• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Compounds of formula <CHEM> in which R<1> is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 6 carbon atoms, alken (3,4,5 or 6)-yl of 3 to 6 carbon atoms or alkyn (3,4,5 or 6)-yl of 3 to 6 carbon atoms; R<2> is -CCl3, -CN, CO2H, -CO2R<7> where R<7> is alkyl of 1 to 6 carbon atoms or <CHEM> where R<8> and R<9> are independently hydrogen or alkyl of 1 to 6 carbon atoms, R<5> and R<6> are independently hydrogen; alkyl of 1 to 4 carbon atoms, halo, alkylamino of 1 to 4 carbon atoms, or alkoxy of 1 to 6 carbon atoms, or a salt thereof are disclosed which are useful as intermediates to compounds having gastric anti-secretory, and in some case diuretic, activity. Also described are processes for preparing the compounds.
    公开号:SU1131469A3
    申请号:SU803220198
    申请日:1980-12-17
    公开日:1984-12-23
    发明作者:К.Скотес Энтони；А.Сантилли Артур
    申请人:Американ Хоум Продактс Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    Rg
    02.28.80 with R
    69
    naphthyridinyl-4) piperazinyl and 4-carbethoxy-1-pi perazinyl,
    RK is hydrogen or methyl, methyl.
    This invention relates to a process for the preparation of new 4-amino-3-carbethoxy- or 3-cyano-derived, 2-dihydro-2-oKco-1, 8-naphthyridine, which can be used in the treatment of peptic ulcer diseases as gastric antisecretory agents.
    The known reaction of the substitution of halogen by an amino group in the aromatic series of P J.
    The aim of the invention is to develop, on the basis of a known method, a method of obtaining new compounds with valuable pharmacological properties.
    The goal has been achieved by a process for the preparation of 4-substituted amino-3-carbethoxy- or Z-cyano-1,2-dihydro-2-OX0-1,8-naphthyridine derivatives of the general formula
    (I)
    de R is methyl, ethyl or allyl,
    R2 is a carbztoxy or cyano group;
    Rg, R / jN —thylamino. diethylamino, 2-hydroxyethylmethylamino, 3-dimethylaminopropylamino group, pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-phenylpiperazinyl, 4-carbethoxypiperazinyl, 4- (1-methyl-1,2-dihydro-2-2-i-o-o-o-piperazinyl, 4- (1-methyl-1,2-dihydro-2-2-o-o-o-pi-azole) 7-methyl-1, 8-naphthyridinyl-4) piperazinyl or 4-morpholins1; .
    2
    R is hydrogen or methyl, or their salts, consisting in the fact that a primary or secondary amine of the general formula
    Rj-NH-R (II)
    where the residue has the indicated value, interacts with a 4-chloro-1,8-naphthyridine derivative of the general formula
    ,
    (1T1)
    di
    where R, Rj and Rj have the indicated meanings, and the target product is isolated in free form or in salt form.
    Derivatives of 1, 8-naphthyridine of the general formula (1), containing the basic amino group in the 4-position, such as the piperazinyl and dialkylaminoalkyl groups, are capable of forming acid addition salts. such salts being conveniently formed from acids such as hydrochloric, hydrobromic. sulfuric, phosphoric, methanesulfonic, nitric, L-toluenesulfonic, acetic, citric, maleic, succinic and the like. In addition, compounds (1) in the form of their free carboxylic acid can be converted to alkali or alkaline earth metal salts. as well as ammonium or primary, secondary or tertiary alkylamine.
