• 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:
    2-Amino- and 2-(substituted amino)-tetrahydro- and -cis-hexahydro-carbazoles, useful for alleviating depression in mammals and intermediate compounds thereto.
    公开号:SU900807A3
    申请号:SU792739109
    申请日:1979-03-16
    公开日:1982-01-23
    发明作者:Джон Флиднер Леонард (Младший)
    申请人:Е.И.Дюпон Де Немур Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    In this process, compounds of formula I t are dissolved or weighed in an appropriate amount of a suitable acidic solvent, such as ice on acetic acid, trifluoroacetic acid or methanolic hydrogen chloride, followed by the addition of sodium cyanoborohydride (NaBHj C)., NaBHs CN, it is usually hygroscopic and, although it can be added to the reaction mixture in solid form, in practice it dissolves in an inert solvent that dissolves easily, such as methyl or ethyl alcohol, followed by the addition of the obtained astvora the reaction mixture. During the addition of NaBHjCN (either in solid form or in solution), it is advisable to withstand the internal temperature of the reaction mixture in the range of 0-50 ° C in order to reduce the exothermicity of the reaction and reduce the evolution of gases during the addition process. k) The pBal ratio of NaBHgCH and the compound of formula i I varies between 1 and 10. The RO is completed and the reaction is completed by stirring the mixture for t and 2 hours from room temperature to. When (sodium borohydride (MaHH4) -carboxylic acid alkylation of ammonia systems) is an alternative effective method for the preparation of compounds of type 1S1, where fi is methyl or ethyl About flR, -R - C, where R, R, Y, and Y The above value. During this process, compounds of Formula I, where all of the above value, with the exception of Rj, covering hydrogen, is agitated at the aaoto atom at position 9 by treatment with excess sodium borohydride and an excess of either formic or acetic acid, depending on the input alkyl substituent , for example, where RJ is methyl (Me) or ethyl (Et), respectively. The reaction is carried out in 8 temperature range from 20 ° to 100 ° C for 1-2 hours with or without the addition of an inert solvent. Suitable inert solvents include ts benzene and tetrahydrofuran. Depending on the molecular plane passing through the C 2 and a atoms and 9a of the compounds of formula I, the H atom in position a can be spatially oriented on the same side position (cis) or on the opposite side {position trans) plane that the H atom in position 9a. Hexahydrocarbazoles of formula I are cis isomers, i.e. H atoms in the positions of ta and 3a are spatially oriented on the same side of the molecular plane passing through the atoms C2 and a. Each of the cis-compounds of the formula (available in two diastereoisomeric forms due to the asymmetry of the atom C e position 2, so that the volume includes both individual diastereoisomers and their mixtures obtained by the above methods. Diastereoisomeric Forms can be divided into optically active pravoreshayuschie ( +) and levorotatory (-) enantiomers by methods well known to the skilled person. Compounds 1 are administered in a therapeutic amount in the human body Gyr and 0.1-50 mg / kg per day. Some of the preferred compounds are administered in amounts e 0.5–10 mg / kg per day, most preferable in the amount of 1–5 mg / kg per day. Standard doses (formulations) suitable for internal administration contain approximately 2.5–250 mg per day. unit. In these headlamps, "laevic compositions are active11 {its onset is usually contained in an amount of about 0, Ot-99 by weight, calculated on the total weight of the composition. The active principle can be administered orally in solid form, for example, in the form of capsules, tablets and powders, or in liquid form (elixirs, syrups and suspensions), it can also be injected parentera Ili stanyart shh doses or else rekta, 8 form of suppositories. Gelatin capsules contain valid onset and carriers in powder form, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents may be used for the manufacture of tablets. Both tablets and capsules can be formulated as delayed release agents for several hours. Pressed tablets can have sugar or destroy bad taste or a protective coating against the effects of atmospheric effects as well as an enteral coating in order to achieve selective disintegration in the