U.S. patent number 3,862,189 [Application Number 05/388,290] was granted by the patent office on 1975-01-21 for aralkyl-substituted purines and pyrimidines as antianginal bronchodilator agents.
This patent grant is currently assigned to Warner-Lambert Company. Invention is credited to Charles F. Schwender.
United States Patent |
3,862,189 |
Schwender |
January 21, 1975 |
ARALKYL-SUBSTITUTED PURINES AND PYRIMIDINES AS ANTIANGINAL
BRONCHODILATOR AGENTS
Abstract
The present invention relates to compounds of formula I:
##SPC1## wherein R.sub.1 is hydroxy, methoxy, mercapto, hydrazino,
substituted hydrazino, chloro, amino, alkylamino, dialkylamino,
hydroxyalkylamino, aralkylamino or substituted aralkylamino and
R.sub.2 is phenylalkyl having 1 to 3 carbon atoms in the alkyl
moiety and at least two alkoxy, alkyl, halogen, hydroxy, nitro,
amino, substituted amino, aminomethyl, acylamino, carboxy,
carboxyalkyl or hydroxymethyl groups in the benzene ring or
naphthylalkyl, tetrahydronaphthylalkyl, quinolylalkyl,
tetrahydroquinolylalkyl or isoquinolylalkyl, each having 1 to 3
carbon atoms in the alkyl moiety and pharmaceutically acceptable
acid addition salts thereof. These compounds are useful as
antianginal or bronchial dilator agents.
Inventors: |
Schwender; Charles F. (Lebanon,
NJ) |
Assignee: |
Warner-Lambert Company (Morris
Plains, NJ)
|
Family
ID: |
23533502 |
Appl.
No.: |
05/388,290 |
Filed: |
August 14, 1973 |
Current U.S.
Class: |
544/264; 544/265;
514/826; 544/277 |
Current CPC
Class: |
C07D
473/00 (20130101); C07D 239/48 (20130101); Y10S
514/826 (20130101) |
Current International
Class: |
C07D
239/00 (20060101); C07D 239/48 (20060101); C07D
473/00 (20060101); C07d 057/38 () |
Field of
Search: |
;260/252,253,254 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
3412093 |
November 1968 |
Podesva et al. |
|
Primary Examiner: Daus; Donald G.
Assistant Examiner: Tighe; Anne Marie T.
Attorney, Agent or Firm: Graddis; Albert H. Chow; Frank
S.
Claims
I claim:
1. A compound of the formula I: ##SPC6##
wherein R.sub.1 is, chloro, hydroxy, mercapto, alkoxy of 1 to 6
carbon atoms, hydrazino, amino, amino substituted by one or two
alkyl groups each of 1 to 6 carbon atoms, amino substituted by
1-naphthylmethyl or benzyl, or hydroxy-alkylamino of 1 to 6 carbon
atoms and R.sub.2 is 1-naphthylmethyl, phenylmethyl, and
phenylethyl substituted on the phenyl group by two or three alkoxy
groups of 1 to 6 carbon atoms, 2 or 3 alkyl groups of 1 to 6 carbon
atoms, or two chloros and pharmaceutically acceptable salts
thereof.
2. A compound according to claim 1 in which R.sub.1 is methoxy and
R.sub.2 is 3,4-dimethoxybenzyl.
3. A compound according to claim 1 in which R.sub.1 is mercapto and
R.sub.2 is 3,4-dimethoxybenzyl.
4. A compound according to claim 1 in which R.sub.1 is
1-naphthylmethylamino and R.sub.2 is 3,4-dimethoxybenzyl.
5. A compound according to claim 1 in which R.sub.1 is amino and
R.sub.2 is 3,4-dimethoxybenzyl.
6. A compound according to claim 1 in which R.sub.1 is hydroxy and
R.sub.2 is 3,4-dimethoxybenzyl.
7. A compound according to claim 1 in which R.sub.1 is benzylamino
and R.sub.2 is 3,4-dimethoxybenzyl.
