SK281507B6 - USE OF BENZOPYRAN ANALOGUE, BENZOPYRAN ANALOGUE, METHODS OF PREPARATION AND PHARMACEUTICAL COMPOSITION WITH THEIR CONTENT - Google Patents

Abstract

Disclosed is the use of benzopyran analogs of formula (I) wherein X, Y, R 2, R 3, R 4, R 5, R 6, R 7, R 8 and R 9 have the characteristic meanings set forth in the specification and the pharmaceutically acceptable salts thereof. These compounds are useful in the treatment and / or prophylaxis of anxiety and / or mania, and / or depression, and / or addictive drug withdrawal effects and / or disorders that can be treated and / or prevented with anticonvulsant agents. Also described are compounds of formulas (Ia), (Ib), (Ic), and (Id), the variables of which are given in the description and are defined in relation to formula (I), as well as their preparation and pharmaceutical composition thereof. obsahom.ŕ

Description

Technical field

The invention relates to novel benzopyran compounds, processes for their preparation and use in medicine.

BACKGROUND OF THE INVENTION

Published European patent application no. 0126311 discloses substituted benzopyran compounds that lower blood pressure, including 6-acetyl-trans-4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.

Also EP-A-0 376 524, EP-A-0 205 292, EP-A-0 250 077, EP-A-0 093 535, EP-A-0 150 202, EP-A-0 076 075 and WO No. 89/05808 (Beecham Group plc) discloses certain benzopyran derivatives having antihypertensive activity.

EP-A-0 350 805 (Biersdorf), EP-A-0 277 611, EP-A-0 277 612, EP-A-0 337 179 and EP-A-0 355 565 (Hoechst Aktiengesellschaft); and EP-A-0 466 131 (Nissan Chemical (I) Industries Ltd) also disclose certain benzopyran derivatives which are believed to have antihypertensive activity.

EP-A-0 430 621 and EP-A-0 385 584 (Beecham Group plc) describe the distinction of certain intermediates useful in the preparation of the compounds described in said patent applications.

EP-A-0 194 884 (E. Lilly) discloses certain amino-substituted benzopyran derivatives having anticonvulsant activity.

It has now surprisingly been found that certain compounds of formula (I) have anxiolytic and anticonvulsant activity and are believed to be useful in the treatment or prevention of mania, depression and addictive withdrawal effects.

SUMMARY OF THE INVENTION

The invention provides the use of the benzopyran anologues of formula (I)

where:

either Y is N and R ² is hydrogen, or Y is CR ¹ wherein:

either one of R ¹ and R ² is hydrogen and the other is selected from hydrogen C ₃ . _g cycloalkyl, Q ^ alkyl optionally interrupted by oxygen or substituted with hydroxy, C _d6 alkoxy or substituted aminocarbonyl, C ₁₆ alkylcarbonyl, C] alkoxycarbonyl, C _{first 6} alkylcarbonyloxy, C ₁₆ alkoxy, C]. ₆ alkylhydroxyalkyl-, nitro, cyano, halo, trifluoromethyl, trifluoromethoxy, CF ₃ S, or a group CF ₃ -A-, where A is -CF _2, -CO-, -CH ₂ - or CH (OH), trifluoromethoxy, C ^ alkylsulfinyl , Ci. C _1-6 alkylsulfonyl, C _1-6 alkoxysulfinyl, C _1-6 alkoxysulfonyl, aryl, aryl C ₃ . ₈ -cycloalkyl. heteroaryl, arylcarbonyl, heteroarylcarbonyl, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl, wherein the aromatic ring is optionally substituted, C _1-6 alkylcarbonylamino, C _1-6 alkyl. _C1-6 alkoxycarbonylamino, C1-6alkylthiocarbonyl, C1-6alkylthio; ₆ alkoxy-thiocarbonyl, C _K6 alkyl-thiocarbonyloxy, l-mercaptoC _{second 7} alkyl, formyl, or aminosulfmyl, aminosulphonyl or aminocarbonyl, aminocarbonylalkyl, any amino group being optionally substituted with one or two a C ₆ alkyl Item PINA, or C ^ alkylsulfinylamino, C ,. _{C 1-6} alkylsulfonylamino, C 1-6 alkoxysulfinylamino or C _1-6 alkylsulfonylamino; ₆ alkoxysulfonylamino, or ethylenyl terminally substituted with C 1-6 alkylcarbonyl, nitro or cyano, or -C (C _1-6 alkyl) NOH or -C (C _1-6 alkyl) NNH ₂ or one of R ¹ and R ² is nitro, cyano or C 1-6 alkylcarbonyl and the other is methoxy or amino optionally substituted with one or two C 1-6 alkyl. C ₆ alkyl or C 1-4 alkanoyl;

one of R ³ and R ⁴ is H or CM alkyl and the other is C | .4 alkyl, or R ³ and R ⁴ together are C 2. ₅ polymethylene;

R ⁵ is C 1-6 alkylcarbonyloxy, benzoyloxy, ONO 2, benzyloxy, phenyloxy or C 1-6 alkoxy and R ⁶ and R ⁹ are hydrogen or R ⁵ is hydroxy and R ⁶ is hydrogen or C 1-2 alkyl and R ⁹ is hydrogen; R ⁷ is mono-, di-, tri-, tetra-, or pentafluorophenyl;

R ⁸ is hydrogen or C 1-6 alkyl; R ⁸ -N-CO-R ⁷ group being trans to the ^R5 group; and X is oxygen or NR ¹⁰ , wherein R ¹⁰ is hydrogen or C 1-4 alkyl, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment and / or prevention of anxiety and / or mania, and / or depression, and / or withdrawal effects addictive substances and / or disorders that can be treated and / or prevented by anticonvulsant agents.

Preferred compounds for use herein are those compounds of formula (I) selected from the group consisting of: trans-6-cyano-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzovlamino) 2H-1-benzopyran-3-ol, (Example 5), trans-6-chloro-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylamino) 2H-1-benzopyran-3-ol, (Example 6), trans-6-trifluoromethyl-4 -14 -fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 7), trans-6-cyano-4- (4-fluorobenzoylmethylamino) -3,4-dihydro-2,2 -dimethyl-2H-1-benzopyran-3-ol, (Example 8), trans-6-ethylcarbonyl-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylamino) 2H-1-benzopyran-3-ol (Example 9), trans-6-ethylcarbonyl-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylmethylamino) 2H-1-benzopyran-3-ol, (Example 10), trans-6- quano-3,4-dihydro-4- (4-fluorobenzoyl) amino) -2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 12), trans -4- (4-fluorobenzoylamino) -3,4-dihydro-2,2- dimethyl-7-nitro-2H-1-benzopyran-3-ol, (Example 13), trans-6-acetyl-4- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 18), trans-6-acetyl-4R- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl- 2H-1-benzopyran-3S-ol, (Example 19), trans-6-acetyl-4S- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol (Example 20), trans-6-cyano-4S- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, (Example 25), trans-6-cyano-4 - (4-fluorobenzoylamino) -3,4-dihydro-2,2,3-trimethyl-2H-1-benzopyran-3-ol, (Example 26), trans -4- (4-fluorobenzoylamino) -3,4- dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran-3-ol, (Example 27), trans -4- (4-fluorobenzoylamino) -3,4-dihydro-6-methoxycarbonyl-2,2 -dimethyl-2H-1-benzopyran-3-ol, (Example 30), trans-6-fluoro-4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran- 3-ol, (Example 34), trans-4- (4-fluoro-benzylmethylamino) -6-trifluoromethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 42), trans-4 - (4-fluorobenzoylamino) -3,4-dihydro-6-iodo-2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 47), and trans-6-aminocarbonomethyl-4- [4-fluorobenzoviaminol-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 49), or a pharmaceutically acceptable salt thereof.

