LT3396B - Heterocyclic compounds, method for their preparation and pharmaceutical composition - Google Patents

Description

The present invention relates to novel heterocycles which are inhibitors of the enzyme 5-lipooxygenase (hereinafter referred to as 5-LO). The invention also relates to methods for the preparation of novel pharmaceutical compositions containing said heterocycles which can be used in the treatment of various inflammatory and / or allergic disorders involving direct and by-products of arachidonic acid oxidation catalyzed 5-LO.

As defined above, the heterocycles described below are inhibitors of 5-LO, the enzyme of which must be involved in the catalysis of arachidonic acid in order to produce leukotrienes active in the cascade process,

B ₄ (LTB ₄ ) and peptide-lipid such as leukotriene C ₄ (LTC ₄ ) and various metabolites (metabolic oxidation would be obtained such as physiologically leukotriene leukotrienes, D ₄ (LTD ₄ ) and products).

The biosynthetic dependence and physiological properties of leukotrienes are outlined in G.W. Taylor and S.R. In Clark's Journal of General Directions in Pharmacological Sciences (G.W. Taylor and S.R. Clarke in Trends in Pharmacological Sciences), 1986,7,100-103. Leukotrienes and their metabolites are involved in the emergence and development of various inflammatory and allergic diseases, such as gouty disease, asthma, allergic rhinitis, atopic dermatitis, psoriasis, cardiovascular and cerebrovascular disease. In addition, leukotrienes are mediators of inflammatory diseases due to their ability to modulate lymphocytic and leukocytic function. Other physiologically active metabolites of arachidonic acid, such as prostaglandins and thromboxanes, are produced by the action of the cyclooxygenase enzyme on arachidonic acid.

The present inventors have now discovered that some heterocycles are potent inhibitors of the enzyme 5-LO and thus leukotriene biosynthesis. Thus, such compounds are useful as therapeutic agents in the treatment of, for example, allergic conditions, psoriasis, asthma, cardiovascular lesions and / or inflammatory and gouty (arthritic) conditions which are wholly or partially mediated by one or more leukotrienes. .

The present invention provides a heterocycle of formula I (below) wherein Q is a 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety having one or two nitrogen atoms optionally substituted with one, two, or three substituents selected from halogen, oxy, carboxy, cyano, amino, (1-4C) alkyl, (1-4C) alkoxy, fluoro (1-4C) alkyl, (1-4C) alkylamino, di [(1-4C) -alkyl] -amino-, oxy- (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- (1-4C) -alkyl groups, and wherein the phenyl group in the specified phenyl (1-4C) -alkyl substituent may optionally be substituted with a halogen, (1-4C) -alkyl and (14C) -alkoxyl wherein A is (1-6C) -alkylene, (3-6C) -alkenylene, where X is oxy, thio, sulfinyl, sulfonyl or imino, wherein Ar is phenylene , which can have one or two packs selected from halogen, oxy, amino, nitro, cyano, ureido, 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 - groups, 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) -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

Is a 6 membered heterocyclic residue containing up to three nitrogen atoms which may be substituted by one or two substituents selected from halo, oxy, amino-cyano, (14C) -alkyl, (1-4C) -alkoxy, ( 1-4C) alkylamino and di [(1-4C) alkyl] amino;

R ¹ is hydrogen, (1-6C) alkyl, (3-6C) alkenyl, (3-6C) alkynyl, cyano (1-4C) alkyl or (2-4C) alkanoyl, or R ¹ is benzoyl which may be substituted with halogen, (1-4C) alkyl and (14C) alkoxyl;

and R ² , R ³ together form a group of formula -A ² -X ² -A ³ - which, taken together with the carbon to which A and A are attached, forms a ring having 4 to 7 atoms in the ring in which A and A, the same or different, each being (1-4C) alkylene, and X is oxy-thio, sulfinyl, sulfonyl or imino, and the ring may have one or two substituents, which may be the same or different, selected from oxy -, (1-4C) alkyl, (14C) alkoxy, (1-4C) alkylthio, (1-4C) alkylthionyl and (1-4C) alkylsulfonyl, or which ring may have (1) - (C) -alkylenedioxy substituent;

or a pharmaceutically acceptable salt thereof (heterocycle).

According to a further aspect of the present invention there is provided a heterocycle of formula I wherein Q is a 6 membered bicyclic heterocyclic residue containing one or two nitrogen atoms optionally substituted with one or two substituents selected from halogen, oxy, oxo, carboxy, cyano -, amino, (1-4C) alkyl, (1-4C) alkoxy, fluoro (1-4C) alkyl, (1-4C) alkylamino, di [(1-4C) alkyl] - amino, oxy (1-4C) alkyl, amino- (14C) alkyl, (1-4C) alkylamino- (1-4C) alkyl, di [(1-4C) alkyl] amino- ( 1-4C) alkyl, amino- (2-4C) alkoxy, (14C) alkylamino- (2-4C) alkoxy, and di [(1-4C) alkyl] amino- (2-4C) -alkoxy;

A is (1-6C) -alkylene, (3-6C) -alkenylene, (3-6C) alkynylene or cyclo- (3-6C) -alkylene;

X is oxo, thio, sulfinyl, sulfonyl or imino;

Ar is phenylene which may be substituted with one or two substituents selected from halogen, oxy, 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] carbamoyl, N, N-di [(1-4C) alkyl] carbamoyl , (2-4C) alkanoylamino, cyano (14C) alkoxy, carbamoyl (1-4C) alkoxy, amino (2-4C) alkoxy, (1-4C) alkylamino (2). -4C) alkoxy, di- [(14C) alkylamino- (2-4C) alkoxy and (1-4C) alkoxycarbonyl (1-4C) alkoxy; or

Is a 6 membered heterocyclic residue containing up to three nitrogen atoms which may optionally be substituted with one or two substituents selected from halo, oxy, amino, cyano, (1-4C) alkyl, (1-4C) - alkoxy, (1-4C) alkylamino and di- [(1-4C) alkyl] amino;

R ¹ is hydrogen, (1-6C) alkyl, (3-6C) alkenyl, (3-6C) alkynyl, cyano (1-4C) alkyl or (2-4C) alkanoyl, or R ¹ is benzoyl optionally substituted with halo, (1-4C) alkyl or (1-4C) acoxy; and

R ² and R ³ together form a group of formula -A ² -X ² -A ³ - which, taken together with the carbon atom to which A and A are attached, forms a ring having 4 to 7 atoms in the ring in which A and A may be the same or different, each being (1-4C) alkylene, and X ² is oxo, thio, thionyl, sulfonyl, or imino, and the ring may have one or two substituents, which may be the same or different , selected from oxo, (1-4C) alkyl, (1-4C) alkylthio, (1-4C) alkoxy, (1-4C) alkylthionyl and (1-4C) alkylsulfonyl groups or which ring may carrying a (1-4C) alkylenedioxy substituent;

or a pharmaceutically acceptable salt thereof (heterocycle).

The chemical formulas given in this description in Roman numerals are provided for convenience on a separate sheet below.

In the description of the present invention, the general term alkyl refers to both linear and branched alkyl groups. However, the individual alkyl groups mentioned, such as propyl, are specific to linear chains only, and references to individual branched alkyl groups such as isopropyl are only accurate for branched chains. An analogous conditional certificate is used for other generic terms as well.

It is to be understood that since some of the compounds of formula I described above may exist in optically active or racemic forms, the invention encompasses any such optically active or racemic form of novel compounds which possesses the ability to inhibit one or more substituents having asymmetric carbon atoms. -LO. Synthesis of optically active forms may be accomplished by standard organic chemistry techniques well known in the art, e.g., by synthesis of optically active starting materials or by racemic partitioning. Similarly, inhibitory properties against 5-LO can be assessed by standard laboratory procedures below.

Further, since some of the compounds of Formula I above may represent a tautomeric phenomenon, e.g., a compound of Formula I wherein Q is oxo or oxo substituent, and whereas any of the formulas represented by this description may be but one. of the possible tautometric forms, the definition of the invention includes any tautomeric form of the compounds of formula I which has the property of inhibiting 5-LO and is not limited to any one tautomeric form.

The specific meanings of the radicals above are the meanings given below.

A particular value for Q when Q 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, cinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl or naphthyridinyl; a hydrogenated derivative thereof such as, for example, 1,2-dihydropyridyl or 1,2-dihydroquinolyl. The heterocyclic residue may be attached to any available nitrogen atom, or it may be substituted at any position by attachment to 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 from any of two cycles of the bicyclic heterocyclic residue.

Preferably, Q is, e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 2-pyrimidinyl, 4LT 3396B pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 2quinolyl, 3-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 6-cinolyl, 7-cinolyl, 2-quinazolyl, 4-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 1-phthalazinyl, 6-phthalazinyl, 1,5-naphthyridin-3-yl, 1,5-naphthyridin-3-yl, 1,6-naphthyridin-3-yl, 1,6-naphthyridin- 7,

1,7-naphthyridin-3-yl, 1,7-naphthyridin-3-yl, 1,8-naphthyridin-3-yl, 2,6-naphthyridin-6-yl or 2,7-naphthyridin-3-yl.

Suitable values for the halogen substituent which may be attached to Q, Ar or R ¹ are, for example, fluorine, chlorine, bromine or iodine.

Suitable values for the (1-4C) -alkyl substituent which may be on Q, Ar or R ¹ are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or fluorobutyl.

Suitable values for the (1-4C) -alkoxyl substituent which may be on Q, Ar or R ¹ are, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl or butoxyl.

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

Suitable values for A when it is (1-6C) alkylene are, for example, methylene, ethylene, ethylidene, trimethylene, propylidene or pentamethylene; when it is (3-6C) alkenylene, a suitable value is, for example, 1-propenylene, 2-methylpropen-1-ylene, 1-butenylene or 2-butenylene; and when it is (3-6C) -alkynylene, a suitable value is e.g.

1-propynylene, 3-methylpropyn-1-ylene, 1-butynylene or 2-butynylene.

Suitable values for A in the case of cyclo- (3-6C) -alkylene are, for example, cyclopropylidene, 1,2-cyclopropylene, cyclohexylidene or 1,4-cyclohexylene.

A suitable value for Ar when Ar is phenylene is e.g.

1,3-phenylene or 1,4-phenylene.

Suitable values for Ar when Ar is a 6-membered heterocyclic residue containing up to three nitrogen atoms are, for example, pyridylene, pyrimidinylene, pyridazinylene or 1,3,5-triazinylene. The desired value of A when A is present

A 6-membered heterocyclic residue containing up to three nitrogen atoms is e.g. 2,4-, 2,5-, 3,5- or 2,6-pyridylene, 2,4-, 2,5- or 4,6-pyrimidinylene , 3,5 or 3,6-pyridazinylene, or 2,5- or 2,6-pyrazinylene.

Suitable values for substituents that may be Q or Ar are, for example:

For (1-4C) -alkylamine: methylamine, ethylamine, propylamine or butylamine, for di- {(1-4C) -alkyl] -amine: dimethylamine, diethylamine and dipropylamine, for amino- (2-4C) -alkoxyl: 2-aminoethoxyl, 3-aminopropoxyl and 4-aminobutoxyl, for (1-4C) -alkylamino (2-4C) -alkoxyl:

2-methylaminoethoxyl, 3-methylaminopropoxyl and 2-ethylaminoethoxyl, di [(1-4C) -alkyl] -2-dimethylaminoethoxyl, 3-amino- (2-4C) -alkoxyl: dimethylaminopropoxyl and 2-diethylaminoethoxyl,

Suitable values for Q substituents are, for example, for oxy (1-4C) alkyl:

for amino (2-4C) alkyl:

For (1-4C) alkylamino (1-4C) alkyl:

for di [(1-4C) alkyl] amino- (1-4C) alkyl:

for phenyl- (1-4C) alkyl:

Valid values include, for example:

For (3-4C) -alkenyloxy:

(1-4C) Alkyl:

alternatively, oxymethyl, 1-oxyethyl, 2-oxypropyl and 3-oxypropyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 2-aminopropyl and 3-aminopropyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, ethylaminomethyl and 2-ethylaminoethyl, dimethylaminoethyl, 2-dimethylaminoethyl. , 3-dimethylamino propyl, diethylaminomethyl and 2-diethylaminoethyl, benzyl, phenethyl, and 3-phenylpropyl which may be attached to A, allyloxyl, methylallyloxyl, buten-2-yloxy and buten-3-yloxy, methylthio, ethylthio, propylthio, isopropylthio and butylthio,

10th 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, ethoxy- carbonyl, tert-butoxycarbonyl, N, N-di [(1-4C) alkyl] - N, N-dimethylcarbamoyl and N, N- for carbamoyl: diethylcarbamoyl, For (2-4C) -alkanoylamine: acetamide, propionamide, butyramide for cyano (1-4C) alkoxyl: cyanomethoxyl, 2- cyanoethoxyl and 3- cyanopropoxyl, carbamoyl (1-4C) - carbamoylmethoxyl, 2- for alkoxyl: carbamoylmethoxyl and 3- carbamoylpropoxyl, (1-4C) alkoxycarbonyl- methoxycarbonylmethoxyl, 2- For (1-4C) alkoxyl: methoxycarbonylethoxyl, ethoxycarbonylmethoxyl and 2- ethoxycarbonylethoxyl,

Suitable values for R ¹ when it is (1-6C) alkyl are, for example, methyl, ethyl, propyl, butyl, amyl or hexyl.

Suitable values for R ¹ when it is (3-6C) -alkenyl are, for example, alcohols, 2-butenyl or 3-butenyl, and when it is (3-6C) -alkynyl is e.g. propynyl or 2-butynyl.

Suitable values for R ¹ when (2-4C) -alkanoyl are, for example, acetyl, propionyl and butyryl.

Suitable values for R ¹ when cyano (1-4C) alkyl are e.g. cyanomethyl, 2-cyanoethyl, 3cyanopropyl.

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, forms a ring having 4 to 7 atoms in the ring, 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, which may be 20 in the specified 4-7 member cycle, include, for example:

For (1-4C) -alkyl: methyl, ethyl, propyl, isopropyl and butyl, for (1-4C) -alkoxyl:

(1-40-Alkylthio-butyl-thionyl) - (1-40-Alkyl-sulfonyl) - (1-40-Alkyl-thionyl) - (1-40-Alkyl-sulfonyl) , ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and butylsulfonyl, for (1-4C) alkylenedioxy: methylenedioxy and ethylenedioxy.

A suitable pharmaceutically acceptable salt of the heterocycle of the present invention wherein the heterocycle is basic is an acid addition salt such as an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, phosphorous, trifluoroacetic, citric or maleic acids. In addition, a suitable pharmaceutically acceptable salt of the heterocycle of the present invention having a sufficiently acidic character (e.g., a heterocycle of the present invention having a carboxyl group) is an alkali metal salt such as sodium or potassium, an alkaline earth metal salt, e.g. ., a calcium or magnesium salt, an ammonium salt or an organic base salt which is a physiologically acceptable cation, e.g. a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-oxyethyl) -amine.

The most interesting novel compounds of the present invention are, for example, heterocycles of formula I wherein:

a) Q is 2-pyridyl, 3-pyridyl, 3-pyridazinyl, 2-pyrimidinyl or 2-pyrazinyl, which may be singly substituted with chlorine, oxy, cyano, methyl, methoxy and trifluoromethyl; A, X, Ar, R ¹ , R and R have any of the meanings defined above;

b) Q represents 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl or 2-pyrazinyl; A represents 1-propenylene or 1-propynylene; X represents an oxy group, and Ar, R ¹ , R ² and R ³ have any of the meanings defined above;

c) Q represents 2-quinolyl, 3-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 7-isoquinolyl, 3-cinolyl, 2-quinazolinyl, 6LT 3396 B-quinazolinyl, 2-quinoxalinyl, 2-quinolalinyl, , 1,7-naphthyridin-3-yl, 1,7-naphthyridin-3-yl, 1,8-naphthyridin-3-yl or 2,7-naphthyridin-3-yl, which may be substituted with one or two fluorine substituents , chlorine, oxy, oxo, cyano, methyl, methoxy and trifluoromethyl; and A, X, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;

d) Q represents 3-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinazolinyl, 6-quinazolinyl or 6-quinoxalinyl which may be substituted with one, two or three substituents. fluoro, chloro, oxy, oxo, methyl, ethyl, propyl, trifluoromethyl, 2-fluoroethyl, 2-dimethylamino ethyl, and benzyl; A, X, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;

e) Q represents 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 be mono- or di-substituted, selected from fluoro, chloro, cyano, methyl, methoxy and trifluoromethyl, and A, X, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;

f) Q represents 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- oxoquinoline which may be substituted with one or two substituents selected from fluoro, chloro, methyl, ethyl, propyl, trifluoromethyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl; A, X, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;

g) Q represents 1,2-dihydro-2-oxoquinolin-3-yl, 1,2-dihydro-2-oxoquinolin-5-yl, 1,2-dihydro-oxoquinolin6-yl or 1,2-dihydro-2-oxoquinolin-3-yl. 7, who carries

A 1-substituent selected from methyl, ethyl, propyl, 2-fluoroethyl, 2-dimethylaminoethyl and benzyl, which may be substituted by fluorine, chlorine and trifluoromethyl; A, X, Ar, R, R and R have any of the meanings defined above;

h) Ar represents methylene, ethylene, trimethylene, 1-propenylene, 2-methylprop-1-enylene or 1-propynylene, A, X, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;

(i) A represents methylene, 1-propenylene and 1-propynylene; Q, X, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;

j) X is oxy and Q, A, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;

k) X-oxy or imino; Q, A, Ar, R ¹ , R ² and R ³ have any of the meanings defined above;

l) Ar represents 1,3-phenylene or 1,4-phenylene which may be substituted with one substituent selected from fluoro, chloro, oxy, amino, nitro, methyl, methoxy, methylthio, methylthionyl, methylsulfonyl, methylamino, dimethylamino, trifluoromethyl, acetamido, cyanomethoxy and carbamoylmethoxy; Q, A, X, R ¹ , R ² and R ³ have any of the meanings defined above;

m) Ar represents 1,3-phenylene or 1,4-phenylene which may be substituted with one or two substituents selected from fluoro, chloro, oxy, amino, nitro, ureido, methyl, methoxy, dimethylamino, trifluoromethyl, acetamido and cyanomethoxy; Q, A, X, R ¹ , R ² and R ³ have any of the meanings defined above;

n) Ar represents 2,4-, 2,5-, 3,5- or 2,6-pyridylene or

4,6-pyrimidinylene, which may be singly substituted with chloro, methyl and methoxy; A, X, Q, R, R and R have any of the meanings defined above;

o) Ar represents 3,4-pyridylene and 3,5-pyridazinylene; A, X, Q, R, R and R have any of the meanings defined above;

p) R ¹ represents hydrogen, methyl, ethyl, alkyl, 2-propynyl or cyanomethyl; A, Q, X, Ar, R ² and R ³ have any of the meanings defined above;

r) R ¹ represents methyl, ethyl, alkyl or 2-propynyl; A, Q, X, Ar, R ² and R ³ have any of the meanings defined above;

s) R ² and R ³ together form a group of the formula -A ² -X ² -A ³ - which, taken together with the carbon atom to which A and A ^{3 are} attached, forms a ring having 4-7 atoms in the ring wherein A and A may be the same or different and each represents methylene, ethylene, trimethylene or tetramethylene, and X represents methylene, ethylene, trimethylene or tetramethylene, and X ² represents an oxygen atom, thio, thionyl, or sulfonyl, and the (group) ring may be substituted. selected from oxy, methyl, methoxy, ethoxy, methylthio, methylthionyl, methylsulfonyl and methylenedioxy; A, X, Ar, R ¹ , Q have any of the meanings defined above;

t) R and R together form a group of the formula -A-X -A - which, taken together with the carbon atom to which A and A ^{3 are} attached, forms a ring having 5 to 7 atoms in the ring in which A and A which may be the same or different, each being methylene, ethylene or trimethylene, and X represents an oxy group, which ring may have one or two substituents selected from oxy, methyl, ethyl and methoxy; A, Q, X, Ar, R ¹ have any of the meanings defined above;

or a pharmaceutically acceptable salt thereof (heterocycle).

