Method of producing derivatives of 1,8-naphthiridine or salts thereof

专利摘要:
The present invention relates to a 1,8-naphthyridine derivative of the formula wherein R1, R2 and R3 are the same or different and each hydrogen or lower alkyl having 1 to 5 carbon atoms; and esters thereof and salts thereof and processes for preparation thereof. These compounds show excellent antibacterial activity and are useful antibacterial agents.
公开号:SU1445558A3
申请号:SU853885803
申请日:1985-04-29
公开日:1988-12-15
发明作者:Мацумото Дзюн-Ити；Накамура Синити；Миямото Теруюки；Уно Хитоси
申请人:Дайниппон Фармасьютикал Ко, Лтд (Фирма)；
IPC主号:

专利说明:


cm
This invention relates to a process for the preparation of new 1,8-naphtyridine derivatives of general formula 1
COOY
thirty
Bleeding antibacterial activity, which can be used in medicine.
The chain of the invention is a method 15 for obtaining new 1,8-naphderidine derivatives with anthakteridnoe activity, exceeding the activeness of the known derivatives of IfS-naphthyridine.
When to e-p L Preparation of 7- (3 amino-1-pyrrhalide) - 1-cycle opr opil-6-fluoro 154-dihydro 4-oxo-1,8 - caffe-rydin-3-carbonose acid hydrochloride - reed, .- 25
 Ethyl 6 (3-acetyls, mino-1 pyrrol1-dinyl) 2 G1 1 Cyclopropyl H- (2-ethoxy

Sicarbonylethyl) aMHHoJ 5-fluoro-niko1 n-nat (5.0 g) is dissolved in dry tert-butyl alcohol (60 mp), potassium tert-butylate (Sjl g) is added to this solution and this mixture is chopped or mixed with at room temperature 1., 5 hours. After the solvent is evaporated under reduced pressure, iodine acetic acid KHCJEOTy is added to neutralize the residue, after which the residue is extracted with chloroform (70 mi). Next, the extract is dried over sodium-sulphide-free sodium sulfate. The reaction product is ethyl 7- (3-acetyl-amino-1-pyrrpidol 1-chl) -grkl opr opyl-b-fluoro-15, 2,3,4-tetrahydro 4 - oxo - 1 b-naphthyridine-3-carboxypat according to its data. NMR spectrum.
To this solution in chloroform is added dropwise bromine (1 g, C) at room temperature and. After stirring for 1 hour, the reaction mixture was pressed in succession with an aqueous solution of thiosulfate and in an aqueous solution of sodium bi-carbonate and in water, then evaporated over anhydrous sodium sulfate. The chloroform is boiled, the residue is recrystallized from ethyl acetate; I get ethyl 7- (3-acetylamino-1-pyrrolidical) 1-cyclopropyl-6-fluoro ™ 1,4-dihydro-4-: “j
40
45
.55
0
0
50
five
40
45
55
oxo-1,8-naphthyridine 3-carboxylate (3.2 g) with so pl. 24b-248 S.
A mixture of this compound with 20% hydrochloric acid was heated for 10 hours under reflux. The solvent was evaporated under reduced pressure, and ethanol was added to the residue. The resulting crystals are filtered off to give 7- (3-amino-1-pyrrolidinyl) -1-cnclopropyl-6-fluoro-1,4-dihydro-4-oKco-1, 6-naphthyridine-3-carboxylic acid hydrochloride (2.4. G) mp, 275 280 ° C (decomposition).
Example 2 Preparation of 7- (3-methylamino-1-pyrrolidinyl) -, 4-dihydro 4-oxo-1,8-naphthyridn-3 carboxylic acid hydrochloride 1-cyclo pro-saw-6-fluoro .. :
The methyl (H-acetylmethylamino) -1-pyrrhalide vBVij -2 - N-CYCLE opropyl -N- (2- j-toxycarbonylethyl) amino1 -5 fluoro cotinate (2.3 g) is dissolved in dry toluene (50 ml) . To a solution of add-1l-1b 60% cat hydride (480 mp) and stirred for 2 hours at 10 ° C, the reaction is treated as in example 1, section 1 is ethyl 7 - 3 - (M-cet-shnetil ai -iHHo) - i-pyrrho-olidinyl-cyclic opropyl-b-fluoro-1, 2,3, 4-tetrahydro-4-oxo-1,8-naph tyrid. n 3-carboxylate.
