U.S. patent application number 09/918040 was filed with the patent office on 2002-03-14 for method for inhibiting neoplastic cells and related conditions by exposure to 2,9-disubstituted purin-6-ones.
Invention is credited to Pamukcu, Rifat, Piazza, Gary A..
Application Number | 20020032209 09/918040 |
Document ID | / |
Family ID | 22539746 |
Filed Date | 2002-03-14 |
United States Patent
Application |
20020032209 |
Kind Code |
A1 |
Pamukcu, Rifat ; et
al. |
March 14, 2002 |
Method for inhibiting neoplastic cells and related conditions by
exposure to 2,9-disubstituted purin-6-ones
Abstract
A method for inhibiting the growth of neoplastic cells by
exposure to 2,9-disubstituted purin-6-ones.
Inventors: |
Pamukcu, Rifat; (Spring
House, PA) ; Piazza, Gary A.; (Doylestown,
PA) |
Correspondence
Address: |
Cell Pathways, Inc.
702 Electronic Drive
Horsham
PA
19044
US
|
Family ID: |
22539746 |
Appl. No.: |
09/918040 |
Filed: |
July 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09918040 |
Jul 30, 2001 |
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09151665 |
Sep 11, 1998 |
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6268372 |
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Current U.S.
Class: |
514/263.35 ;
514/151; 514/263.36 |
Current CPC
Class: |
A61K 31/522
20130101 |
Class at
Publication: |
514/262 ;
514/151 |
International
Class: |
A61K 031/522; A61K
031/655 |
Claims
We claim:
1. A method for inhibiting the growth of neoplastic cells
comprising exposing the cells to a growth inhibiting effective
amount of a compound of Formula 107wherein R.sub.1 is selected from
the group consisting of straight-chain or branched alkyl with 2 to
10 carbon atoms, which is optionally substituted by phenyl, which
in turn may be substituted by halogen, nitro, cyano, or by
straight-chain or branched alkyl with up to 6 carbon atoms; R.sub.2
is selected from the group consisting of hydrogen, hydroxy, azido,
or a straight-chain or branched alkyl with up to 6 carbon atoms, or
a group with the formula --O--SO.sub.2R.sub.5; R.sub.5 is selected
from the group consisting of a straight-chain or branched alkyl
with up to 4 carbon atoms or phenyl; R.sub.3 is selected from the
group consisting of hydrogen or R.sub.2 and R.sub.3 together form a
group of the formula .dbd.O; R.sub.4 is selected from the group
consisting of hydrogen or a straight-chain or branched alkyl with
up to 4 carbon atoms; and A is selected from the group consisting
of a moiety of the formula: 108or a straight-chain or branched
alkyl with up to 20 carbon atoms, or a cycloalkyl with 3 to 7
carbon atoms, phenyl wherein said moiety, alkyl, cycloalkyl or
phenyl groups are optionally substituted with one or two groups
independently selected from the group consisting of halogen,
carboxyl, trifluoromethyl, nitro, hydroxy, cyano, or straight-chain
or branched alkyl, alkoxycarbonyl, or alkoxy, each with up to 5
carbon atoms, which in turn may be substituted by phenyl, said ring
structures optionally substituted by phenyl, which in turn may be
substituted by straight-chain or branched alkoxy with up to 5
carbon atoms; and their tautomers and salts.
2. The method according to claim 1 wherein R.sub.1 is selected from
the group consisting of straight-chain or branched alkyl with 2 to
8 carbon atoms, which is optionally substituted by phenyl, which in
turn may be substituted by fluorine; chlorine, bromine, nitro,
cyano, or by straight-chain or branched alkyl with up to 4 carbon
atoms, R.sub.2 is selected from the group consisting of hydrogen,
hydroxy, azido, or for straight-chain or branched alkyl with up to
4 carbon atoms, or a group with the formula --O--SO.sub.2R.sub.5;
R.sub.5 is selected from the group consisting of straight-chain or
branched alkyl with up to 3 carbon atoms, or phenyl; R.sub.4 is
selected from the group consisting of hydrogen or for
straight-chain or branched alkyl with up to 3 carbon atoms; and A
is selected from the group consisting of a moiety of the formula
109or straight-chain or branched alkyl with up to 19 carbon atoms,
or for cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or for
phenyl, which optionally are substituted with one or two groups
independently selected from the group consisting of fluorine,
chlorine, bromine, carboxyl, nitro, hydroxy, or by straight-chain
or branched alkyl, alkoxycarbonyl, or alkoxy, each with up to 4
carbon atoms, which in turn may be substituted by phenyl, said ring
structures optionally are optionally substituted by phenyl, which
in turn may be substituted by straight-chain or branched alkoxy
with up to 4 carbon atoms and their tautomers and salts.
3. The method according to claim 1 wherein R.sub.1 is selected from
the group consisting of straight-chain or branched alkyl with 2 to
7 carbon atoms, which is optionally substituted by phenyl, which in
turn may be substituted by fluorine, chlorine, bromine, nitro,
cyano, or by straight-chain or branched alkyl with up to 3 carbon
atoms; R.sub.2 is selected from the group consisting of hydrogen,
hydroxy, azido, or a straight-chain or branched alkyl with up to 3
carbon atoms, or for a group with the formula --O--SO.sub.2R.sub.5;
R.sub.5 is selected from the group consisting of straight-chain or
branched alkyl with up to 3 carbon atoms or phenyl, R.sub.3 is
selected from the group consisting of hydrogen or R.sub.2 and
R.sub.3 jointly form the group of the formula .dbd.O, R.sub.4 is
selected from the group consisting of hydrogen or a straight-chain
or branched alkyl with up to 3 carbon atoms; and A is selected from
the group consisting of a group of the formula 110or for
straight-chain or branched alkyl with up to 18 carbon atoms, or
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or for phenyl,
which optionally are substituted up to twice with the same or
different substituents consisting of fluorine, chlorine, bromine,
carboxyl, nitro, hydroxy, or by straight-chain or branched alkyl,
alkoxycarbonyl, or alkoxy, each with up to 3 carbon atoms, which in
turn may be substituted by phenyl, and/or the rings are optionally
substituted by phenyl, which in turn may be substituted by
straight-chain or branched alkoxy with up to 3 carbon atoms; and
their tautomers and salts.
