• 专利附录
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    • 专利摘要:
    The invention relates to compounds having the gener formula (I) wherein n is zero, 1 or 2; each of R1 and R2 is independently: a) hydrogen, halogen, trifluoromethyl or C1-Ce alkyl; b) hydroxy, C1-C6 alkoxy or C3-C4 alkenyloxy; c) nitro, amino, formylamino or C2-C8 alkanoylamino; R3 represents hydrogen or C1-C8 alkyl; R4 is: a') C1-C20 alkyl, unsubstituted or substituted by e') pyridyl, unsubstituted or substituted by one or two wherein each of Ra and Rb is Independently phenyl or C1-C6 alkyl, or Ra and Rb, taken together with the nitrogen atom to which they are linked, form a N-pyrrolidinyl, N-piperazinyl, hexahydroazepin-1-yl, thiomorpholino, morpholino or piperidino ring, wherein said heterocyclic rings may be unsubstituted or substituted by C1-C6 alkyl or phenyl; b') C5-C10 cycloalkyl, unsubstituted or substituted by methyl; c') 2- or 3-pyrrolidinyl, piperidyl of 2-piperazinyl, wherein said heterocyclic rings may be unsubstituted or substituted by C1-C6 alkyl; d') isoxazolyl or thiazolyl, wherein said heterocyclic rings may be unsubstituted or substituted by C1-C6 alkyl; substituents chosen independently from halogen, C1-C6 alkyl and C1-C6 alkoxy; or f) phenyl, unsubstituted or substituted by one or two substituents chosen independently from halogen, CF3,C1-C6 alkyl, C1-C6 alkoxy, amino, nitro, formylamino and C2-C8 alkanoylamino, and the pharmaceutically acceptable salts thereof, which possess immunomodulating activity and are useful e.g. in the treatment of neoplastic diseases and acute and chronic infections of both bacterial and viral origin in mammals.
    公开号:SU1563592A3
    申请号:SU884355119
    申请日:1988-02-01
    公开日:1990-05-07
    发明作者:Дория Джанфедерико；Мария Изетта Анна；Феррари Марио；Трицио Доменико
    申请人:Фармиталиа Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new derivatives of cinnolinecarboxamides or their pharmaceutically acceptable salts having an immunomodulating effect.
    The purpose of the invention is a method for producing new derivatives of cinnolinecarboxamides, which by their immunostimulatory activity are superior to structural analogues possessing the same activity.
    Example 1. 4-hydroxy-Zinnolyn-3-carboxylic acid (4 g) is reacted with SOClj (33 g) at reflux temperature 2 h. After cooling the reaction
    the mixture is evaporated to dryness in vacuo, then the residue (4-oxycinnolyn-3-carbonyl-chloride) is suspended in dichloroethane (700 ml) and reacted with 3-aminopyridine (3.95 g) with stirring at room temperature for 2 hours. Precipitates filtered and washed with dichloroethane and then with water until neutral. The product obtained is purified on a SiO column using chloroform: methanol: acetic acid as an eluent in a ratio of 95: 5: 1. After washing with boiling methanol, 2.6 g of pure 4-hydroxy-M- (3-pyridyl) - cenolyn-3-carboxamide are obtained, m.p. 326- 328 ° C.
    SP
    Od SO Sp

    cm
    NQR spectrum (dimethyl sulfoxide, dfe), “G, ppm: 3.3 (m) (7H, C-4 and C-6 pyridyl protons and phenyl protons); 8.87 (d) (1H, pyridyl proton); 11.95 (broad s.) (1H, CONH-).
