U.S. patent application number 15/197025 was filed with the patent office on 2016-10-27 for ribofuranosyl purine compounds, methods for preparing the same and use thereof.
The applicant listed for this patent is BEIJING KBD PHARMACEUTICALS CO., LTD., BEIJING UNIVERSITY OF CHEMICAL TECHNOLOGY. Invention is credited to Zhongren Ding, Hongguang Du, Guocheng Liu, Shuming Wang.
Application Number | 20160311844 15/197025 |
Document ID | / |
Family ID | 46580223 |
Filed Date | 2016-10-27 |
United States Patent
Application |
20160311844 |
Kind Code |
A1 |
Du; Hongguang ; et
al. |
October 27, 2016 |
RIBOFURANOSYL PURINE COMPOUNDS, METHODS FOR PREPARING THE SAME AND
USE THEREOF
Abstract
The present invention relates to the compounds of the formulae
(I) and (I-1) and the process for preparing the same, uses of the
compounds for the treatment of diseases associated with platelet
aggregation and in the manufacture of a medicament for the
treatment of diseases associated with platelet aggregation, and
relates to a pharmaceutical composition and a pharmaceutical
formulation containing the compounds, wherein the definitions of
R.sub.1, R.sub.2, R.sub.3 and R.sub.2a in the formulae are the same
as those in the description. ##STR00001##
Inventors: |
Du; Hongguang; (Beijing,
CN) ; Liu; Guocheng; (Beijing, CN) ; Ding;
Zhongren; (Shanghai, CN) ; Wang; Shuming;
(Beijing, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BEIJING UNIVERSITY OF CHEMICAL TECHNOLOGY
BEIJING KBD PHARMACEUTICALS CO., LTD. |
Beijing
Beijing |
|
CN
CN |
|
|
Family ID: |
46580223 |
Appl. No.: |
15/197025 |
Filed: |
June 29, 2016 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13981694 |
Sep 17, 2013 |
|
|
|
PCT/CN2012/000104 |
Jan 20, 2012 |
|
|
|
15197025 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07H 19/167 20130101;
A61P 9/00 20180101; A61P 35/00 20180101; A61K 31/7076 20130101;
A61P 9/12 20180101; A61P 31/12 20180101; A61P 9/10 20180101; C07H
19/16 20130101; A61P 35/02 20180101; A61P 7/02 20180101 |
International
Class: |
C07H 19/16 20060101
C07H019/16 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 26, 2011 |
CN |
201110028107.3 |
Claims
1. A compound represented by the formula (I-1) or a
pharmaceutically acceptable salt thereof ##STR00013## wherein
R.sub.1 represents an unsubstituted or R.sub.4-substituted
C.sub.1-C.sub.8 hydrocarbyl, or an unsubstituted or
R.sub.5-substituted 5- to 6-membered cyclic group; R.sub.2a
represents an unsubstituted or R.sub.5-substituted C.sub.3-C.sub.8
saturated or unsaturated aliphatic hydrocarbyl, an unsubstituted or
R.sub.5-substituted C.sub.3-C.sub.8 alicyclic group, an
unsubstituted or R.sub.6-substituted C.sub.6-C.sub.10
aryl-C.sub.2-C.sub.4 alkyl, an unsubstituted or R.sub.6-substituted
5- to 10-membered heterocyclyl-C.sub.1-C.sub.4 alkyl, or an
unsubstituted or R.sub.6-substituted 5- to 10-membered
heteroaryl-C.sub.1-C.sub.4 alkyl; R.sub.3 represents H or R.sub.2a;
R.sub.4 represents halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxyl, halogenated C.sub.1-C.sub.4 alkyl, halogenated
C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl,
carboxyl, nitro, cyano, C.sub.1-C.sub.4 alkylthio, or
C.sub.1-C.sub.4 alkyl-CO--; R.sub.5 represents C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4
alkyl, carboxyl, nitro, cyano, C.sub.1-C.sub.4 alkylthio or
C.sub.1-C.sub.4 alkyl-CO--; and R.sub.6 represents halogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl
C.sub.1-C.sub.4 alkyl, carboxyl, nitro, cyano, C.sub.1-C.sub.4
alkylthio, or C.sub.1-C.sub.4 alkyl-CO--; provided that when
R.sub.1 is --CH.sub.3 and R.sub.3 is H, R.sub.2a is not cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, decalinyl,
3-methyl-2-pentenyl, 2-methyl-3-hydroxyl-1-propenyl,
3-methyl-4-hydroxyl-1-butenyl, furfurylmethylene,
3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methylbutyl,
3-methyl-4-hydroxylbutyl, 3-methyl-4-hydroxyl-2-butenyl or
3-methyl-4-hydroxyl-3-butenyl; or when R.sub.1 is propyl, R.sub.2a
is not cyclopentyl, isopropyl, n-propyl or n-butyl.
2. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 represents an
unsubstituted or R.sub.4-substituted C.sub.1-C.sub.6 alkyl, wherein
R.sub.4 represents halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxyl, halogenated C.sub.1-C.sub.4 alkyl, halogenated
C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl,
carboxyl, nitro, cyano, C.sub.1-C.sub.4 alkylthio, or
C.sub.1-C.sub.4 alkyl-CO--.
3. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof, wherein R.sub.2a represents an
unsubstituted or R.sub.5-substituted C.sub.3-C.sub.6 alkyl, an
unsubstituted or R.sub.5-substituted C.sub.3-C.sub.6 cycloalkyl, an
unsubstituted or R.sub.6-substituted 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, an unsubstituted or
R.sub.6-substituted phenyl-C.sub.2-C.sub.4 alkyl, or an
unsubstituted or R.sub.6-substituted 5- to 6-membered
heterocyclyl-C.sub.1-C.sub.4 alkyl, wherein R.sub.5 is selected
from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl, carboxyl, nitro,
cyano, C.sub.1-C.sub.4 alkylthio and C.sub.1-C.sub.4 alkyl-CO--;
and R.sub.6 is selected from the group consisting of halogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl
C.sub.1-C.sub.4 alkyl, carboxyl, nitro, cyano, C.sub.1-C.sub.4
alkylthio, and C.sub.1-C.sub.4 alkyl-CO--.
4. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 represents C.sub.1-C.sub.6
alkyl; R.sub.2a represents C.sub.3-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, an unsubstituted or R.sub.6-substituted
phenyl-C.sub.2-C.sub.4 alkyl, an unsubstituted or
R.sub.6-substituted 5- to 6-membered heteroaryl-C.sub.1-C.sub.4
alkyl, or an unsubstituted or R.sub.6-substituted 5- to 6-membered
heterocyclyl-C.sub.1-C.sub.4 alkyl, wherein R.sub.6 is selected
from the group consisting of halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl,
carboxyl, nitro, cyano, C.sub.1-C.sub.4 alkylthio and
C.sub.1-C.sub.4 alkyl-CO--.
5. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 represents C.sub.1-C.sub.4
alkyl; R.sub.2a represents C.sub.3-C.sub.6 alkyl, C.sub.5-C.sub.6
cycloalkyl, unsubstituted or C.sub.1-C.sub.4 alkyl-substituted or
C.sub.1-C.sub.4 alkoxyl-substituted phenyl-C.sub.2-C.sub.4 alkyl,
unsubstituted or C.sub.1-C.sub.4 alkyl-substituted or
C.sub.1-C.sub.4 alkoxyl-substituted 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, or unsubstituted or
C.sub.1-C.sub.4 alkyl-substituted or C.sub.1-C.sub.4
alkoxyl-substituted 5- to 6-membered heterocyclyl-C.sub.1-C.sub.4
alkyl.
6. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof, wherein R.sub.1 represents methyl, ethyl,
n-propyl, isopropyl or butyl; R.sub.2a represents n-hexyl,
cyclohexyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,
methoxylphenylethyl, 2-thienylethyl, furylmethyl, or
tetrahydrofurylmethyl.
7. The compound according to claim 1 or a pharmaceutically
acceptable salt thereof, wherein R.sub.3 represents H or
C.sub.3-C.sub.6 alkyl.
8. (canceled)
9. A process for preparing the compound according to claim 1,
##STR00014## wherein R is acyl; R.sub.1, R.sub.2 and R.sub.3 are as
defined in claim 1; which comprises: using guanosine 1 as the
starting material, firstly conducting the conventional
esterification protection of three hydroxyl groups on the ribose
ring of guanosine with an acid anhydride or an acyl halide, then
halogenating the isomerized hydroxyl group at 6-position using the
conventional halogenating reagent to obtain
2-amino-6-halogenated-9-(2',3',5'-tri-O-acetyl-.beta.-D-ribofuranosyl)
purine 3, then under an anhydrous condition diazotizing the amino
at 2-position of 3 with a conventional diazotization reagent, and
then reacting with disulfide to obtain the corresponding
2-alkylthio-6-halogenated-9-(2',3',5'-tri-O-acetyl-.beta.-D-ribofuranosyl-
)purine 4, eventually conducting the nucleophilic substitution
reaction with amine under the action of an alkaline, and removing
the protecting group by the catalysis of alkali metal alkoxides to
obtain the final product compound of the formula (I-1).
10. A pharmaceutical composition, comprising the compound according
to claim 1 or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical formulation, comprising the compound according
to claim 1 or a pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier.
12-16. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention relates to ribofuranosyl purine
compounds, methods for preparing the same and use thereof in the
manufacture of a medicament for the treatment of diseases
associated with platelet aggregation. More specifically, the
present invention relates to compounds having
9-.beta.-D-ribofuranosyl purine as the parent structure, and
comprising a substituted amino group at 6-position and a
substituted hydrosulfuryl at 2-position, and relates to methods for
preparing the same and use thereof for the treatment of diseases
associated with platelet aggregation and in the manufacture of a
medicament for the treatment of diseases associated with platelet
aggregation, and relates to pharmaceutical compositions and
formulations comprising said compounds.
BACKGROUND ART
[0002] Due to the biological importance of purine and the
pharmacologists' studies on purine antineoplastic and antiviral
medicines, purine chemistry develops rapidly. The research shows
that purine compounds have important biological activities such as
anti-viral, anti-cancer, blood pressure decreasing activities. The
compounds prepared by using purine derivatives as the intermediates
have special efficacy on cancers, AIDS, thrombosis and the like.
The medicines such as from the earliest acyclovir to the lately
developed ganciclovir, valganciclovir, abacavir, fludarabine and
the like are widely and clinically applied (Bioorg. Med. Chem.
Lett. 2009, 19, 242-246 and Synthesis 2008, 20, 3253-3260). In
WO02004/058791A2, it is disclosed that 6-(substituted) benzylamino
adenosine derivatives are thought to have anticancer, mitotic,
immunosuppressive and antisenescent properties. In WO2010/130233A1,
it is disclosed that 2-substituted-6-(substituted)benzylamino
purine riboside derivatives are thought to have antiapoptotic,
anti-inflammatory and differentiation activities.
[0003] Anthony H. Ingall et al. disclosed in 1994 (WO 94/18216)
N-alkyl-2-substituted ATP analogues having the following formula,
and methods for preparing the same,
##STR00002##
wherein R.sup.1 and R.sup.2 independently represent H or halogen;
R.sup.3 and R.sup.4 independently represent phenyl or
C.sub.1-6alkyl optionally substituted by one or more substitute(s)
selected from the group consisting of OR.sup.5, C.sub.1-6
alkylthio, NR.sup.6R.sup.7, phenyl, COOR.sup.8 and halogen;
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 independently represent H or
C.sub.1-6 alkyl; and X represents the acidic moiety. Such PCT
application further provides the representative data of the in
vitro anti-platelet aggregation activity test of the compounds, in
which the tests were carried out by using human platelet treated
with water. Anthony H. Ingall et al. further disclosed in 1999 a
process for preparing
2-alkylthio-6-(alkyl)amino-5'-substituted-9-.beta.-D-ribofurano-
syl purine compounds (AR-C compounds) having the following
formula
##STR00003##
and the results of the activity measurement of ADP-induced platelet
aggregation resistance carried out by using human platelet treated
with water. The results show the above compounds have the activity
of ADP-induced human platelet aggregation resistance (J. Med. Chem.
