DIBENZ(B,E)OXEPIN DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: A pharmaceutical composition contains, as the active ingredient, a dibenz [b,e] oxepin derivative represented by the following formula: wherein R₁ represents an alkyl group having 1 to 5 carbon atoms or a halogen atom; R₂ and R₃ may be same or different group and each represent an alkyl group having 1 to 5 carbon atoms and the pharmaceutically acceptable acid addition salts thereof

Description: This invention relates to novel dibenz[b,e]oxepin derivatives, the pharmaceutically acceptable acid addition salts thereof and a pharmaceutical composition containing, as the active ingredient, a dibenz[b,e]oxepin derivative. More particularly, the present invention pertains to a novel dibenz[b,eoxepin derivative represented by the following general formula (Ia): EMI1.1 wherein iil represents an alkyl group having 1 to 5 carbon atoms or a halogen atom, R2' and R3, may be same or diferent group and each represent an alkyl group having 1 to 5 carbon atoms; provided that when R2 and R3' represent a methyl group, R11 does not represent 2 methyl group, a fluorine atom, a chlorine atom or a bromine atom; and the pharmaceutically acceptable acid addition salts thereof. In addition, the present invention pertains to a pharmaceutical composition comprising a pharmaceutical carrier and, as an active ingredient, an effective amount of a dibenzfb,e]oxepin derivative represented by the following general formula (I) EMI2.1 wherein R1 represents an alkyl group having 1 to 5 carbon atoms or a halogen atom, R2 and R3 may be same or different group and each represent an alkyl group having to 5 carbon atoms; and the pharmaceutically acceptable acid addition salts thereof. A dibenz[b,e]oxepin derivative or tne present invention and the pharmaceutically acceptable acid addition salts thereof have antiasmathic ativity and are therefore useul as an antiasthami agent. Among the compounds represented by the general formula (I), compounds wherein R2 and R3 represent a methyl group and R1 represents a methyl group, a fluorine atom, a chlorine atom or a bromine atom are known compounds which are descibed in Eur. J. Med. Chem. Chimica Therapeu tica 9, 259 (1974). while it is described in the reference that such compounds have antidepresant and periphearl anticholinergic activities, it is not disclosed or suggested that the compounds have an antiasthmatic activity. The present inventions have first found that compound I has an antiasthmatic activity. The present invention is described in detail below. In the definition of R1', R2' and R3' in the general formula (Ia) and R1, R2 and R3 in the general formula (I); the alkyl group having 1 to 5 arbon atoms includes a methyl group, an ethyl group, a propyl group a butyl group, an amyl group, etc.; and the halogen atom includes a fluorine atom, a chlorine atom, a bromne atom, and an iodine atom. The acid addition salts of the general formulae (Ia) and (I) include inorganic acid addition salts such as hydrochloride, sulfate, hydrobrmide, phosphate, etc. and organic acid addition salts such as acetate, maleate, fumarate, tartrate, citrate, oxalate, benzoate, etc. A