Method of obtaining derivatives of bicyclic pyramidine-5-on or their salts with pharmaceutically acc

专利摘要:
The method of producing bicyclic pyrimidin-5-one derivatives of the general formula I N. Ri R3 R Q lower alkyl; hydrogen atom, lower alkyl or aryl; . R is a hydrogen atom or lower alkyl; Alk - lower alkanediyl L - dvuhsvalentny radical of the formula. C or - C N - C; R is attached to an S atom by a carbon atom, where R, R and R are each independently selected from the group consisting of hydrogen and lower alkyl, and where R and R can also supplement a saturated or unsaturated 5- or 6-membered carbocyclic ring ; Q is a group of formula X - Ar, in which X is a member selected from O, CH - OH, C
公开号:SU1138032A3
申请号:SU823455997
申请日:1982-06-24
公开日:1985-01-30
发明作者:Эдмон Жозефин Кеннис Людо；Каролус Мертенс Йозефус
申请人:Жансен Фармасетика Н.В.(Фирма)；
IPC主号:

专利说明:

is reacted with a piperidine derivative of the general formula R, where R, R and R have the indicated meanings, in an inert organic solvent, and the desired product is expressed in free form or as a salt with a pharmaceutically acceptable acid, or. as cis or trans isomer. Priority signs: 15.07.81 - R - lower alkyl; I am a water atom, lower alkyl; . R is a hydrogen atom, Alk is a lower alkanediyl; A - - CHj - CHj-, - C C -, - C N - attached to the S atom by a carbon atom, where R, R and R are each independently selected from the group consisting of hydrogen or lower alkyl, and where R and R can also complement a single or unsaturated 5 or 6 membered carbocyclic ring. Q - Ar - C O, 138032 where or where the swarm of C or number or where Ar is phenyl or phenyl substituted by a halogen atom, Q is a radical of the formula R - a hydrogen atom or lower alkyl; 1.04.82 - R2 - aryl; - lower alkyl, - a group of formula X-Ar, in which X is a member selected from - OH, / C (O - lower alkyl) 2 C. (CH2) g, where R is an integer of 0 °, equal to 2 or 3, or C N-OH5 g is phenyl or phenyl, substituted with a. Of halogen, Q is a radical of the formula R3 R a hydrogen atom or lower alkyl; halogen atom.
This invention relates to a process for the preparation of novel bicyclic pyrimidine-5-one derivatives of the general formula
/ Vn
(-VT 11
L
And UT - O
where R is lower alkyl,
R is a hydrogen atom, lower alkyl or aryl;
hydrogen atom or lower
alkyl ,. lower alkanediyl;
divalent radical of the formula CH2 - ,, -CH2 -, -C-C-
,four
or
ten
attached to the S atom by a carbon. atom, where R and R and B are each independently selected from the group consisting of, propandiccarboxylic acid, ethanedicarboxylic (2) -2-ependicarboxylic, (R) -2-ethanedicarboxylic, 2-hydroxyethanedicarboxylic, 2, 3-dioxy-ethanedicarboxylic, 2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-acrylic, o-phenol-oxus} on, methanesulfo-, ethanesulfo-, benzolesulfo-, 4-methylbenzenesulfo-, cyclohexanesulfo -, 2-oxybenzoic, 4-amino-2-hydroxybenzoic acids and the like. Conversely, the obtained salts can be converted by treatment with alkali into free bases. A number of intermediates and starting materials used in these methods are known compounds, others can be obtained by methods known in this branch of the art for the preparation of similar compounds, and the methods for synthesizing some of them are given below. Intermediates of formula II can be prepared by converting the hydroxyl group of the corresponding alcohols, for example, by conducting the reaction of the alcohols with thionyl chloride, sulfuryl chloride, phosphorus pentabromide, phosphorus oxychloride, 4-methylbenzyl chloride sulfonyl, and the like. Preparation of intermediate products. Example 1. A mixture of 40 h of 4-methyl-2-thiazolamine, 30 h, H-acetyl-4, 5-dihydro-2 (3N) -furanone and 225 h of methylbenzene is stirred and heated under reflux for 2.5 h. in conjunction with 0.6 parts of hydrochloric acid. After cooling to room temperature, 170 parts of phosphoryl chloride are added, the mass is gradually heated to approximately 110 ° C and stirred for an additional 2 hours at this temperature. The reaction mixture is evaporated and the residue is drunk on crushed ice. Ammonium hydroxide is added to a pH of 8. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as a means to remove from the adsorbent. The pure fractions are collected and the solvent is evaporated. The residue is crystallized from a mixture of 2,2-oxy-bis-propane and 2-prapanol, which gives 19.3 parts of 6- (2-chloroethyl) -3,7-dimethyl-5H-thiazoloSZ, 2-a) pyrimidine-5-one (intermediate 1 product) “6- (2-chloroethyl) -2,3-dihydro-7-methyl-5H-thiazolo (3,2-a) pyrimidin-5-one (intermediate 2 product) and 3- ( 2-chloroethyl) -758-dihydro-2-methyl-4H, 6H-cyclopenta (4,5), thiazolo (3,. 