JPS6125712B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to pyridicalcarboimide derivatives useful as intermediates for the synthesis of a series of novel guniazine derivatives. The new guanidine derivative is a compound represented by the general formula or a tautomer thereof. In the formula, a cyanoguanidyl group having a substituent R ¹ is substituted at the 2, 3- or 4-position of the pyridine ring, and R ¹ is a linear or branched, saturated or unsaturated, carbon number group. 1 to 8 aliphatic hydrocarbon groups,
It means a cycloalkyl group, an aryl group, or an aralkyl group having 3 to 8 carbon atoms. R ² is hydrogen source,
It means a halogen atom, lower alkyl or alkoxyl group. More specifically, R ¹ is a methyl group, an ethyl group, a pwapyl group, an isopropyl group, an isobutyl group, a butyl group, a sec-butyl group, a tertiary-butyl group, or a pentyl group such as tertiary-pentyl or neopentyl; It represents a hexyl group such as 1-methyl-1-ethylpropyl, a heptyl group such as 1,1-diethylpropyl, or an alkenyl group corresponding thereto. R ¹ also represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a dimethylcyclobutyl group, a methylcyclopentyl group, a cyclohexyl group, a cycloheptyl group, a phenyl group, or a phenyl group having a substituent, a benzyl group, or a phenylethyl group. When the above compound contains one or more asymmetric carbon atoms, the compound may be a stereoisomer. The above novel compounds also include such stereoisomers and racemic mixtures thereof. The present invention further includes non-toxic pharmaceutically acceptable acid salts of compounds of formula. It has surprisingly been revealed that the above-mentioned new compound is an excellent antihypertensive agent having a remarkable antihypertensive effect. The compound has low toxicity and therefore a high therapeutic ratio. This effect was not expected from the literature, and it has been reported in the literature (Journal of Medicinal Chemistry, Vol. 11, p. 811 (1968), J.
Med.Chem.Vol.11, p.811 (1968))

Although the cyanoguanidines represented by the formula have antihypertensive effects, the effect is much lower than that of the compounds of the present invention, and furthermore, if a substituent is introduced into the unsubstituted amino group, It has been reported that the antihypertensive effect is completely abolished. In view of these descriptions, it appears that the compounds of the present invention may, for example,
The discovery that "Guancydine" is the most effective among those described in the above literature, that is, has superior efficacy to that of N-cyano-N'-tertiary pentylguanidine, This is very noteworthy. It has been revealed that the above-mentioned novel compounds exhibit strong and sustained antihypertensive effects when administered orally or parenterally in various animal species. In the dosage range of antihypertensive agents, as well as in higher dosages, these compounds have no effect on the central nervous system. The only side effect observed is compensated tachycardia. It is believed that these compounds express their antihypertensive effects through their effects on peripheral blood vessels. Thus, it is noteworthy that the above compound alleviates the symptoms of hypertension, does not show any adverse effects in preliminary experiments, and is well tolerated, even when administered orally.
It was revealed that parenteral administration also has a favorable therapeutic index. The above compound is produced by the method shown below. That is, in the first synthesis method, 2 expressed by the formula
-, 3-, or 4-pyridylcarbodiimide (wherein R ¹ and R ² are as defined above) is reacted with cyanide. The reaction can be carried out at or near room temperature, with or without the use of conventional solvents. In many cases it is desirable to accelerate the reaction by adding a basic catalyst such as a tertiary amine. In addition, in the compound (), R ¹ is a linear or branched saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms,
Pyridylcarbodiimides in which R ² is a hydrogen atom are objects of the present invention. In the second synthesis method, a compound represented by the formula R'-N=C=N-CN (wherein R' is the previously defined R ¹ or ^2- , 3- or 4-pyridyl group) is reacted with the amine NH ₂ R''.
