• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Novel substituted N-[(4-piperidinyl)alkyl] bicyclic condensed oxazol- and thiazolamines of formula <CHEM> wherein L is a radical <CHEM> the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds have anti-depressive, anti-Parkinson and enterokinetic activity; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
    公开号:SU1524809A3
    申请号:SU864027244
    申请日:1986-04-14
    公开日:1989-11-23
    发明作者:Эдуард Жансенс Франс；Терезия Йоннес Теофилус；Ван Оффернверт Мария；Антуан Стокброекс Раймон；Робин Бор Бернар
    申请人:Жансен Фармасетика, Н.В. (Фирма)；
    IPC主号:
    专利说明:

    niloxy group, in an inert solvent, followed by separation of the desired product in the free
    in the form or in the form of a pharmaceutically acceptable acid addition salt. 6 tab.
    The invention relates to the preparation of new heterocyclic compounds, in particular derivatives of L (4-piperidinyl) alkyl-bicyclic oxazole or thiazolamines, which possess enterokinetic activity and properties of xylazine antagonists.
    The purpose of the invention is to create, on the basis of known methods, a method of producing new compounds with valuable pharmacological properties, namely, the properties of xylazine antagonists, which may allow:. use them as antidepressants.
    Example 1. A mixture of 3.8 parts of 2- - (brommetsh1) -2,3-dihydro-1, A-benzodioxyma, 6.3 hours. N- (4-piperidinylmethyl) -2-benzothiazolamine dihydrobromide , 10 parts of sodium carbonate, 0.1 parts of sodium iodide and 68 parts of N, H-dimethylformamide are stirred for 48 hours at 70 ° C. The reaction mixture is poured into water and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and scrubbed. The oily residue is crystallized from acetonitrile to give 2.8 parts of N-, 5-dihydro-1,4-benzodioxin-2-yl) methyl} -4-piperidinyl} I TiinJ-2-benzothiazolamine, mp. 139, (compound 1).
    In a similar way also receive
    4- 2-benzothiazolylaminomethyl (-1-) 2-phenoxyethyl J-4-piperidinol dihydro chloride, m.p. 209, (compound 2)
    N-t1- (2-phenoxyethyl) -4-piperidinylmethylJ-2-benzothiazolamine, m.p. 116.1 ° C (compound 3),
    N- 1- (3-phenoxypropyl) -4-piperidinedylmethyl -2-benzothiazolamine; t, pl. 113, (compound 4);
    4- 2-benzothiazolylaminomethyl (-1-) 2, 3-dihydro-1,4-benzodioxin-2-yl methyl-4-piperidinol, m.p. 176.2 ° C (compound 5).
    Example 2. A mixture of 2.7 parts of (R) -, 3-dihydro-1,4-benzodioxin-2- -methanol 4-methylbenzenesulfonate ester 3.2 parts of parts- (4-piperidinylmethyl) -2-benzothiazole 1Ina dig0
    five
    0
    five
    0
    five
    0
    five
    0
    five
    the robromide hemihydrate, 2.5 parts of sodium carbonate and 76.5 parts of N, and K-dimethylformamide are stirred overnight at 70 ° C. After cooling, the reaction mixture is poured into water. The product is extracted three times with 4-methyl-2-pentanone. The combined extracts are dried, filtered and evaporated. The residue is purified by high performance reverse phase chromatography (HPLC) on a LI Chropeen RP 18 using a mixture of trichloromethane, hexane and methanol (10: 10: 1 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from acetonitrile. The product is filtered off and dried, yielding 1.3 parts (38.6%) of (S) - (-) - (2,3-dihydro-1,4-benzodioxin--2-yl) methyl} -4-piperidinyl methyl J-2- benzothiazolamine, m.p. 133, (with () j, -15.8698 (with 0.5% in trichloromethane) (compound 6).