2-a) pyrimidin-4-one. That pl. 11 ° C (intermediate 3 product), Example 2. A mixture of 75 hours 2-. -benzothiazolamine, 76 parts of 3-acetyl-4, 5-dihydro-2 (3N) -furanone, 2.4 parts of 12-hydrochloric acid and 270 parts of methylbenzene are measured and heated under reflux for 2 hours using a water separator, The reaction mixture is cooled and 323 parts of phosphoryl chloride are added at 20–25 ° C. Together, they are gradually / H heated to 110 C and stirring is continued for 2 hours at this temperature. The solvent is evaporated and the residue is injected onto a mixture of crushed ice with ammonium hydroxide. The product is extracted with trichlormeaan. The extract is dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (92: 8 by volume) for washing from the adsorbent. Pure fractions are collected and the solvent is diluted. The residue is crystallized from a mixture of 2-propanol with 2,2-oxibispropane, which gives 39 h, 3- (2-chloroethyl) -2-methyl-4H-pyrido (2,1-b) benzathiazol-4-one t. Pl, 144 C. (intermediate 4 product),. . Similarly, one obtains also e-6- (2-chloroethyl) -2-, 7-dimesh-1-5H1, 3,4-thiadiazolo (3,2-a) pyrimidin-5-one; t, pl, 118 C (intermediate 5 product) and 6- (2-chloroethyl) -7-methyl-5H-thiazolo- (3,2-a) pyrimidin-5-one (intermediate 6 product), Example 3 Mixture 30 h, 4-hydroxy-2-mercapto-6-metsh1-5-pyrimidine ethanol, 6.8 parts of sodium hydroxide, 15 parts of sodium bicarbonate and 100 hours, 2-propanone is stirred at room temperature, then 180 hours is added of tetrahydrofuran and 170. of water. Next, 25 hours, 3-chloro-2-butanone and 0.2 parts of N, N, N-triethylbeisolethanamine-chloride are added at once and the whole is stirred and heated for 1 hour at 60 C. The mixing is continued overnight at room temperature. The reaction mixture is filtered and the filtrate is salted out. The organic phase is separated, dried, filtered and extruded, giving 36 parts of 5- (2-hydroxyethyl) -6-methyl-2 (1-methyl-2-oxopropyl) thio-4- (3N) pyrimidinone in the form of oily residue (intermediate 7 product). Example 4. A mixture of 30 parts of 4-ox-2-mercapto-6-methyl-5-pyrimidine ethanol, 25 parts of potassium carbonate, 270 parts of N, N-dimethylacetamide and 75 hours of water is stirred at room temperature and added 36 hours. 1,3-dibromopropane immediately, the temperature rises to 50 Co. All together is stirred overnight at room temperature. The reaction mixture is evaporated, water is added to the residue. The solid product is rinsed with water and; dried under vacuum at that gives 21 hours (58%) of 3,4-dihydro-7 - (2-hydroxyethyl) -8-methyl-2A, bH-pyrim to (2,1-b) (1,3) thiazin-6-one; m.p. 155 ° C (intermediate product The same 2,3-dihydro-6- (2-hydroxyethyl) -7-methyl-5H-thiazolo- (3,2-a) pyrimidin-5-one} t.p. 148.7 ° C (intermediate product 9), EXAMPLE 5. A mixture of 20 parts of 3,4-dihydro-7- (2-oxysthyl) -8-methyl-2H-6H-pyrimido (2, 1-6) (1,3) thiazin-6-one, 50 parts of acetic acid and 180 hours of hydrobromic acid in the form of a 67% acetic acid solution are stirred and heated under reflux. Stirring is continued all night at boiling point The reaction mixture is sintered and the solid residue is grown in 2-propanone. Product filters they are dried and dried, giving 24 hours (100%) of 7- (2-bromoethyl) -3,4-dihydro-8-methyl-2H, bH-pyrmchido (2, -b) - (1,3) thiazine- 6-he-monohydrobromide (mp 215 C, (intermediate product 10). In the same way, the same 6- (2-bromoethyl) -2-3-dihydro-7 methyl-5H-thiazol- (3,2 -a) pyrimidine-5-one-monohydrobromide, melting point 237.2 .G, (intermediate product 11) Example 6. Mixture 36 parts 5- (2-hydroxyethyl) -6-methyl-2- (1-methyl -2-oxoprrpyl) (3N) -pyrimidinone and 240 parts of a 60% aqueous solution of hydrobromic acid in acetic acid are stirred and heated for 4 hours at 90 ° C. The reaction mixture is ground in and the residue is suspended in 400 hours. 2- ropanona. The solid product is filtered off, washed with 2-propanone and dried, yielding 44 parts of 6- (2-bromoethyl) -2,3,7-trimeish1-5H-thiazole (3,2-a) pyrimidine-5-, -one monohydrobromide m.p. (intermediate 12 product). Example 7. To the interlaced and heated Grignard compound, previously prepared from. 14.6 hours of magnesium and l05 parts of 1-bromo-4-fluorobenzene in 450 parts of -oxybisethane, a solution of 94 parts of 4-phenyl-1- (phenylchethyl) -4-piperidinecarbonohydrochloride in 360 hours, methylbenzene is added dropwise . About 250 parts of 1,1-oxybisethane are distilled at an internal temperature of 60-65 ° C. The turbid solution is stirred and heated under reflux for 5 hours. The reaction mixture is decomposed with a saturated solution of ammonium chloride in water. The layers are separated and the organic phase is dried, filtered and evaporated. The oily residue is boiled in a dilute hydrochloric acid solution. After cooling, the reaction mass is basified with ammonium hydroxide and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol with 2,2-oxybispropane, which gives 91 -h. (81%) (4-fluorophenyl) {4-phenyl-1- (fensh1methyl) -4-piperidinyl methanone; m.p. 147.6 C (intermediate 13 product). Following the method of Grignard, (4-fluorophenyl) 4-methyl-1- (phenylmethyl) -4-piperidinylmeanone is also obtained in the form of an oily residue (yielding 14 products). Example 8. To a stirred mixture, 79 parts of (4.