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    • 专利摘要:
    NEW MATERIAL:A 1,8-naphthylidine derivative of formula I (X is halogen; R is amino; R1 is lower alkyl, lower alkenyl, lower alkynyl; R2 is H, lower alkyl), and its salt. EXAMPLE:6 -Chloro-1-ethyl-1, 4-dihydro-4-oxo-7-pyrrolidino-1, 8-naphthylidine-3- carboxylic acid. USE:Antibacterial agent especially effective to gram negative bacteria including Pseudomonas aeruginosa. Medicine, animal drug, fish drug, food preservative, intermediate of various compounds, etc. PROCESS:The title compound I is prepared, e.g. by reacting a compound II (Y is a functional group which can be replaced with amine group) with an amine R-H in an inert solvent such as ethanol, etc., at 20-180 deg.C, pref. 50-150 deg.C, for 20-60 minutes. The compound II is also novel.
    公开号:SU1037841A3
    申请号:SU802976304
    申请日:1980-09-03
    公开日:1983-08-23
    发明作者:Мацумото Юн-Ити；Такасе Есиюки；Насимура Есиро
    申请人:Дайниппон Фармасьютикал Ко,Лтд (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new naphthyridine derivatives that may be used in medicine.
    A known method of producing 7-piperazine derivatives of 1,8-naphthyridine by reacting 7-halogen derivatives of 1,8-naphthyridine with piperazines 1 J.
    The purpose of the invention is to obtain new biologically active compounds.
    The goal is achieved according to the method for preparing the naphthyridine derivatives of the formula
    about
    X ... L COOH
    SP
    "ABOUT
    N 1G
    where is x. represents a fluorine or chlorine atom, ethyl or vinyl; hydrogen atom or lower
    alkyl;
    or pharmaceutically acceptable salts thereof, comprising: that the compounds of the general formula
    Cl)
    where Y is a halogen atom, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylsulfonyloxy, or arylsulfonyloxy group; X, K1i1, the indicated values, are reacted with piperazine in the presence of an inert solvent at 20-150 ° C, followed by isolation of the target product in the free state or in the form of salts.
    Salts of naphthyridine compounds are formed by reacting the naphthyridine compound with acids or bases.
    Acids can be inorganic or organic: hydrochloric, acetic, lactic, succinic, and methanesulfonic acid.
    The bases are any inorganic or organic bases capable of producing salts with carboxyl groups of the compounds of formula (1), for example, metal hydroxols, such as sodium or calcium hydroxides and metal carbonates, such as sodium or potassium carbonates.
    Preferred salts of formula (I) are chlorides or methanesulfonates.
    Depending on the conditions, the naphthyridine compounds of the formula (I may be isolated in the form of hydrates.
    The reaction of substitution of the hydrogen atom of the 7th position of formula (1) with a piperazyl group
    /
    -n
    carried out by heating the LQ compounds of the formula. (II) and piperazine in a solvent, if necessary, using a sealed reaction vessel. Preferably, the reaction is carried out in the presence of a base dp neutralizing an acid, such as bicarbon, sodium, sodium carbonate, Kli carbonate, triethylamine, pyridine or picoline.
    Compounds are taken in stoichiometric amounts. In addition, an excess of piperazine compound can also be used to neutralize the acid.
    The solvent used in the reaction is chosen taking into account the properties of the initial substances. Examples of dissolve. The bodies can be aliphatic alcohols, such as ethanol or propanol, aromatic hydrocarbons, such as benzene, toluene, haloalkyls, such as dichloroethane or chloroform, ethers, such as tetrahydrofuran, dioxane or diphenyl ether,. acetonitrile, dimethyl sulfoxide, di. Methyl formamide and water. They can be used25, called both in pure form and mixed with each other.
    Compounds of this invention. obtained by the above method, are isolated and purified by conventional methods.
    40 Compounds of general formula (I) are obtained in free form or as a salt, depending on the choice of starting materials and the reaction conditions. They can be converted to pharmaceutically applicable salts by treating them with acid or base. Various organic and inorganic acids are used as acids: succinic, lactane, oxalic and
    5Q methanesulfonic.
    The novel 1,8-naphthyridine derivatives related to this invention have, as shown in the examples given, high antibacterial activity. Therefore, these
     The compounds can be used as drugs for treating or preventing bacterial infections of warm-blooded animals and humans.
