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    • 专利摘要:
    NEW MATERIAL:The pyridone derivative of formula I (X1 and X2 are halogen; Y is N, CH or CF; R1 is lower alkyl, lower alkenyl or cycloalkyl; R2 and R3 are H, lower alkyl or cycloalkyl; k is 3, 4 or 5; m and n are 0, 1 or 2), its ester and its salt. EXAMPLE:7-(3-Amino-4-fluoro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4 -dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride. USE:An antibacterial agent useful for the preservative for pharmaceuticals, agricultural chemicals and foods, or its intermediate. PREPARATION:The compound of formula I can be produced by reacting the carboxylic acid of formula II (Z is reactive functional group such as halogen, arylsulfonyl, etc.) or its ester (preferably lower alkyl ester) with the cyclic amine derivative of formula III.
    公开号:SU1456015A3
    申请号:SU864023809
    申请日:1986-02-14
    公开日:1989-01-30
    发明作者:Мацумото Юн-Ити；Накано Юндзи；Тиба Кацуми；Накамура Синити
    申请人:Дайниппон Фармасьютикал, Ко., Лтд (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the field of production of new heterocyclic compounds, in particular, 1,8-naphthyridine derivatives of the general formula
    ABOUT
    soon
    I- MN SNG
    where X is J or C1;
    R is H, methyl or ethyl, exhibiting antibacterial activity.
    The purpose of the invention is to create, on the basis of known methods, a method of obtaining new low-toxic compounds with a broad spectrum of activity and high bactericidal activity.
    Example 1. 7- - (trans-3-aminomethyl-4-fluoro-1-pyrrolidinyl-1-cyclopropyl-6-fluoro-1,4-di-hydro-4-oKco-1, 8-naphthyridine- hydrochloride 3-carboxylic acid (compound 1 - trans, hydrochloride).
    1. To a solution of ethanol containing 1.4 g of trans-3-acetylaminomethyl-4-fluoropyrrolidine, 2.2 g of methyl-7-chloro-1-cyclopropyl-b-fluoro-1,4-dihydro was added. -4-oxo-1,8-naphthyridine-3-carboxylate and 3 ml of triethylamine, the mixture is heated under reflux for 2 hours. After evaporation of the solvent, water is added to the residue and the mixture is extracted with chloroform. The extract is dried, the solvent is evaporated, and the resulting residue is chromatographed on silica gel to obtain ethyl 7- (trans-3-acetylamino-1-4-fluoro-1-pyrrolidinyl) -1-cyclo-propyl-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.3 g), so pl. 211-213 ° C.
    2. A mixture of the indicated compound (1.3 g) and 15% hydrochloric acid (40 ml) is refluxed for 3 hours. The hydrochloric acid is evaporated under reduced pressure, the residue is dissolved in a small amount of water and the solution is cooled. The resulting crystals are collected by filtration to obtain the hydrochloride
     7- (trans-3-aminomethyl-4-fluoro-1-pyrro lidinyl) -1-cyclopropyl-6-fluoro-1,4-β-DIGIDRO-4-OXO-1,8-naphthyridine-3-
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    -carboxylic acid (0.75 g), so pl. 269-272 ° C (decomposition).
    EXAMPLE 2: 7- (cis-3-aminomethyl-4-fluoro-1-pyrrolidinyl-1-cyclopropyl-b-fluoro-1,4-dihydro-4-oxo-4, 8- naphthyridine-3-carboxylic acid and its hydrochloride (compound 1 - cis and its hydrochloride).
    1. Analogously to the method described in Example 1.1, except that instead of trans-3-acetylaminomethyl-4-fluoropyrrolidine, cis-3-acetylamino-methyl-4-fluoropyrrolidine is used, methyl-7-cis (3-cis-3-acetic) tylaminomethyl-4-fluoro-1-pyrrolidinyl) -1 -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 179-18t C.
    2. Similarly to the method described in Example 1.2, from this compound, 7- (cis-3-aminomethyl-4-fluoro-1-pyrrolidinyl) hydrochloride -1 -1-cyclopropyl-6-fluoro-1,4-dihydro-1 - hydrochloride is obtained. 4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 284-286 C (decomposition).
    3. A concentrated aqueous ammonia solution is added to the indicated hydrochloride and the mixture is slightly alkaline. After cooling, the crystals are collected by filtration to give 7- (cis-3-aminomethyl-4-α-fluoro-J-pyrrolidinyl) -1-cyclopr opyl-β-fluoro-1,4-dihydro-4-oxo-1,8 -naphthiridine-3-carboxylic acid, m.p. 217-218 C.
    Pr and measures 3. 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-b-fluoro-1,4-dihydro-4-oxo--1,8-naphthyridine -3-carboxylic acid and its hydrochloride (compound 2 - cis and its hydrochloride). I, -.