-fluorophenyl) 4-phenyl-1 - (phenylmethyl) -4-piperidinylDmethanone and 630 parts of methylbenzene are added dropwise for 32 hours, ethyl carbonate at room temperature, ffo At the end, stirring is continued for 5 hours at boiling point. The reaction mixture was evaporated and (chloromethyl) benzene was distilled off in vacuo (pump). The oily residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (982 by volume) as an agent for washing from the adsorbent. The pure fractions are collected and the solvent is stripped. The residue is crystallized from a mixture of 2,2-oxybispropane with a small amount of petroleum ether, which gives 35.5 parts of ethyl A (-4-fluorobenzoyl) -4-phenyl-T-piperidinecarboxylate; m.p. 91.7 C (intermediate 15 product). In a similar manner, ethyl 4- (4-fluorobenzoyl) -4-methyl-1-piperidinecarboxylate is also obtained as a residue (intermediate 16 product) Example 9. A mixture of 14 parts ethyl, 4- (4-fluorobenzoyl) -4-phenyl- 1-Piperidinecarboxylate and 150 parts of a 48% aqueous solution of hydrobromic acid are stirred and heated under reflux for 30 minutes. The reaction mixture is diluted with 100 parts of water and the reaction mixture is left under stirring until it cools to room temperature. The precipitated product is filtered off (the filtrate 1 is deposited), washed with methyl benzene and stirred in a 2-prop, non. The filtrate is again filtered (the G1 filtrate is deposited) and dried, giving a first fraction consisting of 4.3 hours, (4-fluorophenyl) (4-phenyl-4-piperidinyl) methanone-hydrobromide hemihydrate. The filtrate G and II are added and the residue the solids are stirred in 4-metsh-2-pentanone. The product is filtered and dried, giving a second fraction consisting of 6.2 parts of (4-fluorophenl) (4-phenyl-4-piperidinyl) -methanone hydrobromide hemihydrate; m.p. 173.4 C. Total yield: 73% (intermediate 17 product; Similarly, (4-fluorofensch1) (4-methyl-4-piperidinyl) methanone hydrobromide (intermediate 18 product) is also obtained. Example 10: Mixable mixture 100 parts of pyridine, 53 parts of 5-fluoro-1H-indole and 270 parts of benzene are added dropwise 57 parts of benzoyl chloride. At the end, stirring is continued overnight at room temperature. The reaction mixture is poured into a dilute hydrochloric acid solution and the layers are separated. The organic phase is dried, filtered and embedded. The residue is purified twice by chromatography on silica gel. To wash out the adsorbent, a mixture of trichloromethane and methanol (95: 5 by volume) is used. The pure fractions are collected and the solvent is evaporated, which gives 80 parts of 1-benzoyl-4- (5-fluoro-1H-indole-3 -yl) -1,4-dihydropyridine as a residue (intermediate product 19). Similarly, 1-benzoyl-1,4-dihydro-4- (1H-Indol-3-yl) -3-methylpyridine is also obtained as oily residue (intermediate 20 product). Example 11. A mixture of 65 parts of 1-benzoyl-4- (5-fluoro-1H-indol-3-yl) -1, 4-dihydropyridine and 270 parts of N, N-dimethylacetamide is hydrogenated at normal pressure at room temperature 10 including catalyst in the form of 10% palladium on activated carbon. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue is poured onto water and the product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue was purified by silica gel column chromatography, using a mixture of trichloromethane and methanol (95: 5 by volume) to wash the adsorbent. The pure fractions are collected and the solvent is injected, giving 5 parts of 1-benzoyl-4- (5-fluoro-1H-indol-3-yl) piperidine as a residue (intermediate 21 products). Similarly, cis-1-benzoyl-4- (1H-indole-3-np) -3-methylpiperidine is also prepared; m.p. 230.7 C (intermediate product 22). Example 12. A mixture of 21 parts of cis-1-benzoyl-4- (1H-indol-3-yl) -3-methylpiperidine, 60 parts of potassium hydroxide 385 parts of 1,2-ethanediol and 80 hours, water is stirred and heated under reflux (about 130 ° C) overnight. After the mixture has cooled, about 200 parts of water are added, and
the product crystallizes. The whole is further cooled, the solid is filtered off, washed with plenty of water and 2,2-oxybispropane, then dried. Yield 11.2 parts (80%) of cis-3- (3-methyl-4-piperidinyl) -1H-indole 23 product).
Similarly, 5-fluoro-3- (4-piperidinyl) -1-Nindole is also prepared (intermediate 24 products).
Obtaining target compounds.
Example 13. A mixture of 3.3 parts of 6- (2-chloroethyl) -2, 3-dihydro-7-methyl-5H-tyazole (3,2-a) pyrimidine-5-one, 3 parts (4-fluorophenyl ) (D-piperidinyl) methanone hydrochloride, 8 parts sodium carbonate and 120 1. 4-methyl-2-pentanone is stirred at reflux temperature for 20 hours using a water separator. The reaction mixture was filtered hot over Hyflo, and then the filter cake was washed with trichloromethane. The resulting filtrate was isolated. The residue was purified through column chromatography on silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. Pure francs are collected and the eluent is evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2-hydroxy-propane, to give 2 parts of 6-G 2 -4- (4-fluorobenzoyl) -1-piperidinyl ethe-1, 3, dihydro-7-methyl-5H-thiazolo (3 , 2-a) pyrimidin-5-one, mp.165.6 ° C (compound 1), yield
 40%. ; ,
In a similar manner, 7- {2- 4- (A-fluorobenzoyl) -1-piperidium | nyl ztsh1 -3, 4-dihydro-8-methyl 2H, 6H-pyrimido 2,1 -D d thiazin-6-one J is obtained m.p. 165.2 ° C (compound 2); yield 52% and 3,4-dihydro-7 2- (4-1H-Indol-3-shl) -1 - piperid nilD-methyl-8 -methyl-2H-bH-yirimido (2,1-in) (1 , 3) tizin-6-oHj t. Pl. 227.1 C (compound 3), yield 42%.
Example 14. A mixture of 3.75 parts of 6- (2-chloroethyl) -3,7-dimethyl-5H-thiazo-ls1- (3,2-a) pyrimidine-5-one; 3.6 parts of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride, 12 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 hours of 4-methyl-2-pentanone are stirred and refluxed. for 22 h, using a water trap. The reaction mixture is filtered hot on Hyflo and the resulting filtrate is added. The residue is purified on a silica gel chromatography column using a mixture of trichloromethane and methanol (90:10 by volume) as the solvent.
