PL170763B1 - Method of obtaining novel derivatives of imidazo[2,1-b]benzazepin - Google Patents

Abstract

1. A method for the preparation of new derivatives of im idazo [2,1-b] [3] benzazepines in formula 1 wherein each dotted line independently represents an optional bond, R 1 represents a hydrogen atom, a halogen atom, C 1 -C 4 -alkyl or C 1 -C4-alkoxy; R2 is hydrogen, halogen, C1 -C4-alkyl or C1 -C4-alkoxy, R3 is hydroxymethyl, formyl or hydroxycarbonyl, R4 is hydroxymethyl, 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 -C4-alkoxycarbonyl -C1 -C4 -aicoxy, hydroxycarbonyl-C1 -C4-alkoxy, C1 -C4 -alkoxycarbonylamino group, C1 -C4 -alkylaminocarbonyl group, C1 -C4 -alkyl aramcarbonylamino group, C1 -C4 -allaloaminothiocarbonylamino group , aryloxy group 1 aryl carbonyl group, C 1 -C 6 -alkyl substituted with both hydroxy and 1 aryloxy, C 3 -C 6 - Gralkenyl, C 3 -C 6 -alkenyl substituted with aryl, in which groups each aryl is phenyl or phenyl substituted with halogen atom, cyano, hydroxy, C1-C4-alk il, C1 -C4-alkoxylyin, aminocarbonyl or phenyl substituted with C1-C4-alkyloxycarbonyl or hydroxycarbonyl group, or L is a radical of the formula-A lk-Y -H et1 (al), -Alk-NH-CO-Het2 ( a-2) or -Alk-H et3 (a-3) in which formulas 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 - C 4 -alkyl, hydroxycarbonyl, C 1 -C 4 -alkoxycarbonyl or one or two C 1 -C 4 -alkyl substituents, thiadiazolyl 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, hydroxy or halogen; imidazo [4,5-c] pyridinyl-2; and Het3 can also be 4,5-dihydro-5-keto-1H-tetrazolyl substituted C1 -C4-alkyl m, 2-keto-3-oxazohidinyl, 2,3-dihydro-2-keto-1H-benzimidazolyl -1 or a radical of formula 2 or 3, wherein R6 is hydrogen or C1 -C4-alkyl and AZ is -S-CH = CH-, -S-CH2 -CH2, -S-CH2 -CH2 - CH2, -CH = CH-CH = C-, -CH2 -CH2 -CH2 -CH2 -, -N (CH 3) -C (CH3) = CH - or -CH = C (CH 3) -O -; excluding 6, 1 1-dihydro-11 - (piperidine lidene-4) -5H-imidazo [2,1-b] [3] benzazepine, its pharmaceutically acceptable addition salts or stereochemically isomeric forms, characterized by y that the compound of formula 7, wherein R 1. R2, R5 and L are as defined above, they are reacted with formaldehyde, optionally in the presence of a carboxylic acid-carboxylate mixture, 1 optionally further oxidation of the compound 1b and 1d to the corresponding aldehyde or carboxylic acid, of formula I into a therapeutically active non-toxic addition salt form by treatment with acid or base, or conversely, by treatment with a base or acid, respectively, by treatment with a base or acid, or its stereochemically isomeric form is prepared.

Description

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

The international publication WO 88/03138 describes benzo [5,6] cycloheptapyridines with antiallergic and anti-inflammatory effects. EP-A-0339978 describes (benzo- or pyrido) cycloheptaheterocyclic compounds with PAF-antagonistic, antihistamine and / or anti-inflammatory activity. The compounds disclosed in the present invention differ from these in their pharmacological activity

The fact that they have no PAF-antagonistic activity but have a specific antihistamine effect.

The international publication WO 92/06981 describes 6.11 dihydrol 1- (piperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepine and 1-aceto-445,6-dihydro-1 1H -imidazolo [1,2-b [[3] benzazepinoylidene-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 profile. In this publication they are described as having activity against platelet aggregation stimulating factor (PAF) without any reference to their antihistamine activity.

