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    • 专利摘要:
    The invention relates to tricyclic pyridone derivatives, in particular the preparation of compounds of the general formula I @ where R A is phenyl, halophenyl R B and R C together with α-carbon form an unsubstituted or substituted by halogen, lower alkyl or NO 2 group of the formula: a) Σ @ -S-CH = CH-, b) Σ @ -CH = CH-S-, c) Σ @ -CH = CH-CH = CH- R D - - (AO) m -C (O) -NR 3 R 4 when M = 0 or 1, A - lower alkylene and R 3 and R 4 - H, lower alkyl or alkoxyalkyl NR 3 R 4 - 3-7-membered nitrogen heterocycle, which may be substituted by OH, lower alkyl, alkoxy, oxyalkyl or alkoxyalkyl (it may contain an oxygen atom) R E - H, lower alkyl, alconoyl, aryl lower alkyl R F - H, lower alkyl, with muscle relaxant, sedative-hypothetical, anxiolytic and / or anticonvulsant action. The goal is to create new substances of the specified class with activity that is uncharacteristic for it. The synthesis includes a) reduction of a compound of formula I without a substituent R E with an alkali metal borohydride or its derivative in the presence or absence of formic acid, b) alkylation or acylation with R E -X, where X is a leaving group, R b -R E , but without hydrogen, or c) reacting a compound of formula I, where R D is (A) M -OH, with a reaction derivative of an acid of formula R 3 R 4 -NC (O) -OH, d) isolating the desired product in its free form. New substances can be used to treat convulsions and states of fear, their toxicity LD 50 3000 - 5000 mg / kg, effective dose ED 50 to 18.4 mg / kg. 1 tab.
    公开号:SU1598879A3
    申请号:SU884355854
    申请日:1988-06-03
    公开日:1990-10-07
    发明作者:Видмер Улрих
    申请人:Ф.Хоффманн-Ля Рош Унд Ко.Аг (Фирма)；
    IPC主号:
    专利说明:

    (21) 4355854 / 23-04
    (22) 03/06/88
    (31) 2206/87; 1297/88
    (32) 06/12/87; 08: 04.88
    (33) CH
    (6) 10/07/90. Bul Number 37
    (71) F.Hoffmann-L Rosh und Co., AG (SI)
    (72) Ulrich Widmer (CH) (53) 547.852.7.07 (088.8)
    ; L. - C 07 P 495/14, lI i.85.
    ™ i, ss3 ™ s; if
    (57) The invention relates to tricyclic pyridone derivatives, in particular the preparation of compounds of general f-ly
    Rd Yas
    Re
    where RO is phenyl, halo-phenyl; R and R, together with the carbon, form an unsubstituted or substituted by halogen, lower alkyl or NOj group f-ly-. A), b) C CH CH-S-, c) CH CH CH-CH-; (AO) -CCU; O
    -NRjR at or 1, A is lower alkylene and R3R-n, lower alkyl or alkoxyalkyl; - 3-7-membered azo-heteropicl, which may be substituted by OH, lower alkyl, alkoxy, oxyalkyl or alkoxyalkyl (it may contain an oxygen atom); Rg — H, lower alkyl, alkanoyl, aryl-lower alkyl; Rf - H, lower alkyl, with miorelaksiruyu1 shm, sedative-hypnotic, anxiolytic and / or anticonvulsant action. The goal is to create new substances of the specified class with activity that is uncharacteristic for it. The synthesis includes a) reduction of the compound f-ly I without a Re substituent with an alkali metal borohydride or its derivative in the presence or absence of formic acid,
    b) alkylation or acylation with Re-X, where X is a cleavable group, but without hydrogen, or
    c) interaction of the compound f-ly I, where R o1 - (A) -OH, with the reaction derivative of the acid f-ly (0) -OI,
    d) vyde. the desired product in free form. New substances can be used to treat convulsions and states of fear, their toxicity is DC 3000–5000 mg / kg, effective dose is up to 18.4 mg / kg. 1 tab.
    i
    CO SG
    Sd
    CO 00 00

    about
    The invention relates to a method for the preparation of new tricyclic pyridone derivatives, which have a value of 1-1, pharmacological properties, in particular, muscle relaxant, sedative-hypnotic, anxiolytic: and / or anticonvulsant action.
    The purpose of the invention is to obtain new tricyclic pyridone derivatives, manifest miorelaxing, sedative-hypnotic, anxiolytic and anticonvulsant: an action that is not typical for compounds of an analogous structure.

    CM
    31598
    Examples of the synthesis of the starting compounds.
    Example 1. 13.9 g of 7-nitro-1- (2H) -phthalazinone and 16.3 g of the reagent according to Lawson in 170 np of acetonitrile are heated under reflux for 45 minutes. The reaction mixture is filtered hot. The resulting filtrate is cooled in an ice bath and the resulting crystals are aspirated. After drying in vacuum and recrystallization, 7-nitro-1 (2H) -phthalazine thione is obtained in the form of yellow crystals, m.p. 233-234 C (from a mixture of methanol and acetonitrile).
    EXAMPLE 2. A. 66.95 g of thieno G2,3-dZpiridazin-7 (6H) -thione are suspended in 3200 MP of methylene chloride in an argon atmosphere, and then 102.7 g of anhydrous chloride is added dropwise (/ -bromophenylacetic acid. This mixture is stirred at room temperature for about 30 minutes, then 121 ml of triethylamine is added dropwise, cooled to 25 ° C. The mixture is stirred for approximately 40 minutes. After the solvent is added in vacuum, the residue is poured in 1000 ml of water and 200 ml of diethyl ether, and then stirred for about 30 minutes. The deposited crystals are sucked off, washed with water and diethyl ether and dried overnight.The dried crystals are again mixed with 100 ml of water.After suction, the red-violet crystals are washed with water and dried under vacuum.The 3-hydroxy-2-phenylthiazolo hydroxide 3, no2,3-dJ pyridazine-4 is obtained -and (internal salt), mp 260-264 0 (with decomposition).
    B. In a similar manner, 7-ChLOR-1 (2H) -phthalazine-thione and chlorine anhydride with o / -bromophenylacetic acid are obtained after recrystallization of 9-chloro-3-hydroxy-2-phenylthiazolo hydroxide (2,3-a ) phthalazin-4-and (internal salt with so pl. 296-298 0 (from chloroform).
    . From 4-methylthieno 2,3-ё5-pyridazine 7- (6H) -thione and acid chloride (/ -bromophenylacetic acid, 7-hydroxy-4-methyl-8-phenipthiazolo 3,2-methyl-thieno 2,3-d pyridazine hydroxide is obtained -6-i (internal salt) with mp. 294-296 O (from chloroLorm).
    PRI me R 3. A. 0.41 g of 7-nitro-1 (2H) -phthalazin-thione and 0.37 g of 3-phenyl-2,2-oxyrandicarbonitrile in 10 ml


    five

    S
    acetone is heated under reflux for 30 hours. After cooling in an ice bath, the resulting violet crystals are sucked off, washed with diethyl ether and in vacuo. The hydroxide 9-nitro-3-hydroxy-2-phenyl-1-thiazolo {; 2,3-a phthalazin-4-i (inner salt) is obtained, m.p. 303-305 0. i
    B. In a similar manner, 7-ChLOR-1 (2H) -phthalazine-thione and 3-Cp-chlorophenyl) -2,2-oxirane dicarbonitrile-9-chloro-2- (p-chlorophenyl) -3-oxythiazolo C2,3- hydroxide is obtained from A.J. phthalazine (inner salt), m.p. 3000 (from a mixture of N, N-dimethylformamide and diethyl ether).
    - B. From 7-chloro-1 (2H) -phthalazine-thione and 3- (t-chlorophenyl) -2,2-oxirane dicarbonitrile, 9-chloro-2- (t-chlorophenide) -3-oxythiazolo hydroxide is obtained - (2,3-a) phthalazini. (internal salt) m.p.298- (from N, N-dimethylformamide).
    G. From 7-chloro-1 (2H) -phthalazine-thione and 3- (o-chlorophenyl) -2,2-oxirane dicarbonitrile, 9-chloro-2- (o-chlorophenyl) -3-oxythiazolo-1 hydroxide is obtained. ; 2,3-HF phthalazini (internal salt) with so pl. 289-291 0 (from H, K-dimethyl (Loamamide).
    Example4.A. 13.5g of 3-hydroxy-2-phenylthiazole hydroxide 3,2-aZftalazini (inner salt) and 8.1 ml of I
    propyl ester propyl ester
    Acids are heated in 200 mp of toluene with a reflux condenser without access of humidity c. for 24 hours. Then the mixture is cooled and stirred in an ice bath for 1 hour. The crystals obtained are filtered off with suction, dried and, finally, recrystallized from toluene. Methyl 4-oxo-3-phenyl-4H-pyrido-C2,2-a-phthalazine-1-carboxylic acid ester is obtained in the form of crystals, m.p. 174-175 0.
