Method of producing derivatives of alpha [2-oxo-2, 4, 5, 6,-7- hexahydro-5-thieno (3, 2-c) pyridyl]-

专利摘要:

公开号:SU1389679A3
申请号:SU864010535
申请日:1986-01-22
公开日:1988-04-15
发明作者:Бадорк Ален；Фреэль Даниель；Маффран Жан-Пьер；Валле Эрик
申请人:Санофи (Фирма)；
IPC主号:

专利说明:

(21) 4010535/23-04
(22) 01.22.86
(31) 8501908
(32) 01/31/85
(33) FR
(46) 04/15/88. Bul Number 14
(71) .Sanofi (FR)
(72) Alain Badork, Daniel Freel, Jean-Pierre Maffran and Eric Balle (FR)
(53) 547.82.07 (088.8)
(56) Patent of France No. 2495156, cl. C 07 D 495/04, published 1984
Heterocyclic Compounds, Ed. R. Elderfield. M .: Foreign Literature Publishing House, 1953, Vol. 1, p. 32.1.
Weidand-Hilgetag. Experimental methods in organic chemistry. M .: 1968, p. 413-419.
(54) METHOD FOR PREPARING PROBLEMS OF E / - G2-OXO-2,4,5, 7a-HEXAGILRO-5-THIENO- (3,2-e) PIRYDYL-PHENYL-ACUS ACID or THEIR PHARMACEUTICAL SUBSTANCES
(57) The invention relates to the preparation of pyridine derivatives, in particular compounds of the total f l
where a) Y-OH or OR; R or iso-alkyl, (CH 2) 11, ;; n is an integer of 1-4; R, and R each C t-C-alkyl, b) Y-NRjR; ReI R4 is independently H, or isoalkyl, -heteroalkyl or NR3R -pyrupidine or morpholine XH, C, -C-alkyl, halogen, 4 alkoxy, which inhibit platelet aggregation and can be used in medicine. The goal is to create new active substances of the specified class. Their synthesis includes: the condensation of 4,5,6,7-tetrahydrothieno (3,2-c) pyridine with (.) 3C-Cl in the presence of a base; lithium derivative treatment BuLi; condensation with al-it kilborate (tri-n-butylborate); oxidation of the () 2B group to (R O), B-O-; hydrolysis (cleavage (R o) of B-gryppa) first with water and extraction, and then hydrolysis in an acidic medium (98% to HCOOH) cleavage of the C () eZ group, condensation with a halo-phenyl-acetic derivative in the presence of a base in an inert solvent at 60 C and isolation of the desired product, which, if necessary, is hydrolyzed in an acidic medium (translation of the group OR - OH) at room temperature or converted into pharmaceutically acceptable salts. New substances have low toxicity and have a degree of inhibition of platelet aggregation of 46-96%. 3 tab.
I
WITH
00
with so
with

