamino, cyano- (1-4C) -alkoxy, carbamoyl- (1-4C) -alkoxy, amino (2-4C) -alkoxy, (1-4C) -alkylamino (2-4C) alkoxy, di - [(1-4C) alkyl] amino (2-4C) alkoxy and (1-4C) alkoxycarbonyl (1-4C) alkoxy. or
Ar is a 6-membered heterocyclene residue containing up to three nitrogen atoms, which optionally can bear one or two substituents selected from halo, hydroxy, amino, cyano, (1-4C) -alkyl, (1-4C ) alkoxy, (1-4C) alkylamino and di - [(1-4C) alkyl] amino groups;
R ¹ is hydrogen, (1-6C) -alkyl, (3-6C) -alkenyl, (3-6C) -alkynyl, cyano- (1-4C) -alkyl or (2-4C) -alkanyl, or R ¹ is benzoyl, which optionally may have a substituent selected from halogen, (1-4C) alkyl and (1-4C) alkoxy group
R ² and R ³ together form a group of the formula -A ² -X ² -A ³ - which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having from 4 to 7 atoms in a ring in which A ² and A ³ , which may be the same or different, each is (1-4C) alkenylene, and X ² is oxo, thio, thionyl, sulfonyl or imino, and the ring of which may have one or two substituents, which may be the same or different, selected from hydroxy, (1-4C) alkyl, (1-4C) alkylthio, (1-4C) alkoxy, (1-4C) alkylthionyl and (1 -4C) -alkylsulfonyl, or cat cycle Roy can wear (1-4C) alkylenedioxy substituent;
or a pharmaceutically acceptable salt thereof (heterocycle).

 The chemical formulas referred to in this description in Roman numerals are presented on a separate sheet below.

 In the description of the invention, the general term "alkyl" includes straight and branched chains of alkyl groups. However, references to individual alkyl groups, such as “propyl,” are specific for straight chains only, and references to individual branched chains of alkyl groups, such as “isopropyl,” are accurate only for branched chains. A similar designation applies to other general terms.

 It is understood that since some of the compounds of Formula I described may exist in optically active or racemic forms based on the presence of one or more substituents containing an asymmetric carbon atom, the invention excludes any thin optically active or racemic form of new compounds that has the property of inhibiting 5-LO . The synthesis of optically active forms can be carried out according to standard methods of organic chemistry, well known in this field, for example, by synthesis from optically active starting materials or by separation of the racemic form. The inhibitory properties against 5-LO can be assessed using standard laboratory techniques presented below.

 In addition, since some of the specific compounds of formula I may exhibit tautomerism, for example, a compound of formula I in which Q has an oxo or hydroxy substituent, and since any formula shown in the present description can represent only one of the possible tautomeric forms, the invention includes in its definition any tautomeric form of a compound of formula I that has the property of inhibiting 5-LO, and should not be limited to any one tautomeric form.

 The specific meanings of the radicals represented are those given below.

 A specific value for Q when it represents a 6-membered monocyclic or 10-membered bicyclic heterocyclic residue containing one or two nitrogen atoms is, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxanilinyl or fartyridinyl, or a hydrogenated derivative thereof, such as, for example, 1,2-dihydropyridinyl or 1,2-dihydroquinolyl. The heterocyclic residue may be attached to any available nitrogen atom or it may have a substituent in any position, including on any available nitrogen atom.

 When Q is a 10-membered bicyclic heterocyclic residue containing one or two nitrogen atoms, Q can be attached to A with any of two cycles of the bicyclic heterocyclic residue.

 Preferably Q means, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 3-cinnolyl, 6-cinnolyl, 7-cinnolyl, 2-quinazolinyl, 4-quinazolinyl, 6- quinazolinyl, 7-quinazolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 1-phthalazinyl, 6-phthalazinyl, 1,5-naphthyridin-2-yl, 1,5-naphthyridin-3-yl, 1,6- naphthyridin-3-yl, 1,6-naphthyridin-7-yl, 1,7-naphthyridin-3-yl, 1,7-naphthyridin-6-yl, 1,8-naphthyridin-3-yl, 2,6- naft iridin-3-yl or 2,7-naphthyridin-3-yl.

A suitable value for the halogen substituent which may be present on Q, Ar or R ¹ is, for example, fluorine, chlorine, bromine or iodine.

A suitable value for the (1-4C) alkyl substituent which may be present on Q, Ar or R ¹ is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl.

A suitable value for the (1-4C) alkoxy substituent that may be present on Q, Ar or R ¹ is, for example, methoxy, ethoxy, propoxy, isopropoxy, or butoxy.

 Suitable values for the fluoro (1-4C) alkyl substituent which may be present on Q or Ar are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or pentafluoroethyl.

 A suitable value for A when it is (1-6C) alkylene is, for example, methylene, ethylene, ethylidene, trimethylene, propylidene, tetramethylene or pentamethylene; when it is (3-6C) alkenylene, is, for example, 1-propenylene, 2-methylpropen-1-ylene, 3-methylpropen-1-ylene, 1-butenylene or 2-butenylene; and when it is (3-6C) alkynylene, it is, for example, 1-propynylene, 3-methylpropin-1-ylene, 1-butynylene or 2-butynylene.

 A suitable value for A when it is cyclo- (3,6C) -alkylene is, for example, cyclopropylidene, 1,2-cyclopropylene, cyclopentylidene, 1,2-cyclopentylene, cyclohexylidene or 1,4-cyclohexylene.

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

 A suitable value for Ar when it is a 6-membered heterocyclic residue containing up to three nitrogen atoms is, for example, pyridylene, pyrimidinyl, pyridazinylene, pyrazinyl or 1,3,5-triazinyl. It is desirable for A when it is a 6-membered heterocyclic radical containing up to three nitrogen atoms, for example, 2,4-, 2,5-, 3,5- or 2,6-pyridylene, 2,4-, 2,5- or 4,6-pyrimidinyl, 3,5- or 3,6-pyridazinylene, or 2,5- or 2,6-pyrazinyl.

Suitable values for substituents that may be present on Q or Ar are, for example:
for (1-4C) -alkylamino: methylamino, ethylamino, propylamino and
butylamino;
for di [(1-4C) alkyl] amino: dimethylamino, diethylamine and
dipropylamino;
for amino (2-4C) alkoxy: 2-aminoethoxy, 3-aminopropoxy and
4-aminobutoxy;
for (1-4C) -alkylamino
- (2-4C) alkoxy: 2-methylaminoethoxy, 3 methylaminopropoxy
and 2-ethylaminoethoxy;
for di - [(1-4C) -alkyl]
amino (2-4C) alkoxy: 2-dimethylamylethoxy,
3-dimethylaminopropoxy
and 2-diethylaminoethoxy
Suitable values for substituents that may be present on Q include, for example:
for hydroxy (1-4C) alkyl: hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2-hydroxypropyl and 3-hydroxypropyl;
for amino (2-4C) alkyl: aminomethyl, 1-aminoethyl, 2-aminoethyl,
2-aminopropyl and 3-aminopropyl
for (1-4C) -alkylamino
- (1-4C) -alkyl: methylaminomethyl, 2-methylaminoethyl,
3-methylaminopropyl / ethylaminomethyl and
2-ethylaminoethyl;
for di - [(1-4C) -alkyl]
-amino (1-4C) -alkyl: dimethylaminomethyl, 2-diethylaminoethyl,
3-dimethiaminopropyl, diethylaminomethyl and
2-diethylatinoethyl;
for phenyl (1-4C) alkyl: benzoyl, phenethyl and 3-phenylpropyl.

Suitable values for substituents that may be present on A include, for example:
for (3-4C) alkenyloxy: allyloxy, methylallyloxy,
buten-2-yloxy and buten-3-yloxy;
for (1-4C) -alkylthio: methylthio, ethylthio, propylthio,
isopropylthio and butylthio;
for (1-4C) -alkylthionyl: methylthionyl, ethylthionyl, propylthionyl,
isopropylthionyl and butylthionyl;
for (1-4C) -alkylsulfonyl: methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl and
butylsulfonyl;
for (1-4C) -alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl
and tert-butoxycarbonyl;
for N, N-di [(1-4C) -alkyl]
β-carbamoyl: N, N-dimethylcarbamoyl and
N, N-diethylcarbamoyl;
for (2-4C) alkanoylamino: acetamido, propionamido and butyramido;
for cyano- (1-4C) alkoxy: cyanomethoxy, 2-cyanoethoxy and
3-cyanopropoxy;
for carbamoyl- (1-4C) -alkoxy: carbamoyletoxy, 2-carbamoylethoxy and
3-carbamoylpropoxy;
for (1-4C) -alkoxycarbonyl-
- (31-4C) alkoxy: methoxycarbonylmethoxy,
2-methoxycarbonylethoxy,
ethoxycarbonylmethoxy and 2-ethoxycarbo-
nilethoxy.

A suitable value for R ¹ when it is (1-6C) -alkyl is, for example, methyl, ethyl, propyl, butyl, amyl or hexyl.

A suitable value for R ¹ when it is (3-6C) alkenyl is, for example, allyl, 2-butenyl or 3-butenyl; and when it is (3-6C) -alkynyl, is, for example, 2-propynyl or 2-butynyl.

A suitable value for R ¹ when it is (2-4C) alkanoyl is, for example, acetyl, propionyl or butyryl.

A suitable value for R ¹ when it is cyano- (1-4C) -alkyl is, for example, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl.

When R ² and R ³ together form a group of the formula -A ² -X ² -A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having from 4 to 7 atoms in the ring, then then a suitable value for A ² or A ³ , which may be the same or different when each is (1-4C) alkylene, is, for example, methylene, ethylene, trimethylene or tetramethylene.

Suitable values for one or two substituents that may be present on the indicated 4- to 7-membered ring include, for example:
for (1-4C) -alkyl: methyl, ethyl, propyl, isopropyl and butyl;
for (1-4c) alkoxy: methoxy, ethoxy, propoxy, isopropoxy and
butoxy;
for (1-4C) -alkylthio: methylthio, ethylthio, propylthio, isopropylthio and
butylthio;
for (1-4C) -alkylthionyl: methylthionyl, ethylthionyl, propylthionyl,
isopropylthionyl and butylthionyl;
for (1-4C) -alkylsulfonyl: methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl and
butylsulfonyl;
for (1-4C) -alkylenedioxy: methylenedioxy and ethylenedioxy.

 A suitable pharmaceutically acceptable salt of the heterocycle of the present invention, when the heterocycle is basic, is an addition salt of acids, for example, an inorganic or organic acid, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition, a suitable pharmaceutically acceptable salt of the heterocycle of the present invention, when it is sufficiently acidic in nature (for example, the heterocycle of the present invention that contains a carboxyl group), is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example calcium or a magnesium salt or an organic base salt that provides a physiologically acceptable cation, for example a salt with methylamine, dimethylamine, triethylamine, piperidine, sorfoline or trans- (2-hydroxyethyl) -amine.

The most interesting compounds of the invention are, for example, heterocycles of formula I, in which:
a) Q is 2-pyridyl, 3-pyridyl, 3-pyridazinyl, 2-pyrimidiline or 2-pyrazinyl, which may have one substituent selected from chloro, hydroxy, cyano, methyl, methoxy and trifluoromethyl; and A, X, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;
b) Q is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl or 2-pyrazinyl: A is 1-propenylene or 1-propynylene; and X represents an oxy group, and Ar, R ¹ , R ² and R ³ have any of the meanings given above;
c) Q represents 2-quinolyl, 3-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 3-cinnolyl, 2-quinazolinyl, 6-quinazolinyl, 2-quinoxanilyl, 6- quinoxanylyl, 6-phthalazinyl, 1,7-naphthyridin-3-yl, 1,7-naphthyridin-6-yl, 1,8-naphthyridin-3-yl or 2,7-naphthyridin-3-yl, which may have one or two substituents selected from fluoro, chloro, hydroxy, oxo, cyano, methyl, methoxy and trifluoromethyl; and A, X, Ar, R ¹ , R ² and R ³ has any of the meanings defined above;
d) Q is 3-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinazolinyl, 6-quinazolinyl or 6-quinoxalinyl, which may have one, two or three substituents, selected from fluorine, chlorine, hydroxy, oxo, methyl, ethyl, propyl, trifluoromethyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl; and A. X, Ar, R ¹ , R ² and R ³ have any of the meanings given above;
e) Q is 1,2-dihydro-2-oxoquinolin-3-yl, 1,2-dihydro-2-oxoquinolin-6-yl, 1,2-dihydro-2-oxoquinolin-7-yl, 3,4- dihydro-4-oxoquinazolin-6-yl, 1,2-dihydro-2-oxo-1,7-naphthyridin-3-yl or 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl, which may carry one or two substituents selected from fluorine, chlorine, cyano, methyl, methoxy and trifluoromethyl; and A, X, Ar, R ¹ , R ² and R ³ have any of the meanings given above;
e) Q is 1,2-dihydro-2-oxoquinolin-3-ml, 1,2-dihydro-2-oxoquinolin-5-yl, 1,2-dihydro-2-oxoquinolin-6-yl or 1,2- dihydro-2-oxoquinoline, which may carry one or two substituents selected from fluorine, chlorine, methyl, ethyl, propyl, trifluoromethyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl; and A, X, Ar, R ¹ , R ² and R ³ have any of the meanings given above;
g) Q is 1,2-dihydro-2-oxoquinolin-3-yl, 1,2-dihydro-2-oxoquinolin-5-yl, 1,2-dihydro-2-oxoquinolin-6-yl or 1,2- dihydro-2-oxoquinolin-7-yl, which has a 1-substituent selected from methyl, ethyl, propyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl, and which may carry a substituent selected from fluorine, chlorine and trifluoromethyl; and A, X, Ar, R ¹ , R ² and R ³ have any of the meanings given above;
h) Ar is methylene, ethylene, trimethylene, 1-propenylin, 2-methylprop-1-ethylene or 1-propynylene, and Q, X, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;
i) A is methylene, 1-propenylene and 1-propynylene; and Q. X, Ar, R ¹ , R ² and R ³ have any of the meanings given above;
j) X is an oxy group, and Q, A, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;
k) X is an oxy group or an imino group; and Q, A, Ar, R ¹ , R ² and R ³ have any of the meanings given above;
m) Ar is 1,3-phenylene or 1,4-phenylene, which may have one substituent selected from fluoro, chloro, hydroxy, amino, nitromethyl, methoxy, methylthionyl, methylsulfonyl, methylamino, dimethylamino , trifluoromethyl, acetamido, cyanomethoxy and carbamoylmethoxy groups; and Q, X, A, R ¹ , R ² and R ³ have any of the meanings given above;
m) Ar is 1,3-phenylene or 1,4-phenylene, which may bear one or two substituents selected from fluorine, chlorine, hydroxy, amino nitro, ureido, methyl, methoxy, dimethylamino, trifluoromethyl , acetamido and cyanomethoxy groups; and Q, A, X, R ¹ , R ² and R ³ have any of the meanings given above;
o) Ar represents 2,4-, 2,5-, 3,5- or 2,6-pyridylone, or 4,6-pyrimidinyl, which may be substituted by one substituent selected from chlorine, methyl and methoxy groups; and Q, A, X, R ¹ , R ² and R ³ have any of the meanings given above;
o) A is 3,5-pyridylene or 3,5-pyridazinylene; and Q, A, X, R ¹ , R ² and R ³ have any of the meanings given above;
p) R ¹ represents hydrogen, methyl, ethyl, allyl, 2-propynyl or cyanomethyl; and Q, A, X, Ar, R ² and R ³ have any value as defined above;
c) R ¹ represents methyl, ethyl, allyl or 2-propynyl; and Q, A, X, Ar, R ² and R ³ have any of the meanings given above;
r) R ² and R ³ together form a group of the formula -A ² -X ² -A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a cycle having from 4 to 7 atoms in the cycle, in which A ² and A ³ may be the same or different, and each of them represents methylene, ethylene, trimethylene or tetramethylene, and X ² represents methylene, ethylene, trimethylene, or tetramethylene, and X ² represents an oxygen atom, thio-, thionyl or sulfonyl, and the cycle of which (the group) may be carried by a substituent selected from hydroxy, methyl, methoxy, ethoxy, methylthio, methylthionyl, etilsulfonila and methylenedioxy groups; and Q, A, X, Ar and R ¹ have any of the meanings given above; or
s) R ² and R ³ together form a group of the formula -A ² -X ² -A ³ - which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having from 5 to 7 atoms in the ring, which A ² and A ³ may be the same or different, and each of them is methylene, ethylene or trimethylene, and X ² represents an oxy group, and the cycle of which may bear one or two substituents selected from hydroxy, methyl, ethyl and methoxy -groups; and Q, A, X, Ar and R ¹ have any of the meanings given above; or a pharmaceutically acceptable salt thereof (heterocycle).

A particular compound of the present invention includes a heterocycle of formula I in which Q is pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl or quinoxalinyl, which optionally can carry one, two or three substituents selected from fluoro, chloro, hydroxy, oxo, methyl, ethyl, propyl, trifluoromethyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl; in which a represents methylene, 1-propenylin or 1-propynylene; in which X represents a group or an imino group; in which Ar represents 1,3-phenylene or 1,4-phenylene, which optionally can carry one or two substituents selected from fluorine, chlorine, hydroxy, amino, nitro, ureido, methyl, methoxy, dimethylamino , trifluoromethyl, acetamido and cyanomethoxy groups, or Ar is 3,5-pyridylone or 2,6-pyridazinylene; in which R ¹ represents methyl, ethyl, allyl or 2-propynyl; and in which R ² and R ³ together form a group of the formula -A ² -X ² -A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having from 5 to 7 atoms in the ring in which A ² and A ³ may be the same or different, and each of them is methylene, ethylene or trimethylene, and X ² represents an oxy group and the cycle of which may bear one or two substituents selected from hydroxy, methyl, ethyl and methoxy groups; or a pharmaceutically acceptable salt thereof (heterocycle).

Additionally, a particular compound of the invention includes a heterocycle of formula I in which Q is 2-pyridyl, 3-pyridyl, 3-pyridazinyl, 2-pyrimidinyl or 2-pyrazinyl, which may carry one substituent selected from chloro, hydroxy, cyano, methyl , methoxy groups and trifluoromethyl, or Q represents 2-quinolyl, 3-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 3-cinnolyl, 2-quinazolinyl, 6-quinazolinyl, 2-quinoxalinyl, 6-quinoxalininyl, 6-phthalazinyl, 1,7-naphthyridin-3-yl, 1,7-naphthridin-6-yl, 1,8-naphthyridin-3-yl or 2,7-naphthyridin-3- silt which ozhet bear one or two substituents selected from fluoro, chloro, hydroxy, oxo, cyano, methyl, methoxy and trifluoromethyl; A represents methylene, ethylene, trimethylene, 1-propenylene, 2-methylprop-1-enylene or 1-aprpinylene; Ar is 1,3-phenylene or 1,4-phenylene, which optionally may have one substituent selected from fluoro, chloro, hydroxy, amino, nitro, methyl, methoxy, methylthio, methylthionyl, methylsulfonyl, methylamino , dimethylamino, trifluoromethyl, acetamido, cyanomethoxy, and carbonylmethoxy groups, or Ar is 2,4-, 2,5- 3,5- or 2,6-pyridylene or 4,6-pyrimidinyl, which optionally can be carried alone a substituent selected from chlorine, methyl and methoxy groups; R ¹ represents methyl, ethyl, allyl and 2-propynyl; and R ² and R ³ together form a group of the formula -A ² -X ² -A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, define a ring having from 4 to 7 atoms in the ring, which A ² and A ³ may be the same or different, and each of them represents methylene, ethylene, trimethylene or tetramethylene, and X ² represent an oxy group of thio-, sulfinyl or sulfonyl, and the cycle of which may have a substituent selected from oxy-, methyl , methoxy, ethoxy, methylthio, methylthionyl, methylsulfonyl and methylenedioxy groups; or a pharmaceutically acceptable salt thereof (heterocycle).

