JPH0482154B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention is based on the general formula () The present invention relates to a novel tricyclic compound having the following formula, an acid addition salt thereof, and a method for producing the same. (Prior Art) Research on benzo[b]thieno[2,3-C]pyridine and benzo[b]furano[2,3-C]pyridine or their derivatives was carried out by Gerhard Wolff, Ferricks Timorkovsky, Archib Wehrmazy ( Gerhard Wolf and
Felix Zymalkowski, Arch.Pharm.) 279, 309
(1976) or Rudolph A Abramovitch et al J.Org.
Chem.) 690, 48 (1983), etc., the ester, carboxylic acid, and acid chloride of the present invention are substituted at the 3-position.
Cyclic compounds have not yet been invented. (Problems to be Solved by the Invention) As a result of intensive research into the production method of the tricyclic compound having the general formula (), the present inventors found that the tricyclic compound represented by the general formula () has an anticonvulsant effect, It is intended to be a compound useful as a medicine having muscle relaxant and psychotropic effects. (Means for solving the problem) The present invention is based on the general formula () The present invention relates to a novel tricyclic compound having the following formula, an acid addition salt thereof, and a method for producing the same. In the above formula, A represents a sulfur atom or an oxygen atom, and R represents an OR' group (wherein R' is a lower alkyl group having up to 6 C atoms or a hydrogen atom) or a halogen atom. ] As preferred compounds represented by the above general formula (), R is hydroxymethyl, hydroxyethyl,
Examples thereof include lower hydroxyalkyl groups having 1 to 6 carbon atoms such as hydroxypropyl and hydroxyhexyl, hydroxyl groups, or chlorine atom compounds. Representative compounds of the tricyclic compound of the present invention are shown below. benzo[b]thieno[2,3-C]pyridine-
3-Carboxylic acid methyl ester benzo[b]thieno[2,3-C]pyridine-
3-Carboxylic acid ethyl ester benzo[b]thieno[2,3-C]pyridine-
3-Carboxylic acid propyl ester benzo[b]thieno[2,3-C]pyridine-
3-Carboxylic acid hexyl ester benzo[b]furano[2,3-C]pyridine-
3-Carboxylic acid ethyl ester benzo[b]furano[2,3-C]pyridine-
3-Carboxylic acid propyl ester "Production method" The compound having the general formula () of the present invention is
It was obtained by the following synthesis method. [In the formula, A and R' are the same as above] The method for obtaining the compound () from the present invention () is as follows:
Gerhard Wolf and Felix ZymalKowski
Arch.Pharm.) 279, 309 (1976). For the present invention (), formalin is usually 1-
It is good to use 10 equivalents, preferably 1 to 3 equivalents. Further, the solvents used in this method include water, lower alcohols such as methanol, ethanol, isopropanol, and ethylene glycol, and ethers such as diethyl ether, tetrahydrofuran, and dioxane. Preferably, no solvent is used. This reaction is carried out at 10-100℃,
Generally, it takes about 1 to 10 hours to complete. A method for obtaining compound () () () from compound () is described by Ets. Earl Sinider, Kurtius D. Smith, Journal American Chemistry Society (HR
Snyder and Curtis W.Smith J.Am.Chem.Soc.)
350, Vol66 (1944) as a reference. The solvent used in the method of synthesizing compound () from compound () is diethyl ether,
These are ethers such as tetrahydrofuran and dioxane. This reaction is carried out at 10 to 120°C and is generally completed in about 1 to 30 hours. Alkali metals such as lithium, sodium, and potassium are also used. The solvent used in the method for synthesizing compound () from compound () is water or a mixed solvent of water and a lower alcohol such as methanol, ethanol, propanol. Further, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, etc. are used. This reaction is carried out at 10 to 100°C and is generally completed in about 1 to 10 hours. The solvent used in the method of synthesizing compound () from compound () is water. Also, sodium hydroxide, potassium hydroxide, etc. are used. This reaction is carried out at 10 to 100°C and is generally completed in about 1 to 30 hours. The method to obtain compound () from compound () is
Nobuo Izumiya, Tetsuo Kato, Motonori Ohno, Higashihiko Aoyagi, Synthetic Chemistry Series Peptide Synthesis (Maruzen) 66, Experimental Examples 3 and 2 were used as reference. The solvent used in this method is lower alcohols such as methanol, ethanol, propanol, hexanol and the like. Further, as an acid catalyst, thionyl chloride, sulfuric acid, hydrochloric acid gas, p-toluenesulfonic acid, etc. are used. This reaction is carried out at a temperature of 10 to 100°C, preferably 10 to 30°C. Generally 1~
