EP0000108B1 - Benzo(b)thiéno-pyridines, leur procédé de préparation et composition thérapeutique les contenant - Google Patents
Benzo(b)thiéno-pyridines, leur procédé de préparation et composition thérapeutique les contenant Download PDFInfo
- Publication number
- EP0000108B1 EP0000108B1 EP78400006A EP78400006A EP0000108B1 EP 0000108 B1 EP0000108 B1 EP 0000108B1 EP 78400006 A EP78400006 A EP 78400006A EP 78400006 A EP78400006 A EP 78400006A EP 0000108 B1 EP0000108 B1 EP 0000108B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- benzo
- thieno
- phenyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
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- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- DGEYTDCFMQMLTH-UHFFFAOYSA-N methanol;propan-2-ol Chemical compound OC.CC(C)O DGEYTDCFMQMLTH-UHFFFAOYSA-N 0.000 description 1
- QKASDIPENBEWBU-UHFFFAOYSA-N methyl 2-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=CC=C1CBr QKASDIPENBEWBU-UHFFFAOYSA-N 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000006504 o-cyanobenzyl group Chemical group [H]C1=C([H])C(C#N)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 235000012751 sunset yellow FCF Nutrition 0.000 description 1
- 239000004173 sunset yellow FCF Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 230000036346 tooth eruption Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000012345 traction test Methods 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/58—Radicals substituted by nitrogen atoms
Definitions
- the present invention relates to new benzo [b] thienopyridine derivatives, to a process for their preparation and to their applications in human and veterinary medicine.
- lower alkyl or “lower alkoxy” is meant groups having from 1 to 6 carbon atoms.
- the invention also includes the addition salts of the derivatives of formula I with mineral or organic acids.
- these derivatives are described as having tranquilizing properties, while the derivatives of the present invention exhibit sedative and inhibitory properties of platelet aggregation, which is completely different.
- the subject of the invention is also a process for preparing the compounds of formula (I), characterized in that compounds of formula (II) are cyclized in which R 1 , R 2 , R 3 and R 4 have the meanings given for formula (I), by heating in polyphosphoric acid at temperatures between 60 and 80 ° C.
- the cyclization is preferably carried out in the presence of an inert gas, in particular nitrogen.
- the compounds of formulas (I) for which R 1 is different from hydrogen can also be obtained by condensation of the corresponding compounds of formula (I) in which R 1 is hydrogen, with a compound of formula R 1 X in which X is a halogen atom.
- the reaction is normally carried out in an inert solvent such as ethanol or dimethylformamide, in the presence of a base such as an alkali metal carbonate, for example potassium carbonate.
- a base such as an alkali metal carbonate, for example potassium carbonate.
- X is chlorine or bromine
- the halogenomethyl-2 or -3 benzo (b) thiophenes can be prepared according to: S. AVAKIAN, J. MOSS and G.J. MARTIN, J. amer. chem. Soc., 1948, 70, 3,075; N.B. CHAPMAN, K.CLARKE; B. GORE and S.N. SAWHNEY, J. chem. Soc. (C), 1968, 514; N.B. CHAPMAN, K. CLARKE and B. IDDON, J. chem. Soc. (C), 1965, 774.
- Formyl-2 and -3 benzo (b) thiophenes can be prepared according to: D.A. SHIRLEY and M.J. DANZIG, J.
- the addition salts are prepared with mineral acids (for example hydrochloric, sulfuric acid, etc.) or organic acids (for example methane sulfonic, maleic, tartaric, citric acid, etc.) by usual conventional methods.
- mineral acids for example hydrochloric, sulfuric acid, etc.
- organic acids for example methane sulfonic, maleic, tartaric, citric acid, etc.
- N-methylation of 8-chloro-3-methyl-4-phenyl-1,2,3,4-benzo (b) thieno [3,2-c] pyridine (example 1) is carried out by condensation with methyl iodide, in ethanol, in the presence of potassium carbonate, or by Leuckart reaction (heating in the presence of formaldehyde and formic acid).
- Benzyl bromide is condensed with 8-chloro-3-methyl-4-phenyl-1,2,3,4-benzo (b) thieno [3,2-c] pyridine (Example 1) according to the process described in example 6.
- Methanesulfonate white crystals, F> 260 ° C (acetonitrile), yield: 63%.
- O-nitrobenzyl chloride is condensed with 8-chloro-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (example 3), according to the process described in l 'example 6.
- O-cyanobenzyl bromide is condensed with 4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (Example 4), according to the method of Example 6.
