PL170771B1 - Method of obtaining novel derivatives of imidazo[2,1-b][3]benzazepin - Google Patents

Abstract

1. There are ways of creating new derivatives of im id azo (2, 1 -b) [3] benzazep and the formula 1 in which each dotted line denotes independently an optional bond, R denotes a hydrogen atom, a halogen atom, C1 -C4-alkyl or C1-C4-alkoxy, R2 is hydrogen, halogen, C1-C4-alkyl or C1-C4-alkoxy, R3 is hydrogen, C1-C1-C4 alkyl, ethenyl substituted with hydroxycarbonyl or C1-C4-alkoxycarbonyl, C1-C4-alkyl substituted with hydroxycarbonyl or C1-C4-alkoxycarbonyl, hydroxy-C1-C4-alkyl, formyl or hydroxycarbonyl, R4 is odor, C1-C4- alkyl, hydroxy-C1-C4-alkyl, phenyl or halogen, R is odor, C1-C4-alkyl or halogen, L is hydrogen, C1-C6-alkyl, C1-C6-alkyl substituted with one selected substituent from the group consisting of hydroxyl, halogen, C1-C4-alkoxy, hydroxycarbonyl, C1-C4-alkoxycarbonyl, C1-C4-alkoxycarbonyl-C1-C4-alkoxy, hydroxycarbonyl-C1- C4-alkoxy, C1-C4-alkoxycarbonylamino group, C1-C4-alkylaminocarbonyl group, C1-C4-alkylaminocarbonylamino group, C1-C4-alkylaminothiocarbonylamino group, aryl group, aryloxy group and arylcarbonyl group, both C1-C6-alkyl hydroxy as aryloxy, C3-C6-alkenyl, C3-C6-alkenyl substituted with aryl, in which groups each aryl is phenyl or phenyl substituted with a halogen atom, cyano, hydroxy, C1-C4-alkyl, C1- C4-alkoxy, aminocarbonyl or phenyl substituted with C1-C4-alkyl and loxycarbonyl or hydroxycarbonyl, or L is a radical of formula -Alk-Y -Her1, -Alk-NH-CO-Het2 or -Alk-H et3 in which the formulas A lk is C1-C4-alkanediyl, Y is O, S or NH, Het1, Het2 and Het are each furanyl, thienyl, oxazolyl, thiazolyl or imidazolyl, each optionally substituted with one or two substituents C1-C4-alkyl, pyrrolyl or pyrazolyl optionally substituted with formyl, hy droxy-C 1 -C 4 -alkyl, hydroxycarbonyl, C 1 -C 4 -alkoxycarbonyl or one or two substitutes for nickam on C 1 -C 4 -alkyl, uadiazohl or oxadiazohl optionally substituted with amine or C 1 -C 4 -alkyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each optionally substituted with C1-C4-alkyl, C1-C4-alkoxy, amino, hydroxyl or halogen, im idazo [4,5-c] pyridine1-2, and Het can also be 4, 5-dihydro-5-keto-1H-tetrazohl substituted with C 1 -C 4 -alkyl, 2-keto-3-oxazolidinyl, 2,3-dihydro-2-keto-1 H -benzo-idazol-1 or a radical of formula wherein where R6 is hydrogen or C1-C4-alkyl and A -Z is -S-CH = CH-, -S-CH2-CH2 -, -S-CH2-CH2-CH2-, -CH = CH -CH = CH -, -CH2-CH2 -CH2-CH2-, -N (CH3) -C (CH3) = CH- or -CH = C (CH3) -O-, excluding 6.1 1 -d and h yd ro l 1- (piperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepines, pharmaceutically acceptable addition salts or stereochemically isomeric forms thereof, characterized by dehydrating add the alcohol of formula 4 or 5 in the presence of a dehydrating reagent to obtain a compound of formula 1 in which there is a double bond between the piperidinyl and the tricyclic group, PL PL

Description

The subject of the invention is a process for the preparation of new imidazo [2,1-b] [3] benzazepine derivatives.

The international publication WO 88/03138 describes benzo [5,6] cycloheptapyridines with antiallergic and anti-inflammatory effects. EP-A-0339978 describes a (benzo-or pyrido) -cycloheptaheterocyclic compound having PAF-antagonistic, antihistamine and / or anti-inflammatory activity. The compounds disclosed in the present invention differ in their pharmacological activity in that they have no PAF-antagonistic activity but have a specific antihistamine effect.

International publication WO 92/06981 describes 6,11-dihydro-1 1- (piperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepine and 1-acetyl-4- (5,6-dihydro -1 1 H -imidazolo [1,2-b] [3] benzazepinoylidene-1 1) piperidine, the latter useful as a PAF antagonist. These compounds differ from the compounds according to the invention by the substituent on the nitrogen atom of the piperidine ring and by their pharmacological profile. In this publication they are described as having activity against platelet aggregation stimulating factor (PAF) without any reference to their antihistamine activity.

J. Mcd.Chem., 26 (1983), 974-980 describes certain 1-methyl-4-piperidinylidene-9 substituted pyrrolo [2,1-b] [3] benzazepine derivatives with neuroleptic properties. The tests included there predict their psychotic effects, e.g. central dopaminergic effects. There is no information in this publication that these compounds have antihistamine activity.

The compounds according to the invention are structurally different from the cited known compounds and exhibit antihistaminic activity. The new compounds are specific and peripherally acting histamine antagonists. Their specificity is proved by the lack of PAF antagonism. The benefits of their peripheral action are that they are non-sedating, i.e. they do not have central nervous system effects such as dopaminergic effects.

170 771

The invention relates to a process for the preparation of new imidazo [2, i-b] [3] benzazepine derivatives of the formula