It will finish in about 48 hours. The method for obtaining compound () () from compound () is described by Fumiko Hamaguchi et al., Pharmaceutical Journal, 1635, Vol98
(1978) as a reference. The solvent used in the method of synthesizing compound () from compound () is
Aprotic polar solvents such as dimethylformamide and dimethylsulfoxide. Also, amine solvents such as triethylamine, tributylamine, and pyridine are used. Diethyl cyanophosphate is used as a condensing agent. This reaction is 0~
The temperature is preferably 100°C, preferably 0 to 10°C. Generally, it takes about 1 to 5 hours to complete. The solvent used in the method for synthesizing compound () from compound () is an aromatic solvent such as benzene, toluene, and xylene. Further, acidic solvents such as phosphorus oxychloride, phosphorus pentachloride, polyphosphoric acid, phosphorus trichloride, and sulfuric acid are used. This reaction is carried out at 10-150°C, preferably 70-100°C.
It is better to do it in Generally, it takes about 1 to 3 hours to complete. The above reaction can also be explained by the following reaction steps. The method for obtaining compound () from compound () via compound () was based on JP-A-56-43283. Formalin is generally used in an amount of 1 to 10 equivalents, preferably 3 to 5 equivalents, relative to compound (). Additionally, water is a preferred solvent used in this method. Also used are sodium hydroxide, potassium hydroxide, and the like.
This reaction is carried out at 10-100°C, preferably at 50°C.
~60℃. The reaction time is 1 to 30 hours, preferably 20 to 30 hours. Solvents used in the method for obtaining compound (XI) from compound () are lower alcohols such as methanol, ethanol, propanol, hexanol, and the like. Further, as an acid catalyst, thionyl chloride, sulfuric acid, hydrochloric acid gas, p-toluenesulfonic acid, etc. are used. This reaction is carried out at a temperature of 10 to 100°C, preferably 10 to 30°C.
Generally, it takes about 1 to 48 hours to complete. The solvents used in the method for synthesizing compound () from compound (XI) include xylol, mesitylene, toluol, chlorobenzole, and diphenyl ether. Subsequently, elemental sulfur is added, the amount of which is determined to be approximately 1 molar equivalent of sulfur per double bond. The reaction mixture is boiled under reflux for several hours. Another method is to use DDQ (dichlorodicyanobenzoquinone) or chloroanneal to treat benzole, toluol, xylol, dioxane,
The dehydrogenation is carried out in tetrahydrofuran, methylene chloride and dimethoxyethane at a temperature of 0°C to 60°C with a reaction time of 0.5 to 4 hours. Furthermore, another method is dehydrogenation with noble metal catalysts such as finely powdered platinum, palladium black or palladium on charcoal in xylol, mesitylene or cumol at 120-180°C and reaction time of 2-16 hours. be able to. In the general formula () of the present invention, when R is a hydroxy group or a halogen atom, it can be synthesized by the following method. The solvent used in the method for synthesizing compound (XII) from compound () is water or a mixed solvent of water and an alcoholic solvent such as methanol or ethanol. ~80℃. Generally, it takes about 1 to 5 hours to complete. Next, by reacting with hydrochloric acid, sulfuric acid, etc., compound (XII) in which R is a hydroxy group can be obtained. Thionyl chloride and thionyl bromide are used in the method for synthesizing compound () from compound (XII), and this reaction is carried out at 10 to 100°C, preferably 60 to 80°C. Generally 1~
It will be completed in about 6 hours. Compound () is an important intermediate of general formula (). Further, the compound having the general formula () can be made into a pharmacologically acceptable acid addition salt form. Examples of pharmacologically acceptable acid addition salts include:
Examples include acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, or organic acids such as maleic acid and tartaric acid. (Actions and Effects of the Invention) The compound according to the present invention exhibits the following specific anticonvulsant action, muscle relaxant action, and psychotropic action. a Anticonvulsant action The compounds according to the invention exhibit anticonvulsant action in mice. Using ICR male mice (6 weeks old), β-carboline-3-carboxylic acid methyl ester 3 mg/Kg
The inhibitory effect of this compound on clonic convulsions induced by IV was investigated. This compound is 1%
It was used as a methylcellulose suspension. The results are shown in Table 1.

