Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-26
2003-05-27
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S278000
Reexamination Certificate
active
06569863
ABSTRACT:
This application is a 371 of PCT/EP00/02865 filed Apr. 3, 2000.
The invention relates to compounds having glycoprotein hormone agonistic or antagonistic activity, in particular to compounds having Luteinizing Hormone (LH) agonistic activity. The invention furthermore relates to byciclic heteroaromatic derivative compounds, to pharmaceutical compositions containing the same as well as to the use of these compounds in medical therapy, particularly for use as a control of fertility.
Gonadotropins serve important functions in a variety of bodily functions including metabolism, temperature regulation and the reproductive process. The hypophyseal gonadotropin FSH for example plays a pivotal role in the stimulation of follicle development and maturation whereas LH induces ovulation (Sharp, R. M. Clin Endocrinol. 33:787-807, 1990; Dorrington and Armstrong, Recent Prog. Horm. Res. 35:301-342, 1979). Currently, LH is applied clinically, in combination with FSH, for ovarian stimulation i.e. ovarian hyperstimulation for in vitro fertilisation (IVF) and induction of ovulation in infertile anovulatory women (Insler, V., Int. J. Fertility 33:85-97, 1988, Navot and Rosenwak, J. Vitro Fert. Embryo Transfer 5:3-13, 1988), as well as for male hypogonadism and male infertility.
Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. The actions of these pituitary and placental hormones are mediated by specific plasma membrane receptors that are members of the large family of G-protein coupled receptors. They consist of a single polypeptide with seven transmembrane domains and are able to interact with the Gs protein, leading to the activation of adenyl cyclase.
Gonadotropins destined for therapeutic purposes can be isolated from human urine sources and are of low purity (Morse et al, Amer. J. Reproduct. Immunol. and Microbiology 17:143, 1988). Alternatively, they can be prepared as recombinant gonadotropins.
As with other therapeutic proteins, it is necessary to administer gonadotropins either subcutaneous or intra-muscular. It would be advantageous, however, to activate the receptor with a small molecule that could be administered through e.g. the oral or transdermal route.
The present invention describes the preparation of such low molecular weight hormone analogs that selectively activate one of the gonadotropin receptors. This should be considered as one of the major advantages of the present invention.
Thus, the invention resides in bicyclic heteroaromatic derivatives according to general formula I, or a pharmaceutically acceptable salt thereof,
wherein
R
1
is NR
5
R
6
, OR
5
, SR
5
or R
7
, preferably R
1
is R
7
;
R
5
and R
6
are independently selected from H, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-8C)cycloalkyl, (2-7C)heterocycloalkyl, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, (6-14C)aryl or (4-13C)heteroaryl, or R
5
and R
6
together are joined in a (2-7C)heterocycloalkyl ring;
R
7
is (3-8C)cycloalkyl, (2-7C)heterocycloalkyl, (6-14C)aryl or (4-13C)heteroaryl; preferably R
7
is (6-14C)aryl or (4-13C)heteroaryl;
R
2
is (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, or (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted with one or more substituents selected from (1-8C)alkyl, (1-8C)alkylthio, (1-8C)(di)alkylamino, (1-8C)alkoxy, (2-8C)alkenyl, or (2-8C)alkynyl;
R
3
is (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-8C)cycloalkyl, (2-7C)heterocycloalkyl, or (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted with one or more substituents selected from (1-8C)alkyl, (1-8C)(di)alkylamino or (1-8C)alkoxy; preferably R
3
is (1-8C)alkyl, more preferably (1-4C)alkyl, even more preferably R
3
is isopropyl or tert-butyl;
X is S, O or NR
4
);
R
4
is H, (1-8C)alkyl, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl or (6-14C)aryl(1-8C)alkyl;
Y is CH or N, preferably Y is N;
Z is NH
2
or OH;
A is S, N(H), N(R
9
), O or a bond and
R
9
can be selected from the same groups as described for R
2
and
B is N(H), O, or a bond.
The alkyl group, alkenyl group or alkynyl group, if present in R
5
and/or R
6
in the above mentioned formula may optionally be substituted with one or more substituents selected from hydroxyl, (6-14C)aryl, (1-8C)alkoxy, (1-8C)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (1-8C)alkoxycarbonyl, (6-14C)aryloxycarbonyl, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, amine, (1-8C)alkylaminocarbonyl, (6-14C)alkylaminocarbonyl, (1-8C)alkylcarbonylamino, (6-14C)arylcarbonylamino, (6-14C)(di)arylamino and/or (1-8C)(di)alkylamino.
