Peptide derivatives

Details Peptide derivatives Peptide derivatives

1998-04-28

2001-05-08

Borin, Michael (Department: 1631)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S330000

Reexamination Certificate

active

06228841

ABSTRACT:

TECHNICAL FIELD
The present invention relates to peptide derivatives exhibiting pharmaceutical activities such as analgesic activity through action on opioid receptors and the like.
BACKGROUND ART
The existence of opioid receptors to which opioids such as morphine bind was verified in the early 1970's. At present, opioid receptors are mainly classified into three types, i.e., &mgr;, &dgr; and &kgr;. Morphine mostly acts on the &mgr; acceptor as an agonist and exhibits pharmaceutical activities such as analgesic activity, enterokinetic inhibition, and respiratory inhibition.
Since 1975, several endogenous morphine-like substances that bind to the opioid receptors have been successively discovered. All of these substances found to date are peptide compounds and are collectively referred to as opioid peptides. The pharmaceutical activities of the opioid peptides are believed to be basically the same as those of morphine. They are expected to be potentially safer drugs than morphine since they are substances naturally exist in living bodies. However, natural opioid peptides have problems from the pharmacokinetical standpoint, and they have not been used as clinical medicaments.
In the 1980's, Delmorphine that contains D-alanine was isolated from cutises of frogs. It was found that Delmorfine has about 1000-fold higher analgesic effect than morphine at intraventricular administration and is relatively stable in living bodies. Since then, synthetic opioid peptides containing D-amino acids have been prepared. In particular, synthetic opioid peptides with high &kgr; acceptor selectivity are considered as hopeful non-narcotic analgesics and clinical trials have begun. However, the probability of their success as clinical medicaments is doubtful from the viewpoints of efficacy, possible side effects probably due to properties as &kgr; agonists, and commercial practicability.
Furthermore, it is impossible to use these synthesized opioid peptides as orally available medicaments, and accordingly, they can not be substitutive drugs for MS contin, e.g., which is an orally available controlled release preparation comprising morphine sulfate that has been widely used recently as a medicament for treatment of cancerous pain. However, daily dose of MS contin may occasionally be increased up to gram order, which sometimes leads to difficulty in oral administration. In some cases, its administration cannot be continued because of side effects such as pruritus due to its activity on the release of histamine. Therefore, substitutive medicaments are desired which have higher safety and efficacy than morphine.
DISCLOSURE OF THE INVENTION
In order to achieve the aforementioned objects, the inventors of the present invention conducted various studies aimed at providing opioid peptide derivatives having excellent analgesic activity and oral absorbability. As a result, they found that oligopeptide derivatives and their salts having a basic structure of L-Tyr-(L or D)-Arg-Phe and an amidino group at the N-terminal have the desired properties, and filed patent applications pertaining to these peptide derivatives (Japanese Patent Applications Nos. (Hei) 6-40989/1994 and (Hei) 7-49894/1995). The inventors conducted further studies and found that the aforementioned peptide derivatives modified at the amidino group at the N-terminal have the desired properties. The present invention was achieved on the basis of these findings.
That is, the peptide derivatives of the present invention are represented by the following Formula I:
Y-L-Tyr-Q-NR
1
—CH(CH
2
C
6
H
5
)—CO—X.
According to the present invention, a medicament consisting of said compound or a salt thereof, and a analgesic pharmaceutical composition comprising said compound or a salt thereof as an active ingredient are provided. Use of said compound or a salt thereof for manufacture of the aforementioned pharmaceutical composition; and method for preventive and/or therapeutic treatment of pain comprising a step of administering to an mammal an effective amount of said compound or a salt thereof are also provided according to the present invention.
BEST MODE FOR CARRYING OUT THE INVENTION
As for the substituents in the above formula, Q represents D-Arg (D-arginine residue) or L-Arg (L-arginine residue), and R
1
represents hydrogen atom or a C
1-6
(having 1-6 carbon atoms) alkyl group. Among them, those compounds where Q is D-Arg and R
1
is hydrogen atom are preferred. The term C
1-6
alkyl referred to in the present specification is used to embrace a linear alkyl group, a branched alkyl group, a cyclic alkyl group, and a linear or branched alkyl group substituted with a cyclic alkyl group. As the C
1-6
alkyl group, for example, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, sec-butyl group, tert-butyl group, cyclopropylmethyl group, cyclobutyl group and the like may preferably be used.
R
2
represents a benzyl group which may optionally be substituted. When the benzyl group is substituted, it may have one or more substituents at any substitutable positions. When it has two or more substituents, they may be the same or different. As substituents on the phenyl ring, for example, a C
1-6
alkyl group, an amino group which may optionally be substituted, a guanidino group which may optionally be substituted, hydroxyl group and the like may be used. Among them, unsubstituted benzyl group is preferred.
Y represents two hydrogen atoms of N-terminal amino group of L-Tyr, or one or two functional groups substituting for one or two of the hydrogen atoms. The functional group is selected from the group consisting of: a C
1-6
alkyl group which may have an amino group, a C
1-6
alkyl group which may have a carboxyl group, a C
1-6
alkylcarbonyl group which may have an amino group, a sulfonyl group which may have an alkyl group, a pyrimidyl group which may optionally be substituted, an imidazolinyl group which may optionally be substituted, and a group represented by the following formula: HN═C(R
3
)— (wherein R
3
represents hydrogen atom, a C
1-6
alkyl group, a phenyl group which may optionally be substituted, a hydroxyamino group which may optionally be substituted, or a hydrazino group which may optionally be substituted). When the two hydrogen atoms are replaced by the above functional groups, each of the functional groups is independently selected from the above group, and may be the same or different to each other.
Methyl group, ethyl group, isopropyl group, cyclopropylmethyl group and the like are preferred as the C
1-6
alkyl group represented by Y. When the C
1-6
alkyl group represented by Y has amino group or carboxyl group, examples include the groups of H
2
N—CH
2
—, H
2
N—(CH
2
)
2
—, HOOC—CH
2
—, HOOC—(CH
2
)
2
— and the like. When the C
1-6
alkylcarbonyl group has amino group, examples include H
2
N— CH
2
—CO—, H
2
N—(CH
2
)
2
—CO—and the like. An example of a sulfonyl group having a C
1-6
alkyl group is, for example, the group of CH
3
SO
2
—.
2-Pyrimidyl group and 2-imidazolin-2-yl group and the like can be preferably used as the pyrimidyl group and the imidazolinyl group represented by Y, respectively. The pyrimidyl group and the imidazolinyl group may be either substituted or unsubstituted. When the pyrimidyl group or the imidazolinyl group is substituted, a C
1-6
alkyl group and the like may be used as the substituent, and when these groups have two or more substituents, they may be the same or different. An example of the substituted pyrimidyl group includes 4,6-dimethyl-2-pyrimidyl group, and an example of the substituted imidazolinyl group includes 4-methyl-2-imidazolin-2-yl group.
R
3
represents hydrogen atom, a C
1-6
alkyl group, a phenyl group which may optionally be substituted, a hydroxyamino group which may optionally be substituted, or a hydrazino group which may optionally be substituted. Methyl group, ethyl group, n-propyl group and the like are preferred as the C
1-6
alkyl group represented by R
3
, and methyl group is particularly preferred. As for the phenyl group,

Affiliated with

Also associated with

Rating

Peptide derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Peptide derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Peptide derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2490830