    In a similar way also receive
    (R) - (+) - N- 1- (2, 3-dihydro-1,4-benzodioxin-2-yl) methyl-4-piperidinyl methyl -2-benzothiazolamine, mp. 133, (o /) 5J5 +16.6497 (c - 0.5% in trichloromethane) (compound 7);
     - (2,3-dihydro-1,4-benzodioxin-2-yl) methylJ-4-piperidinylJmethyl-thiazolo (5,4-in) pyridin-2-amine, m.p. 158.4 ° C (compound B),
    (-f) (3,4-dihydro-2H-1-benzociran-2-yl) methyl J-4-piperidinyl methyl 1-2-benzothiazolamine. m.p. 144 ,, (o /) 5vb +68.93 C, (with 1% in methanol), (compound 9);
    (+) - (R) (2, 3-dihydro-1,4-benzodioxin-2-yl) methyl 1-4-piperidinyl methyl} -K-methyl-2-benzothiazole-amine, m.p. 111 ,, (f) +1 7.07 ° (with 0.5% in trichloromethane), (compound 10) j
    (-) -; s) -N-rLl- (2,3-dihydro-1,4-benzodioxin-2-yl) methyl} -4-piperidinyl} methyl -Y-methyl-2-benzothiazole-amine m.p. 103.5 C, (o) p -15.81 C (with 0.5% in trichloromethane), (compound 11);
    (4) (8) (2,3-dihydro-1,4-benzodioxin-2-yl) methyl-4-piperidinyl) methyl (3,4-in) pyridine-2-amine, t. square 159.6 C, W) d - +17.00 (from 0.5% in trichloromethane) (compound 12) j
    (-) - (8) (2,3-dihydro-1,4-benzodioxin-2-yl) methyl-4-piperidinylCmetall thiazolo (5,4-b) pyridine -2 -2-amine, m.p. . 160.5 C, U) in -17.48 (with 0.5% in trichloromethane) (compound 13) {
    (-) - K- (1- (b, 4-dihydro-2H-1-benzopyran-2-yl) methyl} -4piperidinyl metnn thiazole (5,4-c) pyridin-2-amine, t mp 177.4 C, (oO 49.44 (with 1% in trichloromethane), (compound 14) -,
    1- (2,3-dihydro-1,4-benzo-dioxyn-2-yl) methyl} -4-piperidinyl-methyl J-5,7-methoxy-2-benzothiazolamine, mp. 165.8 ° C (compound 15).
    Example 3. A mixture of 1.9 parts of 2- (bromo-type) -2,3-dihydro-1,4-benzodioxin, 3.3 parts of 6-chloro-K- (4-piperidinylmethyl) -2 -benzothiazolamine dihydride of robromide, 5 parts of sodium carbonate, 0.2 parts of potassium iodide and 67.5 parts of N, N-dimethylacetamide stirred overnight at about 75 ° C. Water was added to the reaction mixture and the product was extracted with 4-methyl-2-penta non. The extract is dried, filtered and evaporated. The oily residue is crystallized from a mixture of 1,1-oxybisethane 2,2-oxybispropane. The product is filtered and dried to give 1.8 parts (59.8%) of 6-chloro-K-1- (2,3-dihydro-1, 4-benzodioxin-2-yl) methyl perchdinyl Zmethyl j-2 -benzothiazolamine, so pl. 155.8 ° C. (compound 16).
    In a similar way also receive
    N-f 1 - 2- (2,6-dichlorophenoxy) ethyl J-4-piperidinyl methyl -2-benzothiazole-amine dihydrobromide, m.p. 222.3 C (compound 17)
     (2,6-dimethoxyphenoxy) ethyl-4-piperidinyl} methyl j-2-benzothiazolamine dihydrobromide, m.p. 171.3 C (compound 18) -,
    N-O C (2,3-dihydro-1,4-benzodioxin-2-yl) methyl-piperidinyl methyl-6-fluoro-2-benzothiazolamine, m.p. 152, (compound 19);
     (2,3-dihydro-1,4-benzo-DIOXIN-2-Sh1) methyl-4-piperidinyl methyl-4-fluoro-2-benzothiazolamine, mp. 159.8 C (compound 20) -,
    I52A809
    0
    five
    0
    five
    0
    five
    0
    five
    0
    N-f 1-G (2, -) - dihydro-1,4-benzodioxin-2-yl) methyl-4-piperidinyl methyl - -6-methyl-2-benzothiazolamine, so pl. 123.6 C (compound 21),
    4-chloro-Y-1- (32,3-dihydro-1,4-benzodioksin-2-np) methyl-4-piperidinyl} methyl -2-benzothiazolamine dihydrobromide, mp. 249.8 ° C (compound 22).
    Example 4. A mixture of 3.2 parts of 1- (3-chloropropoxy) -4-fluoro-2- (phenylmethoxy) benzene, 4.1 parts of N- (4-piperidinylmetip) -2-benzothiazolamide dihydrobro —mida, 6 parts sodium carbonate, 0.1 parts sodium iodide and 67.5 parts H, K-dimethyl-acetamide is stirred overnight at. Water is added and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The oily residue is extracted with acetonitrile. The product is filtered off and dried, yielding 3.3 parts (65.2%) of N-3-4-fluoro-2- (phenylmethoxy) phenoxy-propyl-4-piperidinylJmethylJ-2-benzothiazolamine, mp. 129.5 C (compound 24).
