CS197303B2 - Method of produucing cyclic derivatives of 1,4-benzoxazine and 1,4-benzothiazine - Google Patents

Description

The present invention relates to a process for the preparation of cyclic derivatives of 1,4-benzoxazine and 1,4-benzothiazine of the general formula I,

Q is an oxygen or sulfur atom,

R and R 1 are each hydrogen, C 1 -C 6 alkyl or a group of the formula

where x is zero or an integer from 1 to 6,

R e is hydrogen or C 1 -C 6 alkyl and

R 7, R 8 and R 9 are each hydrogen or halogen, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, hydroxyl or carboxyl or one of -OR 10, -SO 2 R 10 or -COOR 10 wherein R 10 represents an alkyl group having 1 to 6 carbon atoms,

R2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a group

in which

R 7, R 8 and R 9 are as defined above,

R 3 is carbamoyl, thibarbamoyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, wherein any alkyl, alkenyl or alkynyl group is optionally substituted with one to three substituents selected from the group consisting of halogen, carboxyl, hydroxyl, C 1 -C 6 alkoxy, one of -SO 2 R 11, -COOR 11 or -COR 11 in which R 11 is C 1-6 alkyl or

wherein R 7, R 8 and R 9 are as defined above, a group

wherein R 7, R 8 and R 9 are as defined above, one of the radicals —N \

R13 or

R12

OF

-C — N,

II \

Q R13 in which

Q is as defined above, and

R 12 and R 13 are each hydrogen or C 1 -C 6 alkyl, or R 12 and R 13 taken together with the nitrogen atom together form a 5- or 6-membered saturated or unsaturated heteromonocyclic ring, optionally containing as nitrogen, sulfur or oxygen as another heteroatom, and optionally substituted with one to three alkyl groups having 1 to 6 carbon atoms or a group

where X, Re, R7, Re and R9 are as defined above, R and R are each hydrogen, halogen, amino, C ₂ -6ahfatickou acylamino group or an alkyl group having 1 to 6 carbon atoms, trihaloalkyl group morn 6 carbon atoms, hydroxyl group, carboxyl group, C1-C6 alkoxy group, R10-SO2-NH-, wherein R10 is as defined above, one of -SO2R11 and -COOR, wherein R11 is as defined above or R a and R 5 together form a group -CH 2 -O-CH 2 - or R 4 and R 5 together with the two adjacent carbon atoms of the benzene ring together form a C 5-6 carbocyclic ring, Z represents a group -CH-CH,

R 1a or _ (CH) _n -A-,

Wherein R14 is C1 -C6 alkyl or

wherein x, R5, R7, R6 and R9 are as defined above, n is zero or 1 and A is -CH2 or = C = Q, wherein Q is as defined above, when Z is -CH-CH2- ,

R14 then has a meaning other than hydrogen. The invention also relates to pharmaceutically acceptable salts of the compounds of formula I. The alkyl, alkenyl and alkynyl groups may be either branched or straight chain groups.

In the group

x preferably has a value of 1 or 2, especially 1, and R e preferably represents a hydrogen atom.

The C 1 -C 6 trihaloalkyl group is preferably trifluoromethyl.

when R 12 and R 13 together with the nitrogen atom together form a heterocyclic ring, this ring is preferably one of the following groups: piperidyl, pyrrolidinyl, piperazinyl, oxazolinyl, thiazolinyl or imidazolinyl.

When R 6 and / or R 8 are acylamino groups, it is preferably a straight or branched chain aliphatic acylamino group, in particular a C 1 -C 6 alkylamino group.

When R 6 and R 6, together with two adjacent carbon atoms of the benzene ring, together form a carbocyclic ring, this ring preferably contains 5 or 6 ring carbon atoms and preferably one or two double bonds:

Pharmaceutically acceptable salts of the compounds of formula I are either salts of these compounds with inorganic acids such as hydrochloric and sulfuric acid, or with organic acids such as citric, tartaric, malonic, mandelic, fumaric and methanesulfonic acids, or with inorganic bases such as sodium, potassium, calcium or aluminum hydroxides, or with organic bases such as lysine, triethylamine, procaine, dibenzylamine, N-benzyl- [beta] -phenethylamine, N, N'-dibenzylethylenediamine, dehydroabethamine, N-ethylpiperidine and the like.

Preferred compounds are those of formula (II),

wherein Q and n are as defined above, R ‘9 R 1‘ respectively represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or a group

wherein R 2, R 6 and R 8 are as defined above, R 6 represents a hydrogen atom, a C 1 -C 6 alkyl group or a group

¹ wherein R 7, R 'and R9' denote individually a hydrogen or halogen atom, an alkyl group having 1 to 6 carbon atoms, trifluormethyloivou, hydroxyl. group or alkoxy having 1 to 6 carbon atoms, ^L 3 represents an alkyl group having 1 to 6 carbon atoms optionally substituted with one to three substituents selected from the group consisting of carboxy, hydroxy §kupina alkoxy group having 1 to 6 carbon atoms, , —COORto, where Rio is as defined above,

Where R7, R6 and R9 are as defined above, one of the radicals

R12

Z —N \

Rď £ Í

Rl2 *

From —C — N,

Q R 13 'in which Q is as defined above and R 12 and R 6 are each hydrogen or C 1 -C 6 alkyl, or R 12' and ph 'together with the nitrogen atom together form a heterocyclic ring which is pyrrolidinyl, piperidyl, piperazinyl, oxazolinyl, thiazolinyl or imidazolinyl optionally substituted by C 1 -C 6 alkyl, preferably methyl or ethyl, R 6 'and R 6' are each hydrogen or halogen, amino, C 1-6 alkylamino carbon, trifluoromethyl, hydroxyl or carboxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or one of the radicals

R10-SO2-NH and -SO2R11, in which R10 and R11 are as defined above, R 1a represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a group

wherein R 7 ‘, R b‘ and R g ‘are as defined above, and pharmaceutically acceptable salts thereof.

Particularly preferred compounds are those of formula III,

wherein Q and Rž are as defined above, R "and R 1" respectively represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms or a group

wherein R 1, R e 'and R 9' are as defined above, R 3 'represents an alkyl group having 1 to 6 carbon atoms, optionally substituted with one to three substituents selected from the group consisting of carboxyl, hydroxyl, alkoxy C 1 -C 10, wherein R 10 is as defined above, one of the radicals

Riz '/

-On

R12 "/

-C-N,

Q 'Ris' in which Q is as defined above and R12' and R13 'are each a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R''andRs' are each a hydrogen or halogen atom, an amino group, an acetamide group, a trifluoromethyl group group, a hydroxyl group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a CH3-SO2-NH or -SOzRn ^1, wherein R 'is an alkyl group having 1 to 6 carbon atoms or residue

G wherein R 7 ', R * and R 9 have the abovementioned ^l above known and their pharmaceutically acceptable salts Ne.

