Pentapeptide LHRH antagonists

Details Pentapeptide LHRH antagonists Pentapeptide LHRH antagonists

1999-08-12

2001-10-02

Moezie, F. T. (Department: 1654)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Lutenizing hormone releasing factor ; related peptides

C530S330000, C530S333000, C530S338000, C530S339000, C530S344000, C530S345000, C514S017400, C514S908000

Reexamination Certificate

active

06297354

ABSTRACT:

TECHNICAL FIELD OF INVENTION
The present invention relates to novel analogs of LHRH. The novel analogs provide pentapeptides truncated from both the N-terminus and the C-terminus of LHRH antagonist peptides. The invention also relates to processes for preparing the disclosed compounds, pharmaceutical compounds containing such compounds, and use of such compounds for modulating levels of sex hormones in male or female mammals.
BACKGROUND OF THE INVENTION
Luteinizing hormone releasing hormone (LHRH) is released from the hypothalamus and binds to a receptor on the pituitary gland causing the release of gonadotropin hormones. The gonadotropin hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), secreted from the anterior pituitary gland, regulate the fundamental reproductive processes, such as ovarian release and gamete maturation. These hormones play a major role in regulating the synthesis of the steroidal reproductive hormones from the gonads, ie. estrogen and progesterone in females and testosterone in males.
The ongoing system of feedback between hypothalamus, the anterior pituitary gland, and the gonads modulates the fundamental processes related to the reproductive cycle. The feedback process, described by A. V. Schally et al.,
Fertility and Sterility
, 22:11 (1971), provides a web of complex relationships related to reproductive function. Pulsatile release of the gonadotropin hormones controls levels of steroidal hormone circulating in the mammalian reproductive cycle. Manipulation of the release of these hormones provides an avenue for the design of novel compounds useful in treating various conditions related to dysfunction of the reproductive cycle and hormone dependent diseases. Several agonists of natural LHRH have been shown to be clinically useful.
Natural mammalian releasing hormone LHRH isolated and purified from porcine and human hypothalami has been characterized as having the sequence:
 (Pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
  SEQ ID NO:1
as described in A. V. Schally,
Science
, 202:6 (1978). Substitutions and derivatizations of amino acyl residues have been developed to achieve novel compounds useful in treating various disorders related to mammalian reproductive systems.
Synthetic analogs of LHRH have been described in a number of U.S. patents for exhibiting activity as LHRH agonists or as antagonists of LHRH. For the most part; these compounds contain nine or ten amino acyl residues, substituting naturally-occurring or non-naturally occurring amino acid residues at one or more positions in the natural sequence of LHRH. U.S. Pat. No. 5,110,904 describes nonapeptide and decapeptide LHRH antagonists wherein the nitrogen atom of at least one of the amide bonds has been alkylated. The decapeptide and undecapeptide analogs described in U.S. Pat. No. 5,502,035 have an acyl-substituted N-terminal nitrogen atom.
Truncated peptide compounds have been developed as a series of smaller peptide analogs also exhibiting biological activity and having the added advantage of possibly improved oral bioavailability. These reduced-size peptides, described in U.S. Pat. No. 5,140,009, exhibit effective LHRH agonist or antagonist activity. They are “pseudo” hexapeptide, heptapeptide, octapeptide and nonapeptide analogs of LHRH, which have the 1 to 3 amino acids eliminated from the N-terminus of a decapeptide sequence to achieve activity as LHRH antagonists. Copending U.S. application Ser. No. 09/133,055, now abandoned, and U.S. application Ser. No. 09/232,425, filed Jan. 15, 1999, disclose and describe a class of heptapeptide LHRH analogs wherein the 10 to 8 amino acids are eliminated from the C-terminus of a decapeptide LHRH antagonist.