process for production of a compound represented by the general formula (I) (hereinafter referred to as compound I) is shown below. EMI3.1 Compound II Compound III Compound I wherein R1, R2 and R3 have the same meanings as defined above. Equimolecular qunatities of compound II and compound III (or an acid addition salt of compound III) are dissolved in an inert solvent such as chloroform, methylene chloride, toluene, tetrahydrofuran, N,N-dimethylformamide, etc. and the mixture is stirred at room temperature to the boiling point of the inert solvent used or 30 :ninutes to 2 hours. Then, the solvent is removed crom the reaction solution to obtain a crude salt of compound I as a rescue. The crude product is dissolved in an aqueous basic solution, and then the mixture is extracted wit an organic solvent hard to be mixed with water such as diethylether, whereby the desired compound is obtained in the form of free base. Because of unlikeliness to crystallize, the product, if necessary, is subjected to purifi- cation by column chromatography, etc. and then, an appro- priate acid is added thereto to obtain an acid addition salt thereor, which is more tractable. Further F necessary, the acid addition salt may be converted to a highly-purified preparate by a suitable recrystallization operation. It goes, without saying, that the aforesaid residual crude product after removal of the reactIon solvent is immediately subjected to a recrystallization treatement without the liberation process whereby a purified preparate is obtained As an appropriate acid, a physiologically usable inorganic aid such as hydrochloic acid, sulfuric acid, hydrobromic acid and phosphoric acid or an organic acid such as acetic acid, maleic acid, fumaric acid, tartaric acid, citric acid, oxalic acid and benzoic acid may be used. Compound II; an starting material for compound I is a known compound which is disclosed in Japanese Published Unexamind Patent Application Nos. 150082/81 and 150083/81, and compound III is on the market and readily available. Results of acute toxicity test and antiasthmatic activity test of compound I are shown below. Acute toxicity test Groups of male dd-strain mice (each group consisting of five mice) weighing 20 # 1 g are used. Compound I arre adminstered orally (po : 0.3 mg/g) or intrapritoneally (ip : 0.1 mg/g). The MLD (minimum lethl dose) is calculated from the mortality for 7 days after the administration to obtain the results given in Table 1. Table 1 EMI4.1 <tb> <SEP> MLD <SEP> (mg/Kg) <tb> <SEP> Compound <SEP> po <SEP> ip <tb> Compound <SEP> 1 <SEP> > 300 <SEP> > 100 <tb> <SEP> " <SEP> 2 <SEP> > 300 <SEP> > 100 <tb> <SEP> " <SEP> 3 <SEP> > 300 <SEP> > 100 <tb> <SEP> " <SEP> 4 <SEP> > 300 <SEP> > 100 <tb> <SEP> " <SEP> 5 <SEP> > 300 <SEP> 100 <tb> <SEP> " <SEP> 6 <SEP> > 300 <SEP> > 100 <tb> <SEP> " <SEP> 7 <SEP> > 300 <SEP> > 100 <tb> <SEP> " <SEP> 8 <SEP> > 300 <SEP> > 100 <tb> <SEP> " <SEP> 9 <SEP> > 300 <SEP> > 100 <tb> <SEP> " <SEP> 10 <SEP> > 300 <SEP> > 100 <tb> <SEP> " <SEP> 11 <SEP> > 300 <SEP> > 100 <tb> Typical examples (compounds 1-11) of compound I are designated as