U.S. patent number RE39,112 [Application Number 11/057,854] was granted by the patent office on 2006-05-30 for purine derivatives and adenosine a2 receptor antagonists serving as preventives/remedies for diabetes.
This patent grant is currently assigned to Eisai Co., Ltd.. Invention is credited to Osamu Asano, Hitoshi Harada, Tatsuo Horizoe, Yorihisa Hoshino, Takashi Inoue, Seiichi Kobayashi, Manabu Murakami, Junsaku Nagaoka, Kaya Ohashi, Nobuyuki Yasuda, Seiji Yoshikawa.
United States Patent |
RE39,112 |
Asano , et al. |
May 30, 2006 |
Purine derivatives and adenosine A2 receptor antagonists serving as
preventives/remedies for diabetes
Abstract
The present invention provides a preventive or therapeutic agent
of a new type for diabetes mellitus and diabetic complications on
the basis of an adenosine A2 receptor antagonist action. A purine
compound represented by the formula (I), its pharmacologically
acceptable salt or hydrates thereof has an adenosine A2 receptor
antagonistic action and is useful for prevention or therapy of
diabetes mellitus and diabetic complications. In addition,
adenosine A2 receptor antagonists having different structures from
those of the compounds described above, for example KW6002, are
also effective for prevention or therapy of diabetes mellitus and
diabetic complications. ##STR00001## In the formula, W is
--CH.sub.2CH.sub.2--, or --CH.dbd.CH-- or --C.ident.C--; R.sup.1
is: ##STR00002## (in the formula, X is hydrogen atom, hydroxyl
group, a lower alkyl group, a lower alkoxy group, etc.; and R.sup.5
and R.sup.6 are the same as or different from each other and each
represents hydrogen atom, a lower alkyl group, a cycloalkyl group,
etc.) and the like; R.sup.2 is an amino group, etc. which maybe
substituted with a lower alkyl group, etc.; R.sup.3 is a cycloalkyl
group, an optionally substituted aryl group, etc.; and R.sup.4 is a
lower alkyl group etc. ##STR00003##
Inventors: |
Asano; Osamu (Ushiku,
JP), Harada; Hitoshi (Ushiku, JP), Hoshino;
Yorihisa (Tsukuba, JP), Yoshikawa; Seiji
(Ibaraki, JP), Inoue; Takashi (Tsukuba,
JP), Horizoe; Tatsuo (Ushiku, JP), Yasuda;
Nobuyuki (Ushiku, JP), Ohashi; Kaya (Tokyo,
JP), Nagaoka; Junsaku (Tsukuba, JP),
Murakami; Manabu (Tsukuba, JP), Kobayashi;
Seiichi (Lexington, MA) |
Assignee: |
Eisai Co., Ltd. (Tokyo,
JP)
|
Family
ID: |
11476226 |
Appl.
No.: |
11/057,854 |
Filed: |
December 24, 1998 |
PCT
Filed: |
December 24, 1998 |
PCT No.: |
PCT/JP98/05870 |
371(c)(1),(2),(4) Date: |
July 05, 2000 |
PCT
Pub. No.: |
WO99/35147 |
PCT
Pub. Date: |
July 15, 1999 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
09582840 |
Jul 5, 2000 |
06579868 |
Jun 17, 2003 |
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Foreign Application Priority Data
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Jan 5, 1998 [JP] |
|
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10-000526 |
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Current U.S.
Class: |
514/211.08;
514/263.3; 540/481; 540/524; 544/118; 544/264; 544/265; 544/277;
544/61; 540/492; 514/263.4; 514/263.22; 514/227.8; 514/234.2;
514/263.2; 514/211.15 |
Current CPC
Class: |
A61K
31/52 (20130101); A61P 3/10 (20180101); C07D
473/30 (20130101); C07D 473/34 (20130101); C07D
473/00 (20130101) |
Current International
Class: |
C07D
473/34 (20060101); A61K 31/52 (20060101); A61K
31/522 (20060101); C07D 473/00 (20060101); C07D
473/30 (20060101) |
Field of
Search: |
;540/481,492,524
;514/263.4,263.2,227.8,234.2,211.08,211.15,263.3,263.22
;544/61,118,264,265,277 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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5-222045 |
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Aug 1993 |
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JP |
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9-124648 |
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May 1997 |
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JP |
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WO 9206976 |
|
Apr 1992 |
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WO |
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WO 9701551 |
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Jan 1997 |
|
WO |
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WO 9746560 |
|
Dec 1997 |
|
WO |
|
Other References
Zhange, Metabolism 46, 273 (1997). cited by examiner .
Sonnenberg, Curr. Opinion Nephrol. Hypertens. 7, 551 (1998). cited
by examiner .
Seyama, JACS 110, 2192 (1988). cited by examiner .
Zielenkiewicz et al., Journal of Thermal Analysis, vol. 43, pp.
775-779 .quadrature..quadrature.(1995). cited by examiner .
Tanji et al., Chemical & Pharmaceutical Bulletin, vol. 36, No.
6, pp. 1935-1941. cited by examiner .
Legraverend et a;., Bioorganic & Medicinal Chemistry Letters,
vol. 8, pp. 793-798 (1998). cited by examiner .
Camaion et al., Bioorganic & Medicinal Chemistry Letters, vol.
6, pp. 523-533 (1998). cited by examiner.
|
Primary Examiner: Berch; Mark L.
Attorney, Agent or Firm: Birch, Stewart, Kolasch &
Birch, LLP
Parent Case Text
This application is the national phase under 35 U.S.C. .sctn.371 or
PCT International Application No. PCT/JP98/05870 which has an
International filing date of Dec. 24, 1998, which is designated the
United States of America.
Claims
What is claimed is:
1. A purine compound represented by the formula (I), or its
pharmacologically acceptable salt thereof, ##STR00264## wherein in
the formula (I), R.sup.1 represents: 1) formula: ##STR00265##
wherein X is a hydrogen atom, a hydroxyl group, an optionally
substituted lower alkyl group, an optionally substituted lower
alkoxy group, an optionally substituted aryl group, an optionally
substituted heteroaryl group, an optionally substituted acyl group,
an optionally substituted acyloxy group or an optionally
substituted amino group; and R.sup.5 and R.sup.6 are the same as or
different from each other and each represents a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
saturated or unsaturated C.sub.3-8 cycloalkyl group, an optionally
substituted C.sub.3-8 cycloalkyl-C.sub.2-6 alkyl group, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, an optionally protected carboxyl group or an
optionally substituted four- to six-membered ring having at least
one hetero atom; optionally R.sup.5 and R.sup.6 is either an oxygen
atom or a sulfur atom together, or R.sup.5 and R.sup.6 are a ring
which may have a hetero atom being formed together with a carbon
atom to which they are bonded; wherein said ring may be
substituted; or 2) a five- or six-membered aromatic ring that may
have a substituent group and a hetero atom; W represents formula
--CH.sub.2CH.sub.2--, --CH.dbd.CH-- or --C.ident.C--; R.sup.2
represents a hydrogen atom, an optionally substituted lower alkyl
group, a hydroxyl group or a formula --NR.sup.7R.sup.8, wherein
R.sup.7 and R.sup.8 are the same as or different from each other
and each represents a hydrogen atom, a hydroxyl group, an
optionally substituted lower alkyl group, and optionally
substituted acyl group, an optionally substituted C.sub.3-8
cycloalkyl group, an optionally substituted aryl group or an
optionally substituted heteroaryl group; optionally R.sup.7 and
R.sup.8 are a saturated ring which is formed together with a
nitrogen atom to which they are bonded, said saturated ring is
selected from the group consisting of aziridine, azetidine,
pyrrolidine, piperidine, perhydroazepine, perhydroazocine,
piperazine, homopiperazine, morpholine and thiomorpholine; wherein
the ring optionally has a substituent selected from the group
consisting of a lower alkyl group, a halogen and an acyl group;
R.sup.3 represents an optionally substituted C.sub.3-8 cycloalkyl
group, an optionally substituted aryl group, an optionally
substituted heteroaryl group or an optionally substituted C.sub.2-6
alkenyl group; and R.sup.4 represents a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
C.sub.3-8 cycloalkyl group, an optionally substituted aryl group,
an optionally substituted heteroaryl group, an optionally
substituted C.sub.2-6 alkenyl group, an optionally substituted
C.sub.2-6 alkynyl group or an optionally substituted cyclic ether
group; wherein when W is --CH.sub.2CH.sub.2--, then X is not a
hydrogen atom or an alkyl group.
2. The purine compound or its pharmacologically acceptable salt
thereof as claimed in claim 1, wherein W is --C.ident.C--.
3. The purine compound, or its pharmacologically acceptable salt
thereof, as claimed in claim 1 or 2, wherein R.sup.2 is formula
--NR.sup.7R.sup.8, and R.sup.7 and R.sup.8 have the same meanings
as defined above.
4. The purine compound as claimed in claim 1, or its
pharmacologically acceptable salt thereof, wherein R.sup.3 is an
optionally substituted aryl group or an optionally substituted
heteroaryl group.
5. The purine compound as claimed in claim 1, or its
pharmacologically acceptable salt thereof, wherein R.sup.4 is an
optionally substituted lower alkyl group, an optionally substituted
aryl group or an optionally substituted heteroaryl group.
6. The purine compound as claimed in claim 1, or its
pharmacologically acceptable salt thereof, wherein R.sup.1 is a
formula: ##STR00266## wherein X represents a hydroxyl group, an
acyloxy group or an optionally substituted lower alkyl group; and
R.sup.5 and R.sup.6 are the same as or different from and each
represents an optionally substituted lower alkyl group or a ring
being formed together with the carbon atom to which they are bonded
which may have a hetero atom and may be substituted.
7. The purine compound as claimed in claim 1, or its
pharmacologically acceptable salt thereof, wherein R.sup.1 is a
formula: ##STR00267## wherein X represents a hydroxyl group or a
lower aliphatic acyloxy group; and R.sup.5 and R.sup.6 are the same
as or different from each other and each represents an optionally
substituted lower alkyl group or an optionally substituted
C.sub.3-8 cycloalkyl group being formed with the carbon atom to
which they are bonded; and R.sup.2 is a formula --NR.sup.7R.sup.8,
wherein R.sup.7 and R.sup.8 are the same as or different from and
each represents a hydrogen atom, a lower alkyl group or an acyl
group.
8. The purine compound as claimed in claim 1, or its
pharmacologically acceptable salt thereof, wherein R.sup.1 is a
formula: ##STR00268## wherein X represents a hydroxyl group or a
lower aliphatic acyloxy group; and R.sup.5 and R.sup.6 are the same
as or different from each other and each represents an optionally
substituted lower alkyl group or an optionally substituted
C.sub.3-8 cycloalkyl group being formed together with the carbon
atom to which they are bonded; and R.sup.2 is a formula
--NR.sup.7R.sup.8, wherein both R.sup.7 and R.sup.8 represent
hydrogen atoms.
9. The purine compound as claimed in claim 1, or its
pharmacologically acceptable salt thereof, wherein R.sup.1 is a
formula: ##STR00269## wherein X represents a hydroxyl group or a
lower aliphatic acyloxy group; and R.sup.5 and R.sup.6 are the same
as or different from and each represents a linear or branched lower
alkyl group or cyclobutyl group, cyclopentyl group or cyclohexyl
group being formed together with the carbon atom to which they are
bonded, and the ring may be substituted with a hydroxyl group, a
lower aliphatic acyloxy group, a linear or branched lower alkyl
group, a lower alkoxy group or a halogen atom; R.sup.2 is a formula
--NR.sup.7R.sup.8, wherein both R.sup.7 and R.sup.8 are hydrogen
atoms; R.sup.3 is a phenyl group which may be substituted with
hydroxyl group, a halogen atom, a linear or branched lower alkyl
group, a lower alkoxy group, an acyl group, amino group, a mono- or
di-lower alkylamino group or a cyano group; and R.sup.4 is a lower
alkyl group which may be substituted with a hydroxyl group, a
halogen atom, a cyano group, an amino group, a mono- or di-lower
alkylamino group, a lower alkoxy group, a carbamoyl group, a mono-
or di-substituted carbamoyl group, a carboxyl group or a lower
alkyloxycarboxyl group.
10. The purine compound, or its pharmacologically acceptable salt
thereof, as claimed in claim 1, wherein R.sup.1 is a formula:
##STR00270## wherein X represents a hydroxyl group; and R.sup.5 and
R.sup.6 are the same as or different from and each represents a
lower alkyl group or a cyclobutyl group, a cyclopentyl group or a
cyclohexyl group being formed with the carbon atom to which they
are bonded; R.sup.2 is a formula --NR.sup.7R.sup.8, wherein both
R.sup.7 and R.sup.8 are hydrogen atoms; R.sup.3 is an optionally
halogen-substituted phenyl group; and R.sup.4 is a lower alkyl
group.
11. The purine compound, or its pharmacologically acceptable salt
thereof, as claimed in claim 1 selected from the group consisting
of: 1)
1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cycl-
opentanol; 2)
1-{2-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclo-
pentanol; 3)
1-{2-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cycl-
opentanol; 4)
1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cycl-
obutanol; 5)
1-{2-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclo-
butanol; 6)
1-{2-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cycl-
obutanol; 7)
1-{2-[6-amino-9-dimethylaminophenyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-et-
hynyl}-1-cyclohexanol; 8)
1-{2-[6-amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1--
cyclopentanol; 9)
1-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-o-
l; 10)
4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-but-
yn-2-ol; 11)
4-[6-amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-butyn-2-o-
l; 12)
4-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-bu-
tyn-2-ol; and 13)
1-{2-[6-amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1--
cyclobutanol.
12. A 2,6-dihalo-substituted purine compound represented by the
formula (II): ##STR00271## wherein A and B represent halogen atoms;
R.sup.3 represents an optionally substituted C.sub.3-8 cycloalkyl
group, an optionally substituted aryl group or an optionally
substituted heteroaryl group; and R.sup.4 represents an optionally
substituted linear or branched lower alkyl group, an optionally
substituted aryl group or an optionally substituted heteroaryl
group.
13. A method for the manufacturing of a 6-amino-2-ethynylene
compound represented by the formula (V): ##STR00272## wherein
R.sup.3 represents an optionally substituted C.sub.3-8 cycloalkyl
group, an optionally substituted aryl group or an optionally
substituted heteroaryl group; R.sup.4 represents a linear or
branched alkyl group, an optionally substituted aryl group or an
optionally substituted heteroaryl group; R.sup.1 represents: 1)
formula: ##STR00273## wherein X is a hydrogen atom, a hydroxyl
group, an optionally substituted lower alkyl group, an optionally
substituted lower alkoxy group, an optionally substituted aryl
group, an optionally substituted heteroaryl group, an optionally
substituted acyl group, an optionally substituted acyloxy group or
an optionally substituted amino group; and R.sup.5 and R.sup.6 are
the same as or different from and each represents a hydrogen atom,
an optionally substituted lower alkyl group, an optionally
substituted cycloalkyl group, an optionally substituted aryl group,
an optionally substituted heteroaryl group, an optionally protected
carboxyl group or an optionally substituted four- to six-membered
ring having at least one hetero atom; optionally, R.sup.5 and
R.sup.6 is either an oxygen atom or a sulfur atom together or are a
ring which may have hetero atom being formed together with a carbon
atom to which they are bonded; wherein the ring may be substituted;
or 2) a five- or six-membered aromatic ring which may have
substituent group and hetero, to give a 2-ethynylene-6-halopurine
compound represented by the formula (IV): ##STR00274## wherein A is
a halogen atom, and R.sup.1, R.sup.3 and R.sup.4 have the same
meanings as defined above; and R.sup.21 and R.sup.22 are the same
as or different from each other and each represents a hydrogen atom
or an optionally substituted lower alkyl group or a saturated 3- or
8-membered ring being formed together with the nitrogen atom to
which they are bonded and the ring containing said nitrogen atom
optionally has another heteroatom of nitrogen or oxygen or is
substituted; comprising the steps of: a) reacting a
2,6-dihalo-substituted purine compound represented by the formula
(II): ##STR00275## wherein A and B represent halogen atoms, and
R.sup.3 and R.sup.4 are defined as above, with an ethynylene
compound represented by the formula (III): R.sup.1C.dbd.CH (III)
wherein in the formula (III) R.sup.1 is defined as above in formula
(V); and b) reacting the resulting compound with HNR.sup.21R.sup.22
to form said 6-amino-2-ethynylene compound represented by the
formula (V).
14. A method for the manufacture of a 6-amino-2-ethynylene compound
represented by the formula (V): ##STR00276## wherein R.sup.3
represents an optionally substituted C.sub.3-8 cycloalkyl group, an
optionally substituted aryl group or an optionally substituted
heteroaryl group; R.sup.4 represents a linear or branched alkyl
group, an optionally substituted aryl group or an optionally
substituted heteroaryl group; R.sup.1 represents: 1) formula:
##STR00277## wherein X is a hydrogen atom, a hydroxyl group, an
optionally substituted lower alkyl group, an optionally substituted
lower alkoxy group, an optionally substituted aryl group, an
optionally substituted heteroaryl group, an optionally substituted
acyl group, an optionally substituted acyloxy group or an
optionally substituted amino group; and R.sup.5 and R.sup.6 are the
same as or different from and each represents a hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
cycloalkyl group, an optionally substituted aryl group, an
optionally substituted heteroaryl group, an optionally protected
carboxyl group or an optionally substituted four- to six-membered
ring having at least one hetero atom; optionally, R.sup.5 and
R.sup.6 is either an oxygen atom or a sulfur atom together or are a
ring which may have hetero atom being formed together with a carbon
atom to which they are bonded; wherein the ring may be substituted;
or 2) a five- or six-membered aromatic ring which may have
substituent group and hetero, to give a 2-ethynylene-6-halopurine
compound represented by the formula (IV): ##STR00278## wherein A is
a halogen atom, and R.sup.1, R.sup.3 and R.sup.4 have the same
meanings as defined above; and R.sup.21 and R.sup.22 are the same
as or different from each other and each represents a hydrogen atom
or an optionally substituted lower alkyl group or a saturated 3- or
8-membered ring being formed together with the nitrogen atom to
which they are bonded and the ring containing said nitrogen atom
optionally has another heteroatom or is substituted, comprising the
steps of: a) reacting a 2,6-dihalo-substituted purine compound
represented by the formula (II): ##STR00279## wherein A and B
represent halogen atoms, and R.sup.3 and R.sup.4 are defined as
above, with ammonia or a primary or secondary amine to give a
6-amino-2-halopurine compound represented by the formula (VI):
##STR00280## wherein B, R.sup.3, R.sup.4, R.sup.21 and R.sup.22
have the same meanings as defined above; and b) reacting the
resulting compound with an ethynylene compound represented by the
formula (III): R.sup.1--C.ident.H (III) wherein R.sup.1 has the
same meaning as defined above.
15. A preventive or therapeutic composition comprising: the purine
compound as claimed in claim 1, or its pharmacologically acceptable
salt thereof, as an active ingredient, and a pharmaceutically
acceptable carrier.
16. A method of treating a disease or condition selected from the
group consisting of diabetes mellitus, diabetic complications,
.[.hypoglycemia,.]. .Iadd.hyperglycemia, .Iaddend.impaired glucose
tolerance and obesity, said method comprising: administering an
effective amount of the purine compound of claim 1 to a patient in
need thereof.
17. The method according to claim 16, wherein said disease or
condition is impaired glucose tolerance.
18. The method according to claim 16, wherein said disease or
condition is obesity.
19. The method according to claim 16, wherein said disease or
condition is .[.hypoglycemia..]. .Iadd.hyperglycemia..Iaddend.
20. The method according to claim 16, wherein said disease or
condition is diabetes mellitus.
21. The method according to claim 16, wherein said disease or
condition is diabetic complications.
22. A method of potentiating insulin sensitivity, said method
comprising administering an effective amount of the purine compound
of claim 1 to a patient in need thereof.
Description
TECHNICAL FIELD TO WHICH THE INVENTION BELONGS
The present invention relates to a novel purine compound having an
adenosine receptor antagonism and to a preventive or therapeutic
agent for diabetes mellitus and diabetic complication comprising an
adenosine receptor antagonist having a hypoglycemic action and a
glucose tolerance improving action on the basis of an inhibiting
action to .[.saccharogenesis.]. .Iadd.glucose production
.Iaddend.and a promoting action to .[.saccharide.]. .Iadd.glucose
.Iaddend.utilization at the periphery. More particularly, it
relates to a preventive or therapeutic agent for diabetes mellitus
and diabetic complications in which an adenosine receptor
antagonist is an adenosine A2 receptor antagonist.
PRIOR ART
With regard to therapeutic agents for diabetes mellitus, various
biguanide compounds and sulfonylurea compounds have been used.
However, the biguanide compounds induce a lactic acidosis and,
therefore, their use is limited while the sulfonylurea compounds
often result in a severe hypoglycemia due to their strong
hypoglycemic action and, therefore, their use is to be careful.
An object of the present invention is to provide a preventive or
therapeutic agent for diabetes mellitus and diabetic complications
on the basis of a new action mechanism which is different from that
of conventional biguanide compounds and sulfonylurea compounds
having several limitations in actual use.
DISCLOSURE OF THE INVENTION
The present inventors have carried out various investigations and,
as a result, they have found that antagonists to adenosine
receptors can be preventive or therapeutic agents of a new type for
diabetes mellitus. Thus, hyperglycemia of spontaneous diabetic mice
was relieved by an adenosine receptor antagonist. Such an action is
presumed to be the results of inhibition of the gluconeogenic
action and the glycogenolytic action, promoted by endogenous
adenosine, from liver by an antagonist. Based upon such a finding,
the present inventors have carried out an investigation for the
compounds having excellent hypoglycemic action and glucose
tolerance improving action as a preventive or therapeutic agent and
have found novel purine compounds represented by the following
formula (I). As a result of further investigation of their action
mechanism in detail, they have found that, among the adenosine
receptor antagonistic action, the adenosine A2 receptor
antagonistic action is the real substance for showing the
hypoglycemic and glucose tolerance improving action and have
accomplished the present invention where adenosine A2 receptor
antagonist is a preventive or therapeutic agent of a new type for
diabetes and diabetic complications.
The novel purine compound according to the present invention is
represented by the following formula (I).
A purine compound represented by the formula (I), its
pharmacologically acceptable salt or hydrates thereof.
##STR00004##
In the formula R.sup.1 means: 1) formula: ##STR00005## (in the
formula, X represents hydrogen atom, hydroxyl group, an optionally
substituted lower alkyl group, an optionally substituted lower
alkoxy group, an optionally substituted aryl group, an optionally
substituted heteoaryl group, an optionally substituted acyl group,
an optionally substituted acyloxy group or an optionally
substituted amino group; and R.sup.5 and R.sup.6 are the same as or
different from each other and each represents hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
saturated or unsaturated C.sub.3-8 cycloalkyl group, an optionally
substituted C.sub.3-8cycloalkyl-C.sub.2-6alkyl group, an optionally
substituted aryl group, an optionally substituted heteroaryl group,
an optionally protected carboxyl group or an optionally substituted
four to six membered ring having at least one hetero atom.
Alternatively, R.sup.5 and R.sup.6 may represent an oxygen atom or
a sulfur atom together or may represent a ring being formed
together with the carbon atom to which they are bonded which may
have a hetero atom. This ring may be substituted.); or 2) a five-
or six-membered aromatic ring which may have substituent group and
hetero atom.
W represents a formula --CH.sub.2CH.sub.2--, --CH.dbd.CH-- or
--C.ident.C--.
R.sup.2 represents hydrogen atom, an optionally substituted lower
alkyl group, hydroxyl group or a formula --NR.sup.7R.sup.8 (in
which R.sup.7 and R.sup.8 are the same as or different from each
other and each represents hydrogen atom, hydroxyl group, an
optionally substituted lower alkyl group, an optionally substituted
acyl group, an optionally substituted C.sub.3-8 cycloalkyl group,
an optionally substituted aryl group or an optionally substituted
heteroaryl group. Alternatively, R.sup.7and R.sup.8 may be a
saturated ring which is formed together with a nitrogen atom to
which they are bonded. This ring may further have a hetero atom or
a substituent).
R.sup.3 represents hydrogen atom, an optionally substituted
C.sub.3-8 cycloalkyl group, an optionally substituted aryl group,
an optionally substituted heteroaryl group or an optionally
substituted C.sub.2-6 alkenyl group.
R.sup.4 represents hydrogen atom, an optionally substituted lower
alkyl group, an optionally substituted C.sub.3-8 cycloalkyl group,
an optionally substituted aryl group, an optionally substituted
heteroaryl group, an optionally substituted C.sub.2-6 alkenyl
group, an optionally substituted C.sub.2-6 alkynyl group or an
optionally substituted cyclic ether.
However, the case where (1) W is --CH.sub.2CH-- and X is hydrogen
atom and an alkyl group or where (2) W is --C.ident.C--, R.sup.3 is
hydrogen atom and R.sup.4 is an optionally substituted cyclic ether
is excluded.
There has been no report that an adenosine A2 receptor antagonist
is effective for prevention and therapy of diabetes mellitus and
diabetic complications.
The present invention provides a preventive or therapeutic agent
for diabetes, a preventive or therapeutic agent for diabetic
complications, a hypoglycemic agent, an improving agent for
impaired glucose tolerance, a potentiating agent for insulin
sensitivity obesity which comprises a purine compound of the
formula (I), its pharmacologically acceptable salt or hydrates
thereof as an active ingredient.
The present invention provides a method or a use by administering a
pharmacologically or clinically effective amount of purine compound
of the formula (I), its pharmacologically acceptable salt or
hydrates thereof to a patient for prevention or therapy of diabetes
mellitus, for prevention or therapy of diabetic complications, for
prevention or therapy of a disease against which a purine compound
of the formula (I), its pharmacologically acceptable salt or
hydrates thereof is effective for its prevention or therapy, for
hypoglycemia, for improvement of impaired glucose tolerance, for
potentiation of insulin sensitivity, of for prevention and therapy
of obesity.
The present invention provides a pharmaceutical composition
containing a pharmacologically or clinically effective amount of a
purine compound of the formula (I), its pharmacologically
acceptable salt or hydrates thereof.
Adenosine is a nucleoside widely existing in living body and has a
physiological action to a cardiovascular system, a central nervous
system, a respiratory system, kidney, an immune system, etc. The
action of adenosine is achieved via at least four receptors--A1,
A2a, A2b and A3--in which G protein is participated (Fredholm, B.
B. et al., Pharmacol. Rev., 46, 143-156, 1994.). In 1979, adenosine
receptor was at first classified into A1 and A2 on the basis of
their pharmacological action and participation in adenylate cyclase
(Van Calker, D. et al., J. Neurochem., 33, 999-1003, 1979.). Then
A2 receptor has classified into the subtypes of A2a and A2b on the
basis of high and low affinity to adenosine and to adenosine A2
agonists, i.e. NECA and CGS-21680 (Burns, R. F. et al., Mol.
Pharmacol., 29, 331-346, 1986.; Wan, W. et al., J. Neurochem., 55,
1763-1771, 1990.). Although gradually, physiological and
pathological significance of those receptors has been clarified in
a central nervous system, a circulatory system, etc.
With regard to .[.saccharometabolism,.]. .Iadd.glucose metabolism,
.Iaddend.the following reports have been available. In an
experiment using skeletal muscles, adenosine lowers the insulin
sensitivity due to an agonistic action to the A1 receptor
suppressing the .[.incorporation of saccharide.]. .Iadd.glucose
uptake .Iaddend.while an A1 receptor antagonist increases the
insulin sensitivity (Challis, R. A., Biochem. J., 221, 915-917,
1984; Challis, R. A. , Eur. J. Pharmacol. 226, 121-128, 1992.). In
fat cells, adenosine enhances the sensitivity of insulin via an A1
receptor, whereby .[.incorporation of saccharide.]. .Iadd.glucose
uptake .Iaddend.is promoted (Vannucci, S. J., et al., Biochem. J.,
228, 325-330, 1992). Further WO 95/18128 and WO 98/03507 disclose a
therapeutic agent for diabetes mellitus comprising an A1 receptor
antagonist. This, there have been many reports concerning an A1
receptor. With regard to an adenosine A2 receptor, there is a
simple description in WO 97/01551 suggesting a therapeutic agent
for diabetes mellitus comprising the A2a receptor antagonist
although any group therefor is not mentioned at all. In Collis, M.
G. et al., Trends Pharmacol. Sci., 14, 360-366, 1993.,
participation of the adenosine A2 receptor in the promotion of
gluconeogenesis in hepatic cells is suggested but there is no
specific description at all. On the contrary, WO 98/01459 describes
a therapeutic agent for diabetes mellitus comprising the A2
receptor agonist but thee is no description for the adenosine A2
receptor antagonist at all. As such, the positioning of the
adenosine A2 receptor antagonist as a therapeutic agent for
diabetes mellitus has been in a chaotic state.
The adenosine A2 receptor antagonist of the present invention as a
preventive or therapeutic agent for diabetes mellitus and for
diabetic complications is selected, for example, from the following
compounds 1) to 4). 1) Formula (I) ##STR00006##
In the formula R.sup.1 represents: (1) formula: ##STR00007## (in
the formula X is hydrogen atom, hydroxyl group, an optionally
substituted lower alkyl group, an optionally substituted lower
alkoxy group, an optionally substituted aryl group, an optionally
substituted heteroaryl group, an optionally substituted acyl group,
an optionally substituted acyloxy group or an optionally
substituted amino group; and R.sup.5 and R.sup.6 are the same as or
different from each other and each represents hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
saturated or unsaturated C.sub.3-8 cycloalkyl group, an optionally
substituted C.sub.3-8 cycloalkyl-C.sub.2-6 alkyl group, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, an optionally protected carboxyl group or an
optionally substituted four- to six-membered ring having at least
one hetero atom. Alternatively, R.sup.5 and R.sup.6 represents an
oxygen atom or a sulfur atom together or represents a ring which
may have hetero atom being formed together with the carbon atom to
which they are bonded. This ring may be substituted); or (2) a
five- or six-membered aromatic ring which may have substituent
group and hetero atom.
W represents formula --CH.sub.2CH.sub.2--, --CH.dbd.CH--, or
--C.ident.C--.
R.sup.2 represents hydrogen atom, an optionally substituted lower
alkyl group, hydroxyl group or a formula --NR.sup.7R.sup.8 (in
which R.sup.7 and R.sup.8 are the same as or different from each
other and each represents hydrogen atom, a hydroxyl group, an
optionally substituted lower alkyl group, an optionally substituted
acyl group, an optionally substituted C.sub.3-8 cycloalkyl group,
an optionally substituted aryl group or an optionally substituted
heteoaryl group. Alternatively, R.sup.7 and R.sup.8 represents a
saturated ring which is formed together with a nitrogen atom to
which they are bonded. This ring may further have hetero atom or
substituent.)
R.sup.3 represents hydrogen atom, an optionally substituted
C.sub.3-8 cycloalkyl group, an optionally substituted aryl group,
an optionally substituted heteroaryl group or an optionally
substituted C.sub.2-6 alkenyl group.
R.sup.4 represents hydrogen atom, an optionally substituted lower
alkyl group, an optionally substituted C.sub.3-8 cycloalkyl group,
an optionally substituted aryl group, an optionally substituted
heteroaryl group, an optionally substituted C.sub.2-6 alkenyl
group, an optionally substituted C.sub.2-6 alkynyl group or an
optionally substituted cyclic ether group.
However, the case where (1) W is --CH.sub.2CH.sub.2-- and X is
hydrogen atom and an alkyl group or where (2) W is --C.ident.C--,
R.sup.3 is hydrogen atom and R.sup.4 is an optionally substituted
cyclic ether is excluded.
That is, the present invention is the purine compound of the above
formula (I), its pharmacologically acceptable salt or hydrates
thereof.
Among these compounds, the preferred examples are those where W is
ethylene group or ethylene group and the more preferred example is
that where W is ethynylene group.