The present invention also provides the benzopyran analogues of formula (Ia) or pharmaceutically acceptable salts thereof

(Ia) wherein the variables Y, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ and X are as defined in claim 1 in relation to formula (I) and R ⁷ is 2- or 3 -fluorophenyl or R ⁷ is 2,4- or 3,4-difluorophenyl.

Preferred compounds of formula (Ia) or pharmaceutically acceptable salts thereof are: trans-6-cyano-3,4-dihydro-2,2-dimethyl-4- (3-fluorobenzamino) 2H-1-benzopyran-3-ol, (Example 1) trans-6-cyano-3,4-dihydro-2,2-dimethyl-4- (2-fluorobenzoylamino) 2H-1-benzopyran-3-ol (Example 2) trans-6-trifluoromethoxy-3,4-dihydro-2,2-dimethyl -4- (3-fluorobenzoylamino) 2H-1-benzopyran-3-ol, (Example 3), trans-6-cyano-4S- (3-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran- 3R-ol, (Example 21), trans-6-cyano-4R- (3-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol, (Example 22), trans-6-cyano-4S - ('2-fluorobenzovlamino') - 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, (Example 24), trans-6-cyano-4S-12,4 -difluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, (Example 28), trans-6-acetyl-4- [3- (3-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H) -1-benzopyran-3-ol, (Example 31), trans -4- (2-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-a] -c] pyridin-3-ol, (Example 38), trans -4- (3-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3- ol, (Example 39), trans-6-cyano-4- (3,4-difluorobenzoylmethylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 41) and trans-6-kvano-4S (3,4-difluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, (Example 44), or a pharmaceutically acceptable salt thereof.

A second group of compounds of the present invention are the benzopyran analogs of formula (Ib) or pharmaceutically acceptable salts thereof

(Ib) wherein the variables R ^3, R ^4, R ^5, R ^s, R ^7, R ^8, R ⁹ and X are as defined in Claim 1 in relation to formula (I) and Y is CR ^1, wherein R ¹ and R ² are both hydrogen or one of ^R1 and ^R2 is trifluoromethoxy, C ₁₆ alkyl optionally interrupted by oxygen or substituted with hydroxy, C _{first 6-} alkoxy or substituted aminocarbonyl, CF ₃ A, wherein A CF ₂ , -CO-, CH ₂ ; or CH (OH), arylsulfonyl, arylC ₃ . ₈ cycloalkyl, heteroaryl, alkoxy _w arylcarbonyl, heteroarylcarbonyl arylsulfmyl, heteroarylsulfinyl, heteroaiylsulfonyl in which any aromatic moiety is optionally substituted, and R is hydrogen expensive.

Preferred compounds of formula (Ib) or pharmaceutically acceptable salts thereof are: trans-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzovlamino) 2H-1-benzopyran-3-ol, (Example 4), trans-4- ( 4-Fluorobenzoylamino-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran-3-ol, (Example 14), trans-6-ethyl-4- (4-fluorobenzoylamino) -3,4-dihydro-2.2 -dimethyl-2H-1-benzopyran-3-ol, (Example 15), trans-6-ethyl-4- (4-fluorobenzylethylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 16), trans -4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3-ol, (Example 17), trans-6-ethyl-4 -4- (fluorobenzoylmethylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 23), trans -4- (4-fluorobenzovlaminol-6-dentafluoroethyl-3,4-dihydro-2), 2-dimethyl-2H-1-benzopyran-3-ol, (Example 29), trans-4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-1-benzopyran-3-ol, (Example 32), trans -4- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-6-phenyl-2H-1-benzopyran-3 ol, (Example 33), trans-6-Ethyl-4S- ^{(4-fluórbenzovlamino,)} -3,4-dihydro-2,2-dimethyl-2H-benzopyran-3R-ol (Example 35), trans-4R- (4-fluorobenzovlamino) -3,4-dihydro-6- (1-hydroxyethyl) -2,2-dimethyl-2H-1-benzopyran-3S-ol, (Example 36), trans -4S-14-fluorobenzovlamino) -3,4-dihydro-6- (1-hydroxyethyl) -2,2-dimethyl-2H-1-benzopyran-3R-ol, (add. 37), trans -4- (4-fluorobenzoylmethylamino) -3,4-dihydro- 2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 43), trans-6-tert-butyl-4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1- benzopyran-3-ol, (Example 46), trans -4- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-6-cyclopentyl-2H-1-benzopyran-3-ol, (Example 48), and trans -4- (4-fluorobenzovlamino) -3,4-dihydro-6-methoxy-2,2-dimethyl-2H-1-benzopyran-3-ol, (Example 50), or a pharmaceutically acceptable salt thereof.

The present invention also provides benzopyran analogs of formula (Ic) or pharmaceutically acceptable salts thereof

(Ic).

wherein the variables R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and X are as defined in claim 1 in relation to formula (I) and Y is N and R ² is hydrogen.

Preferred compounds of formula (Ic) or a pharmaceutically acceptable salt thereof according to claim 7 are: trans-4- (2-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridine-3- ol, (Example 38) trans -4- ('3-fluorobenzovlamino') - 3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3-ol, (Example 39) trans-4- 4-Fluorobenzovinolin-3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3-ol (Example 40), or a pharmaceutically acceptable salt thereof.

A fourth group of the present invention are the benzopyran analogs of formula (1d) or pharmaceutically acceptable salts thereof

D .MZYXR.

wherein the variables Y, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined in claim 1 in relation to formula (I) and X is NR ¹⁰ wherein R ¹⁰ is hydrogen or C 1-6 alkyl.

A preferred compound of formula (1d) or a pharmaceutically acceptable salt thereof is: trans-6-cyano-4- (4-fluorobenzovlamino) -2,2-dimethyl-1,2,3,4-tetrahydroquinolin-3-ol, (Example 45) or pharmaceutically acceptable salts thereof.

A process for preparing benzopyran analogs of formula (Ib) or pharmaceutically acceptable salts thereof is to acylate a compound of formula (IIb):

wherein R ¹ 'and R ² ' are both hydrogen or one R ¹ and R ² is trifluoromethoxy, C 1. ₆ alkyl optionally interrupted by oxygen or substituted with hydroxy, C _w alkoxy or substituted aminocarbonyl, CF ₃ A, wherein A is CF _2, -CO-, CH _2; or CH (OH), arylsulfonyl, arylC _3-8 cycloalkyl, C _1-6 alkoxy heteroaryl arylcarbonyl, heteroarylcarbonyl arylsulfinyl, heteroarylsulfinyl, heteroarylsulfonyl, wherein any aromatic group is optionally substituted and the other R is hydrogen or a group convertible to any of said groups; R ⁵ 'is R ⁵ as defined in formula (I) and R ³ , R ⁴ , R ⁶ , R ⁸ , R ⁹ and X are as defined in formula (I), the group R ⁸ NH is in the trans position to the group R ⁵ ', with acylating agent of formula (IIIb):

R ⁷ CO 1 (III b), wherein R ⁷ is as defined in formula (I) and L 1 is a leaving group; then optionally or if necessary, and in an appropriate order, one of the groups R ¹ ', R ² ' and R ⁵ 'is converted to R ¹ , R ² and R ⁵ , followed by an intermediate conversion of R ⁸ if hydrogen is C |. ₆ alkyl, and the enantiomers separated, forming a pharmaceutically acceptable salt or solvate thereof.