follows. Compound Name of compound 1 2-methyl-11-[2-(dimethylamino)ethyl]thio 6,11-dihydrodibenz[b,e]oxopin 2 2-methyl-11-[2-(diethylamino)ethly]thio-6,11 dihydrodibenz[b,e]oxepin 3 4-methyl-11-[2-(diethylamino)ethyl]thio-6,11 dihydrodibenz[b,e]oxepin 4 2-chloro-11-[2-(diethylamino)ethyl]thio-6,11 dihydrodibenz[b,e]oxepin 5 2-ethyl-11-[2-(diethylamino)ethyl]thio-6,11 dihydrodibenz[b,e]oxepin 6 2-fluoro-11-[2-(diethylamino)ethyl]thio-6,11 dihydrodibenz[b,e]oxepin 7 2-ethyl-11-[2-(diethylamino)ethyl]thio-6,11 dihydrodibenz[b,e]oxepin 8 2-fluoro-11-[2-(diethylamino)ethyl]thio-6,11 dihydrodibenz[b,e]oxepin 9 2-ethyl-11-[2-(diethylamino)ethyl]thio 6,11-dihydrodibenz[b,e]oxepin 10 2-fluoro-11-[2-(diethylamino)ethyl]thio 6,11dihydrodibenz[b,e]oxepin 11 3-methyl-11-[2-(diethylamino)ethyl]thio-6,11 dihydrodibenz[b,e]oxepin Antisthamic acitivity test [Experimetal method] antiasthamic ativity is evaluatd according to passive cutaneous anaphylaxis response (PCA response). Antiserum is collected from Wistar strain male rats weighing 200 to 250 5. PCA response is evaluated using Wistar strain male rats weighing 100 to 120 g. (A) preparation of antiserum: One mg egg albumin is dissolved in 0.5 ml of pertussisdiphteria mixed veccine, and the rsulting solution is mixed with 0.5 ml of inomplet adjuvant. The resulting emulsion is used as antigen and administered to rats subcutaneously through the sole. In the 12th day after the admisitration, heads of the rats are cut to collected blood. Thus, antiserum is prpared. Upon evaluating antiasthamic activity, concentation of the antiserum is adhusted so that diameter of blue-dyed portion is about 8 to about 10 mm. (B) PCA repsonse (evaluatio of antiasthamic aitivity): Six rats are use per group. 0.05 ml of the antiserum is intracutaneously administered to each of the previously back-shaved rats to sensitive. After 17 hours, compound 1 or the solutions thereof (pysiological salt solution or CMC solution) are respectively administered and, after 60 minutes, an antigen mixture (1% Evans' Blue physiological salt solution containing 0,2 % egg albumin) is injected intravenously in an amount of 0.5 ml/100 g to induce PCA response. After 30 minutes, rats are choked to death followed by cutting cut skin to measure the diameter of blue-dyed portion. The results are evaluated by awarding a score accoriding to the diameter of blue-dyed portion. Furthermore, ratics of the diameters to that od solvent (physiological salt solution or CMC) administered group are determined. Compounds snowing a depressing ration of 50% or more calculatd according to the following formula are concluded to show positive antiasthamic ativity. Also, the minimum effective dose (MED) is determined from the results with respective doses to compare the strngth of antiasthamic acitivity. Results thus obtained are tabulated in Table 2. EMI7.1 <tb> <SEP> Score <SEP> Blue-dyed <SEP> Portion <tb> <SEP> (# <SEP> <SEP> mm) <tb> <SEP> 5 <SEP> # <SEP> 10 <SEP> <SEP> mm <tb> 4 <SEP> 8.0 <SEP> - <SEP> 9.9 <SEP> " <tb> 3 <SEP> 6.0 <SEP> - <SEP> 7.9 <SEP> " <tb> <SEP> 2 <SEP> 4.0 <SEP> - <SEP> 5.9 <tb> <SEP> 1 <SEP> 2.0 <SEP> - <SEP> 3.9 <tb> <SEP> 0 <SEP> 0-1.9 <tb> Depresslng ratio (%) = Diameter for solvent- Diameter for test comp adminstrated group - pound-administered group x 10C Diameter for solvent-administered group Table 2 EMI7.2 <SEP> C <SEP> 25e <tb> <SEP> :ound <SEP> nS/"-SC <tb> <SEP> I <SEP> El <SEP> "9 <tb> <SEP> 2.5 <SEP> mpourd <SEP> 1 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 81 <SEP> 49 <SEP> 2.5 <tb> <SEP> 2 <SEP> 2 <SEP> 1 <SEP> 100 <SEP> 100 <SEP> 1 <SEP> 190 <SEP> 52 <SEP> 40 <SEP> 20 <SEP> 1 <SEP> - <SEP> 10.0 <tb> It <SEP> 3 <SEP> 52 <SEP> 14 <SEP> - <SEP> - <SEP> i <SEP> - <SEP> - <SEP> - <SEP> I <SEP> iv . <tb> <SEP> 11 <SEP> 4 <SEP> 100 <SEP> 100 <SEP> 46 <SEP> 10 <SEP> - <SEP> | <SEP> - <SEP> - <SEP> 50.0 <tb> <SEP> .. <SEP> 5 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 56 <SEP> 36 <SEP> 1 <SEP> - <SEP> 10.0 <tb> <SEP> 6 <SEP> 100 <SEP> 100 <SEP> 84 <SEP> 3 <SEP> - <SEP> t <SEP> - <SEP> 25.0 <tb> <SEP> 7 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 81 <SEP> 30 <SEP> - <SEP> | <SEP> 5.0 <tb> 8 <SEP> 8 <SEP> 8 <SEP> - <SEP> 100 <SEP> 100 <SEP> 100 <SEP> 33 <SEP> 23 <SEP> - <SEP> - <SEP> 1 <SEP> 25.0 <tb> <SEP> 9 <SEP> 9 <SEP> 100 <SEP> 100 <SEP> 67 <SEP> 22 <SEP> - <SEP> - <SEP> - <SEP> it <SEP> 25.0 <tb> <SEP> " <SEP> 10 <SEP> 73 <SEP> 11 <SEP> i <SEP> 11 <SEP> 0 <SEP> 1 <SEP> - <SEP> - <SEP> 30.0 <SEP> 1 <tb> 11 <SEP> 61 <SEP> 61 <SEP> 61 <SEP> ! <SEP> 28 <SEP> o <SEP> ! <SEP> - <SEP> 5C.D <tb> As is apparent rom Table 2, compound I has an antiasthmatic activity and is useful as an antiasthmatic agent. Compound I may be used in various pharmaceutical forms for administration. Pharmaceutical compositions of the present invention are prepared by uniformly mixing an effective amount of compound I as the active ingredient, in free form or as an acid addition salt, with a pharma- ceutically acceptable carrier The carrier may take various forms depending on the pharmaceutical form suitable for administration. It is preferable that the pharmaceutical composition is in single administration form suitable for administration orally or by injection. To prepare the compositions of the present invention for oral administration, any useful pharmaceutical carrier may be used. For example, oral liquid preparations such as suspensions and syups can be prepared using water, sugar (e.g. sucrose, sorbitol anc ructose), glycols (e.g. polyethyleneglycol and propyleneglycol), oils (e.g. sesame oil, olive, oil and soybean oil), antiseptics (e.g an alkyl parahydroxybenzoate), flavours (e.g. strwberry flavour an pepermint) and the like. Powdes, pills, capsules and tablets can me prepared using excipients (e.g. lactose, glucose, sucrose and mannitol), disintegrators (e.g. strach and sodium alginate), lubricants (e.g. magnesium stearate and tacl), binders (e.g. polyvinyl alcohol, hydroxypropylcellulose acd gelatin), surfactants (e.g. sucrose fatty acid ester) , plasticizers (e.g. glycerin) and the like. Tablets and capsules are the most useful single oral administration forms because of th ase of administration. To make tablets and capsules solid pharmaceutical carriers are used. An injection solution can be prepared