wherein each dotted line independently represents an optional bond; R ¹ is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; R ² is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; R ³ is hydrogen, C 1 -C 6 alkyl, ethenyl substituted with hydroxycarbonyl or C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl substituted with hydroxycarbonyl or C 1 -C 6 alkoxycarbonyl; hydroxy-Ci-C6-alkyl, formyl or hydroxycarbonyl; R ⁴ is hydrogen, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, phenyl or halogen, R 4 is hydrogen, C 1 -C 6 -alkyl or halogen; L is hydrogen, C1-C6-alkyl, C1-C6-alkyl substituted with one substituent selected from the group consisting of hydroxyl, halogen, C1-C6-alkoxy, hydroxycarbonyl, C1-C4-alkoxycarbonyl, C1-C6-alkoxycarbonyl-C1 -C1-C6-alkoxy, hydroxycarbonyl-C1-C6-alkoxy, C1-C6-alkoxycarbonylamino, C1-C6-alkylaminocarbonyl, C1-C6-alkylaminocarbonylamino, C1-C6-alkylaminothiocarbonylamino, aryl, arylcarbonyl group; C1-C6-alkyl substituted with both hydroxy and aryloxy; C3-C6-alkenyl; Aryl substituted C ₃ -C 6 alkenyl; wherein each aryl is phenyl or phenyl substituted with halogen, cyano, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, aminocarbonyl or phenyl substituted with C1-C6alkyloxycarbonyl or hydroxycarbonyl; or L represents a radical of the formula -Alk-YHet, -Alk-NH-Co-Het2 -Alk-Het ³ ; wherein Alk is C1-C6-alkanediyl; Y is O, S or NH; Heti Het2 and Het3 are each furanyl, thienyl, oxazolyl, thiazolyl or imidazolyl, each optionally substituted with one or two Ci-Ctalkyl substituents; pyrrolyl or pyrazolyl optionally substituted with formyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl, C1-C6-alkoxycarbonyl or with one or two C1-C6-alkyl substituents; thiadiazolyl or oxadiazolyl optionally substituted with amino or C1-C6alkyl; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each optionally substituted with C1-C4-alkyl, C1-C6-alkoxy, amino, hydroxy or halogen; imidazo [4,5c] pyridineI-2; and Het ³ may also represent ^{4,5-dihydro-5-oxo-1H-tetrazolyl,} Cica-substituted alkyl, 2-oxo-3-oxazolidinyl, 2,3-dihydro-2-oxo-IH-benzimidazolyl, or-I a radical of the formula

pattern 2 pattern 3

Wherein R ⁶ is hydrogen or C 1 -C 6 -alkyl; and AZ is -S-CH = CH-, -S-CH2-CH2-, -S-CH2-CH2-CH2-, -CH = CH-CH = CH-, -CH2-CH2-CH2-CH2-, - N (CHs) C (CH3) = CH- or -CH = C (CH3) -O-; excluding 6,11-dihydro-1 1- (piperidinylidene-4) -5Himidazo [2,1-b] [3] benzazepine; their pharmaceutically acceptable addition salts and isomeric stereochemical forms.

The term halogen as used in the above definitions denotes fluorine, chlorine, bromine and iodine; C1-C4-alkyl denotes a straight chain or branched saturated hydrocarbon radical containing 1 to 4 carbon atoms such as e.g. methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl ; C 1 -C 6 -alkyl means C 1 -C 6 -alkyl radicals as defined above and their higher homologues with 5 to 6 carbon atoms, such as, for example, pentyl and hexyl, C 3 -C 6 -alkenyl means straight or branched chain hydrocarbon radicals containing one double bond and 3 to 6 carbon atoms such as, for example, propenyi-2, butenyl-2, butenyl-3, 2-methylpropenyi-2, pentenyi-2, pentenyi-3, 3,3-dimethylpropenyi-2, hexenyl and the like; C 1 -C 6 alkanediyl denotes straight or branched chain divalent hydrocarbon radicals containing from 1 to 4 carbon atoms, such as e.g. methylene, ethanedi1-1.1, ethanediM.2, propanedi1-1.3, butanedi1-1.4 and similar.

The term pharmaceutically acceptable acid addition salt as used hereinbefore means the non-toxic, therapeutically active acid addition salt forms which the compounds of formula 1 are able to form. Compounds of formula I having basic properties can be converted into the corresponding therapeutically active non-toxic acid addition salt forms by treating the compound in the free base form in a known manner with an appropriate amount of the appropriate acid. Examples of suitable acids are, for example, inorganic acids, e.g., hydrohalic acid, e.g., hydrochloric acid, hydrobromic acid and like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as e.g. acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxypropionic acid, 2-ketopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, 2-hydroxysuccinic acid, 2-acid, 3-dihydroxy succinic acid, 1,2,3-hydroxypropane-tricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, and the like.

Compounds of formula I with acidic properties can be similarly converted into the corresponding therapeutically active forms of the non-toxic base addition salts. Examples of such base addition salt forms are, for example, sodium, potassium, calcium, and also salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, N-methyl-D-glucamine, hydrabamine, amino acids, e.g. arginine, lysine. The term pharmaceutically acceptable addition salts also comprises the solvates which the compounds of formula I are able to form, e.g. hydrates, alcoholates and the like.

The term stereochemically isomeric forms as used hereinbefore means the optional various isomeric forms as well as the conformational forms which the compounds of formula 1 may adopt. Unless otherwise mentioned or indicated, the chemical designation of compounds means a mixture of all possible stereochemically and conformational isomeric forms, wherein such a mixture contains all diastereoisomers, enantiomers and / or conformers of the basic molecular structure. All stereochemically isomeric forms of the compounds of formula 1, whether in pure form or in admixture, are within the scope of the present invention.

Certain compounds of the invention may exist in different tautomeric forms, and such tautomeric forms are included within the scope of the invention.

Of interest are those compounds of Formula I wherein each dotted line independently represents an optional bond; R ¹ is hydrogen, halogen, or C 1-6 alkyl; R 2 is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; r3 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, formyl, or hydroxycarbonyl; R ⁴ is hydrogen, C 1 -C 4 -alkyl, hydroxy-C 1 -C 6 -alkyl, phenyl or halogen; R ⁵ is hydrogen; L is a hydrogen atom, C1 -C6-alkyl, C1 -C6-alkyl substituted with hydroxyl, C1 -C6-alkoxy, C1 -C6-alkoxycarbonylamino, C1-C4-alkylamlncarbonyl,

170 771

A C 1 -C 6 alkylaminocarbonylamino group, a C 1 -C 4 alkylaminothiocarbonylamino group, an aryl group or an aryloxy group; C8-C6-alkenyl; Aryl-substituted C3-C6-alkenyl; wherein each aryl is phenyl or phenyl substituted by halogen, C1-C6alkyl, C1 -C6alkoxy; or L is a radical of formula -Alk-Y-Heti -Alk-NH-CO-Het ² or -AlkHet ³ ; wherein Alk is C1-C6-alkanediyl; Y is O, S or NH; Het ¹ , Het2 and Het ³ are each furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl or imidazolyl each optionally substituted with one or two C1-C4-alkyl substituents; thiadiazolyl or oxadiazolyl optionally substituted with amino or C1-6alkyl; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each optionally substituted with C1-C6-alkyl, C1-C6-alkoxy, amino, hydroxy or halogen; imidazo [4,5-c] pyridinb2; and Het ³ may also be 4,5-dihydro-5-keto-IH-tetrazolyl substituted with C 1 -C 6 -alkyl, 2-keto-3-oxazolidinyl, 2,3-dihydro-2-keto-1H-benzimidazolyl-I or a radical of the formula

or

pattern 3

-S-CH2-CH2-, -S-CH2-CH2-CH2-, -CH = CH-CH = CH- or -CH2-CH2-CH2-CH2-; except

6.ii-dihydro-11 - (piperidinylidene-4) -5H-imidazo [2, and -b] [3] benzazepines.

Another group of interesting compounds consists of those compounds of formula I wherein L is

C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted with hydroxycarbonyl or C 1 -C 6 alkoxycarbonyl. Further interesting compounds are those compounds of formula I wherein R ¹ , R ² , k, R 4 and

R ⁵ are hydrogen.

