PL170776B1 - Method of obtaining novel derivatives of imidazo[2,1-b][3]benzazepin - Google Patents

Abstract

1. A method for the preparation of new derivatives and mdazo [2,1-b] [3] benzazepine of the formula wherein each dotted line independently represents an optional bond, R1 represents a hydrogen atom, a halogen atom, C1 - C4-alkyl or C1 -G4 - alkoxy, R2 is hydrogen, halogen, C1 -G4 -alkyl or C4 -G4-alkoxy, R3 is hydrogen, C1 -G4 -alkyl, ethenyl substituted with hydroxycarbonyl or C1-C4-alkoxycarbonyl, C1- C 4 -alkyl substituted with hydroxycarbonyl or C 1 -C 4 alkoxycarbonyl, hydroxy-C 1 -C 4 -alkyl, formyl or hydroxycarbonyl, R 4 is hydrogen, C 1 -G 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, phenyl or halogen , R5 is hydrogen, C1-C4-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-C4-alkoxycarbonyl, C1 -G4 -alkoxycarbonyl-C1-C4-alkoxy, hydroxycarbonyl-C1 -G4-alkoxy, C1 -G4 -alkoxy arbonylamino, C 1 -C 4 -alkylamino unocarbonyl group, C 1 -C 4 -alkylaminocarbonylamino group, C 1 -C 4 -alkylaminothiocarbonylamino group, aryl group, aryloxy group and arylcarbonyl group, C 1 -C6-alkyl substituted with both hydroxy group and aryloxy, C3-C6-alkenyl, C3-C6-alkenyl substituted with aryl, wherein each aryl is phenyl or halogen-substituted phenyl, cyano, hydroxy, C1-C4-alkyl, C1-C4 alkoxy, aminocarbonyl or phenyl substituted with C1 - C4-alkyloxycarbonyl or hydroxycarbonyl group, or L is a radical of formula -Alk-Y-Het1, -Alk-NH-CO-Het2 or -Alk-Het3, in which formula Alk is C1-C4 -alkanediyl, Y is O, S or NH Het1, 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, hydroxy-C1 -C4-alkyl, hydroxycarbon yl, C1-C4-alkoxycarbonyl or one or two C1-C4-alkyl substituents, thiadiazoill 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] pyridinyl-2, and Het can also be 4,5-dihydro-5-keto-1H-tetrazolyl substituted with C1-C4-alkyl, 2 -keto-3-oxazolidinyl, 2,3-dihydro-2-keto-1H-benzimidazohl-1 or a radical of formula wherein R6 is hydrogen or C1 -C4-alkyl and AZ 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 6,11-dihydro-11 - (piperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepine, its pharmaceutically acceptable addition salts or stereochemically isomeric forms, characterized in that the alcohol of formula 4 or the ketone of formula 5 is cyclized in the presence of an acid , Model 1 PL PL

Description

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

The international publication WO 88 / 03I38 describes benzo-3-cycloheptapyridines with antiallergic and anti-inflammatory effects. EP-A-0339978 describes compounds (benzo- or pyridocycloheptaheterocyclic compounds having PAF-antagonistic, antihistamine and / or anti-inflammatory activity. The compounds disclosed in the present invention differ in their pharmacological activity by the fact that they do not perform PAF-activity. antagonistic and have a specific anti-whistamine effect.

International publication WO 92 / 0698I describes 6, ii-dthydro-i - (piperidinylidene-α-6H-imidazo PU-bj-benziaepine and i-acetyl-α- (5,6-dihydro-iif-imidazole [1,2 -b] [33beezzzzpinoylidene-11) 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 activity profile. platelet aggregation promoting factor (PAF), without any reference to their anti-slamine activity.

In the publication of J. Med. Chem., 26 (1983), 974-98O certain i-methyl-4-piperidinylidene-9 substituted pyrrolo [2,1-b] 133beezazepine derivatives with neuroleptic properties are described. 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.

170 776

The invention relates to a process for the preparation of new imidazo [2,1-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 4 alkoxy; R is hydrogen, halogen, C 1 -C 6 -4 Ukyl or C 1 -C 6 acoxy; R ³ is hydrogen, C 1 -C 6 -alkyl ethenyl substituted with hydroxycarbonyl or C 1 -C 6 acoxycarbonyl, C 1 -C 6 -alkyl substituted with hydroxycarbonyl or C 1 -C 6 acoxycarbonyl; hydroxy-C 1-4 C 1-4 Ukyl, formyl or hydroxycarbonyl; R ⁴ is hydrogen, C 1 -C 6 -alkyl, hydroxy-C 1 -C 6 -alkyl, phenyl or halogen; R ⁵ is hydrogen, C 1 -C 6 alkyl or halogen; L is hydrogen, C 1 -C 6 -C 4 alkyl, C 1 -C 8 -C 4 alkyl substituted with one substituent selected from the group consisting of hydroxyl, halogen, C 1 -C 4 -C 1-4 toxic. hydroxycarbonyl, C1-C6-acoxycarbonyl, C1-C; -alkoxyArbonyl-C1-C6-alkoxy, hydroxycarbonylc ^ -Ci-Ci-C ^ Hkoxy, C1-C4-C1-4 (o ^ '^ ^ d ^ indxoyvllonminine, C1-C4- Alkylamlcarbonyl, C 1 -C 6 H 4 HCl, C 1-6 carbonylamino, C 1 -C 4 acrylonmKiocarbonylamino, aryl, aryloxy and arylcarbonyl group; C 1 -C 8 H 4 alkyl substituted with both hydroxy and aryloxy; C 3 -C 6 alkyl group; aakenyl; C 0 -C 6 -alkenyl substituted with aryl; in which groups each aryl is phenyl or phenyl substituted with halogen atom, cyano, hydroxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, aminocarbonyl or phenyl substituted with C 1 -C 4 alkyloxycarbonyl or a hydroxycarbonyl group; or L is a radical of the formula -Alk-YHeti -Alk-NH-CO-Het or -Alk-HeC; in which formulas Alk is C 1 -C 6 -alkanediyl; Y is O, S or NH: Het, Het and Het3 are each furanyl, thienyl, oxazolyl, thiazolyl, or imidazole, each optionally substituted with one or two C1-.'- al4 and iowe; pyrrolyl or pyrazolyl optionally substituted with formyl, hydroxycarbonyl, C1-6aaacoxycarbonyl, hydroxycarbonyl, C1-6Aacoxycarbonyl, or with one or two C1-6alkyl substituents; thiadiazolyl or oxadiazolyl optionally substituted with amino or C1-C6alkyl; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each optionally substituted with C 1 -C 6 alkyl, C 1 -C 6 acoxy, amino, hydroxyl or halogen; imidazoNo-cipyridinyl; and Het3 may also be dAdibydro-S-keto-iH-tetrazolyl substituted with Ci-C [beta] -4H ^ yl, 2-keto-3-xazolidinyl, AdihydroAketo- and H-benziniidazolyl- or a radical of formula