    B .. In a similar manner, Z-hydroxy-2-phenylthiazolo 13,2-3H is synthesized from HYDROXIDE C2,3-d 7-pyridazin-4-u (internal salt) and propiolic acid methyl ester after recrystallization of methyl from acetonitrile 7-oxo-8-phenyl-7H-pyridoC1,2-b3 thieno 2,3-d} pyridazine-10-carboxylic acid ester in the form of yellow crystals with m.p. 198-1991;
    B. From hydrochloride 9-chloro-3-hydroxyphenylthiazolo 2,3-a phthalazin-4-i (internal salt) and methyl propyl ester, after recrystallization from acetonitrile, meth25 is obtained.
    10-chloro-4-oxo-3-phenyl-4H-PYRIDO 2,1-α3-naphthalazine-1-carboxylic acid ester as yellow crystals with m.p. 23 -236 S.
    D. From hydroxide 9-NITRO-3-OXY-2-phenylthiazole C2,3-a7 petalazin-4-i (internal salt) and propiolic acid methyl ester get methyl ester 10-nitro-4-oxo-3-phenyl-4H - pyrioC 2,1-a} -phthalazine-1-carboxylic acid with so pl. 227-230 ° C (from a mixture of K, N-dimethylformamide and methanol).
    D. From 9-chloro-2- (p-chlorophenyl) -3-oxythiazoloH2,3-a-phthalazine hydroxide (inner salt) and propiolic acid methyl ester, methyl ester 10-chloro-3- (p- chlorophenyl) -4-ОКСО-4Н-pyridof2,1-ajphtalazin-1-carboxylic acid with m.p. 233-237 C - (from a mixture of 2-propanol and M, M-dimethylformamide).
    E. From the 7-hydroxy-4-methyl-8-phenylthiazolo gz, 2-b hydroxide, 2-ndi-2,3-dJ pyridazin-6-u (inner salt) and propyolic acid methyl ester are obtained. -7-ox-c-8-phenyl-7H-pyrido 1,2-b thieno 2,3-d pyridazine-10-carboxylic acid with m.p. 183-184 ° C (from ethyl acetate) G. From 9-chloro-2- (t-chlorophenyl) 3-oxythiazolo | C2,3-a hydrochloride hydroxide (inner salt) and propyolic acid methyl ester, methyl ester 10- chloro-3- (t-chlorophenyl) -4-ok-, CO-4H-PIRido 2,1-a phthalazine-1-carboxylic acid with mp. 234-235 C (from a mixture of N, N-dimethylformamide and methanol).
    3. From 9-chloro-2- (o-chloro-phenol) -3-oxythiazolo (2,3-a) -phthalazoline hydroxide (inner salt) and propiol methyl ester: - 10-chloro-methyl ester 3- (o-chlorophenyl) -4-oxo-4H-PIRIDO 2,1-aZftalazin-1-carboxylic 45 acid with m.p. 220-222 ° C (from acetonitrile).
    Froze A. 11 g of methyl 4-oxo-3-phenyl-4H-pi-, 1-α-Zftalazin-1-carboxylic acid ester 50
    1598879
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    thirty
    40
    hydrochloric acid, the pH value is adjusted to 7, and the contamination is removed by multiple extraction with 300 ml of mi-hylene chlorine. The aqueous phase is acidified using an aqueous solution of 2N. hydrochloric acid to pH 1, and the crystals formed are sucked off. After repeated washing with water and drying in 10 cuum, 4-oxo-3-fench1-4H-pyridoG2,1-a} phthalazine-1-carboxylic acid is obtained as yellow crystals, mp 236-237 ° C (decomposed ).
    B. In a similar manner, 15 are prepared from 7-oxo-8-fenp 7H-pyrido 1,2-bJtivo 2,3-dZhfalayaz 1-carboxylic acid methyl ester after recrystallization from dimethylformamide 7-ca-8-phenyl-7H-pyrido 1,2-bDieno-C2,3-dZpyridazin-10-carboxonio acid in the form of yellow crystals with mp 262-264 С (with decomposition).
    B. From methyl 1p-chloro-4 oxo-3-fensh 1-4H-pyrido 2,1-aJ-phthalazine-1-carboxylic acid methyl ester after recrystallization from a mixture of acetonitrim and dimethylformamide, 10-chloro 4-oxo-3- phenyl-4H-pyr1IoG2,1-aJ petalazin- | -carboxylic acid then in the form of yellow crystals with m.p. (with decomposition).
    G. From 4-methyl-7-oxo-8-phenyl-7H-pyrido-1,2-b} thieno 2, 3-a-3-pyridazine-10-carboxylic acid methyl ester, 4-methyl-7-oxo-8- is obtained. phenyl-7P-PIRVDO G1,2-b thieno 2,3-dJpyridineZIN-10-KJarboNOVa acid with T.PL,
    243-245 C (from a mixture of acetonitrile and N, N-dimethylformamide).
    EXAMPLE 6 A. 3.68 g of 4-oxo-3-phenyl-4H-pyrido 2,1-a phthalazine-1-carboxylic acid are suspended in 80 ml of toluene without access to moisture, after which they are added 5, 1 thionyl chloride and 0.2 ml of N, M-dimethylformam1-1-d and stirred at room temperature for about 2 hours. The reaction mixture is evaporated in vacuo, the resulting residue is poured into 50 ml of toluene, and then the mixture is again The acrylics are extracted into ethanol under an argon atmosphere, after which a solution of 3.7 g of potassium hydroxide in 30 ml of water is added to this mixture. This heating mixture: i z - 1Е - -
    and drink in 2200 ml of water. By adding an aqueous solution of 1 and.
    vacuum in vacuum. The carboxylic acid chloride, which is thus pure in its form, is introduced into 90 ml of dioxane, and then sequentially added:
    at room temperature until completion of the reaction. After removing the solvent in vacuo, the resulting residue
    th
    1598879
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    ,
    five
    20
    0
    0
    hydrochloric acid is adjusted to pH 7 and the impurities are removed by extracting 300 ml of methylene chlorozgt twice. The aqueous phase is acidified with an aqueous 2N solution. hydrochloric acid to pH 1, and the crystals formed are sucked off. After repeated washing with water and drying in a vacuum, 4-oxo-3-fench1-4H-pyridoG2,1-a} phthalazine-1-carboxylic acid is obtained in the form of yellow crystals, m.p. 236-237 C (with decomposition).
    B. Similarly, 15 are prepared from 7-oxo-8-fenp-7H-pyrido 1,2-b-2,3-2,3-phthalazine-1-carboxylic acid methyl ester after recrystallization from dimethylformamide of 7-oxy-8-phenyl-7H -pyrido 1,2-bDieno-C2,3-dZpirididin-10-carboxyl acid in the form of yellow crystals with so pl. 262-264 C (with decomposition).
    B. From 1p-chloro-4-oxo-3-fensh 1-4H-pyrido 2,1-aJ-phthalazine-1-carboxylic acid methyl ester, after recrystallization from a mixture of acetonitroxy and dimethylformamide, 10-chloro-4-oxo-3- phenyl-4H-pyr1IoG2,1-aJ petalazin- | -carboxylic acid then in the form of yellow crystals with m.p. (with decomposition).
    G. From 4-methyl-7-oxo-8-phenyl-7H-pyrido-1,2-b} thieno 2, 3-a-3 pyridazine-10-carboxylic acid methyl ester, 4-methyl-7-oxo-8-phenyl is obtained - 7P-PIRVDO G1,2-L thieno 2,3-dJpyridine-10-KARBOVO acid with T .. PL,
    243-245 C (from a mixture of acetonitrile and N, N-dimethylformamide).
    EXAMPLE 6 A. 3.68 g of 4-oxo-3-phenyl-4H-pyrido 2,1-a phthalazine-1-carboxylic acid are suspended in 80 ml of toluene without access to moisture, after which they are added 5, 1 thionyl chloride and 0.2 ml of N, M-dimethylformam1-1-d and stirred at room temperature for about 2 hours. The reaction mixture is evaporated in vacuo, the resulting residue is poured into 50 ml of toluene, and then the mixture is again imprint - - -
    vacuum in vacuum. The carboxylic acid chloride, which is thus pure in its form, is introduced into 90 ml of dioxane, and then sequentially added:
    1E - -
    at room temperature until completion of the reaction. After removing the solvent in vacuo, the resulting residue
    ten
    subjected to interaction with a mixture of 200 ml of water and 100 ml of the above-mentioned aqueous solution of HC1. The reaction mixture is cooled to about and stirred for 30 minutes. The resulting crystals are sucked off and 15 ml of water are washed twice. The crystals thus obtained are dried in vacuo at. The aqueous phase is extracted three times with methylene chlorine; The combined organic phases are washed once with 50 ml of water, dried over sodium sulfate, filtered and ground. The resulting crystals are combined with a flash of the obtained material and stirred with 150 ml of diethyl ether for 30 minutes. Diethyl ether was removed by filtration and the resulting yellow crystals were dried. 3-hydroxy-20 1- (4-oxo-3-phenyl-4H-pyrido 2,1-aJ phthalazin-1-yl) carbonyl acetidine is obtained, m.p. -260-264 C (with decomposition).
