U.S. patent application number 12/343441 was filed with the patent office on 2009-07-30 for novel antigiardial agents and methods of use thereof.
This patent application is currently assigned to University of Mississippi. Invention is credited to Mitchell Avery, Nakul Telang, Larry A. Walker.
Application Number | 20090192152 12/343441 |
Document ID | / |
Family ID | 31715716 |
Filed Date | 2009-07-30 |
United States Patent
Application |
20090192152 |
Kind Code |
A1 |
Avery; Mitchell ; et
al. |
July 30, 2009 |
Novel Antigiardial Agents and Methods of Use Thereof
Abstract
The present invention provides a method of preventing or
treating one or more of the following medical conditions, or
treating symptoms of one or more of the following medical
conditions: amebic infections, giardiasis, estrogen deficient
states, osteoporosis, cardiovascular heart disease, high
cholesterol levels, hyperlipidemia, cancer by administering to a
subject having, or predisposed to, one or more of the conditions, a
therapeutically effective amount of a compound of the present
invention and a pharmaceutically acceptable carrier.
Inventors: |
Avery; Mitchell; (Oxford,
MS) ; Walker; Larry A.; (Oxford, MS) ; Telang;
Nakul; (Richmond, VA) |
Correspondence
Address: |
STITES & HARBISON PLLC
401 COMMERCE STREET, SUITE 800
NASHVILLE
TN
37219
US
|
Assignee: |
University of Mississippi
|
Family ID: |
31715716 |
Appl. No.: |
12/343441 |
Filed: |
December 23, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10523964 |
Feb 7, 2005 |
7468445 |
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PCT/US2003/024938 |
Aug 7, 2003 |
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12343441 |
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60401664 |
Aug 7, 2002 |
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Current U.S.
Class: |
514/233.5 ;
514/254.11; 514/320; 514/422; 514/456 |
Current CPC
Class: |
C07D 311/38 20130101;
C07D 407/12 20130101; C07D 311/36 20130101 |
Class at
Publication: |
514/233.5 ;
514/456; 514/254.11; 514/320; 514/422 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/352 20060101 A61K031/352; A61K 31/497
20060101 A61K031/497; A61K 31/445 20060101 A61K031/445; A61K 31/40
20060101 A61K031/40 |
Goverment Interests
UNITED STATES GOVERNMENT SUPPORT
[0002] This work is a result of research sponsored in part by the
Center for Disease Control Grant # U50/CCU41839. The United States
Government has certain rights in this invention.
Claims
1-11. (canceled)
12. A hormone replacement therapy regimen comprising:
co-administering a therapeutically effective amount of a
combination of mammalian estrogen and a compound of the following
formula: ##STR00018## wherein R.sub.2 and R.sub.4 are each
independently H, alkyl halogen; R.sub.15 and R.sub.16 are each
independently H, alkyl, acyl, alkoxy, aryl, amino, HET, halogen;
and pharmaceutically acceptable salts thereof; and a
pharmaceutically acceptable carrier to a woman having reduced
levels of endogenous estrogen.
13. A method for inhibiting or treating coronary heart disease,
cardiovascular disease, comprising: administering a therapeutically
effective amount of a compound of the following formula:
##STR00019## wherein R.sub.2 and R.sub.4 are each independently H,
alkyl, halogen; R.sub.15 and R.sub.16 are each independently H,
alkyl, acyl, alkoxy, aryl, amino, HET, halogen; and
pharmaceutically acceptable salts thereof; and a pharmaceutically
acceptable carrier to a patient in need thereof.
14. A method of inhibiting or treating osteoporosis, comprising:
administering a therapeutically effective amount of a compound of
the following formula: ##STR00020## wherein R.sub.2 and R.sub.4 are
each independently H, alkyl, halogen; R.sub.15 and R.sub.16 are
each independently H, alkyl, acyl, alkoxy, aryl, amino, HET,
halogen; and pharmaceutically acceptable salts thereof; and a
pharmaceutically acceptable carrier to a patient in need
thereof.
15. A method of inhibiting or treating gastrointestinal disease,
comprising: administering a therapeutically effective amount of a
compound of the following formula: ##STR00021## wherein R.sub.2 and
R.sub.4 are each independently H, alkyl, halogen; R.sub.15 and
R.sub.16 are each independently H, alkyl, acyl, alkoxy, aryl,
amino, HET, halogen; and pharmaceutically acceptable salts thereof;
and a pharmaceutically acceptable carrier to a patient in need
thereof.
16. A method of inhibiting or treating amebic infections
comprising: administering a therapeutically effective amount of a
compound of the following formula: ##STR00022## wherein R.sub.2 and
R.sub.4 are each independently H, alkyl, halogen; R.sub.15 and
R.sub.16 are each independently H, alkyl, acyl, alkoxy, aryl,
amino, HET, halogen; and pharmaceutically acceptable salts thereof;
and a pharmaceutically acceptable carrier to a patient in need
thereof.
17. The method of claim 12, wherein the compound is chosen from:
##STR00023## ##STR00024## ##STR00025## ##STR00026##
18. The method of claim 13, wherein the compound is chosen from:
##STR00027## ##STR00028## ##STR00029## ##STR00030##
19. The method of claim 14, wherein the compound is chosen from:
##STR00031## ##STR00032## ##STR00033## ##STR00034##
20. The method of claim 15, wherein the compound is chosen from:
##STR00035## ##STR00036## ##STR00037## ##STR00038##
21. The method of claim 16, wherein the compound is chosen from:
##STR00039## ##STR00040## ##STR00041## ##STR00042##
22. The method of claim 12, wherein the compound is chosen from:
##STR00043##
23. The method of claim 13, wherein the compound is chosen from:
##STR00044##
24. The method of claim 14, wherein the compound is chosen from:
##STR00045##
25. The method of claim 15, wherein the compound is chosen from:
##STR00046##
26. The method of claim 16, wherein the compound is chosen from:
##STR00047##
27. The method of claim 12, wherein the R.sub.16 is chosen from
pyrrolidine, morpholine.
28. The method of claim 13, wherein the R.sub.16 is chosen from
pyrrolidine, morpholine.
29. The method of claim 14, wherein the R.sub.16 is chosen from
pyrrolidine, morpholine.
30. The method of claim 15, wherein the R.sub.16 is chosen from
pyrrolidine, morpholine.
31. The method of claim 16, wherein the R.sub.16 is chosen from
pyrrolidine, morpholine.
Description
PRIORITY CLAIM
[0001] This Application claims priority to U.S. Application No.
60/401,664, filed Aug. 7, 2002, the contents of which are
incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0003] The present invention relates to novel compounds and a
method of treating or preventing certain medical clinical
conditions with the compounds of the present invention. In
particular, the method of the present invention includes preventing
or treating giardiasis and giardiasis-related infections, including
amebic (protozoal) infections, as well as osteoporosis,
cardiovascular disease, high cholesterol, hyperlipidemia.
BACKGROUND OF THE INVENTION
[0004] Giardia lamblia (also known as Giardia intestinalis) is a
flagellated unicellular protozoan that causes acute or chronic
gastrointestinal disease, giardiasis, in humans and mammals. The
parasite is protected by an outer shell that allows it to survive
outside the body and in the environment for long periods of time.
The parasite is found in every region of the United States and
throughout the world, infecting over 200 million people are
infected with Giardia throughout the world. Although becoming one
of the most commonly recognized causes of waterborne disease
(drinking and recreational) in humans in the United States,
Giardiasis is more widespread in the developing countries where
infection is correlated with poor hygienic conditions, poor water
quality control, and overcrowding. Also, the prevalence of diarrhea
caused by G. lamblia in AIDS patients is higher than those without
AIDS due to suppressed immunity in AIDS patients.
[0005] The treatment of giardiasis has changed over the past 5
years. Quinacrine (1, below) was previously used until 1998 when
its manufacture was halted in the United States. The current
mainstay of treatment for giardiasis is metronidazole (2, below)
with reported cure rates of 80 to 95%. However, due to general
toxicity and occasional drug resistance to metronidazole, an
ongoing search for novel, safe, and efficacious antigiardial agents
is required.
[0006] Biological evaluation of various natural products has
indicated that molecules possessing a flavonoid skeleton such as
geranins A (3, below) and B (4, below), kaempferol (5, below), and
quercetin (6, below) exhibit antigiardial activity. Also,
formononetin (7, below) and pseudobaptigenin (8, below) have been
shown to possess potent antigiardial activity in vitro.
##STR00001##
[0007] In view of these results, the present inventor developed the
isoflavone derivatives of the present invention as an approach to
discover a potent lead while simultaneously developing
structure-activity relationships (SAR).
[0008] The isoflavones are a group of naturally occurring plant
compounds having the aromatic heterocyclic skeleton of isoflavone
itself (2-phenyl-4H-benzopyran-4-one). Soybeans are the most common
and well known source of isoflavones, reported to contain the
isoflavones, daidzin, genistin, glycitin, 6''-dadidzin-O-acetyl,
6''-O-acetyl genistin, 6''-O-malonyl daidzin, and 6''-O-malonyl
genistin. Isoflavones are present in processed soy foods as well,
including miso and soy sauce. Legumes, lupine, fava bean, kudzu and
psoralea may also be important sources. The existence of
isoflavones in Pueraria has long been known, with the roots of
Pueraria containing several isoflavone compounds, such as daidzin,
and puerarin. Even isoflavone itself has been isolated from Primula
malacoides.
[0009] Isoflavones are known in aglucone forms, as well as
7-acetylated and 7-substituted glycosides. Especially important
isoflavones in aglucone form include daidzein, genistein, and
glycitein. Especially important isoflavones in 7-glycoside form
include daidzin, genistin, and glycitin. Genistein is also known to
occur naturally as a 4'-glucoside (sophoricoside), and a 4'-methyl
ether (biochanin A).
[0010] Isoflavones in general, and genistein in particular, have
structural similarities to that of certain human estrogens, and
such compounds are said to have estrogenic activity. Isoflavones
are also said to have other useful biological and pharmacological
activities, including antiangiogenic, antihemolytic, antiischemic,
antileukemic, antimitogenic, antimutagenic, antioxidant,
fungicidal, pesticidal, MAO-inhibition, phytoalexin, and tyrosine
kinase inhibition activities.
[0011] The anticancer effects of genistein are of particular
interest. Genistein may exert antitumor effects in part by
inhibiting angiogenesis, i.e., reducing formation of vasulature and
blood flow to the tumor. Its affinity to estrogenic sites in the
vicinity of cancer cells may also inhibit tumor growth. As a
well-known inhibitor of the enzyme tyrosine kinase, genistein may
also inhibit energy and signaling pathways in tumors.
[0012] Genistein and other isoflavones are also said to be
important contributors to bone health, resulting at least in part
from the ability of these compounds to inhibit protein kinase
activity, and thereby inhibit osteoclast cell activity. The
isoflavones are especially attractive in this regard because they
generally have a low toxicity relative to many other known protein
kinase inhibitors.
[0013] Because of its many beneficial effects, enriched sources of
genistein are marketed to consumers around the world in a wide
variety of nutritional supplements. Many of the health benefits of
soy products are ascribed to the presence of genistein.
[0014] More specifically, isoflavones have been linked to the
following conditions and/or treatments:
[0015] Osteoporosis: Osteoporosis is a systemic skeletal disease,
characterized by low bone mass and deterioration of bone tissue,
with a consequent increase on bone fragility and susceptibility to
fracture. See U.S. Pat. No. 6,593,310. Isoflavones have been shown
to prevent postmenopausal bone loss and osteoporosis. In fact,
genistein has been reported to be as active as estrogens in
maintaining bone mass in ovariectomized rats. Moreover, the
synthetic isoflavone derivative ipriflavone is able to reduce bone
loss in various types of animal models, providing a rationale on
its use in the prevention and treatment of post-menopausal and
senile osteoporosis in humans. The mechanism through which
isoflavones may exert the above-mentioned effects seems to depend,
at least in part, on their mixed estrogen agonist-antagonist
properties. An alternative hypothetical mechanism could derive from
other biochem. actions of isoflavones such as inhibition of enzymic
activity, in particular protein kinases, or activation of an
"orphan" receptor distinct from the estrogen type I receptor.
[0016] Hormone Replacement: Ovarian hormone deficiency is a major
risk factor for osteoporosis in postmenopausal women. Hormone
replacement therapy (HRT) is perhaps the most effective treatment,
as it has been demonstrated to both reduce the rate of bone loss
and risk of fracture, including hip fracture.