using a carrier consisting of salt solution, glucose solution and a mixture of salt and glucose solution. Althoug teh amount of the active ingrednet can be varied over a rather wice range, 1 - 20 mg/kg/day in cne dose or several divided doses is generally considered to be effective. Certain specific embodiments of the invention are illustrated by the following representative exemples. Example 1 In this example, 1.70 g of diethylaminoethylthiolhydrochloride and 2.45 g of 2-methyl-11-chloro-6 ,ll- dihydrodibenz[b,e]oxepin are dissolved in 50 ml of methylene chloride, and the mixture is stirred or 2 hours. The reaction solution is concentrated under reduced pressure to distill off methylene chloride. Recrystallyzation of the residue from 50 ml of ethanol gives 3.25 g of pre crystals of hydrochloride of 2-methyl-11-[2-(diethylmino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin (compound 2) in a yield of 86%. m.p.: (hydrochloride) 202-205 C. IR absorption spectrum: (KBr tablet, cm-1) 2920, 2670, 1495, 1260, 1230, 1015 elemental analysis 0= hydrochloride: C(%) E(%) N(%) Calcd. for C21H27NOS#HCl: 66.73 7.47 3.71 Found: 66.52 7.23 3.90 The resulting hydrochloride is dissolved in a basic water, and then the solution is extraced It diethylether. the extracts is deshydrated and concentrated to obtain an oily ree base. NMR spectrum (CDCl3, #value, ppm): 0.93(t, 6H), 2.22(s, 3H), 1.93-2.79(m,8H), 4.77(d, 1H), 4,89(s, 1H), 6.23(d, 1H), 6.52-7.45(m,7H) Examples 2 to 11 Compounds 1 and 3 though 11 having the physico chemical properties identified in Tables 4 and 5 are obtained a similar manner to that in Example 1 except that the amuno ethylthiochloride and 11-chloro-6,11-dihydrobenz [b,e]oxepin shown in Table 3 are used instead of diethylaminoethylthiohydrochloride and 2-methyl-11-chloro-6,11dihydrodibenz[b,e]oxepin in Example 1. Table 3 EMI10.1 <tb> <SEP> Aminoethyltriolhydrochloride <tb> Example <SEP> |- <SEP> Ws <SEP> /NR <SEP> R <SEP> R <SEP> -:C1 <SEP> ; <SEP> Used <SEP> amount <tb> <SEP> R2 <SEP> R2 <tb> <SEP> 2 <SEP> met:wyl <SEP> i <SEP> methyl <SEP> 1.4 <tb> <SEP> 3 <SEP> ethyl <SEP> et:ivl <SEP> 1.0 <tb> <SEP> = <SEP> eth-: <SEP> o=1 <SEP> l <SEP> 1.4 <tb> <SEP> 5 <SEP> 1 <SEP> - <SEP> ethyl <SEP> 1.7 <tb> ethyl <tb> 6 <SEP> etn" <SEP> e=vl <SEP> 1.7 <tb> 1.4 <SEP> 7 <SEP> eth <SEP> . <SEP> m.e;.-yl <SEP> 1. <SEP> A <tb> 1 <SEP> methyl <SEP> ' <SEP> .. <SEP> :riethy <SEP> 1.4 <tb> <SEP> 9 <SEP> 9 <SEP> i <SEP> 'sopropy <SEP> isopropyl <SEP> 2.0 <tb> <SEP> 1.0 <SEP> 'sopropyl <SEP> isss=rDvl <SEP> 2.0 <tb> <SEP> ; <SEP> me¯.-- <SEP> 1 <SEP> metr::-- <SEP> 2.5 <tb> <SEP> t <tb> Table 3 (.../ ... contd.) EMI11.1 <tb> <SEP> 'Il-cloro-6,11-dihydrodibenz[b,e]oxpFn <tb> <SEP> C1 <tb> <SEP> Example <SEP> y¸01-23R1 <SEP> ;;ou <SEP> l <SEP> <tb> <SEP> (g) <tb> <SEP> R1 <tb> <SEP> 1 <tb> <SEP> 2 <SEP> 2-methyl <SEP> 2.4 <tb> <SEP> 3 <SEP> 4-methyl <SEP> | <SEP> 1.4 <tb> <SEP> 4 <SEP> 2-chloro <SEP> 1 <SEP> 2.2 <tb> <SEP> 5 <SEP> 2methyl <SEP> 1 <SEP> 2.6 <tb> <SEP> 6 <SEP> 2-f1ucro <SEP> ' <SEP> 2.5 <tb> <SEP> 7 <SEP> 2-=1 <SEP> 2.6 <tb> <SEP> 8 <SEP> 2-fuoro <SEP> j <SEP> 2.5 <tb> 9 <SEP> 9 <tb> <SEP> 10 <SEP> -¯i^^ro <SEP> | <SEP> 2.5 <tb> <SEP> 11 <SEP> 3-me¯:.v: <SEP> ; <SEP> 5.2 <tb> Table 4 EMI12.1 <SEP> Obtained <SEP> Physicochemical <SEP> properties <tb> <SEP> amount <SEP> of <tb> Example <SEP> Compound <SEP> the <SEP> desired <SEP> Yield <SEP> m.p. <SEP> ( C) <SEP> IR <SEP> absorption <SEP> spectrum <tb> <SEP> compound <SEP> (%) <SEP> (hydrochloride) <SEP> (hydrochloride, <SEP> KBr <tb> <SEP> (g) <SEP> tablet, <SEP> cm-1) <tb> 2 <SEP> Compound <SEP> 1 <SEP> 1.8 <SEP> 51 <SEP> 166 <SEP> - <SEP> 169 <SEP> 2690, <SEP> 1500, <SEP> 1460, <tb> <SEP> 1260, <SEP> 1230, <SEP> 1015 <tb> 3 <SEP> 3 <SEP> 2.1 <SEP> 97 <SEP> 163 <SEP> - <SEP> 165 <SEP> 2920, <SEP> 2580, <SEP> 2470, <tb> <SEP> 1470, <SEP> 1195, <SEP> 1010 <tb> 4 <SEP> " <SEP> 4 <SEP> 3.1 <SEP> 91 <SEP> 165 <SEP> - <SEP> 167 <SEP> 2920, <SEP> 2620, <SEP> 1485, <tb> <SEP> 1255, <SEP> 1230, <SEP> 1020 <tb> 5 <SEP> " <SEP> 5 <SEP> 3.6 <SEP> 90 <SEP> 157 <SEP> - <SEP> 160 <SEP> 2920, <SEP> 2670, <SEP> 1500, <tb> <SEP> 1255, <SEP> 1235, <SEP> 1010 <tb> 6 <SEP> " <SEP> 6 <SEP> 3.6 <SEP> 94 <SEP> 134 <SEP> - <SEP> 137 <SEP> 2920, <SEP> 2620, <SEP> 1495, <tb> <SEP> 1255, <SEP> 1210, <SEP> 1025 <tb> 7 <SEP> " <SEP> 7 <SEP> 2.9 <SEP> 80 <SEP> 149 <SEP> - <SEP> 151 <SEP> 2920, <SEP> 1505, <SEP> 1260, <tb> <SEP> 1230, <SEP> 1125, <SEP> 1020 <tb> 8 <SEP> " <SEP> 8 <SEP> 3.2 <SEP> 90 <SEP> 169 <SEP> - <SEP> 172 <SEP> 2920, <SEP> 2720, <SEP> 1500, <tb> <SEP> 1260, <SEP> 1230, <SEP> 1025 <tb> <SEP> hydrochloride <SEP> being <SEP> Oily <SEP> free <SEP> base, <tb> <SEP> unable <SEP> to <SEP> crystal- <SEP> NaCl <SEP> cell <tb> 9 <SEP> " <SEP> 9 <SEP> 3.8 <SEP> 98 <SEP> lize, <SEP> and <SEP> fumarate <tb> <SEP> being <SEP> too <SEP> hygro- <SEP> 2970, <SEP> 1500, <SEP> 1260, <tb> <SEP> scopic <SEP> to <SEP> measure <SEP> 1230, <SEP> 1120, <SEP> 1020 <tb> <SEP> Oily <SEP> free <SEP> base, <tb> <SEP> NaCl <SEP> cell <tb> 10 <SEP> " <SEP> 10 <SEP> 3.7 <SEP> 98 <tb> <SEP> 2970, <SEP> 1500, <SEP> 1260, <tb> <SEP> 1225, <SEP> 1160, <SEP> 1020 <tb> 11 <SEP> " <SEP> 11 <SEP> 6.1 <SEP> 98 <SEP> 155 <SEP> - <SEP> 158 <SEP> 2920, <SEP> 2660, <SEP> 1620, <tb> <SEP> 1460, <SEP> 1260, <SEP> 1125 <tb> Table 5 EMI13.1 <tb> <SEP> Example <SEP> NMR <SEP> spectrum <SEP> Elemental <SEP> analysis <tb> <SEP> (CDCl3, <SEP> # <SEP> : <SEP> ppm) <SEP> Calcd.(%) <SEP> Found <SEP> (%) <tb> <SEP> Oily <SEP> free <SEP> base <SEP> C19H23NOS#HCl <tb> <SEP> 2.14(s,6H), <SEP> 2.23(s,3H) <SEP> C <SEP> 65.22 <SEP> 65.20 <tb> <SEP> 2 <SEP> 1.97-2.77(m,4H), <SEP> 4.77 <SEP> (d,1H), <SEP> H <SEP> 6.91 <SEP> 6.84 <tb> <SEP> 4.90 <SEP> (s,1H), <SEP> 6.22(d, <SEP> 1H), <tb> <SEP> 6.59-7.39(m,7H) <SEP> N <SEP> 4.00 <SEP> 3.89 <tb> <SEP> Hydrochloride <SEP> C21H27NOS#HCl <tb> <SEP> 1.22(t,6H), <SEP> 2.20(s,3H), <SEP> C <SEP> 66.73 <SEP> 66.59 <tb> 3 <SEP> 2.6-3.4(m,9H), <SEP> 4.89(d,1H) <SEP> H <SEP> 7.47 <SEP> 7.49 <tb> <SEP> 5.10(s,1H), <SEP> 6.00(d,1H), <tb> <SEP> 6.6-7.5(m,7H) <SEP> N <SEP> 3.71 <SEP> 3.58 <tb> <SEP> 1.27(t,6H), <SEP> 2.6-3.3(m,9H), <SEP> C <SEP> 60.30 <SEP> 60.03 <tb> 4 <SEP> 4.83(d,1H), <SEP> 5.13(s,1H), <tb> <SEP> 6.17(d,1H), <SEP> 6.6-@.6(m-9H) <SEP> H <SEP> 6.32 <SEP> 6.17 <tb> <SEP> 6.1 <SEP> 