The purine compound of the present invention includes an
ethynylenepurine compound represented by the formula (I'):
##STR00008## except the case where R.sup.3 is hydrogen atom and
R.sup.4 is an optionally substituted cyclic ether. 2) A compound
represented by the formula (VII): ##STR00009## (in the formula,
R.sup.1.alpha. and R.sup.2.alpha. are the same as or different from
each other and each represents a C.sub.1-4 lower alkyl group or
allyl group; R.sup.3.alpha. represents hydrogen atom or a C.sub.1-3
lower alkyl group; and R.sup.4.alpha., R.sup.5.alpha.,
R.sup.6.alpha. and R.sup.7.alpha. are the same as or different from
each other and each represents hydrogen atom, a halogen atom, a
C.sub.1-3 lower alkyl group, a C.sub.1-3 lower alkoxy group, nitro
group, amino group or hydroxyl group) or a pharmaceutically
acceptable salt thereof.
Among those compounds, the preferred examples are those where
R.sup.1.alpha., R.sup.2.alpha. and R.sup.3.alpha. are the same as
or different from each other and each represents a C.sub.1-3 lower
alkyl group and any of R.sup.4.alpha., R.sup.5.alpha.,
R.sup.6.alpha. and R.sup.7.alpha. is a C.sub.1-3 lower alkoxy
group, and the more preferred examples are those where
R.sup.1.alpha., R.sup.2.alpha. and R.sup.3.alpha. are the same as
or different from each other and each represents a C.sub.1-3 lower
alkyl group and R.sup.5.alpha. and R.sup.6.alpha. are methoxy
groups. 3) A compound represented by the formula (VII):
##STR00010## (in the formula, E represents an oxygen atom, a sulfur
atom, SO.sub.2 or NH; F represents a C.sub.5-6 cycloalkyl group, a
pyridyl group, a thizolyl group, a C.sub.1-6 alkyl group, an
optionally substituted phenyl group, an optionally substituted
phenyl-C.sub.1-2 alkyl group, a morphoinoethyl group, a furylmethyl
group or a pyridylmethyl group; and G represents a furyl group, a
thienyl group or an isoxazolyl group) or a pharmacologically
acceptable salt thereof.
Among those compounds, the preferred examples are those where E is
NH, F is 2-(4-hydroxyphenyl)ethyl group or 2-(morpholino)ethyl
group and G is a furyl group. 4) A compound represented by the
formula (IX): ##STR00011## (in the formula, the ring M represents
pyrazole or triazole; and P represents a phenyl-(C.sub.1-3)alkyl
group optionally substituted with halogen atom, an alkyl group, an
alkoxy group or cyano, or a C.sub.1-6 alkyl group) or a
pharmacologically acceptable salt thereof.
Among those compounds, the preferred example is that where the ring
M is pyrazole and P is a phenethyl group. 5) A compound represented
by the formula (X): ##STR00012## (in the formula, U represents an
oxygen atom, a sulfur atom or NH group; V represents an optionally
hydroxyl-substituted lower alkyl group, a phenyl or aralkyl group
which may be substituted with a lower alkoxy group, a lower alkyl
group, a halogen atom, hydroxyl group, etc. or a heteroaryl group;
Z.sub.1 represents hydrogen atom, a halogen atom or a lower alkyl
group; and Z.sub.2 represents a heteroaryl group such as a furyl
group) or a pharmaceutically acceptable salt thereof.
Among those compounds, the preferred one is that where U is an
oxygen atom, V is 2,6-dimethoxyphenyl group, Z.sub.1 is hydrogen
atom and Z.sub.2 is a furyl group.
The present invention provides a preventive or therapeutic agent
for diabetes, a preventive or therapeutic agent for diabetic
complications, a hypoglycemic agent, an improving agent for
impaired glucose tolerance, a potentiating agent for insulin
sensitivity or obesity which comprises an adenosine A2 receptor
antagonist, its pharmacologically acceptable salt or hydrates
thereof as an active ingredient.
It is preferred that the above adenosine A2 receptor antagonist its
adenosine A2a and/or A2b receptor antagonist.
Examples of those which are preferred as the adenosine A2a or A2b
receptor antagonist of the present invention are those where the Ki
value showing an affinity to the A2a receptor by the experimental
method which will be mentioned later is not more than 0.5 .mu.M,
those where the IC.sub.50 value showing the suppression of cAMP
production stimulated by NECA in the A2b receptor is not more than
0.7 .mu.M or those satisfying both of them. Examples of those which
are more preferred are those where the Ki value showing an affinity
to the A2a receptor by the experimental method which will be
mentioned later is not more than 0.1 .mu.M, those where the
IC.sub.50 value showing the suppression of cAMP production
stimulated by NECA in the A2b receptor is not more than 0.5 .mu.M
or those satisfying both of them.
The present invention provides a method or a use by administrating
a pharmacologically or clinically effective amount of an adenosine
A2 receptor antagonist, its pharmacologically acceptable salt or
hydrates thereof to a patient for prevention of therapy of diabetes
mellitus, for prevention or therapy of diabetic complications, for
prevention or therapy of a disease against which an adenosine A2
receptor antagonist, its pharmacologically acceptable salt or
hydrates thereof is effective for its prevention or therapy, for
hypoglycemia, for improvement of impaired glucose tolerance, for
potentiation of insulin sensitivity, or for prevention and therapy
of obesity.
The present invention provides a pharmaceutical composition
containing a pharmacologically or clinically effective amount of an
adenosine A2 receptor antagonist, its pharmacologically acceptable
salt or hydrates thereof.
In the formula (I), the term "optionally substituted" used in an
optionally substituted lower alkyl group, an optionally substituted
lower alkoxy group, an optionally substituted cycloalkyl group, an
optionally substituted aryl group, an optionally substituted
heteroaryl group, etc. in the definitions for X, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 represents that each
of the groups may be substituted with a group selected, for
example, from a hydroxyl group; a thiol group; a nitro group; a
cyano group; a halogen atom such as a fluorine atom, a chlorine
atom, a bromine atom and an iodine atom; a lower alkyl group such
as methyl, ethyl, n-propyl and isopropyl; a lower alkoxy group such
as methoxy, ethoxy, n-propoxy, isopropoxy and butoxy groups; a
halogenated alkyl group such as a fluoromethyl group, a
difluoromethyl group, a trifluoromethyl group and a
2,2,2-trifluoroethyl group; an alkylthio group such as methylthio
group, an ethylthio group and an isopropylthio group; an acyl group
such as an acetyl group, a propionyl group and a benzoyl group; a
hydroxyalkyl group such as a hydroxymethyl group, a hydroxyethyl
group and a hydroxypropyl group; an amino group; a monoalkylamino
group such as a methylamino group, an ethylamino group and an
isopropylamino group; a dialkylamino group such as a dimethylamino
group and a diethylamino group; a cyclic amino group such as an
aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a
piperidinyl group, a perhydroazepinyl group and a piperazinyl
group; a carboxyl group; an alkoxycarbonyl group such as a
methoxycarbonyl group, an ethoxycarbonyl group and a propylcarbonyl
group; a carbamoyl group; an alkylcarbamoyl group such as a
methylcarbamoyl group and a dimethylcarbamoyl group; an acylamino
group such as an acetylamino group and a benzoylamino group; an
unsubstituted or C.sub.1-4 alkyl-substituted sulfamoyl group or an
alkylsulfonyl group such as a methylsulfonyl group and an
ethylsulfonyl group; an unsubstituted or substituted arylsulfonyl
group such as a benzenesulfonyl group and a p-toluenesulfonyl
group; an unsubstituted or substituted aryl group such as a phenyl
group, a tolyl group and an anisolyl group, as unsubstituted or
substituted heteroaryl group such as a pyrrole group, a pyrazolyl
group, an imidazolyl group, a triazolyl group, a tetrazolyl group,
a thiazolyl group, a pyridyl group, a pyrimidyl group and a
pyrazinyl group; a carboxyalkyl group; an alkyloxycarbonylalkyl
group such as a methoxycarbonylmethyl group, an
ethoxycarbonylmethyl group and a methoxycarbonylethyl group; a
carboxyalkoxy group such as a carboxymethoxy group; an arylalkyl
group such as a benzyl group and a 4-chlorobenzyl group; a
heteroarylalkyl group such as a pyridylmethyl group and a
pyridylethyl group; an alkylenedioxy group such as a methylenedioxy
group and an ethylenedioxy group; etc.
The halogen atom in the definitions for A and B is fluorine,
chlorine, bromine or iodine.
The lower alkyl group in the definitions for X, R.sup.2, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 means a linear or branched
alkyl group having 1-6 carbon atoms. Its examples are methyl group,
ethyl group, n-propyl group, isopropyl group, n-butyl group,
isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group,
1,2-dimethylpropyl group, 1,1-dimethylpropyl group,
2,2-dimethylpropyl group, 2-ethylpropyl group, n-hexyl group,
1,2-dimethylbutyl group, 2,3-dimethylbutyl group, 1,3-dimethylbutyl
group, 1-ethyl-2-methylpropyl group and 1-methyl-2-ethylpropyl
group.
The lower alkoxy group in the definitions for X means a linear or
branched alkoxy group having 1-6 carbon atoms. Its examples are
methoxy group, ethoxy group, n-propoxy group, isopropoxy group, a
n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy
group, 1,2-dimethylpropyloxy group, 1,1-dimethylpropyloxy group,
2,2-dimethylpropyloxy group, 2-ethylpropyloxy group, n-hexyloxy
group, 1,2-dimethylbutyloxy group, 2,3-dimethylbutyloxy group,
1,3-dimethylbutyloxy group, 1-ethyl-2-methylpropyloxy group and
1-methyl-2-ethylpropyloxy group.
The cycloalkyl group in the definitions for X, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 means a cycloalkyl group
having 3-8carbons such as cyclopropyl group, cyclobutyl group,
cyclopentyl group, cyclohexyl group, cycloheptyl group or
cyclooctyl group.
The cycloalkylalkyl group in the definitions for X, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.8 means a group where
the above cycloalkyl group is bonded to any of the carbon atoms in
the above lower alkyl group.
The lower alkenyl group in the definitions for R.sup.3 and R.sup.4
means a linear or branched alkenyl group having 2-6 carbon atoms
such as vinyl group, 1-propenyl group, 2-propenyl group,
isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl
group, 2-methyl-2-propenyl group, 3-methyl-2-propenyl group,
1-butenyl group, 2-butenyl group and 3-butenyl group.
The lower alkynyl group in the definition for R.sup.4 represents a
linear or branched alkynyl group having 2-6 carbon atoms such as
ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group,
2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group and
2-methyl-3-propynyl group.
The acyl group in the definitions for X and R.sup.2 represents is
group defined from an aliphatic saturated monocarboxylic acid such
as acetyl group, propionyl group, butyryl group, valeryl group,
isovaleryl group and pivaloyl group; a group derived from an
aliphatic unsaturated carboxylic acid such as acryloyl group,
propioloyl group, methacrylolyl group, crotonoyl group and
isocrotonoyl group; a group derived from a carbocyclic carboxylic
acid such as benzoyl group, naphthoyl group, toluoyl group,
hydroatropoyl group, atropoyl group and cinnamoyl group; a group
derived from a heterocyclic carboxylic acid such as furoyl group,
thenoyl group, nicotinoyl group and isonicotinoyl group; a group
derived from a hydroxycarboxylic acid or an alkoxycarboxylic acid
such as glycoloyl group, lactoyl group, glyceroyl group, tropoyl
group, benzyloyl group, salicyloyl group, anisoyl group, vanilloyl
group, piperoniloyl group and galloyl group; a group derived from
various kinds of amino acids; etc.
The aryl group in the optionally substituted aryl group in the
definitions for X, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and
R.sup.8 represents phenyl group, 1-naphthyl group, 2-naphthyl
group, anthracenyl group, etc.
The optionally substituted heteroaryl group in the definitions for
X, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7and R.sup.8
represents a group derived from a monocyte or a condensed ring
containing 1-4 of at least one selected from the group consisting
of sulfur atom, oxygen atom and nitrogen atom. Its examples are
pyrrolyl group, thienyl group, furyl group, thiazolyl group,
oxazolyl group, isothiazolyl group, isoxazolyl group, imidazolyl
group, pyrazolyl group, thiadiazolyl group, oxadiazolyl group,
triazolyl group, tetrazolyl group, pyridyl group, pridazinyl group,
pyrimidinyl group, pyrazinyl group, indolyl group, isoindolyl
group, benzothienyl group, benzofuranyl group, isobenzofuranyl
group, benzimidazolyl group, indazolyl group, benzotriazolyl group,
benzothiazolyl group, benzoxazolyl group, quinolyl group,
isoquinolyl group, cinnolinyl group, phthalazyl group, quinolxalyl
group, naphthyrindinyl group, quinazolinyl group and
imidazopyridinyl group.
The protective group in the optionally protected carboxyl group in
the definitions for R.sup.5 and R.sup.6 is, for example, a lower
alkyl group such as methyl group, ethyl group and tert-butyl group;
a lower alkyl group substituted with an optionally substituted
phenyl group such as p-methoxybenzyl, p-nitrobenzyl,
3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl groups; a
halogenated lower alkyl group such as 2,2,2-trichloroethyl and
2-iodoethyl; a lower alkanoyloxy lower alkyl group such as
pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl,
butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl,
1-pivaloyloxyethyl and 2-pivaloyloxyethyl; a higher alkanoyloxy
lower alkyl group such as palmitoyloxyethyl, heptadecanoyloxymethyl
and 1-palmitoyloxyethyl; a lower alkoxycarbonyloxy lower alkyl
group such as methoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl
and 1-(isopropoxycarbonyloxy) ethyl; a carboxy lower alkyl group
such as carboxymethyl and 2-carboxyethyl; a heteroaryl group such
as 3-phthalidyl; an optionally substituted benzoyloxy lower alkyl
group such as 4-glycyloxybenzoyloxymethyl; a (substituted
dioxolene) lower alkyl group such as
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; a cycloalkyl-substituted
lower alkanoyloxy lower alkyl group such as
1-cyclohexylacetyloxyethyl; a cycloalkyloxycarbonyloxy lower alkyl
group such as 1-cyclohexyloxycarbonyloxyethyl; etc. That may be
also in various acid amides. In short, any group may be a
protective group for the carboxyl group so far as it is decomposed
in vivo by certain means to give a carboxylic acid.
The term "a ring which is formed together with the nitrogen amino
to which they are bonded" in the definitions for R.sup.7, R.sup.8,
R.sup.21 and R.sup.22 represents aziridine, azetidine, pyrrolidine,
piperdine, perhydroazepine, perhydroazocine, piperazine,
homopiperazine, morpholine, thiomorpholine, etc. Such a ring may be
substituted with a lower alkyl group, a halogen atom or acyl group,
etc.
It goes without saying that, in the case of a compound having an
asymmetric atom in the present invention, an optically active
substance thereof is also covered by the present invention. The
present invention further covers a hydrate.
Examples of a pharmacologically acceptable salt in the present
invention are an inorganic salt such as hydrochloride,
hydrobromide, sulfate and phosphate; an organic acid salt such as
acetate, maleate, tartrate, methanesulfonate, benzenesulfonate and
toluenesulfonate; and a salt with amino acid such as aspartic acid
and glutamic acid.
A group of the compounds of the present invention is useful also
from the viewpoint of low toxicity and high safety.
When the compound of the present invention is used for the
above-mentioned diseases, it may be administered either orally or
parenterally. It may be administered in a form of a pharmaceutical
preparation such as tablets, powder, granules, capsules, syrup,
troche, inhalant, suppository, injection, ointment, ophthalmic
ointment, eye drops, nose drops, ear drops, poultice and
lotion.
The dose significantly varies depending upon type of the disease,
degree of the symptom, age, sex and sensitivity of the patient,
etc. but, usually, administration is carried out in a dose of about
0.03-1000 mg, preferably 0.1-500 mg, and more preferably 0.1-100 mg
per day to an adult either once daily or dividing into several
times a day. In the case of an injection preparation, the dose is
usually about 1 .mu.g/kg to 3000 .mu.g/kg, preferably about 3
.mu.g/kg to 1000 .mu.g/kg.
In the manufacture of a pharmaceutical preparation of the compound
of the present invention, that is carried out by a conventional
means using a common pharmaceutical carrier.
Thus, in the manufacture of a solid presentation for oral use,
after addition of filler, binder, disintegrating agent, lubricant,
coloring agent, corrective agents for taste and smell, antioxidant,
etc. to the main ingredient, then the mixture is made into tablets,
coated tablets, granules, powder, capsules, etc. by a conventional
manners.
With regard to the above filler, its examples which may be used are
lactose, corn starch, sucrose, glucose, sorbitol, crystalline
cellulose, silicon dioxide, etc.
With regard to the binder, polyvinyl alcohol, polyvinyl ether,
ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin,
shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
calcium citrate, dextrin, pectin, etc. may be used for example
while, with regard to the lubricant, magnesium stearate, talc,
polyethylene glycol, silica, hydrogenated vegetable oil, etc. may
be used for example.
With regard to the coloring agent, anything may be used so far as
it is permitted to add to pharmaceuticals. With regard to the
corrective agents for taste and smell, cocoa powder, menthol,
aromatic acid, peppermint oil, borneol, cinnamon powder, etc. may
be used. With regard to the antioxidant, anything may be used so
far as it is permitted to add to pharmaceuticals such as ascorbic
acid and .sup..alpha.-tocopherol. It is of course possible that
tables and granules are appropriately coated with sugar, gelatin
and others as required.
On the other hand, in the manufacture of injection, eye drops,
etc., it is possible to manufacture by a conventional means by
adding, if necessary, pH adjusting agent, buffer, suspending agent,
auxiliary solubilizer, stabilizer, isotonizating agent,
antioxidant, preservative, etc. to the main ingredient. In that
case, it is also possible to prepare a freeze-dried preparation, if
necessary. The injection may be administered intravenously,
subcutaneously or intramuscularly.
Examples of the above-mentioned suspending agent are methyl
cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic,
tragacanth, carboxymethyl cellulose sodium and polyoxyethylene
sorbitan monolaurate.
Examples of the auxiliary solubilizer are polyoxyethylene
hydrogenated castor oil, polysorbate 80, nicotinamide and
polyoxyethylene sorbitan monolaurate.
With regard to the stabilizer, sodium sulfite, sodium metasulfite,
ether, etc. may be used for example while, with regard to the
preservative, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate,
sorbic acid, phenol, cresol, chlorocresol, etc. may be used for
example.
In the manufacture of the ointment, it can be manufactured by a
conventional means by addition of stabilizer, antioxidant,
preservative, etc. if necessary.
The novel purine compound of the present invention may be
manufactured by combining the commonly known methods. As hereunder,
main common manufacturing methods for a group of the compounds of
the present invention will be given.
Manufacturing Method A
##STR00013## ##STR00014##
In the above formulae, L.sup.1 and L.sup.2 represent halogen atom;
R.sup.2' represents --NR.sup.7R.sup.8 (wherein --NR.sup.7R.sup.8
has the meaning as defined above); R.sup.9 represents a lower alkyl
group; and R.sup.1, R.sup.3 and R.sup.4 have the meaning as defined
above.
Step A1
This is a step where 4,6-dihalo-5-nitro-2-pyrimidinylacetamide 1
which is a compound synthesized according to a known method is
reacted with an amine compound in a solvent whereupon only one
halogen is substituted with an amine compound to manufacture
4-aminopyrimidine compound 2.
There is no particular limitation for the solvent used therefor so
far as it does not disturb the reaction and is able to dissolve the
starting substance to some extent and its preferred examples are
ether such as tetrahydrofuran, dioxane, dimethoxyethane and
diethylene glycol dimethyl ether; and a halogenated hydrocarbon
such as methylene chloride, chloroform and dichloroehtane. The
reaction temperature varies depending upon the reactivity of the
amine compound used and is preferably -20.degree. C. to 50.degree.
C., and more preferably, about 0.degree. C.
In this step, it is preferred to add an equimolar amount of acetic
acid to suppress the production of a di-substituted substance.
Step A2
This is a step where a nitor group of the nitropyrimidine compound
2 is reduced by means of a catalytic reduction, a reduction with
metal and metal salt, or a metal hydride to manufacture a
pyrimidinylamine compound 3.
The catalytic reduction is carried out in a hydrogen atmosphere in
the presence of a catalyst such as Raney Ni, Pd--C or PrO.sub.2
under ordinary pressure or high pressure at room temperature or
with warming. There is no particular limitation for the solvent
used so far as it does not act as a catalyst poison and is able to
dissolve the starting material to some extent and its suitable
examples are methanol, ethanol, tetrahydrofuran, dioxane, acetic
acid, dimethylformamide and a mixture thereof. Reduction with metal
and metal salt is carried out using zinc dust-hydrochloric acid,
stannous chloride-hydrochloride acid, iron-hydrochloric acid, etc.
in a solvent of an alcohol such as anhydrous methanol or ethanol or
dioxane and tetrahydrofuan. Reduction using a metal hydride is
carried out in a solvent of methanol, ethanol or tetrahydrofuran
using Pd-sodium borohydride, NiCl.sub.2(PPh.sub.3).sub.2-- sodium
borohydride, stannous chloride-sodium borohydride, etc.
Step A3
This is a step where an amino group and an aldehyde which are
adjacent on a pyrimidine ring is condensed with an imidazole ring
to manufacture a purine compound 4.
The reaction is carried out in such a manner that an amino group is
condensed with an aldehyde compound to give Schiff base, and then
it is treated with ferric chloride, etc. to result in a ring
closure.
There is no particular limitation for the solvent used so far as it
does not disturb the reaction and is able to dissolve the starting
material to some extent and its preferred examples are alcohol such
as methanol and ethanol; ether such as tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; and
dimethylformamide. The reaction is carried out at 0 to 100.degree.
C., and preferably, at room temperature. It is preferred to add
acetic acid during the manufacture to Schiff base.
Step A4
This is a step where an acyl group which is a protecting group of
the amino group at position 2 of the above purine compound A is
eliminated to manufacture a 2-aminopurine compound 5.
The reaction is carried out by means of a treatment with a mineral
acid or an alkaline aqueous solution in a solvent such as methanol,
ethanol, dioxane and tetrahydrofuran. Although the reaction
proceeds even at room temperature, it is preferred to carry it out
with heating.
This step may be completed in the above step A3 depending upon the
reducing condition, and in that case, this step is omitted.
Step A5
This is a step where an amino group of the 2-aminopurine compound 5
is subjected to a Sandmeyer reaction to convert into a halogen atom
to manufacture a 2,6-dihalopurine compound 6.
The reaction is carried out in such a manner that the amino group
is diazotized with sodium nitrile or ester nitrous such as amyl
nitrite and isoamyl nitrite to give a diazonium group and then the
diazonium group is converted to a halogen atom using cuprous
halide. When a nitride such as isoamyl nitrite is used in the
diazotization, an acid is not particularly necessary but the amino
group can be converted to a halogen atom by addition of cuprous
halide and methylene halide in a solvent such as dioxane or
tetrahydrofuran followed by heating. In the present invention, it
is most preferred that cuprous iodide is used as a cuprous halide
and diiodemethane is used as a methylene halide to convert into a
2-iodopurine compound.
Step A6
This is a step where a halogen atom at position 2 of the
2,6-dihalopurine compound f is selectively subjected to a coupling
reaction with an ethynyl side chain to manufacture a
2-ethynylene-6-halopurine compound 7.
The reaction is carried out at room temperature or with heating in
the presence of catalytic amounts of dichlorobistriphenylphosphine
palladium (II) and cuprous iodide and a tertiary amine. Examples of
the solvent used are ether such as tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether;
dimethylformamide; and 1-methylpyrrolidinone. Examples of the
tertiary amine used are triethylamine, diisopropylethylamine, DBU
and dimethylaniline. The reaction temperature is preferably 0 to
100.degree. C., and more preferably, room temperature.
Step A7
This is a step where a halogen atom of the
2-ethynylene-6-halopurine compound 7 is reacted with an amine
compound to manufacture a 6-amino-2-ethynylenepurine compound
8.
When the amine compound is gaseous or has a low boiling point, it
is preferred that the reaction is carried out in a sealed tube or
in an autoclave.
There is no particular limitation for the solvent used so far as it
does not disturb the reaction and is able to dissolve the starting
material to some extent and its preferred examples are alcohol such
as methanol and ethanol; ether such as tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; halogenated
hydrocarbon such as methylene chloride, chloroform and
dichloroethane; dimethylformamide; and 1-methylpyrrolidinone.
The reaction temperature is preferably 0 to 150.degree. C., and
more preferably, 50 to 100.degree. C.
Manufacturing Method B
##STR00015##
In the above formula, L.sup.1, R.sup.1, R.sup.2', R.sup.4 and
R.sup.9 have the meanings as defined above.
This manufacturing method B is another method for the manufacture
of the b 2-acylamino-6-halo-5-nitro-4-pyrimidinylamine compound 3
in the manufacturing method A.
Step B1
This is a step where 2-acylamino-4-chloro-5-nitro-6-pyrimidine
compound 1 manufactured by a known method is reacted with an amine
compound to manufacture 2-acyl-amino-4-(substituted
amino)-5-nitro-6-pyrimidone compound 2.
There is no particular limitation for a solvent used so far as it
does not disturb the reaction and is able to dissolve the starting
material to some extent and its preferred examples are ether such
as tetrahydrofuan, dioxane, dimethoxyethane and diethylene glycol
dimethyl ether; and halogenated hydrocarbon such as methylene
chloride, chloroform and dichloromethane. The reaction temperature
varies depending upon the reactivity of the amine compound used and
it is preferably -20.degree. C. to 50.degree. C., and more
preferably, about 0.degree. C.
Step B2
This is a step where an oxo group of the pyrimidone compound is
converted into a halogen atom to manufacture
2-acylamino-6-halo-5-nitro-4-pyrimidinylamine compound 3.
The reaction is carried out in the absence of solvent or by
suspending in a solvent such as acetonitrile, dioxane or
tetrahydrofuran and by treating with a halogenating agent such as
phosphorus oxychloride or phosphorus oxybromide with heating under
reflux. The reaction is accelerated when tetraethylammonium
chloride or dimethylformamide is added to the reaction system.
Manufacturing Method C
##STR00016##
In the above formulae, L.sup.1, L.sup.2, R.sup.1, R.sup.2', R.sup.3
and R.sup.4 have the meanings as defined above.
This manufacturing method C is that where L.sup.1 at position 6 on
a purine ring of the 2,6-dihalopurine compound 6 in the
manufacturing method A is firstly aminated and then L.sup.2 at
position 2 is converted to an ethynylene group to manufacture the
aimed compound.
Step C1
This is a step where a halogen atom at position 6 of the
2,6-dihalopurine compound 1 is reacted with an amine compound to
manufacture a 6-amino-2-halopurine compound 2.
When the amine compound is gaseous or has a low boiling point, it
is referred that the reaction is carried out in an autoclave.
There is no particular limitation for the solvent used so far as it
does not disturb the reaction and is able to dissolve the starting
material to some extent and its preferred examples are alcohol such
as methanol and ethanol; ether such as tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; halogenated
hydrocarbon such as methylene chloride, chloroform and
dichloroethane, dimethylformamide; and 1-methylpyrrolidinone.
The reaction temperature is preferably 0 to 150.degree. C., and
more preferably, 50 to 100.degree. C.
Step C2
This is a step where the aimed compound is prepared by the same
operation as in the above-mentioned step A6.
The reaction is carried out at room temperature or with heating in
the presence of catalytic amounts of dichlorobistriphenylphosphine
palladium (II) and cuprous iodide and a tertiary amide. Examples of
the solvent used are ether such as tetrahydrofuran, dioane,
dimethoxyethane and diethylene glycol dimethyl ether;
dimethylformamide; and 1-methylpyrrolidinone. Examples of the
tertiary amine used are triethylamine, diisopropylethylamine, DBU
and dimethylaniline. The reaction temperature is preferably 0 to
100.degree. C. and, more preferably, room temperature.
Manufacturing Method D
##STR00017##
In the above formulae, Q is an alkylene group, an optionally
substituted arylene group; an optionally substituted heteroarylene
group; an optionally substituted alkylenearylene group; an
optionally substituted alkyleneheteroarylene group; an optionally
substituted arylenealkylene group; or an optionally substituted
heteroarylenealkylene group and R.sup.1, R.sup.2 and R.sup.3 having
the meanings as defined above.
This manufacturing method D is a method where, in the case the
compound 1 manufactured by the manufacturing method A or C has a
cyano group, the cyano group is converted whereupon an amide
compound, an amidine compound or an N-cyanoamidine compound is
manufactured. Accordingly, when a cyano group is present on the
substituents of R.sup.2 and R.sup.3, the above compounds can be
manufactured in a similar manner.
Step D1
This is a step where an amide compound is manufactured from the
cyano compound 1 manufactured by the manufacturing method A or
C.
The reaction is carried out by treating with an aqueous solution of
sodium hydroxide or potassium hydroxide in the presence of a
peracid in a water-miscible solvent such as acetone, dioxane,
tetrahydrofuran, methanol and ethanol. The reaction temperature is
preferably from 0.degree. C. to a refluxing temperature and, more
preferably, room temperature.
Step D2
This is a step where an amidine compound is manufactured from the
cyano compound 1 manufactured by the manufacturing method A or
C.
It is possible to manufacture by various methods. For example, a
mono-substituted substance may be manufactured by a method where a
cyano compound 1 is heated to 200.degree. C. or higher with an
equimolar aromatic amine benezenesulfonate or p-toluenesulfonate;
an N,N-disubstituted substance may be manufactured by a method
where an amine compound is heated with a cyano compound 1 in the
presence of a Lewis acid such as aluminum chloride; and an
unsubstituted substance may be manufactured by a method where a
cyano compound 1 is treated with an aluminum amide reagent
(MeAlClNH.sub.2) or by a method where it is converted into an
imidate hydrochloride with hydrogen chloride-ethanol followed by
treating with ammonia. Alternatively, the mono- or di-substituted
substance may be manufactured by treating the imidate hydrochloride
with a primary or secondary amine.
Step D3
This is a step where an N.sup.2-cyanoamidine compound is
manufactured from the cyano compound 1 manufactured by the
manufacturing method A or C.
A cyano compound 1 is dissolved in dioxane or tetrahydrofuran,
hydrogen sulfide is passed thereinto to saturate, the mixture is
allowed to stand at room temperature to convert into thioamide, and
then the thioamide is treated with iodomethane to give thiomidate.
The thioimidate is treated with cyamide whereupon an N-cyanoamidine
compound 4 is manufactured. When this operation is applied to a
2-iodo-6-purinylamine compound manufactured in the step C1 of the
manufacturing method C and the firstly prepared
2-iodo-N-cyanoamidine compound is coupled with an alkyne reagent, a
cyano compound 1 is manufactured in a similar manner.
Manufacturing Method E
##STR00018## (in the formula, R.sup.12 represents a protective
group for a carboxyl group; R.sup.13 and R.sup.14 are the same as
or different from each other and each represents hydrogen atom, an
optionally substituted lower alkyl group, an optionally substituted
aryl group or an optionally substituted heteroaryl group; and
R.sup.1, R.sup.2' and R.sup.3 have the meanings as defined
above.)
Step E1
This is a step where the protective group is eliminated by an acid
or an alkali or by means of heating to manufacture a carboxylic
acid compound 2.
Examples of the acid used are an aqueous solution of mineral acid
such as hydrochloric acid and sulfuric acid while examples of an
alkali are an aqueous solution of sodium hydroxide, potassium
hydroxide and lithium hydroxide. With regard to a solvent, any
solvent may be used so far as it does not participate in the
reaction and that which is miscible with water such as methanol,
ethanol, tetrahydrofuran and dioxane is preferred. Preferred
reaction temperature is from room temperature to refluxing
temperature.
When the protective group is tetrahydropyranyl group, it can be
eliminated by heating at from 70 to 150.degree. C.
Step E2
This is a step where the carboxylic acid compound 2 previously
prepared is converted into a reactive derivative of the acid and
made to react with a primary or secondary amine to manufacture an
acid amide compound 3.
Examples of the reactive derivative of the acid are an acid halide
such as acid chloride, a mixed acid anhydride such as
ethoxycarbonyl chloride obtained by the reaction with
chloroformate; and an activated ester such as p-nitrophenyl ester.
Examples of the solvent are tetrahydrofuran, dioxane,
dichloromethane, chloroform and dichloroethane. The reaction
temperature is preferably from -10 to 50.degree. C., and more
preferably, from 0.degree. C. to room temperature.
Step E3
This is a step where the ester compound 1 is reacted with an amine
compound to directly manufacture an acid amide compound 3 without
by way of a carboxylic acid compound 2.
With regard to a protective group R.sup.12, a lower alkyl group
such as a methyl group or an ethyl group is preferred. The reaction
is carried out by heating in a sealed tube or in an autoclave. The
reaction temperature is preferably from 50 to 100.degree. C.