4. A method of treating a mammal having precancerous lesions
comprising administering a pharmacologically effective amount of a
compound of Formula I: 111wherein R.sub.1 is selected from the
group consisting of straight-chain or branched alkyl with 2 to 10
carbon atoms, which is optionally substituted by phenyl, which in
turn may be substituted by halogen, nitro, cyano, or by
straight-chain or branched alkyl with up to 6 carbon atoms; R.sub.2
is selected from the group consisting of hydrogen, hydroxy, azido,
or a straight-chain or branched alkyl with up to 6 carbon atoms, or
a group with the formula --O--SO.sub.2R.sub.5; R.sub.5 is selected
from the group consisting of a straight-chain or branched alkyl
with up to 4 carbon atoms or phenyl; R.sub.3 is selected from the
group consisting of hydrogen or R.sub.2 and R.sub.3 together form a
group of the formula .dbd.O; R.sub.4 is selected from the group
consisting of hydrogen or a straight-chain or branched alkyl with
up to 4 carbon atoms; and A is selected from the group consisting
of a moiety of the formula: 112or a straight-chain or branched
alkyl with up to 20 carbon atoms, or a cycloalkyl with 3 to 7
carbon atoms, phenyl wherein said moiety, alkyl, cycloalkyl or
phenyl groups are optionally substituted with one or two groups
independently selected from the group consisting of halogen,
carboxyl, trifluoromethyl, nitro, hydroxy, cyano, or straight-chain
or branched alkyl, alkoxycarbonyl, or alkoxy, each with up to 5
carbon atoms, which in turn may be substituted by phenyl, said ring
structures optionally substituted by phenyl, which in turn may be
substituted by straight-chain or branched alkoxy with up to 5
carbon atoms; and their tautomers and salts.
5. The method according to claim 4 wherein R.sub.1 is selected from
the group consisting of straight-chain or branched alkyl with 2 to
8 carbon atoms, which is optionally substituted by phenyl, which in
turn may be substituted by fluorine; chlorine, bromine, nitro,
cyano, or by straight-chain or branched alkyl with up to 4 carbon
atoms, R.sub.2 is selected from the group consisting of hydrogen,
hydroxy, azido, or for straight-chain or branched alkyl with up to
4 carbon atoms, or a group with the formula --O--SO.sub.2R.sub.5;
R.sub.5 is selected from the group consisting of straight-chain or
branched alkyl with up to 3 carbon atoms, or phenyl; R.sub.4 is
selected from the group consisting of hydrogen or for
straight-chain or branched alkyl with up to 3 carbon atoms; and A
is selected from the group consisting of a moiety of the formula
113or straight-chain or branched alkyl with up to 19 carbon atoms,
or for cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or for
phenyl, which optionally are substituted with one or two groups
independently selected from the group consisting of fluorine,
chlorine, bromine, carboxyl, nitro, hydroxy, or by straight-chain
or branched alkyl, alkoxycarbonyl, or alkoxy, each with up to 4
carbon atoms, which in turn may be substituted by phenyl, said ring
structures optionally are optionally substituted by phenyl, which
in turn may be substituted by straight-chain or branched alkoxy
with up to 4 carbon atoms and their tautomers and salts.
6. The method according to claim 4 wherein R.sub.1 is selected from
the group consisting of straight-chain or branched alkyl with 2 to
7 carbon atoms, which is optionally substituted by phenyl, which in
turn may be substituted by fluorine, chlorine, bromine, nitro,
cyano, or by straight-chain or branched alkyl with up to 3 carbon
atoms; R.sub.2 is selected from the group consisting of hydrogen,
hydroxy, azido, or a straight-chain or branched alkyl with up to 3
carbon atoms, or for a group with the formula --O--SO.sub.2R.sub.5;
R.sub.5 is selected from the group consisting of straight-chain or
branched alkyl with up to 3 carbon atoms or phenyl, R.sub.3 is
selected from the group consisting of hydrogen or R.sub.2 and
R.sub.3 jointly form the group of the formula .dbd.O, R.sub.4 is
selected from the group consisting of hydrogen or a straight-chain
or branched alkyl with up to 3 carbon atoms; and A is selected from
the group consisting of a group of the formula or for
straight-chain or branched alkyl with up to 18 carbon atoms, or
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or for phenyl,
which optionally are substituted up to twice with the same or
different substituents consisting of fluorine, chlorine, bromine,
carboxyl, nitro, hydroxy, or by straight-chain or branched alkyl,
alkoxycarbonyl, or alkoxy, each with up to 3 carbon atoms, which in
turn may be substituted by phenyl, and/or the rings are optionally
substituted by phenyl, which in turn may be substituted by
straight-chain or branched alkoxy with up to 3 carbon atoms; and
their tautomers and salts.
7. A method for regulating apoptosis in human cells comprising
exposing said cells to an effective amount of a compound of the
formula: 114wherein R.sub.1 is selected from the group consisting
of straight-chain or branched alkyl with 2 to 10 carbon atoms,
which is optionally substituted by phenyl, which in turn may be
substituted by halogen, nitro, cyano, or by straight-chain or
branched alkyl with up to 6 carbon atoms; R.sub.2 is selected from
the group consisting of hydrogen, hydroxy, azido, or a
straight-chain or branched alkyl with up to 6 carbon atoms, or a
group with the formula --O--SO.sub.2R.sub.5; R.sub.5 is selected
from the group consisting of a straight-chain or branched alkyl
with up to 4 carbon atoms or phenyl; R.sub.3 is selected from the
group consisting of hydrogen or R.sub.2 and R.sub.3 together form a
group of the formula .dbd.O; R.sub.4 is selected from the group
consisting of hydrogen or a straight-chain or branched alkyl with
up to 4 carbon atoms; and A is selected from the group consisting
of a moiety of the formula: 115or a straight-chain or branched
alkyl with up to 20 carbon atoms, or a cycloalkyl with 3 to 7
carbon atoms, phenyl wherein said moiety, alkyl, cycloalkyl or
phenyl groups are optionally substituted with one or two groups
independently selected from the group consisting of halogen,
carboxyl, trifluoromethyl, nitro, hydroxy, cyano, or straight-chain
or branched alkyl, alkoxycarbonyl, or alkoxy, each with up to 5
carbon atoms, which in turn may be substituted by phenyl, said ring
structures optionally substituted by phenyl, which in turn may be
substituted by straight-chain or branched alkoxy with up to 5
carbon atoms; and their tautomers and salts.