Pattern 2 or

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-, -CH ₂ -CH ₂ -CH ₂ -CH ₂ -, -N (CH ₃ ) -C (CH]) = CH- or -CH = C (CH ₃ ) -O-; excluding 6.11 ^ - ^ ii ^; ^^ ro-11 - j ^ i ^ er ^ dynylide ^ r ^ (^ - 4) -5H-im ^ dt ^ zo [2,1-b] [3 ] bbnnca; epins; their pharmaceutically acceptable addition salts and isomeric stereochemical forms.

The term halogen as used in the above definitions denotes fluorine, chlorine, bromine and iodide; C1-C4-alkyl denotes a straight chain or branched saturated hydrocarbon radical containing 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2, -methylpropyl and 1, 1-12 Vimethylethyl; C 1 -C 6 -kyl denotes the above-defined C 1 -C 6 -alkyl radicals and their higher homologues with 5 to 6 carbon atoms, such as, for example, pentyl and hexyl, C ₃ -C ₆ -C 4 Ikenyl denotes straight or branched chain hydrocarbon radicals containing one double a bond of 1 with 3 to 6 carbon atoms, such as e.g. propeny1-2, butenyl-2, butenyl-3, 2-methylp (Όpenyl-2, pentenyl-2, pentenyl-3, 3,3-dimethylpropen-2, hexenyl and the like; C - C6- ^ H ^^ and ^^ diyl denote straight or branched chain divalent hydrocarbon radicals containing from 1 to 4 carbon atoms, such as e.g. methylene, ethanediyl -, -, ethanediyl-1,2 , 1,3-propanediyl, 1,4-butanediyl, and the like.

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 the like, 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, e.g., sodium, potassium, calcium, and also salts with pharmaceutically acceptable amines such as, e.g., 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 denotes 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 denomination 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; R1 is hydrogen, halogen, C-C4-alkyl; R2 is hydrogen, halogen, C1-C4-alkyl or C1-C4-alkoxy; R] is hydrogen, C1-C4-acyl, hydroxy C1-C4-alkyl, formyl, or hydroxycarbonyl; R t is hydrogen, C 1 -C 4 -alkyl, hydroxy-C 1 - (C 1 -4 -alkyl, phenyl or halogen; R ⁵ is hydrogen; L is hydrogen, C 1 -alkyl, C 1-— alkyl substituted with hydroxyl, C1-C4-alkoxy, C1-C4-αI-carbonyl, amino, C1-C4-αIkiioammocarbonyl,

170 776

A C1-C4-alkylaminocarbonylamino group, a C1-C4-alkylaminothiocarbonylamino group, an aryl group or an aryloxy group; C3-C6-alkenyl; Aryl-substituted C3-C6-alkenyl; in which each aryl is phenyl or phenyl substituted with a halogen atom, C1-C4-alkyl, C1-C4-alkoxy, or L is a radical of the formula -Alk-Y-Het ¹ , -Alk-NH-CO-Het ² or -AlkHet ³ ; wherein Alk is Ci-C4-alkanediyl; Y is O, S or NH: Het ¹ , Het ² and Het ³ are each furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl or imidazolyl, each optionally substituted with one or two C1-C4-alkyl substituents; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each optionally substituted with Ci-C4-alkyl, _Ci-C4 alkoxy ^ amino, hydroxy or halo; imidazo [4,5-c] pyridinyl-2; and Het ³ may also be 4, 4-dihydro-5-keto-1H-tetrazolyl substituted with C 1 -C 4 -alkyl, 2-keto-3-oxazolidinyl, 2,3-dihydro-2-keto-1H-benzimidazohl-1 or a radical pattern

wherein R ⁶ is hydrogen or C 1 -C 4 -alkyl; and AZ is -S-CH = CH-, -S-CH2-CH2-, -S-CH ₂ -CH ₂ -CH ₂ -, -CH = CH-CH = CH- or -CH2-CH2-CH2-CH2 -; excluding 6,11-dihydro-11 - (piperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepine.

Another group of interesting compounds consists of those compounds of formula 1, wherein L is C1-C4-alkyl or C1-C4-alkyl substituted with hydroxycarbonyl or C1-C4-alkoxycarbonyl.

Further interesting compounds are those compounds of formula I wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are hydrogen.

Yet another group of interesting compounds of formula 1 are compounds of formula

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

Those compounds of formula I are preferred, wherein R ³ is hydrogen, C ₁ -C ₄ -alkyl, formyl, hydroxy-C ₁ -C ₄ -alkyl or hydroxycarbonyl; R ⁴ is hydrogen, halogen or hydroxy-C ₁ -C ₄ -alkyl; and L represents hydrogen, Ci-Ce-alkyl, _halo-Ci-C4 alkyl, hydroxycarbonyl-Ci-C4-alkyl, _{Ci-C4 -alkoksykarbonylo-Ci-4} alkyl, _Ci-C4 alkoxy karbonyloamino- _Ci-C4 alkyl, _aryl-Ci-4 alkyl, propenyl, or L is a radical of formula -Alk-Y-Het ^1, -Alk-NH-CO-Het or -Alk-Het ^3; in which the formulas Het ¹ , Het ² and Het ³

Are each furanyl, oxazolyl, or thiazolyl, each optionally substituted with C1-C6-alkyl, thiadiazolyl optionally substituted with amino; pyridinyl or pyrimidinide each optionally substituted with hydroxyl; imidazo [4,5-clpyridinyl-2; and Het ³ may also be a radical of formula 3.