[0017] As used herein, the term "hormone replacement therapy" means
a treatment of a human female having reduced levels of endogenous
estrogen in which a mammalian estrogen is administered to the
female in combination with at least one other compound, where the
other compound is administered to inhibit the estrogen's tissue
proliferative effects in the breast or uterus. See U.S. Pat. No.
6,326,366.
[0018] However, not all women who may benefit from HRT are willing
to initiate this treatment due to fear of cancer and
contraindications. Other therapeutic agents currently available are
also associated with certain adverse effects. As a result,
postmenopausal women are more inclined to use natural remedies such
as isoflavones to alleviate postmenopausal symptoms and help reduce
their risk for chronic diseases such as osteoporosis. Recent
reports support the notion that certain bioactive constituents,
e.g., phytoestrogens, in plants play a role in maintaining or
improving skeletal health.
[0019] Cardiovascular Disease: Isoflavones, including genistein in
various types of diseases such as osteoporosis, cardiovascular
diseases, menopausal symptoms by accumulating evidence from mol.
and cellular biol. expts., animal studies, and, to a limited
extent, human clin. trials. This review suggests that
phytoestrogens may potentially confer health benefits related to
various diseases such as cardiovascular disorder, menopausal
symptoms, and osteoporosis.
[0020] Antiproliferative Effects: Isoflavones, such as genistein,
have been found to be a potent agent in both prophylaxis and
treatment of cancer as well as other chronic diseases. The great
interest that has focused on genistein led to the identification of
numerous intracellular targets of its action in the live cell. At
the molecular level, genistein inhibits the activity of ATP
utilizing enzymes such as: Tyr-specific protein kinases,
topoisomerase II, and enzymes involved in phosphatidylinositol
turnover. Moreover, genistein can act via an estrogen
receptor-mediated mechanism. At the level 1 step higher, i.e., at
the cellular level, genistein induces apoptosis and differentiation
in cancer cells, inhibits cell proliferation, modulates cell
cycling, exerts antioxidant effects, inhibits angiogenesis, and
suppresses osteoclast and lymphocyte functions. These activities
make genistein a promising innovative agent in the treatment of
cancer. Additionally, genistein health beneficial effects were
shown in osteoporosis, cardiovascular diseases, and menopause.
Genistein was also successfully used as an immunosuppressive agent
both in vitro and in vivo. All these effects at the 3 biol. levels
of action need varied genistein concns. and only some of them are
relevant in people consuming soy-rich diet. The others would occur
after purified genistein administration at higher doses. The main
genistein advantage as a potential drug is its multidirectional
action in the live cell and its very low toxicity.
[0021] The present inventor has discovered that the compounds of
the present invention possess the benefits and usefulness of
isoflavone, but are advantageous in that, among other things, have
increased bioavailability and are more easily synthesized.
[0022] To more fully describe the state of the art to which this
invention pertains, the following references are provided: [0023]
Adam, R. D. Biology of Giardia lamblia. Clinical Microbiology
Reviews 2001, 14, 447-475. [0024] Gillin, F. D.; Reiner, D. S.;
McCaffery, J. M. Cell biology of the primitive eukaryote Giardia
lamblia [0025] Barat, L. M.; Bloland, P. B. Drug resistance among
malaria and other parasites. INFECTIOUS DISEASE CLINICS OF NORTH
AMERICA 1997, 11, 969-987. [0026] Wilson, M. E. Public Health &
Preventive Medicine; 14th ed.; Appleton & Lange: Stamford,
Conn., 1998; pp pp. 252-254. [0027] Vesy, C. J.; Peterson, W. L.
Review article: the management of Giardiasis. ALIMENTARY
PHARMACOLOGY AND THERAPEUTICS 1999, 13, 843-850. [0028] Marshall,
M. M.; Naumovitz, D.; Ortega, Y.; Sterling, C. R. Waterborne
protozoan pathogens. Clinical Microbiology Reviews 1997, 10, 67-85.
[0029] Levy, D. A.; Bens, M. S.; Craun, G. F.; Calderon, R. L.;
Herwaldt, B. L. Surveillance for waterborne-disease
outbreaks--United States, 1995-1996. MORBIDITY AND MORTALITY WEEKLY
REPORT. CDC SURVEILLANCE SUMMARIES 1998, 47, 1-34. [0030]
Moolasart, P. Giardia lamblia in AIDS patients with diarrhea.
JOURNAL OF THE MEDICAL ASSOCIATION OF THAILAND 1999, 82, 654-659.
[0031] Angarano, G.; Maggi, P.; Di Bari, M. A.; Larocca, A. M.;
Congedo, P.; Di Bari, C.; Brandonisio, O.; Chiodo, F. Giardiasis in
HIV: a possible role in patients with severe immune deficiency.
EUROPEAN JOURNAL OF EPIDEMIOLOGY 1997, 13, 485-487. [0032] Upcroft,
P.; Upcroft, J. A. Drug targets and mechanisms of resistance in the
anaerobic protozoa. Clinical Microbiology Reviews 2001, 14,
150-164. [0033] Calzada, F.; Cerda-Garcia-Rojas, C. M.; Meckes, M.;
Cedillo-Rivera, R.; Bye, R.; Mata, R. Geranins A and B, New
Antiprotozoal A-Type Proanthocyanidins from Geranium niveum.
Journal of Natural Products 1999, 62, 705-709. [0034] Meckes, M.;
Calzada, F.; Tapia-Contreras, A.; Cedillo-Rivera, R. Antiprotozoal
properties of Helianthemum glomeratum. Phytotherapy Research 1999,
13, 102-105. [0035] Calzada, F.; Meckes, M.; Cedillo-Rivera, R.
Antiamoebic and antigiardial activity of plant flavonoids. PLANTA
MEDICA 1999, 65, 78-80. [0036] Khan, I. A.; Avery, M. A.; Burandt,
C. L.; Goins, D. K.; Mikell, J. R.; Nash, T. E.; Azadegan, A.;
Walker, L. A. Antigiardial Activity of Isoflavones from Dalbergia
frutescens Bark. Journal of Natural Products 2000, 63, 1414-1416.
[0037] Brandi, M. L. Natural and synthetic isoflavones in the
prevention and treatment of chronic diseases. Calcified Tissue
International 1997, 61, S5-S8. [0038] Ruenitz, P. C. Drugs for
osteoporosis prevention: mechanisms of bone maintenance. Curr. Med.
Chem. 1995, 2, 791-802. [0039] Gennari, C. Calcitonin, bone-active
isoflavones and vitamin D metabolites. Osteoporosis International
1999, 9, 81-90. [0040] Yamaguchi, M. Isoflavone and bone
metabolism: its cellular mechanism and preventive role in bone
loss. Journal of Health Science 2002, 48, 209-222. [0041] Arjmandi,
B. H. The role of phytoestrogens in the prevention and treatment of
osteoporosis in ovarian hormone deficiency. Journal of the American
College of Nutrition 2001, 20, 398S-402S. [0042] Messina, M.
Soyfoods and soybean phyto-estrogens (isoflavones) as possible
alternatives to hormone replacement therapy (HRT). European Journal
of Cancer 2000, 36, S71-S72. [0043] Brandi, M. L. Phytoestrogens
and menopause. Environmental Toxicology and Pharmacology 1999, 7,
213-216. [0044] Suthar, A. C.; Banavalikar, M. M.; Biyani, M. K.
Pharmacological activities of genistein, an isoflavone from soy
(Glycine max): Part II-Anti-cholesterol activity, effects on
osteoporosis & menopausal symptoms. Indian Journal of
Experimental Biology 2001, 39, 520-525. [0045] Polkowski, K.;
Mazurek, A. P. Biological properties of genistein a review of in
vitro and in vivo data. Acta Poloniae Pharmaceutica 2000, 57,
135-155. [0046] Goldwyn, S.; Lazinsky, A.; Wei, H. Promotion of
health by soy isoflavones: efficacy, benefit and safety concerns.
Drug Metabolism and Drug Interactions 2000, 17, 261-289. [0047]
Sun, W.-C.; Gee, K. R.; Klaubert, D. H.; Haugland, R. P. Synthesis
of fluorinated fluoresceins. Journal of Organic Chemistry 1997, 62,
6469-6475. [0048] Della Valle, F.; Romeo, A. 2-Haloresorcinols.
Eur. Pat. Appl.; (Fidia S.p.A., Italy). Ep, 1985, 31 pp. [0049]
Kiehlmann, E.; Lauener, R. W. Bromophloroglucinols and their methyl
ethers. Can. J. Chem. 1989, 67, 335-344. [0050] Yang, J.-J.; Su,
D.; Vij, A.; Hubler, T. L.; Kirchmeier, R. L.; Shreeve, J. n. M.
Synthesis of 4-fluororesorcinol and 4-trifluoromethylresorcinol.
Heteroatom Chemistry 1998, 9, 229-239. [0051] Lal, G. S.; Pez, G.
P.; Syvret, R. G. Electrophilic NF Fluorinating Agents. Chemical
Reviews (Washington, D.C.) 1996, 96, 1737-1755. [0052] Wahala, K.;
Hase, T. A. Expedient synthesis of polyhydroxyisoflavones. J. Chem.
Soc., Perkin Trans. 1 1991, 3005-3008. [0053] Keister, D. B. Axenic
culture of Giardia lamblia in TYI-S-33 medium supplemented with
bile. TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND
HYGIENE 1983, 77, 487-488. [0054] Wright, C. W.; Melwani, S. I.;
Phillipson, J. D.; Warhurst, D.C. Determination of anti-giardial
activity in vitro by means of soluble formazan production. Trans.
R. Soc. Trop. Med. Hyg. 1992, 86, 517-519. [0055] Chudgar, N. K.;
Mani, N. V.; Sethna, S. Studies in isoflavones. I. Bromination,
iodination, and nitration of 7-hydroxyisoflavone. J. Inst. Chem.
(India) 1967, 39, 203-208. [0056] Khan, Ikhlas A.; Avery, Mitchell
A.; Goins, D. Keith; Walker, Larry A.; Burandt, Charles L.
Isoflavones for treating giardiasis and malaria. PCT Int. Appl.
(1999), 16 pp. WO 9949862 A1 19991007 [0057] ElSohly, Hala N.;
Joshi, A. S.; Nimrod, A. C. Antigiardial isoflavones from
Machaerium aristulatum. Planta Medica (1999), 65(5), 490. [0058]
Khan, I. A.; Avery, M. A.; Burandt, C. L.; Goins, D. K.; Mikell, J.
R.; Nash, T. E.; Azadegan, A.; Walker, L. A. Antigiardial Activity
of Isoflavones from Dalbergia frutescens Bark. Journal of Natural
Products (2000), 63(10), 1414-1416. [0059] U.S. Pat. Nos.
6,593,310; 6,326,366; 6,592,910; 6,599,536; 6,391,309;
6,541,613.
SUMMARY OF THE INVENTION
[0060] The present invention provides a method of preventing or
treating one or more of the following medical conditions, or
treating symptoms of one or more of the following medical
conditions: amebic infections, giardiasis, estrogen deficient
states, osteoporosis, cardiovascular heart disease, high
cholesterol levels, hyperlipidemia, cancer.
[0061] The present invention further provides a method or
preventing or treating the symptoms of one or more of the
aforementioned medical conditions by administering to a subject
having, or predisposed to, one or more of the conditions, a
therapeutically effective amount of a compound of the present
invention and a pharmaceutically acceptable carrier.
DESCRIPTION OF THE INVENTION
[0062] As stated above, the compounds of the present invention are
useful for treating and/or preventing various medical conditions.
In particular, the compounds of the present invention are useful in
the treatment and prevention of giardial (giardiasis) or other
amebic (protozoal) infections. Compounds of the present invention
are also useful in the treatment of estrogen deficient states such
as the chronic treatment of osteoporosis, and for pre- and
post-menopausal estrogen replacement therapy. They can be useful as
cardioprotective agents in controlling the progression of
cardiovascular heart disease, and for lowering cholesterol levels
and treating hyperlipidemia. Further, compounds of the present
invention have antiproliferative anticancer activity, and cancer
preventative utility.
[0063] The compounds of the present invention may be readily
synthesized and optimized for a particular property by parallel
methods either on solid-phase or in solution-phase, or can be
prepared as combinatorial libraries. Identified single compounds
are easily synthesized by a variety of economically feasible
methods well known in the art.