Yet another group of interesting compounds of formula I are compounds of formula

R is the formula Ia wherein R 1, R 2, R 3, R ⁴ , R ⁵ and L are as defined above for formula i.

Those compounds of formula I are preferred, wherein R 3 is hydrogen, C 1 -C 6 -alkyl, formyl, hydroxy-C 1 -C 6 -alkyl or hydroxycarbonyl; R4 is hydrogen, halogen or hydroxy-Ci-C6-alkyl; and L is hydrogen, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, hydroxycarbonyl-C 1 -C 4 -alkyl and, C 1 -C 4 -alkoxycarbonyl-C 1 -C 6 -alkyl, C 1 -G-alkoxycarbonylamino-C 1 -C 4 -C 6 -alkyl, aryl-C 1 -C 6 -alkyl, propenyl, or L is a radical of formula -Alk-Y-Het,

Λ 19 3

-Alk-NH-CO-Het2 or -Alk-Het; in which the formulas Het, Het and Het 'are each furanyl, oxazolyl or thiazolyl, each optionally substituted with C1-6alkyl; thiadiazolyl optionally substituted with amino, pyridinyl, or pyrimidinyl, each optionally substituted with hydroxyl; imidazo [4,5-c] pyridine 1-2; and Het ³ may also be a radical of formula 3.

More preferred compounds are those preferred compounds, wherein R 1 is hydrogen or halogen; R2 is hydrogen, halogen or C1-C4-alkoxy; and L is C1-C4-alkyl, halo-C1-C4-alkyl, hydroxycarbonyl-C1-C4-alkyl, C1-C4alkoxycarbonyl-C1-C4-alkyl, or a group of the formula -Alk-Y-Het wherein Y is NH.

Even more preferred are those compounds wherein R4 is hydrogen or halogen; and L is hydrogen, C1-C4-alkyl, hydroxycarbonyl-C1-C4-alkyl, C1-C4-alkoxycarbonyl-C1-C4-alkyl, or a group of the formula -Alk-Y-Het! wherein Het is thiazolyl or imidazo [4,5-c] pyridin1-2.

The most advantageous compounds are:

5,6-dihydro-11 - (1-methylpiperidinylidene-4) -11H-imidazo- [2,1-b] [3] benzazepine; 9-fluoro-6,11-dihydro-11 - (1-methylpiperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepma;

11- (1-methylpiperidinylidene-4) -11H-imidazo- [2,1-b] [3] -benzazepine;

6,11-dihydro-11 - (1-methylpiperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepinyl-3-methanol;

8-fluoro-6,11-dihydro-11 - (1-methylpiperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepine; aldehyde 6,11-dihydro-1 1- (1-methylpiperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepinyl-3-formic;

6,11-dihydro-11 - (1-methylpiperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepine-3 carboxylic acid;

7-fluoro-6,11-dihydro-11 - (1-methylpiperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepine; 4- (8-fluoro-5,6, -dihydro-11H-imidazo [2,1-b] [3] benzazepinylidene-11) piperidine-1-propionic acid dihydrate, stereoisomers and pharmaceutically acceptable acid addition salts thereof.

In the following description, in order to simplify the structural formulas of the compounds of formula I and the intermediates involved in their preparation, the imidazo [2,1-b] [3] -benzazepine group was designated by the symbol T.

pattern 6

170 771

Compounds of formula 1 in which a double bond exists between piperidinyl and the imidazo [2,1-b] [3] benzazepine group can be prepared by dehydrating the alcohol of formula 4 or 5 (Scheme 1)

pattern 5

Scheme 1

Said dehydration reaction may conveniently be carried out using known dehydrating reagents by methods known in the art. Suitable dehydrating reagents are, for example, acids, e.g. sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonic acid, carboxylic acids, e.g. acetic acid, trifluoroacetic acid and mixtures thereof, anhydrides, e.g. acetic anhydride, phosphorus pentoxide and the like; other suitable reagents, for example, zinc chloride, thionyl chloride, boron trifluoride etherate, pyridine phosphoryl chloride salt, potassium bisulfate, potassium hydroxide. In some cases, said dehydration reaction may require heating the reaction mixture, especially at reflux temperature. Again, only those compounds of formula I in which L is a group stable under the reaction conditions can be prepared according to the above-mentioned reaction method. It is particularly noteworthy that the latter reaction, when carried out on an intermediate of formula 4 where the dotted line does not indicate an optional bond, may also in some cases yield a compound of formula 1 with a double bond on the tricycle and a single bond. bridging the tricyclic part with the piperidine part (scheme 2).

170 771

pattern 4

Scheme 2

Intermediates of formula IV can be prepared by adding a Grignard reagent of formula 7 to a ketone of formula 8 in a reaction-inert solvent, e.g. tetrahydrofuran (Scheme 3).

Scheme 3

The tricyclic ketones of formula 8 are in turn prepared from intermediates of formula 9 by oxidation with a suitable oxidizing agent in a run-inert solvent (scheme 4).

170 771

pattern 9 pattern 8

Scheme 4

Suitable oxidizing reagents are, for example, manganese dioxide, selenium dioxide, cerammonium nitrate and the like. Solvents inert to the course of the reaction are, for example, halogenated hydrocarbons, e.g., dichloromethane, trichloromethane and the like.

Compounds of formula 9 in which the dotted lines do not represent an optional bond may be prepared from the corresponding compounds of formula 9 in which the dotted lines represent an optional bond by proceeding as known for hydrogenation, e.g. by reacting with hydrogen in the presence of a hydrogenation catalyst (diagram 5).

R pattern 9 pattern 9a

Scheme 5

Intermediates of formula 9a can be prepared from a benzazepine of formula 10 by reacting it with a reagent of formula 11 and cyclizing the thus obtained intermediate of formula 12 in an acidic medium 6). Wis of the formula U R is C 1 -C 4 -alkyl or both R together are C 1 - 6 -alkanediyl, e.g., ethanediM.2, propanedi1-1.3, 2,2-dimotylpropanediyl 1,3.

170 771

pattern 10 pattern 11

compound of formula 9a

Scheme 6

Compounds of formula I2 are conveniently prepared by mixing and heating the reactants in a reaction-inert solvent such as, for example, an alcohol, e.g., methanol, ethanol, and the like.

The cyclization reaction to the intermediates of formula 9-a is carried out by stirring and heating the starting material of formula I2 in a carboxylic acid such as e.g. acetic acid, propionic acid, optionally in admixture with an inorganic acid such as e.g. hydrochloric acid.

Intermediates of formula 9 can also be prepared by cyclizing an intermediate of formula I3 (scheme 7).

Scheme 7

170 771

This cyclization reaction is conveniently carried out in the presence of a Lewis acid, e.g. aluminum chloride, and the like. In some cases it may be appropriate to supplement the reaction mixture with a sufficient amount of sodium chloride.