Pure fractions are collected and the eluent is evaporated. The resulting residue was crystallized from a mixture of acetonitrile and 2,2-oxy-propane, to obtain 5 parts of (4-fluorobenzoyl) -1-piI peridinyl ethyl-3,7-di-1-methyl-5H-thiazolo (3,2-a) pyrimidine-5 -she is; m.p.
199.7С (compound 4), yield 82%.
In the same way, using equivalent equivalence amounts of the corresponding starting materials, we obtain:
(4-fluorobenzoyl) -1-piperidinyl} ethyl1-7-methyl-5H-thiazolo (3,2-a) pyrimidin-5-one {m.p. 147.9 C (compound 5), yield 22%;
3-H2-4- (4-fluorobenzoyl) -1-piperidinyl etyl1-2-methyl-4H-pyrimido (2,1-in) benzothiazol-4-one; mp.175.4 (compound 6), yield 33%,
6-Gz-4- (4-fluorobenzoyl) -1-piperidinyl ethyl 5 (-2, 7-dimethyl-5H-1,3,4-thiodiazolo (3,2-a) pyrimidine-5-one; mp 198.2 s (compound 7), yield 51%;
3-G2-4- (4-fluorobenzoyl) -1-piperidinyl D 3 -tilL-7,8-dihydro -2-methyl-4H,. 6H-cyclopenta (4,5) thiazolo, 2-a pyrimidin-4-one; m.p. 183.8 195 .8С (compound 8) ,. yield 42%, 6-G2-4- (4-fluorobenzoyl) -4-methyl-.1-piperidinyl methyl-7-methyl-5H-thiazolo (3, 2-a) pyrimidine-5-one monohydrochloride, t. pl. 177, (compounds 9), yield 45%;
(4-fluorobenzoyl) -4-phenyl-1-piperidine ethyl-7-methyl-5Hiazolo (3,2-a) pyrimidin-5-one; mp 161.1 s (compound 10), yield 53/5.
Example 15. A mixture of 3.75 parts of 6- (2-chlorostil) -3,7-dimethyl-5H-thiazo lo (3,2-a) pyrimidin-5-one, 3 parts of 3- (4-piperidinyl) -1H-indole, 10 parts sodium carbonate; 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone are stirred and heated under reflux for 20 hours with a water separator. Then the reaction mixture was filtered hot on Hyflo and the resulting filtrate was evaporated. The residue is purified on a silica gel column chromatography using a mixture of trichloromethane and 13 methanol (90:10 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from ethanol to give 3.25 parts of 6 - ((1H-indol-3-yl) -1-piperidinyl-e, 7-dimethyl-5H-thiaeolo (3,2-a) pyrimidine-5-one, M.P. 274, (compound 11), yield 53%. In the same way, using equivalent amounts of the corresponding starting materials, receive: (1H-indol-3-yl) -1-piperidinelDethyl1-7-methyl-5H-thiazolo (3 , 2-a) pyrimidin-5-one; mp 218.5 (compound 12), yield 45% 3- 2- 4- (1 H-indol-3-yl) -1-piperidinyl ethyl -2- methyl 4H-pyrimidio (2,1-b) benzothiazol-4-one | mp 274.9 ° C (compound 13), yield 50% 4- (1 H-indole-3-yl) -1- piperidinyl ethyl -2,7-dimethyl-5H-1,3., 4-thiadiazolo (3., 2-a) pyrimide n-5-one / mp. 260.1 ° C (compound 14), yield 7 7% I. 2,3-dihydro-6 -. (1 H-indol-3-yl) -1-piperidinyl | ethyl -7-methyl-5H-thiazolo (3,2-a) pyrimidin-5-one m.Pl. 238.2-241.7 ° С (with decomposition (compound 15), 55% code J 2-methyl- H- (.2- 4-methyl (1 H-indol-3-yl) -1-piperidinyl-methyl-4H-Pyrimido (2,1-c) benzothiazol-4-one); pl. 270, (compound 16 ), yield 76%; 7,8-dihydro-3-2-4- (1H-indole-3-yl) -1-piperidinyl1-ethyl -2-methyl-4H, bH-cyclopenta (4.5) thiazolo (3,2-a) pyrimidin-4-one; m.p. 242.9 ° C (compound 17), yield 69%; 3,7-dimethyl-6- 2- 4- (2-methyl-1H-indol-3-yl) -1-piperidinyl ethyl-5H-thiazolo (3,2-a) pyrimidin-5-one, mp . 187.9-188.7 ° C (compound 1, yield 48%, 7-methyl-6- 2- 4- (2-methyl-1H-indol-3-yl) -1-piperidinyl2-ethyl | -5Nthiazolo ( 3,2-a) pyrimidine-5-one, mp 170, (compound 19), yield 12%, 6-j2-C4- (5-FTOR-1 H-indol-3-yl) -1 -piperidinyl 3, 7-dimethyl-5H-thiazolo (3,2-a) pyrimidin-5-one T. pl. 270.6 ° C (compound 20), yield 50% i6-2-14- (5-hlrr- 1H-indol-3-yl) -1-piperidinyl} -ethylCH-7-methyl-5H-thiazolo (3., 2-a) pyrimidin-5-one 2 T.PL.224, bS (compound 21), progress 20% J p ((5-fluoro-1 H-indol-3-yl) -1-piperidinyl ethyl-7-methyl-5H-: thiazolo (3,2-a) pyrimidine-5-one 1 mp. 244, (compound 22), yield 51%, cis-2,3-DIGIDRO-6-C2-4 - (1H-indol-3-yl) -Zmethyl-1-piperidinyl ethyl -7- methyl 5H-thiazole (3,2-a) pyrimidin-5-one; mp 234, (compound 23), 61% yield. Example 16. A mixture of 5.85 h, 6- (2-bromoethyl) - 2,3,7-trimethyl-5H-thiazolo (3,2-a) pyrimidin-5-one monohydrobromide, 4 parts (4-fluorophenyl) (4-piperidinyl) methanone-hydrochloride, 10% sodium carbonate, 3 hours 30% a solution of sodium methoxide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed for 20 hours using a water separator. The reaction mixture was filtered hot on Hyflo and the filtrate was evaporated. The residue is purified on a silica gel chromatography column using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of acetonitrile and 2,2-oxybispropane (3: 1 by volume) to give 1 part of (4-fluorobenzoyl) -1-piperidinyl ethyl-2, 3,7-trimethyl-5H-thiazolo (3,2- a) pyrimidine-5-one; m.p. 159, (compound 24), yield 14%. In a similar way, 6- (1H-indol-3-yl) -1-piperidinyl} ethyl} -2.3, 7-trimethyl-5H-Thiazolo (3,2-a) pyrimidin-5-one is obtained. Pl. . 240.2®C (compound 25), vkod 30%, 6-G2-G4- (4-fluorophenyl hydroxymethyl) -1-piperidinylJ-ethylJ-3,7-dimethyl75H-thiazolo (3,2-a) pyrimidine-5 - he t. pl. 138, (compound 26), yield 27%; (4-fluorophenyl hydroxymethyl) .- 1-piperidinyl-ethyl-3, 4-dihydro-8-methyl-2H, bH-pyrimido (2,1-b) (1,3-thiazin-6-one), t „ square 174.1C (connection 27), yield 52%. PRI me R. 17. Stirring and heated suspension 4 hours -12- 4- (1H-indol-3-yl) -1-piperidyl3, 7-dimethyl-5H-thiaz olo3, 2-a) pyrimidin-5-one in 80 h This I ol is acidified with phosphoric acid.
