Note: Descriptions are shown in the official language in which they were submitted.
-`" 11C3~5~
This invention relates to new compounds of value as antihypertensives
and more particularly to new s-triazolo~1,5-a~pyridine derivatives and their
pharmacologically acceptable acid addition salts.
The novel s-triazolo[1,5-a~pyridine derivatives of the present invention
can be represented by the general formula (I),
(I)
N ~N
N~``R
wherein R represents -CH=N-N-(CH3)2 or -(CH2) -N N-R , wherein R represents
phenyl, 2-methoxyphenyl, benzyl, 2-chlorobenzyl or 2-pyridyl, and n
represents 3 or 5.
The novel compounds of the present invention can be prepared by the
following procedures.
The compound represented by the general formula (I), wherein R represents
-CH=N-N-(CH3)2, can be prepared by reacting 2-dihalogenomethyl-s-triazolo
ll,5-a~Pyridine ("halogeno" being chlorine, bromine or iodine) with the
corresponding substituted hydra~ine in a solvent as, for example, dimethyl-
formamide, and preferably in the presence of a base as, for example,
potassium carbonate.
The 2-dihalogenomethyl-s-triazolo a,5-aJpyridine starting compounds can
be prepared by reacting 1,2-diaminopyridinium iodide with methyl dihalogeno-
acetate.
20The compounds represented by the general formula (I), wherein R
represents -(C112)n-N~___N-R , in which -R and n are as already defined,
can be prepared by reacting a compound having the general formula (II),
.~,
. --1-- `
.: '
-.
` 11(~C~5~4
~'~
IN (II)
N
(CH2) n~X
wherein X represents halogen (chlorine, bromine or iodine) and n is as already
defined with a compound having the general formula (III),
HN N-R2
(III)
wherein R is as already defined, in a solvent as, for example, ethanol,
dimethylformamide or toluene, and preferably in the presence of an equimolar or
greater amount of a base as, for example, potassium carbonate or triethyl-
amine at a temperature near the boiling point of the solvent used.
The fol:Lowing examples serve to illustrate the invention.
Reference examples:
1) 2-Dichloromethyl-s-triazolo~L,~-37pyridine
A solution of 24 g of 1,2-diaminopyridinium iodide and 6.6g of sodium
hydroxide in 200 ml of ethanol was stirred at 50-60C for 1 hour. To the
reaction mixture was added 17.2g of methyl dichloroacetate and the mixture was
refluxed with stirring for 4 hours. The mixture was concentrated under
reduced pressure, water was added followed by extraction with chloroform.
The chloroform layer was evaporated to give crude crystalline product,
which was recrystallized from 60 ml of benzene. Colorless needles, mp 133-134 C,
in the amount of ~6.8g were obtained.
Analysis:
Calcd. for C7115N3C12 : C, 41.61; H, 2.49; N, 20-80-
--2--
110~?50~
Found:
C, 41.91; H, 2.55; N, 20.83.
2) 2-(3-Chloropropyl)-s-triazolo~1,5-a7pyridine
A) A mixture of 24g of 1,2-diaminopyridinium iodide, 17.2g of ~-butyro-
lactone and 57g of potassium carbonate in 100 ml of diethy]cellosolve was
refluxed with stirring for 8 hours. The mixture was evaporated under reduced
pressure and the residue, extracted with hot dichloromethane. The solvent was
removed to give crude 2-(3-hydroxypropyl)-s-triazolo~i,5-a~pyridine, which was
recrystallized from ethyl acetate as colorless needles (16g, 90~=), mp 71.5-
73C.
Analysis:
Calcd. for CgHllON3 : C, 61.00; H, 6.24; N, 23-72-
Found:
C, 60.82; H, 6.14; N, 23.48.
B) To 50 ml of phosphorus oxychloride was added gradually 34.5g of
2-(3-hydroxypropyl)-s-triazolo~1,5-a~pyridine. After the addition was complete,
the mixture was warmed on a water bath at 90-95C for 30 min., cooled and
poured onto cracked ice. The mixture was neutralized with potassium carbonate
and extracted with chloroform. The chloroform layer was dried over anhydrous
sodium sulfate and evaporated to give the crude product, which was recrystal-
lized from cyclohexane as colorless needles (22.5g, mp 56.5-57 C).
Analysis:
Calcd. for CgHloN3Cl : C, 55.25; H, 5-15; N~ 21-48-
Found:
C, 55.2]; H, 5.20; N, 21.55.
3) 2-(5-Chloropentyl)-s-triazoloLl,5-a7pyridine
In the same manner as described in Example for Reference Example 2,
110~5~4
parts A and B, the title compound was prepared by using ~-caprolactone in 45%
total yield and was obtained as an oil, of which the picrate melts at 136-137C.Analysis:
11 14N3Cl.C6H307N3 : C, 45.09; H, 3-78; N~ 18 56
Found:
C, 43.39; H, 3.36; N, 18.75.