The essence of the process for preparing the benzopyran analogs of formula (1c) and their pharmaceutically acceptable salts is by acylating the compound of formula (IIc):

wherein Y is N, R ⁵ 'is R ⁵ as defined in formula (I) or a group convertible to R ⁵ and R ² is hydrogen or a group convertible to hydrogen, R ³ , R ⁴ , R ⁶ , R ⁸ , R ⁹ and X are defined in relation to formula (I), the group R ⁸ NH is in the trans position relative to the group R ⁵ ', with a compound of formula (IIIb): R ⁷ COL' (IIIb) where R ⁷ is as defined in formula (I) and L 1 is a leaving group, then optionally or, if appropriate, and in an appropriate order, the conversion of any one of R ¹ ', R ² ' and R ⁵ 'into R ¹ , R ² and R ⁵ , and intermediate R ⁸ , if hydrogen, to C 1-4 alkyl, then the enantiomers are separated to form a pharmaceutically acceptable salt or solvate.

A process for preparing benzopyran analogs of formula (Id) or pharmaceutically acceptable salts thereof is by acylating a compound of formula (Ild):

R.NH

W.

wherein X 'is NR ¹⁰ ', wherein R ¹⁰ 'is hydrogen or C 1-6. ₆ alkyl or a group which may be convertible thereto, Y ', ^R2' and ^R5 'are Y, ^R2 and ^R5 are as defined in formula (I), or a group that may be convertible thereto, and R ³ , R ⁴ , R ⁶ , R ⁸ and R ⁹ are as defined in formula (I), the group R ⁸ NH is in the trans position relative to the group R ⁵ ', with an acylating agent of formula (IIIb):

R'COL ¹ (IIIb), wherein R ⁷ is as defined in formula (I) and L ¹ is a leaving group; then optionally or, if appropriate, and in an appropriate order, followed by the conversion of any of Y ', R ¹⁰ ', R ^2, or R ⁵ 'into Y, R ¹⁰ , R ² or R ⁵ intermediate R ⁸ , if hydrogen into C 1-4 alkyl, separating the enantiomers and forming a pharmaceutically acceptable salt or solvate.

Pharmaceutical composition for use in the treatment and / or profilaxia of anxiety, and / or mania, and / or depression, and / or addictive drug withdrawal effects and / or disorders that can be treated and / or preventable anticonvulsant agents include an effective amount of a benzopyran analog of Formula (Ia) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Pharmaceutical composition for use in the treatment and / or profilaxia of anxiety, and / or mania, and / or depression, and / or addictive drug withdrawal effects and / or disorders that can be treated and / or preventable anticonvulsant agents include an effective amount of a benzopyran analog of formula (1b) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Pharmaceutical composition for use in the treatment and / or profilaxia of anxiety, and / or mania, and / or depression, and / or addictive drug withdrawal effects and / or disorders that can be treated and / or preventable anticonvulsant agents include an effective amount of a benzopyran analog of Formula (1c) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Pharmaceutical composition for use in the treatment and / or profilaxia of anxiety, and / or mania, and / or depression, and / or addictive withdrawal effects and / or disorders that can be treated and / or preventable anticonvulsant agents include an effective amount of a benzopyran analog of Formula (Id), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Preferred is a compound of formula (I) wherein R ³ and R ⁴ are both methyl or a pharmaceutically acceptable salt thereof, or wherein R ⁵ is hydroxy and R ⁶ and R ⁹ are hydrogen, or a pharmaceutically acceptable salt thereof.

Also preferred are compounds of formula (I) wherein X is oxygen, or a pharmaceutically acceptable salt thereof.

Other preferred compounds of formula (1) are those wherein Y is R ¹ and R ¹ is cyano, methoxy, trifluoromethoxy, chloro, trifluoromethyl, ethylcarbonyl, acetyl, hydrogen, methyl, ethyl, isopropyl, tert-butyl, nitro, C 2 F 5, methoxycarbonyl , phenylsulfonyl, phenyl, fluoro, iodo, cyclopentyl, aminocarbonylmethyl and 1-hydroxyethyl, and R ² is hydrogen, or a pharmaceutically acceptable salt thereof.

Most preferred are those wherein R ¹ is cyano, ethyl or acetyl, and R ² is hydrogen, and wherein R ⁷ is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl or 3,4-difluorophenyl, wherein R ⁸ is hydrogen, methyl or ethyl, or a pharmaceutically acceptable salt thereof.

Examples of suitable R ¹ substituents include cyano, methoxy, trifluoromethoxy, chloro, trifluoromethyl, ethylcarbonyl, acetyl, hydrogen, methyl, ethyl, isopropyl, tert-butyl, nitro, C ₂ F ₅ , methoxycarbonyl, phenylsulfonyl, phenyl, fluoro, iodo, cyclopentyl , aminocarbonylmethyl and 1-hydroxyethyl. Preferably R ^{1 is} cyano, acetyl or ethyl.

R ³ and R ⁴ are both preferably methyl.

R ⁵ is preferably hydroxyl and R ⁶ and R ⁹ are hydrogen or R ⁵ is hydroxyl, R ⁶ is C 1-6 alkyl and R ⁹ is hydrogen, more preferably R ⁵ is hydroxyl and R ⁶ and R ⁹ are hydrogen.

It should be noted that the term fluorophenyl 1 in relation to R ⁷ includes phenyl having 1, 2, 3, 4, or 5 fluorine groups attached to the phenyl ring. Preferably, 1 or 2 fluoro groups are attached to the phenyl ring, and most preferably 1 fluoro group is attached to the ring.

The fluoro group or groups may be in any position on the phenyl ring, preferably in the case of monofluorophenyl the fluorine is in the 3 or 4 position.

In the case of difluorophenyl, fluoro substituents are preferably in the 2,4 or 3,4-position.

R ⁸ is preferably hydrogen or C _1-4 alkyl, more preferably R ⁸ is hydrogen, methyl or ethyl.

X is preferably oxygen.

It should be noted that the compounds of formula (I) may have chiral carbon atoms in the 2, 3 and 4 positions and therefore may exist as enantiomers. The present invention relates to each enantiomer and mixtures thereof including racemates. The compounds of formula (1) preferably exist as 4S, 3R enantiomers.

It should also be noted that certain R ¹ substituents also have chiral centers and therefore may exist as enantiomers. The present invention relates to each enantiomer and mixtures thereof including racemates.

Administration of the agent to a mammal may be oral or parenteral.

The effective amount for the treatment of the disorders described herein will depend upon the present invention. from conventional factors such as the nature and degree of the disorder being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount ranging from 2 to 100 mg, such as 2, 5, 10, 20, 30.40, 50 and 100 mg of the active ingredient. Unit doses will normally be administered once or more than once a day, for example 2, 3, 4, 5 or 6 times, more usually 2 to 4 times per day, so that the total daily dose is normally in the range of 70 kg adult from 1 up to 1000 mg, for example 50 to 500 mg, t. j. in the range of about 0.01 to 50 mg / kg / day, more usually 0.1 to 50 mg / kg / day, for example 1 to 50 mg / kg / day.

It is highly preferred that the compound of formula (I) is administered in the form of a unit dose of the composition, for example, as a unit dose oral, rectal, topical or parental (especially intravenous).

Such compositions are prepared by admixture and are suitably formulated for oral or parenteral administration, and may themselves be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, premixed powders, injectable and infusion solutions or suspensions or suppositories. . Orally administrable compositions, especially shaped oral compositions, are preferred because they are more suitable for general use.

Tablets and capsules for oral administration are usually provided in a unit dose, and contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavors, and wetting agents. The tablets may be coated according to methods known in the art.

Suitable fillers include cellulose, mannitol, lactose and other similar reagents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. A suitable pharmaceutically acceptable wetting agent includes sodium lauryl sulfate.

These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations can be used to disperse the active ingredient in such mixtures using large amounts of fillers. Such operations are conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, emulsions, syrups, or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle prior to administration. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydro-benzoate or sorbic acid and, if desired, flavoring and coloring agents.

