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Патент USA US3074964

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3,074,955
United States Patent 0;
2
1
the product usually crystallized as the dihydrochl-oride of
the substituted guanylurea (II).
In instances where the ldihydrochloride does not ‘precip
3,074,955
PYRIDYLALKYL DICYANDIAMIDES AND
GUANYLUREAS
Seymour L. Shapiro, Hastings-on-Hudson, and Louis
Freedman, Bronxville, N.Y., assignors to US. Vitamin
ita-te, the product is conveniently isolated by adjusting the
pH ‘of the reaction mixture to approximately 5-6 and add
ing sodium nitrate which precipitates the‘guanylureas II,
8: Pharmaceutical Corporation, New York, N.Y., a cor- I
poration of Delaware
No Drawing. Filed Nov. 30, 1960, Ser. No. 72,558.‘
6 Claims. (Cl. 260-295)
- ‘as the nitrate.
Equationstypifying these reactions are shown:
R2
10
This invention is concerned with novel pyridylalkyl di
cyandiamides and guanylureas of the formula shown:
1i’
..
,
Equation 2
H 01
I —> II.2HC1
The process of compounds of this invention will be
1
15 more clearly understood from a consideration of the fol
R1,—N--(l‘IJ-—N-Z
_
Patented Jan. 22, '1963
lowing examples which are given for the purposes of
NH
illustration only and are not to be considered as limiting
the scope of the invention in any way.
wherein R1 is selected from the group consisting ‘of picolyl
land pyridylethyl; R2 is selected from the group consisting ‘
EXAMPLE 1
of hydrogen and methyl, and Z is selected from the group
consisting of cyano (to give the substituted dicyandi 20 ' General procedure for preparation of the pyridylalkylv
amides, I), and carbamido (to give the substituted gua- . V dicyandiamides.—A solution of 0.5 mole of the appropri
ate picolyl or pyridylethyl amine in 500 ml. of n-butanol
was treated under cooling and stirring with 42 ml. of 12.
nylureas, II)
N hydrochloric acid, followed by the addition 1of 55.0 g.
25 (0.5 mole) of sodium dicyananiide. The white suspen
sion Was heated under re?ux for 6 hours with stirring.‘
The hot solution was ?ltered to separate the formed so
dium chloride and after removal of the butanol, the res
The compounds of this invention by virtue of their
pyridine ring system can readily form' salts with the non 30 idue“ of product~ Was ‘recrystallized. 'Typical of the syn
theses, re?ecting this invention, are the compounds listed
toxic miner-al acids. In addition, the guanylureas have
in Table I.
another basic site and can be obtained ‘as their mono- or
di-acid salts.
"
'
‘
'
' Compounds 10 and 11, which are not a part of this
,
The compounds are conveniently prepared by reaction I ' invention, have been prepared to demonstrate the selec
in re?uxing butanol of the appropriately substituted 35 tive-and distinct properties of the compounds of this in
RlRzNH picolyl or pyridylethyl amine hydrochloride with
vention.
'
TABLE I
I
.
Picolyl and Pyridylethyl Dicyandiamides
i" t
R1—I\‘I—IC—N—ON
'
H
.
Analysis, percent
Yield,»
No.
R1
R2
M.p., “0. percent
,
Formula
_4~pyridyl ____________ .7“
142-145
147-150
b 48
57
H
CH:
CH3
78- 81
150-152
158-160
31
39
54
,
Carbon
Calcd.
H
H
,
_
.
Hydrogen
Found
Calcd.
5. 2
5. 2
57.1
57.2 .
.
‘
Found
Calcd.
‘ 40. 0
40. 0
Found '
.H
143-146
H
194-195
36
57. 1
57.2
5. 9
CH3
165-168
b 66
._
59.1
58.9, .
.05v
6. 7
______________ __
CH3
202-204
b 39
CmHrsNs ____ ..-
59. 1
58. 8
6. 5
6. 3
______________ __
H
111-114
‘145
CTH1N5 __________________ _L _________________ __
43.6
44.3
119-121
36
O8H17N5__..___
38. 2
38. 4
(CH3)1N(CH¢)3— _____ __ CH3
54. 1
54. 6
49. 9
57. l
57. 2
‘
5. 1
5. 4
5. 7_
5. 7
6.0
6.0
6.0
67
54. 8
54. 8
49. 7
57.1
57. 1
'
‘ Nitrogen .
52.4
52. 3
5. 7
5. 9
5.9
5. 9
9. 4
.
9. 4
40. 7
36. 3
37.0
37. 0
39.8
35. 7
37. 1
37. 1
37.0
37. 3
37.0
37. 3
N e Rec-rystallizing solvent is isopropyl alcohol-hexane unless otherwise shown.
b Recrystallizing solvent is'acetonitrile.
