Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-14
2002-07-02
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S281000
Reexamination Certificate
active
06413972
ABSTRACT:
TECHNICAL FIELD
The present invention relates to nitrogen-containing heterocyclic compounds exhibiting gonadotropin releasing hormone (GnRH) antagonizing activity, their production and pharmaceutical compositions containing them.
BACKGROUND ART
The secretion of hypophysial anterior lobe hormone is regulated by the peripheral hormone secreted by each target organ and the secretion-promoting or secretion-suppressing hormone secreted by the hypothalamus, which is the center superior to the hypophysial anterior lobe, and this group of hormones hereinafter generically referred to as hypothalamic hormone in this specification. To date, nine hypothalamic hormones have been identified, for example, thyroid-stimulating hormone-releasing hormone (TRH), and gonadotropin releasing hormone [GnRH, also known as luteinizing hormone releasing hormone (LH-RH)], etc. It is conjectured that these hypothalamic hormones exhibit their hormone actions etc. via receptors assumed to be present in the hypophysial anterior lobe, and analyses of receptor genes specific to these hormones, including humans, are ongoing. Antagonists or agonists that act specifically and selectively on these receptors would therefore regulate the action of hypothalamic hormones and hence regulate the secretion of hypophysial anterior lobe hormone. As a result, such antagonists or agonists are expected to prevent or treat diseases depending on these hypophysial anterior lobe hormone.
Known compounds possessing GnRH-antagonizing activity include GnRH-derived linear peptides (U.S. Pat. Nos. 5,140,009 and 5,171,835), a cyclic hexapeptide derivative (JP-A-61-191698), a bicyclic peptide derivative [Journal of Medicinal Chemistry, Vol. 36, pp. 3265-3273 (1993)), and so forth. Non-peptide compounds possessing GnRH-antagonizing activity include compounds described in WO 95/28405, WO 97/14697 and WO 97/14682, etc.
ZA 86/9289 describes 1,4-dihydro-1-ethyl-7-phenylpyrrolo[1,2-a]pyrimidin-4-one in Example 22.
Peptide compounds pose a large number of problems to be resolved with respect to oral absorbability, dosage form, dose volume, drug stability, sustained action, metabolic stability etc. There is strong demand for an oral GnRH antagonist, especially one based on a non-peptide compound, that has excellent therapeutic effect on hormone-dependent cancers, e.g., prostatic cancer, endometriosis, precocious puberty etc., and that does not show transient hypophysial-gonadotropic action (acute action).
DISCLOSURE OF INVENTION
The present inventors produced various nitrogen-containing heterocyclic derivatives, investigated their actions, and found that some nitrogen-containing heterocyclic compounds possess excellent GnRH-antagonizing activity. The inventors conducted further investigation based on this finding, and developed the present invention. Accordingly, the present invention relates to:
[1] A compound of the formula (I):
wherein
one of A and D represents a nitrogen atom and the other represents a carbon atom, or both represent a nitrogen atom;
B represents a nitrogen atom or a carbon atom; m represents an integer from 0 to 3;
R
1
, R
2
and R
3
each represents (i) hydrogen or (ii) a group bound via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom;
R
4
represents a group bound via a carbon atom;
R
5
represents (i) hydrogen, (ii) halogen or (iii) a group bound via a carbon atom or an oxygen atom;
R
6
represents hydrogen or a group bound via a carbon atom;
R
7
represents a homocyclic group which may be substituted or a heterocyclic group which may be substituted; and each dotted line represents a single bond or a double bond, [hereinafter sometimes referred to briefly as compound (I)] or a salt thereof;
[2] a compound of the above [1] or a salt thereof,
wherein R
1
, R
2
and R
3
each is
(1) hydrogen,
(2) a hydrocarbon group which may be substituted,
(3) an acyl group which may be substituted,
(4) a heterocyclic group having a bond in a carbon atom thereof which may be substituted,
