U.S. patent number 5,270,316 [Application Number 07/599,758] was granted by the patent office on 1993-12-14 for condensed purine derivatives.
This patent grant is currently assigned to Kyowa Hakko Kogyo Co., Ltd.. Invention is credited to Akira Karasawa, Kazuhiro Kubo, Takeshi Kuroda, Kenji Ohmori, Tetsuji Ohno, Junichi Shimada, Fumio Suzuki.
United States Patent |
5,270,316 |
Suzuki , et al. |
December 14, 1993 |
**Please see images for:
( Certificate of Correction ) ** |
Condensed purine derivatives
Abstract
There are disclosed condensed purine derivatives represented by
formula; ##STR1## in which R.sup.3 represents hydrogen, lower alkyl
or benzyl; each of X.sup.1 and X.sup.2 independently represents
hydrogen, lower alkyl, aralkyl or phenyl; and n is an integer of 0
or 1; R.sup.1 represents hydrogen, lower alkyl, alicyclic alkyl,
noradamantan-3-yl, dicyclopropylmethyl or styryl; and R.sup.2
represents hydrogen, lower alkyl or alicyclic alkyl; or a
pharmaceutically acceptable salt thereof. The derivatives and
pharmaceutically acceptable salts are useful as diuretics, renal
protecting agents, antiallergic agents and hypotensives.
Inventors: |
Suzuki; Fumio (Mishima,
JP), Shimada; Junichi (Shizuoka, JP),
Kuroda; Takeshi (Shizuoka, JP), Kubo; Kazuhiro
(Shizuoka, JP), Karasawa; Akira (Huntingdon Valley,
PA), Ohno; Tetsuji (Shizuoka, JP), Ohmori;
Kenji (Mishima, JP) |
Assignee: |
Kyowa Hakko Kogyo Co., Ltd.
(Tokyo, JP)
|
Family
ID: |
17527409 |
Appl.
No.: |
07/599,758 |
Filed: |
October 19, 1990 |
Foreign Application Priority Data
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|
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Oct 20, 1989 [JP] |
|
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1-273403 |
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Current U.S.
Class: |
514/267; 544/265;
544/276; 544/273; 544/251 |
Current CPC
Class: |
A61P
13/02 (20180101); A61P 11/00 (20180101); A61P
15/00 (20180101); A61P 13/12 (20180101); A61P
7/10 (20180101); A61P 9/00 (20180101); C07D
471/14 (20130101); A61P 7/00 (20180101); A61P
11/08 (20180101); A61P 9/12 (20180101); A61P
11/06 (20180101); C07D 487/14 (20130101); A61P
13/00 (20180101) |
Current International
Class: |
C07D
471/14 (20060101); C07D 471/00 (20060101); C07D
487/00 (20060101); C07D 487/14 (20060101); A61K
031/52 (); C07D 487/14 () |
Field of
Search: |
;514/262,267
;544/251 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0390111 |
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Oct 1990 |
|
EP |
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0417790 |
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Mar 1991 |
|
EP |
|
Other References
Sepiol et al., Chemical Abstracts, vol. 86: 29222k (1987). .
Ohsaki et al., Chemical Abstracts, vol. 106: 84536x (1987). .
Habraken et al., Chemical Abstracts, vol. 112: 191473v May 21,
1990. .
Temple et al. J. Med. Chem., vol. 23, No. 11, pp. 1188-1198 (1980).
.
Ienaga et al. Liebigs Ann. Chem., vol. 11, pp. 1972-1880
(1979)..
|
Primary Examiner: Shah; Mukund J.
Assistant Examiner: Bernhardt; E.
Attorney, Agent or Firm: Fitzpatrick, Cella, Harper &
Scinto
Claims
What is claimed is:
1. A condensed purin derivative represented by Formula (I):
##STR38## wherein: R.sup.1 represents cycloalkyl having 3 to 6
carbon atoms, noradamantan-3-yl, dicyclopropylmethyl or styryl;
R.sup.2 represents hydrogen, lower alkyl or cycloalkyl having 3 to
6 carbon atoms;
R.sup.3 is lower alkyl;
n is an integer of 0 or 1, and each of X.sup.1 and X.sup.2
independently represents hydrogen, lower alkyl, aralkyl or phenyl;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein n is 0.
3. The compound according to claim 1, wherein the cycloalkyl having
3 to 6 carbon atoms being cyclopropyl, cyclopentyl or
cyclohexyl.
4. The compound according to claim 3, wherein X.sup.1 is
hydrogen.
5. The compound according to claim 3, wherein X.sup.1 is ethyl and
X.sup.2 is hydrogen.
6. A compound which is selected from the group consisting of:
2-cyclopentyl-8-ethyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin
-5-one;
8-ethyl-2-(noradamantan-3-yl)-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1
-i] purin-5-one;
2-(dicyclopropylmethyl)-8-ethyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2
,1-i] purin-5-one;
8-ethyl-1-methyl-4-n-propyl-2-styryl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]
purin-5-one and a pharmaceutically acceptable salt thereof.
7. A compound according to claim 6 or 1, wherein said salt is
selected from the group consisting of a pharmaceutically acceptable
acid addition salt, a pharmaceutically acceptable metal salt, a
pharmaceutically acceptable ammonium salt, a pharmaceutically
acceptable organic amine addition salt and a pharmaceutically
acceptable amino acid addition salt.
8. A pharmaceutical composition comprising a pharmaceutical carrier
and as an active ingredient, an effective amount of the compound as
defined by claim 6 or 1.
Description
BACKGROUND OF THE INVENTION
The present invention relates to novel purine derivatives which
possess diuretic, renal protecting, bronchodilatory, antiallergic
and hypotensive effects.
As condensed purine derivatives which are structurally analogous to
the presently claimed compounds, a compound represented by formula
(A) and having a slight bronchodilatory effect is disclosed in J.
Med. Chem., 23, 1188 (1980): ##STR2##
Compounds represented by formula (B) are disclosed in Liebigs. Ann.
Chem., 11, 1872 (1979): ##STR3## where Q is NH or O.
SUMMARY OF THE INVENTION
An object of the present invention is to provide novel condensed
purine derivatives represented by the formula (I): ##STR4## in
which R.sup.3 represents hydrogen, lower alkyl or benzyl; each of
X.sup.1 and X.sup.2 independently represents hydrogen, lower alkyl,
aralkyl or phenyl; and n is an integer of 0 or 1; R.sup.1
represents hydrogen, lower alkyl, alicyclic alkyl,
noradamantan-3-yl, dicyclopropylmethyl or styryl; and R.sup.2
represents hydrogen, lower alkyl, or alicyclic alkyl (hereinafter
referred to as Compound (I), and other compounds with other
formulae shall be likewise referred to); or a pharmaceutically
acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
In the definitions of the groups in formula (I), the lower alkyl
refers to a straight or branched alkyl having 1 to 6 carbon atoms,
and includes, for example, methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc. The
alicyclic alkyl is those having 3 to 6 carbon atoms, and includes,
for example, cyclopropyl, cyclopentyl, cyclohexyl, etc. The aralkyl
is those having 7 to 15 carbon atoms, and includes, for example,
benzyl, phenethyl, benzhydryl, etc.
The pharmaceutically acceptable salts of Compound (I) include acid
addition salts, metal salts, ammonium salts, organic amine addition
salts, amino acid addition salt, etc.
The pharmaceutically acceptable acid addition salts of Compound
(I), include inorganic acid salt such as hydrochloride, sulfate,
phosphate, etc. and organic acid salts such as acetate, maleate,
fumarate, tartarate, citrate, etc. The pharmaceutically acceptable
metal salts include alkali metal salts such as sodium salt,
potassium salt etc.; alkaline earth metal salts such as magnesium
salt, calcium salt, etc. and further an aluminum salt and a zinc
salt. The pharmaceutically acceptable organic amine addition salts
include addition salt of morpholine, piperidine, etc. The
pharmaceutically acceptable amino acid addition salts include
lysine, glycine, phenylalanine, etc.
The methods for preparing Compound (I) are described below.
When the defined groups are changed under the conditions of the
following processes or are inadequate to proceeding of the
following processes, processes can be readily carried out by a
usual method in the organic synthetic chemistry, for example, by
protection of functional groups, elimination of protecting
groups.
PROCESS 1
Compound (Ia), which is a Compound (I) where ##STR5## is
synthesized according to the following reaction steps. ##STR6##
wherein R.sup.1, R.sup.2, R.sup.3, X.sup.1, X.sup.2 and n have the
same significance as described above
Compound (IV) is obtained by reacting Compound (II) with Compound
(III) in the absence or presence of a solvent. Any solvent is used
so long as it is inert to the reaction. The solvent includes, for
example, dimethylamines such as dimethylformamide,
dimethylacetamide, etc.; kentones such as acetone, methyl ethyl
ketone, etc.; aromatic hydrocarbons such as toluene, xylene, etc.;
halogenated hydrocarbons such as dichloroethane,
1,1,2,2-tetrachloroethane, etc.; dimethylsulfoxide, etc. The
solvent is used alone or in combination. The reaction is carried
out at 50.degree. to 80.degree. C and completed in 5 minutes to 24
hours.
The starting Compound (II) is synthesized by a notorious method [J.
Chem. Soc. Perkin I, 739 (1973)] or by a modified method of Perkin.
The starting Compound (III) is commercially available.
Compound (Ia) is obtained by reacting Compound (IV) with a
halogenating agent or an inorganic acid in the absence or presence
of a solvent.
The halogenating agent includes, for example, thionyl chloride,
phosphorus oxychloride, etc. The inorganic acid includes, for
example, hydrochloric acid, hydrobromic acid, hydroiodic acid,
phosphoric acid, etc.
The solvent includes, for example, halogenated hydrocarbons such as
methylene chloride, chloroform, dichloroethane, etc.;
dimethylformamide, dimethylsulfoxide, etc. The solvent is used
alone or in combination. The reaction is carried out at -10.degree.
to 150.degree. C. and completed in 5 minutes to 24 hours.
PROCESS 2
Compound (Ib) which is Compound (I) where ##STR7## is synthesized
according to the following reaction steps. ##STR8## wherein each of
Hal.sup.a and Hal.sup.b independently represents chlorine, bromine
or iodine; and R.sup.1, R.sup.2, X.sup.1, X.sup.2 and n have the
same significance as described above.
Compound (VII) is prepared by reacting Compound (V) with Compound
(VI) in a solvent in the presence of a silyl compound. Examples of
the silyl compound include bistrimethylsilylacetamide (BSA),
bistrimethylsilyltrifluoroacetamide (BSTA), etc. Any solvent is
used so long as it is inert to the reaction. The solvent includes,
for example, ethers such as tetrahydrofuran, dioxane, etc.;
alcohols such as methanol, ethanol, etc.; dimethylformamide,
dimethylsulfoxide, etc., and is used alone or in combination. The
reaction is carried out at -78.degree. to 150.degree. C. and
completed in 5 minutes to 24 hours.
Compound (Ib) is obtained by reacting Compound (VII) with an acid
in the absence or presence of a solvent. Examples of the acid
include an inorganic acid such as hydrochloric acid, sulfuric acid,
phosphoric acid, etc.; or an organic acid such as methanesulfonic
acid, acetic acid, etc. Any solvent can be used so long as it is
inert to the reaction, and includes, for example, aromatic
hydrocarbons such as benzene, toluene, etc.; alcohols such as
methanol, ethanol, etc., dimethylformamide, etc. The solvent is
used alone or in combination. The reaction is carried out by
heating at 50.degree. to 350.degree. C. and completed in 5 minutes
to 24 hours.
PROCESS 3
Compound (Ic) which is Compound (I) where ##STR9## is synthesized
according to the following reaction steps. ##STR10## wherein Y
represents a leaving group; and R.sup.1, R.sup.2, R.sup.3, X.sup.1,
X.sup.2 and n have the same significance as described above.
Examples of the leaving group denoted by Y include halogen such as
chlorine, bromine, etc.; or methylthio, methanesulfonyloxy,
etc.
Compound (X) is obtained by reacting Compound (VIII) with Compound
(IX) in the absence or presence of a solvent. Any solvent is used
so long as it is inert to the reaction.
The solvent includes, for example, ethers such as tetrahydrofuran,
dioxane, etc.; amides such as dimethylformamide, etc.; alcohols
such as methanol, ethanol, etc.; dimethylsulfoxide, etc., and is
used alone or in combination. The reaction is carried out at
0.degree. to 180.degree. C. and completed in 30 minutes to 24
hours.
The starting Compound (VIII) is synthesized by a notorious method
[Ber., 30, 2400 (1877)] or by its modified method.
Compound (Ic) is obtained by reacting Compound (X) with a
halogenating agent or an inorganic acid.
