Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1996-07-22
2001-02-06
Cintins, Marianne M. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S018700, C530S330000
Reexamination Certificate
active
06184208
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a biologically active peptide; a novel pharmaceutical composition containing the peptide; a method for preparing the peptide; and, uses of the peptide.
BACKGROUND OF THE INVENTION
Hormones are known to control the metabolic processes both in growing and mature organisms. Peptides often act as hormones. They are not only hormonally active themselves but regulate the action of other hormones, which control the vital activity of the organism. However, the potential of such natural compounds is limited. Therefore, many scientific laboratories have tried to develop methods for preparing synthetic derivatives of natural peptides, which are more active than their natural analogues (EP 0136720, 1984; EP 0137904, 1984). Moreover, new peptides have been synthesized, which are absent in the organism but have unique properties. Among them there is a special group of physiologically active peptides directly or indirectly controlling the action of hormones such as the growth hormone. Some of these active peptides increase the growth hormone level in blood (PCT 89/07111, 1989; PCT 91/16923, 1991) while others suppress the hormone (FR 2235701, 1978; FR 2532308, 1982).
A peptide which activates the growth of the epidermal layer in man (PCT 90/13570, 1990), and a metal-containing peptide, which has a significant stimulating effect on hair growth in warm-blooded animals (PCT 91/07431, 1991) have been synthesized. Another peptide analogue has been reported to facilitate hair removal in animals (FR 2487677, 1982).
Different peptide compositions evidently make it possible to control metabolic processes. The most promising task is, however, the development of compounds and preparations with many-sided actions.
At present, there are only a few peptides with comprehensive actions, for instance, the analogue of the P substance described in U.S. Pat. No. 4,680,283. The peptide synthesized as described in the patent has a range of useful properties. Its acts as a biostimulator, and has an analgesic effect similar to that of morphine.
Many studies have shown the importance of synthesizing peptides with opiate-like properties. Unfortunately, the production of morphine-like compounds from natural sources is limited by the complexity of the manufacturing processes (U.S. Pat. No. 4,042,682, 1977). This circumstance resulted in the creation of an arsenal of synthetic analogues (U.S. Pat. No. 4,681,871, 1987; EP 0112036, 1983; EP 0221019, 1986).
Some opiate-like peptides have become known and clinically used in the treatment of brain ischemia (DE 3447720, 1985; U.S. Pat. No. 4,684,624, 1987), for pain relief in pregnant women (EP 0099173, 1984), and only as analgesics. They are reported to be especially effective when used in combination with conventional drug therapy in many diseases (EP 096592, 1983; EP 0099286, 1984; U.S. Pat. No. 4,123,523, 1987).
However, the known synthetic peptides cannot completely satisfy all medical requirements, since they do not have the necessary combination of properties, which would increase their effectiveness. Furthermore, many of them are effective only in large doses that can cause side effects.
SUMMARY OF THE INVENTION
The present inventor has identified a peptide which has a wide range of biological action. In particular, the peptide has been found to influence physiological processes such as weight gain, activities of the epithelium growth zone including hair growth, wound healing, and to stimulate reparative and anabolic processes, and exert analgesic effects. The peptide is particularly useful in applications of veterinary medicine.
Broadly stated the present invention relates to a peptide of the formula I
X-Tyr-Y-Phe-Z-A I
wherein X is hydrogen, arginine, D-arginine, ornithine, D-ornithine, lysine, D-lysine, homoarginine, D-homoarginine, citrulline, D-citrulline; Tyr is tyrosine; Y is D-alanine, D-valine, D-leucine, D-isoleucine, D-phenylalanine, D-asparagine, D-tryptophan, D-proline, D-serine, D-threonine, D-tyrosine, D-hydroxyproline, D-cysteine, D-cysteyl-cysteine, D-methionine, D-lysine, D-homoarginine, D-arginine, D-histidine, D-aspartic acid, D-glutamic acid, D-&bgr;-alanine, or D-ornithine; Phe is phenylalanine; Z is alanine, D-alanine, valine, D-valine, leucine, D-leucine, isoleucine, D-isoleucine, phenylalanine, D-phenylalanine, asparagine, D-asparagine, glycine, glutamine, D-glutamine, tryptophan, D-tryptophan, proline, D-proline, serine, D-serine, threonine, D-threonine, tyrosine, D-tyrosine, hydroxyproline, D-hydroxyproline, cysteine, D-cysteine, cysteyl-cysteine, cysteine-D-cysteine, D-cysteine-cysteine, D-cysteine-D-cysteine, methionine, D-methionine, lysine, D-lysine, arginine, D-arginine, histidine, D-histidine, aspartic acid, D-aspartic acid, glutamic acid, D-glutamic acid, &bgr;-alanine, D-&bgr;-alanine, ornithine, or D-ornithine; and A is hydroxyl or an amide which may be substituted.