A mixture of the named compound, dich1; sor - 5,6-dicyano-154 benzoquinone, ids47 g) and 60 ml of toluene qnt t / 30 min. The solvent is then evaporated, the residue is dissolved in chloroform and the solution is washed with a 1N N aqueous solution of NaOH, followed by drying over. Xporoform v out, ethanol is added to the residue, oh, as much as possible. ethyl 1-cyclo-T1ropyl-b-fluorine 7-f3- (N-acetylmethylamino) -1-pyrr olidi shsh, 4-dihydrs is filtered off
4ox-1J 8-naphthyridine-Z-carboxylate
(1.44 g), m.p-1 / 203-204 ° С (ethanol). The resulting ester (15.34 g) is treated with Example 1; hydrochloride is obtained. G 11scr opil b-fluoro-U- (3-met lamino-1-pyrr olidi ny) -1, 1Hydro-4-oxo -1 V B -naphthyridine-3-carboxylic acid (900 mg), m.p. 284-289 C (decomposition, water-ethanol). i
Hydrochloride obtained above (900 units), converted to 1 -daklo propsh1-b-fluorine 7-: (, pa.-1ino-1 -iriridinyl) -1,4-digkdro-4-oxo 15 8-naphthyridine 3-cage - Lateral acid (8.00 mg), m.p., 233-23 (raelozhegshe),
Example 3. Preparation of 7- (3-amino-4-methyl-1-pyrroneidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-OKco-1, 8-naphthyridine-3- hydrochloride carboxylic acid.
6- (3-Acetylamino-4-methyl-1-pyrrolidium NIL) -2-M-cyclopr opil-N- (2-ethoxycarbonylethyl) amino-5-fluoronicotinate (4.64 g) in tert -butanol - (70 ml) is treated at room temperature with potassium tert-butoxide (2.7 g) for 1.5 h. The reaction mixture is treated as in example 1, ethyl-7- (3-acetylamino-4-methyl-1 -pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,2, 3,4-tetrahydro-4-oxo-1,8-naphthyridine-3-carboxylate. The resulting carboxylate is treated with bromine in Example 1.
After evaporation of the solvent under reduced pressure, water is added to the residue and the mixture is extracted with chloroform. The extracts are washed with dilute hydrochloric acid, then with water, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is chromatographed on silica gel, whereby the following three fractions are obtained, g:
a.Stereoisomer A 1,1
b. A mixture of stereoisomer B and a small amount of stereoisomer A2.8
c.Stereoisomer B 0.1

权利要求:
Claims (2)
[1]
one . Fractions a and c are subjected to recrystallization from ethyl isopropyl ether, and the stereoisomer A is obtained (m.p.
i280-282.5 ° C) and stereoisomer B, (mp.
209-2 U C) ethyl-7- (3-acetal-1-amino-410
directing stereoisomer A, ° m.p. 234- 238 C (decomposition).
NMR (DjO): B 1.32 (3N, d, Hz, CH,); 7.42 (1H, d, I 13 Hz, Su-H), 8.40 (1H, s,).
3. The fraction b (2.9 g) is processed by the method according to p. 2, to obtain 7- (3-amino-4-methyl-1-pyrrolidinyl) hydrochloride - 1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carbonic acid (2.02 g) so pl. 270-278 0 (decomposition).
NMR (V, rO): S
1.32 (ZN, d, Hz,
);
15 CH) J 7.38 (1H, d, I 13 Hz, 8.41 (1H, s,).
It is established that this compound is a mixture of 6 and 94% carboxylic acid chlorohydrates, corresponding to
20 stereoisomers of Ai and B, respectively, using high pressure liquid chromatography methods.
