Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-05-04
2001-10-16
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C260S66500B, C260S66500B
Reexamination Certificate
active
06303577
ABSTRACT:
This application is based on European Patent Application No. 98830310.3 filed on May 21, 1998, the content of which is incorporated hereinto by reference.
This invention relates to the use of a peptide compound for preparing a pharmaceutical composition useful in the treatment of Systemic Lupus Erythematosus as well as a method of treating a patient suffering from Systemic Lupus Erythematosus.
EP-A-752 425 discloses a peptide compound of formula
(H
2
N—X
1
-Thr-X
2
—CO)
n
—R (I)
wherein
X
1
and X
2
, different one another, are an amino acid residue of arginina or tyrosine in configuration L or D, wherein the hydroxy group of threonine and tyrosine and the guanidine moiety of arginine may be protected by a compound conventionally used in peptide chemistry for protecting the hydroxy group and the guanidine moiety, respectively,
n is 1, 2, 3 or 4, and
R, when n is 2, 3 or 4 is a group suitable for forming a dimer, trimer or tetramer, while, when n is 1, R is OH, a single amino acid residue, or a peptide chain comprising up to 7 amino acid residues, useful as a ligand of immunoglobulins.
PCT/EP97/07143 discloses a pharmaceutical composition containing a biologically effective amount of a peptide compound of formula
(H
2
N—X
1
-Thr-X
2
—CO)
n
—R (I)
wherein
X
1
and X
2
have the above mentioned meanings,
n is 2, 3 or 4,
R is a group capable to form a dimeric, trimeric, and respectively tetrameric peptide, and at least a pharmaceutically acceptable inert ingredient.
These compounds proved to be particularly useful in vivo in the treatment of allergic reactions.
The content of EP-A-752 425 and PCT/EP97/07143 is incorporated herein by reference.
Systemic Lupus Erythematosus (SLE) is a chronic, remitting and relapsing, multisystem autoimmune disease that affects predominantly women, with an incidence 1:700 in women between 20 and 60 years old, while the female:male ratio is 10:1.
The main clinical syndrome comprises skin rashes, arthritis, and glomerulonephritis. Hemolytic anemia, thrombocytopenia, and central nervous system involvement are also common.
Many different antibodies are found in patients with SLE. The most frequent are antinuclear, particularly anti-DNA antibodies and anti-ribonucleoproteins, -histones, -nucleolar antigens, -erythrocytes, -platelets antibodies.
So far, Systemic Lupus Erythematosus has been treated with aspirin and other anti-inflammatory drugs, or with antimalarial drugs.
Further, severe disease with vasculitis involvement of nervous system and renal damage, requires immediate corticosteroid therapy in combination with immunosuppressives as methotrexate and cyclosporine.
These drugs, however, may cause serious side effects. The most common side effects of aspirin are liver damages, while antimalarial drugs cause nausea and vomiting. Common side effects of the cortisone-like drugs include weight gain, insomnia and depression, while administration of corticosteroids over a long period of time may lead to osteoporosis and cataracts.
Furthermore, the immunosuppressive drugs can interfere with the formation of blood cells, increase the development of infections, and cause severe renal damages.
Now it has been found that the peptide compound of formula
(H
2
N—X
1
-Thr-X
2
—CO)
n
—R (I)
where X
1
, X
2
, R and n have the meanings given herein below, is useful in the treatment of Systemic Lupus Erythematosus.
Therefore, in a first aspect this invention relates to the use of a peptide compound of formula
(H
2
N—X
1
-Thr-X
2
—CO)
n
—R (I)
where
X
1
and X
2
different one another, are an amino acid residue of tyrosine and arginine, in L or D configuration, wherein the hydroxy group of threonine and the guanidine moiety of arginine may be protected by a compound conventionally used in peptide chemistry for protecting the hydroxy group and the guanidine moiety, respectively,
n is 2, 3, or 4, and
R is a group able to form a dimeric, trimeric, and respectively tetrameric peptide, for preparing a pharmaceutical composition useful in the treatment of Systemic Lupus Erythematosus.