    1, cis-3-Acetylaminomethyl-1-benzyl-4-chloropyrrolidine (3.5 g) was dissolved in ethanol (40 ml). Acetic acid (2 ml) and a 5% palladium carbon catalyst (0.3 g) are added to the solution, and the mixture is hydrogenolized. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The resulting cis-3-acetylaminomethyl-1-4-chloropyrrolidine oily is dissolved in acetonitrile (50 ml). Ethyl-7-ChLOR-1-cyclopropyl-b-fluoro-1, 4-dihydro-4-oxo-1 is added to the solution.
    naphthyridine-3-carboxylate (3.3 g) and triethylamine (8 ml) and the mixture refluxed for 1 hour. After standing at room temperature overnight, the crystals are filtered and then dissolved in a mixture of water and chloroform. The mixture was shaken and the chloroform layer was separated, dried and evaporated. The residue is recrystallized from acetonitrile to give ethyl 7- (cis-3-acetylaminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopro-6-fluoro-1,4-dihydro-oxo-1.8 nafti rydin-3-carboxylate (4.6 g), so pl.
    ..
    2. A mixture of the above compound (2.0 g) and 20% hydrochloric acid (20 ml) is refluxed for 2 hours. The hydrochloric acid is evaporated under reduced pressure and ethanol is added to the residue. The resulting crystals are collected by filtration to give 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-b-fluoro-1,4-dihydro-4-oxo-1,8-hydrochloride naphthyridine-3-carboxylic acid (1.55 g) so pl. 243-248 C (decomposition).
    3. The reduced compound (1.0 g) is dissolved in water. To this solution, a saturated sodium bicarbonate aqueous solution is added to adjust the solution at pH 7.5-8.0 and cool. The crystals are filtered and recrystallized from chloroform-ethanol solution to give 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4- oxo-1,8-naphthyridine 3-carboxylic acid (0.7 g), so pl. 174-177 ° C.
    And pm. 4. 4. 7- (trans-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1, 8-α-naphthyridine-3-carboxylic acid (compound 2-trans).
    1. Similarly to the method described in Example 3.1, except that trans-3-acetylaminomethyl-1-benzyl-4-chloropyrrolidine is used in place of cis-3-acetylaminoethane 1-1-benzyl-4-β-chlorpyrrolidine, ethyl-7- - (trans-3-acetylaminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro--1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, mp . 203-206 S.
    2. Similarly to the method described in Examples 3.2 and 3.3, 7- (trans-3
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    -aminomethyl-4-chloro-1-pyrrolidinyl) -1 -1-cyclopropyl-6-fluoro-1,4-DIHIDRO-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 222-224 C (decomposition).
    EXAMPLE 5 1-Cyclopropyl-6-fluoro-7- (cis-4-fluoro-3-methylaminomethyl-1-pyrrolidinyl) -1,4-dihydro
    -4-OXO-1,8-naphthyridine-Z-carboxylic acid
    acid (compound 3-cis).
    1. In a manner similar to that described in Example 3.1, except that instead of cis-3-acetylaminomethyl-1-benzyl-4-chloropyrrolidine cis-1-benzyl-4-fluoro-3- (L- -methyltrifluoroacetylaminomethyl ) pyrrolidine, get ethyl-1-cyclopropyl-6-fluoro-7-cis-4-fluoro-3- (N-methyltrifluoroacetylaminomethyl) -1-pyrrolidinyl} -1.4-dihydro-4-oxo -1,8-naphthyridine-3-carboxylate, so pl. 177-179 C.
    2. The above compound is heated in a 10% aqueous solution of sodium hydroxide at 90-100 ° C for 1.5 hours. The reaction mixture is adjusted to pH 7.5-8.0 by addition of aqueous acetic acid. The resulting crystals are collected by filtration to obtain 1-cyclopropyl-6-fluoro-7- - (cis-4-fluoro-3-methylaminomethyl-1- -pyrrolidinyl) -1,4-dihydro-4-oxo--1.8- naphthyridine-3-carboxylic acid, so pl. 230-240 ° C.
    PRI me R 6. Hydrochloride of 1-cyclopropyl-7- (cis-3-ethylaminomethyl-4-fluoro-1-pyrrolidinyl) -6-fluoro-1,4-di-hydro-4-oKCo- l, 8-naphthyridine-3-carboxylic acid (compound 4-cis. hydrochloride).
    1. In a manner similar to that described in Example 3.1, with the exception that cis-G-benzyl-3- (N-methylprifter-acetylaminomethyl) -4-fluoropyrrolidine is used instead of cis-3-acetypamino-methyl-1-benzyl-4- chloropyrrolidine, ethyl-1-cyclopropyl-7- (cis-3- - (H-ethyl trifluoroacetylaminomethyl) -4- -fluoro-1-pyrrolidinyl) -6-fluoro-1,4-di-hydro-4-oxo-1 is obtained , 8-naphthyridine-carb-oxylate, m.p. 198-200 ° C.