S
one
This invention relates to the chemistry of producing new derivatives of 5,6,7,7a-tetrahydro-4H-thieno (3,2-c) pyridone of the general formula
where Y is hydroxyl or the group OR, in which R-C, -C4-alkyl, linear or branched, phenethyl, or - (CH) - NRjRi, where n 1-4, each
R-C, -C4-alkyl; or y - N de Rg and R,
independently of each other - hydrogen,. C, -C4-alkyl, linear or branched, heteroaralkyl, or Rg and R4
together with the nitrogen atom form pyrrolidine or morpholine;
X is hydrogen, C-C4-alkyl, halogen, C-C4-alkoxy or their pharmaceutically acceptable salts, which have the properties of inhibitors of platelet aggregation.
The aim of the invention is to search for a series of thioeno (3,2-c) -pyridone derivatives of compounds having anti-thrombotic and anti-aggregation activity.
Example 1. 5-Triphenylmethyl-4, 5,6, 7-tetrahydrothieno -. (3, 2-e) pyridine,
To a solution of 100 g (0.718 mol) of 4, 5,6,7-tetrahydrothieno (3,2-e) pyridine in 200 ml of dichloromethane was added 80, ml (0.789 mol) of triethylamine, then 200.2 g dropwise (200 g). 0.718 mol) triphenylmethyl chloride at room temperature. Leave the reaction mixture to stand overnight at room temperature. The reaction mixture is poured into 2000 ml of water, water is added to Organic and extracted with dichloromethane. The organic extraction phase is washed with water and dried over sodium sulfate. Drying the solvent to dryness gives a residue, which is crystallized from diisopropyl ether. Beige crystals, t, pl, 210 С (with decomposition). Yield 64%
thirty
IR spectrum (KBG):., 675 CM, (SBS1z), m, d: 7.48-6.96 (multiplet, 15H); 6.02 (singlet, 1H); 4.08 (multiplet, 1H) -, 3, 78-1.43 (multiplet, 6H),
P d and ime 3, 5,6,7,7a-Tetra- 2g hydrothieno- (3,2-c) pyridone-2 (II),
56.9 g (O, .143 mol) of 5-triphenylmethyl-5,6,7,7a-tetrahydro-4H-thieno (3,2-s) 40 pyridone-2 are heated at 90 ° C for 1 h ( VIII) in 350 ml of 98% formic acid. After cooling, an excess of a saturated solution of hydrogen chloride gas in diethyl ether is added and the reaction mixture is decanted, dried over sul-45 and concentrated to 100 ml. The mixture is then added with sodium phosphate and evaporated to dryness. Dilute with 1000 ml of diethyl ether and from
and
3896792
To a solution of 27 g (0.0707 mol) of 5-triphenylmethyl-4,5,6,7-tetrahydrothieno- (3,2-e) pyridine (IV) in 300 ml of tetx rafidrofuran is added dropwise at 5.31 ml of boothshit ( 1.6 M solution in hexane (0.085 mol), stirred for 15 minutes at room temperature, then cooled to and at
At this temperature, 23 ml (0.085 mol) of tri-n-butyl borate dissolved in 50 ml of tetrahydrofuran are added dropwise. Stir for 1 hour at 10 ° C. After cooling the reaction medium to
15 -40 ° C, 20.1 ml (Q, 1 77 mol) are added dropwise. 30% by volume of hydrogen peroxide. The temperature is allowed to rise to room temperature and stirred at this temperature for 1 hour. Into the reaction medium
20 water is added and extracted with dichloromethane. The organic extraction phase is washed with water and dried over sodium sulfate. Drying the solvent to dryness gives a residue, which is crystallized from diisopropyl ether. Beige crystals, t, pl, 210 С (with decomposition). Yield 64%
thirty
IR spectrum (KBG):., 675 CM, (SBS1z), m, d: 7.48-6.96 (multiplet, 15H); 6.02 (singlet, 1H); 4.08 (multiplet, 1H) -, 3, 78-1.43 (multiplet, 6H),