    In the same way, (4-fluorophenoxy) propyl-4-piperidine 1 methyl j-2-benzothiazolamine dihydrobromide hemihydrate, m.p. 172.0 ° C (compound 25).
    Example 5. A mixture of 2.8 parts of 2,3- -dihydro-1,4-benzodioxin-2-methanol methanesulfonate (ester), 3.4 parts of 5,6,7-trimethoxy-H- (4-piperi - dinyl methyl) -2-benzothiazolamia, 3 h. sodium carbonate and 67.5 parts of H, N-dimethylacetamide are stirred overnight at about. Water is added. The product is extracted with 4-α-methyl-2-pentanone. The extract is dried, filtered and evaporated, the residue is purified by chromatography on a column of silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. The pure fractions are collected and the solvent is evaporated. The residue is converted to (E) -2-butenioate salt in ethanol and 2-propane. The salt is filtered off and dried, yielding 3.2 parts (48.5%) (2,3-dihydro-1, 4-beisodioxin-2-yl) methyl} -4-piperidinyl metsh-5,6,7-trimeth - C-2-benzothiazapamine (E) -2-butenoate (2: 3), so pl. 171.6 ° C. (compound 26).
    In a similar way also receive
    (2,3-dihydro-1,4-benzodioxy-2-ip) methyl-4-piperidinyl methyl 7-5, 6-dimethoxy-2-benzothiazolamine, m.p. 152.8 ° C (compound 27);
    (2,3-dihydro-1, A-benzodioxin-2-yl) methyl-4-piperidinyl methyl--1,3-dioxolo (4,5-) benzothiazole-6--amin, t. Pl. 160, (compound 28);
    (2,3-Dihydro-1,4-benzodiox-CIN-2-IL) methyl-4-piperidinyl me-, 7-dihydro (1,4) dioxino (2,3-), Q benzothiazole-2-amine m.p. 137.4 C (compound 29);
     (2,3-dihydro-14-benzodioxy-2-yl) methyl J-4-piperidinyl-ethyl. -2-benzothiazolamine "so pl. 121.7 C (compound 30).
    Example 6. A mixture of 3.5 parts of 3,4-β-dihydro-2H-1-benzopyran-2-methanol-4-methylbenzenesulfonate (complex
    / Similarly also get
    N-1 (2,3-dihydro-1,4-benodeodioxy 11-2-yl) methyl} -4-piperidinyl me T il -Y- (2-phenylethyl) -2-6enzothiazolamine (E) -2-butandioate (1: 1), m.p. 174.8 (Compound 41);
    (2,3-dihydro-1,4-benzodi-10Xin-2-yl) methyl} -4-piperidinylLmethyl -2-benzoxazolamine dihydrochloride, m.p. 231, b s (compound 42);
    N- (4-fluorophenoxy) piperidinyl-J-methyl-2-benzothiazolamine
    m.p. 116.8 C (compound 43) -,
    N- (4-fluorophenoxy) -piperidinyl methyl-5,6-dimethoxy-3
    -benzothiazolamine, so pl. 139, (compound 44);
    N- 1- 2- (4-fluorophenoxy) -piperidinyl methyl-5,6,7-trimethoxy -2-benzothiazolamine dihydrobromide, so pl. 220.9 ° C (compound 45);
    (-) - (5) (2,3-dihydro-1,4-benzodioxin-2-yl) methyl | -4-piperidinyl} methyl 7 -5, 6, 7-trimethoxy-2-ben
    zothiazolamine dihydrochloride, so pl. 215 ,, s / 1 -42.73 (with 0.5 methanol) (compound 46);
    (+) - (R) 1 - (2,3-dihydro-1 -, 4- -benzodioxin-2-yl) methyl J-4-piperidinyl methyl -5,6,7-trimethoxy-2-benzothiazolamine dihydrochloride, so pl. 217 ,, “0 +42.77 (with 0.5% methanol) (compound 47),
    ), 4.7 parts of 6,7-dihydro-4-pi-p-p-shchiniyl methyl - (1,4) -dioxino (2,3-f) benzothiazol-2-amine dihydrobromide, 6 parts of sodium carbonate and 67 , 5 hours. N, N-dimethylacetamide is stirred overnight at 70 ° C. Upon addition of water, the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is converted to the hydrobromide salt in 2-11 propanone. The salt is filtered off and dried, yielding 4.5 parts (71.3%) (3,4-di-hydro-2H-1-benzopyran-2-yl) -methyl 7-4-PIP or NIL methyl J- 6, 7-dihydro 1,4-dioxino (1,3-f) benzothiazol-2-am on dihydrobromide, so pl. At 260 ° C (compound 31).