8. The method according to claim 7 wherein R.sub.1 is selected from
the group consisting of straight-chain or branched alkyl with 2 to
8 carbon atoms, which is optionally substituted by phenyl, which in
turn may be substituted by fluorine; chlorine, bromine, nitro,
cyano, or by straight-chain or branched alkyl with up to 4 carbon
atoms, R.sub.2 is selected from the group consisting of hydrogen,
hydroxy, azido, or for straight-chain or branched alkyl with up to
4 carbon atoms, or a group with the formula --O--SO.sub.2R.sub.5;
R.sub.5 is selected from the group consisting of straight-chain or
branched alkyl with up to 3 carbon atoms, or phenyl; R.sub.4 is
selected from the group consisting of hydrogen or for
straight-chain or branched alkyl with up to 3 carbon atoms; and A
is selected from the group consisting of a moiety of the formula
116or straight-chain or branched alkyl with up to 19 carbon atoms,
or for cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or for
phenyl, which optionally are substituted with one or two groups
independently selected from the group consisting of fluorine,
chlorine, bromine, carboxyl, nitro, hydroxy, or by straight-chain
or branched alkyl, alkoxycarbonyl, or alkoxy, each with up to 4
carbon atoms, which in turn may be substituted by phenyl, said ring
structures optionally are optionally substituted by phenyl, which
in turn may be substituted by straight-chain or branched alkoxy
with up to 4 carbon atoms and their tautomers and salts.
9. The method according to claim 7 wherein R.sub.1 is selected from
the group consisting of straight-chain or branched alkyl with 2 to
7 carbon atoms, which is optionally substituted by phenyl, which in
turn may be substituted by fluorine, chlorine, bromine, nitro,
cyano, or by straight-chain or branched alkyl with up to 3 carbon
atoms; R.sub.2 is selected from the group consisting of hydrogen,
hydroxy, azido, or a straight-chain or branched alkyl with up to 3
carbon atoms, or for a group with the formula --O--SO.sub.2R.sub.5;
R.sub.5 is selected from the group consisting of straight-chain or
branched alkyl with up to 3 carbon atoms or phenyl, R.sub.3 is
selected from the group consisting of hydrogen or R.sub.2 and
R.sub.3 jointly form the group of the formula .dbd.O, R.sub.4 is
selected from the group consisting of hydrogen or a straight-chain
or branched alkyl with up to 3 carbon atoms; and A is selected from
the group consisting of a group of the formula 117or for
straight-chain or branched alkyl with up to 18 carbon atoms, or
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or for phenyl,
which optionally are substituted up to twice with the same or
different substituents consisting of fluorine, chlorine, bromine,
carboxyl, nitro, hydroxy, or by straight-chain or branched alkyl,
alkoxycarbonyl, or alkoxy, each with up to 3 carbon atoms, which in
turn may be substituted by phenyl, and/or the rings are optionally
substituted by phenyl, which in turn may be substituted by
straight-chain or branched alkoxy with up to 3 carbon atoms; and
their tautomers and salts.
Description
[0001] This invention relates to a method for the selective
inhibition of neoplastic cells, for example, for the treatment or
prevention of precancerous lesions or other neoplasias in mammals,
in particular by using 2,9-disubstituted purin-6-ones as
therapeutic agents.
BACKGROUND OF THE INVENTION
[0002] Each year in the United States alone, untold numbers of
people develop precancerous lesions, which is a form of neoplasia,
as discussed below. Such lesions exhibit a strong tendency to
develop into malignant tumors, or cancer. Such lesions include
lesions of the breast (that can develop into breast cancer),
lesions of the skin (that can develop into malignant melanoma or
basal cell carcinoma), colonic adenomatous polyps (that can develop
into colon cancer), and other such neoplasms. Compounds that
prevent or induce the remission of existing precancerous or
cancerous lesions or carcinomas would greatly reduce illness and
death from cancer.
[0003] For example, approximately 60,000 people die from colon
cancer, and over 150,000 new cases of colon cancer are diagnosed
each year. For the American population as a whole, individuals have
a six percent lifetime risk of developing colon cancer, making it
the second most prevalent form of cancer in the country. Colon
cancer is also prevalent in Western Europe. It is believed that
increased dietary fat consumption is increasing the risk of colon
cancer in Japan.
[0004] In addition, the incidence of colon cancer reportedly
increases with age, particularly after the age of 40. Since the
mean ages of populations in America and Western Europe are
increasing, the prevalence of colorectal cancer should increase in
the future.
[0005] To date, little progress has been made in the prevention and
treatment of colorectal cancer, as reflected by the lack of change
in the five-year survival rate over the last few decades. The only
cure for this cancer is surgery at an extremely early stage.
Unfortunately, most of these cancers are discovered too late for
surgical cure. In many cases, the patient does not experience
symptoms until the cancer has progressed to a malignant stage.
[0006] In view of these grim statistics, efforts in recent years
have concentrated on colon cancer prevention. Colon cancer usually
arises from pre-existing benign neoplastic growths known as polyps.
Prevention efforts have emphasized the identification and removal
of colonic polyps. Polyps are identified by x-ray and/or
colonoscopy, and usually removed by devices associated with the
colonoscope. The increased use of colon x-rays and colonoscopies in
recent years has detected clinically significant precancerous
polyps in four to six times the number of individuals per year that
acquire colon cancer. During the past five years alone, an
estimated 3.5 to 5.5 million people in the United States have been
diagnosed with adenomatous colonic polyps, and it is estimated that
many more people have or are susceptible to developing this
condition, but are as yet undiagnosed. In fact, there are estimates
that 10-12 percent of people over the age of 40 will form
clinically significant adenomatous polyps.
[0007] Removal of polyps has been accomplished either with surgery
or fiber-optic endoscopic polypectomy--procedures that are
uncomfortable, costly (the cost of a single polypectomy ranges
between $1,000 and $1,500 for endoscopic treatment and more for
surgery), and involve a small but significant risk of colon
perforation which can be fatal. Overall, about $2.5 billion is
spent annually in the United States in colon cancer treatment and
prevention.
[0008] In the breast, breast cancer is often treated surgically,
often by radical mastectomy with its painful and emotional
aftermath. Such surgery is costly, too.
[0009] As indicated above, each lesion carries with it a chance
that it will develop into a cancer. The likelihood of cancer is
diminished if a precancerous lesion is removed. However, many of
these patients demonstrate a propensity for developing additional
lesions in the future. They must, therefore, be monitored
periodically for the rest of their lives for reoccurrence.
[0010] In most cases (i.e. the cases of sporadic lesion formation,
e.g. so-called common sporadic polyps), lesion removal will be
effective to reduce the risk of cancer. In a small percentage of
cases (i.e. cases where numerous lesions form, e.g. the so-called
polyposis syndromes), removal of all or part of the effected area
(e.g. the colon) is indicated. For example, the difference between
common sporadic polyps and polyposis syndromes is dramatic. Common
sporadic polyp cases are characterized by relatively few polyps
that can usually be removed leaving the colon intact. By contrast,
polyposis syndrome cases can be characterized by many (e.g.
hundreds or more) of polyps--literally covering the colon in some
cases--making safe removal of the polyps impossible short of
surgical removal of the colon.