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

A further particular compound of the present invention includes a heterocycle of formula I wherein Q is 2pyridyl, 3-pyridyl, 3-pyridazinyl, 2pyrimidinyl or 2-pyrazinyl which may be substituted with one substituent selected from chloro, oxy, cyano, methyl, methoxy and trifluoromethyl, or Q represents 2-quinolyl, 3-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 6-isoquinolyl, isoquinolyl, 3-cinolyl, 2-quinazolinyl, 6-quinazolinyl, 2-quinazolinyl, 2-quinazolinyl, 6-quinazolinyl, 6-phthalazinyl, 1,7-naphthyridin-3-yl, 1,7-naphthyridin-3-yl, 1,8-naphthyridin-3-yl or 2,7-naphthyridin-3-yl, which may be substituted with one or two substituents selected from fluoro, chloro, oxy, oxo, cyano, methyl, methoxy and trifluoromethyl; A represents methylene, ethylene, trimethylene, 1-propenylene, 2-methylprop-1-enylene or 1-propynylene; X represents an oxy group; Ar represents 1,3-phenylene or 1,4-phenylene which may optionally be substituted with one substituent selected from fluoro, chloro, oxy, amino, nitro, methyl, methoxy, methylthio, methylthionyl, methylsulfonyl, methylamino, dimethylaminotrifluoromethyl, acetamide, cyanomethoxy and carbamoylmethoxy, or Ar represents 2,4-, 2,5-,

3,5- or 2,6-pyridylene, which may optionally be substituted with one substituent selected from chlorine, methyl and methoxy; R ¹ represents methyl, ethyl, filament or 2-propynyl; and R ² and R ³ together form the formula -A ² -X ² -A ³ -, 2 which, taken together with the carbon atom to which A and A are attached, forms a ring having 4 to 7 atoms in the ring in which A and A can be the same or different and each represents methylene, ethylene, trimethylene or tetramethylene, and X represents an oxy, thio, sulfinyl, or sulfonyl, which ring may carry a substituent selected from oxy, methyl, methoxy, ethoxy, methylthio -, methylthionyl, methylsulfonyl and methylenedioxy; or a pharmaceutically acceptable salt thereof (heterocycle).

A further particular compound of the present invention comprises a heterocycle of formula I wherein Q represents 3quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 3isoquinolyl, 2-quinazolinyl, 6-quinazolinyl, or quinoxalinyl of 6LT 3396 B, which may be one, three substituents selected from fluoro, oxy, oxo, methyl, ethyl, 2-fluoroethyl, 2-dimethylaminoethyl or benzyl; wherein A is methylene; wherein X represents an oxo group or an imino group; wherein Ar represents 1,3-phenylene or 1,4-phenylene which may be substituted with one or two substituents selected from fluoro, oxy, amino, ureido, methoxy, trifluoromethyl and cyanomethoxy, or Ar represents 3.5 -pyridylene; wherein R ¹ is methyl, ethyl or allyl; and wherein R and R together form a group of the formula -A-X -A - which, taken together with the carbon atom to which A ² and A ^{3 are} attached, forms a ring having 5 or 6 atoms in the ring wherein A represents

2 is ethylene, A is methylene or ethylene and X is oxy, and the ring may be substituted with one or two substituents selected from the group consisting of oxy, methyl and methoxy;

or a pharmaceutically acceptable salt thereof (heterocycle).

A more preferred compound of the present invention comprises a heterocycle of formula I wherein Q represents 6-quinolyl, 3-isoquinolyl, 2-quinazolinyl, 6-quinazolinyl, 6-quinoxalinyl, 1,2-dihydro-2-oxoquinolin-3-yl, 1,2-dihydro-2-oxoquinoline. -5-yl, 1,2-dihydro-2-oxoquinolin-6-yl, 1,2-dihydro-2-oxoquinolin-7-yl which may be substituted with one or two substituents selected from fluoro, methyl, ethyl, 2-fluoroethyl , 2-dimethylaminoethyl and benzyl;

wherein A represents methylene;

wherein X represents an oxy group;

wherein Ar represents 1,3-phenylene or 1,4-phenylene which may optionally be substituted with one or two substituents selected from fluoro, amino, ureido, methoxy and trifluoromethyl;

wherein R ¹ is methyl, ethyl or allyl; and wherein R ² and R ³ together form a group of formula -A ² -X ² -A ³ - which together with the carbon atom to which A and A are attached form a ring containing 5 or 6 atoms in the ring in which A ² is ethylene , A ³ represents methylene or ethylene and X ² represents an oxy group, the ring of which may be substituted by one or two substituents selected from the group consisting of oxy, methyl and methoxy;

or a pharmaceutically acceptable salt thereof.

A further preferred compound of the present invention is a heterocycle of formula I wherein Q represents 1,2-dihydro-oxoquinolin-3-yl or 1,2-dihydro-2-oxoquinolin-6-yl substituted with an I-substituent selected from methyl, ethyl, 2-. fluoroethyl and benzyl; wherein A represents methylene;

wherein X represents an oxy group;

wherein Ar represents 1,3-phenylene which may carry one or two substituents selected from fluoro, amino and trifluoromethyl;

wherein R ¹ represents methyl, ethyl or allyl; and in which

R ² and R ³ together form a group of formula -A ² -X ² -A ³ - which. . . 2 · 3 together with the carbon atom to which A and A are attached, 2 form a ring containing 5 or 6 atoms in the ring in which A represents ethylene, A represents methylene or ethylene and X represents an oxy group, which ring may be substituted alpha to X ² ;

or a pharmaceutically acceptable salt thereof.

Particularly preferred compounds of the present invention are, for example, the following heterocycles of formula I or pharmaceutically acceptable salts thereof:

4-methoxy-4- [3- (2-pyridyl) -prop-2-yn-1-yloxy) -phenyl] -tetrahydropyran,

4- [5-fluoro-3- (3- (2-pyridyl) -propyl-2-yn-1-yloxy) phenyl] -4-methoxytetrahydropyran,

4- [5-Fluoro-3- (quinoxalin-6-ylmethoxy) -phenyl] -4-methoxy-tetrahydro-pyran, (2RS, 4SR) -4- [5-fluoro-3- (quinoxalin-6-ylmethoxy) phenyl] -4-methoxy -2-methyltetrahydropyran,

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-phtho-3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -phenyl] -tetrahydropyran,

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-methoxy-tetrahydro-pyran,

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] -tetrahydro-pyran, (2RS, 4SR) -4- (5-fluoro-3- ( 1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -phenyl] -4-methoxy-2-methyl-tetrahydropyran, (2RS, 4SR) -4- [5-fluoro-3- (1,2-dihydro- 1-Ethyl-2-oxoquinolin-6-ylmethoxy) -phenyl] -4-methoxy-2-methyl-tetrahydro-pyran, (2RS, 4SR) -4- [5-amino-3- (1,2-dihydro-1-methyl-2-oxo-quinoline-6-) ylmethoxy) -phenyl] -4-methoxy-2-methyltetrahydropyran, (2S, 4R) -4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -phenyl] -4-methoxy-2- methyl tetrahydropyran, (2S, 4R) -4- [5-fluoro-3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -phenyl] -4-methoxy-2-methyltetrahydropyran, (2RS, 4SR) - 3- [5-Fluoro-3- (1,2-dihydro-1-ethyl-2-oxoquinolin-6-ylmethoxy) -phenyl] -3-methoxy-2-methyl-tetrahydro-pyran.

The compound of the present invention comprising a heterocycle of formula I, or a pharmaceutically acceptable salt thereof, can be obtained by any of the methods known for the preparation of related structural compounds. Such methodologies are offered as a further feature of the present invention and are illustrated by the following examples wherein, unless otherwise specifically stated, Q, A, X, Ar, R ¹ , R ² and R 3 have one of the meanings defined above.

(a) alkylating a compound of formula II with a suitable reagent, using a compound of formula QAZ, wherein Z represents a displaceable group; provided that when Q, Ar, R ¹ , R ² or R ³ have an amino, imino, alkylamino, oxy or carboxyl group, any amino, imino, alkylamino or carboxyl group is protected by a conventional protecting group and any oxy group may be protected by a conventional protecting group, or conversely, no oxy group needs protection; followed by removal of any undesired protecting group in Q, Ar, R ¹ , R ² or R ³ by conventional means.

Suitable substitutable group Z is, for example, a halide, sulfonyloxy or oxy group such as chloro, bromo, iodo, methanesulfonyloxy or toluene-para-sulfonyloxy.

Suitable reagents for the alkylation reaction when Z is a halide or sulfonyloxy group are, for example, a suitable base, e.g., carbonate, hydroxide or alkali or alkaline earth metal hydride, e.g., sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide , such as sodium hydride or potassium hydride. The alkylation reaction is preferably carried out in a suitable inert solvent or diluent such as N, N-dimethylsulfoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran at a temperature in the range of -10 to 150 ° C, preferably at about room temperature.

Suitable reagents for the alkylation reaction when Z is a hydroxy group are, for example, the reagent obtained by interaction of a compound of formula QA-OH with azodicarboxylic acid (1-4C) -alkyl ether in the presence of triarylphosphine such as azodicarboxylic acid diethyl ether in the presence of for triphenylphosphine. The alkylation reaction is preferably carried out in an appropriate inert solvent or diluent such as acetone,

1,2-dimethoxyethane or tetrahydrofuran at a temperature in the range of 10 ° to 80 ° C, preferably at about room temperature.

A suitable protecting group for an amino, imino or alkylamino group is, for example, an acyl group such as a (1-4C) alkanoyl group (especially acetyl), a (1-4C) alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tertiary group). -butoxycarbonyl), an arylmethoxycarbonyl group (especially a benzyloxycarbonyl group) or an aroyl group (especially a benzoyl group). The conditions for removal of the protecting group for the above protecting groups inevitably differ in the selection of the protecting group. Thus, for example, an acyl group such as an alkanoyl, alkoxycarbonyl or aroyl group may be removed, for example, by hydrolysis with an appropriate base such as an alkali metal hydroxide, such as lithium or sodium hydroxide. On the other hand, an acyl group such as tert-butoxycarbonyl may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric, phosphoric or trifluoroacetic acid, and an arylmethoxycarbonyl group such as benzyloxycarbonyl may be removed, e.g. , by hydrogenation over a catalyst such as palladium / charcoal.

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

such as

A suitable protecting group for a carboxyl group is, for example, an esterifying group, such as a (1-4C) -alkyl group (especially a group (especially for removal inevitably

Yes, such as methyl or ethyl) or arylmethyl benzyl). The conditions for protecting groups for the above protecting groups differ, and when a protecting group is selected, an esterifying group such as an alkyl or arylmethyl group may be removed, for example, by hydrolysis using an appropriate base such as an alkali metal hydroxide such as lithium or sodium hydroxide. . An esterifying group such as arylmethyl can be removed, for example by hydrogenation over the other side, may be a catalyst such as palladium on charcoal.

A suitable protecting group for a hydroxy group is, for example, an acyl group such as a (1-4C) -alkanoyl group (especially acetyl, aroyl group (especially benzoyl) or arylmethyl group (especially benzyl)). Thus, for example, an acyl group such as an alkanoyl or aroyl group may be removed, for example, by hydrolysis using an appropriate base such as an alkali metal hydroxide such as lithium or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium / charcoal.

The starting materials of formula II may be prepared using conventional organic chemistry techniques. Examples of the preparation of such starting materials are described in the accompanying non-limiting Examples, which are provided by way of illustration only. Other necessary starting materials are obtained using analogous procedures which are described in their modifications, which are within the ordinary skill of the chemist-organician. Thus, for example, the starting material of formula II can be obtained,. 4, for example, removing a protected heterocycle of formula III wherein R is a protecting group and X, Ar, R ¹ , R ² and R ³ have the meanings described above.

Suitable protecting groups R are, for example, arylmethyl (especially benzyl), tri- (1-4C) -alkylsilyl (especially trimethylsilyl or tert-butyldimethylsilyl), aryl (1-4C) -alkylsilyl (especially dimethylphenylsilyl), ( A 14C) alkyl group (especially methyl), a (1-4C) alkoxymethyl group (especially methoxymethyl) or a tetrahydropyranyl group (especially tetrahydropyran-2-yl). The conditions for removal of the protecting group for the above protecting groups inevitably differ in the selection of the protecting group. Thus, for example, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium / charcoal. On the other hand, a trialkylsilyl or aryldialkylsilyl group such as tert-butyldimethylsilyl or dimethylsilyl or dimethylphenylsilyl may be removed, for example, by treatment with an appropriate acid such as hydrochloric, sulfuric, phosphoric or trifluoroacetic acid or an alkali metal or ammonium fluoride such as sodium fluoride or preferably tetrabutylammonium fluoride. Alternatively, the alkyl group may be removed by treatment with a metal (1-4C) alkylsulfide, such as sodium ethyl thiolate, or, e.g. such as boron tribromide. On the other hand, the (1-4C) alkoxymethyl group or the tetrahydropyranyl group may be removed 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) alkylsilyl group which may be removed while protecting any amino, imino, alkylamino,

2 for the carboxyl or oxy group in Ar, R, R or R ³ remains.

The starting protecting agent of Formula III may be obtained by standard organic procedures as provided in the accompanying non-limiting Examples. Thus, for example, a protected starting material of formula III wherein R is as defined above may be obtained by alkylation of a tertiary alcohol of formula IV with an alkylating agent of formula R ¹ -Z wherein Z is a substituted group other than hydroxy in the presence of to the corresponding base as defined above, provided that any amino, imino, 2 3 alkylamino or hydroxy group in the members Ar, R or R is protected with a conventional protecting group.

The tertiary alcohol of the starting material of formula IV may be obtained by reacting a compound of formula R-X-Ar-Z wherein R and Ar have the meanings defined above and Z is a halogen group as defined above and provided that any an amino, alkylamino or hydroxy group in Ar is protected by a conventional protecting group or a metal organic compound of the formula R ⁵ M wherein R ⁵ is a (1-6C) alkyl group such as butyl and M is a metal group, e.g. lithium to form an organo-metal compound of formula R ⁴ -X-Ar-M, or a metal such as magnesium to provide an organo-metal compound of formula R ⁴ -Χ-Α-Μ-Ζ; whereupon any of these organometallic compounds may be reacted ^{with a} ketone of formula R ² -CO-R ³ wherein R ² and R ³ are as defined above and provided that any imino 2,3 or hydroxy group in R and R protected by a conventional protecting group.

(b) alkylation of a compound of formula V in the presence of a corresponding base as defined above, with a compound of formula R ¹ -Z wherein R ¹ and Z have the meanings given above, provided that when amino, iminoalkylamino, hydroxy or carboxyl is present

O, X, Ar, alkylamino,

3

R or R, any amino, imino, hydroxy or carboxyl group is protected with a conventional protecting group; followed by removal of any undesired protecting group in the members O, X, Ar, R ² or R ³ by conventional means.

Starting materials of Formula V may be prepared by standard organic chemistry techniques. Examples of the preparation of such starting materials are described in the accompanying non-limiting Examples, which are provided for purposes of illustration only. Other necessary starting materials may be obtained using analogous procedures to those described, or modifications to procedures which are within the ordinary skill of the chemist-organic. Thus, the tertiary alcohol of the starting material of formula V may be obtained, for example, by alkylation, in the presence of a suitable base, of a compound of formula HXAr-Z wherein Ar has the meaning given above and Z is a halogen group as defined above , A and Z have the meanings as defined above, and provided that any amino, alkylamino, carboxylic or hydroxy group Q or Ar is protected with a conventional protecting group to give a compound of formula QAX-Ar-Z. On the other hand, the compound of the formula QAX-Ar-Z may be obtained, for example, by alkylation in the presence of a corresponding base, a compound of the formula QΑ-ΧΗ in which Q, A and X have the meanings defined above. and Ar is as defined above, by a compound. The reaction product thus obtained can be treated with either an organometallic compound of formula R-M wherein R is a (1-6C) -alkyl group such as butyl and M is a methyl such as lithium to form QA-XAr-. M is an organometallic compound, or a metal such as magnesium to give a compound of the formula QAX-Ar-MZ.

Any of these organometallic compounds may be reacted with a ketone of the formula R ² -CO-R ³ , provided that any imino or oxo group in X, R ² or R ^{3 is} protected with a conventional protecting group to provide a targeted formula V tertiary alcohol of the starting material.

(c) For the preparation of compounds of formula I wherein A is a (3-6C) alkynylene group, the coupling reaction is carried out in the presence of a corresponding organometallic compound between formula QZ, wherein Q is as defined above and Z is a halide group such as iodine, a heterocyclic compound and an ethynyl compound of formula VI wherein A ¹ is (1-4C) alkylene and X, Ar, R ¹ , R ² and R have the meanings defined above.

A suitable organometallic catalyst is, for example, any reagent known in the art. Thus, for example, in such a coupling, the corresponding reagent is formed when bis (triphenylphosphine) palladium chloride or tetrakis (triphenylphosphine) palladium and a copper halide such as copper (I) iodide are mixed together. The coupling reaction is in most cases carried out in a suitable inert solvent or diluent, e.g. acetonitrile, 1,2-dimethoxyethane, toluene or tetrahydrofuran, at a temperature in the range of 10 ° to 80 ° C, preferably about 30 ° C, with a base such as e.g. such as triethylamine, or piperidine.

and in the presence of tri- (1-4C) alkylamine, respectively, a cyclic amine such as

The ethynyl compound of formula VI used as starting material may be obtained, for example, by alkylation, in the presence of a corresponding base, of a compound of formula II wherein X, Ar, R ¹ , R ² and R ³ have the meanings defined above for alkylating HC = CA ^{In a 1} -Z reagent wherein A ¹ has the meaning as defined above, Z is a halide group and provided that any amino, alkylamino, carboxyl or hydroxyl group in Ar, R ¹ , R ² or R ^{3 is} protected by a conventional protecting group .

