Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-12-21
2003-06-24
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S217030, C514S217040, C514S252120, C514S252130, C514S316000, C514S318000, C514S327000, C514S330000, C514S311000, C514S312000, C514S314000, C514S444000, C514S445000, C514S447000, C514S459000, C514S460000, C540S597000, C544S359000, C544S361000, C544S366000, C546S152000, C546S155000, C546S156000, C546S186000
Reexamination Certificate
active
06583179
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel substituted aminoalkylamide derivatives, pharmaceutical compositions containing them and their use in the treatment of reproductive disorders and affective conditions. The compounds of the invention are antagonists of follicle stimulating hormone, a hormone associated with the human reproductive system.
BACKGROUND OF THE INVENTION
Follicle stimulating hormone (FSH) belongs to a family of glycoprotein hormones, which includes lutenizing hormone (LH), thyrotropin (TSH) and chorionic gonadotropin (CG). Each of these hormones is composed of two different non-covalently bound subunits termed &agr; and &bgr;. Within a species the amino acid sequence of the &agr; subunits for these different hormones is identical, while the hormone specific &bgr; subunits exhibit different amino acid sequences (Combarnous, Endocrine Review, 13:670-691 (1992).
In females, follicle stimulating hormone (FSH) stimulates follicular granulosa cell proliferation in the ovary and impacts synthesis of estrogen, a hormone which is integral to follicular maturation and ovulation. An antagonist of FSH therefore acts to limit proliferation of follicular granulosa cells in the ovary, acting as a contraceptive. The FSH antagonist may also delay the maturation of follicles within the ovary, thereby postponing the maturation of a limited number of follicles in women. Such treatments have the potential for increasing the possibility of natural fertilization and pregnancy later in life.
Because of the controlling function of FSH on estrogen synthesis, an FSH antagonist may also be effective in the treatment of estrogen related disorders such as uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer.
An added advantage for an FSH antagonist would be its specific action on ovarian tissue without impact on peripheral tissues containing estrogen receptors. This would be expected to reduce the side effects associated with estrogen receptor antagonists.
Because the proliferation of follicular granulosa cells also impacts the health and development of the oocyte, FSH antagonists may be useful in preventing depletion of oocytes, a common side effect of chemotherapy or similar treatments designed to treat rapidly dividing cells.
In males, follicle stimulating hormone (FSH) is involved in the maturation of sperm cells. More specifically, FSH action in males is directed at the Sertoli cells, which are a recognized target of the hormone and which support the process of sperm maturation (spermatogenesis). FSH antagonists will therefore inhibit sperm maturation without affecting the production of androgens produced from Leydig cells under the control of luteinizing hormone (LH). In addition, FSH receptors have been reported in the epididymis in the male reproductive tract. Thus an FSH antagonist would be expected to affect the viability and motility of sperm by controlling functions of the epididymis.
FSH antagonists also have the potential to modify the rate of germ cell division in males. Because chemotherapy is known to deplete rapidly dividing cells such as spermatocytes, an FSH antagonist may be useful in a planned chemotherapy regimen to prevent spermatocyte depletion.
An FSH antagonist used as a female contraceptive could be used in contraceptive formulations alone or in combination with known contraceptive agents such as progesterone receptor modulators, estrogen receptor modulators, or androgen receptor modulators. An FSH antagonist used as a male contraceptive could be used alone or in combination with androgen receptor modulators, progesterone receptor modulators, or with estrogen receptor modulators. In addition, agents that affect the viability or motility or fertilizability of sperm by acting within the female genital tract may also be used in combination with FSH antagonists concomitantly, or as scheduled in a kit that prevents fertilization during the administration of an FSH antagonist. An example of such an agent is nonoxynol-9.
In recent years, peptide (based) FSH agonists and antagonists have been discovered and developed. Bono, G., et. al., in WO 97/12038 disclose novel amino acid residue peptide useful in stimulating FSH enhancement.
Amino acid based sulfonamide derivatives have also been developed for the treatment of a variety of conditions and disorders. Dumont, R. in WO 93/05014 discloses sulfonamide derivatives useful as inhibitors of Ca
+2
dependent enzymes.
The compounds of the present invention are non-peptide antagonists of FSH useful in the treatment of estrogen related disorders such as uterine fibroids, endometriosis, polycystic ovarian disease, dysfunctional uterine bleeding, breast cancer and ovarian cancer; prevention of depletion of oocytes (a common side effect of chemotherapy or similar treatment); female and male contraception; and prevention of spermatocyte depletion.
Additionally, the generation of chemical libraries on and off solid resins has proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs using high throughput screening (HTPS) techniques. In creating the libraries, the compounds are ideally synthesized in situ in solution phase or on a solid support. However, relatively simple synthetic methods to produce a diverse collection of such derivatives in situ are often not available.
Pharmaceutical drug discovery relies heavily on studies of structure-activity relationships wherein the structure of “lead compounds” is typically altered to determine the effect of such alteration on activity. Alteration of the structure of the lead compounds permits evaluation of the effect of the structural alteration on activity.
Thus, libraries of compounds derived from a lead compound can be created by including derivatives of the lead compound and repeating the screening procedures. In this manner, compounds with the best biological profile, i.e., those that are most active and which have the most ideal pharmacologic and pharmacokinetic properties, can be identified from the initial lead compound.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of the formula (I)
wherein
R
1
and R
2
are independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkylcarbonyl, C
1
-C
6
perhaloalkyl, phenyl, phenylC
1
-C
6
alkyl-, phenylcarbonyl-, pyridyl, pyridylC
1
-C
6
alkyl-, pyridylcabonyl-, thienyl, thienylC
1
-C
6
alkyl- and thienylcarbonyl, wherein the phenyl, pyridyl or thienyl is optionally substituted with one to three substituents independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, trifluoromethyl, trifluoromethoxy or NO
2
;
R
3
is selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C
2
-C
4
alkenyl and C
2
-C
4
alkynyl, where the C
1
-C
6
alkyl is optionally substituted with a phenyl, pyridyl, thienyl or furyl, wherein the phenyl, pyridyl, thienyl or furyl is optionally substituted with one to three substituents independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, trifluoromethyl, trifluoromethoxy or NO
2
;
R
4
is selected from the group consisting of —C
2
-C
6
alkyl-, -cyclopentyl-, -cylcohexyl-, -cyclohexyl-CH
2
—, —CH
2
-cyclohexyl-CH
2
—, —CH
2
-phenyl-CH
2
—, —C(O)—CH
2
-phenyl-CH
2
—, —C(O)—C
1
-C
6
alkyl- and -cyclohexyl-CH
2
-cyclohexyl-;
where the R
4
substituent is inserted into the compound of formula (I) from left to right, as defined;
alternately, R
2
, R
3
, and R
4
can be taken together with the two N atoms of the diamine portion of the molecule to form
alternately, R
3
can be taken together with R
2
as —C
2
-C
3
alkyl-, provided that R
4
is —C
2
-C
6
alkyl-;
L is selected from the group consisting of —C
3
-C
6
cycloalkyl (wherein the cycloalkyl is substituted with R
5
and R
6
), a bicyclic compound of the form
(wherein the point of the attachment of the bicyclic compound is any carbon atom of the alkyl portion and wherein the aromatic portion of the bicyclic compound is optionally substituted with on
Coats Steven J.
Fitzpatrick Louis J.
Hlasta Dennis J.
Lanter Carolina L.
Macielag Mark J.
Ortho-McNeil Pharmaceutical , Inc.
Raymond Richard L.
Truong Tamthom N.
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