In the publication of J. Med. Chem., 26 (1983), 974-980 certain 1-methyl-4-piperidinylidene-9 substituted pyrrolo [2,1-b] [3] benzazepine 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.

The invention relates to a process for the preparation of new imidazo [2,1-b] [3] benzazepine derivatives of the formula 1

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 ² is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 4 alkoxy; R ³ is hydroxymethyl, formyl, or hydroxycarbonyl; R ⁴ is hydroxymethyl, 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-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, arylcarbonyl group and arylcarbonyl group; C1-C6-alkyl substituted with both hydroxy and aryloxy; C3-C6-alkenyl; Aryl-substituted C3-C6-alkenyl; wherein each aryl is phenyl or phenyl substituted with halogen, cyano, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, aminocarbonyl or phenyl substituted with C1-C4-alkoxycarbonyl or hydroxycarbonyl; or L is a radical of formula -Alk-Y-Het, -Alk-NH-CO-Het2 or -Alk-Het, in which formula Alk is C1-C4-al170 763

3 canodiyl; Y is O, S or NH; Het, Het and Het are each furanyl, thienyl, oxazolyl, thiazolyl or imidazolyl, each optionally substituted with one or two C1-Ca-alkyl substituents: pyrrolyl or pyrazolyl optionally substituted with formyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl, C1-C6 -alkoxycarbonyl or with one or two C 1 -C 6 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, amine group, hydroxyl group or halogen; imidazole / co-pyridinyl-T; and Het ³ may also be ^-dihydro-S-keto-1H-tetrazolyl, substituted by C -C-alkyl, 2-keto-3-oxazolidinyl, 2,3-dihydro-2-keto-1H-benzimidazolyl-1 or a radical of the formula

Formula 2 Formula 3 wherein R ⁶ is hydrogen or C 1 -C 6 alkyl; and AZ is -S-CH = CH-, -S-CH ^y -CH2 ^y -h- <OH2-C] U ^c - (R ^ 2 -, - (^] H ^^ - C] H = 0dί- , -CU2C) lC - ^^ l ^ i ^il -CH2- ^- -Nz ^: ic ^from bCS :: C ^ 3 = Cll ^- ub -CIICH'Ctl3) -CH zCH-CKiuem Hll ^ hydrcCll-CpijHrydjHiylideneCH-SH -nrdcbzoCJ-blPjłCnzazepines.icC kirmacetitically permissible themselves a ^p d ^p aryjipy (zl'i and isomerizinyc ⁱⁿ po.it. and stereocliemic ^{1 y} in the above definitions, the term halogen denotes fluorine, chlorine, bromine and bromine atoms Ci --jo ^ u; Cy-ANILE denacc.a naswony radical hoses ^kiwodyr-y O ^y of .ańcucho rostym lubroz ^t ga of ępionym and -ha- ^{1 and} Cy 1 to 4 houses ^ those Naki I oy idoto ^g. Pyu k -th ^yh in 1-metytoetyk Igatyk temotyte op ^ ^{11!. s} -mePylopro yl and ^p. J-dimethylethyl; R znal'zi odefiηί <.η-ι, .ηί 'wwżcj roclmte and ^p ^ DOWO wyżiie tom-k ^ 5 6 -tomach in ^zy- N tożak example. perlt.y ^'and ihekpy] C3-Cz-alkecyl ιζπροοι radicals towottoroweo ^ ^pm usahy straight 1u ^c ^ .ztonym notoriety for ^v-1 epaj Cejo ^{p. c} no podwiOzo ^p0 in -snteio ^{ρ 0} ptympoh to coals, the text ^- and ^p example. pnyariyl-2 bpien - ^ ^k uleny ^dust 2 -metytepro ^y eny ⁱ -2, ppotod ^o k2 ^- pePtenyW, 33teremk-cl ^0. ! ·, P ^ o ^-1 - ^2, hckscny ^{1 -} po ^ o ^- ^ n3; C ^- C ^c lplkzno ^of iyl ozruwza dwitwzriościowe rodnilsi ^of hoses k) wodonowe of kmcuwhu Prost tob ropgałęcionym of atziera ^ca cn miHdod carbon Hung ^- a, ^p Lakic going eg. Methyl ^o- here eScipdi ^rZ ~ l, l, ETAB o ° iyl-1, 2, pro ^p oeo ^yizt - ^j , ^c , rocking ^pz y ^z -Mi py dyta—