    25
    thirty
    Similarly, 4-oxo-3-phenyl-4H-pyrido 2,1-a is prepared with phthalazine-1-carboxylic acid.
    B. From morpholine get oxo-3-phenyl-4H-pyrido C2,1-a phthalazin-1-yl carbonyl morpholine with so pl. 246-248 seconds (from acetonitrile).
    B. From (K) -2- (methoxymethyl) -pyrrolidine receive (Yu-2- (methoxymethyl) -1-4-oxo-3-phenyl-4H-pyrido-; 2,1-a phthalazin-1 -yl carbonyl pyrrolidine with mp (from ethyl acetate). 35
    G. From dimethylamine, N, N-dimethyl-4-oxo-3-phenyl-4H-pyrido-2,1-a phthalazine-1-carboxamide with mp. 239-240 ° C (from ethanol).
    15988798
    t2,1-ajphtalazin-1-yl carbonyl3-3-methoxyazetidine with m.p. 238-240 0 (from acetonitrile).
    I. From dimethylamine, N, N-dimethyl-10-chloro-4-oxo-3-phenyl-4H-pyrido 2,1-aJ petalazine-1-carboxamide with m.p. 244-24b with (from ethanol)
    I. From (K) -Z-methoxypyrrolidine receive (K) -1-G 10-chloro-4-oxo-3-phenyl-4H-pyrndo 12,1-a and phthalazin-1-yl carbonyl-3-methoxy pyrrolidine with t .pl. 204-206 s (from acetonitrile).
    K. From (5) -3-methoxypyrrolidine, (S) -1- {jflO-chloro-4-oxo-3-phenyl-4H-pyridoC2,1-a phthalazin-1-yl I carbonyl-3-methoxypyrrolidine is obtained from m.p. 204-206 C (from acetonitrile).
    L. From (8) -prolinol, (S) - 1- {10-chloro-4-oxo-3-phenyl-4H-pyrido C 2,1-a-distilled zin-1-yl) onon-J-2- is obtained pyrrolidine-methanol with m.p. 245-255 C (with decomposition of acetonitrile).
    Similarly, 4-methyl-7-oxo-8-phenyl-7H-pyrido-1,2-bi is prepared with thieno2,3-dZpyridazine-10-capanoic acid.
    M. From dimethylamine, N, N-4-trimethyl-7-oxo-8-phenyl-7H-pyrido 1,2-b thieno 2,3-d pyridazin-10-carb is obtained. - oxamide st.pl. 244-246 ° C (from ethanol).
    N. From 3-methoxyazetidine, 3-methoxy-1-4-methyl-7-oxo-8-phenyl 7H-pyridoC1,2-b thieno 2,3-d pyridazin-10-yl) carboxyl-azetidine is obtained with m.p. . 240241 with (from ethanol).
    O. From (K) -2- (methoxymethyl) -pyrrolidine, (K) -2- (methoxymethyl) -1.4-methnp-7-Lxo-8-fench1-7H-pyrido is obtained.
    D. From (K) -3-methoxy-pyrrolidine at-40 1,2-b thienot2,3-dJ pyridazin-10-yl
     ....----. g ..
    carbonyl pyrrolidine with so pl. 209-212 0 (from ethanol).
    P. From (K) -proline get (R) - 1- {4-metsh1-7-oxo-8-phenyl-7H-pyrido
    (R) -3-methoxy-1-f4-ox o-Zphenyl-4H-pyrnzo 2, 1-a phthalazin-1-yl are obtained
    carbonylZpyrrolidine m.p. 208-209.c
    (from ethanol).
    E. From (5) -3-methoxy-pyrrolidine according to 45,2-b-thieno 2,3-dJ pyridazin-10-yl. (8) -3-methylxy-1 4-cccc-4-carbonyl -2 -pyrrolidine with so pl.
    . phenyl-4H-pyrido (2,1-a) phthalazin-1-yl
    carbonyl pyrrolidine with so pl. 205-206 С
    (from acetonitrile).
    50
    In a similar manner, 10-chloro-4-oxo-3-phenyl-4H-pyrido Cz, 1-a phthalazine-1-carboxylic acid is obtained.
    G. From N-ethyl-N- (2-methoxyethyl) amine, N-ethyl-N- (2-metoxyethyl) -10-chloro-4-oxo-3-fench1-4H-pyrido t2,1-a phthalazine- 1-carboxamide with so pl. 167 C (from ethyl acetate).
    3. From 3-methoxyazetidine get 1-10-chloro-4-oxo-3-phenyl-4H-pyrido
    55
    271-274 ° C (from ethanol).
    Synthesis of the proposed compounds.
    Apply p.7. A. To 1.26 g of chloro-4-oxo-3-phenyl-4H-pyrido 2,1-a phthalazin-1-yl carbonyl-3-methoxy-acetidine and 0.75 g of sodium cyanoborohydride in 30 ml of methanol are added Metholic hydrochloric acid is added dropwise at room temperature under argon atmosphere. The reaction is completed in a short time. The reaction mixture was sprayed into 70 ml of ice water and the resulting yellowish
    N. From 3-methoxyazetidine, 3-methoxy-1-4-methyl-7-oxo-8-phenyl 7H-pyridoC1,2-b thieno 2,3-d pyridazin-10-yl) carboxyl-azetidine is obtained with m.p. . 240241 with (from ethanol).
    O. From (K) -2- (methoxymethyl) -pyrrolidine, (K) -2- (methoxymethyl) -1.4-methnp-7-Lxo-8-fench1-7H-pyrido is obtained.
     1,2-b thienot2,3-dJpyridazin-10-yl
    ...----. g ..
    carbonyl pyrrolidine with so pl. 209-212 0 (from ethanol).
    P. From (K) -proline get (R) - 1- {4-metsh1-7-oxo-8-phenyl-7H-pyrido
    1,2-b thieno 2,3-dJpyridine-10-ylj carbonyl -2-pyrrolidinmethanol with m.p.
    1,2-b thieno 2,3-dJpyridine-10-ylj carbonyl -2-pyrrolidinmethanol with m.p.
    271-274 ° C (from ethanol).
    Synthesis of the proposed compounds.
    Apply p.7. A. To 1.26 g of chloro-4-oxo-3-phenyl-4H-pyrido 2,1-a phthalazin-1-yl carbonyl-3-methoxy-acetidine and 0.75 g of sodium cyanoborohydride in 30 ml of methanol are added Metholic hydrochloric acid is added dropwise at room temperature under argon atmosphere. The reaction is completed in a short time. The reaction mixture was sprayed into 70 ml of ice water and the resulting yellowish
    the crystals are filtered off. They are washed three times in 2 ml each and dried under vacuum. After recrystallization of the crude product from a mixture of ethyl ester of acetic acid and acetone (1: 1 ratio), 1-f 1 O-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-pyridos 2,1-a phthalazine -1-yl carbonylJ-3-methoxyacetidine as yellowish crystals, mp 238239 s.
    Instead of methanol, it is also possible to use a mixture of tetrahydrofuran and yicacetic acid as a solvent, in which case it is not necessary to add methanolic hydrochloric acid.
    B. Dialogically obtained from H-etsh1-10-chloro-K- (2-methoxy- - ethyl) -4-oxo-3-fenst-4H-pyridoG2,1-aJ phthalazine-1-carboxamide in a mixture of methanol and ice acetic acid (10: 1), but without the addition of N-ethyl-25 1 O-chloro-6,7-dihydro-M- (2-methoxy-ethyl) -4-oxo-3- saturated methanol hydrochloric acid phenyl-4H-pyrido 2,1-a phthalazine-1-carboxamide with m.p. 184-185 ° C (from ethyl acetate).
    B. From 10-chloro-G, M-dimethyl-4-oxozo 3-phenyl-4H-pyrido 2, 1-a; 1-phthalazine-1-carboxamide in a mixture of methanol and glacial acetic acid (10: 1 ), but without the addition of saturated methanolic hydrochloric acid, 1O-chloro-6,7-dihydro-N, N-dimethyl-4-oxy-3-phenyl-4H-PYRIDO G2,1-a: phthalazin-1-carbox- mid with t.pl. 250-252 ° C (from ethanol).