2=,-) <SEP> , <SEP> 6.6-7. <SEP> 6:n <SEP> '7..) <SEP> N <SEP> 3.52 <SEP> 3.66 <SEP> <tb> Hydrochloride <SEP> C22H29NOS#HCl <tb> <SEP> 0.9-1.6(m,9H), <SEP> 2.3-3.5(m, <SEP> C <SEP> 67.41 <SEP> 67.37 <tb> <SEP> 5 <SEP> 10H), <SEP> 4.83 <SEP> (d,1H), <SEP> 5.09(s, <SEP> H <SEP> 7.71 <SEP> 7.80 <tb> <SEP> 1H), <SEP> 6.07(d,1H), <SEP> 6.6-7.6 <tb> <SEP> (m,7H), <SEP> 11.9(br,1H) <SEP> N <SEP> 3.57 <SEP> 3.39 <tb> <SEP> Hydrochloride <SEP> C20H24FNOS#HCl <tb> <SEP> 1.27(t,6H), <SEP> 2.5-3.5(br,8H), <SEP> C <SEP> 62.90 <SEP> 63.01 <tb> <SEP> 6 <SEP> 4.82(d,1H), <SEP> 5.17(s,1H), <SEP> H <SEP> 6.60 <SEP> 6.47 <tb> <SEP> 6.03(d,1H), <SEP> 6.7-7.6(m,7H), <tb> <SEP> 11.8(br,1H) <SEP> N <SEP> 3.67 <SEP> 3.51 <tb> <SEP> Hydrochloride, <SEP> CDCl3 <SEP> + <SEP> d6DMSO <SEP> C20H25NOS#HCl <tb> <SEP> 1.17(t,3H), <SEP> 2.4-3.6(m,13H), <SEP> C <SEP> 66.00 <SEP> 66.05 <tb> <SEP> 7 <SEP> 4.87(d,1H), <SEP> 5.25(s,1H), <SEP> H <SEP> 7.20 <SEP> 6.98 <tb> <SEP> 6.03(d,1H), <SEP> 6.6-7.6(m,7H) <SEP> N <SEP> 3.85 <SEP> 3.69 <tb> <SEP> Hydrochloride, <SEP> CDCl3 <SEP> + <SEP> d6DMSO <SEP> C18H20NOS#HCl <tb> <SEP> 2.4-3.6(m,11H), <SEP> 4.80(d,1H), <SEP> C <SEP> 61.09 <SEP> 61.32 <tb> <SEP> 8 <SEP> 5.29(s,1H), <SEP> 5.97(d,1H), <SEP> H <SEP> 5.98 <SEP> 6.09 <tb> <SEP> 6.7-7.6 <SEP> (m,7H) <SEP> N <SEP> 3.96 <SEP> 4.26 <tb> Table 5 (.../,,, contd.) EMI14.1 <tb> <SEP> Example <SEP> NMR <SEP> spectrum <SEP> Elemental <SEP> analysis <tb> <SEP> (CDCl3, <SEP> # <SEP> : <SEP> ppm) <SEP> Calcd.(%) <SEP> Found <SEP> (%) <tb> <SEP> Oily <SEP> free <SEP> base <SEP> C24H33NOS <tb> <SEP> 0.91(d,12H), <SEP> 1.20(t,3H), <SEP> C <SEP> 75.15 <SEP> 75.02 <tb> <SEP> 9 <SEP> 2.3-3.2(m,8H), <SEP> 4.80(d,1H), <SEP> H <SEP> 8.67 <SEP> 8.58 <tb> <SEP> 4.91(s,1H), <SEP> 6.29(d,1H), <tb> 6.7-7.5(m,7H) <SEP> N <SEP> 3.65 <SEP> 3.77 <tb> <SEP> Oily <SEP> free <SEP> base <SEP> C22H28FNOS <tb> <SEP> 0.93(d,12H), <SEP> 2.47(s,4H), <SEP> C <SEP> 70.74 <SEP> 70.49 <tb> <SEP> 10 <SEP> 2.7-3.2(m,2H), <SEP> 4.80(d,1H), <SEP> H <SEP> 7.56 <SEP> 7.31 <tb> <SEP> 4.85(s,1H), <SEP> 6.22(d,1H), <tb> <SEP> 6.7-7.5(m,7H) <SEP> N <SEP> 3.75 <SEP> 3.84 <tb> Hydrochloride, <SEP> CDCl3 <SEP> + <SEP> d6DMSO <SEP> C24H33NOS <tb> <SEP> 2.22(s,3H), <SEP> 2.4-3.3(m,11H), <SEP> C <SEP> 65.22 <SEP> 55.08 <tb> <SEP> 11 <SEP> 4.82(d,1H), <SEP> 5.23(s,1H), <SEP> H <SEP> 6.91 <SEP> 7.03 <tb> <SEP> 6.12(d,1H), <SEP> 6.5-7.6(m,7H), <SEP> N <SEP> 4.00 <SEP> 3.88 <tb> Example 12: Preparation of tablet A tablet comprising the following components is prepared in a conventional manner. Component Hydrochloride of compound 1 30 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar pigment q.s. Example 13: Preparation of powder A powder comprising the following components is prepared in a conventional manner. Component Hydrochloride of compound 2 30 mg Lactose 270 mg Example 14 : Preparation of syrup A syrup comprising the following components is prepared in a conventional manner. Component Hydrochloride of compound 7 300 mg Sucrose 40 g Methyl para-hydroxybenzoate 40 mg Propyl para-hydroxybenzoate 10 mg Strawberry flavour 0.1 cc Water is added to the above components until the total volume is 100 cc.