S tpeowane here popcoedrn of uMeme fnπcnaypjyczn ^t 3 ^l dopuypnzh so full of these itocteeyjne kwasarrn pynayza ntetoksyczoO ^and the open-eu ^l and ^{p l} of EZN podoite sol ^- which pbw ^- - twOTzyć ązki those of the first wzoroe Co. ^ k of the formula ^y w'ła of ^{s and} wośeplch zidh ^y y ^y c ^h may rp ^p-t oz kzo.ta ^C ydpewiedyiz czynio twapeuiycyme ^p os1pc.te UIC ykzyco.o ^{s' and} c - sat mldycWnyO ⁰ and tennis., tr ^m toj ⁿ c ywi ^ek w. sow ^- according to the base in many spcs ^ correspond ^ uą RoścU z iWywionlme ^p o kwąsm (© zylck-dy wwrm ozi ^y oivtejizm-i kwysaIni w ^- e.g. kżasy ll ^; pyrgnmcz.no ii ^- .

ch ^d n'cause. eg. IMCOS chlprowodorowy, baomowodorowy and under-ton-i ^ kwaw was attenuated ^c) O. square aoytow.gkcm- ^e osf'orow ^y and similar kpmty; teb acids or ^by manual e.g., ^{c, j} and ^y i t ^ey example. ocicmy tems. Ις ^ ίκ ^y rop ^s yno-f ^o , kwam ^y y dro ^p z ^b ortow ^o , kwae l ^ ydrok- ^ petroleum, kway2- ^c ytopropky-ow ^y . ⁱ sw ^ lzcyaw ^ ow ^y , Iswcs melon, bui-htyny kwes, malcr cwo ^s i, ^ eto ^r omzrow ^jh acid 2c ^o yairo ^p jybossz-ynow ^o , tecas 23-biahy ^y rokj ^y bcrjatyoowy ^y Wyc2-h ^j tórz) ks ^oa to ^y anz) lr ( ^j Jkarbh ^h sy ¹ ose ^hbi .2 ⁱ 3 ^{, y} cry mctanosuteonmwy, eu.tneohlf acid (mhw yle ^s w ^ s benzene sulflonic ^ kwo 4-mPt ^jy benzene sulfosw ^o , ^ row p ^yh to ^{c Y} are as ootern anoyulfem ^{t e} r iP ^{YEZ e} sybenzyhsow'y, kwoe 4 pm ^on -hydroxy SW ^{0 y} O ^Y bensyesow ^{Cl t} podotas kwosy. ^{m -} ązte of WCS-KLP on the ^{y j} yiwc ^j c ^- acidic echoes ^- you can swell the mixture ^-1 into pocktenes y in a way to respond to yzynez 1esis ^y eutyyyote beers in nimtotics zz ^1- additive li with life. ^- c-sodium, post-base, 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. addition also includes e the solvates which the compounds of formula I can 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; R ¹ is hydrogen, halogen or C 1 -C 6 -alkyl; R ² is hydrogen, halogen, C1-C4-alkyl or C1-C4-alkoxy; R 6 is hydroxymethyl, formyl, or hydroxycarbonyl; R ⁴ is hydroxymethyl; R ⁵ is hydrogen; L represents a hydrogen atom, C1-C6-alkyl, C1-C6-alkyl substituted with hydroxyl, C1-C4-alkoxy, C1-C4-alkoxycarbonylamino, C1-C4-alkylaminocarbonyl, C1-C4-alkylaminocarbonylamino, C1- A C4-alkylaminothiocarbonylamino group, an aryl group or an aryloxy group; C3-C6-alkenes1; Aryl-substituted C3-C6-alkenyl; wherein each aryl is phenyl or phenyl substituted by halogen, C1-C4-alkyl, C1-C4-alkoxy; or L is a radical of the formula -Alk-Y-Het ¹ , -Alk-NH-CO-Het ² or -AlkHer 5 in which formulas Alk is C1-C4-alkanediyl; Y is O, S or NH; Het, Het ² and Her 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-C4-alkyl; pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each optionally substituted with C1-C4-alkyl, C1-C4-alkoxy with an amino group, a hydroxyl group or a halogen atom; imidazo [4,5-c] pyridinyl-2; and Het ³ may also be 4,5-dihydro-5-keto-1H-tetrazolyl substituted with C 1 -C 6 -alkyl, 2-keto-3-oxazolidinyl, 2,3-dihydro-2-keto-1H-benzirnide; azolyl-1 or a radical pattern