    G. From 4-G4-oxo-3-phenyl-4H-pyri to 2, 1-a phthalazin-1-yl} -carbonyl of mor-pol in a mixture of methanol and glacial acetic acid (10: 1 ), but without the addition of saturated methanolic hydrochloric acid, 7-dihydro-4-oxo-3-phenyl-4H-pyrido 2,1-a -phthalazin-1-s or carbonyl morpholine with m.p. 254-257 C (from acetonitrile).
    D. From 7-oxo-8- methyl ester;
    enyl-7E1-pyrido 1, 2-b} thieno-2,3-c1 Ji
    and 15idazine-10-carboxylic acid in acetic acid, methyl 4,5-dihydro-7-oxo-8-phenyl-7H-irido 1,2-b is prepared. Methyl 2,3-a pyridazine-10-arboxylic acid, m.p. 218 ° C (from cetonitrile).
    E. From (K) -1-10-chloro-4-oxo-3-phen-IL-4H-Pyrido 2, 1-a-Zftalazin-1 -yl
    arbonyl -2- (methoxymethyl) pyrrolidine receive (R) -1-1 O-chloro-6,7-dihydro 50
    1598879
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    25
    zo
    .p s
    ;
    i
    4-oxo-3-fensht-4H-pyridoG2,1-a phthalazin-1-sh1 carbonyl; -2- (methoxymethyl) pyrrolidine m.p. 1b1-1b4 s (from a mixture of ethyl acetate and dieth.aic ester), J. From 4- {10-chloro-4-oxo-3-chienyl-4H-Pyrido 2,1-a phthalazin-1-yl carbonyl 1-morpholine 4-f10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido 10 2,1-a1-phthalazin-1-yl) carbonyl is obtained; morpholine with m.p. 256-258 0 (from acetonitrile).
    3. From (K) -1- {1P-chloro-4-oxo-3-e-nyl-4H-pyrido 2, 1-a J-phthalazin-1 -yl j carbonyl J-3-methoxypyrolidine receive (R) - J-SOP-chloro-b, 7-DIHIDRO-4-OXO-3-phenyl-4H-pyrido 2,1-a1-phthalazin-1-. Il} Carbon1 L3-methoxypyrrolidine with m.p. 180-181 ° C (from acetonitrile),
    I. From (8) -1-10-chloro-4-oxo-3-phenyl-4H-pyridoG2,1-a3-phthalazin-1-yl carbonylJ-3-methoxypyrrolidine, receive (S) -1- {1О -chloro-6,7-DIHCHDRO-4-OK-co-3-phenyl-H4-pyrcto 2, 1-aj-phthalazine-1 -yl carbonyl-3-methoxypyrrolidine with so pl. 179-181 ° C (from acetonitrile),
    I. From () - {7-oxo-8-phenyl-7H-pyri-, 2-bJ thienoH2,3-d J-pyridazin-10-yl} carbonylJ-2-pyrrolidinmethanol, (R) -1-4, are obtained 5-DIHIDRO-7-OXO-8-phenyl-7H-pyrido 1, 2-h thieno {2,3-d J pyridazin-10-yl carbonyl J-2-pyrrolidinemethanol with m.p. 218-219 ° C (from methanol).
    K. From K-ethyl-H- (2-methoxyztil) -7-oxo-8-phenyl-7H-pyridoG1,2-b thieno 2, 3-d pyridazine-10-carboxamide,
    H-eth1-1,5-dihydro-K- (2-methoxyeggsh) 7-oxo-8-phenyl-7H-pyrido (1,2-b) thieno 2,3-dI pyr dazin-10-cbc with t. square 148-149 ° C (from ethyl acetate).
    L. From N- (3-metoksipropil) -7-okko-8-phenyl-7H-pyrPch1o 1,2-b thieno 2,3-d 3 pyridazine-10-carboxamide get
    4,5-dihydro-H- (3-methoxypropyl) -7-oxy-8-phenyl-7I-pyrido 1,2-b thieno 2,3-d pyridazine-10-carboxamide c; mp. 220-22Gs (from acetonitrile). M. From (U-3-methoxy {7-oxo-8-fe-0-yl-7H-pyrido; 1,2-b thieno 2,3-dJ pyridazin-10-yl carbonyl pyrrolidine gives (R) -t - G4,5-dig shro-7-oxo-8-phenyl-7H-pyrido 1,2-h J-thieno G2,3-d J tordhdazin-10-yl) carbonyl b3-methoxypyrrolidine with m.p. 160-161 with (from ethyl acetate).
    , 1. - p-oxo-8-fensh1-7H-pyrnzo 12 S 3-c 7-pyridazin-10-yl 5
    J. - y - - J .jn.n I
    carbonyl Dmorpholine get 4-Cf4,5 dihydro-7-ox. o-8-phenyl-7H-pyrido 1,2-t) thieno C2,3 - "1 pyridazin-10-ylucarbonyl-7 morpholine with tgr. 275-278 ° C (from acetonitrile) ...
    O. From 3-methoxy-1-4-methyl-7-pkso-8-phenyl-7H-pyrido C1,2-b thieno C2,3-d J pyridazin-10-yl} carbonylDazetidine, rac-1-C f4, 5-dihydro-4-methyl-7-oxo-8 - () enyl-7H-pyrido Cl 2 -b-thieno rj 2,3-L pyridazin-10-yl} carbonyl} -3-methoxyazetidine, t. square 169-170 C (from ethanol).
    P. From 3-.metbxy-1-CC7-oxo-8-phenyl-7H-pyrido 1,2-J J-thieno-C2,3-d pyrida- with ZIN-10-yl} carbonyl azetidine get 4.5 -dihydro-7-oxo-8-phenyl-7H-pi-, 2-b ZtienoG2,3-d J-pyridazin-10-Sh1} carbonyl-3-methoxyazetidine with m.p.
    X. From 3-methoxy-1-G4-oxo-3-phenyl-4H-pyrido (2,1-a) -phthalazin-1-yl j carbonyl azetidine get 1-ff6,7dihydro-4-oxo- 3-phenyl-4H-pyrido. 2,1-a Zftalazin-1-yl) carbonyl-3-methoxyazetidine, m.p. 196-197 0 (from ethanol).
    PRI me R 8. A. 2.7 g of 10-chloro-H, K-diethyl-4-oxo-3-phenyl-4H-pyrido C2,1-a1-phthalazine-1-carboxamide are suspended in 65 MP of tetrahydrofuran in an argon atmosphere, after which 150 mg of lithium borohydride are added to this mixture, stirred at room temperature for 4 hours, 75 mg of lithium borohydride are added again, and stirring is continued until completion of the reaction and. The reaction mixture was discharged from 242-255 ° C (from a mixture of N, N-dimethylforma-2o and poured into 300 ml of ice-cold water, hence, methanol).
    R. From N, N-diethyl-7-oxo-8-phenyl-7H-Pyrid o (1,2-b) thieno, 3-d} pyridazin-10-carboxamide get N, N-dimethyl-4,5 -dihydro-7-oxo-8-phenyl-7H-pyrido 1 "2-b thieno 12,3-d pyridazine-10-carboxamide, m.p. 179-180 ° C (from ethyl acetate).
    C. From H, K-dimethyl-7-oxo-8-phenyl-7H-Pyrido11,2-b} thieno-2,3-d} pyridazine-10-carboxamide, 4,5-dihydro-b, b are obtained -dimethyl-7-oxo-8-phenyl-7H-pyrido 1,2-b thieno 2,3-d pyridazine-10-carboxamide, m.p. 246-250 C (from a mixture of ethanol and H, N-dimethylformamide).
    T. From (8) -2-methoxymethyl-1-G7-oxo-8-phenyl-7H-pyrido-G1,2-b thieno C2, 3-dZpyridazin-10-yl carbonyl.} Pyrrolidine get (8) , 5-dihydro-7-oxo-8-soienyl-7H-pyrido 1,2-β-thieno-C 2,3-d pyridazin-10-yl J carbonyl 3-2- (methoxymethyl) pyrrolidine with t. square 172-173 0 (from ethanol).
    W. From (K) -2- (methoxymethyl) oxo-8-phenyl-7H-pyrido 1,2-l7thieno 2,3-dZpyridazin-10-yl carbonylD pyrrolidine, we obtain (K) 5-dihyd-; ro-7-oxo-8-phenyl-7H-pyrido 1,2-Ь1
    The resulting product crystallizes. The crude product obtained is chromatographed on silica gel. Recrystallization from toluene gives 10-xnop-N, N-diethyl-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido 2,1-aZ-phthalazine-1-carboxamide, mp. 192-194 0 (toluene).