[Table] From the above results, this compound was found to have a clear anticonvulsant effect. b Muscle relaxant effect The compound according to the present invention exhibits muscle relaxant effect on mice. After administering this compound to ICR male mice (6 weeks old), the forelimbs were placed on a horizontally stretched wire with a diameter of 2 mm, and it was observed whether the hindlimbs were placed on the wire within 10 seconds. Two trials were conducted, and it was determined that there was a muscle relaxing effect if the hind limb could not be hung on the wire both times.
The results are shown in Table 2.

[Table] The compound of the present invention was found to have a clear muscle relaxing effect. c Psychotropic effects The compounds according to the invention exhibit an effect on mouse threshold responses. ICR male mice were kept in isolation from the age of 3 weeks, and
When two animals are placed in the same cage, they fight within 30 seconds.
Those that were reliably recognized were used in the test as a pair. After administration of benzo[b]thieno[2,3-C]pyridine-3-carboxylic acid propyl ester (i.
v.), mice were paired again, and if no fighting was observed after 60 seconds or more, it was determined that there was a suppressive effect. benzo[b]thieno[2,3-C]pyridine-
3-carboxylic acid propyl ester 50mg/Kg (iv)
When administered intravenously to three pairs of mice (total of 6 mice) and observed for fighting 8 minutes later, all three pairs of mice showed signs of fighting.
Fighting was not allowed. The compounds of the present invention all have specific anticonvulsant,
It can be used therapeutically as a muscle relaxant and psychotropic agent. (Example) The present invention will be described below with reference to Examples.
The present invention is not limited to these examples. Example 1 Benzo[b]thieno[2,3-C]pyridine-
3-carboxylic acid methyl ester could be obtained by the following method. Gerhard Wolf and Felix ZymalKowski
Arch. (Pharm.) 279, 309 (1976) was used as a reference. 35.75 g of benzo[b]thiophene, 26.6 g of 37% formalin, and 26.6 ml of concentrated hydrochloric acid were vigorously stirred for 3 hours while blowing hydrochloric acid gas at room temperature. After the reaction was completed, 200 ml of methylene chloride and 100 ml of water were added for extraction. The methylene chloride layer was dried with magnesium sulfate and then distilled under reduced pressure. 38.3 g of 3-chloromethylbenzo[b]thiophene was obtained. (yield 79%) bp,
0.5 115~120℃
Double Smith, Journal American
Chemistry Society HRSnyder and
Curtis W.Smith J.Am.Chem.Soc., 350, Vol66
(1944), the following reaction was performed. Cut 5.30 g of metallic sodium into small pieces, add to 700 ml of dry dioxane, and further add 50 g of acetaminomalonic acid diethyl ester at room temperature. Reflux agitation for 1 day, add 32.3 g of 3-chloromethylbenzo[b]thiophene, and reflux stir for 1.5 days. After the reaction was completed, the temperature was returned to room temperature, 20 ml of methanol was added, and the mixture was stirred for 30 minutes. The reaction solution was filtered, and the solution was concentrated under reduced pressure. The concentrate was separated and purified using a silica gel column. (Developing solvent chloroform) 30.5 g (yield 47%) of ethyl α-acetamino-α-carbetroxy-β-(3-benzo[b]thiophene)-propionate was obtained. IR (ν _nax , cm ^-1 ) 3275, 1740, 1640, 1510 NMR (δ, CDCl ₃ ) 1.30 (t, J=6Hz, 6H),
1.95 (s, 3H), 3.67 (s, 2H), 4.17 (q, J=6
Hz, 4H), 6.50-8.00 (m, 5H) Add 30.5 g of ethyl α-acetamino-α-carbetroxy-β-(3-benzo[b]thiophene)-propionate to 250 ml of methanol, and add 13.45 g of sodium hydroxide to water. The solution dissolved in 500 ml was added to the methanol solution. Reflux stirring was performed for 2 hours. Methanol was distilled off under reduced pressure. Water layer with concentrated hydrochloric acid
The pH was set to 1.0. The aqueous layer was extracted twice with 300 ml of chloroform. The chloroform layer was dried over magnesium sulfate and evaporated under reduced pressure. α-acetamino-α-carboxy-β-(3