(5) a group of the formula: —COOR
21
wherein R
21
is hydrogen, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted,
(6) a group of the formula: —CO—NR
15
R
16
wherein R
15
is hydrogen, a hydrocarbon group which may be substituted or a C
1-10
alkoxy group; and R
16
is hydrogen or a hydrocarbon group which may be substituted; or R
15
and R
16
form, taken together with the adjacent nitrogen atom, a cyclic amino group which may be substituted,
(7) a cyano group,
(8) a nitro group,
(9) a group of the formula: —NR
8
R
9
wherein R
8
is (i) hydrogen, (ii) a hydrocarbon group which may be substituted, (iii) an acyl group which may be substituted, (iv) a group of the formula: —O—R
13
wherein R
13
is hydrogen, a C
1-10
hydrocarbon group which may be substituted, a C
1-20
acyl group which may be substituted, a C
1-20
alkylsulfonyl group which may be substituted, a C
6-14
arylsulfonyl group which may be substituted or a heterocyclic group which may be substituted, (v) a heterocyclic group which may be substituted or (vi) a group of the formula: —S(O)t-R
12
wherein t is an integer from 0 to 2, and R
12
is hydrogen or a C
1-10
hydrocarbon group which may be substituted;
R
9
is hydrogen, a hydrocarbon group which may be substituted or an acyl group which may be substituted; or
R
8
and R
9
form, taken together with the adjacent nitrogen atom, a cyclic amino group which may be substituted,
(10) a group of the formula: —O—R
13
wherein R
13
is as defined above, or
(11) a group of the formula: —S(O)t-R
14
wherein t is an integer from 0 to 2, and R
14
is hydrogen, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
R
4
is
(1) a hydrocarbon group which may be substituted,
(2) an acyl group which may be substituted,
(3) a heterocyclic group having a bond in a carbon atom thereof which may be substituted,
(4) a group of the formula: —COOR
21
wherein R
21
is as defined above,
(5) a group of the formula: —CO—NR
15
R
16
wherein each symbol is as defined above, or
(6) a cyano group;
R
5
is
(1) hydrogen,
(2) halogen,
(3) a hydrocarbon group which may be substituted,
(4) an acyl group which may be substituted,
(5) a heterocyclic group having a bond in a carbon atom thereof which may be substituted,
(6) a group of the formula: —COOR
21
wherein R
21
is as defined above,
(7) a group of the formula: —CO—NR
15
R
16
wherein each symbol is as defined above,
(8) a cyano group, or
(9) a group of the formula: —O—R
13
wherein R
13
is as defined above;
R
6
is
(1) hydrogen,
(2) a hydrocarbon group which may be substituted,
(3) an acyl group which may be substituted,
(4) a heterocyclic group having a bond in a carbon atom thereof which may be substituted,
(5) a group of the formula: —COOR
21
wherein R
21
is as defined above,
(6) a group of the formula: —CO—NR
5
R
16
wherein each symbol is as defined above, or
(7) a cyano group;
R
7
is
(i) a C
6-10
aryl or C
3-7
cycloalkyl group, each of which may be substituted by 1 to 6 substituents selected from the group consisting of (1) C
1-15
alkyl which may be substituted by 1 to 3 halogen, (2) C
3-10
cycloalkyl, (3) C
2-10
alkenyl, (4) C
2-10
alkynyl, (5) C
3-10
cycloalkenyl, (6) C
6-10
aryl, (7) C
7-20
aralkyl, (8) nitro, (9) hydroxy, (10) mercapto, (11) oxo, (12) thioxo, (13) cyano, (14) carbamoyl, (15) carboxyl, (16) C
1-6
alkoxy-carbonyl, (17) sulfo, (18) halogen, (19) C
1-6
alkoxy, (20) C
6-10
aryloxy, (21) C
1-6
alkanoyloxy, (22) C
1-6
alkylthio, (23) C
6-10
arylthio, (24) C
1-6
alkylsulfinyl, (25) C
6-10
arylsulfinyl, (26) C
1-6
alkylsulfonyl, (27) C
6-10
arylsulfonyl, (28) amino, (29) C
1-6
alkanoylamino, (30) mono- or di- C
1-4
alkylamino, (31) C
3-8
cycloalkylamino, (32) C
6-10
arylamino, (33) C
1-6
alkanoyl, (34) C
6-10
aryl-carbonyl and (35) 5- to 6-membered heterocyclic group, or
(ii) a heterocyclic group which may be substituted,
in which “hydrocarbon group” is a C
1-20
hydrocarbon group selected from C
1-15
Furuya Shuichi
Imaeda Toshihiro
Sasaki Satoshi
Balasubramanian Venkataraman
Foley & Lardner
Raymond Richard L.
Takeda Chemical Industries Ltd.
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