Intermediates of formula 4 can also be prepared by cyclizing an intermediate of formula 14 in the presence of an acid in a reaction-inert solvent (scheme 8).

pattern 14 pattern 4

Scheme 8

A suitable acid for the above reaction is, for example, a Lewis acid, e.g., tin (IV) chloride, and the like. A suitable solvent inert to the course of the reaction is, for example, a halogenated hydrocarbon, for example, dichloromethane, 1,2-dichloroethane, and the like.

Intermediates of formula V can be prepared by reacting a ketone of formula 15 with an intermediate of formula 9 in the presence of e.g. lithium diisopropylamide in a reaction-inert solvent, e.g. tetrahydrofuran (Scheme 9).

pattern 9 pattern 5

Scheme 9

170 771

Ketones of formula 14 can be prepared by adding a compound of formula 16 to the reagent of formula 17 (scheme 10).

L— N

V- C pattern 16 (

N

Ketones of formula 14 in which the dotted line does not represent an optional double bond can be prepared by N-alkylation of an intermediate of formula 16 with a reagent of formula 18 in which W is a reactive leaving group as defined above (scheme 11).

pattern 14

Scheme 11

Said N-alkylation reaction may conveniently be carried out in a reaction-inert solvent such as, for example, an aromatic hydrocarbon, e.g., benzene, methylbenzene, dimethylbenzene and the like; an alkanol, e.g., methanol, ethanol, butanol-1 and the like; a ketone e.g. propanone-2,4-methylpentanone-2 and the like; an ether, e.g., tetrahydrofuran, 1,4-dioxane, diethyl ether and the like; a bipolar aprotic solvent, e.g., Ν, Ν-dimethylformamide, N, N-dimethylformamide, N, N-dimethylformamide, dimethylsylphoxide, nitrobenzene, 1-methylpyrrolidinone-2 and the like; a halogenated hydrocarbon, e.g., dichloromethane, 1,2-dichloroethane and the like; or a mixture of such solvents. Addition of a suitable base such as e.g. carbonate, bicarbonate, alkoxide, hydride, amide, alkali metal or alkaline earth metal hydroxide or oxide, e.g. sodium carbonate, sodium bicarbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butanol, sodium hydride, sodium amide, sodium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide and the like; or an organic base such as e.g. an amine, e.g. N, N-diethylethylamine, N- (1-methylethyl) -2-propylamine, 4-ethylmorpholine, pyridine and the like can be used to bind the acid released during the reaction. The addition of an iodide salt, preferably an alkali metal iodide, is suitable in some cases. Slightly elevated temperature and stirring may increase the rate of the reaction. Alternatively, said N-alkylation may be carried out using known conditions for catalyzed phase transfer reactions.

Furthermore, ketones of formula 14 wherein the dotted line does not represent an optional bond can also be prepared by reductive N-alkylation of compounds of formula 16. This reductive N-alkylation reaction may conveniently be carried out by reducing the reaction mixture in a suitable solvent inert to the reaction. by following the known procedure for reducing N-alkylation. In particular, the reaction mixture may be stirred and / or heated to increase the rate of the reaction. Suitable solvents are, for example, water; CrC6-alkanols, e.g. methanol, ethanol, butanol-1 and the like; esters, e.g., ethyl acetate, γ-butyrolactone and the like; ethers, e.g., tetrahydrofuran, 1,4-dioxane, diethyl ether, 2-methoxyethanol and the like; halogenated hydrocarbons, e.g., dichloromethane, trichloromethane and the like; bipolar aprotic solvents, e.g., N, N-dimethylformamide, dimethyl sulfoxide and the like; carboxylic acids, e.g., acetic acid, propionic acid and the like; or mixtures of such solvents. The term known reductive N-alkylation procedure means that the reaction is carried out either with sodium cyanoborohydride, sodium borohydride, formic acid or a salt thereof, e.g. ammonium formate and similar reducing agents, or alternatively in a hydrogen atmosphere, optionally at elevated temperature and / or under increased pressure in the presence of a suitable catalyst such as, for example, palladium on carbon, platinum on carbon and the like. In order to prevent the undesirable further hydrogenation of certain functional groups in the reactants and reaction products, a suitable catalyst poison, e.g., thiophene, quinoline, and sulfur, and the like may be advantageously added to the reaction mixture. In some cases it may also be advantageous to add alkali metal salts, e.g. potassium fluoride, potassium acetate and the like to the reaction mixture.

Intermediates of formula 16 are conveniently prepared from an ester of formula 19 by reaction with a protected imidazole derivative of formula 20 by reaction with a strong base such as e.g. methyllithium, butyllithium, sodium amide, dialkyl amide, e.g. lithium diisopropylamide, or mixtures thereof, in a reaction-inert solvent, e.g., tetrahydrofuran, hexane, methylbenzene and the like, or mixtures thereof (Scheme 12).

ABOUT

-OCi-4alkyl

compound of formula 16 formula 19

Scheme 12

170 771

In the formula, P represents a protective group such as, for example, a di (C 1 -C 6 -alkoxy) methyl group, a C 1 -C 6 alkoxymethyl group, a benzenesulfonyl group, a trimethylsilylethoxymethyl group, a N, N-dialkylaminomethyl group, which can be removed by acid hydrolysis. The reaction of a compound of formula I9 with a compound of formula 20 may conveniently be carried out at low temperature. For example, the reagent of Formula 20 can be added at a temperature of between about -80 ° C to about -40 ° C to the strong base. The ester of formula I9 is then added and the reaction mixture is allowed to gently warm to room temperature. The product thus obtained is converted into an intermediate of formula I6 by very mild acid hydrolysis and is isolated in a known manner.

Ketones of formula I4 where L is methyl can be prepared from ketones where L is hydrogen by reductive N-alkylation with formaldehyde by proceeding as previously described.

Ketones of formula i4 where L is hydrogen (formula i4b) are prepared by hydrolyzing a carbamate of formula i4a in acidic or basic media using known methods (scheme i3). Compounds of formula i4a are hydrolyzed in acidic or basic conditions in a known manner. For example, concentrated acids such as hydrobromic acid, hydrochloric acid or sulfuric acid may be used, or alternatively bases such as alkali metal or alkaline earth metal hydroxides in water, an alkanol or a mixture of water and alkanol may be used. Suitable alkanols are methanol, ethanol, b'2-propane and the like. In order to increase the rate of the reaction, the reaction mixture is preferably heated, especially to reflux temperature.

Reductive N-alkylation (CH, O)

With n

Scheme I3

170 771

Intermediates of formula 14a can be prepared by reacting an acid halide of formula 21 with an imidazole derivative of formula 22 (scheme 14).

the compound of Formula 14a

Scheme 14

This reaction is conveniently carried out while stirring and heating the reactants in the presence of a base such as, for example, an amine, e.g., N, N-diethylethylamine, N-methylmorpholine, and the like, in a suitable solvent such as, for example, pyridine, acetonitrile or mixtures thereof.