In NH ₂ R″, R″ is 2-, 3- or 4- with the substituent R ² if R′ is R ¹
pyridyl group, R′ has a substituent R ² 2
-, 3- or 4-pyridyl group,
R means ¹ group. The reaction can be carried out, if necessary, in a suitable solvent at temperatures from about 0° C. to about the boiling point of the solvent used. Equimolar amounts of the reactants can be used, but it is preferred to use an excess of the amine H ₂ NR''. Suitable solvents include diethyl ether, chloroform, acetone, pyridine, acetonitrile and ethanol. In some cases,
The amine R″—NH ₂ could also be used as a reaction medium. In a third synthesis method, a compound of the formula (In the formula, R' is as defined above, and X means a halogen, preferably a chlorine atom, a _lower alumylthio group or a lower alkoxy group.) ). The reaction is preferably carried out in an inert organic solvent, and when X is a halogen atom, it is preferred to use an excess of an amine, such as a tertiary amine, or other deoxidizing agent. In the fourth synthesis method, a compound represented by the formula (wherein R ¹ , R ² and X are as defined above) with cyanamide under conditions similar to those described above. The starting materials for this reaction are known compounds or analogous compounds that can be prepared in the same manner as known compounds. In yet another specific method, thiourea represented by the formula (wherein R ¹ and R ² have the meanings given above) is treated with a salt of cyanide, preferably a metal salt such as a lead salt, to synthesize a compound corresponding to the compound represented by the formula. The compound represented by the formula is a novel compound, and the corresponding ureas or thioureas are prepared by conventional methods such as triphenylphosphine, carbon tetrachloride and triethylamine in anhydrous methylene chloride. Alternatively, it can be synthesized by treatment with phosgene, preferably at low temperature, in an inert solvent such as tetrahydrofuran. The target compound can be synthesized by adding a tertiary amine to the generated imidochloride (imide chloride). The starting material represented by the formula can be prepared in a similar manner by
It can be synthesized from the corresponding N-cyano-substituted urea or N-cyano-substituted thiourea. The starting material represented by the formula (in the formula, X means a lower alkoxy or alkylthio group) is obtained by reacting cyanamide with pyridyl isocyanate or pyridyl isothiocyanate in the presence of a tertiary amine, and then reacting with lower iodide. It can be synthesized by treatment with an alkyl compound. Some of the starting materials of the formula (wherein X means a lower alkylthio group) may alternatively be
It can be synthesized by reacting di-lower alkyl cyanodithioimide carbonate with a suitable amine. This alternative method is also well known in the literature. When X means a chlorine atom in the compound represented by the formula, these imidochlorides (chloroimides) can be obtained from N-cyano-substituted ureas or N-cyano-substituted thioureas as described above. . When X means a chlorine atom in the compound of the formula, such imidochloride (chloroimide)
can be obtained from the corresponding ureas or thioureas as described above. In each of the above-mentioned methods, the desired stereoisomer can be obtained by using the corresponding isomer as a starting material. On the other hand, stereoisomers can be isolated by using the racemate as a starting material and subjecting the resulting mixture to racemic resolution, for example by crystallizing a suitable salt with an optically active strong acid, in a well-known manner. It can also be synthesized. An object of the present invention is to provide a pharmaceutical composition useful for treating hypertension. To this end, the compositions contain as active ingredients at least one of the compounds represented by the formula and their non-toxic, pharmaceutically acceptable salts with acids, together with solid and Contains liquid pharmaceutical carriers (excipients) and/or other auxiliary drugs (adjuvants). The composition contains at least a therapeutically active compound.
It contains 0.1% and is administered in various dosage forms. That is, by mixing a compound of formula or a non-toxic salt thereof with a carrier and/or an auxiliary drug, tablets,
Form into pills, sugar-coated pills, capsules, sustained-release tablets, suspensions, suppositories, and injections. Compositions containing the compounds according to the invention can be prepared using pharmaceutical organic or inorganic, solid or liquid carriers and/or ancillary agents suitable for oral administration. Gelatin, lactose, starch, magnesium stearate, talc, animal and vegetable oils, gums, polyalkylene glycols, buffers or other well-known carriers and/or pharmaceutical auxiliaries are all suitable. The compositions may further contain other therapeutic agents used in the treatment of hypertension, as well as well-known adjuvant agents. Such compounds include, for example, beta-adrenergic blockers, diuretics, reserpine and alpha methyldopa. Among them,
The concomitant use of beta-adrenergic blockers may cause side effects to the antihypertensive effects of the compound.