More preferred compounds are those preferred compounds wherein R? is hydrogen or halogen; R ² is hydrogen, halogen or C 1 -C 6 alkoxy; and L is C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, hydroxycarbonybr, C 1 -C 6 -alkyl, C 1 -C 6 -Bkoxycarbonyl-C 1 -C 6 -alkyl, or a group of formula -Alk-Y-Het wherein Y is NH .

Even more preferred are those compounds, wherein R ⁴ is hydrogen or halogen; aL is hydrogen, C 1 -C 3 -alkyl, hydroxycarbonyl-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxycarbonyl-C 1 -C 4 -alkyl, or a group of formula -Alk-Y-Het where Het is thiazolyl, or imidazo [4,5-c] pyridinyl-2.

The most advantageous compounds are:

5,6-dihydro- ii - (i - methylpyridinylid-4) -11H-imidazo [2, i-b] [3-benzazepine;

9-fluoro-6, i -dihydro-i i - (i -meth 1 opiperidinylidene-4) - 5H-imidazo [2, i-b] [3] benzazepine;

ii - (i -methylpiperidinyl-4) -i and H-imidazo [2, i-b] [3] benzazepine;

6, ii-dihydro-ii - (i-mey-piperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepine 13-methanol;

8-fluoro-6,11-dihydro-ii - (i -meCylpiperidinylidene-4) -5H-imidazo [2, i-b] [3] benzazepine;

aldehyde 6, i-dihydro-i i- (i -methylpiperidinylidene-4) -5H-imidazo [2, i-bj [3] benzazepinyl-3-formic;

6, i -dihydro- ii - (i -meCylpiperidinylldene-4) -5H-imidazo [2, i-b] [3] benzazepine-3 carboxylic acid;

7-fluoro-6, i -dihydro- ii - (i -methylpiperidinylidin-4) -5H-imidazo [2, i-b] [3] benzazepine;

4- (8-fluoro-5,6-dihydro-iH-midazo [2, i-b1benzotazpinylidene-i) piperidine- and -propionic acid dihydrate, stereoosomers 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 of the intermediates involved in their preparation, the imidazo [2,1-b] [3] benzazepine group was designated by the symbol T.

pattern 6

Compounds of formula I can be prepared by cyclizing an alcohol of formula 4 or a ketone of formula 5 (scheme i).

i70 776

Scheme i

This cyclization reaction is conveniently carried out. by treating an intermediate of formula A or 5 with an appropriate acid, thereby obtaining a reactive intermediate which cyclizes to a compound of formula I. Suitable acids are, e.g., strong acids, especially very acidic systems, e.g. methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, methanesulfonic acid / boron trifluoride, hydrofluoric acid / boron trifluoride, or Lewis acids, e.g., aluminum chloride and the like. Of course, only those compounds of formula I in which L is a group stable under the reaction conditions can be prepared in the above-mentioned reaction method. In the case of very strong acids, the reaction is preferably carried out in an excess of such acid; in the case of solid Lewis acids, e.g., aluminum chloride, the reaction may be carried out by fusing the starting material with the reagent, preferably in the presence of an additional salt such as sodium chloride. The dehydration cyclization reaction using trimethylsilyl iodide is conveniently carried out in a reaction-inert solvent such as, for example, a halogenated hydrocarbon, for example trichloromethane. It is particularly noteworthy that the latter reaction can also be carried out on intermediates of the formulas A or 5, wherein L is C 1 -C 6 aacoxycarbonyl; or in this case - in addition to cyclization with dehydration - the cleavage of the carbamate is also observed and a compound of formula I is obtained in which L is hydrogen.

i70 776

The reaction mixture is worked up in the known manner and the reaction product is isolated and, if necessary, further purified.

Compounds of formula I may be further converted to each other using known functional group conversion methods.

For example, compounds of formula I in which L contains a C1-C4-III-dkoxycarbonyl group can be hydrolyzed to compounds of formula I in which L has a hydroxycarbonyl group in the presence of an acid or a base.

Compounds of formula I in which L is C1-C6aacoxyphenyl-C1-Cfi-alkyl can be converted to a compound of formula I in which L is hydroxyphenyl-C1-C6-aalkyl by treatment with an acid such as e.g. hydrobromic acid , hydroiodic acid or Lewis acid, e.g. boron trifluoride, aluminum chloride and the like.

Intermediates of formula a can be prepared from the corresponding ketones of formula 5 by reduction (scheme 2).

reducing a compound of formula 5 ----------------- »a compound of formula a

Scheme 2

Said reduction may conveniently be carried out by reacting the starting ketone of formula 5 with hydrogen in a solvent such as, for example, an alcohol, e.g. methanol, ethanol; an acid, e.g. acetic acid; an ester, e.g. ethyl acetate; in the presence of a hydrogenation catalyst, e.g. palladium on carbon, platinum on carbonate, Raney nickel.

The reaction mixture may be heated to increase the rate of the reaction and pressurize hydrogen gas if desired.

Alternatively, alcohols of formula A may also be prepared by reducing ketones of formula 5 with a reducing agent such as, for example, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride and the like, in a suitable solvent such as, for example, an ether, e.g., ethyl ether, tetrahydrofuran and similar; an alcohol, e.g., methanol, ethanol, and the like.

Ketones of formula 5 can be prepared by adding a compound of formula 7 to the reagent of formula 8 (scheme 3).