Intermediates of formula 14c can also be prepared from an ester of formula 23 by reaction with an imidazole of formula 22 in the presence of a strong base such as e.g. methyl lithium, butyl lithium, sodium amide, dialkyl lithium amide, e.g. lithium diisopropyl amide, or mixtures thereof in a suitable a solvent inert to the course of the reaction, for example, in tetrahydrofuran, hexane, methylbenzene and the like, or a mixture thereof (scheme 15).

This reaction is conveniently carried out at low temperature. For example, the reagent of formula 22 can be added at a temperature between about -80 ° C to about -40 ° C to the strong base. The ester is then added and the reaction mixture is allowed to gently warm to room temperature.

relationship for a relationship of Fr.

--- - ¹ font ' ^{1 In} Formula 22 Formula 14c

CH ₃ - N

About kc

1-4 alkyl formula 23

Scheme 15

The compounds of formula I, especially those where L is (C1-C6-alkyl or phenyl) oxycarbonyl, C1-C4-alkylcarbonyl, pharmaceutically acceptable acid addition salts, and their stereochemically isomeric forms thereof, have useful pharmacological properties. They are in particular active antiallergic agents, the activity of which can be clearly demonstrated from the test results obtained in various indicative tests.

Antihistaminic activity can be demonstrated by the Protection of Rats from Compound 48/80 - induced Lethality 's test (Arch. Int. Pharmacodyn. Ther., 234, 164-176, 1978);

170 771

Histamine - induced Lethality in Guinea Pig's test (Arch. Int. Pharmacodyn. Ther., 251, 39-51, 1981); and a broad antiallergic activity can be demonstrated in the Passive cutaneous anaphylaxis in Rat's test (Drug Dev. Res., 5, 137-145, 1985) (For some compounds this test was modified by replacing compound 48/80 with Ascaris allergens) and Ascaris Allergy in Dog's assay (Arch. Int. Pharmacodyn. Ther., 251, 39-51, 1981 and Drug Dev. Res., 8, 95-102, 1986).

The compounds according to the invention show a broad spectrum of antiallergic profile as evidenced by the results obtained in the various test procedures cited above.

A second advantageous feature of the compounds according to the invention is their excellent oral action; these compounds have been found to be practically the same potency when administered orally as when administered subcutaneously.

An especially important feature of most of the compounds of the invention is their lack of sedative properties at therapeutic dose levels, which are a troublesome side effect of many antihistaminic and antiallergic compounds. The lack of sedative properties of the compounds according to the invention can be demonstrated, for example, by the results obtained in a study on the sleep-wake cycle of rats (Psychopharmacology, 97, 436-442, 1989).

Another interesting feature of the compounds of the invention relates to their rapid onset of action and the favorable duration of their action.

Due to their antiallergic properties, compounds of formula I wherein L is (C1-C4-alkyl or phenyl) oxycarbonyl, C1-C4-alkylcarbonyl and their acid addition salts are very useful for the treatment of a wide range of allergic diseases such as e.g., allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma and the like.

Due to their useful antiallergic properties, the compounds according to the invention may be formulated for administration in various pharmaceutical forms. To prepare antiallergic compositions containing the compounds of the present invention, an effective amount of a specific compound, in the form of a base or in the form of an acid addition salt as active ingredient, is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take various forms. depending on the form of preparation desired for administration. The pharmaceutical compositions are desirably in unit dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in the form of oral dosage units, any of pharmaceutical media such as, for example, water, glycols, oils, alcohols, and the like for oral liquid preparations such as suspensions, syrups, elixirs, and solutions or solid carriers. such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier is usually at least in large part sterile water, although other ingredients may be added, for example, to aid dissolution. For example, injection solutions can be prepared in which the carrier is a saline solution, a glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared from which suitable liquid carriers, suspending agents and the like can be used. In the compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally in combination with suitable minor additives of any kind, which additives do not have any significant deleterious effects on the skin. These additives may facilitate application to the skin and / or may be helpful in formulating the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on application or as an ointment. Acid addition salts of the subject compounds, due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.

170 771

For ease of administration and uniformity of dosage, it is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form. Dosage unit form as used herein and in the claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored and coated tablets), capsules, pills, powder packs, wafers, injection solutions or suspensions, teaspoons, tablespoons and the like, and segregated multiples thereof.

The compounds according to the invention are used to treat warm-blooded animals suffering from the above-mentioned allergic diseases by administering to these warm-blooded animals an antiallergically effective amount of the compounds of the formula I or their pharmaceutically acceptable acid addition salts.

Typically, an antiallergically effective amount is considered to be from about 0.001 mg / kg to about 20 mg / kg body weight, and more preferably from about 0.01 mg / kg to about 5 mg / kg body weight.

The following examples are intended to illustrate and not to limit the scope of the invention.

Example 1: Mixture of 6 g of 11 - (1-methylpiperidinyl-4) -2-phenyl-11H-imidazo [2,1-b] [3] benzazepinoIu-11 (interm. 32, m.p. 239.8 ° C) and 300 ml of methanol was hydrogenated under normal pressure at room temperature in the presence of 3 g of 10% palladium on carbon as a catalyst. After the calculated amount of hydrogen was bound, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; CH 2 Cl 2 / CH 3 OH 95: 5 -> CH 2 Cl 2 / CH 3 OH (NH 3) 95: 5. The eluent from the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried to give 3.2 g ( 53.5%) 6,11-dihydro-1 1- (1-methylpiperidinyl-4) -2-phenyl-5H-imidazo [2,1-b] [3] benzazepinol-1 1, mp 225.3 ° C (interm. 33).

A mixture of 2.2 g of intermediate (33), 10 ml of sulfuric acid and 10 ml of methanesulfonic acid was stirred for 2 hours at 70 ° C. The reaction mixture was poured into ice water and basified with aqueous NaOH solution. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH 2 Cl 2 / CH 3 OH 95: 5 CH 2 Cl 2 / CH 3 OH (NH 3) 90:10). The eluent from the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.73 g (34.2%) of 6.11-dihydro-1 1- (1-methylpiperidinylidene-4) -2-phenyl-5H-imidazo [2,1-b] [3] benzazepine; mp. 171.5 ° C (comp. 4.01).

Example II. A mixture of 10 ml of tetrahydrofuran and 1.24 g of magnesium was stirred under a nitrogen atmosphere. 1 crystal of iodine was added, then 1.2 g of bromoethane was added dropwise, and a solution of 6.7 g of 4-chloro-1-methyl-piperidine in 25 ml of tetrahydrofuran was added under reflux. After heating for 1 hour at reflux, the reaction mixture was cooled (0 ° C). Then 25 ml of tetrahydrofuran were added and 9.8 parts of intermediate (30) were added portionwise keeping the temperature below 10 ° C. The mixture was stirred for 1 hour at room temperature and decomposed with aq. NH 4 Cl. The product was extracted with trichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 / CH3OH (NH3) 95: 5). The eluent from the second fraction was evaporated and the residue was crystallized from acetonitrile in two fractions, yielding 4.76 parts (32.2%) of 11- (1-methylpiperidinyl-4) -1 1 H -imidazo [2,1-b] [3] -benzazepinol-11, m.p. 152.2 ° C (interm. 31).