    The dosage of the proposed compound is 60 total for-1ula (I) or its salts when administered. And a person can be determined based on age, body weight and condition of the patient, method of use, frequency of administration of the drug, etc.  A typical adult dose of aufi is 0.1-7 g per day, preferably 0.2-5 g per day.  The proposed compounds can be used as medicaments, for example in the form of pharmaceutical compositions in admixture with organic or inorganic solid or liquid auxiliary substances suitable for pharmaceutical use, suitable for oral administration or topical administration.  Pharmaceutical useful excipients are substances that do not react with the compounds of the invention.  Example E can be water, gelatine, lactose, starch, cellulose (preferably microcrystalline cellulose), carboxymethyl cellulose, methyl cellulose, sorbitol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, propylene glycol, polialkilenglikoil, metiloksalilmochevina and others known in the pharmacy tick auxiliary substances, pharmaceutical compositions can be powders, granules, tablets, ointments, suppositories, creams, capsules, t. d.  They may be sterilized and / or contain adjuvants, such as preservatives, stabilizing or wetting agents, and may contain other therapeutically valuable substances depending on the purpose of the preparation.  The process for the preparation of the novel compounds of general formula (I) and their salts, as well as their pharmacological activity, are given below.  Examples A-C demonstrate the pharmacological activity of a compound of the general formula f and their salts in comparison with control compounds beyond the scope of this iso.  E) eteny.  .  , Q The compounds given in the examples and standard procedures were investigated by elemental analysis, IR spectroscopy, NMR spectroscopy, mass spectrometry and chromatography in a thin layer.  Comparative method 1.  Preparation of the starting compound of formula 5 COOH xy C1 - A mixture of 1-ehil-b-fluoro-1,4-dihydro-7-oxy-4-oxy-1,8-naphthyridine-3-carboxylic acid 1h, 25 g) and chloro phosphoryl hydrochloride (30 ml.) is heated under reflux for 5 minutes.  After removing the excess phosphoryl chloride by distillation, 30 g of ice-water mixture is added to the residual distillation with simultaneous alternation, and the mixture is kept at room temperature overnight.  The precipitated precipitate is removed by filtration, washed and recrystallized from acetonitrile, the result is 3.2 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-OKCO-1, 8-naphthyridine-3-carbon acids, with t. square  265-267t.  Elemental analysis.  Found,%: C 48.89; H 2.92, N10.33i Cl 13.21.  F 7.07.  .  C I N OjClF%: C 48.81; H 2.98; Calculated N10.35; C1 13.10; F 7.02.  IR (KBr), cm-3, - 1710, 1630.  Example 1 Preparation of the compound of general formula (I).  To a stirred mixture (maintained at 70 ° CJ anhydrous piperazine (7.96 g) and acetonitrile (200 ml)) is added a hot solution of 7-chloro-1-methyl-6-fluoro-1,4-DIGIDRO-4-oxo -1, 8-naphthyridine-3-carboxylic acid (5.0 g) in 200 ml of acetonitrile.  The reaction mixture was kept at 70 ° C for 1 hour while stirring.  After the acetonitrile has been removed by distillation, 150 ml of an aqueous 3% acetate acid solution are added to the residual distillation.  The insoluble material is filtered off and the filtrate is evaporated to dryness under reduced pressure.  100 ml of water and 10 ml of a 28% aqueous solution of ammonia are added to the evaporation residue, the mixture is heated for a few minutes and cooled in an ice bath.  The resulting solid product is recovered, washed with water and recrystallized from mixture e. tanol with chloroform, resulting in 5.4 g of 1-ethyl-6-fluoro-1, 4-DIHYDRO-4-OXO-7- (1-pceperazinyl) -1,8-naphthyridine-3-carboxylic acid with t . square  220-224C.  Elemental analysis.  Found,%: C 56.35; H 5.37, 17.38; F 5.87.   