Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-31
2002-07-30
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S182000, C548S187000
Reexamination Certificate
active
06426357
ABSTRACT:
FIELD OF THE INVENTION
This invention relates broadly to novel thiazolidinones. More specifically, the invention relates to thiazolidinones which modulate Follicle Stimulating Hormone (FSH) activity.
BACKGROUND OF THE INVENTION
Approximately 400,000 germ cells are stored in the ovaries of the human female at the time of puberty. No further germ cells are made. Beginning at the time of puberty and ending at menopause, there are approximately 400 ovulatory menstrual cycles which consume essentially all of the germ cells in the human ovary. About 1,000 germ cells are consumed in each menstrual period. However, in any one menstrual cycle, only one germ cell, developed in what becomes the dominant follicle, is ovulated and available for pregnancy.
Although the details are not accurately known, the mechanism by which a single egg is selected each month to become the dominant egg is dependent upon a complex interaction between one or more hormones from the ovary, hypothalamus and the pituitary. Three glycoprotein hormones (luteinizing hormone (LH), follicle stimulating hormone (FSH) and chorionic gonadotropin (hCG)) act on the ovary to stimulate steroid synthesis and secretion. LH and FSH are secreted by the pituitary and together play a central role in regulating the menstrual cycle and ovulation. hCG is secreted by the developing placenta from the early stages of pregnancy and its role is to maintain steroid secretion by the corpus luteum, which is necessary to prevent ovulation during pregnancy.
In the normal cycle, there is a mid-cycle surge in LH concentration which is followed by ovulation. An elevated estrogen level, which is brought about by the endogenous secretion of LH and FSH, is required for the LH surge to occur. The estrogen mediates a positive feedback mechanism which results in the increased LH secretion.
Oral contraceptive agents have been used by over 200 million women worldwide and by 1 of 4 women in the United States under the age of 45. Such agents are popular because of ease of administration, low pregnancy rate (less than 1 percent) and a relatively low incidence of side effects. Typically, oral contraceptives inhibit ovulation by suppressing FSH and LH secretion. As a consequence, the secretion of all ovarian steroids is also suppressed, including estrogen, progesterone and androgen. These agents also exert minor direct inhibitory effects on the reproductive tract, altering the cervical mucus, thereby decreasing sperm penetration and decreasing the motility and secretions of the fallopian tubes and uterus.
Thiazolidinones are a class of small molecule organic compounds which have found limited pharmaceutical use. For example, thiazolidinones have been found to have central nervous system activity. See, for example, Tripathi, et al., “Thiazolidinone congeners as central nervous system active agents.”
Arzneimittelforschung
43:632-5 (1993). CNS activities which have been identified include, for example, antipsychotic properties. See, Mutlib, et al., “Metabolism of an atypical antipsychotic agent, 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5-trimethyl-4-thiazolidinone (HP236).”
Drug Metab. Dispos
. 24:1139-50 (1996). Other thiazolidinones have been found to be CNS antiischemic agents. See, Ruterbories, et al., “Pharmacokinetics of a novel butylated hydroxytoluene-thiazolidinone CNS antiischemic agent LY256548 in rats, mice, dogs and monkeys.”
Drag Metab. Dispos
. 18:674-9 (1990). Thiazolidinones have also been used as antimicrobial agents. See, for example, Ley, et al., “Inhibition of multiplication of Mycobacterium leprae by several antithyroid drugs.”
Am. Rev. Respir. Dis
. 111:651-5 (1975).
The synthesis of novel thiazolidinones offers the promise for discovering new pharmaceutical agents with applications in areas as diverse as, for example, antimicrobial therapy and the treatment of strokes with CNS antiischemic agents. Of particular interest is the use of novel thiazolidinones as regulators of mammalian fertility.
Although a number of oral contraceptives are commercially available, there still remains a need for new fertility-regulating agents which are useful for both in vivo and in vitro applications. A class of small molecule FSH receptor antagonist compounds which are inexpensive to prepare, easily purified, easily administered and which exhibit a broad range of activities would represent a significant advance in the field of oral contraceptive agents. Quite surprisingly, the present invention provides such small molecule thiazolidinone FSH receptor antagonists.
SUMMARY OF THE INVENTION
The present invention provides a class of novel thiazolidinones possessing a range of pharmaceutical applications and activities. Thus, in one aspect, the present invention provides novel thiazolidinones having the formula:
wherein,
R
1
is a member selected from the group consisting of aryl and substituted aryl, alkyl and substituted alkyl;
R
2
is a member selected from the group consisting of heterocyclic and substituted heterocylic groups;
R
3
and R
4
are independently members selected from the group including hydrogen and —(CH
2
)
m
CONR
5
R
6
;
R
5
and R
6
are independently members selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, heterocyclicalkyl and substituted heterocyclicalkyl groups;
X is a member selected from the group consisting of S, S═O, and O═S═O;
m is a number from 0 to 3.
In a second aspect, the present invention provides novel thiazolidinones
wherein,
R
1
is a member selected from the group consisting of aryl and substituted aryl alkyl and substituted alkyl;
R
21
, R
22
, and R
23
are members independently selected from the group consisting of H, halogen, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, phenyl, substituted phenyl, aryloxy, substituted aryloxy, alkynyl, substituted alkynyl and nitro groups. Preferred aryloxy groups are phenoxy and benzyloxy and preferred substituted aryloxy groups are substituted phenoxy and substituted benzyloxy.
Y is a member selected from the group consisting of —O—, —S— and NR
24
wherein R
24
is H or lower alkyl.
R
5
and R
6
are independently members selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl, heterocyclicalkyl and substituted heterocyclicalkyl groups; and
X is a member selected from the group consisting of S, S═O, and O═S═O.
In another aspect, the invention provides a class of FSH receptor antagonists, wherein the receptor antagonists are noncompetitve with FSH for the receptor FSH binding site.
In yet another aspect, the invention provides a class of compounds that modulate FSH hormone activity, the compounds having: (a) a molecular weight of from about 200 daltons to about 1000 daltons; and (b) an FSH antagonist activity corresponding to an IC
50
standard of no more than 25 &mgr;M, preferably no more than 11 &mgr;M; wherein the antagonist activity of this class of compounds to the FSH receptor is competitively inhibited by a compound described above.
In a preferred embodiment, this class of compounds has a molecular weight of about 300 daltons to about 800 daltons. In another preferred embodiment, this class of compounds has an FSH receptor antagonist activity, as expressed by an IC
50
standard, of no more than 11 &mgr;M.
In still another aspect, the invention provides methods of using the compounds, i.e., thiazolidinones, for diverse pharmaceutical applications including, for example, CNS antiischemic agents, agents with antipsychotic or other psychoactive properties, antimicrobial agents and mammalian fertility regulating agents. When used as mammalian fertility regulating agents, the thiazolidinones are preferably antagonists of the FSH receptor.
As such, in another aspect, the present invention provides pharmaceutical compositions which contain one or more of the compounds of the invention i
Barrett Ronald W.
Gopalsamy Ariamala
Holmes Christopher P.
MacLean Derek
Ruhland Beatrice
Affymax, Inc.
Brobeck Phleger & Harrison LLP
Wright Sonya N.
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