Oral formulations also include conventional delayed release formulations, such as enteric coated tablets or granules.

For parenteral administration, liquid unit doses are prepared containing the agent and a sterile vehicle. The agent may be either suspended or dissolved depending on the vehicle and concentration. Parenteral solutions are normally prepared by dissolving the substance in a vehicle and filtered and sterilized prior to filling into suitable vials or ampoules and sealed. Adjuvants such as local anesthetics, preservatives and buffering agents, also dissolved in the vehicle, are preferred. To increase stability, the mixture may be frozen after filling into a vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the substance is suspended in the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide prior to suspension in the sterile vehicle. Preferably, surfactants or wetting agents are included in the composition to facilitate uniform distribution of the compound of the invention.

As is common practice, the compositions will usually be accompanied by written or printed instructions for use in therapy.

In general, the compounds of formula (I) may be prepared by processes generally described or analogous to those described in EP-0126311, EP-0376524, EP-205292, EP-0250077, EP-0093535, EP-0150202, EP-0076075 , WO / 89/05808, EP-0350805, EP-0277611, EP-0277612, EP-0337179, EP-0355565 and EP-0466131.

The invention also provides a process for the preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof, which comprises acylating a compound of formula (II '):

D NU

wherein Y ', R ² ' and R ⁵ 'are the desired variables Y, R ² and R ⁵ as defined in formula (I) or groups that can be converted to them and R ³ , R ⁴ , R ⁶ , R ⁸ , R ⁹ and X are the desired variables as defined in formula (I), the group R ⁸ NH is in the trans position relative to the group R ⁵ , with an acylating agent of formula (IIIb):

R ⁷ CO 1 (III b), wherein R ⁷ is as defined in formula (I) and L ¹ is a leaving group; then optionally or, if necessary, and in an appropriate order, one of the groups R ¹ ', R ² ' and R ⁵ 'is converted to R ¹ , R ² and R ⁵ , and / or followed by an intermediate R ⁸ if hydrogen is on C 1-6 alkyl, separating the enantiomers and forming a pharmaceutically acceptable salt or solvate.

The invention also provides a process for the preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof, which comprises acylating a compound of formula (IIa):

R MU

wherein Y ', R ² ' and R ⁵ 'are Y, R ² and R ⁵ as defined in formula (I) or groups which may be converted to them and R ³ , R ⁴ , R ⁶ , R ⁸ , R ⁹ and X are as defined in formula (I), the group R ⁸ NH is in the trans position relative to the group R ⁵ ', with an acylating agent of formula (IIIa):

R ^7a COL '(IHa) wherein R ^7a is 2- or 3-fluorophenyl or 2,4- or 3,4-difluorophenyl and L ¹ is a leaving group; thereafter optionally or as necessary and in any appropriate order converting any Y ', R ^2' and R ⁵ 'to Y, ^R2 and ^R5 respectively, interconverting ^R8 when hydrogen to _C-alkyl, separating any enantiomers, and forming a pharmaceutically acceptable salt or solvate.

The present invention also provides a process for the preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof, which comprises acylating a compound of formula (IIb):

wherein R ¹ 'and R ² ' are both hydrogen or one of R ¹ and R ² is trifluoromethoxy, C 1-6. ₆ alkyl optionally interrupted with oxygen or substituted with hydroxy, C ^ alkoxy or substituted aminocarbonyl, _CF3 A- (where A is -CF ₂ -, - CO-, _-CH2) or CH (OH)), aryl, arylsulfonyl, arylC ₃ . _with cycloalkyl, C ₁ . ₆ alkoxy, heteroaryl, arylcarbonyl, heteroarylcarbonyl, arylsulfinyl, heteroarylsulfinyl, heteroarylsulfonyl, in which the aromatic group is optionally substituted and the other is hydrogen, or groups which can be converted to them; R ⁵ 'is R ⁵ as defined in formula (I) or a group which may be converted thereto and R ³ , R ⁴ , R ⁶ , R ⁸ , R ⁹ and X are as defined in formula (I), a group R ⁸ NH is in trans position relative to R ⁵ ', with the compound of formula (IIIb):

R ⁷ CO 1 (III b) wherein R ⁷ is as defined in formula (I) and L ¹ is a group leaving; then optionally or, if necessary, and in an appropriate order, converting any one of R ¹ ', R ² ' and R ⁵ 'to R ¹ , R ² and R ⁵ , of the intermediate R ⁸ when hydrogen is C 1. _And isolating the enantiomers and forming a pharmaceutically acceptable salt or solvate.

The present invention also provides a process for preparing compounds of formula (Ic) or a pharmaceutically acceptable salt thereof, which comprises acylating a compound of formula (IIc):

wherein Y is N, R ⁵¹ is R ⁵ as defined in relation to formula (I) or a group that can be converted to R ⁵ and R ² is hydrogen or a group that can be converted to hydrogen, R ⁶ , R ³ , R ⁴ , R ⁸ , R ⁹ and X are as defined in formula (I), the group R ⁸ NH is in the trans position relative to the group R ⁵ ', with an acylating agent of formula (IIIb):

R'COL ¹ (IIIb) wherein R ⁷ is as defined in formula (I) and L 1 is a group leaving; then optionally or, if appropriate, and in an appropriate order, converting any one of R ² 'or R ⁵ ' to hydrogen or R ⁵ , the intermediate R ⁸ if hydrogen to C 1-4 alkyl, separating the enantiomers and forming a pharmaceutically acceptable salt or solvate .

The present invention also provides a process for the preparation of compounds of formula (I) or pharmaceutically acceptable salts thereof, which comprises acylating a compound of formula (Ild):

wherein X 'is NR ¹⁰ ', wherein R ¹⁰ 'is hydrogen or C _1-6 alkyl or a group which may be converted thereto, Y', R ² 'and R ⁵ ' are Y, R ² and R ⁵ such as as defined in formula (I), or groups which can be converted thereto, and R ³ , R ⁴ , R ⁶ , R ⁸ and R ⁹ are as defined in formula (I), the group R ⁸ NH is in the trans position relative to the group R ⁵ ', with acylating agent of formula (IIIb):

R ⁷ CO 1 (III b) wherein R ⁷ is as defined in formula (I) and L ¹ is a leaving group; then optionally or, if necessary, and in an appropriate order, converts any of the groups Y ', R ¹⁰ ', R ² 'or R ⁵ ' to Y, R ¹⁰ , R ² or R ⁵ , of intermediate R ⁸ when hydrogen is on C 1-6 alkyl, separation of enantiomers and formation of a pharmaceutically acceptable salt or solvate.

Examples of suitable leaving groups L ¹ include those set forth in said patents, in particular EP-AO 126 311 or are conventional in the art.

The reaction conditions that may be used to carry out the above reactions are as described or analogous to those described in the aforementioned patents, in particular EP-A-O 126 311.

In particular, a leaving group (L ') is a group that is exchangeable by a primary or secondary amine nucleophile. Examples of such a group include C _1-4 alkylcarbonyloxy and halogen such as chloro and bromo. When the leaving group (I ') is any of these examples, the acylating agent of formula (IIIa) or (IIIb) is either an acid anhydride or an acid halide. When it is an acid anhydride, it is preferably a mixed anhydride which can be prepared in situ from an aromatic or heteroaromatic carboxylic acid and an alkyl chlorocarbonate such as ethyl chloroformate.

If the acylating agent of formula (IIIa) or (IIIb) is an acid anhydride, the acylation of the compound of formula (IIa), (IIb), (IIc) or (IIId) is preferably performed using the anhydride as solvent in the presence of an acid acceptor such as sodium acetate .

