JPS6037097B2 - Guanidine derivative and antihypertensive composition containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a series of novel guanidine derivatives and antihypertensive agents containing them.

The novel compound of the present invention is a compound represented by general formula 1 or a tautomer thereof. In the formula, the cyanoguanidyl group having the substituent RI is 2-, 3-1 or 4-of the pyridine ring.
is substituted at the 1-position, and RI is linear or branched,
a saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms,
It means a cycloalkyl group, aryl group or aralkyl group having 3 to 8 carbon atoms.

R2 means a hydrogen atom, a halogen atom, a lower alkyl or an alkoxyl group. To be more specific,
RI is a methyl group, an ethyl group, a propyl 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, neobentyl, or 1-methyl-1-ethylpropyl. xyl group, heptyl group such as 1,1-jetylpropyl,
Alternatively, it represents an alkenyl group corresponding thereto. R.I.
Also cyclopropyl group, cyclobutyl group, cyclobentyl group dimethylcyclo. It represents a butyl group, methylcyclobentyl group, cyclohexyl group, cycloheptyl group, phenyl group, or a phenyl group, penzyl group, or phenylethyl group having a substituent. When a compound of the invention contains one or more asymmetric carbon atoms, the compound may be a stereoisomer.

The novel compounds of the present invention also include such stereoisomers and racemic mixtures thereof.

The present invention further includes non-toxic, pharmaceutically acceptable acid salts of compounds of Formula 1.

It has surprisingly been revealed that the novel compound of the present invention is an excellent antihypertensive agent having a significant antihypertensive effect.

The compound has low toxicity and therefore a high therapeutic ratio. This effect is unexpected from the literature;
Literature (Journal of Medicinal Chemistry, Volume 11, Page 811 (1968), J.Med
-Chem-, V.

1-11, p-811 (1968), the cyanoguanidines represented by have a hypotensive effect, but the effect is much lower than that of the compound of the present invention, and furthermore, it does not have the substituent. It has been described that the antihypertensive effect disappears when a substituent is introduced into the amino group.

In view of these descriptions, it appears that the compounds of the present invention may, for example,
“Guansidine” (GMneydine), which is the most effective among those mentioned in the above literature, is N-cyano-N.
It is very remarkable that it was found to have superior efficacy over that of tertiary benzylguanidine. The novel compounds of the present invention have been shown to exhibit strong and sustained antihypertensive effects in various animal species when administered orally or parenterally.

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 forehead pulsation. It is believed that these compounds express their antihypertensive effects through their effects on peripheral blood vessels. Thus, it is noteworthy that the compounds of the present invention alleviate the symptoms of hypertension,
Furthermore, preliminary experiments have shown that the compound exhibits no adverse effects, has good customer resistance, and has a favorable therapeutic index when administered both orally and parenterally. Ta.

The compound of the present invention is produced by the method shown below.

That is, in the first synthesis method, 2-, 3-, or 4-pyridylcarbodiimide represented by formula 0 (wherein R
1, R2 is as defined above.

) is reacted with cyanamide. 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 the second synthesis method, a compound R′ represented by formula m
-N=C=N-CN m (wherein, R' means a 2-, 3-, or 4-pyridyl group having the substituent R1 or R2 defined above).

) is reacted with the amine NH2R''. In NQR'', R'' is a 2-, 3- or 4-pyridyl group bearing the substituent R2 if R' is RI;
When it is a 2-, 3- or 4-pyridyl group having two substituents, it means an RI 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.

Although the reactants can be used in equimolar amounts, it is preferable to use an excess amount of the amine.

Suitable solvents include diethyl ether, chloroform, acetone, pyridine, acetonitrile and ethanol.

In some cases, the amine R''-N ratio could be used as the reaction soot. In a third synthesis method, a compound of formula W, where R' is as defined above,
X represents a halogen, preferably a chlorine atom, a lower alkylthio group or a lower alkoxy group.

) is reacted with the amine NH2-R'', where R'' is as defined above. The reaction is preferably carried out in an inert organic solvent, and when x is a halogen atom, an excess of an amine, such as a tertiary amine, or other oxygen scavenger is preferably used. In a fourth synthesis method, a compound of formula V (wherein R1, R2 and X are as defined above) is prepared.

) is reacted 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. Yet another one
In one specific method, a thiourea of the formula where RI and R2 have the meanings previously described.

