SU1192617A3 - Method of producing quinolones - Google Patents

Abstract

Method of producing quinolones of general formula 1 O 8

Description

This invention relates to synthetic organic chemistry, namely to a method for producing quinolones of the general formula

8 (0) LISS

N

where at a fixed O or J

RJ - nodorod,. Chor or Mf

goxigroupia; R. - chlorine, fluorine, trifluoromeTPC

. - alkyl or meth1) to "l group, and with n equal to 2 R - hydrogen, Rg - fluorine, which have anti-hypertensive action and with the introduction of warm-blooded animals in non-toxic dopes increased pressure Kpi vi.

The purpose of the invention is to obtain new biologically active quinolone derivatives with valuable pharmacological action.

PRI me R 1. Dimethyl sulfate (2.2 ml) is added dropwise to a stirred mixture of 7 chloro-6-methoxy-3-methylthio-4-quinolop (5.42 g, containing some amount of e-chloroisomer), anhydrous potassium carbonate (3.2 g) and butanone (400 ml). The mixture was boiled at overnight temperature and then filtered while hot. The hot filtrate is cooled, and the product 7-chloro-6-methoxy-1-methyl-3-methylthio-4-quinolone crystallizes, m.p. 220-222. Output 2.4 g.

The starting material for the above described reaction is prepared as follows.

Sodium (7.65 g) is dissolved in anhydrous methanol (4.50 ml) and the solution is evaporated to dryness. The resulting sodium methylate is suspended in anhydrous diethyl ether (300 ml). The suspension is transferred with and then methyl methylthioacetate (40 g) is added dropwise to it. The mixture is stirred at 0 ° C for 1 hour and then treated dropwise with methyl formate (21 g). (; the mixture is stirred at

. h h;) at room temperature: mixing is continued overnight. The resulting solid suspension was extracted with water (300 ml) and the volume of the aqueous extract was adjusted to 333 MJT with the addition of water. Methyl-3-hydroxy-2-methyl 1-thioacrylate containing sodium salt, sodium salt

10 (0.33 mol) is added to the mixed solution of 3-chloro-4-methoxyaniline (52 g) in a mixture of iodine (800 ml) and 11.6 hydrochloric acid (33 ml) at. The mixture is stirred for 30 minutes and the product is collected by filtration, resulting in a new intermediate methyl 3- (3-chloro-4-methoxy-one, lino) -2-methylthio-acrylate, m.p. 11020 1.12s. Yield 77.6 g. Acrylate (77.6 g) is added to diphenyl ether (200 ml), which is stirred at 250 ° C under a nitrogen atmosphere. After stirring at 250 ° C in those

After 15 minutes, the mixture is cooled. The resulting precipitate is collected by filtration, resulting in a new intermediate 7-chloro-6-methoxy-3-methyl3Q thio-quinolone, m.p. 288-290 C. Exit 7.5 g. The study using thin-layer chromatography showed the presence of a small amount of the corresponding 5-chlorine isomer.

 Example 2. 7-chloro-6-methoxy-1-methyl-3-methylthio-4-quinolone (1.5 g) is dissolved in dichloromethane (75 ml) and the resulting solution. treated drop by drop at -20 ° C with a solution of 3-chloroperbenzoic acid (85%, 1.203 g) in dichloromethane (75 ml). The reaction mixture is poured into a saturated aqueous solution of sodium bicarbonate (300 ml) and the mixture is extracted with dichloromethane (4 x 50 ml). The organic peroxide-free extract is dried and evaporated. The resulting solid is recrystallized.