    2. The reduced compound is hydrolyzed in a manner similar to that described in Example 5.2. The reaction mixture is then acidified with hydrochloric acid and concentrated. The resulting crystals are filtered to give 1-cyclopropyl-7- (cis-3-ethylaminomethyl-4-fluoro-1-pyrROLIDINLKL) -6-Fluoro-1, 4-DIHYDRO-4-OXO5145601 hydrochloride.
    -1,8-naphthyridine-Z-carboxylic acid, so pl. 275-280 С,
    Example. Hydrochloride 1-cyclopropyl-7- (trans-3-ethylaminomethyl-4-fluoro-1-pyrrolidinyl) -6-fluoro-1,4-dihydro 4-oxo-1,8-naphthyridine-3-car- bonic acid (compound 4 trans. hydrochloride).
    1. In a way similar to that described in Example 3.1, except that trans-1-benzyl-3- (H-ethyltrifluoroacetylaminomethyl) -4-fluoropyrrolidine is used in place of cis-3-acetylamine 1 yl -1-benzyl-4-chloropyrrolidine-15na gives ethyl-1-dicloprop-7- (trans-3- (L-ethyl trifluoroacetylamino-methyl) -4-fluoro-1-pyrrolidinyl) -6-fluoro-1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, so pl. 150-153 seconds 20
    2. The reduced compound is hydrolyzed in Example 5.2. The reaction mixture is acidified with hydrochloric acid and concentrated. The resulting crystals are collected by filtration to obtain the hydrochloride salt.
    1-cyclopropyl-7- (trone-3-ethlaminomethyl-4-fluorop-1-pyrrolidinyl) -6-fluorop-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid m.p. 268-ZO.
    PRI me R 8. Hydrochloride of 1-cyclopropyl-7- (trans-3-ethylaminomethyl- - 4-fluoro-1-pyrrolidinyl) -6-fluoro-1,4-dihydro-4-oKCO-l , 8-naphthyridine-3- j. -carboxylic acid (compound 4 - transhydrochloride).
    1. In a manner similar to that described in Example 3.1, except that trans-3- (acetyl-N-ethylamino to methyl) -1-benzyl-4-fluoropyrrolidine is used instead of cis-3-adylaminoethane 1-1-benzide- 4-chloropyrrolidine5PO-.
    learn ethyl-1-cyclopropyl-7- (trans-3- (L-ethylaminomethyl) -4-fluoro-
    -1-PYRROLIDIKIL) -6-fluoro-1 54-DIHYDRO-4-oxo-1, 8-naphthyridine-3-carboxylate, mp 105-107 C.
    2. In the same manner as in Example 3.2, 1-cycloropyl-7- (trans-3) ethylaminomethyl-4-fluoro-1-pyrrolidinyl) -6-fluoro-1,4-DIGIDRO-4- hydrochloride is obtained from the above compound. OXO-1,8-naphthyridine-3-carboxylic acid, so pl. 268-270 C. „
    PRI m e r 9. Hydrochloride 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropane 1-6-fluoro-1,4-dihydro-4-oxr-1,8 naphthyridine -3-carboxylic
    56
    acids (compound 2 - cis.hydrochloride).
    1. In a manner analogous to that described in Example 3.1, 7- (cis-3-acetyl-aminomethyl-4-chloro-1-pyrrolidinyl) -1 - cyclopropyl-6-fluoro-1,4-DIGIDRO-4-oxo- 1,8-naphthyridine-3-carboxylic acid is obtained from cis-3-acetylamino methyl-1-benzyl-4-chloropyrrolidine and 7-chloro-1-cyclopropyl-6-fluoro-1,4-di-HYDRO-4-OXO -1,8-naphthyridine-Z-carboxylic acid, so pl. 236-242 s (decomposition).
    2. In a manner similar to that described in Example 3.2, 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) hydrochloride -1 -1-cyclopropyl-6-fluoro-1,4-dihydro-4 is obtained from the indicated compound. - -oxo-1,8-naphthyridine-Z-carboxylic acid, so pl. 243-248 C (decomposition).
    Example 10. 7- - (cis-3-aminomesh1-4-chloro-1-pyrrolidinyl) -1-diclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbonyl hydrochloride acids (compound 1 - cis. hydrochloride).
    1. In a manner analogous to that described in Example 3.1, 7- (cis-3-acetyl-aminomethyl-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-DIGIDRO-4-OK-co -1,8-naphthyridine-3-carboxylic acid is obtained from cis-3-acetylaminomethyl-1-benzyl-4-fluoropyrrolidine and 7-chloro-1-cyclopropyl-6-fluoro-1,4-di-hydro-4 -oxo-1,8-naphthyridine-3-carboxylic acid, so pl. 135-137 ° C.
