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    Novel oxime ethers
    1.
    发明授权
    Novel oxime ethers 失效
    新型肟醚

    公开(公告)号：US4077999A

    公开(公告)日：1978-03-07

    申请号：US749399

    申请日：1976-12-10

    申请人： Zoltan Budai ,  Aranka Lay nee Konya ,  Tibor Mezei ,  Katalin Grasser ,  Eniko Szirt nee Kiszelly ,  Ibolya Kosoczky ,  Lujza E. Petocz

    发明人： Zoltan Budai ,  Aranka Lay nee Konya ,  Tibor Mezei ,  Katalin Grasser ,  Eniko Szirt nee Kiszelly ,  Ibolya Kosoczky ,  Lujza E. Petocz

    IPC分类号： C07C251/58 ,  C07D295/088 ,  C07C131/02 ,  C07C131/04

    CPC分类号： C07D295/088 ,  C07C251/58 ,  C07C2101/08 ,  C07C2101/16 ,  C07C2101/18

    摘要： The invention relates to novel oxime ethers of the formula I ##STR1## wherein R stands for a phenyl group which may be substituted by a halogen atom or by one or more C.sub.1 -C.sub.4 alkoxy, hydroxyl, nitro or di(C.sub.1 -C.sub.3 alkyl)amino groups,R.sup.1 and R.sup.2 denote each a hydrogen atom or together a valence bond,A denotes a C.sub.2 -C.sub.4 straight or branched-chain alkylene group,N denotes an integer from 3 to 10, andR.sup.3 and R.sup.4 denote a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group, furthermore to acid addition salts and quaternary ammonium salts thereof. These new compounds are biologically active, and possess primarily local analgesic, spasmolytic, nicotine-lethality inhibiting, tetrabenazine-antagonistic and tetra-cor-spasm inhibiting effects.

    摘要翻译： 本发明涉及式I（I）的新型肟醚，其中R代表可被卤素原子取代的苯基或一个或多个C 1 -C 4烷氧基，羟基，硝基或二（C1- C 3烷基）氨基，R 1和R 2各自表示氢原子或价键一起，A表示C 2 -C 4直链或支链亚烷基，N DENOTES AN INTEGER为3〜10，R 3和R 4表示氢 原子或C1-C4烷基，此外还涉及其酸加成盐和季铵盐。 这些新化合物具有生物活性，主要具有局部镇痛，解痉，尼古丁致死抑制，四苯并嗪拮抗和四痉挛抑制作用。

    Oxime ethers
    2.
    发明授权
    Oxime ethers 失效
    肟醚

    公开(公告)号：US4083978A

    公开(公告)日：1978-04-11

    申请号：US652806

    申请日：1976-01-27

    申请人： Zoltan Budai ,  Aranka Lay nee Konya ,  Tibor Mezei ,  Katalin Grasser ,  Eniko Szirt nee Kiszelly ,  Ibolya Kosoczky ,  Lujza E. Petocz

    发明人： Zoltan Budai ,  Aranka Lay nee Konya ,  Tibor Mezei ,  Katalin Grasser ,  Eniko Szirt nee Kiszelly ,  Ibolya Kosoczky ,  Lujza E. Petocz

