• 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:
    1. METHOD FOR OBTAINING PYRIDAZIN DERIVATED DERIVATIVES OF GENERAL FORMULA (I) where X is hydrogen, lower alkoxyl or OH group; R is hydrogen, phenyl group; A is an alkylene group with a straight or branched chain containing from 2 to 5 carbon atoms. differs in that 3-chloropyridazine of formula (II) where R and X have the indicated meanings and the available hydroxyl groups are protected as (lower) alkyloxy groups, O) are treated with an amine of formula (III) 3 HzN-A where R, X and A have the indicated value, in an organic solvent, such as alcohol, at the boiling point of the solvent and, if necessary, per 100. shield groups are removed. 2. Method POP.1, characterized in that the process is carried out in the presence of an acceptor of hydrohalic acid — an excess of an amine of formula (III).
    公开号:SU1140685A3
    申请号:SU823476698
    申请日:1982-08-06
    公开日:1985-02-15
    发明作者:Кан Жан-Поль；Бизьер Катлин；Вермут Камиль-Жорж
    申请人:Санофи (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new substituted pyridazine derivatives of the general formula: (3 inl), where X is hydrogen, lower alkoxy or OH group; hydrogen, phenyl group-; straight or branched chain alkylene group; containing from 2 to 5 carbon atoms with valuable pharmacological properties. . Known derivatives of pyridazine of formula 1 - USHR2 - (fu) where R - is hydrogen or a lower alkyl group-, h RJ - group - (CH,) (n 2 or 3, V-2 or a lower alkyl group M -heterocyclic radical), Ar - aromatic residue with psychostimulating action l j. The study of compound (1a), where, and Rr-CKjCHj-N O, Ar is phenyl (minarin), showed that the pharmacological activity of minaprine is characterized by the mechanism of noradrenergic, dopaminergic and serotonergic effects. The purpose of the invention is the preparation of novel substituted pyridazine derivatives. The objective is achieved by the proposed method of producing substituted pyridazine derivatives of general formula (I), based on the method of interaction of halogen derivatives with amino compounds, in some cases in the presence of L2j bases, and concluding that 3-chloropyridazine of formula. where R, X have the indicated meanings, and the existing hydroxyl groups are protected as a (lower) alkyloxy group, treated with an amine of the formula 3 HzN-A where R, X and A have the indicated meanings in an organic solvent, such a kick alcohol, at the boiling point of the solvent and if necessary, protecting groups are removed. The process is preferably carried out in the presence of an acceptor of hydrohalic acid — an excess of the amine of formula (III). Example 1. 3- (2-Morpholinoethylamino) -phenyl-pyridazine-hydrochloride () - CM 30 364 „Mixture of 8 g H-chloro-5-phenyl-pyridazine and 10 g of 2-mor (} 1Olino-ethylamine and HE The MP of butanol is refluxed for 12 hours. The solution is heated to 200 l of water, the precipitate is filtered off and washed with a small amount of ether. The aqueous phase is separated and extracted with ether. The ether phases are combined and extracted with 1N sulfuric acid solution The aqueous solution is made alkaline by adding 10% sodium carbonate solution. After a night, the solid is sucked off , it is recrystallized from isopropanol diisopropyl ether. Calculated: C 53.81j H 6.16; N 15.69. Found: C 53.82; H 6.02; N 15.60. 121 ° C. Dichlorohydrate: 5.5 ml of concentrated hydrochloric acid is added to a solution of 8 g in 50 ml of isopropanol.The crystals are filtered off with suction and recrystallized from isopropanol, mp 250 ° C. Example 1, but the original chlorinated derivative is changed / or used amine, get the products (I), are presented in table.1.
    Table 1
    CM 30 338 CM 30 365 SR 95 001 SR 95 003
    Example 2. 3- (2-Morpholino-ethylamine) -4- (4-hydroxy-phenyl) -pyridazine-dibromohydrate (SR 95050.
    a) 3- (2-Morpholino-ethylamino) -4- (4-methoxy-phenyl) -pyridazine.