    In a similar manner, the following compounds are prepared: 4-hydroxy-K-phenyl-cinnolin-3-carboxamide, m.p. 335- 337 С; 4 hydroxy-N-methyl-N-phenyl-cinnino-3-carboxamide, m.p. 264-266 ° C; 4-hydroxy-1 - (4-methyl-phenyl) -scinnolin-3-carboxamide, m.p. 335-337 С; 4-ox-N (2,6-dimethyl-phenyl) -tsinnolin-3-carboxamide, m.p. 360-365e C (with
    EXAMPLE 2 Methyl ester of 4-hydroxy-ciniolin-3-carboxylic acid (6 g) is reacted with 2-aminopyridine (16.6 g, step-by-step introduction) in polyphosphoric acid, 300 g (160 g H3PO and 140 g PjOj) at 150 ° C and simultaneously stirring for 10 hours. After the solution is cooled with ice water and neutralized with 50% NaOH, the precipitate is filtered and washed with water. After crystallization from dimethylformamide, 4S9 g of 4-hydroxy-M - (2-pyridyl) - cinnoline-3-carboxamide are obtained, m.p. 341-343 ° C.
    Carrying out the process in the same way, the following compounds are obtained; 4-hydroxy Y- (4-pyridyl) -tsinnolin-3-carboxam D, m.p. 358-360 ° C; 4-ca b-K (5-methyl 2 pyridyl) cinnolin-3-carboxamide, mp, 339-341 С „
    EXAMPLE 3 4-hydroxy-Cinninn 3-carboxylic acid (858 g) is dissolved in dichloromethane (600 ml) in the presence of triethylamine (g). In this solution, while stirring, add ethyl chlorofor.rmat (6 g), diluted with dichloromethane (50 ml) at 0-5 ° C. The mixture is reacted at this temperature for 1 hour, then 2-methylaminopiridine (4.55 g) is added. The reaction mixture is kept at 0-5 & C for 1 h9, then at room temperature for 2 h with simultaneous stirring.
    The organic solution is washed with 2.5% NaHC03 and water, then evaporated to dryness in vacuo, the residual evaporation product is purified on a column of SiO using ethyl acetate as a eluent, then an ethyl acetate blender, methanol in a ratio of 95; 65 g of 4-hydroxy-M-methyl-L- (2-pyridyl) -cinnolin-3-carboxamide, mp, 237-239 ° C (from ethanol).
    NQR spectrum (dimethyl sulfoxide, dj), J4 ppm: 3.43 (s) (3N, CHj); 7.0-8.3 (m.) (8H, phenyl and pyridyl protons),
    PRI me R 4. Methyl 4-hydroxy-cinnolyn-3-carboxylic acid (0.6 g) is reacted with 2-aminopyridine (0.56 g) with stirring in xylene (120 ml) at reflux temperature reflux for 48 h. During this reaction, 60 ml of xylene is slowly distilled off. After cooling, the precipitate is filtered and washed with xylene. Obtain 0.35 g of 4-hydroxy-M (2-pyridyl) -cinnol-3 - carboxamide, so pl. 341-343 ° C (from dimethylformamide).
    Carrying out the process in the same way, the following compounds are obtained: 4-hydroxy-N-phenyl-zinc-3-carboxyamide, m.p. 335-337 ° C; 4-hydroxy-H- (3-pyridyl) -cinnol-3-carboxamide, m.p. 326-327 ° C; 4-hydroxy-No- (4-pyridyl) -cinnol-3-carboxamide, m.p. 358-360 ° C.
    EXAMPLE 5 4-hydroxy-K - (3-Pyridyl) -cinnoline-3-carboxamide is dissolved by treatment with an equivalent amount of sodium ethylate in ethanol.
    The solutions are evaporated to dryness and the residual evaporation product is treated with isopropyl ether, then filtered to give the sodium salt of 4-hydroxy-H- (3-pyridyl) cinnolin-3-carboxamide, m.p. 300 ° C. Carrying out the process in the same way, the following compounds are obtained: 4-hydroxy M- (2-pyridyl) -cinnol-3-k arboxamide, trisyl salt, m.p. 300 ° C and 4-hydroxy-No. Phenyl-cinnolin-3-carboxamide, sodium salt, m.p. 300 ° C.
    Biological testing.
    The immunomodulatory activity of the compounds obtained by the proposed method is proved, for example, by the fact that these compounds are effective in enhancing the cytotoxic effect of microphages on tumor cells under in vitro conditions.