) with a salt of cyanamide, preferably a metal salt such as a lead salt, to synthesize a compound that reacts with the compound of formula 1. The compound represented by formula D can be prepared by treating the corresponding urea or thiourea with triphenylphosphine, carbon tetrachloride and triethylamine in anhydrous methylene chloride, or preferably by treating the corresponding urea or thiourea with triphenylphosphine, carbon tetrachloride and triethylamine in anhydrous methylene chloride. can be synthesized by treatment with phosgene at low temperatures in an inert solvent such as tetrahydrofuran.

The target compound can be synthesized by adding a tertiary amine to the produced imidochloride (imido chloride). Starting materials of the formula can be synthesized from the corresponding N-cya/substituted ureas or N-cyano-substituted ureas in a similar manner.

A starting material represented by the formula N, where X means a lower alkoxy or alkylthio group.

) can be synthesized by reacting cyanamide with pyridyl isocyanate or pyridyl isothiocyanate in the presence of a tertiary amine, followed by treatment with lower alkyl iodide. A starting material of formula W (
In the formula, X means a lower alkylthio group. ) can alternatively be synthesized by reacting an S-dilower alkyl cyanodithioimide carbonate with a suitable amine. This alternative method is also well known in the literature. When X in the compound represented by formula N means a chlorine atom, these imidochlorides (imido chlorides) can be obtained from N-cyano-substituted ureas or N-cyano-substituted thioureas as described above. When x in the compound of formula V means a chlorine atom, such imidochloride (imide chloride) 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.

A further 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 of formula 1 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 0.1% of the therapeutically active compound.
It is administered in various dosage forms.

That is, the compound of formula 1 or a non-toxic salt thereof can be mixed with a substance and/or an auxiliary drug to form a tablet, pill, dragee, capsule, sustained release tablet, suspension, suppository, injection. do. Compositions containing the compounds according to the invention may be prepared using pharmaceutical organic or inorganic, body 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-adrenaline.
Brodzka, diuretics, reserpine and alpha-methylludopa.

Among these, the concomitant use of beta-adrenergic flozker may cause side effects to the antihypertensive effect of the compound of the present invention.
This is particularly effective because the compensatory onset of moribundity is avoided. Another object of the present invention is to select a dosage of the compound of the present invention to produce the desired effect without side effects.

In the treatment of humans, the compound and its salts are preferably administered to adults in a dosage unit of 0.01 to 1000, preferably 0.02 to 200, of the compound of formula 1. .

The term dosage unit herein refers to a unit dose, ie, a single dose that can be given to a patient.

The unit quantity is a materially stable quantity which is easy to handle and package, and which contains the active ingredient (as is) or together with a solid or liquid pharmaceutical diluent or carrier. The compound may be administered in a form containing unit dosages, once or more times per day, depending on the patient's condition, as directed by the clinician.
Administered at appropriate intervals.

For continuous treatment of hypertensive patients, it is preferable to administer the drug in the form of tablets or capsules, especially sustained-release tablets, 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, a number of ureas and thioureas are characterized by their melting points. They include, for example, 1 to 1.5 equivalents of the amine and 1 equivalent of pyridyl isocyanate, pyridyl isothiocyanate, or S-methylpyridylthiocarbamate in a suitable inert solvent such as jetyl, 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 AZ=S * Hydrate, ** Hydrochloric acid.

When the expression "lower" is used in the above and below descriptions with respect to organic groups, it means 1 to 6
This means that it contains 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-pyridylguanidiso N-tert-butyl-N'-3-pyridylcarbodimide (5.25 g) was added to cyanamide at room temperature with stirring. (1.36g).

A catalytic amount of N,N-diisopropylethylamine was added and the mixture was left to stand for a while, during which crystallization gradually progressed and was 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 slightly excess amount of 0.5N hydrochloric acid, treated with activated carbon, filtered through Celite, and recrystallized by adding an excess amount of a saturated aqueous solution of ammonium carbonate to the solution.
Melting point: 205.0-206.5oo. Infrared absorption spectrum (KBr method): 2170 Hada-1 (1C3N) showed strong absorption. The starting material, carbodiimide, was synthesized as follows.