The halogenating agent includes, for example, thionyl chloride,
phosphorus oxychloride, etc. The inorganic acid includes, for
example, hydrochloric acid, phosphoric acid, etc. The reaction is
carried out at 0.degree. to 180.degree. C. and completed in 5
minutes to 24 hours.
PROCESS 4
Compound (I-1) is Compound (I) where R.sup.2 represents groups
other than hydrogen and Compound (I-2) obtained in Processes 1
through 3 is Compound (I) where R.sup.2 represents hydrogen.
Compound (I-1) is obtained by reacting Compound (I-2) with Compound
(XI) represented by the following formula in the presence or
absence of a base.
wherein Z represents a leaving group and R.sup.2a has the same
significance as that of R.sup.2 except for hydrogen.
Examples of the leaving group denoted by Z include halogen such as
chlorine, bromine, iodine, etc.; alkylsulfonyloxy such as
methanesulfonyloxy, etc.; arylsulfonyloxy such as
phenylsulfonyloxy, p-toluenesulfonyloxy, etc.
The base includes, for example, alkali metal carbonates such as
potassium carbonate, sodium carbonate, etc.; hydrated alkali metals
such as sodium hydride, etc.; alkali metal alkoxides such as sodium
methoxide, sodium ethoxide, etc.
The solvent is used alone or in combination, and includes, for
example, ethers such as tetrahydrofuran, dioxane, etc.; amides such
as dimethylformamide, etc.; alcohols such as methanol, ethanol,
etc.; dimethylsulfoxide and the like. The reaction is carried out
at 0.degree. to 180.degree. C. and completed in 30 minutes to 24
hours.
PROCESS 5
Compound (Ic) can be prepared according to the following reaction
steps. ##STR11## wherein Tr represents triphenylmethyl; and
R.sup.1, R.sup.3, Y, Z, X.sup.1, X.sup.2 and n have the same
significance as defined above.
Compound (XIII) is obtained by reacting Compound (XII) with TrCl,
preferably in the presence of a base.
The solvent and base to be used in the reaction and the reaction
condition are the same as mentioned in Process 4.
The starting Compound (XII) can be synthesized by a notorious
method [J. Amer. Chem. Soc., 76, 5633 (1954)] or by its modified
method.
Compound (XV) is obtained by reacting Compound (XIII) with Compound
(XIV), preferably in the presence of a base.
The solvent and base to be used in the reaction and the reaction
condition are the same as mentioned in Process 4.
Compound (XVI) is obtained by reacting Compound (XV) with Compound
(IX) in the absence or presence of a solvent.
The solvent to be used in the reaction and the reaction condition
are the same as mentioned in the step of Compound (VIII) to
Compound (X) in Process 3.
Compound (Ic) is obtained by reacting Compound (XVI) with a
halogenating agent or an inorganic acid.
The halogenating agent includes, for example, thionylchloride or
phosphorus oxychloride, etc.
The inorganic acid includes, for example, hydrochloride or
phosphoric acid, etc.
The reaction is performed at 0.degree..about.180.degree. C. and
completed in 5 minutes to 24 hours.
The intermediates and objective compounds in the respective methods
described above can be isolated and purified by purification
methods conventionally used in organic synthesis chemistry, for
example, filtration, extraction, washing, drying, concentration,
recrystallization, various column chromatographies, etc.
Furthermore, the intermediates may also be provided in the
subsequent reaction, without being further purified.
In the case that it is desired to obtain salts of Compound (I),
when Compound (I) is obtained in the form of its salt, Compound (I)
may be purified as it is. Further in the case that Compound (I) is
obtained in the free form, its salts may be formed in a
conventional manner, for example, Compound (I) is suspended or
dissolved in an appropriate solvent, and an acid or base is added
to the solution or suspension.
Furthermore, Compound (I) and pharmaceutically acceptable salts
thereof may also be present in the form of addition products to
water or to various solvents; in this case, the addition products
are also included in the present invention.
Furthermore, some of Compounds (I) may have optical isomers. In the
present invention, all possible stereoisomers and their mixtures
are all included.
Specific examples of Compound (I) are shown in Tables 1-1 through
1-3.
TABLE I-1
__________________________________________________________________________
##STR12## Compound No. R.sup.1 R.sup.2 R.sup.3 n X.sup.1 X.sup.2
__________________________________________________________________________
1 H CH.sub.3 (CH.sub.2).sub.2 CH.sub.3 0 8-H 7-H 2 " H " " " " 3 "
CH.sub.3 " 1 " " 4 " " " 0 8-C.sub.2 H.sub.5 " 5 " " " " 8-H
##STR13## ##STR14## H " " " 7-H 7 " CH.sub.3 " " " " 8 " H " "
8-C.sub.2 H.sub.5 9 H " ##STR15## " 8-H " 10 " CH.sub.3 " " " " 11
##STR16## H (CH.sub.2).sub.2 CH.sub.3 " " ##STR17## 12 " " " "
##STR18## 7-H 13 " " " " 8-CH(CH.sub.3).sub.2 " 14 " " " "
8-CH.sub.3 8-CH.sub.3 15 " " " " ##STR19## 7-H 16 " " " "
8-CH.sub.3 " 17 " " " " 8-(CH.sub.2).sub.2 CH.sub.3 " 18 " " " "
8-H 7-C.sub.2 H.sub.5 19 " " " " " 7-CH.sub.3 20 ##STR20## " " "
8-C.sub.2 H.sub.5 7-H 21 ##STR21## " " " " " 22 ##STR22## CH.sub.3
" " " " 23 H H " " 8-H ##STR23##
__________________________________________________________________________
TABLE I-2 ______________________________________ ##STR24## Compound
No. R.sup.2 R.sup.1 ______________________________________ 24 H H
25 CH.sub.3 H 26 (CH.sub.2).sub.3 CH.sub.3 H 30 H ##STR25## 31 H
##STR26## 32 H ##STR27## ______________________________________
TABLE I-3 ______________________________________ ##STR28## Compound
No. R.sup.1 R.sup.2 R.sup.3 n
______________________________________ 27 H CH.sub.3
(CH.sub.2).sub.3 CH.sub.3 0 28 " " " 1 29 " H CH.sub.3 0 33
##STR29## CH.sub.3 (CH.sub.2).sub.3 CH.sub.3 " 34 ##STR30## " " "
35 ##STR31## " " " 36 ##STR32## " " 1 37 ##STR33## " " " 38
##STR34## " " " 39 ##STR35## H CH.sub.3 0 40 ##STR36## " " " 41
##STR37## " " " ______________________________________
Compound (I) or its pharmaceutically acceptable salts have
diuretic, renal protecting, bronchodilatory and hypotensive
activities, etc. Accordingly, Compound (I) or its pharmaceutically
acceptable salts are useful as diuretics, renal protecting agents,
bronchodilatory agents, antiallergic agents and hypotensives.
Next, pharmaceutical activities of Compound (I) are explained
below.
(1) Acute Toxicity
The compounds were orally administrated to male dd-mice weighing
20.+-.1 g. Minimum lethal dose (MLD) was determined by observing
the mortality for seven days after the administration.
The results are shown in Table 2.
TABLE 2 ______________________________________ MLD Compound (mg/kg)
______________________________________ 1 >300 4 >300 5
>300 9 Sa >300 10 Sa >300 11 Sa >300 12 Sa >300 14
Sa >300 15 Sa >300 17 Sa >300 18 Sa >300 19 Sa >300
24 >300 25 >300 ______________________________________ *Sa is
hydrochloride of the Compound.
(2) Diuretic Activity
Wistar male rats weighing 150 to 300 g were used after they were
fasted for 18 hours. A test compound or saline (control) was orally
administered to rats and urine was collected for 6 hours. The test
was performed using 3 groups per the test compound, and each group
consists of 3 animals. The urine was metered by a measuring
cylinder and electrolytes (Na.sup.+ and K.sup.+) in the urine were
assayed with a flame photometer (model 775A manufactured by Hitachi
Ltd.).
The results are shown in Table 3.
Parameters in Table 3 are all expressed by relative value for
control.
TABLE 3 ______________________________________ Dose Urine Excretion
Excretion (mg/ volume of Na.sup.+ of K.sup.+ Compound kg) (%) (%)
(%) Na.sup.+ /K.sup.+ ______________________________________
Control -- 0 0 0 1.00 5 25 165 197 77 1.67 6 1.6 121 102 30 1.55 7
25 128 114 56 1.37 8 6.25 42 46 1 1.45 9 Sa 25 88 65 31 1.26 12 Sa
1.6 159 102 33 1.52 13 Sa 6.25 140 92 18 1.63 14 Sa 6.25 113 75 43
1.23 25 145 162 31 2.00 15 Sa 6.25 137 153 9 2.32 25 95 90 26 1.51
16 Sa 1.6 80 99 31 1.52 17 Sa 6.25 138 158 18 2.91 18 Sa 25 92 65
37 1.20 19 Sa 25 111 87 31 1.43 Furosemide** 25 75 64 57 1.07
______________________________________ *Sa is hydrochloride of the
Compound **The Merck Index 11th ed., 4221 (1989)
(3) Effect on Renal Protecting Activity (Glycerol-induced Renal
Deficient Model)
Renal insufficiency is the condition that homeostasis of body fluid
failed to maintain by disorder of renal function. It is well known
that subcutaneous or intramuscular administration of glycerol to
rat induce acute renal insufficiency characterized by renal tubular
disturbance [Can J. Physiol. Pharmacol., 65, 42 (1987)].
Wistar male rats (fasted both food and water for 18 hours) were
used. A test compound or saline (control) was intraperitoneally
administered (dose: 10 mg/kg) to rats. After 30 minutes rats were
anesthesized with ether and the back skin was picked up and 0.8
ml/100 g of 50% glycerol was subcutaneously administered. 24 hours
after the glycerol injection, the rats were anesthesized with ether
and 5 ml of the blood was collected from the descending aorta. To
obtain the serum, after allowing it to stand for 30 minutes or
longer, the blood sample was centrifuged at 3000 rpm for 10
minutes. Creatinine in the serum sample was determined using
autoanalyzer (AU510, Olympus) or clinical analysis kit of
creatinine (Creatinine Test Wako; by Wako Pure Chemical Ind.,
Japan). Urea nitrogen in the serum was determined using
autoanalyzer (AU510; made by Olympus Optical Co., Ltd, Japan) or
clinical analysis kit of urea nitrogen (Urea nitrogen test wako; by
Wako Pure Chemical Ind., Japan).
The results are shown in Table 4.
Further, the left kidneys of test compound-treated groups and
control groups were taken out from the animals and the kidneys were
prepared for pathological sample.
As the result of pathologic autopsy for kidneys, it was indicated
that the renal insufficiency was improved by the test compounds as
shown in Table 4.
TABLE 4 ______________________________________ Creatinine in serum
Urea nitrogen in serum (mg/dl) (mg/dl) Glycerol treated Glycerol
treated Test Test compound compound administrated administrated
Compound (Significance (Significance No. Control for control*)
Control for control*) ______________________________________ 1 2.64
.+-. 1.94 .+-. 0.16 0.27 P < 0.005 2 2.49 .+-. 1.63 .+-. 0.19
0.43 P < 0.1 6 5.01 .+-. 1.81 .+-. 0.12 0.19 P < 0.001 7 3.63
.+-. 1.70 .+-. 0.17 137.9 .+-. 64.3 .+-. 7.1 0.29 P < 0.001 8.5
P < 0.001 8 4.64 .+-. 3.17 .+-. 0.32 147.0 .+-. 121.2 .+-. 9.0
0.24 P < 0.01 5.8 P < 0.05 14 Sa 4.81 .+-. 2.62 .+-. 0.40
168.5 .+-. 94.8 .+-. 14.3 0.09 P < 0.01 3.5 P < 0.01 15 Sa
4.81 .+-. 2.34 .+-. 0.12 168.5 .+-. 101.8 .+-. 11.8 0.09 P <
0.001 3.5 P < 0.01 16 Sa 4.81 .+-. 2.38 .+-. 0.24 168.5 .+-.
80.9 .+-. 9.5 0.09 P < 0.001 3.5 P < 0.001 17 Sa 4.31 .+-.
2.35 .+-. 0.11 147.1 .+-. 88.0 .+-. 4.9 0.12 P < 0.001 4.4 P
< 0.001 18 Sa 4.31 .+-. 2.85 .+-. 0.33 147.1 .+-. 101.2 .+-. 9.9
0.12 P < 0.01 4.4 P < 0.01 Amino- 2.03 .+-. 1.72 .+-. 0.07
46.2 .+-. 30.6 .+-. 2.0 phylline** 0.18 N.S. 6.5 P < 0.05 Furo-
3.22 .+-. 4.17 .+-. 0.41 110.7 .+-. 150.3 .+-. 13.7 cemide*** 0.35
N.S. 9.4 P < 0.05 Normal Glycerol untreated Glycerol untreated
control 0.50 .+-. 0.02 15.2 .+-. 0.9
______________________________________ *Student-t test was used for
level of significance **The Merck Index 11th 477 (1989) ***The
Merck Index 11th 4221 (1989) N.S. No significant difference Sa is
hydrochloride of the compound.