1999, 42, 213-220). The AR-C compound--Canrgelor is thought to have
the advantages of high activity, fast effect, short half-life,
reversibility, direct inhibition of platelet activation and the
like (Eur. Heart. J. Suppl. 2008, 10, 133-137 and Recent Patents on
Cardiovascular Drug Discovery, 2008, 3, 194-200), and has the
prospect of being developed into a new class of antithrombotics
medicines. Thus studies on the activity of anti-platelet
aggregation of such 5'-substituted-9-.beta.-D-ribofuranosyl purine
compounds have become one of hotspots in the field of drug
research.
[0004] However, the AR-C compounds have a complex structure, a
longer synthesis routes, and a very tedious post-treatment process,
in particular a biochemical reagent is required for introducing a
substituted triphosphoric acid side chain into the 5'-position, and
the said compounds have a bad oral availability. Thus there is an
urgent need to develop a candidate medicine for anti-platelet
aggregation having a simple structure, easy to synthesize, a better
therapeutic effect and a lower side effect.
[0005] During the studies on the platelet aggregation inhibitors,
the inventor of the present invention discovered a series of novel
2-substituted hydrosulfuryl-6-substituted
amino-9-.beta.-D-ribofuranosyl purine compounds having notable
activity of anti-platelet aggregation and a simple structure, and
measured the in vitro anti-platelet aggregation activity of the
compounds, so as to achieve the present invention.
CONTENTS OF THE INVENTION
[0006] One object of the present invention is to provide a compound
of the following formula (I) having the activity of anti-platelet
aggregation, or a pharmaceutically acceptable salt thereof, as well
as the uses thereof as platelet aggregation inhibitors or in the
manufacture of a medicament for the treatment or prevention of
diseases associated with platelet aggregation:
##STR00004##
wherein:
[0007] R.sub.1 represents an unsubstituted or R.sub.4-substituted
C.sub.1-C.sub.8 hydrocarbyl, or an unsubstituted or
R.sub.5-substituted 5- to 6-membered cyclic group;
[0008] R.sub.2 represents an unsubstituted or R.sub.5-substituted
C.sub.3-C.sub.8 saturated or unsaturated aliphatic hydrocarbyl, an
unsubstituted or R.sub.5-substituted C.sub.3-C.sub.8 alicyclic
group, an unsubstituted or R.sub.6-substituted C.sub.6-C.sub.10
aryl-C.sub.1-C.sub.4 alkyl, an unsubstituted or R.sub.6-substituted
5- to 10-membered heterocyclyl-C.sub.1-C.sub.4 alkyl, or an
unsubstituted or R.sub.6-substituted 5- to 10-membered
heteroaryl-C.sub.1-C.sub.4 alkyl;
[0009] R.sub.3 represents H or R.sub.2;
[0010] R.sub.4 represents halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxyl, halogenated C.sub.1-C.sub.4 alkyl,
halogenated C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl
C.sub.1-C.sub.4 alkyl, carboxyl, nitro, cyano, C.sub.1-C.sub.4
alkylthio, or C.sub.1-C.sub.4 alkyl-CO--; [0011] R.sub.5 represents
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl
C.sub.1-C.sub.4 alkyl, carboxyl, nitro, cyano, C.sub.1-C.sub.4
alkylthio or C.sub.1-C.sub.4 alkyl-CO--; and
[0012] R.sub.6 represents halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl,
carboxyl, nitro, cyano, C.sub.1-C.sub.4 alkylthio, or
C.sub.1-C.sub.4 alkyl-CO--.
[0013] Another object of the present invention is to provide a
novel compound of the formula (I) having the structure of the
following formula (I-1), or a pharmaceutically acceptable salt
thereof:
##STR00005##
wherein
[0014] R.sub.1 represents an unsubstituted or R.sub.4-substituted
C.sub.1-C.sub.8 hydrocarbyl, or an unsubstituted or
R.sub.5-substituted 5- to 6-membered cyclic group;
[0015] R.sub.2a represents an unsubstituted or R.sub.5-substituted
C.sub.3-C.sub.8 saturated or unsaturated aliphatic hydrocarbyl, an
unsubstituted or R.sub.5-substituted C.sub.3-C.sub.8 alicyclic
group, an unsubstituted or R.sub.6-substituted C.sub.6-C.sub.10
aryl-C.sub.2-C.sub.4 alkyl, an unsubstituted or R.sub.6-substituted
5- to 10-membered heterocyclyl-C.sub.1-C.sub.4 alkyl, or an
unsubstituted or R.sub.6-substituted 5- to 10-membered
heteroaryl-C.sub.1-C.sub.4 alkyl;
[0016] R.sub.3 represents H or R.sub.2a;
[0017] R.sub.4 represents halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxyl, halogenated C.sub.1-C.sub.4 alkyl,
halogenated C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl
C.sub.1-C.sub.4 alkyl, carboxyl, nitro, cyano, C.sub.1-C.sub.4
alkylthio, or C.sub.1-C.sub.4 alkyl-CO--;
[0018] R.sub.5 represents C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl, carboxyl, nitro,
cyano, C.sub.1-C.sub.4 alkylthio or C.sub.1-C.sub.4 alkyl-CO--;
and
[0019] R.sub.6 represents halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl,
carboxyl, nitro, cyano, C.sub.1-C.sub.4 alkylthio, or
C.sub.1-C.sub.4 alkyl-CO--;
[0020] provided that
[0021] when R.sub.1 is --CH.sub.3 and R.sub.3 is H, R.sub.2a is not
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl,
3-methyl-2-pentenyl, 2-methyl-3-hydroxyl-1-propenyl,
3-methyl-4-hydroxyl-1-butenyl, furfurylmethylene,
3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methylbutyl,
3-methyl-4-hydroxylbutyl, 3-methyl-4-hydroxyl-2-butenyl or
3-methyl-4-hydroxyl-3-butenyl; and
[0022] when R.sub.1 is propyl, R.sub.2a is not cyclopentyl,
isopropyl, n-propyl or n-butyl.
[0023] Another object of the present invention is to provide a
process for preparing the compound of the formula (I) (including
the compound of the formula (I-1) (when R.sub.2.dbd.R.sub.2a in the
formula (I))), comprising using guanosine 1 as the starting
material, firstly conducting the conventional esterification
protection of three hydroxyl groups on the ribose ring of guanosine
with anhydride or acyl halide, for example, acyl chloride, then
halogenating the isomerized hydroxyl group at 6-position (using the
conventional halogenating reagent, such as phosphorus oxyhalide
POX.sub.3)) to obtain
2-amino-6-halogenated-9-(2',3',5'-tri-O-acetyl-.beta.-D-ribofuranosyl)
purine 3, then diazotizing the amino at 2-position of 3 under the
anhydrous condition (with the conventional diazotization reagents,
such as isoamyl nitrite and the like), and then reacting with
disulfide to obtain the corresponding
2-alkylthio-6-halogenated-9-(2',3',5'-tri-O-acetyl-.beta.-D-ribofuranosyl-
) purine 4, and eventually conducting the nucleophilic substitution
reaction with amine under the action of alkaline, and removing the
protecting group by the catalysis with organic bases, e.g. alkali
metal alkoxides such as sodium, potassium methoxide, sodium
ethoxide or potassium ethoxide, to obtain the final product
2-substituted hydrosulfuryl-6-substituted
amino-9-.beta.-D-ribofuranosyl purine compound of the formula (I)
or (I-1) (when R.sub.2.dbd.R.sub.2a in the formula (I)). Such
synthetic process has a simple operation, less reaction steps and a
relatively higher yield. The synthetic route is shown as
follows:
##STR00006##
wherein R is acyl; X is halogen; R.sub.1, R.sub.2, R.sub.2a and
R.sub.3 are as defined in the compound of the above formula (I) or
(I-1).
[0024] Another object of the present invention is to provide a
pharmaceutical composition and formulation comprising the compound
of the formula (I) (including the compound of the formula (I-1)
(when R.sub.2.dbd.R.sub.2a in the formula (I))) or a
pharmaceutically acceptable salt thereof.
[0025] Another object of the present invention is to provide the
use of the compound of the formula (I) (including the compound of
the formula (I-1) (when R.sub.2.dbd.R.sub.2a in the formula (I)))
or a pharmaceutically acceptable salt thereof in the manufacture of
a medicament for the treatment or prevention of diseases associated
with platelet aggregation.
[0026] Another object of the present invention is to provide a
method for the treatment or prevention of diseases associated with
platelet aggregation, including administering an effective amount
for the treatment or prevention of the compound of the formula (I)
(including the compound of the formula (I-1) (when
R.sub.2.dbd.R.sub.2a in the formula (I))) or a pharmaceutically
acceptable salt thereof to a mammal who needs it.
[0027] In the present invention, the term "C.sub.1-C.sub.8
hydrocarbyl" represents a linear or branched, saturated or
unsaturated hydrocarbyl having 1 to 8 carbon atoms, comprising
C.sub.1-C.sub.8 linear or branched alkyl, C.sub.1-C.sub.8 linear or
branched alkenyl and C.sub.1-C.sub.8 linear or branched alkynyl,
e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,
tert-butyl, n-amyl, isoamyl, neopentyl, n-hexyl, 2-methylpentyl,
3-methylpentyl, 2,3-dimethylbutyl, 2-methylhexyl, 3-methylhexyl,
2,3-dimethylpentyl, 2,2,3-trimethylbutyl, 2,3,3-trimethylbutyl,
n-heptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl,
3-ethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl,
2,5-dimethylhexyl, n-octyl, allyl, 2-butenyl, 2-pentenyl,
2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 2-octenyl, 3-octenyl,
4-octenyl, propargyl, 2-butynyl, 2-pentynyl, 2-hexynyl, 3-hexynyl,
2-heptynyl, 3-heptynyl, 2-octynyl, 3-octynyl, 4-octynyl and the
like, wherein C.sub.1-C.sub.6 hydrocarbyl is preferred.
[0028] The term "5- to 6-membered cyclic group" represents 5- to
6-membered, saturated or unsaturated alicyclic non-aromatic carbon
ring group or 5- to 6-membered, saturated or unsaturated
heterocyclyls, wherein said heterocyclyls comprise heteroatoms
selected from the group consisting of N, O and S; 6-membered cyclic
group is particularly preferred. Said cyclic group includes, but is
not limited to, e.g. cyclopentyl, cyclohexyl, cyclopentenyl,
cyclohexenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl
tetrahydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl,
oxazolidinyl, pyrrolyl, dihydropyrrolyl, imidazolyl,
dihydroimidazolyl, pyrazolyl, dihydropyrazolyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, furyl, dihydrofuryl, thienyl,
dihydrothienyl, pyranyl, dihydropyranyl, oxazolyl, dihydrooxazolyl,
isoxazolyl, dihydroisoxazolyl, thiazolyl, dihydrothiazolyl,
isothiazolyl and the like.
[0029] In the present invention, the term "C.sub.3-C.sub.8
saturated or unsaturated aliphatic hydrocarbyl group" represents a
linear or branched, saturated or unsaturated hydrocarbyl having 3
to 8 carbon atoms, including C.sub.3-C.sub.8 linear or branched
alkyl group, C.sub.3-C.sub.8 linear or branched alkenyl and
C.sub.3-C.sub.8 linear or branched alkynyl. Said hydrocarbyl group
includes, but is not limited to, e.g. propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, n-amyl, isoamyl, neopentyl, n-hexyl,
2-methylpentyl, 3-methy pentyl, 2,3-dimethylbutyl, 2-methylhexyl,
3-methylhexyl, 2,3-dimethyl pentyl, 2,2,3-trimethylbutyl,
2,3,3-trimethylbutyl, n-heptyl, 2-methylheptyl, 3-methylheptyl,
4-methylheptyl, 3-ethylhexyl, 2,3-dimethylhexyl, 2,
4-dimethylhexyl, 2,5-dimethylhexyl, n-octyl, allyl, isopropenyl,
2-butenyl, 2-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl,
3-heptenyl, 2-octenyl, 3-octenyl, 4-octenyl, propargyl, 2-butynyl,
2-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl,
2-octynyl, 3-octynyl, 4-octynyl and the like.
[0030] In the present invention, the term "C.sub.3-C.sub.8
alicyclic group" represents 3- to 8-membered saturated or
unsaturated alicyclic carbon ring group, and the said group
includes, but is not limited to, e.g. cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,
cyclohexenyl and the like.