Examples of specific compounds of this invention:

1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-imidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2, 3, 3a, 4-tetrahydro-2 methyl-imidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2- (2'-carbamoyletthyl) Jimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2- (1'-carbamoylethylimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H 2,3 _and 3, 4-tetrahydro-2- (l-methyl-l-carbamoylmethyl) imidazo [5, c]] l 4Jbenzoxazin-l-one, lH, 2,3,3a, 4-tetrahydro- -2- (2'-dimethylamino-ethyl) imidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2 '(3'-dimethylaminopropyl Jimidazole [5] 1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-8-chloroimidazo] 5,1-c] [1,4] benzoxazin-1 -one, 1H, 2,3,3a, 4-tetrahydro-2- (2'-carbamoylethyl) -8-chloroimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3 , 3a, 4-tetrahydro-2-carbamoylmethyl-8-fluoro-imidazo ^[5,1-c], [1,4] benzoxazin-1-one H, 2,3,3a, 4-tetrahydro-2- carbamoylmethyl-8-hydroxyimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2 -carbamoylmethyl-8-amino-imidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-8-methylimidazo] 5,1- c] [1,4] benzoxazin-1-one, 1H ₎ 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-8-trifluoromethylimidazo [5,1-c] [1,4] benzoxazin-1-one, 1 H, 2 S, 5a-tetrahydro-2-carbamoylmethyl-8-methoxyimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl- 8-carboxyimidazo [5,1-c] [1,4] benzoxazin-1-one;

1973Q3 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-8-acetamidoimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro- 2-carbamoylmethyl-8-methylsulfonylimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-8-methylsulfonamidoimidazo [5, 1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2- (3'-diinethylaminopropyl) -4-phenylimidazo [5,1-c] (1, 4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-1,1-dimethyl-2-carbamoylmethylimidazo [5,1-c] [1,4] beinsoxazine, 1H, 2,3 _J 3a 4-tetrahydro-2-carbamoylmethyl-4-phenylimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2- (2'-carbamoylethyl) ) -4-Phenylidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2- (1'-carbamoylethyl) -4-f enylimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2- (Γ-methyl-1 H -carbamoylethyl) -4-phenylimidazo [5] 1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2- (2'-dimethylaminoethyl) -4-phenylimidazo [5,1-c] [1] 4] benzoxazin-1-one, 1H, 2,3,3a, 4 -tetrahydro-2- (3'-dimethylaminopropyl) -4-phenyl-8-chloro-imidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro -2-carbamoylmethyl-4-phenyl-8-chloroimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-4- phenyl-8-fluorimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-4-phenyl-1-8-hydroxyimidazo [5] 1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-4-phenyl-8-aminoimidazo [5,1-c] [1, 4] benzoxazin-one, lH, _J 2,3, 3a, 4-tetrahydro-2-karbamoylmethyl-. 4-Phenyl-8-methyl-limidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-4-phenyl-8-trifluoromethylimidazo [ 5,1c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-4-phenyl-8-methoxyimidazo [5,1-c] [1] 4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-4-phenyl-8-carboxyimidazo [5,1-c] [1,4] benzoxazine-1-one; on, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-4-phenyl-8-acetamidoimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a 4-tetrahydro-2-carbamoylmethyl-4-phenyl-8-methylsulfonylimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2 -carbamoylmethyl-4-phenyl-8-methylsulfonamidoimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-4- (2'- methoxyphenyl) imidazo] 5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-4- (4'-chlorophenyl) imidazo [5] 1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-methyl-3α-phenyl-imidazo [5,1-c]; [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydr 0-2- (2'-k arbamoylethyl] -3a-phenylimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3, a, 4-tetrahydro-2- (1H-carbamoylethyl) -3a-phenylimidazo [5] 1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2- (1-methyl-Γ-carbamoylethyl) -3a-phenylimidazo [5,1-c] ] - [1,4] benzoxazin-1-one, 1H, 2,3, 3a, 4-tetrahydro-2- (2'-dimethylaminoethyl) -3a-phenylimidazo [5,1-c1 (1,4) benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2- (3'-dimethylaminopropyl] -3a-phenylimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-3a-phenyl-8-chloroimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4 -tetrahydro-2-carbamoylmethyl-3α-phenyl-8-fluorimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl- 3α-Phenyl 1-8-hydroxyimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-3α-phenyl-8- aminoimidazo [5,1-c] [1,4] benzoxazin-1-one, 1n, 2,3,3M-tetrahydro-2'-capamylmethyl-3-enyl-8-methylimidazo [5,1-c] [1 4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbampylmethane ethyl-3-phenyl-1-8-methylimidazo [5,1-c] [1,4] benzoxazin-one, lH, 2.3 _t 3a, 4-tetrahydro-2-karbamoylrnethyl3a-phenylpropan-8 -trifluoromethyl-limidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbainoylthienyl-3α-phenyl-8-methoxyimidazo [5,1-c H 1,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoyl-ethyl-3α-phenyl-8-carboxyimidazo [5,1-c] [1,4] benzoxazine-1- on, 1H, 2,3,3a, 4-tetrahydro-2-carbainoylmethyl 3a-phenyl-8-acetamidoimidazo [5,1-c] [1,4] benzoxazin-1-one, 1H, 2,3,3a, 4 -tetrahydro-2-carbamoylmethyl-3α-phenyl-8'-ethylenediamine-quinolinazo [5,1-c] [11,4] benzoxazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethylimidazo [5] 1-c] [1,4] benzothiazin-1-one, 1H, 2,3,3a, 4-tetrahydro-2-carbamoyimethyl-8-chloroimidazo [5,1c] [1,4] benzothiazine- 1-one, 1,2,3,4,4a, 5-hexiahydro-1-phenyl-3-methylpyrazo [2,1-c] [1,4] benzoxazine, 1,2,3,4,4a, 5 -hexahydro-1-phenyl-3-carbamoylmethylpyrazo [2,1-c] [1,4] benzoxazine, 1,2,3,4,4a, 5-hexahydro-1-phenyl-3-carbamoylmethyl-9-chloropyrazo [ 2,1-c] [ 1,4] benzoxazine, 1,2,3,4,4a, 5-hexahydro-1-phenyl-3'-carbamoylmethylpyrazo [2,1-c] [1,4] benzoxazin-2-one, 1,2,3 4,4a, 5-hexahydro-1'-phenyl-3-carbamoyimethyl-9-chloropyrazo [2,1-c] [1,4] benzoxazin-2-one, 1, 2,3,4,4a, 5 ' hexahydro-3-carbamoylmethyl-pyrazo] 2,1-c] [1,4] benzoxazin-2-one, 1,2,3,4,4a, 5-hexahydro-3-carbarooylmethyl-9-chloropyrazo [2,1-c J [1,4] benzoxazin-2-one, 1,2,3,4,4a, 5-oxahydro-3-carbamoylraetbylpyrazo [2,1-c} [1,4] benzoxazin-1-one, 1,2 3,4,4a, 5-hexahydro-3-carbamoylmethyl-9-chloropyrazo [2,1-c] [1,4] benzoxazin-1-one,