(4) Effects on Passive Schultz-Dale Reaction (Bronchodilatory
Effects)
Guinea pigs were passively sensitized as follows. Hartley male
guinea pigs weighing 350 to 500 g were injected intraperitoneally
with rabbit anti-egg albumin (EWA) serum prepared by the method of
Koda et al. [Folia pharmacol., Japon 66, 237, (1970)]. After 24
hours, the guinea pigs were stunned and exsanguinated, and then
trachea was excised. The zig-zag strips of the trachea were
prepared by the method of Emmerson and Mackay [J. Pharm.
Pharmacol., 31, 798, (1979)]. The strips were suspended in
Krebs-Henseleit solution at 37.degree. C. under aeration of a mixed
gas of 95% oxygen and 5% carbon dioxide, and incubated for one
hour. Antigen (EWA) was then introduced in the solution (final
concentration; 1 .mu.g/ml), and the contraction was measured by
isotonictrasducer (TD-112s, made by Nihon Kohden K.K., Japan) and
recorded on a recorder (Type 3066, made by Yokogawa-Hokushin Denki,
K.K. Japan). After the contraction curves reached plateau the
compounds were successively added in order to get cumulative
concentration-relaxation curves. Concentration of 50% relaxation
rate (IC50) was calculated from the regression line, which was
obtained from cumulative concentration-relaxation curves.
The results are shown in Table 5.
(5) Inhibition Effect on Platelet Activating Factor (PAF)-induced
Mortality
The experiment was performed by a minor modification of method of
Carlson et al. [Agents and Actions, 21, 379 (1987)]. Groups each
consisting of 10 male dd mice (weighing 28 to 32 g) were used, and
100 mg/kg of test compound or a saline (control) was orally
administrated. One hour after the administration of test compound,
40 .mu.g/kg of PAF (manufactured by Avanti Polar Lipids Co., Ltd.)
was intravenously administered. Two hours after PAF injection, the
mortality rate of the animals was observed. The compound whose
mortality rate was significantly (p<0.05: Fischer's accurate
probability tests) lower than control is regarded as having
inhibitory effect on PAF-induced mortality, and the results in
Table 5 were represented by minimum effective dose (MED).
TABLE 5 ______________________________________ Passive S -
PAF-induced mortality Compound D reaction inhibition No. IC.sub.50
(.mu.M) MED (mg/kg) ______________________________________ 1 0.0030
>100 2 21 100 4 0.036 >100 5 32 NT*.sup.3 6 >40 50 7 8.1
>100 8 72 NT*.sup.3 9 >40 100 10 Sa 9.7 NT*.sup.3 14 Sa 11
100 15 Sa >40 100 Theophylline*.sup.2 23 100
______________________________________ *.sup.2 The Merck Index 11th
ed., 9212 (1989) *.sup.3 not determined Sa is hydrochloride of the
compound.
(6) Effects on Experimental Asthma
Guinea pigs were passively sensitized as follows. Hartley male
guinea pigs weighing 350 to 500 g were intraperitoneally injected
with 1 ml of rabbit anti-egg alubmin (EWA) serum prepared by the
method of Koda et al. [Folia pharmacol., Japon, 66, 237 (1970)].
The animals were treated with intraperitoneal injection of
diphenhydramine (20 mg/kg) and propranolol (5 mg/kg), 30 minutes
before administration of test compounds. 17 hours after the
sensitization, the test compounds (50 mg/kg) or saline (control)
were orally administered to sensitized animals. After one hour from
the administration of the test compounds, the guinea pigs were
placed in plastic observation box and were exposed to an aerosal
antigen of 1.5% EWA.
The time until the onset of respiratory distress-like symptom
[collapse time (second)] was measured as a result of experimental
asthma.
The results are shown in Table 6.
TABLE 6 ______________________________________ Experimental asthma
Compound Collapse time (sec) ______________________________________
2 552 .+-. 20 5 542 .+-. 36 10 Sa 357 .+-. 65 13 Sa 374 .+-. 76
Theophylline* 414 .+-. 47 Control 254 .+-. 18
______________________________________ *The Merck Index 11th ed.,
9212 (1989) Sa is hydrochloride of the compound.
Compounds (I) or their pharmaceutically acceptable salts are used
directly or in various dosage forms. In the present invention,
pharmaceutical compositions are prepared by homogeneously mixing an
effective amount of Compound (I) or its pharmaceutically acceptable
salt with pharmaceutically acceptable carrier. It is desirable that
the pharmaceutical compositions are an appropriative dosable unit
for oral administration or injection administration.
In the preparation of orally administrated forms, any of useful
pharmaceutically acceptable carriers are used. In the case of
orally administrated liquid preparates such as suspensions and
syrups, for example, water, saccharides such as sucrose, sorbitol,
fructose, etc., glycols such as polyethyleneglycol,
propyleneglycol, etc., oils such as sesame oil, olive oil, soybean
oil, etc., antiseptics such as p-hydroxybenzoic acid esters, etc.,
and flavors such as strawberry flavor, peppermint etc. are used. In
the case of powder, pills, capsules and tablets; vehicles such as
lactose, glucose, sucrose, mannitol, etc.; disintegrators such as
starch, sodium alginate, etc.; lubricants such as magnesium
stearate, talc, etc.; binders such as polyvinyl alcohol,
hydroxypropyl cellulose, gelatin, etc., surfactants such as fatty
acid esters etc., and plasticizers such as glycerine, etc., are
used. Tablets and capsules are most useful dosage form for oral
administration because of easy administration. In the preparation
of tablets and capsules, solid medicament carriers are used.
Injection solutions are prepared with such a carrier as distilled
water, a salt solution, a glucose solution, or a mixture of a salt
solution and a glucose solution.
Effective dose and the number of administration of Compound (I) or
its pharmaceutically acceptable salt depend on modes of
administration and ages, body weight, and symptoms, etc. of
patients. It is preferable to usually administer 1 to 50 mg/kg of
Compound (I) or its pharmaceutically acceptable salt daily in 3 to
4 portions.
Furthermore, Compound (I) is administrated by inhalation in the
form of aerosol, finely pulverized powders, or spray solution. In
the case of aerosol administration, the present compound are
dissolved in a pharmaceutically acceptable solvent, for example,
ethyl alcohol or a combination of miscible solvents and then mixed
with a pharmaceutically acceptable propellant.
Hereafter the present invention is described by referring to
examples of the present invention and reference examples.
EXAMPLE 1
1-Methyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-5-one
(Compound 1)
After 50 ml of ethanolamine was added to 5.00 g of Compound a
obtained in Reference Example 1, the mixture was heated at
160.degree. C. for an hour. After cooling, the reaction mixture was
concentrated to the half in volume under reduced pressure. Ethanol
was added to the concentrate and the precipitate was collected by
filtration. Recrystallization from ethanol gave 3.52 g (67%) of
3,7-dihydro-6-(2-hydroxyethylamino)-7-methyl-3-n-propyl-2H-purin-2-one
(Compound ml) as white plates.
Elemental analysis: as C.sub.11 H.sub.17 N.sub.5 O.sub.2 Found (%):
C 52.41 H 6.80 N 27.54. Calcd. (%): C 52.58 H 6.82 N 27.87.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 6.82(brs, 1H),
4.87 (brs, 1H), 3.92(s, 3H), 3.91(t, 2H), 3.63-3.40 (m, 4H),
1.80-1.45(m, 2H), 0.88(t, 3H).
After 15 ml of phosphorus oxychloride was added to 3.50 g (13.9
mmol) of Compound ml under ice cooling, the mixture was refluxed
for 2 hours. Then the mixture was concentrated under reduced
pressure. After neutralizing with 2N aqueous sodium hydroxide
solution, the mixture was extracted 3 times with chloroform. After
washing with saturated sodium chloride aqueous solution, the
extract was dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure. The residue was isolated and
purified by silica gel column chromatography (eluting solvent: 2%
methanol/chloroform) and then recrystallized from toluene to afford
1.27 g (39%) of Compound 1 as white needles.
Melting point: 109.9.degree.-111.6.degree. C. (toluene).
Elemental analysis: as C.sub.11 H.sub.15 N.sub.5 O Found (%): C
56.49 H 6.57 N 30.23. Calcd. (%): C 56.64 H 6.48 N 30.02.
IR (KBr) .nu.max (cm.sup.-1): 1685, 1657.
.sup.1 H-NMR (CDCl.sub.3) .delta. (ppm): 7.43(s, 1H), 4.15-4.05(m,
2H), 3.95(s, 3H), 4.05-3.90(m, 4H), 1.90-1.70(m, 2H), 0.97(t,
3H).
EXAMPLE 2
4-n-Propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-5-one
(Compound 2)
The procedure was performed in a manner similar to Example 1 except
for using 4 g (17.9 mmol) of Compound b obtained in Reference
Example 2. Thus, 3.24 g (77%) of
3,7-dihydro-6-(2-hydroxyethylamino)-3-n-propyl-2H-purin-2-one
(Compound m2) was obtained as a white powder.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 7.82(s, 1H),
7.50 (brs, 1H), 3.88(t, 2H), 3.80-3.00(m, 5H), 1.90-1.40(m, 2H),
0.86(t, 3H).
Using 3.50 g (14.8 mmol) of the Compound m2, cyclization with
phosphorus oxychloride was performed in a manner similar to Example
1 to afford 2.05 g (63%) of Compound 2 as a white powder.
Melting point: 282.8.degree.-284.9.degree. C. (water).
Elemental analysis: as C.sub.10 H.sub.13 N.sub.5 O Found (%): C
54.54 H 6.05 N 32.15. Calcd. (%): C 54.78 H 5.98 N 31.94.
IR (KBr) .nu.max (cm.sup.-1): 1718, 1660, 1550
.sup.1 H-NMR (DMSO-d.sub.6 -DCl) .delta. (ppm): 7.70(s, 1H),
4.12-3.85 (m, 6H), 1.80-1.60(m, 2H), 0.88(t, 3H)
.sup.13 C-NMR (DMSO-d.sub.6) .delta. (ppm): 151.0, 149.1, 146.7,
143.9, 100.3, 45.3, 45.2, 20.6, 10.7.
EXAMPLE 3
1,4,5,7,8,9-Hexahydro-1-methyl-4-n-propylpyrimido[2,1-i]purin-5-one
(Compound 3)
The procedure was performed in a manner similar to Example 1 except
for using 2.45 g (10.3 mmol) of Compound a obtained in Reference
Example 1 and 10 ml of propanolamine. Thus, 2.39 g (88%) of
3,7-dihydro-6-(3-hydroxypropylamino)-7-methyl-3-n-propyl-2H-purin-2-one
(Compound m3) was obtained as a white powder
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 7.79(s, 1H),
7.15-6.85(br, 1H), 4.50-4.10(br, 1H), 3.87(s, 3H), 3.86(t, 2H),
3.65-3.30(m, 4H), 1.90-1.40(m, 4H), 0.83(t, 3H).
After 20 ml of thionyl chloride was added to 1.84 g (6.94 mmol) of
Compound m3, the mixture was stirred for 20 minutes. After
concentration under reduced pressure, the reaction mixture was
neutralized with 2N aqueous sodium hydroxide solution under ice
cooling followed by extraction 3 times with chloroform. After
washing with aqueous saturated sodium chloride solution, the
extract was dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (eluting solvent: 5%
methanol/chloroform) to afford 1.72 g (quantitative) of Compound 3
as white needles.
Melting point: 107.1.degree.-108.6.degree. C.
IR (KBr) .nu.max (cm.sup.-1) 1679, 1643, 1542, 1484
.sup.1 H-NMR (CDCl.sub.3) .delta. (ppm): 7.33(s, 1H), 3.98(s, 3H),
4.00-3.86(m, 4H), 3.54(t, 2H), 2.05-1.90(m, 2H), 1.85-1.65(m, 2H),
1.03-0.88(m, 6H).
.sup.13 H-NMR (CDCl.sub.3) .delta. (ppm): 150.8, 144.5, 141.6,
139.4, 107.4, 44.6, 43.7, 42.1, 34.4, 21.5, 20.9, 11.2,
MS (m/e) 247(M.sup.+), 218, 204, 135.
EXAMPLE 4
8-Ethyl-1-methyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-5-one
(Compound 4)
Using 4.00 g (16.8 mmol) of Compound a obtained in Reference
Example 1 and 10 ml of 2-amino-1-butanol, the procedure was
performed in a manner similar to Example 1 to afford 3.34 g (71%)
of
3,7-dihydro-6-(1-ethyl-2-hydroxyethylamino)-7-methyl-3-n-propyl-2H-purin-2
-one (Compound m4) as a white powder.
