JPH024225B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel thiophene compounds and acid adducts thereof. This compound exhibits a very novel pharmacological profile in that it has β-blocking properties comparable to propranolol and/or diuretic properties comparable to thiazide compounds. The invention also relates to a process for the preparation of the above-mentioned compounds and to their application in therapy. Furthermore, the invention relates to intermediate compounds for synthesizing the above compounds. The compound of this invention has the formula (1) (Here, R is an alkyl group having 1 to 5 carbon atoms, preferably an ethyl group, R ₁ is an alkyl group having 1 to 5 carbon atoms, preferably an isopropyl group or a tert-butyl group, and R ₂ is hydrogen. , an alkyl group having 1 to 5 carbon atoms or a halogen, or a cyclohexyl group forming a condensed ring with the thiophene, preferably hydrogen or a methyl group, n is 0, and a carboxamide chain is at the 2- or 3-position of the thiophene ring. combined). The compounds of this invention can be prepared by reacting the base NH ₂ -R ₁ (R ₁ is as defined above) with a compound of the following formula without a solvent or in a common organic solvent such as alcohol at 20°C to 150°C. synthesized by (where R ₂ , R and n are as described above) A compound of the formula It can be obtained by reacting a phenolic compound represented by (where R ₂ , R and n are as described above) with epihalohydrin, particularly epichlorohydrin or epibromohydrin. The phenolic compound of the formula is premetalized with conventional metalating agents such as sodium hydroxide, potassium hydroxide, alcoholate or sodium hydride at 20°C to 150°C in a dilute alcoholic medium or a solvent such as DMF. . The above-mentioned method is a known method, and only a low yield and an irregular compound can be obtained.
The inventors have developed a new process consisting of reacting a phenolic compound of the formula with excess epichlorohydrin at 110°C to 130°C in the presence of a catalyst such as benzyltrimethylammonium chloride. By this method it is possible to obtain completely crystalline compounds in good yields. Compounds of formula are prepared by preparing the acid chloride of the corresponding thienylcarboxylic acid in the presence of a base such as triethylamine in a solvent such as acetone or benzene.
-Amino-2-carbalkoxyphenol. Non-toxic addition salts of compounds of the formula are obtained by reacting the compounds of the formula with inorganic or organic acids in a manner known per se. Examples of acids that can be used include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, 4-toluenesulfonic acid, methanesulfonic acid, cyclohexylsulfamic acid, oxalic acid,
Succinic acid, formic acid, maleic acid, aspartic acid,
These are cinnamic acid, glutamic acid, N-acetylaspartic acid, N-acetylglutamic acid, ascorbic acid, malic acid, fumaric acid, lactic acid and benbrotic acid. The novel compounds of this invention have remarkable pharmacological properties and are used as β-blockers of the propranolol type and/or as diuretics of the thiazide type. The compounds of this invention may simultaneously exhibit these two properties in the treatment of hypertension. Additionally, these compounds are substantially non-toxic and cardioselective. A particularly preferred subgenus A of compounds of this invention is:
In the formula, the carboxamide chain is directly connected to the thiophene ring (n=0), and the 2