60 parts of water are added and the ip is boiled. The undissolved part is filtered off and the resulting filtrate is allowed to crystallize. The resulting product is filtered and dried, yielding 4.5 hours (80%) (IH-indol-3-yl) 1-piperidinyl 2-esh14-3, 7-dcmethyl 5H-thiazolo (3,2-a) pyridine-5-amino acid ( 2; 3) monohydrate so pl. ZlAjA c (compound 28), yield 80%.
In the same way receive:
6-G2- 4- (1 H-indol-3-yl) -1-piperidnyl}, T-gdimetil-ZN-thiazolo (3, 2-a) pyrimidin-5-one sulfate (1: 1) monohydrate t. square 244.3 C (compound 29), yield 80%,
 (IH-indole-3-yl) -1-piperidinyl ethyl1-3,7-dimesh1-5H-thiazolo (3,2-a) pyrimidine-5-one-2-hydroxy-1,2,3-propantprncarboxylate (2 : 1) monohydrate so pl. 190.5 C (compound 30), yield 25Z;
/ + / - 6 ((IH-indole-3-yl) -1-piperidinyl 1ethyl-3,7-dimesh1-511-thiazolo (3,2-a) pyrimidin-5-one (K- / K,) - 2, 3-dioxybutanedionate (2: 1) monograd; mp 177, (compound 31), input 40%;
6-f2- 4- (1H-ichdol-3-yl) -1-piperidine ethyl ethyl-3, 7-dimethyl-5H-thiazolo (3,2-a) pyrimidine-5-ca (2) -2-butanedionate ( 1: 1); m.p. 150, (compound 32), yield 35%. .
Example 18. A mixture of 6.8 parts of 6- (2-bromoethyl) -2, 3-dihydro-7-methyl-5H-thiazolo (3,2-a) pyrimidine-5-oa, 3.15 h, b (- (4-orophenyl) -4-piperidinemetakopa; 4.8 parts of sodium carbonate; 0.1 hours, potassium iodide and 200 hours; 4-methyl-2-pentanone is stirred
: and boil with a REFRIGERATOR in
24 hours. The reaction mixture is cooled, dried with 50 parts of water, dried, 4 "drilled and evaporated. The residue is purified on a chromatographic column and on a silica gel using a mixture of trichloromethane n methanol (90:10 by volume) as eluent. Pure / fractions are collected and the eluent is evaporated. The residue is solidified by trituration in acetylnitrile of Prodzkt filtering off, washed twice with acetonitrile and dried, yielding 2.5 parts (42%) (4-fluorophene1 oxyyutil) -1-piperidinyl} ethyl -2,3-dihyd, po-7 metsh1 5H -thiazolo (3,2-a) pyrimi8032 16
din-5-she, so pl. 204, (compound 33), yield 42%.
Similarly, CYN-6-f2- {4- (1H-indole-Z-yl) -3-methyl-15-piperidinyl-ethyl-3,7-dimethyl-5H-thiazolo (3,2-a) pyrimidine 5th; m.p. 212.8 C (compound 34), yield 18%.
Example 19. A mixture of 9.3 parts of (bromethyl) -3,7-dimethyl-5Niazolo (3,2-a) pyrimidin-5-one monohydrobromide 6.5 parts of (4-fluorophenyl) -1,3-dioxane-1 Piperidine 2-yl; 10.2 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone are stirred and refluxed overnight. The reaction mixture is cooled and water is added. Lunches are divided. The organic phase is dried, filtered and evaporated. The residue is purified on a chromatographic column on silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eu to. Pure fractions are collected and the eluent is evaporated. The residue is recrystallized from 2,2-oxybispropane. The resulting product is filtered. And suaat to give 4 parts (35%) of 6- | 2- 4- (2-) 40 -fluorofens13-1,3-dioxalan-2-yl (-1-piperidinyl) ethyl} -3, 7-dimethyl-5H-thiazolo (3,2-a) pyrimidine-5-one / t. Pl. 140 C (compound 35), yield 35%.
five . ..
Example 20. A mixture of% 3 parts of 6-f2-C4- (4-fluorobenzoyl) -1-piperidine3-ethyl-3, 7-yes methyl-5H-thiazolo (3,2-a) pyrimidin-5-one, 10 h
0 1.1, 1 - (methylidedentis / hydroxy) trisethane, 4 parts 4-methylbenzenesulfonic acid and 80 parts ethanol are stirred and heated under reflux for 72 hours. After cooling
5 ammonia gas is introduced. The image of the solid precipitate is filtered off and the polluted filtrate is ground. The residue is purified on a silica gel column chromatography using
0 a mixture of trichloromethane and etenla (Jaog Shch by volume) as eluent. Pure fractions collect and eluent you: Soar. The residue is further purified by reverse phase chromatography.
5 on Li Chroprep. R R 18 using a mixture of water containing 0.5% ammonium acetate and methanol containing O, tZ, L- (11-methyl 1) -2-propanamine (15:85
by volume), as eluent. Pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2-oxybispropane to give 0, 6-H2-A- (diethoxy) 4-fluorophenyl-methyl (1-piperidinyl), 7-dimethyl-5H-thiazolo (3,2-a) pyrimidine-5-one Jg. 115.6 С With (compound 36), you-. asod 6%. .
Example 21. A mixture of 4 parts of 6-G2-4- (D-fluorobenzoyl) -1-piperidinyl2 stage1-2, 3-dihydro-7-methyl-5H-thiazrel (3,2-a) -pyrimidine-5-one - 0.7 hours hydroxylamine hydrochloride; 1 h. H, N-dieth-1-ethane-amine and 20 Cho ethanol are stirred and heated under reflux for 5 hours. The reaction mixture is mixed and the residue is stirred with water. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue was chromatographed on silica gel using a mixture of trichloromethane and methanol (95: 5 vol.) As eluent. The first fraction of the L (E) -isomer is collected and the eluent is evaporated. The residue is crystallized from 2-propanol to give 1 part (24%) of (E) -6 - (((4-fluorophenyl) (hydroxy-imino) -methyl - (1-piperidinyl) -3, 3-dihydro-7-methyl-5H -thiazolo- (3,2-a) pyrimidin-5-one, mp 214.1 ° С ..
The second fraction (2) -isomer is collected and the eluent is evaporated. The residue is crystallized from 2-propanol to give 0.2 parts (4.6%) (2) (4-fluorophenyl) (hydroxy-imine .o) -mutil1- (1-piperidinyl) ethyl -2, 3-dihydro -7-methyl-5H-thiazolo-, 2-a) pyrididin-5-one; m.p. 220.8 ° C .-,
The compounds of the formula D or their pharmaceutically acceptable salts, acid addition products, have a pronounced psychotropic, antihistamine and antiserotonic activity.