Scheme 3

Ketones of formula V in which the dotted line does not represent an optional double bond can be prepared by N- 6alkylated intermediate of formula 7 with a reagent of formula 9 in which W is a reactive leaving group as defined above (scheme a).

i70 776

Diagram a

Said N-akylation 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, and the like; a ketone e.g. 2-propanone, n-methylpentanone-2 and the like; an ether, e.g. tetrahydrofuran, and, 4-dioxane, diethyl ether and the like; a bipolar aprotic solvent, e.g., N, N-dimethylformamide, KN-dimethylacetamide, dimethylsulfoxide, nitrobenzene, 2-methylpyrrolidinone and the like; a halogenated hydrocarbon, e.g., dichloromethane, and, 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, 3rd order. potassium butoxide, 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, -diethylethylamine, N- (i-methylethyl) -2-propyanoanine, eydomorpholine, 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-akylation may be carried out using known conditions for catalyzed phase transfer reactions.

In addition, ketones of formula V in which the dotted line does not represent an optional bond can also be prepared by reductive Ndylation of compounds of formula 7. This reductive N-alkylation reaction may conveniently be carried out by reducing the reaction mixture in a suitable solvent inert to the reaction. 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, C 1 -C 6 acanols, e.g. methanol, ethanol, butanol and the like; esters, e.g., ethyl acetate, γ-butyrolactone and the like; ethers, e.g., tetrahydrofuran, i, α-dioxane, diethyl ether, 2-netυxyethanol 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 procedure for reducing N-loading ^{1 1} means that the reaction is carried out either with sodium cyanoborohydride, sodium borohydride, formic acid or a salt thereof, e.g. formate and similar reducing agents, or alternatively in a hydrogen atmosphere, possibly 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

170 776 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 7 are conveniently prepared from an ester of formula 10 by reaction with a protected imidazole derivative of formula 11 by reaction with a strong base such as, for example, methyllithium, butyllithium, sodium amide, lithium dialkylamide, e.g. lithium diisopropylamide, or mixtures thereof. , in a solvent inert to the reaction, for example tetrahydrofuran, hexane, methylbenzene and the like, or mixtures thereof (scheme 5).

L— N µl

C1-4 alkyl

compound of formula 7 formula 10

Scheme 5

In formula 11, P represents a protecting group, such as, for example, a di (C1-C4-alkoxy) methyl group, a C1-C4-alkoxymethyl group, a benzenesulfonyl group, a trimethylsilylethoxymethyl group, a N, N-dialkocoaminomethyl group, which can be removed by acid hydrolysis. The reaction of the compound of formula 10 with the compound of formula 11 may conveniently be carried out at low temperature. For example, the reagent of formula 11 can be added at a temperature between about -80 ^° C to about -40 ° C to the strong base. The ester of formula 10 is then added and the reaction mixture is allowed to gently warm to room temperature. The product thus obtained is converted into the intermediate of formula VII by very mild acid hydrolysis and is isolated in the known manner.

Ketones of formula V where L is methyl can be prepared from ketones where L is hydrogen by reductive N-alkRation with formaldehyde following the procedure previously described for preparing ketones of formula V in which the dotted line does not indicate an optional bond .

Ketones of formula 5, where L is hydrogen, are prepared by hydrolysis of the carbamate of formula 5-a in acidic or basic medium (compounds of formula 5-b, 5-c) using known methods (scheme 6). Compounds of formula 5-a are hydrolyzed in an acidic or basic medium 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, propaneh 2 and the like. In order to increase the rate of the reaction, the reaction mixture is preferably heated, especially to reflux temperature.

170 776

Reductive N-alkylation ^lCIi 2 ⁰⁾ n CH _3-n pattern

R ¹ R ² \ _Z

Scheme 6

Intermediates of formula 5-a can be prepared by reacting an acid halide of formula 12 with an imidazole derivative of formula 13 (scheme 7).

formula 12 compound of formula 5-a formula 13

Scheme 7

170 776

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

Intermediates of formula 5-c can also be prepared from an ester of formula 14 by reaction with an imidazole of formula 13 in the presence of a strong base such as, for example, methyllithium, butyllithium, sodium diamide, di-lithium amide, e.g. diisapropyl lithium amide, or mixtures thereof. in a suitable solvent inert to the reaction, for example, tetrahydrofurool, hexane, methylbenzene and the like, or in a mixture thereof (scheme 8).

This reaction is conveniently carried out at low temperature. For example, the reagent of Formula 13 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 temperature

alkyl is a compound of the compound of formula 5-c of formula 13

Scheme 8

The compounds of formula I, especially those in which L is (C1-C6-alkyl or phenyl-xycarboyl, C1-C6-alkyl or phenyl-xycarboyl, C1- ^ 4- ^ 11, and carbonaceous compounds, their pharmaceutically acceptable acid addition salts and their stereochemically isomeric forms) have useful pharmacological properties. In particular, they are active antiallergic agents, the activity of which can be clearly demonstrated by the results of trials obtained in various trials.

The antihistamine activity can be demonstrated by the Protectlao of Rats from Compauod 48/80 - ioduced Lethality's test (Arch. Lot. Pharmacodyo. Ther., 234, 164- 176, 1978); Histamioe-induced Lethality io Guioea Pig's test (Arch. Int. Pharmacodyn. Ther., 251, 39-51, 1981); and a broad antiallergic activity can be demonstrated in the Passive cutaneons ónaphy1axis io Rat's test (Drug Dev. Res., 5, 137-1-45, 1985). (For some compounds this assay was modified by replacing compound 48/80 with Ascaris allergens) and Ascaris Allergy io Dog's test (Arch. Iot. Pharmacodyo. Ther., 251, 39-51, 1981 and Drug Dev. Res., 8, 95- 102, 1986).

The compounds according to the invention show a broad spectrum of anti-allergic 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; When administered orally, these compounds have been found to exhibit virtually the same potency as when administered subcutaneously.