Formula 3 wherein 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- 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-alkoxycarbopyl.

Further interesting compounds are those compounds of formula 1, wherein R ^L, R ² and R 5 are hydrogen.

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

170 763

And cc

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

Preferred are those compounds of formula 1, wherein R ³ is formyl, hydroxymethyl or hydroxycarbonyl; R ⁴ is hydroxymethyl; and L is hydrogen, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, hydroxycarbonyl-C 1 -C 6 -alkyl, C 1 -C 6 alkoxycarbonyl-C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonylamino-C 1 -C 6 -alkyl, aryl-C 1 -C 6 -alkyl, propenyl, or L is a radical of the formula -Alk-Y-Het, -Alk-NH-CO-Het ² or -Alk-Het ³ ; wherein the formulas Heti, Het ² and Het3 are each furanyl, oxazolyl or thiazolyl, each optionally substituted with C1-6alkyl; thiadiazolyl optionally substituted with an amino group; pyridinyl or nyl pyrimidines, each optionally substituted with hydroxyl; imidazo-6-pyridinyl-Z; and Het may also be a radical of formula 3.

More preferred compounds are those preferred compounds, wherein R 1 is hydrogen or halogen; R ² is hydrogen, halogen or C 1 -C 6 alkoxy; and L is C1-C6-alkyl, halo-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6alkoxycarbonyl-C1-C6-alkyl, or a group of formula -Alk-Y-Her where Y is NH.

The most advantageous compounds are:

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

aldehyde 6, and iclihydro- i- (i-methylpiperidinylidene-4) -5H-imidazo [2, i-b] [3] benzazepinyl-3-formic;

6, ii-dihydro-ii - (i-methylpiperidinylidene-4) -5H-imidazo [2, i-b] [3] benzazepine-3-carboxylic acid; their stereoisomers and pharmaceutically acceptable acid addition salts.

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, i-b] [3] -benzazepine group was designated T.

pattern 6

170 763

5

The present invention consists in that the compound of formula 7 wherein R, R, R, and L are as defined above is formylated with formaldehyde, optionally in the presence of a mixture of the corresponding carboxylic acid karboksylanern ₆ preferably acetic acid-oclan acetate , and the like. In order to increase the rate of the reaction, the reaction mixture is preferably heated to reflux temperature.

pattern 1b pattern 7

The thus obtained compounds of formulas 1b and 1d can be further oxidized to the corresponding aldehyde or carboxylic acid by reaction with the appropriate reagents, preferably manganese (IV) oxide and silver nitrate, respectively.

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 in Protection of Rats from Compound 48/80 - induced Lethality's test (Arch. Int. Pharmacodyn. Ther., 234, 164-176, 1978); 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-C6-alkyl or phenyl) oxycarbonyl, C1-C4-alkylcarbonyl, and their addition salts with

The acids are very useful in the treatment of a wide range of allergic diseases, such as, for example, allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma and the like.

Due to their useful antiallergic properties. the compounds of the present 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, transdermally, or by parenteral injection. For example, in preparing the compositions in oral dosage unit form, any of a pharmaceutical medium may be used, 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 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 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.

For example, the preparation of dosage unit formulations of conventional pharmaceutical compositions suitable for systemic or topical administration to warm-blooded animals is described below.