Example 4. Preparation of 7- (325 amino-2-methyl-1-pyrrolidinyl) -1-ciclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride. ,
A mixture of 6- (3-acetopylamine-2-methyl-1 -
30 Pyrrolidinyl) -2-N-cyclopropyl-H- (2-ethoxycarbonylethyl) amino-5-fluorotonate (2.32 g), sodium ethoxide (820 mg) and dioxane (30 ml) are boiled for 1 h. The reaction mixture is worked up according to Example 1, ethyl-7- (3-acetylamino-4-methyl-1-pyrhodoynyl) -1-cyclopr opil-6-fluoro-1,2,3, 4-tetrahydro-4 is obtained. -oxo-1,8-naphthyridine-3-carboxylate.
40 A mixture of the resulting carboxylate tetrachloro-1,4-benzoquinone (1.6 g) and xylene (60 mgg) is boiled for 30 minutes. The reaction mixture is treated according to example 1, poluchaut. Chlorine-
 methyl 1-pyrrolidinyl) -1-cyclopropyl-b-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, respectively. 45 7-3 (amino-2-methyl-1 -pyrrolidinyl) 1-cyclopropyl-b-fluoro-1, 4-dihydro-40
directing stereoisomer A, ° m.p. 234- 238 C (decomposition).
NMR (DjO): B 1.32 (3N, d, Hz, CH,); 7.42 (1H, d, I 13 Hz, Su-H), 8.40 (1H, s,).
3. The fraction b (2.9 g) is processed by the method according to p. 2, to obtain 7- (3-amino-4-methyl-1-pyrrolidinyl) hydrochloride - 1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carbonic acid (2.02 g) so pl. 270-278 0 (decomposition).
NMR (V, rO): S
1.32 (ZN, d, Hz,
);
5 CH) J 7.38 (1H, d, I 13 Hz, 8.41 (1H, s,).
It is established that this compound is a mixture of 6 and 94% carboxylic acid chlorohydrates, corresponding to
0 stereoisomers of Ai and B, respectively, using high pressure liquid chromatography methods.
Example 4. Preparation of 7- (35 amino-2-methyl-1-pyrrolidinyl) -1-ciclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride. ,
A mixture of 6- (3-acetopylamine-2-methyl-1 -
0 Pyrrolidinyl) -2-N-cyclopropyl-H- (2-ethoxycarbonylethyl) amino-5-fluorotonate (2.32 g), sodium ethoxide (820 mg) and dioxane (30 ml) are boiled for 1 h. The reaction mixture was worked up according to example 1, and ethyl-7- (3-acetylamino-4-methyl-1-pyrhodinyl) -1-cyclopr opil-6-fluoro-1,2,3, 4-tetrahydro-4 was obtained. -oxo-1,8-naphthyridine-3-carboxylate.
0 A mixture of the resulting carboxylate tetrachloro-1,4-benzoquinone (1.6 g) and xylene (60 mgg) is boiled for 30 minutes. The reaction mixture is treated according to example 1, poluchaut. Chlorine-
5 7-3 (amino-2-methyl-1-pyrrolidinyl)
2. A mixture of the stereoisomer A ester (0.97 g) and a 20% aqueous solution of hydrochloric acid (10 mp) was boiled for 3 h. After mixing under reduced pressure, ethanol was added to the residue, and the crystals were filtered and recrystallized from a mixture of water-ethanol, carboxylic acid hydrochloride is obtained, i.e. 7- (3-Amino-4-methyl-1-pyrpolydinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (0, 57 g), corresponding
[2]
oxo-1,8-naphthyridine-3-carboxylic acid, lots. The stereoisomer A (3) 2 hydrate (0.27 g), so pl. 215-217 C.
NMR (NaOD-D O): S 1.03 (3N, d, I 6 Hz, qHj), 7.63 (1H, d, I 13 Hz, Su-H); 8, 32 (1H, s,) and mixture. stereoisomers A and B (3) 2 hydrate (0.81 g), so pl. 276-280 s- (decomposition). The ratio is established by high pressure liquid chromatography.
NMR of stereoisomer B (NaOV-B O): 1.17 (3N, d, Hz, CH,); 7.75
(1H, d, Hz, CS-H) J 8.33 (1H,
". h
q-h).
Example 5. Preparation of 7- (4-amino-2-methyl-1-pyrrolidinyl) -1-cyclopropyl-6CH tor-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbonyl acid hydrochloride.