    Similarly (table) also receive compounds
    0
    five
    0
    five
    0
    (2-methoxyphenoxy) -4-piperidinylSmethyl7-2-benothiazolamine, m.p. 121.14 (compound 48)
    N 1-H 2- (2-methylphenoxy) -piperidinyl methyl-J-2-benzothiazole; amine, m.p. 126.4 ° C. (compound 49),
     -2- (4-fluorophenoxy) ztil-4- -piperidinyl ethyl 7-5,7-dimethoxy -2- -benzothiazolamine, m.p. 131.8 ° C (compound 50);
    N-l- 2- (4-fluorophenoxy) -piperidinyl methyl-5,7-dimethoxy-2-benzothiazolamine, dihydrobromide, t. Pl. 249.2 ° C (compound 51);
    Cis-M- 1- 2- (4-fluorophenoxy) etip-β-3-methyl-4-piperidinyl methyl -2-benzothiazolamine, mp. 95.9 ° C (compound 52).
    In a similar way also receive
    (2,3-Dihydro-1, 4-benzodioxin-2-yl) methylZ-4-piperidinyl 7 propyl-5,6-dimethoxy-2-benzothiazole-amine (compound 53).
    Example 7. A mixture of 3.2 parts of 3,4-β-dihydro-2H-1-benzopyran-2-methyl 4-methyl-benzenesulfonate (complex), 4.2 hours of K- (4-piperidinylmethyl) -2 -benzothiazolamine dihydrobromide hemihydrate, 5.3 parts of sodium carbonate, 240 hours. 4-methyl -2-pentanone is stirred and refluxed for 24 hours using a water separator. The reaction mixture is cooled, washed with water.
    dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. Collect the pure fractions and evaporate the eluent. The residue is crystallized from 2,2-oxybis-propane. The product is filtered off and dried, yielding 1.92 parts (48.8%) of N- (3,4-dihydro-2H-1-benzopyran-2-yl) methyl-4-piperidinelmethyl J-2-benzothiazolamine, m. square (compound 54).
    In a similar way also receive
    (+) (2, 3-dihydro-2-methyl--1,4-benzodioxin-2-yl) methyl-4-piperidinyl methyl J-2-benzothiazolamine, mp. 126.2 C (compound 55);
    (-) (3,4-dihydro-2H-1- -benzopyran-2-yl) methyl2-4-piperidinyl} metipJ-2-benzothiazolamine, m.p. 145 ° C (compound 56).
    Example 8. A mixture of 4.2 part 2, 3-dihydro-1,4-benzodioxin-2-methanol-4-methylbenzenesulfonate (ester), 5.1 parts (4-piperidinylmethyl) amino-3 -6-benzothiazolol dihydrobromide, 10.5 parts of N, N-diethyl ethanolamine and 67.5 parts of N, N-dimethyl acetamide are stirred overnight at 80 C. Water is added. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is converted to the hydrochloric salt in 2-propanol. All evaporated. The oily residue is crystallized from a mixture of ethanol and acetonitrile. The product is filtered off and dried, yielding 2.2 parts (36.4%) (2-dihydro-1,4-benzodioxin-2-yl) methyl} -4-hyperphenylnyl methyl jaminoj-6-benzotiazolol dihydrochloride, m.p. 218.6 ° C. (compound 57).
    Example 9. Work according to the methods of examples 5-8 and use the appropriate starting materials.