(d) To obtain compounds of formula I wherein Ar has an alkylthionyl or alkylsulfonyl substituent wherein X is a sulfanyl or sulfonyl group, or wherein R ² and R ³ together form a -A ² -X ² -A ³ group which is has one or two alkylthionyl or alkylsulfonyl groups and X ² is a sulfinyl or sulfonyl group, are oxidized compounds of formula I wherein A is an alkylthio substituent or wherein R ² and R ³ together form -A ² -X ² -A ³ - a group having one or two alkylthio groups and wherein X ² is a thio group.

Suitable oxidizing agents are, for example, any reagent known in the thio group oxidation to sulfinyl (and / or sulfonyl peroxide, acid or peracetic acid), e.g. hydrogen (such as 3-chloroperbenzoic alkali metal persulfate (such as such as potassium monosulfate, chromium trioxide or gaseous oxygen in the presence of platinum Oxidation is, in most cases, performed under mild conditions where possible and using the necessary stoichiometric amount of oxidant to reduce the risk of over-oxidation and other functional groups. In general, the reaction is carried out in an appropriate solvent or diluent, such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether, and at a temperature of, for example, about 30 ° C to about 35 ° C with a thionyl group, sodium or potassium metaperiodate, preferably in a polar diluent, such as acetic acid or ethanol. Need temperature, compound with

When required, it should be understood that when a compound of formula I having a sulfonyl group is required, it may be obtained by oxidation of the corresponding thionyl compound as well as the corresponding thio compound.

(e) To obtain compounds of formula I wherein Ar is substituted with an alkanoylamino, acylate a compound of formula I wherein Ar is substituted with an amino.

Suitable acylating agents include, for example, any agent known in the art for acylation of an amino group to an acylamino group, such as an acyl halide such as (2-6C) -alkanoyl chloride or bromide in the presence of an appropriate base; alkanecarboxylic acid such as (2-6C) alkanecarboxylic acid or mixed alkanecarbonic acid such as mixed anhydride;

anhydride, anhydride; anhydride which interacts on an acid with an acid and (1-4C) alkoxycarbonyl halide, such as (1-4C) -alkoxycarbonyl chloride, in the presence of an appropriate base. In general, the reaction is carried out in an appropriate solvent or diluent such as methylene chloride, acetone, tetrahydrofuran or tert-butyl methyl ether, and at or about room temperature, i.e., at room temperature. 15 ° -36 ° C. Examples of the appropriate base include pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, N-methylmorpholine, an alkali metal carbonate such as potassium carbonate or an alkali metal carboxylate such as sodium acetate.

(f) To obtain those compounds of Formula I wherein R ¹ is alkanoyl or benzoyl, an optionally substituted acylating compound of Formula I wherein R ¹ is hydrogen. To obtain the compounds of formula I wherein R ¹ is alkanoyl, the acylation reaction is carried out using, for example, a suitable acylating reagent as defined above. To obtain the compounds of formula I wherein R ¹ is benzoyl optionally substituted, acylation may be carried out using a benzoyl halide, such as chloro or bromobenzoyl, in the presence of an appropriate base as defined above.

(g) Reduction of the corresponding compound wherein A is alkynylene or R ¹ is alkynyl to provide compounds of formula I wherein A is alkenylene or R ¹ is alkenyl. In general, the conditions that are standard in the given art of alkylation or alkynylene reduction are used. Thus, for example, the reduction may be carried out by hydrogenation of the alkynyl or alkynylene compounds in an inert solvent or in the presence of an appropriate metal. A suitable inert diluent is, for example, an alcohol such as methanol or ethanol or an ether such as tetrahydrofuran or tert-butyl methyl ether. A suitable metal catalyst is, for example, palladium or platinum on an inert carrier such as charcoal or barium sulfate.

in diluent, catalyst.

It is preferable to use palladium / barium sulfate catalysts to substantially prevent the reduction of the alkynyl or alkynylene group to the alkyl or alkylene group, respectively. In many cases, the reaction is carried out at a temperature equal to or approximately equal to room temperature, i. y. 15 ° -36 ° C.

Further reduction may be effected by treating the solution of the alkynyl or alkynylene compound in an inert solvent or diluent with a suitable mixture such as a 1: 1 metal organohydride such as di- (16C) -alkylaluminium hydride such as diisobutylaluminium hydride and metalalkyl e.g. , A mixture of (1-6C) -alkyl, such as methyl lithium. Suitable solvents or diluents are, for example, tetrahydrofuran, diethyl ether or tert-butyl methyl ether, and the reaction is generally carried out at a temperature in the range of 25 ° C to room temperature, in particular -10 ° C to 10 ° C.

(h) To obtain compounds of Formula I wherein Q has an alkyl or substituted alkyl substituent on an available nitrogen atom, or wherein Ar has an alkoxy or substituted alkoxy substituent, an alkylating compound of Formula I wherein Q has a hydrogen atom at the designated available nitrogen atom, or in which Ar has a hydroxy substituent.

Suitable alkylating reagents are, for example, any reagents known for alkylation of the nitrogen atom available in the art, through hydroxy groups to alkoxy or substituted alkoxy groups; e.g., alkyl or substituted alkoxy; e.g. alkyl or substituted alkyl halide such as (1-6C) -alkyl chloride, bromide or iodide or substituted (1-4C) -alkyl chloride bromide or iodide in the presence of an appropriate base. Suitable bases for the alkylation reaction are, for example, carbonate, hydroxide or an alkali or earth alkali metal hydride, such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride. The alkylation reaction is preferably carried out in an appropriate inert solvent or diluent such as N, N-dimethylformamide, dimethylsulfoxide, acetone,

1,2-dimethoxyethane or tetrahydrofuran at a temperature in the range of 10 ° to 150 ° C, preferably at about room temperature.

(1) Reduces a compound of formula I wherein Q or Ar has a nitro substituent to give compounds of formula I wherein Q or Ar are substituted with an amino.

A suitable reducing agent is, for example, any reagent known in the art for reducing a nitro group to an amino group. For example, the reduction may be accomplished by hydrogenation of the nitro compound solution in an inert solvent or diluent in the presence of an appropriate metal catalyst, such as a densely ground platinum metal (obtained by in situ reduction of platinum oxide). A suitable inert solvent or diluent is, for example, an alcohol such as methanol, ethanol or isopropanol or an ether such as 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 solution of an acid such as hydrochloric acid). Thus, for example, the reduction may be accomplished by heating the mixture of the nitro compound and the activated metal in a suitable solvent or diluent, such as a water or alcohol mixture such as methanol or ethanol, to a temperature such as 50 ° -150 ° C. , preferably about 70 ° C.

When a pharmaceutically acceptable salt of a novel compound of formula I is required, it may be obtained, for example, by treatment of the said compound with an appropriate acid or base using conventional techniques. When an optically active form of the compound of Formula I is required, it may be obtained using one of the above procedures using an optically active starting material as shown in the accompanying non-limiting Examples of the present invention, or dividing the racemic form of said compound.

Many of the compounds defined in the present invention are novel, e.g., Formula V intermediates, and are provided as a further feature of the present invention.

As previously defined, the heterocycles of formula I are inhibitors of the enzyme 5-LO. The effect of this inhibition can be demonstrated using one or more of the standard procedures outlined below:

(a) In vitro spectrophotometric enzymatic purity system, which evaluates the inhibitory properties of the test compound in a non-secretory system using the enzyme 5LO isolated from porcine neutrophils (neutrophil leukocytes) and described by D. Acharoni and R.L. Stein (D. Aharony and R.L. Stein. J. Biol. Chem. 1986, 261 (25), 11512-11519). This assay yields an evaluation of the inhibitory properties by inhibiting soluble 5-LO in the extracellular environment.

(b) An in vitro assay system comprising incubation of the test compound with heparinized human blood prior to administration of calcium ionophore A23187 and subsequent measurement of the inhibitory effect on enzyme 5-LO by analysis of LTB ₄ using the specific radioimmunoassay described by Keri and Forder (F. Carey and RA Forder, Brit. J. Pharmacol., 84, 34P, 1985) which comprises the conjugate protein-LTB ₄ obtained by the Yang method (Young et al., Prostaglandis, 26 (4), 605-613 (1983)). , usage. The activity of the test compound on the cyclooxygenase enzyme (which is involved in the alternative metabolism of arachidonic acid and leads to prostaglandic, thromboxane and related metabolites) can be measured at the same time using a specific radioimmunoassay for thromboxane B ₂ (TxB ₂ ) described by Keri and Forderio (see . above). This test gives an indication of the effect of the test compound on 5-LO as well as cyclooxygenase in the presence of blood cells and blood proteins. This allows the selectivity of inhibitory activity to 5-LO or cyclooxygenase to be assessed.

c) Ex vivo assay system, which is a variation of assay b) comprising administration of the test compound (usually orally as a suspension by adding a solution of the test compound in dimethylsulfoxide to carboxymethylcellulose), blood collection, its heparinization, A23187 challenge and radioimmune LTB. ₄ and TxB ₂ analysis. This test gives an indication of the bioavailability of the test compound as a 5-LO or cyclooxygenase inhibitor.

(d) An in vitro assay system comprising measuring the inhibitory properties of the test compound against free state (release) LTC ₄ and PGE ₂ induced by zymosan on resident peritoneal mouse macrophages using the Hummus method (JL Humes et al., Biochem. Pharmacol., 1983, 32, 23192322) and conventional radioimmunoassay systems to measure LTC ₄ and PCE ₂ levels. This assay provides an indicator of inhibitory activity against 5-LO and cyclooxygenase in the non-protein system.

e) An in vivo assay system comprising measuring the activity of a test compound to inhibit an inflammatory response to arachidonic acid in a rabbit skin model by D. Aked (D. Aked et al., British J. Pharmacol., 1986, 89, 4331-438). This assay provides an in vivo model for 5-LO inhibitors administered locally and orally.

(f) In vivo assay system comprising the effects of the test compound, administered orally or intravenously, on leukotriene-dependent bronchostasis induced by antigenic guinea-pigs, pre-dosed with an antihistamine (mepiramine), a beta-adrenergic blocking agent (propranolol), and a cyclooxygenase inhibitor. , applying VH Anderson et al. (W.H.Anderson et al., British J. Pharmacology, 78 (I), 67-574 (1983)). This assay yields additional assays in vivo for the detection of 5-LO inhibitors.

Although the pharmacological properties of the compounds of formula I are altered as expected, the compounds of formula I generally exhibit inhibitory activity against 5-LO at the following concentrations or doses in one or more of the above assays a) -f) (ICinhibitory concentration; ED-effective dose) ):

Test a): IC ₅₀ , e.g., in the range 0.01-30 micromolar;

Test b): IC ₅₀ (LTB ₄ ), e.g., in the range 0.01-40 micromolar;

IC ₅₀ (TxB ₂ ), e.g., in the range 40-200 micromolar;

Test c): oral ED ₅₀ (LTB ₂ ), e.g., 5-200 mg / kg;

Test d): IC ₅₀ (LTC ₄ ), e.g., in the 0.001-1 micromolar range;

IC ₅₀ (PGE ₂ ), e.g., in the range of 20-1000 micromoles;

Test e): Inhibition of inflammation within the range, e.g., 0.3-100 micrograms intradermally (dermally);

Test f): ED ₅₀ , e.g. 0.5-10 mg / kg intravenously.

Supertoxicity and other non-target effects do not occur (not obtained) in tests (c), (e) / or (f) when the compounds of the formula I are administered at different repeated doses of the minimum inhibitory dose and concentration.

In this way, examples may include:

A compound 4-methoxy-4- [3- (3- (2-pyridyl) -prop-2-yn-Lilok) -phenyl] -tetrahydopyran have IC _5o = 2.o micromolar against LTB ₄ and more than 40 micromolar against TxB ₂ (b) in the test, and oral ED ₅₀ less than 100 mg / kg against LTB in test ₄ (c);

the compound 4- [5-fluoro-3- (6-chinolilmetoksi) -phenyl] -4-methoxytetrahydropyrans have IC _5O = 0.1 micromolar against LTB ₄ in test b) and an oral ED ₅₀ = 8 mg / kg against LTB ₄ in test c) ;

compound 4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -phenyl] -4-methoxytetrahydropyran has an IC _SO = 0.03 micromoles against LTB _in Test ₄ b) and an oral ED ₅₀ = 3 mg / kg against LTB _in Test ₄ c).

In general, particularly suitable compounds of Formula I are those having an IC _{50 of} less than 1 micromolar against LTB ₄ and greater than 40 micromolar against TxB _in Test b) and an oral ED _{50 of} less than 100 mg / kg against LTB _{4 in} Test c).

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

According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a heterocycle of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The composition may be in a form suitable for oral use, e.g., in the form of a tablet, capsule, aqueous or ointment, suspension or emulsion;

for topical (topical) application, such as as a cream, ointment, gel or aqueous or oily solution or suspension; for nasal application, such as nasal medicated powder, spray or nasal application; for vaginal or rectal use, e.g., in the form of suppositories; for inhalation, in the form of a finely powdered or liquid aerosol; for sublingual or oral administration (trans buccal), eg in the form; or parenteral intravenous, subcutaneous, intramuscular, vascular and drip) - e.g., as a solution in sterile water or as a suspension. In general, the above mixtures may be obtained by conventional means using generally accepted additives.

for use in tablets or capsules (including

The amount of active ingredient (i.e., a heterocycle of formula I or a pharmaceutically acceptable salt thereof) that is combined with one or more additives to form a single dosage form will inevitably vary depending upon the organism being treated (carrier) and the particular mode of administration. For example, pharmaceuticals for oral use in humans will in most cases contain 0.5 mg to 2 g of active ingredient mixed with an appropriate amount of fillers, which may vary from about 5% to about 98% of the total weight of the mixture. Disposable dosage forms should in most cases contain 1-500 mg of active ingredient.

According to a further feature of the present invention there is provided a heterocycle or a pharmaceutically acceptable salt thereof for use in the treatment of humans or animals therapeutically.

Naturally, the amount of dose for therapeutic or prophylactic purposes using the Formula I heterocycle should vary with the nature and acuity of the condition, the age and sex of the animal or patient, and the mode of administration according to well-known conservative principles. As mentioned above, heterocycles of formula I are useful in the treatment of allergic and inflammatory conditions caused by the action of arachidonic acid metabolites, which are due, in part or in part, to linear metabolism (catalyzed by 5-LO) and in particular to leukotrienes which are intermediates. 5-LO. As mentioned above, such conditions include, for example, asthmatic conditions, allergic shock, allergic reactions, allergic rhinitis, psoriasis, atopic dermatitis, cardiovascular and inflammatory cerebral vascular injury, arthritic and inflammatory joint lesions, inflammatory bowel disease.

When used for therapeutic and prophylactic purposes, the compounds of the formula I should in most cases be administered in such a way that a daily dose of 0.5 to 75 mg per kilogram body weight is obtained, if necessary, in divided total doses. Generally, much lower doses should be administered when parenteral administration is used. This is the case, for example, for intravenous administration in most cases at a dose of 0.5-30 mg / kg body weight. Similarly, for administration by inhalation, a dose, for example 0.5 to 25 mg / kg body weight, should be used.

Although compounds of Formula I are most valuable as therapeutic agents for use in warm-blooded animals (including humans), they are also useful whenever the enzyme 5-LO is inhibited. As such, they are useful as pharmacological standards for use in the development of new bioassays and in the search for new pharmacological tools.

Because of their effects on leukotriene production, the compounds of Formula I have certain cytoprotective effects, e.g., they are useful in reducing or inhibiting some non-steroidal anti-inflammatory (NSPUP) cyclooxygenase inhibitors such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin, gastrointestinal effects. In addition, co-administration of a Formula I inhibitor 5-LO and NSPUP may result in a reduction in the amount of the latter, which is necessary to obtain a therapeutic effect while reducing the likelihood of adverse side effects. According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a heterocycle of formula I, or a pharmaceutically acceptable salt thereof, as defined above, in combination or admixture with a nonsteroidal anti-inflammatory cyclooxygenase inhibitor (such as above) and a pharmaceutically acceptable solvent or carrier.

Cytoprotective effects of compounds of formula I may be demonstrated, for example, in a standard laboratory model that evaluates protection against indomethacin-induced or ethanol-induced wound formation in the rat gastrointestinal tract.

The compositions of the present invention may further comprise one or more therapeutic or prophylactic measures useful in the treatment of disease. For example, known inhibitors of platelet aggregation (platelets), hypolipidemic (anti-lipid lowering agent), antihypertensive (anti-arterial hypertensive), beta-adrenergic blocking agent or vasodilator (vasodilator) may usefully be present in the pharmaceutical composition. treating a cardiovascular disease or condition. Similarly, by way of example, an antihistamine, steroid (such as beclomethasone dipropionate), sodium chromoglucate, a phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefully be present in the pharmaceutical composition of the invention for use in the treatment of lung disorders or conditions.

The compounds of formula I may also be used in combination with leukotriene antagonists such as the antagonists disclosed in EP no. 179619, 199543, 220066, 227241, 242167, 290145, 337765, 337766 and 337767, which are incorporated herein by reference.

The invention should be more fully apparent from the following non-limiting examples, in which, unless expressly stated:

(a) evaporation was by evaporation in a rotary evaporator in vacuo and treatment procedures were adapted to remove any residual solids by filtration;

b) Operations were performed at room temperature, i.e. 18-20 ° C under an atmosphere of an inert gas such as argon;

c) column chromatography (pulsed) and liquid medium pressure chromatography (SVSC) were carried out on a Merk silica gel (Art. 9385) obtained from E. Merk, Darmstadt, Germany;

(d) yields are given for explanation only and are not necessarily maximized;

(e) the target products of formula I have satisfactory microanalyses and their structures have been confirmed by NMR and mass spectral methods;

(f) intermediates were in most cases not fully characterized and purity was assessed by thin layer chromatography, infrared (IR) and NMR spectral analysis;

(g) melting points are uncorrected and were determined using a Metler SP62 automatic melting temperature set-up or an oil-bath apparatus; the melting point of the target products of formula I was determined after recrystallization from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in a mixture; and

(h) In-plane polarized light specific rotation (alpha) ^t was determined using Sodium Dline (5890 Angstroms) at 20 ° C and in many cases using sample concentrations of approximately 1 g per 100 ml of solvent.

EXAMPLE A mixture 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 DMFA was stirred at room temperature for 15 hours. The mixture is partitioned between methylene chloride and aqueous layers. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over 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. 3.5 g (92%) of 4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-3-ylmethoxy) -phenyl] -4-methoxytetrahydropyran are thus obtained with a melting point of 135 ° C.