.sup.1 H-NMR (CDCl.sub.3) .delta. (ppm): 7.42(s, 1H), 6.30-5.70(br,
1H), 4.40-3.50(m, 6H), 4.00(s, 3H), 1.95-1.40 (m, 4H), 1.05-0.70(m,
6H).
Using 3.20 g (11.5 mmol) of the compound m4, cyclization with
phosphorus oxychloride was performed in a manner similar to Example
1 to afford 2.06 g (69%) of Compound 4 as white needles.
Melting point: 123.8.degree.-125.5.degree. C. (cyclohexane).
Elemental analysis: as C.sub.13 H.sub.19 N.sub.5 O.0.3H.sub.2 O
Found (%): C 58.30 H 7.68 N 26.50. Calcd. (%): C 58.54 H 7.41 N
26.26.
IR (KBr) .nu.max (cm.sup.-1): 1698, 1668, 1655
.sup.1 H-NMR (CDCl.sub.3) .delta. (ppm): 7.43(s, 1H), 4.23-4.18(m,
1H), 4.05-3.91(m, 3H), 3.97(s, 3H), 3.64-3.53(m, 1H), 1.90-1.50(m,
4H), 1.08-0.93(m, 6H).
EXAMPLE 5
1-Methyl-7-phenyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-5-on
e (Compound 5)
After 2.00 g (8.20 mmol) of Compound a obtained in Reference
Example 1 was dissolved in 5 ml of dimethylsulfoxide, 5.76 g (42
mmol) of 2-amino-1-phenylethanol was added to the solution. Then
the mixture was heated at 150.degree. C. for an hour with stirring.
After cooling, 100 ml of water was added and the mixture was
extracted 4 times with chloroform. After washing with saturated
aqueous sodium chloride solution, the extract was dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure. The residue was isolated and purified by silica gel
column chromatography (eluting solvent: 10% methanol/chloroform) to
afford 1.67 g (62%) of
3,7-dihydro-6-(2-hydroxy-2-phenyl)ethylamino-7-methyl-3-n-propyl-2H-purin-
2-one (Compound m5) as a white powder.
.sup.1 H-NMR (DMSO-d.sub.6 -D.sub.2 O, 90 MHz) .delta. (ppm):
8.30(s, 1H), 7.60-7.20(m, 5H), 4.94(dd, 1H, J=5, 8Hz), 4.07 (s,
3H), 4.20-3.70(m, 7H), 1.90-1.45(m, 2H), 0.91(t, 3H).
In a manner similar to Example 3, 1.51 g (4.61 mmol) of the
Compound m5 was subjected to cyclization with thionyl chloride to
afford 1.44 g (95%) of Compound 5 as white needles.
Melting point: 152.2.degree.-153.6.degree. C.
(toluene-cyclohexane).
Elemental analysis: as C.sub.17 H.sub.19 N.sub.5 O Found (%): C
66.29 H 6.19 N 22.72. Calcd. (%): C 66.00 H 6.19 N 22.64.
IR (KBr) .nu.max (cm.sup.-1) 1693, 1651
.sup.1 H-NMR (CDCl.sub.3) .delta. (ppm): 7.45(s, 1H), 7.40-7.20(m,
5H), 5.29(dd, 1H, J=5.3, 10.7Hz), 4.49(dd, 1H, J=10.7, 14.8Hz),
3.99(dd, 1H, J=5.3, 14.8Hz), 3.87(t, 2H), 1.80-1.60(m, 2H), 0.90(t,
3H).
EXAMPLE 6
2-Cyclopentyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-5-one
(Compound 6)
The procedure was performed in a manner similar to Example 1 except
for using 5.00 g (17.1 mmol) of Compound e obtained in Reference
Example 5 to afford 4.81 g (89%) of
8-cyclopentyl-3,7-dihydro-6-(2-hydroxyethylamino)-3-n-propyl-2H-purin-2-on
e (Compound m6) as a white powder.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 7.08(brs, 1H),
3.89 (t, 2H), 3.56(s, 3H), 4.00-3.00(m, 6H), 2.20-1.45 (m, 10H),
0.88(t, 3H).
In a manner similar to Example 3, 3.08 g (10.1 mmol) of the
Compound m6 was subjected to cyclization with thionyl chloride to
afford 3.00 g (quantitative) of Compound 6 as white crystals.
Melting point: 214.9.degree.-216.1.degree. C. (dioxane).
Elemental analysis: as C.sub.15 H.sub.21 N.sub.5 O.1.3H.sub.2 O
Found (%): C 57.90 H 7.29 N 22.63. Calcd. (%): C 57.97 H 7.65 N
22.53.
IR (KBr) .nu.max (cm.sup.-1) 1712, 1670, 1588
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 4.28-4.16(m, 2H),
4.12-3.90 (m, 4H), 3.40-3.25(m, 1H), 2.20-2.00(m, 2H), 1.90-1.60(m,
8H), 0.90(t, 3H).
EXAMPLE 7
2-Cyclopentyl-1-methyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin
-5-one (Compound 7)
The procedure was performed in a manner similar to Example 1 except
for using 1.30 g (4.25 mmol) of Compound f obtained in Reference
Example 6. Thus, 1.26 g (93%) of
8-cyclopentyl-3,7-dihydro-6-(2-hydroxyethylamino)-7-methyl-3-n-propyl-2H-p
urin-2-one (Compound m7) was obtained as a white powder.
.sup.1 H-NMR (DMSO-d.sub.6, 90MHz) .delta. (ppm): 3.93(s, 3H),
3.92(t, 2H), 3.70-3.10(m, 5H), 2.10-1.45(m, 10H), 0.88(t, 3H).
In a manner similar to Example 3, 1.10 g (3.44 mmol) of Compound m7
was subjected to cyclization with thionyl chloride to afford 583 mg
(56%) of Compound 7 as a white needle.
Melting point: 245.5.degree.-247.1.degree. C. (propanol-water).
IR (KBr) .nu.max (cm.sup.-1): 1712, 1686, 1662.
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 3.95(s, 3H), 3.87(t,
2H), 3.85(s, 4H), 3.40-3.20(m, 1H), 2.10-1.95(m, 2H), 1.90-1.60(m,
8H), 0.86(t, 3H).
MS (m/e) relative intensity: 301(M.sup.+), 272, 260.
EXAMPLE 8
2-Cyclopentyl-8-ethyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-
5-one (Compound 8)
The procedure was performed in a manner similar to Example 1 except
for using 3.00 g (10.3 mmol) of Compound e obtained in Reference
Example 5. Thus, 2.63 g (77%) of
8-cyclopentyl-3,7-dihydro-6-(1-ethyl-2-hydroxyethyl)amino-3-n-propyl-2H-pu
rin-2-one (Compound m8) was obtained as a white powder.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 7.60(brs, 1H),
4.12 (t, 2H), 4.30-3.00(m, 7H), 2.35-1.10(m, 12H), 0.97(t, 3H),
0.68(t, 3H).
In a manner similar to Example 3, 2.20 g (6.60 mmol) of the
Compound m8 was subjected to cyclization. The crude product was
dissolved in 10 ml of methanol. 1 ml of methanol solution saturated
with hydrogen chloride was added under ice cooling. The mixture was
concentrated under reduced pressure. The resulting light yellow
powders were recrystallized from ethanol to afford 542 mg (26%) of
the hydrochloride of Compound 8 as a light yellow needle.
Melting point: 208.8.degree.-209.6.degree. C.
Elemental analysis: as C.sub.17 H.sub.25 N.sub.5 O.HCl Found (%): C
58.22 H 7.63 N 19.74. Calcd. (%): C 58.03 H 7.45 N 19.90.
IR (KBr) .nu.max (cm.sup.-1): 1717, 1687, 1588
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 14.0-13.4(br, 1H),
11.2-10.7 (br, 1H), 4.40-4.25(m, 2H), 3.98(t, 2H), 3.90-3.80 (m,
1H), 3.45-3.30(m, 1H), 2.20-2.05(m, 2H), 1.90-1.60(m, 8H), 0.97(t,
3H), 0.90(t, 3H).
EXAMPLE 9
4-Benzyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-5-one (Compound
9)
The procedure was performed in a manner similar to Example 1 except
for using 2.20 g (8.08 mmol) of Compound i obtained in Reference
Example 8. Thus, 2.28 g (99%) of
3-benzyl-3,7-dihydro-6-(2-hydroxyethylamino)-2H-purin-2-one
(Compound m9) was obtained as a light yellow powder.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 7.80(s, 1H),
7.75-7.45(br, 1H), 7.40-7.00(m, 5H), 5.12(s, 2H), 3.70-3.45(m,
5H).
Using 2.04 g (7.15 mmol) of Compound m9, cyclization with
phosphorus oxychloride was performed in a manner similar to Example
1 to afford 830 mg (44%) of the hydrochloride of Compound 9 as a
light yellow powder.
Melting point: 300.8.degree.-301.9.degree. C. (decomposed).
IR (KBr) .nu.max (cm.sup.-1) 1711, 1671.
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 13.0-11.0(br, 1H),
8.35(s, 1H), 7.50-7.25(m, 5H), 5.23(s, 2H), 4.32-4.21 (m, 2H),
4.16-4.02(m, 2H).
MS (m/e) 267(M.sup.+), 91.
EXAMPLE 10
4-Benzyl-1-methyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-5-one
(Compound 10)
The procedure was performed in a manner similar to Example 1 except
for using 2.20 g (7.69 mmol) of Compound h obtained in Reference
Example 8. Thus, 1.83 g (80%) of
3-benzyl-3,7-dihydro-6-(2-hydroxyethylamino)-7-methyl-2H-purin-
2-one (Compound m10) was obtained as a white powder.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 7.83(s, 1H),
7.30-7.05(m, 5H), 6.93(brs, 1H), 5.08(s, 2H), 5.05-4.60(br, 1H),
3.90(s, 3H), 3.80-3.30(m, 4H).
Using 1.86 g (6.22 mmol) of Compound m10, cyclization with thionyl
chloride was performed in a manner similar to Example 3 to afford
1.15 g (55%) of the hydrochloride of Compound 10 as light yellow
needles.
Melting point: 168.0.degree.-170.0.degree. C. (acetonitrile).
Elemental analysis as C.sub.15 H.sub.15 N.sub.5 O.HCl.H.sub.2 O
Found (%): C 53.63 H 5.52 N 20.84. Calcd. (%): C 53.65 H 5.40 N
20.86.
IR (KBr) .nu.max (cm.sup.-1) 1709, 1678, 1593.
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 11.8-11.4(br, 1H),
8.39(s, 1H), 7.45-7.20(m, 5H), 5.21(s, 2H), 4.30-4.18(m, 2H),
4.10-3.98(m, 2H), 4.02(s, 3H).
The same procedures as in Example 5 were performed in Examples 11
to 19 except that amino alcohols shown in Table 7 and 3.00 g (10.3
mmol) of Compound e obtained in Reference Example 5 were used.
The physicochemical data of Compounds 11 to 19 were given in Table
8.
EXAMPLE 11
2-Cyclopentyl-7-phenyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin
-5-one (Compound 11)
EXAMPLE 12
8-Benzyl-2-cyclopentyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin
-5-one (Compound 12)
EXAMPLE 13
2-Cyclopentyl-8-isopropyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]pu
rin-5-one (Compound 13)
EXAMPLE 14
2-Cyclopentyl-8,8-dimethyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]p
urin-5-one (Compound 14)
EXAMPLE 15
2-Cyclopentyl-8-phenyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin
-5-one (Compound 15)
EXAMPLE 16
2-Cyclopentyl-8-methyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin
-5-one (Compound 16)
EXAMPLE 17
2-Cyclopentyl-4,8-di-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-5-o
ne (Compound 17)
EXAMPLE 18
2-Cyclopentyl-7-ethyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-
5-one (Compound 18)
EXAMPLE 19
2-Cyclopentyl-7-methyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin
-5-one (Compound 19)
TABLE 7 ______________________________________ Example No.