It is connected to the position. Compounds of this type exhibit excellent diuretic and β-blocking properties at the same time. Subgenus B, in which n is 0 and the carboxamide chain is attached to the 3-position, has good β-blocking activity with diuretic properties. In addition, in the formula, subgenus C, where n is 1 and the carboxamide chain is bonded to the 2nd position, and subgenus D, where n is 1 and the carboxamide chain is bonded to the 3rd position, are nondiuretic. It is a β-blocking compound. Furthermore, in the formula, R ₂ is hydrogen or 4-
Compounds that are methyl groups are of particular interest. This compound is particularly superior to those with a 5-methyl substituent on the thiophene. Therefore, n is 0, the carboxamide chain is in the 2-position of the thiophene, and R ₂ is H or 4-
Compound E, which is methyl, is of particular interest. In human therapy, compounds of formula and non-toxic acid addition salts thereof may be administered particularly orally. It is recommended to use capsules or tablets containing 50 to 300 mg of a compound of the invention together with a physiologically acceptable carrier. The compounds of this invention have the advantage of simplifying therapeutic treatment. The compounds of subgenus A also have a very unique pharmacological activity with respect to the combination of β-blocking and diuretic properties in the treatment of hypertension. Other cases include angina pectoris,
Examples include arrhythmia and migraine. Examples, production examples, and reference examples of this invention will be described below. Production Example 1 1-[2-ethoxycarbonyl-4-(5-methyl-2-thiophenecarboxamide)phenoxy]-2,3-epoxypropane In a flask,
2-ethoxycarbonyl-4-(5-methyl-2
- Thiophenecarboxamide) A mixture of 35 g of phenol and 175 ml of epichlorohydrin was heated to 110 DEG C. and then 2.9 g of benzyltrimethylammonium chloride was added. The mixture was heated under reflux for 30 minutes and cooled. Water when the temperature drops to 50℃
200ml was added and stirred vigorously. After decanting, the aqueous phase was extracted twice with ether and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was solidified in ether. After washing three times with 50 ml of isopropyl ether, 1-
[2-ethoxycarbonyl-4-(5-methyl-2
-thiophenecarboxamide) phenoxy]-2,
30 g of 3-epoxypropane were obtained in the form of white crystals. Melting point: 109℃. Example 1 1-[2-Ethoxycarbonyl-4-(5-methyl-2-thiophenecarboxamide)phenoxy]3-tert-butylamino-2-propanol In a flask, 14 g of the epoxide obtained in Preparation Example 1
(in tert-butylamine 30ml) and ethanol 100
ml was heated under reflux for 8 hours. The solution was dried under reduced pressure and 150 ml of water, 5 ml of glacial acetic acid and 100 ml of isopropyl acetate were added to the residue. After removing the organic phase by decantation, the acidic aqueous phase was neutralized with ammonia aqueous solution and extracted twice with 50 ml of chloroform. After drying over magnesium sulfate, the chloroform phase was filtered and concentrated under reduced pressure. The resulting oil was added to hot isopropyl acetate. The solution was hot filtered and cooled. The precipitated product was thoroughly washed with ether. Thus, 1-[2
-ethoxycarbonyl-4-(5-methyl-2-
4 g of thiophenecarboxamide) phenoxy]3-tert-butylamino-2-propanol were obtained in the form of white crystals. With a melting point of 110°C, this compound has the formula where R is -C ₂ H ₅ and R ₁ is