Additionally, a particular compound of the invention includes a heterocycle of formula I in which Q is 3-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 2-quinazolinyl, 6-quinazolinyl or 6-quinoxalinil, which can carry one, two or three substituents selected from fluorine, hydroxy, oxo, methyl, ethyl, 2-fluoroethyl, 2-dimethylaminoethyl or benzyl; in which a represents methylene; in which X represents an oxy group or an imino group; in which Ar represents 1,3-phenylene or 1,4-phenylene, which may carry one or two substituents selected from fluorine, hydroxy, amino, ureido, methoxy, trifluoromethyl and cyanomethoxy groups, or Ar represents 3 5-pyridylene; in which R1 is methylene, ethyl or allyl; and in which R ² and R ³ together form a group of the formula -A ² -X ² -A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having 5 or 6 atoms in a ring, in which A ² represents ethylene, A ³ represents methylene or ethylene, and X ² represents an oxy group, and the cycle of which may bear one or two substituents selected from oxy, methyl and methoxy groups; or a pharmaceutically acceptable salt thereof (heterocycle).

A preferred compound of the present invention includes a heterocycle of formula I in which Q is 6-quinolyl, 3-isoquinolyl, 2-quinazolinyl, 6-quinazolinyl, 6-quinoxalinyl, 1,2-dihydro-2-oxoquinolyl-3-yl, 1,2 -dihydro-2-oxoquinolin-5-yl, 1,2-dihydro-2-oxo-quinolin-6-yl or 1,2-dihydro-2-oxoquinolin-7-yl, which may have one or two substituents selected from fluorine, methyl, ethyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl; in which a represents methylene; in which X represents an oxy group; in which Ar is 1,3-phenylene- or 1,4-phenylene, which optionally may bear one or two substituents selected from fluoro, amino-ureido, methoxy and trifluoromethyl; in which R ¹ is methyl, ethyl and allyl; and in which R ² and R ³ together form a group of the formula -A ² -X ² -A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, define a ring having 5 or 6 atoms in a ring, in which A ² is ethylene, A ³ is methylene or ethylene, and X ² is an oxy group and the cycle of which may bear one or two substituents selected from oxy, methyl and methoxy groups; or a pharmaceutically acceptable salt thereof.

An additional preferred compound of the present invention includes a heterocycle of formula I, in which Q is 1,2-dihydro-2-oxoquinolin-3-yl or 1,2-dehydro-2-oxoquinolin-6-yl, which is 1-substituent selected from methyl, ethyl, 2-fluoroethyl and benzyl; in which a represents methylene; in which X represents an oxy group; in which Ar is 1,3-phenylene which may carry one or two substituents selected from fluoro, amino, and trifluoromethyl; in which R ¹ represents methyl, ethyl or allyl; and in which R ² and R ³ together form a group of the formula -A ² -X ² -A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having 5 or 6 atoms in a ring, in which A ² represents ethylene, A ³ represents methylene or ethylene, and X ² represents an oxy group, and the cycle of which may be a methyl substituent located in the alpha position to X ² ; or a pharmaceutically acceptable salt thereof.

 Specific preferred compounds of the invention include, for example, the following heterocycles of formula I or pharmaceutically acceptable salts thereof: 4-methoxy-4- [3- (2-pyridyl) prop-2-in-1-yloxy) phenyl] tetrahydropyran, 4 - [5-fluoro-3- (3- (2-pyridyl) propi-2-yn-1-yloxy) phenyl] -4-methoxytetrahydropyran, 4- [5-fluoro-3- (quinoxaline-6-ylmethyloxy ) -phenyl] -4-methoxytetrahydropyran. (2RS, 4SR) -4- [5-fluoro-3- (quinoxaline-6-ylmethoxy) phenyl] -4-methoxy-2-methyltetrahydropyran, 4- [3- (1,2-dihydro-1- methyl-2-oxoquinolin-3-ylmethoxy) phenyl] -4-methoxytetrahydropyran, 4- [5-fluoro-3- (6-quinolylmethoxy) phenyl] -4-methoxytetrahydropyran, 4- [3- (1,2- dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4-methoxy tetragi drop 4- [5-fluoro-3- (1,2-dihydro-1-methyl-2-oxoquinolin-6- ylmethoxy) -phenyl] -4-methoxy-tetrahydropyran, 4-allyloxy-4- [5-fluoro-3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] - tetrahydropyran, 4- [5-fluoro-3- (1,2-dihydro-1- (2-fluoroethyl) -2-oxoquinolin-6-yl-methoxy) phenyl] -4-label- sitetrahydropyran, 4- [2,5-difluoro-3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4-methoxytetrahydropyran, 4- [3- ( 1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -5-trifluoromethylphenyl] -4-methoxytetrahydropyran, 4-allyloxy-4- [3- (1,2-dihydro-1-methyl- 2-oxo-quinolin-6-ylmethoxy) -5-trifluoromethyl-phenyl] -tetrahydropyran, (2RS, 4SR) -4- [5-fluoro-3- (1,2-dihydro-1-methyl-2-oxoquinolin- 6-ylmethoxy) phenyl] -4-methoxy-2-methyltetrahydropyran, (2RS, 4SR) -4- [5-fluoro-3- (1,2-dihydro-1-ethyl-2-oxoquinolin-6-ylmethoxy ) -phenyl] -4-methoxy-2-methyltetrahydropyran, (2RS, 4SR) -4- [5-amino-3- (1,2-dihydro-1-methyl-2-oxoquine olin-6-ylmethoxy) phenyl] -4-methoxy (2S, 4R) -4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4- methoxy-2-methyltetrahydropyran, (2S, 4R) -4- [5-fluoro-3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4-meth - xi-2-methyltetrahydropyran and (2RS, 3SR) -3- [5-fluoro-3- (1,2-dihydro-1-ethyl-2-oxoquinolin-6-ylmethoxy) phenyl] -3-methoxy -2-methyltetrahydrofuran.

A compound of the present invention, comprising a heterocycle of formula I or a pharmaceutically acceptable salt thereof, can be prepared by any method known to be useful for preparing structurally related compounds. Such techniques are offered as an additional feature of the present invention and are illustrated by the following examples, in which, unless otherwise indicated, Q, A. X, Ar, R ¹ , R ² and R ³ have any of the meanings defined above.

(a). Alkylation, in the presence of a suitable reagent, of a compound of formula II with a compound of formula Q-A-Z in which Z is a substituted group, provided that when there is an amino, imino, alkylamino, hydroxy or carboxyl group in Q, Ar , R ¹ , R ² or R ³ , any amino, imino, alkylamino or carboxyl group is protected by a conventional protecting group and any hydroxy group can be protected by a conventional protecting group or, conversely, no hydroxy group needs protection; after which any undesirable protecting group in Q, Ar, R ¹ , R ² or R ³ is removed using conventional methods.

 A suitable substituted group Z is, for example, a halide, sulfonyloxy or hydroxy group, for example, a chloro, bromo, iodo, methanesulfonyloxy or toluene-para-sulfonyloxy group.

A suitable reagent for the alkylation reaction when Z is a halide or sulfonyloxy group is, for example, a suitable base, for example, an alkali or alkaline earth metal carbonate, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. The alkylation reaction is preferably carried out in a suitable inert solvent or diluent, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range of, for example, from -10 to 150 ^o C, preferably at or near ambient temperature.

A suitable reagent for the alkylation reaction when it is a hydroxy group is, for example, a reagent obtained by reacting a compound of the formula Q-A-OH with azodicarboxylic acid di- (1-4C) alkyl ether in the presence of triarylphosphine, for example diethyl ether azodicarboxylic acid in the presence of triphenylphosphine. The alkylation reaction is preferably performed in a suitable inert solvent or diluent, for example acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature ranging, e.g., from 10 to 80 ° ^C, preferably at about ambient temperature.

 A suitable group for an amino, imino or alkylamino group is, for example, an acyl group, for example a (1-4C) alkanoyl group (especially acetyl) -, (1-4C) alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert- butoxycarbonyl), an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl). The deprotection conditions for said protecting groups inevitably differ with the choice of protecting group. Thus, for example, an acyl group, such as an alkanoyl, alkoxycarbonyl or arsyl group, can be removed, for example, by hydrolysis with an appropriate base, such as an alkali metal hydroxide, for example, lithium or sodium hydroxide. Alternatively, an acyl group, such as a tert-butoxycarbonyl group, can be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric or phosphoric acid, or trifluoroacetic acid, and an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group, can be removed. for example, by hydrogenation over a catalyst such as palladium on charcoal.

 On the other hand, an amino protecting group located, for example, a benzylidene group, is formed by reacting an amino group and a benzaldehyde, such as, for example, benzaldehyde itself. The benzylidene protecting group can be removed, for example, by oxidative hydrolysis in the presence of an appropriate acid, such as hydrochloric, sulfuric or phosphoric acid. A suitable oxidizing agent is, for example, an alkali or alkaline earth metal zeanate, such as, for example, sodium or potassium cyanate.

 A suitable protecting group for a carboxyl group is, for example, an esterifying group, for example, a (1-4C) alkyl group (especially methyl or ethyl) or an arylmethyl group (especially benzyl). The deprotection conditions for the above protecting groups inevitably differ with the choice of protecting group. Thus, for example, an esterifying group, such as an alkyl or arylmethyl group, can be removed, for example, by hydrolysis with an appropriate base, such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an esterifying group, such as an arylmethyl group, can be removed, for example, by hydrogenation over a catalyst such as palladium on charcoal.

 A suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (1-4C) alkanoyl group (especially acetyl), an aroyl group (especially benzoyl) or an arylmethyl group (especially benzyl). The deprotection conditions for the above protecting groups must inevitably differ with the choice of protecting group. For example, an acyl group, such as an alkanesyl or aroyl group, can be removed, for example, by hydrolysis with an appropriate base, such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an arylmethyl group, such as a benzyl group, can be removed, for example, by hydrogenation over a catalyst, such as palladium on charcoal.

The starting materials of formula II can be obtained using conventional methods of organic chemistry. The preparation of examples of such starting materials is described in the accompanying non-limiting examples, which are offered for illustrative purposes only. Other necessary starting materials are obtained by similar methods, which are described or by modifying them, which are in the possibilities of the usual skill of an organic chemist. For example, a starting material of formula II can be obtained, for example, by removing protection from a protected heterocycle of formula III in which R ⁴ is a protecting group and X, Ar, R ¹ , R ² and R ³ are as defined above.

A suitable protecting group R ⁴ is, for example, an arylmethyl group (especially benzyl), a tri- (1-4C) alkylsilyl group (especially trimethylsilyl or tert-butyldimethylsilyl), an aryldi (1-4C) alkylsilyl group (especially dimethylphenylsilyl), (1-4C) -alkyl group (especially methyl), (1-4C) -alkoxymethyl group (especially methoxymethyl) or tetrahydropyryl group (especially tetrahydropyran-2-yl). The deprotection conditions for said protecting groups must inevitably change with the choice of protecting group. For example, an arylmethyl group, such as a benzyl group, can be removed, for example, by hydrogenation over a catalyst, such as palladium on charcoal. Alternatively, a trialkylsilyl or aryl dialkylsilyl group, such as a tert-butyldimethylsilyl or dimethylphenylsilyl group, can be removed, for example, by treatment with an appropriate acid, such as hydrochloric, sulfuric, phosphoric or trifluoroacetic acid, or with alkali metal or ammonium fluoride such as sodium fluoride, preferably tetrabutylammonium fluoride. Alternatively, the alkyl group can be removed, for example, by treatment with a (1-4C) -alkyl metal sulfide, such as sodium ethyl thiolate, or, for example, by treatment with an alkali metal diaryl phosphide, such as lithium diphenyl phosphide, or, for example, by treatment with boron or aluminum trihalide, such as boron tribromide. Alternatively, the (1-4C) alkoxymethyl group or tetrahydropyryl group can be removed, for example, by treatment with an appropriate acid, such as hydrochloric or trifluoroacetic acid.

The protecting group R ⁴ may be, for example, a tri- (1-4C) -alkyl group which can be removed, while a protecting group for any amino, imino, alkylamino, carboxyl or hydroxy group in Ar , R ¹ , R ² or R ^{3 is} retained.

The protected starting material of formula III can be obtained by standard methods of organic chemistry, as presented in non-limiting examples. For example, a protective starting material of formula III in which R ⁴ is as defined above can be obtained by alkylation of a tertiary alcohol of formula IV with an alkylating agent of formula R ¹ -Z, in which Z is a substituted group as defined above, except hydroxy -groups, in the presence of an appropriate base, as defined above, and provided that any amino, imino, alkylamino or hydroxy group in Ar, R ² or R ^{3 is} protected by a conventional protecting group.

The tertiary alcohol of the starting material of formula IV can be obtained by reacting a compound of the formula R ⁴ —X — Ar — Z, in which R ⁴ and Ar are as defined above, and Z is a halide group, as defined above, and provided that any the amino, alkylamino or hydroxy group in A is protected by a conventional protecting group or with an organometallic compound of the formula R ⁵ -M, in which R5 is a (1-6C) -alkyl group, such as boryl, and M is a metal group, for example lithium to obtain the organometallic compound form R ⁴ —X — AM — either with a metal such as magnesium to obtain an organometallic compound of the formula R ⁴ —X — Ar — M — Z; after which any of these organometallic compounds can be reacted with a ketone of the formula R ² —CO — R ³ in which R ² and R ³ are as defined above, and provided that any imino or hydroxy group in R ² and R ^{3 is} protected by a conventional protecting group.

(b) Alkylation, in the presence of a corresponding base as defined above, of a compound of formula V with a compound of formula R ¹ -Z, in which R ¹ and Z are as defined above, provided that when amino, imino, alkylamino, hydroxy, or a carboxyl group a Q, X, Ar, R ² or R ³ , any amino, imino, alkylamino, hydroxy or carboxyl group is protected by a conventional protecting group; after which any undesirable protecting group in Q, X, Ar, R ² or R ³ is removed by conventional means.

The starting materials of formula V can be obtained by standard methods of organic chemistry. Examples of the preparation of such starting materials are described in non-limiting examples of the invention, which are offered for the purpose of explanation only. Other necessary starting materials can be obtained by similar methods that are described, or by modifying the methods that are within the capabilities of the ordinary skill of an organic chemist. Thus, the tertiary alcohol of the starting material of formula V can be obtained, for example, by alkylation, in the presence of an appropriate base, of a compound of the formula HX-Ar-Z, in which Ar is as defined above and Z is a halide group, as defined above, with a compound of the formula Q-A-Z, in which Q, A and Z are as defined above, and provided that any amino, alkylamino, carboxyl and hydroxy group in Q or Ar is protected by a conventional protecting group to obtain a compound formulas Q-A-X-Ar-Z. On the other hand, a compound of formula Q-A-X-Ar-Z can be obtained, for example, by alkylation, in the presence of an appropriate base, of a compound of formula Q-A-XN, in which Q, A and X are as defined above, with a compound of the formula Z-Ar-Z, in which Z and Ar are as defined above. The reaction product thus obtained can be treated with either an organometallic compound of the formula R ⁵ -M, in which R ⁵ is a (1-6C) -alkyl group, such as butyl, and M is a metal group, for example, lithium, to obtain an organometallic compound of the formula Q-A-X-Ar-M, or with a metal such as magnesium, to obtain an organometallic compound of the formula Q-A-X-Ar-M-Z. Any of these organometallic compounds may be reacted with a ketone of formula R ² —CO — R ³ , provided that any imino or hydroxy group in X, R ² or R ^{3 is} protected by a conventional protecting group to give the desired tertiary alcohol of the starting material. substances of the formula V.

(in). To obtain those compounds of formula I in which A represents a (3-6C) alkynylene group, the coupling reaction is carried out in the presence of an appropriate organometallic compound between a heterocyclic compound of the formula QZ in which Q is as defined above and Z is a halide group, such as iodine, and an ethynyl compound of the formula VI in which A ¹ is (1-4C) alkynylene and X, Ar, R ¹ , R ² and R ³ are as defined above.

A suitable organometallic catalyst is, for example, any reagent known in the art for such a coupling reaction. For example, the corresponding reagent is formed when, for example, bis (triphenylphosphine) palladium chloride or tetrakis (triphenylphosphine) palladium and copper halide, for example copper (I) iodide, are mixed. The coupling reaction is conducted in most cases in a suitable inert solvent or diluent, for example atsetonitrale, 1,2-dimethoxyethane, toluene or tetrahydrofuran, at a temperature ranging, e.g., from 10 to 80 ° ^C, preferably at or near 30 ^{° C,} and in the presence of an appropriate base, such as, for example, tri- (1-4C) -alkylamine, such as triethylamine, or a cyclic amine, such as piperidine.

An ethyl compound of formula VI used as a starting material can be obtained, for example, by alkylation, in the presence of an appropriate base, of a compound of formula II in which X, Ar, R ¹ and R ³ are as defined above, with an alkylating reagent of formula H -C≡C-A ¹ -Z, in which A ¹ has the meaning defined above, and Z is a halide group, and provided that any amino, alkylamino, carboxyl or hydroxy group in Ar, R ¹ , R ² or R ^{3 is} protected by a conventional protecting group.

(g). To obtain those compounds of formula I in which Ar is an alkylsulfinyl or alkylsulfonyl substituent, in which X is a sulfinyl or sulfonyl group, or in which R ² and R ³ together form a group of the formula -A ² -X ² -A ³ -, which is one or two alkylsulfinyl or alkylsulfonyl groups, and X ² is a sulfinyl or sulfonyl group, oxidize a compound of formula I in which Ar carries an alkylthio substituent. X-thio group, or in which R ² and R ³ together form a group of the formula -A ² -X ² -A ³ -, which bears one or two alkylthio groups in which X ² is a thio group.

A suitable oxidizing agent is, for example, any reagent known in the art for oxidizing a thio group to sulfinyl and / or sulfonyl, for example hydrogen peroxide, peroxyacid (such as 3-chloroperbenzoic or peracetic acid), alkali metal persulfate (such as monopersulfate potassium), chromium trioxide or gaseous oxygen in the presence of platinum. Oxidation is in most cases translated under as mild conditions as possible and with the required stoichiometric amount of oxidizing agent in order to reduce the risk of excessive oxidation and damage to other functional groups. In general, the reaction is carried out in an appropriate solvent with a diluent, such as methylene chloride, chloroform, acetone, tetrahydrofuran or tetrabutyl methyl ether, and at a temperature, for example, or tert-butyl methyl ether, and at a temperature, for example, at or near ambient temperature, i.e. in the range from 15 to 35 ^C. When the connection is required tionilnoy group can be used as a soft oxidant, for example sodium or potassium metaperiodate, preferably in a polar solvent such as acetic sour one or ethanol. It should be understood that when a compound of formula I containing a sulfonyl group is desired, it can be obtained by oxidation of the corresponding thionyl compound as well as the corresponding thio compound.

 (e). To obtain those compounds of formula I in which Ar carries an alkanesylamine substituent, a compound of formula I in which Ar carries an amino substituent is acylated.

A suitable acylating reagent is, for example, any reagent known in the art for acylating an amino group to an acylamino group, for example an acyl halide, for example (2-6C) alkanoyl chloride or bromide, in the presence of an appropriate base; alkanecarboxylic acid anhydride, for example, (2-6C) alkanecarboxylic acid anhydride; or mixed alkane carboxylic acid anhydride, for example mixed acid anhydride formed by the reaction of alkane carboxylic acid and (1-4C) alkoxycarbonyl halide, for example (1-4C) alkoxycarbonyl chloride, in the presence of an appropriate base. Generally the reaction is carried out in a suitable solvent or diluent such as methylene chloride, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example at or near ambient temperature, that is in the range from 15 to 35 ^C. The corresponding the base, if required, is, for example, niridine, 4-dimethylaminoniridine, triethylamine, ethyldiisopropylamine, N-methylformolin, an alkali metal carbonate, for example potassium carbonate, or an alkali metal carboxylate, for example sodium acetate.