If the acylating agent of formula (IIIa) or (IIIb) is an acid halide, the acylation of the compound of formula (IIa), (IIb), (IIc) or (IIId) is preferably carried out in a non-aqueous medium such as dichloromethane in the presence of an acid acceptor, such as triethylamine, trimethylamine or pyridine.

Examples of suitable groups that can be converted to Y (or R ¹ ), R ² and R ⁵ include the groups described in said patents or which are conventional in the art.

Intermediates of R ⁸ , when hydrogen, to C _1-6 alkyl can be carried out using conventional alkylation procedures, for example using alkyl halides in the presence of a base.

It will be appreciated that the racemates of formula (I) may be resolved, or enantiomerically purified compounds of formula (I) may be prepared using procedures conventional in the art, and in particular using the procedures described in EP-0430631 and EP-0355584.

Suitably, the procedures described in or analogous to those described in Example 35 herein can be used to prepare specific enantiomers of the compounds of formula (I).

Compounds of formula (I), (IIIa), (IIb), (IIc) and (IId) can be prepared from readily available starting materials using the procedures described or analogous to those described in said patents.

Compounds of formulas (IIIa) and (IIIb) are either commercially available or can be prepared according to conventional procedures known in the art of organic chemistry.

Compounds of formulas (I), (IIIa), (IIb), (IIc) or (IId) form one aspect of the invention.

Compounds of formula (I) wherein R ⁵ is hydroxyl, R ⁶ is C _1-2 alkyl and R ⁹ is hydrogen can be prepared according to the procedures described in R. Gericke et al. J. Med. Chem. Vol. 34, p. 3074 (1991).

The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

SK 281507-6

DETAILED DESCRIPTION OF THE INVENTION

The following examples and pharmaceutical test results illustrate the invention.

The following compounds were prepared by methods analogous to those described in the aforementioned patent publications.

Example 1 trans-6-Cyano-3,4-dihydro-2,2-dimethyl-4- (3-fluorobenzoylamino) 2H-1-benzopyran-3-ol.

Mp 193-194 ° C.

Example 2 trans-6-Cyano-3,4-dihydro-2,2-dimethyl-4- (2-fluorobenzoylamino) 2H-1-benzopyran-3-ol. Mp 163-165 ° C.

Example 3 trans-6-Trifluoromethoxy-3,4-dihydro-2,2-dimethyl-4- (3-fluorobenzoylamino) 2H-1-benzopyran-3-ol. Mp 127-130 ° C.

Example 4 trans-3,4-Dihydro-2,2-dimethyl-4- (4-fluorobenzovlamino) 2H-1-benzopyran-3-ol. Melting point: 174-175 ° C.

EXAMPLE 5 trans-6-Cyano-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylamino) -2H-1-benzopyran-3-ol, mp 229-230 ° C.

3R, 4S isomer (Compound B). Melting point: 224 ° C to 225 ° C.

Example 6 trans-6-Chloro-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylamino) 2H-1-benzopyran-3-ol. Melting point: 177-179 ° C.

Example 7 trans-6-Trifluoromethyl-4- (4-fluorobenzovinyl) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Melting point: 185 ° C to 187 ° C.

Example 8 trans-6-Cyano-4- (4-fluorobenzoylmethylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Melting point 230-234 ° C.

Example 9 trans-6-ethylcarbonyl-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylamino) 2H-1-benzopyran-3-ol. Mp 205-207 ° C.

Example 10 trans-6-Ethylcarbonyl-1-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylmethylamino) 2H-1-benzopyran-3-ol. Mp 210-212 ° C.

EXAMPLE 12 trans-6-Cyano-3,4-dihydro-4- (4-fluorobenzoyl-ethylamino-2,2-dimethyl-2H-1-benzopyran-3-ol) Melting point 172-175 ° C.

Example 13 trans -4- (4-Fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran-3-ol. Mp 231-233 ° C.

Example 14 trans-4- (4-Fluorobenzoylamino) -3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran-3-ol.

Mp 185-186 ° C.

Example 15 trans-6-ethyl-4- [4-fluorobenzoylamino] -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Mp 235-237 ° C.

Example 16 trans-6-ethyl-4- (4-fluorobenzoyl-ethylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Melting point 175 ° C.

Example 17 trans -4- (4-Fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3-ol. Mp 235-236 ° C.

EXAMPLE 18 trans-6-Acetyl-4- (4-fluorobenzoylaminol-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol) Melting point 203 ° C.

Example 19 trans-6-Acetyl-4R- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol. Melting point 162-163 ° C.

Example 20 trans-6-Acetyl-4S- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol. Melting point 164 ° C.

EXAMPLE 21 trans-6-Cyano-4S- (3-fluorobenzoylaminol-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol) Melting point 221 ° C.

Example 22 trans-6-Cyano-4R-3-fluoro-enzoylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol. Mp 221 ° C.

Example 23 trans-6-Ethyl-4- (4-fluorobenzoylmethylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Melting point 162-164 ° C.

Example 24 trans-6-Cyano-4S-η 2 -fluorobenzoylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol. Mp 163-165 ° C.

Example 25 trans-6-Cyano-4S-4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol. Melting point: 224 ° C to 225 ° C.

Example 26 trans-6-Cyano-4- (4-fluorobenzoylamino) -3,4-dihydro-2,2,3-trimethyl-2H-1-benzopyran-3-ol. Mp 218-220 ° C.

Example 27 trans -4- (4-Fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran-3-ol. Mp 197-198 ° C.

Example 28 trans-6-Cyano-4S - (2,4-difluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol. Melting point 175-176 ° C.

Example 29 trans -4- (4-Fluorobenzoylamino) -6-pentafluoroethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Mp 181 ° C.

Example 30 trans -4- (4-Fluorobenzovlamino) -3,4-dihydro-6-methoxycarbonyl-2,2-dimethyl-2H-1-benzopyran-3-ol. Melting point 198 ° C.

Example 31 trans-6-Acetyl-4- (3-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Mp 212 ° C.

Example 32 trans -4- (4-Fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-1-benzopyran-3-ol. Mp 239-240 ° C.

Example 33 trans -4- (4-Fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-6-phenyl-2H-1-benzopyran-3-ol. Mp 164-165 ° C.

Example 34 trans-6-Fluoro-4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Mp 164-165 ° C.

Example 35 trans-6-Ethyl-4S- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol.

(-) - Mandelic acid was used to separate the residue from the decomposition of trans-4-amino-6-ethyl-2,2-dimethyl-chroman-3-ol (to give the 3S, 4R enantiomer - as described in EPA 412 760) from standard partitioning conditions using acetone as a recrystallization solvent. This provided trans-4S-amino-6-ethyl-2,2-dimethyl-chroman-3R-ol D-mandelate.

4S, 3R-Aminoalcohol almond (4.0 g) was dissolved in dichloromethane (250 mL) and triethylamine (3.34 mL) and cooled in an ice bath. To this stirred solution was added 4-fluorobenzoyl chloride (1.7 g) dropwise. After the addition was complete, the reaction mixture was allowed to reach room temperature and was stirred overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (150 mL). This solution was washed with 5% sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. Filtration, evaporation, and recrystallization of the residue from ethyl acetate-hexane gave the title compound of Example 35. Melting point 132-136 ° C. dD / 20 +69.1 (methanol c = 1.0). NMR (CDCl 3) (1.21 (3H, t, J = 8Hz) 1.28 (3H, s) 1.49 (3H, s)

2.88 (2H, q, J = 8Hz)

3.76 (1 H, d, J = 9 Hz)

4.46 (1H, broad s) 5.21 (1H, t, J = 9.8 Hz) 6.41 (1H, d, J = 8 Hz) 6.80 (1H, d, J = 9 Hz) 7.07 (2H, irregular m) 7.17 (2H, t, J = 9Hz) 7.24 (2H, m)

Example 36 trans-4R- (4-Fluorobenzovlamino) -3,4-dihydro-6- (1-hydroxyethyl) -2,2-dimethyl-2H-1-benzopyran-3S-ol. M.p. 132-133 ° C.