    Each of the antisecretory agents was found to be active in the following gastric antisecretory activity test. 3 Male rats of Charles Rnver of the Sprapiis Dawley strain and having a body weight of 190-240 g deprive themselves of food for 2 d but give them water without restriction before the test. Groups of ten rats each are prescribed treatment or control, or medication. Under ether anesthesia and at the opening of the abdominal cavity in the midline, ligation of the pyloric process is performed and prescribed inside the duodenal or control carrier (0.25 methylcellulose), or the drug in the control carrier. Four hours after ligation of the pylorus, the rats are killed by stifling the carbon with acid gas. The stomachs are removed and the stomach contents are placed in graduated centrifuge tubes. Samples of the contents of the stomachs are centrifuged for 20 minutes, and the samples, obviously contaminated with food, blood or feces, are discarded. The volume of gastric fluid is recorded and the acid concentration is measured in 1.0 milliliter amounts of samples by electrometric titration to pH 7.0 0.1 n. sodium hydroxide. Based on the calculated amount of the product, the volume of the stomach (meq / l), the total acid distribution (HVAC, MWP / 4 h) is evaluated over the four-hour test period. From these data, an abnormality analysis is performed to determine a statistically significant (p less than 0.05) discrepancy between the control and drug treated groups. The compounds can be administered using conventional oral or parenteral administration in the form of solids, liquids, or isotonic solutions. Conventional excipients can be mixed with compounds (|) to produce compositions and solutions for purposes of administration, although it is considered appropriate and desirable to use the compounds in pure form or without additives other than necessary for the creation of suitable pharmaceutically acceptable solid or liquid dosage units. The following examples illustrate the preparation of 1,8-naphthyrizine derivatives of general formula (J). The index of gastric anti-secretory activity of drug compound 94 is given at the end of the group. These data, expressed as percent inhibition, show a decrease in acid secretion in the drug-treated groups compared to the control groups with intraduodenal administration of 32 mg / kg of the test compound. Example 1. 1-Methyl-1,2-dihydro-2-oxo-4- (1-pyrrolidinyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester. A stirred mixture of 2.7 g (0.01 mol) of 4-chloro-1, 2-dihydro-1-methyl-2-oxo-1, 8-naphthyridine-3-carboxylic acid ethyl ester, 0.7 g (OjOl mol ) pyrrolidine and 1.06 g (0.01 mol) of sodium carbonate in 25 ml of ethanol are heated under reflux for 5 hours, filtered and the filtrate is cooled with ice. The precipitate formed is collected and dissolved in 20 ml of ethyl acetate. The solution is diluted with petroleum ether until turbid. The precipitate is collected, yielding 0.5 g of product, m.p., 118120 ° C. Found,%: C 63.46; H 6.51j N 14.01. C, 6H, gNj03. Calculated,%: C, 63.77; H, 6.36; N, 13.95. The percentage of inhibition is 55%. Example 2. 1, 7-dimethyl-1,2-dihydro-2-oxo-4- (1-pyrrolidinyl) -1.8-naphthyridine-3-carboxylic acid ethyl ester. 4-Chloro-1, 7-dimethyl-1,2-dihydro-2-OXO-1, 8-naphthyridine is reacted with pyrrolidine in Example 1 to give the title compound, so pl. 108-11lc. Found: C, 64.78; H, 6.66; N, 13.40. With „H iNjOj. Bitumens,%: C 64.74, H 6.71, N 13.33. The percentage of inhibition is 78%. Example 3. 1-methyl-1,2-dihydro-4- (4-methyl-1-piperazinyl) -2-oxo-1 ,, 8-naphthyrydine-3-carboxylic acid methyl ester. The target compound is prepared analogously to example 1 using N-methylpiperazine instead of pyrrolidine as an amine reagent, t. 231-234 C (decomp;). Found,%: C 5A, 19, H 6.3i; N 14.74. C, 7H23CIN4q}. / 2 NaO Calculated,%: C 54.33, H 6.44, N 14.91. The percentage of inhibition is 74%. Example 4. Ethyl 1,7-dimethyl-1,2-dihydrr-4- (4-methyl -1-piperazinyl) -2-oxo-1,8-naphthyridine-3-carboxylic acid ester. The target compound was prepared in analogy to Example 2 by replacing pyrrolidine with L-methyl-iperazine, I m. Pl. 278-280 € (decomp.). Found%: C 55.66J H 6.51 14.50. 1/2. C.f &amp; Ha5CIN, 0 ,. C 55.45; H 6.72J Calculated,%: 14.37. Inhibition percentage 98%. Example 5. 