[Formula], R ₂ was -CH ₃ at the 5th position, and n was 0. Example 2 1-[2-Ethoxycarbonyl-4-(5-methyl-2-thiophenecarboxamide)phenoxy]-3-isopropylamino-2-propanol Example except that isopropylamine was used instead of tertiary butylamine. The same operation as 1 was performed. Finally, the residue was recrystallized from ethyl acetate and
-[2-ethoxycarbonyl-4-(5-methyl-
2-thiophenecarboxamide) phenoxy]-
3-isopropylamino-2-propanol 6g
was obtained in the form of white crystals. Melting point: 121℃. This compound has the formula where R is -C ₂ H ₅ , R ₁
but

[Formula], R ₂ was CH ₃ at the 5th position, and n was 0. Production example 2 1-[2-ethoxycarbonyl-4-(5-chloro2-thiophenecarboxamide)phenoxy]2,3-epoxypropane 2-ethoxycarbonyl 4-(5-chloro2-
The same operation as in Production Example 1 was carried out using 11 g of thiophenecarboxamide (thiophene carboxamide) phenol, 60 ml of epichlorohydrin and 1 g of benzyltrimethylammonium chloride to obtain 7 g of an amorphous oily product. This compound has _the formula where R is _-C2H5 ,
R ₂ was Cl at the 5-position and n was 0. Example 3 1-[2-ethoxycarbonyl 4-(5-chloro2-thiophenecarboxamide)phenoxy]
Hydrochloride of 3-tert-butylamino-2-propanol The oily product obtained in Preparation Example 2 was directly dissolved in 50 ml of tert-butylamine, and the mixture was refluxed for 8 hours. Next, it was treated in the same manner as in Example 1. The obtained crystals were added to 100 ml of acetone, and to this was added 10 ml of an ether solution of hydrochloric acid. The precipitate was filtered, washed with acetone and then with ether to obtain 700 mg of hydric chloride of 1-[2-ethoxycarbonyl 4-(5-chloro2-thiophenecarboxamide)phenoxy]3-tert-butylamino-2-propanol.
was obtained in the form of white crystals. Melting point 165℃. This compound has _the formula in which R is _-C2H5 ,
R ₁ is

[Formula], R ₂ was Cl at the 5th position and n was 0. Production example 3 1-[2-ethoxycarbonyl 4-(4-methyl 2-thiophenecarboxamide) phenoxy]
2,3-Epoxypropane The procedure was the same as in the examples. An oil was obtained using 30 g of 2-ethoxycarbonyl 4-(4-methyl 2-thiophenecarboxamide)phenol, 3 g of benzyltrimethylammonium chloride and 150 ml of epichlorohydrin, and after treatment was extracted twice with 100 ml of ether. dry the ether phase;
After concentration under reduced pressure, 1-[2-ethoxycarbonyl 4-(4-methyl 2-thiophenecarboxamide)
Phenoxy]2,3-epoxypropane was obtained in the form of white crystals. Melting point: 118℃. This compound has the formula where R is -C ₂ H ₅ , R ₂
was that of -CH ₃ at the 4th position and n was 0. Example 4 1-[2-ethoxycarbonyl 4-(4-methyl 2-thiophenecarboxamide) phenoxy]
Hydrochloride of 3-tert-butylamino 2-propanol The procedure was the same as in Example 1. 6 g of crystals were obtained from 10 g of the epoxide obtained in Production Example 3 and 50 ml of tert-butylamine and dissolved in a minimum amount of ether. An ethereal solution of hydrochloric acid was poured into the solution until the pH became about 1, and the precipitate was collected by filtration. Recrystallization from ethanol gave 1-[2-ethoxycarbonyl 4-(4-methyl 2-thiophenecarboxamide) phenoxy] 3-tert-butylamino 2-propanol in the form of white crystals. Melting point 186℃. This compound has the formula where R is -C ₂ H ₅ , R ₁
but

[Formula], R ₂ is -CH ₃ at the 4th position and n is 0. Production example 4 1-[2-ethoxycarbonyl 4-[2-(4,
5,6,7-tetrahydro)thianaphthenecarboxamide]phenoxy]2,3-epoxypropane 2-ethoxycarbonyl 4-[2-(4,5,6,7-tetrahydro)
Thianaphthenecarboxamide] 1-[2-ethoxycarbonyl 4-[2-(4,5,6,7-tetrahydro)] from phenol, benzyltrimethylammonium chloride and epichlorohydrin
Thianaphthene carboxamide [phenoxy] 2,
3-Epoxypropane was obtained. This compound has the formula where R is ~ _{C 2} H ₅ and R ₂ is

[Formula] and n were 0. Example 5 1-[2-ethoxycarbonyl 4-[2-(4,
5,6,7-tetrahydro)thianaphthenecarboxamide]phenoxy]3-tert-butylamino-2-propanol Following the procedure of Example 1, 1-[2-ethoxy Carbonyl 4-[2-(4,5,6,7-tetrahydro)thianaphthenecarboxamide]phenoxy]3-tert-butylamino 2-propanol was obtained. This compound has the formula in which R is -
C ₂ H ₅ , R ₁ is