The above eliminating reaction and amidation reaction can be used
for the case where R.sup.1 or R.sup.3 has a protected carboxyl
group as well to manufacture a product.
Manufacturing Method F
##STR00019## (in the formulae, n represents an integer of from 2 to
6 and R.sup.2', R.sup.3, R.sup.12, R.sup.13 and R.sup.14 have the
meanings as defined above.)
Step F1
This is a step where a purine compound 1 having a
hydroxyl-substituted alkyl group is oxidized to manufacture a
carboxylic acid compound 2.
With regard to an oxidizing agent, ruthenium tetraoxide,
permanganic acid, chromic acid, etc. may be used. With regard to a
solvent, carbon tetrachloride, chloroform, methylene chloride,
acetonitrile, pyridine, water or a mixed solvent thereof may be
used. The reaction is carried out preferably at 0 to 50.degree. C.,
and more preferably, at room temperature.
A carboxylic group of the carboxylic acid compound 2 manufactured
as such is then protected and, after that, conversion into a
2-ethynylenepurine compound is carried out by the same operation as
in the step A6 of the manufacturing method A.
When there is a hydroxyl-substituted alkyl group is present in
R.sup.3, the same method is applied whereupon a 2-ethynylenepurine
compound having a carboxylic group in R.sup.3 is manufactured by
the same method.
Manufacturing Method G
##STR00020## (in the formulae, R.sup.2' is an amino group or a
halogen atom; and R1, R.sup.3 and R.sup.4 have the meaning as
defined above.)
Step G1
This is a step where the amino group or the halogen atom at
position 6 of the purine skeleton is hydrolyzed to manufacture a
6-hydroxypurine compound 2.
The hydrolysis is carried out in the presence of an acid or an
alkali and it is preferred to carry out in the presence of an
alkali. Examples of the alkali used are sodium hydroxide, potassium
hydroxide, etc. The reaction is carried out at from 0 to
100.degree. C.
Step G2
This is a step where the amino group at position 6 is diazotized
and heated to eliminate the nitrogen whereupon a 6-unsubstituted
purine compound is manufactured.
The reaction is carried out in such a manner that the amino group
is diazotized with sodium nitrite or nitrous ester such as amyl
nitrite, isoamyl nitrite, etc. in dioxane, tetrahydrofuran or an
aqueous solvent thereof and then the diazonium group is eliminated
by heating under refluxing.
Incidentally, a method for the manufacture of the compound
represented by the formula (VII) is described in JP-A 6-16559 and
JP-A-211856, J. Med. Chem., 36, 1333-1342, 1993, etc.; a method for
the manufacture of the compound represented by the formula (VIII)
is described in JP-A 5-97855 and WO 94/14812; a method for the
manufacture of the compound represented by the formula (IX) is
described in WO 95/01356 and Eur. J. Med. Chem., 28, 569-576,
1993.; and a method for the manufacture of the compound represented
by the formula (X) is described in WO 98/42711.
Now, in order to explain the excellent effect of the purine
compounds of the present invention, pharmacological experiments
will be shown as hereunder.
Effects of Novel Purine Compounds
1) Suppressing Action to NECA-Stimulated .[.Saccharogenesis.].
.Iadd.Glucose Production .Iaddend.in Hepatic Cells of Primary
Culture of Rats
Hepatic cells were separated by a collagenase perfusion method from
liver of male rats of Wistar strain and subjected to a primary
culture in a William's Medium E containing 5% of calf serum,
10.sup.-6 M of dexamethasone and 30 ng/ml of .[.pertussal.].
.Iadd.pertussis .Iaddend.toxin. After one day, the hepatic cells
were washed with a Krebs-Ringer Bicarbonate buffer (pH 7.4 (KRB))
containing 10 mM of HEPES and 0.1% of bovine serum albumin and
incubated with KRB at 37.degree. C. After 30 minutes, 0.1 .mu.M of
NECA (N-ethylcarboxamide adenosine) and a test compound were added
thereto at the same time, the mixture was incubated for additional
one hour and the amount of glucose released into an incubation
medium was measured.
The result is shown in Table 1.
TABLE-US-00001 TABLE 1 Suppressing Action to NECA-Stimulated
.[.Saccharogenesis.]. .Iadd.Glucose Production .Iaddend. in Hepatic
Cells of Primary Culture of Rats Example 8 0.49 (sulfate) Example
19 0.47 Example 31 0.13 Example 64 0.73 (sulfate) Example 89 0.43
Example 133 0.20 Example 169 0.48 Example 170 0.50 Example 171 1.01
Example 208 0.27 Example 210 0.52 Example 215 0.22 Example 235
1.27
2) Action to Hyperglycemia of Spontaneous Diabetic Mice
(KK-A.sup.y/Ta Jcl) (Single Administration)
Animals: Five male KK-A.sup.y/Ta Jcl mice for each group (purchased
from Nippon Clair) Preparation and Administration of Test Compound:
A test compound in a dose as shown in Table 1 was suspended in a
0.5% aqueous solution of methyl cellulose and was orally
administered in a .[.dose.]. .Iadd.volume .Iaddend.of 10 ml/kg.
Collection of Blood Samples and Determination of Blood .[.Sugar:.].
.Iadd.Glucose: .Iaddend.Blood was collected from tail vein
immediately before adminstration of the test compound and also five
hours after the administration and blood .[.sugar.]. .Iadd.glucose
.Iaddend.was determined. Method: Tail vein of a mouse was injured
by a razor without an anesthetization to bleed slightly. The blood
(15 .mu.l) was collected and immediately mixed with 135 .mu.l of a
0.6 M perchloric acid. Glucose in the supernatant obtained by a
centrifugal separation (at 1500 g for 10 minutes at 4.degree. C.
using a cooling centrifuge GS-6KR of Beckmann) was determined by a
Glucose CII Test Wako (Wako Pure Chemicals).
The result for each experiment is shown in Table 2-1 to 2-3.
The result is shown in terms of "(% ratio of the blood .[.sugar.].
.Iadd.glucose .Iaddend.after 5 hours from the administration to the
blood .[.sugar.]. .Iadd.glucose .Iaddend.before the
administration).+-.(standard error)". The data were subjected to a
one-way layout analysis of variance and then subjected to a
multiple comparison of a Dunnett type. The case where p<0.05 was
judged to be that a significant difference was available.
TABLE-US-00002 TABLE 2-1 Action of spontaneous diabetic mice
(KK-A.sup.7/Ta Jcl) to hyperglycemia Test Compound Dose (mg/kg)
.times. .times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. .times..times. .times..times.
.times..times. .times. .times..times. ##EQU00001## Sig- nificance
Solvent 72.4 .+-. 4.4 Example 8 10 47.8 .+-. 4.8 ** (sulfate)
Example 19 10 51.8 .+-. 2.9 ** (**; p < 0.01 vs. Solvent)
TABLE-US-00003 TABLE 2-2 Action of spontaneous diabetic mice
(KK-A.sup.7/Ta Jcl) to hyperglycemia Test Compound Dose (mg/kg)
.times. .times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. ##EQU00002## Sig- nificance Solvent
67.6 .+-. 2.4 Example 64 10 42.3 .+-. 4.8 ** Example 89 30 38.3
.+-. 4.4 ** (**; p < 0.01 vs. Solvent)
TABLE-US-00004 TABLE 2-3 Action of Spontaneous Diabetic Mice
(KK-A.sup.7/Ta Jcl) to hyperglycemia Test Compound Dose (mg/kg)
.times. .times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. ##EQU00003## Sig- nificance Solvent
70.7 .+-. 4.6 Example 210 10 51.5 .+-. 4.6 * (*; p < 0.05 vs.
Solvent)
As such, the compounds of the present invention showed a clear
effect to the pathological models. In addition, the compounds of
the present invention showed an improving action in the
investigation for impaired glucose tolerance in a glucose tolerance
test and were confirmed to act not only in liver but also in
periphery.
Now, representative compounds of the novel purine compounds
according to the present invention will be illustrated and it goes
without saying that the object is to facilitate the understanding
of the present invention and that the present invention is not
limited thereby.
EXAMPLE 1
3-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-p-
urinyl}benzonitrile
1)
N.sup.1-[4-(3-Cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]ac-
etamide
To a solution of 2.54 g of 3-cyanoaniline in 25 ml of
tetrahydrofuran were gradually added 1.23 ml of acetic acid at
0.degree. C. To this solution were added 2 g of
4-chloro-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinylacetamide at
0.degree. C. and the mixture was stirred for 3.5 hours. The
reaction solution was filtered and the solid collected thereby was
washed with 10 ml each of water, methanol, tetrahydrofuran and
ether successively. The resulting product was dried at room
temperature to give 2.58 g of
N.sup.1-[4-(3-cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]aceta-
mide. The yield was 96%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.2.18 (s, 3H), 7.56-7.60 (m, 1H), 7.67-7.70
(m, 1H), 7.83-7.87 (m, 1H), 8.07 (s, 1H), 11.05 (s, 1H), 11.69 (br
s, 2H).
2)
N.sup.1-[4-Chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide
N.sup.1-[4-(3-Cyanoanilino)-5-nitro-6-oxo-1,6-dihydro-2-pyrimidinyl]aceta-
mide (2.5 g) was suspended in 50 ml of acetonitrile, then 2.64 g of
tetraethylammonium chloride, 1 ml of N,N-dimethylaniline and 4.5 ml
of phosphorus oxy-chloride were added and the mixture was heated
under reflux for 5 hours. The reaction solution was returned to
room temperature and added to ice-water and the mixture was stirred
for 30 minutes. The resulting crystals were collected by filtration
washed with water and dried to give 2.5 g of
N.sup.1-[4-chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide.
The yield was 93%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6) .Iaddend.2.18 (s, 3H), 7.56-7.60 (m, 1H), 7.67-7.70
(m, 1H), 7.83-7.87 (m, 1H), 8.07 (s, 1H), 11.05 (s, 1H), 11.69 (br
s, 2H).
2) 3-[(2,5-Diamino-6-chloro-4-pyrimidinyl)amino]benzontrile
N.sup.1-[4-Chloro-6-(3-cyanoanilino)-5-nitro-2-pyrimidinyl]acetamide
(2.37 g) was dissolved in 237 ml of ethanol, 8.04 g of stannous
chloride was added and then 135 mg of sodium borohydride was added
thereto with heating at 60.degree. C. After stirring at 60.degree.
C. for 3 hours, the mixture was returned to room temperature and
concentrated to dryness. The resulting residue was diluted with
water and the resulting precipitates were collected by filtration
and washed with water to give 3.2 g of crude crystals of
3-[(2,5-Diamino-6-chloro-4-pyrimidinyl)amino]benzonitrile. This was
used for the next step without purification.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.4.24 (s, 2H), 6.08 (s, 2H), 7.38-7.42 (m,
1H), 7.44-7.49 (m, 1H), 7.97-8.02 (m, 1H), 8.31-8.34 (m, 1H), 8.62
(s, 1H).
4)
3-[2-Amino-6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]benzonitrile
Crude crystals (3.2 g) of
3-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]benzonitrile were
dissolved in 64 ml of methanol, then 3.2 ml of acetic acid and 1.7
ml of 3-fluorobenzaldehyde were added thereto and the mixture was
stirred at room temperature for 2 hours. The reaction solution was
concentrated and was subjected to an azeotropy with toluene for two
times. The resulting residue after concentration was dissolved in
ethanol, a solution of 1.72 g of ferric chloride in 10 ml of
ethanol was added and the mixture was heated under reflux for 1
hour. The reaction solution was returned to room temperature,
concentrated to dryness and added to ice-water and the resulting
crystals were collected by filtration to give 2.6 g of the title
compound, i.e.,
3-[2-amino-6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]benzonitrile.
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
5.09 (s, 2H), 7.06-7.10 (m, 1H), 7.11-7.15 (m, 1H), 7.18-7.28 (m,
2H), 7.40-7.44 (m, 1H), 7.53-7.57 (m, 1H), 7.62-7.64 (m, 1H),
7.70-7.73 (m, 1H).
5)
3-[6-Chloro-8-(3-fluorophenyl-2-iodo-9H-9-purinyl]benzonitrile
3-[2-Amino-6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]-benzonitrile
(2.6 g) was dissolved in 105 ml of tetrahydrofuran, then 2.9 ml of
isoamyl nitrite, 5.8 ml of diiodomethane and 1.37 g of cuprous
iodide were added thereto and the mixture was heated under reflux
for 1 hour. After the resulting mixture was cooled to room
temperature, it was filtered to remove unnecessary substances and
washed with 100 ml of ethyl acetate. The filtrate was concentrated
to dryness and purified by a silica gel column (50 g of silica
gel). It was eluted with ethyl acetate and hexane (1:1). The
fractions containing the aimed product were collected, concentrated
and suspended in 100 ml of a mixed solvent of ethyl acetate and
hexane (1:4), and the resulting precipitates were collected by
filtration to give 1.7 g of
3-[(6-chloro-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]benzonitrile.
The yield was 50%.
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
7.19-7.27 (m, 2H), 7.31-7.40 (m, 2H), 7.57-7.60 (m, 1H), 7.64-7.66
(m, 1H), 7.53-7.57 (m, 1H), 7.68-7.72 (m, 1H), 7.84-7.87 (m,
1H),
6)
3-{6-Chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9-
H-9-purinyl}benzonitrile
1-3-[6-Chloro-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]benzonitrile
(2.1 g) was dissolved in 54 ml of dioxane, then 660 mg of
1-ethynylcyclohexanol, 310 mg of bis-triphenylphosphine palladium
dichloride, 169 mg of cuprous iodide and 0.39 ml of trethylamine
were added thereto and the mixture was stirred at room temperature
in a nitrogen atmosphere for hours. The reaction solution was
diluted with 100 ml of dichloromethane and washed with 100 ml of a
saturated ethylenediaminetetraacetic acid. The organic layer was
washed with 20 ml of brine and dried over anhydrous sodium sulfate.
After the resulting solution was concentrated to dryness, the
resulting residue was suspended in 100 ml of dichloromethane and
the resulting crystals were collected by filtration to give 1.8 g
of
3-{6-chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H
9-purinyl}benzonitrile. The yield was 86%. NMR (400 MHz,
.[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3); 1.27-1.40 (m,
1H), 1.57-1.78 (m, 7H), 2.01-2.08 (m, 2H), 2.13 (s, 1H), 7.18-7.24
(m, 1H), 7.25-7.28 (m, 1H), 7.32-7.40 (m, 2H), 7.55-7.58 (m, 1H),
7.66-7.72 (m, 2H), 7.83-7.86 (m, 1H).
7)
3-[6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxyhexyl)-1-ethynyl]-9H-9-pu-
rinyl]benzonitrile
3-{6-Chloro-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}-9H-9-
-purinyl]benzonitrile (2.0 g) was suspended in 200 ml of a 20%
ammonia/ethanol and reacted at 100.degree. C. in an autoclave for 8
hours. The resulting mixture was cooled to room temperature,
concentrated to dryness and purified by a silica gel column (40 g
of silica gel). It was eluted with dichloromethane containing 5% of
methanol. The fractions containing the aimed product were
collected, concentrate to dryness, suspended in 100 ml of a mixed
solvent of ethyl acetate and hexane (1:1) and the resulting product
was collected by filtration and washed with hexane to give 1.4 g of
the title compound. The yield was 73%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.26-1.41 (m, 1H), 1.46-1.75 (m, 7H);
1.99-2.07 (m, 2H), 2.32 (s, 1H), 5.81 (br s, 2H), 7.12-7.18 (m,
2H), 7.21-7.25 (m, 1H), 7.30-7.36 (m, 1H), 7.54-7.57 (m, 1H),
7.60-7.64 (m, 1H), 7.68-7.70 (m, 1H), 7.75-7.79 (m, 1H).
Compounds of Example 2 to Example 11 were synthesized by the same
manner as in Example 1 using the corresponding material and they
were all obtained as hydrochlorides by a conventional method.
EXAMPLE 2
1-{2-[6-Amino-8-(3-fluorophenyl)-9-phenyl-9H-2-purinyl]-1-ethynyl}1-cycloh-
exenol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.16-1.28 (m, 1H) 1.37-1.63 (m, 7H),
1.72-1.80 (m, 2H), 7.22-7.26 (m, 3H), 7.36-7.42 (m, 3H), 7.50-7.57
(m, 3H), 7.68 (br s, 1H). FAB MASS; 428 (M.sup.++1).
EXAMPLE 3
1-{2-[6-Amino-9-[4-(dimetylamino)phenyl]-8-(3-fluorophenyl)-9H-2-purinyl]--
1-ethynyl}-1-cyclohexanol Dihydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.28 (m, 1H), 1.38-1.62 (m, 7H),
1.74-1.82 (m, 2H), 2.98 (s, 6H), .[.6.87 (d, J=8.7 Hz, 2H), 7.14
(d, J=8.7 Hz, 2H),.]. .Iadd.6.87 (d, J=8.7 Hz, 2H), 7.14(d, J=8.7
Hz, 2H), .Iaddend.7.23-7.33 (m, 3H), 7.90-8.45 (m, 1H), m.p.;
255-260.degree. C.; FAB MASS; 471 (M.sup.++1).
EXAMPLE 4
1-[6-Amino-8-(3-fluorophenyl)-9-(4-morpholinophenyl)-9H-2-purinyl]-1-ethyn-
yl}-1-cyclohexanol Dihydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.40-1.64 (m, 7H),
1.74-1.82 (m, 2H), 3.20 (br, 4H), 3.76 (br, 4H), .[.7.06 (d, J=9.2
Hz, 2H), 7.23 (d, J=9.2 Hz, 2H),.]. .Iadd.7.06 (d, J=9.2 Hz, 2H),
7.23(d, J=9.2 Hz, 2H), .Iaddend.7.24-7.34 (m, 3H), 7.39-7.45 (m,
1H). FAB MASS; 513 (M.sup.++1).
EXAMPLE 5
1-{2-[6-Amino-8-(3-fluorophenyl)-9-(4-methoxyphenyl)-9H-2-purinyl]-1-ethyn-
yl}-1-cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.17-1.28 (m, 1H), 1.40-1.64 (m, 7H)
1.75-1.84 (m, 2H), 3.80 (s, 3H), .[.7.08 (d, J=8.3 Hz, 2H),
7.26-7.29 (m, 3H), 7.34 (d, J=8.3 Hz, 2H),.]. .Iadd.7.08 (d, J=8.3
Hz, 2H), 7.26-7.29(m, 3H), 7.34(d, J=8.3 Hz, 2H),
.Iaddend.7.39-7.45 (m, 1H), FAB MASS; 458 (M.sup.++1).
EXAMPLE 6
2-Amino-5-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl-
]-9H-9-purinyl}benzonitrile Dihydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.16-1.30 (m, 1H), 1.35-1.64 (m, 7H),
1.72-1.85 (m, 2H), .[.6.85 (d, J=9.0 Hz, 1H),.]. .Iadd.6.85 (d,
J=9.0 Hz, 1H), .Iaddend.7.25-7.36 (m, 4H), 7.42-7.49 (m, 1H),
.[.7.55 (d, J=2.4 Hz, 1H)..]. .Iadd.7.55 (d, J=2.4 Hz, 1H).
.Iaddend.FAB MASS 458 (M.sup.++1).
EXAMPLE 7
4-{(6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9--
purinyl}benzonitrile Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.17-1.28 (m, 1H), 1.36-1.64 (m, 7H),
1.73-1.81 (m, 2H), 7.18-7.20 (m, 1H), 7.27-7.32 (m, 2H), 7.39-7.45
(m, 1H), .[.7.64 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.4 Hz, 2H)..].
.Iadd.7.64 (d, J=8.4 Hz, 2H), 8.04(d, J=8.4 Hz, 2H). .Iaddend.FAB
MASS; 453 (M.sup.++1).
EXAMPLE 8
1-{2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclob-
utanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.33 (t, J=7.2 Hz, 3H),.].
.Iadd.1.33 (t, J=7.2 Hz, 3H), .Iaddend.1.78-1.90 (m, 2H), 2.20-2.36
(m, 2H), 2.40-2.50 (m, 2H), .[.4.39 (q, J=7.2 Hz, 2H),.].
.Iadd.4.39 (q, J=7.2 Hz, 2H), .Iaddend.6.19 (s, 1H), 7.51-7.57 (m,
1H), 7.70-7.76 (m, 3H). FAB MASS; 352 (M.sup.++1); m.p.;
160-163.degree. C.
EXAMPLE 9
1-[(6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-3-ethyl-1-pentyn-3-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.01 (t, J=7.2 Hz, 6H),
1.27 (t, J=7.2 Hz, 3H),.]. .Iadd..delta., DMSO-d.sub.6); 1.01(t,
J=7.2 Hz, 6H), 1.27(t, J=7.2 Hz, 3H), .Iaddend.1.60-1.75 (m, 4H),
.[.4.30 (q, J=7.2 Hz, 2H),.]. .Iadd.4.30 (q, J=7.2 Hz, 2H),
.Iaddend.7.44-7.50 (m, 1H), 7.63-7.70 (m, 3H). FAB MASS; 368
(M.sup.++1); m.p.; 150-153.degree. C.
EXAMPLE 10
4-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-1-buthyn-2-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.32 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.32(t, J=7.2 Hz, 3H), .Iaddend.1.52
(s, 6H), .[.4.39 (q, J=7.2 Hz, 2H),.]. .Iadd.4.39 (q, J=7.2 Hz,
2H), .Iaddend.5.76 (s, 1H), 7.51-7.57 (m, 1H), 7.60-7.75 (m, 3H).
FAB MASS; 340 (M.sup.++1); m.p.; 193-196.degree. C.
EXAMPLE 11
Ethyl
3-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]--
9H-9-purinyl}benzoate
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
1.24-1.42 (m, 1H), .[.1.37 (t, J=7.1 Hz, 3H),.]. .Iadd.1.37 (t,
J=7.1 Hz, 3H), .Iaddend.1.47-1.55 (m, 1H), 1.46-1.78 (m, 6H),
1.97-2.08 (m, 2H), 2.48 (s, 1H), .[.4.37 (q, J=7.1 Hz, 2H),.].
.Iadd.4.37 (q, J=7.1 Hz, 2H), .Iaddend.5.83 (br s, 2H), 7.06-7.12
(m, 1H), 7.17-7.21 (m, 1H), 7.22-7.31 (m, 2H), 7.48-7.53 (m, 1H),
.[.7.58 (t, J=7.8 Hz, 1H),.]. .Iadd.7.58 (t, J=7.8 Hz, 1H),
.Iaddend.7.98-8.02 (m, 1H), 8.14-8.18 (m, 1H).
EXAMPLE 12
3-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycylohexyl)-1-ethynyl]-9H-9-pu-
rinyl}benzamide Hydrochloride
3-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9--
purinyl}benzonitrile (1.4 g) obtained in Example 1 was dissolved in
70 ml of methanol, then 1.55 ml of a 30% aqueous hydrogen peroxide
and 1.55 ml of a 1N aqueous solution of sodium hydroxide were added
thereto and the mixture was stirred for 4 hours. The resulting
crystals were collected by filtration, washed with water and dried
to give 1.14 g of a free compound of the title compound. The free
compound was suspended in 30 ml of ethanol, 5 ml of a 6N aqueous
solution of hydrochloric acid were added and the mixture was
concentrated to dryness. The resulting residue was suspended in 50
ml of diethyl ether, filtered, washed and then dried to give 1.2 g
of the title compound. The yield was 76%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.15-1.28 (m, 1H), 1.25-1.63 (m, 7H),
1.72-1.80 (M, 2H), 7.22-7.30 (m, 3H), 7.37-7.43 (m, 1H), 7.54-7.58
(m, 1H), 7.60-7.64 (m, 1H), 7.77 (br s, 1H), 7.89-7.91 (m, 1H),
8.01-8.04 (m, 1H), 8.08 (s, 1H), FAB MASS; 471 (M.sup.++1).
Compounds of Examples 13 and 14 were obtained by the same manner as
in Example 12.
EXAMPLE 13
4-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}-9H-9-p-
urinyl]benzamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6) .Iaddend.1.16-1.28 (m, 1H), 1.35-1.64 (m, 7H),
1.72-1.81 (m, 2H), 7.22-7.29 (m, 3H), 7.39-7.44 (m, 1H), .[.7.50
(d, J=8.2 Hz, 2H), 7.55 (s, 1H), 7.99 (d, J=8.2 Hz, 2H),.].
.Iadd.7.50 (d, J=8.2 Hz, 2H), 7.55(s, 1H), 7.99(d, J=8.2 Hz, 2H),
.Iaddend.8.13 (s, 1H. FAB MASS; 471 (M.sup.++1).
EXAMPLE 14
2-Amino-5-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl--ethynyl}--
9H-9-purinyl]benzamide Dihydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6) .Iaddend.1.14-1.27 (m, 1H), 1.27-1.63 (m, 7H),
1.65-1.82 (m, 2H), 6.79-6.84 (m, 1H), 7.17-7.18 (m, 1H), 7.19 (br
s, 1H), 7.24-7.30 (m, 1H), 7.33-7.38 (m, 2H), 7.42-7.48 (m, 1H),
7.60-7.63 (m, 1H), 7.72 (br s, 1H). FAB MASS; 486 (M.sup.++1).
EXAMPLE 15
1-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}9H-puri-
nyl]benzoic Acid Hydrochloride
An ethyl ester of Example 11 was dissolved in ethanol, a 1N aqueous
solution of sodium hydroxide was added and the mixture was stirred
at room temperature. After the reaction solution was concentrated,
the resulting residue was dissolved in small amount of water, the
solution was adjusted to pH 2 with 1N hydrochloric acid and the
resulting crystals were collected by filtration and washed with
water and ether to give the title compound.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.18-1.28 (m, 1H), 1.36-1.62 (m, 7H),
1.72-1.81 (m, 2H), 7.20-7.28 (m, 2H), 7.37-7.42 (m, 1H), 7.63-7.69
(m, 3H), 7.93-7.95 (m, 1H), 8.04-8.07 (m, 1H), FAB MASS; 472
(M.sup.++1).
EXAMPLE 16
4-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}-9H-9-p-
urinyl]benzoic Acid Hydrochloride
The title compound was obtained by the same manner as in Example
15.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.16-1.28 (m, 1H), 1.37-1.64 (m, 7H),
1.72-1.83 (m, 2H), 7.20-7.22 (m, 1H), 7.27-7.32 (m, 2H), 7.39-7.44
(m, 1H), .[.7.54 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H)..].
.Iadd.7.54 (d, J=8.4 Hz, 2H), 8.07(i d, J=8.4 Hz, 2H). .Iaddend.FAB
MASS; 472 (M.sup.++1).
EXAMPLE 17
3-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl}-9H-9-p-
urinyl]benzenecarboxamidine Dihydrochloride
A cyano compound of Example 1 was treated with MeAlClNH.sub.2 to
give the title compound.
NMR (400 MHz, .[..delta.,.]. .Iadd..delta.,.Iaddend.CD.sub.3OD);
1.34-1.47 (m, 1H), 1.60-1.86 (m, 7H), 2.00-2.11 (m, 2H), 7.26-7.34
(m, 1H), 7.36-7.52 (m, 3H), 7.62-7.67 (m, 1H), 7.78-7.84 (m, 1H),
8.02-8.08 (m, 1H), 8.13-8.17 (m, 1H), FAB MASS; 470
(M.sup.++1).
EXAMPLE 18
N.sup.2-Cyano-{3-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1--
ethynyl]-9H-9-purinyl}benzene}carboxamidine Dihydrochloride
3-[6-Chloro-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl] benzonitrile
obtained in the fourth step of Example 1 was treated with ammonia
to give
3-{6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl}benzonitrile.
This was treated with hydrogen sulfide to convert the cyano group
to thioamide and then alkylated with iodomethane to give a methyl
thioimidate. This was reacted with cyanamide to give
N.sup.2-cyano-{3-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]-benzene-
}carboxamidine. After that, like in the sixth step of Example 1,
the resulting compound was dissolved in dioxane, then
1-ethynylcyclohexanol, bis-triphenylphosphine palladium dichloride,
cuprous iodide and triethylamine were added thereto and the mixture
was reacted at room temperature in a nitrogen atmosphere to give
the title compound.
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CD.sub.3OD);
1.37-1.49 (m, 1H), 1.59-1.88 (m, 7H), 2.02-2.13 (m, 2H), 7.29-7.35
(m, 1H), 7.36-7.40 (m, 1H), 7.44-7.51 (m, 2H), .[.7.79 (t, J=8.1
Hz, 1H),.]. .Iadd.7.79 (t, J=8.1 Hz, 1H), .Iaddend.8.09-8.14 (m,
1H), 8.17-8.24 (m, 1H). FAB MASS; 495 (M.sup.++1).
EXAMPLE 19
1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclo-
pentanol Sulfate 1)
N.sup.1-(4-Chloro-6-methylamino-5-nitro-2-pyrimidinyl)acetamide
A mixed solution (reagent A) of 2 liters of a 40% aqueous solution
of methylamine and 1.5 liters of acetic acid previously prepared at
not higher than 10.degree. C. was weighed and taken out in an
amount of 1.8 liters and added dropwise into a solution of 1.5 kg
of N.sup.1-(4,6-dichloro-5-nitro-2-pyrimidinyl)acetamide in 15
liters of tetrahydrofuran with stirring under ice-cooling over 1
hour. The addition was carried out keeping the bulk temperature at
4.degree. C. or lower. After the mixture was stirred for 30 minutes
under ice-cooling, 450 ml of the reagent. A was further added.
After further 30 minutes, 450 ml of the reagent A was added again
followed by stirring for 40 minutes. Ice (4.5 kg) was added to the
reaction mixture followed by adding 10 liters of cold water. The
resulting crystals were collected by filtration and washed with 1
liter of water twice and with 1 liter of ether twice. Then it was
dried at 50.degree. C. for 6 hours to give 1253 g of
N.sup.1-(4-Chloro-6-methylamino-5-nitro-2-pyrimidinyl)acetamide.
The yield was 85%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.2.27 (s, 3H), .[.2.97 (d, J=4.4 Hz, 3H),
8.55 (d, J=4.4 Hz, 1H),.]. .Iadd.2.97 (d, J=4.4 Hz, 3H), 8.55(d,
J=4.4 Hz, 1H), .Iaddend.10.80 (s, 1H).
2) 6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinylamine
N.sup.1-(4-Chloro-6-methylamino-5-nitro-2-pyrimidinyl)acetamide
(2050 g) was suspended in 20 liters of methanol, 2 liters of acetic
acid were added and 2 kg of Raney nickel (used after washing with
water and methanol) were added and the mixture was stirred in
hydrogen for 12 hours. The reaction solution was diluted with 20
liters of tetrahydrofuran and filtered through Celite. The residue
was washed with methanol for three times (3.times.1 liter), then
washed with a mixed solvent of methanol and tetrahydrofuran (1:1)
and combined with the filtrate and the mixture was concentrated to
dryness. The resulting residue was subjected to an azeotropy with
toluene, the residue was dissolved in 20 liters of methanol, then
276 ml of acetic acid and 1 liter of 3-fluorobenzaldehyde were
added and the mixture was stirred at room temperature for 12 hours.
The reaction solution was concentrated and subjected to an
azeotropy with toluene. Concentrated residue was suspended in 17
liters of ethanol, 3 liters of ethanol solution of 1.5 kg of
anhydrous ferric chloride were added and the mixture was heated
under reflux for 1 hour. The reaction solution was returned to room
temperature and concentrated to dryness and the residue was diluted
with 12 liters of ethyl acetate followed by washing with 12 liters
of water and 4.5 liters of brine. The organic layer was
concentrated to dryness, the residue was dissolved in 10 liters of
tetrahydrofuran, 1.96 liters of a 1N hydrochloric acid were added
thereto and the mixture was heated under reflux for 30 minutes. The
reaction solution was cooled to room temperature, 10 kg of ice were
added and the mixture was further diluted with 10 liters of water.
The resulting crystals were collected by filtration and washed with
water twice (2.times.1 liter) and with ether twice (2.times.1
liter) to give 1.0 kg of
6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl-amine. The
overall yield was 47%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.73 (s, 3H), 7.01 (s, 2H), 7.40-7.46 (m,
1H), 7.60-7.66 (m, 1H), 7.68-7.74 (m, 2H).