Aminoalcohol Yield (%) ______________________________________ 11
2-Amino-1-phenylethanol 64 12 2-Benzyl-2-aminoethanol 71 13
2-Amino-3-methylbutanol 61 14 2-Amino-2-methyl-1-propanol 42 15
2-Phenylglycinol 49 16 2-Amino-1-propanol 85 17 2-Amino-1-pentanol
65 18 1-Amino-2-butanol 86 19 1-Amino-2-propanol 73
______________________________________
TABLE 8
__________________________________________________________________________
Melting point (.degree.C.) Elemental MS (Recrystal- analysis (%) IR
(m/e) .sup.1 H-NMR Compound lization (upper: found (KBr) Relative
(measuring solvent) No. Properties solvent) lower: calcd.) .nu.max
(cm.sup.-1) intensity .delta.(ppm)
__________________________________________________________________________
11 Sa white 240.8-265.2 C.sub.21 H.sub.25 N.sub.5 O.HCl 1714, 363
(M.sup.+, 15.0-12.0(brs, 1H), powder (ethanol) C H N 1681, 100)
7.50-7.30(m, 5H), 5.68 63.38 6.82 17.57 1589 (dd, J=4.5, 10.5Hz,
1H), 63.07 6.55 17.51 4.52(t, J=10.5Hz, 1H), 4.15-3.95(m, 3H),
3.40-3.25 (m, 1H), 2.30-2.15(m, 2H), 2.05-1.65(m, 8H), 0.90(t, 3H)
12 Sa white 215.2-220.8 C.sub.22 H.sub.27 N.sub.5 O.HCl 1722, 377
(M.sup.+, 12.00-10.00(brs, 1H), powder (ethanol) C H N 1682, 4),
7.40-7.20(m, 5H), 4.75-4.65 63.68 7.14 16.82 1591 336 (6), (m, 1H),
4.21(dd, J=9.5, 63.83 6.82 16.92 286 (100), 9.0Hz, 1H), 4.15-4.00
244 (18) (m, 3H), 3.40-3.25(m, 1H), 3.23(dd, J=4.5, 14.0Hz, 1H),
3.00(dd, J=8.0, 14.0Hz, 1H), 2.30-2.15 (m, 2H), 2.00-1.65(m, 8H),
0.95(t, 3H) 13 Sa light 109.0-112.5 C.sub.18 H.sub.27 N.sub.5
O.1/2HCl.H.sub.2 O 1717, 329 (M.sup.+, 11.32(brs, 1H), 4.40-4.00
brown (cyclo- C H N 1681, 8), (m, 6H), 3.40-3.20(m, powder hexane-
59.11 8.29 18.81 1593 286 (100), 1H), 2.25-2.10(m, 4H), toluene)
59.12 8.13 19.15 244 (18) 2.00-1.60(m, 6H), 1.15-0.90(m, 9H) 14 Sa
white 221.8-231.8 C.sub.17 H.sub.25 N.sub.5 O.HCl 1722, 315
(M.sup.+, 4.11(t, 2H), 4.04(s, 2H), powder (toluene- C H N 1683,
20), 3.35-3.20(m, 1H), 2.25-2.10 ethanol) 58.13 7.78 19.81 1591 300
(100), (m, 4H), 2.00-1.60(m, 58.03 7.45 19.90 258 (18) 8H), 1.62(s,
6H). 0.99(t, 3H) 15 Sa mud 215.2-219.0 C.sub.21 H.sub.25 N.sub.5
O.HCl.0.2H.sub.2 O 1726, 363 (M.sup.+, 7.45-7.25(m, 5H), 5.54
yellow (chloro- C H N 1690, 100) (dd, J=7.5, 10.5Hz, 1H), powder
form- 62.61 6.99 16.93 1594 4.72(dd, J=10.5, 11.5Hz), ether) 62.51
6.59 17.33 4.18(dd, J=7.5, 11.5Hz, 1H), 4.12(t, 2H), 3.35-3.20 (m,
1H), 2.25-2.10(m, 1H), 2.00-1.65(m, 8H), 1.00(t, 3H) 16 Sa light
186.3-192.2 C.sub.16 H.sub.23 N.sub.5 O.HCl.0.2H.sub.2 O 1712, 301
(M.sup.+, 4.60-4.50(m, 1H), 4.43 yellow (ethyl- C H N 1670, 31),
(dd, J=10.0, 11.0Hz, 1H), needles acetate) 56.48 7.63 20.51 1587
286 (100), 4.11(t, 2H), 3.88(dd, J=7.0, 56.28 7.20 20.51 244 (27)
11.0Hz, 1H), 3.30-3.20 (m, 1H), 2.20(m, 2H), 1.95-1.65(m, 8H),
1.86(d, 3H), 0.99(t, 3H) 17 Sa white 202.3-204.4 C.sub.18 H.sub.27
N.sub.5 O.HCl 1719, 329 (m.sup.+, 4.50-4.30(m, 2H), 4.10 powder
(ethyl- C H N 1692, 14), (t, 2H), 3.95-3.85(m, 1H), acetate) 59.17
7.88 19.48 1588 286 (100), 3.30-3.15(m, 1H), 2.20-2.05 59.08 7.71
19.14 244 (20) (m, 2H), 1.95-1.40(m, 10H), 1.05-0.90(m, 6H) 18 Sa
light 160.4-163.3 C.sub.17 H.sub.25 N.sub.5 O.HCl.2H.sub.2 O 1717,
315 (M.sup.+, 4.30-3.85(m, 5H), yellow (isopro- C H N 1652 76),
3.30-3.15(m, 1H), powder panol- 52.92 7.65 18.07 286 (100),
2.25-2.60(m, 10H), 1.14 ethyl- 52.88 7.78 18.14 244 (25) (t, 3H),
1.00(t, 3H) acetate) 19 Sa white 162.0-163.9 C.sub.16 H.sub.23
N.sub.5 O.HCl.2H.sub.2 O 1715, 301 (M.sup.+, 4.50-4.35(m, 1H), 4.16
powder (ethyl- C H N 1674 100) (t, 2H), 4.10-3.80(m, 2H), acetate)
51.57 7.29 19.05 3.30-3.15(m, 1H), 2.20-2.05 51.64 7.53 18.82 (m,
1H), 2.00-1.60(m, 6H), 1.71(d, 3H), 1.00(t,
__________________________________________________________________________
3H) Sa is hydrochloride of the compound.
EXAMPLE 20
8-Ethyl-2-(noradamantan-3-yl)-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-
i]purin-5-one (Compound 20)
The procedure was performed in a manner similar to Example 5 except
for using 3.00 g (8.72 mmol) of Compound k obtained in Reference
Example 10 and 4.14 ml (43.6 mmol) of 2-amino-1-butanol. Thus 3.00
g (yield, 89%) of
3,7-dihydro-6-(1-ethyl-2-hydroxyethylamino)-8-(noradamantan-3-yl)-3-n-prop
yl-2H-purin-2-one (Compound m20) was obtained as a light yellow
powder.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 4.00-3.70(m, 5H),
2.82(t, 1H), 2.30-1.35(m, 16H), 1.05-0.85(m, 6H).
Using 2.78 g (7.22 mmol) of Compound m20, cyclization with thionyl
chloride was performed in a manner similar to Example 8 to afford
1.52 g (yield, 52%) of hydrochloride of Compound 20 as light yellow
needles.
Melting point: 196.3.degree.-201.3.degree. C. (ethylacetate).
Elemental analysis: as C.sub.21 H.sub.29 N.sub.5 O.HCl.0.25H.sub.2
O Found (%): C 61.66 H 7.51 N 17.00. Calcd (%): C 61.75 H 7.53 N
17.15.
IR (KBr) .nu.max (cm.sup.-1) 1714, 1681, 1594.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 4.50-3.90(m, 5H),
2.70(t, 1H), 2.55-1.60(m, 16H), 1.10(t, 3H), 0.96(t, 3H).
EXAMPLE 21
2-(Dicyclopropylmethyl)-8-ethyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,
1-i]purin-5-one (Compound 21)
The procedure was performed in a manner similar to Example 5 except
for using 2.60 g (8.17 mmol) of Compound l obtained in Reference
Example 11 and 5 ml of 2-amino-1-butanol. Thus, 2.17 g (yield, 74%)
of
8-(dicyclopropylmethyl)-3,7-dihydro-6-(1-ethyl-2-hydroxyethylamino)-3-n-pr
opyl-2H-purin-2-one (Compound m21) was obtained as a light yellow
powder.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 12.2(brs, 1H),
7.20 (brs, 1H), 4.30-3.30(m, 6H), 2.00-0.10(m, 21H)
Using 2.03 g (5.65 mmol) of Compound m21, cyclization with thionyl
chloride was performed in a manner similar to Example 8 to afford
1.66 g (yield, 86%) of hydrochloride of Compound 21 as a light
yellow powder.
Melting point: 153.1.degree.-157.2.degree. C.
(cyclohexane-toluene).
Elemental analysis: as C.sub.19 H.sub.2 N.sub.5 O.HCl.1/4H.sub.2 O
Found (%): C 59.62 H 7.46 N 18.40. Calcd (%) C 59.67 H 7.51 N
18.31.
IR (KBr) .nu.max (cm.sup.-1): 1720, 1678, 1591
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 4.50-3.90(m, 3H),
4.05(t, 2H), 2.00-1.60(m, 5H), 1.25-0.25(m, 16H),
MS (m/e, relative intensity): 341(M.sup.+, 12), 312(100).
EXAMPLE 22
8-Ethyl-1-methyl-4-n-propyl-2-styryl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]pu
rin-5-one (Compound 22)
The procedure was performed in a manner similar to Example 5 except
for using 1.72 g (5.06 mmol) of Compound n obtained in Reference
Example 13. Thus, 1.49 g (yield, 77%) of
3,7-dihydro-6-(1-ethyl-2-hydroxyethylamino)-7-methyl-3-n-propyl-8-styryl-2
H-purin-2-one (Compound m22) was obtained as a light yellow
powder.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 7.70(d, J=15.0Hz,
1H), 7.65-7.15(m, 5H), 6.86(d, J=15.0Hz, 1H), 4.50-3.55(m, 5H),
3.97(s, 3H), 2.00-1.45(m, 4H), 1.15-0.80(m, 6H).
Using 1.30 g (3.41 mmol) of Compound m22, cyclization with thionyl
chloride was performed in a manner similar to Example 8 to afford
530 mg (yield, 39%) of hydrochloride of Compound 22 as a white
powder.
Melting point: 198.7.degree.-203.4.degree. C. (isopropanol).
IR (KBr) .nu.max (cm.sup.-1): 1706, 1670.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 8.05-7.75(m,
3H), 7.60-7.30(m, 4H), 4.45-3.80(m, 5H), 4.20(s, 3H), 2.00-1.60(m,
4H), 1.10-0.85(m, 6H).
MS (m/e, relative intensity): 363(M.sup.+, 17), 334(100).
EXAMPLE 23
7-Phenyl-4-n-propyl-1,4,7,8-tetrahydro-5H-imidazo[2,1-i]purin-5-one
(Compound 23)
The procedure was performed in a manner similar to Example 5 except
for using 3.00 g (13.4 mmol) of Compound b obtained in Reference
Example 2 and 9.10 g (67.0 mmol) of 2-amino-1-phenylethanol. Thus,
3.66 g (yield, 87%) of
3,7-dihydro-6-(2-hydroxy-2-phenyl)ethylamino-3-n-propyl-2H-purin-2-one
(Compound m23) was obtained as a white powder.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 7.87(s, 1H),
7.65-7.20(m, 5H), 5.80(brs, 1H), 4.80(dd, J=5.0, 9.0Hz, 1H),
4.00-3.50(m, 4H), 1.80-1.45(m, 2H), 0.89(t, 3H).
Using 3.47 g (11.1 mmol) of Compound m23, cyclization with thionyl
chloride was performed in a manner similar to Example 8 to afford
1.95 g (yield, 60%) of Compound 23 as white needles.
Melting point: 258.2.degree.-263.5.degree. C. (ethanol).
Elemental analysis: as C.sub.16 H.sub.17 N.sub.5 O.HCl.0.1H.sub.2 O
Found (%): C 57.47 H 5.38 N 21.19. Calcd. (%): C 57.61 H 5.50 N
20.99.
IR (KBr) .nu.max (cm.sup.-1): 1709, 1670, 1588.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 8.11(s, 1H),
7.43 (s, 5H), 5.80(dd, J=5, 10Hz, 1H), 4.53(dd, J=10, 10Hz, 1H),
4.15-3.80(m, 3H), 1.85-1.50(m, 2H), 0.88(t, 3H).
MS (m/e, relative intensity): 295(M.sup.+, 100), 266(41),
253(20).
EXAMPLE 24
1,5,6,7,8,10-Hexahydropyrido[1,2-a]purin-10-one (Compound 24)
After 15.1 g (0.0933 mol) of 4-amino-5-carboxyamidoimidazole
hydrochloride was suspended in 400 ml of tetrahydrofuran, 68 ml
(0.279 mol) of bistrimethylsilylacetamide was dropwise added to the
suspension. After 30 minutes, 18.8 g (0.121 mol) of 5-chlorovaleryl
chloride was added to the mixture under ice cooling. After stirring
at room temperature for one hour, the solvent was evaporated under
reduced pressure. After adding 200 ml of water, the mixture was
neutralized with 50% sodium hydroxide under ice cooling followed by
extraction with ethyl acetate. The extract was washed with brine
and dried over anhydrous sodium sulfate. Evaporation of the solvent
under reduced pressure gave 23.5 g (100%) of
4-amino-5-(N-5'-chlorovaleryl)carboxyimidazole (Compound m24) as
white crystals.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 7.80(s, 1H),
3.70 (t, 2H, J=7Hz), 3.04(t, 2H, J=7Hz), 1.86-1.55 (m, 4H).