5 from ethyl acetate, methanol, whereby 7-chloro-6-methoxy-1-methyl-3-methylsulfinyl-4-quinolone is obtained; m.p. 263-265 ° C. Output 0.92 g. Example 3. Analogously to Example 1, the corresponding) -substituted xnolones are methylated, resulting in the following compounds (a) - (e). Compounds (f) - (h) (from ethanol). Yield 2.55 g from 5.0 g sulphide. Example 8. According to the method described in Example 2, the mixed isomeric product 1,6-trimethyl-3-methylthio-4-quinolone and 1,5,6-trimethyl-3-methylthio-4-quinolone (1.2 g) oxidized to the corresponding sulfoxide. The product is purified by liquid chromatography on silica gel at high pressure to give 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone, t, pl.226-228 ° C. Exit 0.5 g. Example 9. (a) Similarly Examples 1 and 3- (3,4-dimethoxy-N-methyl-anilino) -2-methylthioacrylate (3.74 g) are cyclized to give 6.7-dimethoxy-1-methyl-3-methyl-thio-4-quinoline, t, 1%. 183-185 s. Exit 6g. (c) Similarly to the method described in Example 2, the above mentioned compounds (6.62 g) were oxidized with 3-chloroperbenzoic acid to give 6,7-dimethoxy-1-methyl-3-methylsulfinyl-4-chi nolone, m.p. . Yield 3.06 g. NMR data for compounds prepared according to Examples 1-9. Example 1.S (DMSO dg) B.1 (S, 1p, 5-H); 7.85 (s, 1p, 2H); 7.7 (s, 1p, 8H); 4.05 (s., 3 p, OCH); 3. (s, sp, n-ch,); 2.45 (s, Sp, S CH) Example 2.8 (DMSO d) 8.1 (a, IP, 5H); 7.9 (s, IP, 2H); 7.7 (s, IP, 8H), 3.9 (s., 3p, N-CH,); 2. (s, 3p, SOCH). Example 3. (a) R (COC1e); 8.5 (d, Ip, 5H); 7.8 (s, Ip, 2H); 7.55 (m, 2p, 6 or 8H); 3.8 (s, 3p, N-CR.); 2.4 (s, 3p, SCH,); (B) (CDCl) 8.26 (d, Ip, 5H); 7.72 (s, Ip, 2H); 7.35-7.40 (m, 2p, 6 and 8H); 3.80 (s, 3p, 1-CH,) .32 (s, 3p, SCH,); 1.56 (s, 9p,,) (c) (DMCO dj 8.15 (s, Ip, 5H); 8.0 (s, IP, 2H); 7.05 (s, Ip, 8H); 4.10 (s, 3p, 7-OCK ); s790 (s, 3p, l-CH); 2.40 (s, 3p, SCH,); (d) (CDCl,) 7.87 (d, IP, 5H); 7.75 (s, Ip, 2H); 7.07 ( d, Ip, 8H); 4.05 (s, 3p, 6-OCHE); 3.85 (s, 1-CH, .Z.45 (s, 3p, SCH,). Example 4. (a) 5 (DMSO d) 8.35 (d, IP, 5H); 8.25 (s, .Ip, 2H); 8.10 (s, Ip, 8H); 7.75 (d, Ip, 6H); 4.00 (i, Ip, 1-CH ); 2.80 (s, 3p, 1-CH,); (b) S (CDCl,) 8.2 (d, Ip, 5H); 7.85 (s, Ip, 2H); 7.15-7.50 (m, 2p, 6- H 8H); 3.95 (s, 3p, 1-CH,); 2.95 (s., 3p, SOCH,); 1.43 (s, 9p,). Example 5. 8 (DMSO d) 8.1 (d, Ip, 5H ); 8.03 (s, IP, 2H); 7.40 (s, IP, 8H); 7.23 (d, Ip, 6H); 3.80 (s, 3p, l-CH,); 2.73 (q, 2p, CH .g); 2.27 (s, 3p, SCR,); 1.20 (t, 3p, CH,)., Example 6. b (CDCl,) 8.24 (d, Ip, 5H); 7.88 (s, Ip, 2F) ; 7.087 .48 (m, 2p, 6H and 8H); 3.92 (s., 3p, 1-SNCh); 2.92 (s, 3p, SOCK,); 2.84 (a, 2p, CHj,); T. 34 (t, 3p, CH). Example 7. S (DMSOdj) 8.73 (s, IP, 2H); 8.35 (d, Ip, 5H);, 7.20-7.90 (m, 2 p, 6H and 8 H); 3.96 (s, 3p, l-CHj); 3.26 (s, 3p, SO.CH). Example 8. 8 (DMSOdg) 8.26 (q, Ip, 5H); 8.12 (s, Ip, 2H); 7.67 (d of d, Ip, 8H); 7.34- (m, Ip, 6H); 3.95 (s, 3p, N-CHg); 2.82 (s, 3p, OCHj). Example 9. 5 (DMSOdg) 2.81 (E, 3p, OCH,); 3.98, 3.97, 3.87 (3 x8, 2 X OSI ,, 1 СНз); 7.10 (s, ip, 8h); 7.56 (s, Ip, 5H); 7.99 (s, Ip, 2H) .I The therapeutic activity of compounds of the general formula 1 is studied in standard laboratory animals. Such tests include, for example, (A) the stomatological application of compounds to a group of rats with spontaneous hypertension and (B) the intraduodenal use of compounds to a group of rats with normal pressure. In test (A), groups of four rats are isolated at night and their blood pressure is measured as follows. The rats are placed in a crate in which the temperature is maintained so that their tails protrude from the hole made in the crate. After 30 minutes, the blood pressure is measured using a blow-up cuff that is fixed around the base of the tail. At the very beginning, a pressure is created in the cuff that exceeds the expected blood pressure, and then with a slow decrease in the pressure in the cuff, it is necessary to monitor the occurrence of arterial pulsations; the pressure in the cuff at that moment is the blood pressure sought. The rats are removed from the crate and by the dental method.