    B. In a similar manner, 30 (S) -l4 IO-chloro-4-oxo-3-phenyl-4H-pyrido-2,2-a 3-phthalazin-1-yl carboxy-1-2 (methoxymethyl) is obtained pyrrolidine (S) - .1 - 110-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido-2,1-a} -phthalazin-1-yl3 carbonyl J-2- ( methoxymethyl) pyrrolidine with so pl. 16-6-167 C (from ethyl acetate). B. From (K) -1- {4-methyl-7-oxo-8-phenyl-7H-pyrido 1,2-LJ-thieno 2,3-d pyridazin-10-yl} carbonyl -2- (methoxy- 40 methyl) -pyrrolidine receive (R) -1- (4,5-dihydro-4-metsh1-7-oxo-8-phenyl-7H-pyrido 1,2-l) thienoC2,3-dJ pyridazin-10-yl carbonyl } -2- (methoxymethyl) pyrrolidine with m.p. 150-155 ° C (from a mixture of 5 toluene and diethyl ether).
    G. From (8) -1-10-chloro-4-oxo-3-rzenenyl-4H-pyrido 2,1-a3-phthalazin-2-yl carbonyl 2-pyrrolidine-methanol obtained
    thieno 2,3-d pyridazin-10-ylJcarbonyl) - (S) -1-10-chloro-6,7-dihydro-4-ca-2- (methoxymethyl) pyrrolidine with t. co-3-phenyl -4H-pyridot2,1-a3-phthalazin 170-172 C (from ethanol).
    F. From N, N, 4-trimethyl-7-oco-8-fe-NILE-7H-Pyrido 1,2-b3-thieno 2,3-d-pyridazine-10-carboxamide, 4,5-dihydro-N, N is obtained , 4-trimethyl-7-oxo-8-phenyl-7H-pyrido111,2-hTyenoC2,3-J3-pyridazine-10-carboxamide c. Mp. 172-174 C (from toluene).
    X. From 3-methoxy-1-G4-oxo-3-phenyl-4H-pyrido (2,1-a) -phthalazin-1-yl j carbonyl azetidine get 1-ff6,7dihydro-4-oxo- 3-phenyl-4H-pyrido. 2,1-a Zftalazin-1-yl) carbonyl-3-methoxyazetidine, m.p. 196-197 0 (from ethanol).
    PRI me R 8. A. 2.7 g of 10-chloro-H, K-diethyl-4-oxo-3-phenyl-4H-pyrido C2,1-a1-phthalazine-1-carboxamide are suspended in 65 MP of tetrahydrofuran in an argon atmosphere, after which 150 mg of lithium borohydride are added to this mixture, stirred at room temperature for 4 hours, 75 mg of lithium borohydride are added again, and stirring is continued until completion of the reaction and. A reactive mixture resulting in the resulting product crystallizing. The crude product obtained is chromatographed on silica gel. Recrystallization from toluene gives 10-xnop-N, N-diethyl-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido 2,1-aZ-phthalazine-1-carboxamide, m.p. 192-194 0 (toluene).
    B. In a similar manner, IO-chloro-4-oxo-3-phenyl-4H-pyrido-2,2-a 3-phthalazin-1-yl carbonyl 1-2- (methoxymethyl) pyrrolidine ( S) - .1 - 110-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido-2,1-a} -phthalazin-1-yl 3 carbonyl J-2- (methoxymethyl) pyrrolidine with so pl. 16-6-167 C (from ethyl acetate). B. From (K) -1- {4-methyl-7-oxo-8-phenyl-7H-pyrido 1,2-LJ-thieno 2,3-d pyridazin-10-yl} carbonyl -2- (methoxy- methyl) -pyrrolidine receive (R) -1- (4,5-dihydro-4-metsh1-7-oxo-8-phenyl-7H-pyrido 1,2-l) thieno-C2,3-dJ pyridazin-10-yl carbonyl} -2- (methoxymethyl) pyrrolidine with m.p. 150-155 ° C (from a mixture of toluene and diethyl ether).
    G. From (8) -1-10-chloro-4-oxo-3-rzenenyl-4H-pyrido 2,1-aZ-phthalazin-2-yl carbonyl 2-pyrrolidin-methanol to give
    1-yl carbonyl32-pyrrolidin methanol with so pl. 222-225 0 (from a mixture of methanol and H, K-dimethylformamide).
    D. From K, M-dimesh-1-4-oxo-3-phenyl-4H-pyrido 2,1-a-petalazin-1-carboxamide, 6.7-dihydro-y, N-dimethyl-4- oxo-3-phenyl-4H-pyrido 2, l-aj phthalazine-1-carboxamide with m.p. 266131598879
    N, N-dimethylformamide
    14
     (from mixture and ethanol).
    E. From (K) -3-methoxy-1-A-oxo-3-phenyl-4H-pyrido C2,1-a -phthalazin-1-yl carbonyl pyrrolidine, (R) -1-6,7-dihydro- 4-oxo-3-phenyl-4H-pyri-, 1-a phthalazin-1-yl -carbonyl-J-3-methoxy 11I11rolidine, m.p. 175-176 0 (from toluene).
    G. From (8) -3-methoxy-1-C 4-oxa-3-phenyl-4P-pyrido 2,1-a-phthalazin-1-yl} carbonyl pyrrolidine get (S) -1- С f6,7 -dihydro-4-oxo-3-phenyl-4H-pyri-, 1-a phthalazin-1-yl} carbonyl J-3-methoxypyrrolidine, mp 174-175 ° 0 (from toluene).
    3. From 10- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) 8-phenyl-7H-pyrido 1,2-b thieno 2,3-dJpyridazin-7-one get 1O- ( Z-cyclopropyl-1,2,4-oxadiazol-5-Sh1) -4,5-dihydro-7-oxo-8-phenyl-7H-pyrido 1,2-b thieno 2,3-dJ pyridazine with t .pl. 202-204 С (from that-- luola).
    I. From methyl 10-nitro-4-oxo-3-phenyl-4H-pyrido-2,1-ad-phthalazine-1-carboxylic ester, 6.7-dihydro-10-nitro-4-oco-methyl ester is obtained. 3-phench: -4H-pyrido 2, 1-a phthalazine-1-carboxylic acid, m.p. 232-233 ° C (from N,. N-dimethylformamide).
    I. From 7-oxo-8-fe10 methyl ester
    B. Similarly, 3-methoxy-1-ff 7-oxo-o-phenyl-7H-pyri, 2-bJ thienoG2,3-dJpyridazin-10-sh: azetidine carbonyl 1-G4,5-dihydro-5 methyl is obtained -7-oxo-8-phenyl-7H-pyrido f1.2-b thieno 2,3-d pyridazin-10-yl} carboxyl 3-methoxyazetidine with m.p. 221-222 s (from methanol).
    B. From N, N-dimethyl-7-ox-8-phenyl-7H-pyrido 1,2-hJeno 2,3-dJ pyridide and 10-carboxamide get 4,5-dihydro S, K-trimethyl-7-oxo-8 -o-enyl-7H-pyrido (1,2-b) thieno (2,3-d} pyridazin-10J5 carboximide; with mp. 247-249 ° C (from methanol).
    D. From (K) -2- (methoxymethyl) -1-C {7-oxo-8-phenyl-7H-pyrido 1 2-LJ thieno G2,3-dJ pyrichchdazin-10-yl} carbonylZpir-
    Rolidine 20 gives (R) -1-C 4,5-dihydro-5-methyl-7-oxo-8-phenyl-7H-pyrido -. 1,2-bZtienoC2,3-d pyridazin-10-yl h carboni.p J-2- (methoxymethyl) pyrrolidine, mp. 204-207 s (from ethanol).
    D. From (S) -1-fG7-oxo-8-phenyl-7H-pyrido 1,2-bjthieno 2,3-dJpyrnazazin-10-shI carbonyl-D-2- (methoxymethyl) pyrrolidine receive (S) , 5-dihydro-5-methyl-7-oxo-8-phenyl-7H-pyrido
    30 C1,2-b thieno 2,3-d} pyridazin-10-yl} carbonyl -2- (methoxymethyl) -pyrrolidine, m.p. 208-209 s (from zantol),
    E .. Of H, H, 4-trimethyl-7-oxo-8-fen-NIL-7H-PIRIDO 1,2-bjTHeHoC2,3-dJnHpH25
    nyl-7H-pyrido 152-b7thieno 2,3-dIpyri-, dazin-10-carboxamide get 4,5-dazin-10-carboxylic acid get Dihydro-S, K-4,5-tetramethyl-7-oxo-84, 5 -dihydro-10- (hydroxymethyl) -8-phenyl-7H-pyrido 1, 2-Ü ITHBHO 2,3-dJpyridazin-7-one with so pl. 205-206 С (from acetonitrile) .40
    Example 9 A. To 0.34 g methyl ester of 7-oxo-8-phenyl-7H-pyrido 1,2-b. Styled 2,3-dJpyridazine-10-carboxylic acid in 10 ml of formic acid is added dropwise. , 31 g of sodium cyanoborohydride in 2 mp of tetrahydrofuran in an argon atmosphere at 25-30 ° C. This mixture is stirred at room temperature for 24 hours. The resulting solution is poured into 50 ml of ice water. The resulting yellowish crystals are filtered and washed with water. After drying in vacuo, they are recrystallized from acetic complex, phenyl-7H-pyrido 1, 2-b thieno 2,3-dJ pyridazin-10-carboxamide, m.p. 189-191 ° С (from toluene).