Example 37 trans -4S-η 4 -Fluorobenzovlamino-1,3-dihydro-6- (1-hydroxyethyl) -2,2-dimethyl-2H-1-benzopyran-3R-ol. Melting point: 133 ° C to 134 ° C.

Example 38 trans -4,4-Fluoro-benzoamido-3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3-ol. Melting point 254 ° C.

Example 39 trans -4- (3-Fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3-ol. Melting point 259-261 ° C.

Example 40 trans -4- (4-Fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3-ol. Melting point 254-255 ° C.

Example 41 trans-6-Cyano-4- (3,4-difluorobenzoylmethylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Melting point 199 ° C to 200 ° C.

Example 42 trans -4- (4-Fluorobenzylmethylamino) -6-trifluoromethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Melting point 196-197 ° C.

Example 43 trans -4- (4-Fluorobenzoylmethylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Mp 160-161 ° C.

Example 44 trans-6-Cyano-4S- (3,4-difluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol. Melting point 227 ° C.

Example 45 trans-6-Cyano-4- (4-fluorobenzoylamino) -2,2-dimethyl-1,2,3,4-tetrahydroquinolin-3-ol.

Mp 244-248 ° C.

Example 46 trans-6-tert-Butyl-4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Mp 163-166 ° C.

Example 47 trans -4- (4-Fluorobenzovlamino) -3,4-dihydro-6-iodo-2,2-dimethyl-2H-1-benzopyran-3-ol. Mp 204-205 ° C.

Example 48 trans -4- (4-Fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-6-cyclopentyl-2H-1-benzopyran-3-ol. Mp 173-174 ° C.

Example 49 trans-6-Aminocarbonylmethyl-4- (4-fluorobenzamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol. Mp 190 ° C.

SK 281507-6

Example 50 trans -4- (4-Fluorobenzoylamino) -3,4-dihydro-6-methoxy-2,2-dimethyl-2H-1-benzopyran-3-ol. Mp 155-156 ° C.

Pharmacological data

1. Geller-Seifter procedure

Potential anxiolytic properties were evaluated using the Geller-Seifter procedure based on the procedure originally described by Geller and Seifter (1960) in Psychopharmacologia, 1, 482-492. This procedure has been shown to be selective for drugs with anxiolytic properties (Cook and Sepinwall, (1975) "Mechanism of Action of Benzodiazepines" (Costa, E., and Greengard, P., Raven Press, New York, pp. 1-28).

Rats were trained according to a program of varying 30 seconds (VI30) to depress the lever to obtain food reward. The 5 minute VI30 program exercises were alternated with a 2 to 5 minute program (FR5) in which every fifth lever press is followed by the appearance of a food granule associated with a 0.5 second slight foot shock. The total study took approximately 30 minutes. Rats typically responded with high frequencies of lever depression during the VI30 program and with low frequencies of response during the FR5 "conflict" program. Anxiolytic drugs increase the suppressed response rates of rats in a “conflict” program.

Drugs are administered intraperitoneally or orally to groups of 3 to 8 rats 30 to 60 minutes prior to testing.

The results are expressed as percent increase in square root of the total number of lever presses in the FR5 "conflict" program. Square root transformation is needed to standardize data for statistical analysis using parametric methods.

The compound of Example 4 had a significant increase in response in the "conflict" program at 10 mg / kg p. about.

2. MES test

The maximum electroshock seizure (MES) test in rodents is one of the most widely used models of human major epileptic seizure *. In this model, anticonvulsant reagents raise the threshold of electrically induced seizures, while proconvulsants lower the seizure threshold.

method

Mice (male, Charles River, UK CD-1 genus, 25 to 30 g) were randomly assigned to groups of 10 to 20 and given an oral or intraperitoneal dose volume of 10 ml / kg with various doses of the substance (1 to 100 mg / ml). kg) or vehicle. Mice were then subjected to an alternating voltage (0.1 second, 50 Hz, sinusoidal wave) electros shock 30 or 60 minutes post-dose using a buccal and subcutaneous electrode. The mean voltage and standard error required to induce a tonic seizure in 50% (CV ₅₀ ) of the mice in the group was determined by the "up and down" method of Dixon and Mood (1948) ² . Statistical comparisons between vehicle and drug treated groups were made using the method of Litchfield and Wilcoxon (1949) ³ .

In control animals, the CV ₅₀ is typically 40 V to 50 V. Therefore, the first animal in the control group is subjected to a voltage of 45 V. If the tonic seizure does not follow, the voltage for the next mouse is increased. If a tonic convulsion occurs, then the voltage is reduced, and so on, until all animals in the group are tested.

The increase or decrease in the percent CV50 for each group is calculated compared to the control group.

The studies were performed using a Heathkit shock generator with a totally variable shock level control from 0 V to 200 V and the voltage varied in 5 V steps.

Drugs were suspended in 1% methylcellulose.

literature

1. Swinyard, E.A. (1972). Electrically-induced convulsions. (Electrically induced convulsions), in Experimental Models of Epilepsy ed. Purpura, D.P. et al., 433-458, Raven Press, New York.

2. Dixon W.J. and Mood, A.M. (1948). J. Amer. Stat. Assn., 43, 109-1 126.

3. Litchfield, J.T. and Wilcoxon, F. (1949). J. Pharmacol. Exp. Ther. 96.99- 113.

The results

The compounds of Examples 1 to 3, 5, 7, 8, 18, 20, 21, 25, 30, 31, 35 and 37 and Compound X showed a significant increase in CV ₅₀ at 10 mg / kg po

3. X-maze

introduction

The X-Maze of Anxiety (Handley and Mithani, 1984) examines the exploratory response of naïve rats in the vicinity, providing anxiogenic (open arms) and relatively non-anxiogenic (closed arms) spaces. A selective increase in the open arms survey following drug administration is then considered to indicate anxiolytic effects.

method

The X-maze was raised 70 cm above the floor and consisted of two closed arms 45 cm (long) x 15 cm (wide) x 10 cm (high) and two open arms 45 xx 10 x 1 cm arranged so that two arms of each type were against each other. Both arms were marked in two equal sections. Rats were placed in the center of the X-maze and observed for 10 minutes at which time the following parameters were recorded: 1) Number of arm entrances and time spent in (a) open arms, (b) closed arms, (c) at end (d) at the end of the closed arms. 2) Number of sections passed. Fear raised in open arms exceeds fear in closed arms, and rats typically have a clear preference for closed arms. Anxiolytic drugs increase the number of arm entrances and the time spent on the outer half of the open arms, as well as the percentage of arm entrances and the time spent in the fully open arms. These four anxiety rates, as well as the total number of sections passed, were counted for each animal. Drugs were administered intraperitoneally or orally to groups of 6 to 12 rats 30 to 60 minutes prior to testing. Statistical comparisons between vehicle and drug treated groups were made using the Mann-Whitneya U-test (bilateral).

S.L. Handley and S. Mithani, Ar. Pharmacol., 1984 327-5.

The results

The compound of Example 21 caused a significant increase in open arm entrances at 30 mg / kg p. about.