[0031] In the present invention, the term "C.sub.6-C.sub.10 aryl"
represents 6- to 10-membered, aromatic, monocyclic or bicyclic
carbon ring group, wherein one ring of the bicyclic carbon ring
group may be hydrogenated, includes, e.g. phenyl, naphthyl,
dihydronaphthyl, tetrahydronaphthyl and the like.
[0032] Said "C.sub.6-C.sub.10 aryl-C.sub.1-C.sub.4 alkyl" includes,
but is not limited to, e.g. benzyl, phenylethyl, phenylpropyl,
phenylisopropyl, phenylbutyl, phenylisobutyl, phenyl t-butyl,
menaphthyl, naphthylethyl, naphthylpropyl, naphthylbutyl,
dihydromenaphthyl, dihydronaphthylethyl, dihydronaphthylpropyl,
dihydronaphthylbutyl, tetrahydromenaphthyl,
tetrahydronaphthylethyl, tetrahydronaphthylpropyl,
tetrahydronaphthylbutyl and the like.
[0033] In the present invention, the term "5- to 0-membered
heterocyclyl" represents 5- to 10-membered, monocyclic or bicyclic,
alicyclic heterocyclyl containing heteroatoms selected from the
group consisting of N, O and S. Said heterocyclyl includes, but is
not limited to, tetrahydrofuryl, tetrahydrothienyl, 1,3-dioxolanyl,
1,3-dithiolanyl, tetrahydropyranyl, 1,4-dioxanyl, 1,3-dioxanyl,
1,3-oxathianyl, dihydrofuryl, dihydrothienyl, dihydropyranyl,
dihydrooxazolyl dihydrothiazolyl and the like.
[0034] In the present invention, the term "5- to 10-membered
heteroaryl group" represents 5- to 10-membered, aromatic,
monocyclic or bicyclic heterocyclyl containing heteroatoms selected
from the group consisting of N, O and S. Said heteroaryl group
includes, but is not limited to, e.g. pyridyl, pyridazinyl,
pyrimidinyl, pyrazinyl, furyl, imidazolyl, pyranyl, pyrazolyl,
oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, thienyl, purinyl,
benzofuranyl, benzothiophenyl, diazinyl, isobenzothiophenyl,
isobenzofuranyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl and
the like.
[0035] In the present invention, the term "halogen" represents
fluorine, chlorine, bromine, iodine.
[0036] In the present invention, the term "pharmaceutically
acceptable salt" represents a salt formed by reacting a
pharmaceutically acceptable nontoxic acid with the alkaline moiety
of the compound of the formula (I) or (I-1) of the present
invention, including, e.g. hydrochlorides, acetates, hydrobromides,
sulfates, bisulfates, carbonates, bicarbonates, sulfites,
phosphates, biphosphates, oxalates, malonates, pentanoate, borates,
p-toluene sulphonates, mesylates, tartrates, benzoates, lactates,
citrates, maleates, fumarates, malates, salicylates, amygdalates,
succinates, gluconates, lactobionates and the like. Such salt may
be prepared by the method well known by those skilled in the
art.
[0037] In one embodiment of the compound of the formula (I) or
(I-1) of the present invention, R.sub.3 represents H or
C.sub.3-C.sub.6 alkyl.
[0038] In one preferred embodiment of the compound of the formula
(I) or (I-1) of the present invention, R.sub.1 represents an
unsubstituted or R.sub.4-substituted C.sub.1-C.sub.6 alkyl, wherein
R.sub.4 represents halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxyl, halogenated C.sub.1-C.sub.4 alkyl, halogenated
C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl,
carboxyl, nitro, cyano, C.sub.1-C.sub.4 alkylthio,
C.sub.1-C.sub.4-alkyl-CO--.
[0039] In one preferred embodiment of the compound of the formula
(I) of the present invention, R.sub.2 represents an unsubstituted
or R.sub.5-substituted C.sub.3-C.sub.8, preferably C.sub.3-C.sub.6
alkyl, an unsubstituted or R.sub.5-substituted C.sub.3-C.sub.6
cycloalkyl, an unsubstituted or R.sub.6-substituted
phenyl-C.sub.1-C.sub.4 alkyl, an unsubstituted or
R.sub.6-substituted 5- to 6-membered heteroaryl-C.sub.1-C.sub.4
alkyl, or an unsubstituted or R.sub.6-substituted 5- to 6-membered
heterocyclyl-C.sub.1-C.sub.4 alkyl, wherein R.sub.5 is selected
from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl, carboxyl, nitro,
cyano, C.sub.1-C.sub.4 alkylthio and C.sub.1-C.sub.4 alkyl-CO--;
and R.sub.6 is selected from the group consisting of halogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl
C.sub.1-C.sub.4 alkyl, carboxyl, nitro, cyano, C.sub.1-C.sub.4
alkylthio and C.sub.1-C.sub.4 alkyl-CO--.
[0040] In one preferred embodiment of the compound of the formula
(I-1) of the present invention, R.sub.2a represents an
unsubstituted or R.sub.5-substituted C.sub.3-C.sub.8, preferably
C.sub.3-C.sub.6 alkyl, an unsubstituted or R.sub.5-substituted
C.sub.3-C.sub.6 cycloalkyl, an unsubstituted or R.sub.6-substituted
phenyl-C.sub.2-C.sub.4 alkyl, an unsubstituted or
R.sub.6-substituted 5- to 6-membered heteroaryl-C.sub.1-C.sub.4
alkyl, or an unsubstituted or R.sub.6-substituted 5- to 6-membered
heterocyclyl-C.sub.1-C.sub.4 alkyl, wherein R.sub.5 is selected
from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl, carboxyl, nitro,
cyano, C.sub.1-C.sub.4 alkylthio and C.sub.1-C.sub.4 alkyl-CO--;
and R.sub.6 is selected from the group consisting of halogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl
C.sub.1-C.sub.4 alkyl, carboxyl, nitro, cyano, C.sub.1-C.sub.4
alkylthio and C.sub.1-C.sub.4 alkyl-CO--.
[0041] In one preferred embodiment of the compound of the formula
(I) of the present invention, R.sub.1 represents an unsubstituted
or R.sub.4-substituted C.sub.1-C.sub.6 alkyl; R.sub.2 represents an
unsubstituted or R.sub.5-substituted C.sub.3-C.sub.6 alkyl, an
unsubstituted or R.sub.5-substituted C.sub.3-C.sub.6 cycloalkyl, an
unsubstituted or R.sub.6-substituted 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, an unsubstituted or
R.sub.6-substituted phenyl-C.sub.1-C.sub.4 alkyl, or an
unsubstituted or R.sub.6-substituted 5- to 6-membered
heterocyclyl-C.sub.1-C.sub.4 alkyl; and R.sub.3 represents H or
C.sub.3-C.sub.6 alkyl; wherein R.sub.4 represents halogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxyl, halogenated
C.sub.1-C.sub.4 alkyl, halogenated C.sub.1-C.sub.4 alkoxyl,
hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl, carboxyl, nitro, cyano,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4-alkyl-CO--; R.sub.5 is
selected from the group consisting of C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl,
carboxyl, nitro, cyano, C.sub.1-C.sub.4 alkylthio and
C.sub.1-C.sub.4 alkyl-CO--; and R.sub.6 is selected from the group
consisting of halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl, carboxyl, nitro,
cyano, C.sub.1-C.sub.4 alkylthio and C.sub.1-C.sub.4
alkyl-CO--.
[0042] In one preferred embodiment of the compound of the formula
(I-1) of the present invention, R.sub.1 represents an unsubstituted
or R.sub.4-substituted C.sub.1-C.sub.6 alkyl; R.sub.2a represents
an unsubstituted or R.sub.5-substituted C.sub.3-C.sub.6 alkyl, an
unsubstituted or R.sub.5-substituted C.sub.3-C.sub.6 cycloalkyl, an
unsubstituted or R.sub.6-substituted 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, an unsubstituted or
R.sub.6-substituted phenyl-C.sub.2-C.sub.4 alkyl, or an
unsubstituted or R.sub.6-substituted 5- to 6-membered
heterocyclyl-C.sub.1-C.sub.4 alkyl; and R.sub.3 represents H or
C.sub.3-C.sub.6 alkyl; wherein R.sub.4 represents halogen,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxyl, halogenated
C.sub.1-C.sub.4 alkyl, halogenated C.sub.1-C.sub.4 alkoxyl,
hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl, carboxyl, nitro, cyano,
C.sub.1-C.sub.4 alkylthio, or C.sub.1-C.sub.4-alkyl-CO--; R.sub.5
is selected from the group consisting of C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl,
carboxyl, nitro, cyano, C.sub.1-C.sub.4 alkylthio and
C.sub.1-C.sub.4 alkyl-CO--; and R.sub.6 is selected from the group
consisting of halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl, carboxyl, nitro,
cyano, C.sub.1-C.sub.4 alkylthio and C.sub.1-C.sub.4
alkyl-CO--.
[0043] In another preferred embodiment of the compound of the
formula (I) of the present invention, R.sub.1 represents
C.sub.1-C.sub.6 alkyl; R.sub.2 represents C.sub.3-C.sub.6 alkyl,
C.sub.5-C.sub.6 cycloalkyl, an unsubstituted or R.sub.6-substituted
phenyl-C.sub.1-C.sub.4 alkyl, an unsubstituted or Re-substituted 5-
to 6-membered heteroaryl-C.sub.1-C.sub.4 alkyl, or an unsubstituted
or R.sub.6-substituted 5- to 6-membered
heterocyclyl-C.sub.1-C.sub.4 alkyl, wherein R.sub.6 is selected
from the group consisting of halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl
and C.sub.1-C.sub.4 alkylthio.
[0044] In another preferred embodiment of the compound of the
formula (I-1) of the present invention, R.sub.1 represents
C.sub.1-C.sub.6 alkyl; R.sub.2a represents C.sub.3-C.sub.6 alkyl,
C.sub.5-C.sub.6 cycloalkyl, an unsubstituted or R.sub.6-substituted
phenyl-C.sub.2-C.sub.4 alkyl, an unsubstituted or
R.sub.6-substituted 5- to 6-membered heteroaryl-C.sub.1-C.sub.4
alkyl, or an unsubstituted or R.sub.6-substituted 5- to 6-membered
heterocyclyl-C.sub.1-C.sub.4 alkyl, wherein R.sub.6 is selected
from the group consisting of halogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxyl, hydroxyl, hydroxyl C.sub.1-C.sub.4 alkyl
and C.sub.1-C.sub.4 alkylthio.
[0045] In another preferred embodiment of the compound of the
formula (I) of the present invention, R.sub.1 represents
C.sub.1-C.sub.4 alkyl; R.sub.2 represents C.sub.3-C.sub.6 alkyl,
C.sub.5-C.sub.6 cycloalkyl, or C.sub.1-C.sub.4 alkyl-substituted or
C.sub.1-C.sub.4 alkoxyl-substituted phenyl-C.sub.1-C.sub.4 alkyl,
unsubstituted or C.sub.1-C.sub.4 alkyl-substituted or
C.sub.1-C.sub.4 alkoxyl-substituted 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, or unsubstituted or
C.sub.1-C.sub.4 alkyl-substituted or C.sub.1-C.sub.4
alkoxyl-substituted 5- to 6-membered heterocyclyl-C.sub.1-C.sub.4
alkyl; and R.sub.3 represents H or C.sub.3-C.sub.4 alkyl.
[0046] In another preferred embodiment of the compound of the
formula (I-1) of the present invention, R.sub.1 represents
C.sub.1-C.sub.4 alkyl; R.sub.2a represents C.sub.4-C.sub.6 alkyl,
C.sub.5-C.sub.6 cycloalkyl, C.sub.1-C.sub.4 alkyl-substituted or
C.sub.1-C.sub.4 alkoxyl-substituted phenyl-C.sub.2-C.sub.4 alkyl,
unsubstituted or C.sub.1-C.sub.4 alkyl-substituted or
C.sub.1-C.sub.4 alkoxyl-substituted 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, or unsubstituted or
C.sub.1-C.sub.4 alkyl-substituted or C.sub.1-C.sub.4
alkoxyl-substituted 5- to 6-membered heterocyclyl-C.sub.1-C.sub.4
alkyl; and R.sub.3 represents H or C.sub.3-C.sub.4 alkyl.