    At the same time receive:
    ten
    15
    20
    25
    ethyl 3-benzothiazolamine ethanedioate (1: 2), t. pl. (compound 60
    N- 1- (2,3-dihydro-G, 4-benzodi CIN-2-IL) methylJ-4-piperidinshyl meti -N- (4-fluorophenyl) methylJ-2-benzothia amine ztandioate (1: 1), t pl. 136 ° C (compound 61)}
     (2, 3-dihydro-1,4-benzodio syn-2-yl) methyl-4-piperidinyl meth-Y-methyl-2-benzothiazolamine, mp. 124, (compound 62);
    N- (2-benzothiazolyl) f (2,3-dihydro-1,4-benzodioxin-2-yl} -methyl) -4-piperidinyl methyl 2-furanc boxamide monohydrochloride, t, pl. 2 (compound; 63), N- (2-benzothiazolyl) -N-1- (2,3-dihydro-1,4-benzodioxin-2-yl (methyl) -4-piperidinyl methylJ-4-tags benzamide, t Pl. 125 s (compound 64);
    L- (2-benzothiazolyl) -M-fl- (2,3-dihydro-1,4-benzodioxin 2-yl-methyl-4-piperidinyl methyl-4- (methyl methyl) benzamide, mp 147 , (comp. 65);
    N- (2-benzothiazolyl) -N-f G1 (2,3-dihydro-1, 4-benzodioxin-2-yl) methyl-4-piperidinyl methyl-3,4-di-methoxybenzoamide, m.p. 135, (compound 66);
    N- (2-benzothiazolyl) -N-CCl C (2,3-dihydro-1,4-benzodioxin-2-yl) methyl-4-piperidinyl methyl -2-thiazole carboxamide. m.p. 125 ° C (compound 67):
     (2, 3-dihydro-1,4-benzodi 4Q syn-2-yl) methyl-4-piperidinyl meth-6-methoxy-2-benzothiazolamine, mp (compound 68).
    Pharmacological testing.
    The test for loss of reflex orientation 45 (for self-righting reflex).
    In the test, seven female Wistar rats were used, the weight of 1x 220-270 60 minutes before the observations, the rats were treated with the test compound or
    thirty
    35
    (2, 3-dihydro-1,4-benzodiok- “saline, 30 min
    syn-2-yl) methyl-4-piperidinyl methyl; thiazolo (4,5-c) pyridin-2-amine, m.p. 146, (compound 58)
    N-LI (2,3-dihydro-1,4-benzodioxin-2-yl) methyl-4-pipercidine} methyl J-thiazolo (5,4-d) pyrimidine-2,7-diamine, m.p. . 190 ° C (compound 59);
    N- 1 - 1 - (2,3-dihydro-1,4-benzo-DIOXIN-2-IL) methylJ-4-piperidinylj
    55
    Later, all animals received an intraperitoneal injection of 20 mg / kg into the xylazine body.
    Twenty minutes after the injection, the animals were pretreated with saline (the controls were usually in a state of lox motor activity, while others were depressed or abolished
    0
    five
    0
    five
    ethyl 3-benzothiazolamine ethanedioate (1: 2), t. pl. (compound 60);
    N- 1- (2,3-dihydro-G, 4-benzodiox-CIN-2-IL) methyl J-4-piperidinshyl methyl 1 -N- (4-fluorophenyl) methyl J-2-benzothiazole-amine ztandioate (1: 1 ) t. pl. 136 ° C (compound 61)}
     (2, 3-dihydro-1,4-benzodioxin-2-yl) methyl-4-piperidinyl methyl--Y-methyl-2-benzothiazolamine, mp. 124, (compound 62);
    N- (2-benzothiazolyl) f (2,3-β-dihydro-1,4-benzodioxin-2-yl} methyl) -4-piperidinyl methyl 2-furancarboxamide monohydrochloride, t, pl. 218 with (compound; 63), N- (2-benzothiazolyl) -N-1- (2,3-dihydro-1,4-benzodioxin-2-yl (methyl) -4-piperidinyl methyl-4-methoxy- Benzamide, mp 125 s (Compound 64);
    L- (2-benzothiazolyl) -M-fl- (2,3- -dihydro-1,4-benzodioxin 2-yl-methyl-4-piperidinyl methyl-4- (trifluoromethyl) benzamide, m.p. 147, (compound 65);
    N- (2-benzothiazolyl) -N-f G1 (2,3-dihydro-1, 4-benzodioxin-2-yl) methyl-4-piperidinyl methyl-3,4-di-methoxybenzoamide, m.p. 135, (compound 66);
    N- (2-benzothiazolyl) -N-CCl C (2,3-dihydro-1,4-benzodioxin-2-yl) methyl-4-piperidinyl methyl -2-thiazolecarboxamide. m.p. 125 ° C (compound 67):
     (2, 3-dihydro-1,4-benzodiox-Q syn-2-yl) methyl-4-piperidinyl methyl - -6-methoxy-2-benzothiazolamine, mp. (compound 68).
    Pharmacological testing.