Claims (17)

PATENT CLAIMS 1. Use of benzopyran analogues of formula (I) SK 281507 Β6 (i), where: either Y is N and R ² is hydrogen, or Y is CR ¹ wherein: either one of R ¹ and R ² is hydrogen and the other is selected from hydrogen C 3-8 cycloalkyl, C 1-6 alkyl optionally interrupted by oxygen or substituted with hydroxyl, C 1-6 -alkoxy or substituted aminocarbonyl, C 6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonyloxy, C 1-6 alkoxy, C 1-6 alkylhydroxyalkyl, nitro, cyano, halogen, trifluoromethyl, trifluoromethoxy, CF 3 S or CF 3 -A-, wherein A is -CF 2, -CO-, -CH 2 - or CH (OH), trifluoromethoxy, C 1-6 alkylsulfinyl , C 1-6 alkylsulfonyl, C 1-6 alkoxysulfinyl, C 1-6 alkoxysulfonyl, aryl, aryl C 1-6 cycloalkyl heteroaryl, arylcarbonyl, heteroarylcarbonyl, arylsulfinyl, heteroarylsulfinyl, arylsulfonyl, heteroarylsulfonyl, in which the aromatic nucleus is optionally substituted, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbonylamino, 6alkyl-thiocarbonyl, C 1-6 alkoxy-thiocarbonyl, C 16 alkyl-thiocarbonyloxy, 1-mercaptoC 2-7 alkyl, formyl, or aminosulfinyl, aminosulfonyl or aminocarbonyl, aminocarbonylalkyl, any amino group being optionally substituted one or two C 1-6 alkyl groups, or C 1-6 alkylsulfinylamino, C 1-6 alkylsulfonylamino, C 1-6 alkoxysulfinylamino or C 1-6 alkoxysulfonylamino, or ethylenyl terminally substituted with C 1-6 alkylcarbonyl, nitro or cyano, or -C 1 -C 6 alkyl; | 6alkyl) NNH 2, or one of ^R1 and ^R2 is nitro, cyano or Cb3alkylkarbonyl and the other is methoxy or amino optionally mono- or di-C |, ₆ alkyl or _C2 -7 alkanoyl; one of R ³ and R ⁴ is hydrogen or C 1-4 alkyl and the other is C 1-4 alkyl or R ³ and R ⁴ together are C 2-5 polymethylene; R ⁵ is C _1-6 alkylcarbonyloxy, benzoyloxy, ONO ₂ , benzyloxy, phenyloxy or C _1-6 alkyl; ₆ alkoxy and R ⁶ and R ⁹ are hydrogen or R ⁵ is hydroxy and R ⁶ is hydrogen or C 1-6 alkyl and R ⁹ is hydrogen; R ⁷ is mono-, di-, tri-, tetra-, or pentafluorophenyl; R ⁸ is hydrogen or C 1-4 alkyl; R ⁵ -N-CO-R ⁷ is in the trans position to R ⁵ ; and X is oxygen or NR ¹⁰ , wherein R ¹⁰ is hydrogen or C 1-6 alkyl, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment and / or prevention of anxiety, and / or mania, and / or depression, and / or effects associated with substance withdrawal and / or disorders that can be treated and / or prevented by anticonvulsant agents. Use of benzopyran analogues of general formula (I) according to claim 1, selected from the group consisting of: trans-6-cyano-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylamino) 2H-1-benzopyran-3-ol trans-6-chloro-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylamino) -2H-1-benzopyran-3-ol, trans-6-trifluoromethyl-4- (4-fluorobenzoylamino) - 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans-6-cyano-4- (4-fluorobenzylmethylamino) -3,4-dihydro-2,2-dimethyl-2H-1 - benzopyran-3-ol, trans-6-ethylcarbonyl-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzoylamino) 2H-1-benzopyran-3-ol, trans-6-ethylcarbonyl-3,4-dihydro-2,2-dimethyl- 4- ⁽ 1,4-Fluorobenzoylmethylamino) 2H-1-benzopyran-3-ol, trans-6-cyano-3,4-dihydro-4- (4-fluorobenzyl) lamino-2,2,2-dimethyl-2H-1-benzopyran- 3-ol, trans-4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-7-nitro-2H-1-benzopyran-3-ol, trans-6-acetyl-4R- (4- Fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans-6-acetyl-4S- (4-fluorobenzoylamino) -3,4-di hydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, trans-6-cyano-4S- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran- 3R-ol, trans-6-cyano-4- (4-fluorobenzovoyl) -3,4-dihydro-2,2,3-trimethyl-2H-1-benzopyran-3-ol, trans -4,4-fluorobenzovlamino-1-ol -3,4-dihydro-2,2-dimethyl-6-nitro-2H-1-benzopyran-3-ol, trans -4- (4-fluorobenzovlamino) -3,4-dihydro-6-methoxycarbonyl-2,2-dimethyl-2H-1 -benzopyran-3-ol, trans-6-fluoro-4- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans-4- [4-fluorobenzoylmethylamino] ) -6-Trifluoromethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans -4- (4-fluorobenzovinyl) -3,4-dihydro-6-iodo-2,2-dimethyl -2H-1-benzopyran-3-ol and trans-6-aminocarbonylmethyl-4- (4-fluorobenzoylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, or their pharmaceutically acceptable salts. Benzopyran analogs of formula (Ia) or pharmaceutically acceptable salts thereof wherein the variables Y, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ and X are as defined in claim 1 in relation to formula (I). I) and R ⁷ is 2- or 3-fluorophenyl or R ⁷ is 2,4- or 3,4-difluorophenyl. The benzopyran analogues of formula (Ia) or the pharmaceutically acceptable salts thereof according to claim 3, selected from: trans-6-cyano-3,4-dihydro-2,2-dimethyl-4- (3-fluorobenzovlamino) 2H-1-benzopyran-3 -ol, trans-6-cyano-3,4-dihydro-2,2-dimethyl-4- (2-fluorobenzovlamino) 2H-1-benzopyran-3-ol, trans-6-trifluoromethoxy-3,4-dihydro-2,2- dimethyl-4- (3-fluorobenzoylamino) 2H-1-benzopyran-3-ol, trans-6-cyano-4S-1,3-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran- 3R-ol, trans-6-cyano-4R- (3-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3S-ol, trans-6-cyano-4S- (2-fluorobenzovlamino) -3.4 dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol, trans-6-cyano-4S-1,2,4-difluorobenzovinol-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran -3-R-ol, trans-6-acetyl-4- (3-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans-6-cyano-4- (3 4-difluorobenzoylmethylamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, and trans-6-cyano-4S- (3,4-difluorobenzoylamino) -3,4-dihydro -2,2-dimethyl-2H-1-benzopyran-3R-ol or a pharmaceutically acceptable salt thereof. The benzopyran analogs of formula (1b) or pharmaceutically acceptable salts thereof wherein the variables R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and X are as defined in claim 1 in relation to formula (I) and Y is CR ¹ , wherein R ¹ and R ² are both hydrogen or one of R ¹ and R ² is trifluoromethoxy, C |. ₆ alkyl optionally interrupted by oxygen or substituted with hydroxy, C _{i. 6-} alkoxy or substituted amino carbonyl, CF ₃ A, wherein A CF ₂ , -CO-, CH ₂ ; or CH (OH), arylsulfonyl, arylC ₃ . ₈ cycloalkyl, C _1-6 alkoxy heteroaryl arylcarbonyl, heteroarylcarbonyl arylsulfinyl, heteroarylsulfinyl, heteroarylsulfonyl, wherein any aromatic group is optionally substituted and the other R is hydrogen. 