[0064] The compounds of the present invention are useful in the
treatment of acute infections of giardiasis, tricomoniasis,
shyphilitc disease, and other protozoan or amebic diseases;
treatment of chronic osteoporosis due to low estrogen levels in pre
and postmenopausal women; treatment of proliferative disorders such
as cancer of the prostate, breast, ovary, uterus, testes and other
tissues; for estrogen replacement therapy in low-hormone or
postmenopausal women; as a cardioprotective agent in coronary
artery disease; a mediator of cholesterol and lipid levels; and as
a cancer preventative agent.
[0065] Compounds of the present invention include those listed
below, as Formulae I-VI:
##STR00002##
[0066] wherein:
[0067] R, and R.sub.1-R.sub.5 are each independently be H, a lone
pair of electrons, halogen, alkyl, aryl, amino, a Het group, N, O,
S, SO, SO.sub.2, SO.sub.2NH, COO--, CONH--, COS--, CONR--, and C=0,
each substituent being substituted or unsubstituted.
[0068] The substituents include alkyl, heterosubstituted alkyl,
cycloalkyl, alkenyl, heterosubstituted alkenyl, cycloalkenyl,
alkynyl, heterosubstituted alkynyl, heteroaryl, heterocyclic,
arylalkyl, heterosubstitutedaryl, arylalkenyl, heterosubstituted
alkenylaryl, arylalkynyl, heterosubstituted alkynylaryl,
alkylheteroaryl, heterosubstituted alkylheteroaryl,
alkenylheteroaryl, heterosubstituted alkenylheteroaryl,
alkylheterocyclic, heterosubstitutedalkyl-heterocyclic,
alkenylheterocyclic, and heterosubstitutedalkenyl-heterocyclic
systems.
[0069] X is O, S, NR, NH, N-Aryl or N-Het.
[0070] Y is O, S, NR, NH, N-Aryl or N-Het, NSO.sub.2R,
NSO.sub.2Ar.
[0071] Throughout this application, unless specifically otherwise
noted, all R groups are independent from one another.
[0072] With respect to Formulae IV and VI, R.sub.6 and R.sub.7 have
the same definition as R.sub.15, above, and X is O, S, SO,
SO.sub.2, SONHR.sub.8, SO.sub.2NR.sub.9R.sub.10, NR, NH, NAryl,
N-Het, NSO.sub.2R, NSO.sub.2Ar, wherein R.sub.8-10 have the same
definition as R.sub.15, above, in addition to R.sub.9 and R.sub.10
also being able to form an aryl or Het ring. Y is O, S, SO,
SO.sub.2, SONHR.sub.8, SO.sub.2NR.sub.9R.sub.10, NR, NH, NAryl,
N-Het, NSO.sub.2R, NSO.sub.2Ar, wherein R.sub.8-10 have the same
definition as above.
[0073] Embodiments of the present invention including the following
compounds of Formula VII:
##STR00003##
[0074] wherein R.sub.2 and R.sub.4 are each independently H, alkyl,
halo.
[0075] R.sub.15 and R.sub.16 are each independently H, alkyl, acyl,
alkoxy, aryl, amino, HET.
[0076] As discussed further below, the compounds of the present
invention may be used in pharmaceutical compositions, comprising a
compound of the present invention and a pharmaceutically acceptable
carrier.
[0077] Additionally, the compounds of the present invention can be
targeted for delivery to the intestine by prodrug formation such as
to a polymeric material, or by incorporation into a hydrogel. The
term "prodrug" used herein refers to a compound that can be
metabolized to form a second compound of interest. Typical prodrugs
include glucopyranosides of a functional group such as a phenolic
group, esters, carbonates, and urethanes.
[0078] As used herein, the term alkyl or alkyl group is to be
understood in the broadest sense to mean hydrocarbon residues which
can be linear, i.e., straight-chain, or branched, and can be
acyclic or cyclic residues or comprise any combination of acyclic
and cyclic subunits. Further, the term alkyl as used herein
expressly includes saturated groups as well as unsaturated groups
which latter groups contain one or more, for example, one, two, or
three, double bonds and/or triple bonds. The term alkyl includes
substituted and unsubstituted alkyl groups.
[0079] All these statements also apply if an alkyl group carries
substituents or occurs as a substituent on another residue, for
example, in an alkyloxy residue, or an arylalkylamino residue.
Examples of alkyl residues containing from 1 to 20 carbon atoms are
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,
decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, and
eicosyl, the n-isomers of all these residues, isopropyl, isobutyl,
1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl,
2-methylpentyl, 3-methylpentyl, isohexyl, 2,3,4-trimethylhexyl,
isodecyl, sec-butyl, tert-butyl, or tert-pentyl.
[0080] Unsaturated alkyl residues are, for example, alkenyl
residues such as vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl,
3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, or
1,3-pentadienyl, or alkynyl residues such as ethynyl, 1-propynyl,
2-propynyl (=propargyl), or 2-butynyl. Alkyl residues can also be
unsaturated when they are substituted.
[0081] Examples of cyclic alkyl residues are cycloalkyl residues
containing 3, 4, 5, 6, 7, or 8 ring carbon atoms like cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl
which can also be substituted and/or unsaturated. Unsaturated
cyclic alkyl groups and unsaturated cycloalkyl groups like, for
example, cyclopentenyl or cyclohexenyl can be bonded via any carbon
atom. The term alkyl as used herein also comprises
cycloalkyl-substituted alkyl groups like cyclopropylmethyl-,
cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-,
cycloheptylmethyl-, cyclooctylmethyl-, 1-cyclopropylethyl-,
1-cyclobutylethyl-, 1-cyclopentylethyl-, 1-cyclohexylethyl-,
1-cycloheptylethyl-, 1-cyclooctylethyl-, 2-cyclopropylethyl-,
2-cyclobutylethyl-, 2-cyclopentylethyl-, 2-cyclohexylethyl-,
2-cycloheptylethyl-, 2-cyclooctylethyl-, 3-cyclopropylpropyl-,
3-cyclobutylpropyl-, 3-cyclopentylpropyl-, 3-cyclohexylpropyl-,
3-cycloheptylpropyl-, or 3-cyclooctylpropyl- in which groups the
cycloalkyl subgroup as well as acyclic subgroup also can be
unsaturated and/or substituted.
[0082] Of course, a group like (C.sub.1-C.sub.8)-alkyl is to be
understood as comprising, among others, saturated acyclic
(C.sub.1-C.sub.8)-alkyl, (C.sub.3-C.sub.8)-cycloalkyl,
cycloalkyl-alkyl groups like
(C.sub.3-C.sub.7)-cycloalkyl-(C.sub.1-C.sub.5)-alkyl- wherein the
total number of carbon atoms can range from 4 to 8, and unsaturated
(C.sub.2-C.sub.8)-alkyl like (C.sub.2-C.sub.8)-alkenyl or
(C.sub.2-C.sub.8)-alkynyl. Similarly, a group like
(C.sub.1-C.sub.4)-alkyl is to be understood as comprising, among
others, saturated acyclic (C.sub.1-C.sub.4)-alkyl,
(C.sub.3-C.sub.4)-cycloalkyl, cyclopropyl-methyl-, and unsaturated
(C.sub.2-C.sub.4)-alkyl like (C.sub.2-C.sub.4)-alkenyl or
(C.sub.2-C.sub.4)-alkynyl.
[0083] Unless stated otherwise, the term alkyl preferably comprises
acyclic saturated hydrocarbon residues containing from 1 to 6
carbon atoms which can be linear or branched, acyclic unsaturated
hydrocarbon residues containing from 2 to 6 carbon atoms which can
be linear or branched like (C.sub.2-C.sub.6)-alkenyl and
(C.sub.2-C.sub.6)-alkynyl, and cyclic alkyl groups containing from
3 to 8 ring carbon atoms, in particular from 3 to 6 ring carbon
atoms. A particular group of saturated acyclic alkyl residues is
formed by (C.sub.1-C.sub.4)-alkyl residues like methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and
tert-butyl.
[0084] The alkyl groups (and all other substitutent groups (aryl,
amino, etc.)) of the present invention can in general be
unsubstituted or substituted by one or more, for example, one, two,
three, or four, identical or different substituents. Any kind of
substituents present in substituted alkyl residues can be present
in any desired position provided that the substitution does not
lead to an unstable molecule. Examples of substituted alkyl
residues are alkyl residues in which one or more, for example, 1,
2, 3, 4, or 5, hydrogen atoms are replaced with halogen atoms.
[0085] Examples of substituted cycloalkyl groups are cycloalkyl
groups which carry as substituent one or more, for example, one,
two, three, or four, identical or different acyclic alkyl groups,
for example, acyclic (C.sub.1-C.sub.4)-alkyl groups like methyl
groups. Examples of substituted cycloalkyl groups are
4-methylcyclohexyl, 4-tert-butylcyclohexyl, or
2,3-dimethylcyclopentyl.
[0086] The term aryl refers to a monocyclic or polycyclic
hydrocarbon residue in which at least one carbocyclic ring is
present. In a (C.sub.6-C.sub.14)-aryl residue from 6 to 14 ring
carbon atoms are present. Examples of (C.sub.6-C.sub.14)-aryl
residues are phenyl, naphthyl, biphenylyl, fluorenyl, or
anthracenyl. Examples of (C.sub.6-C.sub.10)-aryl residues are
phenyl or naphthyl. Unless stated otherwise, and irrespective of
any specific substituents bonded to aryl groups, aryl residues
including, for example, phenyl, naphthyl, and fluorenyl, can in
general be unsubstituted or substituted by one or more, for
example, one, two, three, or four, identical or different
substituents. Aryl residues can be bonded via any desired position,
and in substituted aryl residues the substituents can be located in
any desired position.
[0087] In monosubstituted phenyl residues, the substituent can be
located in the 2-position, the 3-position, or the 4-position, the
3-position and the 4-position being preferred. These positional
nomenclatures (numbering schemes) refer to the residue itself, for
the isoflavone ring system is itself numbered starting from O-1 to
C-2, . . . C-4a, C-5, and so on up to C-8a. The C-2 phenyl ring of
an isoflavone is numbered with prime numbers. Thus, formonnonetin 7
possess a 4'-methoxy group. If a phenyl group carries two
substituents, they can be located in 2,3-position, 2,4-position,
2,5-position, 2,6-position, 3,4-position, or 3,5-position. In
phenyl residues carrying three substituents, the substituents can
be located in 2,3,4-position, 2,3,5-position, 2,3,6-position,
2,4,5-position, 2,4,6-position, or 3,4,5-position. Naphthyl
residues can be 1-naphthyl and 2-naphthyl. In substituted naphthyl
residues, the substituents can be located in any positions, for
example, in monosubstituted 1-naphthyl residues in the 2-, 3-, 4-,
5-, 6-, 7-, or 8-position and in monosubstituted 2-naphthyl
residues in the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position. Biphenylyl
residues can be 2-biphenylyl, 3-biphenylyl, or 4-biphenylyl.
Fluorenyl residues can be 1-, 2-, 3-, 4-, or 9-fluorenyl. In
monosubstituted fluorenyl residues, bonded via the 9-position the
substituent is preferably present in the 1-, 2-, 3-, or
4-position.
[0088] Unless stated otherwise, substituents that can be present in
substituted aryl groups are, for example, (C.sub.1-C.sub.8)-alkyl,
in particular (C.sub.1-C.sub.4)-alkyl, such as methyl, ethyl, or
tert-butyl, hydroxy, (C.sub.1-C.sub.8)-alkyloxy, in particular
(C.sub.1-C.sub.4)-alkyloxy, such as methoxy, ethoxy, or
tert-butoxy, methylenedioxy, ethylenedioxy, F, Cl, Br, I, cyano,
nitro, trifluoromethyl, trifluoromethoxy, hydroxymethyl, formyl,
acetyl, amino, mono- or di-(C.sub.1-C.sub.4)-alkylamino,
((C.sub.1-C.sub.4)-alkyl)carbonylamino like acetylamino,
hydroxycarbonyl, ((C.sub.1-C.sub.4)-alkyloxy) carbonyl, carbamoyl,
optionally substituted phenyl, benzyl optionally substituted in the
phenyl group, optionally substituted phenoxy, or benzyloxy
optionally substituted in the phenyl group.
