• 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:
    Cyclic derivatives of 1,4-benzoxazine and 1,4-benzothiazine are disclosd, such as, for instance, 1H,2,3,3a,4-tetrahydro-2-carbamoylmethyl-imidazo[5,1-c][1,4]benzoxazin -1-one and 1H,2,3,3a,4-tetrahydro-2-carbamoylmethyl-8-chloro-imidazo[5,1-c][1,4]b enzoxazin-1-one. These compounds are active on the central nervous system, and function as antidepressant agents.
    公开号:SU812181A3
    申请号:SU782579299
    申请日:1978-02-16
    公开日:1981-03-07
    发明作者:Меллони Пьеро；Монджелли Никола；Лаурия Франческо；Росси Алессандро；Томмасини Раффаеле
    申请人:Фармиталия Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    de A, B, R, R ,, R ,, Cd 5 have the values indicated above, supporting the connection with a joint, common orchestra.
    R. - "III de R4 has the stated value of a /,
    Ø is a halogen atom or the residue of an active ester of pyrite, in an environment of an organic solvent at a temperature of 5-150 ° C,. and the desired product is isolated in free form or as an acid addition salt.
    The compounds of general formula I have activity in relation to the central nervous system, in particular by activeness as antidepressants,
    The activity of the compound as antidepressants was evaluated in mice by the ability of the compound to prevent reserpine 20 induced blepharospasm and hypothermia. Reserpine was administered intravenously at a dosage of 2.5 mg / kg, and test compounds were orally administered 30 minutes before administration of reserpine. An hour later, and then 25 hours later, four hours after administration of reserpine, registration was made of blepharospasm.
    The dosage of the compounds of the general formula I, for example 1H, 2.3 Over, 4-tetrahydro-2-carbamoylmethyl-imidazo, 1-e (t, i) benzoxazn-1-one and 1H, 2, 3, Za-4-tetrahydro-2- "arbamoylmethyl-8-chlorimidazo, 5,1-s (1.,) Benzoxazin-1-one, is preferably 20-50 mg per dose 2-4 times a day.
    Example 1. To a solution of 1H, 2,3, Za, 4-tetrahydroimidazo 5,1-e (1, Mbenoxoxazin-1-one (3.5 g, 1.85 40 10 mol) in dimethylformeshimnde (70 mp), 50% NaH (0.89 g, 1.85) are added. The solution is stirred for 1 hour at room TiM, and chlorine chlorides 44 (1.75 g, 1.85-102 mol) are dissolved, {Shy in dimethylformamide (20 mp). The mixture is stirred at room temperature for 20 hours, then poured into water and the mixture is extracted with the CHC). When evaporation to dry osTfTKa, 1H, 2,3,3a, 4 strap-2-k "(rbgi-4-methylmethyl-imidazo 5,1-s (%, L) benzoxazin-1-one (2.8 g, t. Pl. . 230-231 "C) .. JJ
    Similarly, the following compounds are obtained:
    1N, 2.3, Za, 4-Tetragonpo-2-methyl-imidazo 5,1-e (1,) beneoxazine-1-one, t. Pl. 135-136 C, 40
    1H, 2,3, Za, 4-Tetrahydro-2- (2-carbamrylate) -imidazo f 5.1 g-s (1.4) beneoxazin-1-one, so pl. 1b2-1b4s,
    1H, 2,3, Za, 4-Tetrahydro-2- (1-carbgsshoylstil) -imidazo 5; 1-cl. 45
    (1,4) benzoxazin-1-one, t. Pl, 203205 C,
    1H ,, Za, 4-Tetrahydro-2- (2-dimethylMonostil) -imidazo 5,1-c (1,4) benzoxazin-1-one, so pl. 180182 C (hydrochloride)
    1H, 2,3, Za, 4-tetrahydro-2- (3-dimethylaminopropyl) -imidazo 5.1-0 (1,4) benzoxazin-1-one, t, pl. 54570С,
    1H, 2,3, Za, 4-Tetrahydro-2-propargylimidazo 5,1-0 (1,4) benzocoazin-1-one, so pl. 113-115 C,
    1H, 2,3, Za, 4-Tetrahydro-2-carbamo-methyl-8-: lorimidazo 5,1-oa, 4 jOeH-co-azin-1-one, so pl. 214-216 ° C
    1H, 2.3 V Za, 4-Tötrapidpo-2-carbamoylmethyl-8-methylimidazo 5, 1-0 (1,4) benzocoazin-1-one, so pl. 235237С,
    1H, 2,3, Za, 4-Tetragipoo-2-kaobamoylmethyl-8-stoksimimidazo 5,1-o, (1,4) bsnzokoazin-1-one, so pl. 179181 ° C ..