To a mixture of 6- (3-acetylamino-5-methyl-1-pyrodinyl) -2-s-cy1Sopropsh1-N- (2-ethoxy, arbonyletsh1) amino | -5-fluorotnototinate (2.32 g), sodium shavings (300 mg) and xylisla (30 ml) ethanol (0.5 ml) is added and the mixture is boiled in
14455586
boil for 3 h. The reaction mixture is treated as in Example 3; 7- (3-amino-3-methyl-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro chloro hydrate is obtained. -4-oxo-1,8-naphthyridine-3-carbono10
acid (5) 4 hydrate (0, .63 g), so pl. 285-287 with (decomposition).
NMR (1.74 (3N, s, CH,); 7.45 (1H, d, I 13 Hz, Su-H), 8.42 (1H, s, C.-H).
Example 7 Preparation of 1-cyclopropyl-6-fluoro-b- (4-methyl-3-methylamino-1-pyrrolidinyl) hydrochloride - for 1 h. The reaction mixture is formed with 1,4-dihydro-4-oxo-1, 8-naphthyridine-3- was prepared as in Example 1, a carboxylic acid was obtained.
ethyl 7- (3-acetyl: no-5-methyl-1-pyr-Ethyl-2-N-cyclopropyl-N- (2-ethoxycyrene) 1 -1-cyclopropyl-6 fluoro-1,2, 3, 4-tetrahydro-4-oxo-1,8-naphthyridine-.
carbonylethyl) amino-5-fluoro-6- (4-methyl-1-3-methylamino-1-pyrrolidinyl) -3-carboxylate.
A mixture of N-bromosuccinimide carboxylate carboxylate (1.2 g) and SCC (60. ml) was stirred for 1 h at room temperature. The reaction mixture is treated as in example 3, 7- (4-aiswHo-2-MeTHn-1-nHp-rolidinyl) -1-cyclopropyl-b-fluoro-1,4-dihydro-4-oKco-1, 8-naphthyridine hydrochloride is obtained -3-carboxylic acid, stereoisomer A (5) 4 hydrate (0.19 g), m.p. 2bЗ-2b7 s (decomposition).
NMR (NaOD-DjO): and 1.29 (3N, d, 1 6 Hz, CH) -, 7.74 (1H, d, I 13 Hz,); 8.39 (1H, s, C „-H),
A mixture of stereoisomers A and B (2 guide
rat), (0,66 r) .j so pl. 205-208 С and 241-244 С (decomposition). The ratio is established by method # 1. bone chromatography at high pressure.
NMR stereoisomer B: 1.28 (ZN, d 1 6 Hz, SI,); 7.70 (1H, d, I 13 Hz, Su-N); 8.39 (1H, s,).
Example 6. Obtaining the hydrochloride of 7- (3-amino-3-methyl-1-pyrrole dinyl) -1-cycloprop-1-t-6-fluoro-1,4-di-HYDRO-4-OK-CO-1,8- naphthyridine-3-carboxylic acid.
Ethyl 6- (3-acetylamino-3-methyl-1-pyrrolidinyl) -2-N-cyclopropyl-N- (2-ethoxycarbol-dal) amino-5-fluoro-nicotinate (2.32 g) in tert-butanol is treated tert-bytoc potassium hydroxide of example 1 gives ethyl 7- (3-acetic. amino-3-methyl-1-pyrrolidinyl) -1. cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-4 - OXO-1,8-naphthyridine-3 carbocanlate
A mixture of the resulting carboxylate, n-hexane (20 MP) and acetone (20 ml)
boil for 3 h. The reaction mixture is treated as in Example 3, 7- (3-amino-3-methyl-1-pyrrolide-nyl) -1-cyclopropyl-6-fluoro-1,4-dihydrochloride is obtained. -4-oxo-1,8-naphthyridine-3-carbono
acid (5) 4 hydrate (0, .63 g), so pl. 285-287 with (decomposition).
NMR (1.74 (3N, s, CH,); 7.45 (1H, d, I 13 Hz, Su-H), 8.42 (1H, s, C.-H).