    Follow the procedure of Example 1, starting from 3-chloro-4- (4-methoxy-phenyl) -pyridazium.
    The resulting crude product is used for the next step (step). Calculated,%: C 41.57 EI 4.79;
    N 12.12.
    Found,%: C 41.48; H 4.89; N 12.00.
    b) SR-95050. For 6 h, boil with reverse
    refrigerator, a solution of 15 g of the obtained product in 150 ml of a 2: 1 mixture of 48% hydrobromic acid and acetic acid. Expel dry. A brownish oil remains which crystallizes in the ethanol-ether mixture. After recrystallization from water
    Tanola dibromohydrate melts at.
    Elemental analysis.
    SM 30 338:
    Calculated,%: C 60.97; H 6.05;
    N 12.93. Found,%: C 60.89; H 6.16;
    N 12.91. CM 30 365: Calculated,%: C 61.00; H 6.00;
    N 12.93. Found,%: C 60.85; H 5.95;
    N 12.86.
    SP 95 011: (with O, 5 molecules of water of crystallization) Calculated,%: C 52.46; H 6.32 N 15.29. Found,%: C 52.61; H 6.17;
    N 14.95.
    SR 95 003 (with 0.1 molecule of water of crystallization) Calculated,%: C 50.37; H 6.46;
    N 13.82.
    Found,%: C 50.54; H 6.63; N 14.02. Basis: 98 / -iij ЛЧ1 Urlrt L.n2 (diisopropyl ether) dichlorohydrate 214 (isopropanol) Basis: 15A chromate-CHjCHj graph, (dihydrochloride), (isopropanol) Dichlorohydrate (1/2 H20), 202 (isopropanol) Dichlorhydride ) -OCHj-CHy-CHj Compounds (I) can be converted to salts by exposing the acid to a hot base solution, and the choice of solvent provides for the crystallization of the salt upon cooling. The 3-chloro-pyridazines used as starting materials are obtained from the corresponding 3-2H-pyridazones by exposure to an excess of phosphorus oxychloride. The production of 3-2H-pyridazones by the action of hydrazine on keto acids or their active derivatives is known. New 4- (or 5 -) - phenyl-3-amino-pyridazines and their salts antagonize reserpine-induced ptosis, which indicates noradrenergic activity, they are inert in the test of reaction of the source and in the test of movement in a circle, indicating a lack of dopaminergic effect. The test for antagonism to ptosis caused by reserpine is implemented on a female CDI mouse (Charles River) weighing 2011. Reserpine causes ptosis after 1 hour. After its intravenous injection, some antidepressants counteract this ptosis, which indicates the presence of a noradrenergic effect. The test substances are administered intraperitoneally. Reserpine is simultaneously administered intravenously at a dose of 2 mg / kgf 1 h after administration of reserpine, the number of animals that do not have ptosis is noted. This test is carried out on batches of 10 mice each, the results of the percentage of animals not having ptosis, and taking an average of at least two experiments. I The reaction test is carried out on a CDI (Charles River) female mouse weighing 18-23g according to the Rogsolt method. A mouse placed in a narrow vessel (chamber) filled with water flounders, then after 2-4 minutes it becomes stationary, floats on the abdomen with a curved back and hind legs under the body and makes only a few movements necessary to support the head out of the water . This reaction is called the reaction of despair, which indicates the mechanism of exposure to the dopaminergic type. Some dopaminergic psychotropic drugs lengthen the time during which the mouse flounders. The test products are administered intraperitoneally, 1 hour before the test. For this test, animals are placed in a narrow chamber, a vessel of 10-10-10 cm, filled with water, up to a height of 6 cm, and the water temperature is 24i2 ° C. The animals are left for 6 minutes in water and the time from which the animal remains stationary is measured between the 2nd and 6-1 minutes. The shorter the time, the more active the substance. Each substance is examined in batches of 10 mice. Results are an average of at least two experiments. The dopaminomimetic activity of the products of the invention has also been studied at mouse dopaminergic receptor receptors according to a circular motion test. Unilateral lesion (disease) dopaminergic nigropolosatyh. neurons lead to increased sensitivity of dopamine receptors at the Striaturn level. The asymmetry that occurs as a result of this is found in the rotation of the animal in the counter-side towards the most intensely stimulated receptors. After the test products were injected intraperitoneally for 2 minutes, the number of revolutions was counted, and there are still a few live. Changes relative to the control group that did not receive the test product are expressed as a percentage. Table 2 shows the comparative results obtained in the three tests described for 3- (2-morpholino-ethylamino) -5-phenyl-pyridazine hydrochloride (CM 30 364) and for minaprine as a standard product.