In an embodiment of the invention a peptide of the formula I is provided, wherein X is Arg, D-Arg, D-Orn, homoarginine, D-homoarginine, or citrulline; Y is D-Orn, D-Ala, or D-Arg; Z is D-Ala, Gly, Pro, D-Pro or &bgr;-Ala; and A is OH or NH
2
. Preferred peptides of the present invention comprise peptides of the formula I wherein X is Arg, homoarginine, D-homoarginine, citrulline, or D-citrulline; Y is D-Ala, D-Orn, or D-Arg; Z is D-Ala; and A is OH or NH
2
. In another preferred embodiment, X is Arg; Y is D-Ala; Z is D-Pro, Pro, or &bgr;-Ala; and, A is OH.
Preferred peptides of the present invention include H-D-Arg-Tyr-D-Arg-Phe-D-Ala-NH
2
, H-D-Orn-Tyr-D-Ala-Phe-D-Ala-OH, H-Arg-Tyr-D-Ala-Phe-&bgr;-Ala-OH, H-Arg-Tyr-D-Ala-Phe-Gly-OH; H-Har-Tyr-D-Arg-Phe-D-Ala-NH
2
; H-D-Har-Tyr-D-Arg-Phe-D-Ala-NH
2
; H-Cyt-Tyr-D-Arg-Phe-D-Ala-NH
2
; H-D-Cyt-Tyr-D-Arg-Phe-D-Ala-NH
2
; H-Arg-Tyr-D-Ala-Phe-Pro-OH; H-Arg-Tyr-D-Ala-Phe-D-Pro-OH; H-Arg-Tyr-D-Ala-Phe-D-Ala-OH; H-Arg-Tyr-D-Orn-Phe-D-Ala-OH; H-Arg-Tyr-D-Arg-Phe-D-Ala-OH; H-Arg-Tyr-D-Arg-Phe-D-Ala-NH
2
; and H-Tyr-D-Orn-Phe-D-Glu-OH.
The invention also relates to analogs of the peptides of the invention and cyclized peptides. The term “peptide” or “peptides” used herein includes these analogs and cyclized peptides.
The invention also relates to a pharmaceutical composition comprising one or more peptides of the invention and a pharmaceutically acceptable carrier.
The invention still further relates to the use of a peptide of the Formula I to modulate physiological processes in a subject such as weight gain, activities of the epithelium growth zone including hair growth, wound healing, and to stimulate reparative and anabolic processes, and exert analgesic effects.
Further, the invention relates to a method of modulating physiological processes in a subject such as weight gain, activities of the epithelium growth zone including hair growth, and wound healing. The invention also relates to a method of stimulating reparative and anabolic processes, and exerting analgesic effects.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
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patent: 4042682 (1977-08-01), Spector
patent: 4123523 (1978-10-01), Dutta et al.
patent: 4490365 (1984-12-01), Panaretto et al.
patent: 4496543 (1985-01-01), Bauer et al.
patent: 4680283 (1987-07-01), Veber et al.
patent: 4681871 (1987-07-01), Teschemacher et al.
patent: 4684624 (1987-08-01), Hosobuchi et al.
patent: 5312899 (1994-05-01), Schiller
patent: 5486505 (1996-01-01), Bowers et al.
patent: 5602100 (1997-02-01), Brown et al.
patent: 0 096 592 (1983-12-01), None
patent: 0 099 173 (1984-01-01), None
patent: 0 099 286 (1984-01-01), None
patent: 0 112 036 (1984-06-0
Deigin Vladislav I.
Yarova Yelena
Cintins Marianne M.
Delacroix-Muirheid C.
Immunotech Developments Inc.
Merchant & Gould P.C.
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