3,4,4a, 5-tetrahydro-3'-carbainoylmethylpyrazof 2,1-c] [1,4] benzoxazine, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethylimidazof 5,1-c] [1] 4] benzoxazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2- [2'-carbamoylethyl] imidazo [5,1-c] [1,4] benzoxazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2- (1'-carbamoylethyl) imidazo [5,1-c] [1,4] benzoxazine-1-thione, 1H, 2,3,3,3a, 4- tetrahydro-2- (1'-methyl-1'-carbamoyl-limidazo [5,1-c], [1,4] benzoxazine-1-thlon, 1H, 2,3,3a, 44-tetrahydro-2- (1 ') -methyl-8-chloroimidazo [5,1-c] [1,4] benzoxazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethylimidazo [5,1-c] [1,4] benzothiazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-8-chloroimidazo [5,1-c] i [1,4] benzothiazine-1-thione, 1H, 2,3 3a, 4-tetrahydro-2-carbamoyl-ethyl-3a-phenyl-limidazo] 5,1-c] [1,4] benzoxazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl 4-Phenylimidazo [5,1-c] [1,4] benzoxazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylraethyl-4,4-dimethyl-limidazo [5,1-c] [1 , 4 benzoxazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-3a-phenylimidazo [5,1-c] [1,4] benzothiazine-1-thione, 1H, 2, 3,3a, 4-tetrahydro-2-carbamoylmethyl-4-phenyl-limidazo [5,1-c] [1,4] benzothiazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-carbamoyl-methyl -4,4-dimethylimidazo [5,1-c] [1,4] benzothiazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-thiocarbamoylmethylimidazo] 5,1c] [1,4] benzoxazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-thiocarbamoylmethylimidazo] 5,1-c] [1,4] benzothiazine-1-thione, 1H, 2,3,3a, 4 -tetrahydro-2-thiocarbamoylmethyl-3α-phenyl limidazo [5,1-c] [1,4] benzothiazin-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-thiocarbamoylmethyl-4-phenylimidazo [ 5,1-c] [1,4] benzoxazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-thiocarbamoylmethyl-4,4-dimethylimidazo [5,1-c] [1,4] benzoxazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-thiocarbamoylmethyl-3a-phenylimidazo [5,1-c] [1,4] benzothiazine-1-thione, 1H, 2,3, 3a, 4-tetrahydro-2-thiocarbamoylmethyl-4-phenylimidazo [5,1-c] [1,4] benzothiazine-1-thione, 1H, 2,3,3a, 4-tetrahydro-2-thiocarbamoylmethyl-4,4-dimethylimidazo [5,1-c] [1,4] benzothiazin-1-one, and pharmaceutically acceptable salts thereof. The essence. The preparation of the cyclic derivatives of 1,4-benzoxazine and 1,4-benzothiazine of the aforementioned general formula (I) by the process according to the invention is characterized in that the compound of the general formula (X)

wherein Z, Q, R, R 1, R 2, R 1 and R 5 are as defined above, or a salt thereof, in reaction with a compound of formula XI,

R3-X, (XI) wherein R3 is as defined above and X is a halogen atom or an active alcohol ester moiety, and / or optionally a compound of formula I is converted to another compound of formula I, and / or optionally a compound of formula I is converted into its salt, and / or optionally the compound of formula I is liberated from the salt, and / or the mixture of stereoisomers is optionally resolved into the individual isomers.

In the compound of formula XI, when X is a halogen atom, it is preferably a chlorine, bromine or iodine atom; when X represents an active ester residue of alcohol, it is preferably a radical -O-SO2-Ri6 wherein Rie is alkyl, for example alkyl having 1-6 ⁴ carbon atoms or an aryl group: where R w is alkyl, it is preferably Preferably, when R 1 is alkyl, it is methyl, while R 11 is aryl, it is preferably a phenyl group, preferably substituted with an alkyl group, especially a methyl group in the para position, i. tosylskuplna.

¹⁴

In the compound of formula (X), when Z is - (CH) _n —A—,

R 14 wherein n is as defined above, and A represents a group \

C = O, /

the compound of formula X is preferably reacted with a compound of formula XI in the form of a salt, especially an alkali metal salt, which can be prepared by known methods, for example by treating a compound of formula X wherein Z is as defined above with an alkali metal hydride, for example sodium hydride, or with lithium diethylamine or diisopropylamide or directly with an alkali metal, and treatment with the compound of formula XI is preferably carried out in either anhydrous aprotic solvents such as dimethylformamide, dimethylacetamide or dimethylsulfoxide or other solvents such as benzene, toluene, dioxane or tetrahydrofuran at temperatures ranging from about 50 ° C to about 150 ° C.

When, in the compound of formula (X), Z is other than that indicated above, the compound of formula (X) is preferably treated with the compound of formula (XI) in free form, i.e. not in salt form, and preferably carried out in the presence of strong acid acceptors. such as normal or alkali metal or caustic earth metal bicarbonate, in an organic solvent, for example dimethylformamide, dimethylacetamide, dimethylsulfoxide or aliphatic alcohols, for example tertiary butyl alcohol, at temperatures ranging from about 50 ° C to about 150 ° C.

If, in the reactions described above, as well as in the reactions described below, the starting materials contain one or more groups which may interfere in the reaction, these groups are protected, if necessary, in a conventional manner, and then at the end the reaction is also removed in a conventional manner.

For example, if R 3 is a C 1 -C 6 alkyl group substituted with -COR 11 in which R 1 is as defined above, and if desirable to carry out the reduction with LiAlH 6 without reducing the keto group, the keto group may be protected by conversion to the ketal group; this conversion can be carried out by reaction with ethylene glycol using an acid, for example p-toluenesulfonic acid, as a catalyst, either in the absence or in the presence of solvents such as benzene or toluene. The ketal group can be converted back to the keto group by acid hydrolysis, for example with a strong acid such as hydrochloric acid.

When R3 is a C2-6 alkenyl group and if the catalytic reduction is carried out in the presence of Pd / C at room temperature and atmospheric pressure, the alkenyl group may be protected from reduction by conversion to the epoxide by treatment with a peracid such as peracetic or m-chloroperbenzoic acid, in organic solvents such as methylene chloride, chloroform, and back converting the epoxide to the double bond by alkaline or acid hydrolysis followed by dehydration.

As mentioned above, a compound of formula I can be converted to another compound of formula I by conventional organic chemistry methods.

For example, a compound of formula I wherein Z is \

C = O,

Z may be converted to a compound of formula I wherein Z is \

C = S,

Treatment with phosphorus pentasulphide; this reaction may be carried out either by melting both compounds or by refluxing their solution in a solvent such as benzene or toluene.

A compound of formula I wherein R 3 is an alkyl group substituted with a radical

R12

From —C — N,

II \

Q R 13 wherein Q is as defined above, and R 12 and R 13 are each hydrogen or C 1 -C 6 alkyl, may be converted to a compound of formula I wherein R 3 is an alkyl group substituted by a radical

R12

From —N, \

R13 in which R12 and R13 are as hereinbefore defined, by reduction, for example by treatment with LiAlFU under the conditions customary for this kind of reaction.

A compound of formula (I) wherein R 3 is an alkyl group substituted with a radical

R12

From —C — N,

II \

About R13 in which R12 and R13 are as defined above may be converted to a compound of formula I wherein R3 is an alkyl-substituted group substituted with a radical

R12

From —C — N,

II \

With R 13 where R 12 and R 13 are as defined above, by treatment, for example, with phosphorus sulfide either by melting or heating to reflux as described above.