[0089] The above statements relating to aryl groups correspondingly
apply to divalent residues derived from aryl groups, i.e., to
arylene groups like phenylene which can be unsubstituted or
substituted 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene, or
naphthalene which can be unsubstituted or substituted
1,2-naphthalenediyl, 1,3-naphthalenediyl, 1,4-naphthalenediyl,
1,5-naphthalenediyl, 1,6-naphthalenediyl, 1,7-naphthalenediyl,
1,8-naphthalenediyl, 2,3-naphthalenediyl, 2,6-naphthalenediyl, or
2,7-naphthalenediyl.
[0090] The above statements also correspondingly apply to the aryl
subgroup in arylalkyl-groups. Examples of arylalkyl-groups which
can also be unsubstituted or substituted in the aryl subgroup as
well as in the alkyl subgroup, are benzyl, 1-phenylethyl,
2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,
1-methyl-3-phenyl-propyl, 1-naphthylmethyl, 2-naphthylmethyl,
1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl,
2-(2-naphthyl)ethyl, or 9-fluorenylmethyl.
[0091] The "Het" group comprises groups containing 3, 4, 5, 6, 7,
8, 9, or 10 ring atoms in the parent monocyclic or bicyclic
heterocyclic ring system. In monocyclic Het groups, the
heterocyclic ring preferably is a 3-membered, 4-membered,
5-membered, 6-membered, or 7-membered ring, particularly
preferably, a 5-membered or 6-membered ring. In bicyclic Het
groups, preferably two fused rings are present, one of which is a
5-membered ring or 6-membered heterocyclic ring and the other of
which is a 5-membered or 6-membered heterocyclic or carbocyclic
ring, i.e., a bicyclic Het ring preferably contains 8, 9, or 10
ring atoms, more preferably 9 or 10 ring atoms.
[0092] Het comprises saturated heterocyclic ring systems which do
not contain any double bonds within the rings, as well as
mono-unsaturated and poly-unsaturated heterocyclic ring systems
which contain one or more, for example, one, two, three, four, or
five, double bonds within the rings provided that the resulting
system is stable. Unsaturated rings may be non-aromatic or
aromatic, i.e., double bonds within the rings in the Het group may
be arranged in such a manner that a conjugated pi electron system
results. Aromatic rings in a Het group may be 5-membered or
6-membered rings, i.e., aromatic groups in a Het group contain 5 to
10 ring atoms, and are in accordance by definition with Huckel's
rule of aromaticity, that those systems defined as aromatic must
have 4n+2.pi. electrons (n=1, 2, etc.). Aromatic rings in a Het
group thus comprise 5-membered and 6-membered monocyclic
heterocycles and bicyclic heterocycles composed of two 5-membered
rings, one 5-membered ring, and one 6-membered ring, or two
6-membered rings. In bicyclic aromatic groups in a Het group, one
or both rings may contain heteroatoms. Aromatic Het groups may also
be referred to by the customary term heteroaryl for which all the
definitions and explanations above and below relating to Het
correspondingly apply.
[0093] Unless stated otherwise, in the Het groups and any other
heterocyclic groups, preferably 1, 2, 3, or 4 identical or
different ring heteroatoms selected from nitrogen, oxygen, and
sulfur are present. Particularly preferably, in these groups 1 or 2
identical or different ring heteroatoms selected from nitrogen,
oxygen, and sulfur are present. The ring heteroatoms can be present
in any desired number and in any position with respect to each
other provided that the resulting heterocyclic system is known in
the art and is stable and suitable as a subgroup in a drug
substance. Examples of parent structures of heterocycles from which
the Het group can be derived are aziridine, oxirane, thiirane,
azetidine, pyrrole, furan, thiophene, dioxole, imidazole, pyrazole,
oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole,
1,2,4-triazole, tetrazole, pyridine, pyran, thiopyran, pyridazine,
pyrimidine, pyrazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine,
1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine,
1,2,4-triazine, 1,3,5-triazine, azepine, 1,2-diazepine,
1,3-diazepine, 1,4-diazepine, indole, isoindole, benzofuran,
benzothiophene, 1,3-benzodioxole, indazole, benzimidazole,
benzoxazole, benzothiazole, quinoline, isoquinoline, chromane,
isochromane, cinnoline, quinazoline, quinoxaline, phthalazine,
pyridoimidazoles, pyridopyridines, pyridopyrimidines, purine, or
pteridine, as well as ring systems which result from the listed
heterocycles by fusion (or condensation) of a carbocyclic ring, for
example, benzo-fused, cyclopenta-fused, cyclohexa-fused, or
cyclohepta-fused derivatives of these heterocycles.
[0094] The Het residue may be bonded via any ring carbon atom, and
in the case of nitrogen heterocycles, via any suitable ring
nitrogen atom. Thus, for example, a pyrrolyl residue can be
1-pyrrolyl, 2-pyrrolyl, or 3-pyrrolyl, a pyrrolidinyl residue can
be 1-pyrrolidinyl (=pyrrolidino), 2-pyrrolidinyl, or
3-pyrrolidinyl, a pyridyl residue can be 2-pyridyl, 3-pyridyl, or
4-pyridyl, and a piperidinyl residue can be 1-piperidinyl
(=piperidino), 2-piperidinyl, 3-piperidinyl, or 4-piperidinyl.
Furyl can be 2-furyl or 3-furyl, thienyl can be 2-thienyl or
3-thienyl, imidazolyl can be 1-imidazolyl, 2-imidazolyl,
4-imidazolyl, or 5-imidazolyl, 1,3-oxazolyl can be 1,3-oxazol-2-yl,
1,3-oxazol-4-yl, or 1,3-oxazol-5-yl, 1,3-thiazolyl can be
1,3-thiazol-2-yl, 1,3-thiazol-4-yl, or 1,3-thiazol-5-yl,
pyrimidinyl can be 2-pyrimidinyl, 4-pyrimidinyl (=6-pyrimidinyl),
or 5-pyrimidinyl, and piperazinyl can be 1-piperazinyl
(=4-piperazinyl=piperazino) or 2-piperazinyl. Indolyl can be
1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl,
or 7-indolyl. Similarly, benzimidazolyl, benzoxazolyl, and
benzothiazolyl residues can be bonded via the 2-position and via
any of the positions 4, 5, 6, and 7, benzimidazolyl also via the
1-position. Quinolyl can be 2-quinolyl, 3-quinolyl, 4-quinolyl,
5-quinolyl, 6-quinolyl, 7-quinolyl, or 8-quinolyl, and isoquinolyl
can be 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,
6-isoquinolyl, 7-isoquinolyl, or 8-isoquinolyl. In addition to
being bonded via any of the positions indicated for quinolyl and
isoquinolyl, 1,2,3,4-tetrahydroquinolyl and
1,2,3,4-tetrahydroisoquinolyl can also be bonded via the nitrogen
atoms in the 1-position and 2-position, respectively.
[0095] Unless stated otherwise, and irrespective of any specific
substituents bonded to Het groups or any other heterocyclic groups
which are indicated in the definition of compounds of the present
invention, the Het group can be unsubstituted or substituted on
ring carbon atoms with one or more, for example, one, two, three,
four, or five, identical or different substituents like
(C.sub.1-C.sub.8)-alkyl, in particular (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.8)-alkyloxy, in particular
(C.sub.1-C.sub.4)-alkyloxy, (C.sub.1-C.sub.4)-alkylthio, halogen,
nitro, amino, ((C.sub.1-C.sub.4)-alkyl)carbonylamino like
acetylamino, trifluoromethyl, trifluoromethoxy, hydroxy, oxo,
hydroxy-(C.sub.1-C.sub.4)-alkyl such as, for example,
hydroxymethyl, 1-hydroxyethyl, or 2-hydroxyethyl, methylenedioxy,
ethylenedioxy, formyl, acetyl, cyano, methylsulfonyl,
hydroxycarbonyl, aminocarbonyl, (C.sub.1-C.sub.4)-alkyloxycarbonyl,
optionally substituted phenyl, optionally substituted phenoxy,
benzyl optionally substituted in the phenyl group, or benzyloxy
optionally substituted in the phenyl group. The substituents can be
present in any desired position provided that a stable molecule
results. Of course an oxo group cannot be present in a fully
aromatic ring. Some degree of aromaticity exists for cross
conjugated rings like para-quinone, but it is less in magnitude
than the aromaticity assigned to benzene itself of approximately 36
Kcal/M. Each suitable ring nitrogen atom in a Het group can
independently of each other be unsubstituted, i.e., carry a
hydrogen atom, or can be substituted, i.e., carry a substituent
like (C.sub.1-C.sub.8)-alkyl, for example, (C.sub.1-C.sub.4)-alkyl
such as methyl or ethyl, optionally substituted phenyl,
phenyl-(C.sub.1-C.sub.4)-alkyl, for example, benzyl, optionally
substituted in the phenyl group, hydroxy-(C.sub.2-C.sub.4)-alkyl
such as, for example, 2-hydroxyethyl, acetyl, or another acyl
group, methylsulfonyl or another sulfonyl group, aminocarbonyl, or
(C.sub.1-C.sub.4)-alkyloxycarbonyl. Nitrogen heterocycles can also
be present as N-oxides or as quaternary salts. Ring sulfur atoms
can be oxidized to the sulfoxide or to the sulfone. Thus, for
example, a tetrahydrothienyl residue may be present as
S,S-dioxotetrahydrothienyl residue or a thiomorpholinyl residue
like 4-thiomorpholinyl may be present as 1-oxo-4-thiomorpholinyl or
1,1-dioxo-4-thiomorpholinyl. A substituted Het group that can be
present in a specific position of compounds of formula I can
independently of other Het groups be substituted by substituents
selected from any desired subgroup of the substituents listed
before and/or in the definition of that group.
[0096] The explanations relating to the Het residue correspondingly
apply to divalent Het residues including divalent heteroaromatic
residues which may be bonded via any two ring carbon atoms and in
the case of nitrogen heterocycles via any carbon atom and any
suitable ring nitrogen atom or via any two suitable nitrogen atoms.
For example, a pyridinediyl residue can be 2,3-pyridinediyl,
2,4-pyridinediyl, 2,5-pyridinediyl, 2,6-pyridinediyl,
3,4-pyridinediyl, or 3,5-pyridinediyl, a piperidinediyl residue can
be, among others, 1,2-piperidinediyl, 1,3-piperidinediyl,
1,4-piperidinediyl, 2,3-piperidinediyl, 2,4-piperidinediyl, or
3,5-piperidinediyl, and a piperazinediyl residue can be, among
others, 1,3-piperazinediyl, 1,4-piperazinediyl, 2,3-piperazinediyl,
or 2,5-piperazinediyl. The above statements also correspondingly
apply to the Het subgroup in the Het-alkyl-groups. Examples of such
Het-alkyl-groups which can also be unsubstituted or substituted in
the Het subgroup as well as in the alkyl subgroup, are
(2-pyridyl)methyl, (3-pyridyl)methyl, (4-pyridyl)methyl,
2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, or 2-(4-pyridyl)ethyl.
[0097] Alkoxy as used herein means an alkyl-O-- group in which the
alkyl group is as previously described. Exemplary alkoxy groups
include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy
and polyethers including --O--(CH.sub.2).sub.2 OCH.sub.3.
[0098] An acyl group is defined as a group --C(O)R where R is an
alkyl or aryl radical and includes acetyl, trifluoroacetyl, benzoyl
and the like.
[0099] An example of an amino group is NR.sub.1R.sub.2.
[0100] Where terms are used in combination, the definition for each
individual part of the combination applies unless defined
otherwise. For instance, arylalkylthio refers to an aryl group, as
defined above, alkyl group as defined above, and a thio group. An
example is alkylamino, which is defined as a nitrogen atom
substituted with an alkyl of 1 to 12 carbon atoms. Also, thioalkyl,
or alkylthio as used herein means an alkyl-S-- group in which the
alkyl group is as previously described. Thioalkyl groups include
thiomethyl and the like. Examples of alkylthio groups of compounds
of the present invention includes those groups having one or more
thioether linkages and from 1 to about 12 carbon atoms, further
examples have from 1 to about 8 carbon atoms, and still further
examples have 1 to about 6 carbon atoms. Alkylthio groups having 1,
2, 3 or 4 carbon atoms are further examples.