170 763

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

Example 1 a) A mixture of 2.5g4- (5,6-dihydro-11H-imidazo [2,1-b] [3] benzazepinylidene-11) piperidinecarboxylan-1-ethyl and 50 ml of 40% formaldehyde was stirred for 1 week at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The whole was basified with NH4OH, stirred for 1/2 hour and extracted with dichloromethane. The extract was dried, filtered and evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2 / CH3OH 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 0.45 g (16.3%) of 4- (5,6-dihydro-3- (hydroxymethyl) -11H-imidazo [2,1-b] [3] benzazepinylidene-11) piperidinoc ethyl-1 oxylate; mp. 191.9 ° C (comp. 1).

b) A mixture of 20 g of 4- (5,6-dihydro-11H-imidazo [2,1-b] [3] benzazepinylidene-11) piperidinecarboxylate-1-ethyl and 400 ml of 40% formaldehyde was stirred for 2 weeks at reflux under with a reflux condenser. The reaction mixture was evaporated and the residue was taken up in water. After basification with NH4OH, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2 / CH3OH 95: 5 - XH3Cl2 / CH3OH (NH3) 95: 5). The eluent from the third fraction was evaporated, yielding 4.1 g (17.2%) of 4- (5,6-dihydro-2,3-bis (hydroxymethyl) -11H-imidazo [2,1-b] [3] benzazepinylidene- 11) ethyl-1-piperidinecarboxylate; (comp. 8).

Example II. A mixture of 4 g 6,11-dihydro-3-methyl-11- (1-methylpiperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepine, 2 ml acetic acid, 3 g sodium acetate and 20 ml 37% formaldehyde was stirred for 50 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The whole was made basic with an aqueous NaOH solution and extracted with a mixture of dichloromethane and methanol. The extract was dried, filtered and evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2 / CH3OH 95: 5 - CH2Cl2 / CH3OH (NH3) 90: 10). The eluent from the desired fraction was evaporated and the residue was crystallized from a mixture of acetonitrile and isopropyl ether. The product was filtered off and dried to give 0.4 g (9.2%) of 6,11-dihydro-3-methyl-11 - (1-methylpiperidinylidene-4) -5H-imidazo [2,1-b] [3] benzazepinyl -2-methanol; mp 166.8 ° C.

Example III. A mixture of 1 g of ethyl 4- (5,6-dihydro-3- (hydroxymethyl) -11H-imidazo [2,1-b] [3] benzazepinylidene-11) piperidinecarboxylate, 5 g of manganese (IV) oxide and 100 ml trichloromethane was stirred for 2 hours at reflux temperature. The reaction mixture was filtered hot through diatomaceous earth. After evaporation, the residue was purified by column chromatography (silica gel; CH2O2 / CH3OH 95: 5). The eluent from the desired fraction was evaporated and the residue was crystallized from diethyl ether. The product was filtered off and dried to give 0.48 g (48.6%) of 4- (3-formyl-5,6-dihydro-11H-imade: ^^ or2,1-b] [3] -benzases (epiir / li ( 11) ethyl-1-piperidinecarboxylate, mp. 138.2 ° C (comp. 5).

Example IV. To a stirred solution of 9.7 g of the compound of Example 3 in 100 ml of water, a solution of 13.7 g of AgNO3 in 50 ml of water was added dropwise, followed by a solution of 13.7 g of potassium hydroxide in 50 ml of water. After stirring for 18 hours, the reaction mixture was filtered and the filtrate was acidified with hydrochloric acid. After evaporation, the residue was stirred in methanol, the precipitate was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; NH4OAC / H2O / CH3OH 55: 0.5: 0.45). The eluent from the desired fraction was evaporated, and the residue was stirred in 2-propanone with activated carbon. The precipitate was filtered off and the filtrate was evaporated. The residue was crystallized first from isopropyl ether and then from acetonitrile. The product was filtered off and dried to give 0.3 g (3%) of 1 l- (ll-ethoxicaabboyloipeeyddynlideeni4) -6.1 lldihyyrri5H-iπndaaoi2,1-b]] 3] beezaazpin-3-carboxylic acid; mp. 182.2 ° C (comp. 7).

