Condensed-ring thiophene derivatives, their production and use

Details Condensed-ring thiophene derivatives, their production and use Condensed-ring thiophene derivatives, their production and use

2000-09-29

2003-02-04

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...

C514S253040, C514S233800, C514S226800, C514S228200, C514S241000, C514S242000, C514S249000, C514S252040, C514S252100, C514S256000, C514S258100, C514S259500, C514S261100, C514S297000, C514S298000, C514S266400, C544S061000, C544S127000, C544S333000, C544S238000, C544S362000, C544S264000, C544S257000, C544S353000, C544S284000, C546S102000, C546S108000, C546S114000

Reexamination Certificate

active

06514988

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a pharmaceutical composition for antagonizing a gonadotropin-releasing hormone (GnRH) containing a condensed-bycyclic compound consisting of a homo or hetero 5 to 7-membered ring group and a homo or hetero 5 to 7-membered ring group. The present invention also relates to novel condensed-ring thiophene derivatives and salts thereof. The present invention further relates to methods for manufacturing the novel condensed-ring thiophene derivatives and the salts thereof.
BACKGROUND ART
Secretion of anterior pituitary hormone undergoes the control by peripheral hormone secreted from target organs for the respective hormones and by secretion-accelerating or -inhibiting hormone from hypothalamus, which is the upper central organ of anterior lobe of pituitary (in this specification, these hormones are collectively called “hypothalamic hormone”). At the present stage, as hypothalamic hormones, nine kinds of hormones including, for example, thyrotropin releasing hormone (TRH) or gonadotropin releasing hormone {GnRH: sometimes called as LH-RH (luteinizing hormone releasing hormone)} are confirmed their existence (cf. Seirigaku 2, compiled by M. Iriku and K Toyama, published by Bunkohdo, p610-618, 1986). These hypothalamic hormones are assumed to show their actions via the receptor which is considered to exist in the anterior lobe of pituitary (cf. ibid), and observatinal studies of receptor genes specific to these hormones, including cases of human, have been developed (Receptor Kiso To Rinshô, compiled by H. Imura, et al., published by Asakura Shoten, p297-304, 1993). Accordingly, antagonists or agonists specifically and selectively acting on these receptors control the action of hypothalamic hormone and controlling the secretion of anterior pituitary hormone. As the results,they are expected to be useful for prophylactic and therapeutic agents of anterior pituitary hormone dependent diseases.
Leuprorelin acetate [Fujino et al., Biological and Biophysical Research Communications, Vol.60, 00.406-413, 1974); Oliver, R. T. D. et al., British Journal of Cancers, Vol.59, p.823, 1989; and Toguchi et al., Journal of International Medical Research, Vol.18, pp.35-41], which is a highly potent derivative of gonadotropic hormone-releasing hormone, one of the hypothalamic hormones, (hereinafter sometimes abbreviated as GnRH) [Schally A. V. et at., Journal of Biological Chemistry, Vol. 246, pp.7230-7236, 1971; and Burgus, R. et al., Proceeding of Natural Academic Science, USA, Vol.69, pp278-282, 1972], by administration of multiple doses, lowers release production of gonadotropic hormone in pituitary, causing lowering of reactivity on gonadotropic hormone is spermary and ovary to suppress secretion of testosterone and estrogen. Leuprorelin acetate has, therefore, been known to show antitumor activity on such hormone-dependent cancers as exemplified by prostate cancer, and has been widely used in the clinical field. Leuprorelin acetate has been widely used clinically also as a therapeutic agent of e.g. endometriosis and precocious puberty. The high antitumor activity of leuprorelin acetate is assumed to be due to its high resistance, as compared with natural GnRH, against protease,and to high affinity to GnRH receptor causing desensitization of GnRH due to decrease in number of receptors. However, as leuprorelin acetate is an ultra-agonist on GnRH receptor, it has been known that, immediately after the first administration, a transient aggravation accompanied with the rise of serum testosterone concentration due to pituitary-gonadotropic action (acute action) is observed. Circumstances being