• 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 antihypertensive 3-piperidinyl-indazole derivatives of formula <CHEM> wherein R<1> is hydrogen or C1-6alkyl; R<2> is hydrogen; C1-6alkyl; substituted C1-6alkyl; optionally substituted phenyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl or phenylcarbonyl, wherein phenyl may be substituted; R<3> and R<4> are hydrogen, halo, hydroxy, C1-6alkyloxy or C1-6alkyl; Q is a bicyclic heterocyclic radical of formula <CHEM> the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are antihypertensive agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.
    公开号:SU1720489A3
    申请号:SU894742322
    申请日:1989-08-29
    公开日:1992-03-15
    发明作者:Ванденберк Ян；Эдмон Жозефин Кеннис Людо；Хендрикус Мария Терезия Ван Хэртум Альбертус
    申请人:Жансен Фармасетика Н.В. (Фирма)；
    IPC主号:
    专利说明:

    Table 1
    eleven
    N SNE
    G V
    1 .N-CH2-CH2-N
    Table 2
    N R2
     N
    7TTI
    Connected - Prm-R2T.pl., ° C
    measures
     .
    64I259.7
    73cHj143,8
    83C% - (HS 98.3
    Table3
    / Zjvc
    (A-N J1-CH2-CH 2 -NQ4jN
    V // 3
    Compound- When - Z-A-R2R So., ° C
    measures
    93-CH CH-CH CH103-CH CH-CH CH113-CH CH-CH CH123-CHrCH-CKUCH133 (CH2) 4
    143- (CH2) 4153- (CH2) 4163-3-C1BCH173-S-CH CH183-S-CH CH
    193-S-CH CH204-S-CH C (CHj) 213-S-CH C (CH3) 224-S-CH C (CH3) 233-S-CHrC (CH3) 243-S-C1I C (CH3) 253 -3- (CH,) g

    F F F F F F F F F
    147.5 259.5 149.8 131.4 236.2 16S, 1,162.1
    232.4
    190.1
    139.9
    127.6
    165.0 170.0 232.4 F 141.1 F 180.0 F 157.6
    #

    13
    1/2 (E) -2-butandioate / H2O 2HCl (E) -2-butandioate (1: 1)
    1720489
    14 Continuation of tab. 3
    Study of the pharmacological activity of the compounds of formula (I)

    Risperidone, t gm
    / vJv 3
    4.Ny4 / xN About
    oft.
    Mr
    Table
    Table 5
    Lowering blood pressure in rats with spontaneous hypertension

    -140
    -40
    -130
    -120
    -90
    -170
    -140
    - zo
    -70
    -80
    -20
    -100
    -90
    -110
    -60
    -ten
    - zo
    -90 -80 -70 -90 -10
    - zo
    -55 -60 -10 -65 -60 -85 -45
    权利要求:
    Claims (1)
    [1]
    Formula of the invention A method for producing 3-piperidinyl-indazole of the general formula (I)
    Ri Λ where Ri is hydrogen;
    R2 is hydrogen, St-Cb-alkyl, phenyl substituted with one halogen atom, Ci-Cb-alk yl carbon yl, Ci-Cb-alkyloxycarbonyl or phenylcarbonyl in which phenyl is substituted with one halogen atom;
    R3 is hydrogen, halogen or C 1-Sb-alkyl oxy;
    Aik is C1-C4 alkanediyl;
    Q is a bicyclic heterocyclic radical of the general formula n
    N Ru NON Ru yes
    9 OO where R 4 is CrSb alkyl; 10
    Ζ - -S-, -CR5 = CR6-, -CH2-: Rs and Re are each independently hydrogen or Ci-Cb alkyl;
    A is a bivalent radical - (CH2B *; (CH2) s-: -CH = CH- or. When Z is -CR5 = CR6-. Then A may be -0-, or its pharmaceutically-acceptable salt acid .15 additions, characterized in that piperidine of the general formula wherein R1-R3 have the indicated meanings, is reacted with an alkylating agent of the general formula a -ALK-W, where Wi is a leaving group;
    Q and Aik have the indicated meanings in a reaction-inert solvent in the presence of a base and an alkali metal iodide when heated to isolate the desired product in a free form or in the form of a pharmaceutically acceptable acid salt, or in the case where R2 is hydrogen, the obtained compound of the general formula where Ri, R3. Q; Aik have the indicated meanings, are reacted with an alkylating or acylating agent of the general formula
    R2a ~ V / 2, where ₽2a _ Ci-Sa-alkyl, phenyl substituted with one halogen atom, Ci-Sa-alkylcarbonyl, Cq-Sa-alkyloxycarbonyl or phenylcarbonyl, wherein phenyl is substituted with one halogen atom;
    W2 is a leaving group, with the isolation of a compound of formula (I), wherein R2 is as indicated, in addition to hydrogen, in its free form or as a pharmaceutically acceptable addition salt.