8. A compound according to claim 1 in which R.sub.1 is
2-hydroxyethylamino and R.sub.2 is 3,4-dimethoxybenzyl.
9. A compound according to claim 1 in which R.sub.1 is chloro and
R.sub.2 is 3,4-dimethoxybenzyl.
10. A compound according to claim 1 in which R.sub.1 is hydrazino
and R.sub.2 is 3,4-dimethoxybenzyl.
11. A compound according to claim 1 in which R.sub.1 is
1-propylamino and R.sub.2 is 3,4-dimethoxybenzyl.
12. A compound according to claim 1 in which R.sub.1 is chloro and
R.sub.2 is 2-(3,4-dimethoxyphenyl)ethyl.
13. A compound according to claim 1 in which R.sub.1 is amino and
R.sub.2 is 2-(3,4-dimethoxyphenyl)ethyl.
14. A compound according to claim 1 in which R.sub.1 is chloro and
R.sub.2 is 1-naphthylmethyl.
15. A compound according to claim 1 in which R.sub.1 is amino and
R.sub.2 is 1-naphthylmethyl.
16. A compound according to claim 1 in which R.sub.1 is propylamino
and R.sub.2 is 1-naphthylmethyl.
17. A compound according to claim 1 in which R.sub.1 is
1-hydroxyethylamino and R.sub.2 is 1-naphthylmethyl.
18. A compound according to claim 1 in which R.sub.1 is amino and
R.sub.2 is 3,4-dimethylbenzyl.
19. A compound according to claim 1 in which R.sub.1 is chloro and
R.sub.2 is 3,4-dichlorobenzyl.
20. A compound according to claim 1 in which R.sub.1 is amino and
R.sub.2 is 3,4-dichlorobenzyl.
Description
The present invention is concerned with novel compounds and, more
particularly, the present invention is concerned with
aralkyl-substituted purines and pyrimidines having structural
formula I: ##SPC2##
wherein R.sub.1 is hydroxy, methoxy, mercapto, hydrazino,
substituted hydrazino, chloro, amino, alkylamino, dialkylamino,
hydroxyalkylamino, aralkylamino or substituted aralkylamino and
R.sub.2 is phenylalkyl having 1 to 3 carbon atoms in the alkyl
moiety and at least two alkoxy, alkyl, halogen, hydroxy, nitro,
amino, substituted amino, aminomethyl, acylamino, carboxy,
carboxyalkyl or hydroxymethyl groups in the benzene ring or
naphthylalkyl, tetrahydronaphthylalkyl, quinolylalkyl,
tetrahydroquinolylalkyl or isoquinolylalkyl, each having 1 to 3
carbon atoms in the alkyl moiety and pharmaceutically acceptable
acid addition salts thereof.
In addition, esters or amides of the above compounds utilizing
alkanoyl or aralkanoyl, such as acetyl, propionyl, benzoyl,
succinoyl and the like, and the pharmaceutically acceptable acid
addition salts are also within the scope of this invention.
In the above definitions for R.sub.1, the term "alkyl" means an
aliphatic hydrocarbon having 1 to 6 carbon atoms, for example,
methyl, propyl, isopropyl, isobutyl and the like. The term "aryl"
denotes an aromatic hydrocarbon having 6 to 14 carbon atoms, for
example, phenyl, naphthyl, anthryl and the like. The term "aralkyl"
designates a combination of the hereinbefore defined alkyl and aryl
groups. Substituted hydrazino denotes hydrazino substituted on
either nitrogen atom or both nitrogen atoms by one or more alkyl or
aryl groups.
In the above definitions for R.sub.2, the term "alkyl" stands for
an aliphatic hydrocarbon of 1 to 6 carbon atoms, unless otherwise
specified, and applies to the alkyl residues of the alkoxy and acyl
moieties. Substituted amino includes within its scope amino groups
substituted by alkyl and aryl groups defined in the preceding
paragraph. Halogen encompasses all of the halo groups, chloro,
bromo, iodo and fluoro.
