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Novel Tetracyclic Compounds Having Anti-Allergic and Anti-Asthmatic Activities, Their Preparation and Use

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Novel Tetracyclic Compounds Having Anti-Allergic and Anti-Asthmatic Activities, Their Preparation and Use Europaisches Patentamt J Patent Office European A2 (") Publication number: 0 421 823 Office europeen des brevets EUROPEAN PATENT APPLICATION C07D C07D 471/14, © Application number: 90310979.1 © int. ci.5: 487/04, A61K 31/55, //(C07D487/04, © Date of filing: 05.10.90 241:00,221:00),(C07D471/14, 241 :00,223:00,221 :00) Priority: 05.10.89 JP 260592/89 Tokyo 140(JP) 29.03.90 JP 81513/89 Inventor: Sugiyama, Mitsuo, c/o Sankyo Company Limited Date of publication of application: No. 2-58, 1-chome Hiromachi, Shinagawa-ku 10.04.91 Bulletin 91/15 Tokyo 140(JP) Inventor: lizuka, Yoshio, c/o Sankyo Company Designated Contracting States: Limited SE AT BE CH DE DK ES FR GB GR IT LI LU NL No. 2-58, 1-chome Hiromachi, Shinagawa-ku Tokyo 140(JP) Limited Applicant: Sankyo Company Inventor: Yamaguchi, Takeshi, c/o Sankyo 5-1 Nihonbashi Honcho 3-chome Chuo-ku Company Limited Tokyo(JP) No. 2-58, 1-chome Hiromachi, Shinagawa-ku Tokyo 140(JP) Inventor: Fukumi, Hiroshi, c/o Sankyo Company Limited No. 2-58, 1-chome Hiromachi, Shinagawa-ku 0 Representative: Gibson, Christian John Robert Tokyo 140(JP) Inventor: Sakamoto, Toshiaki, c/o Sankyo etal 57/60 Lincoln's Inn Fields Company Limited MARKS & CLERK No. 2-58, 1-chome Hiromachi, Shinagawa-ku London WC2A 3LS(GB) © Novel tetracyclic compounds having anti-allergic and anti-asthmatic activities, their preparation and use. © Compounds of formula (I): CM < CO CM CO M Q. LU Xerox Copy Centre EP 0 421 823 A2 H H C C / \ / \ HC C-CH2-C CH R2-}- II I II HC C C CH \ / \ / \ X , Q N-CH C R1 (I ) / \ H H2C CH2 \ / H2C-N [in which; Q is nitrogen or =CH-; R1 and R2 are hydrogen, alky!, alkoxy, hydroxy, trifluoromethyl or halogen; and R3 is various specific substituted alkyl groups] and pharmaceutically acceptable salts thereof have valuable anti- allergic and anti-asthmatic activities. They may be prepared by reacting a corresponding compound where R3 is replaced by a hydrogen atom with a compound to introduce the group R3. EP 0 421 823 A2 NOVEL TETRACYCLIC COMPOUNDS HAVING ANTI-ALLERGIC AND ANTI-ASTHMATIC ACTIVITIES, THEIR PREPARATION AND USE The present invention relates to a new series of tetracyclic compounds having two or three ring nitrogen atoms, which we have found to have valuable anti-allergic and anti-asthmatic activities, and provides methods and compositions using them, as well as processes for their preparation. The compounds of the present invention may be generally described as dibenzo-pyrazino-azepine or 5 benzo-pyrido-pyrazino-azepine derivatives. Certain compounds of this type are known. For example, mianserin, which has the formula (A): H H C C 10 II \ I \ HC C-CH2-C CH I II II HC C C CH \ / \ I \ I 15 HC N-CH CH (A) / \ H2C CH2 \ / H2C-N 20 x CH3 mirtazapine, which has the formula (B): 25 H H C C // \ // \ HC CH 30 C-CH2-C ! il ! II • HC C C CH \ I \ ! \ I N N-CH CH (B) 35 / \ H2C CH2 \ H2C-N \ 40 CH3 aptazapine, which has the formula (C): 45 50 EP 0 421 823 A2 H C // \ HC C-CH2-N CH 5 I I! I I! HC C C CH (C) \\ / \ I \ I HC N-CH CH 10 H2C CH2 \ / H2C-N \ CH3 2-(2-hydroxyethyl)-1 ,3,4,1 4b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, which has the formula (D): 20 H C // \ HC C-CH2-N CH 25 ! i! i || HC C C CH (D) W / \ I \ I HC N-CH CH / \ 30 H2C CH2 \ / H2C-N \ CH2CH2OH 35 2-methoxycarbonylmethyl-1 ,3,4,1 4b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, which has the formula (E): 40 Hu C / \ HC C-CH2-N CH I II I II 45 HC C C CH (E) \\ / \ 1 \ 1 HC N-CH CH / \ H2C CH2 50 \ / H2C-N \ CH2COOCH3 55 and 2-(2-carboxamidoethyl)-1 ,2,3,4,1 0,1 4b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, which has the for- mula (F): EP 0 421 823 A2 H C C / \ / \ HC C-CH2-C CH 5 i II I II HC C C CH \ / \ I \ I HC N-CH CH (F) / \ 10 H2C CH2 \ / H2C-N \ CH2CH2CONH2 are disclosed in US Patent Specification No. 4 025 513, US Patent Specification No. 4 062 848, European Patent Specification No. 1585 and PCT Application No. WO-88/07997, and are said to have various activities, including anti-depressant activity and anti-histamine activity. 