    63
    350
    ten
    5 (4-7)
    6 (5-8)
    15
    10 mg / kg:
    Inactive 35% 20
    Inactive 91%
    From Table 2 it follows that the product released according to the invention possesses the antidepressant activity of the noradrenergic type of the same order as the standard compound, causes a slight toxicity and is devoid of the activity of the dopaminergic type.
    权利要求:
    Claims (2)
    [1]
    1. METHOD FOR PRODUCING SUBSTITUTED PYRIDAZINE DERIVATIVES of General Formula (I) characterized in that
    3-chloropyridazine of the formula (II)
    NN where R and X have the indicated meanings and the available hydroxyl groups are protected as a (lower) alkyloxy group, treated with an amine of formula (III) 'h 2 na where X is hydrogen, lower alkoxy or OH group; >
    R is hydrogen, phenyl group;
    A is a straight or branched chain alkylene group containing from 2 to 5 carbon atoms, where R, X and A are as defined in an organic solvent, such as alcohol, at the boiling point of the solvent and, if necessary, the protective groups are removed.
    [2]
    2. The method according to claim 1, characterized in that the process is carried out in the presence of an acceptor of hydrohalic acid - an excess of the amine of the formula (III).
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1140685A3|1985-02-15|Method of obtaining pyradizine substituted derivatives
    US4721711A|1988-01-26|Pyridazine derivatives active on the central nervous system, and medicaments in which they are present
    JP2002047288A|2002-02-12|Substituted thiazolidinedione derivative
    US4234584A|1980-11-18|Substituted phenylpiperazine derivatives
    SU1274623A3|1986-11-30|Method of producing 4-cyanopyridazines or pharmaceutically compatible salts thereof
    KR880002710B1|1988-12-26|Preparing method for 4-methyl 6-phenyl pyridazine
    KR840001965B1|1984-10-26|Process for the preparation of anthracene-9,10-bis-carbonyl-hydrazones derivatives
    HU189608B|1986-07-28|Process for producing pyridazine derivatives
    FR2539741A1|1984-07-27|DIAZOTE HETEROCYCLIC CORE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS ACTIVE ON THE CENTRAL NERVOUS SYSTEM CONTAINING THE SAME
    US3141019A|1964-07-14|Chaohj
    US4540696A|1985-09-10|1-Piperazinyl 4-phenylquinazoline compounds having antidepressant properties and drugs containing same
    US4367239A|1983-01-04|Nitrosourea derivatives, pharmaceutical compositions thereof and method of preparation
    US4384140A|1983-05-17|2-Chloroethyl urea derivatives
    US2723269A|1955-11-08|Piperidino tertiary amino alcohols
    PT89992B|1994-05-31|PROCESS FOR THE PREPARATION OF DERIVATIVES AND ISOMERS OF 4,5,6,7-TETRAHYDROISOTIAZOLE | PYRIDINE
    EP0073345A2|1983-03-09|Sydnonimine derivatives, process for production thereof, and use thereof
    CA1142183A|1983-03-01|Nitrosourea derivatives, pharmaceuticalcompositions thereof and method ofpreparation