That is, N-tert-butyl-N'-3-pyridylthiourea (12.6 g) was suspended in anhydrous tetrahydrofuran (125') at 0°C, to which 1.2 g of phosgeso
A solution of M in toluene (69') was added with vigorous stirring. The mixture was left at 0° C. for 5 hours and then evaporated under reduced pressure. A small amount of tetrahydrofuran was added shallowly and the evaporation process was repeated. The residue was suspended in tetrahydrofuran (100ml) at 0°C, and N,N-diSof was added to the suspension. Lopylethylamine (20.4') was added.
After the slurry was evaporated to dryness under reduced pressure, the remaining bamboo was extracted with petroleum ether (200%), and the extract was decolorized with activated carbon and filtered. The desired carbodimide was obtained in a quantitative yield by evaporating the liquor to dryness. Infrared absorption spectrum (
Chloroform solution): 2120-2140 Ka-1 (-N
=C=N-). Example 2 N-cyanoN-(1-ethyl-1-methylpropyl)-N'-3-pyridylguanidine Following the procedure of Example 1, except that in place of N-tertbutyl-N'-3-pyridylcarbodiimide, N -(1-ethyl-1-methylpropyl)-N'-cyano N-(1-ethyl-1-methylpropyl)-N with a melting point of 184.5 to 186.0 pm by using -N'-3-pyridylcarbodiimide
'-3-pyridylguanidine was obtained.

Example 3 N''-cyano N-(1,1-dimethylbutyl)N'
-3-pyridylguanidine Following the procedure of Example 1, except that instead of N-tert-butyl-N'-13-pyridylcarbodiimide, 1 N-(1,1-dimethylbutyl)-N
By using '-3-pyridylcarbodiimide,
Melting point 188.0-188. is 0 N''-Syanor N-
(1,1-dimethylbutyl)-N'-3-pyridylguanidine was obtained.

Example 4 N'-cyano N-(1,1-diethylpropyl)-N
'-3-Pyridylguanidine Following the procedure of Example 1,
However, instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-(1,1 diethylpropyl)-N
'By using 3-pyridylcarbodiimide,
N″-cyano N- with melting point 192.5-193.5q0
(1,1-diethylpropyl)-N'-3-pyridylguanidine was obtained.

Example 5 N'-CyanoN-tert-benthyl-N'-3-pyridylguanidine Following the procedure of Example 1, except that in place of N-tert-butyl-N'-3-pyridylcarbodiimide, N
- By using tertiary benzyl N'-3-pyridylcarbodiimide, N with a melting point of 187.0 to 187.5°C
'-Cyano-N-tertiary benzene-N'-pyridylguanidine was obtained.

Example 6 N″-cyanoN-neobentyl-N′-13-pyridylguanidine Following the procedure of Example 1, but with the exception that N-3
By using N-neobenyl N'-3-pyridylcarbodiimide instead of butyl-N'-3-pyridylcarbodiimide, the melting point is 214.0 to 215.00.
0 N''-cyano N-neobenthyl N'-3-pyridylguanidine was obtained.

Example 7 N''-cyano N-isopropyl-N'-3-pyridylguanidine Follow the procedure of Example 1, except that N-tertiary
By using N-isopropyl-N'-3-pyridylcarbodiimide instead of butyl-N'-3-pyridylcarbodiimide, the melting point is 154.5 to 155.00.
0 N''-cyano-N-isopropyl-N'-3-pyridylguanidine was obtained.

Note: The reaction was highly exothermic.

Example 8 N''-cyano N-1-ethylpropyl-N'-3-pyridylguanidine Follow the procedure of Example 1, except that N
- By using N-1-ethylpropyl-N'-3-pyridylcarbodiimide instead of tertiary-butyl-N'-3-pyridylcarbodiimide, the melting point is 109.5-1.
10.5 o'clock N''-cyano N-1-ethylph.

Lopyl-N'-3-pyridylguanidine was obtained. Example 9 N-normal butyl-N''-cyano-N'-13-pyridylguanidine Following the procedure of Example 1, but in place of N-tert-butyl-N'-13-pyridylcarbodiimide.
The target compound having a melting point of 96.0 to 97.0 qo was obtained by using monobutyl-N'-3-pyridylcarposimide.

CAUTION: Exothermic reaction. Example 10 N-tert-butyl-N''-cyano-N'-3-pyridylguanidine Following the procedure of Example 1, except that in place of N-tert-butyl-N'-3-pyridylcarbodiimide, N
By using -sec-butyl-N'-3-pyridylcarbodiimide, the target compound with a melting point of 133.5-135.0°C was obtained.

Example 11 N''-cyano N-normalbenzene N'-3-pyridylguanidine Following the procedure of Example 1, but replacing N-tert-butyl-N'-3-pyridylcarbodiimide with N
By using Kazumasa benzyl N'-3-pyridylcarbodimide, the target compound with a melting point of 130.4-131.6°C was obtained.

Example 12 N″-cyano N-1-methylcyclobutyl-N′-
3-pyridylguanidine Following the grafting method of Example 1, but by using N-1-methylcyclobutyl-N'-3-pyridylcarbodiimide in place of N-tert-butyl-N'-3-pyridylcarbodiimide. , melting point 21
0.5-211.5 qo of the target compound was obtained.