A mixture of 14.7 g of intermediate (31) and 150 ml of acetic anhydride was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. It was basified with an aqueous NaOH solution and then extracted with dichloromethane and the extract was dried, filtered and evaporated and the residue was purified by column chromatography (silica gel;

170 771

CH 2 Cl 2 / CH 3 OH 95: 5 -> CH 2 Cl 2 / CH 3 OH (NH 3) 95: 5). The eluent from the desired fraction was evaporated and the residue was taken up in diethyl ether. It was filtered and the filtrate was treated with activated charcoal. After filtration, the solution was evaporated and the residue was triturated with isopropyl ether. The product was filtered off and dried to give 6 g (ii, 5%) of the product. The second fraction was also evaporated and the residue was taken up in diethyl ether. It was filtered and the filtrate was combined with the isopropyl ether filtrate of the first fraction and evaporated to give an additional 8.2 g (59.1%) of product. Overall yield: 9.8 g (70.6%) of ii- (imethylpiperidinylidene-4) -1H-imidazo [2, i-b] [3] benzazepine; mp. 35.8 ° C (comp. 6.0i).

All compounds listed in Tables 1-7 were prepared following the preparation methods described in Examples 1-2.

Table i

L-N

Relationship no L- Physical data and 2 3 i.0i CH3- 1.1 209.3 ° C / CF3SO3H i.02 CH3- 11.and 54.5 ° C i.03 H5C2OOC- 1.1 and 70.6 ° C i.04 H- 1.1 and 92.5 ° C / and / 2 H 2 O 2 fumarate i.05 C2H5- 1.1. and 84.2 ° C / 2 maleate i.06 CH3CH (CH3) - 1.1. and 83.6 ° C / 2 maleate i.07 CH2 = CH-CH2- 1.1. and 60.8 ° C / 2 maleate i.08 CH2 = C (CH3) -CH2- 11. and 79.5 ° C / 3/2 fumarate i.09 CH3-C (CH3) = CH-CH2- 1.1. and 27.2 ° C i.i0 C6H5-CH = CH-CH2- 11. and 72.2 ° C / fumarate i.ii C6H5-CH2- 1.1. 207.2 ° C

170 771 c d table 1

and 2 3 i.i2 C ^H 3 ° ^ J> - < ^CH 2) 2- t1. 1880.5 ° C / 2 (COOH) 2 i.i3 mp 18I, 8 ° C i.i4 ^r V ^{x (ch} p ₂ - (CH ₂ ) ₂ - 0 1.1. I97.8 ° C / H2 <O · fumarate i.i5 ^ 3 © ^ 2 ^} 2 ~ mp 163.8 ° C i.i6 © H, 1.t. 99.0 ° C i.i7 ^h 2n ^ n ^ ch ₃ CH, ¢ 9¾ ^- mp 257.4 ° C i.i8 O- ^CH 2 1.t. I60.3 ° C i.i9 ^CH '1> ^{c 2} ' mp I62.1 ° C / H20-2 fumarate i.20 (^^ N ^- (CH ₂ ) 2 ^_ 1.t. 1888.8 ° C / 3/2 fumarate i.2i K = .N t t 170.7 ° C / 2 maleate i.22 0 HNSł- (CH,), - ⁵ and i. 194.7 ° C about

170 771 c d table 1

1 2 3 1.23 C ₂ H5-O- (CH ₂ ) 2- 1.1. 176.5 ° C / 2 maleimane 1 24 CH -Hc- NH — C- (CH ₂ ) ₂ - mp 165.5 ° C 1 25 H5C ₂ OOC-NH- (CH ₂ ) 2- 1.1 167.2 ° C / 2 fumarate 1.26 NC-CH2- mp 220.4 ° C 1.27 H ₂ N- (CH ₂ ) 2- 1 28 H ₂ N- (CH ₂ ) 2- 1.1. 186.6 ° C / 1/2 H ₂ O 3 fumarate 1.29 ho- (ch ₂ ) 2- 1.1. 225.1 ° C / CF ₃ SO ₃ H 1.30 ho- (ch ₂ ) 2- t t 145.7 ° C / 2 maleimane 1.31 © _ /> - o- (ch ₂ ) ₂ - 1.1 172.6 ° C / 2 maleimane 1.32 / _ζ > ~ νη- (οη ₂ ) ₂ - X_N 1.1. 165.1 ° C 1.33 N— N h ₂ n © _s © nh- (ch ₂ ) ₂ - 1.1. 251.4 ° C 1.34 / © © nh- (ch ₂ ) _? - 1.1. 205.5 ° C / 1 / 2H2O / 4 s cyclohexanesulfamimane 1.35 ^ _jLkH- (CH) - 1.1. 202.9 ° C / 2 maleimane 2 2 0 1.36 CHj-NH-C-NH- (CH ₂ ) ₂ - 1.1. 178.1 ° C 1.37 SCN- (CH ₂ ) ₂ -

170 771

c. d table 1

1 2 3 1.38 © V ^NH2 3 'NH-fi-NH- (CH ₂ ) ₂ - 1.39 H NH- (CH ₂ ) ₂ - 1.1. 203.0 ° C / 1/2 H2O 3 fumarate 1 40 S CH ₃ -NH-C-NH- (CH ₂ ) ₂ - 1.t. 155.2 ° C / 1/2 H2O 1.41 C1- (CH2) 2- 1.1. 169.9 ° C / 2 maleate 1.42 S- (CH ₂ ) ₂ - mp 265.4 ° C (dec.) / 2-cyclohexylsulfamate 1.43 e.g. N-CH,? 3 II ³ CH ₅ O-CH-CH ₂ -NH-C-NH- (CH ₂ ) ₂ - HJ 1 44 CH, and H <-y _N H- (CH ₂ ) ₂ - - N mp 153.9 ° C / ₂ H ₂ O -3 cyclohexanesulfamate 1.45 , ^, »H- (ch ₂ ) ₂ - 1.1. 234.8 ° C / 2 H ₂ O 3HC1 Sr 0 1.46 C- (CH ₂ ) _r 11,161.0 ° C

170 771

170 771

Relationship no L- R ¹ Physical data 1 2 3 4 2 01 CH3- F. 1.1. 195.7 ° C / 2 fumarate 2.02 H5C2OOC- F. 1.1. 175.2 ° C 2.03 H- F. 11 180.1 ° C