3) 6-Chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine
6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinylamine (960 g) was
dissolved in 9.6 liters of tetrahydrofuran and then 774.3 g of
cuprous iodide and 1.49 liters of diodomethane were added thereto.
Isoamyl nitrite (1.49 liters) was added dropwise during 1 hour into
the mixture with heating under reflux. The reaction solution was
heated under reflux for 15 minutes, cooled, diluted with 4 liters
of ethyl acetate and then filtered through Celite followed by
washing with ethyl acetate three times (3.times.2 liters). The
filtrate and the washings were combined and washed with 8 liters of
water and 8 liters of brine. The organic layer was dried over 2 kg
of anhydrous sodium sulfate and concentrated to about 3 liters. The
concentrated solution was diluted with 10 liters of hexane and the
resulting crystals were filtered and washed with 1 liter of hexane.
The crystals were then dried at 50.degree. C. for 4 hours to give
1076 g of 6-chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine.
The yield was 75%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.89 (s, 3H), 7.49-7.56 (m, 1H), 7.66-7.72
(m, 1H), 7.76-7.82 (m, 2H).
4)
1-{2-[6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1--
cyclopentanol
6-Chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine (1076 g) was
dissolved in 10 liters of tetrahydrofuran and 97.2 g of
bistriphenylphosphine palladium dichloride, 26.4 g of cuprous
iodide and 248 g of 1-ethynylcyclopentanol were added thereto. Into
this mixture were added dropwise 331 ml of triethylamine within 15
minutes keeping the bulk temperature at not higher than 26.degree.
C. in a nitrogen atmosphere. After reacting at room temperature for
4 hours, the reaction solution was diluted with 10 liters of ethyl
acetate and washed with 4 liters of a saturated ammonium chloride
solution and 1 liter of brine. The organic layer was dried over 2
kg of anhydrous sodium sulfate and filtered followed by
concentrating to an extent of 3 liters. The resulting residue was
diluted with 4 liters of hexane-ethyl acetate (1:1), filtered and
washed with 1 liter of hexane to give 732 g of
1-{2-[6-chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyc-
lopentanol. The yield was 88%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.67-1.85 (m, 4H), 1.87-2.03 (m, 4H), 3.92
(s, 3H), 5.61 (s, 1H), 7.50-7.56 (m, 1H), 7.66-7.73 (m, 1H),
7.78-7.84 (m, 2H).
5)
1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclopentanol
1-{2-[6-Chloro-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl)-1-ethynyl}-1-cyc-
lopentanol (732 g) was dissolved in 16 liters of dimethoxyethane, 8
liters of a concentrated aqueous ammonia were added and the mixture
was stirred at 70.degree. C. for 5 hours using a sealed tube
reactor. After the reaction solution was cooled in room
temperature, it was diluted with 20 liters of ethyl acetate and
washed with water twice (8 liters and 4 liters). The organic layer
was concentrated to about 15 liters and the resulting residue was
diluted with 15 liters of hexane, filtered and washed with hexane
twice. Then it was dried at 50.degree. C. for 2.5 hours to give 620
g of the product. The yield was 89%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.62-1.78 (m, 4H), 1.79-1.95 (m, 4H), 3.78
(s, 3H), 5.41 (br s, 1H), 7.36-7.50 (m, 3H), 7.58-7.72 (m, 3H).
6)
1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl}-1-ethynyl]-1-c-
yclopentanol Sulfate
1-{2-(6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cycl-
opentanol (1.59 g) was suspended in 10 mL of methanol and 1 mL of a
methanol solution of 440 mg of concentrated sulfuric acid was added
dropwise thereinto at room temperature. The resulting solution was
evaporated until the amount of the solution became about one half
followed by adding 4 mL of ether thereto. The resulting crystals
were collected by filtration, washed with ether and dried to give
1.79 g of the sulfate.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.62-1.80 (m, 4H), 1.82-1.98 (m, 4H), 3.80
(s, 3H), 7.40-7.46 (m, 1H), 7.60-7.72 (m, 3H), 8.01-8.03 (m,
1H).
A hydrochloride was prepared by a conventional method.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.66-1.82 (m, 4H), 1.87-2.00 (m, 4H), 3.86
(s, 3H), 7.43-7.50 (m, 1H), 7.63-7.70 (m, 1H), 7.71-7.77 (m, 2H).
FAB MS; 352 (M.sup.++1); m.p.; 230-232.degree. C.
The compounds of Examples 20-68, 70-201, 203 and 205 were prepared
by the same manner as in Example 19 using the corresponding
materials.
EXAMPLE 20
4-[-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-3-butyn-1-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 2.58 (t, J=6.7 Hz, 2H),
3.59 (t, J=6.7 Hz, 2H), 3.88 (s, 3H), 6.77 (dd, J=1.7 Hz, 3.6 Hz,
1H), 7.25 (d, J=3.6 Hz, 1H), 8.00 (d, J=1.7 Hz, 1H)..].
.Iadd..delta., DMSO-d.sub.6); 2.58(t, J=6.7 Hz, 2H), 3.59(t, =6.7
Hz, 2H), 3.88(s, 3H), 6.77(dd, J=1.7 Hz, 3.6 Hz, 1H), 7.25(d, J=3.6
Hz, 1H), 8.00(d, J=1.7 Hz, 1H). .Iaddend.m.p.; 161-164.degree.
C.
EXAMPLE 21
8-(2-Furyl)-2-(1-hexynyl)-9-methyl-9H-6-purineamine
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 2.62 (t, J=6.7 2H), 3.79
(t, J=6.7 2H),.]. .Iadd.DMSO-d.sub.6); 2.62(t, J=6.72H), 3.79(t,
J=6.72H), .Iaddend.3.98 (s, 3H), 6.60 (m, 1H), 7.10 (m, 1H), 7.62
(m, 2H). m.p.; 178-181.degree. C.
EXAMPLE 22
N-[8-(2-Furyl)-9-methyl-2-(2-phenyl-1-thienyl)-9H-6-pyrinyl]-N-phenethylam-
ine Hydrochloride
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
3.10 (br, 2H), 4.12 (s, 3H), 3.98 (s, 3H), 4.19 (br, 1H), 4.38 (m,
2H), 6.68 (m, 1H), 6.72 (br, 1H), 7.20-7.53 (m, 9H). m.p.;
148-151.degree. C.
EXAMPLE 23
4-[6-Amino-8-(2-furyl)-9-methyl-9H-2-piurinyl]-3-butyn-2-ol
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.36 (d, J=7.5 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.36(d, J=7.5 Hz, 3H), .Iaddend.3.84
(s, 3H), 4.45-4.60 (m, 1H), .[.5.56 (d, J=7.5 Hz, 1H),.].
.Iadd.5.56 (d, J=7.5 Hz, 1H), .Iaddend.6.74 (m, 1H), .[.(7.20 (d,
J=3.5 Hz, 1H),.]. .Iadd.7.20 (d, J=3.5 Hz, 1H), .Iaddend.7.46 (s,
2H), 7.98 (s, 1H).
EXAMPLE 24
1-[6-Amino-8-(2-furyl)-9-ethyl-9H-2-purinyl]-4-methyl-1-pentyn-3-ol
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.96 (t, J=7.5 Hz, 6H),.].
.Iadd..delta., DMSO-d.sub.6); 0.96(t, J=7.5 Hz, 6H),
.Iaddend.1.76-1.86 (m, 1H), 3.84 (s, 3H), 4.20 (m, 1H), .[.5.52 (d,
J=7.5 Hz, 1H), 6.76 (dd, J=1.5 Hz, 3.7 Hz, 1H), 7.20 (d, J=3.7 Hz,
1H),.]. .Iadd.5.52 (d, J=7.5 Hz, 1H), 6.76(dd, J=1.5 Hz, 3.7 Hz,
1H), 7.20(d, J=3.7 Hz, 1H), .Iaddend.7.46 (br, 2H), 7.97 (m, 1H),
m.p.; 148-152.degree. C.
EXAMPLE 25
1-{2-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentano-
l Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.62-1.98 (m, 8H), 3.88 (s, 3H), 4.20 (m,
1H), .[.6.77 (dd, J=1.6 Hz, 3.5 Hz, 1H), 7.23 (d, J=3.5 Hz, 1H),
7.99 (d, J=1.6 Hz, 1H)..]. .Iadd.6.77 (dd, J=1.6 Hz, 3.5 Hz, 1H),
7.23(d, J=3.5 Hz, 1H), 7.99)d, J=1.6 Hz, 1H). .Iaddend.m.p.;
168-172.degree. C.
EXAMPLE 26
1-{2-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl-1-ethynyl}-1-cyclohexanol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.21-1.34 (m, 1H), 1.43-1.70 (m, 7H),
1.82-1.90 (m, 2H), 3.90 (s, 3H), 6.78-6.81 (m, 1H, 7.25-7.28 (m,
1H), 8.01-8.03 (m, 1H). FAB MS; 338 (M.sup.++1).
EXAMPLE 27
4-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn-2-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.48 (s, 6H), 3.90 (s, 3H), 6.78-6.81 (m,
1H), 7.22-7.28 (m, 1H), 8.00-8.03 (m, 1H). ESI MS; 298.1
(M.sup.++1).
EXAMPLE 28
1-{2-[6-Amino-8-(2-furyl)-9-phenyl-9H-2-purinyl]-1-ethynyl}-1cyclopentanol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.60-1.72 (m, 4H), 1.77-1.90 (m, 4H),
.[.6.04 (d, J=3.3 Hz, 1H), 6.53 (dd, J=1.9,3.3 Hz, 1H), 7.48-7.50
(m, 2H), 7.61-7.63 (m, 3H), 7.81 (d, J=1.9 Hz, 1H..]. .Iadd.6.04
(d, J=3.3 Hz, 1H), 6.53(dd, J=1.9,3.3 Hz, 1H)7.48-7.50(m, 2H),
7.61-7.63(m, 3H), 7.81(d, J=1.9 Hz, 1H). .Iaddend.FAB MS; 386
(M.sup.++1).
EXAMPLE 29
1-[6-Ethoxy-8-(2-furyl)-9-methyl-9H-2-purinyl]-4-methyl-1-pentyn-3-ol
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3;)
1.13 .[.((dd, J=6.8 and 1.6 Hz, 6H), 1.52 (t, J=7.1 Hz, 1H), 4.70
(q, J=7.1 Hz, 2H),.]. .Iadd.(dd, J=6.8 and 1.6 Hz, 6H), 1.52(t,
J=7.1 Hz, 1H), 4.70(q, J=7.1 Hz, 2H), .Iaddend.6.62-6.64 (m, 1H),
7.33-7.35 (m, 1H), 7.64-7.66 (m, 1H). FAB MS; 341 (M.sup.++1).
EXAMPLE 30
1-{2-6-Amino-9-methyl-8-phenyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.32 (m, 1H), 1.44-1.66 (m, 7H),
1.81-1.88 (m, 2H), 3.79 (s, 3H), 7.57-7.60 (m, 3H), 7.85-7.88 (m,
2H). FAB MS; 348 (M.sup.++1).
EXAMPLE 31
1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]1-ethynyl}-1-cycloh-
exanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.45-1.66 (m, 7H),
1.83-1.86 (m, 2H), 3.78 (s, 3H), 7.40-7.45 (m, 1H), 7.60-7.66 (m,
1H), 7.69-7.72 (m, 2H). FAB MS; 366. (M.sup.++1). m.p.;
230-232.degree. C.
EXAMPLE 32
1-{2-[6-Amino-9-methyl-8-(2-thienyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohexan-
ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.42-1.70 (m, 10H), 3.88 (s, 3H), 7.26-7.29
(m, 1H), 7.80-7.83 (m, 2H). m.p.; 171-175.degree. C.
EXAMPLE 33
2-(4-Cyclohexyl-1-butynyl)-8-(2-furyl)-9-methyl-9H-6-purinamine
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.82-0.96 (m, 2H), 1.08-1.24 (m, 3H),
1.30-1.50 (m, 3H), 1.58-1.76 (m, 5H), .[.2.48 (t, J=7.3 Hz, 2H),
3.88 (s, 3H), 6.78 (dd, J=1.8 Hz, 3.7 Hz, 1H), 7.25 (d, J=3.7,
1H),.]. .Iadd.2.48 (t, J=7.3 Hz, 2H), 3.88(s, 3H), 6.78(dd, J=1.8
Hz, 3.7 Hz, 1H), 7.25(d, J=3.7, 1H), .Iaddend.8.00 (m, 1H). m.p.;
165-169.degree. C.
EXAMPLE 34
1-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-4-methyl-1-pentyn-3-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.97 (t, J=6.8 Hz, 6H),.].
.Iadd..delta., DMSO-d.sub.6); 0.97(t, J=6.8 Hz, 6H),
.Iaddend.1.78-1.83 (m, 1H), 3.88 (s, 3H), .[.4.22 (d, J=6.4 Hz,
1H),.]. .Iadd.4.22 (d, J=6.4 Hz, 1H), .Iaddend.6.78-6.79 (m, 1H),
7.20-7.23 (m, 1H), 7.99 (s, 1H). FAB MS; 312 (M.sup.++1).
EXAMPLE 35
1-[2-(6-Amino-8-cyclohexyl-9-methyl-9H-2-purinyl)-1-ethynyl]-1-cyclohexano-
l Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 2H), 1.35-1.77 (m, 12H),
1.78-1.86 (m, 4H), 1.93-2.00 (m, 2H), 3.07-3.17 (m, 1H), 3.73 (s,
3H). FAB MS; 354 (M.sup.++1).
EXAMPLE 36
2-(2-Cyclohexyl-1-ethynyl)-8-(2-furyl)-9-methyl-9H-6-purinamine
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.24-1.88 (m, 8H), 2.60-2.74 (m, 1H), 3.88
(s, 3H), 6.78 (br, 1H), *.[.7.25 (d, J=3.3, 1H),.]. .Iadd.7.25 (d,
J=3.3, 1H), .Iaddend.8.00 (br, 1H). m.p.; 155-160.degree. C.
EXAMPLE 37
1-}2-[6-Amino-9-methyl-8-(2-pyridinyl)-9H-2-purinyl]-1-ethynyl}-1-cyclohex-
anol Dihydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.22-1.33 (m, 1H), 1.46-1.71 (m, 7H),
1.84-1.94 (m, 2H), 4.13 (s, 3H), 7.58-7.61 (m, 1H), 8.05-8.10 (m,
1H), 8.26-8.28 (m, 1H), 8.77-8.79 (m, 1H). FAB MS; 349
(M.sup.++1).
EXAMPLE 38
1-{2-[6-Amino-8-(4-chlorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclo-
hexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.19-1.30 (m, 1H), 1.42-1.65 (m, 7H),
1.80-1.88 (m, 2H), 3.77 (s, 3H), .[.7.64 (d, J=8.0 Hz, 2H), 7.88
(d, J=8.0 Hz, 2H)..]. .Iadd.7.64 (d, J=8.0 Hz, 2H), 7.88(d, J=8.0
Hz, 2H). .Iaddend.FAB MS; 382 (M.sup.++1) FAB.
EXAMPLE 39
1-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-3-isopropyl-4-methyl-1-penty-
n-3-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.96 (d, J=7.0 Hz, 6H),
1.01 (d, J=7.0 Hz, 6H),.]. .Iadd..delta., DMSO-d.sub.6); 0.96 (d,
J=7.0 Hz, 6H), 1.01(d, J=7.0Hz, 6H), .Iaddend.1.86-1.94 (m, 2H),
3.87 (s, 3H), 6.78-6.80 (m, 1H), 7.22-7.26 (m, 1H), 8.01 (s, 1H).
FAB MS; 354 (M.sup.++1).
EXAMPLE 40
1-[2-(6-Amino-9-benzo[b]furan-2-yl-9-methyl-9H-2-purinyl)-1-ethynyl]-1-cyc-
lohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.68 (m, 8H), 1.80-1.88 (m, 2H), 3.99
(s, 3H), 7.32-7.46 (m, 2H), 7.66-7.81 (m, 3H). FAB MS; 388
(M.sup.++1).
EXAMPLE 41
8-(2-Furyl)-9-methyl-2-[3-morpholino-1-propynyl)-9H-purinamine
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
2.70 (t, J=5.0 Hz,4H), 3.78 (t, J=5.0 Hz,4H),.]. .Iadd.2.70 (t,
J=5.0 Hz,4H), 3.78(t, J=5.0 Hz,4H), .Iaddend.3.79 (s, 2H), 4.02 (s,
3H), 5.99 (br s, 2H), 6.62-6.65 (m, 1H), 7.10-7.13 (m, 1H),
7.65-7.68 (m, 1H). FAB MS; 339 (M.sup.++1).
EXAMPLE 42
1-{2-[6-Amino-8-(3-fluorophenyl-4-methoxyphenyl)-9-methyl-9H-2-purinyl]-1--
ethynyl}-1-cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.42-1.68 (m, 7H),
1.80-1.88 (m, 2H), 3.79 (s, 3H), 3.92 (m, 3H), 7.34-7.39 (m, 1H),
7.66-7.76 (m, 2H). FAB MS; 396 (M.sup.++1).
EXAMPLE 43
2-(3-Amino-4-methyl-7-1-pentynyl)-8-(2-furyl)-9-methyl-9H-6-purinamine
Dihydrochloride
NMR (400 MHz; .[..delta., d.sub.6-DMSO); 1.05 (t, J=7.0 Hz, 6H),.].
.Iadd..delta., DMSO-d.sub.6); 1.05(t, J=7.0 Hz, 6H),
.Iaddend.2.12-2.20 (m, 1H), 3.88 (s, 3H), 4.25-4.30 (m, 1H),
6.78-6.80 (m, 1H), 7.22-7.24 (m, 1H), 8.00 (s, 1H), 8.72 (br s,
2H). FAB MS; 311 (M.sup.++1).
EXAMPLE 44
4-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-tetrahy-
dro-2H-4-pyranol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.66-1.75 (m, 2H), 1.83-1.92 (m, 2H),
3.54-3.59 (m, 2H), 3.74-3.79 (m, 2H), 3.79 (s, 3H), 7.39-7.43 (m,
1H), 7.60-7.72 (m, 3H). FAB MS; 368 (M.sup.++1).
EXAMPLE 45
Ethyl
3-{6-Amino-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9-methyl-9H-8-purin-
yl}benzoate Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), .[.1.33 (t, J=7.1 Hz,
3H),.]. .Iadd.1.33 (t, J=7.1 Hz, 3H), .Iaddend.1.44-1.68 (m, 7H),
1.82-1.89 (m, 2H), 3.82 (s, 3H), .[.4.35 (q, J=7.1 Hz, 2H), 7.74
(t, J=7.7 Hz, 1H), 8.12-8.17 (m, 2H), 8.44 (d, J=0.7 Hz, 1H)..].
.Iadd.4.35 (q, J=7.1 Hz, 2H), 7.74(t, J=7.7 Hz, 1H), 8.12-8.17(m,
2H), 8.44(d, J=0.7 Hz, 1H). .Iaddend.FAB MS; 420 (M.sup.++1).
EXAMPLE 46
2-(3,3-Diphenyl-1-butynyl)-8-(3-fluorophenyl)-9-methyl-9H-6-purinylamine
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.79 (s, 1H), 7.24-7.28 (m, 2H), 7.33-7.37
(m, 4H), 7.39-7.45 (m, 1H), 7.56-7.59 (m, 4H), 7.60-7.65 (m, 1H),
7.69-7.73 (m, 2H). FAB MS; 450 (M.sup.++1).
EXAMPLE 47
Ethyl
2-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]--
9H-9-purinyl}acetate
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.17-1.37 (m, 1H), .[.1.21 (t, J=7.1 Hz,
3H),.]. .Iadd.1.21 (t, J=7.1 Hz, 3H), .Iaddend.1.46-1.76 (m, 7H),
1.99-2.14 (m, 2H), 3.70 (br s, 2H), .[.4.19 (q, J=7.1 Hz, 2H),.].
.Iadd.4.19 (q, J=7.1 Hz, 2H), .Iaddend.4.99 (s, 2H), 6.43 (br s,
2H), 7.17-7.26 (m, 1H), 7.34-7.51 (m, 3H).
EXAMPLE 48
1-{2-[6-Amino-8-(3-fluorophenyl)-9-(2-methoxyethyl)-9H-9-2-purinyl]-1-ethy-
nyl}-1-cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.42-1.67 (m, 7H),
1.82-1.88 (m, 2H), 3.07 (s, 3H), .[.3.62 (t, J=5.3 Hz, 2H), 4.40
(t, J=5.3 Hz, 2H),.]. .Iadd.3.62 (t, J=5.3 Hz, 2H), 4.40(t, J=5.3
Hz, 2H), .Iaddend.7.40-7.46 (m, 1H), 7.59-7.65 (m, 1H), 7.68-7.74
(m, 2H). FAB M; 410 (M.sup.++1).
EXAMPLE 49
1-2-[6-Amino-8-(3-fluorophenyl)-9-(2-hydroxyethyl)-9H-2-purinyl]-1-ethynyl-
}-1-cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.21-1.32 (m, 1H), 1.42-1.68 (m, 7H),
1.81-1.89 (m, 2H), .[.3.73 (t, J=5.3 Hz, 2H), 4.28 (t, J=5.3 Hz,
2H),.]. .Iadd.3.73 (t, J=5.3 Hz, 2H), 4.28(t, J=5.3 Hz, 2H),
.Iaddend.7.40-7.45 (m, 1H), 7.59-7.65 (m, 1H), 7.73-7.79 (m, 2H).
FAB MS; 396 (M.sup.++1).
EXAMPLE 50
3-(6-Amino-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9-methyl-9H-8-purinyl}ben-
zonitrile Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.40-1.70 (m, 7H),
1.80-1.84 (m, 2H), 3.80 (s, 3H), .[.7.78 (t, J=7.8 Hz, 1H), 8.02
(d, J=7.8 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H),.]. .Iadd.7.78 (t, J=7.8
Hz, 1H), 8.02(d, J=7.8 Hz, 1H), 8.18(d, J=7.8 Hz, 1H),
.Iaddend.8.32 (s, 1H). FAB MS; 373 (M.sup.++1).
EXAMPLE 51
1-[2-[6-Amino-8-(3-chlorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclo-
hexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.42-1.64 (m, 7H),
1.80-1.89 (m, 2H), 3.79 (s, 3H), 7.54-7.60 (m, 2H), 7.82-7.85 (m,
1H), 7.92 (br, 1H). FAB MS; 382 (M.sup.++1). m.p.; 194-199.degree.
C.
EXAMPLE 52
1-{2-[6-Amino-9-methyl-8-[3-(trifluoromethyl)phenyl-9H-2-purinyl]-1-ethyny-
l}-1-cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.42-1.70 (m, 7H),
1.80-1.89 (m, 2H), 3.81 (s, 3H), .[.7.82 (t, J=11.0 Hz, 1H), 7.93
(d, J=11.0 Hz, 1H), 8.19 (d, J=11.0 Hz, 1H),.]. .Iadd.7.82 (t,
J=11.0 Hz, 1H), 7.93(d, J=11.0 Hz, 1H), 8.19(d, J=11.0 Hz, 1H),
.Iaddend.8.21 (s, 1H). FAB MS; 416 (M.sup.++1).
EXAMPLE 53
1-{2-[6-Amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.18-1.30 (m, 1H), 1.42-1.68 (m, 7H),
1.81-1.90 (m, 2H), 3.82 (s, 3H), 7.49-7.54 (m, 1H), 7.58-7.64 (m,
2H). FAB MS; 384 (M.sup.++1).
EXAMPLE 54
1-{2-[6-Amino-9-methyl-8-(3-methylphenyl)-9H-2-purinylp9
-1-ethynyl}-1-cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.08-1.31 (m, 1H), 1.42-1.71 (m, 7H),
1.82-1.92 (m, 2H), 2.40 (s, 3H), 3.81 (s, 3H), .[.7.41 (d, J=7.6
Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H),.].
.Iadd.7.41 (d, J=7.6 Hz, 1H), 7.48(t, J=7.6 Hz, 1H), 7.67(d, J=7.6
Hz, 1H), .Iaddend.7.69 (s, 1H). FAB MS; 362 (M.sup.++1).
EXAMPLE 55
1-{2-[6-Amino-8-(3-fluorophenyl)-9-(3-methoxyphenyl)-9H-2-purinyl]-1-ethyn-
yl}-1-cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.44-1.68 (m, 7H),
1.83-1.91 (m, 2H), 3.83 (s, 3H), 7.18-7.20 (m, 1H), 7.41-7.42 (m,
1H), 7.43-7.46 (m, 1H), 7.51-7.55 (m, 1H). FAB MS; 378
(M.sup.++1).
EXAMPLE 56
1-{2-[6-Amino-8-(4-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclo-
phexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.43-1.68 (m, 7H),
1.81-1.89 (m, 2H), 3.79 (s, 3H), 7.42-7.47 (m, 2H), 7.90-7.96 (m,
2H). FAB MS; 366 (M.sup.++1).
EXAMPLE 57
1-{2-[6-Amino-8-(3-dimethylamino)phenyl]-9-methyl-9H-2-purinyl}-1-ethynyl}-
-1-cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.18-1.30 (m, 1H), 1.42-1.70 (m, 7H),
1.80-1.92 (m, 2H), 3.05 (s, 6H), 3.85 (s, 3H), 7.32-7.70 (m, 4H).
FAB MS; 391 (M.sup.++1).
EXAMPLE 58
1-{2-Amino-9-cyclopentyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethylnyl}-1-cy-
clohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.40-1.64 (m, 9H),
1.80-1.84 (m, 2H), 1.90-2.04 (m, 4H), 2.26-2.38 (m, 2H), 4.60-4.74
(m, 1H), 7.40-7.50 (m, 3H), 7.58-7.64 (m, 1H). FAB MS; 420
(M.sup.++1). m.p.; 196-200.degree. C.
EXAMPLE 59
1-{2-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}1-cycloh-
exanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.32 (m, 1H), 1.42-1.66 (m, 7H),
1.80-1.86 (m, 2H), 3.58 (s, 3H), 7.39-7.48 (m, 2H), 7.63-7.72 (m,
2H). FAB MS; 366 (M.sup.++1). m.p.; 151-155.degree. C.
EXAMPLE 60
8-(3-Fluorophenyl)-9-methyl-2-[2-(3-pyridinyl)-1-ethynyl]-9H-6-purinamine
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.81 (s, 3H), 7.40-7.51 (m, 2H), 7.60-7.76
(m, 4H), .[.7.90 (dt, J=7.8.]. .Iadd.7.90 (dt, J=7.8.Iaddend.and
1.6 Hz, 1H), 8.64-8.67 (m, 1H). FAB MS; 345 (M.sup.++1).
EXAMPLE 61
3-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}phenyl
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.13 (s, 1H), 3.81 (s, 3H), 6.85-6.89 (m,
1H), 6.93-6.96 (m, 1H), 7.00-7.05 (m, 1H), .[.7.25 (t, J=8.0 Hz,
1H),.]. .Iadd.7.25 (t, J=8.0 Hz, 1H), .Iaddend.7.39-7.46 (m, 1H),
7.59-7.80 (m, 3H). FAB MS; 360 (M.sup.++1).
EXAMPLE 62
1-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-4-methyl-1-pentyl-3-o-
l Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.97 (dd, J=6.8 Hz, 7.7
Hz, 6H),.]. .Iadd..delta., DMSO-d.sub.6); 0.97(d, J=6.8 Hz, 7.7 Hz,
6H), .Iaddend.1.78-1.86 (m, 1H), 3.80 (s, 3H), .[.4.24 (dd, J=6.1
Hz, 1H),.]. .Iadd.4.24 (d, J=6.1 Hz, 1H), .Iaddend.7.40-7.45 (m,
1H), 7.60-7.66 (m, 1H), 7.69-8.30 (m, 2H). FAB MS; 340 (M.sup.++1).
m.p.; 170-173.degree. C.
EXAMPLE 63
1-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]1-pentyn-3-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.97 (t, J=7.5 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.97(t, J=7.5 Hz, 3H),
.Iaddend.1.62-1.70 (m, 1H), 3.80 (s, 3H), 7.40-7.45 (m, 1H),
7.60-7.66 (m, 1H), 7.69-7.76 (m, 2H). FAB MS; 326 (M.sup.++1).
EXAMPLE 64
4-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn-2-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.47 (s, 6H), 3.81 (s, 3H), 7.40-7.47 (m,
1H), 7.60-7.67 (m, 1H), 7.69-7.74 (m, 2H). FAB MS; 326 (M.sup.++1).
m.p.; 181-182.degree. C.
EXAMPLE 65
1-{2-[6-Amino-8-(3-fluorophenyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.40-1.70 (m, 7H),
1.82-1.94 (m, 2H), 5.70 (s, 1H), 7.42-7.50 (m, 1H), 7.60-7.70 (m,
1H), 8.00-8.14 (m,2H). FAB MS; 353 (M.sup.++1).
EXAMPLE 66
1-{2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclo-
hexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.70 (t, J=7.3 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.70(t, J=7.3 Hz, 3H),
.Iaddend.1.20-1.31 (m, 1H), 1.42-1.68 (m, 9H), 1.81-1.88 (m, 2H),
.[.4.22 (t, J=7.3 Hz, 3H),.]. .Iadd.4.22 (t, J=7.3 Hz, 3H),
.Iaddend.7.41-7.47 (m, 1H), 7.61-7.67 (m, 3H). FAB MS; 394
(M.sup.++1).
EXAMPLE 67
1-{2-[6-Amino-8-(3-fluorophenyl)-9-isopropyl-9H-2-purinyl]-1-ethynyl}-1-cy-
clohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.31 (m, 1H), 1.42-1.68 (m, 7H),
.[.1.59 (d, J=6.8 Hz, 6H), 1.82-1.91 (m, 2H), 4.61 (sept, J=6.8 Hz,
1H),.]. .Iadd.1.59 (d, J=6.8 Hz, 6H), 1.82-1.91(m, 2H), 4.61(sept,
J=6.8 Hz, 1H), .Iaddend.7.45-7.54 (m, 3H), 7.45-7.54 (m, 3H),
7.63-7.68 (m, 1H). FAB MS; 394 (M.sup.++1).
EXAMPLE 68
N.sup.1-Ethyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-e-
thynyl]-9H-9-purinyl]butaneamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.91 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.91(t, J=7.2 Hz, 3H),
.Iaddend.1.20-1.32 (m, 7H), 1.78-1.87 (m, 4H), .[.1.93 (t, J=7.1
Hz, 2H), 2.94 (dq, J=5.5, 7.2 Hz, 2H), 4.25 (t, J=7.1 Hz, 2H),.].
.Iadd.1.93 (t, J=7.1 Hz, 2H), 2.94(dq, J=5.5,7.2 Hz, 2H), 4.25(t,
J=7.1 Hz, 2H), .Iaddend.7.40-7.45 (m, 1H), 7.58-7.65 (m, 3H),
.[.7.72 (t, J=5.5 Hz, 1H)..]. .Iadd.7.72 (t, J=5.5 Hz, 1H).
.Iaddend.FAB MS; 465 (M.sup.++1).
EXAMPLE 69
N.sup.1-Ethyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-e-
thynyl]-9H-9-purinyl]propaneamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.90 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.90(t, J=7.2 Hz, 3H),
.Iaddend.1.18-1.33 (m, 1H), 1.42-1.68 (m, 7H), 1.80-1.88 (m, 2H),
.[.2.55 (t, J=7.5 Hz, 2H), 2.93 (dq, J=5.5, 7.2 Hz, 2H), 4.43 (t,
J=7.5 Hz, 2H),.]. .Iadd.2.55 (t, J=7.5 Hz, 2H), 2.93(dq, J=5.5,7.2
Hz, 2H), 4.43(t, J=7.5 Hz, 2H), .Iaddend.7.39-7.45 (m, 1H),
7.58-7.66 (m, 3H), .[.7.90 (t, J=5.5 Hz, 1H)..]. .Iadd.7.90 (t,
J=5.5 Hz, 1H). .Iaddend.FAB MS; 451 (M.sup.++1).