-benzo[b]thiophene)-propionic acid 16.75
I got g. (Yield 65%) IR ( _nax , cm ^-1 ) 1730, 1635, 1540 NMR (δ, CDCl ₃ ) 1.87 (s, 3H), 3.45 (m,
2H), 7.17-8.00 (m, 5H), 9.33 (s, 2H) α-acetamino-α-carboxy-β-(3
-benzo[b]thiophene)-propionic acid 30g
was added to 200 ml of water and refluxed for 3 hours.
Return the reaction temperature to room temperature and add 15.6 g of sodium hydroxide.
was added little by little. Reflux stirring was performed for 2.5 days. After the reaction is complete, return to room temperature and add 100% chloroform.
Washed with ml. The aqueous layer was adjusted to pH 4.0 with concentrated hydrochloric acid. 1
After standing in the refrigerator overnight, α-amino-(3-benzo[b]thiophene)-propionic acid was removed and dried under reduced pressure. 16.0g (Yield74%) IR (ν _nax , cm ^-1 ) 1590, 1420, 1020 NMR (δ, D ₂ O, (CH ₃ ) ₃ Si (CH ₂ ) ₃ SO ₃ Na)
3.00-4.00 (m, 3H), 7.20-5.00 (m, 5H) Nobuo Izumiya, Tetsuo Kato, Motonori Ohno, Higashihiko Aoyagi, Synthetic Chemistry Series Peptide Synthesis (Maruzen) 66 Based on Experimental Example 3.2, perform the following reaction. I went to 640 ml of dry methanol is cooled to 0°C and 20.8 ml of thionyl chloride is slowly added. Stir at 0 °C for 30 min to remove α-amino-(3-benzo[b]thiophene).
- 16.0 g of propionic acid was added at 0°C and stirred for 30 minutes. After drying at room temperature for 2 days, methanol was distilled off under reduced pressure. 300 ml of methylene chloride and 150 ml of 5% sodium bicarbonate water were added to the residue for extraction. The methylene chloride layer was dried over magnesium sulfate and then evaporated under reduced pressure. α-amino-(3-benzo[b]thiophene)-
15.8 g of propionic acid methyl ester was obtained. (Yield 93%) IR (ν _nax , cm ^-1 ) 2975, 1730, 1180 NMR (δ, CDCl ₃ ) 3.0-3.37 (m, 3H), 4.07
(s, 3H), 7.17-8.00 (m, 5H) The following reaction was carried out with reference to Fumiko Hamaguchi et al. Pharmaceutical Journal 1635, Vol. 98 (1978). α-amino-(3-benzo[b]thiophene)-
14.4 g of propionic acid methyl ester was dissolved in 152 ml of dimethylformamide and cooled to 0°C. 99%
2.84g formic acid, 11.08g 90% diethyl cyanophosphate
was added and stirred for 10 minutes. Triethylamine 8.78
ml was added dropwise at a reaction temperature range of 0°C to 5°C, and the mixture was stirred for 1 hour. The mixture was further stirred at room temperature for 1 hour. Add 200ml of benzene, 800ml of ethyl acetate, and add 5% hydrochloric acid water.
It was washed twice with 300 ml, once with 200 ml of 5% sodium bicarbonate water, and once with 200 ml of saturated saline. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. N-formamide-(3-benzo[b]thiophene)-propionic acid ethyl ester 15.9g
I got it. (Yield 99%) IR (ν _nax , cm ^-1 ) 3275, 2960, 1740, 1660,
1510, 1380, 1200 15.9 g of N-formamide-(3-benzo[b]thiophene)-propionic acid methyl ester, 78 ml of dry toluene, and 47 ml of phosphorus oxychloride were mixed at 80°C.
Stir for hours. Remove the solvent under reduced pressure and remove ethyl acetate.
Added 300ml. 150 ml of 10% Na ₂ CO ₃ water was added to perform liquid separation and extraction. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Separation and purification was performed using silica gel column chromatography (developing solvent was chloroform). benzo[b]thieno[2,3-C]pyridine-
7.50 g of 3-carboxylic acid methyl ester was obtained.
(Yield 51%) IR (ν _nax , cm ^-1 ) 1700, 1400, 1285, 1240 NMR (δ, CDCl ₃ ) 4.48 (s, 3H), 7.50-8.50
(m, 4H), 8.87 (s, 1H), 9.27 (s, 1H) Mass (m/e) 243 (M ⁺ ), 213, 185 Example 2, 3, 4 Benzo[b]thieno[2,3 -C]Pyridine-
3-carboxylic acid ethyl ester, benzo[b]thieno[2,3-C]pyridine-3-carboxylic acid propyl ester, benzo[b]thieno[2,3-
C] Pyridine-3-carboxylic acid hexyl ester was added in place of 640 ml of dry methanol in Example 1.
Dry ethanol 920ml, dry propanol 1000ml,
Synthesis was carried out in exactly the same manner except that 1000 ml of dry hexanol was used. The results are shown in Table 3, and the analysis results are shown in Table 4. (However, the yield represents the yield of the final step.)