Calculated,%: C 56.24; H 5.35; 17, 48; F 5.93.  IR (KBr), CM 1l7lO, 1635.  PRI me R 2.  Preparation of the ester compound of the general formula (. Mr. J.  The solution of methyl-1-ethyl-7-ethanesulfonyl-6-fluoro-1, 4-DIHYDRO-4-OXO-1, 8-naphthyridine-3-carboxylate (1.0 g), and anhydrous piperazine (0.6 g) in 60 ml of acetonitrile, heated under reflux for 1 hour.  The mixture is evaporated to dryness under reduced pressure and the residue crystallizes out. ayut u: ethnlatsstat.  The recovered solid product is recrystallized from ethyl acetate, to obtain 0.63 g of ethyl 1-ethyl-6-fluoro-1, -DIGIDRO-4-OXO-7- (1-piperaenil) -1,8-naphthyridine-3-carboxylate , t square  150-15lOc.  Elemental angshiz.  Found,%: C 58.62; H 6.30; N 15.90; F 5.44.  C.  Calculated,%: C 58.61, H 6.08; N i6.08; F 4.58. :), cm -1710, 1680, 1610.  Example 3  Carrying out the process as in Example 1, I get the following compounds.  Compound-1: a) 1-ethyl-6-fluoro-1,4-dihydro-4-oco-7-hydrochloride - (;; l-piperidinyl) -1,8-naphthyridine-3-carboxylic acid.  . square - above .  Elemental analysis.  Found,%: C 50.40, H 5.10, N 15.67; C1 9.86; F 5.18.  СЛ 40эС1Р Calculated,. %: C 50.50; H 5.09, 1 15.70; C1 9.94, F 5.33.  IR (KBG) cm-; 1725, 1535.  b) 1-ethyl-6-flu-1,4-dihydro-4-oxo-7- (1-piperazinyl) -, 8-naphthyridine-3-carboxylic acid methanesulfonate. T. square  above 300 ° С (decomposition).  Elemental analysis.  Found%: C 46.28; H 5.19; I am 13.27 | S 7.74} F 4.58, Q. ,, 0-, SF Calculated,%: C 46.14, H 5.08, N 13.46; S 7.70; F 4.56.  IR (KBr) ci;: 1720, 1625.  c) 1-ethyl-6-fluoro-1,4-di acetate HYDRO-4-OXO-7-1-piperazinyl) -1, -naphtiridine-3-carboxylic acid.  T. square  228-229 0.  Elemental analysis.  Found,%: C 53.80; H 5.78, N 14.60-, F 4.96.  c Y OslCalculated,%: C 53.68; H 5.57 / N 14.73; F 4.99.  IR (KBr), 1705, 1625.  Compound 2.  a) 6-fluoro-1,4-dihydro-4-bxo-7 - (1-piperizinyl) -1-vinyl-1,8-napht reedin-3-carboxylic acid.  T. pl 256-260s (with decomposition).  Elemental analysis; Found%: C 56.55; H 4.77; N 17.51; F 6.05.   C 56.60; H 4.75; Calculated,% :,. .  .  N 17, in; F 5.97.  IR (KBG), CM. U620, b) 6-fluoro-hydrochloride}. , 4-dihyd-4-oxo-7- (1-piperazinyl) -1-vinyl -1,8-naphthyridine-3-carboxylic acid T. square  (with decomposition).  Element analysis.  Found, t: C 50.63; H 4.44; 15.5, C1 9.95; R 5.30.   %: C, 50.78; H 4.55; Calculated 15.79; C1 9.99; F 5.36.  IR (KBr), cm: 1720, 1620.  c) 6-fluoro-1,4-hydro-4-oxo-7- (1-piperazinyl) -1inyl-il, 8-naphthyridine-3-carboxylic acid methanesulfonate.  - T. square  291-293 ° С, (with dilution 1 Elemental analysis.  Found,%: C 46.45; H 4.45 / 13.26; S 7.68; F 4. 47   Calculated,%: C 46,37; H 4.62; 13.52; S 7.74; F 4.58.  IR (KBr), civr. ; 1710, 1620.  Compound 3: 6-chloro-1-ethyl-1,4-diDRO-4-OXO-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid hydrochloride.  square  above 300 C.  Elemental analysis.  Found,%: C 48.26, H 6.10; 14.80; C1 19.22.   Calculated,%: from 48.27; H 4.86; 15.01; CI 19.00.  IR (KBr), cm-; 1710, 1600.  Compound 4: 6-chloro-1,4-dihydro-4-oxo-7- (1 iperazinyl) -1-vinyl-1,8-naphthyridine-carboxylic acid.  T. square  2724 0.  Elemental analysis.  Found,%: C 53.96; H 4.49 / 16.57; C1 10.77.  CJlJj. OaCI WHITE,%: C 53.81, H 4.51) 16.74; C1 10.59.  IR (KBr), cm - 11620.  Example4; Carried out promp as in example 2, get unity.   The I-propyl ester of the general formula {1) -H-propyl-1-6-fluoro-1, 4-DIHYDRO-4-OXO-71-piperazinyl) -1,8-naphthyridine-3-carboxylate.  T. square  133-135 s.  Elemental analysis.  Found,%: C 54.48; H 6.49; 15.41; F 5.40.  Gsleno,%: C 59.66; H 6.40, 15.46; F 5.24.  IR (KBr), cm L-1720,. 1670, 1620.  The n-butyl ester-butyl-1-ethyl-6-fluoro-1, 4-dihydro-oxo-7- (1-piperazinyl) -1,8-naphridine-3-carboxylate.  T. square  1190C.  Elemental analysis.  Found,%: C 60,58; H 6.42; 14, F 5.09.  number,%: C 60.62; H 6.69) 14.88; H 5.05.  