This is particularly effective because compensatory tachycardia is avoided. In the treatment of humans, the compound and its salts are
For adults, 0.01 to 1000 mg of the compound of formula;
Preferably, 0.02 to 200 mg is administered as a unit dose. Here, the term unit dose refers to a unit dose, ie, a single dose that can be given to a patient. The unit amount is a materially stable amount that is easy to handle and package, and also contains the active ingredient as it is or together with a solid or liquid pharmaceutical diluent or carrier. The compound is in a form containing unit dosages;
It is administered once or more times a day at appropriate intervals, depending on the patient's condition, as directed by the clinician. For continuous treatment of hypertensive patients, it is preferable to administer the drug in the form of tablets or capsules, with sustained release tablets being particularly preferred, so that the drug can be administered orally for a sustained effect. Such tablets for use in the treatment of hypertension may contain other active ingredients as described above. Some of the ureas or thioureas used as starting materials are known from the literature; those hitherto unknown can be synthesized according to methods analogous to known methods. In Table A listed below, many ureas and thioureas are
It is characterized by its melting point. They are e.g. 1 to 1.5 equivalents of amine and 1 equivalent of
pyridyl isocyanate, pyridyl isothiocyanate, or S-methylpyridylthiocarbamate in a suitable inert solvent such as diethyl,
It can be synthesized by reaction in ether, ethanol, chloroform, acetone, pyridine, or acetonitrile at a temperature from about 0° C. to around the boiling point of the solvent used, preferably at room temperature.

【table】

【table】

[Table] *Hydrate, *Hydrochloride
When the expression "lower" is used in the above and below descriptions with respect to organic groups,
It means containing 1 to 6 carbon atoms. The invention will be explained in more detail by the following examples, which are not intended to limit the invention. Example 1 N-tert-butyl-N''-cyano-N'-3-pyridylguanidine N-tert-butyl-N'-3-pyridylcarbodiimide (5.25 g) was mixed with cyanamide (1.36 g) at room temperature with stirring. Mixed. Catalyst amount of N, N-
Add diisopropylethylamine and leave as is.
If left for 20 hours, crystallization will gradually proceed.
Completed. The crystals were ground and triturated with petroleum ether followed by water to give the crude product. The crude product was dissolved in a slight excess of 0.5N hydrochloric acid, treated with activated carbon, filtered through Celite, and recrystallized by adding an excess of a saturated aqueous solution of ammonium carbonate to the filtrate. Melting point: 205.0-206.5℃, infrared absorption spectrum (KBr method): 2170cm ^-1 (-C≡
N) showed strong absorption. The starting material, carbodiimide, was synthesized as follows. That is, N-tert-butyl-N'-3
-Pyridylthiourea (12.6g) was suspended in anhydrous tetrahydrofuran (125ml) at 0°C. To this was added a 1.2M solution of phosgene in toluene (69ml) with vigorous stirring. The mixture was heated to 0°C.
After being left for 5 hours, it was evaporated under reduced pressure. A small amount of tetrahydrofuran was added to the residue and the evaporation operation was repeated. The residue was suspended in tetrahydrofuran (100 ml) at 0°C, and to this was added N,N-diisopropylethylamine (20.4 ml). After the slurry was evaporated to dryness under reduced pressure, the residue was extracted with petroleum ether (200 ml), and the extract was decolorized with activated carbon and filtered. When the filtrate was evaporated to dryness, the desired carbodiimide was obtained in quantitative yield. Infrared absorption spectrum (chloroform solution): 2120~
It showed persistent strong absorption at 2140 cm ^-1 (-N=C=N-). Example 2 N″-cyano-N-(1-ethyl-1-methylpropyl)-N′-3-pyridylguanidine Follow the procedure of Example 1, except that N-tert-butyl-N′-3-pyridyl N-(1-ethyl-1-methylpropyl)- instead of carbodiimide
N″-cyano-N- with a melting point of 184.5-186.0℃ by using N′-3-pyridylcarbodiimide
(1-ethyl-1-methylpropyl)-N'-3-
Pyridylguanidine was obtained. Example 3 N″-Cyano-N-(1,1-dimethylbutyl)N′-3-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N′-3-pyridylcarbodiimide N-(1,1-dimethylbutyl)-N'-3
-By using pyridylcarbodiimide,
N″-cyano-N-(1,1
-dimethylbutyl)-N'-3-pyridylguanidine was obtained. Example 4 N″-Cyano-N-(1,1-diethylpropyl)-N′-3-pyridylguanidine Follow the procedure of Example 1, but with the exception of N-tert-butyl-N′-3-pyridylcarbodiimide. Instead, N-(1,1-diethylpropyl)-N'-
By using 3-pyridylcarbodiimide, N″-cyano-N- with a melting point of 192.5-193.5℃
(1,1-diethylpropyl)-N'-3-pyridylguanidine was obtained. Example 5 N″-cyano-N-tert-pentyl-N′-3-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N′-pyridylcarbodiimide, N-tert-pentyl By using -N'-3-pyridylcarbodiimide, the melting point is 187.0 to 187.5℃.