    IPC分类号： C07C251/58 ,  C07D295/088 ,  A61K31/495 ,  C07D295/12

    CPC分类号： C07D295/088 ,  C07C251/58 ,  C07C2101/08 ,  C07C2101/16 ,  C07C2101/18

    摘要： Oxime ethers of the formula ##STR1## wherein R stands for a phenyl group which may be substituted by a halogen chlorine atom or by one to three methoxy groups;R.sup.1 and R.sup.2 denote each a hydrogen atom or together a valence bond;A denotes a C.sub.2 -C.sub.4 straight or branched-chain alkylene group;B is piperazino having a benzyl or C.sub.1-3 alkyl substituent on the nitrogen atom; andn denotes an integer from 3 to 6, have nicotine-lethality inhibiting, tetrabenazine-antagonistic and antiepileptic effects.This invention relates to novel oxime ethers possessing valuable therapeutic effects and their optical isomers and salts.The noval compounds have the general formula I ##STR2## wherein R stands for a phenyl group which may be substituted by a chlorine atom or by one to three methoxy groups;R.sup.1 and R.sup.2 denote each a hydrogen atom or together a valence bond;A denotes a C.sub.2 -C.sub.4 straight or branched-chain alkylene group; is piperazino having a benzyl or C.sub.1-3 alkyl substituent on the nitrogen atom;n denotes an integer from 3 to 6.The scope of the novel oxime ethers of the general formula I comprises obviously also all their possible stereoisomers and the mixtures thereof.The novel compounds of the general formula I can be produced according to the invention in the following ways:A. A ketone of the general formula II ##STR3## wherein R, R.sup.1, R.sup.2 and n have the same meaning as above, whereas Y denotes an oxygen or sulphur atom, is allowed to react with a hydroxylamine derivative of the general formula IIIh.sub.2 n -- o -- a -- b (iii)wherein A and B have the above-specified meaning.Ketones of the general formula II can be produced, e.g., in the way described in J. Am. Chem. Soc. 77, 624 /1955/ or in J. Chem. Soc. 1955, 1126, whereas hydroxylamine derivatives of the general formula III can be prepared, e.g., in the way described in J. Pharm. Sci. 58, 138 /1969/.B. A chlorine compound of the general formula IV ##STR4## wherein R, R.sup.1, R.sup.2 and n have the same meaning as above, is allowed to react with a hydroxylamine derivative of the general formula III, wherein A and B have the above-specified meaning.The compounds of general formula IV can be prepared by reacting 2-(p-chlorobenzal)-cyclohexanone with phosphorus oxychloride.c. An oxime of the general formula V ##STR5## wherein R, R.sup.1, R.sup.2 and n have the same meaning as above, is reacted with a halogen alkylamine derivative of the general formula VIhal -- A -- B (VI)wherein Hal denotes a halogen atom, preferably a chlorine atom, whereas A and B have the above-specified meanings.The oxime of the general formula V can be produced, e.g., in the way described in Org. Synth. Coll. Vol. II, p. 70.d. A compound of the general formula V, wherein R, R.sup.1, R.sup.2 and n have the same meaning as above, is reacted with a dihaloalkane of the general formula VIIIhal -- CH.sub.2 -- A' -- Hal' (VIII)wherein Hal and Hal' denote the same or different halogen atoms, whereas A' denotes a C.sub.1 -C.sub.3 straight or branched-chain alkylene group, and the obtained halogen alkyl ether is aminated.The reaction of the compounds of the general formula II and III (method a/) is carried out preferably in a solvent or a solvent mixture inert for the reaction. Solvents being inert for the reaction are, e.g., alcohols, preferably ethanol, or pyridine, triethyl amine etc. the temperature of the reaction can be varied within very wide limits. Though the reaction takes place according to our experience also at room temperature, the optimum reaction