    3 3 4-F-C ^ F HC1 / mp. 291.5 ° C 4 3 N F Mp 278.9 ° C 5 3 cn 2 -s 6- n 5F Mp 223.5 ° C 53 3 n DOS 32CH1 / 1LO / mp . 244.3 <> C
    T a
    N CH 3
    Compound Example r 2T. pl. ; ° C 6 4 AND 259.7 7 3 Chj 143.8 8 3 cvq.H s98.3
    Table C sn 2 -CH 2 -nQ-CJn * 3
    Compound At-measures -Z-a- r 2R t 0 "T.pl., C 1 2 3. 4 5 6 !9 3 -sn = sn-sn = sn- 4-FC 6 H 4F 147.5 10 3 -sn = sn-sn = sn- H F 259.5 eleven 3 -sn = sn-sn = h: n- CH F 149.8 12 3 -CH = CH-CH-: CH- ch 2 -c 6 h 5 : F 131.4 thirteen 3 ~ (sn 2 ) 4Η 7 F 236.2 14 3 - (sn 2 ) 4 - ch 5F 168.1 fifteen 3 - (CH 2 ) 4 - CHg-Cghg- F 162.1 16 3 -S-CH = CH- 4-FC 6 H 4F 232.4 * 17 3 -S- € H = CH- H F 190.1 ** 18 3 -s-ch = ch CH 3F 139.9 19 3 -S-CH = CH- CH ^ -CgHj. F 127.6 20 4 -S-CH = C (CHj) - 4-F-CeH 4F 165.0 *** '21 3 -S-CH = C (CH 3 ) - CH fF 170.0 22 4 -s-ch = c (ch 3 ) - H F 232,4 23 3 -S-CH = C (C1I 5 ) - CH ^ c e n 5F 141.1 24 3 -S-C11 = C (CH 3 ) - 2-CH 2 -C fi H sF 180.0 25 3 -s- (CH,) x - S1Ts F 157.6
    Continuation of tablZ
    4 2. 3 d g € 26 3 -s- (ch 2 ) 2sn 2 -s 6 n 5F 150.2 27 3 -S- (CH 2 ) 2 - 2-01 ^ - ^ 1¾ F 175.2 28 3 -s (sn 3 ) = sn-sn = sn- n F 213.1 29th 3 -s (sn 3 ) = sn-sn = sn- sn 2 s 6 n 5F 139 thirty 5 -S- (CH Z ) 2 - CH2- (4-0CE, C b N 4 ) F 145.8 31 3 -sn ° s (sn 3 ) -– sn 2 -s 6 H sF 136.1 32 4 -S-CH = C (CH 3 ) - CH 2 - (4-F-qJI + ) F 139.2 33 , 3 -s (sn 3 ) = sn-sn = sn- n 00¾ 2 10.0 34 3 -s-ch “ch- n Och3 183 z 35 3 -S-CHsCH-n N II 196.4 **** 36 5 .- (CH 2 ) 4 -c h 2 -Q F 151.2 *** * 37 3 -s (sn 3 ) -sn-sn = sn HE F 176.0 38 3 - (sn g ) 4-CH 2 CH 2 0H F 140.1 39 3 -s- (cii 2 ) 2 - -CH 2 C11 2 0P F 165.6 40 3 C (CH 3 ) = 011 = CH-CH II H 180,2 41 3 -sn = s (cn 3 ) -o sun 3F 157.7 42 3 ~ (sn 2 ) 4 - n H 188.1 43 3 -S-CIbrCH- -0 ^, 0¾ OH F 197,2 44 5 -, (CH 2 ) 4 - sn 2 -O> F 179.4 45 3 -S-CH 2 -CH 2II H 210.3 46 6 -s (sn 3 ) = sn-sn = sn pine 3F - 47 6 -s (sn e ) = sn-sp = sn- CO (4-C1-C 6 1I S ) - s - 181.6 48 6 -s (cn 3 ) = cn-cn = cn- COOC 2 1I SF 183.1 49 3 -S-CH 2 -CH 2 - Η H - fifty 6 -C (CH 3 ) = SI-CH = CH- pine 3H 160, 7 51 6 - (sn 2 ) 4 - С0С1Ц H 149.3 52 3COCHj H -
    (E) -2-butenedioate ** 1 / 2H g 0 * * * 1/2 (E) -2-butenedioate / Н ”0 **** 2НС1 * ♦ *** (E) -2-butenedioate (1 :1)
    Table 2 !
    The study of the pharmacological activity of the compounds of formula (I)