    FR2530632A1|1984-01-27|NOVEL SUBSTITUTED 2,5-DIAMINO 1,4-DIAZOLE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
    FR2539739A1|1984-07-27|New naphthylpyridazine derivatives active on the central nervous system, process for the preparation of these derivatives and medicaments containing them
    DK149531B|1986-07-14|Analogy process for preparing 3-|ethylamino)-4-methyl-6-phenylpyridazine derivatives or pharmaceutically acceptable acid addition salts thereof
    CH447171A|1967-11-30|Process for the preparation of novel derivatives of 5-amino-methyl-4,5,6,7-tetrahydro-4-oxo-indole
    同族专利:
    公开号 | 公开日
    IE821778L|1983-02-07|
    PL137199B1|1986-05-31|
    CA1174240A|1984-09-11|
    AT12227T|1985-04-15|
    PH18545A|1985-08-09|
    ES514794A0|1983-04-16|
    AU8655382A|1983-02-10|
    CS229940B2|1984-07-16|
    IE53388B1|1988-10-26|
    OA07176A|1984-04-30|
    IE53387B1|1988-10-26|
    DE3269383D1|1986-04-03|
    EG15788A|1986-09-30|
    EP0072726A1|1983-02-23|
    IL66409D0|1982-11-30|
    MA19562A1|1983-04-01|
    IL66409A|1985-09-29|
    EP0074863B1|1986-02-26|
    KR840001145A|1984-03-28|
    DK354482A|1983-02-08|
    EP0072726B1|1985-03-20|
    DK148795B|1985-09-30|
    FI72969C|1987-08-10|
    US4508720A|1985-04-02|
    KR880001624B1|1988-09-02|
    KR840001159A|1984-03-28|
    NO157861B|1988-02-22|
    EP0074863A1|1983-03-23|
    ES8305737A1|1983-04-16|
    AR231637A1|1985-01-31|
    DK148795C|1986-03-10|
    ES514795A0|1983-04-16|
    DK354382A|1983-02-08|
    NO157102B|1987-10-12|
    ZA825513B|1983-06-29|
    CA1179346A|1984-12-11|
    JPH0459312B2|1992-09-21|
    PT75350B|1984-08-01|
    FR2510998B1|1986-01-10|
    IE821779L|1983-02-07|
    AU8655482A|1983-02-10|
    IL66408D0|1982-11-30|
    DK148537C|1986-01-13|
    DD202715A5|1983-09-28|
    NO822509L|1983-02-08|
    NZ201520A|1985-04-30|
    SU1138024A3|1985-01-30|
    JPS5877868A|1983-05-11|
    NO157102C|1988-01-20|
    ZA825512B|1983-06-29|
    AU548931B2|1986-01-09|
    PL130647B1|1984-08-31|
    HU189166B|1986-06-30|
    PT75351B|1984-08-01|
    NO157861C|1988-06-01|
    GR76429B|1984-08-10|
    FI72968C|1987-08-10|
    NZ201518A|1985-04-30|
    DE3262671D1|1985-04-25|
    AU548930B2|1986-01-09|
    KR890001569B1|1989-05-08|
    MA19560A1|1983-04-01|
    GR76430B|1984-08-10|
    PL237808A1|1983-02-28|
    FR2510998A1|1983-02-11|
    FI822748L|1983-02-08|
    FI822747A0|1982-08-06|
    FI72969B|1987-04-30|
    FI822747L|1983-02-08|
    PL237809A1|1983-02-28|
    PT75351A|1982-08-01|
    IL66408A|1985-12-31|
    AT18216T|1986-03-15|
    YU172082A|1985-03-20|
    FI72968B|1987-04-30|
    NO822510L|1983-02-08|
    ES8305738A1|1983-04-16|
    EG15747A|1986-06-30|
    YU171882A|1985-03-20|
    DD202549A5|1983-09-21|
    JPS5877867A|1983-05-11|
    AR231441A1|1984-11-30|
    DK148537B|1985-07-29|
    OA07175A|1984-04-30|
    HU190028B|1986-08-28|
    CS229941B2|1984-07-16|
    PT75350A|1982-08-01|