rate can be attained at the boiling point of the reaction mixture.In the reaction of the compounds of the general formula IV and III (method b/) the components can be allowed to react in an inert solent, in the presence of a base. Suitable inert solvents are, e.g., diethyl ether, dibutyl ether, tetrahydrofurane, dioxane, etc., or aromatic or aliphatic hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane, etc., whereas pyridine, triethyl amine, N-methyl morpholine, etc., can be applied as bases. The reaction can be carried out also without any inert solvent, using only the base as a solvent. The temperature of the reaction can be varied within wide limits. The upper limit is determined by the boiling point of the reaction mixture.When the end products are to be produced by a reaction of the compounds specified by the general formulas V and VI (method c/), the reaction is to be carried out in an inert solvent, in the presence of a basic condensing agent. Benzene and its homologues, e.g., toluene, xylene, cumol, etc., can be mentioned as inert solvents. In this case preferably sodium amide or sodium hydride are applied as condensing agents. Obviously the same result can be atained also by other alkali metal amides or hydrides. In that case the use of alcohols, such as ethyl, propyl, butyl alcohols, proved to be the most suitable. When an alkali hydroxide is applied as condensing agent, also water can be used as solvent.When the compounds of the general formula I are produced by reacting compounds of the general formula V with those of the general formula VIII (method d/), the reaction can be carried out in a solvent or a solvent mixture inert for the reaction. Benzene and its homologues, such as toluene, xylene, cumol, etc., can be mentioned as inert solvents. In this case sodium amide or sodium hydride can be used as condensing agents. The same result can be attained on applying an alkali metal as condensing agent but in that case expediently ethanol is used as solvent. The amination of the obtained halogen alkyl ether is carried out under pressure in an autoclave, in the presence of the corresponding amine.The compounds of the general formula I can be converted in a known way into acid addition or quaternary ammonium salts. For the preparation of the acid addition salts physiologically tolerable acids, such as hydrogen halides, sulphuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, maleic acid, acetic acid, propionic acid, methane-sulphonic acid, succinic acid, etc., can be preferably applied. In order to prepare quaternary ammonium compounds the compounds of the general formula I are allowed to react with compounds suitable for quaternerization, e.g., with an alkyl halide or methanesulphonic acid ester.The biological activity of the novel compounds according to the invention has been proved by a number of various tests. Of the observed effects the local analgesic, nicotine-lethanlity inhibiting, tetrabenazineantagonistic and antiepileptic effects were the most significant ones.The inhibition of nicotine-lethality was determined on mice by the method of Stone (Stone, C.A. et al.: Arch. Intern. Pharmacodynamie 117, 419 /1958/) in groups of 10 mice each, at oral administration. The results are given in Table I. Table I ______________________________________ Compound LD.sub.50 ED.sub.50 Therapeutic (in Example) mg/kg mg/kg index ______________________________________ 2 1450 43 33.7 10 600 56 10.7 6 650 43 15.1 7 400 11 36.4 15 1900 100 19.0 17 1200 40 30.0 18 1000 70 14.3 Trihexyphenidyl (Artane) 365 40 9.13 ______________________________________ +rb Therapeutic index = LD.sub.50ED.sub.50 The antiepileptic effect was investigated on mice, at oral administration. Maximum electroshock (MES) was provoked by means of corneal electrodes, applying the known method of Swinyard (Swinyard et al.: J. Pharmacol. Exp. Ther. 106, 319-330 /1952/). The effect on tetracor-spasm was examined by the modified method of Banziger and Hane (Banziger, R. and Hane, L.D.: Arch. Int. Pharmacodyn. 