    Example. 2. K 1H, 2,3, Za, 4-tetra-hydrohydroimidazo 5,1-c (1,4) benzoxazine (4 g, 2,) in anhydrous dimethyl 6 rmg 1 -mide (80 ml) is added with NaOH (0.05 g), after 30 min of ripti, ethyl acrylate (1.05 g, 2.1.10 mol) is added at room temperature. The mixture is kept at room temperature for 2 hours and for an additional 2 hours at, then poured into water, extraction is carried out with ethyl acetate, evaporated to dryness and the residue is hydrolyzed in methanol 2 and. KOH solution (100 ml) at room temperature for 12 hours. The residue is treated with water and the resulting solution is acidified with 8% HCE, followed by extraction of CH 2 C with drying over SOCI (5 MP) and the mixture is stirred overnight at room temperature. Chloroform is evaporated, the residue is twice toluene and twice evaporated to a dry residue, then taken again with an ethanolic solution, ammonia. The mixture is quenched at rest for 12 hours, ..a for-: after evaporation to dryness, crystallized from 95% ethanol to give 1H, 2.3, 3A, 4-tetrahydro-2- (2-carbamoylethyl) - Ymidazo 5,1-c (t, 4) benzoxazin-1-one (2,3), so pl. 162-1 € 4 pp.
    Example 3. To a solution of 2H-3,4-dihydro-2-phenyl-3-trifluoroacetyl 4-methyl-6-chloro (1, A) benzoxaznane (3.71 g, 0.01 mol) in anhydrous dimethyl-cetamide (50 ml) slowly 50% NaH was added (0.58 g / 0.01 mol with stirring at room temperature). After stirring for 30 minutes at room temperature, 1-chloro-3-dnmethylaminopropane (1.5 g) was added. Mixture heated in
    for 6 hours at, then poured into water and extracted with ethyl ether. After washing with water, it is evaporated to dryness, and the resulting oily product is dissolved in ethyl acetate. With psadc treatment mota-. HOJibHOti pse planted 2H-3,4-DIGIDRO-2-phenyl-3-to-trifluoroacetyl-N- (3-dimethylaminopropyl) aminomethyl-6-chloro- (1) -benzoxazine hydrochloride (3.2 g).
    Example 4. To a stirred solution cooled to 2H-3,4-dihydro: 3 aminomethyl- {1,) benoxazine (16.4 g, 0.1 mol) in SNLSSg (100 MTi) and (14 g, 0 , 15 mol), dropwise to {evolve a solution of trifluoro: acetic anhydride (21 g) in CHj, CE is kept for 1 h and then left to reach room temperature, after which the solution is washed with 5% NaHCO and water . Upon evaporation to dryness, 2H-3,4-dihydro-3-trifluoroacetalaminomethyl- (1,4) benzoxazine (18.1 g) is obtained.
    Froze To a solution of 1H, 2, 3, 4a, 4-tetrahydro-4-fenshmidazo 5, 1-c (1,4) ben-9oxazin-1-one (2.5 g, 0.01 mol) in anhydrous dimethyl acetamide (50 ml) 50% NaH (0.35 g, 0.11 mol) is added. With stirring, fiarpeBaiOT for 30 minutes at 50 ° C. Then the solution is brought to room temperature and chloroacetamide (0.95 g, 0.0105 mol) is added dropwise. Dissolved in anhydrous dimethylacetamide (10 mp. The mixture is heated for 1 hour at, drunk into water and extracted with ethyl acetate; Result stretching over the thief and concentrated. vevEestvo solid are obtained which, after crystallization iz.smesi dimvtilatsetaAosha and water constitutes 1H, 2, FS, Per, 4-tetrahydro-2-kapbamoilmeFiL fenilimidazo-4, l-cj (l, 4) beizoksazin- 1-he (1.5 g).
    Example 6. Starting from 1H, 2,3, Za, 4-tetrahydro-Za-phenylimidazo 5,1-e (1,4) benzxazin-1-one (2.66 g), and using the procedure of 4 procedures of example 1, crystallization .in the form of 99% ethyl alcohol, 1H, 2, .3, Zag4-tetrahydro-2-carbamoylmethyl-Ea-phenylimidazo {5,1-с1 {1,4) benzoxazin-1-oi (2.1 g of t Ш1. 207г-20 с).