[Formula], R ₂ is

[Formula] and n were 0. Production Example 5 1-[2-ethoxycarbonyl4-(2-thienylcarboxamide)phenoxy]2,3-epoxypropane In a flask, 10 g of 4-(2-thienylcarboxamide)2-ethoxycarbonylphenol and 60 ml of epichlorohydrin. After heating the mixture with benzyltrimethylammonium chloride to 110℃
0.9g was obtained. The mixture was heated under reflux for 0.5 h and cooled. Water when the temperature drops to 50℃
Added 150ml. The mixture was stirred and then extracted twice with 50 ml of ether. dry the ether phase;
Evaporated to dryness. The residue was recrystallized from ether to obtain 8 g of 1-[2-ethoxycarbonyl 4-(2-thienylcarboxamido)phenoxy]2,3-epoxypropane. Melting point 110℃. This compound had _a formula in which the amide was in the 2nd position, n was 0, and R was _C2H5 . Production Example 6 1-[2-Ethoxycarbonyl 4-(3-thienylcarboxamide)phenoxy]2,3-epoxypropane According to the method of Production Example 1, 13 g of 4-(3-thienylcarboxamide)2-ethoxycarbonylphenol, epichloro 70 ml of hydrin and 1 g of benzyltrimethylammonium chloride to 1-
[2-Ethoxycarbonyl 4-(2-thienylcarboxamide)phenoxy] 8 g of 2,3-epoxypropane was obtained. Melting point: 119℃. This compound had a formula in which an amide group was bonded to the 3-position, n was 0, and R was _{~ C2H5} . Example 6 1-[2-Ethoxycarbonyl 4-(2-thienylcarboxamido)phenoxy]3-isopropylamino 2-propanol (base) In a flask, 8 g of the epoxide obtained in Preparation Example 5
and isopropylamine 10 in 50 ml of ethanol
ml was heated to 50°C with stirring. After heating at 50° C. for 8 hours, the alcoholic solution was concentrated under reduced pressure and the residue was added to a mixture of 100 ml of isopropyl acetate and 200 ml of water. To this was added 3 ml of cold glacial acetic acid and the mixture was stirred until a clear mass was obtained. After removing the isopropyl acetate by decantation, the acetic acid solution was made basic with cold ammonium. This basic phase was extracted twice with 50 ml of chloroform. After drying the organic phase and concentrating under reduced pressure, a pasty residue was obtained, which was recrystallized from 50 ml of ether. Thus, 1[2-ethoxycarbonyl 4-(2-thienylcarboxamide)phenoxy]3-isopropylamino 2-propanol
4.5g was obtained. Melting point: 108℃. This compound has an amide in the 2-position, n is 0, R is -C ₅ H ₅ and R ₁ is

It was [formula]. Example 7 1-[2-Ethoxycarbonyl 4-(2-thienylcarboxamido)phenoxy]3-tert-butylamino 2-propanol (base) Following the procedure of Example 2, 8 g of the epoxide of Preparation Example 5 and 10 ml of tert-butylamine From 1-[2-
Ethoxycarbonyl 4-(2-thienylcarboxamide)phenoxy]3-tert-butylamino 2-
3.5 g of propanol was obtained. Melting point: 125℃. This compound has an amide in the 2-position, n is 0, R is -C ₂ H ₅ and R ₁ is

It was of [formula]. Example 8 1-[2-Ethoxycarbonyl 4-(3-thienylcarboxamido)phenoxy]3-isopropylamino 2-propanol (base) According to the procedure of Example 2, from 8 g of the epoxide of Production Example 6, 1-[2- Ethoxycarbonyl 4-(3
-thienylcarboxamide) phenoxy] 5.5 g of 3-isopropylamino 2-propanol was obtained.
Melting point: 132℃. This compound has an amide in the 3-position, n is 0, R is -C ₂ H ₅ , and R ₁ is