    2. In a manner similar to that described in Example 3.2, 7- (cis-3-aminomethyl-4-fluoro-1-pyrrolidinyl) hydrochloride -1 -1-cyclopropyl-6-fluoro-1,4-dihydro-1 4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 284-286 ° C (decomposition).
    Example 11. 7- (trans-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-15 4-di-HYDRO-4-OXO-1,8-naphthyridine-3-carboxylic hydrochloride acids (compound 1 - trans. hydrochloride).
    1. In a manner similar to that described in Example 3.1, 7- (trans-3-acetylaminomethyl-4-fluoro-1-pyrrolidinyl) -1 -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid is obtained from trans-3-acetylaminomethyl-1-benzyl-4-fluoro-pyrrole
    Dina and 7-chloro-1-cyclopropyl-6-fluoro-1,4 Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 236- 238 C (decomposition).
    2. In a manner similar to that described in Example 3.2, from this compound, 7- (trans-3-aminomechanic 1-4-fluoro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4- hydrochloride is obtained. oxo-1,8-naphthyridine-3-carboxylic acid, so pl. 269-272 seconds (decomposition
    Example 12. 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-DIGIDRO-4-OXO--1,8-naphthyridine- 3-carboxylic acid A mixture of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.13 g), cis-3 - (t-butoxycarbonylaminomethyl) -4-chloropyrrolidine (1.03 g), triethylamine (530 mg) and acetonitrile (40 ml is heated under reflux for 1 hour. After evaporation in vacuo, water is added to the residue, the precipitate is filtered and then dissolved in trifluoroacetic acid (30 ml). After stirring at room temperature After 1 hour, the solvent is removed under vacuum and water is added to the residue. The suspension is adjusted to pH 7-8 with 20% aqueous sodium hydroxide. The precipitate is collected, washed with water and dried to form 7- (cis- 3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1, 4-β-dihydro-4-oxo-1,8 naphthyridine-3-carboxylic acid (1.13 g), mp 174-177 ° C.
    EXAMPLE 13 7- (cis-Aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclo-prop-1 -6-fluoro-1,4-dihydro-4-oxo--1,8 -naphthyridine-3-carboxylic acid.
    A mixture of 7-chloro-1-cyclopropyl-6-fluoro--1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.13 g), cis- (4-chloro) 3-tritylamino type pyrrolidine (2.26 g), triethylamine (610 mg) and chloroform-ethanol (1: 1). (50 ml) is stirred overnight at room temperature. This reaction mixture is evaporated to dryness in a vacuum conditions. The residue is mixed with water (50 ml) and acetic acid (50 ml). The resulting solid is collected, sequentially washed with water and ethanol and dried
    0
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    The mixture of the compound thus obtained and 30% acetic acid (35 ml) was stirred for 2 hours. The reaction mixture was filtered to remove an insoluble solid, and the filtrate was then evaporated to dryness in vacuo. The residue is mixed with water and adjusted to pH 7-8 with 10% naphtha alcohol. The residue is filtered, washed and dried to form 7- (cis-3-aminomethyl 1-4-chloro-1-pyrrolidinyl) -5 -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (930 mg), so pl. 174-177 ° C.
    Example 14. 7- (cis-3-Aminome-TSH1-4-HLOR-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo--1,8-naphthyridine- Z-carboxylic acid.
    A mixture of 7-chloro-1-cyclopropyl-6-fluoro--1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.13 g), cis-5; -3-aminomethyl -4-chloropyrrolidine
    (605 mg), triethylamine (1.01 g) and methanol (100 ml) are heated under reflux for 3 hours. After evaporation, water is added to the residue and the mixture is neutralized with an aqueous solution of acetic acid. The crystals formed are filtered and recrystallized from a mixture of chloroform and ethanol to form 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-hydro-propyl 4-oxo-1,8-naphthyridine-3-carboxylic acid (1.37 g), m.p. 174-177 ° C.
    Example 15. 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1 -1-cyclopropyl-6-fluoro-1,4-dihydro-4-OXO-1,8-naphthyridine-3 hydrochloride - carboxylic acid. I
    A mixture of isopropyl-7-fluoro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-α-naphthyridine-3-carboxylate (1.30 g), cis-3-aminomethyl- 4-chloropyrrolidine (605 ml), triethylamine (1.21 g), ethanol (50 ml) and chloroform (50 ml) are stirred overnight at room temperature. After evaporation, water was added to the residue and the mixture was extracted with chloroform. Extract the extract under vacuum and the resulting crystals are filtered to form isopropyl-7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1, 4-DIGIDRO-4- OK0
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    The ester is hydrolyzed in Example 3.2 to form 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-DIGIDRO-4-OXO-1 hydrochloride , 8-α-naphthyridine-3-carboxylic acid, T.Sh1. 243-248 C (decomposition).
    Example 18. 7- (cis-1O-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-OXO-1,8-naphthyridine- hydrochloride Z-carboxylic
    acid.