[0101] Some of the compounds of the invention may have stereogenic
centers. The compounds may, therefore, exist in at least two and
often more stereoisomeric forms. The present invention encompasses
all stereoisomers of the compounds whether free from other
stereoisomers or admixed with other stereoisomers in any proportion
and thus includes, for instance, racemic mixture of enantiomers as
well as the diastereomeric mixture of isomers. Thus, when using the
term compound, it is understood that all stereoisomers are
included.
[0102] The compounds of the present invention may be obtained or
used as inorganic or organic salts using methods known to those
skilled in the art. It is well known to one skilled in the art that
an appropriate salt form is chosen based on physical and chemical
stability, flowability, hydroscopicity and solubility.
Pharmaceutically acceptable salts of the present invention with an
acidic moiety may be optionally formed from organic and inorganic
bases. For example with alkali metals or alkaline earth metals such
as sodium, potassium, lithium, calcium, or magnesium or organic
bases and N-tetraalkylammonium salts such as N-tetrabutylammonium
salts. Similarly, when a compound of this invention contains a
basic moiety, salts may be optionally formed from organic and
inorganic acids.
[0103] For example salts may be formed from acetic, propionic,
lactic, citric, tartaric, succinic, fumaric, maleic, malonic,
mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric,
nitric, sulfuric, methanesulfonic, naphthalenesulfonic,
benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly
known acceptable acids. The compounds can also be used in the form
of esters, carbamates and other conventional prodrug forms, which
when administered in such form, convert to the active moiety in
vivo. When using the term compound herein, it is understood that
all salts are included.
[0104] The present invention accordingly provides a pharmaceutical
composition which comprises a compound of this invention in
combination or association with a pharmaceutically acceptable
carrier. In particular, the present invention provides a
pharmaceutical composition which comprises an effective amount of a
compound of this invention and a pharmaceutically acceptable
carrier.
[0105] The term "pharmaceutically acceptable salt" as used herein
is intended to include the non-toxic acid addition salts with
inorganic or organic acids, e.g. salts with acids such as
hydrochloric, phosphoric, sulfuric, maleic, acetic, citric,
succinic, benzoic, fumaric, mandelic, p-toluene-sulfonic,
methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic,
hydroiodic, hydrobromic, and the like. Examples of pharmaceutically
acceptable salts include, but are not limited to, mineral or
organic acid salts of basic residues such as amines; alkali or
organic salts of acidic residues such as carboxylic acids; and the
like.
[0106] Pharmaceutically acceptable salts of the compounds of the
invention can be prepared by reacting the free acid or base forms
of these compounds with a stoichiometric amount of the appropriate
base or acid in water or in an organic solvent, or in a mixture of
the two; generally, nonaqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred. Lists of
suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
disclosure of which is hereby incorporated by reference.
[0107] B. Methods of Using the Compounds of the Present
Invention
[0108] The method of the present invention includes administering
the effective compounds described herein to people or animals by
any route appropriate to the condition to be treated, as determined
by one of ordinary skill in the art. Additionally, physiologically
acceptable acid addition salts of compounds described herein are
also useful in the methods of treating of the present
invention.
[0109] For pharmaceutical use, the compounds described herein may
be taken up in pharmaceutically acceptable carriers, such as, for
example, solutions, suspensions, tablets, capsules, ointments,
elixirs and injectable compositions. Pharmaceutical preparations
may contain from 0.1% to 99% by weight of active ingredient.
Preparations which are in single dose form, "unit dosage form",
preferably contain from 20% to 90% active ingredient, and
preparations which are not in single dose form preferably contain
from 5% to 20% active ingredient. As used herein, the term "active
ingredient" refers to compounds described herein, salts thereof,
and mixtures of compounds described herein with other
pharmaceutically active compounds. Dosage unit forms such as, for
example, tablets or capsules, typically contain from about 0.05 to
about 1.0 g of active ingredient.
[0110] Suitable routes of administering the pharmaceutical
preparations include, for example, oral, rectal, topical (including
dermal, buccal and sublingual), vaginal, parenteral (including
subcutaneous, intramuscular, intravenous, intradermal, intrathecal
and epidural) and by naso-gastric tube. It will be understood by
those skilled in the art that the preferred route of administration
will depend upon the condition being treated and may vary with
factors such as the condition of the recipient.
[0111] According to the methods of the present invention, the
effective compounds described herein may be administered alone or
in conjunction with other pharmaceutically active compounds. It
will be understood by those skilled in the art that
pharmaceutically active compounds to be used in combination with
the compounds described herein will be selected in order to avoid
adverse effects on the recipient or undesirable interactions
between the compounds. As used herein, the term "active ingredient"
is meant to include compounds described herein when used alone or
in combination with one or more additional pharmaceutically active
compounds. The amount of the compounds described herein required
for use in the various treatments of the present invention depend,
inter alia, on the route of administration, the age and weight of
the animal (e.g. human) to be treated and the severity of the
condition being treated.
[0112] It is preferred to administer the compounds of the present
invention as pharmaceutical formulations. Useful formulations
comprise one or more active ingredients and one or more
pharmaceutically acceptable carriers. The term "pharmaceutically
acceptable" means compatible with the other ingredients of the
formulation and not toxic to the recipient. Useful pharmaceutical
formulations include those suitable for oral, rectal, nasal,
topical, vaginal or parenteral administration, as well as
administration by naso-gastric tube. The formulations may
conveniently be prepared in unit dosage form and may be prepared by
any method known in the art of pharmacy. Such methods include the
step of bringing the active ingredient into association with the
carrier, which may constitute one or more accessory ingredients. In
general, the formulations are prepared by uniformly bringing the
active ingredients into association with liquid carriers or finely
divided solid carriers or both, and then, if necessary, shaping the
product.
[0113] Administration of the compositions of the present invention
may be for either a prophylactic or therapeutic use. When provided
prophylactically, a compound of the present invention is provided
in advance of any symptoms such as exposure to conditions
indicative of the methods of treatment of the present
invention.
[0114] Additionally, a compound of the present invention may be
administered during or after treatment to help prevent the
reoccurrence the condition. The prophylactic administration of the
composition is intended as a preventive therapy and serves to
either prevent the condition or arrest or reverse the progression
of the condition.
[0115] When provided therapeutically the composition is provided at
or after the onset of the condition. The therapeutic administration
of the composition of this invention serves to attenuate or
alleviate the condition or facilitate regression of the condition
afflicting the individual. The term individual is intended to
include any animal, preferably a mammal, and most preferably a
human. Veterinary uses are intended to be encompassed by this
definition.
[0116] In one embodiment of this invention, individuals at high
risk for a particular condition treatable by a method of the
present invention, or at high risk of reoccurrence of a condition
or who have known risk factors are prophylactically treated with
the methods and compositions described herein. By way of example,
such individuals may include those with a familial history for
either early or late onset of cancer, and individuals who are being
or have been treated for a cancer or cancer-related illness.
[0117] The daily dose of the compound may be administered in a
single dose or in portions at various hours of the day. Initially,
a higher dosage may be required and may be reduced over time when
the optimal initial response is obtained. By way of example,
treatment may be continuous for days, weeks, or years, or may be at
intervals with intervening rest periods. The dosage may be modified
in accordance with other treatments the individual may be
receiving. One of skill in the art will appreciate that
individualization of dosage may be required to achieve the maximum
effect for a given individual. It is further understood by one
skilled in the art that the dosage administered to a individual
being treated may vary depending on the individuals age, severity
or stage of the disease and response to the course of treatment.
One skilled in the art will know the clinical parameters to
evaluate to determine proper dosage for the individual being
treated by the methods described herein.
[0118] Additional pharmaceutical methods may be employed to control
the duration of action. Controlled release preparations may be
achieved through the use of polymer to complex or absorb the
proteins or their derivatives. The controlled delivery may be
exercised by selecting appropriate macromolecules (for example
polyester, polyamino acids, polyvinyl, pyrrolidone,
ethylenevinylacetate, methylcellulose, carboxymethylcellulose, or
protamine sulfate) and the concentration of macromolecules as well
as the methods of incorporation in order to control release.
Alternatively, instead of incorporating these agents into polymeric
particles, it is possible to entrap these materials in
microcapsules prepared, for example, by coacervation techniques or
by interfacial polymerization.
[0119] When oral preparations are desired, the component may be
combined with typical carriers/excipients, such as lactose,
sucrose, starch, talc magnesium stearate, crystalline cellulose,
methyl cellulose, carboxymethyl cellulose, glycerin, sodium
alginate or gum arabic among others. The only limitation with
resect to the carrier is that it does not deleteriously react with
the active compound or is not deleterious to the recipient
thereof.
[0120] The pharmaceutical preparations can be sterilized and if
desired mixed with auxiliary agents, e.g., lubricants,
preservatives, stabilizers, wetting agents, emulsifiers, salts for
influencing osmotic pressure, buffers, colorings, flavorings and/or
aromatic substances and the like which do not deleteriously react
with the active compounds.
[0121] As stated above, the administration of the compositions or
of each individual component of the present invention may be for
either a prophylactic or therapeutic purpose. The methods and
compositions used herein may be used alone in prophylactic or
therapeutic uses or in conjunction with additional therapies known
to those skilled in the art in the prevention or treatment of
cancer. Alternatively the methods and compositions described herein
may be used as adjunct therapy.
[0122] It will be appreciated that the actual preferred amounts of
active compounds used in a given therapy will vary according to the
specific compound being utilized, the particular compositions
formulated, the mode of application, the particular site of
administration, etc. Optimal administration rates for a given
protocol of administration can be readily ascertained by those
skilled in the art using conventional dosage determination
tests.
[0123] Cancer, as used herein includes, but is not limited to,
malignant tumors, adenocarcinomas, carcinomas, sarcomas, malignant
neoplasms, and leukemias. In particular epithelial cell derived
cancers are intended to be encompassed by this invention. Examples
of epithelial cell derived cancers that may be treated by the
methods described herein include, but are not limited to, breast
cancer, colon cancer, ovarian cancer, lung cancer or prostate
cancer. Such cancers may be caused by, chromosomal abnormalities,
degenerative growth and developmental disorders, mitogenic agents,
ultraviolet radiating (UV), viral infections, oncogenes, mutations
in genes, in-appropriate expression of a gene and presentation on a
cell, or carcinogenic agent.
Experimental Description
Examples/Preparation of Compounds of the Present Invention
[0124] This section is presented as the best mode and for exemplary
purposes. Specifically, the information and examples provided
herein are intended to demonstrate certain embodiments of the
present invention and not to be construed as limiting the scope of
the present invention.
Example 1
Preparation of Compounds of the Present Invention
[0125] This example demonstrates how compounds of the present
invention may be made. Starting halogen-substituted resorcinol
derivatives A1-4 (in the chart, below) may be synthesized by
previously reported methods, while A5 and A6 and all phenylacetic
acids B1-29 were commercially available. The synthetic sequence for
the isoflavone library is depicted in Scheme 1. In the first step,
Friedel-Crafts acylation of resorcinol derivatives A1-6 with
substituted phenyl acetic acids B1-29 was carried out in the
presence of BF.sub.3.Et.sub.2O. The resulting intermediates
I(A1-6,B1-29) were subjected to Vilsmeier-Haack cyclization to
furnish the final products P(A1-6,B1-29). The reaction conditions
were optimized first, and the library 6.times.29 of isoflavones was
generated using a Quest 210 (Argonaut Technologies Inc., CA).
[0126] The following chart shows compounds that may be used as
building blocks for embodiments of the present invention. In the
chart, halogen-substituted resorcinol derivatives are indicated as
A1-6, and phenylacetic acid derivatives are indicated as B1-29.
TABLE-US-00001 A1 ##STR00004## A2 ##STR00005## A3 ##STR00006## A4
##STR00007## A5 ##STR00008## A6 ##STR00009## B ##STR00010## Compd.
R B1 H B2 3,4-di-OH B3 3-Cl-4-OH B4 3-F-4-OH B5 3-OH B6 3-NO.sub.2
B7 4-NMe.sub.2 B8 4-Cl B9 4-F B10 4-OH B11 4-OMe B12 4-NO.sub.2 B13
3,4-di-OMe B14 4-CF.sub.3 B15 4-NH.sub.2 B16 4-Ph B17 4-Br B18
4-OEt B19 3-Me B20 4-Me B21 3,4-di-Cl B22 3,4-di-F B23 3,5-di-F B24
3-CF.sub.3 B25 3-NH.sub.2 B26 3-Br B27 3-Cl B28 3-F B29 3-OMe
[0127] During the parallel synthesis of embodiments of the present
invention, a slight excess of phenyl acetic acids was used in order
to ensure complete consumption of the resorcinols. After on-line
liquid-liquid extraction and solution drying/filtration, further
purification was conducted employing a short plug of silica gel in
parallel fashion under reduced pressure. All the products were
analyzed by mass spectra and HPLC, and the results are summarized
in the following Example, below. Overall yields based on tared
weight ranged from 6 to 86%, and purities were greater than
70%.