170 771

c. d. table 2

1 2 3 4 2.04 CH3-C (CH3) = CH-CH2- F. 1.1. 203.4 ° C / 2 maleate 2.05 ⁿ > / - (ch ₂ ) ₂ - 0 ^(ch 2 ^} 2 - 0 F. mp 168.9 ^O C / 3/2 H2O 5/2 maleate 2.06 F. mp 162.2 ° C / 3/2 H2O 5/2 fumarate U N 4 2 07 (ch ₂ ) ₂ - 0 F. 1.1. 201.9 ° C / 3 fumarate 2.08 2 09 NC-CH ₂ - H ₂ N- (CH2) 2- F. F. t.1. 198.3 ° C 2.10 <\ /> - nh- (ch ₂ ) ₂ - \ - N F. 1.1. 165.1 ° C / 3 maleate 2.11 ^NH " ^(CH 2 ⁾ 2" h ₂ n ^s F. 11238.6 ° C 2.12 2.13 2.14 H- H5C2OOC- CH3- CH3- CH3- CH3- 1.1. 203.1 ° C 1.t. 156.5 ° C 11,214.3 ° C ri ^s Y ^N 7r ^CH 3 2.15 X ^ (ch_) ₂ 0 ^{2 e} CH3- 1.1. 202.2 ° C 2.16 2 17 NC-CH2- H2N- (CH2) 2- CH3- CH3- mp 219.3 ° C / 3 fumarate 2.18 ΜΥ »Η- (ΟΗ ₂ ) ₂ - N CH3- 1.1. 131.1 ° C

170 771 c d table 2

1 2 3 4 2.19 CH3- 1.t. 192.6 ° C / 5/2 (COOH) 2 2.20 V_Zl_c-nh- (ch ₂ ) ₂ - CH3- mp 214.2 ° C / 2 maleate 2.21 CH3- Br 11,213.4 ° C 2.22 1 ^H 3 ^c, ' ³ -V> A _W2 - 0 F. mp 187.2 ° C / H ₂ O

1.1. - melting temperature

170 771

170 771

c. d table 3

1 2 3 4 3.25 ^CH 3 F. t t 211.6 ° C (ch ₂ ) ₂ - 0 3.26 H5CO- ( ^ch 2) ₂ F. mp 149.1 ° C 3.27 0 © X <ch ₂ ) ₂ - Cl oxalate (2: 5), 1/2 ethanolate / mp 170.7 ° C 0 3.28 h ₅ co (ch ₂ ) ₂ - CH3 cyclohexylsulfamate (1 2), H ₂ O / m. t 149.8 ° C 3.29 0 HN ^{/ UxX} N- (CH ₂ ) ₃ - © ch ₃ fumarate (1 2), 1/2 H2O / 1.1. 200.3 ° C 3.30 H0 - <^ - (CH ₂ ) ₂ - ch ₃ fumarate (2-3) 1/2 ethanolate I / 2H2O / L mp 176.0 ° C 3.31 HOOC- (CH2) 2- F. 2H ₂ O / mp 136.1 ° C 3.32 / n ^ nh- (ch ₂ ) ₂ - F. mp 191.2 ° C 3.33 , 9 r — vC-NH- (CH ₂ ) ₂ - F. 1.1. 173.5 ° C ^ Cl

170 771

c. d. table 3

1 2 3 4 3.34 < ^CH 2> ₂ - F. 11. 177.2 ° C IN 3 35 HO ( ^ch 2 ^ 2 F. 3 36 H ₂ N- (CH ₂ ) 2- F. t t 141.5 ° C

Table 4

Relationship no L- R ² R3 R4 Physical data 1 2 3 4 5 6 4.01 CH3- H. H. C6H5 mp 171.5 ° C 4.02 H. H. -CH3 H. t t 167.0 ° C 4 03 CH3- H. -CH3 H. t t 172.2 ° C .N CH 4.04 fi 7 © H. -CH3 H. 11. 212.4 ° C 1-N _v < ^CH 2> 2- 0 4.05 ^CH 3 ιΓ H. -CH3 H. mp 186.3 ° C / 3 (ch ₂ ) ₂ - H2O fumarate 0 4 06 ct ₃ o ^ ^ 7 "( ^CH 2) 2" H. -CH3 H. t t 150.6 ° C / 5/2 (COOH) 2, H2O

170 771

c. d. table 4

and 2 3 4 5 6 4.07 C ^ - ^(ch 2) ₂ - H. -CH3 H. mp 180.2 ° C / 7/2 (COOH) 2 4.08 NC-CH2- H. -CH3 H. 11,226.5 ° C 4.09 H2N- (CH2) 2- H. -CH3 H. - 4.10 Q- nh- (cii ₂ ) ₂ - H. -CH3 H. t t 171.3 ° C 4 ii C2H500C- H. -CH2OH H. mp 191.9 ° C 4.12 H. H. -CH2OH H. 11.> 200 ° C dec / 5/2 fumyrau 4.13 CH-- S. CH, H. -CH2OH H. 1 1. 228.3 C 4.14 Y 0 X YCH ₂ ) ₂ - H. -CH2OH H. 4.15 C2H5OOC- H. -CHO H. mp 138.2 ° C 4.16 CH-- H. -CHO H. mp 171.6 ° C 4.17 C2H5OOC- H. -COOH H. t t 182.2 ° C 4 18 C2H5OOC- H. -CH2OH -CH2OH - 4.19 H- H. -CH2OH -CH2OH - 4.20 CH3- H. -CH2OH -CH2OH 11. 206.3 ° C 4.21 CH-- H. -CH3 -CH2OH t t 166.8 ° C 4.22 CH-- H. -CH3 -Br mp 116.0 ° C 4.23 CH-- H. -COOH H. mp 241.3 ° C 4 24 CH-- F. -CHO H. 1 i. 176.5 ° C 4.25 CH-- F. -CH2OH H. mp. 181.5 ° C 4.26 CH-- F. -CH2OH -CH2OH 1 i. 220.0 ° C 4.27 CH-- H. -CH = CH-COOC2H5 H. - 4.28 CH-- H. -CH = CH-COOH H. fumyrap (3 / 2H 2 O mp. 207.3 ° C) 4.29 CH-- F. -COOH H. 1/2 H20 mp 261.6 ° C 4 30 CH-- H. -CH2-COOCH3 H. - 4.31 CH-- H. -CH2-COOH H. -

t is the melting temperature

170 771

1.1. - melting temperature

170 771

Relationship no L- Physical data 6 01 CH3- 1.1. 135.8 ° C 6.02 C2H5OOC- - 6.03 H- 1.1. 246.9 ° C / 2HBr 1/2 H20 6.04 Y ' ^(CH 2> ₂ - 11 206.4 ° C / 2 (COOH) 2 1/2 H2O 0 6.05 .N CH, CY Y mp 158.9 ° C / > A ₍ ch ₂ > ₂ 0 ^zz 5/2 (COOH) 2 1 / 2H ₂ 0