[0011] Because each lesion carries with it a palpable risk of
cancerous development, patients who form many lesions (e.g.
polyposis syndrome patients) invariably develop cancer if left
untreated. Surgical removal of the colon is the conventional
treatment in polyposis patients. Many polyposis patients have
undergone a severe change in lifestyle as a result of the
disfiguring surgery. Patients have strict dietary restrictions, and
many must wear ostomy appliances to collect their intestinal
wastes.
[0012] The search for drugs useful for treating and preventing
cancer is intensive. Indeed, much of the focus of cancer research
today is on the prevention of cancer because chemotherapy for
cancer itself is often not effective and has severe side effects.
Cancer chemoprevention is important for recovered cancer patients
who retain a risk of cancer reoccurrence. Also, cancer prevention
is important for people who have not yet had cancer, but have
hereditary factors that place them at risk of developing cancer.
With the development of new genetic screening technologies, it is
easier to identify those patients with high-risk genetic factors,
such as the potential for polyposis syndrome, who would greatly
benefit from chemopreventative drugs. Therefore, finding such
anti-cancer drugs that can be used for prolonged preventive use is
of vital interest.
[0013] Known chemopreventative and chemotherapeutic drugs are
believed to kill cancer cells by inducing apoptosis, or as
sometimes referred to as "programmed cell death." Apoptosis
naturally occurs in virtually all tissues of the body, and
especially in self-renewing tissues such as bone marrow, gut, liver
and skin. Apoptosis plays a critical role in tissue homeostasis,
that is, it ensures that the number of new cells produced are
correspondingly offset by an equal number of cells that die. For
example, the cells in the intestinal lining divide so rapidly that
the body must eliminate cells after only three days in order to
prevent the overgrowth of the intestinal lining.
[0014] Recently, scientists have realized that abnormalities of
apoptosis can lead to the formation of precancerous lesions and
carcinomas. Also, recent research indicates that defects in
apoptosis play a major role in other diseases in addition to
cancer. Consequently, compounds that modulate apoptosis could be
used to prevent or control cancer, as well as used in the treatment
of other diseases.
[0015] Unfortunately, even though known chemotherapeutic drugs may
exhibit such desirable apoptosis effects, most chemotherapeutic
drugs have serious side effects that prohibit their long-term use,
or use in otherwise healthy individuals with precancerous lesions.
These side effects, which are a result of nonspecific cytotoxicity
of the drugs, include hair loss, weight loss, vomiting, immune
suppression and other toxicities. For this reason, there is a need
to identify new drug candidates for therapy of patients with
precancerous lesions that do not have such serious side effects in
humans.
[0016] In recent years, several nonsteroidal anti-inflammatory
drugs ("NSAIDs"), originally developed to treat arthritis, have
shown effectiveness in inhibiting and eliminating colonic polyps.
Polyps virtually disappear when the patients take such drugs,
particularly when the NSAID sulindac is administered. However, the
prophylactic use of currently available NSAIDs, even in polyposis
syndrome patients, is marked by severe side reactions that include
gastrointestinal irritations and ulcerations. Once NSAID treatment
is terminated due to such complications, the polyps return,
particularly in polyposis syndrome patients.
[0017] Sulindac has been particularly well received among the
NSAIDs for the polyp treatment. Sulindac is a sulfoxide compound
that itself is believed to be inactive as an anti-arthritic agent.
The sulfoxide is reportedly converted by liver enzymes to the
corresponding sulfide, which is acknowledged to be the active
moiety as a prostaglandin synthesis inhibitor. The sulfide,
however, is associated with the side effects of conventional
NSAIDs. The sulfoxide is also known to be metabolized to sulfone
compound that has been found to be inactive as an inhibitor of
prostaglandin synthesis but active as an inhibitor of precancerous
lesions.
SUMMARY OF THE INVENTION
[0018] This invention includes a method of inhibiting neoplastic
cells by exposing those cells to a pharmacologically effective
amount of those compounds described below. Such compounds are
effective in modulating apoptosis and eliminating and inhibiting
the growth of neoplasias such as precancerous lesions.
[0019] The compounds that are useful in the methods of this
invention include those of Formula I below.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The present invention is a method of treating a patient with
neoplastic lesions by administering to a patient a
pharmacologically effective amount of a pharmaceutical composition
that includes a 2,9-disubstituted purin-6-one of Formula I: 1
[0021] wherein R.sub.1 is selected from the group consisting of
straight-chain or branched alkyl with 2 to 10 carbon atoms, which
is optionally substituted by phenyl, which in turn may be
substituted by halogen, nitro, cyano, or by straight-chain or
branched alkyl with up to 6 carbon atoms;
[0022] R.sub.2 is selected from the group consisting of hydrogen,
hydroxy, azido, or a straight-chain or branched alkyl with up to 6
carbon atoms, or a group with the formula --O--SO.sub.2R.sub.5;
[0023] R.sub.5 is selected from the group consisting of a
straight-chain or branched alkyl with up to 4 carbon atoms or
phenyl;
[0024] R.sub.3 is selected from the group consisting of hydrogen or
R.sub.2 and R.sub.3 together form a group of the formula
.dbd.O;
[0025] R.sub.4 is selected from the group consisting of hydrogen or
a straight-chain or branched alkyl with up to 4 carbon atoms;
and
[0026] A is selected from the group consisting of a moiety of the
formula: 2
[0027] or a straight-chain or branched alkyl with up to 20 carbon
atoms, or a cycloalkyl with 3 to 7 carbon atoms, phenyl wherein
said moiety, alkyl, cycloalkyl or phenyl groups are optionally
substituted with one or two groups independently selected from the
group consisting of halogen, carboxyl, trifluoromethyl, nitro,
cyano, or straight-chain or branched alkyl, alkoxycarbonyl, or
alkoxy, each with up to 5 carbon atoms, which in turn may be
substituted by phenyl, said ring structures optionally substituted
by phenyl, which in turn may be substituted by straight-chain or
branched alkoxy with up to 5 carbon atoms; and their tautomers and
salts.
[0028] Physiologically acceptable salts are preferred in the
practice of the invention. Physiologically acceptable salts can be
salts of the compounds pursuant to the invention with inorganic or
organic acids. Preferred salts are those with inorganic acids, for
example hydrochloric acid, hydrobromic acid, phosphoric acid, or
sulfuric acid, or salts with organic carboxylic acids or sulfonic
acids, for example acetic acid, maleic acid, fumaric acid, malic
acid, citric acid, tartaric acid, lactic acid, benzoic acid, or
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
toluenesulfonic acid, or naphthalenedisulfonic acid.