##STR00011##
[0128] While this method was found to be generally applicable with
some modifications to time and temperature, the conflicting nature
of having a basic moiety such as an amine attached to the nucleus
of the ring system during ring cyclization under highly acidic
conditions (e.g. synthesis of 9) became apparent. Such chemistry
may not be generally suitable for parallel synthesis of amine
substituted products or protonatable heterocyclic ring systems.
Therefore, other methods have been developed for construction of
chroman-4-ones having acid sensitive, or acid reactive groups as
shown in Scheme 2 and 3.
##STR00012##
[0129] L is N or C; R.sub.10 and R.sub.11 are independent from one
another and have the same definition as the above-defined R
groups.
##STR00013##
[0130] For example, as shown in Scheme 2, a 4'-bromo substituted
isoflavone could serve as a gateway compound for introduction of
amines and other polar groups to a preformed chromanone ring
system, avoiding the problematic ring construction step in the
presence of a basic moiety. The amine addition step occurs readily
for example by Pd(0) catalyzed coupling of 10 (or 17 in Scheme 3)
either primary or secondary amines or as the boronate amides
B(NRR.sub.1).sub.3. It may be desirable to prepare libraries by
attaching the 7-phenol to a resin such as a Wang resin, via the
Wang bromide resin, and then conduct reaction and easily workup
libraries before liberation from the solid matrix. The adduct
amines, if removed by HCl, would be obtained as HCl salts. This is
shown in Scheme 4. Additionally, Pd(II) complexes can be used with
appropriate ligation and reductive conditions such that reaction
occurs directly with free primary or secondary amines. This
protocol allows one to generate secondary or tertiary amine analogs
such as 27 without air sensitive reagents or the need for a
separate boron reagent for every amine. Experimental details are
provided in example 4.
##STR00014##
[0131] An advantage of this approach is that the various R groups
can be modified as required to achieve substantial diversity in the
design of compounds of the present invention. For example, R.sub.1
could be a protected hydroxyl group that could be converted to a
triflate for further Pd(0) coupling chemistry at some point while
still attached to the solid phase matrix. The bromoisoflavone 24
can be made by routine chemistry, as outlined in Scheme 1, as well
as other methods.
[0132] Although acceptable embodiments of the present invention,
the present inventor found that syntheses starting with
bromoresorcinols led to poor reactivity and lower yields, compared
to fluoro and chloro analogs. Without being bound by theory, this
is presumably due to the increased sensitivity of C--Br bonds to
the reaction conditions. The IC.sub.50 values reported in Table 1
indicate that several of the halogenated isoflavones possess
significant antigiardial activity. Overall, a fluoro substituent at
C-8 of the isoflavone ring system displayed a substantial effect in
antigiardial activity. However, compounds having a bromo
substituent at C-8 did not show much bioactivity. Without being
bound by theory, since the fluorine is considered to be as small as
hydrogen in size and has higher electronegativity than the bromine,
it is conceivable that electronic factors would be responsible for
these results. Most of halogen substitutions at C-6 yielded less
active or inactive (NA) analogs, which indicates, in general, that
electron-withdrawing groups such as halogens at C-6 are not
well-tolerated for antigiardial potency. As for the phenyl ring on
C-3 of the isoflavone structure, compounds with a 4'-methoxy
substrate showed enhanced potency in the antigiardial assay
(P(A1,B11) and P(A3,B11)). Also, small hydrophobic substituents
such as 3'-methyl (P(A1,B19), P(A3,B19), and P(A4,B19)) and
3'-fluoro (P(A3,B28) and P(A6,B28)) substrates were found to be
preferable for enhanced potency. Regardless of the halogens on C-6
or C-8, incorporation of a hydrophobic bulky group on the phenyl
ring at the C-4' position is not preferred due to less activity
(P(A1,B16), P(A4,B16), P(A5,B16), and P(A6,B16)), implying the
existence of a size-limited region in the binding pocket. The
4'-methoxy compounds, P(A1,B11) and P(A4,B11), had the lowest ClogP
values (3.05 for both) and were therefore expected to provide an
improvement in aqueous solubility. Of these two cases, only
P(A1,B11) exhibited desirable bioactivity. The aqueous solubility
and intrinsic oral bioavailability of P(A1,B11) are currently under
examination.
Example 2
MS, HPLC, and Antigiardial Screening Results of Embodiments of the
Present Invention
TABLE-US-00002 ##STR00015## [0133] [M + H].sup.+ [M + H].sup.+a
Purity.sup.b IC.sub.50 Entry Compd. X.sub.1 X.sub.2 R Calcd Found
(%) (.mu.g/mL) 1 P (A1, B1) F H H 257 257 93 <1.1 2 P (A1, B8) F
H 4'-Cl 291 291 92 >10.0 3 P (A1, B9) F H 4'-F 275 275 94
>10.0 4 P (A1, B11) F H 4'-OMe 287 287 87 <1.1 5 P (A1, B16)
F H 4'-Ph 333 333 >99 NA 6 P (A1, B17) F H 4'-Br 335 335 >99
>10.0 7 P (A1, B18) F H 4'-OEt 301 301 >99 8.8 8 P (A1, B19)
F H 3'-Me 271 271 >99 <1.1 9 P (A1, B20) F H 4'-Me 271 271
>99 <1.1 10 P (A1, B22) F H 3',4'-di-F 293 293 81 <1.1 11
P (A1, B27) F H 3'-Cl 291 291 >99 <1.1 12 P (A2, B1) Cl H H
273 273 95 1.7 13 P (A2, B8) Cl H 4'-Cl 307 307 84 4.5 14 P (A2,
B9) Cl H 4'-F 291 291 92 >10.0 15 P (A2, B11) Cl H 4'-OMe 303
303 78 >10.0 16 P (A2, B17) Cl H 4'-Br 351 351 97 5.7 17 P (A2,
B18) Cl H 4'-OEt 317 317 81 >10.0 18 P (A2, B19) Cl H 3'-Me 287
287 75 >10.0 19 P (A2, B20) Cl H 4'-Me 287 287 72 >10.0 20 P
(A2, B22) Cl H 3',4'-di-F 309 309 75 3.7 21 P (A2, B23) Cl H
3',5'-di-F 309 309 94 <1.1 22 P (A2, B26) Cl H 3'-Br 351 351 97
<1.1 23 P (A2, B27) Cl H 3'-Cl 307 307 97 1.7 24 P (A2, B28) Cl
H 3'-F 291 291 98 5.2 25 P (A2, B29) Cl H 3'-OMe 303 303 81 4.8 26
P (A3, B1) Br H H 317 317 83 1.6 27 P (A3, B8) Br H 4'-Cl 351 351
93 1.9 28 P (A3, B9) Br H 4'-F 335 335 83 6.8 29.sup.c P (A3, B10)
Br H 4'-OEt 361 361 83 9.3 30 P (A3, B11) Br H 4'-OMe 347 347 76
<1.1 31 P (A3, B17) Br H 4'-Br 395 395 >99 >10.0 32 P (A3,
B19) Br H 3'-Me 331 331 >99 <1.1 33 P (A3, B20) Br H 4'-Me
331 331 90 3.9 34 P (A3, B27) Br H 3'-Cl 351 351 85 1.9 35 P (A3,
B28) Br H 3'-F 335 335 93 <1.1 36 P (A4, B1) H F H 257 257
>99 6.2 37.sup.c P (A4, B5) H F 3'-OEt 301 301 >99 NA 38 P
(A4, B8) H F 4'-Cl 291 291 >99 6.4 39 P (A4, B9) H F 4'-F 275
275 80 >10.0 40.sup.c P (A4, B10) H F 4'-OEt 301 301 >99 NA
41 P (A4, B11) H F 4'-OMe 287 287 73 >10.0 42 P (A4, B16) H F
4'-Ph 333 333 >99 NA 43 P (A4, B17) H F 4'-Br 335 335 >99 9.0
44 P (A4, B19) H F 3'-Me 271 271 >99 <1.1 45 P (A4, B20) H F
4'-Me 271 271 >99 >10.0 46 P (A4, B21) H F 3',4'-di-Cl 325
325 92 >10.0 47 P (A4, B22) H F 3',4'-di-F 293 293 >99 9.4 48
P (A4, B28) H F 3'-F 275 275 >99 4.3 49 P (A5, B1) H Cl H 273
273 >99 NA 50 P (A5, B9) H Cl 4'-F 291 291 >99 NA 51 P (A5,
B11) H Cl 4'-OMe 303 303 89 NA 52 P (A5, B16) H Cl 4'-Ph 349 349 79
NA 53 P (A5, B17) H Cl 4'-Br 351 351 >99 >10.0 54 P (A5, B18)
H Cl 4'-OEt 317 317 >99 NA 55 P (A5, B19) H Cl 3'-Me 287 287
>99 2.5 56 P (A5, B20) H Cl 4'-Me 287 287 >99 NA 57 P (A5,
B21) H Cl 3',4'-di-Cl 341 341 >99 9.8 58 P (A5, B22) H Cl
3',4'-di-F 309 309 >99 NA 59 P (A5, B23) H Cl 3',5'-di-F 309 309
90 6.7 60 P (A5, B26) H Cl 3'-Br 351 351 >99 NA 61 P (A5, B27) H
Cl 3'-Cl 307 307 >99 >10.0 62 P (A5, B28) H Cl 3'-F 291 291
85 NA 63 P (A6, B1) H Br H 317 317 >99 5.0 64 P (A6, B8) H Br
4'-Cl 351 351 89 NA 65 P (A6, B9) H Br 4'-F 335 335 >99 NA 66 P
(A6, B16) H Br 4'-Ph 393 393 74 NA 67 P (A6, B19) H Br 3'-Me 331
331 >99 NA 68 P (A6, B20) H Br 4'-Me 331 331 93 >10.0 69 P
(A6, B28) H Br 3'-F 335 335 91 <1.1 70.sup.d 9 H H 4'-NMe.sub.2
282 282 >99 <1.1 71 metronidazole 1.5 72 furazolidone 8.6
.sup.aObserved parent ion peaks via LC-MS analysis. .sup.bPerfomed
using UV detection at 254 nm .sup.cR groups were converted to OEt
in the presence of BF.sub.3.cndot.Et.sub.2O. .sup.dSynthesized
manually from resorcinol and B7.
[0134] Synthesis of compound 9 was manually accomplished with
resorcinol and B7 using similar reaction conditions. As expected,
the dimethylamino moiety in 9 confers enhanced solubility,
especially in aqueous acidic solution.
Example 3
Preparation and Screening Compounds of the Present Invention
[0135] Preparation. All solvents were purchased as reagent grade,
dried appropriately, and stored over dry 4 .ANG. molecular sieves.
Solvent and reagent transfers were accomplished via dried syringe,
and all reactions were performed under argon atmosphere unless
otherwise indicated. Analytical thin-layer chromatography was
performed on precoated silica gel GF 250 microns from Analtech and
visualized with a 254 nm UV light. Parallel silica gel
chromatography was accomplished under reduced pressure using
Supelclean LC-S120 mL tubes from Supelco. Unless otherwise stated,
all NMR spectra were recorded in DMSO-d.sub.6 on a Bruker Avance
DPX 400, using TMS as an internal standard. The chemical shifts are
reported in parts per million (ppm) relative to TMS, and J values
in Hz. Mass spectra were recorded on a ThermoQuest Finnigan AQA
quadrupole LC-MS system, and high-resolution mass spectra (HRMS)
were measured with a Bruker BioApex FTMS system by direct injection
using an electrospray interface (ESI). Analytical HPLC was
performed on an automated Waters Alliance system using a Symmetry
C.sub.18 column, 3.9.times.150 mm i. d., 5 .mu.m, and a flow rate
of 1 mL/min.; .lamda..sub.max=254 nm; mobile phase A: 0.05% TFA in
H.sub.2O and mobile phase B: 0.05% TFA in CH.sub.3CN; linear
gradient 10-90% B in 15 min.