    G. From (R) -2- (methoxymethyl) -1- 4-methyl-7-oxo-8-phenyl-7H-pyrido C1,2-b} thieno 2,3-dJpyridine-10-w carbonyl 3-pyrrolidine is obtained (R) -1- 5-DIHIDRO-4,5-dimethyl-7-oxo-8-5 phenyl-7H-shipidoh, 2-b Cc-1, pyridazin-10-yl} carbonyl-3 (methoxymethyl) pyrrolidine, so pl. 155-157 with (from a mixture of ethyl acetate and diethyl ether).
    3. From 3-methoxy-1-f4-oxo-3-fench 1-4H-pyrido 2,1-a1-phthalazin-1-yl carbonylZazetidine, 1-Cf6.7-dihydro-6-methyl-4-oxo-3 -phenyl-4H-pyrido 2, 1-a phthalazin-1-yl carbonyl J-
    50
    new ether. Get methyl complex 3-methoxyazetidine with so pl. 226-227 C 4,5-dihydro-5-methyl-7-oxo-8-fe- ester (from toluene). nyl-7H-pyrido 1,2-b thienoC2,3-dJpyri-I. From (K) -2-methoxymethyl-1-C i 4-oK-J
    Dazin-10-karyonovoy acid, t.pl.so-3-phenyl-411-pyrido C2,1-a phthalazin 180-181 C. 1-Sh1 carbonic 1 Dipyrrolidine receive
    14
    0
    B. In a similar manner, 3-methoxy-1-ff 7-oxo-o-phenyl-7H-pyri-, 2-bJ thienoG2,3-dJpyridazin-10-sh is prepared from: 1-A4-carbonate of 1-G4,5-dihydro- 5-methyl-7-oxo-8-phenyl-7H-pyrido f1.2-bJ thieno 2,3-d pyridazin-10-yl} carbonylJ 3-methoxyazetidine with m.p. 221-222 s (from methanol).
    B. From N, N-dimethyl-7-oxo-8-phenyl-7H-pyrido 1,2-hJeno 2,3-dJpyridine-10-carboxamide get 4,5-dihydro, K-trimethyl-7-oxo -8-oenyl-7H-pyrido (1,2-b) thieno (2,3-d} pyridazin-105 carboximide; with mp. 247-249 ° C (from methanol).
    G. From (K) -2- (methoxymethyl) -1-C {7-oxo-8-phenyl-7H-pyrido 1 2-LJ thieno G2,3-dJ pyrichchdazin-10-yl} carbonylZpir-;
    Rolidine 0 gives (R) -1-C 4,5-dihydro-5-methyl-7-oxo-8-phenyl-7H-pyrido -. 1,2-bZtienoC2,3-d pyridazin-10-yl h carboni.p J-2- (methoxymethyl) pyrrolidine, mp. 204-207 s (from ethanol).
    D. From (S) -1-fG7-oxo-8-phenyl-7H-pyrido 1,2-bjthieno 2,3-dJpyrnazazin-10-shI carbonyl-D-2- (methoxymethyl) pyrrolidine receive (S) , 5-dihydro-5-methyl-7-oxo-8-phenyl-7H-pyrido
    0 C1,2-b thieno 2,3-d} pyridazin-10-yl} carbonyl -2- (methoxymethyl) -pyrrolidine, m.p. 208-209 s (from zantol),
    E .. Of H, H, 4-trimethyl-7-oxo-8-fen-NIL-7H-PYRIDO 1,2-bjTHeHoC2,3-dJnHpH5
    40
    phenyl-7H-pyrido 1,2-b thieno 2,3-dJ pyridazin-10-carboxamide, m.p. 189-191 ° С (from toluene).
    G. From (R) -2- (methoxymethyl) -1- 4-methyl-7-oxo-8-phenyl-7H-pyrido C1,2-b} thieno 2,3-dJpyridine-10-w carbonyl 3-pyrrolidine is obtained (R) -1- 5-DIHIDRO-4,5-dimethyl-7-oxo-8-5 phenyl-7H-shipidoh, 2-b Cc-1, pyridazin-10-yl} carbonyl-3 (methoxymethyl) pyrrolidine, so pl. 155-157 with (from a mixture of ethyl acetate and diethyl ether).
    3. From 3-methoxy-1-f4-oxo-3-fench 1-4H-pyrido 2,1-a1-phthalazin-1-yl carbonylZazetidine, 1-Cf6.7-dihydro-6-methyl-4-oxo-3 -phenyl-4H-pyrido 2, 1-a phthalazin-1-yl carbonyl J-
    50
     3-methoxyazetidine with so pl. 226-227 C (from toluene). I. From (K) -2-methoxymethyl-1-C i 4-oK-J
    15
    one
    (R) -ir f6,7-digipro-6-methyl-4-oxo-3-phenyl-4H-pyrido 2,1-a phthalazin-1-yl carbonyl -2- (methoxymethyl) pyrrolyline with m.p. 158-159 ° C (from a mixture of ethyl acetate and diethyl ester).
    And, From K, K-dimethyl-4-oxo-3-phenyl-4H-pyridoC2,1-a phthalazin-1-carboxamide, 6.7-dihydro-Y, Y, 6-trimethyl-4- oxo-3-phenyl-4H-pyridoG2, 1-a phthalazine-1-carboxamide with m.p. 131- (from acetonitrile).
    K, From 4-110-oh-4-oxo-3-phenyl-4H-pyrido G2, 1-aj phthalazin-1 -ylcarbo-morpholine, 4-C 10-chloro-6,7-dihydro-6- methyl 4-oxo-3-phenyl-4H-pyrido 2,1-a pyridazin-1-yl C-arbonyl S-morpholine, m.p. 282-284 C (from acetonitrile). .
     L. From 10-chloro-N, K-diethyl-4-oxo-3 phenyl-4H-pyrido 2,1-a phthalazine-1-carboxamide, 10-chloro-K, S, DIETSH1-6,7-dihydro- 6-methyl-4-oxo-3-phenyl-4H-pyrido 2,1-a phthalazin-1-car boxamide with mp. 187-188 0 (from toluene).
    M. From 10-chloro-4-oxo-3-phenyl-N, K, dimethyl-4H-pyrido 2,1-a phthalazin-1-. carboxamide, 1P-chloro-6,7-di hydro-3-phenyl-H, K, 6-trimethyl-4H-pi-, 1-a-3-phthalazine-1-carboxamide with m.p. 231-233 ° C (from acetonitrile).
    Example 10. 0.54 g of methyl 4,5-dihydro-7-oxo-8-phenyl-7H-pyrido 1,2-h-thieno 2,3-dZpi-reidazin-10-carboxylic acid methyl ester is suspended in 16 ml of acetic anhydride and heated to within 3 hours.
    The reaction solution is evaporated in vacuo and the resulting residue is introduced into 32 ml of water and stirred. This. . the mixture is extracted twice with 30 mp and once more with 15 ml of dichloromethane. After drying over sodium sulfate, the mixture is filtered and evaporated in vacuo. The remainder is chromatographed on. silica gel using a mixture of dichloromethane and acetoxide (9: 1 ratio). As a result of recrystallization from diethyl ether, methyl ester of the company 5-acetyl-4,5-dihydro-7-oxo-8-phenyl-7H-Pyrido 1,2-b thieno 2,3-d pyridasium 10-carboxylic acid is obtained. m.p. 132,134 ° C.
    Example 11. A. Analogously to Examples 5,6 and 8, prepared from 10-chloro-3-Cp-chlorophenyl) -4-oxo 4H-pyrioC2,1-a methyl ester phthalazin-1-carboxylic






    sixteen
    ten
    0
    Acids 3-e f10-chloro-3- (p-chlorophenyl) -6,7-dihydro-4-oxo-4H-pyrido C 2,1-aj-phthalazin-1-yl) carbrnyl morpholine, m.p. 238-240 C (from acetonitrile).