lR (KBr), CM-t-1720, 1670, 1610, Primerz.  Preparation of a compound of the general formula (I K To a stirred mixture (maintained at a temperature) of anhydrous piperazine (1/72 g) and acetonitrile (80 ml) is added in a hot solution of 1-ethyl-7-ethyl-b-fluoro- 1,4-DITIDRO-4-OXO-1,8-naphthyridine-3-, carboxylic acid (1.48 in 100 ml of acetonitrile.  The mixture was heated under reflux for 1 hour while stirring.  After removal of the solvent, under reduced pressure, the resulting solid product is recovered, washed with water and recrystallized from a mixture of ethanol and chloroform. 1.7 g of 1-ethyl-6-fluoro-1,4-dihydro-4 oco-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid s, t. square 220-224, Cement Analysis.  .   Found,%: C &6.32; H 5.34; N 17.68; F 5.98.   Calculated,%: C 56.24; H 5.35; N 17.49, D 5.93.   Infrared spectrum JR (KBr), cm 1710, 1635.  .  PRI me R 6.  The radiation of the ethyl ester of a compound of general formula (I).  Ethyl-1-ethyl-7-ethanesul-6-fluoro-1,4-dihydro-4-oxy-1, 8-naphthyridine-3-carboxylate solution (1.7 g} and anhydrous piperazine (1.72 g) in 80 ml of acetonitrile is heated under reflux for 1 h.  The reaction mixture is processed in the same way as Example 2 and 1.32 g of ethyl 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3- carboxylate, t. square  150-151C.  Elemental analysis.  Found,%: C 58.48; H 6.29, N 15.98; F 5.53 Calculated,%: C 58.6i; H 6.08; N 16.08; F 5.45.  3R infrared spectrum (KBrX cm 1710, 1680, 1610.  PRI me R 7.  Getting connected  no general formula (I).  aj To a stirred mixture (maintained at) anhydrous piperazine (1.72 g) and acetonitrile (90 ml), a hot solution of 1-ethyl-6-fluoro-1,4-dihydro-7-methanesulfonyloxy-4 is added dropwise. -oxo-1,8naphthyridine-3-carboxylic acid (1.15 g) in 110 ml of acetonitrile. The mixture is heated under reflux for 1 h with simultaneous stirring.  After distilling off the solvent under reduced pressure, the resulting solid is recovered.  washed with water and recrystallized from a mixture of ethanol and chloroform, the result is 1.24 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3 -carboxylic acid, t. square  220-224 S.  Elemental analysis, Found,%: C 56.13; H 5.29; N 17.52; G 5.98.  C. . O, J5 17 „4 3 Calculated,%: C 56.24; H 5.35, N 17.49, F 5.93.  : 3R (KBr), cm; 1710, 1635.  b) 1-Ethyl-6-fluoro-1 ,, 4-dihydro-7- (ps1pc (-toluenesulfonyloxy) -4-oxo-1, 8-naphthyridine-3-carboxylic to-acid (2; 03 g) is treated anhydrous piperazine (1.72 g) in 200 mp of acetonitrile as in Example 74 and 1.31 g of 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -1.8 -naphthyridine-3-carboxylic acid, t. square  220-224s.  Elemental analysis.  Found,%: C 56.27; H 5.38; N 17.47-, T- 5.88.  C, 5H, -, MdO ,, 1-Calculated,%: C 56.24} H 5.35; .  H 17.49; F 5.93.  JR (KBr), cm-: 1710, 1635.  PRI me R 8.  Preparation of the compound of general formula (I). .  A mixture of D-ethyl-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1, 8-naphthyridine-3-carboxylic acid (1.33 g) and anhydrous piperazine (2.0 g) in 150 ml of acetonitrile is heated under reflux for 1.5 hours  After distilling off the solvent under reduced pressure, the resulting solid product is taken out, washed with water and purified by recrystallization from a mixture of ethanol and chloroform, as a result, 1.0 g is obtained.  1-ethyl-6-fluoro-1,44 dihydro-7- (1-piperazinyl) -4-oxo-1,8-naphthyridine-3-carboxylic acid, t. square  220-224 ° C.  Elemental analysis.  Found,%: C 5b, 13, -H 5.2, N 17.56; F 5.93.  Lb 40s1 Calculated,%: C 56.24; H 5.35; N 17.49; F 5.93.  3R (KBr), cm- 1710, 1635.  Example9.  Preparation of the ethyl ester of the compound of the general formula (1).  Anhydrous piperazine (4.3 g) is added to a solution of ethyl-7-chloro-1-ethyl-6-fluoro-1, 4-dihydro 4-oxo1, 8-naphthyridine-3-carboxylate (2.98 g) in an ethanol mixture ( 50 ml) c. ; loroform (50 ml). The mixture is stirred overnight at room temperature, then evaporated to dryness under reduced pressure.  