EXAMPLE 70
1-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purionyl]-3-isopropyl-4-methyl-
-1-pentyn-3-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.98 (d, J=6.8 Hz, 6H),
1.04 (d, J=6.8 Hz, 6H),.]. .Iadd..delta., DMSO-d.sub.6); 0.98(d,
J=6.8 Hz, 6H), 1.04(d, J=6.8 Hz, 6H), .Iaddend.1.87-1.97 (m, 2H),
3.83 (s, 3H), 7.41-7.48 (m, 1H), 7.62-7.70 (m, 1H), 7.71-7.77 (m,
2H). FAB MS; 382 (M.sup.++1).
EXAMPLE 71
N.sup.1-Isopropyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-1-hydroxycyclohexyl)--
1-ethynyl]-9H-9-purinyl}butaneamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.94 (d, J=7.6 Hz, 6H),.].
.Iadd..delta., DMSO-d.sub.6); 0.94(d, J=7.6 Hz, 6H),
.Iaddend.1.20-1.32 (m, 1H), 1.41-1.68 (m, 7H), 1.78-1.88 (m, 4H),
.[.1.92 (t, J=7.1 Hz, 2H), 3.64-3.74 (m, 1H), 4.25 (t, J=7.6 Hz,
2H),.]. .Iadd.1.92 (t, J=7.1Hz, 2H), 3.64-3.74(m, 1H), 4.25(t,
J=7.6 Hz, 2H), .Iaddend.7.40-7.46 (m, 1H), 7.58-7.65 (m, 3H). FAB
MS; 479 (M.sup.++1).
EXAMPLE 72
N.sup.1-Ethyl-2-{6-amino-8-(3-fluorophenyl-2-[2-(1-hydroxycyclohexyl)-1-et-
hynyl]-9H-9-purinyl}butaneamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.98 (d, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.98(t, J=7.2 Hz, 3H),
.Iaddend.1.18-1.30 (m, 1H), 1.40-1.68 (m, 7H), .[.1.65 (t, J=7.3
Hz, 3H), 1.78-1.88 (m, 2H), 3.08 (dq, J=5.3, 7.2 Hz, 2H), 5.08 (q,
J=7.3 Hz, 1H),.]. .Iadd.1.65 (t, J=7.3 Hz, 3H), 1.78-1.88(m, 2H),
3.08(dq, J=5.3,7.2 Hz, 2H), 5.08(q, J=7.3 Hz, 1H),
.Iaddend.7.39-7.48 (m, 3H), 7.58-7.63 (m, 1H), .[.8.05 (t, J=5.3
Hz, 1H)..]. .Iadd.8.05 (t, J=5.3 Hz, 1H). .Iaddend.FAB MS; 451
(M.sup.++1).
EXAMPLE 73
1-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.00 (t, J=7.2 Hz, 6H),.].
.Iadd..delta., DMSO-d.sub.6); 1.00(t, J=7.2 Hz, 6H),
.Iaddend.1.61-1.71 (m, 4H), 3.81 (s, 3H), 7.40-7.44 (m,1H),
7.61-7.67 (m, 1H), 7.69-7.74 (m, 2H). FAB MS; 354 (M.sup.++1).
EXAMPLE 74
N.sup.1-Ethyl-2-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-e-
thynyl]-9H-9-purinyl]-2-phenylacetamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.00 (t, J=7.1 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.00(t, J=7.1 Hz, 3H),
.Iaddend.1.19-1.30 (m, 1H), 1.40-1.68 (m, 7H), 1.78-1.88 (m, 2H),
3.09-3.20 (m, 2H), 6.47 (s, 1H), 7.00-7.04 (m, 2H), 7.13-7.24 (m,
6H), 7.29-7.35 (m, 1H), .[.8.39 (t, J=5.4 Hz, 1H)..]. .Iadd.8.39
(t, J=5.4 Hz, 1H). .Iaddend.FAB MS; 513 (M.sup.++1).
EXAMPLE 75
8-(3-Fluorophenyl)-2-(3-methoxy-3-methyl-1-butynyl)-9-methyl-9H-6-purinami-
ne Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.50 (s, 6H), 3.34 (s, 3H), 3.83 (s, 3H),
7.41-7.48 (m, 1H), 7.60-7.68 (m, 1H), 7.70-7.76 (m, 2H). FAB MS;
340 (M.sup.++1).
EXAMPLE 76
N-{3-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1,1-dimethyl-2-pro-
pynyl}-N'-ethylurea Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.25 (t, J=7.0 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.25(t, J=7.0 Hz, 3H), .Iaddend.1.68
(s, 6H), .[.3.46 (q, J=7.0 Hz, 2H),.]. .Iadd.3.46 (q, J=7.0 Hz,
2H), .Iaddend.3.98 (s, 3H), 6.32 (s, 1H), 7.45-7.52 (m, 1H),
7.64-7.83 (m, 2H). FAB MS; 396 (M.sup.++1).
EXAMPLE 77
1-{2-(6-Amino-8-(3-fluorophenyl)-9-isobutyl-9H-2-purinyl]-1-ethynyl}-1-cyc-
lohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.63 (d, J=6.6 Hz, 6H),.].
.Iadd..delta., DMSO-d.sub.6); 0.63(d, J=6.6 Hz, 6H),
.Iaddend.1.19-1.33 (m, 1H), 1.40-1.67 (m, 9H), 1.79-1.91 (m, 3H),
.[.4.13 (t, J=7.5 Hz, 2H),.]. .Iadd.4.13 (t, J=7.5 Hz, 2H),
.Iaddend.7.38-7.45 (m, 1H), 7.58-7.68 (m, 3H). FAB MS; 408
(M.sup.++1).
EXAMPLE 78
2-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1ethynyl]-9H-9-pu-
rinyl}ethyloxy N-Ethyl-carbamate Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.86 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.86(t, J=7.2 Hz, 3H),
.Iaddend.1.19-1.32 (m, 1H), 1.41-1.70 (m, 7H), 1.80-1.92 (m, 2H),
.[.2.80 (dq, J=5.5, 7.2 Hz, 2H), 4.19 (t, J=5.7 Hz, 2H). 4.44-4.52
(m, 2H), 6.96 (t, J=5.5 Hz, 1H),.]. .Iadd.2.80 (dq, J=5.5,7.2 Hz,
2H), 4.19 (t, J=5.7 Hz, 2H), 4.44-4.52(m, 2H), 6.96(t, J=5.5Hz,
1H), .Iaddend.7.40-7.48 (m, 1H), 7.58-7.66 (m, 3H). FAB MS; 467
(M.sup.++1).
EXAMPLE 79
1-{2-[6-Amiono-8-(3-fluorophenyl)-9-phenethyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.25-1.72 (m, 8H), 1.87-1.90 (m, 2H),
.[.2.97 (t, J=6.0 Hz, 2H), 4.52 (t, J=6.0 Hz, 2H),.]. .Iadd.2.97
(t, J=6.0 Hz, 2H), 4.52(t, J=6.0 Hz, 2H), .Iaddend.6.81-6.85 (m,
2H), 7.10-7.21 (m, 4H). FAB MS; 456 (M.sup.++1).
EXAMPLE 80
N.sup.1-Ethyl-3-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-e-
thynyl}-9H-9-purinyl]-1-propanesulfonamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.93-1.00 (m, 3H), 1.19-1.32 (m, 1H),
1.40-1.68 (m, 7H), 1.77-1.90 (m, 2H), 1.95-2.14 (m, 2H), 2.75-2.87
(m, 2H), 2.90-2.98 (m, 2H), 4.35-4.42 (m, 2H), 6.94-7.02 (m, 1H),
7.40-7.48 (m, 1H), 7.58-7.78 (m, 3H). FAB MS; 501 (M.sup.++1).
EXAMPLE 81
1-{2-[6-Amino-8-(3-fluorophenyl)-9-(2-hydroxypropyl)-9H-2-purinyl]-1-ethyn-
yl}-1-cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.00-1.10 (m, 3H), 1.18-1.33 (m, 1H),
1.40-1.70 (m, 7H), 1.78-1.90 (m, 2H), 4.00-4.12 (m, 2H), 4.12-4.21
(m, 1H), 7.36-7.43 (m,1H), 7.56-7.63 (m, 1H), 7.71-7.80 (m, 2H).
FAB MS; 410 (M.sup.++1).
EXAMPLE 82
1-{2-[6-Amino-9-(2-butynyl)-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1--
cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.68 (m, 8H), .[.1.75 (t, J=2.0 Hz,
3H), 1.80-1.88 (m, 2H), 5.00 (q, J=2.0 Hz, 2H),.]. .Iadd.1.75 (t,
J=2.0 Hz, 3H), 1.80-1.88(m, 2H), 5.00(q, J=2.0 Hz, 2H),
.Iaddend.7.40-7.45 (m, 1H), 7.62-7.78 (m, 3H). FAB MS; 404
(M.sup.++1).
EXAMPLE 83
1-{2-[6-Amino-8-(3-fluorophenyl)-9-(3-morpholinopropyl)-9H-2-purinyl]-1-et-
hynyl}-1-cyclohexanol Dihydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.19-1.29 (m, 1H), 1.40-1.64 (m, 7H),
1.79-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.84-3.08 (m, 4H), 3.23-3.34
(m, 2H), 3.65-3.78 (m, 2H), 3.82-3.92 (m, 2H), 4.28-4.36 (m, 2H),
7.42-7.48 (m, 1H), 7.60-7.68 (m, 3H). FAB MS; 479 (M.sup.++1).
EXAMPLE 84
1-{3-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl-9H-9-
-purinyl}propyl}2-pyrrolidinone Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.22-1.34 (m, 1H), 1.44-1.72 (m, 7H),
1.78-1.93 (m, 6H), .[.2.14 (t, J=8.0 Hz, 2H), 3.08 (t, J=7.0 Hz,
2H), 3.19 ) t, J=7.0 Hz, 2H), 4.22 (t, J=7.0 Hz, 2H),.]. .Iadd.2.14
(t, J=8.0 Hz, 2H), 3.08(t, J=7.0 Hz, 2H), 3.19(t, J=7.0 Hz, 2H),
4.22(t, J=7.0 Hz, 2H), .Iaddend.7.44-7.50 (m, 1H), 7.59-7.70 (m,
3H). FAB MS; 477 (M.sup.++1).
EXAMPLE 85
1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-cyclope-
ntanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.44-1.66 (m, 8H), 1.76-1.84 (m, 2H),
1.94-2.02 (m, 2H), 3.80 (s, 3H), 7.38-7.44 (m, 1H), 7.58-7.66 (m,
1H), 7.64-7.44 (m, 2H). FAB MS; 380 (M.sup.++1).
EXAMPLE 86
N.sup.1-Cyclopropyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexy-
l)-1-ethynyl]-9H-9-purinyl]butaneamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.25-0.30 (m, 2H), 0.50-0.56 (m, 2H),
1.20-1.34 (m, 1H), 1.40-1.70 (m, 7H), 1.78-1.94 (m, 6H), 2.43-2.54
(m, 1H), .[.4.26 (t, J=7.0 Hz, 2H),.]. .Iadd.4.26 (t, J=7.0 Hz,
2H), .Iaddend.7.41-7.47 (m, 1H), 7.60-7.68 (m, 3H), .[.7.81 (d,
J=4.4 Hz, 1H)..]. .Iadd.7.81 (d, J=4.4 Hz, 1H). .Iaddend.FAB MS;
477 (M.sup.++1).
EXAMPLE 87
1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-ethynyl}-4-methyl--
1-cyclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.89 (d, J=6.0 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.89(d, J=6.0 Hz, 3H),
.Iaddend.1.25-1.53 (m, 5H), 1.63-1.74 (m, 2H), 1.89-1.98 (m, 2H),
3.82 (s, 3H), 7.42-7.48 (m, 1H), 5.62-7.80 (m, 3H). FAB MS; 380
(M.sup.++1).
EXAMPLE 88
1-{9-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]-1,4-cyc-
lohexanediol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.58-1.60 (m, 4H), 1.73-1.79 (m, 2H),
1.93-1.99 (m, 2H), 3.14 (s, 1H), 3.47-3.53 (m, 1H), 3.83 (s, 3H),
7.41-7.47 (m, 1H), 7.62-7.73 (m, 3H). FAB MS; 382 (M.sup.++1).
EXAMPLE 89
1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclo-
butanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.74-1.85 (m, 2H), 2.16-2.27 (m, 2H),
2.34-2.43 (m, 2H), 3.81 (s, 3H), 7.39-7.47 (m, 1H), 7.56-7.77 (m,
3H). ESI MS; 338.0 (M.sup.++1). m.p.; 198-199.degree. C.
EXAMPLE 90
1-{2-[6-Amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.64-1.79 (m, 4H), 1.84-1.97 (m, 4H), 3.82
(s, 3H), 7.48-7.54 (m, 1H), 7.57-7.64 (m, 2H). FAB MS; 370
(M.sup.++1). m.p.; 255-258.degree. C.
EXAMPLE 91
1-{2-{6-Amino-9-methyl-8-[3-(trifluoromethyl)phenyl]-9H-2-purinyl}-1-ethyn-
yl}-1-cyclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.62-1.78 (m, 4H), 1.82-1.96 (m, 4H), 3.81
(s, 3H), 7.79-7.85 (m, 1H), 7.91-7.95 (m, 1H), 8.17-8.21 (m, 2H).
FAB MS; 402 (M.sup.++1).
EXAMPLE 92
1-{2-[6-Amino-8-(3-fluorophenyl-9-(2-hydroxyethyl)-9H-2-purinyl]-1-ethynyl-
}-1-cyclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.72-1.80 (m, 4H), 1.84-1.98 (m, 4H),
.[.3.73 (t, J=5.6 Hz, 2H), 4.27 (t, J=5.6 Hz, 2H),.]. .Iadd.3.73
(t, J=5.6 Hz, 2H), 4.27(t, J=5.6 Hz, 2H), .Iaddend.7.38-7.45 (m,
1H), 7.58-7.64 (m, 1H), 7.71-7.80 (m, 2H). FAB MS; 382
(M.sup.++1).
EXAMPLE 93
1-{2-[6-Amino-8-(2,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.56-1.77 (m, 4H), 1.77-1.95 (m, 4H), 3.60
(s, 3H), 7.45-7.63 (m, 3H). ESI MS; 370 (M.sup.++1).
EXAMPLE 94
1-{2[6-Amino-8-(2,3-difluorophenyl)-9-methyl-9H-2-purinyl}-1-ethynyl}-1-cy-
clopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.64-1.79 (m, 4H), 1.83-1.96 (m, 4H), 3.63
(s, 3H), 7.40-7.45 (m, 1H), 7.52-7.56 (m, 1H), 7.66-7.74 (m, 1H).
FAB MS; 371 (M.sup.++1).
EXAMPLE 95
3-[6-Amino-2-[2-(1-hydroxycyclopenyl)-1-ethynyl]-9-methyl-9H-8-purinyl]phe-
nol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.63-1.79 (m, 4H), 1.83-1.97 (m, 4H), 3.76
(s, 3H), 6.94-6.98 (m, 1H), 7.21-7.27 (m, 2H), .[.7.37 (t, J=7.9
Hz, 1H)..]. .Iadd.7.37 (t, J=7.9 Hz, 1H). .Iaddend.FAB MS; 350
(M.sup.++1).
EXAMPLE 96
1-{2-[6-Dimethylamino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-
-1-cyclopentanol
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
1.76-1.97 (m, 4H), 2.03-2.13 (m, 2H), 2.13-2.22 (m, 2H), 2.22 (s,
1H), 3.58 (br s, 6H), 3.88 (s, 3H), 7.17-7.23 (m, 1H), 7.46-7.57
(m, 3H).
EXAMPLE 97
1-{2-[8-(3-Fluorophenyl)-9-methyl-6-methylamino-9H-2-purinyl]-1-ethynyl}-1-
-cyclopentanol
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
1.72-1.96 (m, 4H), 2.02-2.12 (m, 2H), 2.14-2.22 (m, 2H), 2.26 (s,
1H), 3.25 (br s, 3H), 3.89 (s, 3H), 5.87 (br s, 1H), 7.20-7.25 (m,
1H), 7.44-7.56 (m, 3H).
EXAMPLE 98
1-{2-[6-Benzylamino-8-(3-fluorophenyl)-9-methyl-9H-purinyl]-1-ethynyl}-1-c-
yclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.64-1.80 (m, 4H), 1.86-1.97 (m, 4H), 3.81
(s, 3H), 4.72 (br s, 2H), 7.20-7.25 (m, 1H), 7.28-7.37 (m, 4H),
7.39-7.45 (m, 1H), 7.60-7.66 (m, 1H), 7.68-7.75 (m, 2H), 8.53 (br
s, 1H).
EXAMPLE 99
1-{2-[8-(3-Fluorophenyl)-6-[(2-hydroxyethyl)amino]-9-methyl-9H-2-purinyl]--
1-ethynyl}-1-cyclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.65-1.82 (m, 4H), 1.84-2.02 (m, 4H), 3.59
(br s,4H), 3.82 (s, 3H), 7.41-7.47 (m, 1H), 7.61-7.67 (m, 1H),
7.70-7.76 (m, 2H), 7.98 (br s, 1H).
EXAMPLE 100
1-{2-[6-Cyclopentylamino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethyn-
yl}-1-cyclopentanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.50-1.64 (m, 4H), 1.65-1.81 (m, 6H),
1.82-2.00 (m, 6H), 3.80 (s, 3H), 4.55 (br s, 1H), 7.40-7.46 (m,
1H), 7.61-7.67 (m, 1H), 7.70-7.75 (m, 2H), 8.06 (br s, 1H).
EXAMPLE 101
3-{6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclopentyl)-1-ethynyl]-9H-9--
purinyl}-1,2-propanediol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.60-1.80 (m, 4H), 1.82-1.98 (m, 4H),
3.30-3.40 (m, 2H), 3.80-4.00 (m, 1H), .[.4.13 (dd, J=9.6,14.5 Hz,
1H), 4.32 (dd, J=3.5,14.5 Hz, 1H),.]. .Iadd.4.13 (dd, J=9.6,14.5
Hz, 1H), 4.32(dd, J=3.5,14.5 Hz, 1H), .Iaddend.7.37-7.44 (m, 1H),
7.56-7.64 (m, 1H), 7.74-7.86 (m, 2H). FAB MS; 412 (M.sup.++1).
EXAMPLE 102
4-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-methy-
l-4-piperidinol Dihydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.2.04-2.30 (m, 4H), 2.72 and .[.2.81
(d.times.2,J=6.0 Hz, 3H),.]. .Iadd.2.81 (d.times.2,J=6.0 Hz, 3H),
.Iaddend.3.05 3.49 (m, 4H), 3.80 and 3.82 (s.times.2,3H), 7.39-7.47
(m, 1H), 7.59-7.74 (m, 3H). FAB MS; 381 (M.sup.++1).
EXAMPLE 103
1-{4-[2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]4-hyd-
roxypiperidino}-1-ethanone Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.50 and 1.93 (m, 4H), 1.97-2.00
(s.times.2,3H), 3.14 and 3.79 (s.times.2, 3H), 3.25-3.69 (m, 4H),
7.39-7.45 (m, 1H), 7.59-7.72 (m, 3H). FAB MS; 409 (M.sup.++1).
EXAMPLE 104
4-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-4-piper-
idinol Dihydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.95-2.18 (m, 4H), 3.02-3.20 (m, 4H), 3.80
(s, 3H), 7.38-7.46 (m, 1H), 7.58-7.76 (m, 3H). FAB MS; 449
(M.sup.++1).
EXAMPLE 105
2-{6-Amino-2-[2-(1-hydroxycyclopentyl)-1-ethynyl]-9-methyl-9H-8-purinyl}-6-
-fluorophenol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.60-1.80 (m, 4H), 1.80-1.95 (m, 4H),
3.66-3.73 (m, 3H), 6.94-7.03 (m, 1H), 7.35-7.47 (m, 2H). FAB MS;
368 (M.sup.++1).
EXAMPLE 106
3-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-phenyl-2-propyn-1-o-
l
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.77 (s, 3H), .[.5.60 (d, J=6.0 Hz, 1H),
6.26 (d, J=6.0 Hz, 1H),.]. .Iadd.5.60 (d, J=6.0 Hz, 1H), 6.26(d,
J=6.0 Hz, 1H), .Iaddend.7.29-7.33 (m, 1H), 7.36-7.43 (m, 3H), 7.47
(br s, 2H), 7.50-7.53 (m, 2H), 7.58-7.64 (m, 1H), 7.66-7.71 (m,
2H). FAB MS; 374 (M.sup.++1).
EXAMPLE 107
1-{2-[6-Amino-8-(3-fluoro-2-methylphenyl)-9-methyl-9H-2-purinyl]1-ethynyl}-
-1-cyclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.62-1.79 (m, 4H), 1.83-1.96 (m, 4H),
.[.2.13 (d, J=2.0 Hz, 3H),.]. .Iadd.2.13 (d, J=2.0 Hz, 3H),
.Iaddend.3.50 (s, 3H), 7.33-7.42 (m, 3H). FAB MS; 366
(M.sup.++1).
EXAMPLE 108
1-{2-[6-Amino-9-methyl-8-(1,3-thiazol-2-yl)-9H-2-purinyl]-1-ethynyl}-cyclo-
pentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.61-1.78 (m, 4H), 1.81-1.97 (m, 4H), 4.09
(s, 3H), .[.7.99 (d, J=3.2 Hz, 1H), 8.11 (d, J=3.2 Hz, 1H)..].
.Iadd.7.99 (d, J=3.2 Hz, 1H), 8.11(d, J=3.2 Hz, 1H). .Iaddend.FAB
MS; 341 (M.sup.++1).
EXAMPLE 109
N.sup.1-Ethyl-(1R,3R)-3-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclope-
ntyl)-1-ethynyl]9H-9-purinyl}cyclopentanone-1-carboxamide
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.01 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.01(t, J=7.2 Hz, 3H),
.Iaddend.1.64-2.22 (m, 12H), 2.44-2.68 (m, 2H), .[.3.08 (dq, J=2.7,
7.2 Hz, 2H),1.THETA. .Iaddend..Iadd.3.08 (dq, J=2.6, 7.2 Hz, 2H),
.Iaddend.4.60-4.71 (m, 1H), 7.43-7.49 (m, 1H), 7.50-7.55 (m, 2H),
7.61-7.68 (m, 1H), .[.7.83 (t, J=2.6 Hz, 1H)..]. .Iadd.7.83 (t,
J=2.6 Hz, 1H). .Iaddend.
EXAMPLE 110
1-{2-[6-Amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purionyl]-1-ethynyl}-1--
cyclobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.76-1.86 (m, 2H), 2.20-2.32 (m, 2H),
2.36-2.46 (m, 2H), 3.85 (s, 3H), 7.46-7.55 (m, 1H), 7.56-7.67 (m,
2H). FAB MS; 356 (M.sup.++1).
EXAMPLE 111
1-{2-[-6-Amino-9-cyclopropyl-8-(3-fluorophenyl-9H-2-purinyl]-1-ethynyl}-1--
cyclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.67-0.72 (m, 2H), 1.01-1.07 (m, 2H),
1.62-1.80 (m, 4H), 1.84-1.97 (m, 4H), 3.65-3.73 (m, 1H), 7.36-7.42
(m, 1H), 7.75-7.81 (m, 2H). FAB MS; 378 (M.sup.++1).
EXAMPLE 112
8-(3-Fluorophenyl)-9-methyl-2-(3-phenyl-1-propynyl)-9H-6-purinamine
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.79 (s, 3H), 3.91 (s, 2H), 7.24-7.29 (m,
1H), 7.34-7.44 (m, 5H), 7.59-7.65 (m, 1H), 7.67-7.72 (m, 2H). FAB
MS; 358 (M.sup.++1).
EXAMPLE 113
1-{2-[8-(3,5-Difluorophenyl)-9-methyl-6-(phenethylamino)-9H-2-purinyl]-1-e-
thynyl}-1-cyclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.60-1.78 (m, 4H), 1.78-1.98 (m, 4H),
.[.2.93 (t, J=7.2 Hz, 2H),.]. .Iadd.2.93 (t, J=7.2 Hz, 2H),
.Iaddend.3.60-3.75 (m, 2H), 3.80 (s, 3H), 7.14-7.21 (m, 1H),
7.22-7.32 (m, 4H), 7.44-7.52 (m, 1H), 7.54-7.64 (m, 2H), 8.05-8.12
(m, 1H). FAB MS; 474 (M.sup.++1).
EXAMPLE 114
1-{2-[8-(3,5-Difluorophenyl)-9-methyl-6-methylamino-9H-2-purinyl]-1-ethyny-
l}-1-cyclopentanol
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
1.75-1.94 (m 4H), 2.03-2.12 (m, 2H), 2.12-2.22 (m, 2H), 3.25 (br s,
3H), 3.90 (s, 3H), 5.82 (br s, 1H), 6.95-7.00 (m, 1H), 7.29-7.36
(m, 2H).
EXAMPLE 115
1-{2-[6-Ethylamino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1--
cyclopentanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.19 (d, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.19(t, J=7.2 Hz, 3H),
.Iaddend.1.65-1.81 (m, 4H), 1.84-1.98 (m, 4H), 3.50 (br s, 2H),
3.80 (s, 3H), 5.44 (s, 1H), 7.38-7.45 (m, 1H), 7.59-7.66 (m, 1H),
7.67-7.73 (m, 2H), 7.95 (br s, 1H). FAB MS; 380 (M.sup.++1).
EXAMPLE 116
1-{2-[8-(3-Fluorophenyl)-9-methyl-6-propylamino-9H-2-purinyl]-1-ethynyl}-1-
-cyclopentanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.91 (t, J=7.2 Hz, 3H),
1.62 (sex, J=7.2 Hz, 2H),.]. .Iadd..delta., DMSO-d.sub.6); 0.91(t,
J=7.2 Hz, 3H), 1.62(sex, J=7.2 Hz, 2H), .Iaddend.1.66-1.81 (m, 4H),
1.84-2.00 (m, 4H), 3.43 (br s, 2H), 3.80 (s, 3H), 5.44 (s, 1H),
7.38-7.45 (m, 1H), 7.59-7.67 (m, 1H), 7.68-7.74 (m, 2H), 7.91-7.98
(m, 1H). FAB MS; 394 (M.sup.++1).
EXAMPLE 117
1-{2-[8-(3-Fluorophenyl)-6-isobutylamino-9-methyl-9H-2-purinyl]-1-ethynyl}-
-1-cyclopentanol
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
.[.1.02 (d, J=6.8 Hz, 6H),.]. .Iadd.1.02 (d, J=6.8 Hz, 6H),
.Iaddend.1.68-1.92 (m, 4H), .[.1.97 (sept, J=6.8 Hz, 6H),.].
.Iadd.1.97 (sept, J=6.8 Hz, 6H), .Iaddend.2.02-2.22 (m, 4H), 3.51
(br s, 2H), 3.88 (s, 3H), 5.89 (br s, 1H), 7.18-7.25 (m, 1H),
7.45-7.57 (m, 1H), 7.45-7.57 (m, 3H). FAB MS; 408 (M.sup.++1).
EXAMPLE 118
1-[2-(6-Amino-9-methyl-8-phenyl-9H-2-purinyl)-1-ethynyl]-1-cyclopentanol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.66-1.83 (m, 4H), 1.87-2.00 (m, 4H), 3.83
(s, 3H), 7.59-7.65 (m, 3H), 7.86-7.92 (m, 2H). FAB MS; 334
(M.sup.++1).
EXAMPLE 119
3-[6-Amino)-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-propyn-1-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.79 (s, 3H), 4.30 (s, 2H), 7.38-7.44 (m,
1H), 7.59-7.65 (m, 1H), 7.66-7.72 (m, 2H).
EXAMPLE 120
1-{2-[6-
Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl}-1-ethynyl]-2-meth-
oxy-1-cyclohexanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.13-2.00 (m, 8H), .[.3.07 (d, J=9.6,4.0
Hz, 1H),.]. .Iadd.3.07 (d, J=9.6,4.0 Hz, 1H), .Iaddend.3.39 (s,
3H), 3.80 (s, 3H), 5.69 (s, 1H), 7.39-7.45 (m, 1H), 7.48 (br s,
2H), 7.60-7.75 (m, 3H). ESI MS; 396 (M.sup.++1). m.p.;
281-283.degree. C.
EXAMPLE 121
1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-2-metho-
xy-1-cyclohexanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.12-1.92 (m, 8H), 3.20-3.25 (m, 1H), 3.40
(s, 3H), 3.80 (s, 3H), 5.33 (s, 1H), 7.38-7.45 (m, 1H), 7.48 (br s,
2H), 7.60-7.74 (m, 3H). ESI MS; 396 (M.sup.++1). m.p.;
195-197.degree. C.
EXAMPLE 122
1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-2-cyclo-
penten-1-ol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.2.00-2.12 (m, 1H), 2.30-2.38 (m, 3H), 3.79
(s, 3H), 3.80 (s, 3H), 5.78 (s, 1H), 5.80-5.84 (m, 1H), 5.94-5.98
(m, 1H), 7.39-7.46 (m, 1H), 7.47 (br s, 2H), 7.59-7.74 (m, 3H). ESI
MS; 350 (M.sup.++1). m.p.; 191-193.degree. C.
EXAMPLE 123
1-{2-[6-Amino-8-(2,5-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.74-1.88 (m, 2H), 2.18-2.30 (m, 2H),
2.36-2.45 (m, 2H), 3.65 (m, 3H), 7.53-7.59 (m, 2H), 7.60-7.65 (m,
1H). FAB MS; 356 (M.sup.++1). m.p.; 149-152.degree. C.
EXAMPLE 124
1-[6-Amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-3-ethyl-1-pentyn--
3-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.01 (t, J=7.2 Hz, 6H),.].
.Iadd..delta., DMSO-d.sub.6); 1.01(t, J=7.2 Hz, 6H),
.Iaddend.1.61-1.75 (m, 4H), 3.85 (s, 3H), 7.51-7.57 (m, 1H),
7.60-7.67 (m, 2H). ESI MS; 372 (M.sup.++1). m.p.; 207-210.degree.
C.
EXAMPLE 125
1-{2-[6-Amino-9-methyl-8-(2,3,5-trifluorophenyl)-9H-2-purinyl]-1-ethynyl}--
1-cyclopentanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.65-1.82 (m, 4H), 1.83-1.98 (m, 4H), 3.65
(m, 3H), 5.44 (s, 1H), 7.50-7.60 (m, 3H), 7.81-7.90 (m, 1H). ESI
MS; 388 (M.sup.++1). m.p.; 214-217.degree. C.
EXAMPLE 126
1-{2-[6-Amino-9-methyl-8-(2,3,5-trifluorophenyl)-9H-2-purinyl]-1-ethynyl}--
1-cyclobutanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.73-1.86 (m, 2H), 2.17-2.27 (m, 2H),
2.34-2.43 (m, 2H), 3.65 (s, 3H), 6.00 (S, 1H), 7.50-7.62 (m, 3H),
7.81-7.90 (m, 1H). ESI MS; 374 (M.sup.++1). m.p.; 231-234.degree.
C.
EXAMPLE 127
1-{2-[6-Amino-8-(2,3-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclobutanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.73-1.86 (m, 2H), 2.17-2.27 (m, 2H),
2.34-2.43 (m, 2H), 3.63 (s, 3H), 6.00 (S, 1H), 7.40-7.47 (m, 1H),
7.52-7.60 (m, 3H), 7.66-7.74 (m, 1H). ESI MS; 356 (M.sup.++1).
m.p.; 225-229.degree. C.
EXAMPLE 128
1-[-6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-3,4-dimethyl-1-penty-
n-3-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.01 (dd, J=17.0 and
17.0,6H),.]. .Iadd..delta., DMSO-d.sub.6); 1.01(dd, J=17.0 and
17.0,6H), .Iaddend.1.24 (br s, 1H), 1.41 (s, 3H), 1.73-1.86 (m,
1H), 3.81 (s, 3H). ESI MS; 354.1 (M.sup.++1). m.p.; 191-192.degree.
C.
EXAMPLE 129
1-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purionyl]-3,4,4-trimethyl-1-pe-
ntyn-1-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.04 (s,9H), 1.44 (s, 3H), 3.83 (s, 3H),
7.42-7.48 (m, 1H), 7.58-7.77 (m, 3H). ESI MS; 368.1 (M.sup.++1).
m.p.; 193-194.degree. C.
EXAMPLE 130
1-{2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-4-pheny-
l-1-cycloheanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.60-2.14 (m, 9H), 2.41-2.49 (m, 1H), 3.81
(s, 3H), 7.16-7.76 (m, 8H). ESI MS; 442 (M.sup.++1). m.p.;
247-249.degree. C.