If R
7
is (6-14C)aryl or (4-13C)heteroaryl, aryl may optionally be substituted at the ortho and/or meta position with one or more substituents selected from R
8
, (6-14C)aryl, (4-13C)heteroaryl, (2-7C)heterocycloalkyl, (3-8C)cycloalkyl, NHR
8
, OR
8
and/or SR
8
in which R
8
is (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, the alkyl group of which may be optionally substituted with one or more substituents selected from hydroxyl, (1-8C)alkoxy, (2-7C)heterocycloalkyl((1-8C)alk)oxy, (3-8C)cycloalkyl((1-8C)alk)oxy, (6-14C)aryl((1-8C)alk)oxy, (4-13C)heteroaryl((1-8C)alk)oxy, (2-7C)heterocycloalkyl, (3-8C)cycloalkyl, (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkoxycarbonyl, (6-14C)aryloxycarbonyl, (1-8C)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, amine, (1-8C)alkylaminocarbonyl, (6-14C)alkylaminocarbonyl, (1-8C)alkylcarbonylamino, (6-14C)arylcarbonylamino, (6-14C)(di)arylamino and/or (1-8C)(di)alkylamino. Preferably the substituents at aryl in R
7
are chosen from NHR
8
or OR
8
. R
8
preferably is (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, (1-8C)alkyl. The most preferred substituents in the alkyl group are (2-7C)heterocycloalkyl, (1-6C)(di)alkylamino and amine.
The alkyl group, alkenyl group or alkynyl group, if present in R
9
or R
2
in the above mentioned formula may optionally be substituted with one or more substituents selected from (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, (1-8C)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (6-14C)aryloxycarbonyl and/or (1-8C)alkoxycarbonyl.
The alkyl group, alkenyl group or alkynyl group, if present in R
3
in the above mentioned formula may optionally be substituted with one or more substituents selected from hydroxyl, (1-8C)alkoxy, (6-14C)aryloxy, (3-8C)cycloalkyl((1-8C)alk)oxy, (2-7C)heterocycloalkyl((1-8C)alkoxy, (6-14C)aryl((1-8C)alkoxy, (4-13C)heteroaryl((1-8C)alk)oxy, (2-7C)heterocycloalkyl, (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkoxycarbonyl, (6-14C)aryloxycarbonyl(1-8C)alkylcarbonyloxy, (6-14C)arylcarbonyloxy, (1-8C)alkylcarbonyl, (6-14C)arylcarbonyl, amine, (1-8C)alkylaminocarbonyl, (6-14C)arylaminocarbonyl, (1-8C)alkylcarbonylamino, (6-14C)arylcarbonylamino, (6-14C)(di)arylamino or (1-8C)(di)alkylamino.
Preferred compounds according to the invention are compounds according to general formula I wherein X is S and/or Z is NH
2
. Amongst these preferred compounds those wherein X is S and Z is NH
2
are especially preferred, even more preferred are those compounds wherein in addition Y is N. Most preferred are the compounds which in addition to the above mentioned definitions of X, Z and Y are defined by R
1
being (6-14C)aryl or (4-13C)heteroaryl. Most preferably A is S.
Highly preferred compounds of the invention are the bicyclic heteroaromatic derivative compounds having the general formula I wherein
R
1
is (6-14C)aryl or (4-13C)heteroaryl,
R
2
is (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, or (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted with one or more substituents selected from (1-8C)alkyl, (1-8C)alkylthio, (1-8C)alkoxy, (2-8C)alkenyl, or (2-8C)alkynyl,
R
3
is (1-8C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (3-8C)cycloalkyl, (2-7C)heterocycloalkyl, or (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted with one or more substituents selected from (1-8C)alkyl, (1-8C)(di)alkylamino or (1-8C)alkoxy
X is S, Z is NH
2
, A is S and B is N(H), O, or a bond.
These compounds have the gen
Adang A. E. P.
Gerritsma G. G.
Van Straten N. C. R.
Akzo Nobel NV
Milstead Mark W.
Rao Deepak
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