167, 245-249 /1967/). The results are given in Table II. Table II ______________________________________ Tetracor- spasm in- MES Thera- hibition Thera- Compound LD.sub.50 ED.sub.50 peutic ED.sub.50 peutic (in Example) mg/kg mg/kg index mg/kg index ______________________________________ 2 1450 150 9.7 50 29.0 1 620 105 5.9 74 8.4 Trimethadion (Ptimal) 2100 490 4.3 400 5.3 ______________________________________ The tetrabenazine-reserpine antagonistic effect was investigated on mice in groups of 10 aminals each, at oral administration. The inhibition or suspension of the effect of the observed maximum dose was recorded, and the ED.sub.50 values were calculated on the basis of the dose vs. effect curves. The results are shown in Table III. Table III ______________________________________ Tetra- benazine Reserpine antago- Thera- antagonism Thera- Compound LD.sub.50 nism,ED.sub.50 peutic ED.sub.50, peutic (in Example) mg/kg mg/kg index mg/kg index ______________________________________ 1 620 7 88.6 over 130 4.8 18 1000 28 36.0 about 250 4 Amitriptylin 225 13 17.3 65 3.5 ______________________________________ The new compounds of formula I and their methods of preparation are further illustrated by the aid of the following non-limiting Examples.EXAMPLE 12-Benzal-1-(N-benzylpiperazinylpropoxyimino)-cyclohexaneA solution of 20.1 g (0.1 moles) of 2-benzalcyclohexanone-oxime in 200 ml anhydrous toluene is dropwise added at 85.degree. C under stirring, to a suspension of 2.4 g (0.1 moles) of sodium hydride in 50 ml of anhydrous toluene. The mixture is kept for two hours at 130.degree. C, then a solution of 27.8 g (0.11 moles) of N-benzylpiperazinylpropyl chloride in 50 ml of anhydrous toluene is added. The mixture is kept for 12 hours at 130.degree. C, then cooled and shaken with a solution of 35 g of tartaric acid in 150 ml water. The aqueous phase is cooled to 0.degree.-5.degree. C and made alkaline to pH 10 with ammonium hydroxide. After extraction with dichloroethane, the solvent is distilled off and the residual crude phase processed to fumarate without any distillation.Yield: 35 g (84.3%).Difumarate: m.p. 196.degree. C.Citrate: m.p. 125.degree.-126.degree. C.Maleinate: m.p. 190.degree. C. (under decomposition).Tartrate: m.p. 198.degree.-200.degree. C.Iodomethylate: m.p. 134.degree.-135.degree. C. (under decomposition).Hydrochloride: m.p. 211.degree.-212.degree. C.Analysis: C.sub.35 H.sub.43 N.sub.3 O.sub.9 Calculated: C, 64.70%; H, 6.67%; N, 6.46%. Found: C, 64.35%; H, 6.70%; N, 6.38%.EXAMPLE 22-Benzal-1-(N-methylpiperazinylpropoxyimino)-cyclohexaneOne proceeds in the way as specified in Example 1, with the difference that, instead of N-benzylpiperazinylpropyl chloride, 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride are applied.Yield: 27.4 g (80.5%).Difumarate: m.p. 192.degree. C.Anaylsis: C.sub.29 H.sub.39 N.sub.3 O.sub.9 Calculated: C, 60.71%; H, 6.85%; N, 7.32%. Found: C, 60.58%; H, 7.28%; N, 7.36%.EXAMPLE 31-(N-Methylpiperazinylpropoxyimino)-2-(o-methoxybenzal)-cyclohexaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 23.1 g (0.1 moles) of 2-(o-methoxybenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, on proceeds in the way as specified in Example 1.Yield: 35.2 g (95%).Fumarate: m.p. 189.degree.