6. A compound according to claim 5 selected from the group consisting of trans-3,4-dihydro-2,2-dimethyl-4- (4-fluorobenzovlamino) 2H-1-benzopyran-3-ol, trans -4- (4-fluorobenzoylamino) -3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran-3-ol, trans-6-ethyl-4- (4-fluorobenzoylamino) -3,4-dihydro-2 2-dimethyl-2H-1-benzopyran-3-ol, trans-6-ethyl-4- (4-fluorobenzoylvvvinyl) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans- 4- (4-Fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-6-isopropyl-2H-1-benzopyran-3-ol trans-6-ethyl-4- (4-fluorobenzoylmethylamino) -3,4-dihydro-2,2 dimethyl-2H-1-benzopyran-3-ol, trans-4- (4-fluorobenzovlamino) -6-pentafluoroethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans- 4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-6-phenylsulfonyl-2H-1-benzopyran-3-ol, trans-4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-6-phenyl- 2H-1-benzopyran-3-ol, trans-6-ethyl-4S- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-b enzopyran-3R-ol, trans-4R- (4-fluorobenzovlamino) -3,4-dihydro-6- (1-hydroxyethyl) -2,2-dimethyl-2H-1-benzopyran-3S-ol, trans-4S -4,4-Fluorobenzovlamino-3,4-dihydro-6- (1-hydroxyethyl) -2,2-dimethyl-2H-1-benzopyran-3R-ol, trans -4- (4-fluorobenzovinylmethylamino) -3,4-dihydro- 2,2-dimethyl-2H-1-benzopyran-3-ol, trans-6-tert-butyl-4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, trans-4- (4-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-6-cyclopentyl-2H-1-benzopyran-3-ol, and trans -4- (4-fluorobenzovlamino) -3,4-dihydro-6-methoxy- 2,2-dimethyl-2H-1-benzopyran-3-ol or a pharmaceutically acceptable salt thereof. 7. Benzopyran analogs of formula (Ic) or pharmaceutically acceptable salts thereof R.-N-CO-R, (Ic), wherein the variables R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and X are as defined in claim 1 in relation to formula (I) and Y is N and ^R2 is hydrogen. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof according to claim 7, selected from: trans-4- (2-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3-ol, trans -4- (3-fluorobenzovlamino) -3,4-dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3-ol, trans -4- (4-fluorobenzovlamino) -3,4- dihydro-2,2-dimethyl-2H-pyrano [3,2-c] pyridin-3-ol or a pharmaceutically acceptable salt thereof. 9. Benzopyran analogs of formula (1d) or pharmaceutically acceptable salts thereof (1d). where the variables Y, R ^2, R ^3, R ^4, R ^3, R ^6, R ^7, R ^s and R ⁹ are as defined in Claim 1 in relation to formula (I) and X is NR ^10, wherein R ¹⁰ is H or C 1-4 alkyl, The benzopyran analogs of formula (1d) or the pharmaceutically acceptable salts thereof according to claim 9, which is: trans-6-cyano-4- (4-fluorobenzovlamino) -2,2-dimethyl-1,2,3,4-tetrahydroquinoline-3 -ol, or a pharmaceutically acceptable salt thereof. A process for the preparation of benzopyran analogues of formula (Ib) according to claim 5 or 6, or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (IIb) is acylated: (IIb). wherein R ¹ 'and R ² ' are both hydrogen or one of R ¹ and R ² is trifluoromethoxy, C _1-6 alkyl optionally interrupted by oxygen or substituted with hydroxyl, C ₁₆ -alkoxy or substituted aminocarbonyl, CF ₃ A, wherein A is -CF ₂ , -CO-, CH ₂ -; or CH (OH), arylsulfonyl, arylC ₃ . _{g is} cycloalkyl, C 1-6. ₆ alkoxy, heteroaryl, arylcarbonyl, heteroarylcarbonyl, arylsulphinyl, heteroarylsulphinyl, heteroarylsulphonyl in which any aromatic moiety is optionally substituted, and the other R is hydrogen or a group convertible to any of these groups; R ⁵ is R ⁵ as defined in formula (I) and R ³ , R ⁴ , R ⁶ , R ⁸ , R ⁹ and X are as defined in formula (I), R ⁸ NH is in the trans position to R ⁵ ', with an acylating agent of formula (IIIb): R'COĽ (IIIb), wherein R ⁷ is as defined in formula (I) and L 1 is a leaving group; then optionally or, if necessary, and in an appropriate order, one of the groups R ¹ ', R ² ' and R ⁵ 'is converted to R ¹ , R ² and R ⁵ , followed by an intermediate conversion of R ⁸ if hydrogen is on C 1 and the enantiomers are separated to form a pharmaceutically acceptable salt or solvate. A process for the preparation of benzopyran analogues of formula (1c) according to claim 7 or 8 and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (IIc) is acylated: wherein Y is N, R ⁵ is R ⁵ as defined in formula (I) or a group convertible to R ⁵ and R ² is hydrogen or a group convertible to hydrogen, R ³ , R ⁴ , R ⁶ , R ⁸ , R ⁹ and X are defined in relation to formula (I), the group R ⁸ NH is in the trans position relative to the group R ⁵ ', with a compound of formula (IIIb): R ⁷ CO 2 (IIIb) wherein R ⁷ is as defined in formula (I) and L ¹ is a leaving group, then optionally or, if necessary, and in appropriate order, converting any one of R ¹ ', R ² ' and R ⁵ 'into R ¹ , R ² and R ⁵ , and an intermediate conversion R ⁸ , if hydrogen, to C _1-6 alkyl, then the enantiomers are separated to form a pharmaceutically acceptable salt or solvate. A process for the preparation of benzopyran analogues of formula (1d) according to claim 9 or 10, or a pharmaceutically acceptable salt thereof, characterized in that the compound of formula (Ild) is acylated: wherein X 'is NR ¹⁰ ', wherein R ¹⁰ 'is hydrogen or Cl. R _{6 is} alkyl, or a group which may be converted thereto, Y ', R ² ' and R ⁵ 'are Y, R ² and R ⁵ are as defined in formula (I), or groups which may be converted thereto, and R ³ , R ⁴ , R ⁶ , R ⁸ and R ⁹ are as defined in formula (I), the group R ⁸ NH is in the trans position relative to the group R ⁵ ', with an acylating agent of formula (IIIb): R ⁷ COL (IIIb) wherein R ⁷ is as defined in formula (I) and L 1 is a leaving group; thereafter optionally or as necessary and in any appropriate order, the conversion of one of the groups Y ', R ^10', R ² 'or R ^5' to Y, R ^10, R ² or R ⁵ Interconversions of ^R8 when hydrogen. into C 1-6 alkyl, separating the enantiomers and forming a pharmaceutically acceptable salt or solvate. A pharmaceutical composition for use in the treatment and / or profilaxia of anxiety, and / or mania, and / or depression, and / or addictive drug withdrawal effects and / or disorders that can be treated and / or The composition of claim 1, wherein said effective amount of a benzopyran analogue of formula (Ia) according to claim 3 or 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are prevented by anticonvulsant agents. A pharmaceutical composition for use in the treatment and / or profilaxia of anxiety, and / or mania, and / or depression, and / or addictive drug withdrawal effects and / or disorders that can be treated and / or The composition of claim 1, wherein said effective amount of a benzopyran analogue of formula (1b) according to claim 5 or 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are prevented by anticonvulsant agents. A pharmaceutical composition for use in the treatment and / or profilaxia of anxiety, and / or mania, and / or depression, and / or addictive withdrawal effects and / or disorders that can be treated and / or The composition of claim 1, wherein said effective amount of a benzopyran analogue of formula (Ic) according to claims 7 and 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are prevented by anticonvulsant agents. A pharmaceutical composition for use in the treatment and / or profilaxia of anxiety, and / or mania, and / or depression, and / or addictive withdrawal effects and / or disorders that can be treated and / or The composition of claim 1, wherein said effective amount of a benzopyran analogue of formula (Id) according to claims 9 and 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are prevented by anticonvulsant agents.