N″-cyano-N-tertiary pentyl-N′-pyridylguanidine was obtained. Example 6 N″-cyano-N-neopentyl-N′-3-pyridylguanidine Following the procedure of Example 1, but , by using N-neopentyl-N'-3-pyridylcarbodiimide instead of N-tert-butyl-N'-3-pyridylcarbodiimide, the melting point is 214.0~
N″-cyano-N-neopentyl-N′- at 215.0℃
3-pyridylguanidine was obtained. Example 7 N″-cyano-N-isopropyl-N′-3-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N′-3-pyridylcarbodiimide, N-isopropyl- By using N′-3-pyridylcarbodiimide, the melting point is 154.5~
N″-cyano-N-isopropyl-N′- at 155.0℃
3-pyridylguanidine was obtained. Note: The reaction was highly exothermic. Example 8 N-cyano-N-1-ethylpropyl-N'-
3-Pyridylguanidine Following the procedure of Example 1, but using N-1-ethylpropyl-N'-3-pyridylcarbodiimide instead of N-tert-butyl-N'-pyridylcarbodiimide, the melting point was 109.5.
~110.5°C N″-cyano-N-1-ethylpropyl-N′-3-pyridylguanidine was obtained. Example 9 N-normal butyl-N″-cyano-N′-3-pyridylguanidine Example By following the procedure in 1 but using N-normal butyl-N'-pyridylcarbodiimide instead of N-tert-butyl-N'-3-pyridylcarbodiimide, the target compound with a melting point of 96.0 to 97.0°C can be obtained. Ta. CAUTION: Exothermic reaction. Example 10 N-tert-butyl-N″-cyano-N′-3-pyridylguanidine Following the procedure of Example 1, but substituting N-tert-butyl-N′-3-pyridylcarbodiimide. By using 2-butyl-N'-3-pyridylcarbodiimide, the melting point is 133.5-135.0.
The target compound was obtained at a temperature of . Example 11 N″-cyano-N-normal pentyl-N′-3-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N′-3-pyridylcarbodiimide, N-normal pentyl By using -N'-3-pyridylcarbodiimide, the melting point is 130.4 to 131.6.
The target compound was obtained at a temperature of . Example 12 N″-cyano-N-methylcyclobutyl-N′-
3-Pyridylguanidine Following the procedure of Example 1, but by substituting N-1-methylcyclobutyl-N'-3-pyridylcarbodiimide for N-tert-butyl-N'-3-pyridylcarbodiimide, melting point
The target compound was obtained at 210.5-211.5°C. Example 13 N″-cyano-N-3-pyridyl-N′-1,
1,2-Trimethylpropylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-3-pyridyl-N'-1,1,2-trimethyl By using propylcarbodiimide, the target compound with a melting point of 194.0-195.0°C was obtained. Example 14 N″-cyano-N-3-pyridyl-N′-1,
2,2-Trimethylpropylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-3-pyridyl-N'-1,2,2-trimethyl By using propylcarbodiimide, the target compound with a melting point of 167.5-168.5°C was obtained. Example 15 N″-cyano-N-3-pyridyl-N′-1,
1,3-Trimethylbutylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-3-pyridyl-N'-1,1,3-trimethyl By using butylcarbodiimide, the target compound with a melting point of 180.5-181.5°C was obtained. Example 16 N″-cyano-N-3-pyridyl-N′-1,
1,3,3-Tetramethylbutylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-3-pyridyl-N'-1,1, 3,3
-By using tetramethylbutylcarbodiimide, the target compound with a melting point of 180.5-181.5°C was obtained. Example 17 N-3-(5-bromopyridyl)-N'-third
Butyl-N″-cyanoguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N′-3-pyridylcarbodiimide, N-3-(5-bromopyridyl)-N′-
By using tertiary butyl carbodiimide,
The target compound with a melting point of 153.0-153.5°C was obtained. Example 18 N-tertiary butyl-N''-cyano-N'-5-(2
-Methoxypyridyl)guanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, use N-tert-butyl-N'-5-(2-methoxypyridyl)carbodiimide. By using this, the target compound with a melting point of 156.0-157.0°C was obtained. Example 19 N-tert-butyl-N'-3-(2-chloropyridyl)-N''-cyanoguanidine Following the procedure of Example 1, but with the exception that N-tert-butyl-N'-3-pyridylcarbodiimide Instead, by using N-tert-butyl-N'-3-(2-chloropyridyl)carbodiimide,