-191.degree. C.Analysis: C.sub.30 H.sub.41 N.sub.3 O.sub.10. Calculated: C, 59.69%; H, 6.85%; N, 6.96%. Found: C, 59.43%; H, 7.00%; N, 6.92%.EXAMPLE 41-(N-Methylpiperazinylpropoxyimino)-2-(m-methoxybenzal)-cyclohexaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 23.1 g (0.1 moles) of 2-(m-methoxybenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 31.2 g (84.2%).Fumarate: m.p. 187.degree.-189.degree. C.Analysis: C.sub.30 H.sub.41 N.sub.3 O.sub.10. Calculated: C, 59.69%; H, 6.85%; N, 6.96%. Found: C, 59.45%; H, 7.00%; N, 6.81%.EXAMPLE 51-(N-Methylpiperazinylpropoxyimino)-2-(p-methoxybenzal)-cyclohexaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 23.1 g (0.1 moles) of 2-(p-methoxybenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpipeazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 30.5 g (82.5%).Fumarate: m.p. 190.degree. C.Analysis: C.sub.30 H.sub.41 N.sub.3 O.sub.10. Calculated: C, 59.69%; H, 6.85%; N, 6.96%. Found: C, 59.54%; H, 6.65%; N, 6.92%.EXAMPLE 61-(N-benzylpiperazinylpropoxyimino)-2-(m-methoxybenzal)-cyclohexaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 23.1 g (0.1 moles) of 2-(m-methoxybenzal)-cyclohexanone oxime and 27.8 g (0.11 moles) of N-benzylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 21.3 g (95.5%).Difumarate: m.p. 195.degree.-197.degree. C.Analysis: C.sub.36 H.sub.45 N.sub.3 O.sub.10 Calculated: C, 63.61%; H, 6.67%; N, 6.18%. Found: C, 63.90%; H, 6.78%; N, 6.12%.EXAMPLE 71-[2'-Methyl-3'-(4"-methylpiperazinylpropoxyimino)]-2-(p-methoxybenzal)-cyclohexaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 23.1 g (0.1 moles) of 2-(p-methoxybenzal)-cyclohexanone oxime and 21.0 g (0.11 moles) of N-methylpiperazinylisobutyl chloride, one proceeds in the way as specified in Example 1.Yield: 32.5 g (84.4%).Difumarate: m.p. 186.degree.-190.degree. C.Analysis: C.sub.31 H.sub.43 N.sub.3 O.sub.10 Calculated: C, 60.28%; H, 7.01%; N, 6.81%. Found: C, 59.92%; H, 7.25%; N, 6.74%.EXAMPLE 81-(N-Methyliperazinylpropoxyimino)-2-(3',4'-dimethoxybenzal)-cyclohexaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 26.1 g (0.1 moles) of 2-(3',4'-dimethoxybenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 34.1 g (85%).Difumarate: m.p. 186.degree.-188.degree. C.Analysis: C.sub.31 H.sub.43 N.sub.3 O.sub.11 Calculated: C, 58.76%; H, 6.84%; N, 6.63%. Found: C, 58.58%; H, 6.64%, N, 6.61%.EXAMPLE 91-(N-Methylpiperazinylpropoxyimino)-2-(3',4',5'-trimethoxybenzal)-cyclohexaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 29.1 g (0.1 moles) of 2-(3',4',5'-trimethoxybenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 39.0 g (90.5%).Difumarate: m.p. 185.degree.-186.degree. C.Cyclamate: m.p. 166.degree.-167.degree. C.Analysis: C.sub.32 H.sub.45 N.sub.3 O.sub.12 Calculated: C, 57.92%; H, 6.83%; N, 6.33%. Found: C, 58.24%; H, 7.00%; N, 6.30%.EXAMPLE 101-N-Benzylpiperazinylpropoxyimino)-2-(3',4',5'-trimethoxybenzal)-cyclohexanOn starting from 2.4 g (0.1 moles) of sodium hydride, 29.1 g (0.1 moles) of 2-(3',4',5'-trimethoxybenzal)-cyclohexanone oxime and 27.8 g (0.11 moles) of N-benzylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 46.5 g (92%).Difumarate: m.p. 188.degree.-189.degree. C.Analysis: C.sub.38 H.sub.49 N.sub.3 O.sub.12 Calculated: C, 61.6%; H, 6.7%; N, 5.7%. Found: C, 61.5%; H, 6.9%; N, 5.63%.EXAMPLE 112-Benzal-1-[2'-methyl-3'-(4"-methylpiperazinyl)-propoxyimino]-cyclohexaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 20.1 g (0.1 moles) of 2-benzalcyclohexanone oxime and 20.76 g (0.11 moles) of 2-methyl-3-(4'-methylpiperazinyl)-propyl chloride, one proceeds in the way specified in Example 1.Yield: 29.5 g (83%) of a pale yellow oil.Difumarate: m.p. 190.degree.