P d and ime 3, 5,6,7,7a-Tetra- 2g hydrothieno- (3,2-c) pyridone-2 (II),
The filter is purified by filtration through a layer of silica (elution with dichloromethane), White crystals, m, mp, 95 s (past), yield 96%,
 (CDC1 h) m, d,: 7.57-6.90, (multiplet, 15H); 6.80 (doublet, J: 6.5 Hz, 1H); 6.43 (doublet, 5 Hz, IH); 3.35 (singlet, 14); 3.00-2.33 (multiplet, 4H),
Example 2,5-Triphenylmethyl- 5,6,7,7a-tetrahydro-4H-thieno- (3,2-c) -pyridone.
filter the resulting crystals, which are washed with diethyl ether. The resulting crystals are redissolved in water and the aqueous solution, after being treated with animal charcoal and filtered through a layer of zeolite, is lyophilized. Thus, the obtained crystals are washed successively with acetone, then with diethyl ether and dried. Cream-colored crystals, t, pl, (with decomposition), yield 81%,
IR spectrum (KBG): (. About 1650 cm.
NMR-H (DMCO-dp f ppm; 6.47 (singlet, 1H) - 4.97-4.58 (multiplet, 1H) -, 4.46-3.83 (2 doublets, 2H ).
Example 4. Methyl-y-2-oxo-, 2,4,6,7,7a-hexahydro-5-thieno- (3,2-c) - pyridyl-3- (2-chlorophenyl) -acetate (I: Y OCHj ;) connection 1.
To a solution of 10 g (0.052 mol) of chlorohydrate 5,6, 7, 7.1-tetrahydro-4H-thieno-Q (3,2-c) pyridone-2 (II) in 100 ml of dimethylformamide was added 10.43 g (0,104 mol) of potassium bicarbonate and
8.82 g (0.052 mol) of sodium iodide, then 11.65 g (0.0532 mol) of methyl-o-j5 chloro- (2-chlorophenyl) -acetate (III: Y
OCH; X 2-Cl i). The reaction medium is heated at 60 ° C for 90 minutes. After cooling, the reaction medium is poured into 600 ml of water. Extraction is carried out with ethyl acetate; the organic extract is washed with water. The organic phase is dried over sodium sulfate. Evaporation of the solvent gives a residue, which is purified by filtration through silica gel (eluted with ethyl acetate). The resulting oily product is converted to the chlorohydrate for its last purification. Chlorine hydrate, white crystals, so pl. zo 130 C (with decomposition), yield 58%.
IR spectrum (KBG): Vc-o (complex: ether) 1745 cm Vc o (thiolactone) 1680 cm-
NMR-H (DMCO-dj), ppm; . 7.43 (multiplet, 4H) J 6.27 (singlet, 1H) -, 5.33 and 5.25 (singlet, IH-, 2 diaste-eisomer); 4.77-4.38 (multiplet, 1H) -, 3.67 (singlet, 3N),
Example 5, Methyl-c / - 2-oxo-, Q 2,4,5,6,7,7a-hexahydro-5-thieno- (3, 2-c) -pyridyl-phenylacetate (I: Y OCHji X H ), compound 2,
This compound is prepared according to example 4 by acylation of 5,6,7, with 7a-tetrahydro-4H-thieno (3,2-c) pyriano-2 (11) with methyl-α-chlorophenyl acetate (111: W.SNZ; X H; Gal. C1), Bromhydrate, white crystals, t, pl. 205 ° С (with decomposition), „yield 86%.
IR spectrum (KBG): Vj.p (ester) 1745 cm, sgo thiolactone) 1695 cm-,
NMRH (DMCO-d) M.D.: 7.60 (multiplet, 5H) j 8.57 (singlet, 1H);
5.83 (singlet, 1H); 3.77 (singlet, ZN),
Example 6. Methyl - (/ - 2-oxo-2,4., 5,6, 7, 7a-hexahydro-5-thieno- (3 ,.
2-e) pyridyl- (2-fluorophenyl) -acetate (1GU OCHj; X2F), compound 3,
This compound is prepared according to Example 4 by alkylation of 5,6,7, 7a-tetrahydro-4-H-thieno (3,2-e) -pyridone-2 (II) with methyl a-chloro- (2 -fluorophenyl) -acetate (III: Y OSI 3; X 2F; Gal. C1).
Bromhydrate, white crystals, so pl. 70% yield