MS (m/e): 246(M.sup.+), 244.
To 10 g of Compound m24 was added 60 g of polyphosphoric acid. The
mixture was stirred at 150.degree. C. for 30 minutes. The reaction
mixture was ice-cooled and 100 g of ice was added. The mixture was
neutralized with 50% aqueous sodium hydroxide solution. The
precipitate was collected by filtration to afford 2.8 g (36%) of
Compound 24 as white crystals.
Melting point: above 300.degree. C. (dimethylformamide).
IR (KBr) .nu.max (cm.sup.-1) 1635.
.sup.1 H-NMR (CDCl.sub.3 /CD.sub.3 OD=4/1) .delta. (ppm): 8.03(s,
1H), 4.36 (t, 2H, J=7Hz), 3.07(t, 2H, J=7Hz), 2.22-2.03(m, 4H),
MS (m/e): 190(M.sup.+).
High resolution power MS (m/e): Found: 190.0872. Calcd.: 190.0854
(C.sub.9 H.sub.10 N.sub.4 O).
EXAMPLE 25
1-Methyl-1,5,6,7,8,10-hexahydropyrido[1,2-a]purin-10-one (Compound
25)
After 1.20 g (6.32 mmol) of Compound 24 obtained in Example 24 was
suspended in 20 ml of dimethylformamide, 0.265 g (6.63 mmol) of 60%
sodium hydride was added to the suspension at 0.degree. C. After 30
minutes, 0.433 ml (6.95 mmol) of iodomethane was added and the
mixture was stirred at room temperature for 1.5 hours. The
precipitate was collected by filtration and recrystallized from
isopropanoldiisopropyl ether to afford 0.700 g (54.3%) of Compound
25 as colorless crystals.
Melting point: 158.degree.-161.degree. C. (decomposed).
IR (KBr ) .nu.max (cm.sup.-1) 1719, 1622, 1220.
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 8.25(s, 1H), 4.18(t, 2H,
J=7Hz), 3.98(s, 3H), 2.91(t, 2H, J=7Hz), 2.08-1.84(m, 4H)
MS (m/e): 204(M.sup.+).
High resolution power MS (m/e): Found: 204.0989. Calcd. 204.1011
(C.sub.10 H.sub.12 N.sub.4 O).
EXAMPLE 26
1-n-Butyl-1,5,6,7,8,10-hexahydropyrido[1,2-a]purin-10-one (Compound
26)
After 1.20 g (6.32 mmol) of Compound 24 obtained in Example 24 was
suspended in 20 ml of dimethylformamide, 0.265 g (6.63 mmol) of 60%
sodium hydride was added to the suspension at 0.degree. C. After 30
minutes, 0.755 ml (6.63 mmol) of iodobutane was added and the
mixture was stirred at room temperature for 1.5 hours. The reaction
mixture was filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (eluting solvent; chloroform:methanol=40:1) to
afford 1.10 g (70.8%) of Compound 26 as white crystals.
Compound 26 was dissolved in 30 ml of ethyl acetate, and an excess
of ethyl acetate saturated with hydrogen chloride was added to the
solution. The precipitate was collected by filtration to afford the
hydrochloride of Compound 26 as white crystals.
Melting point: 204.degree.-216.degree. C. (decomposed).
IR (KBr) .nu.max (cm.sup.-1) 1719, 1618, 1227.
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 4.39(t, 2H, J=7Hz),
4.27(t, 2H, J=7Hz), 3.07(t, 2H, J=7Hz), 2.10-1.73(m, 4H),
1.32-1.16(m, 4H), 0.89(t, 3H, J=7Hz).
MS (m/e): 246(M.sup.+).
High resolution power MS (m/e): Found: 246.1461. Calcd.: 246.1480
(C.sub.13 H.sub.18 N.sub.4 O).
EXAMPLE 27
5-n-Butyl-3-methyl-3,5,7,8-tetrahydro-4H-imidazo[2,1-b]purin-4-one
(Compound 27)
After 113 ml (1.87 mol) of ethanolamine was added to 9.00 g (0.0374
mol) of Compound j obtained in Reference Example 9, the mixture was
stirred at an external temperature of 90.degree. C. for 2.5 hours.
The solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (eluting solvent;
chloroform: methanol=15:1) to afford 5.25 g (53.0%) of
5-n-butyl-1,7-dihydro-2-(2'-hydroxyethyl)amino-7-methyl-6H-purin-6-one
(Compound m27) as an oily substance.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 8.13(s, 1H),
3.99(s, 3H), 4.30-3.20(m, 8H), 1.91-1.10(m, 4H), 0.99(t, 3H,
J=7Hz).
MS (m/e): 265(M.sup.+).
After 60 ml of thionyl chloride was added to 3.00 g (0.0113 mol) of
Compound m27 the mixture was stirred at room temperature for one
hour. The solvent was evaporated under reduced pressure. Under ice
cooling, aqueous saturated sodium hydrogen carbonate solution was
added, to the residue and the mixture was extracted with
chloroform. The combined extracts were washed with brine, dried
over anhydrous sodium sulfate and concentrated. The crude product
was purified by silica gel column chromatography (eluting solvent:
chloroform:methanol=30:1) to afford 2.30 g (82.0%) of Compound 27
as white crystals.
Melting point: 122.degree.-124.degree. C. (ethyl acetate).
IR (KBr) .nu.max (cm.sup.-1) 1695, 1384.
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 7.90(s, 1H), 4.10(t, 2H,
J=7Hz), 3.87(t, 2H, J=7Hz), 3.84(s, 3H), 3.87 (t, 2H, J=7Hz),
3.84(s, 3H), 3.83(t, 2H, J=7Hz), 1.62-1.50(m, 2H), 1.38-1.21(m,
2H), 0.90(t, 3H, J=7Hz).
MS (m/e): 247(M.sup.+).
High resolution power MS (m/e): Found: 247.1420. Calcd.: 247.1432
(C.sub.12 H.sub.17 N.sub.5 O).
EXAMPLE 28
5-n-Butyl-3-methyl-3,4,5,7,8,9-hexahydropyrimide[2,1-b]purin-4-one
(Compound 28)
After 27.8 ml (0.374 mol) of propanolamine was added to 3.00 g
(0.0124 mol) of Compound j obtained in Reference Example 9, the
mixture was stirred at an external temperature of 100.degree. C.
for one hour. The solvent was evaporated under reduced pressure.
The crude product was purified by silica gel column chromatography
(eluting solvent; chloroform:methanol=15:1) to afford 3.36 g
(96.5%) of
5-n-butyl-1,7-dihydro-2-(3'-hydroxypropyl)amino-7-methyl-
6H-purin-6-one (Compound m28).
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 8.15(s, 1H),
3.98(s, 3H), 4.41-3.15(m, 8H), 2.01-1.08(m, 6H), 1.00(t, 3H,
J=7Hz).
MS (m/e): 279(M.sup.+).
After 60 ml of thionyl chloride was added to 3.00 g (0.0108 mol) of
Compound m28, the mixture was stirred at room temperature for an
hour. The solvent was evaporated under reduced pressure. Under ice
cooling, aqueous saturated sodium hydrogencarbonate solution was
added to the residue, and the mixture was extracted with
chloroform. The combined extracts were washed with brine, dried
over anhydrous sodium sulfate and concentrated. The crude product
obtained was isolated and purified by silica gel column
chromatography (eluting solvent: chloroform: methanol=50:1) to
afford 1.55 g (55.0%) of free Compound 28 as an oily substance.
Subsequently, the free compound was treated as in Example 26 to
give the hydrochloride of Compound 28.
Melting point: 280.degree.-286.degree. C.
IR (KBr) .nu.max (cm.sup.-1) 1635.
MS (m/e): 261(M.sup.+).
High resolution power MS (m/e): Found: 261.1599. Calcd.: 261.1590
(C.sub.13 H.sub.19 N.sub.5 O).
EXAMPLE 29
5-Methyl-3,5,7,8-tetrahydro-4H-imidazo[2,1-b]purin-4-one (Compound
29)
4.49 g (8.74 mmol) of Compound p obtained in Reference Example 15
was added to the 25 ml (414 mmol) of ethanolamine and the mixture
was stirred for 30 minutes at external temperature 165.degree. C.
Water was added to the mixture, and the mixture was extracted with
chloroform. The extract was washed with saturated brine, and was
dried over magnesium sulfate. After filtration, the solvent was
concentrated. The crude product was purified by silica gel column
chromatography (eluting solvent: chloroform: methanol=20:1) to
afford 0.42 g of
1,2-(2'-hydroxyethyl)amino-1-methyl-9-trityl-1H-purine-6-one
(Compound 29). Compound m29 was added to 8 ml of thionylchloride
and the mixture was stirred for 30 minutes. The solvent was
evaporated under reduced pressure and ethanol was added to the
residue. Trituration of the mixture afforded 0.194 g (yield, 11.6%)
of hydrochloride of Compound 29, as a white powder.
Melting point: 308.degree.-310.degree. C.
IR (KBr) .nu.max (cm.sup.-1) 1714, 1646, 1576.
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 8.17(s, 1H), 4.43(dd,
2H, J.sub.1 =7Hz, J.sub.2 =5.5Hz), 4.00(dd, 2H, J.sub.1 =7Hz,
J.sub.2 =5.5Hz), 3.41(s, 3H).
MS (m/e): 190(M.sup.+ -2), 191(M.sup.+ -1), 192(M.sup.+).
EXAMPLE 30
2-(Noradamantan-3-yl)-1,5,6,7,8,10-hexahydropyrido[1,2-a]purin-10-one
(Compound 30)
Using 4-amino-5-carboxyamido-2-(noradamantan-3-yl)imidazole
hydrochloride, Compound 30 is obtained in a manner similar to
Example 24.
EXAMPLE 31
2-Dicyclopropylmethyl-1,5,6,7,8,10-hexahydropyrido[1,2-a]purin-10-one
(Compound 31)
Using 4-amino-5-carboxyamido-2-dicyclopropylmethyl
imidazolehydrochloride, Compound 31 is obtained in a manner similar
to Example 24.
EXAMPLE 32
2-Styryl-1,5,6,7,8,10-hexahydropyrido[1,2-a]purin-10-one (Compound
32)
Using 4-amino-5-carboxyamido-2-styrylimidazolehydrochloride,
Compound 32 is obtained in a manner similar to Example 24.
EXAMPLE 33
2-(Noradamantan-3-yl)-5-n-butyl-3-methyl-3,5,7,8-tetrahydro-4H-imidazo[2,1-
b]purin-4-one (Compound 33)
Using
2-chloro-8-(noradamantan-3-yl)-1-n-butyl-7-methyl-1,7-dihydro-6H-purin-6-o
ne obtained in Reference Example 16, Compound 33 is obtained in a
similar manner to Example 27.
EXAMPLE 34
2-Dicyclopropylmethyl-5-n-butyl-3-methyl-3,5,7,8-tetrahydro-4H-imidazo[2,1-
b]purin-4-one (Compound 34)
Using
2-chloro-8-dicyclopropylmethyl-1-n-butyl-7-methyl-1,7-dihydro-6H-purin-6-o
ne obtained in Reference Example 18, Compound 34 is obtained in a
manner similar to Example 27.
EXAMPLE 35
2-Styryl-5-n-butyl-3-methyl-3,5,7,8-tetrahydro-4H-imidazo[2,1-b]purin-4-one
(Compound 35)
Using
2-chloro-8-styryl-1-n-butyl-7-methyl-1,7-dihydro-6H-purin-6-one
obtained in Reference Example 18, Compound 35 is obtained in a
manner similar to Example 27.
EXAMPLE 36
2-(Noradamantan-3-yl)-5-n-butyl-3-methyl-3,4,5,7,8,9-hexahydropyrimido[2,1-
b]purin-4-one (Compound 36)
Using
2-chloro-8-(noradamantan-3-yl)-1-n-butyl-7-methyl-1,7-dihydro-6H-purin-6-o
ne obtained in Reference Example 16, Compound 36 is obtained in a
manner similar to Example 28.
EXAMPLE 37
2-Dicyclopropyl-5-n-butyl-3-methyl-3,4,5,7,8,9-hexahydropyrimido[2,1-b]puri
n-4-one (Compound 37)
Using
2-chloro-8-dicyclopropylmethyl-1-n-butyl-7-methyl-1,7-dihydro-6H-purin-6-o
ne obtained in Reference Example 17, Compound 37 is obtained in a
manner similar to Example 28.