    FI822748A0|1982-08-06|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1345880A|1971-06-18|1974-02-06|Cepbepe|Pyridazine derivatives|FR2540113B1|1983-01-27|1985-05-17|Sanofi Sa|
    US4565814A|1983-01-28|1986-01-21|Sanofi|Pyridazine derivatives having a psychotropic action and compositions|
    US4628088A|1984-07-17|1986-12-09|Eli Lilly And Company|Preparation of substituted pyridazines|
    DE3664772D1|1985-01-14|1989-09-07|Boehringer Ingelheim Kg|12-amino pyridazinoû4',5':3,4¨pyrroloû2,1-a¨isoquinolines, process for their preparation and use|
    PT93060B|1989-02-07|1995-12-29|Sanofi Sa|METHOD FOR OBTAINING PYRIDAZINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    US5461053A|1989-02-07|1995-10-24|Sanofi|Pyridazine derivatives|
    FR2642648B1|1989-02-07|1991-06-21|Sanofi Sa|USE OF ALKYL-5 PYRIDAZINE DERIVATIVES AS ACTIVE MEDICAMENTS ON THE CHOLINERGIC SYSTEM|
    FR2642754B1|1989-02-07|1991-05-24|Sanofi Sa|NOVEL PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|
    US5631255A|1989-02-07|1997-05-20|Sanofi|Pyridazine derivatives|
    FR2663326B2|1989-11-17|1992-10-16|Sanofi Sa|PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.|
    FR2654727B1|1989-11-17|1992-03-27|Sanofi Sa|PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.|
    FR2665442B1|1990-07-31|1992-12-04|Sanofi Sa|ALKYL-6 PYRIDAZINE DERIVATIVES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.|
    FR2676444B1|1991-05-16|1995-03-10|Sanofi Elf|NOVEL AMINO-3 PYRIDAZINE DERIVATIVES ACTIVE IN THE CENTRAL NERVOUS SYSTEM, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.|
    US20100210590A1|1995-09-27|2010-08-19|Northwestern University|Compositions and treatments for seizure-related disorders|
    US20030176437A1|2001-08-31|2003-09-18|D.M. Watterson|Anti-inflammatory and protein kinase inhibitor compositions and related methods for downregulation of detrimental cellular responses and inhibition of cell death|
    AT420867T|2002-08-13|2009-01-15|Merck Sharp & Dohme|PHENYLPYRIDAZINE DERIVATIVE AS LIGANDS FOR GABA RECEPTORS|
    JP2008518955A|2004-11-02|2008-06-05|ノースウェスタンユニバーシティ|Pyridazine compounds and methods|
    ES2543813T3|2004-11-02|2015-08-24|Northwestern University|Pyridazine compounds for the treatment of inflammatory diseases|
    US20100168120A1|2006-04-28|2010-07-01|Neuromedix Inc.|Salts of pyridazine compounds|
    EP2063894B1|2006-04-28|2019-08-28|Northwestern University|Formulations containing pyridazine compounds for treating neuroinflammatory diseases|
    WO2007127474A2|2006-04-28|2007-11-08|Northwestern University|Compositions and treatments using pyridazine compounds and cholinesterase inhibitors|
    RU2555969C1|2014-07-09|2015-07-10|Юлия Алексеевна Щепочкина|Ceramic mass for production of facing tile|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8115380A|FR2510998B1|1981-08-07|1981-08-07|NOVEL AMINO DERIVATIVES OF PYRIDAZINE, PROCESS FOR THEIR PREPARATION AND DRINKING ACTS THEREOF|
    [返回顶部]