The target compound with a melting point of 202.0-203.0°C was obtained. Example 20 N-tert-butyl-N''-cyano-N'-2-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N- The target compound was obtained by using tert-butyl-N'-2-pyridylcarbodiimide.The infrared absorption spectrum (KBr method) was 2160
-70cm ^-1 (-C≡N) showed strong absorption. Melting point: 168.0-168.5℃ (decomposed). Example 21 N″-cyano-N-cyclobutyl-N′-3-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N′-3-pyridylgarbodiimide, N-cyclobutyl- The target compound was obtained by using N'-3-pyridyl galbodiimide.The infrared absorption spectrum (KBr method) was 2160
-70cm ^-1 showed strong absorption. Example 22 N″-cyano-N-1,3-dimethylbutyl-
N'-3-Pyridylguanidine Following the procedure of Example 1, but replacing N-tert-butyl-N'-3-pyridylgalbodiimide with N-1,3-dimethylbutyl-N'-3-pyridylgalbodiimide. The target compound was obtained by using diimide. Infrared absorption spectrum (KBr
method) showed strong absorption at 2160-70cm ^-1 . Example 23 N″-cyano-N-phenyl-N′-3-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N′-3-pyridylgarbodiimide, N-phenyl The target compound was obtained by using -N''-3-pyridylgarbodiimide. Melting point: 194-195℃. Example 24 N″-cyano-N-cyclopentyl-N′-5-
(2-methoxypyridyl)guanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylgarbodiimide, N-cyclopentyl-N'-5-(2-methoxypyridyl) The target compound was obtained by using carbodiimide. Infrared absorption spectrum (KBr method) showed strong absorption at 2160-70cm ^-1 . Example 25 N″-cyano-N-cyclopentyl-N′-2-
Pyridylguanidine The target compound can be obtained by following the procedure of Example 1, but using N-cyclopentyl-N'-2-pyridylgalbodiimide instead of N-tert-butyl-N'-3-pyridylgalbodiimide. Obtained. Example 26 N-Orthobutyl-N''-cyano-N'-3-pyridylguanidine N,N-diisopropylethylamine (3.4 ml) was added to a solution of cyanamide (0.95 g) in ethanol (10 ml) at 0°C with stirring. 3-pyridyl isothiocyanate (2.25 g) was then added. The mixture was left at 0° C. overnight and then evaporated to dryness under reduced pressure. The residue was stirred with ether (100 ml) and N-cyano- After crystallizing the N,N-diisopropylethylamine salt of N'-3-pyridylthiourea, it was collected by filtration and washed with ether. [Free thiourea was obtained by suspending the salt in water and using hydrochloric acid. It was possible to separate by making it acidic to pH 3 to 4. Melting point: 184.5 to 185.0°C, infrared absorption spectrum (KBr method): 2145 cm ^-1 (-C≡N)
showed absorption. ) Amine salt (6.25 g) was dissolved in anhydrous dimethylformamide (15 g) while stirring at 0°C.
ml). When methyl iodide (1.65 ml) is added dropwise, the liquid gradually becomes transparent;
After stirring for an hour, the mixture was left at 0°C overnight. After warming the solution to room temperature, it was evaporated under reduced pressure and finally evaporated to dryness under high vacuum at 25°C. Ice water (15 ml) and a saturated aqueous solution of sodium bicarbonate ( _NaHCO3 ) (2.5 ml) were added to the residue, and S-methyl-N'-
Cyano-N-3-pyridylisothiourea was crystallized, collected by filtration, and washed with water. Melting point: 153.5-155.0℃, infrared absorption spectrum (KBr
method): showed absorption at 2160-2180 cm ^-1 (-C≡N). The above isothiourea (2.28g) was mixed with pyridine (25g).
ml), and to this was added normal butylamine (10 ml). The mixture was left at room temperature for 72 hours and then evaporated to dryness under reduced pressure. The residue was stirred with water (30ml) to crystallize. The product was collected by filtration and washed with water to obtain a crude product. The crude product was mixed with acetone.