    Similarly, 1H, 2,3, 3a, 4-tetrahydro-2- (2-kgfbamoylethyl) -a-phenyl-midazo), 1-c (1,4) be zgoxazin-1-one, m.p. 184-185 C. Example 7. With the implementation of the procedure of the example and starting from .1H, 2,3, Za, 4-tetrahydro-4,4-D1metshhimidazo 5,1-s (1,4) bisexases a (2.36 g , 2-DO mol), 1H, 2,3, Za, 4-tetraparido-2-karbmoMoyl methyl-4,4-dimethylI “Dazo 5., 1-with C1,4) benzoxazine T2.3 g) are obtained.
    . Similarly, 1H, 2, -3.3a, 4-tetrahydro-2-methyl-4, 4-dimethylimidazo, 5,1-cJ (1,4) beta lsazine, m.p. 180-18J C.
    Example 8. To a solution of 1H, 2,3, Over, 4, -tetrahydroimidazo fj, lc (1, 4) benzothiazin-1-one (2.0b g, li) in anhydrous dimethylforma de (50 ml) with stirring 50% NaH (0.55 g, 1.1 10 mol), and the mixture. heated at
    o within 30 minutes The temperature is then brought to room temperature and chloroacetamide (O, 95g, 1.05.) Dissolved in anhydrous dimethylacetamide (10 ml) is added dropwise. 1
    5 The mixture is heated at 60 ° C for 1 h, poured into water and extracted with ethyl acetate. The extracts are dried over, filtered, and concentrated to give, after crystallisation.
    0 from a mixture of chloroform and methanol 1H, 2,3,3.a, 4-tetrahydro-2-carboyl-methyl methyl imidazo 5,1-e1 (1,4) benzthiazium-1-one (1.55 g), t. Pl. 235-240 0.
    Similarly, receive 1H, 2,3, Over, 4-tetrahydro-2-gmetilimidazo 5, Irc
    5 (1.4) benzothiazin-1-one, t. Pl. 155156 S.
    Example 9. To a solution of 1, 2,3,4,4a, 5tex agidro-1-phenyl pyrazo {2, 1-s3 (1,4) benzoxazine (2.7 g,
    0) Chloroacetamide (1.12 g, 1.2-DO mol) is added to dimethyl form schide containing excess potassium carbonate. The solution is kept for 8 hours, then poured into water.
    5 and extracted several times with ethyl. ether, the extracts are dried and evaporated to dryness and the resulting product is crystallized from ethyl alcohol. Get 1,2,3,4,
    0 4a, 5-hexahydro-3-carbamoylmethyl-1-feiylpyrazo 2,1-e (1,4) benzoxazine 12.1 g), t. Pl. 200-201 0.
    L, 2, 3, 4, 4a, 5-i-hexagidu-3-methyl-1-phenylpyrazo G2,1-c (1,4) beisoxazine, so-called. 126S.
    Example 10. Starting from 1 2,3,4,4а, 5-hexahydro-1-feiylpyra 30 12,1-с1 (1,4) beisoxazin-2-one
    O (2.85 g, 1: 1 (D mol), and using nptmepa 1, after crystallization from methanol, 1,2,3,4,4a, 5-hexahydro-1-phenyl-3-utilpyraz6 {2, 1-c (1, 1 |) benzox S ZIN-2-OI 2.3 g), t. Pl. 189-192 C.
    Example 11. Starting from 1.2 g3, 4.4a, 5-hexahydropyrazo 2,1-e (1,4) beisoisaziv-2-ph, t. Pl. 245248®С (4.1 g, 2-D mol) and used /
    According to the method of Example 1, 1,2,3,4,4а, 5-hexahydro-3-carbamoylmethylpyrazo t2, l-cj (1,4) benzoxazin-2-oi (3.0 g) are obtained, m.p. 230-232 C.
