Peptide intermediates for making GnRH antagonists

Details Peptide intermediates for making GnRH antagonists Peptide intermediates for making GnRH antagonists

1996-10-07

2004-06-08

Wessendorf, T. D. (Department: 1639)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Lutenizing hormone releasing factor ; related peptides

C530S328000, C530S337000, C930S110000

Reexamination Certificate

active

06747125

ABSTRACT:

This invention relates generally to peptides having unnatural amino acids and to the preparation of new unnatural amino acids, which may be derived from diamino acids, such as Lys, Orn, Dpr and Dbu. More particularly, it relates to GnRH analogs having such unnatural amino acids which can be prepared either in such fully assembled peptides or for incorporation into such peptides as a part of the usual chain elongation synthesis process.
In one more particular aspect, the present invention relates to peptides which inhibit gonadal function and the release of the steroidal hormones, progesterone and testosterone and also to peptides which promote the release of such steroids, as well as to methods of promoting or preventing ovulation.
BACKGROUND OF THE INVENTION
The pituitary gland is attached by a stalk to the region in the base of the brain known as the hypothalamus. In particular, follicle stimulating hormone (FSH) and luteinizing hormone (LH), sometimes referred to as gonadotropins or gonadotropic hormones, are released by the pituitary gland. These hormones, in combination, regulate the functioning of the gonads to produce testosterone in the testes and progesterone and estrogen in the ovaries, and they also regulate the production and maturation of gametes.
The release of a hormone by the anterior lobe of the pituitary gland usually requires a prior release of another class of hormones produced by the hypothalamus. One of the hypothalamic hormones acts as a factor that triggers the release of the gonadotropic hormones, particularly LH, and this hormone is referred to herein as GnRH although it has also been referred to as LH-RH and as LRF. GnRH was isolated and characterized as a decapeptide some 20 years ago, and it was found that analogs of GnRH having a D-isomer instead of Gly in the 6-position, such as [D-Ala
6
]-GnRH (U.S. Pat. No. 4,072,668) having the following formula:
pGlu-His-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-Gly-NH
2
,
have greater binding strength to the receptor and greater biological potency than the native hormone.
Peptides are compounds which contain two or more amino acids in which the carboxyl group of one acid is linked to the amino group of the other acid. The formula for GnRH, as represented above, is in accordance with conventional representation of peptides where the amino terminus appears to the left and the carboxyl terminus to the right. The position of the amino acid residue is identified by numbering the amino acid residues from left to right. In the case of GnRH, the hydroxyl portion of the carboxyl group of glycine at the C-terminus has been replaced with an amino group(NH
2
) i.e. the C-terminus is amidated. The abbreviations for the individual amino acid residues above are conventional and are based on the trivial name of the amino acid, e.g. pGlu is pyroglutamic acid, Glu is glutamic acid, His is histidine, Trp is tryptophan, Ser is serine, Tyr is tyrosine, Gly is glycine, Leu is leucine, Nle is norleucine, Orn is ornithine, Arg is arginine, Har is homoarginine, Pro is proline, Sar is sarcosine, Phe is phenylalanine, Ala is alanine, Val is valine, Nva is norvaline, Ile is isoleucine, Thr is threonine, Lys is lysine, Asp is aspartic acid, Asn is asparagine, Gln is glutamine, and Met is methionine. Except for glycine, amino acids of the peptides of the invention are of the L-configuration unless noted otherwise.