The starting material for 3-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is obtained 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, is added 0.268 g (55% oil suspension) of sodium hydride, followed by cooling in an ice bath. The mixture was allowed to warm to room temperature and then heated to 66 ° C for 1 hour. The mixture was again cooled in an ice bath and 0.41 ml of methyl iodide was added. A further 50 ml of dimethylformamide are added and the mixture is stirred at room 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 are washed with 50 ml of water and evaporated. The residue was triturated with diethyl ether to give 1,2-dihydro-1-methyl-2-oxo-quinoline-3-carbaldehyde as a yellowish 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. 33, 3775 (1985)).

Conversion of 1,2-dihydro-1-methyl-2-oxo-quinoline-3-carbaldehyde to 3-bromomethyl-1,2-dihydroquinolin-2-one.

4- (3-Hydroxyphenyl) -4-methoxytetrahydropyran, used as starting material, is obtained as follows:

3-Methoxymethoxyphenyl bromide is prepared from the reaction of 3-bromophenol with dimethoxymethane using the general procedure described in Synthesis, 1976, 244. The Grignard reagent is prepared by heating 6 g of 3-methoxymethoxyphenyl.

(g) and 34 ml of tetrahydrofuran at 30 ° C for two hours. Grinjaro to room temperature and tetrahydropyran-4-one 2 ml were stirred at room temperature and evaporated.

of bromide, magnesium (0.66 (34 mL)) was added dropwise to the reagent, cooled by dropwise addition of 2.76 g of tetrahydrofuran. The mixture was partitioned between ethyl acetate and

Remaining water.

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

A mixture of the reaction product thus obtained, 10 ml of hydrochloric acid, 40 ml of isopropanol and 160 ml of tetrahydrofuran was stirred at room temperature for 15 hours. The mixture is evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO _4, and evaporated. The residue is purified by column chromatography using a 4: 1 by volume mixture of methylene chloride and diethyl ether as eluent. This gives 0.57 g (56%)

4- (3-hydroxyphenyl) -4-methoxytetrahydropyran as a colorless oil.

EXAMPLE

The alkylation reaction described in Example 1 is repeated, using only the corresponding alkyl halide instead of 3-bromomethyl-1,2-dihydro-1-methylquinolin-2-one and the corresponding phenol instead of 4- (3-hydroxyphenyl) -4-methoxytetrahydropyran. In this way, the compounds described in the following table are obtained.

Table I

Here we go

2 e.g. Q. A Ar Yield (%) Melting point ° C l ^a 2-pyridyl -oc-ch ₂ 1,3-Phenylene 56 oil * 2 ^{b, c} 2-pyridyl -ch ₂ - 5-Fluoro-1,3- phenylene 46th oil ** 3 ^{c, d} 6-quinox linil —Ch ₂ - 5-Fluoro-1,3- phenylene 55 83-85 4 ^c - ^e 1,2-dihydro- 2-oxoquino- lin-3-yl -ch ₂ - 5-Fluoro-1,3- phenylene 12 12 oil 5 ^f 1,2-dihydro- 1-methyl-oxo quinolin-3- ilas -ch ₂ - 5-oxy-1,3 phenylene 11th 195-197 ^6g 1,2-dihydro-1- methyl 2-oxo quinolin-3-yl —Ch ₂ - 5-cyanome- Toxic-1,3- phenylene 80 142 ? _h 1,2-dihydro- l-methyl-2- ch ₂ - 3.5- pyridylene 72 124

oxoquinolin3-yl

OBSERVATIONS

a. 3- (2-Pyridyl) -prop-2-ion-1-lobromide hydrobromide, used as starting material, is obtained as follows:

To a stirred mixture of 23.7 g of 2-brc pyridine, 1.4 g of bis (triphenylphosphine) palladium chi: cide, 21 ml of triethylamine,

A mixture of 1.5 g of copper (I) iodide and 150 ml of acetonitrile was added dropwise to 35 ml of 2-p.opinyl alcohol, then the mixture was stirred at room temperature for 30 minutes, heated to 60 ° C for two hours. The mixture was cooled to room temperature, poured into 200 mL of water and neutralized by addition of aqueous hydrochloric acid. The mixture was extracted with methylene chloride (2 x 500 mL) and the combined extracts washed with 500 mL water, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography eluting with 1: 1 v / v methylene chloride / ethyl acetate to give 14 g (70%) of 3- (2-pyridyl) -prop-2-yn-1-yl alcohol with a melting point of 78-80 ° C. t. (recrystallized from a mixture of hexane and ethyl acetate).

Add 3 ml of bromine solution to 3 ml of methylene chloride

A mixture of 10.1 g of triphenylphosphine and 72 ml of methylene chloride is cooled to -8 ° C in a salted ice bath. A solution of 4.8 g of alcohol obtained immediately above is added to 36 ml of methylene chloride, the mixture is stirred for 10 minutes and cooled to about -10 ° C. The mixture was filtered to give 5.8 g (58%) of 3- (2-pyridyl) -prop-2-ion-1-yl hydrobromide bromide, m.p. 112-114 ° C, which was used without further purification.

b. 2-Chloromethylpyridine chlorohydrate is used as the alkylating agent.

c. 4- (5-Fluoro-3-hydroxyphenyl) -4-methoxytetrahydropyran, used as starting material, is obtained as follows:

12.4 g (50% w / w dispersion in mineral oil) of sodium hydride are added in portions to 26.7 ml of benzyl alcohol and 500 ml of dimethylacetamide and the resulting mixture is stirred at room temperature for 1 hour. Carefully add 50 g of l-bromo-3,5-difluorobenzene to control the resulting vigorous exothermic reaction. The mixture is stirred at room temperature for 2 hours and the solvent is evaporated. The residue is partitioned between methylene chloride and aqueous layers, then the organic phase is washed with water (4 x 50 mL), dried over MgSO ₄ and evaporated. The residue is purified by distillation to obtain the residue

41.8 g (57%) of 2-benzyloxy-1-bromo-5-fluorobenzene as a colorless liquid (m.p. 124-130 ° C at 0.3 mm Hg).

A solution of a portion of this product (9.75 g) is cooled to -75 ° C in 150 mL of tetrahydrofuran and added dropwise with n-butyllithium (1.6 M in hexane, 22 mL). The mixture is stirred at -75 ° C for 1 hour, then allowed to warm to 0 ° C. Add 50 ml of saturated aqueous ammonium chloride solution and separate the organic phase, dry over MgSO ₄ and evaporate. The residue is purified by column chromatography using a 1: 1 by volume mixture of toluene and ethyl acetate as eluent. This gives 7.4 g (71%) of 4- (benzyloxy-5-fluorophenyl) -4-hydroxytetrahydropyran as an oil.

After a corresponding repeat of the above reaction, 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 room temperature for 1 hour, cooled in an ice bath, and 3.75 ml of methyl iodide was added dropwise. The mixture was stirred at room temperature for 18 hours, added 3 drops of 2N aqueous hydrochloric acid and the organic solvent was evaporated. The residue is partitioned between ethyl acetate and water. The organic phase was isolated, washed out with water and saturated sodium chloride solution, dried MgSO ₄ and evaporated. This is how it is obtained

12.5 g (99%) of 4- (3-benzyloxy-5-phthalophenyl) -4-methoxytetrahydropyran as a pale yellow oil which is used without further purification.

A solution of the reaction product thus obtained in 100 ml of ethanol was hydrogenated with 10% palladium on charcoal for 3 hours. The mixture is filtered and evaporated. There was thus obtained 7.7 g (86%) of 4- (5-tert-3-hydroxyphenyl) -4-methoxytetrahydropyran, m.p. 123-124 ° C.

d. 6-Bromomethylquinoxaline for use as an alkylating agent is described in J. Het.Chem. 11, 595 (1974).

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

f. 4- (3,5-Dihydroxyphenyl) -4-methoxytetrahydropyran, used as the phenolic starting material, is obtained as follows:

3.5- Dioxo-iodobenzene (Tech.J.Sci., 1977, 28, 253) is reacted with two equivalents of benzyl bromide according to the procedure described in Example 1 to give

3.5-dibenzyloxyiodobenzene as an oil in 96% yield. This reaction product is reacted with n-butyllithium using the procedure described in the preceding Note except that the reaction is carried out at -110 ° C. The organometallic reagent thus formed reacts with tetrahydropyran-4-one according to the procedure described above;

the reaction product is methylated and then hydrogenated using the procedure described in note c. directly above. 4- (3,5-Dioxyphenyl) -4-methoxytetrahydropyran is obtained in 40% yield, based on 3,5-dibenzoyloxyiodobenzene.

g. The corresponding phenol is obtained as follows:

4- (3,5-Dioxyphenyl) -4-methoxytetrahydropyran is reacted with one equivalent of iodacetonitrile using the procedure described in Example 1 to give 4- (3-cyanomethoxy-5-hydroxyphenyl) -4-methoxytetrahydropyran as an oil (27%).

h. The alkylation reaction is performed at -20 ° C for 15 hours using sodium hydride instead of potassium carbonate as the reaction base. The corresponding phenol is obtained as follows:

3,5-Dibrompyridine is reacted with one equivalent of benzyl alcohol to give 3-benzyloxy-5-brompyridine (56%) using the procedure described in the first paragraph of Note c. This product reacts with n-butyllithium using the procedure described in the second paragraph of Note (c) except that the reaction is carried out at -110 ° C. The organometallic product thus formed reacts with tetrahydrofuran-4-one according to the procedure described in the Notes. The reaction product is methylated and hydrogenated using procedures as well as immediately above in the Notes, c). This affords 4- (5-hydroxypyrid-3-yl) -4-methoxytetrahydropyran in 47% yield, based on 3-benzyloxy-5-bromopyridine.

P ° further described it

*) NMR spectrum:

(CDCl ₃ , δ, md):

1.57-2.07

3.77-3.83

7.03-7.63 (multiplet, 4H), (multiplet, 4H), (multiplet, 7H), 8

2.99 (singlet,

4.95 (singlet, (doublet, 1H).

3H),

2H), **) NMR Spectrum: (CDCl ₃ , δ.md):

1.9 (multiplet, 4H), 2.95 (singlet, 3H), 3.85 (multiplet, 4H), 5.2 (singlet, 2H), 6.6-6.85 (multiplet 3H), 7.25 (triplet, 2H), 7.5 (doublet,

1H), 7.75 (triplet, 1H).

+ NMR Spectrum: (CD ₃ SOCD ₃ , δ, md):

1.8-2.0 (multiplet, 4H), 2.9 (singlet, 3H), 3.6-3.8 (multiplet, 4H), 5.0 (singlet, 2H), 6.75-6.9 (multiplet, 3H), 7.15-8.1 (multiplet, 5H).

EXAMPLE

To 0.61 g of 4- [5-fluoro-3- (2-propynyloxy) -phenyl] -4-methoxytetrahydropyran, 0.52 g of 2-iodopyridine, 0.03 g of bis (triphenylphosphine)-palladium chloride, 0.03 g of copper (I) iodide and 12 ml of acetonitrile mixture is added with 0.35 ml of triethylamine and the mixture is stirred at room temperature for 5 hours. The mixture is partitioned between ethyl acetate and water. The organic phase is separated off and the aqueous phase is extracted with additional ethyl acetate. The combined organic extracts were washed with water, dried over 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. This gives 0.47 g (60%) of 4- [5-fluoro-3- (3- (2-pyridyl) -prop-2in-1-yloxy) -phenyl] -4-methoxy-tetrahydro-pyran as a pale yellow oil.

NMR Spectrum: (CDCl ₃ , δ, md):

1.95 (multiplet, 4H), 3.0 (singlet, 3H), 3.8 (multiplet, 4H), 4.95 (singlet, 2H), 6.72 (triplet, 2H), 6.87 (singlet, 1H), 7.3 (spread singlet, 2H), 7.68 (spread singlet, 1H), 8.6 (spread singlet, 1H).

4- [5-fluoro-3- (2-propynyloxy) -phenyl] -4-methoxytetrahydropyran, used as starting material by alkylation of 4- (5-fluoro-3- (2-hydroxyphenyl) -4-methoxytetrahydropyran with 2-propynyl bromide, using the procedure described for the alkylation reaction in Example 1, except that acetone is used in place of dimethylformamide as the solvent for the reaction, the reaction product is obtained in 95% yield and mp 75-76 ° C.

EXAMPLE

Repeats alkylation reaction except using

6-bromomethylquinoxaline is used in place of 3-bromomethyl-1,2-dihydrol-methylquinolin-2-one, and (2RS, 4SR) -4- (5-fluoro-3-hydroxyphenyl) -4-methoxytetrahydropyran is used in place of 4- (3-hydroxyphenyl) - 4-methoxytetrahydropyran. This gives (2RS, 4SR) -4- [5-fluoro-3- (quinoxalin-6-ylmethoxy) -phenyl] -4-methoxy-2-methyl-tetrahydropyran as an oil (45%).

NMR Spectrum: (CDCl ₃ , δ, md):

1.21 (doublet, 3H), 1.54 (doublet of doublets, 1H),

1.8-2.03 (multiplet, 3H), 2.98 (singlet, 3H), 3.773.97 (multiplet, 3H), 5.3 (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 starting material, using the conventional procedures described in the first two paragraphs of the Notes, paragraph (c), Example 2, except that 2-methyltetrahydropyran-4-one (Amer.Chem.Sci. 1982, 104, 4666) is used in place of tetrahydropyran-4-one.

The residue containing the mixture of diastereoisomers is purified and the isomers are isolated by column chromatography using a 5: 1 by volume mixture of toluene and ethyl acetate as eluent. This gives (2RS, 4SR) 4- (3-benzyloxy-5-fluoro-phenyl) -4-hydroxy-2-methyl-tetrahydropyran as an oil (24%), m.p. The 2-methyl and 4-hydroxy substituents are in trans position relative to one another.

NMR Spectrum: (CDCl ₃ , δ, md):

1.20 (doublet, 3H), 1.58 (spread singlet, ΙΗ, ΟΗ), 1.52 (singlet, 2H), 1.99-2.14 (multiplet, 1H), 3.86-4.02 (multiplet, 3H), 5.05 (singlet, 2H), 6.6 (doublet of triplets, 1H), 6.90 (singlet, 1H), 7.287.48 (multiplet, 5H, aromatic.);

and (2SR, 4SR) -4- (3-benzyloxy-5-fluorophenyl) -4-hydroxy-2-methyl-tetrahydropyran (48%), m.p. 82-83 ° C, m.p. The 2-methyl and 4-hydroxy substituents are present in each other;

NMR Spectrum: (CDCl ₃ , δ, md):

1.21 (triplet, 3H), 1.66 (doublet of doublets, 1H),

1.80 (distributed singlet, ΙΗ, ΟΗ), 1.96 (doublet 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 hydrogenated according to the procedures described in the last two paragraphs of the Note, c. after Table I in Example 2. This produces the target starting material (61), m.p. 127 ° C.

EXAMPLE

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-methyltetrahydropyran. This gives (2SR, 4SR) -4- [5-fluoro-3- (quinoxalin-6-ylmethoxy) -phenyl] -4-methoxy-2-methyl-tetrahydropyran as an oil (72%).

NMR Spectrum: (CDCl ₃ , δ, md):

1.20 (doublet, 3H), 1.64 (doublet of doublets, 1H),

1.94 (triplet (multiplet, 2H), (multiplet, 2H), doublet, 1H), 2.22-2.39

2.90 (singlet, 3H), 3.31-3.48

3.91-4.02 (multiplet, 1H), 5.32 (singlet, 2H), 6.70 (doublet of triplets, 1H), 6.79 (doublet of triplets, 1H), 6.9 (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 H 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 for as starting material from (2SR, 4SR) -4- (3-benzyloxy-5-fluorophenyl) -4-oxy-2-methyltetrahydropyran described in Example 4 for the starting materials for the methylation and subsequent hydrogenation of the benzyl protecting group , using the methodologies described in the last two paragraphs of Note Note (c) below Table I, Example 2. This gives the target starting material (71%), m.p. 116 ° C.

EXAMPLE 6

Using the procedure described in Example 1, the corresponding alkyl halide is treated with the appropriate phenol to give the compounds described in the following table:

Table II

Jung. (%) (0 ° C)

No. 1- ^a- 1,2-Dihydro-1-methyl-1,3-Me 74 97-99

2-Oxoquinolin-6-yl Phenylene

^2b 1,2-Dihydro-1-methyl-1,3-E 52 131-132

2-Oxoquinolin-6-yl Phenylene

3 ^C 1,2-dihydro-1-methyl-1,3-Me 59 112-113

2-oxoquinolin-5-yl phenylene

4 ^for 1,2-dihydro-l-methyl-1,3-Me 74-76 64

2-oxoquinolin-7-yl phenylene

5 ^e 6-chino ks aiin1as 5-fluoro 1,3-Phenyl len No. 51 oil 6 ^f 6-quinolyl 5-fluoro 1,3-Phenyl len Me 53 94-95 7 ⁹ 3-isoquinolyl 5-fluoro 1,3-Phenyl len Me 73 80-81 ^8h 2-quinazolinyl 5-fluoro 1,3-Phenyl len Me 77 foam 9 ¹ 6-quinazolinyl 5-fluoro 1,3-Phenyl len Me 79 126-128 10 ^] 1,2-dihydro-1-methyl- 2-oxoquinolin-3-yl 5-fluoro 1,3-Phenyl len E 75 88-89 ll ^k 1,2-dihydro-6-fluoro 1-methyl-2-oxoquino- lin-3-yl 5-fluoro 1,3- Phenic len Me 52 154-155 12 ¹ 1,2-dihydro-1-ethyl-2- oxoquinolin-3-yl 5-fluoro 1,3-Phenyl len Me 49 97-98 13 ^years 1,2-dihydro-1- (2- fluoroethyl) -2- oxoquinolin-3-yl 5-fluoro 1,3-Phenyl len Me 55 125-126 14 ⁿ 1,2-dihydro-1- (2- dimethylaminoethyl) -2- oxoquinolin-3-yl 5-fluoro 1,3-Phenyl len Me 50 88-90 15 ° 1,2-dihydro-2- oxoquinolin-6-yl 5: - 1, len Me 82 220 16th 1,2-dihydro-1-methyl- 2-oxoquinolin-6-yl 5-fluoro 1,3-Phenyl len Me 88 147

17 ^p.m. 1,2-dihydro-1- (2- fluoroethyl) -2- oxoquinolin-3-yl 5-fluoro 1,3-Phenyl len Me 32 143-144 18 ^r 1,2-dihydro-1-benzyl- 2-oxoquinolin-6-yl 2,5-fluoro 1,3-Phenyl len Me 74 resin 19 ^sec 1,2-dihydro-1-methyl- 2-oxoquinolin-6-yl 2.5-Di fluorine 1,3-Phenyl len Me 73 124-126 20 ^t 6-quinoxalinyl 5-tri- fluorine til-1,3- phenylene Me 70 oil 21 ^u 6-quinoxalinyl 5-tri- fluoro til-1,3- phenylene No. 82 oil 22 ^yrs 6-quinoxalinyl 3,5-pyridine dilen Me 78 98-99 23 ^z 6-quinoxalinyl 5-cyano methoxy 1,3-Phenyl len Me 86 oil

OBSERVATIONS

a. 6-Bromomethyl-1,2-dihydro-1-methylquinolin-2-one, used as starting material, is obtained as follows:

4.4 g of 1,2-dihydro-1,6-dimethylquinolin-2-one (Helv. Chim. Act, 1970, 3, 1903), 4.53 g of N-bromosuccinimide,

Heat a mixture of 0.01 g of azobisisobutyronitrile and 75 ml of carbon tetrachloride to boiling point and reflux for 3 hours. The mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase is washed with water, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 2: 1 by volume mixture of toluene and ethyl acetate as eluent. This gives a solid target starting material (4.8 g, 75%), m.p. Mp 107-108 ° C.