    A mixture of ethyl 7-ethylsulfonyl-1-CICSO-1, 8-naphthyridine-Z-carboxypate (1.34 g), mp, 172-174 C.
    The ester is hydrolyzed in Example Zo2 to form 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1-hydrochloride 1,8-naphthyridine-3-carboxylic acid, m.p. 243-248 C (decomposition).
    PRI me R 16. Chlorohydrate 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1 -1 cyclopropyl-6-fluoro-1,4-dihydro-4-OXO-1, 8 -naphthyridine-3-carboxylic - acid 15 lopropyl-6-fluoro-1,4-dihydro-4-oxo
    A mixture of methyl-6,7-difluoro-1-cycloprop-1,8-naphthyridine-3-carbox-1-dyl-1 4-dihydro-4-oxo-1,8-naphthyridine- (1.47 g), cis-3 -acetylaminoethane1-4- -Tc:; ao sil (a, 1, -12 g), cis-3-ace-; chloropyrrotin) tGmG: Gi; silt and ace-.o s. refrigerator; onitri :; (0, heats the c. Inverse :::: G1P with a fridge for 1 hour. Work on approx. J
    under vacuum, and the residue is recrystallized from acetonitrile to form methyl 7- (cis-3-acetylaminomethyl-4-chloro-1-pyrrolidinyl) -1-CYCLOPROPI L-6-fluoror-1 .4- DIGI11RO-4 oxo-1, 8-naphthyridine-Z-carboxylate (1.63 g).
    The ester is subjected to hydrolysis according to Example 3.2 to form 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-4-oxo-1-hydrochloride-4-oxo-hydrochloride 1,8-naphthyridine-3-carboxylic acid, m.p. 243-248 C (decomposition).
    Example 17. 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oKCo-1, 8-naphthyridine-3- hydrochloride carboxylic acid.
    A mixture of ethyl 7- (p-tolylsulfonyl) -1-cyclohfopyl-6-fluoro-1,4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylate (1.72 g), cis -3-acetylaminomethyl-4-chloropyrrolidine (920 mg), sodium bicarbonate (440 mg) and toluene (100 ml) is heated under reflux for 1 hour. The reaction mixture is processed as in Example 16 to form eth1-7- (cis -3- -acetyl-aminomersh-4-chloro-1-pyrrolidinidin) -1-cyclopropyl-6-fluoro-1,4-di-HYDRO-4-OXO-1,8-naphthyridine-3-carb- oxylate (1.50 g), so pl. 213-214 C.
    -1,8-naphthyridine-Z-carboxylate (1.44 g, mp 213-214 C.
    The ester is hydrolyzed in Example 3.2 to form chloro-30 hydrate of 7- (cis-3-aminomethyl-4-chloro--1-pyrrolidinyl) -1-cyclopropyl-6-flu-1,4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid, m.p. 243-248 С
    (decomposition).
    Example 19. 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxy-1,8-naphthyridine-3-carboxylic hydrochloride
    acid.
    A mixture of ethyl-7-methoxy-1-cyclopropyl-b-fluoro-1,4-dihydro-4-oxo-1,8-α-naphthyridine-3-carboxylate (1.23 g), cis-3-acetylaminomethyl- 4-chloropyrrolidine (920 mg) and dimethyl sulfoxide (40 ml) are heated under reflux for 8 hours.
    I
     The reaction mixture is treated
    similarly, I apply 16 to form 7- (cis-3-acetylaminomethyl-4-chl -1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydrr-4-oxo-1,8-naphthyr din-3 carboxylate (0.18 g) T.PL.21
    35
    40
    50
    214 C.
    The ester is hydrolyzed in Example 3.2 to form 7- (cis-3-aminomethyl-4-chloro-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1.4-DIHYDRO-4-OXO-1,8-naphthyridine 6015 chlorohydrate
    The ester is hydrolyzed in Example 3.2 to form 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-DIGIDRO-4-OXO-1 hydrochloride , 8-α-naphthyridine-3-carboxylic acid, T.Sh1. 243-248 C (decomposition).
    Example 18. 7- (cis-1O-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-OXO-1,8-naphthyridine- hydrochloride Z-carboxylic
    acid.
    A mixture of ethyl-7-ethylsulfonyl-1-CEC
      - 15 lopropil-6-fluoro-1,4-dihydro-4-oxo
    -1,8-naphthyridine-Z-carboxylate (1.44 g), so pl. 213-214 C.
    The ester is hydrolyzed in Example 3.2 to form chloro-0 hydrate of 7- (cis-3-aminomethyl-4-chloro--1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo -1,8-naphthyridine-3-carboxylic acid, so pl. 243-248 С
    (decomposition).
    Example 19. 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1 -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxy-1,8-naphthyridine-3 hydrochloride -carbon
    acid.