- O-methoxycarbonylbenzyl bromide is condensed with 8-chloro-3-methylphenyl-1,2,3,4 tetrahydro-1,2,3,4 benzo (b) thieno [3,2-c] pyridine (Example 1), according to the method described in Example 6.
- Butyl bromide is condensed with 8-chloro-3-methyl-4-phenyl-1,2,3,4-benzo (b) thieno [3,2-c] pyridine (example 1), according to the process described in 1 'example 6.
- Phenethyl bromide is condensed with 3-methyl-4-phenyl-1,2,3,4-tetrahydro benzo (b) thieno [3,2-c] pyridine (Example 2), according to the process described in Example 6 .
- a further subject of the invention is therefore a therapeutic composition having in particular activities which inhibit platelet aggregation and sedation, characterized in that it contains, as active principle, a derivative of formula (I) or a salt thereof. addition with a pharmaceutically acceptable acid thereof, in combination with a therapeutically administrable vehicle.
- the compounds of the invention benefit from excellent tolerance and low toxicity.
- the LD 50/24 h / kg of animal, determined in mice according to the Miller and Tainter method, for the oral route, is greater than 400 mg for all the derivatives.
- a blood sample is taken from the jugular vein. From this citrated blood and after centrifugation, a plasma containing 600,000 ⁇ 20,000 platelets per mm 3 is reconstituted, which will be used in all aggregation measurements.
- 0.4 ml of plasma is placed in a silicone tube provided with a magnetic bar itself silicone.
- the tube is introduced into an aggregometer coupled to a device making it possible to record the variations in optical density.
- 0.5 ml of a solution containing 10 ⁇ of ADP is introduced into the tube. (Adenosine-Di Phosphate).
- the aggregation of platelets then causes an increase in light transmission followed a decrease following the disaggregation phase.
- the maximum variation in optical density thus determined characterizes the intensity of the aggregation.
- A.D.P.'s solution is replaced by a collagen solution (bovine tendon extract).
- test products are administered to mice by the oral route at a dose of 100 mg / kg, thirty minutes before the intraperitoneal injection of a solution of 300 mg of chloral in 20 ml of physiological saline.
- a solution of 300 mg of chloral in 20 ml of physiological saline was administered to mice by the oral route at a dose of 100 mg / kg, thirty minutes before the intraperitoneal injection of a solution of 300 mg of chloral in 20 ml of physiological saline.
- the derivatives of the invention considerably potentiate the action of chloral, in particular with regard to the duration of the induced sleep and the number of sleeping mice.
- mice which have received 100 mg of the derivative to be tested by the oral route. It is considered that the mice have undergone a sedative action when they do not manage, within thirty seconds, to effect a recovery which brings at least one of their hind legs on the wire.
- the animals are tested before the test and those which fail to recover within thirty seconds are eliminated. We see during the tests that only 10%. 100 of the tested animals manage to recover.
- a mouse placed in an enclosure containing 4 electrified plates, receives, with each passage of a plate towards another, an electrical stimulus causing a disorderly leak. After n electric shocks, the mouse no longer moves. It is considered that the degree of sedation obtained is proportional to the number n of electric shocks that the treated mouse will have received before it stops in a corner.
- the derivatives of the invention produce an average percentage increase in the number of electric shocks n of the order of 60% after 15 minutes, of 62% after 30 minutes and 51% after ninety minutes.
- the medicament of the invention can be presented, for oral administration, in the form of tablets, coated tablets, capsules, drops and syrup. It can also be presented, for rectal administration, in the form of suppositories and for parenteral administration, in the form of an injectable solution.
- Each unit dose advantageously contains from 0.010 g to 0.500 g of active principle, the doses administered daily being able to vary from 0.010 g to 1.00 g of active principle depending on the age of the patient and the condition treated.