such as above, GnRH antagonistic drugs which are expected to have substantially the same therapeutic effects as described above but not to cause the above-mentioned transient pituitary-gonadotropic action (acute action) have been desired. As compounds having such GnRH antagonistic activity, a number of compounds including, for example, derivatives of GnRH such as straight-chain peptides, (U.S. Pat. No. 5,140,009, 5,171,835), cyclic hexapeptide derivatives [JPA S61 (1986)-191698] or bicyclic peptide derivatives [Journal of medicinal chemistry, Vol.36, pp.3265-3273, 1993]. These compounds are, however, all peptides, which leave many problems including, for example, dosage forms, stability of drugs, durability of actions and stability on metabolism. For solving these problems, orally administrable GnRH antagonistic drugs, especially non-peptide ones, are strongly desired. At the present stage, however, no report on non-peptide GnRH antagonistic drugs has been made.
The object of the invention lies in providing novel compounds having excellent gonadotropic hormone releasing hormone antagonistic activity as well as excellent gonadotropic hormone releasing hormone antagonistic agents.
DISCLOSURE OF INVENTION
Thus, the present invention provides a pharmaceutical composition for antagonizing a gonadotropin-releasing hormone (GnRH) containing a condensed-bicyclic compound consisting of a homo or hetero 5 to 7 membered ring and a homo or hetero 5 to 7 membered ring. The present invention also provides novel condensed-ring thiophene derivatives and salts thereof. The present invention further provides methods for manufacturing the novel condensed-ring thiophene derivatives and the salts thereof.
More specifically, the present invention provides:
(1) A compound of the formula (I):
wherein R
1
and R
2
are each independently hydrogen or a group bonded through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom;
R
3
is an optionally substituted homo- or hetero-cyclic group;
R
4
is hydrogen, formyl, cyano a lower alkyl group substituted by a group bonded through a sulfur atom or an optionally substituted hydroxyl group, a carbonyl group which may be substituted with an optionally substituted hydrocarbon residue, an esterified or amidated carboxyl group;
R
5
is hydrogen or a group bonded through a carbon atom; n is 0 to 3;
with the proviso that the homo- or hetero-cyclic group shown by R
3
is not substituted by a group, which is described in EP-A-443568 and EP-A-520423, of the formula:
in which R
6
is an optionally substituted 5 to 7 membered heterocyclic group having as a group capable of constituting the ring, carbonyl, thiocarbonyl, an optionally oxidized sulfur atom or a group convertible them, a group capable of forming an anion or a group convertible into an anion;
Z is an optionally substituted aromatic hydrocarbon residue optionally containing a hetero atom or an optionally substituted heterocyclic group;
V is a chemical bond or a spacer group, or a salt thereof,
(2) a compound according to (1), wherein R
3
is a group of the formula:
in which R
7
is hydrogen, halogen or a group bonded through a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom;
R
8
is hydrogen, halogen, nitro, cyano or a hydrocarbon residue which may be. substituted by a group bonded through an oxygen atom, a nitrogen atom or a sulfur atom,
(3) a compound according to (1), wherein either one of R
1
or R
2
is a group of the formula:
R
9
—(CH
2
)m—
in which R
9
is a group bonded through a nitrogen atom; m is 0 to 3, and the other one is a group of the formula:
R
10
—A—
in which R
10
is an optionally substituted phenyl; A is a chemical bond or a spacer group,
(4) a compound of the formula (II):
wherein R
11
is hydrogen, lower alkyl, a group of the formula:
Q—(CH
2
)p-
in which Q is aryl which may be substituted by a) halogen, b) nitro, c) cyano, d) amino, e) an optionally substituted f) carboxyl, lower alkylenedioxy or g) a group of the formula: —A—R
15
in which A is a chemical bond or a spacer group, R
15
is alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group;
R
12
is hydrogen, alkyl, an optionally substituted aryl, an optionally substituted aralkyl, an optionally substituted cycloalkyl; R
13
is an optionally substituted amino,;
R
14
is an optionally substituted aryl;
r is

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