Example 13 N''-cyano N-3-pyridyl-N'-1,1,2-trimethylpropylguanidine Following the procedure of Example 1, but in place of N-tert-butyl-N'-3-pyridylcarbodiimide, N- By using 3-pyridy-N'-1,1,2-trimethylpropylcarbodiimide, the melting point is 194.0 to 195.0oo.
The target compound was obtained.

Example 14 N″-cyano N-pyridyl-N′-1,2,2-trimethylpropylguanidine Following the procedure of Example 1, except that instead of N-tert-butyl-N′-pyridylcarbodiimide, N -3-pyridyl-N'-1,2
, 2-trimethylpropylcarbodimide, the target compound having a melting point of 167.5 to 168.500 was obtained.

Example 15 N″-Cyano N-3-pyridyl-N′-1,1,3-trimethylbutylguanidine Following the procedure of Example 1,
However, instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-tert-butyl-N'-1,1,
By using 3-trimethylbutylcarbodiimide, the target compound with a melting point of 180.5-181.5oo was obtained.

Example 16 N″-cyano-N-3-pyridyl-N′-1,1,3,
3-tetramethylbutylguanidine Following the procedure of Example 1, except that instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-3-pyridyl-N'-1
, 1,3,3-tetramethylbutylcarbodiimide, the target compound having a melting point of 180.5 to 181.5q0 was obtained.

Example 17 N-3-(5-promopyridyl)-N'-tert-butyl-N''-cyanoguanidine Following the procedure of Example 1, but in place of N-tert-butyl-N'-13-pyridylcarbodiimide, N-3-(5-bromopyridyl)-N'
- By using tert-butylcarbodiimide, the target compound with a melting point of 153.0-153.5oo was obtained.

Example 18N-tertiary butyl N''-cyano N'-5
-(2-Methoxypyridyl)guanidine Following the procedure of Example 1, except that instead of N-tert-butyl-N'-13-pyridylcarbodiimide, N-tert-butyl-N'-
By using 5-(2-methoxypyridyl)carbodiimide, the target compound with a melting point of 156.0-157.0oo was obtained.

Example 19 N-tert-butyl-N'-3-(2-chloropyridyl)-
N''-Cyanoguanidine Follow the procedure of Example 1, but instead of N-tert-butyl N'-3-pyridylcarbodiimide, use N-tert-butyl-N'-3-(2-chloropyridyl)carbodiimide. By using this, the target compound with a melting point of 202.0 to 203.000 was obtained.

Example 20N-tert-butyl-N''-cyano-N'-2
- Pyridylguanidine By following the procedure of Example 1 but using N-tert-butyl-N'-2-pyridylcarbodiimide instead of N-tert-butyl-N'-2-pyridylcarbodiimide, the objective A compound was obtained.

Infrared absorption spectrum (KBr method) showed strong absorption at 2160-70 Hada-1 (1C3N). Melting point: 168.
0 to 168.5 qo (decomposition) Example 21 N″-cyano N-cyclobutyl-N′-3-pyridylguanidine Follow the procedure of Example 1, but N-3
The target compound was obtained by using N-cyclobutyl-N'-3-pyridylcarbodiimide in place of butyl-N'-3-pyridylcarbodiimide.

Infrared absorption spectrum (KBr method) showed strong absorption at 2160-70 Hada-1. Example 22 N″-cyano-N-1,3-dimethylbutyl-N′-3
-Pyridylguanidine Following the procedure of Example 1, but substituting N-1,3-dimethylbutyl-N'-3-pyridylcarbodiimide for N-tert-butyl-N'-3-pyridylcarbodiimide, The target compound was obtained.

Infrared absorption spectrum (KBr method) showed strong absorption at 2160-70 Hada-1. Example 23N″-CyanoN-Phenyl-N′-3-pyridylguanidine Example 1
However, instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-phenyl-N
By using '-3-pyridylcarbodiimide,
The target compound was obtained.

Melting point: 194-195 qo. Example 24 N″-Cyano-N-cyclobenthyl N′-5-(2-methoxypyridyl)guanidine Following the procedure of Example 1, but substituting N-tert-butyl-N′-13-pyridylcarbodiimide. , N-cyclobentyl-N'-5-
The target compound was obtained by using (2-methoxypyridyl)carbodiimide.