[0136] Solution-phase parallel synthesis was performed on an
Argonaut Quest 210 using 10 mL teflon reaction vessels (RVs) with
microfrit. Halogenated resorcinols A1-6 (1 equiv., 0.10 mmol) and
phenyl acetic acid derivatives B1-29 (1.1 equiv., 0.11 mmol) were
added manually to each RV, and the RVs were maintained under argon.
BF.sub.3,Et.sub.2O (1 mL) was added manually to each RV via
syringe, and the manifolds were sealed. The reaction mixtures were
agitated for 3-10 h at 90-100.degree. C. to facilitate the
Friedel-Craft acylations. After cooling to room temperature, all
reactions were analyzed by TLC for completion. Thereafter, a
mixture of DMF (0.5 mL) and MeSO.sub.2Cl (0.1 mL), which had been
stirred separately for 30 min., was transferred to each RV via
syringe under argon. The reaction mixtures were agitated for 4-5 h
at 75.degree. C. Aqueous NaOAc (12% w/v, 2 mL) and ethyl acetate (1
mL.times.3) were added to each RV, and on line liquid-liquid
extraction was carried out by agitating the biphasic solutions for
5 min. Combined organic layers were washed with water (2
mL.times.2) and brine (2 mL.times.2) and dried over anhydrous
sodium sulfate within the RVs. The mixtures were collected into 20
mL glass vials. Organic solvent was evaporated under vacuum to
furnish the crude products, which were further purified on a short
plug of silica gel in parallel fashion under reduced pressure,
using hexane/ethyl acetate (80:20 v/v). The yields reported are the
overall yields.
Example 4
Specific Synthesis of Amine Substituted Isoflavones by Parallel
Synthesis Methods
1. General Procedure for Loading of Starting Material on Wang
Resin:
[0137] To a suspension of Wang resin (1 g, 1.11 mmole/g, 100-200
mesh) in THF (10 ml), the isoflavone 1 (1.74 g, 5.5 mmoles) and
triphenylphosphine (1.44 g, 5.5 mmoles) were added and gently
stirred at 0.degree. C. for 30 minutes. DIAD (1.11 g, 5.5 mmoles)
was added dropwise and the mixture was stirred for 24 hours
gradually allowing it to attain room temperature. The resin was
collected by filtration and washed successively with THF (6.times.5
ml), 1:1 THF/water (6.times.5 ml), THF (6.times.5 ml), DCM
(6.times.5 ml), 1:1 DCM/MeOH (6.times.5 ml), MeOH (6.times.5 ml),
DCM (6.times.5 ml) and finally with ether. The resin was dried and
used in the next step.
A) Weight of resin with compound=1.245 gm
[0138] Therefore percentage of compound
loaded=1.245/1.328=93.7%
##STR00016##
[0139] B) IR of the Resin Also Confirmed that the Compound was
Loaded on the Wang Resin
2. General Procedure for Reaction of Amines on Loaded Resin in
Quest:
[0140] To a suspension of resin 2 (200 mg, 0.17 mmol) in anhydrous
NMP (10 ml) in each reaction vessel, Pd.sub.2(dba).sub.3 (7.7 mg,
0.0085 mmol, 5 mol %), ligand 3 (16.2 mg, 0.034 mmol, 20 mol %) and
NaOt-Bu (122 mg, 1.275 mmol) were added and the reaction vessels
were flushed with argon. Subsequently the amines (1.2 mmol) were
added to the reaction vessel and the reaction mixture was heated to
100.degree. C. for 30 hours. The resin was washed successively with
DMF (6.times.5 ml), 1:1 DMF/water (6.times.5 ml), DMF (6.times.5
ml), DCM (6.times.5 ml), 1:1 DCM/MeOH (6.times.5 ml), MeOH
(6.times.5 ml), DCM (6.times.5 ml) and ether (6.times.5 ml). The
resin was dried and suspended in 1:3 TFA/DCM mixture and was
stirred was 4 hours. The resin was filtered and washed with DCM
(3.times.5 ml). The filtrates were combined and NaHCO.sub.3 was
added and stirring till effervescence ceased. The filterate was
evaporated in vacuo.
TABLE-US-00003 ##STR00017## AMINES Product Reagent Mol Wt. Weight
(g) Volume (ml) Density eq mmols Code p-anisidine 123.16 0.125
6.000 1.02 NMA-1 N-methyl aniline 107.16 0.109 0.110 0.989 6.000
1.02 NMA-2 phenethylamine 121.18 0.123 0.130 0.962 6.000 1.02 NMA-3
allylamine 57.1 0.058 0.076 0.763 6.000 1.02 NMA-4 dibutylamine
129.25 0.131 0.172 0.761 6.000 1.02 NMA-5 morpholine 87.12 0.088
0.090 0.996 6.000 1.02 NMA-6 pyrrolidine 71.12 0.072 0.083 0.860
6.000 1.02 NMA-7 m-Cl-aniline 127.57 0.130 0.110 1.206 6.000 1.02
NMA-8 benzylamine 107.16 0.109 0.110 0.982 6.000 1.02 NMA-9
cyclohexylamine 99.18 0.101 0.116 0.867 6.000 1.02 NMA-10 NaOt-Bu
96.11 0.122 7.500 1.275 Pd2(dba)3 915.7 7.7 mg 5 mol % 0.0085
ligand 476.72 16.2 mg 20 mol % 0.034 NMP 3 ml Br-isoflavone on
resin 200 mg 0.17 AMINES Product Reagent Mol Wt Weight (g) Volume
(ml) Density eq mmol Code aniline 93.13 0.095 0.093 1.021 6.000
1.02 NMA-11 butylamine 73.14 0.075 0.100 0.737 6.000 1.02 NMA-12
isopropylamine 59.11 0.060 0.087 0.694 6.000 1.02 NMA-13
diisopropylamine 101.19 0.103 0.143 0.716 6.000 1.02 NMA-14
diethylamine 73.14 0.075 0.110 0.704 6.000 1.02 NMA-15 piperidine
85.15 0.086 0.099 0.861 6.000 1.02 NMA-16 1-N-methylpiperazine
100.17 0.102 0.112 0.903 6.000 1.02 NMA-17 piperonylamine 151.17
0.154 0.127 1.214 6.000 1.02 NMA-18 1-naphthalene methylamine
157.22 0.160 0.150 1.073 6.000 1.02 NMA-19 O-anisidine 123.15 0.125
0.115 1.092 6.000 1.02 NMA-20 sodium tert-butoxide 96.11 0.122
7.500 1.275 Pd2(dba)3 915.7 7.7 mg 5 mol % 0.0085 ligand 476.72
16.2 mg 20 mol % 0.034 NMP 3 ml Br-isoflavone on resin 200 mg
0.17
Results:
TABLE-US-00004 [0141] PROD- MOLEC- MOLEC- UCT ULAR ULAR WEIGHT %
PURITY CODE WEIGHT FORMULA (mg) YIELD (%) NMA-1 359
C.sub.22H.sub.17NO.sub.4 19 mg 31.14 97.29 NMA-2 343
C.sub.22H.sub.17NO.sub.3 11 mg 19 99.10 NMA-3 357
C.sub.23H.sub.19NO.sub.3 11 mg 18.33 93.68 NMA-4 293.11
C.sub.18H.sub.15NO.sub.3 9 mg 18.07 92.60 NMA-5 365.47
C.sub.23H.sub.27NO.sub.3 7 mg 11.3 70.73* NMA-6 323.12
C.sub.19H.sub.17NO.sub.4 20 mg 36.36 93.66 NMA-7 307.12
C.sub.19H.sub.17NO.sub.3 24 mg 46.1 90.93 NMA-8 363.07
C.sub.21H.sub.14ClNO.sub.3 18 mg 30 74.26* NMA-9 343.12
C.sub.22H.sub.17NO.sub.3 23 mg 39.6 92.47 NMA10 335.15
C.sub.21H.sub.21NO.sub.3 10 mg 17.5 45.04* NMA-11 329.35
C.sub.21H.sub.15NO.sub.3 15 mg 26.7 49.91** NMA-12 309.36
C.sub.19H.sub.19NO.sub.3 12 mg 22.6 69.10** NMA-13 295.12
C.sub.18H.sub.17NO.sub.3 16.5 mg 33.0 84.89** NMA-14 337.41
C.sub.21H.sub.23NO.sub.3 22 mg 38.5 83.4** NMA-15 309.36
C.sub.19H.sub.19NO.sub.3 19 mg 36.2 99.60 NMA-16 321.14
C.sub.20H.sub.19NO.sub.3 16 mg 29.3 74.5** NMA-17 336.15
C.sub.20H.sub.20N.sub.2O.sub.3 9 mg 15.7 82.69** NMA-18 387.38
C.sub.23H.sub.17NO.sub.5 6 mg 9.2 82.98** NMA-19 393.43
C.sub.26H.sub.19NO.sub.3 14 mg 21.21 59.42** NMA-20 359.37
C.sub.22H.sub.17NO.sub.4 18 mg 29.5 71.33** *Amines were purified
by column chromatography. **Values are prior to purification.
[0142] Biological Screening. Giardia intestinalis (ATCC #30888) was
maintained anaerobically in acid-washed borosilicate glass tubes in
Keister's modified TYI-S-33 medium at 37.degree. C. Subculturing
was done every 48-72 h under a sterile biosafety hood. Tubes were
chilled in an ice bath for 10 min. in order to detach the
organisms, and 1 mL of cell suspension was added to 14 mL of fresh
medium. To carry out the screening, a suspension of Giardia cells
was prepared at a concentration of 100,000 cells/mL. 100 .mu.L of
the suspension was then added to each well of a Corning 96-well
flat-bottomed tissue culture-treated plate. Blank wells received
medium only. An additional 125 .mu.L of medium was added to each
well, and the plates were incubated at 37.degree. C. for 24 h in an
anaerobic chamber filled with nitrogen. After 24 h, 25 .mu.L of
test samples with concentrations of 10, 3.3, and 1.1 .mu.g/mL was
added in duplicate to test wells. The plates were further incubated
at 37.degree. C. for 24 h. The plates were then processed using a
tetrazolium dye (XTT) procedure. Absorbance readings were taken at
450 nm with background at 630 nm subtracted. Final concentration
that inhibits giardial growth by 50% (IC.sub.50) was estimated
graphically from the dose-response plot.
Example 5
Examples of Embodiments of the Present Invention
[0143] This Example sets forth chemical characteristics of
embodiments of the present invention.
[0144] 8-Chloro-7-hydroxy-3-phenylchromen-4-one (P(A2,B1)): 70%
yield; mp 242-244.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.50 (s, 1H), 7.93 (d, 1H, J=8.4 Hz), 7.57 (d, 2H, J=5.9
Hz), 7.42-7.33 (m, 3H), 7.13 (d, 1H, J=8.4 Hz); HRMS: [M+Na].sup.+
Calcd. for C.sub.15H.sub.9ClO.sub.3 295.0132, Found 295.0150.
[0145] 8-Bromo-7-hydroxy-3-phenylchromen-4-one (P(A3,B1)): 45%
yield; mp 256-258.degree. C. (lit. 253.degree. C.); .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.54 (s, 1H), 7.98 (d, 1H, J=8.8
Hz), 7.58 (d, 2H, J=7.1 Hz), 7.45-7.36 (m, 3H), 7.13 (d, 1H, J=8.8
Hz); HRMS: [M+Na].sup.+ Calcd. for C.sub.15H.sub.9BrO.sub.3
338.9627, Found 338.9661.
[0146] 6-Chloro-7-hydroxy-3-phenylchromen-4-one (P(A5,B1)): 48%
yield; mp 279-280.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.40 (s, 1H), 7.98 (s, 1H), 7.54 (d, 2H, J=7.1 Hz),
7.43-7.34 (m, 3H), 7.05 (s, 1H); HRMS: [M+Na].sup.+ Calcd. for
C.sub.15H.sub.9ClO.sub.3 295.0132, Found 295.0129.
[0147] 6-Bromo-7-hydroxy-3-phenylchromen-4-one (P(A6,B1)): 17%
yield; mp 296-297.degree. C., dec.; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.42 (s, 1H), 8.17 (s, 1H), 7.56 (d, 2H,
J=7.5 Hz), 7.45-7.36 (m, 3H), 7.06 (s, 1H); HRMS: [M+Na].sup.+
Calcd. for C.sub.15H.sub.9BrO.sub.3 338.9627, Found 338.9608.