    Compound Rat Test , UNIT 50 mg / kg APO test on a dog, ED 5o , mg / kg. Apo THREE convulsions THREE hyperemia NOR 2 5 ' 5 0.005 oh, s1 0.002 9 > 10 5 0.08 5 eleven 5 0.31 0.005 0.08 0.12 thirteen > 10 1,125 0.02 oh, s1 0.015 16 > 10 5 0.08 > 10 17 5 5 oh oz 2.0 0.004 18 5 1.25 0.005 1.25 0.2 20 > 10 > 10 0.08 > 10 21 1.25 0.08 0.005 0.31 0.12 25 *10 1.25 0.01 0.31 < 0.015 29th 1.25 5 ^ 0.16 1.25 0.004 zo > 10 10 0.08 5 ". 0.63 31 > 10 1.25 0.02 0.31 0.63 34 > 10 > 10 1.25 1.25 0.01
    Kentas
    rin *> 80 5 0.008 8 Risperi Don ** 0.08 0.08 0,00031 0.16 -
    * Kentaserin j.)
    I * * Risperidone
    Y'-ar
    Table 5
    Lowering blood pressure with spontaneous rat hypertension
    Compound Blood pressure mmHg systole : toe diastelic 2 -140 -100 9 -40 -so eleven -in -90 thirteen -120 -80 18 -90 -70 25 -170 -90 28 -140 -100 29th -so -so thirty -70 -55 31 -80 -60 34 -20 -10 46 -100 -65 47 -90 be 48 -110 -85 53 -60 -45
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    同族专利:
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    NO893523L|1990-03-05|
    DK434789A|1990-03-03|
    PH26456A|1992-07-27|
    JPH02160778A|1990-06-20|
    NO176608C|1995-05-03|
    IL90879D0|1990-02-09|
    NZ230367A|1991-03-26|
    HUT51622A|1990-05-28|
    FI894125A0|1989-09-01|
    IE892829L|1990-03-02|
    AT124410T|1995-07-15|
    KR0145705B1|1998-08-17|
    DE68923231T2|1995-11-09|
    JP2768992B2|1998-06-25|
    EP0357134B1|1995-06-28|
    PT91613B|1995-05-04|
    DK169547B1|1994-11-28|
    CN1024346C|1994-04-27|
    DK434789D0|1989-09-01|
    DE68923231D1|1995-08-03|
    AU614871B2|1991-09-12|
    CA1331610C|1994-08-23|
    NO893523D0|1989-09-01|
    EP0357134A1|1990-03-07|
    NO176608B|1995-01-23|
    IE66511B1|1996-01-10|
    KR900004721A|1990-04-12|
    ZA896741B|1991-05-29|
    ES2076201T3|1995-11-01|
    AU4084889A|1990-03-08|
    HU202232B|1991-02-28|
    GR3017435T3|1995-12-31|
    FI91864C|1994-08-25|
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    PT91613A|1990-03-30|
    CN1040589A|1990-03-21|
    FI91864B|1994-05-13|
    引用文献:
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    US4335127A|1979-01-08|1982-06-15|Janssen Pharmaceutica, N.V.|Piperidinylalkyl quinazoline compounds, composition and method of use|
    US4342870A|1980-03-28|1982-08-03|Janssen Pharmaceutica N.V.|Novel 3--4H-pyrido[1,2-a]pyrimidin-4-one derivatives|