Infrared absorption spectrum (KBr method) showed strong absorption at 2160-70 skin-1. Example 25 N-tert-butyl-N''-cyano-N'-3-pyridylguanidine A.N-tert-butyl-N'-3-pyridylchloroformamidine hydrochloride N-tert-butyl-N'-3-
Pyridylthiourea (12.5 g, 6 hmol) was suspended in dry tetrahydrofuran (125 M) and 1.2 M phosgene in toluene (69 mm) was added dropwise at 0°C.

After being kept at 0° C. for 5 hours, the mixture was evaporated under reduced pressure to obtain the desired compound.

BN-tert-butyl-N''-cyano-N'-3-pyridylguanidine A solution of the compound obtained in step A in dimethylformamide ((125)) was added with cyanamide (3. 5 g, 83 mmol) was added.

Triethylamine (18.2 g, 13 hmol) was added slowly. After stirring overnight at room temperature, the mixture was evaporated under reduced pressure and the residue was treated with water (10%) to give the crude product. This was worked up according to Example 1 to obtain the target compound. Melting point: 205-20 is 0. Example 26 N,N-diisopropyl was added to a solution of N-normal butyl-N''-cyano-N'-3-pyridylguanidine cyanamide (0.95 g) in ethanol (10') while floating at 0°C. Ethylamine (3.4 on) was added followed by 3-pyridylysothiocyanate (2.2 on).

The mixture was left at 0° C. overnight and then evaporated to dryness under reduced pressure. Praise the light with the remaining ether (100'), N.
After the N,N-diisopropylethylamine salt of -cyano N'-3-pyridylthiourea was crystallized, it was collected and washed with ether. [Free thiourea could be separated by suspending the salt in water and acidifying it to pH 3-4 using hydrochloric acid. Melting point 184.5~1
85.0°C, infrared absorption spectrum (KBr method): 214
It showed absorption at 5-arc-1 (1C3N). ] Amine salt (6
．． 25 g) was suspended in anhydrous dimethylformamide (15 cm) with stirring at 0.000 m. Methyl iodide (
When 1.65 of [) was added dropwise, the solution gradually became transparent, and after stirring for 1 hour, it was left at 0°C overnight.
After warming the solution to room temperature, it was evaporated under reduced pressure.
Finally it was evaporated to dryness under high vacuum at 25q0. Ice water (15 mm) and a saturated aqueous solution of sodium bicarbonate (NaHC03) (2.5 mm) were added to the residue, and S-methyl-N'-sia/
-N-3-pyridylysothiourea was crystallized, filtered out and washed with water. Melting point: 153.6-1
55.000. Infrared absorption spectrum (KBr method): 21
60-2180 Hada-1 (1C3N) showed absorption. The above isothiourea (2.28 g) was added to pyridyl (25 kites).
and to this was added normal butylamine (10).

The mixture was left at room temperature for 7 hours and then evaporated to dryness under reduced pressure. The residual water was lit with water (Z of 30) and crystallized. The product was collected and washed with water to obtain a crude product. The crude product was further purified by recrystallization from acetone-petroleum ether. Melting point: 96.0-97.0qo.
Infrared absorption spectrum (KBr method): Strong absorption based on 2165 arc-1 (1C3N) and broad (middle wide) absorption between 1600 and 1550 arc-1 were observed. This infrared absorption spectrum completely matched the spectrum of the right butyl substituted compound synthesized in Example 9. Example 2
7 N'-cyano-N-propyl-N-3-pyridylguanidine Following the procedure of Example 26, but by substituting normal propylamine for normal butylamine,
The target compound having a melting point of 164.0-165.0 was obtained.

Example 28 N''-cyano N-cyclopropyl-N'-3-pyridylguanidine By following the procedure of Example 26 but substituting cyclopropylamine for normal butylamine, a melting point of 171.0-172. 0 target compound was obtained.

Example 29N''-Cyano-N-isobutyl-N'-3
-Pyridylguanidine By following the procedure of Example 26, but using isobutylamine in place of orthobutylamine, the target compound with a melting point of 148.0-149.0oo was obtained.

Example 30 N''-cyano-N-neobentyl-N'-pyridylguanidine Following the procedure of Example 26, but by using neobentylamine, a cut-off of normal butylamine, the melting point was 214.0-215.000 ( This corresponds to the melting point of the compound synthesized in Example 6.

) was obtained. Example 31 N''-cyano N-isobentyl-N'-3-pyridylguanidine By following the procedure of Example 26 but substituting isobenthylamine for normal butylamine, a The target compound was obtained.

Example 32N″-CyanoN-CyclobenruN′
-Pyridylguanidine By following the procedure of Example 26, but using cyclobentylamine in place of normal butylamine, the target compound with a melting point of 155.0 to 156.0 qC was obtained.