A compound of formula I wherein R3 is an alkyl group substituted with —COR11 or COOR11 wherein R11 is as defined above may be converted to a compound of formula I wherein R5 is an alkyl group substituted with a hydroxyl group by reduction, for example with LiAlH4.

A compound of formula I wherein R 3 is an alkyl group substituted with the moiety - COOR 11, wherein R 11 is as defined above, or

R12

OF

-C-N,

II \.

R 13 where R 12 and R 13 are as defined above may be converted to a compound of formula I wherein R 3 is an alkyl group substituted by carboxylic, acidic or alkaline hydrolysis, for example sodium or potassium hydroxide or hydrochloric or sulfuric acid. '

Also, salt formation of the compound of formula I as well as the conversion of the salt to the free compound and resolution of the stereolsomers can be accomplished by conventional methods, as is well known to those skilled in the art. Racemic compounds may be resolved into optical antipodes by, for example, resolution, for example, fractional crystallization, by resolution of mixtures of diastereoisomeric salts, and, if desired, liberating the optical antipodes from the salts.

The compounds of the invention are active on the central nervous system, particularly as antidepressant agents.

Antidepressant efficacy was evaluated in mice based on the prevention of reser197303 pin-induced blepharospasm and hypothermia.

Reserpine was administered endoperltoneally at doses of 2.5 mg / kg and the test compounds were administered orally 30 minutes prior to the administration of reserpine. Blepharospasm record [evaluated at points 18 according to the technique of Rubin B. et al. in J. Pharmacol. 120, 125 (1957)]] and body temperature (rectal thermoelectric cell) measurements were taken one and four hours after reserpine administration respectively, and the results are summarized in the following table.

TABLE

ED50 values of compounds K 11566 and K 11737 for antireserpine activity in mice and rats, with indicative acute toxicity

Antireserpine activity *) mouse, ED 50 mg / kg / os rat, ED 50 mg / kg / os

Acute toxicity, LD 50 mg / kg / pers: * * j

Compound

Blepharospasm (after 1 hour No) Hypoter- mie (after 4 hours) Blepharospasm (after 1 hour No) Hypoter- mie (after 4 hours) mouse rat K 115 66 1.5 9.0 7.0 3.5 800 800 K 117 3.5 4,5 6.8 .7,0 800 800

*) ED 50 values were graphically interpolated from dose / response functions and each dose was administered to at least 10 animals in duplicate.

**) The indicative acute toxicity (LD 50) was evaluated within 7 days after single administrations of several doses ranging from 25 to 800 mg / kg / pers.

K 115 66 is 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethylimidazo [5,1-c] [1,4] benzoxazin-1-one.

K 117 37 is 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-8-chloroimidazo [5,1-c] [1,4] benzoxazin-1-one.

The compounds of the invention are preferably administered orally, although they may also be administered by other conventional means, for example by injection or rectal administration.

A dose of the compounds of this invention, for example 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethylimidazo [5,1-c] [1,4] benzoxazin-1-one and 1H, 2,3,3a, 4 -tetrahydro-2-carbamoylmethyl-8-chloroimidazo [5,1-c] [1,4] benzoxazin-1-one suitable for oral administration to adults is preferably 20 to 50 mg at a dose of 2 to 4 times daily .

Pharmaceutical compositions containing the compounds of the invention are manufactured according to conventional methods with conventional additives.

Thus, pharmaceutical compositions containing the compounds of the invention which are intended for oral administration are preferably tablets, pills or capsules which contain the active ingredient together with diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for example silica, talc. stearic acid, magnesium or calcium stearate and / or polyethylene glycols; or may also contain binders such as starches, gelatin, methylcellulose, acacia, tragacanth, polyvinylpyrrolidone; disintegrating agents such as starches, alginic acid, alginates; effervescent mixtures; dyes; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical compositions are produced in a known manner, for example by the following processes: mixing, granulating, tabletting, sugar coating and film coating.

Also, other pharmaceutical formulations containing the compounds of this invention may be manufactured by known methods and may be, for example, syrups or drops for oral administration, sterile injectable solutions or suppositories.

The following examples illustrate but do not limit the invention.

Example 1

To a solution of 1H, 2,3,3a, 4-tetrahydroimidazo [5,1-c] [1,4] benzoxazin-1-one (3.5 g, 1.85. 10 ^-2 mol) in dimethylformamide (70 50% NaH (0.89 g, 1.85.10 ^-2 mol) was added and after stirring at room temperature for one hour, a solution of chloroacetamide (1.75 g, 1.85.10 ^-2 mol) in dimethylformamide (20 ml) was taken. The mixture was stirred at room temperature for 20 hours, then poured into water and extracted with chloroform to evaporate to dryness to give 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethylimidazof 5,1-c] [1,4] benzoxazine -1-one (2.8 g, mp 230-231 ° C).

The following compounds are obtained analogously:

1 H, 2,3,3a, 4-tetrahydro-2-methyl-imidazo 197303 [5,1-c] [1,4] benzoxazin-1-one, mp 135-136 ° C, 1 H, 2,3,3a, 4-tetrahydro-2- (2'-carbamoylethyl) imidazo [5,1-c] [1,4] benzoxazin-1-one, mp 162-164 ° C, 1H, 2,3,3a, 4-tetrahydrofuran -2- (1'-carbamoylethyl) imidazo [5,1-c] [1,4] benzoxazin-1-one, mp 203-205 ° C, 1H, 2,3,3a, 4-tetrahydro-2- (2'-dimethylaminoethyl) imidazo [5,1-c] [1,4] benzoxazin-1-one, mp 180-182 ° C (as hydrochloride), 1H, 2,3,3a, 4-tetrahydro-2 - (3'-dimethylaminoethyl) imidazo [5,1c] [1,4] beuzoxazin-1-one, mp 54-57 ° C, 1H, 2,3,3a, 4-tetrahydro-2-propargylimidazo [5,1] -c] [1,4] benzoxazin-1-one, mp 113-115 ° C, 1 H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-8-chloroimidazo [5,1-c] [1, 4] benzoxazin-1-one, mp 214-216 ° C, 1 H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-8-methylimidazo [5,1-c] [1,4] benzoxazin-1-one; on, mp 235-237 ° C, 1 H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-8-methoxyimidazo [5,1-c] [1,4] benzoxazin-1-one, mp Mp 179-181 ° C.