(e). To obtain those compounds of formula I in which R ¹ is alkanoyl or benzoyl, optionally having a substituent, as defined above, a compound of formula I in which R ¹ is hydrogen is acylated. To obtain compounds of formula I in which R ¹ is alkanoyl, the acylation reaction is carried out using, for example, a suitable acylating reagent, as defined above. To obtain compounds of formula I in which R ¹ is benzyl, optionally substituted, acylation can be carried out using, for example, benzoyl halide, for example benzoyl chloride or bromide, in the presence of an appropriate base, as defined above.

(g). To obtain those compounds of formula I in which A is alkenylene or R ¹ is alkenyl, the corresponding compound in which A is alkynylene or R ¹ is alkynyl is reduced. Generally, conditions that are standard in the art for reducing an alkynyl or alkynylene group are used. For example, reduction can be carried out by hydrogenating a solution of an alkynyl or alkynylene compound in an inert solvent or diluent in the presence of an appropriate metal catalyst. A suitable inert solvent is, for example, an alcohol, for example methanol or ethanol, or an ether, for example tetrahydrofuran or tert-butyl methyl ether. A suitable metal catalyst is, for example, palladium or platinum on an inert support, for example charcoal or barium sulfate.

Preferably, a palladium-barium sulfate catalyst is used to substantially prevent excessive reduction of the alkynyl or alkynylene group to an alkyl or alkylene group, respectively. The reaction in most cases is carried out at or near ambient temperature, that is, in the range from 15 to 35 ^about C.

Additionally, the reduction can be carried out by treating a solution of an alkynyl or alkynylene compound in an inert solvent or diluent with a suitable mixture, such as a 1: 1 mixture of an organometallic hydride, e.g. di- (1-6C) -alkyl aluminum hydride, such as diisobutyl aluminum hydride, and metal alkyl, e.g. (1 -6C) -alkyl lithium, such as methyl lithium. A suitable inert solvent or diluent is, for example, tetrahydrofuran, diethyl ether or tert-butyl methyl ether, and the reaction is conducted at a temperature, for example in the range from ^-25 ° C to ambient temperature (especially -10 ^to 10 ° C).

 (h). In order to obtain those compounds of formula I in which Q carries an alkyl or substituted alkyl substituent on an available nitrogen atom, or in which Ar carries an alkoxy or substituted alkoxy substituent, a compound of formula I in which Q carries a hydrogen atom on said available nitrogen atom is alkylated or in which Ar carries a hydroxy substituent.

A suitable alkynizing reagent is, for example, any reagent known in the art for the alkylation of an available nitrogen atom, through hydroxy groups to an alkoxy or substituted alkoxy group; for example, alkyl or substituted alkoxy groups; for example, an alkyl or substituted alkyl halide, for example (1-6C) -alkyl chloride, bromide or iodide, or substituted (1-4C) -alkyl chloride, bromide or iodide, in the presence of an appropriate base. A suitable base for the alkylation reaction is, for example, an alkali metal or alkaline earth metal carbonate, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. The alkylation reaction is preferably performed in a suitable inert solvent or diluent, for example N, N-dimethylformamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature ranging, e.g., from 10 to ¹⁵⁰ ° C, preferably at or near ambient temperature.

 (and). To obtain compounds of formula I in which Q or Ar carries an amino substituent, a compound of formula I in which Q or Ar carries a nitro substituent is reduced.

 A suitable reducing agent is, for example, any reagent known in the art for reducing a nitro group to an amino group. For example, reduction can be carried out by hydrogenating a solution of the nitro compound in an inert solvent or diluent in the presence of an appropriate metal catalyst, for example, finely ground platinum metal (obtained by reducing platinum oxide in situ). A suitable inert solvent or diluent is, for example, an alcohol, for example methanol, ethanol or isopropanol, or an ether, for example tetrahydrofuran.

An additional suitable reducing agent is, for example, an activated metal, such as activated iron (obtained by washing the iron powder with a dilute acid solution, such as hydrochloric acid). For example, the reduction may be carried out by heating a mixture of the nitro compound and the activated metal in a suitable solvent or diluent such as a mixture of water and an alcohol, such as methanol or ethanol, to a temperature in the range, for example from 50 to ¹⁵⁰ ° C, preferably at or at about 70 ° ^C.

 When a pharmaceutically acceptable salt of a new compound of formula I is required, it can be prepared, for example, by reacting said compound with an appropriate acid or base, using a conventional procedure. When an optically active form of a compound of formula I is required, it can be obtained by one of the above procedures using the optically active starting material, as shown in the accompanying non-limiting examples of the present invention, or by resolving the racemic form of the compound using a conventional procedure.

 Many of the intermediates defined in the invention are new, for example, intermediates of formula V, and they are provided as an additional feature of the present invention.

As previously established, heterocycles of formula I are inhibitors of the 5-LO enzyme. The effect of this inhibition can be demonstrated using one or more of the standard methods:
a). Spectrophotometric analysis method of an in vitro enzyme test, which evaluates the inhibitory properties of the test compound in a cell-free system, in relation to the 5-LO enzyme made from neutrophils (neutrophilic leukocytes) of guinea pigs; the method described by D. Aharoni and R. L. Stein (D. Ahareny and RL Stein, J. Biol. Chem, 1986, 261 (25), 11512-11519). This test gives the value of its own inhibitory activity against 5-LO dissolved in a cell-free medium.

b) An in vitro assay involves incubating the test compound with human heparin-containing blood prior to the administration of the calcium ionophore A23187, and then directly inhibitory effect of 5-LO is measured by determining the amount of LTV ₄ using a specific radioimmunoassay described by Carey and Forder (F. Carey and RA Forder, Brit. J. Pharmacoe, 1985, 84, 34P), which involves the use of the protein-LTV ₄ conjugate obtained by using the methodology of Yang et al. (Joung et al. P.rostaglandis 1983, 24 (4), 605- 613). The effects of the test compound on the cyclooxygenase enzyme (which is involved in an alternative metabolic pathway for arachidonic acid and leads to prostaglandins, thromboxanes and related metabolites) can be measured at the same time using the specific radioimmunoassay for thromboxane B ₂ (TxB ₂ ) described by Carey and Forder. This test is an indicator of the effects of the test compound against 5-LO, as well as cyclooxygenase in the presence of blood cells and blood proteins. This allows us to assess the selectivity of the inhibitory effect on 5-LO or cyclooxysenase.

c) An ex vivo assay system, which is a variation of test b) above, which includes the administration of the test compound (usually orally in the form of a suspension obtained by adding a solution of the test compound in dimethyl sulfoxide and carboxymethyl cellulose), blood collection, its heparinization, infection with A23187 and radioimmunological analysis of LTV ₄ and TxV ₂ . This test provides an indicator of the bioavailability of the test compound as an inhibitor of 5-LO or cyclooxygenase.

d). An in vitro assay system comprising measuring the inhibitory properties of the test compound against free release (release) of LTS ₄ and PCE ₂ induced by zymosan on resident peritoneal microphages of mice using the Humez method (IL Humes et al. Biochem. Pharmacol. 1983, 32, 2319-2322) and conventional radioimmunoassay systems to measure the amounts of LTS ₄ and RFE ₂ . This test provides an indicator of inhibitory activity against 5-LO and cyclooxygenase in a non-protein system.

 e). An in vivo analysis system, including measuring the action of a test compound in inhibiting the inflammatory response to arachidonic acid on a model of rabbit skin developed by D, Aked et al. (D. Aked et alia British I. Pharmacol. 1986, 89, 431-438). This test provides an in vivo model for 5-LO inhibitors administered locally or orally.

 e). An in vivo analysis system, including measuring the effects of a test compound, administered orally or intravenously on a leukotrione-dependent bronchostenosis, induced by antigenic infection of guinea pigs pre-dosed with antihistamine (mepiramine), beta-adrenergic blocking agent (propanolol), and cyclooxygenesis inhibitor (indole) the methodology of W. H. Anderson et al. (WH Anderson et al. British I. Pharmacology, 1983, 78 (1), 67-574). This test provides an additional in vivo assay for the determination of 5-LO inhibitors.

Although the pharmacological properties of the compounds of formula I change with structural changes, as expected, in general, compounds of formula I have inhibitory effects on 5-LO at the following concentrations or doses in one or more of the above tests a) - e): (1C inhibitory concentration; ED effective dose) Test a): 1C ₅₀ within,
example, 0.01-
30 μmol; Test b): 1C ₅₀ (LTV4) before
Lah, for example, 0.01-
40 μmol;
1С ₅₀ (ТхВ ₂ ) before
lah, for example, 40-
200 μmol; Test c): oral dosage unit ₅₀
(LTV ₄ ) within
example, 5-200 mg / kg; Test d): 1C ₅₀ (LTS ₄ ) before
Lah, for example, 0.001-
1 μmol;
1C ₅₀ (RGE ₂ ) within
e.g. 20-
1000 μmol); Test e): inhibition of inflammation
laziness within
example, 0.3-100 mcg
intradermally (intra-
ribperitoneally); Test e): AU ₅₀ within
example, 0.5-10 mg / kg
intravenously.

 Supertoxicity and other directed effects are not manifested (not given) during tests c); e) and / or e) when the compounds of formula I are administered at various multiple numbers of their minimum inhibitory dose or concentration.

Thus, by way of example, the compound 4-methoxy-4- [3- (3- (2-pyridyl) prop-2-yn-1-yloxy) phenyl] tetrahydropyran has 1C ₅₀ 2.0 μmol against LTV ₄ and more than 40 μmol against ThB ₂ when tested b), and oral ED ₅₀ less than 100 mg / kg against LTV ₄ when tested c), compound 4- [5-fluoro-3- (6-quinolylmethoxy) phenyl] - 4- methoxytetrahydropyran has a lС _{50 of} 0.1 μmol against OTV ₄ when tested b), and an oral ED _{50 of} 8 mg / kg against LTV ₄ when tested c), and compound 4- [3- (1,2-dihydro-1- methyl-2-oxoquinolin-6-ylmethoxy) -phenyl] -4-methoxytetrahydropyran has lC ₅₀ 0.03 μmol against OTV ₄ when tested b), and oral ED ₅₀ 3 mg / kg against LTV ₄ when tested c). In general, particularly preferred compounds of formula I are those having lC ₅₀ less than 1 μmol against LTB ₄ and more than 40 μmol against TxB ₂ in test b) and an oral ED _{50 of} less than 100 mg / kg against LTV ₄ in test c).

 These compounds are examples of heterocycles of the present invention that exhibit selective inhibitory properties for 5-LO, as opposed to cyclooxygenase, the selective properties of which are expected to confer improved therapeutic properties, for example, reducing or eliminating side effects in the gastrointestinal tract often associated with cyclooxygenase inhibitors such as indomethacin.

 According to an additional feature of the invention, there is provided a pharmaceutical composition which comprises a heterocycle of formula I, or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable diluent or carrier.

 The composition may be in a form suitable for oral use, for example, a tablet, capsule, aqueous or oily solution, suspension or emulsion; for local (local) use, for example, cream, ointment, gel, or an aqueous or oily solution or suspension; for nasal (nasal) use, for example, medicinal powder for inhalation through the nose, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example, as a finely ground powder or liquid aerosol; for sublingual or intraoral (buccal) use, for example tablets or capsules; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example, a sterile aqueous or oily solution or suspension. In general, these compositions can be prepared in a conventional manner using conventional excipients.

 The amount of active ingredient (i.e., a heterocycle of formula I or a pharmaceutically acceptable salt thereof) that combine with one or more excipients to form a unit dosage form will inevitably vary depending on the organism being treated (disease carrier) and the particular method of administration. For example, the technology for the preparation of a medicinal product intended for oral administration in most cases will contain, for example, from 0.5 to 2 g of the active ingredient mixed with an appropriate or suitable amount of excipients, which can vary from about 5 to 98 wt. of the total amount of composition. Unit dosage forms in most cases should contain from about 1 mg to about 500 mg of the active ingredient.

 According to an additional feature of the invention, there is provided a heterocycle of formula I, or a pharmaceutically acceptable salt thereof, for use in a therapeutic method for treating humans or animals.

 The invention also includes a method of treating a disease or condition related to conservative treatment of an intermediate (condition) solely or partially by one or more leukotrienes, which (method) comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above. The invention also provides the use of such an active ingredient in the preparation of a new drug for use in a disease or medical condition, when leukotriene is an intermediate.

 The dose size for therapeutic or prophylactic purposes when using a heterocycle of formula I should naturally vary according to the nature and severity of the conditions, age and sex of the animal or patient and the method of administration, according to well-known principles of conservative treatment. As mentioned above, the heterocycles of formula I are useful in the treatment of those allergic and inflammatory conditions that are caused solely or partially by the effects of arachidonic acid metabolites arising from the linear pathway of metabolism (catalyzed by 5-LO) and especially leukotrienes, the preparation of which is intermediate link under the action of 5-LO. As mentioned previously, such conditions include, for example, asthmatic conditions, allergic shock, allergic reactions, allergic rhinitis, psoriasis, atopic dermatitis, cardiovascular and cerebrovascular disorders of an inflammatory nature, arthritic and inflammatory joint damage, and inflammatory intestinal diseases.

 When using the compounds of formula I for therapeutic and prophylactic purposes, in most cases they should be administered so that a daily dose in the range of, for example, from 0.5 to 75 mg per 1 kg of live weight is obtained, providing, if required, in divided total doses. In general, lower doses should be given when the parenteral route of administration is used. For example, for intravenous administration, in most cases a dose is used in the range, for example, from 0.5 to 30 mg per 1 kg of live weight. Similarly, for administration by inhalation, a dose should be used in the range of, for example, from 0.5 to 25 mg per 1 kg of live weight.

 Although the compounds of formula I are mainly valuable as therapeutic agents for use in warm-blooded animals (including humans), they are also useful whenever it is desired to inhibit the 5-LO enzyme. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.

 Due to their actions on the production of leukotriene, the compounds of formula I have certain cytotoxic effects, for example, they are useful in reducing or suppressing some of the adverse gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), inhibition of cyclooxygenase, such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. In addition, the co-administration of a 5-LO inhibitor of formula I together with NSAIDs can lead to a decrease in the amount of the last drug needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side effects. According to a further feature of the present invention, there is provided a pharmaceutical composition which comprises a heterocycle of formula I, or a pharmaceutically acceptable salt thereof, as defined above, in combination or in place with a non-steroidal anti-inflammatory cyclooxygenase inhibitor (such as the one mentioned above), and a pharmaceutically acceptable diluent or carrier .

 The cytoprotective effects of compounds of formula I can be demonstrated, for example, in a standard laboratory model that evaluates protection against indomethacin-induced or ethanol-induced ulcer formation in the gastrointestinal tract of rats.

 The compositions of the present invention may also contain one or more therapeutic or prophylactic agents, which are known to be valuable to the disease during treatment. For example, a known platelet aggregation inhibitor (blood platelets), a lipid-lowering agent (a blood lipid lowering agent), an antihypertensive agent (an anti-arterial pressure increasing agent), a beta-adrenergic blocker or a vasodilator (vasodilator) may also be useful in the pharmaceutical composition of the present invention for use in the treatment of a cardiac or vascular disease or condition. Similarly, as an example, an antihistamine, a steroid (such as beclomethasone dipropionate), sodium cremoglucate, a phosphodiesterase inhibitor, or a beta adrenergic stimulant may also be useful in the pharmaceutical composition of the invention for use in the treatment of pulmonary diseases or conditions.

 The compounds of formula I can also be used in combination with leukotriene antagonists, such as known antagonists.

The invention is illustrated by non-limiting examples, in which, unless otherwise indicated:
a) evaporation was carried out by rotary evaporation under vacuum, and processing procedures were carried out after removal of residual solids by filtration;
b) operations were carried out at room temperature, that is in the range 18-20 ^C and under an atmosphere of an inert gas such as argon;
c) column chromatography (by flash procedure) and medium-pressure liquid chromatography (GHSD) were carried out on Merck kieselguhr silica (Ref. 9385) obtained from E. Merck, Darmstat. West Germany
d) the output is presented only for clarification, and is not necessarily the maximum achieved;
d) the target products of formula I have satisfactory microanalysis and their structures were confirmed by NMR and mass spectral methods;
f) the intermediates in most cases are incompletely characterized, and the purity was assessed using thin-layer chromatography, infrared (IR) or NMR analysis;
g) the melting points are uncorrected and were determined using a Mettler SP62 instrument for automatically determining the melting temperature or an oil-bath apparatus; melting points for the desired products of formula I were determined after recrystallization from a conventional organic solvent, such as ethanol, methanol, acetone, ether or hexane, individually or in a mixture; and
h) a specific rotation (alpha) ^t, of plane polarized light was determined using the sodium D line (5890 Angstroms), at ²⁰ ° C, and in most cases using a sample concentration approximately equal to 1 g per 100 ml solvent.

Example 1. A mixture of 3 g of 3-bromomethyl-1,2-dihydro-1-methylquinolin-2-one, 2.1 g of 4- (3-hydroxyphenyl) -4-methoxytetrahydropyran, 1.67 g of potassium carbonate and 16 ml of dimethylformamide are stirred at ambient temperature for 15 hours. The mixture is partitioned between layers of methylene chloride and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 1: 1 mixture by volume of toluene and ethyl acetate as eluent. Thus, 3.5 g (92%) of 4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-3-ylmethoxy) phenyl] -4-methoxy tetrahydropyran with a melting point of. 135 ^about S.

 The starting material for 3-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is prepared as follows.

To a stirred suspension of 1 g of 1,2-dihydro-2-oxoquinoline-3-carbaldehyde in 10 ml of dimethylformamide, which is cooled in an ice bath, 0.268 g (55 wt% suspension in oil) of sodium hydride is added in portions, then the mixture was chilled in an ice bath. The mixture was allowed to warm to ambient temperature and then heated to ⁶⁰ ° C for 1 h. The mixture was again cooled in an ice bath and to the mixture was added 0.41 ml of methyl iodide. 50 ml of dimethylformamide was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into 50 ml of water and extracted with methylene chloride (3 x 50 ml). The combined extracts were washed with 50 ml of water and evaporated. The residue was triturated under diethyl ether to give 1,2-dihydro-1-methyl-2-oxoquinoline-3-carbaldehyde as a pale yellow solid (0.81 g, 74%).

 The reaction product thus obtained is converted to 3-bromomethyl-1,2-dihydro-1-methylquinolin-2-one using a known procedure (Chem. Pharm. Bull, 1985, 33, 3775) to convert 1,2-dihydro-2 -oxyquinoline-3-carbaldehyde; and 3-bromomethyl-1,2-dihydroquinolin-2-one.

 4- (3-Hydroxyphenyl) -4-methoxytetrahydropyran, used as starting material, is prepared as follows.

3-Methoxymethoxyphenyl bromide is prepared by the reaction of 3-bromophenol and dimethoxymethane using the general procedure described in Synthesis, 1976, 244. The Grignard reagent is obtained by heating a mixture of 3-methoxymethoxyphenyl bromide (6 g), magnesium (0.66 g) and 34 ml tetrahydrofuran and 30 ^{° C} for 2 hours. The Grignard reagent was cooled to ambient temperature and added dropwise to a solution of 2.76 g of tetrahydropyran-4-one in 2 ml of tetrahydrofuran. The mixture was stirred at ambient temperature for 15 hours and evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 9: 1 by volume mixture of methylene chloride and diethyl 4- (3-methoxymethoxyphenyl) tetrahydropyran as an oil.

A mixture of the reaction product thus obtained, 0.74 g (55 wt% dispersion in mineral oil) of sodium hydride and 50 ml of tetrahydrofuran was stirred at ambient temperature for 15 minutes. 1.42 ml of methyl iodide and 0.1 g of 1,4,7,10-13-pentaoxacyclopentadecane (hereinafter 15-crown-5) are added and the mixture is stirred at ambient temperature for 15 minutes. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic layer was separated, washed with water, dried with MgSO ₄ and evaporated. Thus, 1.23 g (91%) of 4-methoxy-4- (3-methoxymethoxyphenyl) tetrahydropyran is obtained in the form of an oil.