【table】

【table】

[Table] Examples 5, 6 Benzo[b]furano[2,3-C]pyridine-
3-carboxylic acid ethyl ester and benzo[b]furano[2,3-C]pyridine-3-carboxylic acid propyl ester were substituted for 35.75 g of benzo[b]thiophene in Examples 2 and 3. It was synthesized in exactly the same manner except that 31.39 g of furan was used. The results are shown in Table 5, and the analysis results are shown in Table 6. (However, the yield represents the yield of the final step.)

【table】

【table】

Claims (1)

[Claims] 1 General formula () [In the formula, A represents a sulfur atom or an oxygen atom, and R represents an OR' group (wherein R' is a lower alkyl group having up to 6 C atoms or a hydrogen atom) or a halogen atom. ] The compound according to claim 1, wherein A is a sulfur atom. 3. The compound according to claim 1, wherein A is an oxygen atom. 4. The compound according to claim 1, wherein R is an OR' group. 5. The compound according to claim 4, wherein R' is a methyl group. 6. The compound according to claim 4, wherein R' is an ethyl group. 7 Claim 4 in which R' is a propyl group
Compounds described in Section. 8 Claim 4 in which R' is a hexyl group
Compounds described in Section. 9. The compound according to claim 4, wherein R' is a hydrogen atom. 10. The compound according to claim 1, wherein R is a chlorine atom. 11 General formula () is benzo[b]thieno[2,
3-C] The compound according to claim 5, which is pyridine-3-carboxylic acid methyl ester. 12 General formula () is benzo[b]thieno[2,
3-C] The compound according to claim 6, which is pyridine-3-carboxylic acid ethyl ester. 13 General formula () is benzo[b]thieno[2,
3-C] The compound according to claim 7, which is pyridine-3-carboxylic acid propyl ester. 14 General formula () is benzo[b]thieno[2,
3-C] The compound according to claim 8, which is pyridine-3-carboxylic acid hexyl ester. 15 General formula () is benzo[b]furano[2,
3-C] The compound according to claim 6, which is pyridine-3-carboxylic acid ethyl ester. 16 General formula () is benzo[b]furano[2,
3-C] The compound according to claim 7, which is pyridine-3-carboxylic acid propyl ester.