The residual product of evaporation-perekrisallizovat from ethyl acetate, the result is 2.85 g of ethyl-G-these-b-fluoro-1, 4-DIHYDRO-4-OXO-7- (1-pin-razinil) -1,8-naphthyridine- Z-carboxyl ta, t. square  150-15l c.  Elemental analysis.  Found,%: C 58.58; H 6.24; N 15.92; F 5.43.   by number, -%: C 58.61, H 6.08; N 16.08; F 5.45.  , JR (KBr), CM. -ITIO, 1680, 1610, PRI me R lO.  Preparation of the compound of general formula (1.  A mixture of 7-chloro-1-ethyl-6-fluoro-1,4. -dihydro-4-OKCO-l, 8-naphthyridine-3-carboxylic acid (2.7 g) and waterless piperazine (3.4 g) in toluene (100 ml) are heated at 120 ° C for 30 minutes at stirring simultaneously.  The mixture is evaporated to dryness under reduced pressure.  10% - Acetic acid is added to the evaporation residue, and the mixture is filtered to remove insoluble material.  The filtrate is alkalinized with 28% ammonia solution, then heated in a steam bath for several minutes and cooled. The resulting solid is recovered, washed with water and recrystallized from a mixture of ethanol and chloroform, to give 2.86 g of 1-ethyl-6- fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-. naphthyridine-3-carboxylic acid, t. 220-224 s.  Elemental analysis; Found,%: C 56.28, H 5.32; N 17.57; F 6.04.   Calculated,%: C 56.24; H 5.35; N 17.49; F 5.93. .  3R (KBr), cm-; 1710, 1635.  Example 11 and 12.  Analogously to Example 2, the following compounds are obtained (see  tab. one).  About F. N JL OOOR2 Ri.  . . .  The following comparative method, ke 2, describes the preparation of a compound not included in the scope of the invention, the preparation of which has not been described previously, with the aim of assessing the pharmacological effect of the new 1,8-naphthyridine compounds according to the invention.  Comparative method 2.  Preparation of comparative compound of formula 9 To a solution of 37% formalin (12 ml) and formic acid (18 ml) 6.0 g of 1-ethyl-6-fluoro-1,4-DIHYDRO-4-OXO-7- (1-piperazinyl) -1, 8-naphthyridine-3-carboxylic.  acids and the mixture is heated at 120-125 ° C for 4 h while stirring simultaneously.  The mixture is then evaporated to dryness under reduced pressure, the residual evaporation product is adjusted to a pH of 8 by adding aqueous 7% sodium bicarbonate solution and extracted with chloroform.  The extract is dried, the solvent is evaporated.  The crystalline residue is recrystallized from a mixture of dichloromethane and ethanol,. . 5.0 g of 1-ethyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-1,8 naphthyridIN-3 carboxylic acid are obtained, t. square  228230 C.  Elemental analysis.  Found,%: C 57.53; H 5.74; N 16.76; F 5, 64.  Calculated,%: C 57.47, H 5.73, N 17.76; P 5.68.  JR (KBr), cm: 1710, 1630.  The pharmacological activities of the predagai compounds of general formula (I) and their salts in comparison with the known antibacterial agents are shown in Examples A to G below.  The following compounds are tested. Compound 1 - 1-ethyl-b {-fluoro-1,4-diHydro-4-oxo-7- (1-piperazinyl J-1, 8-naphthyri {1IN-3-carboxylic acid I v. sO COCfH compound 1-1-ethyl-6-fluoro-1,4-dihydro-4-oxy-7- (1-piperazinyl) -1, "- naphthyridine methanesulfonate O FNy. . A. COOH: lL-DCHD -b3d-conscious compound 2 - 6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1-vinyl-1, 8-naphthyridine-3-carboxylic acid Compound 3 - hydrochloride b-chloro-1-ethyl-1, 4-DIHIDRO-4-OXO-7- (1-piperazinyl) -, 8-naphthyridine-3-carboxylic acid lischericliia coliP-5101 Pseiidonionas acruginosa No. 12 The effectiveness of in vivo with a common infection in Oral mice are listed in Table. 3  From the results table. 3, it follows that compounds 1 and l demonstrate active therapeutic efficacy in the general infection with gram-positive and gram-negative bacteria.  