Among the preferred compounds of this invention are those purine
derivatives wherein R.sub.1 is chloro, amino, hydroxy, hydrazino,
n-propylamino or 2-hydroxyethylamino and R.sub.2 is dimethoxybenzyl
and R.sub.1 is amino and R.sub.2 is dichlorobenzyl,
3,4-dimethylbenzyl.
The compounds of this invention exhibit a unique mode of biological
action in that they produce selective dilation of certain coronary
arteries causing a redistribution of blood flow towards ischemic
areas of the heart enhancing perfusion and reducing anoxia which
cause anginal pains. This biological activity is demonstrated in
accordance with the procedure described in J. Pharmacol. Exp.
Ther., 176,184 (1971). Only nitroglycerin and some
.beta.-adrenergic blockers have been demonstrated to similarly
redistribute blood flow to ischemic areas by large coronary artery
dilation. See Eur. J. Pharmacol., 16, 271 (1971). The compounds of
this invention offer an advantageous treatment of angina without
interference with adrenergic control of the heart or without
resorting to the use of nitrates.
Existing coronary vasodilators such as dipyridamole and chromonar
dilate smaller vessels increasing coronary blood flow without
redistributing flow to needed ischemic areas. In severe ischemia,
dipyridamole actually induced anginal attacks in man since it
diverted blood flow away from ischemic areas through its dilator
action on smaller coronary vessels. See Ann. Rep. Med. Chem., 7, 69
(1972).
Experimentally, this blood flow redistribution is demonstrable in a
dog by measuring changes in resistance to blood flow of larger
coronary arteries (RL) relative to small vessel physical resistance
to flow (RT), using the protocol described in J. Pharmacol. Exp.
Ther., 176, 184 (1971).
Generally, the compounds of this invention at a dose of about 1-10
mg/kg were observed to effect a drop in the RL:RT ratio. Known
coronary vasodilators such as dipyridamole and chromonar caused an
increased RL:RT ratio reflecting a redistribution of blood flow
away from ischemic tissues.
The compounds of this invention, particularly the preferred
species, are indicated in the management of angina pectoris. A
usual dose of 1-10 mg/kg by injection or orally two or three times
daily is suggested to prevent anginal attack. These compounds can
be administered by combining with excipients such as lactose or
water for injection.
In addition to the antianginal effects described above, the
compounds of this invention were also observed to protect guinea
pigs from histamine-induced bronchial spasm. Thus tested in
accordance with the procedure described in J. Pharmacol. Exp.
Ther., 90, 254 (1947) at a dose of 1-50 mg/kg intraperitoneally,
they were effective to protect the guinea pigs against bronchial
spasms which had been induced by the administration of one mg of
histamine. At this dosage level, a mild cardiotonic effect was also
observed. Hence, the compounds of this invention are also useful in
the treatment of bronchial spasms such as in bronchial asthma.
Generally speaking, a dose of 1-50 mg/kg administered orally or by
intramuscular injection is suggested.
According to the present invention, the above compounds are
prepared by processes as illustrated in the following reaction
scheme: ##SPC3##
Referring now to the reaction scheme, in Method A
5-amino-4,6-dichloropyrimidine is condensed with a substituted
amine in butanol and triethylamine. The resultant substituted amino
pyrimidine II is cyclized with triethyl or trimethyl orthoformate
to the 6-chloropurine derivative III as in Method B. Treating said
6-chloropurine derivative with ammonia as brought out in Method C,
or an appropriate nucleophile as in Method D, gives the
6-substituted purine derivative I.
The starting material for the first process,
5-amino-4,6-dichloropyrimidine, is available from commercial
chemical suppliers such as Krishell Laboratories, Inc. The amino
compounds utilized in Method A, triethyl- and trimethyl
orthoformate of Method B and the nucleophiles of Method D are
available from the Aldrich Chemical Company or readily prepared by
methods well known to those skilled in the art.
In addition, treatment of adenine with a substituted benzyl or
aralkyl halide in the presence of a base such as sodium hydride
gives the desired 9-substituted adenine directly. This reaction is
illustrated by the following reaction scheme: ##SPC4##
Adenine, the starting material for the second process is
commercially available from the Aldrich Chemical Company as are the
requisite aralkyl halides, R.sub.2 X.