It was further purified by recrystallization from petroleum ether.
Melting point: 96.0~97.0℃, infrared absorption spectrum (KBr
method): Strong absorption based on 2165 cm ^-1 (-C≡N) and broad absorption from 1600 to 1550 cm ^-1 were observed. This infrared absorption spectrum completely matched the spectrum of the right butyl substituted compound synthesized in Example 9. Example 27 N″-Cyano-N-Propyl-N′-3-Pyridylguanidine Following the procedure of Example 26, but by substituting normal propylamine for normal butylamine, an objective melting point of 164.0-165.0°C was obtained. A compound was obtained. Example 28 N″-cyano-N-cyclopropyl-N′-3-
Pyridylguanidine By following the procedure of Example 26 but using cyclopropylamine in place of normal butylamine, the target compound with a melting point of 171.0-172.0°C was obtained. Example 29 N″-cyano-N-isobutyl-N′-3-pyridylguanidine By following the procedure of Example 26 but using isobutylamine instead of normal butylamine, the target compound with a melting point of 148.0-149.0°C was obtained. Obtained. Example 30 N″-cyano-N-neopentyl-N′-3-pyridylguanidine Following the procedure of Example 26 but using neopentylamine in place of orthobutylamine, the melting point was 214.0 to 215.0. C. (which corresponds to the melting point of the compound synthesized in Example 6) was obtained. Example 31 N″-cyano-N-isopentyl-N′-3-pyridylguanidine By following the procedure of Example 26 but using isopentylamine instead of normal butylamine, the target compound with a melting point of 135.5-136.5°C was obtained. Example 32 N″-cyano-N-cyclopentyl-N′-pyridylguanidine By following the procedure of Example 26 but using cyclopentylamine in place of orthobutylamine, the following was obtained: The target compound was obtained. Example 33 N″-cyano-N-cyclohexyl-N′-3-
Pyridylguanidine By following the procedure of Example 26 but using cyclohexylamine in place of normal butylamine, the target compound with a melting point of 185.0-186.0°C was obtained. Example 34 N″-cyano-N-normal heptyl-N′-3-pyridylguanidine Following the procedure of Example 26, but by using normal heptylamine in place of normal butylamine, an objective melting point of 90.0 to 91.0°C was obtained. A compound was obtained. Example 35 N″-cyano-N-2-ethylhexyl-N′-
3-Pyridylguanidine By following the procedure of Example 26 but using 2-ethylhexylamine in place of normal butylamine, the target compound with a melting point of 84.0-85.0°C was obtained. Example 36 N″-cyano-N-2-methylallyl-N′-3
-Pyridylguanidine By following the procedure of Example 26 but using 2-methylallylamine in place of normal butylamine, the target compound with a melting point of 14.00 to 141.0°C was obtained. Example 37 N-benzyl-N''-cyano-N'-3-pyridylguanidine By following the procedure of Example 26 but using benzylamine in place of normal butylamine, the target compound with a melting point of 189.0-190.0°C was obtained. Obtained. Example 38 N″-cyano-N-2-methylbutyl-N′-3
-Pyridylguanidine The target compound was obtained by following the procedure of Example 26, but using 2-methylbutylamine instead of orthobutylamine. Infrared absorption spectrum (KBr method) showed strong absorption at 2160-70cm ^-1 . Example 39 N″-cyanoN-β-phenylethyl-N′-3
-Pyridylguanidine The target compound was obtained by following the procedure of Example 26, but using β-phenylethylamine instead of orthobutylamine. Melting point:
162-163℃. Example 40 Antihypertensive activity of the compound of Example 1 (hereinafter referred to as P1060) in anesthetized normotensive rats Male white rats of the Sprague Dowley strain were anesthetized with pentobarbital and placed on a fixed plate. I fixed it facing forward. Pull out the left carotid artery,
Insert a polyethylene cannula into this,
This is passed through a Statham pressure transducer to a Grass Polygraph Recorder.
connected to. A cannula for administering P1060 was also inserted into the left femoral vein. P1060 was dissolved in dilute hydrochloric acid. The volume administered did not exceed 0.2 ml. Table 1 summarizes the effects on average blood pressure at the time when drug efficacy reaches its peak.