The activity of the compound as a psychotropic agent is proved by experimental test data with apomorphine (ALO), tryptamine (THREE) and norepinephrine, (NOR) in rats and G tested with APO in dogs. The tests are conducted according to the active me. todikam Experimental data are given in table „t ..
Test with APO, THREE and NOR in rats. Experimental animals (adult male Wistav rats weighing 240 + 10 g after continued
overnight overnight without food processing, melted by subcutaneous injections (1 ml / 100 g) with an aqueous solution of the test compound (time zero) and placed in isolated cells for observation. After 30 min (80 min countdown), 1.25 mg / kg apomorphine hydrochloride (APO) was intravenously administered, after which the rats were observed for 1 h to reveal agitation, anxiety, and stereotypical chewing. By the end of the 1-hour period (counting time 90 min), 40 mg / kg of SRAI was intravenously injected intravenously into the same animals, and typical attacks of the type of apoplexy were noted. Two hours later, after the start of pretreatment (120 minutes), the same animals undergo intravenous injection of HOP (1.25 mg / kg),. then observe the possible mortality for up to 60 minutes.
In tab. 1 shows the values of BDjg at p ° and compounds. Indicator
The EDgg, as used herein, represents a dose that protects 50% of the animals from the effects caused by the action of APO, THREE or HOP.
Test with APO on dogs. (APO dog). The compounds listed in Table. 1, are administered subcutaneously to beagle dogs at various dosages, then after 1 hour the animals undergo
standard treatment
dose of APO 0.31 mg / kg, administered subcutaneously.
In tab. 1 shows the values for a range of compounds. ED indicator
th
in the sense in which it is used here, it represents a dose that protects 50% of animals from vomiting.
The potency of the compounds as serotonin antagonists is visible
according to the results obtained in the subsequent tests in which their antagonistic effect on the use of serotonin was investigated. The results of tests on actions that cause damage to the stomach (the damage was caused artificially by the action of 48/80). Compound 48/80 (a mixture of oligomers obtained by the condensation of 4-methoxy-N-methylbenzeneethanamine with formaldehyde) is a potent agent that promotes the cleavage of vasoactive amines from endogenous reserves, such as histamine or serotonin. In rats injected with compound 48/80, consistent blood supply changes appear. In various vascular formations: auricle cyanosis of the extremities is clearly detected within 5 min after injection of the compound, rats die of shock within 30 min. Shock followed by death can be eliminated if rats are pretreated with. treatment purpose classic H-1 antagonist. However, the stimulating effects on gastric secretion remain undisturbed, so that in rats treated for 48/80 compound and protected from shock by the H-1 antagonist, all signs of intensive action of the gastric glands can appear. A wide dissection of dead animals shows the presence of dilated stomachs with abnormal contents, as well as coarse, nervous, shiny, red patches over the entire mucous membrane corresponding to areas with decayed glands. A number of well-known serotonin antagonists, such as methysergide, cyproheptadine, cynanserin, and others, completely prevent cyanosis of the auricles and peripheral areas, as well as damage; glandular areas of the stomach and its unusual expansion. Table 2 shows a series of compounds of general formula D according to the dose in which gastric expansion is completely absent in 50% of experimental rats (ED50 values). "I Antagonistic activity regarding the effect of protomine on an artery closer to the tail end of the rat's body. LL screening tests use the tail arteries of feedlessly pre-fed male rats (210-235 g). From each artery, two spiral strips 5-6 cm long and 2 mm wide are obtained, which are mounted in a vertical position in the 1QO mp organ bath containing the Krebs-Hehse Bet solution treated with oxygen. Reductions lower than the maximum are obtained by. Adding single doses of serotonin (40 ng / ml) nanograms to the organ bath for 2 minutes, every 10 minutes, the amplitude of the contraction is measured before the addition of the drug and within 5 minutes after. After washing out, the antagonist is added 3 times again to make sure that the contractions are restored and normalized. In tab. Figure 2 shows the values of a series of compounds of the formula D, as well as their pharmaceutically acceptable salts, obtained in the indicated test. In this connection, the values of EBwood are minimal, concentrations of the birlogically active compound, at which the amplitude of the reduction is reduced by at least 50% compared to its normal value. Inhibition of serotonin-induced contraction of the trachea in the guinea pig. Tracheal rings, 5 mm long, obtained from guinea pigs (400,500 g), overdone overnight, are suspended with a preload of 2 g per 100 g of bath, representing Tyrode's solution, carbonated with a mixture of 95% oxygen and 5% carbon dioxide () . Abbreviations are recorded isometrically. 0.30 mg / l serotonin ball (30 min contact time) before and after 30 min of incubation period with a single antagonist concentration are added to the bath-forming fluid at 30 min. At a single antagonist concentration. The response of the anibonist in the presence of an antagonist is compared with the response, Prior to the addition of the antagonist (the drug became unsuitable for time-activity studies). Values as shown in table. 2, are antagonist concentrations at which its effect diminishes. by 50%. The effectiveness of the compounds as histamine antagonists becomes apparent from the results. Protection of rats from death caused by the action of the compound 48/80. Connection 48/80, representing ..