[0029] The compounds of Formula (I) can occur in various
stereochemical forms, which have the nature either of image and
mirror image (enantiomers) or which are not mirror images of one
another (diastereoisomers). The invention involves the use of both
the antipodes and the racemic forms, and mixtures of
diastereoisomers. The racemic forms can be separated, as can the
diastereoisomers, into their stereoisomerically pure components, by
known methods.
[0030] Preferred compounds of Formula (I) are those in which
[0031] R.sub.1 is selected from the group consisting of
straight-chain or branched alkyl with 2 to 8 carbon atoms, which is
optionally substituted by phenyl, which in turn may be substituted
by fluorine; chlorine, bromine, nitro, cyano, or by straight-chain
or branched alkyl with up to 4 carbon atoms,
[0032] R.sub.2 is selected from the group consisting of hydrogen,
hydroxy, azido, or for straight-chain or branched alkyl with up to
4 carbon atoms, or a group with the formula
--O--SO.sub.2R.sub.5;
[0033] R.sub.5 is selected from the group consisting of
straight-chain or branched alkyl with up to 3 carbon atoms, or
phenyl;
[0034] R.sub.3 is selected from the group consisting of hydrogen,
or R.sub.2 and R.sub.3 jointly form the group of the formula
.dbd.O;
[0035] R.sub.4 is selected from the group consisting of hydrogen or
for straight-chain or branched alkyl with up to 3 carbon atoms;
and
[0036] A is selected from the group consisting of a group with the
formula 3
[0037] or straight-chain or branched alkyl with up to 19 carbon
atoms, or for cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or
for phenyl, which optionally are substituted up to twice with the
same or different substituents consisting of fluorine, chlorine,
bromine, carboxyl, nitro, hydroxy, or by straight-chain or branched
alkyl, alkoxycarbonyl, or alkoxy, each with up to 4 carbon atoms,
which in turn may be substituted by phenyl, and/or the rings are
optionally substituted by phenyl, which in turn may be substituted
by straight-chain or branched alkoxy with up to 4 carbon atoms and
their tautomers and salts.
[0038] Especially preferred are compounds of Formula I in which
R.sub.1 is selected from the group consisting of straight-chain or
branched alkyl with 2 to 7 carbon atoms, which is optionally
substituted by phenyl, which in turn may be substituted by
fluorine, chlorine, bromine, nitro, cyano, or by straight-chain or
branched alkyl with up to 3 carbon atoms;
[0039] R.sub.2 is selected from the group consisting of hydrogen,
hydroxy, azido, or for straight-chain or branched alkyl with up to
3 carbon atoms, or for a group with the formula
--O--SO.sub.2R.sub.5;
[0040] R.sub.5 is selected from the group consisting of
straight-chain or branched alkyl with up to 3 carbon atoms or
phenyl,
[0041] R.sub.3 is selected from the group consisting of hydrogen or
R.sub.2 and R.sub.3 jointly form the group of the formula
.dbd.O,
[0042] R.sub.4 is selected from the group consisting of hydrogen or
a straight-chain or branched alkyl with up to 3 carbon atoms;
and
[0043] A is selected from the group consisting of a group of the
formula 4
[0044] or for straight-chain or branched alkyl with up to 18 carbon
atoms, or cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or for
phenyl, which optionally are substituted up to twice with the same
or different substituents consisting of fluorine, chlorine,
bromine, carboxyl, nitro, hydroxy, or by straight-chain or branched
alkyl, alkoxycarbonyl, or alkoxy, each with up to 3 carbon atoms,
which in turn may be substituted by phenyl, and/or the rings are
optionally substituted by phenyl, which in turn may be substituted
by straight-chain or branched alkoxy with up to 3 carbon atoms and
their tautomers and salts.
[0045] The present invention is also a method of treating
individuals with neoplastic lesions by administering a
pharmacologically effective amount of an enterically coated
pharmaceutical composition that includes compounds of this
invention.
[0046] Also, the present invention is a method of inhibiting the
growth of neoplastic cells by exposing the cells to an effective
amount of compounds of Formula I, wherein R.sub.1 etc. are defined
as above.
[0047] In still another form, the invention is a method of inducing
apoptosis in human cells by exposing those cells to an effective
amount of compounds of Formula I, wherein R.sub.1 etc. are defined
as above where such cells are sensitive to these compounds.
[0048] Additionally, in yet another form, the invention is a method
of treating a patient having a disease which would benefit from
regulation of apoptosis by treating the patient with an effective
amount of compounds of Formula I, wherein R.sub.1 etc. are defined
as above. The regulation of apoptosis is believed to play an
important role in diseases associated with abnormalities of
cellular growth patterns such as benign prostatic hyperplasia,
neurodegenerative diseases such as Parkinson's disease, autoimmune
diseases including multiple sclerosis and rheumatoid arthritis,
infectious diseases such as AIDS, and other diseases, as well.
[0049] As used herein, the term "precancerous lesion" includes
syndromes represented by abnormal neoplastic, including dysplastic,
changes of tissue. Examples include dysplasic growths in colonic,
breast, bladder or lung tissues, or conditions such as dysplastic
nevus syndrome, a precursor to malignant melanoma of the skin.
Examples also include, in addition to dysplastic nevus syndromes,
polyposis syndromes, colonic polyps, precancerous lesions of the
cervix (i.e., cervical dysplasia), esophagus, prostatic dysplasia,
bronchial dysplasia, breast, bladder and/or skin and related
conditions (e.g., actinic keratosis), whether the lesions are
clinically identifiable or not.
[0050] As used herein, the term "carcinomas" refers to lesions that
are cancerous. Examples include malignant melanomas, breast cancer,
prostate cancer and colon cancer.
[0051] As used herein, the term "neoplasm" refers to both
precancerous and cancerous lesions and hyperplasia.
[0052] Compounds useful in the practice of this invention may be
formulated into pharmaceutical compositions together with
pharmaceutically acceptable carriers for oral administration in
solid or liquid form, or for rectal or topical administration,
although carriers for oral and parenteral administration are most
preferred.
[0053] Pharmaceutically acceptable carriers for oral administration
include capsules, tablets, pills, powders, troches and granules. In
such solid dosage forms, the carrier can comprise at least one
inert diluent such as sucrose, lactose or starch. Such carriers can
also comprise, as is normal practice, additional substances other
than diluents, e.g., lubricating agents such as magnesium stearate.
In the case of capsules, tablets, troches and pills, the carriers
may also comprise buffering agents. Carriers such as tablets, pills
and granules can be prepared with enteric coatings on the surfaces
of the tablets, pills or granules. Alternatively, the enterically
coated compound can be pressed into a tablet, pill, or granule, and
the tablet, pill or granules for administration to the patient.
