Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Chemical modification or the reaction product thereof – e.g.,...
Reexamination Certificate
1996-08-16
2001-06-12
Borin, M. (Department: 1631)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Chemical modification or the reaction product thereof, e.g.,...
C530S351000, C530S345000, C424S085100
Reexamination Certificate
active
06245900
ABSTRACT:
INDUSTRIAL FIELD OF THE INVENTION
The invention relates to a chemically modified human granulocyte colony stimulating factor polypeptide which is produced by chemically modifying at least one of the amino, carboxyl, mercapto or guanidino group in a polypeptide molecule having human granulocyte colony stimulating factor (hereinafter referred to as hG-CSF) activity, and a platelet production promoting agent comprising said polypeptide, a method for treating a patient with decreased platelet counts comprising administering an effective amount of said polypeptide to the patient, the use of said polypeptide for the production of pharmaceutical compositions which are useful for the treatment of patients with decreased platelet counts, and compositions for treating patients with decreased platelet counts, which comprise an effective amount of said polypeptide in a pharmaceutically acceptable dosage form together with a pharmaceutically acceptable carrier.
BACKGROUND ART
Interleukin 6 [F. Takatsuki et al., Cancer Research, 50, 2885-2890 (1990)], leukemia inhibitory factor [D. Metcalf et al. Blood, 76, 50-56 (1990)], stem cell factor [P. Hunt et al. Blood, 80, 904-911 (1992)], macrophage colony stimulating factor (M-CSF; Japanese Published Examines Patent Application No. 11705/94) and thrombopoietin [de Sauvage et al. Nature, 369, 533 (1994)] are known as substances which possibly promote platelet production. Furthermore, conagenin [Japanese Cancer Association #2235 (1992)], Y25510 [The 113rd annual meeting of Pharmaceutical Society of Japan, PB13-22 (1993)], 2-pyranone derivatives [Japanese Published Unexamined Patent Application No. 213758/93], and FK565 (WO93/23066) are known as low molecular weight substances which possibly promote platelet production.
It is known that hG-CSF is one of the polypeptides essential for hemopoietic stem cell growth and differentiation leading to the formation of various types of hemocytes, and exerts growth-promoting effect on most granulocytes and in particular neutrophils.
As a modified polypeptide exhibiting hG-CSF activity wherein groups are chemically modified with a chemical modifying agent, a chemically modified hG-CSF obtained by modifying at least one amino group of the polypeptide exhibiting hG-CSF activity with a polyethylene glycol derivative is known (Japanese Published Unexamined Patent Application No. 316400/89, WO90/06952, Japanese Published Unexamined Patent Application No. 32559/92). It has not been known that these chemically modified hG-CSF polypeptides exert a platelet production promoting effect.
DISCLOSURE OF INVENTION
The invention relates to a chemically modified polypeptide wherein at least one of the amino, carboxyl, mercapto or guanidine group in the polypeptide molecule having hG-CSF activity is modified chemically, and a platelet production promoting agent comprising said polypeptide, a method for treating a patient with decreased platelet counts comprising administering an effective amount of said polypeptide to the patent, the use of said polypeptide for the production of pharmaceutical compositions which are useful for the treatment of patients with decreased platelet counts, and compositions for treating a patient with decreased platelet counts, which comprise an effective amount of said polypeptide in a pharmaceutically acceptable dosage form together with a pharmaceutically acceptable carrier.
More specifically, the invention relates to a chemically modified polypeptide wherein at least one of the amino, carboxyl, mercapto or guanidino group in the polypeptide molecule having hG-CSF activity is modified chemically with a polyalkylene glycol derivative or a styrene-maleic acid copolymer, and a platelet production promoting agent comprising said polypeptide, a method for treating a patient with decreased platelet counts comprising administering an effective amount of said polypeptide to the patient, the use of said polypeptide for production of pharmaceutical compositions which are useful for the treatment of patients with decreased platelet counts, and compositions for treating a patient with decreased platelet counts, which comprises an effective amount of said polypeptide in a pharmaceutically acceptable dosage form together with a pharmaceutically acceptable carrier.