[0047] In another preferred embodiment of the compound of the
formula (I) of the present invention, R.sub.1 represents methyl,
ethyl, n-propyl, isopropyl or butyl; R.sub.2 represents n-hexyl,
cyclohexyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,
4-phenylbutyl, methoxylphenylethyl, 2-thienylethyl, furylmethyl, or
tetrahydrofurylmethyl; and R.sub.3 represents H or C.sub.3-C.sub.4
alkyl.
[0048] In another preferred embodiment of the compound of the
formula (I-1) of the present invention, R.sub.1 represents methyl,
ethyl, n-propyl, isopropyl or butyl; R.sub.2a represents n-hexyl,
cyclohexyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,
methoxyphenylethyl, 2-thienylethyl, furylmethyl, or
tetrahydrofurylmethyl; and R.sub.3 represents H or C.sub.3-C.sub.4
alkyl.
[0049] The particularly preferred compounds of the formula (I) or
(I-1) (when R.sub.2.dbd.R.sub.2a in the formula (I)) of the present
invention comprise the following compounds and pharmaceutically
acceptable salts thereof:
TABLE-US-00001 ##STR00007## Name of compounds R.sub.1 R.sub.2 or
R.sub.2a R.sub.3 2-propylthio-6-n-hexylamino-9-.beta.-D- propyl
n-hexyl H ribofuranosyl purine
2-ethylthio-6-cyclohexylamino-9-.beta.-D- ethyl cyclohexyl H
ribofuranosyl purine 2-propylthio-6-cyclohexylamino-9-.beta.-D-
propyl cyclohexyl H ribofuranosyl purine
2-isopropylthio-6-cyclohexylamino-9-.beta.- iso- cyclohexyl H
D-ribofuranosyl purine propyl
2-butylthio-6-cyclohexylamino-9-.beta.-D- butyl cyclohexyl H
ribofuranosyl purine 2-ethylthio-6-benzylamino-9-.beta.-D- ethyl
benzyl H ribofuranosyl purine
2-propylthio-6-benzylamino-9-.beta.-D- propyl benzyl H
ribofuranosyl purine 2-butylthio-6-benzylamino-9-.beta.-D- butyl
benzyl H ribofuranosyl purine 2-ethylthio-6-(1-phenylethyl)amino-
ethyl 1- H 9-.beta.-D-ribofuranosyl purine phenylethyl
2-propylthio-6-([4-methoxylbenzyl]- propyl 4-methoxyl- H
amino)-9-.beta.-D-ribofuranosyl purine benzyl
2-methylthio-6-phenylethylamino-9-.beta.-D- methyl phenylethyl H
ribofuranosyl purine 2-ethylthio-6-phenylethylamino-9-.beta.-D-
ethyl phenylethyl H ribofuranosyl purine
2-propylthio-6-phenylethylamino-9-.beta.-D- propyl phenylethyl H
ribofuranosyl purine 2-butylthio-6-phenylethylamino-9-.beta.-D-
butyl phenylethyl H ribofuranosyl purine
2-methylthio-6-([4-methoxylphenylethyl]- methyl 4-methoxyl- H
amino)-9-.beta.-D-ribofuranosyl purine phenylethyl
2-ethylthio-6-([4-methoxylphenylethyl]- ethyl 4-methoxyl- H
amino)-9-.beta.-D-ribofuranosyl purine phenylethyl
2-propylthio-6-([4-methoxylphenylethyl]- propyl 4-methoxyl- H
amino)-9-.beta.-D-ribofuranosyl purine phenylethyl
2-butylthio-6-([4-methoxylphenylethyl]- butyl 4-methoxyl- H
amino)-9-.beta.-D-ribofuranosyl purine phenylethyl
2-ethylthio-6-([3-methoxylphenylethyl]- ethyl 3-methoxyl- H
amino)-9-.beta.-D-ribofuranosyl purine phenylethyl
2-propylthio-6-([3-methoxylphenylethyl] propyl 3-methoxyl- H
amino)-9-.beta.-D-ribofuranosyl purine phenylethyl
2-ethylthio-6,6-(dibutylamino-9-.beta.-D- ethyl butyl butyl
ribofuranosyl purine 2-ethylthio-6-(2-thienylethyl)amino- ethyl 2-
H 9-.beta.-D-ribofuranosyl purine thienylethyl
2-propylthio-6-(2-thienylethyl)amino- propyl 2- H
9-.beta.-D-ribofuranosyl purine thienylethyl
2-ethylthio-6-(3-phenylpropyl)amino- ethyl 3-phenyl- H
9-.beta.-D-ribofuranosyl purine propyl
2-ethylthio-6-(4-phenylbutyl)amino- ethyl 4-phenyl- H
9-.beta.-D-ribofuranosyl purine butyl
2-ethylthio-6-(2-furylmethyl)amino- ethyl 2-furyl- H
9-.beta.-D-ribofuranosyl purine methyl
2-ethylthio-6-(2-tetrahydrofurylmethyl)- ethyl 2-tetrahydro- H
amino-9-.beta.-D-ribofuranosyl purine furylmethyl
[0050] In one embodiment of the process for preparing the compound
of the general formula (I) or (I-1) (when R.sub.2.dbd.R.sub.2a in
the general formula (I)), the process may comprise the following
specific steps:
##STR00008##
[0051] a) adding dried guanosine 1, acetic anhydride or acyl halide
and organic base, such as triethylamine in an molar ratio of about
1:3.5:4 into anhydrous acetonitrile successively, upon being fully
dissolved, adding to the solution 4-dimethylamino pyridine in a
catalytic amount, sharply stirring at room temperature for 0.5 h,
then evaporating the solvent under reduced pressure, and then
recrystallizing the residue with isopropanol to obtain an
intermediate 2;
[0052] b) successively adding the intermediate 2, anhydrous
Et.sub.4NCl, POCl.sub.3 and N,N-dimethylaniline in an molar ratio
of about 1:3:4.5:1.5 into a mixed solvent of anhydrous acetonitrile
and anhydrous 1,2-dichloroethane in a volume ratio of 1:2, heating
and refluxing the mixture for 20-25 min, then slowly pouring the
resulting mixture into brash ice, on being fully dissolved,
separating the liquid, extracting, and combining the obtained
organic phases, adjusting the pH to about 7.0 with 5% sodium
bicarbonate solution, re-separating the liquid and extracting,
drying the organic phase, and then distilling the organic phase
under reduced pressure, recrystallizing the residue with ethanol to
obtain a white crystalline intermediate 3;
[0053] c) adding the intermediate 3 and the corresponding disulfide
in a molar ratio of 1:5 into anhydrous acetonitrile successively,
and then stirring the mixture at room temperature and feeding the
protecting gas for about 20-30 min, to the reaction system
immediately adding 6.2 mol of isoamyl nitrite (i-AmONO),
continuously stirring, then reacting at 60-80.degree. C. for 4-8 h,
separating the resulting mixture by the silica gel column
chromatography to obtain an intermediate 4;
[0054] d) successively adding the intermediate 4, the corresponding
amine and organic base (e.g. triethylamine, sodium hydride,
potassium tertbutoxide and the like) in a molar ratio of about
1:5:1 into an anhydrous alcohol, e.g. ethanol or methanol, heating
and refluxing the mixture for 4-8 h, adding metal sodium or
potassium in a catalytic amount after it is monitored by TLC that
the starting materials disappear, continuously heating and
refluxing the reaction mixture till it is monitored by TLC that the
reaction is completed, and then evaporating the solvent under
reduced pressure, separating the residue by the silica gel column
chromatography neutralized with alkaline, recrystallizing to obtain
the target product compound of the formula (I) or (I-1) (when
R.sub.2.dbd.R.sub.2a in the formula (I)).
[0055] It has been proved by tests that the compound of the formula
(I) of the present invention has notable activities of
anti-platelet aggregation, and can be used for the treatment and/or
prevention of various diseases associated with platelet
aggregation.
[0056] Thus the present invention further provides a pharmaceutical
composition containing the compound of the formula (I-1) or a
pharmaceutically acceptable salt thereof and a pharmaceutically
acceptable carrier.
[0057] The pharmaceutically acceptable carrier may include the
conventional pharmaceutically acceptable carriers in the art, e.g.
fillers, binders, disintegrating agents, lubricants, solvents,
solubilizers, substrates for transdermal patches, substrates for
suppository and the like, including, but not limited to starch,
powdered sugar, calcium phosphate, magnesium stearate, talc powder,
dextrin, cellulose and derivatives thereof, microcrystalline
cellulose, polyethylene glycol, normal saline, glucose solution,
conventional substrates for transdermal patches such as acrylic
pressure-sensitive adhesives, siloxane (silicone)
pressure-sensitive adhesives, polyisobutylene pressure-sensitive
adhesives or combinations thereof, cocoa butter, paraffin and the
like.
[0058] The pharmaceutical composition of the present invention may
also comprise various other common additives, e.g. preservatives,
emulsifying agents, suspending agents, flavoring agents and the
like.
[0059] The pharmaceutical composition of the present invention may
be prepared as any suitable pharmaceutically acceptable dosage
form, e.g. tablets, capsules, pills, granular formulations, syrups,
injections, solutions, suspensions, transdermal patches,
suppository and the like.
[0060] The compound of the formula (I) of the present invention or
a pharmaceutically acceptable salt thereof may be administered to
mammals, e.g. human beings, via any effective routes, including
oral, intravenous, intraperitoneal, intramuscular, topical,
transdermal, intraocular, intranasal, inhalation, subcutaneous,
intramuscular, buccal, sublingual, rectal administration and the
like. They may be administered alone, or in combination with other
active ingredients. The compound of the formula (I) of the present
invention or a pharmaceutically acceptable salt thereof is in an
effective amount of from about 0.01 mg per kg weight per day
(mg/kg/day) to about 100 mg/kg/day, e.g. from about 0.1 mg/kg/day
to about 80 mg/kg/day. The preferred amount can be determined by
those skilled in the art. For example, the doctors in charge can
readily determine the effective amount by the conventional methods
and by observing the results obtained under similar circumstances.
While the effective amount of the compound of the present invention
is determined, many factors should be taken into consideration by
the doctors in charge, including, but not limited to specific
compounds to be administered; combined administration with other
pharmaceuticals; kind, size, age and general health condition of
mammals; severity of the disease; response of individual patients;
method of administration, bioavailability characteristics of the
formulation to be administered; dose scheme to be selected; use of
other concomitant drugs and other related situations.
[0061] The present invention further provides the use of the
compound of the formula (I) of the present invention in the
manufacture of a medicament for the treatment of diseases
associated with platelet aggregation.
[0062] The diseases associated with platelet aggregation include,
but are not limited to, e.g. thrombotic diseases, viral diseases
having a hypercoagulable state, neoplastic diseases, coronary heart
disease, stroke, hypertension, leukemia, disseminated intravascular
coagulation (DIC) and the like.
EMBODIMENTS
[0063] The present invention is further and specifically explained
by the following examples. However, these examples are merely used
for illustrating the present invention, and they shall not be
deemed to limit the protection scope of the present invention.
[0064] In the examples, the abbreviation MeOH represents methanol;
EtOAc represents ethyl acetate; Et.sub.3N represents triethylamine;
Et.sub.4NCl represents tetraethylammonium chloride; P.E. represents
petroleum ether (having a boiling range of from 60 to 90.degree.
C.); CDCl.sub.3 represents deuterated chloroform; DMSO-d.sub.6
represents deuterated dimethyl sulphoxide; ADP represents adenosine
diphosphate; AA represents arachidonic acid; TLC represent
thin-layer chromatography; i-AmONO represents isoamyl nitrite;
Ac.sub.2O represents acetic anhydride; R.sub.1SSR.sub.1 represents
disulfides; EtOH represents ethanol.
[0065] .sup.1H NMR is measured with Varian Mercury 200 (200 MHz),
Varian Mercury Plus 300 (300 MHz), Bruker 400 AMX (400 MHz) or
Bruker 600 AMX (600 MHz) nuclear magnetic resonance apparatus,
wherein s represents singlets; br s represents broadsinglets; d
represents doublets; t represents triplets; q represents quartets;
sextet represents sextets; heptet represents heptets; m represents
multiplets; and Ar represents aryl.