EXAMPLE 131
1-{2-[6-Amino-9-methyl-8-(5-methyl-2-furyl)-9H-2-purinyl]-1-ethynyl}-1-cyc-
loheanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.60-1.80 (m, 4H), 1.82-1.99 (m, 4H), 2.41
(s, 3H), 3.87 (s, 3H), 4.23 (br, 3H), 6.41 (s, 1H), 7.19 (s, 1H).
ESI MS; 38 (M.sup.++1). m.p.; 184-186.degree. C.
EXAMPLE 132
1-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.72 (t, J=7.6 Hz, 3H),
1.01 (t, J=7.6 Hz, 6H),.]. .Iadd..delta., DMSO-d.sub.6); 0.72(t,
J=7.6 Hz, 3H), 1.01(t, J=7.6 Hz, 6H), .Iaddend.1.58-1.73 (m, 6H),
.[.4.24 (t, J=7.6 Hz, 2H),.]. .Iadd.4.24 (t, J=7.6 Hz, 2H),
.Iaddend.7.42-7.49 (m, 1H), 7.63-7.69 (m, 3H). ESI MS; 382
(M.sup.++1). m.p.; 144-147.degree. C.
EXAMPLE 133
1-{2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclop-
entanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.29 (t, J=7.2 Hz, 3H,.].
.Iadd..delta., DMSO-d.sub.6); 1.29(t, J=7.2 Hz, 3H),
.Iaddend.1.66-1.82 (m, 4H), 1.86-2.02 (m, 4H), .[.4.31 (q, J=7.2
Hz, 2H),.]. .Iadd.4.31 (q, J=7.2 Hz, 2H), .Iaddend.7.46-7.52 (m,
1H), 7.64-7.72 (m, 3H). FAB MS; 366 (M.sup.++1). m.p.;
188-191.degree. C.
EXAMPLE 134
2-{2-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1,2,3-p-
ropanetriol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.17 (s, 2H), .[.3.50 (d, J=10.8 Hz, 2H),
3.55 (d, J=10.8 Hz, 2H),.]. .Iadd.3.50 (d, J=10.8 Hz, 2H), 3.55(d,
J=10.8 Hz, 2H), .Iaddend.3.82 (s, 3H), 7.40-7.47 (m, 1H), 7.61-7.75
(m, 3H). ESI MS; 358 (M.sup.++1). m.p.; 233-235.degree. C.
EXAMPLE 135
1-{2-[6-Amino-8-(3,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-1-ethynyl}-1-cy-
clopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.26 (t, J=18.0 Hz,
3H),.]. .Iadd..delta., DMSO-d.sub.6); 1.26(t, J=18.0 Hz, 3H),
.Iaddend.1.64-1.80 (m, 4H), 1.84-1.98 (m, 4H), .[.4.29 (q, J=18.0
Hz, 2H),.]. .Iadd.4.29 (q, J=18.0 Hz, 2H), .Iaddend.7.50-7.58 (m,
3H). ESI MS; 384.0 (M.sup.++1). m.p.; 217-218.degree. C.
EXAMPLE 136
1-[6-Amino-8-(3,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-
-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.01 (t, J=18.0 Hz, 6H),
1.25 (t, J=18.0 Hz, 3H),.]. .Iadd..delta., DMSO-d.sub.6); 1.01(t,
J=18.0 Hz, 6H), 1.25(t, J=18.0 Hz, 3H), .Iaddend.1.58-1.74 (m, 4H),
.[.4.30 (q, J=17.4 Hz, 2H),.]. .Iadd.4.30 (q, J=17.4 Hz, 2H),
.Iaddend.7.47-7.60 (m, 3H). ESI MS; 386.2 (M.sup.++1). m.p.;
204-205.degree. C.
EXAMPLE 137
1-{2-[6-Amino-8-(3,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-1-ethynyl}-1-cy-
clobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.62 (t, J=18.0 Hz,
3H),.]. .Iadd..delta., DMSO-d.sub.6); 1.62(t, J=18.0 Hz, 3H),
.Iaddend.1.76-1.88 (m, 2H), 2.18-2.29 (m, 2H), 2.36-2.44 (m, 2H),
.[.4.30 (q, J=18.0 Hz, 2H),.]. .Iadd.4.30 (q, J=18.0 Hz, 2H),
.Iaddend.7.49-7.59 (m, 3H). ESI MS; 370.0 (M.sup.++1). m.p.;
234-235.degree. C.
EXAMPLE 138
4-[6-Amino-8-(3,5-difluorophenyl)-9-ethyl-9H-2-purinyl]2-methyl-3-butyn-2--
ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.25 (t, J=17.6 Hz,
3H),.]. .Iadd..delta., DMSO-d.sub.6); 1.25(t, J=17.6 Hz, 3H),
.Iaddend.1.48 (s, 6H), .[.4.29 (q, J=17.4 Hz, 2H),.]. .Iadd.4.29
(q, J=17.4 Hz, 2H), .Iaddend.7.49-7.58 (m, 3H). ESI MS; 358.0
(M.sup.++1).
EXAMPLE 139
1-{2-[6-Amino-9-cyclopropyl-8-(3,5-difluorophenyl)-9H-2-purinyl]1-ethynyl}-
-1-cyclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.70-0.78 (m, 2H), 1.02-1.11 (m, 2H),
1.64-1.82 (m, 4H), 1.84-1.99 (m, 4H), 3.67-3.74 (m, 1H), 7.45-7.53
(m, 1H), 7.65-7.73 (m, 2H). ESI MS; 396.1 (M.sup.++1). m.p.;
265-266.degree. C.
EXAMPLE 140
1-{-[6-Amino-9-cyclopropyl-8-(3,5-difluorophenyl)-9H-2-purinyl]-1-ethynyl}-
-1-cyclobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.70-0.78 (m, 2H), 1.02-1.11 (m, 2H),
1.72-1.86 (m, 2H), 2.16-2.28 (m, 2H), 2.30-2.46 (m, 2H), 3.65-3.74
(m, 1H), 7.43-7.53 (m, 1H), 7.64-7.74 (m, 2H). ESI MS; 382.1
(M.sup.++1). m.p.; 228.degree. C.
EXAMPLE 141
4-[6-Amino-9-cyclopropyl-8-(3,5-difluorophenyl)-9H-2-purinyl]-2-methyl-3-b-
utyn-2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.70-0.77 (m, 2H), 1.03-1.11 (m, 2H), 1.48
(s, 6H), 3.66-3.76 (m, 1H), 7.44-7.53 (m, 1H), 7.65-7.73 (m, 2H).
ESI MS; 370.1 (M.sup.++1). m.p.; 245.degree. C.
EXAMPLE 142
1-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-purinyl]-3-ethynyl-1-pentyn-
-3-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.70-0.75 (m, 2H), 0.97-1.10 (m, 8H),
1.60-1.79 (m, 4H), 3.67-3.73 (m, 1H), 7.39-7.45 (m, 1H), 7.59-7.66
(m, 1H), 7.77-7.84 (m, 2H). FAB MS; 380 (M.sup.++1). m.p.;
145-148.degree. C.
EXAMPLE 143
4-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-butyn-
-2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.70-0.75 (m, 2H), 1.00-1.10 (m, 2H), 1.49
(s, 6H), 3.67-3.73 (m, 1H), 7.38-7.45 (m, 1H), 7.59-7.66 (m, 1H),
7.77-7.84 (m, 2H). ESI MS; 352 (M.sup.++1). m.p.; 143-145.degree.
C.
EXAMPLE 144
1-[6-Amino-8-(3,5-difluorophenyl)-9-propyl-9H-2-purinyl]-3-ethynyl-1-penty-
n-8-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.72 (t, J=7.6 Hz, 3H),
1.01 (t, J=7.6 Hz, 6H),.]. .Iadd..delta., DMSO-d.sub.6); 0.72(t,
J=7.6 Hz, 3H), 1.01(t, J=7.6 Hz, 6H), .Iaddend.1.58-1.75 (m, 6H),
.[.4.27 (t, J=7.6 Hz, 2H),.]. .Iadd.4.27 (t, J=7.6 Hz, 2H),
.Iaddend.7.48-7.58 (m, 3H). ESI MS; 400 (M.sup.++1). m.p.;
183-184.degree. C.
EXAMPLE 145
1-{2-[6-Amino-8-(3,5-difluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.72 (t, J=7.6 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.72(t, J=7.6 Hz, 3H),
.Iaddend.1.57-1.81 (m, 4H), .[.4.23 (t, J=7.6 Hz, 2H),.].
.Iadd.4.23 (t, J=7.6 Hz, 2H), .Iaddend.7.48-7.57 (m, 3H). ESI MS;
398 (M.sup.++1). m.p.; 210-211.degree. C.
EXAMPLE 146
1-{2-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclo-
butanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.72-1.85 (m, 2H), 2.17-2.27 (m, 2H),
2.34-2.43 (m, 2H), 3.60 (s, 3H), 6.00 (s, 1H), 7.38-7.59 (m, 4H),
7.61-7.74 (m, 2H). ESI MS; 338 (M.sup.++1). m.p.; 136-138.degree.
C.
EXAMPLE 147
1-{2-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclo-
pentanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.65-1.80 (m, 4H), 1.80-1.96 (m, 4H), 3.59
(s, 3H), 5.47 (s, 1H), 7.41-7.49 (m, 4H), 7.64-7.74 (m, 2H). ESI
MS; 352 (M.sup.++1). m.p.; 166-168.degree. C.
EXAMPLE 148
1-[6-Amino-9-methyl-8-(5-methyl-2-furyl)-9H-2-purinyl]-3-ethyl-1-pentyn-3--
ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.99 (t, J=7.2 Hz, 6H),
1.62 (q, J=7.2 Hz, 2H), 1.64 (q, J=7.2 Hz, 2H),.]. .Iadd..delta.,
DMSO-d.sub.6); 0.99(t, J=7.2 Hz, 6H), 1.62(q, J=7.2 Hz, 2H),
1.64(q, J=7.2 Hz, 2H), .Iaddend.2.40 (s, 3H), 3.17 (s, 1H), 3.86
(s, 3H), .[.6.41 (d, J=0.4 Hz, 1H), 7.18 (d, J=0.4 Hz, 1H)..].
.Iadd.6.41 (d, J=0.4 Hz, 1H), 7.18(dd, J=0.4 Hz, 1H). .Iaddend.ESI
MS; 340 (M.sup.++1). m.p.; 229-230.degree. C.
EXAMPLE 149
1-[6-Amino-8-(2-fluorophenyl)-9-methyl-9H-2-purinyl]-3-ethyl-1-pentyn-1-ol
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.98 (t, J=7.4 Hz, 6H),.].
.Iadd..delta., DMSO-d.sub.6); 0.98(t, J=7.4 Hz, 6H),
.Iaddend.1.58-1.68 (m, 4H), 3.57 (s, 3H), 5.29 (s, 1H), 7.39-7.46
(m, 4H), 7.63-7.71 (m, 2H). ESI MS; 354 (M.sup.++1). m.p.;
199-201.degree. C.
EXAMPLE 150
1-[6-Amino-9-cyclopropyl-8-(3,5-difluorophenyl)-9H-2-purinyl]-3-ethyl-1-pe-
ntyn-3-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.72-0.78 (m, 2H), .[.1.01 (t, J=7.2 Hz,
6H),.]. .Iadd.1.01 (t, J=7.2 Hz, 6H), .Iaddend.1.04-1.12 (m, 2H),
1.58-1.75 (m, 4H), 3.67-3.77 (m, 1H), 7.46-7.54 (m, 1H), 7.65-7.73
(m, 2H). ESI MS; 398.2 (M.sup.++1). m.p.; 225.degree. C.
EXAMPLE 151
4-[6-Amino-8-(3,5-difluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn--
2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.48 (s, 6H), 3.17 (s, 3H), 7.46-7.66 (m,
3H). ESI MS; 344.0 (M.sup.++1). m.p.; 237-238.degree. C.
EXAMPLE 152
1-[6-Amino-8-(2,5-difluorophenyl)-9-methyl-9H-2-purinyl]-3-ethyl-1-pentyn--
3-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.01 (t, J=18 Hz, 6H),
1.60-1.74 (q, J=18 Hz,4H),.]. .Iadd..delta., DMSO-d.sub.6); 1.01(t,
J=18 Hz, 6H), 1.60-1.74(q, J=18 Hz,4H), .Iaddend.3.65 (s, 3H),
7.53-7.65 (m, 3H). ESI MS; 372.2 (M.sup.++1). m.p.; 147-148.degree.
C.
EXAMPLE 153
4-[6-Amino-8-(2,5-difluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-butyn--
2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.50 (s, 6H), 3.67 (s, 3H), 7.54-7.68 (m,
3H). ESI MS; 344.0 (M.sup.++1). m.p.; 177-178.degree. C.
EXAMPLE 154
4-[6-Amino-8-(2,3-difluorophenyl)-9-ethyl-9H-2-purinyl]-2-methyl-3-butyn-2-
-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.25 (t, J=7.2 Hz, 3H),
1.49 (s, 6H), 4.10 (q, J=7.2 Hz, 2H),.]. .Iadd..delta.,
DMSO-d.sub.6); 1.25(t, J=7.2 Hz, 3H), 1.49(s, 6H), 4.10(q, J=7.2
Hz, 2H), .Iaddend.7.41-7.56 (m, 2H), 7.60-7.79 (m, 1H). ESI MS; 358
(M.sup.++1). m.p.; 213-215.degree. C.
EXAMPLE 155
1-[6-Amino-8-(2,3-difluorophenyl)-9-ethyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-
-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.00 (t, J=7.2 Hz, 6H),
1.22 (t, J=7.2 Hz, 3H), 1.64 (q, J=7.2 Hz, 2H), 1.65 (q, J=7.2 Hz,
2H), 4.10 (q, J=7.2 Hz, 2H),.]. .Iadd..delta., DMSO-d.sub.6);
1.00(t, J=7.2 Hz, 6H), 1.22(t, J=7.2 Hz, 3H), 1.64(q, J=7.2Hz, 2H),
1.65(q, J=7.2 Hz, 2H), 4.10(q, J=7.2 Hz, 2H), .Iaddend.7.42-7.57
(m, 2H), 7.69-7.78 (m, 1H). ESI MS: 386 (M.sup.++1). m.p.;
222-224.degree. C.
EXAMPLE 156
4-[6-Amino-8-(2-fluorophenyl)-9-methyl
-9H-2-purinyl]-2-methyl-3-butyn-2-ol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.46 (s, 6H), 3.60 (s, 3H), 5.60 (s, 1H),
7.41-7.54 (m, 4H), 7.64-7.74 (m, 2H). ESI MS; 326 (M.sup.++1).
m.p.; 198-199.degree. C.
EXAMPLE 157
1-{2-[6-Amino-8-(2,3-difluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.23 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.23(t, J=7.2 Hz, 3H),
.Iaddend.1.74-1.86 (m, 2H), 2.18-2.27 (m, 2H), 2.36-2.43 (m, 2H),
.[.4.09 (q, J=14.4 Hz, 2H),.]. .Iadd.4.09 (q, J=14.4 Hz, 2H),
.Iaddend.7.42-7.47 (m, 1H), 7.51-7.55 (m, 1H), 7.69-7.76 (m, 1H).
ESI MS; 370 (M.sup.++1). m.p.; 139-142.degree. C.
EXAMPLE 158
1-{2-[6-Amino-8-(2,3-difluorophenyl)-9-ethyl-9H-2-purinyl]-1-ethynyl}-1-cy-
clopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.24 (t, J=7.0 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.24(t, J=7.0 Hz, 3H),
.Iaddend.1.65-1.80 (m, 4H), 1.85-2.00 (s,4H), 4.05-4.15 (m, 2H),
5.10 (s, 1H), 7.42-7.58 (m, 2H), 7.69-7.78 (m, 2H). ESI MS; 384
(M.sup.++1). m.p.; 138-140.degree. C.
EXAMPLE 159
4-[6-Amino-8-(3,5-difluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-1-butyn--
2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.71 (t, J=7.6 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.71(t, J=7.6 Hz, 3H), .Iaddend.1.49
(s, 6H), 1.57-1.68 (m, 2H), .[.4.25 (t, J=7.6 Hz, 2H),.].
.Iadd.4.25 (t, J=7.6 Hz, 2H), .Iaddend.7.50-7.58 (m, 3H). ESI MS;
372 (M.sup.++1). m.p.; 148-150.degree. C.
EXAMPLE 160
1-{2-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl}-1--
cyclobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.74 (bs, 2H), 1.02-1.11 (m, 2H), 1.76-1.90
(m, 2H), 2.20-2.31 (m, 2H), 2.38-2.50 (m, 2H), 3.69-3.77 (m, 1H),
7.41-7.48 (m, 1H), 7.60-7.67 (m, 1H), 7.79-7.86 (m, 2H). ESI MS;
364 (M.sup.++1). m.p.; 167-170.degree. C.
EXAMPLE 161
1-{2-[6-Amino-8-(2,3-difluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.70 (t, J=7.6 Hz, 3H),
1.64 (tq, J=7.6 Hz, 7.6 Hz, 2H),.]. .Iadd..delta., DMSO-d.sub.6);
0.70(t, J=7.6 Hz, 3H), 1.64(tq, J=7.6 Hz, 7.6 Hz, 2H),
.Iaddend.1.67-1.83 (m, 2H), 2.23-2.32 (m, 2H), 2.39-2.50 (m, 2H),
.[.4.10 (t, J=7.6 Hz, 2H),.]. .Iadd.4.10 (t, J=7.2 Hz, 2H),
.Iaddend.7.44-7.52 (m, 1 Hz), 7.53-7.59 (m, 1H), 7.72-7.81 (m, 1H).
ESI MS; 384 (M.sup.++1). m.p.; 124-127.degree. C.
EXAMPLE 162
1-{2-[6-Amino-8-(2,3-difluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.69 (t, J=7.6 Hz, 3H),
1.63 (tq, J=7.6 Hz, 7.6 Hz, 2H),.]. .Iadd..delta., DMSO-d.sub.6);
0.69(t, J=7.6 Hz, 3H), 1.63(tq, J=7.6 Hz, 7.6 Hz, 2H),
.Iaddend.1.67-1.82 (m, 4H), 1.85-2.00 (m, 4H), .[.4.07 (t, J=7.6
Hz, 2H),.]. .Iadd.4.07 (t, J=7.6 Hz, 2H), .Iaddend.7.43-7.50 (m,
1H), 7.50-7.59 (m, 1H), 7.70-7.79 (m, 1H). ESI MS; 398 (M.sup.++1).
m.p.; 184-188.degree. C.
EXAMPLE 163
4-[6-Amino-8-(2,3-difluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-butyl--
2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.68 (t, J=7.6 Hz, 3H),
1.49 (s, 6H), 1.62 (tq, J=7.6 Hz, 7.6 Hz, 2H), 4.07 (t, J=7.6 Hz,
2H),.]. .Iadd..delta., DMSO-d.sub.6); 0.68(t, J=7.6 Hz, 3H),
1.49(s, 6H), 1.62(tq, J=7.6 Hz, 7.6 Hz, 2H), 4.07(t, J=7.6 Hz, 2H),
.Iaddend.7.43-7.49 (m, 1H), 7.51-7.57 (m, 1H), 7.70-7.78 (m, 1H).
ESI MS; 372 (M.sup.++1). m.p.; 230-233.degree. C.
EXAMPLE 164
1-[6-Amino-8-(2,3-difluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-1-pentyn--
3-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.68 (t, J=7.6 Hz, 3H),
1.01 (t, J=7.6 Hz, 6H), 1.59-1.75 (m, 6H) 4.08 (t, J=7.6 Hz,
2H),.]. .Iadd..delta., DMSO-d.sub.6); 0.68(t, J=7.6 Hz, 3H),
1.01(t, J=7.6 Hz, 6H), 1.59-1.75(m, 6H), 4.08(t, J=7.6 Hz, 2H),
.Iaddend.7.48-7.50 (m, 1H), 7.52-7.57 (m, 1H), 7.71-7.79 (m, 1H).
ESI MS; 400 (M.sup.++1). m.p.; 187-188.degree. C.
EXAMPLE 165
1-{2-[6-Amino-8-(2,5-difluorophenyl)-9-cyclopropyl-9H-2-purinyl]-1-ethynyl-
}-1-cyclobutanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.67-0.72 (m, 2H), 0.89-0.97 (m, 2H),
1.73-1.87 (m, 2H), 2.17-2.28 (m, 2H), 2.35-2.45 (m, 2H), 3.37-3.47
(m, 1H), 7.49-7.56 (m, 2H), 7.59-7.66 (m, 1H). ESI MS: 382
(M.sup.++1). m.p.; 161-164.degree. C.
EXAMPLE 166
1-{2-[6-Amino-8-(2,5-difluorophenyl)-9-cyclopropyl-9H-2-purinyl]-1-ethynyl-
}-1-cyclopentanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.66-0.73 (m, 2H), 0.89-0.97 (m, 2H),
1.63-1.82 (m, 4H), 1.83-1.98 (m, 4H), 3.37-3.46 (m, 1H), 7.49-7.56
(m, 2H), 7.59-7.66 (m, 1H). ESI MS: 396 (M.sup.++1). m.p.;
230-232.degree. C.
EXAMPLE 167
4-[6-Amino-8-(2,5-difluorophenyl)-9-cyclopropyl-9H-2-purinyl]-2-methyl-3-b-
utyn-2-ol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.65-0.73 (m, 2H), 0.88-0.98 (m, 2H), 1.48
(s, 6H), 3.37-3.46 (m, 1H), 7.40-7.75 (br, 2H), 7.48-7.55 (m, 2H),
7.59-7.65 (m, 1H). EST MS; 370 (M.sup.++1). m.p.; 196-198.degree.
C.
EXAMPLE 168
1-[6-Amino-8-(2,5-difluorophenyl)-9-cyclopentyl-9H-2-purinyl]-3-ethyl-1-pe-
ntyl-3-ol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.66-0.73 (m, 2H), 0.89-0.97 (m, 2H),
.[.1.00 (t, J=7.2 Hz, 6H).]. .Iadd.1.00 (t, J=7.2 Hz, 6H),
.Iaddend.1.60-1.73 (m, 4H), 3.39-3.46 (m, 1H), 7.49-7.56 (m, 2H),
7.59-7.65 (m, 1H). ESI MS; 398 (M.sup.++1). m.p.; 215-216.degree.
C.
EXAMPLE 169
1-{2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclo-
pentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.84 (t, J=7.2 Hz, 3H),
1.70-2.22 (m, 10H), 4.37 (t, J=7.4 Hz, 2H),.]. .Iadd..delta.,
DMSO-d.sub.6); 0.84(t, J=7.2 Hz, 3H), 1.70-2.22(m, 10H), 4.37(t,
J=7.4 Hz, 2H), .Iaddend.7.27-7.32 (m, 1H), 7.50-7.59 (m, 3H). ESI
MS; 380 (M.sup.++1). m.p.; 198-200.degree. C.
EXAMPLE 170
1-{2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-cyclo-
butanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.87 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.87(t, J=7.2 Hz, 3H),
.Iaddend.1.79-2.01 (m, 4H), 2.33-2.42 (m, 2H), 2.46 (s, 1H),
2.62-2.71 (m, 2H), .[.4.38 (t, J=7.4 Hz, 2H),.]. .Iadd.4.38 (t,
J=7.4 Hz, 2H), .Iaddend.7.29-7.34 (m, 1H), 7.50-7.60 (m, 3H). ESI
MS; 366 (M.sup.++1). m.p.; 144-146.degree. C.
EXAMPLE 171
4-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-butyn-2-ol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.72 (t, J=18.0 Hz, 3H),
1.58-1.69 (m, 2H), 4.24 (q, J=18.0 Hz, 2H),.]. .Iadd..delta.,
DMSO-d.sub.6); 0.72(t, J=18.0 Hz, 3H), 1.58-1.69(m, 2H), 4.24(q,
J=18.0 Hz, 2H), .Iaddend.7.43-7.49 (m, 1H), 7.61-7.70 (m, 3H). ESI
MS; 354.1 (M.sup.++1). m.p.; 167-168.degree. C.
EXAMPLE 172
1-{2-[2-6-Amino-8-(2,5-difluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-
-cyclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.68 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.68(t, J=7.2 Hz, 3H),
.Iaddend.1.55-1.81 (m, 6H), 1.89-1.98 (m, 4H), .[.4.02 (t, J=7.2
Hz, 2H),.]. .Iadd.4.02 (t, J=7.2 Hz, 2H), .Iaddend.7.50-7.57 (m,
2H), 7.59-7.68 (m, 1H). ESI MS; 398.2 (M.sup.++1). m.p.;
232-234.degree. C.
EXAMPLE 173
1-{2-[6-Amino-8-(2,5-difluorophenyl)-9-propyl-9H-2-purinyl]-1-ethynyl}-1-c-
yclobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.68 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.68(t, J=7.2 Hz, 3H),
.Iaddend.1.56-1.68 (m, 2H), 1.72-1.86 (m, 2H), 2.16-2.28 (m, 2H),
2.32-2.46 (m, 2H), .[.4.03 (t, J=7.2 Hz, 2H),.]. .Iadd.4.03 (t,
J=7.2 Hz, 2H), .Iaddend.7.52-7.58 (m, 2H), 7.60-7.70 (m, 1H). ESI
MS; 384.2 (M.sup.++1). m.p.; 225-226.degree. C.
EXAMPLE 174
1-{2-[6-Amino-8-(2,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-1-ethynyl}-1-cy-
clobutanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.22 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.22(t, I=7.2 Hz, 3H),
.Iaddend.1.72-1.87 (m, 2H), 2.17-2.27 (m, 2H), 2.34-2.43 (m, 2H),
.[.4.07 (q, J=7.2 Hz, 2H),.]. .Iadd.4.07 (q, J=7.2 Hz, 2H),
.Iaddend.7.51-7.59 (m, 2H), 7.59-7.67 (m, 1H). EST MS; 370
(M.sup.++1). m.p.; 141-143.degree. C.
EXAMPLE 175
1-{2-[6-Amino-8-(2,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-1-ethynyl}-1-cy-
clobutanol
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.22 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.22(t, J=7.2 Hz, 3H),
.Iaddend.1.62-1.82 (m, 4H), 1.82-1.99 (m, 4H), .[.4.07 (q, J=7.2
Hz, 2H),.]. .Iadd.4.07 (q, J=7.2 Hz, 2H), .Iaddend.7.48-7.58 (m,
2H), 7.58-7.66 (m, 1H). EST MS; 384 (M.sup.++1). m.p.;
191-194.degree. C.
EXAMPLE 176
4-[6-Amino-8-(2,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-2-methyl-3-butyn-2-
-ol
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.22 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.22(t, J=7.2 Hz, 3H), .Iaddend.1.48
(s, 6H), .[.4.07 (q, J=7.2 Hz, 2H),.]. .Iadd.4.07 (q, J=7.2 Hz,
2H), .Iaddend.7.49-7.58 (m, 2H), 7.58-7.66 (m, 1H). ESI MS; 358
(M.sup.++1). m.p.; 215-218.degree. C.
EXAMPLE 177
1-[6-Amino-8-(2,5-difluorophenyl)-9-ethyl-9H-2-purinyl]-3-ethyl-1-pentyn-3-
-ol
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.00 (t, J=7.2 Hz, 6H),
1.22 (t, J=7.2 Hz, 3H),.]. .Iadd..delta., DMSO-d.sub.6); 1.00(t,
J=7.2 Hz, 6H), 1.22(t, J=7.2 Hz, 3H), .Iaddend.1.58-1.73 (m, 4H),
.[.4.07 (q, J=7.2 Hz, 2H),.]. .Iadd.4.07 (q, J=7.2 Hz, 2H),
.Iaddend.7.50-7.59 (m, 2H), 7.58-7.65 (m, 1H). ESI MS; 386
(M.sup.++1). m.p.; 163-166.degree. C.
EXAMPLE 178
4-[6-Amino-8-(2,5-difluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-butyn--
2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.68 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.68(t, J=7.2 Hz, 3H), .Iaddend.1.48
(s, 6H), 1.55-1.68 (m, 2H), .[.4.03 (t, J=7.2 Hz, 2H),.].
.Iadd.4.03 (t, J=7.2 Hz, 3H), .Iaddend.7.51-7.58 (m, 2H), 7.60-7.68
(m, 1H). ESI MS; 372.1 (M.sup.++1). m.p.; 194-196.degree. C.
EXAMPLE 179
1-[6-Amino-8-(2,5-difluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-1-pentyn--
3-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.67 (t, J=7.2 Hz, 3H),
1.00 (t, J=7.6 Hz, 6H), 1.55-1.74 (m, 6H), 4.03 (t, J=7.2 Hz,
3H),.]. .Iadd..delta., DMSO-d.sub.6); 0.67(t, J=7.2 Hz, 3H),
1.00(t, J=7.6 Hz, 6H), 1.55-1.74(m, 6H), 4.03(t, J=7.2 Hz, 3H),
.Iaddend.7.51-7.58 (m, 2H), 7.60-7.67 (m, 1H). ESI MS; 400.2
(M.sup.++1). m.p.; 164-165.degree. C.
EXAMPLE 180
2-[6-Amino-8-(3-fluorophenyl)-2[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-pu-
rinyl]acetic Acid Hydrochloride
To 137 mg of ethyl
2-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9--
purinyl}acetate of Example 47 were added 1 ml of ethanol and 2 ml
of a 1N aqueous solution of sodium hydroxide and the mixture was
stirred for 30 minutes at room temperature. After the reaction
solution was concentrated, the resulting residue was dissolved in
water and the solution was adjusted to pH 2 with a 1N aqueous
solutoin of HCl. The resulting crystals were collected by
filtration and washed with water and ether to give 231 mg of the
title compound. The yield was 65%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.20-1.30 (m, 1H), 1.41-1.67 (m, 7H),
1.78-1.86 (m, 2H), 7.38-7.43 (m, 1H), 7.52-7.64 (m, 3H). FAB MS;
410 (M.sup.++1).
EXAMPLE 181
3-[6-Amino-2-{2-(1-hydroxycyclohexyl)-1-ethynyl]-9-methyl-9H-8-purinyl}ben-
zoic Acid Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.19-1.31 (m, 1H), 1.42-1.68 (m, 7H),
1.80-1.89 (m, 2H), 3.82 (s, 3H), .[.7.71 (t, J=7.7 Hz, 1H),
8.09-8.14 (m, 2H), 8.45 (d, J=1.3 Hz, 1H)..]. .Iadd.7.71 (t, J=7.7
Hz, 1H), 8.09-8.14(m, 2H), 8.45(d, J=1.3 Hz, 1H). .Iaddend.FAB MS;
392 (M.sup.++1).
EXAMPLE 182
5-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-4-pentynoic
Acid Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.66-1.82 (m, 4H), 1.87-2.00 (m, 4H), 3.86
(s, 3H), 7.43-7.50 (m, 1H), 7.63-7.70 (m, 1H), 7.71-7.77 (m, 2H).
FAB MS; 340 (M.sup.++1).
EXAMPLE 183
(E)
3-{4-{6-Amino-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9-methyl-9H-8-puri-
nyl}phenyl}-2-propenoic Acid Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.21-1.33 (m, 1H), 1.42-1.69 (m, 7H),
1.78-1.89 (m, 2H), 3.81 (s, 3H), 5.54 (br s, 1H), .[.6.66 (d,
J=16.0 Hz, 1H), 7.47 (br s, 2H), 7.68 (d, J=16.0 Hz, 1H),.].
.Iadd.6.66 (d, J=16.0 Hz, 1H), 7.47(br s, 2H), 7.68(d, J-16.0 Hz,
1H), .Iaddend.7.84-7.98 (m, 4H), 12.5 (br s, 1H). FAB MS; 418
(M.sup.++1).
EXAMPLE 184
2-{{8-(3-Fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9-methyl-9H-6-
-purinyl}amino}acetic Acid Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.21-1.32 (m, 1H), 1.41-1.68 (m, 7H),
1.78-1.88 (m, 2H), 3.79 (s, 3H), 5.57 (s, 2H), 7.39-7.44 (m, 1H),
7.59-7.65 (m, 1H), 7.69-7.73 (m, 2H), 8.09-8.12 (m, 1H). FAB MS;
424 (M.sup.++1).