    An experimental 7 procedure to evaluate this action is as follows: groups of mice of 4 pcs. processed by inserting the intraperitoneally tested compounds into them, and then, after 7 days, peritoneal
    the cells are harvested and plated for 2 hours at 37 ° C. After this period, the walls are washed to remove non-bound cells, then the target tumor cells are introduced and incubation continues for 48 hours. At the end of this period, the viability of the target cells is measured by the colorimetric method and quantified. score at 570 nm.
    The table summarizes the immunostimulatory activity of some compounds of this invention, obtained according to the experimental procedure described, with respect to TU5 tumor cells (Eur. J. Itnmunol., 1982, v. 12, p 320), together with the data of the known compound 4- Amino-N-phenyl-cinnin-3-carboxamide (internal code FCE-K) according to EP 205272.
    In table FCE 24089, 4-giscuxy-N- (2-pyridine) -cinnol-3-carb: o.xamide, FCE 25008-4-hydroxy-N-phenyl-cinnin-3-carboxamide, FCE 25051-4 - hydroxy-M-methyl-Y- (2-pyridyl) -tsinnolin-3-carboxamide, FCE 25273 - 4-hydroxy-Y- (5-methyl-2-pyridine) -tsinnin-3-carboxamide, FCE 25512 - 4-hydroxy-N- (2,6-dimethyl-phenyl) -tsinnolin-3-carboxamide, FCE-K - 4-amino-I-phenyl-cinnolin-3-carboxamide.
    Cytotoxic activity is calculated as the percentage inhibition of the growth of TU5 tumor cells using the following formula:
    % inhibition
    (O.D.A-O.D.B) - (O.C.C-O.D.D)
    ------------ where
    O.D.A - optical density from ow
    0
    five
    0
    five
    0
    five
    0
    five
    0
    five
    locally grown TU5 and macrophage-treated excipients; O.D.B — optical density only from macrophages treated with excipients; O.D.C — optical density from co-grown TU5 and macrophage-treated FCE; O.D.D is the optical density only from macrophages treated with the FCE compound.
    The same percent inhibition was demonstrated by the compounds of the present invention under the code FCE 24089, FCE 25008, FCE 25051, FCE 25273 and FCE 25512 in the form of sodium salt. The activity data shown in the table shows that a separate class of compounds in accordance with the proposed method is more active as an immunomodulating agent in comparison with the known structural analogues (4-amino-3-cinnoline carboxamides), disclosed in EP 205272.
    As a preferred example of the proposed compounds with immunomodulatory effects, you can call the compound 4-hydroxy-And- (2-pyridyl) -cinnolin-3-carboxamide (internal code FCE 24089).
    The compounds according to the invention can be safely used in medicine.
    So, for example, acute toxicity () in mice caused by 4-hydroxy-K- (2-pyridyl) -cinnolin-3-carboxamide, determined (when administered through the mouth) in a single injection with increasing doses and measured on the seventh day after the day of treatment, it is more than 800 mg / kg. Similar toxicity data were established for other compounds obtained by the proposed method. Accordingly, the compounds FCE 25008, FCE 25051, FCE 25273, and-FCE 25512 have mg / kg per OS. "
    Thus, the proposed compounds have an immunomodulatory effect and can be used, in particular, as immunostimulators, for example, in the treatment of acute and chronic infectious diseases of both bacterial and viral origin, and in the treatment of neoplastic diseases in mammals.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining cinnolinecarboxamide amides of the formula
    HE
    CON
    I
    “2
    or their pharmaceutically acceptable
    salts,
    where Rf is hydrogen or C —C-alkyl,
    R is a phenyl or pyridyl ring, unsubstituted or substituted by one or two C1-C4 alkyl 5 groups
    characterized in that
    compound of formula
    where Z is a carboxy group or its active functional derivative,
    subjected to interaction with the compound of the formula
     .
    R
    where Rf and R have the indicated meanings, with isolation of the target compound in free form or in the form of a pharmaceutically acceptable salt.
    Compiled by A.Sviridov E.Papp Tehred M.Didyk Editor
    Order 1069
    Circulation 324
    VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab 4/5
    Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101
    Proofreader M „Pojo
    Subscription
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    法律状态:
    优先权:
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