A mixture of the reaction product thus obtained, 10 ml of concentrated hydrochloric acid, 40 ml of isopropanol and 160 ml of tetrahydrofuran was stirred at ambient temperature for 15 hours. The mixture was evaporated and the residue was partitioned between layers of ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 4: 1 mixture by volume of methylene chloride and diethyl ether as eluent. Thus, 0.57 g (56%) of 4- (3-hydroxyphenyl) -4-methoxytetrahydropyran is obtained in the form of a colorless oil.

PRI me R 2. The alkynization reaction described in example 1 is repeated except that the corresponding alkyl halide is used instead of 3-bromomethyl-1,2-dihydro-1-methylquinolin-2-one and the corresponding phenol instead of 4- ( 3-hydroxyphenyl) -4-methoxytetrahydropyrine. Thus, the compounds described in table. 1, in which is indicated:
a). 3- (2-Pyridyl) -prop-2-ion-1-yl bromide hydrobromide used as starting material was prepared as follows: to a stirred mixture, 23.7 g of 2-bromopyridine, 1.54 g of bis- (triphenylphosphine chloride) ) -palladium, 21 ml of triethylamino, 1.5 g of iodide water (1) and 150 ml of acetonitrile are added dropwise 35 ml of 2-propyl alcohol, then the mixture is stirred at ambient temperature for 30 minutes and then heated to 60 ° C. for 2 hours. The mixture is cooled to ambient temperature, poured into 200 ml of water and neutralized by the addition of diluted water solution of hydrochloric acid. The mixture was extracted with methylene chloride (2 x 500 ml) and the combined extracts were washed with 500 ml of water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography, eluting with a 1: 1 by volume mixture of methylene chloride and ethyl acetate to obtain 14 g (70%) of 3- (2-pyridyl) prop-2-yn-1-yl alcohol, mp . 78-80 ^{° C} (recrystallized from a mixture of hexane and ethyl acetate). A solution of 3.1 ml of bromine in 3 ml of methylene chloride was added to a mixture of 10.1 g of triphenylphosphine and 72 ml of methylene chloride, which is (mixture) was cooled to -8 ^{° C} in a salted ice water. A solution of 4.8 g of the alcohol obtained immediately above in 36 ml of methylene chloride dobavdyayut to the mixture and the resulting mixture was stirred for 10 minutes and cooled to approximately -10 ^C. The mixture was filtered to give 5.8 g (58%) of hydrobromide 3- (2-pyridyl) -prop-2-yn-1-yl bromide, mp 112-114 ^about With, which is used without further purification.

 b) 2-Chloromethylpyridine chlorohydrate is used as an alkylating reagent.

in). 4- (4; 5-fluoro-3-hydroxyphenyl) -4-methoxytetrahydropyran, used as a starting material, is prepared as follows: 12.4 g (50 wt. % dispersion in mineral oil) sodium hydride and the resulting mixture was stirred at ambient temperature for 1 hour. 50 g of 1-bromo-3,5-difluorobenzene were added carefully to control the vigorous and resulting exothermic reaction. The mixture was stirred at a temperature and evaporated. The residue was partitioned between methylene chloride and water, then the organic phase was washed with water (4 x 50 ml), dried with MgSO ₄ and evaporated. The residue was purified by distillation to obtain 41.8 g (57%) of 2-benzyloxy-1-bromo-5-fluorobenzene as a colorless liquid (t. Bales. 124-130 ^C at 0.3 mmHg). A solution of a portion (9.75 g) of this product in 150 ml of tetrahydrofuran was cooled to -75 ° C. and n-butyllithium (1.6 M in hexane, 22 ml) was added dropwise. The mixture was stirred at -75 ^{° C} for 1 hour and then allowed to warm to 0 ^C. Add 50 mL of saturated aqueous ammonium chloride solution and the organic phase was separated, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 1: 1 by volume mixture of toluene and ethyl acetate as eluent. Thus, 7.4 g (71%) of 4- (3-benziolxy-5-fluorophenyl) -4-hydroxytetrahydropyran are obtained in the form of an oil.

After the reaction is repeated appropriately, the reaction product thus obtained (12.1 g) is dissolved in 150 ml of tetrahydrofuran and 2.11 g (50% by weight dispersion in mineral oil) of sodium hydride are added in portions. The mixture was stirred at ambient temperature for 1 hour, cooled in an ice bath, and 3.75 ml of methyl iodide was added dropwise. The mixture is stirred at ambient temperature for 18 hours, 3 drops of 2 N are added. aqueous hydrochloric acid and the organic solvent is evaporated. The residue was partitioned between ethyl acetate and water. The organic phase is separated, washed with water and a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. Thus, 12.5 g (99%) of 4- (3-benzyoloxy-5-fluorophenyl) -4-methoxytetrahydropyran are obtained in the form of a pale yellow oil, which are used without further purification.

A solution of the product thus obtained was hydrogenated in 100 ml of ethanol in the presence of a 10% palladium-charcoal catalyst for 3 hours. The mixture was filtered and the filtrate was evaporated. Thus, 7.7 g (86%) of 4- (5-fluoro-3-hydroxyphenyl) -4-methoxytetrahydropyran are obtained with a melting point of 123-124 ^about S.

 d). 6-Bromomethylquinonxaline used as an alkylating agent is described in K. Het, Chem, 1974, 11, 595.

 e). 3-Bromomethyl-1,2-dihydroquinolin-2-one (Chem. Pharm. Bull, 1985, 33, 3775) was used as an alkylating reagent.

e). 4- (3,5-dihydroxyphenyl) -4-methoxytetrahydropyran, used as the phenolic starting material, is prepared as follows: 3,5-dioxiodobenzene (Tech. I. Sci, 1977, 28, 253) reacts with two equivalents of benzyl bromide, using the procedure described in example 1 to obtain 3,5-dibenzyloxy iodobenzene in the form of an oil in 96% yield. This reaction product was reacted with n-butyllithium, using the specified method, except that reaktsiyub conducted at 4110 ^C. The organometallic reagent thus formed is reacted with tetrahydropyran-4-one using the procedure described above; the reaction product is methylated and this product is subjected to hydrogenolysis, using the procedure described in paragraph c). Thus, 4- (3,5-dioxiphenyl) -4-methoxytetrahydropyran is obtained in 40% yield based on 3,5-dibenzoyloxy iodobenzene.

 g). The corresponding phenol is prepared as follows: 4- (3,5-dioxiphenyl) -4-methoxytetrahydropyran is reacted with one equivalent of iodoacetonitrile using the procedure described in Example 1 to obtain 4- (3-cyanomethoxy-5-hydroxyphenyl) -4-methoxytetrahydropyran (27%) as an oil.

h). The alkylation reaction is conducted at ^-20 ° C for 15 hours and sodium hydride is used instead of potassium carbonate as a base in the reaction.

The corresponding phenol is prepared as follows: 3,5-dibromopyridine is reacted with one equivalent of benzyl alcohol to give 3-benzyloxy-5-bromopyridine (56%) using the procedure described in paragraph c). This product is reacted with n-butyllithium, using the specified method, except that the reaction was carried out at -110 ^C. The organometallic product formed thereby is reacted with tetrahydropyran-4-one, using the specified method; the reaction product is methylated and this product is subjected to hydrogenolysis. Thus, 4- (5-hydroxypyrid-3-yl) -4-methoxytetrahydropyran is obtained in a 47% yield based on 3-benziooxy-5-bromopyridine.

g). NMR spectrum: (CDL ₃ , delta magnitude) 1.57-2.07 (multiplet, 3H), 2.99 (singlet, 3H), 3.77-3.83 (multiplet, 4H), 4.95 ( singlet, 2H), 7.03-7.63 (multiplet, 7H), 8.6 (doublet, 1H).

** NMR spectrum (CDL ₃ , delta magnitude) 1.9 (multiplet, 4H), 2.95 (singlet, 3H), 3.85 (multiplet, 4P), 5.2 (singlet, 2H), 6, 6-6.85 (multiplet, 3H), 7.25 (triplet, 2H), 7.5 (doublet, 1H), 7.75 (triplet, 1H).

⁺ NMR spectrum: (CD3SOCD3, delta magnitude) 1.8-2.0 (multiplet, 4H), 2.9 (singlet, 3H), 3.6-3.8 (multiplet, 4H), 5.0 ( singlet, 2H), 6.75-6.9 (m, 3H), 7.15-8.1 (m, 5H).

PRI me R 3. To a mixture of 0.61 g of 4- [5-fluoro-3-2-propynyloxy) phenyl] -4-methoxytetrahydropyran, 0.52 g of 2-iodopyridine, 0.03 g of chloride bis- (triphenylphosphine) -palladium, 0.03 g of copper (I) iodide and 12 ml of acetonitrile add 0.35 ml of triethylamine and the mixture is stirred at ambient temperature for 5 hours. The mixture is separated into layers between ethyl acetate and water. The organic phase is separated into the aqueous phase, extracted with additional ethyl acetate. The combined organic extracts were washed with water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 1 1 v / v mixture of toluene and ethyl acetate as eluent. Thus, 0.47 g (60%) of 4- [5-fluoro-3- (3- (2-pyridyl) prop-2-yn-1-yloxy) phenyl] -4-methoxytetrahydropyran is obtained in the form of a pale yellow oil. NMR spectrum: (CDCl ₃ , delta magnitude) 1.95 (m, 4H), 3.0 (m, 3H), 3.8 (m, 4H), 4.95 (m, 2H), 6.72 (triplet, 2H), 6.87 (singlet, 1H), 7.3 (broad singlet, 2H), 7.68 (broad singlet, 1H), 8.6 (broad singlet, 1H).

4- [5-fluoro-3- (2-propynyloxy) phenyl] -4- methoxytetrahydropyran, used as a starting material, is obtained by alkylation of 4- (5-fluoro-3-hydroxyphenyl) -4-methoxytetrahydropyran 2-pro pinyl bromide using the procedure described for the alkylation reaction in example 1, except that acetone is used instead of dimethylformamide as a solvent for the reaction. The reaction product is obtained in 95% yield, and so pl. 75-76 ^about S.

Example 4. The alkylation reaction described in example 1 is repeated except that 6-bromomethylquinoxaline is used instead of 3-bromomethyl-1,2-dihydro-1-methylquinolin-2-one, and (2RS , 4SR) -4- (5-fluoro-3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran is used instead of 4- (3-hydroxyphenyl) -4-methoxytetrahydropyran. In this way, (2RS, 4SR) -4- [5-fluoro-3- (quinoxaline-6-ylmethoxy) phenyl] -4-methoxy-2-methyltetrahydro-pyro is obtained as an oil (45%). NMR spectrum: (CDCl ₃ , delta magnitude) 1.21 (doublet, 3H), 1.54 (doublet of doublets, 1H), 1.80-2.03 (multiplet, 3H), 2.98 (singlet, 3H), 3.77-3.97 (multiplet, 3H), 5.30 (singlet, 2H), 6.66 (doublet of triplets, 1H), 6.74 (doublet of triplets, 1H), 6.87 (triplet, 1H), 7.85 (doublet of doublets, 1H), 8.18 (multiplet, 2H), 8.89 (singlet, 2H);
Mass spectrum P m / e 382;
Elemental analysis:
Found, C, 68.8; H 6.2; N, 6.6;
C ₂₂ H ₂₃ FN ₂ O ₃
Calculated, C 69.1; H 6.1; N, 7.3.

 (2RS, 4SR) -4- (5-fluoro-3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran used as the starting material was prepared using the procedures described in Example 2, except that 2-methyltetrahydropyran -4-one (Amer. Chem. Soc. 1982, 104, 4666) is used instead of tetrahydropyran-4-one.

The residue containing the mixture of diastereoisomers was purified and the isomers were separated by column chromatography using a 5 1 v / v mixture of toluene and ethyl acetate as eluent. Thus, (2RS, 4SR) -4- (3-benzyloxy-5-fluorophenyl) -4-hydroxy-2-methyltetrahydropyran (24%) is obtained in the form of an oil, i.e., 2-methyl and 4-hydroxy- substituents are in transposition relative to each other; NMR spectrum: (CDL ₃ , delta magnitude) 1.20 (doublet, 3H), 1.58 (broad singlet, 1H, 0H), 1.52 (singlet, 2H), 1.99-2.14 (multiplet , 1H), 3.86-4.02 (multiplet, 3H), 5.05 (singlet, 2H), 6.60 (doublet of triplets, 1H), 6.90 (singlet, 1H), 7.28- 7.48 (multiplet, 5H, aromatic); and (2SR, 4SR) -4- (3-benzyloxy-5-fluorophenyl) -4-hydroxy-2-methyltetrahydropyran (48%), so pl. 82-83 ^about C, i.e. 2-methyl and 4-hydroxy substituents are in cis-relative positions; NMR spectrum (CDL ₃ , delta magnitude) 1.21 (triplet, 3H), 1.66 (doublet of doublets, 1H), 1.80 (broad singlet, 1H, 0H), 1.96 (triplet of doublets, 1H) 2.23-2.35 (multiplet, 2H), 3.30-3.42 (multiplet, 2H), 3.94 (doublet of quartets, 1H), 5.05 (singlet, 2H), 6.64 (doublet of triplets, 1H), 6.79 (doublet of triplets, 1H), 6.87 (singlet, 1H), 7.30-7.42 (multiplet, 5H, aromatic).

The (2RS, 4SR) -isomer is methylated and the benzyl protecting group is hydrogenated using the procedures described in paragraph c). Thus, the desired starting material is obtained (61%), mp. 127 ^about S.

Example 5. The procedure described in example 4 is repeated except that another diastereoisomer is used, namely (2SR, 4SR) -4- (5-fluoro-3-hydroxyphenyl) -4-methoxy-2 methyltetrahydropyrene. Thus, (2SR, 4SR) -4- [5-fluoro-3 (quinoxaline-6-ylmethoxy) phenyl] -4-methoxy-2-methyl-tetrahydropyran is obtained in the form of an oil (72%). NMR spectrum: (CDL ₃ , delta magnitude) 1.20 (doublet, 3H), 1.64 (doublet of doublets, 1H), 1.94 (triplet of doublets, 1H), 2.22-2.39 ( multiplet, 2H), 2.90 (singlet, 3H), 3.31-3.48 (multiplet, 2H), 3.91-4.02 (multiplet, 1H), 5.32 (sinlet, 2H), 6 70 (doublet of triplets, 1H), 6.79 (doublet of triplets, 1H), 6.90 (triplet, 1H), 7.87 (doublet of doublets, 1H), 8.17 (multiplet, 2H), 8.89 (singlet, 2H);
Mass spectrum P m / e 382;
Elemental analysis
Found, C, 70.0; H 6.3; N 6.7
C ₂₂ Y ₂₃ FN ₂ O ₃ · 0.25 C ₆ H ₅ CH ₃
Calculated, C 70.3; H 6.2; N, 6.9.

(2SR, 4SR) -4- (5-fluoro-3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran, used as starting material, is obtained from (2SR, 4SR) -4- (3-benzyloxy-5-fluorophenyl ) -4-hydroxy-2-methyltetrahydropyran described in the part of example 4, which is associated with the preparation of the starting materials in the methylation steps and subsequent hydrogenolysis of the benzyl protecting group using the procedures described in paragraph c) of example 2. Thus, the desired starting material is obtained ( 71%), mp 116 ^about S.

PRI me R 6. Using the procedure described in example 1, the corresponding alkyl halide is subjected to interaction with the corresponding phenol to obtain the compounds shown in table. 2, in which the following notation is adopted:
a). 6-Bromomethyl-1,2-dihydro-1-methylquinolin-2-one, used as starting material, was prepared as follows: a mixture of 4.4 g of 1,2-dihydro-1,6-dimethylquinolin-2-one (Heh Chim. Acta, 1970, 53, 1903), 4.53 g of N-bromosuccinimide, 0.01 g of azobisisobutyronitrile and 75 ml of carbon tetrachloride are heated to reflux for 3 hours. The mixture is evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is washed with water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 2 1 v / v mixture of toluene and ethyl acetate as eluent. Thus, the expected starting material (4.8 g, 75%) is obtained in the form of a solid, mp. 107-108 ^C. NMR Spectrum: (SDCl _3, delta values) 3.7 (s, 3H), 4.57 (s, 2H), 6.7-7.5 (d, 1H), 7, 25-7.65 (multiplet, 4H).

b) 4-Ethoxy-4- (3-hydroxyphenyl) -tetrahydropyran, used as starting material, is prepared as follows: Grignard reagent is obtained by heating a mixture of 3 g of 3- (naphth-2-ylmethoxy) -bromobenzene, 0.23 g of magnesium powder and 12 ml of tetrahydrofuran to 30 ^° C for 1.5 hours. The reagent is cooled to 20 ^° C and a solution of 0.88 ml of tetrahydropyran-4-one in 5 ml of tetrahydropyran is added dropwise. The mixture was heated ^to 30 ° C for 15 hours, evaporated and the residue was separated by layers between ethyl acetate and water. The organic phase is separated, washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 7 3 v / v mixture of methylene chloride and diethyl ether as eluent. Thus, 4-hydroxy-4- [3- (naphth-2-ylmethoxy) phenyl] tetrahydropyran (2.06 g, 42%) was obtained, mp. 130-131 ^about S.

A mixture of a portion (0.68 g) of the reaction product thus obtained, 0.1 g (60 wt. Dispersion in mineral oil) sodium hydride, 0.01 g of 15-crown-5, 0.325 ml of ethyl iodide and 5 ml of dimethylformamide are stirred at ambient temperature for 48 hours. The mixture was partitioned between diethyl ether and water. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 49 1 v / v mixture of methylene chloride and diethyl ether as eluent. Thus, 0.5 (60%) 4-ethoxy-4- [3- (naphth-2-ylmethoxy) phenyl] tetrahydropyran is obtained in the form of an oil.

A mixture of a portion (0.4 g) of the reaction product thus obtained, 0.08 g of a 10% palladium-carbon catalyst and 25 ml of ethanol was stirred under a pressure of 3.3 atm of hydrogen gas for 15 hours. The mixture was filtered and the filtrate was evaporated. . The residue was purified by column chromatography using a 1 1 v / v mixture of methylene chloride and diethyl ether as eluent. Thus, 0.175 g (87%) of the expected starting material are obtained, mp. 124-126 ^about S.

in). 5-Bromomethyl-1,2-dihydro-1-methylquinolin-2-one, used as starting material, is prepared as follows: 0.264 g (55% by weight dispersion in mineral oil) of sodium hydride in 40 ml of dimethylformamide was added 1.59 g of 1,2-dihydro-5-methylquinolin-2-one (Synthesis, 1975, 739), and the mixture was heated ^to 50 ° C for 45 min. The mixture was cooled ^to 0 C and was added dropwise 0.93 mL of methyl iodide. The mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 19 1 v / v mixture of methylene chloride and methanol as eluent. Thus, 1.5 g (87%) of 1,2-dihydro-1,5-dimethylquinolin-2-one are obtained, mp. 107-108 ^about S.

A mixture of a portion (1.21 g) of the reaction product thus obtained, 1.37 g of N-bromosuccinimide, 0.035 g of benzoyl peroxide and 25 ml of carbon tetrachloride is heated to reflux for 40 minutes and irradiated with a 275 W lamp. . The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography, using methylene chloride in turn and then a 4 1 v / v mixture of toluene and ethyl acetate as eluent. Thus, the desired starting material is obtained (1.09 g, 59%), mp. 169 ^about S.

d). 7-Bromomethyl-1,2-dihydro-1-methylquinolin-2-one, used as starting material, was prepared using the following procedure: 1,2-dihydro-7-methylquinolin-2-one (Synthesis, 1975, 739) subjected to interaction with methyl iodide using the procedure of paragraph c). Thus, 1,2-dihydro-1,7-dimethylquinolin-2-one is obtained in a 79% yield, mp. 111-112 ^about S.