NMR Spectrum: (CDCl ₃ , δ, md):

3.7 (singlet, 3H), 4.57 (singlet, 2H), 6.7-7.5 (doublet, 1H), 7.25-7.65 (multiplet, 4H).

b. 4-Ethoxy-4- (3-hydroxyphenyl) -tetrahydropyran, used as starting material, is obtained as follows:

The Grignard reagent is obtained by heating a mixture of 3 g of 3- (naphth-2-methylmethoxy) -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 0.88 ml of tetrahydropyran-4one solution is added dropwise with 5 ml of tetrahydropyran. The mixture is heated to 30 ° C for 15 hours, evaporated and the residue partitioned between ethyl acetate and water. The organic phase is separated off, washed with saturated aqueous sodium chloride solution, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 7: 3 by volume mixture of methylene chloride and diethyl ether as eluent. There was thus obtained 4-hydroxy-4- [3- (naphth-2-ylmethoxy) -phenyl] -tetrahydropyran (2.06 g, 42%), m.p. 130-131 ° C.

A portion of the reaction product thus obtained (0.68 g),

A mixture of 0.1 g (60 wt% dispersion in mineral oil) of sodium hydride, 0.01 g of 15-crown-5, 0.325 ml of ethyl iodide and 5 ml of dimethylformamide is stirred at ambient temperature, the diethyl phase is washed 48 times with saturated solution, dried over MgSO ₄ chromatography, hours. The mixture is partitioned between ether and water. The organic sodium chloride is aqueous and evaporated. The residue is purified using a 49: 1 by volume mixture of methylene chloride and diethyl ether as eluent. 0.5 g (60%) of 4-ethoxy-4- [3-naphth-2-ylmethoxy) -phenyl] -tetrahydro-pyran are obtained in the form of an oil.

A portion of the reaction product (0.4 g) thus obtained,

A mixture of 0.08 g of 10% palladium on charcoal and 25 ml of ethanol is stirred at 3.3 atmospheric pressure for 15 hours. Evaporate the mixture and the filtrate. The residue is purified by column chromatography using a 1: 1 by volume mixture of methylene chloride and diethyl ether as eluent. This gives 0.175 g (87%) of the target starting material, m.p. 124-126 ° C.

hydrogen filtration

c. 5-Bromomethyl-1,2-dihydro-1-methylquinolin-2-one, used as starting material, is obtained as follows:

1.59 g of 1,2-dihydro-5-methylquinolin-2-one (Synthesis, 1975, 739) is added to a stirred suspension of 0.264 g (55% by weight in mineral oil) of sodium hydride in 40 ml of dimethylformamide and the mixture is heated to 50 ° C for 45 minutes. The mixture is cooled to 0 ° C and 0.93 ml of methyl iodide is added dropwise. The mixture is stirred at temperature for 16 hours. The mixture and residue are then partitioned between water and water. The organic phase was washed with aqueous sodium chloride solution, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 19: 1 by volume mixture of methylene chloride and methanol as eluent. Yes it gets

1.5 g (87%) of 1,2-dihydro-1,5-dimethylquinolin-2-one, m.p. Mp 107-108 ° C.

the added room was evaporated with ethyl acetate saturated

A mixture of the product thus obtained (1.21 g), 1.37 g of N-bromosuccinimide, 0.035 g of benzoyl peroxide and 25 ml of carbon tetrachloride is heated to reflux, refluxed for 40 minutes and irradiated with a 275-watt lamp. The mixture is then evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium chloride solution, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using methylene chloride in succession and then a 4: 1 by volume mixture of toluene and ethyl acetate as eluent. This yields the target starting material (1.09 g, 59%), lvd.t. 169 ° C.

d. 7-Bromomethyl-1,2-dihydro-methylquinolinone, used as starting material, is obtained according to the following procedure:

1,2-Dihydro-7-methylquinolin-2-one (Synthesis, 1975, 739) is treated with methyl iodide using the procedure described in Note c). Yes it gets

1,2-dihydro-1,7-dimethylquinolin-2-one in 79% yield, m.p. 111-112 ° C.

The reaction product thus obtained is brominated according to the procedure described in the preceding paragraph of the Notes to give the target starting material in 57% yield, m.p. 170 ° C.

e. The reaction product shows the following characteristics:

NMR Spectrum: (CDCl ₃ , δ, md):

1.1 (doublet, 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).

f. Uses three equivalents of potassium carbonate. 6Chloromethylquinoline chlorohydrate, used as starting material, is obtained as follows:

A mixture of 27.5 g of 4-aminobenzoic acid, 21.3 g of 4-nitrobenzoic acid, 7 g of iron (II) sulphate, 12 g of boric acid, 75 ml of glycerol and 35 ml of concentrated sulfuric acid is brought to reflux and refluxed for 20 hours. The mixture is diluted with 200 ml of water and made alkaline by the addition of 5 N aqueous sodium hydroxide solution. The mixture is filtered and the filtrate is acidified to pH 4-5 with glacial acetic acid. Misi ..., kept at 0 ° C for 2 hours. The precipitate is separated by filtration, washed with water and acetone and dried by heating to 55 ° C under vacuum. 78 g of quinoline-6-carboxylic acid are thus obtained, m.p. 286 ° C.

The resultant reaction product, 600 mL of ethanol and 96 mL of concentrated sulfuric acid was heated to reflux for 5 hours. The ethanol mass is evaporated. Add 200 ml of water and basify the mixture with 5N aqueous sodium hydroxide solution. The mixture is extracted with chloroform. The combined extracts are dried over Na ₂ SO _{4 to} give 17 g of quinoline-6-carboxylic acid ethyl ether in boiling point. 140-145 ° C at 0.05 mm Hg st.

(3x100 mL) evaporated.

A solution of the reaction product thus obtained in 100 ml of diethyl ether is added to a mixture of 3.6 g of lithium aluminum hydride and 200 ml of diethyl ether at a rate sufficient for the mixture to undergo gentle decomposition and reflux. The mixture is then heated to boiling point and refluxed for 20 minutes. Carefully add the wet ether (100 mL) followed by the aqueous sodium hydroxide solution (4.6 g in 30 mL water). The mixture is filtered and the solid washed with diethyl ether. The combined filtrate and washings are washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO ₄ and evaporated. This gives 7 g of 6LT 3396 B hydroxymethylquinoline recrystallized from petroleum ether (boiling point 60-80 ° C) and diethyl ether.

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

g. Uses three equivalents of potassium carbonate. The 3-chloromethylisoquinoline chlorohydrate used as starting material is obtained as follows:

g of phenylaniline, 91 ml (37% w / v in water) of formaldehyde and 310 ml of concentrated hydrochloric acid were stirred and heated to reflux for 4 hours, then at ambient temperature for 16 hours. The precipitate is filtered, washed with cold water and acetone to give 11 g of 1,2,3,4-tetrahydroisoquinoline-3-carbonic acid.

After repeating the above step, the reaction mixture (23.2 g) and methanol (200 ml) were cooled in an ice bath and 15.4 ml of thionyl chloride were added dropwise. Bring the mixture to boiling point and reflux for 4 hours. The mixture was evaporated and the solid residue was triturated with diethyl ether to give 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ether chlorohydrate (23.2 g).

NMR Spectrum: (CDSOCl ₃ , δ, md):

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 (spread singlet, 1H).

A portion (11 g) of the reaction product thus obtained,

A mixture of 19.6 g of potassium acetate and 200 ml of dry ethanol is heated to reflux and 25.4 g of iodine solution in 250 ml of dry ethanol are added over a period of three hours. The mixture is refluxed for 16 hours, cooled and filtered, and the filtrate is evaporated. The residue is partitioned between ethyl acetate and dilute aqueous sodium thiosulfate solution. The organic layer is dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography using ethyl acetate as eluent to give 3 g of isoquinoline-3-carboxylic acid ethyl ether.

Using the methodology described in the last two e. above, the resulting reaction product is reduced and the resulting alcohol is converted to the target starting material.

h. 2-Chloromethylquinazoline, used as an alkylating agent, is described in J. Chem. Soc., 1966, 238. The product exhibits the following characteristic NMR signals:

NMR Spectrum: (CDCl ₃ , δ, md):

1.75-2.03 (multiplet, 4H), 2.93 (singlet, 3H), 3.71-3.91 (multiplet, 4H), 5.46 (singlet, 2H), 6.69 (doublet, 1H), 6.95 (singlet, 1H), 7.69 (triplet, 1H), 7.9-8.1 (multiplet, 3H), 9.45 (singlet, 1H).

i. 6-Bromomethylquinazoline, used as an alkylating agent, is obtained from 6-methylquinazoline (J.Chem.Soc., 1962, 651) using the procedure described in J.Het.Chem., 11, 594, 1974, for the preparation of 6-bromomethylquinoxaline from 6-methylquinoxaline. .

j. 4-Ethoxy-4- (5-fluoro-3-hydroxyphenyl) -tetrahydropyran is obtained as a starting material from 4- (3-benzyloxy-5-fluorophenyl) -4-hydroxytetrahydropyran using the procedure described in Note c. after Table 1 in Example 2 except that ethyl iodide is used in place of methyl iodide. This yields the target starting material in 60% yield, m.p. 112 ° C.

k. The 3-bromomethyl-6-fluoro-1,2-dihydro-1-methylquinolin-2one used as starting material is obtained as follows:

18.2 g of triethylamine and 16.7 g of propionyl chloride are added successively to a solution of 4 g of 4-fluoroaniline cooled to 0 ° C. The mixture was stirred at 5 ° C for 1 hour and partitioned between methylene chloride and water. The organic layer was washed with water, dried over MgSO ₄ and evaporated to give 29.1 g of 4-fluoropropionanilide.

To 11.2 g of dimethylformamide, which is stirred and cooled to -5 ° C, add 50.3 ml of fluorine chloride dropwise. As soon as a white solid begins to form, the mixture is cooled to -15 ° C and the phosphorus chloroxide is added even faster. The resulting white slurry is mixed and left to warm to ambient temperature, then stirred at ambient temperature for 30 minutes. Add a portion (15 g) of the 4fluoropropionaldehyde obtained above and heat the mixture to 75 ° C over 6 hours. The mixture is poured onto ice and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using toluene as eluent. This gives 2-chloro-6-fluoro-3-methylquinoline (1 g, 5%) as a solid.

NMR Spectrum: (CDCl ₃ , δ, md):

2.54 (singlet, 3H), 7.32-7.49 (multiplet, 2H), 7.91 (singlet, 1H), 7.98 (multiplet, 1H).

Accordingly, after repeating the above reaction steps, 10 g of the quinoline thus obtained, 110 ml of 2N aqueous hydrochloric acid solution and 110 ml of ethanol are heated to 80 ° C within 9 hours. The mixture is poured into water and the resulting precipitate is filtered and dried in vacuo at 50 ° C. This gives 7.9 g (87%) of 6-fluoro-1,2-dihydro-1-methylquinolin-2-one.

NMR Spectrum: (CDCl ₃ , δ, md):

2.3 (singlet, 3H), 7.18 (doublet, 1H), 7.2 (multiplet, 1H), 7.4 (doublet of doublets, 1H), 7.6 (singlet, 1H), 12.3 (distributed doublet, 1H).

To a portion (3 g) of the reaction product thus obtained in 80 ml of dimethylformamide, cooled to 0 ° C, is added 0.775 g (55% w / w in mineral oil) of sodium hydride and the mixture is stirred at 0 ° C for 40 minutes. 2.65 g of methyl iodide are added dropwise and the mixture is stirred at 5 ° C for 1 hour and then allowed to warm to room temperature. The mixture is poured into 100 ml of water and the precipitate is filtered off and dried in vacuo at 50 ° C. This gives 2.5 g (78%)

6-Fluoro-1,2-dihydro-1,3-dimethylquinolin-2-one, m.p. 132 ° C.

A mixture of the resulting reaction product (2 g), 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 illuminated by a 275-watt lamp. The mixture is evaporated and the residue partitioned between methylene chloride and water. The organic phase is washed with water, dried over MgSO ₄ and evaporated. The residue was triturated with toluene to give 2 g (71%) of the target starting material, m.p. 212 ° C.

1. 3-Bromomethyl-1-ethyl-1,2-dihydroquinolin-2-one, used as starting material, is obtained as follows:

Repeats the procedure described in the first two paragraphs of Note (j). directly above except that aniline is used instead of 4-fluoroaniline. This gives 2-chloro-3-methylquinoline in 63% yield, m.p. 81-83 ° C.

Using the methodology described in the last three paragraphs of Note Note j. directly above, except that ethyl iodide is used in place of methyl iodide, thus converting the reaction product thus obtained into a target starting solid with 41% yield.

NMR Spectrum: (CDCl ₃ , δ, md):

l. 39 (triplet, 3H), 4.4 (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-2one, used as alkylating agent, is obtained from

1,2-dihydro-3-methylquinolin-2-one using the procedure described in Note c. directly above except that 2-fluoroethyl bromide is used in place of methyl iodide. This yields the target solid starting material with 46% yield.

NMR Spectrum: (CDCl ₃ , δ, md):

4.54 (singlet, 2H), 4.60 (triplet, 1H), 4.7 (triplet, 2H), 4.96 (triplet, 1H), 7.25 (triplet, 1H), 7.45-7.65 (multiplet, 3H), 7.90 (singlet, 1H) .

n. 3-Bromomethyl-1,2-dihydro-1- (2-dimethylaminoethyl) quinolin-2-one bromohydrate, used as starting material, is obtained as follows:

To a suspension of 5.19 g of 1,2-dihydro-2-oxoquinoline-3-carbaldehyde in 90 ml of dimethylformamide is added 2.88 g (55% w / w dispersion in mineral oil) of sodium hydride, followed by stirring at room temperature for 1 hour. Add 4.8 g of 2-dimethylaminoethyl chloride hydrochloride and heat the mixture to 60 ° C over 3 hours. The mixture is filtered and partitioned between methylene chloride and water. The organic layer was washed with water, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 4: 1 by volume mixture of methylene chloride and ethanol as eluent. This gives 1.64 g (22%)

1,2-dihydro-1- (2-dimethylaminoethyl) -2-oxoquinoline-3-carbaldehyde, m.p. 98-99 ° C.

0.285 g of sodium borohydride are added in portions to a solution of the reaction product thus obtained in methanol (35 ml) cooled in an ice bath. The mixture is stirred at room temperature for 2 hours, then evaporated. Adds 5 ml of 2 N aqueous sodium hydroxide solution, followed by sufficient drying agent (MgSO ₄ ) to allow the mixture to dry. The mixture is filtered and evaporated. This gives 1.48 g (92%) of 1,2-dihydro-3-oxymethyl-1- (2-dimethylaminoethyl) quinolin-2-one as a foam.

A mixture of the resultant reaction product (0.74 g) and 10 mL (48% w / v) of concentrated hydrogen bromide was heated to 75 ° C for 4 hours. Allow the mixture to cool to ambient temperature, add 10 ml of ethanol and evaporate the mixture. The process of adding ethanol and evaporating the mixture thus obtained is repeated several times to remove hydrogen bromide. This gives 0.62 g (53%) of the target starting material at 233-238 ° C (dec.).

o. The product is obtained as follows:

0.53 g of 4- [5-fluoro-3- (1,2-dihydro-1- (pivaloyloxymethyl) 2-oxoquinolin-6-yl-ylmethoxy) -phenyl] -4-methoxytetrahydropyran, 0.59 ml of 2N aqueous sodium hydroxide solution and 25 ml of ethanol the mixture was stirred at room temperature for 3 hours. The mixture is evaporated and the residue partitioned between methylene chloride and water. The organic phase was washed with water, dried over MgSO ₄ and evaporated to give 0.42 g (82%) of 4- [5-fluoro-3- (1,2-dihydro-2-oxoquinolin-6-ylmethoxy) phenyl] -4-methoxytetrahydropyran with 220 M.p.

The starting material is obtained by treating 6-bromomethyl-1,2-dihydro-1- (pivaloyloxymethyl) -quinolin-2-one with 4- (5-fluoro-3-oxyphenyl) -4-methoxytetrahydropyran using the procedure described in Example 1. This yields the target solid starting material with 30% yield.

NMR Spectrum: (CDCl ₃ , δ, md):

1.20 (singlet, 9H), 1.85-2.07 (multiplet, 4H), (singlet, 3H), (singlet, 2H), (multiplet, 1H) (triplet, 1H),

3.78-3.89 (multiplet, 4H), 6.33 (singlet, 2H), 6.7-6.75 (multiplet, 2H),

2.98 5.1

6.63

6.83

7.35 (doublet, 1H), 7.58-7.65 (multiplet, 2H), 7.71 (doublet, 1H).

The 6-bromomethyl-1,2-dihydro-1- (pivaloyloxymethyl) -quinolin2-one used as alkylating agent is obtained as follows:

A solution of 33.3 g of cinnamic acid chloro anhydride in 100 ml of methylene chloride is added dropwise to a mixture of 21.4 g of 4-methylaniline, 16.2 g of pyridine and 500 ml of methylene chloride, cooled in an ice bath. The mixture is stirred at 5 ° C for 20 minutes and then allowed to warm to room temperature. The mixture was washed successively with water, aqueous 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. The organic solution was dried over MgSO ₄ and evaporated to give 46 g (97%) of cinnamic acid N- (4-tolyl) -amide as a solid.

NMR Spectrum: (CDCl ₃ , δ, md):

2.32 (singlet, 3H), 6.54 (doublet, 1H), 7.11-7.52 (multiplet, 10H), 7.73 (doublet, 1H).

The resultant mixture of the reaction product portion (5.4 g) and 16.2 g of aluminum chloride is heated vigorously to give a viscous brown liquid. The mixture is then heated on a steam bath for 2 hours. The mixture is poured onto ice, the resulting solid is filtered off and washed with 2N aqueous hydrochloric acid and water. The solid is dried and triturated with ethyl acetate. This gives 3.4 g of 1,2-dihydro-6-methylquinolin-2-one as a solid.