IR spectrum (KBG): V (false ether) 1745, v, (thiolactone) 1690 cm-.
NMR-H (DMCO-d), ppm; 7.48 (multiplet, 4H); 6.43 (singlet, 1H); 5.60 (singlet, 1H); 4.83-3.37 (multiplet, 3H) i 3.72 (singlet, 3N).
Example 7, Ethyl-about - 2-oxo-2,4,5,6,7,7a-hexahydro-5-thieno- (3,2-e) -pyridyl - (2-chlorophenyl) -acetate (I: YX 2-Cl), compound 4,
This compound is prepared according to example 4 by alkylation of 4,6,7, 7a-tetrahydro-4H-thieno (3,2-c) pyridote on -2 (II) with ethyl-oi-chlorophen (2-chlorophenyl) -acetate (III: Y iOC5H5; X 2-Cl: Gal. Cl),
Bromhydrate, white crystals, so pl. 200 ° C, yield 64%.
IR spectrum {KBG): Vj ... g (ester) 1755, d (high tone) 1680 cm-.
NMR-H (DMSO-d), MD: 7.52 (multiplet, 4H); 6.53 (singlet, 1H); 5.78 (singlet, 1H) -, 4.30 (multiplet, 2H), 1.18 (triplet, -j 7 Hz,
ZN) ..
Example 8. Ethyl-o-C2-oxo-2,4,5,6,7,7a-hexahydro-5-thieno- (3, 2-e) -pyridyl - (2-methylphenyl) -acetate (I: YX 2-CH3), compound 5,
This compound is prepared according to example 4 by alkylation of 5,6,7, 7a-tetrahydro-4H-thieno- (3,2-c) pyridone-2 (II) with ethyl-c-chloro- (2-methylphenyl) -acetate (III: YX 2-СНз, Gal. С1),
Bromhydrate, crystals of white color, t, .Sh1. 222 ° C (with decomposition), yield 79%,
IR spectrum (KBG): Oj .., p (ester) 1745 cm -Jj-.Q (thiolactone)
-one
1685 cm
NMR H (DMSO-d) ppm: 7.38 (multiplet, 4H) -, 6.60 (singlet, 1H), 5.60 (singlet, 1H) and 4.23 (multiplet.
2H), 2.53 (single, 3N); 1.13 (triplet, J = 7 Hz, 3N).
Example 9. Isopropyl-o / - 2-oxo-2,4,5,6,7,7a-hexahydro-5-thieno (3,2-e) pyridylJ- (2-chlorophenyl) -acetate (I: Y OCH (CH3); X 2-C1), compound 6.
This compound is prepared according to Example 4 by alkylation of 5,6,7, 7a-tetrahydro-4H-thieno- (3,2-e) pyridone-2 (II) with isopropyl-c / - chloro- (2-chlorophenyl a) acetate (III: Y OCHCCHj); X 2-Cl, Gal. Cl).
Incomplete sulphate, beige crystals, m.p. 110 ° C, yield 69%.
IR spectrum (KBg): (ester) 1750 cm, (. O thiolactone) 1690 cm-.
NMR and (DMSO-d), M.D.: 7.50 (cartoon, 4H); 6.36 and 6.28 (singlet, 1H, 2 diastereoisomers); 5.36 and 5.28 (singlet, 1H, 2 diastereoisomers) -j 1.33-0.87 (multiplet, 6H).
Example 10. Tert-butyl - (/ - C 2-oxo-2,4,5,6,7,7a-hexahydro-5-thieno- (3,2-e) pyridylJ- (2-chlorophenyl) - acetate ( I: Y OS (CH3) C; X 2-C1), compound 7.
This compound is prepared according to Example 4 by alkylation of 5,6,7, 7a-tetrahydro-4H-thieno (3,2-c) pyridone-2 (11) with tert-butyl-c / -. chlorine (2-chlorophenyl) -acetate (III: Y OS (CH3) h; X 2-C1; Gal, C1).
Oily base, 69% yield. .
, IR spectrum (film): J.Q. (ester) 1740 cm, (, (t11olactone) 1690 cm-H
NMR
 and (DMCO-d), MD: 7.36 (multiplet, 4H); 6.02 (singlet, 1H); 4.63 (singlet, 1H) 4.76-4.13 (multiplet, 1H) -, 1.40 (multiplet, 9H).
Example 11. M-o / 2-Okeo-2.4, 5,6,7,7a-hexahydro-5-thieno- (3,2-e) -pyridyl-3- (2-chlorophenyl)} acetylpyrolidine (I: Y ,), connection 8.
To a solution of 4.5 g (0.023 mol) of 5,6,7,7a-tetrahydro-4H-thieno- (3,2-e) pyridone-2 (II) hydrochloride in 45 ml of dimethylformamide was added 4.7 g (0.047 g). mol) potassium bicarbonate, then -3.5 g (0.023 mol) sodium iodide. To this reaction medium, add 6.1 g (0.023 mol) of 0-chloro- (2-chlorophenyl) acetylpyrrolidine (III: Y
 t
X 2-C1, Gal, C1), and all
0