The reaction product thus obtained was brominated using the indicated procedure to obtain the target starting material in a 57% yield, mp. 170 ^about S.

e). The reaction product shows the following characteristics: NMR signals: (CDL ₃ , delta magnitude) 1.1 (triplet, 3H), 1.9-2.1 (multiplet, 4H), 3.1 (quartet, 2H), 3, 75-3.95 (multiplet, 4H), 5.3 (singlet, 2H), 6.62-6.9 (multiplet, 3H), 7.85 (doublet, 1H), 8.15 (doublet, 2H) 8.85 (singlet, 2H).

e). Three equivalents of potassium carbonate are used. The 6-chromomethylquinoline hydrochloride used as starting material is prepared as follows: a mixture of 27.5 g of 4-aminobenzoic acid, 21.3 g of 4-nitrobenzoic acid, 7 g of iron (II) sulfate, 12 g of boric acid, 75 ml of glycerol and 35 ml of concentrated sulfuric acid is heated to reflux for 20 hours. The mixture is diluted with 200 ml of water and made basic by adding 5N. an aqueous solution of sodium hydroxide. The mixture was filtered and the filtrate was acidified to pH 4-5 by the addition of glacial acetic acid. The mixture was stored at ⁰ ° C for 2 hours. The precipitate was isolated by filtration, washed with water and acetone, and dried by heating to 55 ^{° C} under vacuum. Thus, 78 g of quinoline-6-carboxylic acid are obtained, mp. 286 ^about S.

A mixture of the reaction product thus obtained, 600 ml of ethanol and 96 ml of concentrated sulfuric acid was heated to reflux for 5 hours. The ethanol was evaporated. Add 200 ml of water and the mixture is alkalinized by adding 5 N. an aqueous solution of sodium hydroxide. The mixture was extracted with chloroform (3 x 100 ml). The combined extracts were dried with Na ₂ SO ₄ and evaporated. Thus, 17 g of ethyl quinoline-6-carboxylic acid t.pl.140-145 ^C. at 0.05 mm Hg

A solution of the reaction product thus obtained in 100 ml of diethyl ether was added to a mixture of 3.6 g of lithium aluminum hydride and 200 ml of diethyl ether at a rate sufficient to warm the mixture to a gentle boil under reflux. The mixture is then heated to reflux for 20 minutes. Wet ether (100 ml) is carefully added and then an aqueous solution of sodium hydroxide (4.6 g in 30 ml of water) is added. The mixture was filtered and the solid was washed with diethyl ether. The combined filtrate and washes were washed with saturated aqueous sodium chloride, dried with Na ₂ SO ₄ and evaporated. Thus po- Luciano 7 g of 6-hydroxymethylquinoline, recrystallized from a mixture of petroleum ether (bp. 60-80 ° ^C) and diethyl ether.

 A saturated solution of hydrogen chloride in diethyl ether was added to a solution of the reaction product thus obtained in 25 ml of methanol, which was cooled in an ice bath. The precipitate of 6-hydroxymethylquinoline hydrochloride thus formed is filtered off and washed with diethyl ether. A mixture of the reaction product thus obtained and thionyl chloride was heated to reflux for 3 hours. The mixture was evaporated, toluene was added and the mixture was evaporated again. The residue was triturated with diethyl ether to give 6-chloromethylquinoline hydrochloride.

 g). Three equivalents of potassium carbonate are used. The 3-chloromethylisoquinoline hydrochloride used as starting material was prepared as follows: a mixture of 40 g of phenylaniline, 91 ml (37 w / v in water) formaldehyde and 310 ml of concentrated hydrochloric acid was stirred and heated to reflux for 4 h, and then kept at ambient temperature for 16 h. The precipitate is filtered off, washed with cold water and acetone to obtain 11 g of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

After repeating this step appropriately, a mixture of the reaction product thus obtained (23.2 g) and 200 ml of methanol is cooled in an ice bath and 15.4 ml of thionyl chloride are added dropwise. The mixture was heated to reflux for 4 hours. The mixture was evaporated and the solid was triturated with diethyl ether to give 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester hydrochloride (23.2 g ) NMR spectrum: (SD ₃ SOSD ₃ , delta magnitude) 3.1-3.4 (multiplet, 2H), 3.8 (singlet, 3H), 4.32 (singlet, 2H), 4.5-4, 6 (quartet, 1H), 7.3 (singlet, 4H), 10.2 (broad singlet, 1H).

A mixture of a portion (11 g) of the reaction product thus obtained, 19.6 g of potassium acetate and 200 ml of dry ethanol is heated to reflux and a solution of 25.4 g of iodine in 250 ml of dry ethanol. The mixture was heated to reflux for 16 hours, cooled and filtered, and the filtrate was evaporated. The residue was partitioned between ethyl acetate and a dilute aqueous sodium thiosulfate solution. The organic layer was dried with Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate, to give 3 g of isoquinoline-3-carboxylic acid ethyl ester.

 Using the procedure described in paragraph e), the reaction product thus obtained is reduced and the resulting alcohol is converted into the target starting material.

h). 2-Chloromethylquinazoline used as an alkylating agent is described in J. Chem. Soc. 1966, 238. The product shows the following characteristic NMR signals (CDL ₃ , delta magnitude) 1.75-2.03 (multiplet, 4H), 2.93 (singlet, 3H), 3.71-3.91 (multiplet, 4H), 5.46 (singlet, 2H), 6.69 (doublet, 1H), 6.74 (doublet, 1H), 6.95 (singlet, 1H), 7.69 (triplet, 1H), 7, 9-8.1 (multiplet, 3H); 9.45 (singlet, 1H).

 and). 6-Bromomethylquinazoline used as an alkylating agent to produce 6-methylquinazoline (J. Chem. Soc. 1962, 561) using the procedure described in J.Het.Chem. 1974, 11, 595 to obtain 6-bromomethylquinoxaline from 6-methylquinoxaline.

to). 4-Ethoxy-4- (5-fluoro-3-hydroxyphenyl) tetrahydropyran, used as starting material, is prepared from 4- (3-benzyloxy-5-fluorophenyl) -4-hydroxytetrahydropyran using the procedure described in paragraph c). in example 2, except that ethyl iodide is used instead of methyl iodide. Thus, the desired starting material is obtained in a 60% yield, mp. 112 ^about S.

l). 3-Bromomethyl-6-fluoro-1,2-dihydro-1-methylquinolin-2-one used as starting material was prepared as follows: To a solution of 20 g of 4-fluoroaniline, which was cooled ^to 0 ° C, was added a queue of 18.2 g of triethylamine and 16.7 g of propitonyl chloride. The mixture was stirred at ⁵ ° C for 1 hour and the layers separated between methylene chloride and water. The organic layer was washed with water, dried with MgSO ₄ and evaporated to obtain 29.1 g of 4-fluoropropionanilide.

To 11.2 g of dimethylformamide, which was stirred and cooled to ^-5 ° C, was added dropwise 50.3 mL oxychloride fluorine. Once starts to form a white solid, the mixture was cooled to ^-15 ° C and phosphorus oxychloride was added more quickly. The white sludge thus formed is stirred and allowed to warm to ambient temperature, and then stirred at ambient temperature for 30 minutes. A portion (15 g) of the obtained 4-ftorpropionaldegida added portionwise and the mixture was heated to 75 ^{° C} for 6 hours. The mixture was poured onto ice and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using toluene as eluent. Thus, 2-chloro-6-fluoro-3-methylquinoline (1 g, 5%) is obtained as a solid. NMR spectrum: (CDL ₃ , delta magnitude) 2.54 (singlet, 3H), 7.32-7.49 (multiplet, 2H), 7.91 (singlet, 1H), 7.98 (multiplet, 1H) .

After a corresponding repeat of the indicated reaction steps, a mixture of 10 g of the quinoline thus obtained, 110 ml of 2N aqueous hydrochloric acid and 110 ml of ethanol was heated to ⁸⁰ ° C for 9 hours. The mixture was poured into water and the precipitate was filtered off and dried under vacuum at 50 ^C. There was thus obtained 7.9 g (87%) of 6-fluoro- 1,2-dihydro-1-methylquinolin-2-one. NMR spectrum: (CDL ₃ , delta magnitude) 2.3 (singlet, 3H), 7.18 (doublet, 1H), multiplet, 1H), 7.4 (doublet of doublets, 1H), 7.6 (singlet , 1H), 12.3 (broadened tubercle (hump), 1H).

To a solution of (3 g) thus obtained reaction product in 80 ml dimethylformamide which was cooled ^to 0 ° C, was added portionwise 0.775 g (55 mas. Nye dispersion in mineral oil) of sodium hydride and the mixture was stirred at ⁵ ° C within 40 minutes Was added dropwise 2.65 g of methyl iodide and the mixture was stirred at ⁵ ° C for 1 hour and then allowed to warm to ambient temperature. The mixture was poured into 100 ml of water and the precipitate was filtered off and dried under vacuum at 50 ^C. There was thus obtained 2.5 g (78%) of 6-fluoro-1,2-dihydro-1,3-dimethyl-2-one, t. pl. 132 ^about S.

A mixture of a portion (2 g) of the reaction product thus obtained, 1.86 g of N-bromosuccinimide, 0.01 g of azobisisobutyronitrile and 50 ml of carbon tetrachloride is heated to reflux for 1.5 hours and irradiated with light from a lamp at 275 Tue The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase is washed with water, dried with MgSO ₄ and evaporated. The residue was triturated in toluene to give 2 g (71%) of the desired starting material, mp. 212 ^about S.

m). 3-Bromomethyl-1-ethyl-1,2-dihydroquinolin-2-one, used as starting material, is prepared as follows: the procedure described in paragraph l) is repeated, except that aniline is used instead of 4-fluoroaniline. Thus, 2-chloro-3-methylquinoline is obtained in 63% yield, mp. 81-83 ^about C. Using the indicated procedure, except that ethyl iodide is used instead of methyl iodide, the reaction product thus obtained is converted into the target starting material in 41% yield as a solid. NMR spectrum: (CDL ₃ , delta magnitude) 1.39 (triplet, 3H), 4.40 (quartet, 2H), 4.55 (singlet, 2H), 7.24 (triplet, 1H), 7.37 (doublet, 1H), 7.58 (multiplet, 2H), 7.37 (singlet, 1H).

m). 3-Bromomethyl-1,2-dihydro-1- (2-fluoroethyl) -quinolin-2-one, used as an alkylating reagent, is prepared from 1,2-dihydro-3-methylquinolin-2-one using the procedures described in paragraph c) except that 2-fluoroethyl bromide is used instead of methyl iodide. Thus, the expected starting material is obtained in 46% yield as a solid. NMR spectrum: (CDL ₃ , delta magnitude) 4.54 (singlet, 2H), 4.60 (triplet, 1H), 4.70 (triplet, 2H), 4.96 (triplet, 1H), 7.25 (triplet, 1H), 7.45-7.65 (multiplet, 3H), 7.90 (singlet, 1H).

about). 3-Bromomethyl-1,2-dihydro-1- (2-dimethylaminoethyl) -quinolin-2-one bromide, used as starting material, is prepared as follows: 5.19 g of 1,2-dihydro-2-oxoquinoline are added to a suspension Of 3-carbaldehyde in 90 ml of dimethylformamide, 2.88 g (55 wt% dispersion in mineral oil) of sodium hydride are added in portions, then the mixture is stirred at ambient temperature for 1 h. 4.8 g of 2-dimethylaminoethyl chloride hydrochloride are added. and the mixture was heated to ⁶⁰ ° C for 3 hours. The mixture was filtered and the layers separated between methylene chloride and water. The organic layer was washed with water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 4 1 v / v mixture of methylene chloride and ethanol as eluent. Thus, 1.64 g (22%) of 1,2-dihydro-1- (2-dimethylaminoethyl) -2-oxoquinoline-3-carbaldehyde are obtained with a melting point of 98-99 ^about S.

To a solution of the reaction product thus obtained in methanol (35 ml), which was cooled in an ice bath, 0.285 g of sodium borohydride was added portionwise. The mixture was stirred at ambient temperature for 2 hours and then evaporated. Add 5 ml of 2 N. an aqueous solution of sodium hydroxide, followed by a sufficient amount of a drying agent (MgSO ₄ ) to dry the mixture. The mixture was filtered and evaporated. Thus, 1.48 g (92%) of 1,2-dihydro-3-hydroxymethyl-1 (2-dimethylaminoethyl) -quinolin-2-one is obtained in the form of a foamy substance.

A mixture of a portion (0.74 g) thus obtained reaction product and 10 ml (48% w / v) of concentrated hydrobromic acid was heated to 75 ^{° C} for 4 hours. The mixture was allowed to cool to ambient temperature, 10 ml of ethanol and the mixture is evaporated. The process of adding ethanol and evaporating the mixture thus obtained is repeated several times to remove hydrobromic acid. Thus, 0.62 g (53%) of the expected starting material are obtained with a melting point of 233-238 ^{° C} (decomposed).

P). The product is prepared as follows: a mixture of 0.53 g of 4- [5-fluoro-3- (1,2-dihydro-1- (pivaloyloxymethyl) -2-oxoquinolin-6-yl-methoxy) -phenyl, 0.59 ml 2 n. an aqueous solution of sodium hydroxide and 25 ml of ethanol was stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was partitioned between layers of methylene chloride and water. The organic phase is washed with water, dried with MgSO ₄ and evaporated to give 0.42 g (82%) of 4- [5-fluoro-3- (1,2-dihydro-2-oxoquinolin-6-ylmethoxy) phenyl] - Ropiran 4-methoxytetrahydride with mp 220 ^about S.

The starting material was prepared by reacting 6-bromomethyl-1,2-dihydro-1- (pivaloyloxymethyl) -quinolin-2-one with 4- (5-fluoro-3-hydroxyphenyl) -4-methoxytetrahydro-pyran using the procedure described in Example 1. Thus, the target starting material is obtained in 30% yield, in the form of a solid. NMR spectrum: (CDL ₃ , delta magnitude) 1.20 (singlet, 9H), 1.85-2.07 (multiplet, 4H), 2.98 (singlet, 3H), 3.78-3.89 ( multiplet, 4H), 5.1 (singlet, 2H), 6.33 (singlet, 2H), 6.63 (multiplet, 1H), 6.7-6.75 (multiplet, 2H), 6.83 (triplet , 1H), 7.35 (doublet, 1H), 7.58-7.65 (multiplet, 2H), 7.71 (doublet, 1H).

6-Bromomethyl-1,2-dihydro-1- (pivaloyloxymethyl) -quinolin-2-one, used as an alkylating reagent, is prepared as follows: a solution of 33.3 g of cinnamic acid chloride in 100 ml of methylene chloride is added dropwise to a stirred mixture of 21.4 g of 4-methylaniline, 16.2 g of pyridine and 500 ml of methylene chloride, which was cooled in an ice bath. The mixture was stirred at ⁵ ° C for 20 minutes and then allowed to warm to ambient temperature. The mixture is washed in turn with water, 1 N. a solution of hydrochloric acid in water, a saturated aqueous solution of sodium bicarbonate and water. The organic solution was dried with MgSO ₄ and evaporated to give 46 g (97%) of cinnamic acid N- (4-tolyl) amide as a solid. NMR spectrum: (CDL ₃ , delta magnitude) 2.32 (singlet, 3H), 6.54 (doublet, 1H), 7.11-7.52 (multiplet, 10H), 7.73 (doublet, 1H) .

A mixture of a portion (5.4 g) of the reaction product thus obtained and 16.2 g of aluminum chloride is heated strongly until a brown, viscous liquid forms. The mixture was then heated in a steam bath for 2 hours. The mixture was poured onto ice and the resulting solid was filtered off and washed with 2N. aqueous hydrochloric acid and water. The solid is dried and triturated in ethyl acetate. Thus, 3.4 g of 1,2-dihydro-6-methylquinolin-2-one are obtained in the form of a solid. NMR spectrum: (CD ₃ SOCD ₃ , delta magnitude) 2.33 (singlet, 3H), 6.44 (doublet, 1H), 7.19 (doublet, 1H), 7.31 (doublet of doublets, 1H) 7.42 (singlet, 1H); 7.80 (doublet, 1H); 11.6 (broad singlet, 1H).

Using the procedure described in paragraph c), the reaction product thus obtained is reacted with trimethylacetic acid chloromethyl ether (chloromethyl pivalate) to obtain 1,2-dihydro-6-methyl-1- (pivaloyloxymethyl) -quinolin-2-one with 45% yield as a solid. NMR spectrum: (CDL ₃ , delta magnitude) 1.18 (singlet, 9H), 2.41 (singlet, 3H), 6.31 (singlet, 2H), 6.65 (doublet, 1H), 7.16 -7.40 (multiplet, 3H); 7.64 (doublet, 1H).

 Using the procedure described in paragraph a), the thus obtained reaction product in quantitative yield, in the form of an oil, which is used without further purification.

R). 6-Bromomethyl-1,2-dihydro-1- (2-fluoroethyl) -quinolin-2-one, used as an alkylating reagent, is prepared from 1,2-dihydro-6-methylquinolin-2-one using the procedures described in paragraph c), except that 2-fluoroethyl bromide is used instead of methyl iodide. Thus, the desired starting material is obtained in 48% yield as a solid. NMR spectrum: (CDL ₃ , delta magnitude) 4.56 (singlet, 2H), 4.5-4.9 (multiplet, 4H), 6.72 (doublet, 1H), 7.3-7.8 ( multiplet, 4H).

 from). The product is obtained by alkylation of 4- [5-fluoro-3- (1,2-dihydro-2-oxoquinolin-6-ylmethoxy) phenyl] -4-methoxytetrahydropyran (Example 6, compound 15) with benzyl bromide using the procedure described in paragraph c).

The product shows the following characteristic NMR signals: (CDL ₃ , delta magnitude) 1.80-2.01 (multiplet, 4H), 2.96 (singlet, 3H), 3.75-3.87 (multiplet, 4H), 5 05 (singlet, 2H), 5.57 (singlet, 2H), 6.60 (multiplet, 1H), 6.7-6.84 (multiplet, 3H), 7.18-7.37 (multiplet, 6H) ), 7.49 (multiplet, 1H), 7.63 (doublet, 1H), 7.75 (doublet, 1H).

t). 4- (2,5-Difluoro-3-hydroxyphenyl) -4-methoxytetrahydropyran, used as starting material, is prepared as follows: using the procedure described in paragraph c) in Example 1, 1-bromo-2,3,5- trifluorobenzene is reacted with benzyl alcohol, the reaction product thus obtained is reacted with n-butyl lithium, and the resulting organometallic compound is reacted with tetrahydropyran-4-one. Thus, 4- (3-benzyloxy-2,5-difluorophenyl) -4-hydroxytetrahydropyran is obtained in 16% yield as an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.36-1.41 (doublet, 2H), 1.80 (multiplet, 1H), 1.96-2.08 (multiplet, 2H), 3.5- 3.66 (multiplet, 4H), 4.78 (singlet, 2H), 6.32-6.36 (multiplet, 1H), 6.39-6.5 (multiplet, 1H), 7.0-7, 1 (multiplet, 5H).

Using the procedures described in paragraph y), the reaction product thus obtained is methylated and the benzyl group is subjected to hydrogenolysis. Thus, the desired starting material is obtained in 53% yield, in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 2.0-2.06 (multiplet, 4H), 3.0 (singlet, 3H), 3.72-3.77 (multiplet, 4H), 6.3- 6.4 (multiplet, 1H), 6.5-6.6 (multiplet, 1H), 9.38 (singlet, 1H).

y). The product shows the following characteristic NMR signals: (CD ₃ SO-CD ₃ ) 1.9-2.0 (multiplet, 4H), 2.9 (singlet, 3H), 3.6-3.8 (multiplet, 4H), 5.55 (singlet, 2H), 7.1-7.3 (multiplet, 1H), 7.4 (singlet, 2H), 7.9-8.3 (multiplet, 3H), 9.0 (singlet, 2H).