    US4443451A|1981-07-15|1984-04-17|Janssen Pharmaceutica N.V.|Bicyclic pyrimidin-5-one derivatives|
    JPH033669B2|1982-03-17|1991-01-21|Chugai Pharmaceutical Co Ltd|
    US4485107A|1982-11-01|1984-11-27|Janssen Pharmaceutica N.V.|[[Bismethylene]-1-piperidinyl]alkyl-pyrimidinones|
    US4670447A|1983-08-22|1987-06-02|Hoechst-Roussel Pharmaceuticals Inc.|Antipsychotic 3-- and 3--1H-indazoles|
    HU198036B|1983-08-22|1989-07-28|Hoechst Roussel Pharma|Process for production of derivatives of 3-piperidil-/1h/-indasole and medical preparatives containing them|
    US4716161A|1984-04-17|1987-12-29|Mitsubishi Chemical Industries Limited|Phenylpiperazine derivatives and their acid addition salts|
    CA1246074A|1984-12-05|1988-12-06|Albertus H.M.T. Van Heertum|Derivatives of hydroxy- or amino-substitutedquinazolines|
    EP0192935B1|1985-01-23|1991-02-27|Hoechst-Roussel Pharmaceuticals Incorporated|3--1h-indazoles a process for their preparation and their use as medicaments|
    US4804663A|1985-03-27|1989-02-14|Janssen Pharmaceutica N.V.|3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles|
    US4711883A|1985-09-30|1987-12-08|Ortho Pharmaceutical Corporation|Substituted 3-alkylquinazolin-2,4- diones, methods of preparation, compositions and method of use|
    NZ223654A|1987-03-09|1990-03-27|Janssen Pharmaceutica Nv|1-alkyl-substituted-benzimidazole-4-piperidinamines and pharmaceutical compositions|
    CA1317939C|1987-07-01|1993-05-18|Janssen Pharmaceutica Naamloze Vennootschap|¬methyl and -hetero| substituted hexahydro-1h-azepines and pyrrolidines|US5776963A|1989-05-19|1998-07-07|Hoechst Marion Roussel, Inc.|3--1- alkyl!pyrrolidines and 3--1- alkyl!pyrrolidines and related compounds and their therapeutic untility|
    US5364866A|1989-05-19|1994-11-15|Hoechst-Roussel Pharmaceuticals, Inc.|Heteroarylpiperidines, pyrrolidines and piperazines and their use as antipsychotics and analetics|
    WO2004069828A1|2003-02-04|2004-08-19|Mitsubishi Pharma Corporation|Piperidine compound and medicinal use thereof|
    EP3609883A4|2017-04-11|2020-12-09|Sunshine Lake Pharma Co., Ltd.|Fluorine-substituted indazole compounds and uses thereof|
    法律状态:
    2007-12-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20060830 |
    优先权:
    申请号 | 申请日 | 专利标题
    US23991588A| true| 1988-09-02|1988-09-02|
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