    B. From 10-chloro-3- ((t-chlorophenyl) -4-oxo-4H-pyrido 2,1-aJ phthalazine-1-carboxylic acid methyl ester, 10-chloro-3- (1n-chlorophenyl) -6 , 7-dihydro-4-oxo-4H-pyrido-G 2,1-a phthalazin-1-yl} carbonyl morpholine, mp 256-259 ° C (from a mixture of N, N, dimethylformamide and methanol).
    B. Methyl Bqro 10-chloro-3-5 (o-chlorophenyl) -4-oxo-4H-pyrioC2,1-aJ phthalazine-1-carboxylic acid ester gives 4-P0-chloro-3- (o-chlorophenyl) - 6, 7-di-hydro-4-oxo-4H-pyrido-2,1-ad-phthalazine-1 yl} carbonyl-S-morpholine, t, pl. 0 200-202 s (from ethyl acetate).
    Example 12. A. 1.26 g of chloro-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido 2,1-a1 phthalazin-1-yl carbonyl D morpholine is dissolved in 30 ml of dichloro-5 methane in an argon atmosphere, after which 1.01 g of tetrabiutylammonium hydrogensulfate was added to this solution. 1.4 g ethyl iodide and 1.45 ml of 50% sodium hydroxide solution. This solution is stirred at room temperature until completion of the reaction. 3 ml of water was added to the reaction mixture, the organic phase was separated and dried, and the solvent was removed in vacuo. The residue obtained is chromatographed on silica gel. As a result of recrystallization, 4-l 6-ethyl-10-chloro-6,7-dihydro-4-oco-3-phenyl-4H-pyrido 2,1-a phthalazin-1-yl morpholine carbonyl is obtained as yellow crystals .pl. 288-289 C (from acetonitrile).
    B. In a similar manner, 4- 1 10-chloro-b, 7-diHYDRO-4-OXO-3-phenyl-411-pyrido., 1-a phthalazin-1 -yl morpholine carbonite and benzyl chloride 4- {6-methyl-10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido 2,1-a phthalazin-1-yl j Kap6oHmiJ morpholine, m.p. 180-183 G (from a mixture of toluene and diethyl ether).
    Example 13. 2.62 g of 4,5-dihydro, 10- (hydroxymethyl) -8-phenyl-7H-pyrido 1,2-b thieno 2,3-dJpyridazin-7-ona is dissolved in 80 ml of M, K - dimethylforma- 5 MIDa and cooled in an ice bath to 3 ° C. To this mixture 440 mg of 55% NaH dispersion was added in portions and, after the last portion was added, the mixture was stirred for another 1 hour. After this added 0
    0
    five
       159887918
    a solution of 1.5 g of N-chlorocarbon is dripped. 1 g (10-chloro-6,7-digtsro-4-oxobonylmorpholic in 3 ml of N, N-dimethyl-form - o l ,,, „„ „/ п t
    - Phenyl-411-pyrido12,1-aJLtalazine-1-amide. The resulting mixture is stirred. j.
    ten

    still at about 5 ° C for 45 NraH, after which the reaction mixture is poured into 800 ml of ice water, and the crude product crystallizes. After washing with water and drying, the crude product is purified by chromatography on silica gel and recrystallization. 4,5-dihydro-7-oxo-8-phenyl-7H-pyridoG1,2-b thieno 12,3-d Zpyridazin-10-yl-methyl-4-morpholinecarboxylate is obtained, m.p. 210 0 (from acetonitric).
    The starting compounds have pronounced muscle relaxant, sedative-hypnotic, anticonvulsant and / or anxiolytic properties and show only minor toxicity. These properties are proved, for example, by a test for lack of response to pentetrazole (Antipenttetrazol test), the use of which is generally accepted for detecting similar properties.
    silt) carbonic 11-3-methoxyaze11in,
    I
    f G. 10-chloro-b, 7-dihydro-K, K-dimethyl 4-oxo-phenyl-4H-pyridoG2,1-a} phthalazine-1-carboxamide;
    L. (R) -1-G (4,5-dihydro-7-oxo-8-phenyl-7H-pyrido 1,2-b1-thienoG 2,3-dJepi-dazin-10-yl) carbonylJ-3-methoxypyrp - polilidine;
    E. 1-C (4,5-digidro-4-metsh1 -7-oxo-j 8-fensh1-7H-pyrido 1,2-З; t) dieno G2,3-dJ pyridazin-10-yl) carbonyl-3 azetidine;
    ; G, 1-C (4,5-dihydro-5-methyl-7-oxo-8-phenyl-7H-pyrido 1,2-LJ thieno 2,3-d pyridazin-10-yl) carbonyl I-3-methoxy- azetidine;
    3. 4,5-dihydro-K, K-dimesh1-7-oxo7 8-phenyl-7H-pyrylo C1,2-l 1thieno1; 2,3-d} pyridazine-10-carboxamide.
    I. N-ethyl-10-chloro-6,7-diTydro-N- (2-methoxyethyl) -4-oxo-3-phenyl-4H-pyrido C2,1-aZftalazin-1-carboxamide;
    20
    In this test, which is carried out with rats, the test compound is orally administered to the animals and after 30 minutes intraperitoneally 120 mg / kg of pentetrazole, which in unprotected animals 1-4 minutes after injection of penterazole causes
    K. (K) -1-G (455-dihydro 7-oxo 0 phenyl-7H-pyrido 1,2-b} thieno-2, 3-dJ pi ridazin-10-yl) -carbonyl J-2-pyrrolidine methanol;
    L. 4,5-dihydro-M- (3-methoxyprotein 7-oxo-8-phenyl-7H-pyrido P, 2-dTypheno 2,3-d Zpiridazin-10-carboxamide;
    M (4,5-dihydro-7-oxo-8-phenyl-7H
    thirty
    tonic extension of the anterior and / or 35 pyridoS1,2-b} tieno 2,3-dzn) idazin40
    45
    hind limbs. For each dose of the test substance, 10 experimental animals are used. After counting the protected animals, the dose of Sflsft is determined. EDdd is the dose at which 50% of experimental animals are protected from seizures caused by pentetrazole. The table summarizes the test results obtained with representative representatives of the class of proposed compounds. In addition, the table shows the data of acute toxicity (LD oo) with a single oral administration in the following compounds.
    A. 4- (10-chloro-6, 7) -dihydro-4-oxo-3-phenyl-4n-pyrido 2,1-a} phthalazin-1-yl) carbonyl 3 morpholine;
    10-yl) methyl 4-morpholinecarboxylate;
    N. C4- (6,7-dign, t; go-4-oxo-3-fench 10-chloro-4H-benzo a quinolysic-1-yl) carbonyl-2,6-dimethylmorpholine.
    The proposed compounds may be administered in the form of pharmaceutical preparations. Pharmaceutical preparations should be administered orally, for example, in the form of tablets, lacquer tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, for example, in the form of suppositories, or parenterally, for example, in injections.
    The proposed products can be used to treat or prevent diseases, in particular for the treatment of seizures and anxiety, as well as
    B. (R) -1- (10-chloro-6,7-dihydro-4- for drug preparation, I have | oxo-3-phenyl-4P-pyrido 2, 1-a phthalazin1-yl) carbonyl 3-2 ( methoxymethyl) -pyr- (rolidine;
    muscle relaxants, sedative-hypnotic, anticonvulsant and / or anxiolytic properties.
    - Phenyl-411-pyrido12,1-aJLtalazin-1-. j.
    0
    five
    silt) carbonic 11-3-methoxyaze11in,
    I
    f G .. 10-chloro-b, 7-dihydro-K, K-dimethyl-4-oxo-phenyl-4H-pyrido-2,1-a} phthalazine-1-carboxamide;
    L. (R) -1-G (4,5-dihydro-7-oxo-8-phenyl-7H-pyrido 1,2-b1thienoG 2,3-dJ pyrididin-10-yl) carbonyl J-3- metocipiprolidine;
    E. 1-C (4,5-digidro-4-metsh1-7-oxo-8-fensh1-7H-pyrido 1,2-ЗZtyeno G2,3-dJ pyridazin-10-yl) carbonylJ-3-methoxy-azetidine ;
    ; G, 1-C (4,5-dihydro-5-methyl-7-oxo-8-phenyl-7H-pyrido 1,2-LJ thieno 2,3-d pyridazin-10-yl) carbonyl I-3-methoxy- azetidine;
    3. 4,5-dihydro-K, K-dimesh1-7-oxo7 8-phenyl-7H-pyrylo C1,2-l 1thieno1; 2,3-d} pyridazine-10-carboxamide.