EXAMPLE 185
2-[3-(Dimethylamino)-1-propynyl]-8-(3-fluorophenyl)-9-methyl-9H-6-purinami-
ne Dihydrochloride
6-Chloro-8-(3-fluorophenyl)-2-iodo-9-methyl-9H-purine (200 mg) was
reacted with an ammonia-saturated methanol at 70.degree. C. for 30
minutes in a sealed tube. The reaction mixture was evaporated and
then filtered to give 138 mg of
8-(3-fluorophenyl)-2-iodo-9-methyl-9H-6-purinamine.
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
3.84 (s, 3H), 5.76 (br s, 2H), 7.20-7.30 (m, H), 7.42-7.54 (m,
3H).
After that, a solution of 50 mg of
8-(3-fluorophenyl)-2-iodo-9-methyl-9H-6-purinamine previously
obtained, 10 mg of dichlorobis(triphenylphosphine)palladium (II), 3
mg of copper (I) iodide, 22 ml of 1-dimethylamino-2-propyne and 28
ml of triethylamine in 2 ml of DMF was stirred in nitrogen
atmosphere at 80.degree. C. for 20 minutes. Since the reaction was
slow, 66 ml of 1-dimethylamino-2-propyne were further added and the
mixture was stirred at 80.degree. C. for 1 hour more. The solvent
was evaporated and the resulting residue was diluted with
chloroform. After blowing hydrogen sulfide for about 20 seconds
thereinto, a saturated aqueous solution of EDTA was added thereto
and the mixture was neutralized with sodium carbonate and extracted
with chloroform. The organic layer was dried over magnesium
sulfate, purified by a silica column chromatography (5%
methanol/dichloromethane) and converted into a hydrochloride by a
common method to give 16 mg of the title compound.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.2.85 (s, 6H), 3.80 (s, 3H), 4.35 (s, 2H),
7.39-7.96 (m, 1H), 7.60-7.72 (m, 31H). FAB MS; 325 (M.sup.++1).
The compounds of Examples 186-201 were prepared similarly using the
corresponding 6-chloro-2-iodo compounds where a chlorine group at
position 6 was firstly converted to an amino group and then an
iodine group at position 2 was converted to the corresponding
ethynyl group.
EXAMPLE 186
1-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-4-methyl-1-pentyn-1-one
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
1.18 .[.(d, J=6.3,6H),.]. .Iadd.(d, J=6.3,6H), .Iaddend.2.66-2.80
(m, 1H), 4.08 (s, 3H), 5.64 (br, 2H), .[.6.64 (dd, J=2.0 Hz,0.9 Hz,
1H), 7.15 (d, J=2.0, 1H),.]. .Iadd.6.64 (dd, J=2.0 Hz,0.9 Hz, 1H),
7.15(d, J=2.0, 1H), .Iaddend.7.68 (m, 1H).
EXAMPLE 187
3-[6-Amino-8-(2-furyl)-9-methyl-9H-2-purinyl]-1-phenyl-2-propyn-1-one
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
4.10 (s, 3H), 5.66 (br, 2H), .[.6.66 (dd, J=1.8 Hz, 3.7 Hz, 1H),
7.18 (d, J=3.7, 1H),.]. .Iadd.6.66 (dd, J=1.8 Hz, 3.7 Hz, 1H),
7.18(d, J=3.7, 1H), .Iaddend.7.44-7.50 (m, 3H), 7.69 (m, 1H),
8.04-8.10 (m, 2H).
EXAMPLE 188
N.sup.1-Isopropyl-3-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-p-
ropynamide
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.10 (d, J=6.0 Hz, 6H),.].
.Iadd..delta., DMSO-d.sub.6); 1.10(d, J=6.0 Hz, 6H), .Iaddend.3.80
(s, 3H), 3.86-3.98 (m, 1H), 7.38-7.45 (m, 1H), 7.58-7.74 (m, 3H),
.[.8.90 (d, J=7.7 Hz, 1H)..]. .Iadd.8.90 (d, J=7.7 Hz, 1H).
.Iaddend.FAB MS; 353 (M.sup.++1).
EXAMPLE 189
N.sup.1-Cyclohexyl-8-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2--
propynamide
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.02-1.30 (m, 5H), 1.50-1.60 (m, 1H),
1.64-1.80 (m, 4H), 3.54-3.64 (m, 1H), 3.80 (s, 3H), 7.39-7.45 (m,
1H), 7.58-7.74 (m, 3H), .[.8.91 (d, J=8.2 Hz, 1H)..]. .Iadd.8.91
(d, J=8.2 Hz, 1H). .Iaddend.
EXAMPLE 190
N.sup.1-Phenyl-3-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-prop-
ynamide
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.80 (s, 3H), 7.08-7.12 (m, 1H), 7.30-7.36
(m, 2H), 7.39-7.45 (m, 1H), 7.60-7.74 (m, 5H), 11.10 (s, 1H). FAB
MS; 387 (M.sup.++1).
EXAMPLE 191
3-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-purinyl]-1-piperidino-2-propyn-1-
-one
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.42-1.64 (m, 6H), 3.50 (br, 2H), 3.72 (br,
2H), 3.80 (s, 3H), 7.40-7.45 (m, 1H), 7.60-7.78 (m, 3H). FAB MS;
379 (M.sup.++1).
EXAMPLE 192
3-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-morpholino-2-propyn-
-1-one
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 3.66 (t, J=4.1 Hz, 2H),
3.74 (t, J=4.1 Hz, 2H),.]. .Iadd..delta., DMSO-d.sub.6); 3.66(t,
J=4.1 Hz, 2H), 3.74(t, J=4.1 Hz, 2H), .Iaddend.3.80 (s, 3H),
7.38-7.45 (m, 1H), 7.60-7.74 (m, 3H).
EXAMPLE 193
2-[2-[4-Aminophenyl]-1-ethynyl]-8-(3-fluorophenyl)-9-methyl-9H-2-purinamin-
e Dihydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.3.10 (s, 3H), 6.69-6.78 (br s, 2H),
7.34-7.40 (m, 2H), 7.41-7.47 (m, 1H), 7.60-7.74 (m, 5H). FAB MS;
359 (M.sup.++1).
EXAMPLE 194
N-[3-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1,1-dimethyl-2-pro-
pyl]methanesulfonamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.62 (s, 6H), 3.19 (s, 3H), 3.83 (s, 3H),
7.40-7.47 (m, 1H), 7.60-7.66 (m, 2H), 7.67-7.75 (m, 2H). FAB MS;
403 (M.sup.++1).
EXAMPLE 195
Ethyl-N-{3-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1,1-dimethyl-2--
propyl}carbamate Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.18 (t, J=7.0 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.18(t, J=7.0 Hz, 3H), .Iaddend.1.56
(s, 6H), 3.80 (s, 3H), .[.4.00 (q, J=7.0 Hz, 2H),.]. .Iadd.4.00 (q,
J=7.0 Hz, 2H), .Iaddend.7.39-7.45 (m, 1H), 7.49 (br s, 2H), 7.54
(br s, 1H), 7.59-7.66 (m, 1H), 7.78-7.74 (m, 2H). FAB MS; 397
(M.sup.++1).
EXAMPLE 196
4-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-phenyl-3-buten-2-ol
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
1.93 (s, 3H), 2.86 (br s, 1H), 3.90 (s, 3H), 5.72 (br s, 2H),
7.21-7.29 (m, 1H), 7.29-7.33 (m, 1H), 7.35-7.41 (m, 2H), 7.47-7.57
(m, 3H), 7.73-7.78 (m, 2H).
EXAMPLE 197
3-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-(2-methoxyphenyl)-2-
-propyn-1-ol
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
3.48 (s, 1H), 3.88 (s, 3H), 3.92 (s, 3H), 5.95 (br s, 2H),
6.91-6.94 (m, 1H), 6.96-7.01 (m, 1H), 7.21-7.26 (m, 1H), 7.28-7.34
(m, 1H), 7.46-7.56 (m, 3H), 7.62-7.66 (m, 1H).
EXAMPLE 198
4-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-(3-pyridyl)-3-butyn-
-2-ol
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
1.93 (s, 3H), 3.87 (s, 3H), 6.20 (br-s, 2H), 7.20-7.37 (m, 2H),
7.42-7.57 (m, 3H), 8.01-8.09 (m, 1H). ESI MS; 389 (M.sup.++1).
EXAMPLE 199
3-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-(3-methoxy)-2-propy-
n-1-ol
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
3.83 (s, 3H), 3.88 (s, 3H), 5.71 (br-s, 1H), 5.92 (br, 2H),
6.85-6.90 (m, 1H), 7.16-7.33 (m, 4H), 7.45-7.56 (m, 3H).
EXAMPLE 200
3-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-(4-methoxyphenyl)-2-
-propyn-1-ol
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.CDCl.sub.3);
3.80 (s, 3H), 3.86 (s, 3H), 5.68 (br-s, 1H), 6.28 (br s, 2H),
.[.6.88 (d, J=8.8 Hz, 2H),.]. .Iadd.6.88 (d, J=8.8 Hz, 2H),
.Iaddend.7.20-7.26 (m, 1H), 7.43-7.56 (m, 5H).
EXAMPLE 201
4-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-(4-pyridinyl)-3-but-
yn-2-ol
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.74 (s, 3H), 3.80 (s, 3H), 6.63 (s, 1H),
7.38-7.46 (m, 1H), 7.48-7.76 (m, 7H), 8.61 (br, 2H).
EXAMPLE 202
N.sup.1-Ethyl-4-[6-Amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl-1-et-
hylnyl)-9H-9-purinyl]butaneamide Hydrochloride
1) 4-[6-Amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoic
Acid
To 1.50 g of
4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanol were
added 30 ml of chloroform, 30 ml of acetonitrile, 45 ml of water,
73 mg of ruthenium tetraoxide hydrate and4.10 g of sodium periodate
and the mixture was vigorously stirred in a nitrogen stream for 5
hours at room temperature. The reaction was stopped by 2-propanol
and the insoluble matters were filtered off followed by washing
with 1000 ml of chloroform-methanol (1:1). The filtrate was
concentrated, the residue was suspended in water, and the
suspension was adjusted to pH 2-3 with 1N hydrochloric acid and the
crystals were collected by filtration. The crystals were washed
with water and ether to give 1.41 g of the title compound. The
yield was 91%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.76-1.94 (m, 2H), .[.2.13 (t, J=7.0 Hz,
2H), 4.20 (t, J=7.2 Hz, 2H),.]. .Iadd.2.13 (t, J=7.0 Hz, 2H),
4.20(t, J=7.2 Hz, 2H), .Iaddend.7.36-7.47 (m, 1H), 7.54-7.68 (m,
3H), 7.74 (br s, 2H).
2) Methyl
4-[6-amino-8-(3-fluorophenyl)-2-iodod-9H-9-purinyl]butanoate
Thionyl chloride (1.2 ml) was added dropwise into a mixture of 1.41
g of 4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoid
acid and 75 ml of methanol over 15 minutes during the mixutre was
stirred at 0-5.degree. C. in a nitrogen stream. This was raised to
room temperature and stirred for 45 minutes and the solvent was
evaporated. The resulting residue was dissolved in ethyl acetate
and then the solutionw as washed with a saturated aqueous solution
of sodium bicarbonate twice and then with brine once. The orgnaic
layer was dried over anhydrous sodium sulfate and concentrated to
give 1.45 g of the title compound. The yield was 100%.
3) Methyl
4-{6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethy-
nyl]-9H-9-purinyl}butanoate]
To 162 mg of methyl
4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoate were
added 8 ml of N,N-dimethylformamide, 30 mg of copper(I) iodide, 30
mg of dichlorobis(triphenylphosphine)palladium(II)l, 80 mg of
1-ethylcyclohexanol and 74 .mu.l of triethylamine and the mixutre
was stirred in a nitrogen stream at 70.degree. C. for 2.5 hours.
After it was allowed to cool, the solvent was evaporated and the
resulting reside was subjected to a silica gel column
chromatography (25 g of silica gel; chloroform-methanol
(100:0-100:1-50:1) to give 144 mg of the title compound. The yield
was 90%.
4N.sup.1-Ethyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-
-ethynyl]-9H-9-purinyl]butanoate Hydrochloride
To 663 mg of methyl
4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl-9H-9-p-
urinyl]butanoate were added 20 ml of a 70% aqueous solution of
ethylamine and the mixture was stirred in a sealed tube at
80.degree. C. for 5 hours. The reaction solution was cooled to room
temperature and the solvent was concentrated. The resulting resiude
was subjected to a silica gel column chromatography (25 g of silica
gel; dichloromethane-methanol (100:0-100:1-50:1-40:1-30:1-20:1) to
give 439 mg of a crude product. This was suspended in ethyl
acetate, collected by fitlration and washed with ethyl acetate and
ether to give 396 mg of the desired free compound. This was
converted into a hydrochloride by a conventional method to give 400
mg of the title compound. The yield was 54%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.91 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.91(t, J=7.2 Hz, 3H),
.Iaddend.1.20-1.32 (m, 1H), 1.40-1.67 (m, 7H), 1.78-1.87 (m, 4H),
.[.1.93 (t, J=7.1 Hz, 2H), 2.94 (dq, J=5.5,7.2 Hz, 2H), 4.25 (t,
J=7.1 Hz, 2H),.]. .Iadd.1.93 (t, J=7.1 Hz, 2H), 2.94(dq, J=5.5,7.2
Hz, 2H), 4.25(t, J=7.1 Hz, 2H), .Iaddend.7.40-7.45 (m, 1H),
7.58-7.65 (m, 3H), .[.7.72 (t, J=5.5 Hz, 1H)..]. .Iadd.7.72 (t,
J=5.5 Hz, 1H). .Iaddend.FAB MS (m/z); 465 (M.sup.++1).
Similarly were prepared the compounds of Examples 69 and 204.
EXAMPLE 203
N.sup.1-Ethyl-4-[amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-eth-
ynyl]-9H-9-purinyl]acetamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.96 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.96(t, J=7.2 Hz, 3H),
.Iaddend.1.18-1.31 (m, 1H), 1.41-1.67 (m, 7H), 1.78-1.90 (m, 2H),
.[.3.06 (dq, J=5.5,7.2 Hz, 2H),.]. .Iadd.3.06 (dq, J=5.5,7.2 Hz,
2H), .Iaddend.4.84 (s, 2H), 7.38-7.44 (m, 1H), 7.52-7.63 (m, 3H),
.[.8.40 (t, J=5.5 Hz, 1H)..]. .Iadd.8.40 (t, J=5.5 Hz, 1H).
.Iaddend.FAB MS; 437 (M.sup.++1).
EXAMPLE 204
4-[6-Amino-9-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1-ethynyl]-9H-9-p-
urinyl]butaneamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.19-1.33 (m, 1H), 1.40-1.70 (m, 9H),
1.79-1.91 (m, 4H), .[.1.97 (t, J=7.3 Hz, 2H), 4.25 (t, J=7.4 Hz,
2H),.]. .Iadd.1.97 (t, J=7.3 Hz, 2H), 4.25(t, J=7.4 Hz, 2H),
.Iaddend.6.74 (br s, 1H), 7.24 (br s, 1H), 7.40-7.46 (m, 1H),
7.59-7.68 (m, 3H). FAB MS; 437 (M.sup.++1).
EXAMPLE 205
N.sup.1-Phenyl-4-[6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxycyclohexyl)-1--
ethynyl]-9H-9-purinyl]butaneamide Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.18-1.32 (m, 1H), 1.40-1.68 (m, 7H),
1.79-1.88 (m, 2H), 1.90-2.01 (m, 2H), .[.2.21 (t, J=7.2 Hz, 2H),
4.32 (t, J=7.2 Hz, 2H), 6.98 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.6 Hz,
2H), 7.34-7.41 (m, 1H), 7.46 (d, J=7.6 Hz, 2H),.]. .Iadd.2.21 (t,
J=7.2 Hz, 2H), 4.32(t, J=7.2 Hz, 2H), 6.98(t, J=7.6 Hz, 1H),
7.23(t, J=7.6 Hz, 2H)5, 7.34-7.41(m, 1H), 7.46(d, J=7.6 Hz, 2H),
.Iaddend.7.54-7.59 (m, 1H), 7.64-7.67 (m, 2H), 9.82 (s, 1H). FAB
MS; 513 (M.sup.++1).
EXAMPLE 206
1-{2-[8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanol
A methanesulfonate (470 mg) prepared from
1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cycl-
ohexanol by a conventional method was dissolved in 25 ml of
tetrahydrofuran, 0.44 ml of isoamyl nitride was added thereto and
the mixture was heated under reflux for 1 hour. The reaction
solution was concentrated to dryness and purified by a silica gel
column (eluting with dichloromethane:methanol=95:5) to give 20 mg
of the title compound.
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., CDCl.sub.3); 1.26-1.39
(m, 1H), 1.50-1.82 (m, 7H), 2.04-2.15 (m, 2H), 7.26-7.33 (m, 1H),
7.50-7.65 (m, 3H), 9.08 (s, 1H). FAB MS; 351 (M.sup.++1).
EXAMPLE 207
8-(3-fluorophenyl)-2-[2-(1-hydroxycyclopentyl)-1-ethynyl]-9-methyl-9H-6-pu-
rinol
To 50 mg of
1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cycl-
opentanol were added 3.0 ml of allyl alcohol and 1.0 ml of 5M NaOH,
the mixture was stirred at room temperature for 10 minutes, 1.0 ml
of THF was added thereto and the mixture was stirred again at room
temperature for 15 hours and 40 minutes. The solvent was evaporated
and then 200 ml of ethyl acetate and water (1:1) were added and an
extraction was carried out. The aqueous lyaer was extracted with
100 ml of ethyl acetate again and the all organic layers were
combined and washed with water and with brine once each. The
organic layer was dried over anhydrous sodium sulfate and the
solvent was evaporated. The resulting residue was purified by a
p-TLC (CH.sub.2Cl.sub.2:MeOH=10:1), the resulting yellowish white
crystals were suspended in diethyl ether and the suspenion was
filtered to give 217 mg of the title compound as white crystals.
The yield was 36%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.68-1.81 (m, 4H), 1.92-2.00 (m, 4H), 3.82
(s, 3H), 5.62 (s, 1H) 7.39-7.43 (m, 1H), 7.60-7.71 (m, 3H), 12.86
(s, 1H).
EXAMPLE 208
1-[(E)-2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl}-1-c-
yclopentanol Hydrochloride
A solution of 500 mg of
1-[(E)-2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]-1--
cyclopentanol in 5 ml of tetrahydrofuran was added dropwise into a
solution of 170 mg of lithium aluminum hydride in 10 ml of
tetrahydrofuran at a temperature lower than 7.degree. C. in a
nitrogen atmosphere, followed by stirring for 30 minutes. Water
(0.2 ml), 0.2 ml of 5N sodium hydroxide and 0.6 ml of water were
added dropwise into the reaction mixture was ice-cooling to stop
the reaction. The insoluble matters were filtered off, washed with
ethyl acetate and the filtrate was concentrated. The resulting
residue was subjected to a silica gel column chromatography (20 g
of silica gel; dichloromethane-dichloromethane:methanol=40:1-20:1)
and then to the same (20 g of NH silica gel;
dichloromethane-dichloromethane:methanol=150:1-100:1-40:1) to give
160 mg of a free substance of 3. The resulting free compound was
dissolved in methanol, five drops of 5N hydrochloric acid were
added and the mixture was concentrated. The resulting residue was
suspended in ether and the crystals were collected by filtration
and washed with ether to give 108 mg of the title compound. The
yield was 19%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.64-1.92 (m, 8H), 3.90 (s, 3H), .[.6.70
(d, J=15.6 Hz, 1H),.]. .Iadd.6.70 (d, J=15.6 Hz, 1H),
.Iaddend.7.46-7.52 (m, 1H), .[.7.51 (d, J=15.6 Hz, 1H),.].
.Iadd.7.51 (d, J=15.6 Hz, 1H), .Iaddend.7.65-7.71 (m, 1H),
7.73-7.80 (m, 2H). ESI MS; 354. m.p.; >290.degree. C.
Similarly were prepared the compounds of Examples 209-212 using the
corresponding materials.
EXAMPLE 209
1-[(E)-2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethenyl]-1-cy-
clobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.31 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.31(t, J=7.2 Hz, 3H),
.Iaddend.1.72-1.85 (m, 2H), 2.15-2.30 (m, 4H), .[.4.38 (q, J=7.2
Hz, 2H), 6.64 (d, J=15.6 Hz, 1H),.]. .Iadd.4.38 (q, J=7.2 Hz, 2H),
6.64(d, J=15.6 Hz, 1H), .Iaddend.7.47-7.53 (m, 1H), 7.64-7.74 (m,
4H). ESI MS; 354. m.p.; 178-180.degree. C.
EXAMPLE 210
(E)-4-[6-Amino--9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-buten--
2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.30 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.30(t, J=7.2 Hz, 3H), .Iaddend.1.32
(s, 6H), .[.4.36 (q, J=7.2 Hz, 2H), 6.62 (d, J=15.6 Hz, 1H), 7.38
(d, J=15.6 Hz, 1H).]. .Iadd.4.36 (q, J=7.2 Hz, 2H), 6.62(d, J=15.6
Hz, 1H), 7.38(d, J=15.6 Hz, 1H), .Iaddend.7.46-7.53 (m, 1H),
7.61-7.72 (m, 3H). ESI MS; 342.
EXAMPLE 211
(E)-4-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-2-methyl-3-buten--
2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.32 (s, 6H), 3.90 (s, 3H), .[.6.62 (d,
J=16.0 Hz, 1H), 6.44 (d, J=16.0 Hz, 1H),.]. .Iadd.6.62 (d, J=16.0
Hz, 1H), 6.44(d, J=16.0 Hz, 1H), .Iaddend.7.45-7.52 (m, 1H),
7.65-7.72 (m, 1H), 7.73-7.79 (m, 2H). ESI MS: 328. m.p.;
>290.degree. C.
EXAMPLE 212
(E)-1-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-ethyl-3-pente-1-o-
l Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.85 (t, J=7.2 Hz, 6H),
1.59 (q, J=7.2 Hz,4H),.]. .Iadd..delta., DMSO-d.sub.6); 0.85(t,
J=7.2 Hz, 6H), 1.59(q, J=7.2 Hz,4H), .Iaddend.3.90 (s, 3H), .[.6.62
(d, J=15.6 Hz, 1H), 7.32 (d, J=15.6 Hz, 1H),.]. .Iadd.6.62 (d,
J=15.6 Hz, 1H), 7.32(d, J=15.6 Hz, 1H), .Iaddend.7.45-7.52 (m, 1H),
7.64-7.71 (m, 1H), 7.72-7.79 (m, 2H). ESI MS; 356;
EXAMPLE 213
1-[(E) and
(Z)-2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethe-
nyl]-1-cyclopentanol Hydrochloride
1) 1-[(E) and
(Z)-2-(1,1,1-Tributylstannyl)-1-ethenyl]-1-cyclopentanols
A mixture of 10 g of 1-ethynyl-1-cyclopentanol, 30 ml of tributyl
in hydride and 190 mg of azobis (isobutyronitrile) was stirred in a
nitrogen atmosphere at 90.degree. C. for 3 hours. The reaction
mixture was evaporated to give 27 g of a mixture of E- and
Z-substances (E:Z=15:1) of b.p. 135.degree. C. (0.2 mmHg).
NMR (400 MHz, .[.CDCl.sub.3).delta.;.]. .Iadd..delta., CDCl.sub.3);
.Iaddend.0.80-0.98 (m, 9H), 1.25-1.92 (m, 26H), .[.5.86 (d, J=13.2
Hz,.]. .Iadd.5.86 (d, J=13.2 Hz, .Iaddend..dbd.CHSn of Z isomer),
6.14 (s, 2H, HC.dbd.CH of E isomer), .[.6.61 (d, J=13.2 Hz,.].
.Iadd.6.61 (d, J=13.2 Hz, .Iaddend..dbd.CH of Z isomer).
2)-1-[(E) and
(Z)-2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1-cyc-
lopentanol Hydrochloride
The above prepared mixture (17.93 g) of 1-[(E) and
(Z)-2-(1,1,1-tributylstannyl)-1-ethynyl]-1-cyclopentanols, 11 g of
8-(3-fluorophenyl)-2-iodod-9-methyl-9H-6-purinamine, 8.25 g of
tetrabutylammonium chloride and 671 mg of palladium acetate were
suspended in 165 ml of toluene and the suspension was stirred in a
nitrogen atmosphere at 90.degree. C. for 3.5 hours. The reaction
mixture was diluted with 165 ml of ethyl acetate and washed with a
saturated ammonium chloride solution and brine. The organic layer
was dried over anhydrous magneisum sulfate and then concentrated.
The resulting residue was subjected to a silica gel column
chromatography (350 g of silica gel; hexane, hexane:ethyl acetate
(4:1, 1:1, 1:2 and 1:4) and ethyl acetate) and then the resulting
crystals were washed with ethyl acetate/hexane to give 6.6 g of
crude
1-[(E)-2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1--
cyclopentanol. This was suspended in 70 ml of methanol, dissolved
by addition of 7 ml of 5N hydrochloric acid and the solution was
concentrated. After suspending with ether/ethyl acetate, the
crystals were collected by filtration, washed with ether and
air-dried at 60.degree. C. for 10 hours to give 5.92 g (51% yield)
of
1-[(E)-2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1--
cyclopentanol hydrochloride which was the same as that obtained in
Example 208. NMR and MS were the same as those mentioned above.
The filtrate was concentrated and re-purified to give 450 mg (4%
yield) of
1-[(Z)-2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-
-1-cyclopentanol hydrochloride.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.62-1.88 (m, 6H), 1.90-2.03 (m, 2H), 3.86
(s, 3H), .[.6.35 (d, J=13.2 Hz, 1H), 6.44 (d, J=13.2 Hz, 1H),.].
.Iadd.6.35 (d, J=13.2 Hz, 1H), 6.44(d, J=13.2 Hz, 1H),
.Iaddend.7.44-7.52 (m, 1H), 7.64-7.72 (m, 1H), 7.72-7.78 (m, 2H).
ESI MS; 354.
Similarly were synthesized the compounds of Examples 214 to
227.
EXAMPLE 214
1[(E)-2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethenyl]-1-cyc-
lopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.30 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.30(t, J=7.2 Hz, 3H),
.Iaddend.1.64-1.90 (m, 8H), .[.4.36 (q, J=7.2 Hz, 2H), 6.69 (d,
J=15.6 Hz, 1H), 7.47 (d, J=15.6 Hz, 1H),.]. .Iadd.4.36 (q, J=7.2
Hz, 2H), 6.69(d, J=15.6 Hz, 1H), 7.47(d, J=15.6 Hz, 1H),
.Iaddend.7.47-7.53 (m, 1H), 7.65-7.71 (m, 3H). ESI MS; 368.
EXAMPLE 215
1-[(E)-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1-cyc-
lobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.73-1.84 (m, 2H), 2.14-2.32 (m, 4H), 3.92
(s, 3H), .[.6.64 (d, J=16.0 Hz, 1H),.]. .Iadd.6.64 (d, J=16.0 Hz,
1H), .Iaddend.7.46-7.52 (m, 1H), 7.65-7.72 (m, 1H), .[.7.73 (d,
J=16.0 Hz, 1H),.]. .Iadd.7.73 (d, J-16.0 Hz, 1H),
.Iaddend.7.74-7.80 (m, 2H). ESI MS; 340. m.p.; 181-184.degree.
C.
EXAMPLE 216
1-[(E)-2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethenyl]-1-c-
yclohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.22-1.36 (m, 1H), 1.46-1.74 (m, 9H), 3.90
(s, 3H), .[.6.65 (d, J=15.6 Hz, 1H), 7.44-7.52 (m, 1H), 7.48 (d,
J=15.6 Hz, 1H),.]. .Iadd.6.65 (d, J=15.6 Hz, 1H), 7.44-7.52(m, 1H),
7.48(d, J=15.6 Hz, 1H), .Iaddend.7.64-7.71 (m, 1H), 7.73-7.79 (m,
2H). ESI MS; 368. m.p.; 222-225.degree. C.
EXAMPLE 217
1-[(E)-2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl]-1-cy-
clohexanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.31 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.31(t, J=7.2 Hz, 3H),
.Iaddend.1.47-1.72 (m, 10H), .[.4.37 (q, J=7.2 Hz, 2H), 6.65 (d,
J=16.0 Hz, 1H), 7.47-7.54 (m, 1H), 7.59 (d, J=16.0 Hz, 1H),.].
.Iadd.4.37 (q, J=7.2 Hz, 2H), 6.65(d, J=16.0 Hz, 1H), 7.47-7.54(m,
1H), 7.59(d, J=16.0 Hz, 1H), .Iaddend.7.65-7.72 (m, 3H). ESI MS;
382.
EXAMPLE 218
(E)-1-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-3-ethyl-3-penten-3-
-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.85 (t, J=7.2 Hz, 6H),
1.30 (t, J=7.2 Hz, 3H), 1.58 (q, J=7.2 Hz,4H), 4.36 (q, J=7.2 Hz,
2H), 6.62 (d, J=16.0 Hz, 1H), 7.30 (d, J=16.0 Hz, 1H),.].
.Iadd..delta., DMSO-d.sub.6); 0.85(t, J=7.2 Hz, 6H), 1.30(t, J=7.2
Hz, 3H), 1.58(q, J=7.2 Hz,4H), 4.36(q, J=7.2 Hz, 2H), 6.62(d,
J=16.0 Hz, 1H), 7.30(d, J=16.0 Hz, 1H), .Iaddend.7.47-7.53 (m, 1H),
7.64-7.72 (m, 3H ). ESI MS; 370.
EXAMPLE 219
(E)-4-[6-Amino-8-(3-fluorophenyl)-9-phenyl-9H-2-purinyl]-2-methyl-3-buten--
2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.26 (s, 6H), .[.6.50 (d, J=16.0 Hz, 1H),
7.19 (d, J=16.0 Hz, 1H),.]. .Iadd.6.50 (d, J=16.0 Hz, 1H), 7.19(d,
J=16.0 Hz, 1H), .Iaddend.7.22-7.35 (m, 3H), 7.42-7.51 (m, 3H),
7.56-7.62 (m, 3H). ESI MS; 390.
EXAMPLE 220
1-[(E)-2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethenyl]-1-c-
yclobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.74 (t, J=7.2 Hz, 3H),
1.66 (sex, J=7.2 Hz, 2H),.]. .Iadd..delta., DMSO-d.sub.6); 0.74(t,
J=7.2 Hz, 3H), 1.66(sex, J=7.2 Hz, 2H), .Iaddend.1.71-1.85 (m, 2H),
2.14-2.30 (m, 4H), .[.4.33 (t, J=7.2 Hz, 2H), 6.64 (d, J=16.0 Hz,
1H),.]. .Iadd.4.33 (t, J=7.2 Hz, 2H), 6.64(d, J=16.0 Hz, 1H),
.Iaddend.7.46-7.53 (m, 1H), 7.64-7.74 (m, 4H). ESI MS; 368.
EXAMPLE 221
1-[(E)-2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethenyl]-1-c-
yclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.74 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.74(t, J=7.2 Hz, 3H),
.Iaddend.1.60-1.93 (m, 10H), .[.4.32 (t, J=7.2 Hz, 2H), 6.69 (d,
J=15.6 Hz, 1H),.]. .Iadd.4.32 (t, J=7.2 Hz, 2H), 6.69(d, J=15.6 Hz,
1H), .Iaddend.7.46-7.54 (m, 1H), .[.7.50 (d, J=15.6 Hz, 1H),.].
.Iadd.7.50 (d, J=15.6 Hz, 1H), .Iaddend.7.64-7.72 (m, 3H). ESI MS;
382.
EXAMPLE 222
1-[(E)-2-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-1-ethenyl]-1-c-
yclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.74 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.74(t, J=7.2 Hz, 3H),
.Iaddend.1.23-1.37 (m, 1H), 1.47-1.60 (m, 9H), 1.66 (sex, 2H),
.[.4.32 (t, J=7.2 Hz, 2H), 6.65 (d, J=16.0 Hz, 1H), 7.46-7.52 (m,
1H), 7.54 (d, J=16.0 Hz, 1H),.]. .Iadd.4.32 (t, J=7.2 Hz, 2H),
6.65(d, J=16.0 Hz, 1H), 7.46-7.52(m, 1H), 7.54(d, J=16.0 Hz, 1H),
.Iaddend.7.66-7.72 (m, 3H). ESI MS; 396.
