Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-14
2003-06-24
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C514S313000, C514S267000, C546S082000, C546S083000, C546S156000, C546S159000, C544S250000
Reexamination Certificate
active
06583153
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to novel 7-heterocyclyl quinoline and thieno[2,3-b]pyridine derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions associated with gonadotropin releasing hormone (GnRH). The compounds of the invention are antagonists of GnRH, useful in the treatment of infertility, prostate cancer, benign prostate hyperplasia (BPH), and useful as contraceptives.
BACKGROUND OF THE INVENTION
Gonadotropin-releasing hormone (GnRH), also referred to as luteinizing hormone-releasing hormone (LHRH) is a linear decapeptide amide, pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
, originally isolated from porcine (Matsuo, H., et. al.,
Biochem. Biophys. Res. Commun.
1972, 43,1334-1339) and ovine (Burgus, R., et. al.,
PNAS,
USA, 1972, 69, 278-282) sources. GnRH plays a key role in the reproductive system. The hormone is released from the hypothalamus and acts on the pituitary gland to stimulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH released from the pituitary gland is primarily responsible for the regulation of gonadal steroid production in both males and females, whereas FSH regulates spermatogenesis in males and follicular development in females.
GnRH-based therapies using peptidic GnRH agonists and antagonists have been shown effective in the treatment of conditions associated with LH/FSH release, such as endometriosis, uterine fibroids, polycystic ovarian disease, precocious puberty and some gonadal steroid-dependent neoplasia, particularly prostate cancer, breast cancer and ovarian cancer. GnRH agonists and antagonists are also useful in the treatment of fertility and as a contraceptive in both males and females.
Although the compounds of the present invention are useful primarily for the treatment of disorders and conditions associated with the reproductive system, they may also be useful for the treatment of other GnRH mediated disorders and conditions including pituitary gonadotrope adenomas, sleep disorders, benign prostate hyperplasia, and prostate cancer.
Peptide-like GnRH antagonists are known, for example, derivatives of straight-chain peptides (U.S. Pat. Nos. 5,140,009 and 517,835), cyclic hexapeptide derivatives (Japanese Patent Application Laid-open No. 61(1986)-191698), and bicyclic peptide derivatives (J. Med. Chem. 1993, 36, 3265). However, due to a lack of bioavailability, these compounds are limited to intravenous and subcutaneous administration.
Recently, small molecule, non-peptide GnRH antagonists have been disclosed. Kato, et al., in EP0679642 disclose isochroman derivatives which have gonadotropin releasing hormone receptor antagonizing activity, as well as calcium-antagonizing and monoamine-uptake inhibiting activities.
Ohkawa et al., in WO96/38438 disclose tricyclic diazepine derivatives which have gonadotropin releasing hormone receptor antagonist activity. Ohkawa et al., in WO95/29900 disclose condensed heterocyclic compounds which have GnRH receptor antagonistic action and/or an action of improving sleep disturbances.
Furuya et al., in WO97/14682 disclose quinolone derivatives as GnRH antagonists, useful as prophylactic or therapeutic agents for the prevention or treatment of sex hormone dependent disease.
Goulet et al., in WO97/44037 and in WO97/44041, Goulet et al., in WO97/44321 and Goulet et al., in WO97/44339 disclose non-peptide antagonists of GnRH useful for the treatment of a variety of sex-hormone related conditions in men and women. Goulet et al., in WO97/21703 and in WO97/21707 disclose non-peptide antagonists of GnRH useful for the treatment of a variety of sex-hormone related conditions in men and women.
Furuya et al., in WO95/28405 disclose bicyclic thiophene derivatives with gonadotropin releasing hormone receptor antagonizing activity. Furuya et al., in WO97/41126 disclose 4,7-dihydro-4-oxothieno[2,3-b]pyridine derivatives having GnRH antagonistic activity. Furuya, et al., in WO97/14697 disclose thieno[2,3-b]pyridine derivatives as GnRH antagonists.
SUMMARY OF THE INVENTION
The present invention is directed to a compound of formula (I) or (II):
wherein
L
1
is selected from the group consisting of CH
2
, CH(CH
3
) and C(CH
3
)
2
;
R
1
and R
2
are independently selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocycloalkyl; wherein the aryl, heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, alkyl, alkoxy, nitro, NH
2
, NH(alkyl), N(alkyl)
2
, —C(O)-alkyl, —C(O)-aryl or —C(O)-cycloalkyl;
X is selected from the group consisting of O, S and NR
A
; where R
A
is selected from hydrogen, alkyl, aryl or aralkyl;
R
4
is selected from the group consisting of —C(O)—R
B
, —C(O)O—R
B
, —C(O)NH
2
, —C(O)—NHR
B
, —C(O)—N(R
B
)
2
, and —C(O)NHNH
2
;
wherein R
B
is selected from the group consisting of alkyl, aryl, aralkyl and cycloalkyl;
alternatively X is N and is taken together with R
4
to form a ring structure selected from the group consisting of pyrazolyl, dihydropyrazolyl, isoxazolinyl and dihydropyrimidinyl; wherein the ring structure is optionally substituted with one or more R
C
;
wherein each R
C
is independently selected from the group consisting of oxo, alkyl, alkoxy, amino, alkylamino, dialkylamino, aryl, —O-aryl, aralkyl and —O-aralkyl;
L
2
is selected from the group consisting of alkyl;
R
3
is selected from the group consisting of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocycloalkyl; wherein the cycloalkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, alkyl, alkoxy, nitro, NH
2
, NH(alkyl), N(alkyl)
2
, cyano or sulfonamido;
R
5
is selected from the group consisting of halogen, cycloalkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl; wherein the cycloalkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, nitro, NH
2
, NH(alkyl), N(alkyl)
2
, cyano or sulfonamido;
provided that when X is O, then R
5
is selected from the group consisting of heteroaryl or heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, nitro, NH
2
, NH(alkyl), N(alkyl)
2
, cyano or sulfonamido;
and pharmaceutically acceptable salts, esters and pro-drugs thereof.
In an aspect of the present invention is the compound 4,7-dihydro-2-(4-methoxyphenyl)-7-[(2-methoxyphenyl)methyl]-3-[[methyl(phenylmethyl)amino]methyl]-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid hydrazide, and pharmaceutically acceptable salts, esters and prodrugs thereof.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating disorders or diseases which respond to antagonism of GnRH, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
An example of the invention is a method for treating infertility, prostate cancer or benign prostate hyperplasia (BPH), in a subject in need thereof comprising administering to the subject an effective amount of any of the compounds or pharmaceutical compositions described above.
A further example of the invention is a method of female or male contraception, in a subject in need thereof comprising administ
Lanter James C.
Macielag Mark
Sui Zhihua
Huang Evelyn Mei
Ortho-McNeil Pharmaceutical , Inc.
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