I. PREPARATION EXAMPLES OF COMPOUNDS
Example 1
Preparation of
2-amino-6-hydroxyl-9-(2',3',5'-tri-O-acetyl-.beta.-D-ribofuranosyl)purine
(2)
##STR00009##
[0067] At room temperature, dried guanosine 1 (11.3 g, 40 mmol),
triethylamine (22.9 mL, 158.4 mmol) and acetic anhydride (13.6 mL,
144 mmol) were respectively dissolved in 500 ml anhydrous
acetonitrile, and 4-dimethylamino pyridine (366 mg, 3 mmol) was
added therein. The resultant mixed solution was sharply stirred at
room temperature for 30 min, and then continuously stirred for 10
min after 5 ml anhydrous methanol was added. The solvent was
evaporated under reduced pressure, and the resultant solid was
recrystallized with 180 mL isopropanol to obtain white crystals 2
(15.7 g, 96%), m.p 229-231.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 10.75 (1H, br s), 7.94 (1H, s), 6.55 (2H, br
s), 5.98 (1H, d, J=4.8 Hz), 5.79 (1H, t, J=5.5 Hz), 5.59 (1H, t,
J=5.5 Hz), 4.40-4.24 (3H, m), 2.11 (3H, s), 2.04 (3H, s), 2.03 (3H,
s).
Example 2
Preparation of
2-amino-6-chloro-9-(2',3',5'-tri-O-acetyl-.beta.-D-ribofuranosyl)
purine (3)
##STR00010##
[0069] Anhydrous acetonitrile (15 mL) and anhydrous
1,2-dichloroethane (30 mL) were placed into a 100 ml three-necked
bottle. While stirring at room temperature, 10.0 g (24.4 mmol)
compound 2, 11.0 g (66.4 mmol) Et.sub.4NCl and 16.8 g (10.0 mL,
109.6 mmol) POCl.sub.3, and 4.78 g (5.0 mL, 35.1 mmol)
N,N-dimethylaniline were successively added therein, and rapidly
heated to reflux. After holding 20-25 min, the resultant mixed
solution was slowly and dropwise added to brash ice and stirred,
and 10 mL 1,2-dichloroethane was supplemented. After brash ice was
completely dissolved, the resultant mixed solution was poured into
a 250 mL separating funnel for separation. After the aqueous phase
was extracted three times with 50 mL 1,2-dichloroethane, the
organic phases were combined together and adjusted to a pH of 7
with cold 5% sodium carbonate solution, then a liquid separation
was carried out. The organic phase was washed three times with 50
mL cold water, and dried over anhydrous MgSO.sub.4, filtered and
evaporated under reduced pressure to remove the solvent, and then
70 mL anhydrous ethanol was added to the residue which was
recrystallized therefrom as a white crystal 3 (8.56 g, with a yield
of 81.9%), m.p 155-156.degree. C.; .sup.1H NMR (600 MHz,
CDCl.sub.3) .delta. 7.88 (1H, s), 5.99 (1H, d, J=4.8 Hz), 5.93 (1H,
t, J=4.9 Hz), 5.72 (1H, t, J=4.9 Hz), 5.27 (2H, br s), 4.35-4.44
(3H, m), 2.13 (3H, s), 2.09 (3H, s), 2.07 (3H, s).
[0070] The intermediate compound 4 was prepared according to the
following reaction route.
##STR00011##
Example 3
Preparation of
2-methylthio-6-chloro-9-(2',3',5'-tri-O-acetyl-.beta.-D-ribofuranosyl)
purine (4a)
[0071] Compound 3 (2.5 g, 5.85 mmol) and dimethyl disulfide (29.25
mmol) were respectively added to 35 mL anhydrous acetonitrile, then
nitrogen gas was fed to the mixed solution, and at room
temperature, the mixed solution was stirred for 30 min, and then
isoamyl nitrite (4.25 g, 36.3 mmol) was immediately added to the
mixed solution. The resultant mixed solution was continuously
stirred at room temperature for 10 min, and then transferred to an
oil bath at 60.degree. C., and heated for 4-8 hours. After it was
detected with TLC (EtOAc-P.E., 1:1) that the starting materials
disappeared, the solvent was evaporated under reduced pressure, and
the residue was isolated by column chromatography (silica gel,
EtOAc-P.E., 2:3, 1:1) to obtain a light yellow oily liquid 4a, with
a yield of 66%; .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.09
(1H, s), 6.09 (1H, d, J=4.5 Hz), 5.97 (1H, t, J 5.4 Hz), 5.62 (1H,
t, J=5.4 Hz), 4.45-4.43 (1H, m), 4.42-4.39 (11H, m), 4.32-4.26 (1H,
m), 2.61 (3H, s), 2.12 (3H, s), 2.08 (3H, s), 2.06 (3H, s).
Example 4
Preparation of
2-ethylthio-6-chloro-9-(2',3',5'-tri-O-acetyl-.beta.-D-ribofuranosyl)
purine (4b)
[0072] The preparation method above-mentioned in Example 3 was
used, except that dimethyl disulfide was replaced with diethyl
disulfide, and the residue was isolated by column chromatography
(silica gel, EtOAc-P.E., 2:3, 1:1) to obtain a light yellow liquid
4b, with a yield of 62%; .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
8.10 (1H, s), 6.09 (1H, d, J=4.5 Hz), 5.93 (1H, t, J=5.4 Hz), 5.59
(1H, t, J=5.4 Hz), 4.45-4.43 (1H, m), 4.42-4.40 (1H, m), 4.32-4.30
(1H, m), 3.21 (2H, q, J=7.3 Hz), 2.14 (3H, s), 2.09 (6H, s), 1.41
(3H, t, J=7.3 Hz).
Example 5
Preparation of
2-propylthio-6-chloro-9-(2',3',5'-tri-O-acetyl-.beta.-D-ribofuranosyl)
purine (4c)
[0073] The preparation method above-mentioned in Example 3 was
used, except that dimethyl disulfide was replaced with dipropyl
disulfide, and the residue was isolated by column chromatography
(silica gel, EtOAc-P.E., 2:3, 1:1) to obtain a light yellow liquid
4c, with a yield of 57%; .sup.1H NMR (600 MHz, DMSO-d.sub.6):
.delta. 8.69 (1H, s), 6.29 (1H, d, J=4.5 Hz), 6.01 (1H, t, J=5.4
Hz), 5.58 (1H, t, J=5.4), 4.42-4.40 (1H, m), 4.39-4.38 (1H, m),
4.25-4.22 (1H, m), 3.19 (2H, t, J=7.3 Hz), 2.11 (3H, s), 2.06 (3H,
s), 1.97 (3H, s), 1.77-1.71 (2H, m), 1.01 (3H, t, J=7.3 Hz).
Example 6
Preparation of
2-isopropylthio-6-chloro-9-(2',3',5'-tri-oxy-acetyl-.beta.-D-ribofuranosy-
l) purine (4d)
[0074] The preparation method above-mentioned in Example 3 was
used, except that dimethyl disulfide was replaced with diisopropyl
disulfide, and the residue was isolated by column chromatography
(silica gel, EtOAc-P.E., 2:3, 1:1) to obtain a light yellow liquid
4d, with a yield of 43%; .sup.1H NMR (300 MHz, CDCl.sub.3): .delta.
8.10 (1H, s), 6.11 (1H, d, J=4.8 Hz), 5.90 (1H, t, J=5.4 Hz), 5.57
(1H, t, J=5.4 Hz), 4.44-4.42 (1H, m), 4.40-4.38 (1H, m), 4.33-4.28
(1H, m), 4.00 (1H, heptet, J=7.3 Hz), 2.13 (3H, s), 2.09 (3H, s),
2.08 (3H, s), 1.44 (6H, d, J=7.3 Hz).
Example 7
Preparation of
2-butylthio-6-chloro-9-(2',3',5'-tri-O-acetyl-.beta.-D-ribofuranosyl)
purine (4e)
[0075] The preparation method above-mentioned in Example 3 was
used, except that dimethyl disulfide was replaced with dibutyl
disulfide, and the residue was isolated by column chromatography
(silica gel, EtOAc-P.E., 2:3, 1:1) to obtain a light yellow liquid
4e, with a yield of 50%; .sup.1H NMR (600 MHz, CDCl.sub.3): .delta.
8.11 (1H, s), 6.14 (1H, d, J=4.8 Hz), 5.89 (1H, t, J=5.4 Hz), 5.58
(1H, t, J=5.3), 4.45-4.43 (1H, m), 4.42-4.40 (1H, m), 4.34-4.31
(1H, m), 3.20 (2H, t, J=7.3), 2.13 (3H, s), 2.10 (3H, s), 2.08 (3H,
s), 1.76-1.71 (2H, m), 1.51-1.45 (2H, m), 0.95 (3H, t, J=7.3
Hz).
[0076] The compound of the formula (I) or (I-1) (when
R.sub.2.dbd.R.sub.2a in the formula (I)) of the present invention
was prepared according to the following reaction route.
##STR00012##
Example 8
Preparation of 2-propylthio-6-n-hexylamino-9-.beta.-D-ribofuranosyl
purine
[0077] Compound 4c (2 mmol) was dissolved in 20 mL anhydrous
ethanol, and then triethylamine (1 mmol) and n-hexylamine (10 mmol)
were added successively and refluxed for 8 hours. After it was
detected with TLC (MeOH-EtOAc, 1:15, v/v) that the starting
materials disappeared, a catalytic amount of the metal sodium (0.05
mmol) was added to remove the protecting group of acetyl. After it
was monitored by TLC that the reaction was completed, the solvent
was evaporated under reduced pressure, and the residue was isolated
by column chromatography (Et.sub.3N-neutralized silica gel,
gradient elution, MeOH-EtOAc, 1:30, 1:15, v/v). Upon
recrystallizing with methanol and washing with water, the title
compound was obtained as white crystals with a yield of 84%, m.p
186-188.degree. C.; .sup.1H NMR (600 MHz, DMSO-d.sub.6): .delta.
8.19 (1H, s), 7.92 (1H, br s,), 5.80 (1H, d, J=6.0 Hz), 5.37 (1H,
d, J=6.0 Hz), 5.13 (1H, d, J=4.8 Hz), 5.06 (1H, t, J=5.4 Hz), 4.58
(1H, ddd, J=5.6, 5.8, 6.0 Hz), 4.13 (1H, ddd, J=3.8, 4.8, 5.6 Hz),
3.92 (1H, ddd, J=3.8, 4.4, 5.4 Hz), 3.66-3.63 (1H, m), 3.55-3.52
(1H, m), 3.44 (2H, br s), 3.07 (2H, t, J=7.3 Hz), 1.72-1.67 (2H,
m), 1.60-1.56 (2H, m), 1.28 (6H, m), 0.99 (3H, t, J=7.3 Hz), 0.86
(3H, t, J=6.5 Hz).
Example 9
Preparation of
2-ethylthio-6-cyclohexylamino-9-.beta.-D-ribofuranosyl purine
[0078] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with cyclohexylamine
for 10 hours; the residue was separated by column chromatography
(Et.sub.3N-neutralized silica gel, gradient elution, MeOH-EtOAc,
1:30, 1:15, v/v) and recrystallized with EtOAc, the title compound
was obtained as white crystals with a yield of 80%, m.p
166-168.degree. C.; .sup.1H NMR (600 MHz, CDCl.sub.3): .delta. 7.74
(1H, s), 6.10 (1H, br s), 5.76 (1H, d, J=6.7 Hz), 5.43 (1H, d,
J=6.1 Hz), 5.19 (1H, d, J=4.8 Hz), 5.03 (1H, t, J=5.4 Hz), 4.43
(1H, br s), 4.29 (1H, br s), 4.11-4.05 (1H, m), 3.94-3.92 (1H, m),
3.76-3.74 (1H, m), 3.08 (1H, dt, J=7.3, 14.6 Hz), 2.94 (1H, dt,
J=7.3, 14.6 Hz), 1.81-1.65 (9H, m), 1.34 (3H, t, J=7.3 Hz),
1.27-1.25 (2H, m).