' ‘
»»
Y
5 Isolated, and analyses shown as monohydrate.
d Recrystallizlng solvent is ethanol-ether.
sodium dicyanarnide, to give upon work-up, the required 65
dicyandiamide (I). Other solvents such as propanol, or
aqueous butanol may be substituted.
EXAMPLE 2
General procedure for the preparation of the picolyl
and pyridylethyl guanylureas-A suspension of 0.025
mole of the dicyandiamides described in Table I in a mix
ture of 12 ml. of isopropyl alcohol and 6 ml. of 12 N hy
chloric acid. The preferred alcohol for this hydrolysis is 70 drochloric acid was heated under re?ux, with stirring, over
a period of 2-3 hours. When cool, the formed product
isopropyl alcohol although other lower alcohols are
as the dihydrochloride, separated and was ?ltered and re
equally applicable. After an appropriate re?ux period,
The dicyandiamide (I), in turn, is readily hydrolyzed
upon treatment with alcoholic solutions of 12 N hydro
3,074,955
3
4
crystallized. In those instances wherein the product did
of hydrogen and methyl, and Z is selected from the group
not crystallize, the reaction mixture was diluted with
Water (70 ml.) and neutralized (to methyl red) with 10‘ N
consisting ‘of cyano and carbamido; and the nontoxic
mineral acid salts thereof.
2. The compound
sodium hydroxide and 5.3 g. of sodium nitrate added.
The precipitated mo-nom'trate salt of the product was sep- 5
arated and recrystallized.» The salts of the product, on
H
H
N C N
suspension in water or a lower alcohol, and treatment with
CH?‘ _ H T “ON
an equivalent quantity of base afforded the free base of
NH
the guanylurea. Typical of the compounds prepared, are
N/
those described in Table II.
TABLE II
Analysis, percent
No.
R;
R;
HX
M. p.,° O.
Yield,9
Formula
Carbon
Hydrogen
Nitrogen
Calcd. Found Calcd. Found Calcd. Found
2picolyl _________ __ H
3-pico1yl _________ ._ H
193-194
175-177
9b"--27%..."
CMHHNBOS ..... __
GBHHNQOJ ...... -_
36.9
37.5
36.8
37.7
2.6
4.7
2.6
4.3
23.7
32.5
24.1
33.0
2-py'ridylethyl.__-_ H
4-pyridylethyl_____ H
198-200
220-221
18%..." CQHiiClzNsO .... ..
33nd"--. CQHuClnNsO ____ _-
ass
38.6
39.2
38.5
5.4
5.4
5.4
5.2
25.0
25.0
24.7
24.5
2-pyridylethyl_____ CH;
183-184
35w".-. C10I‘I!70l2N60__--_
40.8
40.0
5.8
6.0
23.8
23.5
4-pyridylethyl_._._ CH3
189-191
3241"... OroHwNaO; ..... -.
42.3
43.1
5.7
5.7
29.6
29.5
B Reerystallizing solvent: aa=80% methanol; al0=Water; ac=Methyl cellosolve-acetonitrlle; ad=Methyl cellosolve; ae=Methanol-benzene; af=
Ethanol-hexane.
b HPic=Picric acid.
The compounds of this invention have important pharmacological properties and, ‘in particular, the dicyandiamides (I) are relatively nontoxic compounds (LDDMn
3. The compound
CH3
750-1,000 mg./kg.) which are particularly active as po- 40
I
tentiators of central nervous system depressant drugs.
By contrast, the (4-pyridyl)-dicyandiamide is toxic at
N’
4. The compound
20 mg./kg. s.c. and shows no distinctive pharmacological
properties.
In addition, the N-methyl-dimethylarnino propyl di- 45
1?
cyandiamide,
prepared little
for purposes
comparison,
while
having also
substantially
toxicity of(LDmin
1,000
mg./kg.) is without import-ant pharmacological effect.
The pyridylalkyl guanylureas manifest their eifects, par
1'1
©CHzCHz-—N—(I'|J—N—CE
NH
N
ticularly in lowering as well as raising blood pressure, as 50
the groups are varied. Additionally, they potentiate as
well as inhibit adrenalin signi?cantly, as the groups are
5 - The compound
varied.
I
It is to be understood that it is intended to cover all
changes and modi?cations of the examples herein chosen 55
for the purposes of illustration which vdo not constitute
departure from the spirit and scope of the invention.
H
11
CH _IlI__C_IlI_O NH
a
2
N
6_ The compound
We claim:
(EH: H
1. The compound
VOHaOHr-N-?-N-(?-NH:
NH
65
References Cited in the ?le of this patent
UNITED STATES PATENTS
wherein R1 is selected from the group consisting of picolyl,
2,455,894
Lechcr et 1a1 ___________ .... Dec. 7, ‘1948
‘and pyridylethyl, R2 is selected from the group consisting
2,455,896
Nagy ---- ------.---.---.--- D?c- 7; 1948
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