-191.degree. C.Analysis: C.sub.30 H.sub.41 N.sub.3 O.sub.9 Calculated: C, 61.31%; H, 7.03%; N, 7.15%. Found: C, 61.15%; H, 7.19%; N, 7.28%.EXAMPLE 122-(m-Chlorobenzal)-1-[3'-(4"-methylpiperazinyl)-propoxyimino]-cyclohexaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 23.5 g (0.1 moles) of 2-(m-chlorobenzal)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 26.8 g (71.4%).Difumarate: m.p. 194.degree.-196.degree. C.Analysis: C.sub.29 H.sub.38 ClN.sub.3 O.sub.9 Calculated: C, 57.25%; H, 6.3%; Cl, 5.84 %; N, 6.4%. Found: C, 57.10%; H, 6.2%; Cl, 5.73%; N, 6.29%.EXAMPLE 132-(p-Chlorobenzyl)-1-[3'-(4"-methylpiperazinyl)-propoxyimino]-cyclohexaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 23.74 g (0.1 moles) of 2-(p-chlorobenzyl)-cyclohexanone oxime and 19.5 g (0.11 moles) of N-methyl-piperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 33.8 g (89.5%).Difumarate: m.p. 194.degree.-195.degree. C.Analysis: C.sub.29 H.sub.40 ClN.sub.3 O.sub.9 Calculated: C, 57.09%; H, 6.60%; Cl, 5.31%; N, 6.89%. Found: C, 57.13%; H, 6.82%; Cl, 5.77%; N, 6.84%.EXAMPLE 142-Benzal-1-[3'-(4"-methylpiperazinyl)-propoxyimino]-cycloheptaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 21.5 g (0.1 moles) of 2benzalcycloheptanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 26.5 g (72.5%).Difumarate: m.p. 196.degree.-197.degree. C (under decomposition).Analysis: C.sub.30 H.sub.41 N.sub.3 O.sub.9 Calculated: C, 61.31%; H, 7.03%; N, 7.15. Found: C, 61.20%; H, 6.94%; N, 7.10%.EXAMPLE 152-Benzal-1-[3'-(4"-methylpiperazinyl)-propoxyimino]-cyclopentaneOn starting from 2.4 g (0.1 moles) of sodium hydride, 18.7 g (0.1 moles) of 2-benzalcyclopentanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 31.3 g (95.8%).Difumarate: m.p. 205.degree.-206.degree. C (under decomposition).Analysis: C.sub.28 H.sub.37 N.sub.3 O.sub.9 Calculated: C, 60.09%; H, 6.66%; N, 7.51%. Found: C, 59.83%; H, 6.50%, N, 7.53%.EXAMPLE 162-Benzal-1-[2'-methyl-3'-(4"-methylpiperazinyl)-propoxyimino]-cyclohexaneThe solution of 20.1 g (0.1 moles) of 2-benzalcyclohexanone oxime in 200 ml of anhydrous toluene is dropwise added at 85.degree. C, under continuous stirring, to the suspension of 2.4 g (0.1 moles) of sodium hydride in 50 ml of anhydrous toluene. After boiling the reaction mixture for 2 hours, 18.86 g (0.11 moles) of 1-bromo-3-chloro-2-methylpropane are added, and the reaction mixture is boiled for a few hours. After cooling the mixture to 80.degree. C, a solution of 11 g (0.11 moles) of N-methylpiperazine in 20 ml of anhydrous toluene is dropwise added and the reaction mixture is kept for further 6 hours at this temperature. After cooling and washing with water, a solution of 22 g of fumaric acid in 220 ml of anhydrous ethanol is poured to the toluene solution, the mixture is cooled, and the precipitated crystals are filtered off. Yield in difumarate: 48 g (81.7%); m.p. 190.degree.-191.degree. C. The produce is identical with that described in Example 11.EXAMPLE 171-(N-Methylpiperazinylpropoxyimino)-2-benzal-cyclooctane difumarateOn starting from 2.4 g (0.1 moles) of sodium hydride, 22.9 g (0.1 moles) of 2-benzalcyclooctanone oxime and 19.5 g (0.11 moles) of N-methylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 33.8 g (95%).Fumarate: m.p. 206.degree.-207.degree. C.Analysis: C.sub.31 H.sub.43 N.sub.3 O.sub.9 Calculated: C, 61.88%; H, 7.20%; N, 6.98%. Found: C, 61.38%; H, 7.05%; N, 6.92%.EXAMPLE 182-Benzal-1-[3'-(4"-benzylpiperazinyl)propoxyimino]-cyclopentane difumarateOn starting from 2.4 g (0.1 moles) of sodium hydride, 18.7 g (0.1 moles) of 2-benzalcyclopentanone oxime and 27.8 g (0.11 moles) of N-benzylpiperazinylpropyl chloride, one proceeds in the way as specified in Example 1.Yield: 37.4 g (94%).Difumarate: m.p. 210.degree.-211.degree. C.Analysis: C.sub.34 H.sub.41 N.sub.3 O.sub.9 Calculated: C, 64.22%; H, 6.50%; N, 6.61%. Found: C, 64.12%, H, 6.61%, N, 6.60%.