It was of [formula]. Example 9 1-[2-Ethoxycarbonyl 4-(3-thienylcarboxamide)phenoxy]3-tert-butylamino 2-propanol (base) Following the procedure of Preparation Example 2, the epoxide of Preparation Example 6 was prepared.
5.6g to 1-[2-ethoxycarbonyl 4-(3
3.5 g of 3-tert-butylamino-2-propanol (thienylcarboxamide) phenoxy] were obtained.
Melting point 126℃. _This compound has an amide in the 3-position, n is 0, R is ~ _C2H5 , and _R1 is

It was of [formula]. Reference Example 1 1-[2-Ethoxycarbonyl 4-(2-thienylacetamido)phenoxy]2,3-epoxypropane 2-ethoxycarbonyl 4-(2-thienylacetamido)phenoxy was prepared according to the method of Production Example 1.
19.3 g and 1.9 g of benzyltrimethylammonium chloride gave 22.5 g of an oily product, which was used in the following synthesis. _This compound had an amide in the 2-position, where n was 1 and R was _-C2H5 . Reference Example 2 1-[2-Ethoxycarbonyl 4-(3-thienylacetamido)phenoxy]3-tert-butylamino-propanol (base) According to the procedure of Example 2, the epoxide of Reference Example 1 was prepared.
From 11.5 g and 50 ml of tert-butylamine, 1-
[2-ethoxycarbonyl 4-(3-thienylacetamido)phenoxy]3-tert-butylamino 2
-3.5 g of propanol were obtained. Melting point: 118℃. This compound has an amide in the 2-position, z is 1, R is -C ₂ H ₅ , and R ₁ is

It was of [formula]. Reference Example 3 1-[2-ethoxycarbonyl 4-(3-thienylacetamido)phenoxy]2,3-epoxypropane 2-ethoxycarbonyl 4-(3-thienylacetamido)phenol according to the method of Production Example 1
27.4 g and 2.7 g of benzyltrimethylammonium chloride gave 30 g of an oily product, which was used in the following synthesis. _This compound had an amide in the 3-position, where n was 1 and R was _-C2H5 . Reference Example 4 1-[2-ethoxycarbonyl 4-(3-thienylacetamido)phenoxy]tert-butylamino 2-propanol The epoxide of Reference Example 3 was prepared according to the method of Example 2.
From 15 g and 50 ml of tert-butylamine, 1-[2
-Ethoxycarbonyl 4-(3-thienylacetamido)phenoxy]3-tert-butylamino 2-
2.8 g of propanol was obtained. Melting point: 117℃. This compound has an amide in the 3-position, n is 1, R is -C ₂ H ₅ , and R ₁ is

It was of [formula]. Reference Example 5 1-[2-Ethoxycarbonyl 4-(3-thienylacetamido)phenoxy]3-isopropylamino 2-propanol (base) According to the method of Example 2, the epoxide of Example 18 was prepared.
From 12.5 g and 50 ml of isopropylamine, 1-
3.5 g of [2-ethoxycarbonyl 4-(3-thienylacetamido)phenoxy]3-isopropylamino 2-propanol was obtained. Melting point 130℃. This compound has an amide in the 3-position, n is 1, R is -C ₂ H ₅ , and R ₁ is