A particularly important feature of most of the compounds produced by the inventive process is their lack of sedative properties at therapeutic dose levels, which are a troublesome side effect of many antihistamines and antiallergic compounds. The lack of sedative properties of the compounds of the invention can be demonstrated, op., By the results obtained during the seo-awakening cycle test in rats (Psychopharmóca1ogy. 97, 436-442, 1989).

An interesting feature of the compounds according to the invention resides in their rapid onset of gout and the favorable duration of their action.

Due to its anti-corrosive properties. Compounds of Formula I wherein L is (C1-C6-alkyla or feoylo) oxacarbooyl, C1-C4-alkylcorbooyl 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 desirable in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in formulating oral dosage unit forms, any of a pharmaceutical medium such as, for example, water, glycols, oil, 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, 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.

For ease of administration and uniformity of dosage, it is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form. Dosage unit forms as used herein and throughout the claims refer 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 mentioned allergic diseases by administering to these warm-blooded animals an antiallergically effective amount of the compounds of the formula and 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 0.0 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: A mixture of 2.5 g of the intermediate (i- [2-3 - chlorphenyl) ethyl [-IHimidazolyl-2} (i-methylpiperidinyl-a) methanol (compound 26) and 10 ml of trifluoromethanesulfonic acid was stirred under nitrogen atmosphere for 72 hours at 110 ° C. After cooling, the reaction mixture was poured into ice water and the whole was basified with aqueous solution

170 776 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; CH2Cl2 / CH3OH (NH3) 95: 5). The eluent from the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.95 g (40%) 8-chloro-6,11-dihydro-ii - (i -methylpiperidinylldene-4) -5H-imidazo [2, i-b] [33-benzazepma; mp. 186.6 ° C (comp. 3.10).

Example II. A mixture of 2 g of intermediate {1-2-3-methoxyphenyl) ethyl-1H-imidazolyl-2} (1-methylpiperidinyl-4) methanone (intermediate 27) and 10 ml of methanesulfonic acid was stirred for 1 hour at 100 ° C. 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 O H (NH 3) 95: 5). The eluent from the desired fraction was evaporated and the residue converted into the maleic acid salt (1: 2) in 2-propanone. The salt was filtered off and dried to give 1 g (30.8%) of (1: 2) 6,11-dihydro-8-methoxy-11-1-methylpiperidinylldene-4) -5H-ireidazo [2,1-b1 [ Sjbbezazepine; mp. 190.3 ° C (comp. 3.01).

Example III. a) 41.2 g of methanesulfonyl chloride were added dropwise to a cooled (0 ° C) mixture of 4.62 g of 3- (luorophenylethanol. ± 0 ml of N N -diethylethylamine and 500 ml of dichloromethane, keeping the temperature below 5 ° C. After stirring for 18 hours, at room temperature, the reaction mixture was diluted with water and extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 81 g (100%) of 2-3-fluoro-phenykoytanolLi methanesulfonate (ester) (intermediate 3a).

b) A mixture of 72 g of intermediate 3a, ± 5 g of IH-midazole, 55.5 g of potassium carbonate and 1000 ml of tetrahydrofuran was stirred over a weekend at reflux temperature. The reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 / CH3OH 95: 5). The eluent of the desired fraction was evaporated and the residue was distilled (53.2 Pa; 130 ° C), yielding 37.8 g of a portion (60.2%) of 1- and 2-3-luorophenyl) ethylol-1H-midazole (interm. 35).

c) To a cooled (-70 ° C) mixture of 5.5 g of 2-methyl-N- (1-4-3 and 100 ml of tetrahydrofuran under nitrogen atmosphere, 22 ml of butyllithium was added dropwise, and after stirring for 15 minutes at -40 ° C). C, 9.5 g of intermediate 35, at -70 ° C. Stirring at -70 ° C. was continued for 1 hour, then 9.1 g of ethyl methyl ethyl carboxylate was added. The mixture was stirred for 8 hours at room temperature, decomposed with water and evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH 2 G 2 / CH 3 OH 95: 5 CH 2G2 / CH3OH 80:20). The eluent of the desired fraction was evaporated to give 8 g (50.7%) of {1- [2-3-fluorophenyl) ethyl-1H-imldazol-2} (1-methylpiperidinyl-4) methanone (interm. 36).

d) A mixture of 8 g of intermediate 36, 2 g of aluminum chloride and 10.3 g of sodium chloride was stirred at 140 ° C until the entire mixture was melted. Stirring was continued for 1 hour at 120 ° 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 triturated in isopropyl ether and recrystallized from

4-methylpentanone-2. The product was filtered off and dried, yielding 0.58 g (10.8%) of 8-fluoro-6.11-dihydro-11- (1- (eethylpiperidinylldene-4) -5H-imidaz [2,1-b] 13-beezazepine; mp 152.4 ° C (comp. 3.15)

Example IV. a) 69.2 g of ethyl 4-chloroIkareonylpiperidinecareoctylate-1-ethylate (temperature <20 ° C) was added dropwise to a cooled mixture of 5 .2 g of 1--2-phenylethyl) -1H-1-imidazole, 3 .7 g of N4-dimethylamma and 50 ml of pyridine ) And then 30 ml of acetonitrile. The mixture was stirred for 2 hours at room temperature and for ± hours at reflux temperature

170 776 under a reflux condenser. After cooling, 30 ml of 50% NaOH was added and reflux was continued for 1/2 hour. The cooled reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 / CH3OH 97: 3). The eluent of the desired fraction was evaporated and the residue was dried, yielding 38 g (33.9%) of ethyl 4 {[1- (2-phenylethyl) -1H-imidazol-2] carbonyl} piperidinecarboxylate (interm. 1).

b) A mixture of 9 g of intermediate (1) and 50 ml of 48% hydrobromic acid was stirred for 5 hours at 80 ° C. The reaction mixture was evaporated and the residue was heated in refluxing 2-propanol. After cooling, the precipitate was filtered off and dried, yielding 10.85 g (97.5%) of [1- (2-phenylethyl) -1H-imidazolyl-2] (4-piperidinylmethanone) dibromide; mp 275.3 ° C (interm. 2 ).