NMR Spectrum: (CDCl ₃ , δ, md):

2.33 (singlet, 3H), 6.44 (doublet, 1H), 7.19 (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 methodology described in Note c. directly above, the reaction product thus obtained is treated with chloromethyl ether of trimethylacetic acid (chloromethyl pivalate) to give 1,2-dihydro-6-methyl-1- (pivaloyloxymethyl) -quinolin-2-one with a yield of 45% as a solid.

NMR Spectrum: (CDCl ₃ , 6, md):

1.18 (singlet, 9H), 2.41 (singlet, 3H), 6.31 (singlet, 2H), 6.65 (doublet, 1H), 7.16-7.4 (multiplet, 3H), 7.64 (doublet, 1H).

Using the methodology described in Notes a. directly above thus obtains an oil-like reaction product which is used without further purification.

p. 6-Bromomethyl-1,2-dihydro-1- (2-fluoroethyl) -quinolin-2one, used as alkylating agent, is obtained from

1,2-dihydro-6-methylquinolin-2-one using the procedures described in Note c. directly above except that 2-fluoroethyl bromide is used in place of methylene iodide. This yields a solid target starting material with 48% yield.

NMR Spectrum: (CDCl ₃ , δ, md):

4.56 (singlet, 2H), 4.5-4.9 (multiplet, 4H), 6.72 (doublet, 1H), 7.3-7.8 (multiplet, 4H).

r. The product is obtained by alkylation of 4- [5-ptor-3- (1,2-dihydro-2-oxoquinolin-ylmethoxy) -phenyl] -4-methoxytetrahydropyran (Example 6, Compound # 15) with benzyl bromide using the procedure described above in Note c. .

The product displays the following NMR signals:

NMR Spectrum: (CDCl ₃ , δ, md):

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).

s. 4- (2,5-Difluoro-3-hydroxyphenyl) -4-methoxytetrahydropyran, used as starting material, is obtained as follows:

Using the procedure described in the first paragraph Notes c), below Table I in Example 1, 1-bromo-2,3,5-trifluorobenzene is treated with benzyl alcohol, then the reaction product thus obtained is treated with n-butyllithium and the resulting organometallic compound is treated with tetrahydropyran-4-one. This gives 4- (3-benzyloxy-2,5-difluorophenyl) -4-hydroxytetrahydropyran as an oil in 16% yield.

NMR Spectrum: (CDCl ₃ , δ, md):

1.36-1.41 (doublet, 2H), 1.80 (multiplet, 1H), 1.962.08 (multiplet, 2H), 3.5-3.66 (multiplet, 4H), 4.78 (singlet, 2H), 6.32-6.38 (multiplet, 1H), 6.39-6.5 (multiplet, 1H), 7.0-7.1 (multiplet, 5H).

Having used the methodologies described in the third and fourth paragraphs of the Notes, paragraph t. immediately below, the reaction product thus obtained is methylated and the benzyl group hydrogenated. This gives the target starting material as an oil in 53% yield.

NMR Spectrum: (CDCl ₃ , δ, md):

2.0-2.06 (multiplet, 4H), 3.0 (singlet, 3H), 3.723.77 (multiplet, 1H), 6.3-6.4 (multiplet, 1H), 6.56.6 (multiplet, 1H), 9.38 (singlet, 1H).

t. The product shows the following characteristic NMR spectra:

(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).

4- (3-Hydroxy-5-trifluoromethylphenyl) -4-methoxytetrahydropyran, used as starting material, is obtained as follows:

To a mixture of 9.82 ml benzyl alcohol and 136 ml dimethylacetamide, cooled in an ice bath, is added 4.36 g (55% dispersion in mineral oil) of sodium hydride. The mixture is stirred at room temperature for 1.5 hours, then cooled again in an ice bath. A solution of 22.1 g of 3fluoro-5-trifluoromethylbromobenzene in 136 ml of dimethylacetamide is added to the resulting mixture and the resulting mixture is stirred at room temperature for 2 hours. The mixture is evaporated and the residue partitioned between diethyl ether and water. The organic phase is washed with saturated sodium chloride solution, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using hexane as eluent. This gives 23.1 (77%) of 3-benzyloxy-5-trifluoromethyl bromobenzene as 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) is added dropwise to a solution of the compound thus obtained (13.75 g) in 150 mL of tetrahydrofuran which is cooled to -70 ° C. The mixture is stirred at that temperature for 1 hour, dropwise added to a solution of 4.15 g of tetrahydropyran-4-one in tetrahydrofuran and stirred at -70 ° C for one hour, then allowed to warm to 0 ° C. 100 ml of a saturated aqueous solution of ammonium chloride are added and the mixture is extracted with diethyl ether. The organic phase is washed with saturated aqueous sodium chloride solution, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 4: 1 by volume mixture of toluene and ethyl acetate as eluent. 11.5 g (79%) of 4- (3-benzyloxy-5-trifluoromethylphenyl) -4-oxytetrahydropyran are obtained in the form of a solid.

NMR Spectrum: (CDCl ₃ , δ, md):

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).

0.262 g (55% w / w dispersion in mineral oil) of sodium hydride are added to a mixture of the resulting reaction product portion (1.92 g) and 12 ml of dimethylformamide cooled to -5 ° C. The mixture was stirred at -5 ° C for 30 minutes. Adds 0.38 ml of methyl iodide dropwise and the mixture is stirred at ambient temperature for 90 minutes. The mixture is poured onto ice and extracted with diethyl ether. The organic phase is washed with water, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 10: 1 by volume mixture of toluene and ethyl acetate as eluent. This gives 1.76 g of 4- (3-benzyloxy-5-trifluoromethylphenyl) -4-methoxytetrahydropyran as an oil (88%).

NMR Spectrum: (CDCl ₃ , δ, md):

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 product thus obtained, 0.32 g of 10% palladium on charcoal and 25 ml of isopropanol, under a hydrogen atmosphere, was stirred for 2 hours. The mixture was filtered and the filtrate evaporated to give the target starting material (1.14 g, 89%), m.p. 132-134 ° C.

NMR Spectrum: (CDCl ₃ , δ, md):

1.9-2.1 (multiplet, (multiplet, 4H), (multiplet, 1H), (singlet, 1H).

4H), 3.0 (singlet, 3H), 3

5.95 (singlet, 1H),

7.1 (multiplet, 1H),

8-4.0

7.0

7.2

u. The product displays the following characteristic NMR signals:

(CD ₃ SOCl ₃ , δ, md):

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).

The 4-ethoxy-4- (3-hydroxy-5-trifluoromethylphenyl) tetrahydropyran used as starting material is obtained as follows:

To a solution of 2.17 g of 4- (3-benzyloxy-5-trifluoromethyl-phenyl) -4-hydroxytetrahydropyran in 15 ml of dimethylsulfoxide is added 1.5 g of potassium hydroxide powder and the mixture is stirred at room temperature for 10 minutes. Add 1.24 ml of ethyl iodide and stir the mixture at room temperature for 4 hours. The mixture was poured into a mixture of diethyl ether and ice. The organic phase is separated off, washed with water, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 10: 1 by volume mixture of toluene and acetate as eluent. This gives 1.75 g (74%) of 4- (3-benzyloxy-5-trifluoromethylphenyl) -4-ethoxytetrahydropyran as an oil.

NMR Spectrum: (CDCl ₃ , δ, md):

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) ).

The product thus obtained, a mixture of 0.35 g of 10% palladium on charcoal and 25 ml of isopropanol, is stirred at atmospheric pressure for 3.5 hours. The mixture is filtered and evaporated. This gives the target starting material as an oil (1.3 g, 97%).

NMR Spectrum: (CDCl ₃ , δ, md):

1.1-1.2 (triplet, 3H), 1.9-2.1 (multiplet, 4H),

3.05-3.15 (quartet, 2H), 3.8-4.0 (multiplet, 4H),

7.0 (multiplet, 1H), 7.1 (multiplet, 1H), 7.2 (singlet, H).

v. The alkylation reaction is carried out at -20 ° C rather than room temperature and uses sodium hydride as the base (55 wt% dispersion in mineral oil) instead of potassium carbonate.

z. The product displays the following characteristic NMR signals:

(CDCl ₃ , δ, md):

1.75-2.25 (multiplet, 4H), 3.0 (singlet, 3H), 3.64.0 (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).

EXAMPLE

Using the procedure described in Example 1, the corresponding alkyl halide is treated with the appropriate phenol to give the compounds described in the following table:

Table III

e.g. Q Ar R ¹ R Yield Melting point.

Jung. (%) (° C)

No. 1 ^a 1,2-Dihydro-1-5-fluoro-Me alpha-Me 54 foam Irethyl 2-oxo-1,3-phenyl.

quinolin-6-yl

2 ^b 1,2-dihydro- l-methyl-2- oxoquinoline 6-il 5-fluoro 1,3-phenyl Me beta-Me 41 oil 3 ^C 1,2-dihydro-1- ethyl 2-oxo quinolin-6-yl 5-Fluoro-1,3- phenylene Me alpha-Me 50 oil 4 ^December 1,2-dihydro- l-methyl-2- oxoquinoline 6-il 5-fluoro 1,3- phenylene Me beta-Me 73 foam Fig. 5 1,2-dihydro- l-methyl-2- oxoquinoline 3-il 5-fluoro 1,3- phenylene Me alpha 73 121-122 6th 1,2-dihydro- l-methyl-2- oxoquinoline 6-il 5-amino 1,3- phenylene Me alpha-Me 39 foam Fig. 7 ^f 1,2-dihydro- 1-methyl-2- oxoquinoline 6-il 5-ureido 1,3- phenylene Me alpha-Me 70 191

OBSERVATIONS

a. (2RS, 4SR) -4- (5-Fluoro-3-hydroxyphenyl) -4-methoxy-25-methyltetrahydropyran having 2-methyl and 2-hydroxy groups in the trans position is used as the corresponding phenol.

The product displays the following characteristic NMR signals:

(CDCl ₃ , δ, md):

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, which has 2-methyl and 4-methoxy groups, is used as the corresponding phenol.

The product displays the following characteristic NMR signals:

(CDCl ₃ , δ, md):

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). typical NMR signals: c. The product shows such (CDCl3, δ, ppm): 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 procedure described in the Notes, c). after Table II in Example 6 except that ethyl iodide is used instead of methyl iodide. This yields the target oil starting material in 21% yield.

NMR Spectrum: (CDCl ₃ , δ, md):

1.38 (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 displays the following characteristic NMR signals:

(CDCl ₃ , δ, md):

1.20 (doublet, 3H), 1.39 (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 displays the following characteristic NMR signals:

(CD ₃ SO-C1 ₃ / CF ₃ COOD / CD ₃ COOD, δ, ppm):

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- (N-Benzylideneamino) -3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran is used as starting material and the resulting reaction product is stirred with 2N aqueous hydrochloric acid at room temperature for 12 hours. The mixture was neutralized by the addition of 2N aqueous sodium hydroxide solution and extracted with diethyl ether. The organic phase is washed with water, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using ethyl acetate as eluent. This yields a target product with 39% yield.

(2RS, 4SR) -4- (5- (N-Benzylideneamino) -3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran is obtained as the starting material as follows:

Using the procedure described in the first paragraph, Notes c), below Table I, Example 2, benzyl alcohol is treated with 3,5-dinitrododobenzene to give 3-benzyloxy-5-nitroiodobenzene in 54% yield, m.p. 79-90 ° C.

Using the methodology detailed in the Notes section

c. below Table I in Example 2, except that the reaction is carried out at -110 [deg.] C. and the reaction product thus obtained is treated with n-butyl lithium, then the organometallic reagent thus obtained is reacted with 2-methyltetrahydropyran-4-one (the reaction mixture is stirred at -100 ° C for 30 minutes and then allowed to warm to room temperature) to give 4- (3-benzyloxy-5-nitrophenyl) -4-hydroxy-2-methyl-tetrahydropyran in the form of a mixture of diastereoisomers. The mixture of isomers thus obtained is chromatographed using a 4: 1 by volume mixture of diethyl ether and petroleum ether (boiling point 40-60 ° C) as eluent. Each isomer is methylated using the conditions described in these Notes. This yields the less polar diastereoisomer, (2RS, 4SR) -4- (3-benzyloxy-5-nitrophenyl) -4-methoxy-2-methyltetrahydropyran, in 16% yield, calculated from 3-benzyloxy-5-nitro-iodobenzene, m.p. 85-86 ° C; and the more polar diastereoisomer, (2RS, 4RS) -isomer in 22% yield, m.p. 106-107 ° C.

The resultant mixture of less polar isomer (1.5 g), 0.3 g of 5% palladium on charcoal and 25 ml of ethanol was stirred under hydrogen atmosphere for 2 hours. The mixture was filtered and the filtrate evaporated. The residue was purified by column chromatography using a 1: 1 by volume mixture of toluene and ethyl acetate as eluent. The reaction product thus obtained was (2RS, 4SR) -4- (5-amino-3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran as an oil (0.83 g, 84%).

NMR Spectrum: (CDCl ₃ , δ, md)

1.2 (doublet, 3H), 1.4-2.2 (multiplet, 4H), 3.0 (singlet, 3H), 3.25-4.1 (multiplet, 4H), 3.0 (singlet, 3H), 3.25-4.1 (multiplet, 6H), 6.1- 6.4 (multiplet, 3H).

A mixture of the product thus obtained (0.8 g), 0.55 g benzaldehyde, 1 g magnesium sulfate and 10 ml methylene chloride was stirred at room temperature for 12 hours. The mixture is filtered and the filtrate is evaporated. This yields an oil-like target starting material with quantitative yield.

f. This product is obtained by treating the precursor product with sodium cyanate as follows:

To 0.23 g of (2RS, 4SR) -4- [5-amino-3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy-phenyl] -4-methoxy-2-tetrahydropyran, 0.5 ml of 2N aqueous hydrochloric acid, 3 ml of water and 2 ml of ethanol was added 0.085 g parts of sodium cyanate and the mixture was stirred at room temperature for 12 hours. the mixture was evaporated and the residue separates the layers between ethyl acetate and water. the organic phase was dried MgSO ₄ and evaporated and the residue is ground into a powder with methylene chloride to give the target product in 70% yield.

EXAMPLE

Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is treated 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-dimethyl-tetrahydropyran in 83% yield.

NMR Spectrum: (CDCl ₃ , δ, md):

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-dimethyl-tetrahydropyran, used as starting material, is obtained as follows:

2.72 g of 2,3-dihydro-2,2-dimethylpyran-4-one (J. Org.Chem. 687, 1963), 0.27 g of 10% palladium on charcoal and 80 ml of a mixture of ethanol under hydrogen atmosphere. hours. The mixture was filtered and the filtrate evaporated. This gives 2.05 g (74%) of 2,2-dimethyltetrahydropyran-4-one in liquid form. (IR spectrum 1730 cm @ ^-1 ).

Using the procedure described in the second paragraph Notes to c), below Table I in Example 2, 1.34 g

3-Benzyloxybenzene is treated with 0.65 g of 2,2-dimethyltetrahydropyran-4-one to give 1.14 g (72%) of 4- (3-benzyloxyphenyl) -4-hydroxy-2,2-dimethyltetrahydropyran as an oil.

Using the methodology described in the second paragraph of Note t. after Table II in Example 6, which relates to the preparation of starting materials, the reaction product is treated with methyl iodide to give 1.06 g (89%) of 4- (3-benzyloxyphenyl) -4-methoxy-2,2-dimethyltetrahydropyran as an oil.

NMR Spectrum: (CDCl ₃ , δ, md):

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

EXAMPLE

Using the procedure described in Example 1, 3- (2-pyridyl) -prop-2-yn-1-yl bromide bromohydrate is treated with (2RS, 4SR) -3- (3-hydroxyphenyl) -3-methoxy-2-methyltetrahydrofuran, to give (2RS, 3SR) -3-methoxy-2-methyl-3- [3- (3- (2-pyridyl) -prop-2-yn-1-yloxy) -phenyl] -tetrahydrofuran as an oil in 90% yield.

NMR Spectrum: (CDCl ₃ , δ, md):

1.19 (doublet, 3H), 2.49 (triplet, 2H), 3.18 (singlet, 3H), 3.72 (quartet, 1H), 3.72 (quartet,

1H), 4.08 (multiplet, 2H), 4.95 (singlet, 2H),

6.85-7.5 (multiplet, 8H).

The (2RS, 3SR) -3- (3-hydroxyphenyl) -3-methoxy-2-methyltetra5 hydrofuran used as starting material is obtained as follows:

Uses the procedure described in Example 1, which relates to the preparation of starting materials, except that 2-methyltetrahydrofuran-3-one is used in place of tetrahydropyran-4-one. This yields the target starting material with a yield of 54%, m.p. 170-171 ° C; in addition, the 2-methyl and 3-methoxy groups are in the eis position.

EXAMPLE 10

Using the procedure described in Example 1, the corresponding alkyl bromide is treated with the appropriate phenol to give the compounds described in the following table:

Table IV

CH ₂ - o

Ar

Me

Example 10 Jung. No. Q. Ar R ¹ Yield (%) Melting point (° C) 1 6-quinoxalyl 1,3-Phenylene Me 82 89-90 2 1,2-dihydro-1-methyl-2- oxoquinolin-6-yl 1,3-Phenylene Me 75 120 3 1,2-dihydro-1-methyl- 1,3-Phenylene Me 65 43-53

2-oxoquinolin-5-yl

4a 1,2-dihydro-1-methyl- 2-oxoquinolin-7-yl 1,3-Phenylene Me 41 oil 5b 1,2-dihydro-1-methyl- 2-oxoquinolin-6-yl 5-Fluoro-1,3- phenylene E 61 110-112 6c 1,2-dihydro-1-methyl- 2-oxoquinolin-6-yl 5-Fluoro-1,3- phenyl Me 78 115-122 7d 1,2-dihydro-1-ethyl-2- oxoquinolin-6-yl 5-Fluoro-1,3- phenylene Me 78 oil

OBSERVATIONS

a. The product displays the following characteristic NMR signals:

NMR Spectrum (CDC1 _3, δ, ppm): 1.19 (doublet, 3H), 2.48 (multiplet, 2H), 3.16 (single, 3H), 3.73 (single, 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-hydroxy-phenyl) -2-methyl-tetrahydro-furan, used as starting material, is obtained as follows:

Grignard reagent is obtained by heating a mixture of 4.2 g of 3-benzyloxy-5-phthalophenyl bromide, 0.365 g of magnesium powder and 20 ml of tetrahydrofuran to 40 ° C for 1 hour. Grignard reagent is cooled to room temperature and 1.16 ml of 2-methyltetrahydrofuran-3-one are added dropwise. The mixture is stirred at ambient temperature for 3 hours and then partitioned between ethyl acetate and water. The organic layer was washed with water, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 19: 1 by volume mixture of methylene chloride and diethyl ether as eluent. This gives 2.3 g of (2RS, 3SR) -3- (3-benzyloxy-5-fluorophenyl) -3-hydroxy-2-methyl-tetrahydrofuran (64% yield), m.p.