Example 33 N''-cyano N-cyclohexyl-N'-3-pyridylguanidiso Following the procedure of Example 26 but using cyclohexylamine in place of orthobutylamine, the melting point was 185.0-186.00. The target compound marked ○ was obtained.

Example 34 N''-Cyano-N-normal hepty-N'-3-pyridylguanidine By following the procedure of Example 26 but using normal heptylamine in place of normal butylamine, a melting point of 90.0-91. 000 target compounds were obtained.

Example 35 N''-cyano-N-2-ethylhexyl-N'-3-pyridylguanidine Following the procedure of Example 26, but with the exception that:
By using 2-ethylhexylamine instead of normal butylamine, the melting point is 84.0-85. The target compound of 0.5% was obtained.

Example 36N″-CyanoN-2-methylarylN
'1-3-Pyridylguanidine Following the procedure of Example 26, but using 2-methylallylamine in place of orthobutylamine, the melting point was 14.00-141. The target compound with 0 and 0 was obtained.

Example 37 N-benzyl-N''-cyano N'-13-pyridylguanidine By following the procedure of Example 26 but using penzylamine instead of normal butylamine, the target compound with a melting point of 189.0 to 190.0 qo was obtained. .

Example 38 N''-cyano N-2-methylbutyl-N'-3-pyridylguanidine The desired compound was obtained by following the procedure of Example 26, but using 2-methylbutylamine in place of orthobutylamine.

Infrared absorption spectrum (KBr method) is 2160 - 70 -
1 showed strong absorption. Example 39 N″-cyano N-8-phenylethyl-N′-3-pyridylguanidine Following the procedure of Example 26, but with the exception that
The target compound was obtained by using 8-phenylethylamine in place of normal butylamine.

Melting point: 162-163oo Example 40 Compound of Example 1 in anesthetized normotensive rats (hereinafter referred to as pl060).

) antihypertensive active Sprague Dowry (Sprague D)
A male white mouse of the A. owley strain was anesthetized with pentobarbital and fixed on its back on a fixation plate. The left carotid artery was extracted and a polyethylene cannula was inserted into it, which was connected to a multimeter recorder (GrassPolygraph Reoder) through a Staham pressure transducer. PI060 also in the left femoral vein.
A cannula was inserted for administration. PI060
was dissolved in dilute hydrochloric acid. The volume administered did not exceed 0.2 kite'. Table 1 summarizes the effects on average blood pressure at the time when drug efficacy reaches its peak.・Example 41 Compounds of Examples 1, 2, 3, 4 and 5 (hereinafter referred to as P) in rats with congenital hypertension without anesthesia
I06uPI060PI067, PI068 and PI
It is called 075.

) antihypertensive activity Okamoto (0kamot) in congenital hypertension
Male white rats of strain o) were fasted for 1 hour before the experiment and used. A conscious rat was placed in a plastic cage and secured with a blood pressure band wrapped around its tail. The band was connected to an electronic blood pressure recorder, and systolic blood pressure and cardiac frequency at 2, 4, 6, and 2 special intervals were measured after administration. Each compound was suspended or dissolved in a 0.5% solution of carboxymethyl cellulose. The volume administered was less than 0.5 secretions 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, approximate values of LD5o for oral administration using mice are also listed. Table 2 HP: mean arterial blood pressure (day 9) HR: thin heart rate (times/min), LDso: oral (mouse)
*Minoxidil: 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piverid-1-ylpyrimidine Example 42 Antihypertensive activity in conscious normotensive dogs Male and female mongrel dogs were fasted for 1 hour before the experiment. ,used.

Blood pressure is measured using an ultrasonic measuring device (Arteliosonde ■10).
10, Roche Medical Electronics Department, ~teriosond
e■1010, Roche Medical Electr
PI060 or PI
Recordings were made indirectly before and 1, 2, 3 and 4 hours after administration of 075. Each compound was administered orally in a gelatin capsule. Table 3 shows the results obtained using the above two compounds. 3 BP: Mean arterial blood pressure (lateral Hg) HR: Cardiac record frequency (times/min) W: Urine volume Example 43 Antihypertensive effects and various cardiovascular and autonomic nervous reactions in cats The mice were anesthetized by 40 intraperitoneal injections of pital.