gastrointestinal tract. Liquid unit doses may contain for oral administration colourants or flavoring agents to increase the patient's willingness to take them. In the general complexity, water, suitable oils, brine, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene, and glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active principle, appropriate stabilizers and, if appropriate, buffering agents. Antioxidants like sodium bisulfite, sodium sulfite or ascorbic acid in pure form or in combination with one another are suitable stabilizers. Citric acid and its salts and ethylenediaminetetraacetic acid are also used. Additionally, parenteral solutions may contain preservatives such as benzalkonium chloride, methyls propyl-paraben, and chlorobutanol. Suppositories contain the active principle in a suitable oily or soluble base in water. The first group includes cocoa butter and fats with similar properties, and water soluble salts include polyethylene glycols. Example 1. M- (cis-1,3, a, 9,9a-Hexahydro-2H-carbazol-2-yl) ac amide hydrochloride (compound 1a). A solution of 5.70 g (0.025 mol) of M- (1, 3,., 9-tetrahydro-2H-carbazol-2-yl) acetamide in ml of glacial acetic acid is stirred at room temperature and for a period of min. Drop by drop dropwise. a solution of 1.57 g (0.025 mol) of NaBHjCN in 15 ml of MeOH. The reaction is slightly exothermic with some gas evolution. After stirring overnight (approximately 16 hours) at room temperature, glacial acetic acid is evaporated, and the residue is mixed with 150 ml of water. Then concentrated hydrochloric acid () was added dropwise and, after stirring for 0.5-1 hours, the insoluble product was removed by filtration. The clear, colorless filter is basified with an excess of 50% NaOH, and the product is extracted with chloroform. The extracts are washed with water, dried, the residue is evaporated, recrystallized from i-RhOH to give 3.64 g (yield 70%) of a white solid, mp. 190-191С. A solution of the free base in methanol is treated with an excess of hydrogen chloride. Upon addition of anhydrous ether, the title compound precipitates, which after cooling is filtered and recrystallized, m.p. 2 5-247 C. In analogy to Example 1, 1 g of compound is obtained. During the process (scale 0.025 mol), glacial acetic acid is evaporated, the residue is treated with 60 ml of water. Upon addition of concentrated hydrochloric acid to bring the pH to 1-2, the hydrochloride salt precipitates directly from the original clear solution, which is isolated (1 1тратра). The tenfold molar amount of NaBHjCN used to obtain 1x (table) is divided into 2 identical portions, added separately after 7 hours. Then stirred overnight at room temperature. The compounds in the table are determined and tested for biologic effect either as free bases or their hydrochloride salts ( column with formulas.) Example 2. M- (cis-9-ethyl-1, Bta, 9, 9a-hexahydro-2H-carbazol-2-yl) acetamide (compound 2y). i Solution 9.0 g (0 , 15 mol) of glacial acetic acid in 75 ml of THF is treated in portions of 1.89 g (0.05 mol) of NaBH4, keeping the temperature at. After the termination of the release of Hj (approximately 3 hours), 2.30 g (0 , 01 mol) L- (cis-1,3, a, 9 9a-hexahydro-2H-carbazol-2-yl) acetamide, treating the resulting solution under reflux for 3 hours. After cooling, THF is evaporated in vacuo, the residue is dissolved in chloroform. The chloroform solution is washed with 1N aqueous NaOH and then dried with anhydrous KjCOj. After that, it is filtered, evaporated | Chloroform and a white yastatok is obtained, which after recrystal 79008078
    lization from ethyl acetate-cyclohexane by the DN method of Example 2, from H (, 3, melted at 150-151 ° C (yield: 2.3 g of 4, 9.9a-hexahydro-2H-carbazole called compound), 2-yl) -acetamide is obtained M- (cis-1,
    With the substitution of formic acid s-carbazol-2-yl) -acetamide (compound of acetic acid, otherwise with the same e- to table).
    3 ,,, 9 9a-hexahydro-9-methyl-2H
    SonHN1 EtOH, „Н НСЕ
    CO SOMENN2 J.PrOH, FMjO NS
    SOMeNN1,5MbON 253-25 С N.t C1N,
    COMEHNT 95 EtOH ,,, H, T8rNj, 0-HCl
    SOMENET EtOH 232-233C tgHjoNjO-HCt
    SOMEHN1 35 EtOH 2 0-2 "1C dNad gO / HCE
    COfteNI EtOH-2HjO284-285С ,,,, N, 5,
    Coma H HI N. About
    NN 1 f.PrW196-198SdN GM Og
    NN 1}; РгОН190-192t H | 0
    IN 1. RgON17 -176CfgHigNjOj
    HH 1.-РгОН17 -176CtgHjeNjOj.