Preferred enteric coatings include those that dissolve or
disintegrate at colonic pH such as shellac or Eudraget S.
[0054] Pharmaceutically acceptable carriers include liquid dosage
forms for oral administration, e.g., pharmaceutically acceptable
emulsions, solutions, suspensions, syrups and elixirs containing
inert diluents commonly used in the art, such as water. Besides
such inert diluents, compositions can also include adjuvants such
as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring and perfuming agents.
[0055] Pharmaceutically acceptable carriers for topical
administration include DMSO, alcohol or propylene glycol and the
like that can be employed with patches or other liquid-retaining
material to hold the medicament in place on the skin so that the
medicament will not dry out.
[0056] Pharmaceutically acceptable carriers for rectal
administration are preferably suppositories that may contain, in
addition to the compounds of this invention excipients such as
cocoa butter or a suppository wax, or gel.
[0057] When the present invention is used as a medicine for such
diseases, it is administered by oral, intravenous or parenteral
administration. The dose thereof varies depending upon the extent
of symptom; the age, sex, weight and drug sensitivity of a patient;
the method, timing and interval of administration; the type of
pharmaceutical preparation; the type of a medicine to be
administered together therewith; the type of an active ingredient
and so forth.
[0058] With intravenous administration, it is recommended to
administer amounts of about 0.01 to 10 mg/kg of body weight,
preferably about 0.1 to 10 mg/kg. Nevertheless, it may be necessary
to deviate from the amounts mentioned, specifically depending on
the body weight or the method of administration, on individual
behavior toward the medication, on the type of formulation, and the
time or intervals at which administration occurs. Thus, in some
cases, it may be sufficient to get by with less than the
aforementioned minimum amounts, while in other cases the mentioned
upper limits have to be exceeded. It may be advisable when
administering larger amounts to divide them into several individual
doses throughout the day.
[0059] A method for preparing the compounds of Formula I involves
reacting compounds of Formula II 5
[0060] (where R.sub.1, R.sub.2, R.sub.3, and R.sub.4 have the
meanings given above) with compounds of Formula III:
A--CO--Cl (III)
[0061] in which A has the meanings given above, in an inert solvent
and in the presence of a base. This reaction produces a compound of
Formula IV: 6
[0062] in which A, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 have the
meanings given above. Such compounds are cyclized in a second step
in an inert solvent and in the presence of a base, and the
substituents R.sub.1, R.sub.2, R.sup.3, and R.sub.4 are introduced
and derivatized by acylation, oxidation, and/or azide exchange.
[0063] The method of producing such compounds can be illustrated by
way of example by the following schematic diagram: 7
[0064] Inert organic solvents that do not change under the reaction
conditions are suitable for the first step of the method. Preferred
examples of them are ethers, for example diethyl ether, dioxane,
tetrahydrofuran, ethylene glycol mono- or dimethyl ether,
halogenated hydrocarbons such as di-, tri-, or tetrachloromethane,
dichloroethylene, trichloroethylene, ethyl acetate, toluene,
acetonitrile, hexamethylphosphoric triamide, pyridine, and acetone.
Of course it is possible to use mixtures of solvents.
Tetrahydrofuran, toluene, or pyridine are especially preferred.
[0065] Suitable bases include alkali metal hydrides or alkoxides
(e.g.,sodium hydride or potassium t-butoxide), cyclic amines (e.g.,
piperidine, pyridine, dimethylaminopyridine), or
C.sub.1-C.sub.4-alkylami- nes (e.g., triethylamine). Sodium
hydride, pyridine, and dimethylaminopyridine are preferred.
[0066] The base should be used in an amount of 1 mole to 4 moles,
preferably from 1.2 moles to 3 moles, per mole of the compounds of
Formula II.
[0067] The reaction temperature in general reportedly can be varied
over a rather broad range. The operating temperature is generally
in the range from -20.degree. C. to 200.degree. C., preferably from
0.degree. C. to 25.degree. C.
[0068] In a variant, the reaction is carried out in pyridine to
which has been added a catalytic amount of DMAP. Toluene can also
optionally be added.
[0069] Suitable solvents for the cyclization are the usual organic
solvents. Preferred solvents are alcohols such as methanol,
ethanol, propanol, isopropanol, or butanol, or ethers such as
tetrahydrofuran or dioxane, or dimethylformamide or dimethyl
sulfoxide. It is especially preferred to use alcohols such as
methanol, ethanol, propanol, or isopropanol. It is likewise
possible to use mixtures of the solvents mentioned.
[0070] Suitable bases for the cyclization are the usual inorganic
bases. Preferred bases for this purpose are alkali metal hydroxides
or alkaline earth hydroxides, for example sodium hydroxide,
potassium hydroxide, or barium hydroxide, or alkali metal
carbonates such as sodium or potassium carbonate, or sodium
bicarbonate, or alkali metal alkoxides such as sodium methoxide,
sodium ethoxide, potassium methoxide, potassium ethoxide, or
potassium t-butoxide. Especially preferred are potassium carbonate
and sodium hydroxide.
[0071] When carrying out the cyclization, the base is usually used
in an amount of 2 to 6 moles, preferably from 3 to 5 moles, per
mole of the compounds of Formula IV.
[0072] The cyclization is usually carried out in the temperature
range of 0.degree. C. to 160.degree. C., preferably at the boiling
point of the particular solvent.
[0073] The cyclization is usually carried out at atmospheric
pressure. However, it is also possible to carry out the process at
elevated or reduced pressure (for example, in the range from 0.5 to
5 bar).
[0074] The reaction with alkylsulfonyl chlorides occurs, starting
from the corresponding free hydroxy compounds, in one of the
solvents listed above and one of the bases, preferably with
dichloromethane and triethylamine, in a temperature range from
-20.degree. C. to +20.degree. C., preferably at 0.degree. C. and
atmospheric pressure.
[0075] The azide group is usually introduced by reacting the
corresponding alkylsulfonyloxy-substituted compounds with sodium
azide in one of the solvents listed above, preferably
dimethylformamide, in a temperature range of 50.degree. C. to
+120.degree. C., preferably at 100.degree. C. and atmospheric
pressure.
[0076] The ketones are prepared by known methods (Swern Oxidation)
from the corresponding hydroxy compounds.
[0077] The enantiomerically pure compounds are available by the
usual methods, for example by chromatography of the racemic
compounds of the general formula (I) on chiral phases.
[0078] Many compounds of Formula III are reportedly known.