    权利要求:
    Claims (2)
    [1]
    1,2,3,4,4a, 5-hexahydro-2- (3-dimethylaminopro-5) -pyrazo 2 1-c (1,4) benzoxaen-2-one, m.p. SE-IO C. Example 12. Solid 1H, 2.3, Za, 4-tetrahydro-2- (3-dimethyl aminopropyl) -4-phenyl-8-chlorimidazo G5,1-c3 (1,4) benzoxazin-1 - he TT. square 38-50 C, 18 g), obtained from 1H 2,3, Za, 4-tetrahydro-4-phenyl-87-chloroimidazo 5,1-c (1,4) benzoxazn-1-oaa and 3-dimethylaminopropyl chloride according to the method according to example 1, it is dissolved in ethanol (300 ml), after which a 7% ethanolic solution of HCt is added to the solution. After evaporation of the mixture to dryness and recrystallization from a mixture of dimethylacetamide and water, they are obtained. 1H, 2,3, Ze 4-tetrahydro-2- (3-dimethylgilinopropyl) -4-fvnil-8-hl6rimidazo 5,1-e} (1,4) -1-oi hydrochloride (t. Pl. 195-215 C, 28.5 g). Claims of Invention I A method for the preparation of cyclic derivatives of 1,4-benzoxoxine or 1,4-benzthiazine of the general formula. HCH Wi where R is, hydrogen or lower alkyl carbon, hydrogen, lower alkyl or phenyl; R is a hydrogen atom or phenyl; R is lower alkyl, lower alkyl, carbamoyl (lower) alkyl or (lower) dialkyl but no (lower) alkyl; R. is a hydrogen atom, a halogen atom, a lower or a lower alkoxy radical; B is an oxygen atom or Cetzc, A-methyl, the group, -CH-CHj, -CH-C-, -CH „-C-or-C-CHН1 I II 2 and Cfc O O O or their acidic additive salts, characterized in that the compound of the general formula L — H — H — R5 where A, B, R are of the specified & e values, is reacted with the compound of the general formula W. (Ill) where Cd is uqa & nte higher than the value of i; - a halogen atom or a residue of a reactive ester or alcohol, in an organic solvent medium with S-1SO c texture, and the target product is isolated in free form or as an acid addition salt. Sources of information taken into account during the examination 1.Mgishsovsky MD Medicines. M., Medicine, t. 1, p. 140.
    [2]
    2. Byuler K. and Pearson D. Organic syntheses. M., Mir, 1973, p. 1, p. 504.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU812181A3|1981-03-07|Method of preparing cyclic derivatives of 1,4-benzoxazine or their acid-additive salts
    RU2049771C1|1995-12-10|Quinone derivatives and their pharmacologically acceptable salts
    PL190034B1|2005-10-31|Novel heterocyclic derivatives and their pharmaceutic application
    CH633796A5|1982-12-31|THERAPEUTICALLY ACTIVE DIPYRIDOINDOLES.
    US4818772A|1989-04-04|Derivatives of 4-aminoethoxy-5-isopropyl-2-methylbenzenes: methods of synthesis and utilization as medicines
    SU1342415A3|1987-09-30|Method of producing derivatives of pyridazine
    US4291039A|1981-09-22|Tetrahydro β-carbolines having anti-hypertensive activity
    JP2931986B2|1999-08-09|Aralkylamine derivatives
    PT874849E|2002-01-30|2,7-SUBSTITUTED OCTA-HYDRO-PYRROLE-1,2-A | PYRAZINE DERIVATIVES
    US4176194A|1979-11-27|Oxyalkanoic acid derivatives
    SU1364623A1|1988-01-07|5,10-dihydro-11h-dibenzo-|-diazepine-11-ons substituted in position 5 or their physiologically compatible salts with inorganic or organic acids showing antiulcerous and secretion-suppressing activity
    US3923996A|1975-12-02|3-Substituted-oxindoles in compositions and methods of treating obesity
    Webb1953|The Chemistry of Bipyrryls. II. The Preparation and Resolution of A 1, 1'-Disubstituted 2, 2'-Bipyrryl Exhibiting Restricted Rotation
    FI63578C|1983-07-11|ANALOGIFICATION OF THE PHARMACOLOGICAL COMPARTMENT 1,3,4,14B-TETRAHYDRO-2H-10H-PYRAZINO | PYRROLO | | BENZODIAZEPINE
    US4563477A|1986-01-07|Process for the preparation of alpha-|-derivative acids, the salts and esters thereof; alpha-|-phenylacetic acids, the esters thereof, pharmaceutical compositions containing them and therapeutical applications thereof
