GnRH antagonists being modified in positions 5 and 6

Details GnRH antagonists being modified in positions 5 and 6 GnRH antagonists being modified in positions 5 and 6

2000-01-03

2001-04-10

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S800000, C530S313000, C530S328000, C930S110000

Reexamination Certificate

active

06214798

ABSTRACT:

This invention relates generally to peptides which are antagonists of human gonadotropin releasing hormone (GnRH) and which have advantageous physical, chemical and biological properties. More particularly, the present invention relates to decapeptides which inhibit gonadal function and the release of the steroidal hormones progesterone and testosterone for periods of longer duration, and to methods of administering pharmaceutical compositions containing such decapeptides for such purpose and particularly to manage conditions resulting from the hypersecretion of gonadal steroids.
BACKGROUND OF THE INVENTION
Follicle stimulating hormone (FSH) and luteinizing hormone (LH), sometimes referred to as gonadotropins or gonadotropic hormones, are released by the pituitary gland which is attached by a stalk to the hypothalamus.
Hormone release by the anterior lobe of the pituitary gland usually requires prior release of hormones produced by the hypothalamus, such as the GnRH decapeptide.
The administration of GnRH analogs that are antagonistic to the normal function of GnRH has been used to suppress secretion of gonadotropins generally in mammals and to suppress or delay ovulation.
The search for improved GnRH antagonists has resulted in the making of Antide, i.e. [Ac-D-2Nal
1
, D-4ClPhe
2
, D-3Pal
3
, Lys(Nic)
5
, D-Lys(Nic)
6
, ILys
8
, D-Ala
10
]-GnRH; and Cetrorelix, i.e. [Ac-D-2Nal
1
, D-4ClPhe
2
, D-3Pal
3
, D-Cit
6
, D-Ala
10
]-GnRH. U.S. Pat. No. 5,516,887 describes GnRH antagonists which are said to be more effective than Antide in suppressing plasma testosterone, e.g.[Ac-D-2Nal
1
, D-4ClPhe
2
, D-3Pal
3
, D-N
&egr;
-carbamoyl Lys
6
, Ilys
8
, D-Ala
10
]-GnRH, which is referred to as Antarelix.
U.S. Pat. No. 5,296,468, issued Mar. 22, 1994, discloses the design and synthesis of a number of GnRH antagonists wherein the side chains of selected residues are reacted to create cyanoguanidino moieties, some of which subsequently spontaneously convert to a desired heterocycle, e.g. a 3-amino-1,2,4-triazole(atz). Such cyanoguanidino moieties are built upon the omega-amino group in an amino acid side chain, such as lysine, ornithine, 4-amino phenylalanine (4Aph) or an extended chain version thereof, such as 4-amino homophenylalanine (4Ahp). GnRH antagonists having such significantly modified or unnatural amino acids in the 5- and 6-positions exhibit good biological potency, and those built upon Aph are generally considered to be preferred. One that is especially preferred is Azaline B, i.e. [Ac-D-2Nal
1
, D-4ClPhe
2
, D-3Pal
3
, 4Aph(atz)
5
, D-4Aph(atz)
6
, ILys
8
, D-Ala
10
]-GnRH. U.S. Pat. No. 5,506,207 discloses biopotent GnRH antagonists wherein amino-substituted phenylalanine side chains of residues in the 5- and 6-positions are acylated; one particularly potent decapeptide is Acyline, i.e. [Ac-D-2 Nal
1
, D-4CiPhe
2
, D-3Pal
3
, 4Aph(Ac)
5
, D-4Aph(Ac)
6
, ILys
8
, D-Ala
10
]-GnRH.
Despite the attractive properties of this group of GnRH antagonists, the search has continued for still further improved GnRH antagonists, particularly those which exhibit long duration of biological action. It can frequently be important that a peptide analog should exhibit a long duration of activity with respect to LH secretion, a property which may be enhanced by the peptide's resistance to proteolytic enzyme degradation in the body for both short-term and long-term treatment indications. In addition, to facilitate administration of these compounds to mammals, particularly humans, without significant gelling, it is considered extremely advantageous for such GnRH antagonistic decapeptides to have high solubility in water at normal physiologic pH, i.e. about pH 5 to about pH 7.4.
SUMMARY OF THE INVENTION