The polyalkylene glycol derivatives include, for example, polyethylene glycol derivatives, polypropylene derivatives, and polyethylene-polypropylene copolymer derivatives.
With more specific reference to the agents for chemically modifying at least one of amino, carboxyl, mercapto and guanidino groups, the amino group-chemical modifying agent includes, for example, polyalkylene glycol derivatives having the formula (I):
R
1
—(M)
n
—X—R
2
(I)
wherein R
1
represents an alkyl or alkanoyl group; M represents the formula:
—OCH
2
CH
2
—, —OCH
2
CH
2
CH
2
—,
or
—(OCH
2
CH
2
)
r
—(OCH
2
CH
2
)
s
—
wherein r and s have any variable positive integral values, which are the same or different; n has any variable positive integral values; X represents a single bond, O, NH, or S; and R
2
represents the formula:
wherein R
3
represents OH, halogen, or the formula:
—X
a
—(M
a
)
na
—R
1a
wherein X
a
, M
a
R
1a
and na have the same meanings as the above-mentioned X, M, R
1
and n, respectively, and Y represents halogen or the formula:
—Z—(CH
2
)
p
—(O)
m
—W
wherein Z represents O, S, or NH; W represents a carboxyl group, an active derivative thereof, or the formula:
wherein R
4
represents an alkyl group; and Hal represents halogen, and p has an integral value of 1 to 6; and m has a value of 0 or 1,
—(CO)
ma
—(CH
2
)
t
—W
a
wherein W
a
and ma have the name meanings as the above-mentioned W and m, respectively; and t has an integral value of 0 to 6, or
wherein Hal
a
, pa and R
4a
have the same meanings as the above-mentioned Hal, p and R
4
, respectively, and styrene-maleic acid copolymers having the formula (II):
wherein u and v have any variable positive integral values, which are the same or different; and R
5
represents a hydrogen atom, or an alkyl group. The carboxyl group-chemical modifying agents include, for example, polyalkylene glycol derivatives having the formula (III):
R
1b
—(M
b
)
nb
—NH
2
(III)
wherein M
b
, R
1b
and nb have the same meanings as the above-mentioned M, R
1
and n, respectively. The mercapto group-chemical modifying agent are polyalkylene glycol derivatives having the formula (IV):
wherein M
c
, R
1c
, and nc have the same meanings as the above-identified M, R
1
, and n, respectively, and styrene-maleic acid copolymers having the formula (V):
wherein R
5a
, ua, and va have the same meanings as the above-identified R
5
, U, and V, respectively, and one of Q and R represents a carboxyl group, and the other represents the formula:
wherein pb has the same meanings as the above-identified p. The guanidino group-chemical modifying agent includes, for example, polyalkylene glycol derivatives having the formula (VI):
wherein q has a value of 1, or 2, and M
d
, R
1d
, and nd have the same meanings as the above-identified M, R
1
, and n, respectively.
In the chemical modifying group as used in the present invention, the alkyl group represented by R
1
, R
4
, and R
5
includes, for example, linear or branched groups having from 1 to 18 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, isooctyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl; the alkanoyl groups represented by R
1
include, for example, linear or branched groups having from 1 to 18 carbon atoms such as formyl, acetyl, propionyl, butyryl, valeryl, pivaroyl, pentanoyl, lauroyl, myristoyl, palmitoyl, and stearoyl; the halogen represented by R
3
, Y, and Hal includes, for example, chlorine, bromine, and iodine atoms; the active derivatives of a carboxyl group represented by W includes, for example, acid halides such as acid chloride and acid bromide, active esters such as p-nitr
Kobayashi Ken
Maruyama Kumiko
Okabe Masami
Suzawa Toshiyuki
Yamasaki Motoo
Borin M.
Kyowa Hakko Kogyo Co. Ltd.
Nixon & Vanderhye
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