Example 2

To 1H, 2,3,3a, 4-tetrahydro-imidazo [5,1-c] [1,4] benzoxazine (4 g, 2.1.10 ^-2 mol) in anhydrous dimethylformamide (80 mL) was added NaH (0, 05 g); After standing at room temperature for 30 minutes, ethyl acrylate (1.05 g,

2.1.10 ^-2 mol). The mixture was allowed to stand at room temperature for 2 hours and a further two hours at 50 ° C, then poured into water, extracted with ethyl acetate, evaporated to dryness and hydrolyzed with methanolic 2 N KOH (100 mL) at room temperature for 12 hours. After evaporation to dryness, the residue is dissolved in water, acidified with 8% HCl and extracted with chloroform; after drying Na 2 SO 4, SOCl 3 (5 mL) was added and the mixture was stirred overnight at room temperature. The chloroform was evaporated, the residue was distilled off twice with toluene and then redissolved in ethanolic ammonia solution; the mixture was allowed to stand for 12 hours and evaporated to dryness and crystallized from 95% ethanol to give 1H, 2,3,3a, 4-tetrahydro-2- (2'-carbamoylethyl) imidazo [5,1-c] [ 1,4] benzoxazin-1-one, 2.3 g, mp 162-164 ° C.

Example 3

A mixture of 2H-3,4-dihydro-2-phenyl-3- [N- (3'-di20 methylaminopropyl) -N- (trifluoroacetyl) aminomethyl] -6-chloro [1,4] benzoxazine (3g;

5.8.10 ^{- 3} mol) in methanolic KOH (100 ml) was allowed to stand under a nitrogen atmosphere for 8 hours at room temperature. The solution is evaporated to dryness, the residue is extracted with ethyl ether and dried over Na2SO4, evaporated to dryness and crystallized from isopropyl alcohol to give 2H-3,4-dihydro-2-phenyl-3- [N- (3'-dimethylaminopropyl) aminoethyl] - 6-chloro [1,4] benzoxazine.

Example 4

To a solution of 2H-3,4-dihydro-2-phenyl-3-trifluoroacetylaminomethyl-6-chloro- [1,4] benzoxazine (3.71 g, 1.10 ^-2 mol) in anhydrous dimethylacetamide (50 mL) was slowly added. 50% NaH (0.58 g, 1.10 ^-2 mol) was added with stirring at room temperature. After stirring at room temperature for 30 minutes, 1-chloro-3-dimethylaminopropane (1.5 g) was added;

The mixture was heated at 60 ° C for 6 hours, then poured into water and extracted with ethyl ether. After washing with water and evaporation to dryness, the remaining oil was dissolved in ethyl acetate. Treatment with methanolic HCl precipitates 2H-3,4-dihydro-2-phenyl-3- [N- (trifluoroacetyl) -N- (3'-dimethylaminopropyl) aminoethyl] -6-chloro- [1,4] benzoxazine hydrochloride (3.2 g).

Example 5

To a solution of 2H-3,4-dihydro-3-aminomethyl [1,4] benzoxazine (16.4 g, 1.10 ^-1 mol) and Et 3 N (14 g, 1.5.10 ^-1 mol) in CH 2 Cl 2 (100 mL) After cooling to -30 ° C, a solution of trifluoroacetic anhydride (21 g) in CH 2 Cl 2 was added dropwise. The solution was allowed to stand for 1 hour at -30 ° C, then allowed to stand to reach room temperature, then washed with 5% NaHCO 3 and water; evaporation to dryness gave 2H-3,4-dihydro-3-trifluoroacetylaminomethyl- [1,4] benzoxazine (18.1 g) ·

Example 6

To a solution of 1H, 2,3,3a, 4-tetrahydro-4-phenylimidazo [5,1-c] [1,4] benzoxazin-1-one (2.5 g,

1.10 ^{- 2} M) in anhydrous dimethylacetamide (50 mL) was added 50%. NaH (0.55 g, 1.1.10 ^-2 mol) and the solution was heated to 50 ° C with stirring for 30 minutes. After cooling to room temperature, chloroacetamide (0.95 g, 1.05.10 ^-2 mol) dissolved in anhydrous dimethylacetamide (10 mL) was added dropwise to this solution. The mixture was heated at 60 ° C for 1 hour, poured into water and extracted with ethyl acetate. The resulting solution was dried with Na 2 SO 4, concentrated to give a solid which crystallized from dimethylacetamide-water to give 1H, 2,3,3a, 4-te, trahydro-2-carbamoylmethyl-4-phenylimidazo [5,1c] [1,4] Benzoxazin-1-one (1.5 g).

Example 7

A solution of 2H-2-phenyl- [1,4] benzoxazine (60 g, 0.277 mol) and Na 2 O 5 (52.7 g, 0.27 mol) and KCN (55.5 g, 0.84 mol) in dimethylformamide (1000 mL) · and water (200 ml) was stirred at room temperature for 70 hours, then the mixture was poured into water and extracted with chloroform; extracts were washed with dilute NaOH and then with water. The solid residue obtained by evaporation is triturated in benzene to give 2H-3,4-dihydro-3-cyano-2-phenyl [1,4] benzoxazine (41.6 g).

Example

To a solution of 1-phenyl-1- (o-nitrophenoxy jacetyl chloride (10 g, 3.43.10 ^-2 mol) in anhydrous toluene (50 mL) was added 5% Pd on BaSO 3 (1.5 g) and the solution boiled under The hydrogen stream was bubbled through the solution for 6 hours while the HCl evolution had ceased, the catalyst was removed, the toluene was distilled off under reduced pressure, and crystallized from isopropyl alcohol to give 2H-2-phenyl [1,4] benzoxazine (5, 6). 5 g) Example 9

To 1-phenyl-1- (o-nitrophenoxy) acetic acid (30 g, 1, 09.10 ^-1 mol) was added SOCH (200 mL) and the mixture was refluxed for 30 minutes. After evaporation to dryness, the solution was dissolved twice in toluene, decolorized and evaporated twice to dryness. Trituration of the resulting solid in the spetrol ether gave 1-phenyl-1- (o-nitrophenoxy) acetic acid chloride (28.0 g), mp 61-63 ° C. Example 10

A solution of 1-phenyl-1- (o-nitrophenoxy) acetic acid ethyl ester (452 g, 1.5 mol) in acetic acid (1.5 L) and water (600 mL) was refluxed for 60 hours. After evaporation to dryness, the solution was distilled off twice with toluene. The residue was dissolved in ethyl ether and extracted with 5% NaHCO 3. The basic extract was immediately acidified with 23% HCl, extracted again with ethyl ether, repeatedly washed with water, dried over Na 2 SO 4, decolorized and evaporated to dryness. The resulting oily residue solidifies by vigorous stirring in water; After filtration and washing with water, the dried solid residue was triturated in pentane to give 1-phenyl-1- (o-nitrophenoxy) acetic acid (275 g, mp 94-97 ° C).

They did

To a solution of sodium o-nitrophenolate (322 g, 2 mol) in anhydrous dimethylacetamide was added dropwise ethyl acetate of 1-chloro-1-phenylacetic acid (398 g, 2 mol) under a stream of nitrogen. The mixture was heated at 70 ° C for 45 minutes, then 1-chloro-1-phenyl-acetic acid ethyl ester (39.8 g) was added and the temperature was maintained at 70 ° C for an additional 45 minutes: the resulting solution was cooled, poured into ice-water and extracted with ethyl ether. Evaporation of the ether yielded an oil which solidified by treatment with pentane to give 1-phenyl-1- (o-nitrophenoxy) acetic acid ethyl ester (324g, mp 59-61 ° C).