Example 1. 2-(N,N-Dimethylhydrazonomethyl):s-triazoloLl,5-a~pyridine
A mixture of ll.Og of 2-dichloromethyl-s-triazoloC1,5-a~pyridine, 7.6g
of potassium carbonate, 300 mg of sodium iodide and 12g of N,N-dimethylhydrazinein 160 ml of dimethylformamide was refluxed with stirring for 12 hours. rhe
solvent was removed under reduced pressure and to the residue was added 200 ml
of water saturated with sodium chloride. The mixture was extracted with
chloroform. The extracts were evaporated and the residue was recrystallized
from benzene-n-hexane to give colorless crystals (5.6g, mp 132-133C).
Analysis:
Calcd. for CgllllN5 : C, 57.12; H- 5.86; N, 37.02.
Found:
C, 57.18; H, 5.97; N, 37.19.
Example 2. 2-~3-(4-Phenylpiperazino)propyl7-s-triazoloLl,5-a~pyridine
A solution of 5.7g of 2-(3-chloropropyl)-s-triazolo~1,5-a7pyridine,
5.2g of ]-phenylpiperazine and 10 ml of triethylamine in 140 ml of dimethyl-
formamide was refluxed for 10 hours. rhe reaction mixture was evaporated under
reduced pressure and lN-aqueous sodium hydroxide (50 ml) was added to the
residue. rne mixture was extracted with chloroform and the extracts were
evaporated to give the crude product, which was purified by alumina column
chromatography to obtain 7.1g of oily product. The oily product was converted
to a salt with maleic acid in the conventional way. llle maleate was re-
crystallized from ethanol-petroleum ether (10:4) to yield colorless prisms,
)S~
mp 167.5-168.5 C. The yield was 50%.
Analysis:
Calcd. for ClgH23N3.C4H4O4 : C, 63.14; H, 6.22; N, 16-01-
Found:
C, 63.03; H, 6.22; N, 16.14.
Example 3. 2-~3-(4-o-Methoxyphenylpiperazino)propyl~-s-triazoloLL,5-a~pyridine
A solution of 3.9g of 2-(3-chloropropyl)-s-triazoloLl,5-a~pyridine,
3.8g of l-o-methoxyphenylpiperazine and 2.8g of potassium carbonate in 150 ml
of dimethylformamide was refluxed from 8 hours. Then the reaction mixture was
processed in the same manner as described in Example 2. The product compound
was recrystallized from cyclohexane to give colorless prisms, mp 55-55.5 C,
yield 60%.
Analysis:
Calcd. for C20H250N5 : C, 68.35; H, 7.:L7; N, 19-53-
Found:
C, 68.20; H, 6.94; N, 20.21.
The compounds of Examples 4 to 8 were prepared in a manner analogous
to that described in Example 3.
I N
N ~ (CH2) -N N-R
n
--5--
llQ~5~4
. .
.
Analysis
Example n R2 Yield mp Recryst. alcd. C H N
t%) ( C) solvent Found. C H N
.
4 3-CH ~ 40 picrate E 48.43 3.94 19.41
2 234-236 48.37 4.10 19.39
3-CH2 ~ 57 maleate E 55.85 5.36 11.63
Cl ~ 172-173 55.85 5.56 11.~2
6 3 ~ 42 77.5 c*2 67.05 6.88 26.07
67.09 6.84 25.99
7 5 ~ 56 oil*3
8 5 ~ 60 oil 4
CH30~--
1 E : ethanol
2 C : cyclohexane
3 Structure confirmed by mass spectral analysis, m/e 349 (M ).
4 Structure confirmed by mass spectral analysis, m/e 379 (M ).
The antihypertensive effect of the compounds of this invention is shown
given in Table 1 to follow.
Blood pressure was determined under unanesthetized and unrestrained
conditions in spontaneously hypertensive rats (SH rat) which had been
implanted chronically with a cannula into the femoral vein. The results are
presented as the mean decreased percent in blood pressure determined at 15,
30, 60, 120 and 180 minutes after intraperitoneal (i.p.) or oral (p.o.)
administration of the test compounds.
The compounds of this invention showed more potent antihypertensive
effect in SH rats than the reference drugs, and are thus promising as
antihypertensive drugs.
S~4
Table 1. Antihypertensive effect in SH rats
.
.
-
Example Decreased % in blood pressure
~o .
i.p. : p.o.
30 mg/kg 10 mg/kg ::. 30 mg/kg. 100 mg/kg
1 24 8 16
2 30 ` 7 26
3 14 11 27
4 22
16
6 17 14 12
7 27 14
8 14 38
Hexamethonium 11
Guanethidine 12
_ . _
. .
. --7--