[0148] 7-Hydroxy-3-[4-(4-methoxy-phenylamino)-phenyl]-chromen-4-one
(NMA-1): 31.14% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
7.97 (d, 1H, J=3.6 Hz), 7.36 (d, 2H, J=8.4 Hz), 6.86 (d, 2H, J=8.4
Hz), 7.36 (d, 2H, J=8.8 Hz), 7.055 (d, 2H, J=8.8 Hz), 6.92 (d, 2H,
J=8.0 Hz), 6.84 (s, 1H), 3.575 (s, 3H).
[0149] 7-Hydroxy-3-[4-(N-methylphenylamino)-phenyl]-chromen-4-one
(NMA-2): 19% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.94
(d, 1H, J=8.8 Hz), 6.37 (dd, 1H, J=2, 8.8 Hz), 6.24 (d, 1H, J=2
Hz), 7.23 (t, 2H, J=8.4, 7.2 Hz), 7.18 (d, 2H, J=8.0 Hz), 6.94 (m,
4H), 6.89 (t, 1H, J=7.4 Hz), 3.276 (s, 3H).
[0150]
7-Hydroxy-3-[4-{N-(2-phenyl)ethyl}amino)-phenyl]-chromen-4-one
(NMA-3): 18.33% yield. .sup.1HNMR (.sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 7.897 (6, 1H), 7.57 (d, 2H, J=8.2 Hz), 7.33
(d, 2H, J=8.4 Hz), 7.27 (d, 1H, J=5.6 Hz), 7.0 (d, 1H, J=6 Hz),
6.87 (m, 3H), 6.837 (s, 1H), 6.68 (d, 2H, J=8.4 Hz), 3.284 (t, 2H,
J=6.8, 7.2 Hz), 2.83 (t, 2H, J=7.2, 7.2 Hz).
[0151] 7-Hydroxy-3-[4-{N-allylamino)-phenyl]-chromen-4-one (NMA-4):
18.07% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.206 (s,
1H), 7.92 (d, 1H, J=8 Hz), 7.04 (d, 1H, J=8 Hz), 7.23 (d, 2H, J=8
Hz), 6.89 (s, 1H), 6.50 (d, 2H, J=8 Hz), 4.012 (m, 3H), 3.81 (t,
2H, J=6.8, 7.0 Hz).
[0152] 7-Hydroxy-3-[4-(N,N-dibutylamino)-phenyl]-chromen-4-one
(NMA-5): 11.3% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
7.99 (d, 1H, J=7.8 Hz), 7.928 (s, 1H), 6.862 (s, 1H), 7.49 (d, 2H,
J=8.4 Hz), 7.22 (d, 1H, J=8.0 Hz), 7.06 (d, 2H, J=8.4 Hz), 3.025
(t, 2H, J=9.2, 9.6 Hz), 2.946 (t, 2H, J=8.6 Hz), 1.31 (m, 4H),
1.263 (t, 2H, J=6.8, 6.8 Hz), 1.15 (t, 2H, J=7.2, 7.2 Hz), 0.85 (m,
6H).
[0153] 7-Hydroxy-3-[4-morpholino)-phenyl]-chromen-4-one (NMA-6):
36.36% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.159 (s,
1H), 7.81 (d, 1H, J=8.8 Hz), 7.10 (d, 2H, J=8.4 Hz), 6.81 (d, 2H,
J=8 Hz), 6.309 (d, 1H, J=7.2 Hz), 6.183 (s, 1H), 3.696 (m, 4H),
3.023 (m, 4H).
[0154] 7-Hydroxy-3-[4-pyrrolidino)-phenyl]-chromen-4-one (NMA-7):
46.1% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 7.83 (d,
1H, J=8.8 Hz), 7.625 (d, 1H, J=8.8 Hz), 7.5 (s, 1H), 7.34 (d, 2H,
J=8.2 Hz), 6.853 (s, 1H), 6.39 (d, 2H, J=8 Hz), 3.14 (t, 2H, J=8.0,
8.4 Hz), 2.971 (t, 2H, J=8.2, 8.2 Hz), 1.886 (m, 4H)
[0155]
7-Hydroxy-3-[4-(N-{3-chlorophenyl}amino)-phenyl]-chromen-4-one
(NMA-8): 30% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.25
(s, 1H), 7.98 (d, 1H, J=8.8 Hz), 7.48 (d, 2H, J=8 Hz), 7.38 (s,
1H), 7.226 (t, 1H, J=7.6, 8.0 Hz), 7.12 (d, 1H, J=8.4 Hz), 6.92 (d,
1H, J=8.4 Hz), 6.86 (s, 1H), 6.81 (d, 1H, J=7.6 Hz), 6.66 (d, 2H,
J=8 Hz).
[0156] 7-Hydroxy-3-[4-(N-benzylamino)-phenyl]-chromen-4-one
(NMA-9): 39.6% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
7.85 (d, 2H, J=8.8 Hz), 7.65 (s, 1H), 7.25 (s, 1H), 7.16 (d, 2H,
J=7.2 Hz), 7.13 (t, 2H, J=7.6, 8.0 Hz), 7.04 (t, 1H, J=6.4, 6.8
Hz), 6.82 (s, 1H), 6.69 (dd, 1H, J=2, 8.8 Hz), 6.45 (d, 2H, J=8
Hz), 4.14 (s, 2H).
[0157] 7-Hydroxy-3-[4-(N-cyclohexylamino)-phenyl]-chromen-4-one
(NMA-10): 17.5% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
8.205 (s, 1H), 7.45 (d, 1H, J=8 Hz), 7.26 (d, 1H, J=8 Hz), 6.853
(s, 1H), 6.59 (d, 2H, J=8 Hz), 6.49 (d, 2H, J=8 Hz), 3.216 (m, 1H),
1.564 (m, 4H), 1.328 (m, 2H), 1.21 (m, 4H).
[0158] 7-Hydroxy-3-[4-(N-phenylamino)-phenyl]-chromen-4-one
(NMA-11): 26.7% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
7.97 (d, 1H, J=8.4 Hz), 7.82 (d, 1H), 7.35 (d, 2H, J=8.4 Hz), 7.33
(m, 3H), 7.15 (d, 1H, J=8.4 Hz), 7.05 (d, 2H, J=8 Hz), 6.82 (s,
1H), 6.75 (d, 2H, J=8 Hz).
[0159] 7-Hydroxy-3-[4-(N-butylamino)-phenyl]-chromen-4-one
(NMA-12): 22.6% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
8.213 (s, 1H), 7.92 (d, 1H, J=8.4 Hz), 7.47 (d, 2H, J=8 Hz), 7.01
(d, 1H, J=8.4 Hz), 6.85 (s, 1H), 6.56 (d, 2H, J=8.4 Hz), 2.99 (t,
2H, J=7.6, 8 Hz), 1.5 (m, 4H), 1.15 (m, 3H).
[0160] 7-Hydroxy-3-[4-(N-isopropylamino)-phenyl]-chromen-4-one
(NMA-13): 33% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
8.21 (s, 1H), 7.88 (d, 1H, J=7.6 Hz), 7.51 (d, 2H, J=7.6 Hz), 7.13
(d, 1H, J=8 Hz), 6.85 (s, 1H), 6.51 (d, 2H, J=8 Hz), 4.02 (m, 1H),
1.27 (d, 6H, J=8 Hz).
[0161] 7-Hydroxy-3-[4-(N,N-diisopropylamino)-phenyl]-chromen-4-one
(NMA-14): 38.5% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
8.29 (s, 1H), 7.91 (s, 1H), 7.60 (d, 1H, J=8 Hz), 7.21 (d, 1H, J=8
Hz), 7.31 (d, 2H, J=8.4 Hz), 6.54 (d, 2H, J=8.4 Hz), 3.986 (m, 2H),
1.21 (d, 12H, J=8.2 Hz).
[0162] 7-Hydroxy-3-[4-(N,N-diethylamino)-phenyl]-chromen-4-one
(NMA-15): 36.2% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
8.16 (s, 1H), 7.93 (d, 1H, J=8.4 Hz), 7.91 (d, 2H, J=8.4 Hz), 7.42
(d, 2H, J=8 Hz), 6.75 (s, 1H), 6.5 (d, 2H, J=8.4 Hz), 3.246 (q, 4H,
J=6.8, 7.2, 6.8 Hz), 1.05 (t, 6H, J=6.8, 6.8 Hz).
[0163] 7-Hydroxy-3-[4-(piperidino)-phenyl]-chromen-4-one (NMA-16):
29.3% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.12 (s,
1H), 7.92 (d, 1H, J=8 Hz), 7.09 (d, 1H, J=8.4 Hz), 7.32 (d, 2H,
J=8.4 Hz), 6.62 (d, 2H, J=8.4 Hz), 6.85 (s, 1H), 3.14 (t, 2H, J=8,
8.4 Hz), 3.05 (t, 2H, J=7.6, 8 Hz), 1.567 (m, 6H).
[0164] 7-Hydroxy-3-[4-(N-methylpiperazino)-phenyl]-chromen-4-one
(NMA-17): 15.7% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
8.13 (s, 1H), 7.92 (d, 1H, J=8 Hz), 7.33 (d, 2H, J=7.6 Hz), 7.17
(d, 1H, J=8.4 Hz), 6.85 (s, 1H), 6.74 (d, 2H, J=8 Hz), 3.78 (m,
4H), 2.71 (s, 3H), 2.205 (m, 4H).
[0165]
7-Hydroxy-3-[4-{N-(c-Benzo[1,3]dioxol-5-yl-methyl}amino)-phenyl]-ch-
romen-4-one (NMA-18): 9.2% yield. .sup.1HNMR (400 MHz,
DMSO-d.sub.6) .delta. 8.19 (s, 1H), 7.93 (d, 1H, J=7.6 Hz), 7.46
(d, 2H, J=8.4 Hz), 7.22 (d, 1H, J=7.6 Hz), 7.16 (d, 1H, J=8 Hz),
7.02 (s, 1H), 6.91 (s, 1H), 6.77 (d, 1H, J=8.4 Hz), 6.58 (d, 2H,
J=8.4 Hz), 5.98 (s, 2H), 4.17 (s, 2H).
[0166]
7-Hydroxy-3-[4-{(N-naphthalen-1-ylmethyl)amino}-phenyl]-chromen-4-o-
ne (NMA-19): 21.21% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6)
.delta. 8.12 (s, 1H), 7.933 (d, 1H, J=8 Hz), 7.72 (m, 2H), 7.62 (d,
1H, J=7.6 Hz), 7.53 (d, 1H, J=8 Hz), 7.42 (d, 2H, J=8.4 Hz), 7.23
(m, 3H), 7.13 (d, 1H, J=7.6 Hz), 6.82 (s, 1H), 6.61 (d, 2H, J=8.4
Hz), 4.5 (s, 2H).
[0167]
7-Hydroxy-3-[4-{(2-methoxyphenyl)amino}-phenyl]-chromen-4-one
(NMA-20): 29.5% yield. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.
8.13 (s, 1H), 7.94 (d, 1H, J=7.6 Hz), 7.23 (d, 1H, J=8 Hz), 6.84
(s, 1H), 7.51 (d, 2H, J=8.4 Hz), 7.04 (d, 2H, J=8.4 Hz), 6.87 (m,
3H), 6.65 (d, 1H, J=8.4 Hz), 3.81 (s, 3H).
[0168] It will be apparent to those skilled in the art that various
modifications and variations can be made in the present invention
without departing from the scope or spirit of the invention. Other
embodiments of the invention will be apparent to those skilled in
the art from consideration of the specification and practice of the
invention disclosed herein. It is intended that the Specification
and Example be considered as exemplary only, and not intended to
limit the scope and spirit of the invention.
[0169] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as reaction conditions,
and so forth used in the Specification and Claims are to be
understood as being modified in all instances by the term "about."
Accordingly, unless indicated to the contrary, the numerical
parameters set forth in the Specification and Claims are
approximations that may vary depending upon the desired properties
sought to be determined by the present invention.
[0170] Notwithstanding that the numerical ranges and parameters
setting forth the broad scope of the invention are approximations,
the numerical values set forth in the experimental or example
sections are reported as precisely as possible. Any numerical
value, however, inherently contain certain errors necessarily
resulting from the standard deviation found in their respective
testing measurements.
[0171] Throughout this application, various publications, including
journal articles and patents are referenced. All such references
are incorporated herein by reference in their entirety.
* * * * *