The therapeutic efficacy of compound 2 against gram-positive bacteria is lower than that of compounds 1 and 1, but in the case of gram-negative ba. Its therapeutic efficacy is higher.  Coordination 2 is therefore particularly useful for the treatment of a common infection caused by Pseudomonas aeruginosa.  Compounds 1.1 and 2 demonstrate better therapeutic efficacy in the general infection with gram-positive bacteria, especially Pseu domonae aeruginosa, than compounds A and C, compounds; E and F, which are industrial synthetic antibacterial agents, and Compounds G, Ne F, which are industrial antibiotics.  Compounds 1 and l have greater therapeutic efficacy than compounds D against gram-positive bacteria in vivo.  Compounds 1, 2 are much better than Compounds D in therapeutic efficacy in vivo against gram-negative bacteria, including Pseudomonas aeruginosa Compound ethyl ester (.  1 1 is convenient as an intermediate product for the synthesis of compounds 1 and 1.  It also demonstrates high anti-bacterial activity in vivo against gram-positive and gram-negative bacteria.  Example C. (therapeutic efficacy in vivdj.  The therapeutic efficacy of compounds 1,2 and D was tested in mice against an upcoming kidney infection, caused by Pseud monas aeruginosa no. 12, according to the following procedure.  In females (ddx) weighing 22-30 under intravenous pentobarbital anesthesia (50 mg / kg), a small suprapubic. a cut, the bladder is opened and 0.1 ml diluted in a ratio of 1:10 is injected. 000 cultures of Pseudoroonas aerugunosa 12, grown for 20 hours, using a 0.25 ml syringe and 0.25 mm needle.  Mice are restricted to drink for a period of 1 day before and 1 day after infection, for 3 days after infection, they are treated with drugs twice a day.  To reveal the bacteria on day 5 after infection, the kidneys are removed, cross sections are prepared, placed in King A agar solution, and incubated overnight.  At the same time, no bacteria from an upcoming kidney infection were found in the kidneys.  The value of E) is calculated using averaged analyzes.  The in vivo efficacy of the compounds during ascending infection of kidney Pseudomonas aeruginosa No. 12 in mice is given in Table. four.  From the results table. 4, it follows that the therapeutic efficacy of compounds 1 and 2 against an upcoming infection of the kidney caused by Pseudomonas aeruginosa is much better than that of compound D.  Example D (acute toxicity).  A solution containing each of compounds 1-4 and compounds B - F, in various concentrations, is orally administered: to American ddT (in groups from 4 to 8 each) in a dose of 0.1 t-ui for every 10 g weight of the mouse.  The number of dead mice is calculated in 7 days. , and in accordance with the method of Behrens-Kaerbera calculate the average lethal dose (JJDgoMr / Kr).   The results obtained are presented in Table. five.  From the results table. 5 shows that compounds 1-4 have a very low toxicity, compounds B obtained by introducing the methyl group at position 4 in the 1-piperazinyl group of compound (1) show the same or higher antibacterial activity than the compounds of the invention, as shown in table. 1 and 2, however, has very high toxicity.  , PRI me R E (subacute toxicity).  Compound 1 was orally administered to six MELSHAM-self (TCL-ICR lines), having an average weight of 20 g, in an amount of 2 g / kg at a time in one of 14 days.  During the test.  For each period, each mouse is weighed.  On the 15th day a hematological examination was performed.  After the hematological examination, the mice were euthanized, weighting of each of the organs was carried out, as well as histopathological observation.  Get the following results.  Abnormality was not observed in the group of mice administered with compound 1, based on body weight and organs, hematological examination and histopathological observation compared with the control group of mice.  