Example 12

A solution of 1-phenyl-1- (o-nitrophenoxy) -acetic acid ethyl ester (20 g, 0.6.10 ^-2 mol) and methyl iodide (31 mL, 5.10 ^-1 mol) was dissolved in dimethylformamide under a stream of nitrogen. ° C NaH (19.2 g) was added in portions, after which the mixture was allowed to equilibrate to room temperature and then left at room temperature for 2 hours, evaporated to dryness in vacuo, diluted. The ethereal solution was washed with water, dried over Na 2 SO 4 and evaporated to dryness, and the resulting oil solidified by trituration in pentane to give 1-phenyl-1- (o-nitrophenoxy) -propionic acid ethyl ester (17.3 g).

Example 1 d

Starting from 1H, 2,3,3a, 4-tetrahydro-3a-phenylimidazo [5,1-c] [1,4] benzoxazin-1-one (2.26 g, 1.10 ^-2 mol) which is worked up as described in Example 1, crystallizing from 99% ethanol to give 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-3α-phenylimidazo [5,1-c] [1, 4] benzoxazin-1-one (2.1 g, mp 207-209 ° C).

The following compounds are obtained analogously:

1 H, 2,3,3a, 4-tetrahydro-2-methyl-3α-phenylimidazo [5,1-c] [1,4] benzoxazin-1-one, mp 184-185 ° C, 1 H, 2,3, 3a, 4-Tetrahydro-2- (2'-dimethylaminoethyl) -3a-phenylimidazo [5,1-c] [1,4] benzoxazin-1-one, mp 141-143 ° C.

Example 1 4

A mixture of 2H-3,4-dihydro-3-aminomethyl-3-phenyl [1,4] benzoxazine (2 g) and urea (0.72 g) was melted in a nitrogen stream at 140 ° C for 3 hours and then for a further 2 hours at 180 [deg.] C. After trituration in water, filtration and crystallization from toluene, 1H, 2,3,3,3a, 4-tetrahydro-3a-phenylimidazo [5,1-c] [1,4] benzoxazine-1 is obtained. -on (1.5 g, mp 258-260 ° C) EXAMPLE 1 5

A solution of 2H-3,4-dihydro-3-cyano-3-phenyl (1,4] benzoxazine (10 g, 4.2.10 ^-2 mol) in ethanol (300 mL) was first saturated with NH 3 and then reduced with Raney nickel at After 4 hours the reduction is complete After filtration, evaporation to dryness and crystallisation from ethyl ether,

2H-3,4-dihydro-3-aminomethyl-34enyl [1,4] benzoxazine (5.4 g, m.p. 87-89 ° C). Example 16

Treatment of the starting 1H, 2,3,3a, 4-tetrahydro-4,4-dimethylimidazo [5,1-c] [1,4] benzoxazine (2.36 g, 2.10 ^-2 mol) according to the procedure described in of Example 1, 1 H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-4,4-dimethylimidazo [5,1-c] [1,4] benzoxazine (2,3 g) was obtained.

The following compounds are obtained analogously:

1H, 2,3,3a, 4-tetrahydro-2-methyl-4,4-dimethylimidazo [5,1-c] (1,4) benzoxazine, mp 180-183 ° C.

Example 17

To a solution of 2H-2,2-dimethyl-3-succinimidomethyl [1,4] benzoxazine (2.74 g, 1.10 ^-2 mol) in methanol was added NaBH 6 (1 g); after stirring at room temperature for three hours, the solution was poured into After evaporation to dryness, the solution was basified with saturated Na 2 CO 3 solution and extracted with chloroform, the extracts washed with water, dried over Na 2 SO 4 and evaporated to dryness to give 2H-3,4-dihydro-2 after crystallization from anhydrous ethanol. 2-dimethyl-3-aminomethyl [1,4] benzoxazine (2.3 g), mp > 280 ° C (dihydrochloride).

EXAMPLE 18 1-Succinimido-3,3-dimethyl-3- (o-nitrophenoxy) -2-propanone (3 g) was catalytically reduced at room temperature to 10% Pd / C (0.3 g) at 0.4 MPa. After 4 hours, the solution was filtered through 2H-2,2-dimethyl-3-succinimidomethyl-1,4] benzoxazine (1.8 g, mp 177-178 ° C).

Example 19

To a suspension of NaH (1.6 g, 3.3.10 ^-2 mol) in dimethylformamide (100 mL) under nitrogen was added succinimide (3.25 g, 3.3.10 ^-2 mol); the solution was stirred at room temperature for 1 hour, then cooled to 0 ° C and a solution of 1-bromo-3,3-dimethyl-3- (o-nitrophenoxy) -2-propanone (10 g, 3.3.10) was added dropwise. ^-2 mol) in dimethylformamide. The solution was allowed to stand at 0 ° C for 2 hours, then poured into water and extracted with EtOAc. The extracts were dried, treated with charcoal and concentrated to precipitate 1-succinimidido-3,3-dimethyl-3- (o-nitrophenoxy) -2-propanone (0.75 g, mp 90-93 ° C).

Example 20

A solution of 2- (nitrophenoxy) -2-methylproplonylchloridu (28.5 g, 1,17.10 ^-2 mol] in ethyl ether (500 ml) at 0 ° C dropwise to a solution of diazomethane (14.8 g, 3 «51 ^-2 mol) The mixture was allowed to stand until the temperature of the mixture was at room temperature and HBr was bubbled at this temperature for 40 minutes, then water was added, the resulting solution was washed with 10% Na 2 CO 3 and finally with water until neutral. Drying of Na 2 SO 4 and evaporation to dryness gave 1-bromo-3,3-dimethyl-3- (o-nitrophenoxy) -2-propanone (27.7 g) as an oil which solidified spontaneously, the solid having mp 32-34 ° C.

Example 1 a d 2 1

To a solution of 1H, 2,3,3a, 4-tetrahydroimidazo (5,1-c) [1,4] benzothiazin-1-one (2.06 g, 1. 10 ^-2 mol) in anhydrous dimethylacetamide ( 50 ml) was added with stirring 50% NaH (0.55 g, 1.1.10 ^-2 mol) and the mixture was heated to 50 ° C for 30 minutes. The solution was then allowed to stand at room temperature, then chloroacetamide (0.95 g; 1.05.10 ^-2 mol) in anhydrous dimethylacetamide (10 mol) was added dropwise. The mixture was heated at 60 ° C for 1 hour, poured into water and extracted with ethyl acetate. The extracts were dried over Na 2 SO 4, filtered and concentrated; crystallization from chloroform-methanol gave 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethylimidazo [5,1-c] [1,4] benzothiazin-1-one (1.65 g, mp 235-240) Deň: 32 ° C.

The following compound is obtained analogously:

1H, 2,3,3a, 4-tetrahydro-2-methylimidazo [5,1-c] [1,4] benzothiazin-1-one, m.p.

156 [deg.] C.