There are reasons for desiring to prevent ovulation in female mammalians, and the administration of GnRH analogs that are antagonistic to the normal function of GnRH have been used to suppress or delay ovulation. For this reason, analogs of GnRH which are antagonistic to GnRH are being investigated for their potential use as a contraceptive or for regulating conception periods. GnRH antagonists may also be used for the treatment of precocious puberty and endometriosis. The GnRH superagonists can also be used for these purposes. Such antagonists have also been found useful to regulate the secretion of gonadotropins in male mammals and can be employed to arrest spermatogenesis, e.g. as male contraceptives for treatment of male sex offenders, and for treatment of prostatic hypertrophy. More specifically, GnRH antagonists can be used to treat steroid-dependent tumors, such as prostatic and mammary tumors, and for the control of the timing of ovulation for in vitro fertilization. In the female, they can also be used to treat hirsutism.
On the other hand, GnRH agonists function in the same manner as GnRH in promoting the release of LH and FSH, and agonists which exhibit greater biopotency and/or longer duration of action are considered valuable.
In one aspect, it is desired to provide improved peptides which either are strongly antagonistic to endogenous GnRH and prevent secretion of LH and FSH and the release of steroids by the gonads of mammals or are strong agonists of GnRH. Of particular interest are compounds which are more effective in vivo when administered orally.
SUMMARY OF THE INVENTION
The present invention provides unnatural amino acids that can be prepared de novo or by modifying a previously prepared peptide, but which are preferably prepared as a part of a protected peptide-resin, containing a desired overall sequence which includes one or more amino acid residues having a side chain amino group which is to be modified. The resultant preferred amino acids have a side chain which contains either a modified guanidino group or a guanidino equivalent or a derivative that is obtained by further elucidation of a modified guanidino group, as set forth hereinafter, and most preferably it contains a triazole moiety.
In another particular aspect, the invention provides peptides which inhibit the release of gonadotropins in mammalians, including humans, and it also provides methods for inhibiting the release of steroids by the gonads of male and female mammalians. The invention also provides improved GnRH analogs which are strong agonists of GnRH and can be used to promote the reproduction processes of mammalians. As mentioned above, these GnRH antagonists may be used to inhibit the production of gonadotropins and sex hormones under various circumstances, including precocious puberty, hormone dependent neoplasia, dysmenorrhea, endometriosis and steroid-dependent tumors.
The invention provides unnatural amino acids having the following formula U*:
where W is (CH
2
)
n
or
n is an integer from 1 to 6 and is preferably 1,2,3 or 4; j is 1,2 or 3; Y=N—CN, N—CONHR
9
, O, S or CH—NO
2
, where R
9
is H, Ac, alkyl (preferably C
1
to C
4
), naphthyl, pyridyl, pyrimidyl, pyrazinyl, indolyl, quinolinyl or imidazolyl, which alkyl and cyclic groups are unsubstituted or substituted (preferably by chloro, fluoro, bromo, amino, nitro, alkyl (C
1
to C
4
) and alkoxy (C
1
to C
4
)); X═NH, O, N
3
, M
1
—(CH
q
)
p
—M
2
or M
1
—(CH
2
)
p′
—M
2
(CH
2
)
p″
—M
3
, where M
1
is NR
10
, N, O or CHR
3
wherein R
3
is methyl, ethyl, propyl, phenyl, pyridinyl, pyrimidinyl or purinyl; q=1 or 2; p, p′ and p″ are integers between 0 and 6; R
10
is H, methyl, ethyl, propyl, phenyl or substituted phenyl (preferably by Cl, F, NO
2
or NH
2
); and M
2
and M
3
═M
1
, COOH, CONH
2
, COOR
3
or CN (preferably X is NH or O); R
1
═H, alkyl (preferably C
1
to C
6
and most preferably C
1
to C
4
), modified alkyl (preferably C
1
to C
5
, the terminal carbon of which is either substituted with NH
2
, OH, Cl, Br or F or is replaced with CF
3
or CF
2
CF
3
), alkenyl (preferably C
2
to C
4
), such as CH
2
CH═CHR
3
, alkynyl (preferably C
2
to C
4
), such as CH
2
C≡CR
3
, aryl such as benzyl, tolyl, p-amino-benzyl (anilinyl) and pCl-benzyl or a direct bond to X; R
2
═R
1
, OH, NH
2
, NHR
1
, heterocycle (preferably as illustrated hereinafter) or desR
2
, with R
2
being desR
2
when X═N
3
. Optionally R
2
and X can be interconnected, or R
1
and R
2
can be connected to each other via a branched or unbranched methylene bridge of type —(CH
2
)
m
— or —(CH
2
)
m
—M—(CH
2
)
m′
—. In suc

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