the reactants are kept for 2 hours. After cooling, ethyl acetate is added. The organic solution is washed with water, then dried over sodium sulfate. It is evaporated to dryness and the residue is purified over sodium sulfate. It is evaporated to dryness and the residue is purified by filtration through a layer of silica (eluent is ethyl acetate). The latter is purified by conversion to hydrochloride in diethyl ether.
Hydrochloride, white crystals, so pl. , yield 69%. .
IR spectrum (KBG): v c o (thiolactone) 1690 IU,% s, o (amide) 1650 cm.
NMR-H (CBC15), ppm: 7.31 (multiplet, 4H); 5.90 (singlet, 1H); 4.90 (singlet, 1H).
Example 12. N, M-Dimethyl- / - C2-oxo-2,4,5,6,7,7a-hexahydro-5-5 thieno- (3,2-e) pyridyl - (2-chlorophenyl) - acetamide (I: Y, N (.CK) j; X 2-Cl), compound 9,
This compound is prepared according to example 11 by alkylation of 5,6, 7,7a-tetrahydro-4H-thieno- (3,2-e) pyridone-2 (11) with the help of -x-N-N, N dimethyl- (2 -chlorophenyl) -acetamide. (III:: Y N (CH) jL ;; X 2-Cl; Gal. C1).
0
35
Hydrochloride, white crystals, so pl. 145 ° C. Yield 73%.
IR (KBr) (thiolactone) 1690. (amide 1655 unit-
NMR-H (DMCO-dj)., Ppm : 7.70 (multiplet, 4H) -, 6.08 and 6.00 (singleton, 1H, 2 diastereoisomers), 2.93 (singleton, 6H).
Pr.im er 13. (2-Phenylethyl) G2-ocean-2,4,5,6,7,7a-hega-hydro-5-thieno (3,2-c) pyridyl - (2-chloro NF) - acetate (15 OCHjCH C Hj; X 2-Cl),
This compound is prepared according to Example 4 by alkylation of 5,6,7, 7a-tetrahydro-4H-thieno (3,2-e) pyridone-2 (II) e with (2-fenshtayl) -0 / chloro (2-chlorophenyl) -acetate: (T11: U; OCHsCHiC Hs; X 2 -Ci; Gal. C1).
Hydrochloride, beetroot kinetalli, so pl. 175 ° C (acetone), 71% yield. IR-Spectrum (KVg): V ester) 1755 cm, -Oj.-o (thiolactone) 1690 cm
NMRH (DMCO-dj) M.D.: 7.80-6.83 (multiplet, 9H, aromatic); 6.28 (singlet, 1H), 5.46 and 5.28 (singlet, 1H, 2 diasteresisomers).
Example 14. W - (/ - G2-Oxo-2,4,6,7,7a-hexahydro-5-thieno- (3,2-c) - pyridyl- (2-chlorophenyl)} acetylmorpholine (I; Y M Otx 2-C1).
This compound is prepared according to example 11 by alkylation of 5.6, 7.7a-tetrahydro-4H-thieno- (3,2-c) pyridine-2 (II) with c-chloro- (2-chlorophenyl) - acetylmorpholine (III: Y
  2-Cl Gal. Cl).
Hydrochloride, hydrate, white crystals, so pl. 150 ° C, yield 60%
IR spectrum (KBG): (thiolactone) 1690 cm-,) 1660 cm-
NMR- (DMSO-dt), M.D .: 7.51 (multiplet, 4H) -, 6.45 and 6.26 (singlet, 1H, 2 diastereoisomers) j 4.86 and 4.73 (singlet, 1H , 2 diaster eoisomer). ,
Example 15. K- (3-Pyridsh1methyl) -o / - 2-oxo-2,4,5,6,7,7a-hexahydro-5-thieno (3,2-c) pyridyl - (2 -chlorine-
phenyl) -acetamide (I: Y .TJHCH o-V; X 2 -C1). - -VNV
This compound is prepared according to example 11 by alkylation of 5,6,7, 7a-tetrahydro-4H-thieno (3,2-e) pyri-2-II (II) with (α-chloro-K- (3-pyri- dilmethyl) - (2-chlorophenyl) -acetamide I.,. (III: Y NHCH2-2-C1; Galr C1).:. N
Hydrochloride, hydrate, beige crystals, tsh, 165 C yield 55%.
IR spectrum (KBG): (thiolactone) 1690 1660 cm-.
NMR-H (DMCO-d) g M.D.: 8.95-7.38 (multiplet, 8H); 6.38 and 6.32 (singlet, 1H, 2 diastereoisomers), 5.52 and 5.43 (singlet, 1H, 2 diastereoisomers).
Example 16. Ethyl-o (—C2-oxo-.2,4,5,6,7,7a-hexahydro-5-thieno- (3, 2-e) pyridyl- (4-methoxy-peNIL) -acetate (I, : YX 4-OCH3).
This compound is prepared according to Example 4 by alkylation of 5,6,7, 7a-tetragilro-4-H-thieno (3,2-c) pyridone-2 (11) with ethyl-c / chloro
ten
15
20