    Test for loss of orientation reflex (5) (righting reflex).
    In the test, seven female Wistar rats were used, the weight of 1x 220-270 g. 60 minutes before the observations, the rats were treated with the test compound or
    0
    five
    five
    After that, all animals received an intraperitoneal injection of 20 mg / kg body weight of xylazine.
    Twenty minutes after injection, animals pretreated with saline (control) were usually in a state of loxomotor activity, while others were depressed or abolished and my tone was reduced and the orientation reflex was compensated. The degree to which the orientation reflex was compensated was estimated to be 0-3 depending on the animal's response, therefore, how it carefully lay on its back on the floor surface. Grade 3: complete loss of correct orientation, grade 2: see some correctly oriented movements, but they fall as a result of body rotation by 180, grade 1: correct movements are made when the body turns 180, but the process smiles significantly more time than normal animals 0 rating: orientation is performed at the same speed as normal rats. The value of AU was determined as a 20 dose, mg / kg body weight, capable of causing a loss of orientation reflex with a rating of 3 (i.e. 2 or 1) in 50% of the test animals. The EDU values for a series of compounds of formula (I) are given in Table. 2
    Those 50% of animals are rated 2 and 1, which retain the ability to orientate.
    In tab. 3 shows the comparative 30th data of a known compound, and Table. 4 - proposed.
    The proposed compounds have antagonism to the loss of orientation reflex caused by xylazine, while 35 known compounds do not possess such activity at all.
    Data on enterokinetic activity: an increase in fecal extracts in rats.40
    or and cetive tivny radik about
    a)
    b)
    c)
    d)
    In a cat can replace amino coxy radic
    where n
    Rats, which were given water and food without restriction, were weighed and placed in the morning in a metabolic cage. Animals were injected subcutaneously with a test substance of formula (I) or a physiological suspension.
    The administration of more than 2.5 g of faeces during the first hour after the administration of the test substance was considered positive, since the control animals had only 0.50 + 0.05 g of feces.
    In tab. 5 shows the ED values for a range of substances of formula (I). The ED value used here is an effective dose that causes 50% of the animals to defecate.
    Toxicological data.
    The technique. Rats were injected in various doses of the test substances. The LD5o value was defined as the lethal dose, expressed in mg / kg body weight, at which 50% of the test animals died.
    The results are presented in table 6.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining substituted N - {(4- -piperidinyl) alkyl-bicyclic oxazole or thiazolamines of the total form
    -( , (one)
    mules
    or their stereoisomers, or their pharmaceutically acceptable acid additive salts, where A is a bivalent radical selected from the groups of the following general formulas
    a) -CH CH-CH CH-;
    b) -N CH-CH CH-;
    c)
    d) -N CH-N-CH,
    In which up to three hydrogen atoms can be independently substituted with halogen, hydroxylene, amino. C, -C, -alkyl or coxy, or two adjacent atoms in radical a) can be substituted by a bivalent radical of the formula
    0- (CHj) n-0-,
    where n is 1 or 2,
    Z - O or S,
    Q - With alkanediyl,
    R, is hydrogen, alkyl, hydroxyl
     hydrogen, C-C-alkyl, aryl-carbonyl aryl-C, -C4-alkyl where aryl is phenyl, possibly substituted by one or two substituents selected from the group: halogen, CF.J, C-C-alkyloxy or 2- -furanylcarbonyl or 2-thiazolyl carbonyl, L is a group of the general formula
    (h)
    lUIH
    (i)
    O-ALKWhere ALK X
    s R4 and R
    "five
    C 1-C j-alkanediyl; -O- or, hydrogen or Cj-C-apkyl, independently of each other, can be a substituent selected from hydrogen, halogen, Ci-C-alkyl, alkoxy or phenyl C, -C.-alkoxy,
    provided that when Z is oxygen,
    L - is a group of general formula
    (h) where X O and Rj are hydrogen, Q and
    ALK groups R, and R
    A is a group a)
    different
    compound of general formula
     - hydrogen so that
    xc 0,5Z in dichloromethane.
    table 2
    N
    B
    -iGfA H-
    (Ii)
    where R ,, R Q Z and A have specified
    values
    or its dihydrobromide N-alkylate compound of the General formula
    L - W, (III)
    where W is halogen or sulfonyloxy. Group,
    in the medium, inert solvent, followed by allocation of the target product in free form or in the form of a pharmaceutically acceptable acid addition salt.