  Ethyl-2-N-cyclopropyl-N- (2-ethoxy
i-.
carbonylethyl) amino-5-fluoro-6- (4-methyl-1-3-methylamino-1-pyrrolidinyl)
thirty
35
40
45
cotinate (2.18 g) in tert-butanol is treated with potassium tert-butoxide in example 1. Ethyl-1-1 is obtained (iclopro-1-tal-6-fluoro-7- (4-methyl-3-methylamino--1-pyrrolidinyl) , 2,3,4-tetra1 id $) - 25 4 oxo-1,8-naphthyridine-3-carboxylate.
A mixture of the resulting carboxylate, 5% Pc1 / s (3 g) and ethanol (50 ml) t 1 t. After filtration, dissolve; The body is evaporated under reduced pressure. The residue is hydrolyzed according to Example 13: 1-cycloprosch-6-fluoro-7- (4-methyl-3-methylamino-1-pyr rolidinyl) -1,4-dihydro-4-oxd-1,8-naphthyridine-3- hydrochloride is obtained. carboxylic acid (5) 4 hydrate (0.89 g), so pl. 258-277 s (decomposition).
NMR (NaOD-Dj, 0): S 1.07 (3N, d, 1 6 Hz, CH,), 2.34 (3N, s, 1, -CH); 7.52 (1H, d, I 13 Hz, Su-N) -; 8.27 (Ш, с, С, -Н).
EXAMPLE 8 Preparation of Chlorine Delta 7- (3-amino-4-ethyl-1-pyrrolidishot) -1 cyleslopropyl-b-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid
Ethyl 6- (3-amino-4-ethyl-1-1-Sh1-rrolidinyl) -2-y-cy1-yl-Propsh-1-H- (2-ethoxy-carbonylethyl) amino-5-fluoro-nicotinate (2.18 g) in tert-butanol treated with potassium t-butacid in example 1, ethyl-7- (3-amino-4-ethyl-1-pyr rolidinyl) -T-cyclopropyl-b-tor-1,2,3,4-tetrahydro-4 is obtained -oxo-1,8-naphthyridine-Z-carboxylate.
The mixture of the resulting carboxylate in
55 Diphenyl ether (20 ml) is heated at 250 ° C for 5 minutes. After cooling, the mixture is added to the mixture of n-hexane. The precipitate obtained is filtered 71445558
rut and hydrolyze according to example 1, get hydrochloride 7- (3-amino-4-ethyl-1-pyrrolidinil) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 - carboxylic acid (0.79 g), mp, 232-237 C (decomposition). - NMR (NaOD-DaO): 0.95 (ZN, t, 1 7 Hz, -), 1.66 (2H, quartet, Hz,), 7.55 (1H, d, y Hz, Cj-H) , 8.33 (1H, s,).
Example 9. Preparation of 7- (3-H-propylamino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-OKCo-1, 8-naphthyridine-3 chlorohydrate -carboxylic acid.
Ethyl (N-acetylpropylamino) -1-pyrrolidinyl -2-m cyclopropyl-M- (2-ethoxycarbonylated) amino-5-fluorotinate (2.46 g) in tert-butyl 20 alcohol (60 ml) is treated with tert-butylate potassium in Example 1, (N-acetylpropanoamino) -1-pyrrolidinyl} -1-cyclopropyl-6-fluoro-1,2, is obtained
eight
Example 11. Preparation of hydrochloride 1 over 7- (3-amino-1-pyrrolidinyl) -1 cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
Methyl 6- (3-acetylamino-1-pyrrolidinyl) -2-Gy-cy1scoprosh1L-K- (2-methoxy carbonylethyl) amino-5-fluoronicotinate (2.1 g), obtained by the method of reference example, is treated by the method Example 1, get the target product (0.92 g), so pl. 275-280 s (decomposition).
Reference example. The preparation of the starting compound is eth1-6- (37: acetyl amino-1-pyrrolidinyl) -2-NY-cycl6propan-N- (2-toxycarbonylethyl) amino-5-f ornicotinate.
one). .2.6-Dichloro-5-fluoro-nicotinonitrile (32.5 g) in ethanol (40 O ml) is treated at room temperature with the potassium salt of p-thiocresol, obtained from p-thiocresol (23.2 g) and
35
40
3,4-tetrahydro-4-oxo-1,8-naphthyridine-25 potassium hydroxide (12.2 g),
3-carboxylate, which is treated
bromine and hydrolyzed in example 1.