    摘要翻译： 式（Ⅺ）的肟醚，其中R代表可被卤素氯原子取代的苯基或一至三个甲氧基; R1和R2各自表示氢原子或价键一起; A表示C2-C4直链或支链亚烷基; B是在氮原子上具有苄基或C1-3烷基取代基的哌嗪基; 和N DENOTES IN INTEGER从3到6，具有非口服抑制作用，TETRABENAZINE-ANTAGONISTIC和抗体效应。

    Oxime ethers and pharmaceutical compositions containing the same
    3.
    发明授权
    Oxime ethers and pharmaceutical compositions containing the same 失效
    肟醚和含有它的药物组合物

    公开(公告)号：US4395413A

    公开(公告)日：1983-07-26

    申请号：US162674

    申请日：1980-06-24

    申请人： Zoltan Budai ,  Aranka Lay nee Konya ,  Tibor Mezei ,  Lujza Petocz ,  Katalin Grasser ,  Ibolya Kosoczky ,  Eniko Szirt nee Kiszelly ,  Peter Gorog

    发明人： Zoltan Budai ,  Aranka Lay nee Konya ,  Tibor Mezei ,  Lujza Petocz ,  Katalin Grasser ,  Ibolya Kosoczky ,  Eniko Szirt nee Kiszelly ,  Peter Gorog

    IPC分类号： A61K31/15 ,  A61K31/495 ,  A61P25/04 ,  C07C67/00 ,  C07C239/00 ,  C07C249/10 ,  C07C251/58 ,  C07D295/02 ,  C07D295/088 ,  C07D295/08

    CPC分类号： C07D295/088 ,  Y10S514/926 ,  Y10S514/927

    摘要： The invention relates to novel oxime ethers of the general formula /I/ and acid addition salts and quaternary ammonium derivatives thereof, ##STR1## wherein A represents a C.sub.2-6 straight or branched alkylene chain,R and R.sup.1 each represent a C.sub.1-6 alkyl group or they form together with the adjacent nitrogen atom a heterocyclic ring containing 4 to 7 carbon atoms and optionally a further hetero atom, i.e. an oxygen, sulfur or nitrogen atom, and said ring may be optionally substituted by a C.sub.1-3 alkyl, phenyl or benzyl group,R.sup.2 and R.sup.3 each denote a hydrogen atom or together form a valency bond,R.sup.4 denotes a C.sub.1-10 alkyl or C.sub.2-10 alkenyl group, andn denotes an integer from 3 to 7.The compounds of the general formula /I/ are prepared according to the invention by reacting a cycloalkane derivative of the general formula /II/ ##STR2## wherein R.sup.2, R.sup.3, R.sup.4 and n have the same meaning as above, whereasY denotes an oxygen or sulphur atom or a .dbd.N--OH group with an aminoalkyl derivative of the general formula /III/ ##STR3## wherein R, R.sup.1 and A have the same meaning as stated above andZ means a halogen atom or a H.sub.2 N--O-- group or a salt thereof in the presence of a basic condensing agent.The new compounds of the general formula /I/ possess valuable nicotine-lethality inhibiting, local anaesthetic, analgesic effects, which are, in case of certain compounds, complemented by anti-hypertensive, maximum electroshock and tetracorspasm inhibiting, ulcus inhibiting and motility inhibiting effects, and can be applied to advantage in the therapy.

    摘要翻译： 本发明涉及通式I I的新型肟醚及其酸加成盐和季铵衍生物，其中A表示C2-6直链或支链亚烷基链，R和R1各自表示C1 -6烷基，或者它们与相邻的氮原子一起与含有4至7个碳原子的杂环和任选的另外的杂原子（即氧，硫或氮原子）一起形成，并且所述环可以任选地被C 1-3 烷基，苯基或苄基，R2和R3各自表示氢原子或一起形成价键，R4表示C1-10烷基或C2-10烯基，n表示3至7的整数。 根据本发明通过使通式/ II / IMAGE / II /的环烷烃衍生物与其中R2，R3，R4和n具有与上述相同的含义反应制备通式/ I / I，而Y表示氧或 硫原子或a =具有氨基烷基衍生物的N-OH基团 通式/ III / / III /其中R，R 1和A具有与上述相同的含义，Z表示在碱性缩合剂存在下的卤素原子或H 2 N-O-基或其盐。 新型化合物/ I /具有有价值的尼古丁杀伤力抑制，局部麻醉，止痛作用，在某些化合物的情况下，补充有抗高血压，最大电休克和四疣抑制作用，抑制溃疡和运动抑制作用 ，并且可以在治疗中有利地应用。

    Cyclododecanone oximes
    7.
    发明授权
    Cyclododecanone oximes 失效
    环十二酮肟

    公开(公告)号：US4285942A

    公开(公告)日：1981-08-25

    申请号：US099507

    申请日：1979-12-03

    申请人： Zoltan Budai ,  Aranka Lay nee Konya ,  Tibor Mezei ,  Katalin Grasser ,  Lujza Petocz ,  Eniko Kiszelly ,  Ibolya Kosoczky

    发明人： Zoltan Budai ,  Aranka Lay nee Konya ,  Tibor Mezei ,  Katalin Grasser ,  Lujza Petocz ,  Eniko Kiszelly ,  Ibolya Kosoczky