The 4- (3-hydroxy-5-trifluoromethylphenyl) -4-methoxytetrahydropyran used as the starting material was prepared as follows: 9.42 ml of benzyl alcohol and 136 ml of dimethylacetamide, which was cooled in an ice bath, were added in portions 4, 36 (55 wt% dispersion in mineral oil) sodium hydride. The mixture was stirred at ambient temperature for 1.5 hours and then re-cooled in an ice bath. A solution of 22.1 g of 3-fluoro-5-trifluoromethylbromobenzene in 136 ml of dimethylacetamide was added to the resulting mixture and the contents were stirred at ambient temperature for 2 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using hexane as eluent. Thus, 23.1 g (77%) of 3-benzyloxy-5-trifluoromethylbromobenzene are obtained in the form of a colorless liquid. NMR spectrum: 5.07 (singlet, 2H), 7.15-7.35 (3 singlets, 3H), 7.36-7.42 (multiplet, 5H).

A solution of n-butyllithium (25.9 ml of a 1.6 M solution in hexane) was added dropwise to a solution of (13.75 g) of the thus obtained compound in 150 ml of tetrahydrofuran which had been cooled to -70 ^C. The mixture was stirred at this temperature for 1 hour. a solution of 4.15 g of tetrahydropyran-4-one in 5 ml of tetrahydrofuran and the mixture was stirred at ^-70 ° C for 1 hour and then allowed to warm to 0 ^C. to the mixture was added 100 ml a saturated aqueous solution of ammonium chloride and the mixture was extracted with diethyl ether. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 4 1 v / v mixture of toluene and ethyl acetate as eluent. Thus, 11.5 g (79%) of 4- (3-benzyloxy-5-trifluoromethylphenyl) -4-hydroxytetrahydropyran are obtained in the form of a solid. NMR spectrum: (CDL ₃ , delta magnitude) 1.6-1.72 (multiplet, 2H), 2.05-2.25 (multiplet, 2H), 3.6-4.0 (multiplet, 4H), 5.12 (singlet, 2H); 7.1-7.5 (multiplet, 8H).

To a mixture of (1.92 g) thus obtained reaction product and 12 ml dimethylformamide which was cooled to ^-5 ° C, was added 0.262 g (56 wt. Dispersion in mineral oil) sodium hydride. The mixture was stirred at -5 ^C for 30 min. 0.38 ml of methyl iodide was added dropwise and the mixture was stirred at ambient temperature for 90 minutes. The mixture was poured onto ice and extracted with diethyl ether. The organic phase is washed with water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 10 1 v / v mixture of toluene and ethyl acetate as eluent. Thus, 1.76 g (88%) of 4- (3-benzyloxy-5-trifluoromethylphenyl) -4-methoxytetrahydropyran is obtained in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.9-2.1 (multiplet, 4H), 3.0 (singlet, 3H), 3.8-3.9 (multiplet, 4H), 5.1 ( singlet, 2H), 7.0-7.5 (multiplet, 8H).

A mixture of the reaction product thus obtained, 0.32 g of a 10% palladium-charcoal catalyst and 25 ml of isopropanol was stirred under a hydrogen atmosphere for 2 hours. The mixture was filtered and the filtrate was evaporated to obtain the desired starting material (1.14 g, 89%), mp 132-134 ^C. NMR Spectrum: (SDSl _3, delta values) 1.9-2.1 (m, 4H), 3.0 (s, 3H), 3.8-4.0 (m, 4H ), 5.95 (singlet, 1H), 7.0 (multiplet, 1H), 7.1 (multiplet, 1H), 7.2 (singlet, 1H).

f). The product shows the following characteristic NMR signals: (CD ₃ SO-CD ₃ , delta magnitude) 0.9-1.1 (triplet, 3H), 1.8-2.0 (multiplet, 4H), 2.9-3, 1 (quartet, 2H), 3.6-3.8 (multiplet, 4H), 5.5 (singlet, 2H), 7.1-7.4 (multiplet, 3H), 7.9-8.0 ( multiplet, 1H), 8.1-8.2 (multiplet, 1H), 8.2 (multiplet, 1H), 8.5 (singlet, 2H).

4-Ethoxy-4- (3-hydroxy-5-trifluoromethyl-phenyl) -tetrahydropyran used as a starting material was prepared as follows: 2.17 g of 4- (3-benzyloxy-5-trifluoromethylphenyl) -4- solution hydroxytetrahydropyran in 15 ml of dimethyl sulfoxide, 1.5 g of powdered potassium hydroxide are added and the mixture is stirred at ambient temperature for 10 minutes. 1.24 ml of ethyl iodide was added and the mixture was stirred at ambient temperature for 4 hours. The mixture was poured onto a mixture of diethyl ether and ice. The organic phase is separated, washed with water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 10 1 v / v mixture of toluene and ethyl acetate as aluent. Thus, 1.75 g (74%) of 4- (3-benzyloxy-5-trifluoromethylphenyl) -4-ethoxytetrahydropyran is obtained in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.1-1.2 (triplet, 3H), 1.8-2.1 (multiplet, 4H), 3.0-3.1 (quartet, 2H), 3.75-3.95 (multiplet, 4H), 5.1 (singlet, 2H), 7.1-7.5 (multiplet, 8H).

A mixture of the product thus obtained, 0.35 g of a 10% palladium-charcoal catalyst and 25 ml of isopropanol was stirred under an atmosphere of hydrogen for 3.5 hours. The mixture was filtered and evaporated. Thus, the expected starting material (1.3 g, 97%) is obtained in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.1-1.2 (triplet, 3H), 1.9-2.1 (4H multiplet), 3.05-3.15 (quartet, 2H), 3 8-4.0 (multiplet 4H), 7.0 (multiplet, 1H), 7.1 (multiplet, 1H), 7.2 (singlet, 1H).

x). The alkylation reaction is conducted at ^-20 ° C rather than at ambient temperature and using sodium hydride (55 mas. Nye dispersion in mineral oil) rather than potassium carbonate as the base. h). The product shows the following characteristic NMR signals: (CDL3, delta magnitude) 1.75-2.25 (multiplet, 4H), 3.0 (singlet, 3H), 3.6-4.0 (multiplet, 4H), 4, 75 (singlet, 2H), 5.30 (singlet, 2H), 6.5-6.85 (multiplet, 3H), 7.75-7.95 (multiplet, 1H), 8.0-8.25 ( multiplet, 2H), 8.85 (multiplet, 2H).

PRI me R 7. Using the procedure described in example 1, the corresponding alkyl halide is subjected to interaction with the corresponding phenol to obtain the compounds shown in table. 3, where are indicated:
a). (2RS, 4SR) -4- (5-fluoro-3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropairan having the 2-methyl and 4-methoxy groups in the trans position are used as the corresponding phenol.

The product shows the following characteristic NMR signals: (CDL ₃ , delta magnitude) 0.97 (doublet, 3H), 1.32 (doublet of doublets, 1H), 1.63-1.80 (multiplet, 3H), 2.75 (singlet, 3H), 3.51 (singlet, 3H), 3.57-3.73 (multiplet, 3H), 4.88 (singlet, 2H), 6.40 (multiplet, 1H), 6.5- 6.62 (multiplet, 3H); 7.15-7.5 (multiplet, 4H).

 b) (2SR, 4SR) -4- (5-fluoro-3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran having 2-methyl and 4-methoxy groups in the cis position is used as the corresponding phenol.

The product shows the following characteristic NMR signals: (CDL ₃ , delta magnitude) 1.19 (doublet, 3H), 1.61 (doublet of doublets, 1H), 1.96 (multiplet, 1H), 2.2-2.34 (multiplet, 2H), 2.88 (singlet, 3H), 3.32-3.49 (multiplet, 2H), 3.72 (singlet, 3H), 3.97 (multiplet, 1H), 5.10 ( singlet, 2H), 6.66 (multiplet, 1H), 6.6-6.8 (multiplet, 2H), 6.83 (triplet, 1H), 7.39 (doublet, 1H), 7.6-7 7 (multiplet, 3H).

in). The product shows the following characteristic NMR signals (CDL ₃ , delta magnitude) 0.97 (doublet, 3H), 1.14 (triplet, 3H), 1.32 (doublet of doublets, 1H), 1.60-1.80 ( multiplet, 3H), 2.75 (singlet, 3H), 3.56-3.73 (multiplet, 3H), 4.15 (quartet, 2H), 4.87 (singlet, 2H), 6.39 (multiplet , 1H), 6.51 (multiplet, 1H), 6.52 (doublet, 1H), 6.59 (triplet, 1H), 7.19 (doublet, 1H), 7.35-7.48 (multiplet, 3H).

6-Bromomethyl-1,2-dihydro-1-ethylquinolin-2-one, used as starting material, is obtained from 1,2-dihydro-6-methylquinolin-2-one using the procedures described in paragraph c) Example 6, except that ethyl iodide is used instead of methyl iodide. Thus, the desired starting material is obtained in 21% yield, in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.33 (triplet, 3H), 4.35 (quartet, 2H), 4.57 (singlet, 2H), 6.72 (doublet, 1H), 7.63 (doublet, 1H), 7.1-7.6 (multiplet, 3H).

d). The product shows the following characteristic NMR signals: (CDL ₃ , delta magnitude) 1.20 (doublet, 3H), 1.37 (triplet, 3H), 1.62 (doublet of doublets, 1H), 1.92 (multiplet, 1H ), 2.21-2.38 (multiplet, 2H), 2.90 (singlet, 3H), 3.3-3.5 (multiplet, 2H), 3.96 (multiplet, 1H), 4.37 ( quartet, 2H), 5.10 (singlet, 2H), 6.65-6.85 (multiplet, 4H), 7.38-7.48 (multiplet, 1H), 7.59-7.72 (multiplet, 3H).

e). The product shows the following characteristic NMR signals: (CD ₃ SO-CD ₃ / CF ₃ COOD / SD ₃ SOD), 1.0 (doublet, 3H), 1.1-2.25 (multiplet, 4H), 2.9 ( singlet, 3H), 3.65 (singlet, 3H), 3.6-4.0 (multiplet, 3H), 5.25 (singlet, 2H), 6.65 (doublet, 1H), 6.9-7 2 (multiplet, 3H); 7.45-8.05 (multiplet, 4H).

(2RS, 4SR) -4- (5- (11-benzylidenamino) -3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran is used as the phenolic starting material and the reaction product thus obtained is stirred with 2N. aqueous hydrochloric acid at ambient temperature for 12 hours. The mixture is neutralized by adding 2 N. aqueous sodium hydroxide solution and extracted with diethyl ether. The organic phase is washed with water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using ethyl acetate as eluent. Thus, the desired product is obtained in 39% yield.

(2RS, 4SR) -4- (5- (11-benzylidinamino) -3-hydroxyphenyl) - -4-methoxy-2-methyltetrahydropyran as the starting material, is prepared as follows: using the procedure described in paragraph c) of example 2, benzyl the alcohol is reacted with 3,5-dinitroiodobenzene to obtain 3-benzyloxy-5-nitroiodobenzene in 54% yield, mp. 79-80 ^about S.

Using the procedure described in paragraph a) of Example 2, except that the reaction was carried out at -110 ^{° C,} thus obtained reaction product is reacted with n-butyllithium and the thus obtained organometallic reagent is reacted with 2-methyltetrahydropyran-4- oxazolidinone (reaction mixture is stirred at -100 ^C for 30 minutes and then allowed to warm to ambient temperature) to give 4- (3-benzyloxy-5-nitrophenyl) -4-hydroxy-2-methyltetrahydropyran, as a mixture of diastereoisomers. The mixture of isomers thus formed were separated by chromatography using 4: 1 by volume mixture of diethyl ether and petroleum ether (bp. 40-60 ^C.) as eluant. Each isomer is methylated using the indicated conditions. Thus, a less polar diastereoisomer, (2RS, 4SR) -4- (3-benzyloxy-5-nitrophenyl) -4-methoxy-2-methyltetrahydropyran, is obtained in 16% yield based on 3-benzyloxy-5 nitroiodobenzene, mp 85-86 ^about C; and more polar diastereomer, (2RS, 4RS) -isomer, with a 22% yield, mp 106-107 ^about S.

A mixture of the less polar isomer (1.5 g) thus obtained, 0.3 g of a 5% palladium-charcoal catalyst and 25 ml of ethanol was stirred under a hydrogen atmosphere for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using a 1 1 v / v mixture of toluene and ethyl acetate as eluent. The reaction product thus obtained (2RS, 4SR) -4- (5-amino-3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran (0.83 g, 84%), in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.2 (doublet, 3H), 1.4-2.2 (multiplet, 4H), 3.0 (singlet, 3H), 3.25-4.1 ( multiplet, 6H), 6.1-6.40 (multiplet, 3H).

 A mixture of the reaction product thus obtained (0.8 g), 0.55 g of benzaldehyde, 1 g of magnesium sulfate and 10 ml of methylene chloride was stirred at ambient temperature for 12 hours. The mixture was filtered and the filtrate was evaporated. Thus, the desired starting material is obtained in quantitative yield, in the form of an oil.

e). This product is obtained by reacting the preceding product with sodium cyanate as follows: to a mixture of 0.23 g (2RS, 4SR) -4- [5-amino-3- (1,2-dihydro-1-methyl-2-oxoquinoline-6 -ylmethoxy) - phenyl] -4-methoxy-2-tetrahydropyran, 0.5 ml of 2 N. 0.085 g of sodium cyanate are added portionwise to aqueous hydrochloric acid, 3 ml of water and 2 ml of ethanol and the mixture is stirred at ambient temperature for 12 hours. The mixture is evaporated and the residue is partitioned between ethyl acetate and water. The organic phase was dried with MgSO ₄ and evaporated, and the residue was triturated with methylene chloride. Thus, the desired product is obtained in 70% yield.

Example 8. Using the procedure described in example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is reacted with 4- (3-hydroxyphenyl) -4-methoxy- 2,2-dimethyltetrahydropyran to give 4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] 4-methoxy-2,2-dimethyltetrahydropyran with 83 % yield. NMR spectrum: (CDL ₃ , delta magnitude) 1.2 (singlet, 3H), 1.49 (singlet, 3H), 1.75 (doublet, 1H), 1.9-2.1 (multiplet, 3H) 2.95 (singlet, 3H), 3.69-3.79 (multiplet, 4H), 3.99-4.11 (multiplet, 1H), 5.12 (singlet, 2H), 6.7-6 8 (doublet, 1H), 6.89-7.1 (multiplet, 3H), 7.1-7.5 (multiplet, 2H), 7.6-7.8 (multiplet, 3H).

4- (3-hydroxyphenyl) -4-methoxy-2,2-dimethyltetrahydropyran, used as starting material, was prepared as follows: a mixture of 2.72 g of 2,3-dihydro-2,2-dimethylpyran-4-one (J. Arg. Chem. 1963, 687), 0.27 g of a 10% palladium-charcoal catalyst and 80 ml of ethanol were stirred under a hydrogen atmosphere for 6 hours. The mixture was filtered and the filtrate was evaporated. Thus, 2.05 g (74%) of 2,2-dimethyltetrahydropyran-4-one is obtained in the form of a liquid. (IR spectrum 1730 cm ^-1 ).

 Using the procedure described in paragraph c) of Example 2, 1.34 g of 3-benzyloxybromobenzene is reacted with 0.65 g of 2,2-dimethyltetrahydropyran-4-one to obtain 1.14 g (72%) of 4- (3- benzyloxyphenyl) -4-hydroxy-2,2-dimethyltetrahydropyran, in the form of an oil.

Using the procedure described in paragraph y) of Example 6, which is related to the preparation of starting materials, the reaction product thus obtained is reacted with methyl iodide to obtain 1.06 g (89%) of 4- (3-benzyloxyphenyl) -4-methoxy -2,2-dimethyltetrahydropyran in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.18 (singlet, 3H), 1.45 (singlet, 3H), 1.71 (doublet, 1H), 1.93-2.03 (multiplet, 3H) 2.92 (singlet, 3H), 3.66-3.77 (multiplet, 1H), 3.94-4.10 (multiplet, 1H), 5.07 (singlet, 2H), 6.88 (doublet , 1H), 6.97 (doublet, 1H), 7.02 (singlet, 1H), 7.15-7.46 (multiplet, 6H).

 A mixture of the reaction product thus obtained, 0.44 g of a 10% palladium-charcoal catalyst and 45 ml of isopropanol was stirred under a hydrogen atmosphere for 3 hours. The mixture was filtered and the filtrate was evaporated to obtain 0.74 g (96%) of the target starting material that is used without further purification.

Example 9. Using the procedure described in example 1, 3- (2-pyridyl) -prop-2-yn-1-ylbromide bromide is reacted with (2RS, 3SR) -3- (3-hydroxyphenyl) -3-methoxy-2-methyltetrahydrofuran to obtain (2RS, 3SR) -3-methoxy-2-methyl-3- [3- (3- (2-pyridyl) prop-2-in-1-in-oxy ) -phenyl] -tetrahydrofuran, in the form of an oil in 90% yield. NMR spectrum: (CDL ₃ , delta magnitude) 1.19 (doublet, 3H), 2.49 (triplet, 2H), 3.18 (singlet, 3H), 3.72 (quartet, 1H), 4.08 (multiplet, 2H), 4.95 (singlet, 2H), 6.85-7.5 (multiplet, 8H).

(2RS, 3SR) -3- (3-hydroxyphenyl) -3-methoxy-2-methyltetrahydrofuran used as the starting material was prepared as follows: the procedure described in Example 1 was repeated, except that instead of tetrahydropyran-4- she use 2-methyltetrahydrofuran-3-one. Thus, the target starting material is obtained in 54% yield, mp. 170-171 ^about C; wherein the 2-methyl and 3-methoxy groups are in the cis position.

PRI me R 10. Using the procedure described in example 1, the corresponding alkyl bromide is reacted with the corresponding phenol to obtain the compounds shown in table. 4, in which are indicated:
a). The product shows the following characteristic NMR signals: (CDL ₃ , delta magnitude) 1.19 (doublet, 3H), 2.48 (multiplet, 2H), 3.16 (singlet, 3H), 3.73 (singlet, 3H), 3.74 (multiplet, 1H), 4.10 (multiplet, 2H), 5.21 (singlet, 2H), 6.6-7.5 (multiplet, 9H).

b) (2RS, 3SR) -3-Ethoxy-3- (5-fluoro-3-hydroxyphenyl) -2-methyltetrahydrofuran, used as starting material, is prepared as follows: Grignard reagent is obtained by heating a mixture of 4.2 g of 3-benzyloxy- 5-ftorfenilbromida, 0.365 g of magnesium powder and 20 ml of tetrahydrofuran ^to 40 ° C for 1 hour. The Grignard reagent was cooled to ambient temperature and added dropwise 1.16 ml of 2-methyltetrahydrofuran-3-one. The mixture was stirred at ambient temperature for 3 hours and then partitioned between ethyl acetate and water. The organic layer was washed with water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 19 1 v / v mixture of methylene chloride and diethyl ether as eluent. Thus, 2.3 g of (2RS, 3SR) -3- (3-benzyloxy-5-fluorophenyl) -3-hydroxy-2-methyltetrahydrofuran (64% yield) are obtained, mp. 83-84 ^{° C;} wherein the 2-methyl and 3-hydroxy groups are in cis positions.

 A portion (1.1 g) of the reaction product thus obtained was reacted with ethyl iodide using the procedure described in paragraph b) of Example 6. Thus, 0.82 g (68%) of (2RS, 3SR) -3- (3 -benzyloxy-3-fluorophenyl) -3-ethoxy-2-methyltetrahydrofuran, in the form of an oil.

A mixture of the reaction product thus obtained, 0.1 g of 10% palladium on charcoal and 5 ml of ethanol was stirred at ambient temperature under a hydrogen atmosphere for 4 hours. The mixture was filtered and evaporated. Thus, 0.54 g (92%) of the target starting material are obtained, mp. 136-137 ^about S.

in). (2RS, 3SR) -3- (5-fluoro-3-hydroxyphenyl) -3-methoxy-2-methyltetrahydrofuran used as the starting material was prepared as follows: the procedures described in paragraph b) were repeated, except that instead of ethyl iodide, methyl iodide is used in the alkylation step. The target starting material is obtained in a total yield of 45% mp. 148-152 ^about S.

d). The product shows the following characteristic NMR signals: (CDL ₃ , delta magnitude) 1.21 (doublet, 3H), 1.36 (triplet, 3H), 2.5 (multiplet, 2H), 3.16 (singlet, 3H), 3.7 (quartet, 1H), 4.05 (quartet, 2H), 4.4 (quartet, 2H), 5.1 (singlet, 2H), 6.5 (multiplet, 8H).