It was of [formula]. Production Example 7 1-[2-Methoxycarbonyl 4-(2-thienylcarboxamide)phenoxy]2,3-epoxypropane According to the method of Production Example 1, 35 g of 2-methoxycarbonyl 4-(2-thienylcarboxamide 5-phenol, epichloro An oily product was obtained from 210 ml of hydrin and 3 g of benzyltrimethylammonium chloride, which was recrystallized from isopropyl acetate to yield 17 g of 1-[2-methoxycarbonyl4-(2-thienylcarboxamido)phenoxy]2,3-epoxypropane. The compound had an amide in the 2-position, n was 0 and R was _-CH3 . Example 10 1-[2-methoxycarbonyl 4-( 2-thienylcarboxamide) phenoxy]3-tert-butylamino 2-propanol (base) Following the procedure of Example 2, the epoxide of Example 21
From 3.6 g and 10 ml of tert-butylamine, 1-[2
-methoxycarbonyl 4-(2-thienylcarboxamide)phenoxy]3-tert-butylamino 2
- 1 g of propanol was obtained. Melting point 136℃. This compound has an amide in the 2-position, n is 0, R is ~ _CH3 , and _R1 is

It was of [formula]. The structural formulas of the compounds obtained in Examples 1 to 10, Production Examples 1 to 7, and Reference Examples 1 to 5 are summarized below. Biological Evaluation Diuretic Activity in Rats The diuretic activity of the compounds of this invention in rats was determined as follows. Male fasted rats (Sprague-Dawley,
Iffa, Credo, 130-140g) was used. The exam is
The animals were first given 2.5 ml of water per 100 g of body weight and then administered orally with the excipient or test substance in the form of a suspension. Rats were divided into two groups and housed in metabolic cages. Urine was collected in graduated cylinders at 0-6 hour intervals and analyzed for sodium content using standard methods. Result is,
The geometric mean of the three cages was calculated for each dose level and expressed in milliliters of 6-hour urine and milliequivalents of electrolytes. β-Adrenergic Neuroleptic Activity The β-adrenergic neuroleptic activity of the compounds of this invention in dogs was determined as follows.
Mixed breed dogs of either sex weighing 10-18 kg were treated with 30 mg/day of pentobarbital sodium salt.
Anesthetize using 4 boluses in Kg, then
3mg. Gently irrigated with Kg ^-1 h ^-1 . All dogs were artificially ventilated and oxygenated by RPP volumetric pumps. A cannula was inserted into the carotid artery and connected to a Statham P23Db pressure transducer for blood pressure recording. Walton sewn myocardial contractile force into the left ventricle.
Recorded by Brodie strain meter. All signals were amplified and recorded continuously on a polygraph (Beckman R411). All injections were made into the cannulated saphenous vein. Controlling effects on contractile force and diastolic arterial pressure were obtained by injecting submaximal doses of isoprenaline (isoproterenol). Animals were used only once for each test substance. Different intravenous doses of the same drug were given every 30 minutes. Isoproterenol hemodynamic effects after each test article injection were compared to isoproterenol control values and the percent inhibition of isoproterenol response at each dose level was calculated. Based on these results, the dose
Response curves were generated and the evaluated dose (ID50) that produced a hemodynamic change that was a 50% inhibition of contractile force or diastolic arterial pressure was determined. The most important compound (Example 7) was evaluated for both diuretic and β-blocking activity in rats after oral administration. Diuretic activity was assessed as described above, whereas oral β-blocking activity was determined as follows. β-adrenergic neuroleptic activity in sane rats β-adrenergic neuroleptic activity of compounds of this invention in sane rats
- Agonist neuroleptic activity was measured as follows. Continuously implanted Sprague-Dawley rats were used. β-adrenergic neuroblockade was determined by rigorously constructed dose-response curves for isoproterenol-induced tachycardia or hypotension before and after oral administration of test compound (1 h, 5 h). was evaluated. Linear regression (Iinear
The ED50 value, determined by regression), was defined from this curve as the dose of isoproterenol that elicited 50% of the maximal effect observed.
These were considered to be a measure of β-adrenergic neuroleptic activity. Results The results of the first two tests are summarized in Table 1 below. Furthermore, the β-blocking and diuretic activities of UP788-42 (Example 7) are shown in Table 2 below.