oligomers obtained by the condensation of 4-methoxy-M-methyl-phenethylamine with formaldegil, an effective and potent histamine-releasing agent, has a definitive effect on the fatal abrupt decrease in blood circulation caused by compound 48/80, is a simple way of quantifying the anti-histamine effect of your heart, 48/80 . For the experiments, male Wistar rats weighing 240-260 g were born from parents that are related to each other. After feeding without overnight, the rats are transferred to air-conditioned rooms for further processing (21 j-1 C, relative humidity 65 + 5%).
The rats are treated by subcutaneous injection or the test compound is fed, or a pure solvent (0.9% sodium chloride solution). After 1 hour after this treatment, the compound 48/80, freshly dissolved in water at a dosage of 0.5 mg / kg (0.2 ml / 100 body weight), was administered intravenously.
In control experiments, among 250 animals treated with the solution to which the standard dose of compound 48/80 was injected by injection, not only 2.8% of the animals survived after 4 hours. Therefore, such control experiments are considered as a reliable criterion for evaluating the protective effect when administering a drug for therapeutic purposes.
3222
In tab. 2 shows the Kdjo values for a series of compounds of the formula I and their pharmaceutically acceptable salts, obtained with the indicated
test In this case, the ED50 values represent the minimum doses of compounds administered for therapeutic purposes by subcutaneous route, with 50% of the rats being protected from death as a result of exposure to 48/80. Due to the pharmacological effects of the compounds of the general formula F or their salts with a pharmaceutically acceptable acid, they can be used for the treatment of psychotropic diseases, as well as for the treatment of a number of diseases in which the release of serotonin
crucial (blocking serotonin-recognized contractions of bronchial tissues, arteries and veins), Compounds can also be used as sedatives, relieving anxiety, nervous tension, anti-aggressive, protecting muscles and the cardiovascular system. Consequently, the compounds and salts are suitable for the protection of warm-blooded animals, for example, in stressful situations, dichrr, in particular, during transport, and t, p. Optional connections
useful as a protective
agents for endotoxin shock, as well as anti-diarrhea agents.
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权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING BICYCLIC PYRIMIDIN-5-ONE DERIVATIVES OR THEIR SALTS WITH PHARMACEUTICALLY ACCEPTABLE ACIDS, OR THEIR CIS-OR TRANS-ISOMERS, (57) Method for the preparation of derivatives of bicyclic pyrimidin-1-alkyl-5-one thereof; ,
R ² is a hydrogen atom, lower alkyl or aryl;
. R ³ is a hydrogen atom or lower alkyl;
Aik - lower alkanediyl;
A is a divalent radical of the formula.
-C = C - or - c = N 'l I - I attached to the S atom by a carbon atom, where R *, R ^ and R ^{6 are} each independently selected from the group consisting of hydrogen and lower alkyl, and where R ⁴ and R 9 may also complement saturated or unsaturated 5- or
6 membered carbocyclic ring;
Q is a group of the formula X - Ar, in which X is a member selected from> C = 0,> CH - OH,> C (0 - lower alkyl) ₂ or / C θ (CH ₂ ) g, where g is an integer equal to 2 or 3, or) / - C = N - OH, Ar is phenyl or substituted with a halogen atom phenyl, or Q is a radical of the formula
R ⁸ where R ⁸ is a hydrogen atom or lower alkyl; ''
R ⁹ is a hydrogen or halogen atom, or their salts with pharmaceutically acceptable acids, or their cisyl trans isomers, characterized in that the compound of the general formula M hl * ¹ wherein R ¹ , Aik and A have the indicated meanings;
W is a halogen atom,
SU <„, 1138032>
they are reacted with a piperidine derivative of the general formula fTl where Ar is phenyl or phenyl substituted with a halogen atom or Q is a radical of the formula wherein R ² , R ³ and Q are as defined in an inert organic solvent and the desired product is isolated in free form or in the form of a salt with a pharmaceutically acceptable acid, or. in the form of a cis or trans isomer.
Prize priority:
07.15.81 - R * - lower alkyl, *
R ² 7 a hydrogen atom, lower alkyl; . R ³ is a hydrogen atom, '
Aik - lower alkanediyl;
in · where R® is a hydrogen atom or lower alkyl;
04/21/82 - R ² - aryl;
R ³ is lower alkyl;
Q is a group of the formula X-Ar in which X is a member selected from) CH - OH, / C (O - lower alkyl) ₂ or / 0. ; (CH ₂ ) g, where g is an integer ^X O ⁷ number equal to 2 or 3, or / C = N-OH;
Ag is phenyl or phenyl substituted with a halogen atom, or Q is a radical of the formula attached to an S atom by a carbon atom, where R ⁴ , R $ and R are each independently selected from the group consisting of hydrogen or lower alkyl, and where R ⁴ and R can also complement a saturated or unsaturated 5- or 6-membered carbocyclic ring,
Q - Ar - C = O, where R ⁸ is a hydrogen atom or lower alkyl;
about '
R ⁷ is a halogen atom.