    A mixture of ethyl-7-methoxy-1-cyclopropyl-b-fluoro-1,4-dihydro-4-oxo-1,8-α-naphthyridine-3-carboxylate (1.23 g), cis-3-acetylaminomethyl- 4-chloropyrrolidine (920 mg) and dimethyl sulfoxide (40 ml) are heated under reflux for 8 hours.
    I
     The reaction mixture is treated
    similarly, I apply 16 to form 7- (cis-3-acetylaminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydrr-4-oxo-1,8-naphthyridine-3 carboxylate (0.18 g) T.PL.2135
    0
    0
    214 C.
    The ester is hydrolyzed in Example 3.2 to form 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro--1.4-DIGIDRO-4-OXO-1,8-chlorohydrate naphthyridine11
    -3-carboxylic acid, so pl. 243-248 С (decomposition).
    PRI me R 20. Chlorohydrate 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1 -1 cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid.
    A mixture of ethyl-7-eth1thio 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-β-naphthyridine-3-carboxylate (1.35 g), cis-3-acetylaminomethyl-4 -chlorpyrrolidine (920 mg) and dimethylformamide (40 ml) are heated under reflux14
    Nick for 8h.
    The reaction mixture is treated analogously to example 16 to form ethyl-7- (cis-3-acetylaminomethyl-4-chloro-1-pyrrolidinyl-1-cyclopropyl-b-fluoro-1,4-dihydro-4-oxo-1.8 -naphthyridine-3-carboxylate (0.78 g), mp 213-214 C.
    The ester is subjected to hydrolysis according to example 3.2 to form 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1 hydrochloride, 8-naphthyridine-3-carboxylic acid, so pl. 243-248 C (decomposition).
    Example 21. 7- (cis-3-α-aminomethyl-4-chloro-1-pyrrolidinyl) -1-CYCLOPROPIL-6-fluoro-1, 4-DIHYDRO-4-OKso-1, 8-naphthyridine-3-carbonoE hydrochloride acids
    A mixture of ethyl-7-ethylsulfonyl-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo--1,8-naphthyridine-3-carboxylate (1.41 g) cis-3-acetylaminomethyl-4 - -chlorpyrrolidine (920 mg), triethyl-amino (530 mg) and acetonitrile (40 ml) are heated under reflux for 1 h. The reaction mixture is treated as in Example 6 to give ethyl-7- (cis-3-acetylaminomethyl -4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.32 g), so pl. 213-214 C.
    The ester is hydrolyzed in Example 3.2 to form 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1 chloro hydrate, 8-naphthyridine-3-carboxylic acid, so pl.
    243-248 C (decomposition).
    PRI me R 22. 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-hydrochloride naphthyridine-3-carboxylic acid.

    ten
    15
    20
    thirty
    35
    you
    45
    p-gg
    - -
    45601512
    A mixture of ethyl 7- (p-tolylsulfonyl-oxy) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-pkso-1,8-naphthyridine-3-carboxylate (1.79 g) , cis-3-acetylaminomethyl-4-chloropyrrolidine (920 mg), triethylamine (530 mg) and acetonitrile (40 ml) are heated under reflux for 1 h.
    The reaction mixture is treated according to example 16 with the formation of ethyl-7- - (CIS-3-acetylaminomethyl-4-chloro-1-β-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1 , 8-naphthyridine-3-carboxylate (1.41 g), mp. 213– 214 C.
    The ester is hydrolyzed in Example 3.2 to form 7- (cis-3-aminomethyl-4-chloro--1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1-chlorohydrate 1,8-naphthyridine-3-carboxylic acid, T.PL.243-248 C (decomposition).
    Example 23. 7- (cis-25 -3-aminomethyl-4-chloro-1-pyrrolidinyl) -1 -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxy-1,8-naphthyridine- hydrochloride 3-carboxylic acid.
    A mixture of ethyl-7-methylsulfonyloxy--1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo -1,8-naphthyridine-3-carboxylate (1.48 g), cis-3-acetylaminomethyl-4 - -chlorpyrrolidine (920 mg), triethyl-amine (530 mg) and tetrahydrofuran (40 ml) are heated under reflux for 1 hour. The reaction mixture is treated according to example 16 to form 7- (cis-3-acetylaminomethyl-4 -chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.48 g), so pl. 213-214 C.
    The ester is hydrolyzed in Example 3.2 to form 7- (cis-3-aminomethyl-4-chloro-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1 chlorohydrate , 8-naphthyridine-3-carboxylic acid, m.p. 243-248 ° C (decomposition).
    Acute toxicity study.
    A solution containing each of the compounds: 1 - cis. HC1, 1 - trans. HC1; 2 - CIS.NS1 - and 4 - trans. HC1 administered in various concentrations through the mouth to male mice (ddl) at up to 40
    at 0.1 g per 10 g body weight. The number of dead mice is counted after 7 days, the value of the average flying dose (, mg / kg) is calculated
    1314
    according to the Behren sa-Karbera method. The results are shown in table 3.