    HH 1 EtOH150-131C ,, HjgNjOj
    NN 1 EtOH197-199C oH N O
    HH 1 l.-PrOH183-184Cj, H,
    HEN 1 i.-PrOH 90-191C H oM O
    HH l.lHeOH210-212С ,, N, 5 NjOHCE
    NN 1.5Et ° OH235-236C; H oNiO-HC t
    n HH 1.5i.-PrOH184-185 "(
    ,;
    253-25 C «H NiOi-HCt
    权利要求:
    Claims (1)
    [1]
    “Q-.h hFi. HCOjMe HH HMe HE HMe HCOMe Claim for the Preparation of Carbazole Derivatives of the General Formula Where R is Hydrogen, Methyl Ethyl or R-C RJ, is hydrogen or methyl; RJ is hydrogen, methyl or ethyl. U is hydrogen, fluorine, chlorine, bromine, hydroxy, methyl, benzyloxy or alkoxy with 1-6 C; 900807 Continuation of the table T HH I.BEtOH-Et O1t 7- l 9C, H. HH 1.5 MeOH-EtjO20k-2Q5С ,,, H, | N, 0jHCt HH 2 MeOH30i -306C, H, bNj 2HC HH 5 MeOH275-277C, H, | N -2HCt HH 5 HeOH273-275C H Nj-2HCt MeH 10 MeOH-Et O2 3-2 5C HjpN2-2HCf HEt - EtOAc-C H, 150-151C, 6 H „Yj - hydrogen or chlorine, provided that V7 - chlorine, only if Y, - chlorine, characterized in that the tetrahydrocarbazole derivative of the general formula where R (jRj, R, Y and Y - have the above values, is subjected to reduction in an acidic environment. Information sources taken into account during examination 1. G, W, Gribble, I. Am. Chem. Sor., 6, 7812, 197.
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    同族专利:
    公开号 | 公开日
    FI790904A|1979-09-18|
    ES478741A1|1980-01-16|
    DK29079A|1979-09-18|
    EP0004342B1|1981-07-15|
    NZ189928A|1981-02-11|
    HU177424B|1981-10-28|
    DE2960473D1|1981-10-22|
    EP0004342A1|1979-10-03|
    GR66500B|1981-03-24|
    AU524626B2|1982-09-23|
    PH14329A|1981-05-29|
    CA1107287A|1981-08-18|
    AU4515079A|1979-09-20|
    ZA791225B|1980-03-26|
    AR222169A1|1981-04-30|
    PT69354A|1979-04-01|
    US4254134A|1981-03-03|
    JPS54130563A|1979-10-09|
    NO790904L|1979-09-18|
    IL56890D0|1979-05-31|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3642816A|1967-08-10|1972-02-15|Sterling Drug Inc|3-acetamido-1 2 3 4-tetrahydrocarbazole|US4343812A|1978-03-17|1982-08-10|E. I. Du Pont De Nemours And Company|Antidepressant 2-amino-and-2--cis-hexahydro-carbazoles, compositions and use|
    EP0073849A1|1981-09-03|1983-03-16|Schering Corporation|Novel phenyl-1,2,3,4-tetrahydrocarbazoles, their preparation and pharmaceutical compositions containing them|
    GB8517854D0|1985-07-15|1985-08-21|Roussell Lab Ltd|Chemical compounds|
    US5100891A|1991-01-18|1992-03-31|Hoechst-Roussel Pharmaceuticals Inc.|Substituted 1,2,3,4-tetrahydrocyclopent[b]indoles, 1,2,3,3a,4,8a-hexahydrocyclopent[B]indoles and related compounds|
    GB9113802D0|1991-06-26|1991-08-14|Smithkline Beecham Plc|Medicaments|
    TW339325B|1995-07-05|1998-09-01|Hoffmann La Roche|Novel azepane derivatives, process for the preparation thereof and pharmaceutical composition containing the same|
    EP1434578A1|2001-10-09|2004-07-07|PHARMACIA & UPJOHN COMPANY|Arylsulphonyl-substituted tetrahydro- and hexahydro-carbazoles as 5-ht-6 receptor ligands|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/887,799|US4254134A|1978-03-17|1978-03-17|Antidepressant 2-amino- and -2--cis-hexahydro-carbazoles|
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