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同族专利:

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公开号 | 公开日

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DK316582A|1983-01-16|

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NO822439L|1983-01-17|

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FI75828B|1988-04-29|

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AU547967B2|1985-11-14|

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IE53400B1|1988-11-09|

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IE821689L|1983-01-15|

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DK160314C|1991-07-29|

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FI822511L|1983-01-16|

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KR840000568A|1984-02-25|

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CS227690B2|1984-05-14|

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NZ201266A|1985-01-31|

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PL136680B1|1986-03-31|

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FI822511A0|1982-07-14|

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GR76006B|1984-08-03|

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KR870000868B1|1987-04-30|

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PL237492A1|1984-02-27|

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ES513976A0|1983-08-16|

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EP0070053A3|1984-03-21|

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PT75247B|1985-01-07|

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NO166327B|1991-03-25|

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HU186952B|1985-10-28|

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CA1207765A|1986-07-15|

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DD215553A5|1984-11-14|

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PT75247A|1982-08-01|

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YU154682A|1985-03-20|

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MA19536A1|1983-04-01|

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US4443451A|1984-04-17|

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DK160314B|1991-02-25|

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EP0070053B1|1986-04-16|

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PH18120A|1985-03-22|

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FI75828C|1988-08-08|

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NO166327C|1991-07-10|

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ES8308327A1|1983-08-16|

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EP0070053A2|1983-01-19|

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DE3270589D1|1986-05-22|

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AU8575982A|1983-01-20|

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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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US28359081A| true| 1981-07-15|1981-07-15|

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US06/370,653|US4443451A|1981-07-15|1982-04-21|Bicyclic pyrimidin-5-one derivatives|

---