    From the results shown in Table 3, it can be seen that the compounds of the general formula I according to the invention have low toxicity when administered by mouth.
    Study of bactericidal activity.
    In vitro bactericidal activity is shown in Table 1. The numbers in Table 1 show the minimum inhibitory concentrations (MICs), µg / ml, calculated for the free base. The minimum inhibitory concentration is determined by the two-fold method of agar dilution using Müller-Hinton agar. One loop of an overnight culture of the test organisms in Müller-Hinton broth is inoculated onto 10 ml agar salts containing drugs in Petri dishes. Bacterial inoculums contain approximately 10 colony-forming units. Bacterial growth was observed after 20 hours of cultivation at 37 ° C. The MIC is defined as the lowest concentration of drug that prevents visible bacterial growth.
    The efficacy of in vivo against ob-PC1X infections in mice is shown in Table 2.
    Each compound is dissolved in deionized water. Each of the solutions was administered intravenously (iv) infected with each of the tested microorganisms under the conditions shown


    below, and the average effective dose () is calculated by probit analysis. The numbers in Table 2 show the value of ED50) mg / kg calculated for the free base.
    Experimental conditions.
    Mice: males (ddl-S) weighing about 20 g. Infection.
    Staphylococcus aureus 50774. Intravenous infection of 5x 10 cells per mouse suspended in saline.
    Streptococcus pyogenes A-65 .. Intra-abdominal ZxYu infection of cells on
    MUSHI |
    suspended in broth.
    poured into the core of the brain.
    five
    14
    Administration of the test compound: twice, immediately and 6 hours after infection.
    The observation was also carried out for 14 days in the case of Staphylococcus aureus-50774, for 7 days in the case of Streptococcus pyogenes A65.
    Invention Formula
    1. Method for preparing 1,8-naphthyridine derivatives of general formula 1
    ABOUT
     V
    soon
    25
    20 K-TilH-CRf

    where X is a fluorine or chlorine atom;
    R is a hydrogen atom, methyl or
    ethnl,
    or their acid addition salts, i.e., in that the compound of the general formula II
    ABOUT
    COOY
    where Z is a halogen atom, arylsulfonyl, lower alkylsulfonyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, arylsulfonyloxy, or lower alkylsulfonyloxy; Y is a hydrogen atom or a lower one.
    alkyl,
    subjected to interaction with the pyrrolidine derivative of the general formula III
    VN
    Ljih
    -CHV

    /
    where R, a hydrogen atom or a protecting group, is selected from acyl, alkoxycarbonyl or trityl.
    15145601
    Ch & K have the indicated meanings to form a compound of the general formula
    COOY
     AT
    xm -N-CHo
    /
    IR;
    where R, R ,, X and Y have the indicated values,
    which are then subjected to acid or alkaline hydrolysis, provided that R and Y are not hydrogen atoms simultaneously, followed by separation of the desired product as an acid addition salt.
    2. A method for preparing 1,8-naphthyridine derivatives of general formula I
    COOY 25
    R - NR-CH2
    516
    where X is a fluorine or chlorine atom
    R is a hydrogen atom, methyl or
    ethyl,
    or their acid addition salts, characterized in that the compound of the general formula IV
    ten
    COOY
    {-sn
    /
    where R is a hydrogen atom or a protecting group selected from acyl, alkoxycarbonyl or trityl; Y is a hydrogen atom or a lower one.
    alkyl
    R1 and X - have the indicated meanings and provided that R (and V are not hydrogen atoms at the same time, are subjected to acid or alkaline hydrolysis followed by separation of the target product as a base or as an acid-acid salt.
    Table 1 In vitro bactericidal activity, µg / ml
    S.aureus Smith S.aureus 50774
    0.025 0.025 0.025 0.025

    0.025 0.025 0.0125 0.0125 0.0125 0.025
    E. coli P-5101 E. coli P-51208 E. coli P-51209
    0,0125 0,0063 0,78 0,78 0,78 0,78
    0.025 0.025 0.025 0.025
    0.1 0.05 0.2 0.025
    0.0125 0.0125 0.39 0.05 0.0125 0.0125 0.1 0.025 0.025 0.05 0.39 0.05
    0,0125 0,78 0,78
    0.39 0.025 6.25 3.13 12.5 3.13
     Compound A: 7- (3-aminomethyl-1-pyrrolidinyl) -1-ethyl-6-fluoro--1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride, the free form of which is disclosed in example 1 of the uploaded description to Europatent 0106489, published. 1984
    p COOH
    HCl-T HgCHg
    Cghs
    Compound B: 7- (3-aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-b-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride, the free form of which disclosed in example 55 of the laid out description of Euro-patent No. 0153163, published. 1985.