Example 10
Preparation of
2-propylthio-6-cyclohexylamino-9-.beta.-D-ribofuranosyl purine
[0079] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4c reacted with cyclohexylamine
for 7 hours; the residue was separated by column chromatography
(Et.sub.3N-neutralized silica gel, gradient elution, MeOH-EtOAc,
1:30, 1:15, v/v) and recrystallized with EtOAc, the title compound
was obtained as white crystals with a yield of 82%, m.p
162-164.degree. C.: .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
8.21 (1H, s), 7.72 (1H, br s), 5.81 (1H, d, J=5.9 Hz), 5.42 (1H, d,
J=6.1 Hz), 5.18 (1H, d, J=4.8 Hz), 5.10 (1H, t, J=5.4 Hz), 4.59
(1H, ddd, J=5.0, 5.9, 6.1 Hz), 4.14 (1H, ddd, J=3.4, 4.8, 5.0 Hz),
3.94 (1H, ddd, J=3.4, 4.6, 6.0 Hz), 3.69-3.62 (1H, m), 3.58-3.51
(1H, m), 3.04 (2H, t, J=7.3 Hz), 1.90-1.87 (2H, m), 1.76-1.73 (2H,
m), 1.71-1.28 (9H, m), 0.99 (3H, t, J=7.3 Hz).
Example 11
Preparation of
2-isopropylthio-6-cyclohexylamino-9-.beta.-D-ribofuranosyl
purine
[0080] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4d reacted with cyclohexylamine
for 9 hours; the residue was separated by column chromatography
(Et.sub.3N-neutralized silica gel, gradient elution, MeOH-EtOAc,
1:30, 1:15, v/v) and recrystallized with EtOAc, the title compound
was obtained as white crystals with a yield of 77%, m.p
136-138.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.20 (1H, s), 7.72 (1H, br s), 5.80 (1H, d, J=5.8 Hz), 5.39 (1H, d,
J=6.1 Hz), 5.15 (1H, d, J=4.8 Hz), 5.07 (1H, t, J=5.4 Hz), 4.57
(1H, ddd, J=5.6, 5.8, 6.1 Hz), 4.00 (1H, ddd, J=3.7, 4.7, 5.6 Hz),
3.91 (1H, ddd, J=3.5, 4.7, 6.1 Hz), 3.87-3.82 (1H, m), 3.66-3.61
(1H, m), 3.52 (1H, heptet, J=6.1 Hz), 1.88-1.86 (2H, m), 1.76-1.73
(2H, m), 1.63-1.60 (1H, m), 1.37 (6H, d, J=6.1 Hz), 1.32-1.11 (6H,
m).
Example 12
Preparation of
2-butylthio-6-cyclohexylamino-9-.beta.-D-ribofuranosyl purine
[0081] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4e reacted with cyclohexylamine
for 9 hours; the residue was separated by column chromatography
(Et.sub.3N-neutralized silica gel, gradient elution, MeOH-EtOAc,
1:30, 1:15, v/v) and recrystallized with EtOAc, the title compound
was obtained as white crystals with a yield of 88%, m.p
138-140.degree. C.: .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.20 (1H, s), 7.72 (1H, br s), 5.80 (1H, d, J=5.6 Hz), 5.40 (1, d,
J=5.8 Hz), 5.15 (1H, d, J=4.8 Hz), 5.08 (1H, t, J=5.4, 5.6 Hz),
4.57 (1H, ddd, J=4.9, 5.6, 5.8 Hz), 4.12 (1H, ddd, J=3.2, 4.5, 4.9
Hz), 4.03 (18, br s), 3.91 (1H, ddd, J=3.2, 4.6, 6.0 Hz), 3.67-3.62
(1H, m), 3.56-3.50 (1H, m), 3.06 (2H, t, J=7.3 Hz), 1.89-1.87 (2H,
m), 1.77-1.74 (2H, m), 1.68-1.61 (3H, m), 1.47-1.42 (2H, m),
1.38-1.11 (6H, m), 0.92 (3H, t, J=7.3 Hz).
Example 13
Preparation of 2-ethylthio-6-benzylamino-9-.beta.-D-ribofuranosyl
purine
[0082] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with benzylamine for
8 hours; the residue was separated by column chromatography
(Et.sub.3N-neutralized silica gel, gradient elution, MeOH-EtOAc,
1:50, 1:25, v/v) and recrystallized with EtOAc, the title compound
was obtained as white crystals with a yield of 82%, m.p
172-174.degree. C.; .sup.1H NMR: (600 MHz, DMSO-d.sub.6): .delta.
8.51 (1H, br s), 8.24 (1H, s), 7.33-7.28 (4H, m), 7.21 (1H, t,
J=7.0 Hz), 5.82 (1H, d, J=5.9 Hz), 5.39 (1H, d, J=6.1 Hz), 5.15
(1H, d, J=4.8 Hz), 5.04 (1H, t, J=5.4 Hz), 4.66 (2H, br s), 4.58
(1H, ddd, J=5.6, 5.9, 6.1 Hz), 4.12 (1H, ddd, J=3.4, 4.7, 5.6 Hz),
3.91 (1H, ddd, J=3.4, 4.7, 5.7 Hz), 3.65-3.62 (1H, m), 3.55-3.51
(1H, m), 3.00 (2H, q, J=7.3 Hz), 1.28 (3H, t, J=7.3 Hz).
Example 14
Preparation of 2-propylthio-6-benzylamino-9-.beta.-D-ribofuranosyl
purine
[0083] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4c reacted with benzylamine for
8 hours; the residue was separated by column chromatography
(Et.sub.3N-neutralized silica gel, gradient elution, MeOH-EtOAc,
1:50, 1:25, v/v) and recrystallized with EtOAc, the title compound
was obtained as white crystals with a yield of 79%, m.p
168-170.degree. C.; .sup.1H NMR: (600 MHz, DMSO-d.sub.6): .delta.
8.51 (1H, br s), 8.24 (1H, s), 7.33-7.28 (4H, m), 7.21 (1H, t,
J=7.0 Hz), 5.82 (1H, d, J=5.9 Hz), 5.39 (1H, d, J=6.1 Hz), 5.15
(1H, d, J=4.8 Hz), 5.04 (1H, t, J=5.4 Hz), 4.66 (2H, br s), 4.58
(1H, ddd, J=5.4, 5.7, 6.0 Hz), 4.12 (1H, ddd, J=3.2, 4.5, 5.4 Hz),
3.91 (1H, ddd, J=3.2, 4.3, 5.8 Hz), 3.65-3.62 (1H, m), 3.55-3.51
(1H, m), 3.00 (2H, q, J=7.3 Hz), 1.28 (3H, t, J=7.3 Hz).
Example 15
Preparation of 2-butylthi-6-benzylamino-9-.beta.-D-ribofuranosyl
purine
[0084] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4e reacted with benzylamine for
8 hours; the residue was separated by column chromatography
(Et.sub.3N-neutralized silica gel, gradient elution, MeOH-EtOAc,
1:50, 1:25, v/v) and recrystallized with EtOAc, the title compound
was obtained as white crystals with a yield of 80%, m.p
170-172.degree. C.; .sup.1H NMR (600 MHz, DMSO-d.sub.6): .delta.
8.50 (1H, br s), 8.24 (1H, s), 7.28-7.31 (4H, m), 7.21 (1H, t,
J=7.0 Hz), 5.81 (1H, d, J=5.9 Hz), 5.39 (1H, d, J=6.0 Hz), 5.14
(1H, d, J=4.8 Hz), 5.04 (1H, t, J=4.8 Hz), 4.67 (2H, br s), 4.59
(1H, ddd, J=5.5, 5.9, 6.1 Hz), 4.13 (1H, ddd, J=4.3, 4.7, 5.5 Hz),
3.92 (1H, ddd, J=3.6, 4.6, 5.4 Hz), 3.66-3.62 (1H, m), 3.55-3.51
(1H, m), 3.00 (2H, t, J=7.3 Hz), 1.59-1.54 (2H, m), 1.35-1.31 (2H,
m) 0.89 (3H, t, J=7.3 Hz).
Example 16
Preparation of
2-ethylthio-6-(1-phenylethyl)amino-9-.beta.-D-ribofuranosyl
purine
[0085] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with
1-phenylethylamine for 8 hours; the residue was separated by column
chromatography (Et.sub.3N-neutralized silica gel, gradient elution,
MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized with cyclohexane,
the title compound was obtained as white crystals with a yield of
72%, m.p 84-86.degree. C.; .sup.1H NMR (600 MHz, DMSO-d.sub.6):
.delta. 8.40 (1H, br s), 8.24 (1H, s), 7.40 (2H, d, J=7.1 Hz), 7.30
(2H, t, J=7.5 Hz), 7.18 (1H, t, J=7.3 Hz), 5.80 (1H, d, J=5.9 Hz),
5.41 (1H, m), 5.38 (1H, d, J=6.1 Hz), 5.13 (1H, d, J=4.8 Hz), 5.05
(1H, t, J=5.4 Hz), 4.58 (1H, ddd, J=5.7, 5.9, 6.1 Hz), 4.12 (1H,
ddd, J=3.7, 4.8, 5.7 Hz), 3.92 (1H, ddd, J=3.6, 4.2, 4.3 Hz),
3.64-3.62 (1H, m), 3.54-3.51 (1H, m), 2.98 (2H, q, J=7.3 Hz), 1.53
(3H, d, J=6.8 Hz), 1.21 (3H, t, J=7.3 Hz).
Example 17
Preparation of
2-propylthio-6-([4-methoxylbenzyl]amino)-9-.beta.-D-ribofuranosyl
purine
[0086] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4c reacted with
4-methoxylbenzylamine for 11 hours; the residue was separated by
column chromatography (Et.sub.3N-neutralized silica gel, gradient
elution, MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized with
EtOAc, the title compound was obtained as white crystals with a
yield of 81%, m.p 152-154.degree. C.; .sup.1H NMR (200 MHz,
DMSO-d.sub.6): .delta. 8.46 (1H, br s), 8.25 (1H, s), 7.26 (2H, d,
J=8.6 Hz), 6.86 (2H, d, J=8.6 Hz), 5.84 (1H, d, J=6.0 Hz), 5.47
(1H, d, J=6.0 Hz), 5.22 (1H, d, J=4.8 Hz), 5.14 (1H, t, J=5.4 Hz),
4.61 (2H, br s), 4.58 (1H, ddd, J=5.8, 6.0, 6.1 Hz), 4.16 (1H, ddd,
J=3.4, 4.8, 5.8 Hz), 3.95 (1H, ddd, J=3.4, 3.9, 4.6 Hz), 3.70 (3H,
s), 3.64-3.61 (1H, m), 3.60-3.55 (1H, m), 3.02 (2H, t, J=7.3 Hz),
1.54-1.72 (2H, m), 0.92 (3H, t, J=7.3 Hz).
Example 18
Preparation of 2-methylthio-6-phenylethy
amino-9-.beta.-D-ribofuranosyl purine
[0087] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4a reacted with
2-phenylethylamine for 9 hours; the residue was separated by column
chromatography (Et.sub.3N-neutralized silica gel, gradient elution,
MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized with EtOAc, the
title compound was obtained as white crystals with a yield of 85%,
m.p 156-158.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 8.22 (1H, s), 8.02 (1H, br s), 7.30-7.25 (3H, m), 7.20-7.17
(2H, m), 5.83 (1H, d, J=5.5 Hz), 5.45 (1H, d, J=5.5 Hz), 5.20 (1,
d, J=4.8 Hz), 5.08 (1H, t, J=5.4 Hz), 4.60 (1H, ddd, J=5.4, 5.5,
5.6 Hz), 4.14 (1H, ddd, J=3.4, 4.2, 4.6 Hz), 3.92 (1H, ddd, J=3.4,
4.5, 4.9 Hz), 3.68-3.65 (2H, m), 3.57-3.51 (2H, m), 2.90 (2H, t,
J=7.6 Hz), 2.50 (3H, s).