This demonstrates the high security of compound 1.  PRI me R I- (level.  In the plasma of two male Beagle weighing 12 kg each, capsules containing one of compounds 1 and 2 in a dose of 25 mg / kg of body weight per dog with 200 ml of milk, respectively, are orally administered.  Blood samples are taken from the veins of each dog through O, 5, 1.2. , 3, 6, 8, and 10 hours after administration, and centrifuging each sample, the plasma was separated.  The level of the drug in the blood is determined by thin layer plate chromatography using Kscher chia coli Kr.  as an indicator The results obtained with this are shown in Table. 6  From the results table. 6, it can be seen that compounds 1 and 2 are well absorbed by the body when administered orally and the plasma level of the drug has remained at a high level for quite a long time.  In particular, compound 1 demonstrates a higher plasma level than the MIC values (see  tab. 2), against most bacteria during 1 to 10 hours after administration.  Compound 2 showed the same plasma level over time at least 2 hours and even higher levels 10 hours after administration.  For example, plasma 1 (5.9 mg / mp) is 8 times higher than the MIC against Pseudomonas aeru inosa 12 and Staptylococcus aureus No. 507704, and 60 times higher than the MIC against Escherichia coli P-5101.  Compounds 1 and 2 demonstrate fairly high plasma levels and the high antibacterial activity of the drug is observed at low doses in the treatment of a common infection caused by various bacteria.  Example C (urinary excretion) The urines of the dogs used in Example F are collected for 24 hours, and compounds 1 and 2 in the urine are determined as in Example F.  The results are shown in Table. 7,
    Example Connection
    The propyl ether of the compound of the general formula (1
    Butyl ester of the compound of the general form. (I)
    : i :::::: :::
    M.p.
    -CjHy-CHgCHjCHj 133-135
    -CjHj-CH2 (CH2) 2CH 119-120 From the results of Table 7 it follows that the excretions of compounds 1 and 2 in the urine are quite good, and constitute about 30-40% of the preparation. Administered orally, during 24 hours, the level preparations 1 and 2 (326–205 mg / ml) in urine exceeds from 13 to 6000 times the MIC (0.1–25 mg / ml) of various bacteria, as shown in Table 2; respectively, compounds 1 and 2 demonstrate higher efficacy at lower doses in the treatment of urinary tract infection caused by various bacteria. As follows from Tables 1-7, the proposed compounds, especially Compounds 1.1 and 2, demonstrate high therapeutic efficacy in severe infections with gram-positive and gram-negative bacteria and, after oral administration, they retain a high level in plasma and urine over time. much longer. Moreover, they are low toxic. According to these compounds, they are effective for treating infections of the urinary tract and general infections caused by various bacteria. In contrast, known compounds A and C are inferior in antibacterial activity in vitro and in vivo against gram-positive and gram-negative bacteria, as shown in Tables 2 and 3. Nalidine nalidixic acid J acid - Compound E and pimemidinic PipcmidicJ acid - Compound F which are industrially available synthetic antibacterial drugs, and carindacillin Cajrindaciriin - compound G, ampicillin ampleill in) - compound H and cephalexin fCephalexinJ compound E, which are the industrially available antibiotics, inferior to compounds 1.1 and 2 in therapeutic effect (see Table 3 in vivo against gram-positive bacteria, in particular Pseudomanas aeruginosa). Table 1
    Continued tabl, 2
    StaphylococcUs
    Proteus morganii
    Enterobacter
    cloacal
    P-2540
    1.56
    Continuation of table 2,
    3.13 2QQ
    200
    Pseudomonas.aerugino The "ED value" is calculated according to the .Reference-Caerber Arcli method. Ecr. Paih. Plarm 162,480 (.19311 Crushed for free carboxylic acid.