PRI me R 11. A mixture of 4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4-hydroxytetrahydropyran (0.25 g), hydride sodium (60% dispersion in mineral oil, 0.06 g) and 20 ml of dimethylformamide are stirred at ambient temperature for 30 minutes. 1 mm allyl bromide was added and the mixture was stirred at ambient temperature for 36 hours. The mixture was layered between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 4 1 v / v mixture of methylene chloride and diethyl ether as eluent. Thus, 0.17 g (61%) of 4-allyloxy-4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] tetrahydropyrene is obtained in the form of an oil. NMR spectrum: (CDL ₃ , delta value) 2.0 (multiplet, 4H), 3.5-4.0 (multiplet, 6H), 3.72 (singlet, 3H), 5.10 (multiplet, 1H) , 5.12 (singlet, 2H), 5.28 (multiplet, 1H), 5.76 (multiplet, 1H), 6.6-7.5 (multiplet, 9H).

4- [3 (1,2-Dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4-hydroxytetrahydropyran, used as starting material, is prepared as follows: using a reaction procedure The Grignard described in Example 1 was reacted with 3-benzyloxy-sibromobenzene with tetrahydropyran-4-one to obtain 4- (3-benzyloxyphenyl) -4-hydroxytetrahydropyran in 77% yield, mp. 84-86 ^about S.

A mixture of the reaction product thus obtained (1 g), 0.1 g of palladium-charcoal catalyst and 10 ml of ethanol was stirred under a hydrogen pressure of 2 atm for 6 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using a 50 50 1 by volume mixture of methylene chloride, diethyl ether and methanol and the quality of the eluent. Thus, 4-hydroxy-4- (3-hydroxyphenyl) -tetrahydropyran (0.325 g, 48%) is obtained, mp. 165-169 ^about S.

Using the procedure described in Example 1, the reaction product thus obtained was reacted with 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one to obtain the desired starting material in 70% yield, mp. 165-167 ^about S.

PRI me R 12. Using the procedure described in example 11, allyl bromide is reacted with the corresponding 4-hydroxytetrahydropyran to obtain the compounds shown in table 5, where
a). The product shows the following characteristic NMR signals: (CDCl ₃ , delta magnitude) 1.85-2.10 (multiplet, 4H), 3.54-3.64 (multiplet, 2H), 3.73 (singlet, 3H), 3 75-4.00 (m, 4H), 5.10-5.25 (m, 4H), 5.75-5.97 (m, 1H), 6.63 (m, 1H), 6.73 -6.84 (multiplet, 3H), 7.37-7.43 (multiplet, 1H), 7.59-7.68 (multiplet, 3H).

4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -5-fluorophenyl-4-hydroxy-tetrahydropyran used as the starting material, is prepared as follows: using the procedure, described in paragraph c) of Example 2, 4- (3-benzyloxy-5-fluorophenyl) -4-hydroxytetrahydropyran are hydrogenolized to obtain 4- (5-fluoro-3-hydroxyphenyl) -4-hydroxytetrahydropyran with 79% output, mp 158-160 ^about C.

Using the procedure described in example 1, the reaction product thus obtained was reacted with 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one to obtain the target starting material in 72% yield as a solid . NMR spectrum: (CDL ₃ , delta magnitude) 1.74 (broad signal, 1H), 2.04-2.22 (multiplet, 4H), 3.73 (singlet, 3H), 3.81-4.0 (multiplet, 4H), 5.10 (singlet, 2H), 6.6 (multiplet, 1H), 6.73 (doublet, 1H), 6.83 (multiplet, 1H), 6.95 (triplet, 1H) 7.35-7.43 (multiplet, 1H); 7.54-7.70 (multiplet, 3H).

b) The product shows the following characteristic NMR signals: (CDL ₃ , delta magnitude) 1.9-2.1 (multiplet, 4H), 3.56-3.59 (multiplet, 2H), 3.73 (singlet, 3H), 3 85-3.95 (multiplet, 4H), 5.0-5.3 (multiplet, 2H), 5.15 (singlet, 2H), 5.1-5.31 (multiplet, 1H), 6.71 -6.76 (m, 1H); 7.1-7.69 (m, 7H).

 4- [3- (1,2-Dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -5-trifluoromethylphenyl] -4-hydroxytetrahydropyran used as the starting material was prepared as follows: using the procedure described in step y) of Example 6, 4- (3-benzyloxy-5-trifluoromethylphenyl) -4-hydroxytetrahydropyran is hydrogenated to obtain 4-hydroxy-4- (3-hydroxy-5-trifluoromethylphenyl) -tetrahydropyran in 90% yield , in the form of oil.

Using the procedure described in Example 1, the reaction product thus obtained is reacted with 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one to obtain the desired starting material in 70% yield. NMR spectrum: (CDL ₃ , delta magnitude) 1.64-1.69 (doublet, 2H), 1.93 (singlet, 1H), 2.09-2.25 (multiplet, 2H), 3.73 ( singlet, 3H), 3.88-3.99 (multiplet, 4H), 5.16 (singlet, 2H), 6.7-6.75 (doublet, 1H), 7.26-7.7 (multiplet, 6H).

PRI me R 13. A solution of 0.26 g of 4- [5-fluoro-3- (2-propynyloxy) phenyl] -4-methoxytetrahydropyran in 1.5 ml of acetonitrile was added to a mixture of 0.21 n 3-iodopyridine , 0.01 g of bis (triphenylphosphine) palladium chloride, 0.15 ml of triethylamine, 0.01 g of copper (I) iodide and 1.5 ml of acetonitrile, and the resulting mixture is stirred and heated to 60 ° C for 4 hours. The mixture is cooled to ambient temperature and layered between ethyl acetate and water. The organic phase is washed with water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 3 1 v / v mixture of hexane and ethyl acetate as eluent. Thus, 0.25 g (74%) of 4- [5-fluoro-3- (3- (3-pyridyl) prop-2-ynloxy) phenyl] -4-methoxytetrahydropyran is obtained, m.p. 82-83 ^about S.

4- [5-fluoro-3- (2-propynyloxy) phenyl] -4-methoxytetrahydropyran used as the starting material was prepared as follows: a mixture of 5.34 g of 4- (5-fluoro-3-hydroxyphenyl) -4 -methoxytetrahydropyran, propargyl bromide (80 wt% by volume in toluene, 4.46 ml), 5.52 g of potassium carbonate and 150 ml of acetone are heated to reflux for 16 hours. The mixture is filtered and evaporated. The residue was partitioned between ethyl acetate and water. The organic phase is washed with water and with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 2 1 v / v mixture of ethyl acetate and hexane as eluent. Thus, 5.77 (91%) of the expected starting material are obtained, mp. 71-72 ^about S.

PRI me R 14. The procedure described in example 13 is repeated, except that instead of 3-iodopyridine use 3-chloro-2-iodopyridine. Thus, 4- [3- (3- (3-chloropyrid-2-yl) -prop-2-ynloxy) -5-fluorophenyl] -4-methoxytetrahydropyres is obtained in a 59% yield, mp. 80-82 ^about S.

3-Chloro-2-iodopyridine, used as starting material, is prepared as follows: a mixture of 0.74 g of 2,3-dichloropyridine and a saturated solution of sodium iodide in a mixture of 20 ml of methyl ethyl ketone and 1 ml of water is heated to reflux and add an aqueous solution of hydroiodic acid (55 wt.% per volume, 0.5 ml). The mixture was heated to reflux for 16 hours, cooled to ambient temperature, filtered and evaporated. The residue was dissolved in 10 ml of water and the solution was alkalinized to pH 11 by adding sodium hydroxide plates. The stock solution was extracted with ethyl acetate. The organic phase is washed with water, dried with MgSO ₄ and evaporated to obtain the target starting material as an oil (0.66 g, 55%), which is used without further purification.

Example 15. The procedure described in example 13 is repeated, except that 1-iodisoquinoline is used instead of 3-iodopyridine (Chem. Pharm. Bull. Jap. 1982, 30, 1731). Thus, 4- [5-fluoro-3- (3- (1-isoquinolyl) -prop-2-inyloxy) phenyl] -4-methoxytetrahydropyran is obtained in 67% yield as an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.8-2.1 (multiplet, 4H), 2.9 (singlet, 3H), 3.7-3.9 (multiplet, 4H), 5.1 ( singlet, 2H), 6.7-7.9 (multiplet, 7H), 8.25 (doublet, 1H), 8.5 (doublet, 1H).

EXAMPLE 16. Using the procedure described in example 11, 4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -5-trifluoromethylphenyl] -4- is reacted hydra with the iodide method to obtain 4- [3 - [(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -5-trifluoromethylphenyl] -4-methes in a 95% yield, mp. 103 ^about S.

 PRI me R 17. Using the procedure described in example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is reacted with (2RS, 4RS) -4- (3-amino -5-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran to obtain (2RS, 4RS) -4- [3- (1,2-dihydro-1-methyl-2-oxoquinoline-6-hydroxyphenyl] 4-methoxy- 2-Methyltes in 46% yield, as an oil.

NMR spectrum: (CD ₃ SOCD ₃ , delta magnitude) 1.05 (doublet, 3H), 1.1-2.4 (multiplet, 4H), 2.8 (singlet, 3H), 3.0-3, 5 (multiplet, 2H), 3.65 (singlet, 3H), 3.6-3.9 (multiplet, 1H), 4.35 (doublet, 2H), 5.95-6.3 (multiplet, 3H) 6.65 (doublet, 1H); 7.4-7.75 (multiplet, 3H); 7.9 (doublet, 1H); 8.0 (multiplet, 1H).

(2RS, 4RS) -4- (3-amino-5-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran, used as starting material, was prepared as follows: a mixture of 1 g of (2RS, 4RS) -4- (3- non-nitroxy-5-nitrophenyl) -4-methoxy-2-methyltetrahydropyran, 0.1 g of a 5% palladium-charcoal catalyst, 10 ml of ethanol and 10 ml of methylene chloride are stirred under an atmosphere of hydrogen for 2 hours. The mixture is filtered and the filtrate evaporated. The residue was purified by column chromatography using a 1 1 v / v mixture of toluene and ethyl acetate as eluent. Thus, 0.67 g (99%) of the expected starting material are obtained in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.2 (doublet, 3H), 1.4-2.5 (multiplet, 4H), 2.95 (singlet, 3H), 3.25-4.15 ( multiplet, 6H), 6.0-6.5 (multiplet, 3H).

Example 18. Using the procedure described in example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is reacted with (3RS, 4SR) -3-hydroxy-4- (3-Hydroxyphenyl) -4-methoxytetrahydropyran to obtain (3RS, 4SR) -4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -3-hydroxy- 4-methoxy-tetrahydropyran in 84% yield, mp. 62-66 ^C. NMR Spectrum: (SDCl _3, delta values) 1.85 (m, 1H), 2.5 (m, 1H), 2.96 (s, 3H), 3.58 (m, 1H), 3.72 (singlet, 3H), 3.72-4.25 (multiplet, 4H), 5.13 (singlet, 2H), 6.66-7.72 (multiplet, 9H).

(3RS, 4SR) -3-hydroxy-4- (3-hydroxyphenyl) -4-methoxytetrahydropyran, used as starting material, was prepared as follows: a mixture of 12.5 g of 4-hydroxy-4- (3-benzyloxyphenyl) -tetrahydropyran , 80 g of molecular sieves with a pore size of 5 Angstroms and 90 ml of toluene are heated to 80 ^° C for 9 hours. The mixture is filtered and the residue washed successively with toluene and acetone. The filtrate and washes were combined and evaporated. The residue was purified by column chromatography using methylene chloride as eluent. Thus, 10.5 g (88%) of 2,3-dihydro-4- (3-benzyloxyphenyl) -6H-pyran is obtained in the form of an oil.

To a stirred suspension of (2.5 g) thus obtained reaction product, 1.18 g of sodium bicarbonate and 30 ml of methylene chloride, which was cooled ^to 0 ° C, was added 2.42 g of m-chloroperbenzoic acid and the mixture was stirred at ⁰ C for 1 h, and then at ambient temperature for 15 h. The mixture was filtered and the residue washed with methylene chloride. The combined filtrate and washes were washed with dilute aqueous sodium hydroxide and water, dried with Mo O ₄ and evaporated. The epoxide thus obtained (2.3 g, 90%) was used without further purification.

 Use the technique described in Tet. Les. 1968, 24, 1755 to react the resulting epoxide with sodium hydroxide. The reaction product thus obtained was purified by column chromatography using a 4 1 v / v mixture of methylene chloride and diethyl ether as eluent. Thus, 1.78 (73%) of (3RS, 4SR) -3,4-dioxo-4- (3-benzyloxyphenyl) tetrahydropyran is obtained in the form of an oil; 3- and 4-hydroxy groups are in trans positions.

A mixture of 1.76 g of the reaction product thus obtained, 2 g of imidazole, 2.26 g of tert-butyldimethylsilyl chloride and 6 ml of dimethylformafide was stirred at ambient temperature for 15 hours. The mixture was partitioned between diethyl ether and water. The organic layer was washed with water, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 9 1 v / v mixture of methylene chloride and diethyl ether as eluent. Thus, 1.9 (78%) (3RS, 4SR) -4- (3-benzyloxyphenyl) -3- (tert-butyldimethylsilyloxy) -4-hydroxytetrahydropyran is obtained, m.p. 90-92 ^about S.

 The reaction product thus obtained is methylated using the procedure described in Example 1, which is related to the preparation of starting materials. Thus, 1.69 g (89%) of (3RS, 4SR) -4- (3-benzyloxyphenyl) -3- (tert-butyldimethylsiloxy) -4-methoxytetrahydropylene is obtained in the form of an oil.

To a mixture of the compound thus obtained and 32 ml of tetrahydrofuran, tetra-n-butylammonium fluoride (1 M solution in tetrahydrofuran; 16 ml) was added and the mixture was stirred at ambient temperature for 15 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 9 1 v / v mixture of methylene chloride and diethyl ether as eluent. Thus, 1.06 g (86%) of (3RS, 4SR) -4-methoxytetrahydropyran are obtained, m.p. 85-86 ^about S.

A mixture of the reaction product thus obtained, 0.1 g of a 10% palladium-charcoal catalyst and 20 ml of ethanol was stirred at ambient temperature under an atmosphere of hydrogen for 15 hours. The mixture was filtered and evaporated to give the desired starting material (0 7 g, 92%), mp 159-160 ^about C.

Example 19. Using the methylation procedure described in Example 1, (3RS, 4SR) -4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) - is reacted phenyl] -3-hydroxy-4-methoxy-tetrahydropyran with methyl iodide in the presence of 15-crown-5 to obtain (3RS, 4SR) -4- [3- (1,2-dihydro-1-methyl-2-oxoquinoline -6-ylmethoxy) phenyl] -3,4-dimethyl sieve 78% yield in the form of a glassy substance. NMR spectrum: (CDL ₃ , delta magnitude) 1.85 (m, 1H), 2.5 (m, 1H), 2.95 (m, 6H), 3.07 (m, 1H), 3.72 (singlet, 3H), 3.72-3.94 (multiplet, 4H), 5.14 (singlet, 2H), 6.66-7.5 (multiplet, 9H).

Example 20. Using the procedure described in example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is reacted with (2S, 4R) -4- (3-hydroxyphenyl ) -4-methoxy-2-methyltetrahydropyran to obtain (2S, 4R) -4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4- methoxy-2-methyltetrahydropyran in 69% yield, mp. 88-90 ^about S.

(2S, 4R) -4- (3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran, used as starting material, is prepared as follows: Grignard reagent is obtained by heating a mixture of 4.2 g of 3-benzyloxybromobenzene, 0.4 g magnesium and 10 ml of tetrahydrofuran to a boiling temperature under reflux for 30 minutes The mixture was allowed to cool to approximately 40 ^{° C} and a solution of 1,55 (2S) -2-methyltetrahydropyran-4-one in 7 ml of tetrahydrofuran was added dropwise. The mixture was stirred and heated ^to 40 ° C for 3 hours. The mixture was separated by layers between ethyl acetate and a cold dilute solution of hydrochloric acid in water. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried with MoO ₄ and evaporated. The residue was purified by column chromatography using a 10 3 v / v mixture of toluene and ethyl acetate as eluent. Thus, in the form of a mixture of diastereoisomers, (2S, 4R) - and (2S, 4S) -4- (3-benzyloxyphenyl) -4-hydroxy-2-methyltetrahydropyran (3.71 g, 92%) are obtained in as an oil that is partially separated to give a fraction (2.33 g) that is enriched in the less polar diastereoisomer.

To the solution thus obtained enriched fraction (2.33 g) in 16 ml dimethylformamide which was cooled to ^-5 ° C, was added sodium hydride (55 wt. Dispersion in mineral oil, 0.39 g) and the resulting mixture was stirred at this temperature for 1 hour. 0.61 ml of methyl iodide is added and the mixture is stirred for 2 hours and allowed to warm to ambient temperature. The mixture was layered between ethyl acetate and ice with chilled water. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 20 1 v / v mixture of toluene and ethyl acetate as eluent. Thus, 1.99 (92%) of (2S, 4R) -4- (3-benzyloxyphenyl) -4-methoxy-2-methyltetrahydropyran is obtained in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.2 (doublet, 3H), 1.5-1.65 (multiplet, 1H), 1.9-2.05 (multiplet, 3H), 2.96 ( singlet, 3H), 3.8-4.0 (multiplet, 3H), 5.1 (singlet, 2H), 6.85-7.05 (multiplet, 3H), 7.2-7.5 (multiplet, 6H).

 A mixture of 1.62 g of the reaction product thus obtained, 0.28 g of a 10% palladium-carbon catalyst and 50 ml of isopropanol was stirred under a hydrogen atmosphere for 5 hours. The mixture was filtered and the filtrate was evaporated. Thus, the desired starting material is obtained in quantitative yield, in the form of an oil.

(2S) -2-Methyltetrahydropyran-4-one, used as starting material, as shown above, is prepared as follows: 29 g of (-) - (2S, 3S, 4S) -2,3-epoxyhept-6 solution -one-4-ol (.. J.Ong Chem 1983, 48, 5093, the compound N (-) - 14) in 1100 ml of tetrahydrofuran which was cooled to ^-15 ° C, was added within 30 min bis (2- methoxyethoxy) -aluminium hydride (3.4 M solution in toluene, 200 ml) and the resulting mixture was stirred for 16 hours and allowed to warm to ambient temperature. The mixture is cooled in an ice bath and a dilute aqueous solution of sulfuric acid (10 wt. Per volume, 1350 ml) is slowly added. Sodium chloride is added to obtain two layers. The organic phase is separated, and the aqueous layer is extracted with ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium chloride, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 2 3 v / v mixture of hexane and ethyl acetate as eluent. Thus, 20 g (67%) of (2S-4S) -hept-6-en-2,4-diol are obtained in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.23 (doublet, 3H), 1.63 (triplet, 2H), 2.18-2.4 (multiplet, 4H), 3.93-4.38 ( multiplet, 2H), 5.08-5.25 (multiplet, 2H), 5.70-5.96 (multiplet, 1H).

A solution of (5.6 g) thus obtained reaction product in 875 ml of methanol was cooled to ^-20 ° C and the current ozone-containing oxygen (approximately 5% ozone) is passed into the solution for 130 minutes. Oxygen gas and then argon are bubbled through the solution to remove any excess ozone. 20 ml of dimethyl sulfide are added and the mixture is allowed to warm to ambient temperature. The mixture was evaporated and the residue was purified by column chromatography using ethyl acetate as eluent. Thus, they are obtained in the form of a mixture of diastereoisomers (2S, 4R, 6R) - and (2S, 4R, 6S) -4,6-dioxy-2-methyltetrahydropyranes (3.7 g 67%), in the form of an oil.