EXAMPLE 38
2-Styryl-5-n-butyl-3-methyl-3,4,5,7,8,9-hexahydropyrimido[2,1-b]purin-4-one
(Compound 38)
Using
2-chloro-8-styryl-1-n-butyl-7-methyl-1,7-dihydro-6H-purin-6-one
obtained in Reference Example 18, Compound 38 is obtained in a
manner similar to Example 28.
EXAMPLE 39
5-Methyl-2-(noradamantan-3-yl)-3,5,7,8-tetrahydro-4H-imidazo[2,1-b]purin-4-
one (Compound 39)
Using
2-Benzylthio-1-methyl-8-(noradamantan-3-yl)-9-trityl-1,7-dihydro-6H-purin-
6-one obtained in Reference Example 22, Compound 39 is obtained in
a manner similar to Example 29.
EXAMPLE 40
2-Dicyclopropylmethyl-5-methyl-3,5,7,8-tetrahydro-4H-imidazo[2,1-b]purin-4-
one (Compound 40)
Using
2-Benzylthio-8-dicyclopropylmethyl-1-methyl-9-trityl-1,7-dihydro-6H-purin-
6-one obtained in Reference Example 23, Compound 40 is obtained in
a manner similar to Example 29.
EXAMPLE 41
2-Styryl-5-methyl-3,5,7,8-tetrahydro-4H-imidazo[2,1-b]purin-4-one
(Compound 41)
Using
2-benzylthio-1-methyl-8-styryl-9-trityl-1,7-dihydro-6H-purin-6-one
obtained in Reference Example 24, Compound 41 is obtained in a
manner similar to Example 29.
REFERENCE EXAMPLE 1
3,7-Dihydro-7-methyl-6-methylthio-3-n-propyl-2H-purin-2-one
(Compound a)
Under an argon atmosphere, 10.7 g (268 mmol) of 60% sodium hydride
was washed 3 times with n-hexane. The solvent was evaporated under
reduced pressure to dry. To the residue was added 300 ml of
dimethylformamide. A suspension of 3-n-propyl-6-thioxanthine
(Japanese Published Unexamined Patent Application No. 183286/86)
(28.2 g, 134 mmol) in 200 ml of dimethylformamide was dropwise
added to the mixture under ice cooling with stirring. 15 minutes
after, 25.1 ml (403 mmol) of methyl iodide was dropwise added to
the reaction mixture. After stirring was continued for 30 minutes,
50 ml of ethanol was added and the mixture was concentrated. 250 ml
of water was added to the residue and the precipitate was collected
by filtration to give 25.9 g (yield, 81%) of Compound a.
Melting point: 224.7.degree.-226.4.degree. C. (acetonitrile).
Elemental analysis: as C.sub.10 H.sub.14 N.sub.4 OS Found (%): C
50.30 H 5.95 N 23.35. Calcd. (%): C 50.40 H 5.92 N 23.51.
IR (KBr) .nu.max (cm.sup.-1) 1630, 1596, 1557, 1393.
.sup.1 H-NMR (CDCl.sub.3) .delta. (ppm): 7.53(s, 1H), 4.16(t, 2H),
4.01(s, 3H), 2.71(s, 3H), 1.95-1.77(m, 2H), 0.98 (t, 3H).
.sup.13 H-NMR (CDCl.sub.3) .delta. (ppm): 160.9, 154.7, 151.6,
143.3, 114.3, 45.0, 34.7, 21.2, 12.2, 11.2.
REFERENCE EXAMPLE 2
3,7-Dihydro-6-methylthio-3-n-propyl-2H-purin-2-one (Compound b)
Under an argon atmosphere, 9.77 g (244 mmol) of 60% sodium hydride
was washed 3 times with n-hexane. The solvent was evaporated under
reduced pressure to dry. To the residue was added 900 ml of
dimethylformamide. Under ice cooling, 57.0 g (271 mmol) of
3-n-propyl-6-thioxanthine (Japanese Published Unexamined Patent
Application No. 183287/86) was gently added to the mixture. 15
minutes after, 15.2 ml (244 mmol) of methyl iodide was dropwise
added to the reaction solution. After stirring was continued for 30
minutes, 50 ml of ethanol was added and the mixture was
concentrated under reduced pressure. After 400 ml of water was
added to the residue, the precipitate was collected by filtration
to afford 13.9 g (yield, 23%) of Compound b as a light yellow
powder. The filtrate was extracted 5 times with 200 ml of
chloroform. After washing with saturated sodium chloride aqueous
solution, the filtrate was dried over anhydrous sodium sulfate and
the solvent was evaporated under reduced pressure. The residue was
isolated and purified by silica gel column chromatography (eluting
solvent; 10% methanol/chloroform) to afford further 16.0 g (yield,
26%) of Compound b as a light yellow powder.
Melting point: 240.8.degree.-242.5.degree. C.
IR (KBr) .nu.max (cm.sup.-1) 3400(br), 1600, 1588, 1572.
.sup.1 H-NMR (DMSO-d .delta. (ppm): 13.54(brs, 1H), 8.13(brs, 1H),
3.99(t, 2H), 2.57(s, 3H), 1.80-1.62(m, 2H), 0.88(t, 3H).
.sup.13 C-NMR (DMSO-d.sub.6) .delta. (ppm): 160.6(br), 153.8,
149.4(br), 141.9(br), 112.8(br), 44.4, 20.6, 11.3, 11.0.
MS (m/e): 224(M.sup.+), 195, 182, 135.
REFERENCE EXAMPLE 3
8-Cyclopentyl-3-n-propylxanthine (Compound c)
To a suspension of 5,6-diamino-1-propyl-2,4(1H, 3H)pyrimidinedione
(Japanese Published Unexamined Patent Application No. 57517/80) in
600 ml of dimethylformamide were sequentially added 17.7 ml (163
mmol) of cyclopentanecarboxylic acid, 30.0 g (196 mmol) of
hydroxybenzotriazole and 50.5 g (245 mmol) of
dicyclohexylcarbodiimide. The mixture was stirred at room
temperature overnight. Insoluble materials were filtered off and
the solvent was evaporated under reduced pressure After 600 ml of
4N aqueous sodium hydroxide solution was added to the residue, the
mixture was refluxed for 10 minutes under heating. Under ice
cooling, insoluble materials were filtered off and 50 ml of
methanol was added to the filtrate. After neutralization with conc.
hydrochloric acid, the precipitate was collected by filtration to
afford 28.3 g (yield, 66%) of Compound c.
Melting point: 311.3.degree.-313.1.degree. C.
(dimethylformamide).
Elemental analysis: as C.sub.13 H.sub.18 N.sub.4 O.sub.2 Found (%):
C 59.56 H 6.96 N 21.69. Calcd. (%): C 59.52 H 6.92 N 21.36.
IR (KBr) .nu.max (cm.sup.-1) 3150, 2880, 1698, 1669.
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 13.05(brs, 1H), 10.94(s,
1H), 3.86(t, 2H), 3.18-3.04(m, 1H), 2.05-1.55(m, 10H), 0.87(t,
3H).
.sup.13 C-NMR (DMSO-d.sub.6)) .delta. (ppm): 157.7, 154.3, 150.9,
149.4, 106.5, 43.3, 39.0, 31.9, 25.0, 20.9, 10.9.
REFERENCE EXAMPLE 4
8-Cyclopentyl-3-n-propyl-6-thioxanthine (Compound d)
A mixture of Compound c obtained in Reference Example 3 (14.1 g,
53.8 mmol) and phosphorous pentasulfide (19.5 g, 87.7 mmol) in 280
ml of pyridine was refluxed for 4 hours. The reaction mixture was
poured into 600 ml of ice water and the precipitate was collected
by filtration. The filtrate was concentrated under reduced pressure
and the precipitate was collected by filtration again. The filtrate
was combined and 400 ml of 2N aqueous sodium hydroxide solution was
added to the crystals. After insoluble materials were removed, the
system was neutralized with conc. hydrochloric acid and the
precipitate was collected by filtration to afford Compound d as the
crude product. The crude product was recrystallized from
ethanol-water to afford 13.5 g (yield, 90%) of Compound d as light
yellow plates.
Melting point: 214.3.degree.-215.9.degree. C.
Elemental analysis: as C.sub.13 H.sub.18 N.sub.4 O.1/4C.sub.2
H.sub.5 OH Found (%): C 56.17 H 6.76 N 19.44. Calcd. (%): C 55.93 H
6.78 N 19.33.
IR (KBr) .nu.max (cm.sup.-1): 2960, 1663,.1605, 1510, 1403.
.sup.1 H-NMR (DMSO-d.sub.6) .delta. (ppm): 13.03(brs, 1H),
12.04(brs, 1H), 3.90(t, 2H), 3.30-3.10(m, 1H), 2.05-1.55(m, 10H),
0.87(t, 3H).
.sup.13 C-NMR (DMSO-d.sub.6) .delta. (ppm): 173.3, 161.5, 148.9,
145.7, 118.5, 56.0, 43.8, 38.7, 32.0, 25.2, 20.7, 18.5, 10.9.
REFERENCE EXAMPLE 5
8-Cyclopentyl-3,7-dihydro-6-methylthio-3-n-propyl-2H-purin-2-one
(Compound e)
Using 6.00 g (21.6 mmol) of Compound d obtained in Reference
Example 4, the procedure was performed in a manner similar to
Reference Example 2 to afford 4.70 g (yield, 75%) of Compound e as
a light yellow powder.
Melting point: 257.5.degree.-259.2.degree. C.
Elemental analysis: as C.sub.14 H.sub.20 N.sub.4 OS Found (%): C
57.77 H 7.22 N 19.36. Calcd. (%): C 57.51 H 6.89 N 19.16.
IR (KBr) .nu.max (cm.sup.-1): 1599, 1580, 1553, 1513
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 4.24(t, 2H),
3.53-3.15 (m, 1H), 2.10(s, 3H), 2.50-1.50(m, 10H), 0.95 (t,
3H).
REFERENCE EXAMPLE 6
8-Cyclopentyl-3,7-dihydro-7-methyl-6-methylthio-3-n-propyl-2H-purin-2-one
(Compound f)
After 1.50 g (5.4 mmol) of Compound d obtained in Reference Example
4 was dissolved in 23 ml of dimethylformamide, 432 mg (10.8 mmol)
of sodium hydride (60% oily) was gently added to the solution under
ice cooling. The mixture was stirred for 30 minutes under ice
cooling. The reaction mixture was poured into ice water and the
precipitate was collected by filtration. After washing with water
and then with 50% ether/hexane, 1.47 g (yield, 89%) of Compound f
was obtained as a light yellow powder.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 4.15(t, 2H),
3.91(s, 3H), 3.20-2.95(m, 1H), 2.68(s, 3H), 2.20-1.50(m, 10H),
0.90(t, 2H).
REFERENCE EXAMPLE 7
3-Benzyl-6-thioxanthine (Compound g)
Using 31.0 g (128 mmol) of 3-benzylxanthine [Biochemistry, 16, 3316
(1977)], the procedure was performed in a manner similar to
Reference Example 4 to afford 28.7 g (yield, 87%) of Compound g as
a light yellow powder.
Melting point: 261.8.degree.-263.1.degree. C. (DMSO-water).
IR (KBr) .nu.max (cm.sup.-1): 1682, 1600, 1560, 1426.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 13.4(brs, 1H),
12.2 (brs, 1H), 7.99(s, 1H), 7.50-7.05(m, 5H), 5.12 (s, 2H).
REFERENCE EXAMPLE 8
3-Benzyl-3,7-dihydro-7-methyl-6-methylthio-2H-purin-2-one (Compound
h) and 3-benzyl-3,7-dihydro-6-methylthio-2H-purin-2-one (Compound
i)
Using 14 g (54.3 mmol) of Compound g obtained in Reference Example
7, the procedure was performed in a manner similar to Reference
Example 2. The crude product was purified by silica gel column
chromatography. The fraction was concentrated and eluted with 5%
methanol/chloroform, to obtain 5.86 g (yield, 40%) of Compound h as
a light yellow powder.
Melting point: 268.1.degree.-269.8.degree. C.
Elemental analysis: as C.sub.13 H.sub.12 N.sub.4 OS Found (%): C
57.42 H 4.13 N 20.14. Calcd. (%) C 57.34 H 4.44 N 20.57.
IR (KBr) .nu.max (cm.sup.-1) 3420(br), 1600, 1566, 1543.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 13.50(brs, 1H),
8.07 (s, 1H), 7.45-7.05(m, 5H), 5.22(s, 2H), 2.60(s, 3H).
MS (m/e):272(M.sup.+), 257, 225, 91, 65.
The fraction eluted with 2% methanol/chloroform in the silica gel
column chromatography described above was concentrated. Using 7.24
g of the residue obtained, the procedure was performed in a manner
similar to Reference Example 1 to afford 5.13 g (yield, 33%) of
Compound i as a light yellow powder.
Melting point: 214.8.degree.-216.4.degree. C.