【table】

[Table] 50% lethal dose (LD50) Intravenous administration of the compound obtained in Example 7 (),
LD5 was determined for intraperitoneal (IP) and oral (PO) administration in rats and mice. The results are shown in Table 1. The units of all numbers in the table are mg·Kg ^-1 , and the numbers in brackets represent confidence limits.

【table】

Claims (1)

[Claims] 1 formula (Here, R is an alkyl group having 1 to 5 carbon atoms, R ₁ is an alkyl group having 1 to 5 carbon atoms, R ₂ is hydrogen, an alkyl group having 1 to 5 carbon atoms, a halogen, or a fused ring together with the thiophene. The cyclohexyl group formed and the carboxamide chain are bonded to the 2- or 3-position of the thiophene ring) and non-toxic acid addition salts thereof. 2. The compound according to claim 1, wherein R is an ethyl group. 3. The compound according to claim 1 or 2, wherein R ₁ is an isopropyl group or a tert-butyl group. 4. The compound according to claim 1, wherein R ₂ is a 4-position methyl group or hydrogen. 5. The compound according to claim 1, wherein the carboxamide chain is bonded to the 2-position of the thiophene, and R ₂ is hydrogen or a methyl group at the 4-position. 6 1-[2-ethoxycarbonyl 4-(5-methyl 2-thiophenecarboxamide) phenoxy]
3-tert-butylamino 2-propanol, 1-
[2-ethoxycarbonyl 4-(5-methyl 2-thiophenecarboxamide) phenoxy] 3-isopropylamino 2-propanol, 1-[2-ethoxycarbonyl 4-(5-chloro 2-thiophenecarboxamide) phenoxy] 3- Tert-butylamino 2-propanol hydrochloride, 1-[2-ethoxycarbonyl 4-(4-methyl 2-thiophenecarboxamide) phenoxy] 3-tert-butylamino 2-propanol hydrochloride, 1-[2-ethoxycarbonyl 4-[2-(4,5,6,7-tetrahydro)thianaphthenecarboxamide]phenoxy]3-tert-butylamino 2-propanol, 1
-[2-ethoxycarbonyl 4-(2-thienylcarboxamide) phenoxy] 3-isopropylamino 2-propanol (base), 1-[2-ethoxycarbonyl 4-(2-thienylcarboxamide)
Phenoxy] 3-tert-butylamino 2-propanol (base), 1-[2-ethoxycarbonyl 4-
(3-thienylcarboxamide) phenoxy] 3
-isopropylamino 2-propanol (base),
1-[2-ethoxycarbonyl 4-(3-thienylcarboxamide)phenoxy]3-tert-butylamino 2-propanol (base), or 1-[2-
Methoxycarbonyl 4-(2-thienylcarboxamide)phenoxy]3-tert-butylamino 2-
Claim 1 which is propanol (base)
Compounds described in Section. 7 The base represented by the formula NH ₂ −R ₁ is converted to the formula at 20℃ to 150℃. A formula characterized by reacting with an epoxide represented by (Here, R is an alkyl group having 1 to 5 carbon atoms, R ₁ is an alkyl group having 1 to 5 carbon atoms, R ₂ is hydrogen, an alkyl group having 1 to 5 carbon atoms, a halogen, or a fused ring together with the thiophene. The cyclohexyl group and carboxamide chain are bonded to the 2- or 3-position of the thiophene ring) and a method for producing a non-toxic acid addition salt thereof. 8. The method according to claim 7, wherein a non-toxic acid addition salt is produced by adding a non-toxic acid. 9 The epoxide has the formula 8. The method according to claim 7, which is obtained by reacting the phenolic compound represented by the formula with an excess of epichlorohydrin in the presence of a catalyst. 