7- (3-H-propylamino-1-pyrrolidinyl) -1-cyclopropyl-6fluoro-1, 4-dihydro-4-oxo-1,8-naphthyri-JQ hydrochloride is obtained.
din-3-carboxylic acid (820 mg),
m.p. 265-280 C (decomposition).
NMR (Dj, 0): H, 05 (3N, t, I 7 Hz, CHjCHjCH NH); 7.63 (1H, d, I 13 Hz, C5 - H), - 8.54 (1H, S,)
Example 10. Preparation of chlorohydrate of 7- (3-iso-propylamino-1-pyrrolidinyl) - -cyclopropyl-6-fluoro-1,4-dig and hydro-o-4-ca with o-1,8-naphthyridine- 3-carboxylic acid.
Ethyl 7- (3-Na acetylisopropylamino-, 1-pyrrolidinyl) -2 m-cyclopropyl-H- (2-ethoxycarbonylethyl) amino | -5-fluoronicotinate (2.46 g) is treated with tert-butoxide potassium in tert-butanol in Example 1, ethyl-7- (3-N-acetylisopropylamino) -1-pyrrolidinyl-1-cyclopropyl-6-fluorop-1, 2,3,4-tetra-HYDRO-4-OXO-1,8-naphthyridine is obtained -3-carboxylate, which is treated with bromine and then hydrolyzed in Example 1, gives 7- (3-isopropylamino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro- 4-occo -1, 8-naphthyridine-3-carboxylic acid hydrochloride (780 mg) so pl. 273-284 sec.
NMR (): S 1.47 (6H, d, I 6 Hz, (CH j) 2 CHNH); 7.57 (1H, d
45
55
I 13 Hz, C
.n) 8.49 (1H, S,)
2-chloro-6- (p-tolylthio) -5-fluoro-nitric nitrile (42.4 g), m.p. 124-125 s.
2). Anhydrous potassium fluoride (22.2 g) is added to a solution of the indicated compound (36 g) in dry dimethyl sulfoxide (180 ml) and the mixture is heated at 130-135 ° C for an hour with stirring. The solvent is evaporated under reduced pressure and water is added to the residue. The resulting crystals are recrystallized from ethanol to give 2,5-Difluoro-6- (p-tolsttio) -nicotnonitrile (30 g), m.p. 120-121 ° C.
3). The above compound (4 g) in absolute ethanol is treated with dry hydrogen chloride to give ethyl 2,5-difluoro-6- (p-tolylthio) nicotinate (3; g).
four). Ethyl 2,5-difluoro-6- (p-tolylthio) nicotinate (25 g), prepared in PS, is dissolved in dimethylformamide (400 m). Ethyl N-cyclopropylaminopropionate (25.4 g) and sodium bicarbonate (14 g) are added to the solution, then the mixture is heated for 10 hours at 100-110 ° C and under stirring. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with toluene. The extracts were diluted with hydrochloric acid, then water, and dried over anhydrous sodium sulfate. After evaporation of toluene under reduced pressure,
eight
Example 11. Preparation of 7- (3-amino-1-pyrrolidinyl) -1-cycl-propyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride 1H3.
Methyl 6- (3-acetylamino-1-pyrrolidinyl) -2-Gy-cy1scoprosh1L-K- (2-methoxycarbonylethyl) amino-5-fluoronicotinate (2.1 g), obtained by the method of reference example, is treated by the method of example 1, get the target product (0.92 g), so pl. 275-280 s (decomposition).
Reference example. Preparation of the starting compound is eth1-6- (37: acetyl-amino-1-pyrrolidinyl) -2-N-cycl-6-prop-N- (2-toxycarbonylethyl) -amino-5-f ornicotinate.
one). .2.6-Dichloro-5-fluoro-nicotinitrile (32.5 g) in ethanol (40 O ml) is treated at room temperature with the potassium salt of p-thiocresol, obtained from p-thiocresol (23.2 g) and
five
0
Q
five
five
2-chloro-6- (p-tolylthio) -5-fluoro-nicotine nitrile (42.4 g), m.p. 124-125 s.