c) A mixture of 70.6 g of intermediate (2) and 700 ml of methanol was hydrogenated under normal pressure at room temperature in the presence of 2 g of 5% platinum 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 crystallized from acetonitrile. The product was filtered off and dried, yielding 54 g (75.7%) of α- [1- [2-phenylethyl) -1H-imidazolyl-2) piperidinyl-4-methanol; mp. 144.6 ° C (interm. 5).

d) A mixture of 3.5 g of intermediate (5) 10 ml of trifluoromethanesulfonic acid was stirred for 18 hours at 110 ° C. The reaction mixture was poured into ice water and basified with aqueous NaOH solution. The product was extracted with dichloromethane and the extract washed with water, dried, filtered and evaporated. The residue was converted into the fumaric acid salt (1: 2) in ethanol. This salt was recrystallized from ethanol to give 0.8 g (13.3%) of (1: 2) 6,11-dihydro-11- (piperidinyl-4) -5H-imidazo [2.1-b] [3] benzazepine fumarate; mp. 220.2 ° C (comp. 5.01)

All compounds listed in Tables 1-7 were prepared following the preparation methods described in Examples 1-4.

Table 1

Relationship no L- Physical data 1 2 3 1.01 CH3- 1.1. 209.3 ° C / CF3SO3H 1.02 CH3- 1.1. 154.5 ° C 1.03 H5C2OOC- 1.1. 170.6 ° C 1.04 H- 1.1. 192.5 ° C / l / 2 H ₂ O 2 fumarate 1.05 C2H5- 1.1. 184.2 ° C / 2 maleate 1.06 CH3CH (CH3) - t t 183.6 ° C / 2 maleate 1.07 ch ₂ = ch-ch ₂ - mp 160.8 ° C / 2 maleate 1.08 CH ₂ = C (CH3) -CH ₂ - 1.1. 179.5 ° C / 3/2 fumarate 1.09 CH ₃ -C (CH ₃ ) = CH-CH ₂ - mp 127.2 ° C 1.10 C6H ₅ -CH = CH-CH ₂ - 1.1. 172.2 ° C / fumarate 1 11 C6H5-CH2- mp 207.2 ° C

I8

I70 776

I70 776

I9

c. d. table i

1 2 3 1.23 C ₂ H ₅ -O- (CH2) 2- 1.1. 176.5 ° C / 2 maleate 1.24 <pH o CH ₃ -HC- NH-C- (CH ₂ ) ₂ - mp 165.5 ° C 1.25 H ₅ C ₂ OOC-NH- (CH2) 2- 1.1. 167.2 ° C / 2 fumarate 1.26 NC-CH2- 1.1. 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- 1.1. 145.7 ° C / 2 maleate 1.31 ° - <ch ₂ ) ₂ - 1.1 172.6 ° C / 2 maleate 1.32 .— N <\,) - NH- (CH.,) ₂ VN 1.1. 165.1 ° C 1.33 N — N h ₂ n Y _s Ynh- (ch ₂ ) ₂ - 1.1. 251.4 ° C 1 34 - they U ^ © nh ~ (ch ₂ ) ₂ - 1.1. 205.5 ° C / 1 / 2H2O / 4-cyclohexanesulfamate 1.35 \ ι- i> NH- (CH) - 1.1. 202.9 ° C / 2 maleate > - ₂ ' ₂ 0 1.36 CHj-NH-C-NH- (CH ₂ ) ₂ " 1.1. 178.1 ° C 1.37 SCN- (CH ₂ ) 2-

170 776

c. d table 1

1 2 3 1 38 NH-fi-NH- (CH ₂ ) ₂ - H. 1.39 [^ | ^XNX ^ -NH- ^{( CH} ₂ ⁾ 2- mp 203.0 ° C / 1/2 H ₂ O -3 fumarate S. 1.40 CH ₃ -NH-C-NH- (CH ₂ ) ₂ - 1.1. 155.2 ° C / 1/2 H ₂ O 1.41 C1- (CH2) 2- mp 169.9 ° C / 2 malemian F ^H 3 1.42 Λρ ^S - < ^CH 2> 2- 1.1. 265.4 ° C (dec) / 2-cyclohexylsulfamate 1 43 oh ₅ »-c« ₃ CH ₅ O-CH-CH ₂ -NH-C-NH- (CH ₂ ) ₂ - HJ 1.44 CH, and ^b 3 y _N H- (CH2) ₂ -N 1.1. 153.9 ° C / 2H ₂ O-3 cyclohexanesulfamate H .n ^ -Nh- (ch ₂ ) ₂ - 1.45 1.1 234.8 ° C / 2H ₂ O 3HCl 0 / —Θ 1.46 C- (CH ₂ ) ₃ - mp 161.0 ° C

170 776

170 776

c. d. table 1

1 2 3 1.56 Q- < ^CH 2> 1- 1.1. 158.5 ° C C-H II 0 O- ^(CH 2> 2- 1 57 Λ CH ₂ -OH mp 147.4 ° C 1 58 Q- (ch ₂ ) ₂ - II ^{و 5} 0 1.1. 158.5 ° C 1.59 1/2 H ₂ O / mp 166.2 ° C COOH 1 60 HOOC- (CH ₂ ) 2 2 H ₂ O / m mp 154.9 ° C 1.61 ethanolate (1: 1) / vol. 208.6 ° C γ ™ 0

1.1. - melting temperature

Relationship no L- R1 Physical data 1 2 3 4 2.01 CH3- F. 1.1 195.7 ° C / 2 fumarate 2.02 H5C ₂ OOC- F. mp 175.2 ° C 2.03 H- F. mp 180.1 ° C

170 776

170 776

c. d. table 2

1 2 3 4 2.19 CH ^ O- - (ch ₂ ) ₂ - ch ₃ - 1.1. 192.6 ° C / 5/2 (COOH) ₂ 0 0 2.20 V 7 11 C-NH- (ch ₂ ) ₂ - ch ₃ - 1.1. 214.2 ° C / 2 maleate 2.21 ch ₃ - Br 1.1. 213.4 ° C , N - N \ CH, 2.22 X F. mp 187.2 ° C / H ₂ O Rf 0 (ch ₂ ) ₂ -