[0079] Compounds of Formula II can be prepared, for example, by
reacting 2-amino-2-cyanoacetamide of Formula V: 8
[0080] in which R.sub.1, R.sub.2, R.sub.3, and R.sub.4 have the
meanings given above in inert solvents in the presence of triethyl
orthoformate. Solvents suitable for the individual steps of the
process are the usual organic solvents that do not change under the
reaction conditions. Preferred examples of them are ethers such as
diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl
ether, or hydrocarbons such as benzene, toluene, xylene, hexane,
cyclohexane, or petroleum fractions, or halogenated hydrocarbons
such as dichloromethane, trichloromethane, tetrachloromethane,
dichloroethylene, trichloroethylene, or chlorobenzene, or ethyl
acetate, dimethylformamide, hexamethylphosphoramide, acetonitrile,
acetone, or dimethoxyethane. It is likewise possible to use
mixtures of the solvents mentioned. Acetonitrile is especially
preferred.
[0081] The process of the invention is usually carried out in a
temperature range of 0.degree. C. to +180.degree. C., preferably
from +30.degree. C. to +150.degree. C.
[0082] These steps of the process pursuant to the invention are
usually carried out at atmospheric pressure. However, it is also
possible to operate at elevated pressure or reduced pressure (for
example in a range from 0.5 to 5 bar).
[0083] The compound of Formula V can be obtained as described in
the literature [see. Logemann, G. Shaw, Chemistry and Industry,
1980 (13), 541-542].
[0084] The amines of Formula VI can then be prepared by known
methods [see. L. R. Krepski et al., Synthesis, 1986, 301-303].
[0085] There are several methods to produce the 1-substituted
5-acylaminoimidazole-4-carboxamides of Formula IV, that are
generally described below as Methods A and B.
[0086] Method A
[0087] 10 mmoles of the 1-substituted
5-aminoimidazole-4-carboxamide and 15 mmoles (or 30 mmoles if
R.sub.2 is hydroxy) of NaH (60% dispersion in mineral oil) in 50 ml
of absolute THF are stirred for 3 hours at 20.degree. C. (sparingly
soluble imidazoles are refluxed for up to 3 hours). 10 mmoles of
acid chloride (or 20 mmoles if a hydroxy group is present) in 2.5
ml of absolute THF is added dropwise at 20.degree. C. and the
mixture is stirred overnight at room temperature. The solvent is
evaporated under vacuum in a rotary evaporator, and the residue is
taken up in 50 ml of ethyl acetate and extracted with 50 ml of
water. The organic phase is separated, dried over Na.sub.2SO.sub.4,
and the solvent is evaporated under vacuum. The residue is purified
by recrystallization or flash chromatography.
[0088] Method B
[0089] 10 mmoles of the
1-substituted-5-aminoimidazole-4-carboxamide is dissolved in 20 ml
of dry pyridine. After adding 50 mg of 4-dimethylaminopyridine
(DMAP), 11 mmoles of acid chloride (or 22 mmoles if R.sub.2 is
selected from the group consisting of a hydroxy group) is added
dropwise at 20.degree. C. (solid acid chlorides are dissolved in a
little absolute toluene). The mixture is stirred for 1 h at
20.degree. C.; in some cases 1-2 hours of heating at 50.degree. C.
is also necessary (TLC control). The batch is poured into 100 ml of
ice water and extracted 3 times with 50-ml portions of ethyl
acetate. The combined ethyl acetate phases are washed twice with 1N
HCl, once with saturated NaCl solution, dried over
Na.sub.2SO.sub.4, and evaporated under vacuum. The residue is
purified by flash chromatography or recrystallization.
[0090] The 1-substituted 5-acylaminoimidazole-4-carboxamides listed
in Table I are prepared by these two methods:
1TABLE I 9 1) 3) Example 2) Yield No. A. R.sub.4 R.sub.2 R.sub.1
Method (%) R.sub.f I --CH.sub.3 CH.sub.3 10 n-Hexyl A 33 0,40 II
--C(CH.sub.3).sub.3 CH.sub.3 11 n-Hexyl A 28 0,45 III
n-nC.sub.17H.sub.35 CH.sub.3 12 n-Hexyl B 50 0,48 IV
--C.sub.6H.sub.5 CH.sub.3 13 n-Hexyl A 19 0,39 V
-4-Cl--C.sub.6H.sub.5 CH.sub.3 14 n-Hexyl A 15 0,40 VI 15 CH.sub.3
16 n-Hexyl B 52 0,43 VII 17 CH.sub.3 H n-Hexyl A 16 0,38 VIII 18
CH.sub.3 19 20 B 45 0,41 IX 21 H H 22 B 41 X 23 H H 24 B 27,9 XI 25
H H 26 B 17,3 XII 27 H H 28 B 37,9 XIII 29 H H 30 B 29,2 XIV 31 H H
32 B 38,7 XV 33 H H 34 B 15,7 XVI 35 H H 36 B 18,3 XVII 37 H H 38 B
44,7 XVIII 39 H H 40 B XIX 41 H H 42 B 48 XX 43 H H 44 B 34,8 XXI
45 H H 46 B 14,5 XXII 47 H H 48 B 11,4 XXIII 49 H H 50 B 28,7 XXIV
51 H H 52 B 11,7 XXV 53 H H 54 B XXVI 55 H H 56 B XXVII 57 H H 58 B
45 0,41
[0091] Mobile phase: CH.sub.2Cl.sub.2/MeOH 10:1
[0092] There are several methods for making the 2,9-disubstituted
purin-6-ones of Formula I that are set forth in Methods C and D
below:
[0093] Method C
[0094] 1 mole of 1-substituted 5-acylaminoimidazole-4-carboxamide
and 5 moles of potassium carbonate are boiled at reflux overnight
in 20 ml of ethanol and 10 ml of water. The solvent is evaporated
under vacuum, and the residue is taken up in 20 ml of ethyl acetate
and extracted with saturated NaCl solution. The organic phase is
separated, dried over Na.sub.2SO.sub.4, and evaporated under
vacuum. The residue is purified by recrystallization or flash
chromatography.
[0095] Method D
[0096] 1 mmole of 1-substituted 5-acylaminoimidazole-4-carboxamide,
5 mmoles of potassium carbonate, and 1 ml of 30% H.sub.2O.sub.2
solution are boiled at reflux overnight in 10 ml of water and 10 ml
of ethanol (TLC control). The further workup is the same as Method
C. This method is reportedly analogous to that disclosed in EP
Patent Application No. 526,004.