thirty
0
five
O
five
(4-methoxyphenyl) -acetate (llliY OCjEsl X 4-OCH3; Gal, C1).
Hydrochloride, white crystals, so pl. 140 ° C, yield 91%.
IR spectrum (KBG): J (.. o (ether) 1715 cm; V (- g (thiolactone) 1690 cm
LIR-H (DMSO-d), MD: 7.65 (multiplet, 4H) j 6.53 and 6.61 (siglet, 1H, 2 diastereoisomer); 5.73 and 5.63 (singlet, 1H, 2 diastereoisomers); 3.80 (singlet, SN).
Example 17. 2- (K, H-Diethylamino) -ethyl- / - 2-OXO-2,4,5,6,7,7a-tech-hydro-5-thieno- (3,2-c) Pyridyl-J- (2-chlorophenyl) -acetate (I: Y. N () J;. X 2-C 1).
This compound is prepared according to example 4 by alkylation of 5,6,7, 7a-tetrahydro-4H-thieno (3,2-e) pyrido-2 (II) with 2- (N, N-diethyl amino) -ethyl-a; -chloro- (2-chlorophenyl) - a. acetate (III: Y (g); X 2-Cl, Gal, Cl). Oxalate, beige crystals, so pl. , yield 61%.
IR spectrum: (KBG): (ester) 1745 cm, Vc-o (thiolactin) 1685 cm-.
 (DMCO-dg), MD: 7.64-7.25 (multiplet, 4H); 6.23 (singlet, 1H); 4.94 (singlet, 1H).
Note 18. (/ - 2-Oxo-2,4, 5,6,7,7a-hexahydro-5-thieno- (3,2-e) pyridyl} - (2-chlorophenyl) -acetamide (I: Y Shz; X 2-C1).
This compound is prepared according to example 11 by alkylation of 5,6,7, 7a-tetrahydro-4H-thieno (3,2-c) pyriano-2 (II) with o (-chloro (2-chlorophenyl) - acetamide (III: YX 2-Cl, Gal Cl).
Hydrochloride, beige crystals, so pl. 185 ° C, yield 53%.
IR spectrum (KVg): (thiolactone) 1685 cm-; .. d (amide) 1640 cm
Pharmacological and toxicological results. Which are shown below demonstrate the properties of compounds of general formula I, both in terms of toxicity and tolerance, and in terms of their activity (inhibition of platelet aggregation and antithrombotic properties).
Toxicological studies.
The compounds of the proposed method are of low toxicity. Experiments carried out on acute, chronic, subchronic and prolonged toxicity on various species of animals do not allow one to detect any local or general reaction, disorder or abnormality in biochemical, macroscopic or microscopic tests.
The activity of compounds as inhibitors of platelet aggregation.,
The experiment was carried out on a rat that was orally administered. This method consists in adapting the method of Friedman et al. (Am, J. Physiol 1980, 199, 770-774). The cut metal helix (dentist's paste) is placed in the lower hollow
Dinenie. I, take on the analysis of 4 ml of blood according to the Renaud method from the strap vein of anesthetized animal. This rat vein cyt | 5, which receives ratified blood for 2 hours, is used in iz-. Prior to that, the test subjects were orally administered aggregation.
Measurement of aggregate; 11 and platelets with adenosine diphosphate (ADP),
2 ml of citrated blood is rapidly inserted into a small glass placed on a magnetic stirrer and equipped with a magnetic rod. After stirring for several
0.4 mp PA-25 is then introduced into the cup, then released from the thrombus, dried
40
section, containing 0.66 g of ADP per 1 ml. After stirring for 90 s, two 0.5 ml samples of blood are taken: the first is mixed with 0.5 ml of EDTA-formol solution, the second is mixed with 0.5 ml of solution only
edtk
The purpose of adding EDTA-formol is to stabilize the blood and, therefore, fix aggregation, while EDTA, on the contrary, causes disaggregation of all platelet accumulations.