    | Cun
    . Wii
    N
    L
    Table 2 In vivo efficacy against common infections in mice
    1456015 20
    T a and c a 3
    I Medium lethal dose, mg / kg
    2000
    2000
    2000 2000
    权利要求:
    Claims (2)
    [1]
    1,8-naphthyridine of the general formula 1 wherein X is a fluorine or chlorine atom;
    R is a hydrogen atom, methyl or ethyl, or their acid addition salts, characterized in that the compound of general formula II
    COOY where Z is a halogen atom, arylsulfonyl, lower alkylsulfonyl, lower alkoxyl, lower alkylthio, lower alkylsulfinyl, aryleulfonyloxy, or lower alkipsulfonyl group;
    Y is a hydrogen atom or lower alkyl, is reacted with a pyrrolidine derivative of the general formula III where R is a hydrogen atom or a protective group selected from acyl, alkoxycarbonyl or trityl,
    X and R - have the indicated meanings with the formation of a mule;
    - a fluorine or chlorine atom;
    - an atom of hydrogen, methyl or ethyl, acid addition salts, which, characterized by
    COOY or about t compound of General formula IV where R, R ( , X and Y
    COOY have the indicated meanings, which are then subjected to acid or alkaline hydrolysis, provided that R and Y are not hydrogen atoms at the same time, followed by isolation of the target product in the form of a acid-addition salt.
    1. The method of obtaining derivatives
    [2]
    2. A method of obtaining derivatives of 1,8-naphthyridine of the general formula I where R ( hydrogen or protective
    COOY atom group selected from acyl, alkoxycarbonyl or trityl;
    Y is a hydrogen atom or lower alkyl j
    RhX - have the indicated meanings and provided that R <and Y are not hydrogen atoms at the same time, 25 ; they are subjected to acid or alkaline hydrolysis with subsequent absorption of the target product in the form of a base or in the form of an acid-acid salt.
    Table 1
    S.aureus Smith 0,025 0,025 0,025 0,025 Oj 0.05 S.aureus 50774 0,025 0,025 0,025 0,025 0.2 0,025 S.aureus 80 0,025 0,025 0.0125 0.0125 0.39 0.05 S.epidermidis 8 0.0125 0.0125 0.0125 0.0125 0.1 0,025 S.pyogenes A65 0.0125 0,025 0,025 0.05 0.39 0.05
    ! .coli P-5101 0.0125 0.0063 0.0125 0.0125 0.39 0,025 E.coli P-51208 0.78 0.78 0.78 0.78 6.25 3.13 E.coli P-51209 0.78 0.78 0.78 0.78 12.5 3.13
    m P.rettgeri IF0 3850 0.05 0.05 0.05 0.05 0.78 ο, ι m K.pheumoniae 13 0.05 0.05 0.05 0.05 0.39 0.1 M. Lacunata P-7102 6.25 3.13 3.13 3.13 fifty 12.5
    * Compound A: 7- (3-aminomethyl-1-pyrrolidinyl) -1-ethyl-6-fluoro-1,4-dihydro ~ 4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride, the free form of which is disclosed in example 1 of the laid out description to Europatent No. 0106489, published. 1984.
    . ** Compound B: 7- (3-aminomethyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride, the free form of which disclosed in example 55 of the laid out description to Europatent No. 0153163, published. 1985.
    Table 2
    In vivo efficacy against common infections in mice
    Strain Connection example X Icis.HN1 2cis.NS1 4- ;I trans.HC1i j A IN S.aureus -50774 0.274 0.3552.79 0.701 S.pyogenes A65 0.365. 0.235 0.267 3.75 0.601
    _____________________________ T a b _ l and c x 3. Connection Average lethal dose, mg / kg
    cis. HC1 > 2000 trance. HC1 > 2000 cis. HC1 > 2000 trance. HC1 > 2000
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    同族专利:
    公开号 | 公开日
    ZA861074B|1986-09-24|
    JPS61189281A|1986-08-22|
    JPH0635458B2|1994-05-11|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    IE55898B1|1982-09-09|1991-02-14|Warner Lambert Co|Antibacterial agents|
    JPH0373548B2|1983-07-27|1991-11-22|Dainippon Pharmaceutical Co|JPS61243081A|1985-04-19|1986-10-29|Dainippon Pharmaceut Co Ltd|Pyridonecarboxylic acid derivative, and ester and salt thereof|
    JP2603638B2|1987-07-08|1997-04-23|第一製薬株式会社|Analysis and preparative methods for optical isomers|
    EP0486687A4|1989-07-21|1992-06-17|Iolab Corporation|Quinolonecarboxylic acid derivatives|
    WO2010131054A1|2009-05-15|2010-11-18|Bradford Pharma Limited|Redox drug derivatives|
    EP2524911A4|2010-01-08|2013-09-11|Kyorin Seiyaku Kk|Method for producing 3,4-disubstituted pyrrolidine derivative and production intermediate thereof|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP60028998A|JPH0635458B2|1985-02-15|1985-02-15|Pyridonecarboxylic acid derivatives, their esters and their salts|
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