7

The dose of the test compound is administered in the form of a solution or suspension in a 0.25% solution of carboxymethyl cellulose. Blood pressure is measured 1.5 and 5.0 hours after drug administration. Connection defined is active as long as it gives a blood pressure drop of 20% or more, at one or the other of the above intervals.

In the text (B), groups of three rats are injected and a tube is inserted into the carotid artery, and the blood pressure in the duodenum is altered by electronic means through a sensor connected to the arterial tube. The test compound is introduced into the duodenal kigaku in the form of a solution or a suspension in 0.25% carboxymethylcellulose aqueous solution. Blood pressure is measured before the administration of the drug and 30 minutes after the administration. Compounds that lower blood pressure by 10% or more within 30 minutes after drug administration are defined as active,

The known compound with the closest chemical structure and antihypertensive activity is tolmesoxide

SNS

SNZO

S (0) nCH3

eight

Tolmesoksid test in accordance with the method of the text And, as indicated in the invention, and found that he has activity. In test A, compounds are initially tested at doses of 90 mg / kg. If they demonstrate activity at this level, the next test is carried out at a dose of 30 mg / kg and then 10 mg / kg. So

thus, the threshold dose at which the compounds are active in this test is determined. Compounds with high activity at doses of 90 mg / kg, but inactive at doses of 30 mg / kg, refer to compounds with a threshold activity of 30-90 mg / kg. Similarly, compounds with high activity at doses of 30 mg / kg, but inactive at doses of 10 jfi / Kr, are defined as compounds with a threshold activity of 10-30 mg / kg. The threshold activity for tolmeoxide is defined as 30-90 mg / kg. However, at doses of .90 mg / kg, tolmes-oxide gives the undesirable side effects of sedation and lethargy. In some. rats had difficulty breathing and they fall into prostration.

connecting

determine doses (see thresholds

Thus, the compounds of Examples 1-9 are superior to tolmesoxide, since they are either more active or are active in the same doses as tholmeoxide, but do not have serious sterol oxide, in doses of 90

Acrylates Formula III

CH, 78-75 CH, 53-54

CH 115-116

SNS 85-86

Claims (1)

METHOD FOR PRODUCING CHINOLONS R ₍ is hydrogen, chloro or methoxy; R _z is chloro, fluoro, tyl; trifluoromes ₄ -C ₄ - alkyl or mega-group ,. and with η equal to 2 R <is hydrogen; R ^ is fluorine, characterized in that the acrylate is cyclized by the general formula I * 3 where R ₍ and R ^ HMeioT are the indicated values, R _? Is hydrogen or methyl, R ₄ is C ^ -C ^ -alkyl, followed by methylation of compounds in which R j is hydrogen to obtain compounds in which R3 “Methyl, and, if necessary, oxidized to convert compounds in which η is 0, into compounds in which η is 1 or 2, or compounds in which η is 1, into compounds in which η is 2. <e ί 19