After repeating the above steps to a solution of 19 g of the thus obtained reaction product in 90 ml of ethanol which had been cooled in an ice bath was added 90 of a saturated solution of hydrogen chloride drops of ethanol, and the resulting mixture was kept at ⁵ ° C for 16 hours. The mixture was evaporated to get in the form of a mixture of diastereoisomers (2S, 4R, 6R) - and (2S, 4R, 6S) -6-ethoxy-4-hydroxy-2-methyltetrahydropyran in quantitative yield, in the form of an oil, which is used without further purification.

The solution thus obtained reaction product in 45 ml of dimethylformamide was cooled ^to 0 ° C, and then successively added 20.4 g of imidazole and 5 g molecular sieves 4 Angstrom pore size. Was added dropwise 24.3 g of triethylsilyl chloride and the mixture was stirred at ⁰ ° C for 2 hours. The mixture was poured onto ice, and the ethyl acetate extract was taken. The organic phase was dried with MgSO ₄ and evaporated. The residue was dissolved in 300 ml of diethyl ether and the solution was washed with cold water. The organic layer was separated, dried with MgSO ₄ and evaporated to give a mixture of diastereoisomers (2S, 4R, 6R) - and (2S, 4R, 6S) -6-ethoxy-2-methyl-4-triethylsilyloxy-tetrahydropyran ( 36 g, 91%), which is used without further purification.

Alternately, a solution of the thus obtained reaction product in 300 ml of methylene chloride, which was cooled ^to 5 ° C, was added 15.7 g of triethylsilane and 29.1 g of trifluoromethanesulfonic acid trimethylsilyl ester and the mixture was stirred at ⁵ ° C for 30 min. The mixture was poured into 50 ml of ice-cold water and the resulting mixture was stirred for 5 minutes. The mixture is neutralized by adding portionwise sodium bicarbonate. The organic layer was separated and the aqueous layer was saturated with hydrogen chloride and extracted with ethyl acetate. The organic solutions were combined, dried with MgSO ₄ and evaporated. The residue was purified by column chromatography using a 4 1 v / v mixture of hexane and ethyl acetate as eluent. Thus, 6.2 g (41%) of (2S, 4S) -4-hydroxy-2-methyltetrahydropyran are obtained. NMR spectrum: (CDL ₃ , delta magnitude) 1.15-1.25 (multiplet, 4H), 1.4-1.6 (multiplet, 1H), 1.8-2.0 (multiplet, 2H), 3.3-3.5 (multiplet, 2H), 3.7-3.8 (multiplet, 1H), 4.0 (multiplet, 1H).

Jones reagent (J. Chem Soc 1951, 2407;.. 13.3 ml of 8M solution of chromium trioxide in aqueous sulfuric acid) was added dropwise to a solution of the thus obtained reaction product in 250 ml of acetone which had been cooled to 5 ^° C was added approximately 20 drops of isopropanol to decompose the excess oxidizing agent and the mixture is stirred at ambient temperature for 30 minutes. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in 10 ml of diethyl ether and the solution was filtered through silica silica gel 60N and evaporated. Thus, (2) -2-methyltetrahydropyran-4-one (4.85 g, 81%) is obtained in the form of an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.3 (doublet, 3H), 2.2-2.7 (multiplet, 4H), 3.6-3.8 (multiplet, 2H), 4.2- 4.3 (multiplet, 1H).

PRI me R 21. Using the procedure described in example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is reacted with (2S, 4R) -4- (5-fluoro-3 -hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran to obtain (2S, 4R) -4- [5-fluoro-3- (1,2-dihydro-1-methyl-2-oxoquinoline-6- ilmethoxy) phenyl] -4-methoxy-2-methyltetrahydropyran in 66% yield, mp. 91-93 ^about S.

(2S, 4R) -4- (5-fluoro-3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran, used as starting material, was prepared as follows: the procedures described in Example 20 were repeated, except that 3-benzyloxy-1-bromo-5-fluorobenzene is used instead of 3-benzyloxybromobenzene. Thus, in turn, they are obtained: in the form of a mixture of diastereoisomers (2S, 4R) - and (2S, 4S) -4- (3-benzyloxy-5-fluorophenyl) -4-hydroxy-2-methyltetrahydropyran in 87% yield as an oil; (2S, 4R) -4- (3-benzyloxy-5-fluorophenyl) -4-methoxy-2-methyltetrahydropyran in 58% yield as an oil. NMR spectrum: (CDL ₃ , delta magnitude) 1.2 (doublet, 3H), 1.5-1.6 (multiplet, 1H), 1.8-2.0 (multiplet, 3H), 3.0 ( singlet, 3H), 3.8-4.0 (multiplet, 3H), 5.05 (singlet, 2H), 6.6-6.8 (multiplet, 3H), 7.3-7.5 (multiplet, 5H); target starting material in quantitative yield, as an oil; NMR spectral data obtained after adding the chiral shear reagent (-) - 1- (9-anthranyl) -2,2,2-trifluoroethanol show that the reaction product has 98.6% optical purity.

Example 22 Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is reacted with 4- (4-hydroxy-3-methoxyphenyl) -4- methoxytetrahydropyran to give 4- [4- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -3-methoxyphenyl] -4-methoxytetrahydropyran in 49% yield, i.e. pl. 172-173 ^{° C} (recrystallized from ethyl acetate).

4- (4-hydroxy-3-methoxyphenyl) -4-methoxytetrahydropyran, used as starting material, is prepared as follows: using the procedure described in example 1, 2-bromomethylnaphthalene is reacted with 4-bromo-2-methoxyphenol, to obtain 3-methoxy-4- (neft-2-ylmethoxy) -bromobenzene with a 62% yield, mp. 108 ^about S.

Use the procedure described in paragraph c). of Example 2, the reaction product thus obtained is reacted with tetrahydropyran-4-one to obtain 4-hydroxy-4- [3-methoxy-4- (neft-2-ylmethoxy) phenyl] tetrahydropyran in 44% yield , mp 150-151 ^about With (recrystallized from ethyl acetate).

Use the procedure described in paragraph y). of Example 6, the reaction product thus obtained is reacted with methyl iodide to obtain 4-methoxy-4- [3-methoxy-4- (naphth-2-ylmethoxy) phenyl] tetrahydropyran in 52% yield, i.e. pl. 129 ^° C (recrystallized from ethyl acetate).

A mixture of 0.241 g of the reaction product thus obtained, 0.02 g of a 10% palladium-carbon catalyst and 25 ml of ethanol was stirred under an atmosphere of hydrogen for 90 minutes. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography using increasingly increasing polar mixtures of hexane and ethyl acetate as eluent. Thus, 0.142 g (94%) of the expected starting material are obtained with a melting point of 92-93 ^about S.

PRI me R 23. The following examples illustrate typical pharmaceutical dosage forms containing a compound of formula I or its pharmaceutically acceptable salt (hereinafter compound X), for therapeutic or prophylactic use in the treatment of people:
(a) Tablet 1 mg / tablet
Compound X 100
Lactose (European Pharmacopoeia) 182.75
Croscarmellose sodium 12.0
Corn starch paste (5 wt. Per paste) 2.25
Magnesium Stearate 3.0
(b) Tablet 2 mg / tablet
Compound X 50
Lactose (European Pharmacopoeia) 223.75
Croscarmellose sodium 6.0
Polyvinylpyrrolidone (5 wt.% On the volume of paste) 2.25
Magnesium Stearate 3.0
(c) Tablet 3 mg / tablet
Compound X 1.0
Lactose (European Pharmacopoeia) 93.26 Croscarmellose sodium 4.0
Corn starch paste (5 wt. Per paste) 0.75
Magnesium Stearate 1.0
(g) Capsule mg / capsule
Compound X 10 mg
Lactose (European Pharmacopoeia) 488.5
Magnesium Stearate 1.5
(d) Injection 1 (50 mg / ml)
Compound X 5.0 wt. per volume
1 M sodium hydroxide solution 15.0 wt. per volume
0.1 M hydrochloric acid solution (to bring the pH to 7.6)
Polyethylene glycol 400 4.5 wt. per volume
Bring water for injection to 100%
(e) Injection 2 (10 mg / ml)
Compound 1.0 wt. per volume
Sodium Phosphate (British Pharmacopoeia) 3.6 wt. per volume
0.1 M sodium hydroxide solution 15.0 wt. per volume
Bring water for injection to 100%
(g) Injection 3 (1 mg / ml, containing
buffer to pH 6)
Compound X 0.1 wt. per volume
Sodium Phosphate (British Pharmacopoeia) 2.26 wt. per volume
Citric acid 0.38 wt. per volume
Polyethylene glycol 400 3.5 wt. per volume
Bring water for injection to 100%
(h) Aerosol 1 mg / ml
Compound X 10.0
Sorbitol Trioleate 13.5
Trichlorofluoromethane 910.0
Dichlorofluoromethane 490.0
(i) Aerosol 2 mg / ml
Compound X 0.2
Sorbitol trioleate 0.27
Trichlorofluoromethane 70.0
Dichlorodifluoromethane 280.0
Dichlorotetrafluoroethane 1094.0
(k) Aerosol 3 mg / ml
Compound X 2.5
Sorbitol trioleate 3.38
Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6
(l) Aerosol 4 mg / ml
Compound X 2.5
Soy Lecithin 2.7
Trichlorofluoromethane 67.5
Dichlorodifluoromethane 1086.0
Dichlorotetrafluoroethane 191.6
These formulations can be obtained by conventional methods. Tablets (a) to (c) may be enteric coated in a conventional manner, for example, to provide a cellulose acetate phthalate acetate coating. Aerosol formulations (h) - (l) can be used in combination with standard aerosol measuring devices with measured doses, and sorbitan trioleate and soy lecithin suspending agents can be replaced with another suspending agent, such as sorbitan monooleate, sorbitol sexozoleate, polysorbate 80, polyglycerol oleate or oleic acid.

 Chemical formulas used in the description.

(I)
HX-Ar-

(II)
R⁴-X-Ar-

(III)
R⁴-X-Ar-

R² (IV)
Q-A-X-Ar-

R² (V)
-A¹-X-Ar-

(VI)QAX-Ar-

(I)
HX-Ar-

(Ii)
R ⁴ -X-Ar-

(III)
R ⁴ -X-Ar-

R ² (IV)
QAX-Ar-

R ² (V)
-A ¹ -X-Ar-

(Vi)

Claims (9)

1. Heterocyclic compounds of formula 1

where Q is a 6-membered monocyclic or 10-membered bicyclic heterocyclic fragment containing one or two nitrogen atoms, which may have one, two or three substituents selected from halogen, hydroxide, oxo, (C ₁ C ₄ ) -alkyl, fluoro - (C ₁ - C ₂ ) -alkyl, di- (C ₇ C ₂ ) -alkyl amino (C ₁ - C ₂ ) -alkyl and phenyl- (C ₁ C ₂ ) -alkyl, where A (C ₁ - C ₆ ) alkylene or (C ₃ C ₆ ) alkynylene;
X oxy (or imino);
Ar is phenylene, which may have one or two substituents selected from halo, hydroxy, amino, ureido, (C ₁ C ₄ ) alkoxy, fluoro (C ₁ C ₄ ) alkyl and cyano (C ₁ C ₄ ) - alkoxy, or Ar 3,5-pyridylene;
R ′ (C ₁ C ₆ ) -alkyl or (C ₃ C ₆ ) alkenyl, R ² and R ³ together form a group of the formula A ² X ² - A ³ -, which together with the carbon atom to which A ² is attached and A ³ form a cycle having 5 or 6 atoms, with A ² and A ³ , which may be the same or different, each is (C ₁ -C ₄ ) alkylene and X ² hydroxy, and this cycle may have one or two substituents, which may be the same or different, selected from hydroxy, (C ₁ C ₄ ) -alkyl and (C ₁ C ₄ ) -alkoxy,
or their pharmaceutically acceptable salt. 2. The compounds of formula 1, wherein Q is pyridyl, quinolyl, isoquinolyl, quinazolinyl or quinoxalinyl, which may have one, two, or three substituents selected from fluoro, chloro, hydroxy, oxo, methyl, ethyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl;
A methylene or 1-propynylene;
X hydroxy or imino;
Ar 1,3-phenylene or 1,4-phenylene, which optionally can carry one or two substituents selected from fluorine, hydroxide, amino, ureido, methoxy, trifluoromethyl and cyanomethoxy, or Ar 3,5-pyridylene;
R ^{1 is} methyl, ethyl or allyl;
R ² and R ³ together form a group of the formula A ² X ² A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having 5 or 6 atoms in a ring,
wherein A ² and A ³ , which may be the same or different, are each methylene or ethylene; X ² hydroxy, and this cycle may carry one or two substituents selected from hydroxyl, methyl and methoxy,
or a pharmaceutically acceptable salt thereof. 3. The compounds of formula 1 according to claim 1, wherein Q is 2-pyridyl or 3-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 2-quinazolinyl, 6-quinazolinyl or 6-quinoxalinyl, which optionally can carry one or two substituents selected from fluoro, chloro, hydroxide, oxo and methyl;
A methylene or 1-propynylene;
X hydroxy;
Ar 1,3-phenylene or 1,4-phenylene, which optionally carry one substituent selected from fluoro, hydroxide, amino, methoxy, trifluoromethyl and cyanomethoxy, or Ar 3,5-pyridylene;
R ^{1 is} methyl, ethyl or allyl;
R ² and R ³ together form a group of the formula A ² X ² A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having 5 or 6 atoms in the ring, with A ² and A ³ , which may be the same or different, each is methylene or ethylene;
X ^{2 is} hydroxy, and this cycle may carry a substitute selected from hydroxyl, methyl and methoxy.  or a pharmaceutically acceptable salt thereof. 4. The compounds of formula 1 according to claim 1, wherein Q is 3-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 2-quinazolinyl, 6-quinazolinyl or 6-quinoxalinyl, which optionally can carry one two or three substituents selected from fluoro, hydroxyl, oxo, methyl, ethyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl;
A methylene;
X hydroxy or imino;
Ar 1,3-phenylene or 1,4-phenylene, which may optionally carry one or two substituents selected from fluorine, hydroxide, amino, ureido, methoxy, trifluoromethyl and cyanomethoxy, or Ar 3,5-pyridylene;
R ^{1 is} methyl, ethyl or allyl;
R ² and R ³ together form a group of the formula -A ² X ² - A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having 5 or 6 atoms in the ring, where A ² is ethylene A ³ methylene or ethylene;
X ² hydroxy, and this cycle can carry one or two substituents selected from hydroxide, methyl and methoxy,
or a pharmaceutically acceptable salt thereof. 5. The compounds of formula 1 according to claim 1, wherein Q is 6-quinolyl, 3-isoquinolyl, 2-quinazolinyl, 6-quinazolinyl, 6-quinoxalinyl, 1,2-dihydro-2-oxoquinolin-3-yl, 1,2 -dihydro-2-oxaquinilin-5-yl, 1,2-dihydro-2-oxaquinilin-6-yl or 1,2-dihydro-2-oxoquinolin-7-yl, which may optionally carry one or two substituents selected from fluorine, methyl, ethyl, 2-fluoroethyl, 2-dimethylaminethyl and benzyl;
A methylene;
X hydroxy;
Ar 1,3-phenylene or 1,4-phenylene, which may optionally carry one or two substituents selected from fluoro, amino, ureido, methoxy and trifluoromethyl,
R ^{1 is} methyl, ethyl or allyl;
R ² and R ³ together form a group of the formula A ² X ² A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having 5 or 6 atoms in the ring, where A ^{2 is} ethylene, A ³ methylene or ethylene, X ² hydroxy, and this cycle may carry one or two substituents selected from hydroxide, methyl and methoxy,
or a pharmaceutically acceptable salt thereof. 6. The compounds of formula 1 according to claim 1, in which Q is 1,2-dihydro-2-oxoquinolin-3-yl or 1,2-dihydro-2-oxoquinolin-6-yl, which carry one substituent selected from methyl ethyl, 2-fluoroethyl and benzyl;
A methylene;
X hydroxy;
Ar 1,3-phenylene, which may optionally carry one or two substituents selected from fluoro, amino and trifluoromethyl;
R ¹ methyl, ethyl or allyl,
R ² and R ³ together form a group of the formula A ² X ² A ³ -, which, together with the carbon atom to which A ² and A ^{3 are} attached, defines a ring having 5 or 6 atoms in the ring, where A ^{2 is} ethylene; A ^{3 is} methylene or ethylene, X ^{2 is} hydroxy, and this cycle may carry a methyl substituent in the alpha position to X ² ,
or a pharmaceutically acceptable salt thereof.  7. The compounds of formula 1 according to claim 1, selected from 4-methoxy-4- [3- (3-) 2-pyridyl (prop-2-in-2yloxy) phenyl] tetrahydropyran; 4- [5-fluoro-3- (3-) 2-pyridyl (prop-2-in-1-yloxy) phenyl] -4-methoxytetrahydropyran; 4- [5-fluoro-3) - (quinoxaline-6-ylmethoxy) phenyl] -4-methoxytetrahydropyran (2RS, 4SR) -4- (5-fluoro-3) - (quinoxaline-6-ylmethoxy) phenyl] - 4-methoxy-2-methyltetrahydropyran; 4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-3-ylmethoxy) phenyl] 4-methoxytetrahydropyran; 4- [5-fluoro-3- (6-quinolylmethoxy) phenyl] -4-methoxytetrahydropyran; 4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] - 4-methoxytetrahydropyran; 4- [5-fluoro-3- (1,2-dihydro-1-methyl-2 oxoquinolin-6-ylmethoxy) phenyl] -4-methoxytetrahydropyran; 4-allyloxy-4- [5-fluoro-3 (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] tetrahydropyran; 4- [5-fluoro-3- (1,2-dihydro-1-) 2 (fluoroethyl) -2-oxoquinolin-6-ylmethoxy) phenyl] -4-methoxytetrahydropyran; 4- [2,5-difluoro-3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4-methoxytetrahydropyran; 4- [3- (1,2-dihydro-1-methyl- 2-oxoquinolin-6-ylmethoxy (-5-trifluoromethylphenyl] -4-methoxytetrahydropyran, 4-allyloxy-4- [3- (1,2-dihydro- 1-methyl-2-oxoquinolin-6-ylmethoxy) -5-trifluoromethylphenyl] tetrahydropyran, (2RS, 4SR) -4- [5-fluoro-3 - (1,2-dihydro-1-methyl-2-oxoquinoline -6 -ylmethoxy) phenyl] -4-methoxy-2-methyltetrahydropyran, (2RS, 4SR) -4- [5-fluoro-3 - (1,2-dihydro-1-ethyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4- methoxy-2-methyltetrahydropyran; (2RS, 4S) R-4- (5-amino-3-) 1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy (phenyl) - 4-methoxy -2-methyltetrahydropyran, (2S, 4R) -4- [3- (1,2-dihydro-1-methyl -2-oxoquinolin-6-ylmethoxy) phen yl] -4-methoxy-2-methyltetrahydropyran, (2S, 4R) -4- [5-fluoro-3- (1,2-dihydro-1-methyl-2-oxoquinoline-6-ylmethoxy) phenyl] - 4- methoxy-2-methyltetrahydropyran (2RS, 3SR) - 3- [5-fluoro-3- (1,2-dihydro-1-ethyl -2-oxoquinolin-6-ylmethoxy) phenyl] -3-methoxy-2-methyltetrahydrofuran, or their pharmaceutically acceptable salts.  8. The compounds of formula 1 according to claim 1, which is 4- (5-fluoro-3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4-methoxytetrahydropyran or its a pharmaceutically acceptable salt.  9. A pharmaceutical composition having inhibitory activity against 5-lipoxygenase, which contains an active principle and a pharmaceutically acceptable diluent or carrier, characterized in that the active principle comprises a heterocyclic compound of formula 1 or a pharmaceutically acceptable salt thereof according to claim 1 in the following ratio components, wt. Heterocycle of formula 1 or its pharmaceutically acceptable salt 5 98%
Pharmaceutically acceptable diluent or carrier

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