20 The compounds referred to above which are said to possess an anti-allergic activity have been found to be not entirely satisfactory, in that the intensity of the activity is less than would be desired for a useful commercial product, and side effects, such as irritation or depression of the central nervous system, often occur. It would, therefore, be desirable to develop therapeutic agents which, whilst possessing excellent anti-histamic, anti-allergic and anti-asthmatic activities, also have no substantial adverse reactions, such as 25 depression or irritation of the central nervous system. We have now discovered a series of tetracyclic compounds which fulfil these various desiderata. The compounds of the present invention are those compounds of formula (I): H H C C / \ / \ HC C-CH2-C CH R2-J- II I II 35 HC C C CH \ / \ / \ X , Q N-CH C R1 (I ) / \ H H2C CH2 40 \ j H2C-N \* 45 in which: Q represents a nitrogen atom or a group of formula = CH-; R1 and R2 are the same or different and each represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, a hydroxy group, a trifluoromethyl group so or a halogen atom; R3 represents: a substituted alkyl group having from 3 to 7 carbon atoms and substituted by at least one substituent selected from hydroxy groups and groups of formula -COOR*, where R4 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an aryl group, as defined below, or an aralkyl group, as 55 defined below; a group of formula -B-O-D-OR4, where: B represents an alkylene or alkylidene group having from 2 to 4 carbon atoms; D represents an alkylene or alkylidene group having from 2 to 7 carbon atoms or such an alkylene or aikylidene group in which the carbon chain is interrupted by 1 or 2 oxygen atoms; and R4 is as EP 0 421 823 A2 defined above; a group of formula -E-0-G-COOR*, where: E represents an alkylene or alkylidene group having from 2 to 7 carbon atoms; G represents a direct carbon-carbon single bond, an alkylene or alkylidene group having from 1 to 9 carbon atoms or such an alkylene or alkylidene group in which the carbon chain is interrupted 5 by 1 or 2 oxygen atoms, said alkylene or alkylidene group being unsubstituted or being substituted by an aryl group; and R4 is as defined above; a group of formula -E-O-G-CONR5RG, where: E and G are as defined above; and R5 and Rs are the same or different and each represents a hydrogen atom, w an unsubstituted alkyl group having from 1 to 6 carbon atoms, a substituted alkyl group which has from 1 to 6 carbon atoms and which is substituted by at least one of substituents (a), defined below, a cycloalkyl group which has from 3 to 7 ring carbon atoms and which is unsubstituted or is substituted by at least one alkyl group having from 1 to 4 carbon atoms, 75 an aryl group, as defined below, or an aralkyl group, as defined below; or R5 and R6, together with the nitrogen atom to which they are attached, represent a cyclic amino group having from 3 to 6 ring atoms, of which one is said nitrogen atom, 0 or 1 is an additional nitrogen and/or oxygen and/or sulphur hetero-atom and the remainder are carbon atoms, said heterocyclic group being 20 unsubstituted or being substituted by at least one of substituents (c), defined below; or a group of formula -J-CH(OH)-CH2R7, where: J represents an alkylene or alkyiidene group having from 1 to 4 carbon atoms; and R7 represents a hydroxy group, a halogen atom or a group of formula -NR5RS, where R5 and Rs are as defined above; said aralkyl groups are alkyl groups having from 1 to 4 carbon atoms, which are substituted by from 1 to 3 25 aryl groups, as defined below; said aryl groups have from 6 to 10 ring carbon atoms and are unsubstituted or are substituted by at least one of substituents (b), defined below; substituents (a): amino groups; alkylamino groups in which the alkyl group has from 1 to 6 carbon atoms; dialkylamino 30 groups in which the alkyl groups are the same or different and each has from 1 to 6 carbon atoms; and cyclic amino groups having from 3 to 6 ring atoms, of which one is a nitrogen atom, 0 or 1 is an additional nitrogen and/or oxygen and/or sulphur hetero-atom and the remainder are carbon atoms, said heterocyclic group being unsubstituted or being substituted by at least one of substituents (c), defined below; substituents (b): 35 alkyl groups having from 1 to 6 carbon atoms; alkoxy groups having from 1 to 6 carbon atoms; aryl groups, as defined above, provided that they are not themselves substituted by aryl groups; and halogen atoms; substituents (c): alkyl groups having from 1 to 4 carbon atoms; aryi groups, as defined above; and aralkyl groups, as defined above; 40 and pharmaceutically acceptable salts thereof.
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