Claims: WHAT IS CLAIMED IS: 1. A novel dibenz[b,e]oxepin derivative represented by the following general formula (Ia): EMI16.1 wherein R1' represents an alkyl group having 1 to 5 carbon atoms or a halogen atom; R2' and R3' may be same or different group and each represent an alkyl group having 1 to 5 carbon atoms provided that when R2' and R3' represent a methyl group, R1' does not represent a methyl group, a fluorine atoms a chlorine atom or a bromine atom; and me pharmaceutically acceptable acid addition salts thereo=. 2. A derivative of claim 1; namely, 2-methyl-11- [2.(diethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 3. A derivative of claim 1; namely, 4-methyl-li- [2-diethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 4. A derivative of claim 1; namely, 2-chloro-11 [2-(diethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 5. A derivative of claim 1; namely, 2-ethyl-li- [2-(diethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 6. A derivative of claim 1; namely, 2-fluoro-11 [2- ( diethylamino )ethyl)thio-6, 11-dihyrodibenz[b,e]oxepin. 7. A derivative of claim 1; namely, 2-ethyl-il- [2-(dimethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 8. A derivative of claim 1; namely, 2-ethyl-li- [2-(diisopropylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 9. A derivative of claim 1; namely, 2-fluoro-il- [2-(diisopropylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 10. A pharmaceutical composition comprising a pharmaceutical carrier and, as an active ingredient, an effective amount of a dibenz[b,e]oxepin derivative represen.ec by the following general formula (I) EMI17.1 wherein R1 represents an alkyl group having 1 to 5 carbon atoms or a halogen atom, R2 and R3 may be same or Fferent group and each represent an alkyl group having 1 to 5 carbon atoms; and the pharmaceutically acceptable acid addition salts thereof. 11. A pharmaceutical composition according to claim 10, wherein said dibenz[b,e]oxepin derivative is 2-methyl11-[2-(dimethylamino)ethyl-6,11-dihydrodibenz[b,e]oxepin. 12. A pharmaceutical composition according to claim 10, wherein said dibenz[b,e]oxepin derivative is 2-methyl11-[2-(diethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 13. A pharmaceutical composition according to claim 10, wherein said dibenz[b,e]oxepin derivative is 4-methyl11-[2-(diethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 14. A pharmaceutical composition according to claim 10, wherein said dibenz[b,e]oxepin derivative is 2-chloro11-[2-(diethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 15. A pharmaceutical composition according to claim 10, wherein said dibenz[b,e]oxepin derivative is 2-ethyl11-[2-(diethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 16. A pharmaceutical cortposltion according to claim 10, wherein said dibenz[b,e]oxepin derivative is 2-fluoro11-[2-(diethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 17. A pharmaceutical composition according to claim 10, wherein said dibenz[b,e]oxepin derivative is 2-ethyl11-[2-(dimethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 18. A pharmaceutical composition according to claim 10, wherein said dibenz[b,e]oxepin derivative is 2-fluoro11-[2-(dimethylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 19. A pharmaceutical composition according to claim 10, wherein said dibenz[b,egoxepin derivative is 2-ethyl11-[2-(diisopropylamino)ethyl]thio-6,11-dihydrodibenz[b,e]oxepin. 20. A pharmaceutical composition according to claim 10, wherein said dibenz[b,e)oxepin derivative is 2-fluoro 11-[2-(diisopropylamino)ethyl]thio-6,11-dihydrodibenz[b,e3- oxepin. 21. A pharmaceutical composition according to claim 10, wherein said dibenzlb,e]oxepin derivative is 3-methyl 11-[2-(dimethylamino)ethyl3thio-6,11-dihydrodnbenzEbte]- oxepin.

Inventors: HASHIMOTO, TAMOTSU, MORITA, OSAMU, OIJI, YOSHIMASA, TAKIZAWA, HIROSHI
Applicants: KYOWA HAKKO KOGYO CO., LTD
Application year: 1983
Main classification: C07D313
IPC codes: A61K31, A61P11, C07D313