2). Anhydrous potassium fluoride (22.2 g) is added to a solution of the indicated compound (36 g) in dry dimethyl sulfoxide (180 ml) and the mixture is heated at 130-135 ° C for an hour with stirring. The solvent is evaporated under reduced pressure and water is added to the residue. The resulting crystals are recrystallized from ethanol to give 2.5-Difluoro-6- (p-tolsttio) -nicotnonitrile (30 g), m.p. 120-121 ° C.
3). The above compound (4 g) in absolute ethanol is treated with dry hydrogen chloride to give ethyl 2,5-difluoro-6- (p-tolylthio) nicotinate (3; g).
four). Ethyl 2,5-difluoro-6- (p-tolylthio) nicotinate (25 g), prepared in PS, is dissolved in dimethylformamide (400 m). Ethyl N-cyclopropylaminopropionate (25.4 g) and sodium bicarbonate (14 g) are added to the solution, then the mixture is heated for 10 hours at 100-110 ° C and under stirring. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with toluene. The extracts were diluted with hydrochloric acid, then water, and dried over anhydrous sodium sulfate. After evaporation of toluene under reduced pressure,
9144555810
ethyl 6- (p-toluylthio) -2-m-cyclopro Experiment conditions:
saw-Y- (2-ethoxycarbonylethyl) amino - "Male Mouse (ddy-S) with a weight of about
5-fluoric nicotinate (32 g) in the form of about 20 g.
go matsla Streptococcus pneuraoniae infection
five). Ethyl 6- (p-tapwolto) -2s-cyc-1. Intraperitoneal infection
lopropyl-N- (2-ethoxycarbonylethyl) ay-3x10 cells per mouse, suspended Hdj-5-fluoro-nicotinate (16.0 g) is oxidized with m-chloroperbenzoic acid,
get ethyl 6- (p-tolylsulfonyl- "
2- N-cyisopropyl-N- (2-ethoxycarbonyl-funcheal infection 3x10 cells)
ethyl) amino 1-5-fluoro-nicotine (17.0 g), by us, for 1 minute, suspended in
6). This compound (9.56 g) gsh-grevaft 2 h at 120 ° С in dimethylformamide with 3-acetylaminopyrrolidine 15 peritoneal infection - 9x10 ° cage (3.84 g) in the presence of bicarbonate on 1 mouse suspended in
sodium (2.52 g) gives ethyl 6- (3-tryptosoic broth with 4% mu. c.
Acesh1amnno-1-pyrralidinyl) -2-s-Pseudomonas aeruginosa 12. Intra-cyclopropyl-K- (2 ethoxycarboyl-etnl) peritoneal infection l 5x10 cell MUHoj-5-fluorinicotinate (8.0 g) in the form of 20 kami per mouse suspended in
oils. ,, tryptosoevym broth with 4% mucin,,
Drug treatment, In the case of Streptococ.pneumoniae, 4 times immediately after 6.24 and 30 hours after dosing
baths in brain-heart infusion broth
Streptococcus pyogenes. Vnutinfuzionnom broth brain-heart.
Escherichia coli P-5101. Inside 6
The study of the bactericidal activity of compounds I.
Antibacterial activity at
in vitro tests are shown in Table 25 For other organisms immediately
(The numbers in the table show mini - j after 6 h after infection.
Maximum inhibitory concentrations. Observation. In the case of Streptococ.
(MI K) calculated for free pheumon. 1 after 14 days When .
bases. Minimal inhibition
other organisms after 7 days.
Concentrations were determined according to the study of acute toxicity. It is a vegetable method of diluting the agar, it is recommended that each of the compounds is given by the Japanese Hemotherapy Society).
The anti-bactericidal activity of the new compounds I (srav): is made with antibak-., The terrorist activity of known compounds A and B.