    Continuation of table 2
    Ta-bditsa3
    25
    Method of administration
    Compound
    one
    one
    2
    3
    four
    AT
    WITH
    D
    E
    F
    G
    H
    F
    {Values calculated for carbon
    ACIDS
    26
    1037841
    Table
    ED mg / kg 2.4 Orally 0.56
    The same 11 16.1
    table 5
    . "-" "-" i - 1
    T EDjo mg / kg
    More than 4000
    4000 4000 2000 2000 210
    200Q 2000
    1516
    5000 4000 5ODO
    3000
    Table
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives
    1.8- naphthyridine of the general formula
    0 NN At NN 1 to
    where X represents ’atam of fluorine or chlorine;
    - ethyl or vinyl; "
    R „is a hydrogen atom or lower ί alkyl, or pharmaceutically acceptable salts thereof, characterized in that the compounds of the general formula wherein Y is a halogen atom, lower alkoxide, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylsulfonyloxy or arylsulfonyloxy group;
    X, R ^ H RgHMeiqT the indicated values are reacted with piperazine in the presence of an inert solvent at 20-150 ° C, followed by isolation of the target product in a free state or in,
    ABOUT
    FO m 00
    4 ^ read salt.
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    同族专利:
    公开号 | 公开日
    ES8202022A1|1982-01-01|
    JPS5710109B2|1982-02-24|
    JPS5531042A|1980-03-05|
    ES491221A0|1982-01-01|
    SU1075976A3|1984-02-23|
    ZA794478B|1981-04-29|
    PL120155B1|1982-02-27|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPS5770889A|1980-10-21|1982-05-01|Dainippon Pharmaceut Co Ltd|1-ethyl-1,8-naphthyridine derivative and salt thereof|
    JPS5772981A|1980-10-22|1982-05-07|Dainippon Pharmaceut Co Ltd|1,8-naphthyridine derivative and its salt|
    JPH0212229B2|1980-12-24|1990-03-19|Dainippon Pharmaceutical Co|
    JPH0212230B2|1981-02-27|1990-03-19|Dainippon Pharmaceutical Co|
    US4382937A|1981-02-27|1983-05-10|Dainippon Pharmaceutical Co., Ltd.|Naphthyridine derivatives and their use as anti-bacterials|
    JPS57146775A|1981-03-06|1982-09-10|Dainippon Pharmaceut Co Ltd|1,8-naphthyridine derivative and its salt|
    JPH0430396B2|1983-11-21|1992-05-21|
    JPH0374230B2|1983-12-09|1991-11-26|
    DE3508816A1|1985-01-10|1986-07-10|Bayer Ag, 5090 Leverkusen|6,7-DISUBSTITUTED 1-CYCLOPROPYL-1,4-DIHYDRO-4-OXO-1,8-NAPHTYRIDINE-3-CARBONIC ACIDS|
    EP0787720B1|1994-10-20|2003-07-16|Wakunaga Seiyaku Kabushiki Kaisha|Pyridonecarboxylate derivative or salt thereof and antibacterial containing the same as active ingredient|
    DE69729565T2|1996-04-19|2005-06-09|Wakunaga Pharmaceutical Co., Ltd.|New pyridonecarboxylic acid derivatives or salts of these derivatives and antibacterial agents containing these active agents|
    CA2367373C|1999-03-17|2011-09-20|Daiichi Pharmaceutical Co., Ltd.|Medicinal compositions|
    WO2001017991A1|1999-09-02|2001-03-15|Wakunaga Pharmaceutical Co., Ltd.|Quinolinecarboxylic acid derivative or its salt|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP10423578A|JPS5710109B2|1978-08-25|1978-08-25|
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