EXAMPLE 223
(E)-4-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-2-methyl-3-buten--
2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.74 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.74(t, J=7.2 Hz, 3H), .Iaddend.1.32
(s, 6H), .[.1.66 (sex, J=7.2 Hz, 2H), 4.33 (t, J=7.2 Hz, 2H), 6.62
(d, J=15.6 Hz, 1H), 7.43 (d, J=15.6 Hz, 1H),.]. .Iadd.1.66 (sex,
J=7.2 Hz, 2H), 4.33(t, J=7.2 Hz, 2H), 6.62(d, J=15.6 Hz, 1H),
7.43(d, J=15.6 Hz, 1H), .Iaddend.7.46-7.53 (m, 1H), 7.65-7.72 (m,
3H). ESI MS; 356.
EXAMPLE 224
(E)-1-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]-3-ethyl-3-penten--
3-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.73 (t, J=7.2 Hz, 3H),
0.85 (t, J=7.2 Hz, 6H), 1.58 (q, J=7.2 Hz,4H), 1.66 (sex, J=7.2 Hz,
2H), 4.32 (t, J=7.2 Hz, 2H), 6.61 (d, J=15.6 Hz, 1H), 7.29 (d,
J=15.6 Hz, 1H),.]. .Iadd..delta., DMSO-d.sub.6); 0.73(t, J=7.2 Hz,
3H), 0.85(t, J=7.2 Hz, 6H), 1.58(q, J=7.2 Hz,4H), 1.66(sex, J=7.2
Hz, 2H), 4.32(t, J=7.2 Hz, 2H), 6.61(d, J=15.6 Hz, 1H), 7.29(d,
J=15.6 Hz, 1H), .Iaddend.7.45-7.52 (m, 1H), 7.64-7.72 (m, 3H ). ESI
MS; 384.
EXAMPLE 225
1-[(E)-2-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethynyl-
]-cyclobutanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.77-0.84 (m, 2H), 1.08-1.16 (m, 2H),
1.72-1.86 (m, 2H), 2.14-2.32 (m, 4H), 3.78-3.84 (m, 1H), .[.6.64
(d, J=15.6 Hz, 1H),.]. .Iadd.6.64 (d, J=15.6 Hz, 1H),
.Iaddend.7.44-7.51 (m, 1H), 7.62-7.70 (m, 1H), .[.7.70 (d, J=15.6
Hz, 1H),.]. .Iadd.7.70 (d, J=15.6Hz, 1H), .Iaddend.7.81-7.89 (m,
2H). ESI MS; 366.
EXAMPLE 226
1-[(E)-2-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-2-purinyl-1-ethenyl]-
-1-cyclopentanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.77-0.83 (m, 2H), 1.07-1.14 (m, 2H),
1.65-1.93 (m, 8H), .[.3.80 (sept, J=3.6 Hz, 1H), 6.70 (d, J=15.6
Hz, 1H), 7.44-7.50 (m, 1H), 7.50 (d, J=15.6 Hz, 1H),.]. .Iadd.3.80
(sept, J=3.6 Hz, 1H), 6.70(d, J=15.6 Hz, 1H), 7.44-7.50(m, 1H),
7.50(d, J=15.6 Hz, 1H), .Iaddend.7.63-7.70 (m, 1H), 7.81-7.88 (m,
2H). ESI MS; 380.
EXAMPLE 227
(E)-4-[6-Amino-9-cyclopropyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-b-
uten-2-ol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.0.77-0.84 (m, 2H), 1.07-1.55 (m, 2H), 1.33
(s, 6H), .[.3.80 (sept, J=3.6 Hz, 1H), 6.63 (d, J=16.0 Hz, 1H),
7.41 (d, J=16.0 Hz, 1H),.]. .Iadd.3.80 (sept, J=3.6 Hz, 1H),
6.63(d, J=16.0 Hz, 1H), 7.41(d, J=16.0 Hz, 1H), .Iaddend.7.44-7.51
(m, 1H), 7.62-7.70 (m, 1H), 7.80-7.88 (m, 2H). ESI MS; 354.
EXAMPLE 228
(Z)-4-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-buten-2-
-ol Hydrochloride
To a solution of 200 mg of
4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-butyn-2-ol
in 20 ml of methanol were added 5 .mu.l of quinoline and 20 mg of
10% palladium/barium carbonate and the mixture was stirred in a
hydrogen atmosphere at room temperature for 10 minutes. The
palladium/barium carbonate was filtered off and the filtrate was
concentrated and then the resulting residue was subjected to a
silica gel column chromatography (15 g of silica gel;
dichloromethane-dichloromethane/methanol=60:1-40:1) to give
(Z)-4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-b-
uten-2-ol. This was dissolved in methanol and five drops of 5N
hydrochloric acid were added thereto followed by concentrating.
Ethyl acetate and ether were added to the resulting residue and the
crystals were collected by filtration and washed with ether to give
851 mg of the product. The yield was 26%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.33 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.33(t, J=7.2 Hz, 3H), .Iaddend.1.45
(s, 6H), .[.4.31 (q, J=7.2 Hz, 2H), 6.33 (d, J=13.4 Hz, 1H), 6.40
(d, J=13.4 Hz, 1H),.]. .Iadd.4.31 (q, J=7.2 Hz, 2H), 6.33(d, J=13.4
Hz, 1H), 6.40(d, J=13.4 Hz, 1H), .Iaddend.7.47-7.54 (m, 1H),
7.64-7.72 (m, 3H). ESI MS; 342.
EXAMPLE 229
1-2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethyl]-1-cyclopen-
tanol Hydrochloride
To a solution of 300 mg of
1-[2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]-1-cycl-
opentanol in 20 ml of methanol were added six drops of 5N
hydrochloric acid and 63 mg of 10% palladium/carbon and the mixture
was stirred in a hydrogen atmosphere at room temperature for 17
hours. The palladium/carbon was filtered off, the filtrate was
concentrated and the residue was dissolved in ethyl acetate and
saturated sodium hydrogen carbonate. The organic layer was washed
with brine, dried over anhydrous sodium sulfate and concentrated.
The resulting residue was subjected to a silica gel column
chromatography (15 g of silica gel; dichloromethane,
dichloromethane/methanol (40:1, 20:1 and 10:1) to give
1-[2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethyl]-1-cyclop-
entanol. This was dissolved in methanol and then five drops of 5N
hydrochloric acid were added thereto followed by concentrating.
Ether was added to the residue and the crystals were collected by
filtration and washed with ether to give .[.6209.]. .Iadd.209
.Iaddend.mg of the product. The yield was 69%.
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.45-1.80 (m, 8H), .[.2.02 (t, J=8.0 Hz,
2H), 3.00 (t, J=8.0 Hz, 2H),.]. .Iadd.2.02 (t, J=8.0 Hz, 2H),
3.00(t, J=8.0 Hz, 2H), .Iaddend.3.88 (s, 3H), 7.45-7.52 (m, 1H),
7.64-7.71 (m, 1H), 7.72-7.78 (m, 2H). ESI MS; 356.
Similarly were synthesized the compounds of Examples 230 to
237.
EXAMPLE 230
1-[2-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethyl]-1-cyclobu-
tanol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.45-1.58 (m, 1H), 1.60-1.70 (m, 1H),
.[.2.00 (dd, J=6.8 and 8.8 Hz, 4H), 2.06 (t, J=8.0 Hz, 2H), 2.93
(t, J=8.0 Hz, 2H),.]. .Iadd.2.00 (dd, J=6.8 and 8.8 Hz, 4H),
2.06(t, J=8.0 Hz, 2H), 2.93(t, J=8.0 Hz, 2H), .Iaddend.3.89 (s,
3H), 7.45-7.52 (m, 1H), 7.64-7.71 (m, 1H), 7.72-7.78 (m, 2H). ESI
MS; 342.
EXAMPLE 231
1-[6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-3-ethyl-3-pentanol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.84 (t, J=7.2 Hz, 6H),
1.42 (q, J=7.2 Hz, 4H),.]. .Iadd..delta., DMSO-d.sub.6); 0.84(t,
J=7.2 Hz, 6H), 1.42(q, J=7.2 Hz, 4H), .Iaddend.1.82-1.92 (m, 2H),
2.84-2.94 (m, 2H), 3.88 (s, 3H), 7.45-7.52 (m, 1H), 7.64-7.71 (m,
1H), 7.72-7.77 (m, 2H). ESI MS; 358.
EXAMPLE 232
1-[2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-1-ethyl]-1-cyclobut-
anol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.29 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 1.29(t, J=7.2 Hz, 3H),
.Iaddend.1.44-1.57 (m, 1H), 1.58-1.72 (m, 1H), .[.1.99 (dd, J=6.8
and 8.8 Hz, 4H), 2.05 (t, J=8.0 Hz, 2H), 2.93 (t, J=8.0 Hz, 2H),
4.34 (q, J=7.2 Hz, 2H),.]. .Iadd.1.99 (dd, J=6.8 and 8.8 Hz, 4H),
2.05(t, J=8.0 Hz, 2H), 2.93(t, J=8.0 Hz, 2H), 4.34(q, J=7.2 Hz,
2H), .Iaddend.7.47-7.53 (m, 1H), 7.64-7.72 (m, 3H). ESI MS;
356.
EXAMPLE 233
1-[2-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-purinyl]-1-ethyl]-1-cyclopenta-
nol Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 1.29 (t, J=7.2 Hz, 3H),
1.42-1.81 (m, 8H), 2.03 (t, J=8.0 Hz, 2H), 3.00 (t, J=8.0 Hz, 2H),
4.34 (q, J=7.2 Hz, 2H),.]. .Iadd..delta., DMSO-d.sub.6); 1.29(t,
J=7.2 Hz, 3H), 1.42-1.81(m, 8H), 2.03(t, J=8.0 Hz, 2H), 3.00(t,
J=8.0 Hz, 2H), 4.34(q, J=7.2 Hz, 2H), .Iaddend.7.47-7.53 (m, 1H),
7.63-7.72 (m, 3H). ESI MS; 370.
EXAMPLE 234
4-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-2-butanol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.17 (s, 6H), .[.1.29 (t, J=7.2 Hz, 3H),
1.91 (t, J=8.0 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H), 4.33 (q, J=7.2 Hz,
2H),.]. .Iadd.1.29 (t, J=7.2 Hz, 3H), 1.91(t, J=8.0 Hz, 2H),
2.95(t, J=8.0 Hz, 2H), 4.33(q, J=7.2 Hz, 2H), .Iaddend.7.47-7.53
(m, 1H), 7.64-7.72 (m, 3H). ESI MS; 344.
EXAMPLE 235
1-[6-Amino-9-ethyl-8-(3-fluorophenyl)-9-2-purinyl]-3-ethyl]-3-pentanol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.83 (t, J=7.2 Hz, 6H),
1.30 (t, J=7.2 Hz, 3H), 1.42 (q, J=7.2 Hz, 4H),.]. .Iadd..delta.,
DMSO-d.sub.6); 0.83(t, J=7.2 Hz, 6H), 1.30(t, J=7.2 Hz, 3H),
1.42(q, J=7.2 Hz, 4H), .Iaddend.1.83-1.92 (m, 2H), 2.84-2.95 (m,
2H), .[.4.34 (q, J=7.2 Hz, 2H),.]. .Iadd.4.34 (q, J=7.2 Hz, 2H),
.Iaddend.7.47-7.53 (m, 1H), 7.64-7.72 (m, 3H). ESI MS; 372.
EXAMPLE 236
4-[6-Amino-8-(3-fluorophenyl)-9-propyl-9H-2-purinyl]2-methyl-2-butanol
Hydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO); 0.72 (t, J=7.2 Hz, 3H),.].
.Iadd..delta., DMSO-d.sub.6); 0.72(t, J=7.2 Hz, 3H), .Iaddend.1.17
(s, 6H), .[.1.64 (sex, J=7.2 Hz, 3H), 1.91 (t, J=8.0 Hz, 2H), 2.95
(t, J=8.0 Hz, 2H), 4.30 (t, J=7.2 Hz, 2H),.]. .Iadd.1.64 (sex,
J=7.2 Hz, 3H), 1.91(t, J=8.0 Hz, 2H), 2.95(t, J=8.0 Hz, 2H),
4.30(t, J=7.2 Hz, 2H), .Iaddend.7.46-7.53 (m, 1H), 7.64-7.72 (m,
3H). ESI MS; 358.
EXAMPLE 237
4-[6-Amino-9-[4-(dimethylamino)phenyl]-8-(3-fluoro-phenyl)-9H-2-purinyl]-2-
-methyl-2-butanol Dihydrochloride
NMR (400 MHz, .[..delta., d.sub.6-DMSO);.]. .Iadd..delta.,
DMSO-d.sub.6); .Iaddend.1.12 (s, 6H), 1.76-1.82 (m, 2H), 2.82-2.90
(m, 2H), 3.00 (s, 6H), .[.6.89 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8
Hz, 2H),.]. .Iadd.6.89 (d, J=8.8 Hz, 2H), 7.25(d, J=8.8 Hz, 2H),
.Iaddend.7.27-7.37 (m, 3H), 7.44-7.51 (m, 1H). ESI MS; 435.
Structural formulae of the compounds of the above Examples are
shown in Table 3.
TABLE-US-00005 TABLE 3 Ex. No. Structural Formula 1 ##STR00021## 2
##STR00022## 3 ##STR00023## 4 ##STR00024## 5 ##STR00025## 6
##STR00026## 7 ##STR00027## 8 ##STR00028## 9 ##STR00029## 10
##STR00030## 11 ##STR00031## 12 ##STR00032## 13 ##STR00033## 14
##STR00034## 15 ##STR00035## 16 ##STR00036## 17 ##STR00037## 18
##STR00038## 19 ##STR00039## 20 ##STR00040## 21 ##STR00041## 22
##STR00042## 23 ##STR00043## 24 ##STR00044## 25 ##STR00045## 26
##STR00046## 27 ##STR00047## 28 ##STR00048## 29 ##STR00049## 30
##STR00050## 31 ##STR00051## 32 ##STR00052## 33 ##STR00053## 34
##STR00054## 35 ##STR00055## 36 ##STR00056## 37 ##STR00057## 38
##STR00058## 39 ##STR00059## 40 ##STR00060## 41 ##STR00061## 42
##STR00062## 43 ##STR00063## 44 ##STR00064## 45 ##STR00065## 46
##STR00066## 47 ##STR00067## 48 ##STR00068## 49 ##STR00069## 50
##STR00070## 51 ##STR00071## 52 ##STR00072## 53 ##STR00073## 54
##STR00074## 55 ##STR00075## 56 ##STR00076## 57 ##STR00077## 58
##STR00078## 59 ##STR00079## 60 ##STR00080## 61 ##STR00081## 62
##STR00082## 63 ##STR00083## 64 ##STR00084## 65 ##STR00085## 66
##STR00086## 67 ##STR00087## 68 ##STR00088## 69 ##STR00089## 70
##STR00090## 71 ##STR00091## 72 ##STR00092## 73 ##STR00093## 74
##STR00094## 75 ##STR00095## 76 ##STR00096## 77 ##STR00097## 78
##STR00098## 79 ##STR00099## 80 ##STR00100## 81 ##STR00101## 82
##STR00102## 83 ##STR00103## 84 ##STR00104## 85 ##STR00105## 86
##STR00106## 87 ##STR00107## 88 ##STR00108## 89 ##STR00109## 90
##STR00110## 91 ##STR00111## 92 ##STR00112## 93 ##STR00113## 94
##STR00114## 95 ##STR00115## 96 ##STR00116## 97 ##STR00117## 98
##STR00118## 99 ##STR00119## 100 ##STR00120## 101 ##STR00121## 102
##STR00122## 103 ##STR00123## 104 ##STR00124## 105 ##STR00125## 106
##STR00126## 107 ##STR00127## 108 ##STR00128## 109 ##STR00129## 110
##STR00130## 111 ##STR00131## 112 ##STR00132## 113 ##STR00133## 114
##STR00134## 115 ##STR00135## 116 ##STR00136## 117 ##STR00137## 118
##STR00138## 119 ##STR00139## 120 ##STR00140## 121 ##STR00141## 122
##STR00142## 123 ##STR00143## 124 ##STR00144## 125 ##STR00145## 126
##STR00146## 127 ##STR00147## 128 ##STR00148## 129 ##STR00149## 130
##STR00150## 131 ##STR00151## 132 ##STR00152## 133 ##STR00153## 134
##STR00154## 135 ##STR00155## 136 ##STR00156## 137 ##STR00157## 138
##STR00158## 139 ##STR00159## 140 ##STR00160## 141 ##STR00161## 142
##STR00162## 143 ##STR00163## 144 ##STR00164## 145 ##STR00165## 146
##STR00166## 147 ##STR00167## 148 ##STR00168## 149 ##STR00169## 150
##STR00170## 151 ##STR00171## 152 ##STR00172## 153 ##STR00173## 154
##STR00174## 155 ##STR00175## 156 ##STR00176## 157 ##STR00177## 158
##STR00178## 159 ##STR00179## 160 ##STR00180## 161 ##STR00181## 162
##STR00182## 163 ##STR00183## 164 ##STR00184## 165 ##STR00185## 166
##STR00186## 167 ##STR00187## 168 ##STR00188## 169 ##STR00189## 170
##STR00190## 171 ##STR00191## 172 ##STR00192## 173 ##STR00193## 174
##STR00194## 175 ##STR00195## 176 ##STR00196## 177 ##STR00197## 178
##STR00198## 179 ##STR00199## 180 ##STR00200## 181 ##STR00201## 182
##STR00202## 183 ##STR00203## 184 ##STR00204## 185 ##STR00205## 186
##STR00206## 187 ##STR00207## 188 ##STR00208## 189 ##STR00209## 190
##STR00210## 191 ##STR00211## 192 ##STR00212## 193 ##STR00213## 194
##STR00214## 195 ##STR00215## 196 ##STR00216## 197 ##STR00217## 198
##STR00218## 199 ##STR00219## 200 ##STR00220## 201 ##STR00221## 202
##STR00222## 203 ##STR00223## 204 ##STR00224## 205 ##STR00225## 206
##STR00226## 207 ##STR00227## 208 ##STR00228## 209 ##STR00229## 210
##STR00230## 211 ##STR00231## 212 ##STR00232## 213-1 ##STR00233##
213-2 ##STR00234## 214 ##STR00235## 215 ##STR00236## 216
##STR00237## 217 ##STR00238## 218 ##STR00239## 219 ##STR00240## 220
##STR00241## 221 ##STR00242## 222 ##STR00243## 223 ##STR00244## 224
##STR00245## 225 ##STR00246## 226 ##STR00247## 227 ##STR00248## 228
##STR00249## 229 ##STR00250## 230 ##STR00251## 231 ##STR00252## 232
##STR00253## 233 ##STR00254## 234 ##STR00255## 235 ##STR00256## 236
##STR00257## 237 ##STR00258##
Next, in order to facilitate the understanding that the adenosine
A2 receptor antagonist has an antidiabetic action, several examples
where the fundamental skeletons are different in chemical
structures will be shown as hereunder. It goes without saying that
the present invention is not limited thereto.
EXAMPLE 238
Adenosine A1 Receptor Binding Experiment
Human adenosine A1 receptor cDNA was subjected to an
over-expression in CHOK1 cells and its membrane specimen was
suspended in an incubation buffer (20 mM HEPES, 10 mM MgCl.sub.2
and 100 mM NaCl; pH 7.4) to make the concentration 66.7 .mu.g/ml.
To 0.45 ml of this membrane specimen were added 0.025 ml of
tritium-labeled chlorocyclopentyl adenosine (60 nM .sup.3H-CCPA; 30
Ci/mmol) and 0.025 ml of the compound to be tested. The solution of
the compound to be tested was prepared in such a manner that,
firstly, the compound was dissolved in DMSO to make 20 mM
concentration and then successively diluted each 10-fold using an
incubation buffer. The mixture was allowed to stand at 30.degree.
C. for 120 minutes, subjected to a quick suction on a glass fiber
filter (GF/B; manufactured by Whatman) and immediately washed with
5 ml of ice-cooled 50mM Tris-HCl buffer twice. After that, the
glass fiber filter was transferred to a vial bottle, a scintillator
was added and the radioactivity on the filter was measured by a
liquid scintillation counter. Calculation of the inhibition rate of
the test compound to the receptor bond (.sup.3H-CCPA) was carried
out by the following expression and, based upon that, IC.sub.50 was
calculated. Inhibition Rate (%)=[1-{(Binding amount in the presence
of drug-Non-specific binding amount)/(Total binding
amount-Non-specific binding amount)}].times.100
Total binding amount is a .sup.3H-CCPA binding radioactivity in the
absence of the test compound.
Non-specific binding amount is a .sup.3H-CCPA binding radioactivity
in the presence of 100 .mu.M of RPIA.
Binding amount in the presence of drug is a .sup.3H-CCPA binding
radioactivity in the presence of the test compound of various
concentrations.
The inhibition constant (Ki value) in Table was calculated from
Cheng-Prusoff's expression.
The results are shown in Table 4.
EXAMPLE 239
Adenosine A2a Receptor Binding Experiment
A membrane specimen prepared by an over-expression of adenosine A2a
receptor was purchased from Receptor Biology, Inc. and adenosine
A2a receptor binding experiments were carried out using that. The
purchased membrane specimen was suspended in an incubation buffer
(20 mM HEPES, 10 mM MgCl.sub.2 and 100 mM NaCl; pH 7.4) to make the
concentration 22.2 .mu.g/ml. To 0.45 ml of this membrane specimen
were added 0.025 ml of tritium-labeled .sup.3H-CGS21680 (500 nM; 30
Ci/mmol) and 0.025 ml of the test compound. The solution of the
test compound was prepared in such a manner that, firstly, the
compound was dissolved in DMSO to make 20 mM concentration and then
successively diluted each 10-fold using an incubation buffer. The
mixture was allowed to stand at 25.degree. C. for 90 minutes,
subjected to a quick suction on a glass fiber filter (GF/B;
manufactured by Whatman) and immediately washed with 5 ml of
ice-cooled 50 mM Tris-HCl buffer twice. After that, the glass fiber
filter was transferred to a vial bottle, a scintillator was added
and the radioactivity on the filter was measured by a liquid
scintillation counter. Calculation of the inhibition rate of the
test compound to the receptor bond (.sup.3H-CGS21680) of A2a was
carried out by the following expression and, based upon that,
IC.sub.50 was calculated. Inhibition Rate (%)=[1-{(Binding amount
in the presence of drug-Non-specific binding amount)/(Total binding
amount amount-Non-specific binding amount)}].times.100
Total binding amount is a .sup.3H-CGS21680 binding radioactivity in
the absence of the test compound.
Non-specific binding amount is a .sup.3H-CGS21680 binding
radioactivity in the presence of 100 .mu.M of RPIA.
Binding amount in the presence of drug is a .sup.3H-CGS21680
binding radioactivity in the presence of the test compound of
various concentrations.
The inhibition constant (Ki value) in Table was calculated from
Cheng-Prusoff's expression.
The results are shown in Table 4.
TABLE-US-00006 TABLE 4 Human adenosine A1, A2a receptor binding
test A1 receptor A2a receptor Receptor Test Compound Ki (.mu.M) Ki
(.mu.M) ##STR00259## 0.024 0.002 ##STR00260## 0.019 0.0014
##STR00261## 0.054 0.75 ##STR00262## 10< 0.052 ##STR00263##
10< 0.047
EXAMPLE 240
Evaluation of Test Compound in Adenosine A2b Receptor Expressed
Cells Using Suppression of NECA-stimulated cAMP Expression as an
Index
Human adenosine A2b receptor cDNA was over-expressed in CHOK1
cells. The cells were uniformly placed on a 24-well plate at the
rate of 1.5.times.10.sup.5 cells/well, incubated for one night and
then used for the experiments. Affinity of the test compound to the
A2b receptor was evaluated in which the index used was the degree
of suppression of the amount of cAMP produced by stimulation of
NECA (30 nM) which was an adenosine agonist in the presence of the
test compound. Thus, after washing with 2 ml/well of an incubation
buffer (Krebs solution; pH7.4) twice, a pre-incubation was carried
out at 0.5 ml/well for 30 minutes. After that, 100 .mu.l/well of a
mixed solution containing 600 .mu.M of Ro-20-1724
(phosphodiesterase inhibitor), 180 nM of NECA and a test compound
which was 6-fold concentrated in a reaction solution were added.
After 15 minutes, the reaction was stopped by substituting 0.1N HCl
(300 .mu.l/well) for the reaction solution. Measurement of cAMP was
carried out using an Amersham cAMP EIA Kit.
Calculation of the suppression rate of the test compound to the
NECA-stimulated cAMP production was done by the following
expression. Inhibition Rate (%)=[1-{(cAMP amount in the presence of
NECA and test compound-cAMP amount in the case of incubation buffer
only)/(cAMP amount stimulated only by NECA-cAMP amount in the case
of incubation buffer only)}].times.100.
IC.sub.50 .[.(3-fluorophenyl).]. was calculated from the above.
The result is shown in Table 5.
TABLE-US-00007 TABLE 5 suppressing action to NECA-stimulated cAMP
production in adenosine A2b receptor expressed cells Receptor A2b
receptor Compound IC.sub.50 (.mu.M) Compound A 0.028 Compound B
0.070 Compound C 0.10 KW6002 2.85 KF17837 1.36
EXAMPLE 241
Action of Spontaneous Diabetic Mice (KK-A.sup.y/Ta Jcl) to
Hyperglycemia (by Single Administration)
Animals: Five male KK-A.sup.y/TA Jcl mice for each group
(introduced from Nippon Clair) Preparation and Administration of
Test Compound: A test compound in a dose shown in Table 6 was
suspended in a 0.5% aqueous solution of methyl cellulose and was
orally administered .[.in a dose.]. .Iadd.at a volume .Iaddend.of
10 ml/kg. Collection of Blood Samples and Determination of Blood
.[.Sugar.]. .Iadd.Glucose.Iaddend.: Blood was collected from tail
vein immediately before administration of the test compound and
also five hours after the administration and blood .[.sugar.].
.Iadd.glucose .Iaddend.was determined. Method: Tail vein of mouse
was injured by a razor without an anesthetization to bleed
slightly. The blood (15 .mu.l) was collected and immediately mixed
with 135 .mu.l of a 0.6 M perchloric acid. Glucose in the
supernatant obtained by a centrifugal separation (at 1500 g for 10
minutes at 4.degree. C. using a cooling centrifuge GS-6KR of
Beckmann) was determined by a Glucose CII Test Wako (Wako Pure
Chemicals).
The result is shown in Tables 6-1 to 6-4 for each experiment.
The result is shown in terms of "(% ratio of the blood sugar after
5 hours from the administration to the blood sugar before the
administration).+-.(standard error)". The data were subjected to a
one-way layout analysis of variance and then subjected to a
multiple comparison of Dunnett type. The case where p<0.05 was
judged that a significant difference was available.
TABLE-US-00008 TABLE 6-1 Action of spontaneous diabetic mice
(KK-A.sup.7/Ta Jcl) to hyperglycemia Test Compound Dose (mg/kg)
.times. .times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. ##EQU00004## Sig- nificance Solvent
72.4 .+-. 4.4 Compound 10 47.8 .+-. 4.8 ** A Compound 10 51.8 .+-.
2.9 ** B Compounds A and B are administered in a form of sulfate.
(**; p < 0.01 vs. Solvent)
TABLE-US-00009 TABLE 6-2 Action of spontaneous diabetic mice
(KK-A.sup.7/Ta Jcl) to hyperglycemia Test Compound Dose (mg/kg)
.times. .times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. ##EQU00005## Sig- nificance Solvent
69.8 .+-. 2.3 Compound 30 48.5 .+-. 3.4 ** C (**; p < 0.01 vs.
Solvent)
TABLE-US-00010 TABLE 6-3 Action of spontaneous diabetic mice
(KK-A.sup.7/Ta Jcl) to hyperglycemia Test Compound Dose (mg/kg)
.times. .times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. ##EQU00006## Sig- nificance Solvent
76.6 .+-. 3.9 KW6002 100 57.6 .+-. 5.6 * (*; p < 0.05 vs.
Solvent)
TABLE-US-00011 TABLE 6-4 Action of spontaneous diabetic mice
(KK-A.sup.7/Ta Jcl) to hyperglycemia Test Compound Dose (mg/kg)
.times. .times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. .times..times. .times..times.
.times..times. .times..times. ##EQU00007## Sig- nificance Solvent
80.7 .+-. 2.3 KF17837 100 62.0 .+-. 2.8 * (*; p < 0.05 vs.
Solvent)
As such, adenosine A2 receptor antagonist showed a clear
hypoglycemic action in spontaneous diabetic models.
In the experiments for the NECA-stimulated glucose production in
hepatic cells, the antagonist which was specific to adenosine A2a
receptor did not show a .[.saccharogenesis.]. .Iadd.glucose
production .Iaddend.suppressing action and only the compound
showing a strong .[.suppressing action of A2b.]. .Iadd.affinity to
A2b receptor .Iaddend.showed a .[.saccharogenesis.]. .Iadd.glucose
production .Iaddend.suppressing action. In addition, a glucose
tolerance improving action in glucose tolerance test which is an
index for .[.sugar.]. .Iadd.glucose .Iaddend.utilization in
peripheral tissues was noted both in antagonists which were
specific to adenosine A2a and in compounds having a strong
antagonistic action to A2b receptor.
On the other hand, no hypoglycemic action was noted for FK453
(European Journal of Pharmacology, 279, 217-225, 1995.) known as an
antagonist specific to adenosine A1 receptor even at the dose of
100 mg/kg in the present diabetic models. In addition, no glucose
tolerance improving action was noted in glucose tolerance test as
well.
From the above, it is clear that the effect in the present diabetic
models is due to an antagonistic action of adenosine A2 (A2a and/or
A2b) receptor.
REFERENTIAL EXAMPLE
Synthesis of
2-(3-Fluorophenyl)-(4-pyridyl)-3H-imidazo[4,5-b]pyridine
Hydrochloride (Compound C)
N.sup.2-(4-Pyridyl)-2,3-pyridinediamine was dissolved in 20 ml of
methanol, 1 ml of acetic acid and 745 mg of 3-fluorobenzaldehyde
were added and the mixture was stirred at room temperature for 16
hours. The reaction solution was concentrated and subjected to an
azeotropy with toluene for three times. The resulting residue after
concentration was suspended in 30 ml of ethanol, 1.5 g of anhydrous
iron chloride were added thereto and the mixture was heated under
reflux for 5 hours. The reaction solution was returned to room
temperature, concentrated to dryness, diluted with 100 ml of ethyl
acetate and washed with 50 ml of water and 20 ml of brine. The
organic layer was concentrated to dryness and the residue was
purified by a silica gel column chromatography (eluted with ethyl
acetate:n-hexane=3:1) to give 0.36 g of a free compound. The free
compound was dissolved in 20 ml of methanol, 6.5 ml of 1N
hydrochloric acid were added thereto and the mixture was
concentrated to dryness. Ethanol was added to the residue, the
mixture was subjected to an azeotropy, suspended in 10 ml ethyl
acetate and 0.45 g of the title compound was obtained by collecting
by filtration. The overall yield was 46%.
NMR (400 MHz, .[..delta.,.]. .Iadd..delta., .Iaddend.DMSO-d.sub.6);
7.35-7.55 (m, 5H), .[.7.88 (d, J=6.4 Hz, 2H), 8.33 (dd, J=1.6 Hz,
8.0 Hz, 1H), 8.45 (dd, J=1.6 Hz, 4.8 Hz, 1H), 8.94 (d, J=6.4 Hz,
2H)..]. .Iadd.7.88 (d, J=6.4 Hz, 2H), 8.33(dd, J=1.6 Hz, 8.0 Hz,
1H), 8.45(dd, J=1.6 Hz, 4.8 Hz, 1H), 8.94(d, J=6.4 Hz,
2H)..Iaddend.
The purine compound and the adenosine A2 receptor antagonists which
are the compounds of the present invention show a clear
hypoglycemic action in spontaneous diabetic models and also have an
action of improving an impaired glucose tolerance, whereby they are
useful as a preventive or therapeutic agent for diabetes mellitus
and diabetic complications.
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