    Table 1
    45
    Continued table. 2
    152480916
    Table 3
    P 7
    CHg-CHj- N
    Orientation reflex loss caused by xylazine, mg / kg
    5- F
    6- F
    CH2- (
    Table 5
    ten
    710
    Table A
    Continuation of table.5
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1524809A3|1989-11-23|Method of obtaining substituted n/|-alkyl/-bicyclic oxazol or thiazolamine or their stereoisomers or their pharmaceutically acceptable acdi-additive salts
    JP6061857B2|2017-01-18|Morphinan derivatives
    PL169238B1|1996-06-28|Method of obtaining novel derivatives of n-| | carbonamides
    CZ287381B6|2000-11-15|Piperazine derivatives, processes and intermediates for their preparation, their use and pharmaceutical compositions based thereon
    RU98111153A|2000-06-27|CYCLIC AND HETEROCYCLIC N-SUBSTITUTED α-IMINO-HYDROXAMIC AND CARBOXYLIC ACIDS
    AU3254499A|1999-09-20|Glycine transport inhibitors
    CS228506B2|1984-05-14|Method for the production of optical active ester of 1,4-dihydropyridincarboxyl acid
    FR2654104A1|1991-05-10|NOVEL 1,2-BENZISOXAZOLE DERIVATIVES, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
    FI78297C|1989-07-10|FOERFARANDE FOER FRAMSTAELLNING AV FARMACEUTISKT ANVAENDBARA TEOFYLLINDERIVAT.
    WO2007129111A1|2007-11-15|Diazepine derivatives as 5-ht2a antagonists
    US3974158A|1976-08-10|2-|methylmorpholines
    HU191220B|1987-01-28|Process for producing dihydropyridine derivatives and pharmaceutical compositions of antiischemic and vasodilatant activity containing them
    HU0003413A2|2001-07-30|New fused pyridine derivatives, process for their preparation and pharmaceutical compositions containing them
    EP0462696B1|1995-08-09|Novel pyrido [2,3-f][1,4] thiazepines and pyrido [3,2-b][1,5] benzothiazepines
    EP0216247A2|1987-04-01|Use of alpha 2 adrenergic receptor antagonists for the production of pharmaceutical compositions for treating colonic spasm, irritable bowel syndrome and constipation and process for preparing such pharmaceutical compositions
    FR2566404A1|1985-12-27|NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR SALTS, PROCESS FOR THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
    IE52631B1|1988-01-06|N-carboxyalkyl dipeptide derivatives and pharmaceutical compositions thereof
    JP3007203B2|2000-02-07|Piperazine derivative
    SU1395143A3|1988-05-07|Method of producing derivatives of 1,6-naphthyredene in the form of racemates or enantiomers or acid-additive salts thereof
    JP3884177B2|2007-02-21|Novel indanol compounds, processes for producing them and pharmaceutical compositions containing them
    FR2549058A1|1985-01-18|NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS
    KR900005956B1|1990-08-18|Process for preparing asymmetrical ester of 1,4-dihydropyridine -3,5-dicarboxylic acid
    CA1207774A|1986-07-15|1-phenylindazol-3-one compounds, a method ofpreparing them and pharmaceutical compositionscontaining these compounds
    DK154083B|1988-10-10|METHOD OF ANALOGY FOR THE PREPARATION OF HALOGENIC VINCAMO DERIVATIVES OR OPTIC ACTIVE ISOMERS OR ACID ADDITION SALTS THEREOF
    Lavé2019|Structure–activity relationships in pyrrolo [1, 2-c] thiazoles PAF receptor antagonists
    同族专利:
    公开号 | 公开日
    NO163818B|1990-04-17|
    NO163818C|1990-07-25|
    IE860967L|1986-10-15|
    KR860008173A|1986-11-12|
    DK165183C|1993-03-15|
    AU582642B2|1989-04-06|
    IL78487A|1989-12-15|
    PT82368A|1986-05-01|
    NZ215700A|1988-07-28|
    AU5613586A|1986-10-23|
    AT56972T|1990-10-15|
    DK169486A|1986-10-16|