83-84 ° C; in addition, the 2-methyl and 3-oxy groups are in the eis positions.

Part of the reaction product thus obtained (1.1 g) is treated with ethyl iodide using the procedure described in the second paragraph of Note (b) below Table II in Example 6. 0.82 g (68%) of (2RS, 3SR) -3- (3-benzyloxy-5-fluorophenyl) -3-ethoxy-2-methyl-tetrahydrofuran is thus obtained in the form of an oil.

A mixture of the product thus obtained, 0.1 g of 10% palladium on charcoal and 5 ml of ethanol is stirred at ambient temperature and hydrogen pressure for 4 hours. The mixture is filtered and evaporated. This gives 0.54 g (90%) of the target starting material, m.p. 136137 ° C.

c. The (2RS, 3SR) -3- (5-fluoro-3-hydroxyphenyl) -3-methoxy-2-methyltetrahydrofuran used as starting material is obtained as follows:

Repeats the methodologies described in Note b. directly above, except that methyl iodide is used instead of ethyl iodide in the alkylation step. The target starting material is obtained with a total yield of 45%, m.p. 148-152 ° C.

d. The product shows the following characteristic NMR signals:

(CDC1 ₃ , δ, md): 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).

EXAMPLE

4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -4-hydroxytetrahydropyran (0.25 g), sodium hydride (60% w / w dispersion in mineral oil, 0.06 g), and 20 ml of DMF bag at room temperature for 30 minutes. Adds 1 ml of auric bromide and the mixture is stirred at ambient temperature for 36 hours. The mixture is partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with water, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 4: 1 by volume mixture of methylene chloride and diethyl ether as eluent. This gives 0.17 g (61%) of 4-allyloxy-4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -phenyl] -tetrahydro-pyran as an oil.

NMR Spectrum: (CDCl ₃ , δ, md):

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-oxytetrahydropyran, used as starting material, is obtained as follows:

Using the procedure of using the Grignard reaction described in Example 1, in the part concerning the use of starting materials, 3-benzyloxybromobenzene is treated with tetrahydropyran-4-one to give 4- (3-benzyloxyphenyl) 4-hydroxytetrahydropyran in 77% yield, m.p. . 84-86 ° C.

A mixture of the product thus obtained (1 g), palladium on charcoal (0.1 g) and ethanol (10 ml) was stirred under two atmospheres of hydrogen for 6 hours. The mixture was filtered and the filtrate evaporated. The residue was purified by column chromatography using a 50: 50: 1 by volume mixture of methylene chloride, diethyl ether and methanol as eluent. There was thus obtained 4oxy-4- (3-oxyphenyl) -tetrahydropyran (0.325 g, 48%), m.p. 165-169 ° C.

Using the procedure described in Example 1, the reaction product thus obtained is treated with 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one to give the target product in 70% yield, m.p. 165-167 ° C.

EXAMPLE

Using the procedure described in Example 11, kale bromide is treated with the appropriate 4-hydroxytetrahydropyran to give the compounds described in the following table.

Table V.

12 e.g. Jung. No. Q. Ar Yield (%) Melting point (0 ° C) l ^a 1,2-dihydro-1-methyl-2- oxoquinolin-6-yl 5-Fluoro-1,3- phenylene 51 oil

oil

^2b 1,2-Dihydro-1-methyl-2- 5-trifluoro-oxoquinolin-6-ylmethyl-1,3-phenylene

OBSERVATIONS

The product displays the following characteristic NMR signals:

(CDCl ₃ , δ, md): 1.85-2.1 (multiplet, 4H), 3.54-3.64 (multiplet, 2H), 3.73 (singlet, 3H), 3.75-4.0 (multiplet, 4H), 5.10-5.25 (multiplet, 4H) ), 5.755.97 (multiplet, 1H), 6.63 (multiplet, 1H), 6.736.84 (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-hydroxytetrahydropyran, used as starting material, is obtained as follows:

Using the procedure described in the last paragraph of Note (c), below Table I, Example 2, hydrogenate 4- (3-benzyloxy-5-fluorophenyl) -4-hydroxytetrahydropyran to give 4- (5-fluoro-3-hydroxyphenyl) -4-hydroxy- tetrahydropyran in 79% yield, m.p. 158-160 ° C.

Using the procedure described in Example 1, the reaction product thus obtained is treated with 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one to give the target solid starting material in 72% yield.

NMR Spectrum (CDC1 _3, δ, ppm):

1.74 (distributed singlet, 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), 7.54-7.7 (multiplet, 3H).

b. The product displays the following alert BMR signals:

(CDCl ₃ , δ, md):

1.9-2.1 (multiplet, 4H), 3.56-3.59 (multiplet, 2H), 3.73 (singlet, 3H), 3.85-3.95 (multiplet, 4H), 5.05.3 (multiplet, 2H), 5.15 (singlet, 2H), 5.1-5.31 (multiplet, 1H), 6.71-6.76 (multiplet, 1H), 7.17.69 multiplet, 7H).

4- [3- (1,2-Dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) 5-trifluoromethyl] -4-hydroxytetrahydropyran, used as starting material, is obtained as follows:

Using the procedure described in the last paragraph of the Notes, i.e. under Table II, Example 6, hydrogenation of 4- (3-benzyloxy-5-trifluoromethylphenyl) -4-hydroxytetrahydropyran is carried out to give 4-hydroxy-4- (3-hydroxy) as an oil. -5-trifluoromethylphenyl) tetrahydropyran in 90% yield.

Using the procedure described in Example 1, the reaction product thus obtained is treated with 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one to obtain the target starting material in 70% yield.

NMR Spectrum (CDC1 _3, δ, ppm):

1.64-1.69 (doublet, 2H), 1.93 (singlet, 1H), 2.092.25 (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).

EXAMPLE

0.26 g of a solution of 4 [5-fluoro-3- (2-propynyloxy) -phenyl] -4-methoxytetrahydropyran in 1.5 ml of acetonitrile are added to 0.21 g of 3-iodopyridine, 0.01 g of bis- (triphenylphosphine) palladium chloride, 0.15 ml of triethylamine, 0.01 g. of a mixture of copper (I) iodide and 1.5 ml of acetonitrile and stir the resulting mixture to 60 ° C for 4 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase is washed with water, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 3: 1 by volume mixture of hexane and ethyl acetate as eluent. There was thus obtained 0.25 g (74%) of 4- [5-fluoro-3- (-3- (3-pyridyl) -prop-2-ynyloxy) -phenyl] -4-methoxy-tetrahydro-pyran, m.p. 82-83 ° C.

4- [5-Fluoro-3- (2-propynyloxy) -phenyl] -4-methoxytetrahydropyran, used as starting material, is obtained as follows:

A mixture of 5.34 g of 4- (5-fluoro-3-hydroxyphenyl) -4-methoxytetrahydropyran, propargyl bromide (80% w / v toluene, 4.46 ml), 5.52 g of potassium carbonate and 150 ml of acetone is heated to reflux for 16 hours. The mixture is filtered and evaporated. The residue is partitioned between ethyl acetate and water. The organic phase is washed with water and saturated aqueous tri-chloride solution, dried over MgSO ₄ and evaporated. The L-solvent was purified by column chromatography using a 2: 1 by volume mixture of ethyl acetate and hexane as eluent. This gives 5.77 g (91%) of the target starting material, m.p. 71-72 ° C.

EXAMPLE

The procedure described in Example 13 is repeated except that 3-chloro-2-iodopyridine is used in place of 3-iodopyridine. This gives 4- [3- (3-chloropyrid-2-yl) -prop2-ynyloxy) -5-fluorophenyl] -4-methoxytetrahydropyran in 59% yield, m.p. 80-82 ° C.

The 3-chloro-2-iodopyridine used as starting material is obtained as follows:

A mixture of 0.74 g of 2,3-dichloropyridine and saturated sodium iodide in a mixture of 20 ml of methylethylketone and 1 ml of water is heated to reflux and is made up by the addition of hydrogen iodide solution (55% v / v, 0.5 ml). The mixture is heated to reflux and refluxed for 16 hours, cooled to room temperature, filtered and evaporated. Dissolve the residue in 10 ml of water and basify the solution to pH 11 by adding sodium hydroxide plates. The alkaline solution is extracted with ethyl acetate. The organic phase was washed with water, dried over MgSO ₄ and evaporated to give an oil-like target starting material (0.66 g, 55%) which was used without further purification.

EXAMPLE

The procedure described in Example 13 is repeated except that 1-iodoisoquinoline is used in place of 3-iodopyridine (Chem. Pharm. Bull. Jap. 1982, 30, 1731). 4- [5-Fluoro-3- (3- (3- (1-isoquinolyl) -prop-2-ynyloxy) -phenyl] -4-methoxy-tetrahydropyran is obtained in the form of an oil in 67% yield.

NMR Spectrum (CDC1 _3, δ, ppm):

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

Using the procedure described in Example 11, 4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -5-trifluoromethyl] -4-hydroxytetrahydropyran is treated with methyl iodide to give 4- [3- ( 1,2-Dihydro-1-methyl) -2-oxo-methyl 3396 B -nolin-6-ylmethoxy) -5-trifluoromethyl-phenyl] -4-methoxy-tetrahydro-pyran in 95% yield, m.p. 103 ° C.

EXAMPLE

Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is treated with (2RS, 4RS) -4- (3-amino-5-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran to give an oil. (2RS, 4RS) -4- [3- (1,2-dihydro-1-methyl) -2-oxoquinolin-6-methylmethylamino) -5-hydroxyphenyl] -4-methoxy-2-methyltetrahydropyran in 46% yield.

NMR spectrum (CDSOC1 _3, δ, ppm):

1.05 (doublet, 3H), 1.1-2.4 (multiplet, 4H), 2.8

(single, 3H), 2.8 (single, 3H), 3.0-3.5 (multiplet, 2H), 3.65 (single, 3H), 3.6-3.9 (multiplet, 1H), 4.35 (double, 2H), 5.95-6.3 (multiplet, 3H), 6.65 (double, 1H), 7.4-7.75 (multiplet, (multiplet, 3H), 1H). 7.9 (double, 1H) , 8.9

The (2RS, 4RS) -4- (3-amino-5-oxyphenyl) -4-methoxy-2-methyltetrahydropyran used as starting material is obtained as follows:

g (2RS, 4RS) -4- (3-benzyloxy-5-nitrophenyl) -4-methoxy-2-methyltetrahydropyran, palladium on carbon, 10 ml of chloride mixture stirred under pressure for two hours, evaporated

0.1 g of 5% ethanol catalyst and 10 ml of methylene in hydrogen atmosphere The mixture is filtered and the filtrate

The residue was purified by column chromatography using a 1: 1 by volume mixture of toluene and ethyl acetate as eluent. This yields 0.67 g (99%) of the target starting material as an oil.

NMR Spectrum (CDC1 _3, δ, ppm):

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

Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is treated with (3RS, 4SR) -3-hydroxy-4- (3-hydroxyphenyl) -4-methoxytetrahydropyran to give (3RS, 4SR) -4-3- (1,2-Dihydrol-methyl-2-oxo-quinolin-6-ylmethoxy) -phenyl] -3-hydroxy-4-methoxytetrahydropyran in 84% yield, m.p. 62-66 ° C.

NMR Spectrum (CDC1 _3, δ, ppm):

1.85 (multiplet, 1H), 2.5 (multiplet, 1H), 2.96 (singlet, 3H), 3.58 (multiplet, 1H), 3.72 (singlet, 3H), 3.72-4.25 (multiplet, 4H), 5.13 (singlet, 3H) , 6.66 - 7.72 (multiplet, 9H).

The (3RS, 4SR) -3-hydroxy-4- (3-hydroxyphenyl) -4-methoxytetrahydropyran used as starting material is obtained as follows:

12.5 g of 4-hydroxy-4- (3-benzyloxyphenyl) -tetrahydropyran, 80 g of 5-Angstroms pore size molecular sieves and 90 ml of toluene are heated to 80 ° C for 9 hours. The mixture is filtered and the residue is washed successively with toluene and acetone. The filtrate and leachate are combined and evaporated. The residue was purified by column chromatography using methylene chloride as eluent. That way gets it

10.5 g of an oil (88%) of 2,3-dihydro-4- (3-benzyloxyphenyl) -6H-pyran.

To a stirred suspension of the product thus obtained (2.5 g), 1.18 g of sodium bicarbonate and 30 ml of methylene chloride are cooled to Q ° C, 2.42 g of meta-chloroperbenzoic acid are added and the mixture is stirred at 0 ° C for 1 hour and at that ambient temperature for 15 hours. The mixture is filtered and the residue washed with methylene chloride. Fused and the filtrate and washes washouts dilute aqueous sodium hydroxide solution and water, dried MgSO ₄ and evaporated. The epoxide (2.3 g, 90%) thus obtained is used without further purification.

The above epoxy is treated with sodium hydroxide using the procedure described in Tet. Les., 24, 1755 (1968).

The reaction product thus obtained is purified by column chromatography using a 4: 1 by volume mixture of methylene chloride and diethyl ether as eluent. This gives 1.78 g (73%) of the (3RS, 4SR) -3,4-dioxy-4- (3-benzyloxyphenyl) -tetrahydropyran as an oil, the 3- and 4-hydroxy groups being in the trans position.

A mixture of 1.76 g of the product thus obtained, 2 g of imidazole, 2.26 g of tert-butyldimethylsilyl chloride and 6 ml of dimethylformamide is stirred at room temperature for 15 hours. The mixture is partitioned between diethyl ether and water. The organic layer was washed with water, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 9: 1 by volume mixture of methylene chloride and diethyl ether as eluent. This gives 1.9 g (78%) of (3RS, 4SR) -4- (3-benzyloxyphenyl) -3- (tert-butyldimethylsilyloxy) -4-hydroxytetrahydropyran, m.p. 90-92 ° C.

The product thus obtained is methylated using the procedure described in Example 1, part concerning the preparation of starting materials. This gives 1.69 g of (3RS, 4SR) -4- (3-benzyloxyphenyl) -3- (tert-butyldimethylsilyloxy) -4-methoxytetrahydropyran (89%) as an oil.

To a mixture of the compound thus obtained and 32 ml of tetrahydrofuran is added tetra-n-butylammonium (1M solution in tetrahydrofuran, 16 ml) and the mixture is stirred at room temperature for 15 hours. The mixture is evaporated and the residue partitioned between diethyl ether and water. The organic phase is dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 9: 1 by volume mixture of methylene chloride and diethyl ether as eluent. This gives 1.06 g (86%) of (3RS, 4SR) -4-methoxy-tetrahydropyran, m.p. 85-86 ° C.

A mixture of the product thus obtained, 0.1 g of 10% palladium on charcoal and 20 ml of ethanol was stirred at ambient temperature under hydrogen pressure for 15 hours. The mixture was filtered and evaporated to give the target starting material (0.7 g, 92%, mp 159-160 ° C).

EXAMPLE

Using the procedure described in Example 1, which relates to the preparation of starting materials, (3RS, 4SR) -4- [3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) phenyl] -3-hydroxy -4-Methoxytetrahydropyran is treated with methyl iodide in the presence of 15-crown-5 to give (3RS, 4SR) -4- [3- (1,2-dihydro-1-methyl-2-oxo-quinolin-6-ylmethoxy) -phenyl] ] -3,4-dimethoxytetrahydropyran (glass) in 78% yield.

NMR Spectrum (CDC1 _3, δ, ppm):

1.85 (multiplet, 1H), 2.5 (multiplet, 1H), 2.95 (singlet, 6H), 3.07 (multiplet, 1H), 3.72-3.94 (multiplet, 4H), 5.14 (singlet, 2H), 6.66-7.5 (multiplet, 9H).

EXAMPLE

Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is treated with (2S, 4R) -4- (3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran to give (2S, 4R) -4- [3- (1,2-Dihydro-1-methyl-2-oxo-quinolin-6-ylmethoxy) -phenyl] -4-methoxy-2-methyl-tetrahydropyran in 69% yield, m.p. 88-90 ° C.

(2S, 4R) -4- (3-Hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran, as follows:

used as a knitting material receives

Grignard's reagent is obtained by benzyl oxybromobenzene, tetrahydrofuran, until refluxing for 30 minutes.

warms up in layers

While heating the salt in water at 40 ° C, 4.2 g of 30.4 g of magnesium and 10 ml of boiling point are allowed to cool to about 40 ° C and 1.55 g of (2S) -2-methyltetrahydropyran-4one solution is added dropwise to 7 ml. The mixture was stirred for three hours. The mixture is partitioned between ethyl acetate and cold dilute acid. The organic phase is washed with saturated aqueous sodium chloride solution, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 10: 3 by volume mixture of toluene and ethyl acetate as eluent. This gives (2S, 4R) and (2S, 4S) -4- (3-benzyloxyphenyl) -4-hydroxy-2-methyl-tetrahydropyran as a mixture of diastereoisomers (3.71 g, 92%) as an oil which is partially separated to give a fraction (2.33 g) which is enriched in less polar diastereoisomers.

To a solution of the thus-enriched fraction (2.33 g) in 16 ml of dimethylformamide, cooled to -5 ° C, add sodium hydride (55% w / w mineral oil dispersion, 0.39 g) and stir at this temperature for 1 hour. Add 0.61 ml of methyl iodide and stir the mixture for 2 hours and allow to warm to room temperature. The mixture is partitioned between ethyl acetate and ice-cold water. The organic phase is washed with saturated aqueous sodium chloride solution, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 20: 1 by volume mixture of toluene and ethyl acetate as eluent. This gives 1.99 g (92%) of (2S, 4R) -4- (3-benzyloxyphenyl) -4-methoxy-2-methyl-tetrahydropyran as an oil.

NMR Spectrum (CDC1 _3, δ, ppm):

1.2 (doublet, 3H), 1.5-1.65 (multiplet, 1H), 1.92.05 (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 product thus obtained, 0.28 g of 10% palladium on charcoal and 50 ml of isopropanol is stirred under a hydrogen atmosphere for 5 hours. The mixture was filtered and the filtrate evaporated. This yields an oil-like target material in quantitative yield.

The (2S) -2-methyltetrahydropyran-4-one used as starting material as described above is obtained as follows:

To 29 g of (-) - (2S, 3S, 4S) -2,3-epoxyhept-6-en-4-ol (J. Org.Chem., 48, 5093, 1983, compound # (-) - 14 in this article) add 1100 ml of tetrahydrofuran, cooled to -15 ° C, add bis (2-methoxyethoxy)-sodium aluminum hydride (3.4 M solution in toluene, 200 ml) over 30 minutes and stir the resulting mixture for 16 hours. and leave to warm to room temperature. Cool the mixture in an ice bath and slowly add dilute aqueous sulfuric acid (10% v / v, 1350 mL). Sodium chloride is added to give two layers. The organic phase is separated off and the aqueous layer is extracted with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 2: 3 by volume mixture of hexane and ethyl acetate as eluent. This gives 20 g (67%) of (2S, 4R) -hept-6-en2,4-diol as an oil.