The left carotid artery was withdrawn, a polyethylene cannula was inserted, and this was passed through a Statham pressure transducer to a multimeter recorder (GrassPolygraph).
Recorder). In the right femoral vein,
A cannula was inserted to administer PI060. P
I060 was dissolved in dilute hydrochloric acid and administered at a concentration of 0.4'.
Measurements were made on the vasoconstrictor response to intravenous administration of norepinephrine hydrochloride (lmcg/k9) NE and normal carotid artery occlusion (49 sand), CO, before and after intravenous administration of PI060. Both operations are known to produce a pressor effect. Furthermore, preganglionic stimulation (3V, lmsec, 40 days 2,5 seconds) and postganglionic stimulation (3V, lmsec, 40 days 2,5 seconds)
Adjacent membrane contraction evoked by PI060 was measured before and after intravenous administration of PI060. Table 4 shows the results obtained in detail. Table 4 Example 44 N-tert-butyl-N''-cyano-N'-4-pyridylguanidine Following the procedure of Example 1, but replacing N-tert-butyl-N'-3-pyridylcarbodiimide.
By using -tert-butyl-N'-4-pyridylcarbodimide, the target compound with a melting point of 203.0 to 204.0°C was obtained.

Infrared absorption spectrum (KBr method) showed strong absorption at 2175 arc-1 (1C...N). Example 45 N''-Cyano-N-tertiarybenthyl-N'-4-pyridylguanidine Following the procedure of Example 1, N-tertiary-butyl-N'-3-pyridylcarbodiimide was replaced with
The target compound having a melting point of 161.0 to 162.0 qo was obtained by using benzyl N'-4-pyridylcarpodiimide.

Example 46 N″-cyano-N-1-ethylpropyl-N′-4-pyridylguanidine Following the procedure of Example 1, except that N
- By using N-1-ethylpropyl-N'-4-pyridylcarbodiimide instead of tertiary butyl-N'-3-pyridylcarbodiimide, the melting point is 196.0 to
197,000 target compounds were obtained.

Example - 47 N''-cyano N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine Following the procedure of Example 1, but in place of N-tert-butyl-3-pyridylcarbodiimide, N-4 By using -pyridyl-N'-1,2,2-trimethylpropylcarbodiimide, the target compound (monohydrate) having a melting point of 164.0 to 165.0 was obtained.

Example 48 N″-cyano N-4-pyridyl-N′-1,1,3-trimethylbutylguanidine Following the procedure of Example 1,
However, instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-4-pyridyl-N'-1,1,
By using 3-trimethylbutylcarbodiimide, the target compound with a melting point of 155.0 to 156.0°C was obtained.

Example 49 N″-cyano N-1,1-diethylpropyl-N′-
4-Pyridylguanidine Following the procedure of Example 1, except that instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-1,1-diethylpropyl-N'-
By using 4-pyridylcarbodiimide, the target compound with a melting point of 220.0 to 221.000 was obtained.

Example 50N''-cyano N-4-pyridyl-N'-1,1,3,3-tetramethylbutylguanidine Follow the procedure of Example 1, except that N-tertiary butyl-N'-3
- By using N-4-pyridyl-N'-1,1,3,3-tetramethylcarbodiimide instead of pyridylcarbodiimide, the melting point is 197.0 to 198.0°C.
The target compound was obtained.

Example 51 N''-cyano-N-1,5-dimethylhexyl-N'-4-pyridylguanidine Following the procedure of Example 1, but in place of N-tert-butyl-N'-3-pyridylcarbodiimide. , N-1,5-dimethylhexyl-N'-
By using 4-pyridylcarbodiimide, the target compound with a melting point of 136.0 to 137.0 qo was obtained.

Example 52N″-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. , melting point 198.
0 to 199.0oo of the target compound was obtained.

Example 53 N''-cyanoN-neobentyl-N'-4-pyridylguanidine Following the procedure of Example 1, except that instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-neobenyl-N'-4- The target compound was obtained by using pyridylcarbodiimide.

Melting point: 191-19y0 Example 54 N″-cyano-N-4-pyridyl-N′-1,1,2-
Trimethylpropylguanidine Following the procedure of Example 1, but instead of N-tert-butyl-N'-3-pyridylcarbodiimide, N-4-pyridyl-N'-1,1
, 2-trimethylpropylcarbodiimide, the target compound was obtained.

Infrared absorption spectrum (KBr method) is 2160-70cm
-1 showed strong absorption. Example 55 N-penzyl-N''-cyano N'-4-pyridylguanidine Following the procedure of Example 1, but in place of N-tert-butyl-N'-3-pyridylcarbodiimide, N
The target compound was obtained by using -benzy-N'-4-pyridylcarbodiimide.