[Table] Example 41 Antihypertensive effects of the compounds of Examples 1, 2, 3, 4, and 5 (hereinafter referred to as P1060, P1066, P1067, P1068, and P1075, respectively) in rats with congenital hypertension without anesthesia. Activity Male white rats of the Okamoto strain with congenital hypertension were used and fasted for 16 hours before the experiment. A conscious rat was placed in a plastic cage and secured with a blood pressure band tied around its tail. The band was connected to an electronic blood pressure recorder, and systolic blood pressure and cardiac dilatation rate were measured at 2, 4, 6, and 24 hours after administration. Each compound was suspended or dissolved in a 0.5% solution of carboxymethyl cellulose. The volume administered was less than 0.5 ml per rat. Table 2 summarizes the results. For comparison, results obtained for several antihypertensive drugs under the same experimental conditions are also listed. In addition, the approximate value of LD ₅₀ for oral administration using mice is also listed.

【table】

[Table] Example 42 Antihypertensive activity in conscious normotensive dogs Male and female mongrel dogs were fasted for 16 hours before the experiment.
used. Blood pressure is measured using an ultrasonic measuring device (Arteliosonde ^R 1010, Rossier Medical Electronics Department,
Arteiosonde ^R 1010, Roche Medical Electronic
Division) and recorded indirectly before and 1, 2, 3, and 4 hours after administration of P1060 or P1075. Each compound was administered orally in a gelatin capsule. Table 3 shows the results obtained using the above two compounds.

【table】

[Table] Example 43 Antihypertensive effect and various cardiovascular and autonomic nervous reactions in cats Male and female cats were used after being anesthetized by intraperitoneal injection of 40 mg of pentobarbital. Pull out the left carotid artery, insert a polyethylene cannula,
This is passed through a Statham pressure exchanger to a Grass Polygraph Recorder.
connected to. A cannula was also inserted into the right femoral vein to administer P1060. P1060 was dissolved in dilute hydrochloric acid and 0.4 ml was administered. Measurements were performed on the vasoconstrictor response to intravenous administration of norepinephrine hydrochloride (1 mc/Kg) (NE) and normal carotid artery occlusion (45 seconds), (CO) before and after intravenous administration of P1060. . Both operations are known to produce a pressor effect. Furthermore, we investigated the nictitating membrane contractions induced by preganglionic stimulation (3V, 1msec, 40Hz, 5s) and postganglionic stimulation (3V, 1msec, 40Hz, 5s) before and after intravenous administration of P1060. were measured. Table 4 shows the results obtained in detail.

[Table] Example 44 N-tert-butyl-N''-cyano-N'-4-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide By using N-tert-butyl-N'-4-pyridylcarbodiimide, the melting point is 203.0 to 204.0.
The target compound was obtained at a temperature of . The infrared absorption spectrum (KBr method) showed strong absorption at 2175 cm ^-1 (-C≡N). Example 45 N″-cyano-N-tert-pentyl-N′-4-pyridylguanidine Following the procedure of Example 1, N-tert-butyl-
N- instead of N′-3-pyridylcarboimide
By using tertiary pentyl-N'-4-pyridylcarbodiimide, the target compound with a melting point of 161.0-162.0°C was obtained. Example 46 N″-cyano-N-1-ethylpropyl-N′-
4-Pyridylguanidine Following the procedure of Example 1, but by using N-1-ethylpropyl-N'-4-pyridylcarbodiimide instead of N-tert-butyl-N'-3-pyridylcarbodiimide, melting point
The target compound was obtained at 196.0-197.0°C. Example 47 N″-cyano-N-4-pyridyl-N′-1,
2,2-Trimethylpropylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-4-pyridyl-N'-1,2,2-trimethyl By using propylcarbodiimide, the target compound (monohydrate) having a melting point of 164.0 to 165.0°C was obtained. In addition, N-4-pyridyl-N'-1,2,2-
Trimethylpropylcarbodiimide was prepared in Example 1.