After standing for 10 minutes, centrifuging 2 mixtures at a slow speed for 5 minutes and separating the red globules, the platelet-rich plasma supernatant (sweat) is collected, diluted and the platelet count is calculated.
wolled and weighed again. So get the difference, t, e, the average weight of a blood clot,
The antiaggregating activity of the compounds with respect to ADP and collagen is given in Tables 1 and 2, respectively, the antithrombotic activity in the first phase is in Table 3,
Compounds of French patent no. 2495156 with a dose of 5 mg / kg achieve an inhibition activity of only 47-48%,
The compounds of French Patent No. 2495156 at a dose of 5 mg / kg achieve only 17.4% inhibition.
As can be seen from the data presented in the tables, the proposed method allows to obtain compounds possessing a complex of valuable pharmacological properties.
The intensity of aggregation is determined by the ratio of the number of platelets in EDTA-formol to the number of platelets in EDTA and is expressed as the percentage of non-aggregated platelets
Measurement of platelet aggregation with collagen,
About 10 ml of a solution containing 10 µg of collagen per ml was added to 1.5 ml of citrated blood. The medium is kept agitated, platelet count is performed without interruption.
o
9679, 0
The decrease in the number of free platelets depending on time is continuous and allows drawing a curve, the slope of which gives the initial rate of aggregation,
Antithrombotic activity is studied according to the venous thrombosis method with a coil.
This method consists in adapting the method of Friedman et al., (Am, J. Physiol, 1980, 199, 770-774). The cut metal helix (bourre - paste of the dentist) is placed in the lower hollow
5 vein of the rat, which receives 2 hours. Before that, the test compound is orally administered as a suspension in 10 mg / kg of an aqueous 5% gum arabic solution.
After 5 hours, this helix is removed along with the thrombus, which it holds, gently dried with successive tampons on filter paper and weighed.
wolled and weighed again. So get the difference, t, e, the average weight of a blood clot,
The antiaggregating activity of the compounds with respect to ADP and collagen is given in Tables 1 and 2, respectively, the antithrombotic activity in 1 turn of the model is given in Table 3,
Compounds of French patent no. 2495156 with a dose of 5 mg / kg achieve an inhibition activity of only 47-48%,
The compounds of French Patent No. 2495156 at a dose of 5 mg / kg achieve only 17.4% inhibition.
As can be seen from the data presented in the tables, the proposed method allows to obtain compounds possessing a complex of valuable pharmacological properties.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of o / - 2-oxo-2,4,5,6,7,7a-hexahydro-5-thieno- (3,2-e) pyridyl J-phenylacetic acid of the general formula
55
./Л-§
(TnQf-С (SbH5),
thirty
which is treated with a lithium derivative, such as BuLi, followed by condensation of the resulting compound. III
 alkyl borate, such as tri-n-butyl borate, formed by the boron derivative of general formula IV35
B B O
 V-JQO