    PT77133B|1986-01-24|PROCESS FOR THE PREPARATION OF 1,3-DYOXOLE <4,5-G> QUINOLINES
    US4104385A|1978-08-01|Cyclic alkylidenyl N-[6-|-3-pyridazinyl]aminomethylenemalonates
    Kupchan et al.1967|Drug Latentiation. III. 1 Labile Amide Derivatives of Normeperidine
    US3637804A|1972-01-25|Phenylalanine derivatives and preparation thereof
    US3567716A|1971-03-02|1,8-naphthyridine derivatives and intermediates thereof
    US3758546A|1973-09-11|Methoxy amine derivatives and process for preparing them
    US4259332A|1981-03-31|Novel taurine derivatives
    SU1039445A3|1983-08-30|Process for preparing derivatives of cyclophosphathiazene
    US3317544A|1967-05-02|3-tropinyl esters of substituted acrylic and thio acrylic acids
    US3983156A|1976-09-28|Substituted ω-nitroacetophenones
    同族专利:
    公开号 | 公开日
    IT1052009B|1981-06-20|
    JPS5283397A|1977-07-12|
    CA1099267A|1981-04-14|
    CH630383A5|1982-06-15|
    NZ182952A|1980-05-08|
    NO150882B|1984-09-24|
    FI61902B|1982-06-30|
    CS197301B2|1980-04-30|
    FI61902C|1982-10-11|
    IL51091D0|1977-02-28|
    GB1533020A|1978-11-22|
    AT351041B|1979-07-10|
    AU504565B2|1979-10-18|
    BE849919A|1977-04-15|
    DK587476A|1977-07-01|
    ZA767588B|1977-11-30|
    FR2336929A1|1977-07-29|
    NL7614445A|1977-07-04|
    AU2086376A|1978-06-29|
    IL51091A|1984-01-31|
    NO150882C|1985-01-09|
    SE7613778L|1977-07-01|
    ATA985776A|1978-12-15|
    NO764395L|1977-07-01|
    US4134974A|1979-01-16|
    HU176510B|1981-03-28|
    FR2336929B1|1980-04-18|
    DE2658806A1|1977-07-14|
    FI763752A|1977-07-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3929783A|1974-12-06|1975-12-30|Squibb & Sons Inc|1-Substituted-4-phenyl-4H-{8 1,2,4{9 triazolo{8 3,4-C{9 {8 1,4{9 {0 benzothiazines or benzoxazines|
    US4035495A|1975-02-10|1977-07-12|Ayerst Mckenna And Harrison Ltd.|Pyrrolobenzoxazines, pyrrolobenzothiazines and process therefor|US4049422A|1976-03-29|1977-09-20|United States Borax & Chemical Corporation|Herbicidal morpholinobenzimidazoles|
    SE444319B|1977-11-18|1986-04-07|Roussel Uclaf|NEW IMIDAZOBENOXAZINE DERIVATIVES, PROCEDURES FOR PREPARING THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE ASSOCIATIONS|
    US4254118A|1979-08-13|1981-03-03|Ayerst, Mckenna & Harrison Inc.|1-Oxo-5H-pyrimido[2,1-c][1,4]benzthiazine-2-carboxylic acid esters|
    US4254121A|1979-08-13|1981-03-03|Ayerst, Mckenna & Harrison Inc.|3-Oxo-5H-pyrimido[2,1-c][1,4 ]benzoxazines|
    US5166343A|1988-02-05|1992-11-24|Riker Laboratories, Inc.|Triazolo[1,5-c]pyrimido[1,4]-azines as bronchodilators|
    US5089493A|1988-02-05|1992-02-18|Riker Laboratories, Inc.|Triazolo[1,5-C]pyrimido[1,4]azines as bronchodilators|
    PT625982E|1992-02-13|2002-10-31|Upjohn Co|4-OXO- AND 4H-IMIDAZO UZIDE BENZOXAZINS AS BINDING AGENTS TO BENZODIAZEPINE RECEPTOR|
    GB9212486D0|1992-06-12|1992-07-22|Erba Carlo Spa|Derivatives of substituted imidazo benzoxazin-1-one and process for their preparation|
    US5512566A|1993-10-25|1996-04-30|Ortho Pharmaceutical Corporation|Tricyclic compounds having affinity for the 5-HT1A receptor|
    GB9410469D0|1994-05-25|1994-07-13|Erba Farmitalia|Imidazolylalkyl derivatives of imidazo benzoxazin-1-one and process for their preparation|
    AU4547796A|1995-02-03|1996-08-21|Sankyo Company Limited|Hexahydropyrazinoquinoline derivatives|
    MX2008009475A|2006-01-23|2008-10-20|Amira Pharmaceuticals Inc|Tricyclic inhibitors of 5-lipoxygenase.|
    WO2014089904A1|2012-12-10|2014-06-19|Abbvie Inc.|Triazinone compounds|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT30829/75A|IT1052009B|1975-12-30|1975-12-30|IMIDAZO 4.3 C 1.4 BENZOSSAZINO IMIDAZO 4.3 C 1.4 BENZOTIAZINO PIRAZO 2.1 C 1.4 BENZOSSAZINO AND PIRAZO 2.1 C 1.4 BENZOTIAZINO DERIVATIVES|
    [返回顶部]