Example 22

To a suspension of NaBH 6 [7.8 g, 2.1.10 ^-1 mol) in tetrahydrofuran (170 mL) at -5 ° C was added a solution of BF 3 (d = 1.126, 24.2 mL) in ethyl ether. The temperature of the reaction mixture is maintained at -5 ° C and a solution of 1,2,3,4,4a, 5-hexahydro-1-phenyl-3-methylpyrazo [2,1c] [1,4] benzoxazine- is added dropwise at this temperature. 2-one (10 g,

3.4.10 ^-2 mol) in tetrahydrofuran (100 ml). The mixture is allowed to stand so that the temperature of the mixture equals room temperature and is allowed to stand at this temperature for 12 hours. Water was carefully added and the resulting solution was evaporated to dryness; the residue was dissolved in water, basified with 2N NaOH and extracted with diethyl ether. The ether phase is washed with water, dried over Na2SO4 and evaporated to dryness to give a solid which, by recrystallization twice from ethanol, yields 1,2,3,4,4a, 5-hexahydro-1-phenyl-3-methylpyrazo [2,1-b] -c] [1,4] benzoxazine (3.6 g, mp 126-129 ° C).

Example 23

To a solution of 1,2,3,4,4a, 5-hexahydro-1-phenylpyrazo [2,1c] [1,4] benzoxazine (2.7 g, 1.10 ^-2 mol) in dimethylformamide containing an excess of potassium carbonate, chloroacetamide was added (1.12 g, l ~ ^from 2.10 mol). The solution was left at 50 ° C for 8 hours, then poured into water and extracted several times with ethyl ether; the extracts were dried, evaporated to dryness and the residue crystallized from ethanol to give 1,2,3,4,4a, 5-hexahydro-3-carbamoylmethyl-1-phenylpyrazo [2,1-c] [1,4] benzoxazine (2,1) g, mp 200-201 ° C).

The following compound is obtained analogously:

1,2,3,4,4a, 5-hexahydro-3-methyl-1-phenylpyrazo, [2,1-c] [3,4] benzoxazine; mp 126-129 ° C.

Example 24 '

Starting from 1, 2, 4, 4, 4a, 5-hexahydro-1-phenylpyrazo [2,1-c] [1,4] benzoxazin-2-one (2.85 g, 1.10-2 mol) and proceeding as described in Example 1, crystallization from methanol yields 1,2,3,4,4a, 5-hexahydro-1-phenyl-3-methylpyrazo [2,1c] [1,1], 4] benzoxazin-2-one (2.3 g), mp 189-192 ° C.

Example 25

To a solution of 3- (N- (1'-chloro-1'-phenyl) acetyl] aminomethyl [1,4] benzoxazine (26 g, 8.2.10 ^-2 mol) in 90% EtOH (150 mL) was added KI ( 25 grams) and the mixture was refluxed for 3 hours The solid was filtered off, the ethyl ether was evaporated to dryness to give an oil which eluted with [CHCl 3 -MeOH-NH 3 (190: 10: 0.5)] on a silica gel column. gives 1,2,3,4,4a, 5-hexahydro (2,1-c] [1,4] benzoxazin-2-one (19.7 g, mp 216-219 ° C).

Example 26

To a solution of 3-aminomethyl [1,4] benzoxazine (16.4 g, 1.10 ^-1 mol) in CH 2 Cl 2 (1000 mL) and triethylamine (15 mL) at -50 ° C was added 1-chloro-1-phenylacetyl chloride ( 14.7 mL) in CH 2 Cl 2 (200 mL) The solution was allowed to stand at room temperature, washed with 5% sodium bicarbonate solution, then washed with water until neutral, dried and evaporated to dryness 3- [N- (1'-chloro-1'-phenyl) acetyl] aminomethyl [1,4] benzoxazine (22.0 g) was obtained as a pure oil by TLC (silica gel thin layer chromatography).

Starting from 1, 2,3,4,4a, 5-hexahydropyrazo (2,1c) [1,4:] benzoazin-2-one, mp 245-248 ° C (4.1 g, 2.10 ^-1 mol) and, as described in Example 1, 1,2,3,4,4a, 5-hexahydro-3-carbamoylmethylpyrazo (2,1-c) [1,4] is obtained. benzoxazin-2-one (3.0 g), mp 230-232 ° C.

The following compound is obtained analogously:

1,2,3,2,4a, 5-hexahydro-3- (3'-dimethylamino- ²⁸ -propyl) pyrazo (2,1-c] [1,4] benzoxazin-2-one, mp 108-110 ° C.

Example 1 a d 2 8

A solution of 2H-3,4-dihydro-3-succinimidomethyl-4-ethyl lkarboxymethyl [1,4 j benzoxazine (8.8 g, 2,67.10-2 _Mo i) in 37% HCl (88 ml) was refluxed for 8 hours under reflux condenser. After evaporation to dryness, the residue is dissolved in acetone. Filtration gave 2H-3,4-dihydro-3-aminomethyl-4-carboxymethyl [1,4] benzoxazine as hydrochloride as a solid (3.2 g), mp 210 ° C (dec.). 2.1 g (8.1.10 ^-3 mol) of this compound was added to a solution of K 2 CO 5 (0.6 g, 4.35.10 ^-3 mol) in dimethylacptamide (21 mL) and the mixture was boiled for 10 minutes. 100 ml) and filtration of the resulting solution gave 1,2,3,4,4a, 5-hexahydropyrazo [2,1-c] [1,4] benzoxazin-2-one (1.05 g), mp 243 to 245 ° C.

Example 29

A solution of 2H-3,4-dihydro-3-succinimidomethyl-4-ethylcarboxymethyl [1,4] benzoxazine (45.5 g, 1.38.10 ^-1 mol) in 37% HCl (455 mL) was boiled for 8 hours under reflux. The pH of the solution was adjusted to 35% with NaOH

4.5 and then solid Na 2 CO 3 to 8.5. The resulting suspension was refluxed for 3 hours to give a solid which, by filtration, gave 1,2,3,4,4a, 5-hexahydropyrazo [2,1-c] [1,4] benzoxazin-2-one ( 21.8 g), mp 243-245 ° C.

Example 30

To a solution of 2H-3,4-dihydro-3-succinimidomethyl [1,4] benzoxazine (3 g, 1.16.10 ^-2 mol ·) in anhydrous dimethylacetamide (45 mL) was added NaaCO 3 (2.57 g, 1.8.10). ^-2 mol) and ethyl bromoacetate (2.64 g, 1.58.10 ^-2 mol). The mixture was heated to ISO ° C for 24 hours, water was carefully added and the resulting solution was extracted with ethyl ether; drying of Na 2 SO 4 and concentration in vacuo to dryness gave an oil which solidified by treatment with pentane. Crystallization of the solid from isopropanol gave 2H-α, 4-dihydro-3-succinimidomethyl-4-ethylcarboxymethyl [1,4] benzoxazine (2.5 g), mp 105-110 ° C.

Example 31

To a solution of 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethylimidazo [5,1-c] [1,4] benzoxazin-1-one (1 g, 4.10 ^-3 mol) in benzene (50 mL) P2S5 (0.46 g, 2.10 ^-3 mol) was added. The mixture was refluxed for 1 hour 30 minutes, then cooled, poured into water and the organic phase was removed. The aqueous phase is extracted several times with chloroform, the chloroform extracts are combined, dried over Na2SO4 and evaporated to dryness. The residue is chromatographed on a silica gel column (benzene-acetone).