1-ETHYL-1,2-dihydro-4- (4-methyl-1-pi-perazinyl) -2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester. The target compound was prepared analogously to Example 1 from ethyl eLi, pa 4-HLOR-1-ETHYL-1,2-dihydro-2-oxo-1, 8-naphthyridine-3-carboxylic acid and N-methylpiperazine, mp. 23,233 ° C. Found, Z: C 56.49; H 6.59; N 14.50. C, Calculated,%: C 56.76 H 6.62; N 14.71. The percentage of inhibition is 94%. Example. 6. 1-Allyl-1, 2-dihydro-7-methyl-2-oxo-4- (1-pyrrolidinyl) -1,8-naphthyridine-3-carboxylic acid ethyl ester. The title compound is prepared from 1-alpyl-4-chloro-1, 2-dihydro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester and pyrrolidine analogously to Example 1, mp. 97-103c. C, 66.76; H, 6.88; Found,%; 12.28. With „H jNjOj. Calculated,%: C, 66.84; H 6.79, N 12.31. The percentage of inhibition is 46%. . Example 7. 1-ETHYL-1,2-dihydro-7-methyl-2oxo-4- (1-pyrrolidine) -, 8-naphthyridine-3-carbonitrile. The target compound is obtained from 4-chloro-1-ethyl-1,27DI-hydro-7-methyl-2-oco-1, y-naphthipidine-3-carbonitrile and pyrrolidine analogously to example 1, so pl. 211-213 p. Found,%: C 68.24; E 6.57, N 19.84. Cl6Hf6% 0. Calculated.,%: C 68.06, H 6.43 N 19.85. The percentage of inhibition is 41%. Example 8. 1-ETHYL-1,2-dihydro-7-methyl-2-oxo-4- (1-pyrrolidinyl) -1, 8-naphthyridine-3-carboxylic acid ethyl ester. The target compound is prepared analogously to example 1 from pyrrolidine and 4-chloro-1-ethyl-1, 2-dihydro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, mp. 1 13-115 ° C. Found,%: C 65.67; H 6.97, N 12.82. С18Нг5 ЗОЗ-. Calculated,%: C 65.63 {H 12.76. The percent inhibition is 83%. Example 9. 4-diethylamino-1-ethyl-1,2-dihydro-7-methyl-2-oxo-1, 8-naphthyridine-3-ka1) bonoic acid ethyl ester. Similar to Example 8, when using diethylamine instead of pyrrolidine, the desired compound is obtained, so pl. 79-82PC. Found,%: C 64.39; H 7.40, N 12.58. %% Nj03 Calculated,%: C 65.23; H 7.60; N 12.68. The percentage of inhibition is 50%. Example 10, 1-ETHYL-1,2-dihydro-7-metsh-1-4- (4-morpholinyl) -2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester. Analogously to example 8 when using morpholine instead of pyrrolidine get the target compound, so pl. .129-13lc. Found,%: C 62.47; H 66.46; N 11.99. Calculated,%: C 62.52; H 6.71, N 12.17. Inhibition percentage 88%. EXAMPLE 11 1-ETHYL-1,2-dihydro-7-myl-4- {4-methyl-1-piperazinyl) -2-oc ethyl ester hydrochloride: co-1, 8-naphthyridine-3-carboxylic acid.
    权利要求:
    Claims (4)
    [1]
    METHOD FOR PRODUCING 4-REPLACEMENT- * [VALUABLE DERIVATIVES OF AMINO-3-CARBETOXY- OR 3-CYANO-1,2-DIGIDER0-2-OXO-1,8-NAPHTHIR. IDINE OR THEIR SALTS. (57) A process for preparing 4-substituted amino-3-carbethoxyoxyl or 3-cyano-1,2-dihydro-2-oxo-1,8-naphthyridine derivatives of the general formula rZ x r 3 where is methyl, ethyl or allyl;
    R 2 is carbetoca ^ or cyano;
    RjR | N - ethylamino, diethylamino,
    [2]
    2- hydroxyethylmethylamino,
    [3]
    3-dimethylaminopropylamino group, pyrrolidinyl, piperazinyl, 4-methylpipera zinyl, 4-phenylpiperazinyl,
    [4]
    4-carbethoxypiperazinyl, 4- (1-ethyl-1,2-dihydro-2-oxo-3-carbethoxy-7-methyl-1,8-naphthyridinyl-4) piperazinyl or 4-morpholinyl
    R 5 is hydrogen or methyl, or their salts, characterized in that the primary or secondary amine of the general formula r 3 -nh-r a where the residue R } R ^ N has the indicated meanings, interacts with the 4-chloro-1 derivative, 8-naphthyridine of the general formula wherein R ^, Rj, and R§- have the indicated meanings, and the target product is excreted in free form or in the form of a salt.
    Priority n o 'prism to a m:
    04/18/79 at R, is ethyl or allyl R z - ethyl ester of carboxylic acid or carbonitrile '
    R } , R ^ N - 4-methyl-1-piperazinyl, 1-pyrrolidinyl, diethylamino, “4-morpholinyl, 4-phenyl-1-piperazinyl, (2-hydroxyethyl) methylamino, 3-dimethylSU1131469 n opropylamine o, ethylamino, 1-piperazinyl, 4- (1-ethyl-1,2-dihydro-2-oxo-3-carbethoxy-7-methyl-1,8-naphthyridinyl-4) piperazinyl and 4-carbethoxy-1-pi * perazinyl '
    R 6 is hydrogen or methyl.
    02/28/80 at - methyl.
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US3125579A| true| 1979-04-18|1979-04-18|
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