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    • 4. 发明授权
      US4419355A Condensed as-triazine derivatives and method of using the same 失效
    • Condensed as-triazine derivatives and method of using the same
    • 缩合三嗪衍生物及其使用方法
    • US4419355A
    • 1983-12-06
    • US283971
    • 1981-07-16
    • Ibolya Kosoczky , Eva Toncsev, nee Ravasz , Pal Benko , Laszlo Pallos , Lujza Petocz , Sandor Batori , Gyorgy Hajos , Andras Messmer , Katalin Grasser
    • Ibolya Kosoczky , Eva Toncsev, nee Ravasz , Pal Benko , Laszlo Pallos , Lujza Petocz , Sandor Batori , Gyorgy Hajos , Andras Messmer , Katalin Grasser
    • C07D471/04 , A61K31/53 , A61P25/24 , A61P25/26 , C07D253/10 , C07D487/04 , C07D253/08
    • C07D487/04
    • The invention relates to new condensed as-triazine derivatives of the general formula (I) ##STR1## wherein Z represents a buta-1,3-dienyl group or a group of the formula (a), (b), (c) or (d) ##STR2## R.sub.1 denotes a C.sub.1-10 alkyl group, an oxo group or a C.sub.6-10 aryl or C.sub.6-10 aryl-(C.sub.1-3 alkyl) group optionally substituted by one or more identical or different substituents selected from the group consisting of amino, nitro, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy and halogen,R.sub.2 stands for hydrogen, C.sub.1-10 alkyl or amino,R.sub.3 represents hydrogen, C.sub.1-10 alkyl or C.sub.6-10 aryl or C.sub.6-10 aryl-(C.sub.1-3 alkyl) optionally substituted by one or more identical or different substituents selected from the group consisting of nitro, amino, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxy and halogen,X.sup.- denotes an anion, andn is 0 or 1,with the proviso that if n is O, R.sub.1 is other than an oxo group and R.sub.1 ' and R.sub.2 ' form together a double bond, and with the further provisos that if n is 1, R.sub.1 represents an oxo group and the symbols R.sub.1 ' and R.sub.2 ' are not present, and if Z is a buta-1,3-dienyl group and R.sub.1 denotes an oxo group, R.sub.3 is other than unsubstituted phenyl.The new compounds of the general formula (I) can be prepared by cyclizing the compounds of the general formula (II) or (V), wherein R.sub.1, Z, R.sub.3 and X.sup.- have the above defined meanings, R.sub.4 is a leaving group and R.sub.7 represents hydrogen or C.sub.1-10 alkyl.The new compounds of the general formula (I) possess a valuable antidepressant effect and can advantageously be used in the therapy.
    • 本发明涉及通式（I）的新的缩合的三嗪衍生物，其中Z代表丁-1,3-二烯基或式（a），（b），（ c）或（d）R1表示任选被一个或多个相同的C 1-6烷基，氧代基或C 6-10芳基或C 6-10芳基 - （C 1-3烷基） 或选自氨基，硝基，C 1-6烷基，C 1-6烷氧基，羟基和卤素的不同取代基，R 2代表氢，C 1-10烷基或氨基，R 3表示氢，C 1-10烷基或C 6- 芳基或任选被一个或多个相同或不同的选自硝基，氨基，C 1-6烷基，C 1-6烷氧基，羟基和卤素的取代基取代的芳基或C 6-10芳基 - （C 1-3烷基） 表示阴离子，n为0或1，条件是如果n为O，则R1不是氧代基，R1'和R2'一起形成双键，另外条件是，如果n为1， R1代表氧代基团， mbols R1'和R2'不存在，并且如果Z是丁-1,3-二烯基并且R 1表示氧代基，则R 3不是未取代的苯基。 通式（I）的新化合物可以通过使通式（II）或（V）的化合物环化来制备，其中R1，Z，R3和X具有上述定义，R4是离去基团， R 7表示氢或C 1-10烷基。 通式（I）的新化合物具有有价值的抗抑郁作用，可有利地用于治疗。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Global Dossier Espacenet 法律信息 同族专利 专利引用
    • 5. 发明授权
      US4395413A Oxime ethers and pharmaceutical compositions containing the same 失效
    • Oxime ethers and pharmaceutical compositions containing the same
    • 肟醚和含有它的药物组合物
    • US4395413A
    • 1983-07-26
    • US162674
    • 1980-06-24
    • Zoltan Budai , Aranka Lay nee Konya , Tibor Mezei , Lujza Petocz , Katalin Grasser , Ibolya Kosoczky , Eniko Szirt nee Kiszelly , Peter Gorog
    • Zoltan Budai , Aranka Lay nee Konya , Tibor Mezei , Lujza Petocz , Katalin Grasser , Ibolya Kosoczky , Eniko Szirt nee Kiszelly , Peter Gorog
    • A61K31/15 , A61K31/495 , A61P25/04 , C07C67/00 , C07C239/00 , C07C249/10 , C07C251/58 , C07D295/02 , C07D295/088 , C07D295/08
    • C07D295/088 , Y10S514/926 , Y10S514/927
    • 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.