: diethylamine (150: 50: 2)] to give 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethyl-imidazo [5,1-c] [1,4] benzoxazine-1-thione (0.55 g) mp 230-232 ° C dec.). Example 32

To a solution of 1H, 2,3,3a, 4-tetrahydro-2-carbamoylmethylimidazo [5,1-c] [1,4] benzoxazin-1-one (1 g, 4.10 * mol) in toluene (50 mL) was added. add P2S5 (0.92 g, 1.10 ³ mol). The mixture was refluxed for 1 hour, then cooled, poured into water and the organic phase was evaporated. Following the procedure described in Example 48, including elution on a silica gel column, 1 H, 2,3,3a, 4-tetrahydro-2-thiocarbamoylmethylimidazo [5,1-c] [1,4] benzoxazine-1 was obtained. thion (0.36 g).

Claims (2)

A process for the preparation of cyclic 1,4-benzoxazine and 1,4-benzothiazine derivatives of the general formula I, C 2 -C 6 alkynyl or C 2 -C 6 alkynyl, wherein any alkyl, alkenyl, or alkenyl group is optionally substituted with one to three substituents selected from halogen, carboxyl, hydroxyl, alkoxy up to 6 carbon atoms, one of -SO 2 R 11, -COOR 11 and -COR 11 wherein R 11 represents an alkyl group having 1 to 6 carbon atoms or a group in which Q is an oxygen or sulfur atom, R and R 1 are each hydrogen, C 1 -C 6 alkyl or a group of the formula wherein x is zero or an integer of 1 to 6, R 6 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms and R 7, R 8 and R 9 are each hydrogen or halogen, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, hydroxyl, carboxyl, or one of -OR 10, -SO 2 R 10, and -COOR 10 wherein: R 10 represents an alkyl group having 1 to 6 carbon atoms, R2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a group Ru ^R t R _g wherein R e, R 7 and R 9 are as defined above, R 1 represents a carbamoyl group, a thiocarbamoyl group, a C 1 -C 6 alkyl group, an alkenyl group wherein R 7, R 6 and R 8 are as defined above, wherein R 7, R 6 and R 9 are as defined above, one of the radicals R12 OF -N, \ R13 or R12 From —C — N,. II \ Q R 13 wherein Q is as defined above and R 12 and R 13 are each hydrogen or C 1 -C 6 alkyl, or R 12 and R 13 together with the nitrogen atom together form a 5- or 6-membered saturated or unsaturated heterocyclic ring, optionally containing, as another heteroatom, a nitrogen, sulfur or oxygen atom and optionally substituted with one to three alkyl groups of 1 to 6 carbon atoms or a group in which x, R e, R 7, R e and R 9 are as defined above; hydrogen or halogen, amino, C 2 -C 6 aliphatic acylamino, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, hydroxyl, carboxyl, C 1 -C 6 alkoxy, R 10- SO 2 -NH- in which R 10 is as defined above, one of -SO 2 R 11 and -COOR 11 in which R 11 is as defined above, or R and R together form a group - CHz- O-CH2-, or R a and R together with two adjacent carbon atoms of the benzene ring form together · Cs-C7 carbocyclic ring, Z is —CH — CH2—, AND Rta or - (CH) _n —A—, Rta wherein Rta represents a C 1-6 alkyl group or a group wherein x, R e, R 7, R e and R 9 are as defined above, n is zero or 1 and A is a group -CH 2 - or = C = Q wherein Q has as defined above, wherein -11 Z is -CH-CH 2 -, R 1 and R 1 are other than hydrogen, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula X wherein Z, Q, R, R 1, R 2, R a and R 5 are as defined above, or a salt thereof , is reacted with a compound of formula XI R3-X (XI), wherein R3 is as defined above and X is a halogen atom or an active alcohol ester moiety, preferably at a temperature of 50 to 150 ° C and at atmospheric pressure, and / or optionally the compound of formula I is converted to another compound of formula (I) and / or optionally converting a compound of formula (I) into a salt thereof, and / or optionally liberating a compound of formula (I) from the salt, and / or optionally splitting the mixture of stereoisomers into individual isomers. 2. The process according to item 1 for the preparation of cyclic derivatives of 1,4-benzoxazine and 1,4-benzothiazine of the above general formula I, in which Q represents an oxygen or sulfur atom, R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a group of the general formula wherein x is zero or an integer of 1 to 6, R 6 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms and R 7, R 8 and R 8 are each hydrogen or halogen, C 1 -C 6 alkyl, hydroxyl, carboxyl, or one of -OR 10, -SO 2 R 10, and -COOR 10 wherein R 10 is C 1-6 alkyl carbon, R1 and R2 are each hydrogen, R 3 is carbamoyl, thiocarbamoyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, wherein any alkyl, alkenyl or alkynyl group is optionally substituted with one to three substituents selected from halogen, carboxyl, hydroxyl, C 1 -C 6 alkoxy, one of -SO 2 R 11, -COOR 11 and -COR 11 wherein R 11 is C 1-6 alkyl or R ± R ₈ R _g where R7, Re and Rg are as defined above, a group 1 to 6 carbon atoms, one of the radicals -SO 2 R 11 and -COOR 11 in which R 11 is as defined above, or Rd and R 5 together form a group -Cl-I 2 -O-CH2, or Rd and R 5 together with two adjacent atoms the carbon benzene ring together form a C 5 -C 7 carbocyclic ring, Z is —CH — CH2—, Rid or - (CH) n-A-, R 1d wherein R 1d is a C 1 -C 6 alkyl group or a group in which R 7, R 8 and R 8 are as defined above, (g) one of the radicals R12 / - N, \ R13 or Rl2 / -C — N, II \ Q R 13 wherein Q is as defined above and R 12 and R 13 are each hydrogen or C 1 -C 6 alkyl, or R 12 and R 13 together with the nitrogen atom together form a 5- or 6-membered saturated or unsaturated heteromonocyclic ring optionally containing another heteroatom , such as nitrogen, oxygen or sulfur, and optionally substituted with one to three alkyl groups of 1 to 6 carbon atoms, or wherein x, R 5, R 7, R 6 and R 9 are as defined above, n is zero or 1 and A. --CH2 - or = C = Q, wherein Q is as defined above, when Z is --CH2 --CH2 -, R 1d then R 1d is other than hydrogen, and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (X) above wherein Z, Q, R, R 1, R 2, R d and R 5 are as defined above , or a salt thereof, reacts with a compound of the above formula (XI), wherein R 5 is as defined above, except for a hydrogen atom, and X is a halogen atom or an active alcohol ester residue, preferably at 50 to 150 ° C. and / or optionally converting a compound of formula I into another compound of formula I, and / or optionally converting a compound of formula I into a salt thereof, and / or optionally releasing a compound of formula I from the salt, and / or or optionally, the mixture of stereoisomers is resolved into the individual isomers. wherein x, Rg, R7, Re and R9 are as defined above, R 4 and R 5 are each hydrogen or halogen, C 1 -C 6 alkyl, hydroxyl, carboxyl, alkoxy