was prepared from the corresponding starting materials following the same procedure as in . NMR (CDCl ₃ ): δ = 0.98 (s, 9H); 1.33
(d, J=6.5, 3H); 3.52 (q, J=6.5,
1H); 6.93 (m, 2H); 8.43 (m, 2H) (internal reference TMS). Example 48 N″-cyano-N-4-pyridyl-N′-1,
1,3-Trimethylbutylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-4-pyridyl-N'-1,1,3-trimethyl By using butylcarbodiimide, the target compound with a melting point of 156.0-156.0°C was obtained. Example 49 N″-cyano-N-1,1-diethylpropyl-N′-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N′-3-pyridylcarbodiimide, N -1,1-diethylpropyl-N'-4-
By using pyridylcarbodiimide, the target compound with a melting point of 220.0-224.0°C was obtained. Example 50 N″-cyano-N-4-pyridyl-N′-1,
1,3,3-tetramethylbutylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-4-pyridyl-N'-1,1, 3,3
-By using tetramethylbutylcarbodiimide, the target compound with a melting point of 197.0-198.0°C was obtained. Example 51 N″-cyano-N-1,5-dimethylhexyl-N′-4-pyridylguanidine Following the procedure of Example 1, but substituting N-tert-butyl-N′-3-pyridylcarbodiimide , N-1,5-dimethylhexyl-N'-4
- By using pyridylcarbodiimide,
The target compound with a melting point of 136.0-137.0°C was obtained. Example 52 N″-cyano-N-cyclooctyl-N′-4-
Pyridylguanidine Following the procedure of Example 1 but using N-cyclooctyl-N'-4-pyridylcarbodiimide instead of N-tert-butyl-N'-3-pyridylcarbodiimide, the melting point was 198.0.
The target compound was obtained at ~199.0°C. Example 53 N″-cyano-N-neopentyl-N′-4-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N′-3-pyridylcarbodiimide, N-neopentyl- The target compound was obtained by using N′-4-pyridylcarbodiimide. Melting point: 191-193°C. Example 54 N″-cyano-N-4-pyridyl-N′-1,
1,2-Trimethylpropylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-4-pyridyl-N'-1,1,2-trimethyl The target compound was obtained by using propylcarbodiimide. Infrared absorption spectrum (KBr method) showed strong absorption at 2160-70cm ^-1 . Example 55 N-benzyl-N″-cyano-N′-4-pyridylguanidine Follow the procedure of Example 1, but instead of N-tert-butyl-N′-3-pyridylcarbodiimide, N-benzyl- The target compound was obtained by using N′-4-pyridylcarbodiimide. Melting point: 175-177°C. Example 56 N-tert-butyl-N″-cyano-N′-3-
(2,4,6-trimethylpyridyl)guanidine 3-amino-2,4,6-toyumethylpyridine (1.36g) and S-methyl-N-tert-butyl-N'-
Cyanoisothiourea (1.71 g) was dissolved in pyridine (10
ml) for 48 hours. Pyridine was distilled off under reduced pressure, and the residue was recrystallized from water-ethanol to obtain the target compound. Melting point: 187.0~188.0℃. Example 57 N″-cyano-N-tertiary pentyl-N′-3-
(2,4,6-trimethylpyridine)guanidine Follow the procedure of Example 56, but instead of S-methyl-N-tert-butyl-N'-cyanoisothiourea, S-methyl-N-tert-pentyl-
By using N′-cyanoisothiourea,
The title compound was obtained with a melting point of 163.0-164.0°C. Example 58 N-tert-butyl-N''-cyano-N'-3-quinolylguanidine Following the procedure of Example 1, but in place of N-tert-butyl-N'-3-pyridylcarbodiimide, N -By using tert-butyl-N'-3-quinolylcarbodiimide, the melting point is 228.5~
The target compound was obtained at 229.0°C. Example 59 N-tert-butyl-N''-cyano-N'-3-pyridylguanidine N-tert-butyl-N'-3-pyridylthiourea (2.1 g) and lead cyanamide (3.7 g) in ethanol (20 ml) The mixture was filtered and refluxed for 18 hours in a
The filtrate was evaporated under reduced pressure to obtain the crude product. The target compound was obtained by recrystallizing it from water-acetone. Melting point: 205.0~206.5℃. Example 60 Following the procedure for carbodiimide preparation of Example 1, N-1,1-dimethylpropyl-N'-3-pyridylcarbodiimide was prepared from the corresponding starting materials. NMR (CDCl ₃ ): δ=1.00 (3H, t, J=
7); 1.37 (6H, s); 1.63 (2H, q, J=
7); 7.1-7.4 (2H, m); 8.25-8.5 (2H,
m) (internal reference TMS).

Claims (1)

[Claims] 1. General formula In the formula, R ¹ means a linear or branched saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms. A pyricadylcarbodiimide derivative represented by