    PH26181A|1992-03-18|
    CN1019393B|1992-12-09|
    IE59040B1|1993-12-15|
    FI82047B|1990-09-28|
    EP0199400A2|1986-10-29|
    KR930005004B1|1993-06-11|
    ES8702403A1|1987-01-01|
    FI82047C|1991-01-10|
    FI861562A0|1986-04-14|
    NO861442L|1986-10-16|
    DK165183B|1992-10-19|
    JPH08824B2|1996-01-10|
    PT82368B|1988-05-27|
    DE3674448D1|1990-10-31|
    HUT40633A|1987-01-28|
    FI861562A|1986-10-16|
    CA1271474A|1990-07-10|
    DK169486D0|1986-04-14|
    JPS62129282A|1987-06-11|
    GR861014B|1986-08-07|
    CN86102349A|1986-11-19|
    ES553936A0|1987-01-01|
    ZA862776B|1987-11-25|
    IL78487D0|1986-08-31|
    EP0199400B1|1990-09-26|
    HU196393B|1988-11-28|
    EP0199400A3|1987-08-19|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4035369A|1975-10-08|1977-07-12|Janssen Pharmaceutica N.V.|1-Benzazolylalkyl-4-substituted-piperidines|
    DE2545645C2|1975-10-11|1983-04-14|Bayer Ag, 5090 Leverkusen|Thiazolinylamino-piperidine derivatives|
    CA1140119A|1978-04-03|1983-01-25|Joseph Torremans|N-heterocyclyl-4-piperidinamines|
    PH23995A|1984-01-09|1990-02-09|Janssen Pharmaceutica Nv|4-methyl and hetero)piperidines|
    CA1260474A|1984-12-03|1989-09-26|Raymond A. Stokbroekx|Benzoxazol- and benzothiazolamine derivatives|US5120843A|1987-04-27|1992-06-09|Upjohn|Pharmaceutically active amines|
    IL90337D0|1988-05-24|1989-12-15|Pfizer|Aromatic and heterocyclic carboxamide derivatives as antineoplastic agents|
    JP2679745B2|1989-06-29|1997-11-19|明治製菓株式会社|Azole derivatives and antiulcer agents containing them as active ingredients|
    US5089637A|1990-03-21|1992-02-18|Pfizer Inc.|Process and intermediates for 2r-benzyl-chroman-6-carbaldehyde|
    KR100190299B1|1990-07-19|1999-06-01|디르크 반테|Novel oxazolyl derivatives|
    FR2672888B1|1991-02-14|1994-02-04|Fabre Medicament Pierre|NEW UREAS AND THIOUREAS, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS.|
    ZW1992A1|1991-02-25|1993-09-22|Janssen Pharmaceutica Nv|4-/methylamino/-b-/methyl/-1-piperidine ethanol|
    DE4120322A1|1991-06-20|1992-12-24|Bayer Ag|AMINOMETHYL-SUBSTITUTED 2,3-DIHYDROPYRANOPYRIDINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICAMENTS|
    AU4982293A|1993-03-02|1994-09-26|Fujisawa Pharmaceutical Co., Ltd.|Novel heterocyclic compound|
    TW282469B|1993-06-11|1996-08-01|Janssen Pharmaceutica Nv|
    FR2753970B1|1996-10-01|1998-10-30|Synthelabo|N-PIPERIDINE-1-ETHANAMINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION|
    JP2000224822A|1998-06-29|2000-08-11|Mitsubishi Electric Corp|Motor for motor-operated power steering device|
    RU2251419C2|2000-06-21|2005-05-10|Ф. Хоффманн-Ля Рош Аг|Benzothiazole derivatives|
    FR2821356A1|2001-02-23|2002-08-30|Cerep|NOVEL ARYLCARBAMATE AND ARYLUREES DERIVATIVES, PREPARATIONS AND USES|
    US7087761B2|2003-01-07|2006-08-08|Hoffmann-La Roche Inc.|Cyclization process for substituted benzothiazole derivatives|
    PT1753760E|2004-05-24|2008-02-12|Hoffmann La Roche|4-hydroxy-4-methyl-piperidine-1-carboxylic acid -amide|
    EP1812392B1|2004-11-05|2008-07-09|F.Hoffmann-La Roche Ag|Process for preparation of isonicotinic acid derivatives|
    AU2006226669B2|2005-03-23|2011-12-08|F. Hoffmann-La Roche Ag|Acetylenyl-pyrazolo-pvrimidine derivatives as mGluR2 antagonists|
    CA2623721C|2005-09-27|2014-05-13|F. Hoffmann-La Roche Ag|Oxadiazolyl pyrazolo-pyrimidines as mglur2 antagonists|
    法律状态:
    2007-09-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20040415 |
    优先权:
    申请号 | 申请日 | 专利标题
    US72340085A| true| 1985-04-15|1985-04-15|
    [返回顶部]