1.1. - melting temperature

Table 3

Relationship no L- R ² Physical data 1 2 3 4 3.0- ch ₃ - CH3O- mp 190.3 ° C / 2 maleate 3.02 H5C2OOC- CH3O- 1.1. -04.4 ° C 3.03 H- CH3O- 1.1. 184.4 ° C 3.04 H- CH3- t t 221.9 ° C / 2 fumarate 3.05 CH3- CH3- 1.1. 211.0 ° C / 2 fumarate 3.06 R ^S © ^N R ^ ^CH 5 1- cH3- mp 199.8 ° C 0 3.07 S CH, fl V Ί © " CH3- mp 214.2 ° C Ύ (^ 2-

170 776

170 776

c. d. table 3

1 2 3 4 3.25 Jk CH, 1 LY ⁵ (CH ₂ ) _? - 0 F. 1.1 211.6 ° C 3.26 h ₅ co— (CH ₂ ) ₂ - F. mp 149.1 ° C 3 27 YY © Y _(C h ₂ ) ₂ 0 Cl oxalate (2 · 5), 1/2 ethanol / 1.1. 170.7 ° C 3.28 H ₃ ^co - (ch ₂ ) ₂ - ch ₃ cyclohexylsulfamate (1: 2), H ₂ O / m. t 149.8 ° C 3.29 0 HN ^{/ R} ^ N- (CH ₂ ) 3-Y ch ₃ fumarate (1 .2), 1/2 Η ₂ Ο / 1.1. 200.3 ° C 3.30 ho- ^ ^z ~ ^ - (ch ₂ ) ₂ - ch ₃ fumarate (2.3). 1/2 ethanol 1/2 H ₂ O / mp 176.0 ° C 3.31 HOOC- (CH ₂ ) 2- F. 2H ₂ O / mp 136.1 ° C 3.32 ^ _{b <t} .nu- (ch ₂ ) ₂ - N F. mp 191.2 ° C 3.33 , 9, -cC-NH- (CH A \\ ²² ^ 0 F. 1.1. 173.5 ° C

170 776

170 776

c. d table 4

1 2 3 4 5 6 4.07 (CH ₂ ) ₂ - H. -CH3 H. mp 180.2 ° C / 7/2 (COOH) 2 4.08 NC-1H2- H. -CH3 H. i, 226.5 ° C 4.09 H ₂ N- (CH ₂ ) 2- H. -CH3 H. - 4.10 H. -c: H3 H. 11. 171.3 ⁰ C 4.11 C ₂ H 5OOC- H. -ch ₂ oh H. mp 191.9 ° C 4.12 H. H. -ch ₂ oh H. 1.1> 200 ° C dec / 5/2 fumarate 4 13 CH3- H. -CH20H H. t 1 228.3 C s Λ CH, 4.14 li © T H. -CH2OH H. - L_N 1 0 4 15 C ₂ H5OOC- H. -CHO H. 11 138.2 ° C 4.16 CH3- H. -CHO H. 1.1 171.6 ° C 4.17 C ₂ H5OOC- H. -COOH H. mp 182.2 ° C 4.18 C ₂ H5OOC- H. -CH2OH -ch ₂ oh - 4.19 H- H. -CH2OH -CH2OH - 4.20 CH3- H. -ch ₂ oh -CH ₂ OH 1.1. 206.3 ° C 4.21 CH3- H. -CH3 -ch ₂ oh 1.1. 166.8 ° C 4 22 CH3- H. -CH3 -Br t 1.116.0 ° C 4.23 cH3- H. -COOH H. 1 mp, 241.3 ° C 4 24 cH3- F. -CHO H. 1.1. 176.5 ° C 4.25 cH3- F. -CH2OH H. mp 181.5 ° C 4.26 cH3- F. -ch ₂ oh -CH2OH mp 220.0 ° C 4.27 CH3- H. -CH = CH-COOC2H5 H. - 4.28 cH3- H. -CH = CH-GOOH H. fumarate / 3 / 2H ₂ O 1.1. 207.3 ° C 4.29 cH3- F. -COOH H. 1/2 H ₂ O 1.1.261.6 ° C 4 30 cH3- H. -CH2-COOCH3 H. - 4.31 cH3- H. -Clb-COOH H. -

1.1 melting point

I70 776

Table 5

Relationship no L- Physical data 5.01 5.02 5.03 H- ch ₃ - (Yr ^c “ ⁵ 0 1.1. 220.2 ° C / 2 fumarate 1.1. 117.8 ° C / 1/2 H ₂ O 1.1. 221.6 C / 2 (COOH) _2/1/2 H ₂ O 5.04 O- < ^CH 2> 2- mp 170.3 ° C 5 05 ćW ^CH '^ y ^ y <ach ₂ ) ₂ - 0 mp 193.3 ° C 5.06 5.07 NC-CH2- H2N-CH2-CH2- 1.1. 194.7 ° C / 1/2 fumarate 5.08 / ^ - N <^ _ /> - nh- (ch ₂ ) ₂ - 1.1. 175.1 ° C / 7/2 fumarate 5.09 Λ 9 V Ϊ — C nh- (ch ₂ ) ₂ - 1.1. 203.5 ° C 5.10 H.CO- ^ y (CH ₂ ) ₂ - cyclohexylsulfamate (1: 2) 1/2 H ₂ O / m. t 125.4 ° C 5.11 CH3CO- 1.1. 153.8 ° C

1.1. - melting temperature

I70 776

Table 7

Relationship no R ⁵ L- Physical data 1 2 3 4 7.0i -Cl CH3- t ti 8i, 9 ° C 7.02 -ch ₃ ch ₃ - vol. t i 84.2 ^° C N NH- (CH _) _— 7.03 -CH3 (ΤΎ ethanolate (2: 7) and (2 H 2 O) mp 17I, 2 ° C