Example 19
Preparation of
2-ethylthio-6-phenylethylamino-9-.beta.-D-ribofuranosyl purine
[0088] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with
2-phenylethylamine for 9 hours; the residue was separated by column
chromatography (Et.sub.3N-neutralized silica gel, gradient elution,
MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized with EtOAc, the
title compound was obtained as white crystals with a yield of 84%,
m.p 130-132.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 8.23 (1H, s), 8.02 (1H, br s), 7.32-7.26 (3H, m), 7.24-7.17
(2H, m), 5.84 (1H, d, J=5.9 Hz), 5.45 (1H, d, J=6.2 Hz), 5.21 (1H,
d, J=4.8 Hz), 5.11 (1H, t, J=5.5 Hz), 4.60 (1H, ddd, J=5.6, 5.7,
6.1 Hz), 4.16 (1H, ddd, J=3.5, 4.8, 5.6 Hz), 3.95 (1H, ddd, J=3.5,
4.3, 4.8 Hz), 3.67-3.65 (2H, m), 3.58-3.46 (2H, m), 3.11 (2H, q,
J=7.3 Hz), 2.92 (2H, t, J=7.0 Hz), 1.34 (3H, t, J=7.3 Hz).
Example 20
Preparation of
2-propylthio-6-phenylethylamino-9-.beta.-D-ribofuranosyl purine
[0089] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4c reacted with
2-phenylethylamine for 9 hours; the residue was separated by column
chromatography (Et.sub.3N-neutralized silica gel, gradient elution,
MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized with EtOAc, the
title compound was obtained as white crystals with a yield of 80%,
m.p 110-112.degree. C.: .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 8.22 (1H, s), 8.03 (1H, br s), 7.32-7.26 (3H, m), 7.24-7.17
(2H, m), 5.82 (1H, d, J=5.9 Hz), 5.44 (1H, d, J=6.2 Hz), 5.18 (1H,
d, J=4.8 Hz), 5.10 (1H, t, J=5.4 Hz), 4.59 (1H, ddd, J=5.4, 5.9,
6.2 Hz), 4.14 (1H, ddd, J=3.5, 4.2, 4.8 Hz), 3.93 (1H, ddd, J=3.5,
4.6, 5.2 Hz), 3.69-3.64 (2H, m), 3.62-3.50 (2H, m), 3.09 (2H, t,
J=7.3 Hz), 2.91 (2H, t, J=7.0 Hz), 1.74-1.67 (2H, m), 0.97 (3H, t,
J=7.3 Hz).
Example 21
Preparation of
2-butylthio-6-phenylethylamino-9-.beta.-D-ribofuranosyl purine
[0090] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4e reacted with
2-phenylethylamine for 9 hours; the residue was separated by column
chromatography (Et.sub.3N-neutralized silica gel, gradient elution,
MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized with EtOAc, the
title compound was obtained as white crystals with a yield of 81%,
m.p 124-126.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 8.20 (1H, s), 8.01 (1H, br s), 7.31-7.26 (3H, m), 7.25-7.18
(2H, m), 5.80 (1H, d, J=5.6 Hz), 5.41 (1H, d, J=6.1 Hz), 5.16 (1H,
d, J=4.8 Hz), 5.07 (1H, t, J=5.4 Hz), 4.57 (1H, ddd, J=5.6, 5.7,
6.1 Hz), 4.12 (1H, ddd, J=3.7, 4.7, 5.7 Hz), 3.92 (1H, ddd, J=3.7,
4.6, 5.8 Hz), 3.68-3.64 (2H, m), 3.62-3.50 (2H, m), 3.10 (2H, t,
J=7.3 Hz), 2.91 (2H, t, J=7.5 Hz), 1.70-1.63 (2H, m), 1.45-1.36
(2H, m), 0.89 (3H, t, J=7.3 Hz).
Example 22
Preparation of
2-methylthio-6-([4-methoxylphenylethyl]-amino)-9-.beta.-D-ribofuranosyl
purine
[0091] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4a reacted with
4-methoxylphenylethylamine for 12 hours; the residue was separated
by column chromatography (Et.sub.3N-neutralized silica gel,
gradient elution, MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized
with EtOAc, the title compound was obtained as white crystals with
a yield of 82%, m.p 152-154.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 8.24 (1H, s), 7.97 (1H, br s), 7.16 (2H, d,
J=7.9 Hz), 6.85 (2H, d, J=8.0 Hz), 5.87 (1H, d, J=5.9 Hz), 5.47
(1H, d, J=5.9 Hz), 5.24 (1H, d, J=4.8 Hz), 5.12 (1H, t, J=5.4 Hz),
4.63 (1H, ddd, J=5.4, 5.8, 6.2 Hz), 4.19 (1H, ddd, J=3.5, 4.8, 5.4
Hz), 3.97 (1H, ddd, J=3.5, 4.3, 4.6 Hz), 3.70 (3H, s), 3.65-3.66
(2H, m), 3.53-3.49 (2H, m), 2.85 (2H, t, J=7.1 Hz), 2.52 (3H,
s).
Example 23
Preparation of
2-ethylthio-6-([4-methoxylphenylethyl]amino)-9-.beta.-D-ribofuranosyl
purine
[0092] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with
4-methoxylphenylethylamine for 9 hours; the residue was separated
by column chromatography (Et.sub.3N-neutralized silica gel,
gradient elution, MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized
with EtOAc, the title compound was obtained as white crystals with
a yield of 81%, m.p 140-142.degree. C.; .sup.1H NMR (200 MHz,
DMSO-d.sub.6): .delta. 8.25 (1H, s), 7.99 (1H, br s), 7.16 (2H, d,
J=8.0 Hz), 6.85 (2H, d, J=8.0 Hz), 5.86 (1H, d, J=5.9 Hz), 5.47
(1H, d, J=5.9 Hz), 5.22 (1H, d, J=4.8 Hz), 5.13 (1H, t, J=5.4 Hz),
4.63 (1H, ddd, J=5.4, 5.9, 6.2 Hz), 4.17 (1H, ddd, J=3.4, 4.8, 5.4
Hz), 3.98 (1H, ddd, J=3.4, 4.2, 4.6 Hz), 3.70 (3H, s), 3.66-3.60
(2H, m), 3.54-3.44 (2H, m), 3.12 (2H, q, J=7.3 Hz), 2.85 (2H, t,
J=7.1 Hz), 1.35 (3H, t, J=7.3 Hz).
Example 24
Preparation of
2-propylthio-6-([4-methoxylphenylethyl]amino)-9-.beta.-D-ribofuranosyl
purine
[0093] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4c reacted with
4-methoxylphenylethylamine for 12 hours; the residue was separated
by column chromatography (Et.sub.3N-neutralized silica gel,
gradient elution, MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized
with EtOAc, the title compound was obtained as white crystals with
a yield of 83%, m.p 170-172.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 8.21 (1H, s), 8.00 (1H, br s), 7.15 (2H, d,
J=8.0 Hz), 6.85 (2H, d, J=8.0 Hz), 5.81 (1H, d, J=5.9 Hz), 5.42
(1H, d, J=5.9 Hz), 5.17 (1H, d, J=4.8 Hz), 5.08 (1H, t, J=5.4 Hz),
4.59 (1H, ddd, J=5.3, 5.8, 5.8 Hz), 4.13 (1H, br s), 3.92 (1H, ddd,
J=3.5, 4.6, 5.6 Hz), 3.71 (3H, s), 3.64-3.62 (2H, m), 3.55-3.51
(2H, m), 3.09 (2H, t, J=7.3 Hz), 2.84 (2H, t, J=7.5 Hz), 1.74-1.64
(2H, m), 0.98 (3H, t, J=7.3 Hz).
Example 25
Preparation of
2-butylthio-6-([4-methoxylphenylethyl]amino)-9-.beta.-D-ribofuranosyl
purine
[0094] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4e reacted with
4-methoxylphenylethylamine for 12 hours; the residue was separated
by column chromatography (Et.sub.3N-neutralized silica gel,
gradient elution, MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized
with EtOAc, the title compound was obtained as white crystals with
a yield of 80%, m.p 122-124.degree. C.: .sup.1H NMR (400 MHz,
DMSO-ds): .delta. 8.21 (1H, s), 7.98 (1H, br s), 7.15 (2H, d, J=8.0
Hz), 6.85 (2H, d, J=8.2 Hz), 5.80 (1H, d, J=5.8 Hz), 5.41 (1H, d,
J=5.9 Hz), 5.16 (1H, d, J=4.8 Hz), 5.07 (1H, t, J=4.9 Hz), 4.58
(1H, ddd, J=5.2, 5.8, 6.1 Hz), 4.13 (1H, ddd, J=3.8, 4.8, 5.2 Hz),
3.92 (1H, ddd, J=3.8, 4.3, 4.6 Hz), 3.71 (3H, s), 3.67-3.64 (2H,
m), 3.53-3.518 (2H, m), 3.10 (2H, t, J=7.3 Hz), 2.84 (2H, t, J=7.1
Hz), 1.70-1.63 (2H, m), 1.46-1.37 (2H, m), 0.89 (3H, t, J=7.3
Hz).
Example 26
Preparation of
2-ethylthio-6-([3-methoxylphenylethyl]amino)-9-.beta.-D-ribofuranosyl
purine
[0095] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with
3-methoxylphenylethylamine for 11 hours; the residue was separated
by column chromatography (Et.sub.3N-neutralized silica gel,
gradient elution, MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized
with EtOAc, the title compound was obtained as white crystals with
a yield of 84%, m.p 110-112.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 8.22 (1H, s), 8.01 (1H, br s), 7.20 (1H, t,
J 8.0 Hz), 6.81-6.75 (3H, m), 5.82 (1H, d, J=5.9 Hz), 5.43 (1H, d,
J=6.1 Hz), 5.18 (1H, d, J=4.8 Hz), 5.08 (1H, t, J=5.4 Hz), 4.59
(1H, ddd, J=5.4, 5.7, 6.1 Hz), 4.14 (1H, ddd, J=3.7, 4.8, 5.4 Hz),
3.93 (1H, ddd, J=3.7, 4.5, 4.6 Hz), 3.72 (3H, s), 3.70-3.63 (2H,
m), 3.58-3.53 (2H, m), 3.11 (2H, q, J=7.3 Hz), 2.89 (2H, t, J=7.6
Hz), 1.34 (3H, t, J=7.3 Hz).
Example 27
Preparation of
2-propylthio-6-([3-methoxylphenylethyl]amino)-9-.beta.-D-ribofuranosyl
purine
[0096] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4c reacted with
3-methoxylphenylethylamine for 11 hours; the residue was separated
by column chromatography (Et.sub.3N-neutralized silica gel,
gradient elution, MeOH-EtOAc, 1:30, 1:15, v/v) and recrystallized
with EtOAc, the title compound was obtained as white crystals with
a yield of 76%, m.p 120-122.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 8.22 (1H, s), 8.01 (1H, br s), 7.20 (1H, t,
J=8.0 Hz), 6.82-6.75 (3H, m), 5.81 (1H, d, J=6.0 Hz), 5.43 (1H, d,
J=6.1 Hz), 5.18 (1H, d, J=4.8 Hz), 5.09 (1H, t, J=5.5 Hz, 4.60 (1H,
ddd, J=5.7, 5.9, 6.1 Hz), 4.13 (1H, ddd, J=3.4, 4.8, 5.7 Hz), 3.92
(1H, ddd, J=3.3, 4.0, 4.5 Hz), 3.72 (3H, s), 3.67-3.62 (2H, m),
3.57-3.50 (2H, m), 3.09 (2H, t, J=7.3 Hz), 2.89 (2H, t, 3=7.1 Hz),
1.74-1.64 (2H, m), 0.98 (3H, t, J=7.3 Hz).
Example 28
Preparation of
2-ethylthio-6,6-(dibutylamino)-9-.beta.-D-ribofuranosyl purine
[0097] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with n-dibutylamine
for 14 hours; the residue was separated by column chromatography
(Et.sub.3N-neutralized silica gel, gradient elution,
EtOAc-petroleum ether, 1:10, 1:1, v/v) and recrystallized with
n-hexane, the title compound was obtained as white crystals with a
yield of 58%, m.p 152-154.degree. C.; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.24 (1H, s), 5.82 (1H, d, J=6.0 Hz), 5.41
(1H, d, J=6.2 Hz), 5.17 (1H, d, J=4.8 Hz), 5.07 (1H, t, J=5.2 Hz),
4.55 (1H, ddd, J=5.3, 6.0, 6.2 Hz), 4.12 (1H, ddd, J=3.4, 4.9, 5.3
Hz), 3.92 (1H, ddd, J=3.4, 4.6, 6.2 Hz), 3.67-3.62 (2H, m),
3.62-3.49 (4H, m), 3.12-3.04 (2H, m), 1.66-1.56 (4H, m), 1.39-1.34
(4H, m), 1.32 (3H, t, J=7.3 Hz), 0.92 (6H, t, J=6.4 Hz).