2.5
5.0
511
54112
611
9612
Si
5.0
47 ± 12
Hal
25
where X and Y are indicated
HaL is a halogen atom, in the presence of a base in an inert solvent at 60 ° C, followed by isolation of the target product, or a compound of the general formula I, where Y is the OR group, is subjected to selective hydrolysis in an acidic medium at room temperature to obtain the compound of the general formula I, where Y-OH, and the selection of the target product in free form or in the form of pharmaceutically acceptable salts. Table 1
52
0.001
96
0.001
45
0.05
-1,1810,11
2,50,11tO, 03910,001
-2.4810.32-5, 0 О1000.001 -1.71 + 0.52-5, 0 0.15tO, 10910.01 -1.7110.52
5.00.06 tO, 04980.01 -1.9410.16
5,00,5510,24660,01
table 2
five
138967916
Table 3

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同族专利:

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FI860473A|1986-08-01|

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CS253741B2|1987-12-17|

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DK157553B|1990-01-22|

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MA20619A1|1986-10-01|

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TNSN86012A1|1990-01-01|

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PT81946B|1987-12-30|

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NZ214982A|1988-04-29|

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IL77598A|1988-12-30|

---

ES550448A0|1987-03-01|

---

FI860473A0|1986-01-31|

---

AU5242486A|1986-08-07|

---

HUT40440A|1986-12-28|

---

DK157553C|1990-06-11|

---

FR2576901B1|1987-03-20|

---

FR2576901A1|1986-08-08|

---

PL257691A1|1986-11-04|

---

YU11986A|1987-08-31|

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ES8703881A1|1987-03-01|

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DK47186D0|1986-01-30|

---

DD242229A5|1987-01-21|

---

JPS61246186A|1986-11-01|

---

DK47186A|1986-08-01|

---

GR860287B|1986-06-02|

---

EP0192535A1|1986-08-27|

---

CA1265517A|1990-02-06|

---

PL145159B1|1988-08-31|

---

NO162965C|1990-03-14|

---

US4740510A|1988-04-26|

---

HU193625B|1987-11-30|

---

AU581487B2|1989-02-23|

---

PT81946A|1986-02-01|

---

NO162965B|1989-12-04|

---

NO860332L|1986-08-01|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

RU2604733C2|2011-06-27|2016-12-10|Ипка Лэборэториз Лимитед|Antithrombotic compound|FR2495156B1|1980-11-28|1983-08-05|Sanofi Sa|

---

FR2495157B1|1980-11-28|1983-07-08|Sanofi Sa|

---

FR2528848B1|1982-06-16|1984-11-23|Sanofi Sa|

---

FR2530247B1|1982-07-13|1986-05-16|Sanofi Sa|NOVEL THIENO PYRIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC APPLICATION|

---

DE3302125A1|1983-01-22|1984-07-26|Boehringer Ingelheim KG, 6507 Ingelheim|AMINO ACID DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF|FR2652579B1|1989-10-02|1992-01-24|Sanofi Sa|DERIVATIVES OF 2-HYDROXY THIOPHENE AND FURANNE CONDENSED WITH A NITROGEN CYCLE, ON THE PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION.|

---

FI101150B|1991-09-09|1998-04-30|Sankyo Co|A process for the preparation of tetrahydrothienopyridine derivatives useful as medicaments|

---

DE69526443T2|1994-10-07|2002-12-12|Ube Industries|2-SILYLOXY-TETRAHYDROTHIENOPYRIDINE, ITS SALT AND METHOD FOR THE PRODUCTION THEREOF|

---

NZ334389A|1996-08-28|2001-05-25|Ube Industries|Cyclic amine derivatives|

---

HU225741B1|1998-02-27|2007-07-30|Ube Industries|Cyclic amino compounds, use of them for producing pharmaceutical compositions and pharmaceutical compositions containing them|

---

MXPA03000031A|2000-07-06|2003-10-15|Sankyo Co|Hydropyridine derivative acid addition salts.|

---

CA2432644C|2000-12-25|2013-07-23|Fumitoshi Asai|Pharmaceutical composition comprising aspirintm and cs-747|

---

GB0125708D0|2001-10-26|2001-12-19|Generics Uk Ltd|Novel compounds and processes|

---

CZ302135B6|2007-07-09|2010-11-10|Zentiva, A. S.|Process for preparing 5-[2-cyclopropyl-1--2-oxoethyl]-4, 5, 6, 7-tetrahydrothieno[3,2-c]-pyridin-2-yl acetate |

---

US20100261908A1|2007-11-09|2010-10-14|Dr. Reddy's Laboratories Ltd.|Processes for the preparation of prasugrel , and its salts and polymorphs|

---

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---

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---

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---

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---

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---

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---

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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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FR8501908A|FR2576901B1|1985-01-31|1985-01-31|NOVEL DERIVATIVES OF A-PYRIDYL-5) ACETIC PHENYL, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION|

---