IR (KBr) .nu.max (cm.sup.-1) 1633, 1591, 1558.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 7.47(s, 1H),
7.60-7.05 (m, 5H), 5.32(s, 2H), 3.82(s, 3H), 2.67(s, 3H). MS (m/e):
286(M.sup.+), 271, 228, 211, 195, 91.
REFERENCE EXAMPLE 9
1-n-Butyl-2-chloro-1,7-dihydro-7-methyl-6H-purin-6-one (Compound
j)
To a suspension of 2-chloro-7-methyl-1,7-dihydro-6H-purin-6-one
[Ber., 30, 2400 (1897)] (6.68 g, 0.0362 mol) was added 2.03 g
(0.0507 mol) of 60% sodium hydride, and the mixture was stirred for
30 minutes. To the mixture was added 8.24 ml (0.0724 mol) of
iodobutane. The mixture was stirred at an external temperature of
65.degree. C. for further 30 minutes. The solvent was evaporated
under reduced pressure and the obtained residue was purified by
silica gel column chromatography (eluting solvent:
chloroform:methanol=20:1) to afford 5.38 g (61.8%) of Compound j as
light yellow crystals.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 8.23(s, 1H),
4.59(t, 2H, J=7Hz), 4.06(s, 3H), 2.07-1.26(m, 4H), 1.03 (t, 3H,
J=7Hz).
REFERENCE EXAMPLE 10
3,7-Dihydro-6-methylthio-8-(noradamantan-3-yl)-3-n-propyl-2H-purin-2-one
(Compound k)
After 10 g of (30.3 mmol) of
8-(Noradamantan-3-yl)-3-n-propyl-6-thioxanthine was suspended in 90
ml of water, 30 ml of 2N aqueous sodium hydroxide solution and 60
ml of ethanol were added to the suspension. Under stirring, 2.83 ml
(45.5 mmol) of methyliodide was dropwise added to the mixture.
After stirring for 1 hour, the mixture was neutralized and
extracted 3 times with chloroform. The extracts were combined, and
dried over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure to afford 9.81 g (yield, 94%) of Compound k
as an amorphous powder.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 13.3(brs, 1H),
4.23 (t, 2H), 2.80(t, 1H), 2.50-1.45(m, 14H), 1.95(s, 3H), 0.96(t,
3H).
REFERENCE EXAMPLE 11
8-Dicycropropylmethyl-3,7-dihydro-6-methylthio-3-n-propyl-2H-purin-2-one
(Compound l)
Using 2.33 g (7.66 mmol) of
8-dicyclopropylmethyl-3-n-propyl-6-thioxanthine, the procedure was
performed in a manner similar to Reference Example 10 to afford
2.76 g (quantitative) of Compound l as a light yellow powder.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 4.23(t, 2H),
2.10-0.10 (m, 13H), 1.93(s, 3H), 0.93(t, 3H).
REFERENCE EXAMPLE 12
3-n-Propyl-8-styryl-6-thioxanthine (Compound m)
After 4.14 g (14.0 mmol) of 3-n-propyl-8-styrylxanthine was
suspended in 80 ml of pyridine, 5.07 g (22.8 mmol) of
phosphoruspentasulfide was added to the suspension, and the mixture
was refluxed for 2.5 hours under heating. After the mixture was
poured into 300 ml of an ice water, a precipitate was collected by
filtration, and suspended in 150 ml of 2N sodium hydroxide. The
suspension was stirred for 30 minutes at room temperature and
insoluble matters were removed by filtration. A filtrate was
neutralized, and a precipitate was collected by filtration to
afford 4.25 g (yield, 97%) of Compound m as a yellow powder.
Melting point: >290.degree. C. (dioxane-water).
Elemental analysis: as C.sub.16 H.sub.16 N.sub.4 OS.1/2C.sub.4
H.sub.8 O.sub.2 Found (%): C 60.60 H 5.65 N 15.73. Calcd. (%): C
60.65 H 5.65 N 15.72.
IR (KBr) .nu.max (cm.sup.-1) 1689, 1604, 1511.
.sup.1 H-NMR (DMSO-d.sub.6, 90 MHz) .delta. (ppm): 7.85(d,
J=16.0Hz, 1H), 7.70-7.35(m, 5H), 7.20(d, J=16.0Hz, 1H), 3.99(t,
2H), 2.00-1.65(m, 2H), 0.93(t, 3H).
MS (m/e, relative intensity): 312(M.sup.+, 100), 269(35),
252(18).
REFERENCE EXAMPLE 13
3,7-Dihydro-7-methyl-6-methylthio-3-n-propyl-8-styryl-2H-purin-2-one
(Compound n)
Using 2.00 g (6.41 mmol) of Compound m obtained in Reference
Example 12, the procedure was performed in a manner similar to
Reference Example 1 to afford 1.73 g (yield, 79%) of Compound n as
a light yellow powder.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 7.91(d, J=15.5Hz,
1H), 7.70-7.35(m, 5H), 6.92(d, J=15.5Hz, 1H), 4.20 (t, 2H), 4.04(s,
3H), 2.70(s, 3H), 2.10-1.70(m, 2H), 1.02(t, 3H).
REFERENCE EXAMPLE 14
2-Benzylthio-9-trityl-1,7-dihydro-6H-purin-6-one (Compound o)
2.00 g (11.9 mmol) of 2-mercapto-6-hydroxypurine was dissolved in a
solvent mixture of 10 ml of ethanol, 10.9 ml of 2N sodium hydroxide
and 15 ml of water. Under ice cooling with stirring, 2.06 ml (17.9
mmol) of benzylbromide was added to the solution, following
stirring at room temperature for 30 minutes. Again under ice
cooling, the mixture was neutralized with 2N hydrochloric acid and
30 ml of n-hexane was added to the mixture. A precipitated was
collected by filtration, washed with ethyl acetate and dried to
afford 1.32 g (yield, 45%) of 2-benzylthio-6-hydroxypurine as a
crude product.
1.00 g (3.88 mmol) of 2-benzylthio-6-hydroxypurine was dissolved in
20 ml of dimethylformamide and 0.816 ml (5.82 mmol) of
triethylamine was added to the solution. Under ice cooling, 1.62 g
(5.82 mmol) of tritylchloride was added to the mixture following
stirring at room temperature overnight. After 400 ml of water was
added, a precipitate was collected by filtration and washed with
n-hexane and with ethyl acetate. Recrystallization from ethanol
afforded 0.785 g (yield, 40%) of Compound o as a white powder.
Melting point: 267.degree.-270.degree. C.
Elemental analysis: as C.sub.31 H.sub.24 N.sub.4 OS Found (%): C
74.33 H 4.87 N 11.30. Calcd. (%): C 74.38 H 4.83 N 11.19.
IR (KBr) .nu.max (cm.sup.-1): 1683, 1554.
.sup.1 H-NMR (CDCl.sub.3, 90 MHz) .delta. (ppm): 7.76(s, 1H),
6.75-7.61 (m, 20H), 4.38(s, 2H).
MS (m/e): 260(M.sup.+ -C.sub.6 H.sub.5 X.sub.3 +1).
REFERENCE EXAMPLE 15
2-Benzylthio-1-methyl-9-trityl-1,7-dihydro-6H-purin-6-one (Compound
p)
After 500 mg (0.10 mmol) of Compound o obtained in Reference
Example 14 was dissolved in 20 ml of tetrahydrofuran, 0.08 g (0.20
mmol) of 60% sodium hydroxide was added to the solution under ice
cooling. After 30 minutes, 0.125 ml (0.20 mmol) of methyliodide was
added, and the mixture was stirred for 2 hours at 50.degree. C. The
solvent was evaporated under reduced pressure, and water was added
to the residue. The mixture was extracted with chloroform, and the
extract was washed with a saturated aqueous sodium chloride, dried
over anhydrous sodium sulfate and filtered. The solvent was
evaporated under reduced pressure, and the residue was purified by
silicagelcolumchromatography (eluent: chloroform) to afford 300 mg
(yield, 58%) of Compound p as a white powder.
Melting point: 255.degree.-258.degree. C. (isopropanol-water).
Elemental analysis: as C.sub.32 H.sub.26 N.sub.4 OS Found (%): C
75.00 H 5.11 N 10.96. Calcd. (%): C 74.68 H 5.09 N 10.89.
IR (KBr) .nu.max (cm.sup.-1): 1700, 1555.
.sup.1 H-NMR (CDCl.sub.3) .delta. (ppm): 7.64(s, 1H), 7.07-7.46(m,
18H), 6.94-6.98(m, 2H), 3.49(s, 3H), 3.48(s, 2H).
REFERENCE EXAMPLE 16
2-Chloro-8-(noradamantan-3-yl)-1-n-butyl-7-methyl-1,7-dihydro-6H-purin-6-on
The procedure is performed in a manner similar to Reference Example
9 except for using
2-chloro-8-(noradamantan-3-yl)-7-methyl-1,7-dihydro-6H-purin-6-one
to afford the captioned compound.
REFERENCE EXAMPLE 17
2-Chloro-8-dicyclopropylmethyl-1-n-butyl-7-methyl-1,7-dihydro-6H-purin-6-on
e
The procedure is performed in a manner similar to Reference Example
9 except for using
2-chloro-8-dicyclopropylmethyl-7-methyl-1,7-dihydro-6H-purin-6-one
to afford the captioned compound.
REFERENCE EXAMPLE 18
2-Chloro-8-styryl-1-n-butyl-7-methyl-1,7-dihydro-6H-purin-6-one
The procedure is performed in a manner similar to Reference Example
9 except for using
2-chloro-8-styryl-7-methyl-1,7-dihydro-6H-purin-6-one to afford the
captioned compound.
REFERENCE EXAMPLE 19
2-Benzylthio-8-(noradamantan-3-yl)-9-trityl-1,7-dihydro-6H-purin-6-one
The procedure is performed in a manner similar to Reference Example
14 except for using 8-(noradamantan-3-yl)-2-mercapto-6-hydroxypurin
to afford the captioned compound.
REFERENCE EXAMPLE 20
2-Benzylthio-8-dicyclopropylmethyl-9-trityl-1,7-dihydro-6H-purin-6-one
The procedure is performed in a manner similar to Reference Example
14 except for using 8-dicyclopropylmethyl-2-mercapto-6-hydroxypurin
to afford the captioned compound.
REFERENCE EXAMPLE 21
2-Benzylthio-8-styryl-9-trityl-1,7-dihydro-6H-purin-6-one
The procedure is performed in a manner similar to Reference Example
14 except for using 8-styryl-2-mercapto-6-hydroxypurin to afford
the captioned compound.
REFERENCE EXAMPLE 22
2-Benzylthio-1-methyl-8-(noradamantan-3-yl)-9-trityl-1,7-dihydro-6H-purin-6
-one
The procedure is performed in a manner similar to Reference Example
15 using the compound obtained in Reference Example 19 to afford
the captioned compound.
REFERENCE EXAMPLE 23
2-Benzylthio-8-dicyclopropylmethyl-1-methyl-9-trityl-1,7-dihydro-6H-purin-6
-one
The procedure is performed in a manner similar to Reference Example
15 using the compound obtained in Reference Example 20 to afford
the captioned compound.
REFERENCE EXAMPLE 24
2-Benzylthio-1-methyl-8-styryl-9-trityl-1,7-dihydro-6H-purin-6-one
The procedure is performed in a manner similar to Reference Example
15 using the compound obtained in Reference Example 21 to afford
the captioned compound.
PREPARATION EXAMPLE 1
Tablet
Tablet comprising the following composition is prepared in a
conventional manner.
______________________________________ Compound 6 20 mg Lactose 60
mg Potato starch 30 mg Polyvinyl alcohol 3 mg Magnesium stearate 1
mg ______________________________________
PREPARATION EXAMPLE 2
Powder
Powder comprising the following composition is prepared in a
conventional manner.
______________________________________ Compound 1 20 mg Lactose 300
mg ______________________________________
PREPARATION EXAMPLE 3
Syrup
Syrup comprising the following composition is prepared in a
conventional manner.
______________________________________ Compound 7 20 mg Refined
white sugar 30 mg Ethyl p-hydroxybenzoate 40 mg Propyl
p-hydroxybenzoate 10 mg Strawberry flavor 0.1 cc Water to make the
whole volume 100 cc. ______________________________________
PREPARATION EXAMPLE 4
Capsule
Capsule comprising the following composition is prepared in a
conventional manner.
______________________________________ Compound 6 20 mg Lactose 200
mg Magnesium stearate 5 mg
______________________________________
The above components are mixed and the mixture is filled up in a
gelatin capsule.
PREPARATION EXAMPLE 5
Injection
______________________________________ Compound 7 20 mg Sodium
chloride 45 mg ______________________________________
Sterilized water for injection is added to the above components to
make the whole volume 5 ml (volume per ampoule). The solution is
filtered and sterilized in an autoclave.
* * * * *