Table 7

Relationship no R5 L- Physical data 1 2 3 4 7 01 -Cl CH3- 1.1. 181.9 ° C 7.02 -CH3 CH3- 1.1. 184.2 ° C 7.03 -CH3 N NH- (CH -) - (f Ύ Yn ethanolate (2 7) 1/2 H2O / 1.1. 171.2 ° C

170 771

c. d table 7

1 2 3 4 7 04 -CH3 (1 Ί fumarate (2.3) 1 / 2H ₂ O / 162.2 ° C 7.05 -CH3 H2N- (CH2) 2- maleate (13) / mp 192.0 ° C 7.06 -CH3 H. - 7.07 -CH3 H. 2 HCl 7.08 -F CH3- t t 164.6 ° C 7.09 -CH3 NC-CH2- mp 194.1 ° C 7.10 -CH3 OCT mp 224.3 ° C Rl (CH) 0

Publishing Department of the UP RP. Circulation of 90 copies. Price PLN 6.00

Claims (5)

Patent claims A method for the preparation of new imidazo [2,1-b] [3] benzazepine derivatives of formula 1 wherein each dotted line independently represents an optional bond; R ¹ is hydrogen, halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R ² is hydrogen, halogen, C1-C4-alkyl or C1-C4-alkoxy; R ³ is hydrogen, C1-C4-alkyl, ethenyl substituted with hydroxycarbonyl or C) -C 4 -alkoxycarbonyl, Ci-C4-alkyl substituted with hydroxycarbonyl or C1-C4-alkoxycarbonyl; hydroxy-C1-C4-alkyl, formyl or hydroxycarbonyl; ^R4 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, phenyl or halogen; R ⁵ is hydrogen, C 1 -C 4 -alkyl or halogen; L is hydrogen, C1-C6-alkyl, C1-C6-alkyl substituted with one substituent selected from the group consisting of hydroxyl, halogen, C1-C4-alkoxy, hydroxycarbonyl, C1-C1-alkoxycarbonyl, C1-C1-alkoxycarbonyl-C1 - C4-alkoxy, hydroxycarbonyl-C1-C4-alkoxy, C1-C4-alkoxycarbonylamino group, C1-C4-alkylaminocarbonyl group, C1-C4-alkylaminocarbonylamino group, C1-C4-alkylaminothiocarbonylamino group, aryl group, aryloxyl group and arylcarbonyl group; C1-C6-alkyl substituted with both hydroxy and aryloxy; C 3 -C 6 -alkenyl; Aryl-substituted C3-C6-alkenyl; wherein each aryl is phenyl or phenyl substituted with halogen, cyano, hydroxy, C1 -C4-alkyl, C1-C4-alkyl, C1 -Cralkoxy, aminocarbonyl or phenyl substituted with C1-C4-alkyloxycarbonyl or hydroxycarbonyl; or L is a radical of the formula -Alk-Y-He ', -Alk-NH-CO-Het2 or -Alk-Het3; wherein Alk is C1-C4-alkanediyl; Y is O, S or NH; Het, Het2 and Het3 are each furanyl, thienyl, oxazolyl, thiazolyl or imidazolyl each optionally substituted with one or two C1-C4-alkyl substituents; pyrrolyl or pyrazolyl optionally substituted with formyl, hydroxyC1-C4-alkyl, hydroxycarbonyl, C1-C4-alkoxycarbonyl or with one or two C1-C4-alkyl substituents; thiadiazolyl or oxadiazolyl optionally substituted with amino or C1-C4-alkyl; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each optionally substituted with C1-C4-alkyl, C1-C4-alkoxy, amino, hydroxy or halogen; imidazo [4,5-c] pyridine 1-2; and Het ³ can also be 4,5-dihydro-5-ke170 771 to-1H-tetnazohl substituted with C 1 -C 4 -alkyl, 2-keto-3-oxazolidinyl, 2,3-dihydro-2-keto-1H-benzimidazol-1 or a radical of formula 2, formula 3 in which R ⁶ is hydrogen or C 1 -C 4 -alkd; and AZ is -S-CH = CH-, -S-CH2-CH2-, -S-CH2-CH2-CH2-, -CH = CH-CH = CH-, -CH2-CH2-CH2-CH2-, - N (CHs) C (Clfd = CH- or -CH = C (CH3) -O-; excluding 6,11-dihydro-1 1- (piperidinylidene-4) -5Himidazo [2,1-b] [3] benzazepine, pharmaceutically acceptable addition salts or stereochemically isomeric forms thereof, characterized by dehydrating the alcohol of formula 4 or 5 in the presence of a dehydrating reagent to provide a compound of formula 1 wherein there is a double bond between piperidinyl and tricyclic group; pattern 5 And optionally converting the obtained compound of formula I into a therapeutically active non-toxic addition salt form by treatment with an acid or base; or conversely, converting a salt into the free base or acid by treating it with a base or acid, respectively; and or preparing its stereochemically isomeric forms. 2. The method according to p. The process of claim 1, wherein L is C1-C4-alkyl or C1-C4-alkyl substituted with hydroxycarbonyl or C1-C4-alkoxycarbonyl. 3. The method according to p. 1, characterized in that the used substarat, wherein R ³ is hydrogen, C1-C4-alkyl, formyl, hydroxy-C1-C4-alkyl or hydroxycarbonyl; R is hydrogen, halogen or hydroxy-Ci-C4-alkyl; and L is hydrogen, C1-C4-alkyl, halo-C1-C4-alkyl, hydroxycarbonyl-C1-C4-alkyl, C1-C4-alkoxycarbonyl-C1-C4-alkyl, C1-C4-alkoxycarbonylamino-C1-C4- alkyl, aryl-Ci-C4-alkyl, propenyl, or L is a radical of the formula -Alk-Y-HeR -Alk-NH-CO-Het ² or -Alk-Het ³ in which the formulas are Het, Het ² and Het ³ are each furanyl, oxazolyl, or thiazolyl, each optionally substituted with C1-C4-alkyl; thiadiazolyl optionally substituted with an amino group; pyridinyl or pyrimidinyl, each optionally substituted with a hydroxyl group; imidazo [4,5-c] pyridine 1-2; and Het ³ may also be a radical of formula 3. 4. The method according to p. 2. The process of claim 1, wherein the substate in which R1 is hydrogen or halogen; R2 is hydrogen, halogen or C1-C4-alkoxy; and L is hydrogen, C1 -C4-alkyl, halo-C1 -C4-alkyl, hydroxycarbonyl-C1 -C4-alkyl, C1-C4alkoxycarbonyl-C1-C4-alkyl, or a radical of formula -Alk-Y-Het where Y is NH. 5. The method according to p. A process according to claim 1, characterized in that in the preparation of 11- (1-methylpiperidinylidene-4) -1 1 H -imidazo [2,1-b] [3] benzazepine, 11- (1-methylpiperidinyl-4) -11H -imidazo [2,1-b] [3] benzazepine 1-11.