It has now been found that certain other modifications to the 5-position residue, or to the 5- and 6-position residues, in this subclass of GnRH antagonists, which includes Cetrorelix, Antarelix, Acyline, Antide and others, unexpectedly result in compounds which when administered sc exhibit the particularly advantageous property of long duration of bioactivity. These modifications are made to a residue of 4aminoPhe or its equivalent 4Aph or to 4-aminomethyl phenylalanine (4Amf) wherein the primary amino group is bonded to a methyl group attached in the 4- or para-position. In such modifications, the amino group of the side chain is reacted with an isocyanate to form a urea group or reacted with a heterocyclic carboxylic acid containing at least 2 nitrogen atoms arranged to constitute a urea moiety. The preferred heterocyclic reactants are D- or L-hydroorotic acid (Hor) (C
4
N
2
H
5
(O)
2
COOH) and D- or L-2-Imidazolidone-4-carboxylic acid (Imz) (C
3
N
2
H
5
(O)COOH).
Generally, GnRH antagonist decapeptides having the following formula, and closely related analogs and the pharmaceutically acceptable salts, are found to have improved pharmacological properties, particularly long duration of bioactivity:
X-D-Nal-(A)D-Phe-D-Pal-Ser-Xaa
5
-Xaa
6
-Leu-Xaa
8
-Pro-Xaa
10
wherein:
X is an acyl group having up to 7 carbon atoms or Q, with Q being
 and with R being H or lower alkyl;
A is 4Cl, 4F, 4Br, 4NO
2
, 4CH
3
, 4OCH
3
, 3,4Cl
2
or C
&agr;
Me4Cl;
Xaa
5
is Aph(Q
1
) or Amf(Q
1
) with Q
1
being
Xaa
6
, is D-Aph(Q
2
)D-Amf(Q
2
), D-Lys(Nic), D-Cit, D-Hci or D-Pal, with Q
2
being For, Ac, 3-amino-1,2,4 triazole, Q or Q
1
;
Xaa
8
is Lys(ipr), Arg, Har, Arg(Et
2
) or Har(Et
2
); and
Xaa
10
is D-Ala-NH
2
, D-Ala-ol, Ala-ol, NHCH
2
CH
3
, Gly-NH
2
, AzaGly-NH
2
, Ala-NH
2
, Agl-NH
2
, D-Agl-NH
2
, Agl(Me)—NH
2
or D-Agl(Me)-NH
2
, provided however that the &agr;-amino group of Xaa
5
may optionally be methylated; and provided further that when Xaa
6
contains D- or L-Hor or D- or L-Imz, Xaa
5
may have Ac, For or 3-amino-1,2,4-triazole as Q
1
, and that when Xaa
6
contains Q, Xaa
5
may also contain Q.
In another aspect, the invention provides a method for invivo or invitro diagnosis of a condition where GnRH is causing excess hormonal secretion or tumor growth, which method comprises administering a GnRH antagonist peptide of the type described above and monitoring for hormonal secretion or for tumor cell proliferation.
In still another aspect, the invention provides an intermediate for making a GnRH antagonist peptide having the formula:
X
1
-D-Nal-(A)D-Phe-D-Pal-Ser(X
2
)-Xaa
5
-Xaa
6
-Leu-Lys(ipr) (X
4
)-Pro-X
5
wherein:
X
1
is an &agr;-amino-protecting group;
A is 4Cl or 4F;
X
2
is H or an hydroxyl-protecting group;
Xaa
5
is Aph(Q
1
) or Amf(Q
1
) with Q
1
being a D-isomer, an L-isomer or a D/L-isomer mixture of either
Xaa
6
is D-Aph(Q
2
), D-Amf(Q
2
) or D-Pal, with Q
2
being Ac, Q
1
, carbamoyl or methylcarbamoyl;
X
4
is an acid-labile amino-protecting group; and
X
5
is D-Ala-, Gly-, Ala-, Agl-, D-Agl-, Agl(Me)-, or D-Agl(Me)-resin support; N(Et)-resin support; an amide of D-Ala, Gly or Ala; ethylamide; AzaGly-NH
2
; or OH, provided however that the &agr;-amino group of Xaa
5
may optionally be methylated.
These antagonists are particularly useful to suppress the secretion of gonadotropins and as fertility regulators in humans because they exhibit long duration of activity, i.e. continuing to substantially suppress LH secretion for at least about 4 days. They have improved solubility in aqueous buffers at physiologic pHs and acceptable side effects with respect to stimulation of histamine release, i.e. better than the GnRH superagonists which are now being clinically used; they also exhibit minimal gelling upon subcutaneous(sc) injection at effective concentrations. These GnRH antagonists also perform well in an anaphylactoid assay causing a relatively small wheal. As a result, these peptides find particular use in administration to mammals, especially humans, as fertility regulators and for the treatment of pathological conditions such as precocious puberty, hormone-dependent neoplasia, dysmenorrhea, endometriosis, steroid-dependent tumors, and the other short-term and long-term indications mentioned hereinbefore. They are als

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