Example 29
Preparation of
2-ethylthio-6-(2-thienylethyl)amino-9-.beta.-D-ribofuranosyl
purine
[0098] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with
2-thienylethylamine for 4 hours; the residue was separated by
column chromatography (Et.sub.3N-neutralized silica gel,
MeOH-EtOAc, 1:20, v/v) and recrystallized with EtOAc, the title
compound was obtained as white crystals with a yield of 80%, m.p
142-144.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.23 (1H, s), 8.09 (1H, br s), 7.32 (1H, dd, J=1.08, 1.12 Hz,),
6.96-6.91 (2H, m), 5.81 (1H, d, J=5.92 Hz), 5.42 (1H, d, J=6.08
Hz), 5.17 (1H, d, J=4.56 Hz), 5.07 (1H, t, J=6.09 Hz), 4.58 (11, q,
J=5.63, 5.75 Hz) 4.12 (1H, q, J=4.71, 4.50 Hz), 3.91 (1H, q,
J=3.79, 3.79 Hz), 3.71-3.63 (3H, m), 3.56-3.50 (1H, m), 3.15-3.07
(4H, m), 1.33 (3H, t, J=7.24 Hz).
Example 30
Preparation of
2-propylthio-6-(2-thienylethyl)amino-9-.beta.-D-ribofuranosyl
purine
[0099] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4c reacted with
2-thienylethylamine for 5 hours; the residue was separated by
column chromatography (Et.sub.3N-neutralized silica gel,
MeOH-EtOAc, 1:15, v/v) and recrystallized with n-hexane, the title
compound was obtained as white crystals with a yield of 70%,
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.22 (1H, s), 8.09
(1H, br s), 7.32 (1H, dd, J=1.11, 1.11 Hz), 6.96-6.91 (2H, m), 5.80
(1H, d, J=5.92 Hz), 5.41 (1H, d, J=5.96 Hz), 5.17 (1H, d, J=3.89
Hz), 5.07 (1H, t, J=6.22 Hz), 4.58 (1H, q, J=5.63, 5.75 Hz), 4.12
(1H, m), 3.91 (1H, q, J=3.69, 3.69 Hz,), 3.71-3.62 (3H, m),
3.55-3.51 (1H, m), 3.15-3.076 (4H, m), 1.69 (2H, sextet, J=7.29),
0.97 (3H, t, J=7.29 Hz).
Example 31
Preparation of
2-ethylthio-6-(3-phenylpropyl)amino-9-.beta.-D-ribofuranosyl
purine
[0100] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with
3-phenyl-1-propylamine for 4 hours; the residue was separated by
column chromatography (Et.sub.3N-neutralized silica gel,
MeOH-EtOAc, 1:20, v/v) and recrystallized with methanol, the title
compound was obtained as white crystals with a yield of 80%, m.p
180-182.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.22 (1H, s), 8.03 (1H, br s), 7.29-7.15 (5H, m), 5.81 (1H, d,
J=5.98 Hz), 5.41 (1H, d, J=6.09 Hz), 5.17 (1H, d, J=4.83 Hz), 5.07
(1H, t, J=5.05 Hz), 4.58 (1H, q, 1=5.86, 5.97 Hz), 4.12 (1H, q,
J=4.60, 4.71 Hz), 3.91 (1H, q, J=3.91, 3.79 Hz), 3.66-3.61 (1H, m),
3.55-3.46 (3H, m), 3.02 (2H, q, J=7.91, 7.36 Hz), 2.63 (2H, t,
J=7.47 Hz), 1.89 (2H, q, J=7.47 Hz), 1.29 (3H, t, J=7.24 Hz).
Example 32
Preparation of
2-ethylthio-6-(4-phenylbutyl)amino-9-.beta.-D-ribofuranosyl
purine
[0101] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with
4-phenyl-1-butylamine for 5 hours; the residue was separated by
column chromatography (Et.sub.3N-neutralized silica gel,
MeOH-EtOAc, 1:20, v/v) and recrystallized with methanol, the title
compound was obtained as white crystals with a yield of 80%, m.p
146-148.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.20 (1H, s), 7.98 (1H, br s), 7.28-7.14 (5H, m), 5.81 (1H, d,
J=5.85 Hz), 5.42 (1H, d, J=6.06 Hz), 5.18 (1H, d, J=4.70 Hz), 5.08
(1H, t, J=5.17 Hz), 4.59 (1H, q, J=5.69 Hz, 5.85 Hz), 4.12 (1H, q,
J=4.49, 4.60 Hz), 3.91 (1H, q, J=3.97, 3.86 Hz), 3.67-3.61 (1H, m),
3.56-3.47 (m, 3H), 3.05 (2H, dd, J=2.03, 1.88 Hz), 2.60 (2H, t,
J=7.05 Hz), 1.89 (2H, q, J=7.47 Hz), 1.61 (4H, br), 1.31 (3H, t,
J=7.24 Hz).
Example 33
Preparation of
2-ethylthio-6-(2-furylmethyl)amino-9-.beta.-D-ribofuranosyl
purine
[0102] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with
2-furylmethylamine for 5 hours; the residue was separated by column
chromatography (Et.sub.3N-neutralized silica gel, MeOH-EtOAc, 1:15,
v/v) and recrystallized with a mixed solvent of ethyl acetate and
petroleum ether, the title compound was obtained as white crystals
with a yield of 75%, m.p 190-192.degree. C.; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 8.41 (1H, br s), 8.26 (1H, s), 7.55 (1H, s),
6.37 (1H, m), 6.22 (1H, m), 5.82 (1H, d, J=5.92 Hz), 5.43 (1H, d,
J=6.07 Hz), 5.17 (1H, d, J=4.80 Hz), 5.05 (1H, t, J=5.50 Hz),
4.65-4.57 (3H, m), 4.12 (1H, q, J=4.51, 4.66 Hz), 3.92 (1H, q,
J=3.67, 3.67 Hz), 3.67-3.62 (1H, m), 3.56-3.50 (1H, m), 3.07 (2H,
dd, J=2.11, 1.97 Hz), 1.30 (3H, t, J=7.19 Hz).
Example 34
Preparation of
2-ethylthio-6-(2-tetrahydrofurylmethyl)amino-9-.beta.-D-ribofuranosyl
purine
[0103] The preparation method above-mentioned in Example 8 was
used, except that the intermediate 4b reacted with
2-tetrahydrofurylmethylamine for 5 hours; the residue was separated
by column chromatography (Et.sub.3N-neutralized silica gel,
MeOH-EtOAc, 1:15, v/v) and recrystallized with methanol, the title
compound was obtained as white crystals with a yield of 82%, m.p
89-91.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.23
(1H, s), 7.85 (1H, br s), 5.81 (1H, d, J=5.93 Hz), 5.42 (1H, d,
J=6.21 Hz), 5.17 (1H, d, J=4.80 Hz), 5.06 (1H, t, J=5.36 Hz), 4.58
(1H, q, J=5.78, 5.78 Hz), 4.13 (1H, q, J=4.65, 4.93 Hz), 4.09 (1H,
m), 3.92 (1H, q, J=3.81, 3.81 Hz), 3.77 (1H, q, J=7.05, 6.35 Hz),
3.67-3.59 (2H, m), 3.56-3.50 (2H, m), 3.45 (1H, t, J=5.93 Hz),
3.09-3.05 (2H, m), 1.93-1.74 (3H, m), 1.67-1.61 (1H, m), 1.33 (3H,
t, J=7.34 Hz).
II. PREPARATION EXAMPLES OF FORMULATIONS
Formulation Example 1
Preparation of Injection
[0104] 40.0 g of a compound of Example 19 was sufficiently mixed
with 22.56 g of disodium hydrogen phosphate, 0.519 g of sodium
dihydrogen phosphate, 2 g of sodium metabisulfite, 5 g of benzyl
alcohol, 5 g of glycerol. Water for injection was added to 1000 mL,
to obtain the injection containing the compound of the present
invention.
Formulation Example 2
Preparation of Tablets
[0105] 5 g of a compound of Example 18, 12 g of lactose, 8 g of
corn starch, 0.2 g of magnesium stearate and 0.02 g of methyl
cellulose were mixed together and compressed according to the
conventional methods to obtain 100 tablets.
III. BIOACTIVITY ASSAY
[0106] The inventor conducted the anti-platelet aggregation
activity screening for the compounds of the present invention,
carried out the anti-platelet aggregation test by using the blood
platelet which was closed to human physiological state and was not
washed with water, and conducted the activity test of the in vitro
anti-platelet aggregation induced by ADP, and also the activity
test of the in vitro anti-platelet aggregation induced by AA
(arachidonic acid) for some compounds. The present invention
firstly discloses the activity test of the in vitro anti-platelet
aggregation induced by AA conducted with said type of compounds.
The results show that the compounds of the present invention have a
notable anti-platelet aggregation activity.
Evaluation of Anti-Platelet Aggregation Activity
[0107] The anti-platelet aggregation test of the compounds was
conducted by the aggregometer (Model 400VS, Chrono-Log, Haverston,
Pa.) from Chrono-Log Corp. ADP, AA (arachidonic acid), DMSO and
trisodium citrate were purchased from Sigama.
1. Test Method:
[0108] The whole blood was obtained from healthy volunteers who did
not take any anti-platelet medicines within 2 weeks. The fasting
venous blood of the subjects was collected, and placed into a 50 mL
sampling tube containing 3.8% sodium citrate, and mixed
homogeneously in a ratio of 1:9 (v/v) for anticoagulation, and
centrifugalized at 300 rpm/min for 20 min.
[0109] The supernatant was taken to obtain platelet-rich blood
plasma (PRP). The residual blood was then centrifugalized at 900
rpm/min for 10 min, and the supernatant fluid was taken to obtain
platelet-poverty blood plasma (PPP). The analysis of platelet
aggregation was conducted by using the aggregometer (Chrono-Log
Corp.), wherein PRP and PPP were respectively added to two
turbidimetric tubes. In the aggregometer, platelet-poverty blood
plasma (PPP) was used as the control group. DMSO was used as the
negative control. The turbidimetric tubes were incubated at
37.degree. C. for 3 min. The PRP was stirred with a stirring rod at
900 rpm/min for 10-20 s, and the inductive agent ADP (10 uM) or AA
(0.5 mM) was added to PRP, and start to record the aggregated wave
patterns. The chart speed of the recorder (Model 707, Chrono-Log,
Haverston, Pa., USA) was set up to be 1 cm min.sup.-1, and the
aggregation reaction was recorded for not less than 3 min. Finally,
the apparatus automatically delineated the aggregation curve and
calculated the results, i.e. maximum platelet aggregation rate.
When the platelet aggregation was lower than 50% of the control
group, the IC.sub.50 of the compound was calculated.
2. Test Results: See Table 1
TABLE-US-00002 [0110] TABLE 1 Activities of the in vitro
anti-platelet aggregation of the compounds of the present invention
Compounds IC.sub.50 (ADP, .mu.M) IC.sub.50 (AA, .mu.M) Example 8
102 Example 9 104 Example 10 151 Example 11 187 Example 12 83
Example 13 176 Example 14 216 Example 15 202 Example 16 197 Example
17 181 Example 18 36 3 Example 19 29 30 Example 20 52 44 Example 21
59 >300 Example 22 153 Example 23 89 Example 24 267 Example 25
93 Example 26 38 >300 Example 27 69
[0111] The results of the in vitro anti-platelet aggregation tests
have showed that all the compounds have the effect of in vitro
inhibiting ADP-induced platelet aggregation in various extents; and
at the same time, a part of the compounds have a notable effect on
in vitro inhibiting AA (arachidonic acid)-induced platelet
aggregation.
* * * * *