    • 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。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Global Dossier Espacenet 法律信息 同族专利 专利引用
    • 7. 发明授权
      US4083978A Oxime ethers 失效
    • Oxime ethers
    • 肟醚
    • US4083978A
    • 1978-04-11
    • US652806
    • 1976-01-27
    • Zoltan Budai , Aranka Lay nee Konya , Tibor Mezei , Katalin Grasser , Eniko Szirt nee Kiszelly , Ibolya Kosoczky , Lujza E. Petocz
    • Zoltan Budai , Aranka Lay nee Konya , Tibor Mezei , Katalin Grasser , Eniko Szirt nee Kiszelly , Ibolya Kosoczky , Lujza E. Petocz
    • C07C251/58 , C07D295/088 , A61K31/495 , C07D295/12
    • C07D295/088 , C07C251/58 , C07C2101/08 , C07C2101/16 , C07C2101/18
    • 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%.
    • 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。
    • 基本信息 添加关注 加入工作空间 PDF全文 PDF下载 全文下载 相似专利 双屏查看 权利要求书 说明书全文 Espacenet 法律信息 同族专利 专利引用
    • 10. 发明授权
      US4208410A Dibenzo[d,g][1,3,6]dioxazocine derivatives 失效
    • Dibenzo[d,g][1,3,6]dioxazocine derivatives
    • 二苯并[d，g] [1,3,6]二氧杂吖庚因衍生物
    • US4208410A
    • 1980-06-17
    • US927934
    • 1978-07-25
    • Laszlo Rozsa , Lujza Petocz , Katalin Grasser , Ibolya Kosoczky , Eniko Kiszelly , Jozsef Nagy
    • Laszlo Rozsa , Lujza Petocz , Katalin Grasser , Ibolya Kosoczky , Eniko Kiszelly , Jozsef Nagy
    • A61K31/553 , C07D273/00 , C07D273/01 , C07D267/22 , A61K31/395
    • C07D273/00 , Y10S514/818
    • This invention relates to novel dibenzo[d,g][1,3,6]dioxazocine derivatives represented by the general formula I ##STR1## wherein R.sub.1 and R.sub.2 independently represent hydrogen, halogen, cyano or trifluoromethyl,Y stands for hydrogen or a group of formula ##STR2## wherein A stands for a straight or branched chained alkylene having from 2 to 5 carbon atoms andR.sub.3 and R.sub.4 independently stand for an alkyl having from 1 to 4 carbon atoms, orR.sub.3 and R.sub.4 together with the nitrogen atom they are attached to and optionally together with a further nitrogen atom or with an additional oxygen atom may form a five- or six-membered heterocyclic ring optionally substituted with an alkyl having from 1 to 4 carbon atoms,and pharmaceutically acceptable acid addition salts thereof formed with an inorganic or organic acid.The above compounds possess valuable pharmaceutical properties, for instance they are effective local anaesthetics and can be used for treating Parkinson syndrome.
    • 本发明涉及由通式I（I）表示的新的二苯并[d，g] [1,3,6]二氧杂吖庚因衍生物，其中R 1和R 2独立地表示氢，卤素，氰基或三氟甲基，Y代表氢 或一组式（I）其中A代表具有2至5个碳原子的直链或支链链状亚烷基，R3和R4独立代表具有1至4个碳原子的烷基，或R3和R4与氮原子一起 它们与另外的氮原子或与另外的氧原子连接并且可选地与另外的氧原子连接的原子可以形成任选被具有1至4个碳原子的烷基取代的五元或六元杂环，及其药学上可接受的酸加成盐 由无机或有机酸形成。 上述化合物具有有价值的药物性质，例如它们是有效的局部麻醉剂，并且可用于治疗帕金森综合征。
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