Melting point: 176-1770. Example 56 N-tertiary butyl N''-cyano N'-31 (2,4,
6-trimethylpyridyl)guanidi, 3-amino2
, 4,6-trimethylpyridine (1.36 g) and S-methyl-N-tert-butyl-N'-cyanoisothiourea (1
．． 71 g) was refluxed in pyridine (10 g) for 48 hours.

Pyridine was distilled off under reduced pressure, and the remaining residue was recrystallized from water-ethanol to obtain the target compound. Melting point: 187.0
~188.000. Example 57 N'-Cyano-N-tert-benzene N'-3-(2,4,6-trimethylpyridyl)guanidine Following the procedure of Example 56, but with the exception that
By using S-methyl-N-tert-benzene-N'-cyanoisothiourea instead of S-methyl-N-tert-butyl-N'-cyanoisothiourea, the melting point was 163.
0-164.0 qo of the title compound was obtained.

Example 58N-tertiary butyl-N''-cyano-N'-3
-Quinolylguanidine Following the procedure of Example 1, but by using N-tert-butyl-N'-3-quinolylcarbodiimide instead of N-tert-butyl-N'-3-pyridylcarbodiimide. , melting point 228.5-22
The target compound of 9.0 qC was obtained.

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) were dissolved in ethanol (20 ) in which 1 lead poison was refluxed.

Claims (1)

[Claims] 1 General formula I ▲ Numerical formulas, chemical formulas, tables, etc. are included ▼ In the formula, a cyanoguanidyl group having a substituent R^1 is substituted at the 2-, 3- or 4-position of the pyridine ring. R^1 means a linear or branched, saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group, or an aralkyl group. , R^2 means a hydrogen atom, a halogen atom, or a lower alkyl or alkoxyl group. or guanidine derivatives represented by their tautomeric formulas and their non-toxic, pharmaceutically acceptable salts with acids. 2 A cyanoguanidyl group with a substituent R^1 is
The guanidine derivative and its salt according to claim 1, which is substituted at the 3-position of the pyridine ring. 3 A cyanoguanidyl group with a substituent R^1 is
The guanidine derivative and its salt according to claim 1, which is substituted at the 4-position of the pyridine ring. 4 R^1 is a branched pentyl group such as isopropyl group, isobutyl group, sec-butyl group, tertiary-butyl group, tertiary-pentyl and neopentyl, or a branched hexyl group such as 1-methyl-1-ethylpropyl and 1,1-
The guanidine derivative and salt thereof according to claim 1, 2 or 3, wherein the guanidine derivative is a group selected from the group consisting of branched pentyl groups such as diethylpropyl. 5 N-tert-butyl-N''-cyano-N'-3-pyridylguanidine, the guanidine derivative according to claim 2, and its salt with a non-toxic pharmaceutically acceptable acid. 6 N' -cyano-N-tertiary pentyl-N'-3-pyridylguanidine, the guanidine derivative according to claim 2, and its non-toxic, pharmaceutically acceptable salts with acids. 7 N''-cyano -N-(1-ethyl-1-methylpropyl)-N'-3-pyridylguanidine, as claimed in claim 2, and its non-toxic, pharmaceutically acceptable salts with acids. 8 N″-cyano-N-3-pyridyl-N′-1,1,
2-trimethylpropylguanidine, the guanidine derivative according to claim 2, and its non-toxic, pharmaceutically acceptable salts with acids. 9 N″-cyano-N-(1,1-diethylpropyl)
-N'-3-pyridylguanidine, the guanidine derivative according to claim 2, and its non-toxic, pharmaceutically acceptable salts with acids. 10 N″-cyano-N-neopentyl-N′-3-pyridylguanidine, the guanidine derivative according to claim 2, and its non-toxic and pharmaceutically recognized
Salts with acids. 11 As an active ingredient, there are the following formula 1 ▲ mathematical formula, chemical formula, table, etc. ▼ In the formula, a cyanoguanidyl group with a substituent R^1 is substituted at the 2-, 3- or 4-position of the pyridyl ring. ,
R^1 means a linear or branched, saturated or unsaturated, aliphatic hydrocarbon group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group, or an aralkyl group; ^2 means a hydrogen atom, a halogen atom, or a lower alkyl or alkoxyl group. or at least one compound selected from the group consisting of guanidine derivatives represented by the tautomeric formula thereof and their non-toxic, pharmaceutically recognized salts with acids, a pharmaceutical carrier and/or an adjuvant. An antihypertensive composition characterized by: 12. The antihypertensive composition according to claim 11, which contains at least 0.1% as an active ingredient.