[0097] The 2,9-disubstituted purin-6-ones listed in Table II are
prepared by these two methods:
2 59 Example Yield No. A R.sub.4 R.sub.2 R.sub.1 Method (%) R.sub.f
1 --CH.sub.3 CH.sub.3 OH n-Hexyl A 68,6 0,38
(CH.sub.2Cl.sub.2/CH.sub.3OH 10:1) 2 --C(CH.sub.3).sub.3 CH.sub.3
OH n-Hexyl A 49,1 237 (ethyl acetate/diethyl ether) 3
-n-C.sub.17H.sub.35 CH.sub.3 OH n-Hexyl B 24,8 0,52
(CH.sub.2Cl.sub.2/CH.sub.3OH 10:1) 4 --C.sub.6H.sub.5 CH.sub.3 OH
n-Hexyl A 48,9 249 (ethyl acetate/diethyl ether) 5
-4-Cl--C.sub.6H.sub.4 CH.sub.3 OH n-Hexyl A 27,9 235
(C.sub.2H.sub.5OH/Ether) 6 --C.sub.6H.sub.11 CH.sub.3 OH n-Hexyl B
72,9 166 (ethyl acetate/diethyl ether) 7 --C.sub.6H.sub.11 CH.sub.3
OH n-Hexyl A 42,1 154 (ethyl acetate/diethyl ether) 8
--C.sub.6H.sub.11 CH.sub.3 OH 60 B 43,5 0,44
(CH.sub.2Cl.sub.2/CH.sub.3OH 10:1) 9 61 H H 62 A 44,9 162.degree.
C. 10 63 H H 64 A 40,3 212.degree. C. 11 65 H H 66 A 34,2
184.degree. C. 12 67 H H 68 A 49,8 179.degree. C. 13 69 H H 70 A
38,9 0,38 14 71 H H 72 A 44,1 0,41 15 73 H H 74 A 36 194.degree. C.
16 75 H H 76 A 49,3 139.degree. C. 17 77 H H 78 A 41,7 125.degree.
C. 18 79 H H 80 A 19 81 H H 82 A 48,9 149.degree. C. 20 83 H H 84 A
32,5 164.degree. C. 21 85 H H 86 A 35,1 128.degree. C. 22 87 H H 88
A 29,2 235.degree. C. (Zers.) 23 89 H H 90 A 44,6 243.degree. C.
(Zers.) 24 91 H H 92 A 37,1 195.degree. C. 25 93 H H 94 A 42,6
182.degree. C. 26 95 H H 96 A 41,1 245.degree. C. 27 97 H H 98 A
32,7 190.degree. C. 28 99 H H 100 A 35 152.degree. C.
[0098] The following Examples further illustrate compounds useful
in the practice of this invention.
EXAMPLE 29
[0099] 9-(2-Methanesulfonyloxy-3 -Nonyl)-2-Cyclohexylpurin-6-One
101
[0100] 0.36 g (1 mole) of
9-(2-hydroxy-3-nonyl)-2-cyclohexylpurin-6-one (Example 6) and 0.3
ml of triethylamine are stirred in 5 ml of absolute
CH.sub.2Cl.sub.2 at 0.degree. C. 0.1 ml of methanesulfonyl chloride
dissolved in 2.5 ml of absolute CH.sub.2Cl.sub.2 is then added
dropwise. After 30 minutes at 0.degree. C., the mixture is
extracted with 10 ml of saturated NaHCO.sub.3 solution, 10 ml of 2N
HCl solution, and with 10 ml of saturated NaHCO.sub.3 solution. The
organic phase is dried over Na.sub.2SO.sub.4, the solvent is
evaporated under vacuum, and the residue is purified by flash
chromatography with ethyl acetate/CH.sub.2Cl.sub.2/C- H.sub.3OH
10:1 as eluant.
EXAMPLE 30
[0101]
9-(2-Methanesulfonyl-6-Phenyl-3-Hexyl)-2-Cyclohexylpurin-6-One
102
[0102] The title compound is prepared analogously to the method of
Example 29 starting with
9-(2-hydroxy-6-phenyl-3-hexyl)-2-cyclohexylpurin-6-one (Example
8).
EXAMPLE 31
[0103] 9-(2-Azido-3-Nonyl)-2-Cyclohexylpurin-6-One 103
[0104] 0.381 g (0.87 mmole) of
9-(2-methanesulfonyloxy-3-nonyl)-2-cyclohex- ylpurin-6-one (Example
29) and 0.113 g (1.74 mmoles) of sodium azide are stirred overnight
at 100 C in 5 ml of absolute DMF. The mixture is cooled to
20.degree. C., 30 ml of ethyl acetate is added, and the mixture is
washed twice with 50-ml portions of water and once with 50 ml of
saturated NaCl solution. After
EXAMPLE 32
[0105] 9-(2-Azido-6-Phenyl-3-Hexyl)-2-Cyclohexylpurin-6-One 104
[0106] The title compound is prepared analogously to the method of
Example 31 starting with
9-(2-methanesulfonyloxy-6-phenyl-3-hexyl)-2-cyclohexylpu- rin-6-one
(Example 30).
EXAMPLE 33
[0107] 9-(2-Oxo-3-Nonyl)-2-Cyclohexylpurin-6-One 105
[0108] 0.2 ml of absolute DMSO in 3 ml of absolute CH.sub.2Cl.sub.2
is added dropwise at -60.degree. C. to 0.15 ml of oxalyl chloride
in 5 ml of absolute CH.sub.2Cl.sub.2, and stirring is continued for
20 minutes longer. 540 mg (1.5 mmoles) of
9-(2-hydroxy-3-nonyl)-2-cyclohexylpurin-6-- one (Example 6) in 3 ml
of CH.sub.2Cl.sub.2 is then added dropwise and slowly and stirring
is continued for 1 hour at -60.degree. C. 1 ml of triethylamine in
3 ml of CH.sub.2Cl.sub.2 is added dropwise to this solution. The
mixture is allowed to come to room temperature, 7 ml of water is
added, and the organic phase is separated. The organic phase is
washed with 10 ml of 2N HCl and 10 ml of saturated NaCl solution,
dried over Na.sub.2SO.sub.4, and evaporated under vacuum. The
residue is purified by flash chromatography (eluant:
CH.sub.2Cl.sub.2/CH.sub.3OH 40:1)
EXAMPLE 34
[0109] 9-(2-Oxo-6-Phenyl-3-Hexyl)-2-Cyclohexylpurin-6-One 106
[0110] The title compound is prepared analogously to the method of
Example 33 starting with
9-(2-hydroxy-6-phenyl-3-hexyl)-2-cyclohexylpurin-6-one (Example
8).
[0111] It will be understood that various changes and modifications
can be made in the details of procedure, formulation and use
without departing from the spirit of the invention, especially as
defined in the following claims.
* * * * *