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

Table

Relationship no L- R ² R3 R ⁴ Physical data and C2H5OOC- H. -CH2OH H. mp 19-9 ° C 2 H. H. -CH2OH H. mp 200 ° C dec./5/2 fumarate 3 CH3- H. -CH2OH H. mp 228.3 ° C CH ₃ p 1 and H. -CH2OH H. 'tl''- (CH ₂ ) ₂ - 0 5 C2H5OO C- H. -CHO H. mp and 38.2 ° C 6 CH3- H. -CHO H. mp i7i, 6 ° C 7 C 2H 5OO C- H. -COOH H. mp and 82.2 ° C 8 C2H5OO C- H. -CH2OH -CH2OH - 9 H- H. -CH2OH -CH2OH io CH3- H. -CH2OH -CH2OH U. 206.3 ° C ii CH3- H. -COOH H. mp. 2 ° C, 3 ° C i2 CH3- F. -CHO H. mp and 76.5 ° C I3 CH3- F. -CH2OH H. mp i8i, 5 ° C they are CH3- F. -CH2OH -CH2 OH mp 220.0 ° C I5 CH3- F. -COOH H. and / 2 H 2 O mp. 26i, 6 ° C

mp - melting temperature

170 763

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Claims (3)

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; r1 is hydrogen, halogen, C1-C6-alkyl or C1-C4-alkoxy; R ^z is hydrogen, halogen, C1-C4-alkyl or C1-C4-alkoxy; r3 is hydroxymethyl, formyl or hydroxycarbonyl; R ⁴ is hydroxymethyl, 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-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, arylcarbonyl group, and aryl carbonyl group; C1-C6-alkyl substituted with both hydroxy and aryloxy; C3-C6-alkenyl; Aryl-substituted C3-C6-alkenyl; wherein each aryl is phenyl or phenyl substituted with halogen, cyano, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, aminocarbonyl or phenyl substituted with C1-C4-alkyloxycarbonyl or hydroxycarbonyl; or L is a radical of formula -Alk-Y-Het 1 (a-1), -Alk-NH-CO-Het ² (a-2) or -Alk-Het ³ (a-3); wherein Alk is C1-C4-alkanediyl; Y is O, S or NH; Het ¹ , Hef2 and Het3 are each furanyl, thienyl, oxazolyl, thiazolyl or imidazolyl, each optionally substituted with one or two C1- (© -alkyl; pyrrolyl or pyrazolyl optionally substituted with formyl, hydroxy-C1-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] pyridinyl-2; and Het3 may also be 4,5-dihydro-5-keto-1H-tetrazolyl substituted with C1-C4-alkyl, 2- keto-3-oxazolidinyl, 2,3-dihydro-2-keto-1H-benzimidazolyl-1 or a radical of formula 2 or 3, Formula 2 Formula 3 wherein R ⁶ is hydrogen or C 1 -C 4 -alkyl; and AZ is -S-CH = CH-, -S-CH2-CH2-, -S-CH2-CH2-CH2-, -CH = CH-CH = C-, -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; pharmaceutically acceptable addition salts or stereochemically isomeric forms thereof, characterized by _; The compound of formula 7 wherein R, R, R ^J and L are as defined above, is reacted with formaldehyde, optionally in the presence of a carboxylic acid with a carboxylate, CH ₂ OH Formula 1b Formula 1d and optionally further oxidize a compound of Formula 1b and 1d to the corresponding aldehyde or carboxylic acid, and optionally converting a compound of Formula 1 into a therapeutically active non-toxic addition salt form by acid or base treatment; or conversely, converting a salt into the free base or acid by treatment with a base or acid, respectively; and / or its stereochemically isomeric forms are prepared. 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. The process of claim 1, wherein the substrate R1 is hydrogen or halogen; R ² represents hydrogen, halogen or C1-C4-alkoxy; and L is hydrogen, C1-C4-alkyl, halo-C1-C4-alkyl, hydroxycarbonylC1-C4-alkyl, C1-C4-alkoxycarbonyl-C1-C4-alkyl or a radical of formula -Alk-Y-Het ', wherein Y is NH.