- the medicament of the invention can thus be advantageously administered, as a preventive or curative treatment, in the treatment of diseases causing a pathological change in platelet aggregation such as diseases causing a pathological change in platelet aggregation such as diseases thromboembolic.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7716878 | 1977-06-02 | ||
| FR7716878A FR2423494A1 (fr) | 1977-06-02 | 1977-06-02 | Benzo (b) thieno pyridines, leur procede de preparation et leurs applications therapeutiques |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0000108A1 EP0000108A1 (fr) | 1978-12-20 |
| EP0000108B1 true EP0000108B1 (fr) | 1981-08-19 |
Family
ID=9191587
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP78400006A Expired EP0000108B1 (fr) | 1977-06-02 | 1978-06-01 | Benzo(b)thiéno-pyridines, leur procédé de préparation et composition thérapeutique les contenant |
Country Status (10)
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4282227A (en) * | 1980-05-22 | 1981-08-04 | Smithkline Corporation | Renal vasodilating 3,4-dihydroxyphenyltetrahydrothienopyridines |
| JPS5939349A (ja) * | 1982-08-31 | 1984-03-03 | 杉 晤夫 | 米の搗精方法と精米機 |
| JP2570692B2 (ja) * | 1986-06-20 | 1997-01-08 | 株式会社豊田自動織機製作所 | 可変容量式回転型圧縮機 |
| JPH0771637B2 (ja) * | 1986-06-30 | 1995-08-02 | 株式会社佐竹製作所 | 竪軸精米装置 |
| JPS63182041A (ja) * | 1987-01-21 | 1988-07-27 | 株式会社 サタケ | 竪軸型精穀機 |
| JPS63218258A (ja) * | 1987-03-06 | 1988-09-12 | 株式会社 サタケ | 竪軸型精穀機 |
| JPH0822389B2 (ja) * | 1987-07-27 | 1996-03-06 | 株式会社佐竹製作所 | 竪軸型摩擦切削式精米機 |
| JPH01262949A (ja) * | 1988-04-14 | 1989-10-19 | Satake Eng Co Ltd | 竪軸型摩擦切削式精穀機 |
| JP3266167B2 (ja) * | 1993-08-06 | 2002-03-18 | 株式会社サタケ | 竪型研削式精穀機の抵抗体調節装置 |
| JPH0775741A (ja) * | 1993-09-07 | 1995-03-20 | Satake Eng Co Ltd | 研削式竪型精穀機の除糠用多孔性筒状体 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1210106A (en) * | 1967-03-08 | 1970-10-28 | Colgate Palmolive Co | Derivatives of 1,2,3,4-tetrahydrobenzothieno [2,3-c]pyridine and of 1,2,3,4-tetrahydro-5h-benzothieno[2,3-c]azepine |
| US3704237A (en) * | 1971-04-29 | 1972-11-28 | Colgate Palmolive Co | Certain 2-amidino-1,2,3,4-tetrahydrobenzothiene(2,3-c)pyridines |
| US3752820A (en) * | 1972-03-20 | 1973-08-14 | Colgate Palmolive Co | Substituted-1,2,3,4-tetrahydrobenzothieno(3,2-c)pyridine derivatives |
| FR2358150A1 (fr) * | 1976-07-13 | 1978-02-10 | Parcor | Nouvelles thieno (2,3-c) et (3,2-c) pyridines, leur procede de preparation et leur application |
-
1977
- 1977-06-02 FR FR7716878A patent/FR2423494A1/fr active Granted
-
1978
- 1978-05-23 IE IE1022/78A patent/IE46848B1/en unknown
- 1978-05-23 US US05/908,856 patent/US4172134A/en not_active Expired - Lifetime
- 1978-05-29 ES ES470274A patent/ES470274A1/es not_active Expired
- 1978-05-30 GB GB24218/78A patent/GB1572690A/en not_active Expired
- 1978-06-01 EP EP78400006A patent/EP0000108B1/fr not_active Expired
- 1978-06-01 DK DK244878A patent/DK152130C/da not_active IP Right Cessation
- 1978-06-01 DE DE7878400006T patent/DE2860971D1/de not_active Expired
- 1978-06-02 JP JP6660378A patent/JPS543098A/ja active Granted
- 1978-06-02 LU LU79763A patent/LU79763A1/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0000108A1 (fr) | 1978-12-20 |
| IE46848B1 (en) | 1983-10-05 |
| DK152130B (da) | 1988-02-01 |
| JPS543098A (en) | 1979-01-11 |
| DK244878A (da) | 1978-12-03 |
| FR2423494A1 (fr) | 1979-11-16 |
| ES470274A1 (es) | 1979-09-16 |
| LU79763A1 (fr) | 1978-11-28 |
| DE2860971D1 (en) | 1981-11-12 |
| FR2423494B1 (enrdf_load_stackoverflow) | 1980-10-17 |
| JPS6230191B2 (enrdf_load_stackoverflow) | 1987-07-01 |
| US4172134A (en) | 1979-10-23 |
| DK152130C (da) | 1988-08-15 |
| GB1572690A (en) | 1980-07-30 |
| IE781022L (en) | 1978-12-02 |
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