    I. N-ethyl-10-chloro-6,7-diTydro-N- (2-methoxyethyl) -4-oxo-3-phenyl-4H-pyrido C2,1-aZftalazin-1-carboxamide;
    K. (K) -1-G (455-dihydro 7-oxo 0 phenyl-7H-pyrido 1,2-b} thieno-2,3-dJpig readazin-10-yl) -carbonyl J-2-pyrrolidine-methanol;
    L. 4,5-dihydro-M- (3-methoxyprosta) - 7-oxo-8-phenyl-7H-pyrido P, 2-dTyeno 2,3-d Zpyridazin-10-carboxamide;
    M (4,5-dihydro-7-oxo-8-phenyl-7H0
    0
    5 pyrioS1,2-b} thieno 2,3-dzn) idazin
    10-yl) methyl 4-morpholinecarboxylate;
    H. C4- (6,7-dign, t; go-4-oxo-3-fench1-10-chloro-4H-benzo a quinolizic-1-yl) carbonyl-2,6-dimethylmorpholine.
    The proposed compounds can be used in the form of pharmaceutical preparations. Pharmaceutical preparations should be administered orally, for example, in the form of tablets, lacquer tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, for example, in the form of suppositories, or parenterally, for example, in the form of solutions for injections.
    The proposed products can be used to treat or prevent diseases, in particular for the treatment of seizures and anxiety, as well as
    for the preparation of drugs with muscle relaxant, sedative-hypnotic, anticonvulsant and / or anxiolytic properties.
    19 inventions
    The method of obtaining tricyclic pyridone derivatives of the general formula
    where RC is non-substituted or halogen-substituted phenyl;
    Ry and RC, together with the carbon atom denoted by V, are unsubstituted or substituted by halogen, lower alkyl shy NO, a group of the formula COHH-CH CH- (a), CH-S- (6) or CH CH-CH CH -(at),
    .ef group of the formula - (AO) - -CONR Jl,
    where or 1,
    And - N31Sh1Y alkylene,
    Rj and R4 - hydrogen, lower alkyl
    NIWNHYL alkoxyalkyl shl & RZ with nitrogen atom
    and R together
    form a 3-, 7-membered saturated N-heterocycle, which may be substituted by lower alkyl, hydroxy, lower alkoxy, lower oxyalkyl or lower alkoxyalkyl, which may still contain
    oxygen atom;
    R.e is hydrogen, lower alkyl, lower alkanoyl or aryl-lower alkyl and
    Rjp is hydrogen or lower alkyl, different from the fact that the compound of the general formula
    Rarc
    % s
    Sign Priority;
    12.06.87 when R is hydrogen.
    04/08/88 when R is lower alkyl.
    598879 20
    where e (f have the indicated meanings, is reduced with an alkali metal borohydride. or a derivative of this J compound in the presence or absence of formic acid, and the resulting compound of the general formula
    / de have the indicated meanings, if appropriate, alkylate or acylate with a compound of the general formula Re-X,
    where X is a split group;
    RP is lower alkyl, lower alkanoyl or aryl-lower alkyl or, in the case when R. (A) 01l, is a compound of the general formula
    BUT- (A RC
    (14
     Rf
    ABOUT
    where A R H, n "e Rf have the indicated meanings,
    in the presence of a strong or weak base, is reacted with a reactive carboxylic acid derivative of the formula. RjR N-COOH,
    g De R have the indicated meanings, and the resulting compound of formula A is isolated in free form.
    n p and Compound
    3.10 3000
    0.44 3000
    0.56
    0.23
    1.40
    3.30 3000
    8.20 5000
    0.29 5000
    4.9 (intravenous)
    11.4
    18.4
    3.3
    1.2 5000
    3 / Vo, 1 PD,
    mg / kg (p / v.) mg / kg (p / o.)
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining tricyclic pyridone derivatives of the General formula
    Rd Re AA R b R air N N R f 0 I where Ra is phenyl unsubstituted or substituted with 1 halogen;
    R ^ and R c together with the carbon atom designated by. * /, Represent an unsubstituted or substituted halogen, lower alkyl or N0 ^ group of the formula 0 ^ 8-011 = 011- (a),> C £ -CH = CH -S- (6) or> C d < r-CH = CH-CH = CH- (c),
    R J is a group of the formula - (A * 0) -conr s r 4 , where m = 0 or 1,
    A 'is lower alkylene,
    R 3 and Poison - hydrogen, lower alkyl or lower alkoxyalkyl, or AI 3 and R. together with the nitrogen atom form a 3-, 7-membered saturated N-heterocycle, which may be substituted by lower alkyl, hydroxy, lower alkoxy, lower hydroxyalkyl or lower alkoxyalkyl which may still contain an oxygen atom;
    Re is hydrogen, lower alkyl, lower alkanoyl or aryl lower alkyl and Rp is hydrogen or lower alkyl, characterized in that the compound of the general formula where R ^ jR ^ jR ,,, Rj have the indicated meanings, is reduced with alkali metal borohydride or a derivative of this compound in the presence or absence of formic acid and the resulting compound of the general formula / de R c , Rj and Rp are as indicated, respectively, alkylate or acylate with a compound of the general formula 20 R e * -X, where X is a leaving group;
    R 'e - lower alkyl, lower alkanoyl, or aryl-lower alkyl or, slu25 tea, when R ^ = (A 1) w OH, A compound of the general formula wherein A, R 4> R ^, RftpR with u. Rp have the indicated meanings,
    40, in the presence of a strong or weak base, are reacted with a reactive carboxylic acid derivative of the general formula. R 3 R <N-00011,
    45 where | Qi R, have the indicated meanings, and the resulting compound of formula A ′ is isolated in free form.
    Sign priority; ·
    12.06.87 at Rf is hydrogen.
    04/08/88 at Rf - lower alkyl.
    Compound ED G0 , PM ^, mg / kg (p / o.) Mg / kg (p / o.)
    A 3.10 > 3000 B 0.44 > 3000 IN 0.56 - G 0.23 - D 1.40 - E 3.30 3000 F 8.20 > 5000 3 0.29 > 5000 and 4.9 (inside> military) to 11,4 l 18,4 m 3.3 n 1,2 > 5000
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    同族专利:
    公开号 | 公开日
    CN88103535A|1988-12-28|
    DK317388D0|1988-06-10|
    YU108788A|1990-04-30|
    MC1961A1|1989-06-30|
    HUT47273A|1989-02-28|
    FI882750A|1988-12-13|
    NO882558L|1988-12-13|
    KR890000481A|1989-03-14|
    US4889854A|1989-12-26|
    HU201069B|1990-09-28|
    IL86639D0|1988-11-30|
    EP0294599A2|1988-12-14|
    PT87699A|1988-07-01|
    JPS63316779A|1988-12-26|
    US5082842A|1992-01-21|
    DK317388A|1988-12-13|
    NO882558D0|1988-06-10|
    EP0294599A3|1990-05-09|
    AU1742788A|1988-12-15|
    FI882750A0|1988-06-09|
    PT87699B|1992-10-30|
    引用文献:
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    MC1289A1|1978-10-13|1980-07-22|Hoffmann La Roche|PHENYL QUINOLIZIDINES|
    US4650804A|1984-03-30|1987-03-17|Fujisawa Pharmaceutical Co., Ltd.|Quinolizinone compounds and pharmaceutical composition comprising the same, useful as anti-ulcerative and anti-allergic agents|
    ZW17385A1|1984-11-06|1986-02-19|Hoffmann La Roche|Tricyclic pyridine derivatives|
    CA1317945C|1985-12-13|1993-05-18|Ulf Fischer|Tricyclic pyridazopyridone derivatives|CA1317945C|1985-12-13|1993-05-18|Ulf Fischer|Tricyclic pyridazopyridone derivatives|
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    GB9708945D0|1997-05-01|1997-06-25|Merck Sharp & Dohme|Therapeutic agents|
    WO1999028852A1|1997-12-02|1999-06-10|Technical Graphics Security Products, Llc|Security device having multiple security features and method of making same|
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    AU2005295228B2|2004-10-20|2012-02-16|Swimc Llc|Coating compositions for cans and methods of coating|
    US7482345B2|2005-12-05|2009-01-27|Meng-Hsin Chen|P38 kinase inhibiting agents|
    MX338773B|2009-04-09|2016-05-02|Valspar Sourcing Inc|Polymer having unsaturated cycloaliphatic functionality and coating compositions formed therefrom.|
    US8486574B2|2009-07-14|2013-07-16|Ford Global Technologies, Llc|Method and system for power control in an automotive vehicle|
    AU2010295405B2|2009-09-18|2015-09-24|Swimc Llc|Polyurethane coating composition|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    CH220687|1987-06-12|
    CH129788|1988-04-08|
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