NMR Spectrum (CDC1 _3, δ, ppm):

1.23 (doublet, 3H), 1.63 (triplet, 2H), 2.18-2.4 (multiplet, 2H), 3.93-4.38 (multiplet, 2H), 5.085.25 (multiplet, 2H), 5.70-5.96 (multiplet, 1H).

A solution of the product thus obtained (5.6 g) was cooled to -20 ° C in 875 ml of methanol and passed through a stream of ozone-containing oxygen (about 5% ozone) for 130 minutes. Oxygen, followed by argon, is passed through the solution to remove any excess ozone. Adds 20 ml of dimethyl sulfide and leaves the mixture to warm to room temperature. The mixture was evaporated and the residue was purified by column chromatography using ethyl acetate as eluent. This gives (2S, 4R, 6R) and (2S, 4R, 6S) -4,6-dioxo-2-methyltetrahydropyrans in the form of a mixture of diastereoisomers (3.7 g, 67% as an oil). After repeating the above steps, a solution of 19 g of the reaction product thus obtained in 90 ml of ethanol, cooled in an ice bath, is added 90 drops of a saturated aqueous solution of hydrochloric acid in ethanol and the resulting mixture is kept at 5 ° C for 16 hours. The mixture is evaporated to give (2S, 4R, 6R) - and (2S, 4R, 6S) -6-ethoxy-4LT 3396 B oxy-2-methyltetrahydropyran in the form of a mixture of diastereoisomers in quantitative yield (as an oil) which is used without further purification .

A solution of the reaction product thus obtained in 45 ml of dimethylformamide is cooled to 0 [deg.] C., followed by the sequential addition of 20.4 g of imidazole and 5 g of 4 Angstroms pore size molecular sieves. Adds 24.3 g as it drops

At 0 ° C triethylsilyl chloride separates the acyl acetate and the mixture for 2 hours.

Pour the mixture over ice and extract. The organic phase is dried over MgSO ₄ and evaporated. The residue is diluted with 300 ml of diethyl ether and the solution is washed with cold water. The organic layer was separated, dried over MgSO ₄ and evaporated to give (2S, 4R, 6R) - and (2S, 4R, 6S) -6-ethoxy-2-methyl-4-triethylsilyloxytetrahydropyran (36 g, 91%) as a mixture of diastereoisomers. , which is used without additional cleaning.

To a solution of the reaction product thus obtained in succession is added 300 ml of methylene chloride, which is cooled to 5 ° C.

15.7 g of triethylsilane and 29.1 g of trifluoromethanesulphonic acid trimethylsilyl ester are added and the mixture is stirred at 5 ° C for 30 minutes. The mixture is poured into 50 ml of ice-cold water and the resulting mixture is stirred for 5 minutes. The mixture is neutralized by the addition of sodium bicarbonate in portions. The organic layer was separated and the aqueous layer was saturated with hydrogen chloride and extracted with ethyl acetate. The organic solutions are combined, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography using a 4: 1 by volume mixture of hexane and ethyl acetate as eluent. 6.2 g (41%) of (2S, 4S) -4-oxy-2-methyl-tetrahydropyran are thus obtained.

NMR Spectrum (CDC1 _3, δ, ppm):

100

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 8 M sulfuric acid in chromic acid) is added dropwise to 250 mL of acetone, which is cooled to 5 ° C. Adds about 20 drops of isopropanol to disperse the excess oxidant and the mixture is stirred at ambient temperature for 30 minutes. The mixture was filtered and the filtrate evaporated. The residue is dissolved in 10 ml of diethyl ether, filtered through silica gel (Kizelgel 60 H) and evaporated. This gives (2S) -2-methyltetrahydropyran-4-one as an oil (4.85 g, 81%).

NMR Spectrum (CDC1 _3, δ, ppm):

1.3 (doublet, 3H), 2.2-2.7 (multiplet, 4H), 3.6-3.8 (multiplet, 2H), 4.2-4.3 (multiplet, 1H).

EXAMPLE

Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is treated with (2S, 4R) -4- (5-fluoro-3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran to of (2S, 4R) -4- [5-fluoro-3- (1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy) -phenyl] -4-methoxy-2-methyl-tetrahydropyran in 66% yield, m.p. . 91-93 ° C.

The (2S, 4R) -4- (5-fluoro-3-hydroxyphenyl) -4-methoxy-2-methyltetrahydropyran used as starting material is obtained as follows:

The procedure described in Example 20, which relates to the preparation of starting materials, is repeated except that

101 uses 3-benzyloxy-1-bromo-5-fluorobenzene instead of 3-benzyloxybromobenzene. The following are obtained in succession:

diastereoisomers of (2S, 4S) - 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 (CDC1 _3, δ, ppm):

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 with quantitative yield as oil;

obtained by the addition of a chiral (-) - 1- (9-anthranil) -2,2,2 because the reaction product is

NMR spectral data of the displacement reagent trifluoroethanol showed 98.6% optical purity.

EXAMPLE

Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one is treated 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, m.p. 172-173 ° C (recrystallized from ethyl acetate).

4- (4-Hydroxy-3-methoxyphenyl) -4-methoxytetrahydropyran, used as starting material, is obtained as follows:

102

Using the procedure described in Example 1, 2-bromomethylnaphthalene is treated with 4-bromo-2-methoxyphenol to give 3-methoxy-4- (naphth-2-ylmethoxy) -bromobenzene in 62% yield, m.p. 108 ° C.

Using the procedure described in the second paragraph of Note (c) below Table I in Example 2, the reaction product thus obtained is treated with tetrahydropyran-4-one to give 4-oxy-4- [3-methoxy-4- (naphth-2-ylmethoxy) - phenyl] -tetrahydropyran in 44% yield, m.p. 150-151 ° C (recrystallized from ethyl acetate).

Using the procedure described in the penultimate paragraph of the Notes, i.e., under Table II, Example 6, the reaction product thus obtained is treated with methyl iodide to give 4-methoxy-4- [3-methoxy-4 (naphth-2-yl-methoxy) - phenyl] -tetrahydropyran in 52% yield, m.p. 129 ° C (recrystallized from ethyl acetate).

0.241 g of the product thus obtained, 0.02 g of 10% palladium on charcoal and 25 ml of a mixture of ethanol at atmospheric pressure of hydrogen for 90 minutes. The mixture was filtered and the filtrate evaporated. The remainder is purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. This gives 0.142 g (94%) of the target starting material with m.p. 92-93 ° C.

EXAMPLE

The following examples illustrate typical pharmaceutical dosage forms containing a compound of formula I or a pharmaceutically acceptable salt thereof (hereinafter compound X) for therapeutic or prophylactic use in the treatment of humans:

(a) Tablet I

Compound X

Lactose (European Pharmacopoeia)

Croscarmellose sodium

Cornstarch paste (5% by weight of paste by volume)

Magnesium Stearate (b) Tablet II

Compound X

Lactose (European Pharmacopoeia)

Croscarmellose sodium

Polyvinylpyrrolidone (5% by weight of paste volume)

Magnesium Stearate (c) Tablet III

Compound X

Lactose (European Pharmacopoeia)

Croscarmellose sodium

Cornstarch paste (5% by weight of paste by volume)

Magnesium Stearate (d) Capsule

Compound X

Lactose (European Pharmacopoeia) Magnesium stearate mg / tablet

100

182.75

12.0

2.25

3.0 mg / tablet

223.75

6.0

2.25

3.0 mg / tablet

1.0

93.25

4.0

0.75

1.0 mg / capsule

488.5

1.5

104 (e) Injection I Compound X

M sodium hydroxide solution

0.1 M Hydrochloric acid solution (to pH 7.6) Polyethylene glycol

Water for Injections (Make 100%) (f) Injection II Compound X

Sodium phosphate (British Pharmacopoeia)

M sodium hydroxide solution Water for injections (to make 100%) (g) III injection

Compound X

Sodium phosphate (British Pharmacopoeia)

Citric acid

Polyethylene glycol

Water for Injections (Make 100%) (h) Aerosol I Compound X

Sorbitol trioleate

Trichlorofluoromethane

Dichlorodifluoromethane (50 mg / ml)

5.0% w / v

15.0% w / v

4.5% w / v (10 mg / ml)

1.0% w / v

3.6% by volume

15.0% w / v (1 mg / ml buffer pH 6)

1.0 Sv % by volume

2.26 p.m. % by volume

0.38 lbs % by volume

3.5% w / v mg / ml

10.0

13.5

910.0

490.0

105 (i) II aerosol II mg / ml

Compound X 0 · 2

Sorbitol Trioleate 0.27

Trichlorofluoromethane 70.0

Dichlorodifluoromethane 280.0

Dichlorotetrafluoroethane 1094 (j) III aerosol mg / ml

Compound X 2.5

Sorbitol Trioleate 3.38

Trichlorofluoromethane 67.5

Dichlorodifluoromethane 1086.0

Dichlorotetrafluoroethane 191.6 (k) IV aerosol mg / ml

Compound X 2.5

Soya lecithin 2.7

Trichlorofluoromethane 67.5

Dichlorodifluoromethane 1086.0

Dichlorotetrafluoroethane 191.6

NOTE

The above compositions may be prepared according to 5 generally accepted procedures well known in the pharmaceutical art. The tablets (a) - (c) may be enterosolubilized in a commonly accepted manner, for example, to provide a coat of cellulose acetate phthalate.

Aerosol formulations (h) - (k) may be used in conjunction with standard metered dose aerosol meters, and suspending agents LT 3396 B sorbitol may be replaced by trioleate other than

106 and soy lecithin may be suspending agents, sorbitol monooleate, sorbitol sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

OR

Q - A - X - Ar - C - R

OR

OR

I

HX - Ar - C - R ² I

R ³

OH

II

R ⁴ - X - Ar - C - R ²

III

R ⁴ - X - Ar - C - R ²

IV

OH

Q - A - X - Ar - C - R

VI

R

OR ¹

I

- A ¹ - X - Ar - C - R ²

VI

107

DEFINITION OF INVENTION

Claims (5)

DEFINITION OF INVENTION Heterocyclic compounds of the formula I OR ¹ I Q - A - X - Ar - C - R ² wherein Q is a six membered monocyclic or ten membered bicyclic heterocyclic residue containing one or two nitrogen atoms which may be substituted with one, two or three substituents selected from halogen, hydroxy, oxocarboxy -, 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- [(14C) -alkyl ] -amino- (1-4C) -alkyl, amino- (2-4C) -alkoxy, (1-4C) -alkylamino- (2-4C) -alkoxy, di- [(1-4C) -alkyl ] amino- (2-4C) -alkoxy groups and phenyl- (1-4C) -alkyl, and the phenyl group of which may be substituted on the said phenyl (1-4C) -alkyl substituent by (14C) - alkyl and (1-4C) alkoxy; A represents (1-6C) -alkylene, (3-6C) -alkenylene, (3-6C) alkynylene or cyclo- (3-6C) -alkylene; X represents an oxy, thio, sulfinyl, sulfonyl or imino group; wherein Ar represents phenylene which may be substituted with one or two substituents selected from halogen, hydroxy, amino, nitro, cyano, ureido, 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] -aminofluoro- (14C) -alkyl, (1-4C) -alkoxycarbonyl, N - [(1-4C) -alkyl] carbamoyl, N, N-di- [(1-4C) -alkyl] -carbamoyl , (2-4C) - 108 alkanoylamino, cyano (1-4C) alkoxy, carbamoyl (14C) 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 represents a six membered heterocyclic residue containing up to three nitrogen atoms which may be substituted by one or two substituents selected from halogen, hydroxy, amino, cyano, (1-4C) alkyl, (1-4C) alkoxy, (1-4C) alkylamino and di- [(1-4C) alkyl] amino; R ¹ represents hydrogen, (1-6C) -alkyl, (3-6C) -alkenyl, (3-6C) -alkynyl, cyano (1-4C) -alkyl or (2-4C) -alkanoyl; or R ¹ represents benzoyl which may carry a substituent selected from halo, (1-4C) alkyl and (1-4C) alkoxy; and wherein R ¹ and R ² together form a group of the formula -A ² X ² -A ³ - which, taken together with the carbon atom to which A ² and A ^{3 are} attached, forms a ring having 4 to 7 atoms in the ring wherein A ² and A ³ may be the same or different and each is (1-4C) alkylene and X ² is oxy, thio, thionyl, sulfonyl or imino, and the ring 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, (14C) alkylthionyl and (1-4C) alkylsulfonyl, and wherein the ring may be substituted with (1-4C) alkylene-dioxy; their isomers, tautomers and their pharmaceutically acceptable salts. 109 2. The heterocycle of formula I according to claim 1, wherein Q in formula I represents pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl or quinoxalinyl which may be substituted with one, two or three substituents selected from fluoro, chloro, hydroxy, oxo, methyl, ethyl, propyl, trifluoromethyl, 2-fluoroethyl, 2-dimethylaminoethyl, and benzyl; wherein A represents methylene, 1-propenylene or 1-propynylene; X represents an oxy or imino group; Ar represents phenylene-1,3 or 1,4-phenylene which may be optionally substituted with one or two substituents selected from fluoro, chloro, oxy, amino, nitro, ureido, methyl, methoxy, dimethylamino, trifluoromethyl , acetamido, and cyanomethoxy; or Ar represents 3,5-pyridylene or 3,5-pyridazinylene; R ¹ is methyl, ethyl, allyl or 2-propynyl; R and R together form a group of the formula -A-X -A - which, taken together with the carbon atom to which A ² and A ^{3 are} attached, forms a ring having 5 to 7 atoms in the ring in which 2. 3 A and A may be the same or different and each is methylene, ethylene or trimethylene, and X ² is an oxygen atom, and the (group) ring may be substituted with one or two substituents selected from oxy, methyl, ethyl and methoxy; or a pharmaceutically acceptable salt thereof (heterocycle). 3. The heterocycle of formula I according to claim 1, wherein Q in formula I represents 2pyridyl, 3-pyridyl, 3-pyridazinyl, 2-pyrimidinyl 110 or 2-pyrazinyl which may be singly substituted with chloro, oxy, cyano, methyl, methoxy or trifluoromethyl, or Q represents 2-quinolyl, 3-quinolyl, 6-quinolyl, 7-quinolyl, 3-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 3-cinolyl, 2-quinazolinyl, 6-quinazolinyl, 2-quinoxalinyl, 6-quinoxalinyl, 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 be substituted with one or two substituents selected from fluoro, chloro, oxy, oxo, cyano and , methyl, methoxy and trifluoromethyl; A represents methylene, ethylene, trimethylene, 1-propenylene, 2-methylprop-1-enylene or 1-propynylene; X represents an oxy group; Ar represents 1,3-phenylene or 1,4-phenylene which may be substituted with one substituent selected from fluoro, chloro, oxy, amino, nitro, methyl, methoxy, methylthio, methylthionyl, methylsulfonyl, methylamino, dimethylamino, trifluoromethyl, acetamido, cyanomethoxy and carbamoylmethoxy, or Ar represents 2,3-, 2,5-, 3,5 or 2,6-pyridylene or 4,6-pyrimidinylene, which may not necessarily have one; a substituent selected from chlorine, methyl and methoxy; R ¹ represents methyl, ethyl, allyl or 2-propynyl; 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 and A are attached form a ring having 4 to 7 atoms in the ring in which A ² and A ³ may be the same or different and each is methylene, ethylene or trimethylene or tetramethylene, and X is oxygen, thio, thionyl or sulfonyl, and the (group) ring may be substituted by an oxy, methyl, 111 methoxy, ethoxy, methylthio, methylthionyl, methysulfonyl and methylenedioxy groups; or a pharmaceutically acceptable salt thereof (heterocycle). A process for the preparation of a heterocycle of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises: (a) a compound of formula II OR (II), Alkylation of HX-Ar-C-R 1 with a compound of formula QAZ wherein Z is a substituted group in the presence of an appropriate reagent; provided that when Q, Ar, R ¹ , or R ² is amino, imino, alkylamino, hydroxy or carboxy, any amino, imino, alkylamino or carboxyl group is protected with a conventional protecting group and any which hydroxy group may be protected by a conventional protecting group, or any hydroxy group does not need protection; followed by removal of any undesired protecting group in Q, Ar, R ¹ , R ² by generally acceptable means; b) a compound of formula V OH I Alkylation of Q - A - X - Ar - C - R ² or R (V) in the presence of a corresponding base with a compound of formula R ⁷ -Z wherein R ¹ and Z have the meanings given above, provided that when Q , X, 112 With, R ² or R ³ is amino, imino, alkylamino, hydroxy or carboxyl group, any amino, imino, alkylamino, hydroxy or carboxyl group is protected by a conventional protecting group, followed by removal of any 2 3 unwanted protecting group from Q, X, Ar, R or R ways; c) for the preparation of compounds of formula I wherein A is a (3-6C) -alkynylene group, a coupling reaction is conducted in the presence of an appropriate organometallic catalyst, on a heterocyclic compound of formula QZ wherein Q has the meanings defined above and Z is a halide. , with ethynyl of formula VI OR (VI), ξ - A ¹ - X - Ar - C - R ² A compound of Formula 12 wherein A is (1-4C) alkylene and X, Ar, R, R and R are as defined above; d) for the preparation of compounds of formula I wherein A has an alkylthionyl or alkylsulfonyl substituent wherein X is a thionyl or sulfonyl group, or wherein R ² and R ³ together form a group of formula A ² X ² -A ³ has one or two alkylthionyl or alkylsulfonyl groups and X ² is a thionyl or sulfonyl group, a compound of formula I wherein A is an alkylthio substituent, or wherein R and R together form a group of the formula -A ² -X ² -A ³ - which has one or two alkylthio groups, or in which X ² is a thio group; e) acylating the compound of formula I wherein Ar is substituted with amino to obtain those compounds of formula I wherein Ar is substituted with an alkanoylamino substituent; 113 f) acylating a compound of formula I wherein R ¹ is hydrogen to obtain those compounds of formula I wherein R ¹ is alkanoyl or benzoyl optionally substituted as defined herein; g) reduction of the corresponding compound wherein R ¹ is hydrogen to form compounds of formula I wherein A is alkenylene or R ¹ is alkenyl; h) for the preparation of compounds of formula I wherein Q has an alkyl or substituted alkyl substituent on an available nitrogen atom, or wherein Ar has an alkoxy or substituted alkoxy substituent, carries a compound of formula I wherein Q has a hydrogen atom at alkylating a specified available nitrogen atom or wherein Ar is substituted with an oxy substituent; or i) reduction of a compound of formula I wherein Q or Ar is a nitro substituent to give compounds of formula I wherein Q or Ar is substituted with an amino; and when required by treating a compound of the formula with a pharmaceutically acceptable salt thereof, it can be obtained by treating the compound with an appropriate acid or base using a generally accepted methodology. 5. A pharmaceutical composition comprising a heterocycle of formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, together with a pharmaceutically acceptable diluent or carrier.