The following experiments are general procedures for the
preparation of the compounds of this invention: all temperatures
are in degrees centigrade. ##SPC5##
REFERENCES
METHOD A
5-Amino-4-chloro-6-(3,4-dimethoxybenzylamino)pyrimidine. A reaction
mixture containing 1.00 g (6.09 mmols) of
4,6-dichloro-5-aminopyrimidine, 1.22 g (7.30 mmols) of
3,4-dimethoxybenzylamine, 1.02 ml (7.30 mmols) of triethylamine and
35 ml of 1-butanol was refluxed overnight for 17 hours. Evaporation
of the reaction mixture in vacuo gave a residual oil which was
crystallized by trituration with water. The crude yellow solid was
recrystallized from methanol-water to give 1.61 g (90.1 percent),
mp 185.degree.-188.degree., of crystalline product. The analytical
sample was obtained by recrystallization from methanol-water;
yield, 1.36 g (76.9 percent); mp 188.degree.-191.degree..
METHOD B
6-Chloro-9-(3,4-dimethoxybenzyl)purine. To a suspension of 15.6 g
(52.8 mmols) of
5-amino-4-chloro-6-(3,4-dimethoxybenzylamino)-pyrimidine in 100 ml
of triethyl orthoformate was added 149 mg (1.36 mmols) of
ethanesulfonic acid and the resulting mixture was heated at
80.degree. for 15 min. Upon cooling and addition of hexane to the
reaction mixture, a yellow precipitate formed which was collected
by filtration; yield, 15.4 g (95.6 percent) mp
159.degree.-163.degree.. Recrystallization from EtOH--H.sub.2 O
gave the analytical sample; yield 13.2 g (82.2 percent) mp
160.degree.-164.degree..
METHOD C
9-Veratryl-9H-adenine. In a steel bomb was heated a mixture of 4.00
g (13.1 mmols) of 6-chloro-9-veratrylpurine and 20 ml of liquid
NH.sub.3 for 17 hours at 54.degree.. The excess NH.sub.3 was
allowed to evaporate and the white solid residue was recrystallized
from EtOH--H.sub.2 O to give the crude product; yeild 3.42 g (91.3
percent) mp 191.degree.-193.degree.. The analytical sample was
obtained by a second recrystallization from EtOH--H.sub.2 O giving
2.33 g (62.3 percent) mp 192.degree.-194.degree. .
METHOD D
6-Propylamino-9-veratrylpurine. A reaction mixture containing 5.14
g (16.8 mmol) of 6-chloro-9-veratrylpurine, 7.0 ml (84.9 mmol) of
propylamine and 60 ml of EtOH was refluxed for 2.5 hrs. Evaporation
of the reaction mixture gave a residual solid which was
recrystallized from acetone to give the crude product; yield 4.78 g
(87.0 percent) mp 117.degree.-120.degree.. Further
recrystallizations of the crude white material from acetone gave
the analytical material; mp 122.degree.-125.degree. .
METHOD E
9-(3,4-Dimethylbenzyl)adenine (W10,813). An ice cold suspension
containing adenine (10.0 g, 74 mmol), 3.74 g (89.0 mmol) of NaH (57
percent suspension in oil) and 120 ml of DMF was allowed to reach
RT and stirred for one additional hour. 3,4-Dimethylbenzyl chloride
13.7 g (89 mmol) was added to the reaction mixture. The resultant
mixture was allowed to react at RT for 17 hrs with stirring. The
reaction mixture was cooled and the resultant precipitate was
collected by filtration giving the crude reaction product.
Recrystallization of the crude white solid from methanol gave 3.90
g (21 percent) of white crystalline material; mp
206.degree.-209.degree.. The analytical sample was obtained by
recrystallization from methanol; mp 211.degree.-213.degree. .
Anal. Calcd for C.sub.14 H.sub.15 N.sub.5 : C, 66.38; H, 5.97; N,
27.65. Found: C, 66.38; H, 6.10; N, 27.80.
* * * * *