10 formula (Here, R is an alkyl group having 1 to 5 carbon atoms, R ₁ is an alkyl group having 1 to 5 carbon atoms, R ₂ is hydrogen, an alkyl group having 1 to 5 carbon atoms, a halogen, or a fused ring together with the thiophene. A β-blocker containing a thiophene compound represented by the formula (the cyclohexyl group formed and the carboxamide chain is bonded to the 2- or 3-position of the thiophene ring) and its nontoxic acid addition salt as an active ingredient. 11 1-[2-ethoxycarbonyl 4-(5-methyl 2-thiophenecarboxamide) phenoxy] 3-tert-butylamino 2-propanol, 1
-[2-ethoxycarbonyl 4-(5-methyl 2-
thiophenecarboxamide) phenoxy]3-isopropylamino2-propanol, 1-[2-
Ethoxycarbonyl 4-(5-chloro2-thiophenecarboxamide) phenoxy] 3-tert-butylamino 2-propanol hydrochloride, 1-[2-ethoxycarbonyl 4-(4-methyl 2-thiophenecarboxamide) phenoxy] 3 -tert-butylamino 2-propanol hydrochloride, 1-[2-ethoxycarbonyl 4-[2-(4,5,6,7-tetrahydro)thianaphthenecarboxamide]phenoxy]3-tert-butylamino 2-propanol,
1-[2-Ethoxycarbonyl 4-(2-thienylcarboxamide)phenoxy]3-isopropylamino 2-propanol (base), 1-[2-ethoxycarbonyl 4-(2-thienylcarboxamide)phenoxy]3-tert-butyl Amino 2-propanol (base), 1-[2-ethoxycarbonyl 4-(3-thienylcarboxamide) phenoxy]
3-isopropylamino 2-propanol (base), 1-[2-ethoxycarbonyl 4-(3-thienylcarboxamido)phenoxy]3-tert-butylamino 2-propanol (base), or 1
- [2-Methoxycarbonyl 4-(2-thienylcarboxamide) phenoxy] β containing 3-tert-butylamino 2-propanol (base) as the active ingredient
-Blockers. 12 formula (Here, R is an alkyl group having 1 to 5 carbon atoms, R ₁ is an alkyl group having 1 to 5 carbon atoms, R ₂ is hydrogen, an alkyl group having 1 to 5 carbon atoms, a halogen, or a fused ring together with the thiophene. A diuretic containing a thiophene compound represented by the formula (the cyclohexyl group formed and the carboxamide chain is bonded to the 2- or 3-position of the thiophene ring) and its nontoxic acid addition salt as an active ingredient. 13 1-[2-ethoxycarbonyl 4-(5-methyl 2-thiophenecarboxamide) phenoxy] 3-tert-butylamino 2-propanol, 1
-[2-ethoxycarbonyl 4-(5-methyl 2-
thiophenecarboxamide) phenoxy] 3-isopropylamino 2-propanol, 1-[2-
Ethoxycarbonyl 4-(5-chloro2-thiophenecarboxamide) phenoxy] 3-tert-butylamino 2-propanol hydrochloride, 1-[2-Ethoxycarbonyl 4-(4-methyl 2-thiophenecarboxamide) phenoxy] 3 -tert-butylamino 2-propanol hydrochloride, 1-[2-ethoxycarbonyl4-[2-(4,5,6,7-tetrahydro)thianaphthenecarboxamide]phenoxy]3-tert-butylamino 2-propanol,
1-[2-Ethoxycarbonyl 4-(2-thienylcarboxamide)phenoxy]3-isopropylamino 2-propanol (base), 1-[2-ethoxycarbonyl 4-(2-thienylcarboxamide)phenoxy]3-tert-butyl Amino 2-propanol (base), 1-[2-ethoxycarbonyl 4-(3-thienylcarboxamide) phenoxy]
3-isopropylamino 2-propanol (base), 1-[2-ethoxycarbonyl 4-(3-thienylcarboxamide)phenoxy]3-tert-butylamino 2-propanol (base), or 1
A diuretic containing -[2-methoxycarbonyl4-(2-thienylcarboxamide)phenoxy]3-tert-butylamino-2-propanol (base) as an active ingredient.