In a second aspect this invention relates to a method of treating a patient suffering from Systemic Lupus Erythematosus, said method comprising administering to a patient in need thereof an effective amount of a peptide compound of formula
(H
2
N—X
1
-Thr-X
2
—CO)
n
—R (I)
where X
1
, X
2
, R and n have the meanings given above in connection with the first aspect of this invention.
Preferably n is 4.
Each amino acid of the compound of formula (I) can have L or D configuration.
In the present description and in the claims, the terms “dimer” “trimer” and “tetramer” intend to mean peptides comprising two, three and respectively four sequences H
2
N—X
1
-Thr-X
2
—CO— where X
1
and X
2
have the above mentioned meaning.
A typical example of a suitable group for forming a dimer (n=2) is a lysine residue. A typical example of a suitable group for forming a trimer (n=3) is a dipeptide lysil-lysine of formula Lys-Lys. Typical examples of suitable groups for forming a tetramer (n=4) are a branched tripeptide of formula Lys-Lys(&egr;Lys) and a branched tetrapeptide of formula Gly-Lys-Lys(&egr;Lys).
A typical example of a tetramer of formula (I) has the following formula
(H
2
N—X
1
-Thr-X
2
—CO)
4
-(Lys)
2
-Lys-Gly-OH (IA)
where
X
1
and X
2
have the above mentioned meanings, and wherein the hydroxy group of threonine and tyrosine and the guanidine moiety of arginine may be protected by a compound conventionally used in peptide chemistry for protecting the hydroxy group and the guanidine moiety, respectively.
Many groups useful for protecting the hydroxy group are reported in the literature (Grant G. A. “Synthetic peptides: a user's guide”, Freeman, N.Y., 1992).
Typical examples of said protecting groups are the ter-butyl (tBu) (La Joie, G. Crivici, A., Adamson, J. G. et al., “Synthesis”, 571-572, 1990) and the benzyl group (Yojima. “Tetrahedron”, 44, 805-819, 1988).
Many groups useful for protecting the guanidine moiety of arginine are also known from the literature (Grant G. A. “Synthetic peptides: a user's guide”, Freeman, N.Y., 1992).
Typical examples of said protecting groups are: 2,2,5,7,8-pen-tamethylcroman-6-sulphonyl(Pmc) and 4-methoxy-2,3,6-trimethylbenzene (Mtr) (Ramage & Green, “Tetrahedron Letters”, 28, 2287, 1987); Fujino et al. “Chem. Pharm. Bull.”, 29, 2825, 1981).
Specific examples of compound of formula (I) are
(H
2
N-L-Arg(Pmc)-L-Thr(OtBu)-L-Tyr(OtBu)-CO)
4
-(Lys)
2
-Lys-Gly-OH (P-PAM)
(H
2
N-L-Arg-L-Thr-L-Tyr-CO)
4
-(Lys)
2
-Lys-Gly-OH (L-PAM)
(H
2
N-D-Arg-D-Thr-D-Tyr-CO)
4
-(Lys)
2
-Lys-Gly-OH (D-PAM)
As shown in more details in the following examples, the peptide compounds of formula (I) proved to be active in an in vivo test on mice developing Systemic Lupus Erythematosus. More particularly, they proved to decrease the death rate of treated animals, and to reduce the damage on the kidneys caused by the disease.
Additionally, the peptide compounds of formula (I), proved to be well tolerated and devoid of immunogenic properties in mouse acute toxicity tests, either by oral or by intravenous administration.
Preferably, the pharmaceutical compositions according to this invention are prepared in a suitable dosage form comprising an effective dose of at least one peptide compound of formula (I) and at least one pharmaceutically acceptable inert ingredient.
Example of suitable dosage forms are pills, capsules, cover pills, granules, solutions and syrups for oral administration, unguents and plasters for topic administration; suppositories for rectal administration and sterile solutions for injectable, inhalation and ophthalmic administration.
The dosage forms may also contain other conventional ingredients like preservatives, stabilizers, surface-active agents, buffers, salts to regulate osmotic pressure, emulsifying agents, sweeteners, dyes, flavours and the like.
When required by particular therapies, the pharmaceutical composition of this invention may cont
Fassina Giorgio
Marino Maria
Rossi Maria
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Ozga Brett
Tecnogen S.c.P.A.
Witz Jean C.
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