170 776

c. d. table 7

1 2 3 4 7.04 -CH3 X ' ^N <Y ^{/ (CH} 2 ⁾ 2 ^- fumarate (2: 3) 1 / 2H ₂ O / 162.2 ° C 7 05 -CH3 H ₂ N- (CH ₂ ) ₂ - maleate (1: 3) / t. 192.0 ° C 7.06 -CH3 H. - 7.07 -CH3 H. 2 HCl 7.08 -F CH3- 1.1. 164.6 ° C 7.09 -CH3 NC-CH ₂ - 1.1. 194.1 ° C 7.10 -CH3 CM ri (ch ₂ ) ₂ 0 mp 224.3 ° C

170 776

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

Claims (3)

Patent claims 1. Process for the preparation of new imidazo [2,1-b] [3] bees derivatives of the formula Formula 1 wherein each dotted line independently represents an optional bond; Ri is hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy; R ² is hydrogen, halogen, C 1 -C 6 aalkyl or C 1 -C 6 aacoxy; R ³ is hydrogen, C 1 -C 6 alkyl, ethenyl substituted with hydroxycarbonyl or C 1 -C 6 acoxycarbonyl, C 1 -C 6 aalkyl substituted with hydroxycarbonyl or C 1 -C 6 acoxycarbonyl; hydroxy C1-C6 alkyl, formyl or hydroxycarbonyl; R ⁴ is hydrogen, C 1 -C 6 alkyl, hydroxy-C 1 -C 6 aalkyl, phenyl or halogen; R ⁵ is hydrogen, C 1 -C 6 alkyl or halogen; L is hydrogen, C1-C6-acyl, C1-C6-akyl substituted with one substituent selected from the group consisting of hydroxy, halogen, C1-C6 -4Hkoxy, hydroxycarbonyl, C1-C6-alkoxycarbonyl, C1-C4-aacoxycarbonyl -Ci-C6-acoxy, hydroxycarbonyl-C1-C6-alkoxy, C1-C6-alkoxy; .irbonycino, C1-C6-alkylaminocareonyl group, C1-C6-alkylaminocarbonylamino group, C1-C6-aakiioaminothiocarbonylamino group, aryloxy and arylcarbonyl; C1-C6-alkyl substituted with both hydroxy and aryloxy; C3-C6-aakenyl; Aryl substituted Co-Ck-alkenyl; wherein each aryl is phenyl or phenyl substituted with halogen, cyano, hydroxy, C 1 -C 6 aalkyl, C 1 -C 6 aacyl, aminocarbonyl or phenyl substituted with C 1 -C 6 aalkyloxycarbonyl or hydroxycarbonyl; or L is a radical of the formula -Alk-Y-Het, -Alk-TH-CO-Het ⁷ 'or -Alk-Het ³ ; wherein Alk is C 1 -C 6 aacanediyl; 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 k-Ukna substituents; pyrrolyl or pyrazolyl optionally substituted with formyl, hydroxy-C 1 -C 6 -alkyl, hydroxycarbonyl, C 1 -C 6 acoxycarbonyl or with one or two C 1 -C 6 -alkyl substituents; thiadiazolyl or oxadiazolyl optionally substituted with amino or pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each optionally substituted with C1-C4alkyl, C1-C6aacoxy, amino, hydroxy or halogen; imidazofah6-cbpyridineM; and Het3 may also be dk-dibydro-yo-keto- and H-tetrazolyl 170 776 substituted with C 1 -C 6 -alkyl, 2-keto-3-oxazolidine, 2,3-dihydro-2-keto-1H-benzimidazolyl-1 or a radical of formula 2 formula 3 in which R ⁶ is hydrogen or C1-C6-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-11- (piperidine, lidene (o - ^) -. 5Himidazo [2,1-b] [3] benzazepine; its pharmaceutically acceptable addition salts or stereochemically isomeric forms, characterized by cyclizing the alcohol of Formula 4 or a ketone of Formula 5 in the presence of an acid; pattern 5 And optionally converting the obtained compound of formula 1 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-C6-alkyl or C1-C6-alkyl substituted with hydroxycarbonyl or C1-C6-alkoxycarbonyl. 3. The method according to p. The process of claim 1, wherein R ³ is hydrogen, C 1 -C 4 -4 Ukil, formyl, hydroL-sy-Ct-Ca-aaki! or hydroxycarbonyl; R4 is hydrogen, halogen or hydroxy-C 1 -C 6 -alkyl; and L is hydrogen, C 1 -C 6 -alkyl, halo-C 1 -C 4 -Iyl, hydroxycarbonyl, C 1-4 C 1-4 alkyl, C 1-4 -alkyl, thdxycarbonyl-C 1-4 alkyl. Ci-C6- ^ H ^ i ^ lk ^ ^ ^ ^ ^ and ^ lb ^ n ^ l ^ ^ ^ ino-Ci-C6-abc 1, aryl-Ci-C6-alkyl. propenyl or L is a radical of the formula -Alk-Y-Heti -Alk-NH-CO-Het ² or -Alk-Het ³ , in which the formulas Het ¹ , Heta and Het ³ are each furanyl, oxazolyl or thiazolyl, each optionally substituted with C 1 -C 6 alkyl; thiadiazolyl optionally substituted with an amino group, pyridinyl or pyrimidinyl, each optionally substituted with a hydroxyl group; imldazt) [4,5-clpyridin \ '- 2; and Het3 may also be a radical of formula 3. and. The method according to p. and wherein the starting material in which R 1 is hydrogen or halogen is used; R ² is hydrogen, halogen or C 1-4 C 1-4 H 4 oxyl; and L is hydrogen, C1-C6alkyl, halo-C1-C6-alkyl. hydroxycarbonyl-C 1-6 C 1-6 alkyl, C 1 -C 6 -alkoxycarbonyl-C 1 -C 6 -alkyl, or a radical of the formula -Alk-YHeti in which, Y is NH.