Thienopyridine derivatives, their production and use

Details Thienopyridine derivatives, their production and use Thienopyridine derivatives, their production and use

1997-08-14

1999-12-14

Dentz, Bernard

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546114, A61K 31435, C07D49504

Patent

active

06001850&

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel 4,7-dihydro-4-oxothieno[2,3-b]pyridine derivatives and salts thereof. The present invention further relates to method for manufacturing these 4,7-dihydro-4-oxothieno[2,3-b]pyridine derivatives and salts thereof, and pharmaceutical composition containing these 4,7-dihydro-4-oxothieno[2,3-b]pyridine derivatives and 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 secretion-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. These hypothalamic hormones are assumed to show their actions via the receptor which is considered to exist in the anterior lobe of pituitary, and observational studies of receptor genes specific to these hormones, including cases of human, have been developed. Accordingly, antagonists or agonists specifically and selectively control the action of hypothalamic hormone by acting on these receptors and control 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.
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, U.S. Pat. No. 5,171,835), cyclic hexapeptide derivatives (Japanese Patent Application Laid-open No.S61(1986)-191698) or bicyclic peptide derivatives (Journal of Medicinal Chemistry, Vol.36, pp.3265-3273, 1993). Furthermore, as non-peptide compounds having such GnRH antagonistic activity, compounds described in PCT International Publication No. WO 95/28405 are known.
Such peptide compounds leave many problems including, for example, oral administrability, dosage form, stability of the drug, durability of actions, stability on metabolism. It has been desired to obtain GnRH antagonists which have excellent characteristics of high GnRH antagonistic activity, oral administrability, stability in plasma of blood and durability of actions.
The object of the invention lies in providing novel 4,7-dihydro-4-oxothieno[2,3-b]pyridine derivatives having excellent gonadotropin releasing hormone antagonistic activity.


DISCLOSURE OF INVENTION

The present invention provides 4,7-dihydro-4-oxo-thieno[2,3-b]pyridine derivatives having excellent properties of high GnRH antagonistic activity, oral administrability, stability in plasma in blood, and durability of actions.
The present invention is directed to: ##STR1## wherein (A)R.sup.1 is (1)an alkoxy group which is substituted with a group selected from the group consisting of (i)halogen, (ii)cycloalkyl and (iii)alkenyl, R.sup.2 is (1)an alkyl group, (2)an aryl group, (3)a group of the formula: --X--R.sup.41, wherein R.sup.41 is an optionally substituted alkyl group or an optionally substituted cycloalkyl group and X is O or S, and R.sup.3 is a hydrogen atom or an alkyl group; or formula: --X--R.sup.43, wherein when X is O, R.sup.43 is an optionally substituted branched alkyl group, an optionally substituted cycloalkyl group or an optionally substituted 6-membered oxygen-containing heterocyclic group, and when X is S, R.sup.43 is an optionally substituted alkyl group, an optionally substituted cycloalkyl group or an optionally substituted 6-membered oxygen-containing heterocyclic group or (2)a hydroxyl group, and R.sup.3 is a hydrogen atom or an alkyl group, or a salt thereof. alkoxy group which is substituted with a group selected from the group consisting of (i)halogen, (ii)C.sub.3-10 cycloa

REFERENCES:
patent: 5817819 (1998-10-01), Furuya et al.
P. Gilis et al., "Synthesis and antibacterial evaluation of 4,7-dihydro-4-oxothienol[2,3-b]pyridine-5-carboxylic acids", European Journal of Medicinal Chemistry, Chimica Therapeutica, May-Jun., 1978-13, No. 3, pp. 265-269.

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