    IPC分类号： A61K31/15 ,  A61K31/395 ,  A61P21/00 ,  A61P25/02 ,  C07C249/04 ,  C07C251/58 ,  C07D295/088 ,  C07C131/02 ,  A61K31/535

    CPC分类号： C07D295/088

    摘要： The invention relates to novel cyclododecane derivatives of the general formula ##STR1## wherein R.sup.1 and R.sup.2 represent independently from each other a hydrogen atom, a C.sub.1-6 alkyl group or a C.sub.3-8 cycloalkyl group, or R.sup.1 and R.sup.2 form together with the nitrogen atom to which they are attached a heterocyclic ring containing 4 to 7 carbon atoms and optionally a further heteroatom selected from the group consisting of oxygen, sulphur and nitrogen, said ring may be optionally substituted by a C.sub.1-3 alkyl or benzyl group; and A represents a C.sub.2-6 straight or branched alkylene chain, and optically active isomers, acid addition salts and quaternary ammonium derivatives thereof. The invention relates further to an analogous process for the preparation of said compounds, to pharmaceutical compositions containing said compounds as the active ingredient and to a process for the preparation of said pharmaceutical compositions.The cyclododecane derivatives of the invention possess valuable biological properties.

    摘要翻译： 本发明涉及通式为（I）的新的环十二烷衍生物，其中R 1和R 2彼此独立地表示氢原子，C 1-6烷基或C 3-8环烷基，或者R 1和R 2一起形成 与它们所连接的氮原子一起含有4至7个碳原子的杂环和任选的另外的选自氧，硫和氮的杂原子，所述环可任选被C 1-3烷基或苄基取代 ; A表示C2-6直链或支链亚烷基链，以及旋光异构体，其酸加成盐和季铵衍生物。 本发明进一步涉及制备所述化合物的类似方法，含有所述化合物作为活性成分的药物组合物和制备所述药物组合物的方法。 本发明的环十二烷衍生物具有宝贵的生物学特性。

    Pharmaceutical compositions with antianginal activity
    8.
    发明授权
    Pharmaceutical compositions with antianginal activity 失效
    具有抗心绞痛活性的药物组合物

    公开(公告)号：US4621101A

    公开(公告)日：1986-11-04

    申请号：US751623

    申请日：1985-07-02

    申请人： Zoltan Budai ,  Tibor Mezei ,  Aranka Lay nee Konya ,  Lujza Petocz ,  Katalin Grasser ,  Zsuzsanna Orr

    发明人： Zoltan Budai ,  Tibor Mezei ,  Aranka Lay nee Konya ,  Lujza Petocz ,  Katalin Grasser ,  Zsuzsanna Orr

    IPC分类号： A61K31/15 ,  A61P43/00 ,  C07C251/38

    CPC分类号： C07C251/58 ,  C07C2101/14 ,  C07C2101/18

    摘要： The invention relates to pharmaceutical compositions possessing valuable antianginal activity. These compositions show higher activity and more favorable therapeutic indices than the reference compound Prenylamine. Preparation of different kinds of pharmaceutical compositions, such as tablets, dragees, capsules and injectable solutions, containing compounds of general formula (I) ##STR1## or their acid addition salts as active ingredients, is disclosed, wherein in formula (I)R is phenyl or 4-chlorophenyl;R.sup.1 and R.sup.2 each represent hydrogen, methyl or isopropyl;R.sup.3 and R.sup.4 are hydrogen, or together form a chemical bond;n is an integer from 4 to 6;A means trimethylene, if n is 4 or 6; or ethylene, if n is 5.

    摘要翻译： 本发明涉及具有有价值的抗心绞痛活性的药物组合物。 这些组合物显示比参考化合物Prenylamine更高的活性和更有利的治疗指数。 公开了含有通式（I）化合物或其酸加成盐作为活性成分的不同种类的药物组合物如片剂，硫化物，胶囊和可注射溶液的制备，其中在式（I）中R是 苯基或4-氯苯基; R1和R2各自表示氢，甲基或异丙基; R3和R4是氢，或一起形成化学键; n为4-6的整数; 如果n为4或6，则表示三亚甲基; 或乙烯，如果n为5。