Compound A: 7- (3-amino-1-pyrrolidinyl) -1-ethyl-6-fluoro -1,4-dihyd, p o-4-OXO-1pB-naphthyridine-3-carboxylic Q acid hydrochloride.
Compound B: 1-ethyl-6-fluoro-7 - (3-methylamino-1-pyrrolidinsh1) -1,4-dihydro-4-oKco-l, 8-naphthyridin-3 - carbonic acid hydrochloride , Efficacy against in vitro infectious diseases of the body in mice is shown in Table. 2
Each compound is dissolved in
deionized water. Q solution (Formula of an inventive shadow is introduced with a medical purpose through the mouth)
Shh intravenous (iv) msham, infishch-gro-Method of producing derivatives. 1.8v of the test subjects 45
 according to examples 1, 2, 3, 6, orally was administered to mice at various concentrations (DDU), in doses from 0.1 ml: per 10 g of animal weight. The number of deaths was determined on the 7th –day and the lethal dose was read (LDp mg / Ki) c. according to Beh- rens-: Kaerbe r ..
The results of the study of the toxicity of compounds 1 are given in Table. 3,
From tab. 3, it can be seen that the resulting compounds have low oral toxicity.
The data table. 1 and 2 show that compounds of total I have a higher antibacterial activity, and can use S, medicine.
naphthyridine of general formula
MY under the conditions shown below, and calculate the average effective dose Djg) by reliable analysis.
The numbers in the table show the 8Dgg values (mg / kg) calculated for the free base.
3x10 cells per mouse, suspended
  „
3x10 cell fish infection
baths in brain-heart infusion broth
Streptococcus pyogenes. Internally, for 1 minute, suspended in
peritoneal infection - 9x10 ° cage
brain-heart infusion broth.
Escherichia coli P-5101. Inside 6
other organisms after 7 days.
The study of acute toxicity., Flavor, the contents of each of the compounds
Formula of the invented shadow
 according to examples 1, 2, 3, 6, orally was administered to mice at various concentrations (DDU), in doses from 0.1 ml: per 10 g of animal weight. The number of deaths was determined on the 7th –day and the lethal dose was read (LDp mg / Ki) c. according to Beh- rens-: Kaerbe r ..
The results of the study of the toxicity of compounds 1 are given in Table. 3,
From tab. 3, it can be seen that the resulting compounds have low oral toxicity.
The data table. 1 and 2 show that compounds of total I have a higher antibacterial activity, and can use S, medicine.
The method of production
naphthyridine of general formula
55
soon
where R, R ,. and Rj is the same or different, each is hydrogen or €, -05-alkyl, provided that at least one of R and R is hydrogen
 or salts thereof, characterized in that the pyridine derivatives of general formula II
n-
.COOY
t fKN V N-CH.CH.COOY
L- Ri - NH
BUT
where R (, R.i and R) have the indicated meanings;
Y is the same or different, each — C, -Su-alksh1, is subjected to cyclization in the presence of a base in an inert solvent at a temperature of from 10 to 140 ° C and the resulting compound of general formula III
ABOUT
R
COOY
BUT
- where R ,, R, Rj and Y - have indicated
values
dehydrated in the presence of a dehydrating agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetra-chloro-1,4-benzrhinonone, palladium on carbon, bromine or N-bromosucdanimide, at a temperature of from 20 to 140 ° C and and by heating from 30 to 250 ° C and the resulting compound of general formula IV
ABOUT
5 k, l j
Rj-nh
 N K
BUT
where R, R, Rj and Y have the indicated values,
hydrolyzed with the selection of the desired product as a base or as a salt.
Priority on sign .07.83 when R is hydrogen or lower alkyl; R is hydrogen; Rj - water - ROD}
06.06.84 when R is hydrogen or lower alkyl; R is hydrogen or lower alkyl; R is lower alkyl.
Table 1
Note: oral or iv - viutrnveiio.
15144555816
Table 3
Acute toxicity in mice
Compound at
2
3p.2000
LD-d, mg / kg

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同族专利:

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KR900006750B1|1990-09-20|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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JP58138000A|JPH0373548B2|1983-07-27|1983-07-27|

---

JP59117266A|JPH0568477B2|1984-06-06|1984-06-06|

---