Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-01-15
2001-02-20
Moezie, F. T. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S329000, C530S313000
Reexamination Certificate
active
06191115
ABSTRACT:
TECHNICAL FIELD OF INVENTION
The present invention relates to novel analogs of LHRH. The novel analogs provide heptapeptides truncated from 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 anterior 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 fundamental reproductive processes, such as ovarian release and gamete maturation. These 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 functions. 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 agents 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
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 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 1 to 3 amino acids eliminated from the N-terminus of a decapeptide antagonist sequence to achieve activity as LHRH antagonists. Distinctively, the peptides described in this invention have the 10 to 8 amino acids eliminated from the C-terminus. Copending U.S. application Ser. No. 09/373,180 discloses and claims a class of pentapeptide LHRH analogs wherein the 1 to 3 amino acids are eliminated from the N-terminus and the 10 to 8 amino acids from the C-terminus of a decapeptide LHRH antagonist.
The development of synthetic LHRH antagonists truncated from the C-terminus having biological activity provides novel compounds for treatment of hormone dependent diseases in male and female mammals. Smaller synthetic peptide sequences provide significant advantages when compared to decapeptide LHRH analogs. These LHRH antagonists are useful in the treatment of a variety of clinical condition in which the suppression of sex steroids plays a major therapeutic role, including 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
The compounds of the invention comprise a peptide of the formula:
or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:
R
1
is of the formula R
3
(C═O)—, wherein R
3
is lower alkyl;
A is an amino acyl residue selected from the group consisting of:
3-(2-naphthyl)-D-alanyl;
[3-(4-chloro)]-D-phenylalanyl; and
sarcosyl;
B is an amino acyl residue selected from the group consisting of:
3-(1-naphthyl)-D-alanyl; and
[3-(4-chloro)]-D-phenylalanyl;
C is an amino acyl residue selected from the group consisting of:
3-(3-pyridyl)-D-alanyl; and
3-(1-naphthyl)-D-alanyl;
D is seryl;
E is an acyl group selected from the group consisting of:
arginyl;
(N-epsilon-nicotinyl)lysyl;
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-nitro)]-N-methylphenylalanyl;
[4-(N-acetyl)]-phenylalanyl;
tyrosyl;
N-methyltyrosyl; and
1,2,3,4-tetrahydroisoquinoline-3-carbonyl;
F is an amino acyl residue selected from the group consisting of:
D-arginyl;
D-asparaginyl;
D-citrullyl;
D-glutamyl;
D-homocitrullyl;
D-2-amino-6-N
G
,N
G
-diethylguanidinohexanoyl;
(N-epsilon-nicotinyl)-D-lysyl;
[4-(3-amino-1,2,4-triazol-5-yl)]-D-phenylalanyl;
[4-(N-acetyl)]-D-phenylalanyl; and
D-tryptyl;
G is an amino acyl residue selected from the group consisting of:
cyclohexylalanyl;
leucyl; and
N-methylleucyl; and
R
2
is of the formula —NR
4
R
5
; wherein
R
4
is selected from the group consisting of:
hydrogen;
methyl; and
ethyl;
R
5
is selected from the group consisting of:
lower alkyl; and
lower alkyl-R
6
; and
R
6
is selected from the group consisting of amino, guanidino, hydrogen, hydroxy, phenyl, morpholinyl, piperidinyl, pyrrolyl, pyridyl, pyrrolidinyl, pyrrolidinonyl, and quinuclidinyl; and wherein the piperidinyl, pyrrolyl, pyrrolidinyl, and pyrrolidinonyl groups are optionally substituted with a methyl group.
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 relates to novel LHRH analogs of seven amino acyl residues represented by the formula (I), wherein A, B, C, D, E, F, and G represent amino acyl residues as described above. A lower alkyl group of one to ten carbons, represented by R
1
, attaches via a carbonyl moiety to the N-terminal nitrogen atom of the representative amino acyl residue A. An N-alkylated nitrogen atom forms an amide bond with the C-terminal carbon atom of the representative amino acyl residue G.
Compounds of the invention provide LHRH analogs wherein the 10 to 8 amino acids from the C-terminus carboxylic acid moiety of a decapeptide LHRH antagonist sequence is eliminated. The compounds exhibit effective LHRH antagonist activity and are useful in treating disorders related to high levels of reproductive hormones. The lower molecular weight of the present compounds all
Dwight Wesley J.
Greer Jonathan
Haviv Fortuna
Nichols Charles J.
Abbott Laboratories
Moezie F. T.
Sickert Dugal S.
LandOfFree
C-terminus modified heptapeptide LHRH analogs does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with C-terminus modified heptapeptide LHRH analogs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and C-terminus modified heptapeptide LHRH analogs will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2586226