The development of synthetic LHRH antagonists truncated from the C- and N-termini having biological activity provides novel compounds for treatment of hormone dependent diseases in male and female mammals. Smaller synthetic peptides provide significant advantages when compared to decapeptide LHRH analogs. These LHRH antagonists are useful in the treatment of a variety of conditions in which the suppression of sex steroids plays a major therapeutic role that includes delay of puberty, treatment of benign prostatic hyperplasia, palliative treatment or remission of hormonal-dependent tumors of breast and ovaries, palliative treatment or remission of hormonal-dependent tumors of the prostate, the treatment of cryptorchidism, hirsutism in women, gastric motility disorders, dysmenorrhea and endometriosis.
SUMMARY OF THE INVENTION
Compounds of the invention are peptides have the 1 to 3 amino acids eliminated from the N-terminus and the 10 to 8 amino acids eliminated from the C-terminus. The present invention provides a novel LHRH analog having a formula:
as defined herein as well as the preferred and representative compounds described. The compounds provide LHRH analogs having a molecular weight suitable for possible improved oral bioavailability for treatment of disorders related to abnormal levels of reproductive hormones. The compounds of the invention relate to LHRH analogs wherein two amino acids from the N-terminus and three amino acids from the C-terminus of a decapeptide sequence has been eliminated to provide a pentapeptide having LHRH antagonist activity.
Another aspect of the invention relates to pharmaceutical formulations comprising the compounds of the invention or pharmaceutically acceptable salts, esters, or prodrugs thereof.
In another aspect, the invention relates to a method of modulating gonadotropin hormones in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as defined above.
Yet another aspect of the invention relates to a process for preparing compounds of the invention or pharmaceutically acceptable salts, esters, or prodrugs thereof.
DETAILED DESCRIPTION OF THE INVENTION
The invention comprises a compound of the formula:
or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:
R is of the formula wherein X is hydrogen, lower alkyl, alkoxy, or a halide selected
 from the group consisting of bromide, chloride, fluoride, and iodide; Y is hydrogen or loweralkyl; and n is 1-3.
A is an amino acid residue selected from 3-(1-naphthyl)-D-alanyl, 3-(1-naphthyl)-L-alanyl, D-tryptyl, D-3-(4,4′-biphenyl)alanyl, D-(benzthienyl)alanyl, and glycyl.
B is seryl or glycyl.
C is an amino acid residue selected from (N-epsilon-nicotinyl)lysyl, N-methylphenylalanyl, (4-N-nitro)-N-methylphenylalanyl, [4-(3-amino-1,2,4-triazol-5-yl)]phenylalanyl, [4-(3-amino-1,2,4-triazol-5-yl)]-N-methylphenylalanyl, (4-N-acetyl)-N-methylphenylalanyl, (4-N-acetyl)N-phenylalanyl, 1,2,3,4-tetrahydroisoquinoline-7-hydroxy-3-carbonyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, arginyl, sarcosyl, tyrosyl, and N-methyltyrosyl; or where B and C taken together form an amino acid derivative having the formula:
D is an amino acid residue selected from D-arginyl, D-citrullyl, glycyl, D-homocitrullyl, D-diethyl-homoarginyl, D-(N-epsilon-nicotinyl)lysyl, N-methylphenyl-alanyl, phenylalanyl, D-phenylalanyl, D-tryptyl, D-[4-(3-amino-1,2,4-triazol-5-yl)]-phenylalanyl, and D-(4-N-acetyl)-phenylalanyl.
E is an amino acid residue selected from cyclohexylalanyl, glycyl, leucyl, and N-methylleucyl; or where D and E taken together form an amino acid derivative having the formula:
R
1
is selected from the group consisting of—NH(CH
2
)—R
2
, —NR
3
—(CH
2
)
m
—NHR
4
, —NH—(CH
2
)
n
—NR
5
R
6
, and —NH—(CH
2
)
p
—NH—C(═NH)—NH
2
; wherein: l is 0-10, m is 1-2, n is 1-10,p is 1-10; R
2
is hydrogen, hydroxy, amino, amido, methyl, or phenyl; R
3
is hydrogen, methyl, or ethyl; R
4
is hydrogen, methyl, amino or amido; and R
5
and R
6
taken together with the nitrogen atom to which each is attached form an aromatic or non-aromatic ring, having at least one nitrogen atom, and selected from the group consisting of morpholinyl, piperidinyl, pyridyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinonyl, and quinucli

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