Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1994-10-06
2001-11-06
Davenport, Avis M. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S017400, C530S330000
Reexamination Certificate
active
06313095
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to peptide derivatives having antiviral properties and to means for using the derivatives to treat viral infections. More specifically, the invention relates to peptide derivatives (hereinafter called “peptides”) exhibiting activity against herpes viruses, to pharmaceutical compositions comprising the peptides, and to a method of using the peptides to treat herpes infections.
BACKGROUND OF THE INVENTION
The family of herpes viruses is responsible for a wide range of infections that afflict humans and many important domestic animals. The diseases caused by these viruses range from bothersome cold sores to highly destructive infections of the central nervous system (encephalitis). The more common members of this family include herpes simplex virus (types 1 and 2) responsible for cold sores and genital lesions; varicella zoster virus which causes chicken pox and shingles; and Epstein-Barr virus which causes infectious mononucleosis. Although some significant advances have been made in the last decade in antiviral therapy, the need for effective, safe therapeutic agents for treating herpes viral infections continues to exist. For a recent review of current therapeutic agents in this area, see M. C. Nahata, “Antiviral Drugs: Pharmacokinetics, Adverse Effects and Therapeutic Use”, J. Pharm. Technol., 3, 100 (1987).
The present application discloses a group of peptide derivatives having activity against herpes viruses. The relatively selective action of these peptides against herpes viruses, combined with a wide margin of safety, renders the peptides as desirable agents for combating herpes infections.
The association of peptides with anti-herpes activity is uncommon. Instances of reports of such an association include B. M. Dutia et al., Nature, 321, 439 (1986), E. A. Cohen et al., Nature, 321, 441 (1986), J. H. Subak-Sharpe et al., UK patent application 2185024, published Jul. 8, 1987, E. A. Cohen et al., European patent application 246630, published Nov. 25, 1987, R. Freidinger et al., European patent application 292255, published Nov. 23, 1988, and R. Freidinger et al., U.S. Pat. No. 4,814,432, issued Mar. 21, 1989. The subject peptides of the previous reports can be distinguished from the peptides of the present application by characteristic structural and biological differences.
SUMMARY OF THE INVENTION
The peptides of this invention are represented by formula 1
X—NH—CHR
1
—C(W
1
)—NR
2
—CH[CH
2
C(O)—Y]—C(W
2
)—NH—CH[CR
3
(R
4
)—COOH]—C(W
3
)—NH—CHR
5
—Z 1
wherein
X is (1-10C)alkanoyl; (1-10C)alkanoyl monosubstituted with halo, hydroxy or lower alkoxy; (1-10C)alkoxycarbonyl; benzoyl; benzoyl monosubstituted or disubstituted with a substituent selected from halo, hydroxy, lower alkyl, lower alkoxy, phenyl, 2-carboxyphenyl or benzyl; 2,2-diphenylacetyl; phenyl(2-10C)alkanoyl; phenyl(2-10C)alkanoyl monosubstituted or disubstituted on the aromatic portion thereof with a substituent selected from halo, hydroxy, lower alkyl, lower alkoxy or phenyl; phenyl(3-10C) alkenoyl; (lower cycloalkyl)carbonyl; (lower cycloalkyl)carbonyl substituted with one to four substituents selected from halo or lower alkyl; cyclohexylcarbonyl substituted at position 2 with lower alkanoyl, phenyl(lower)alkanoyl or phenyl(lower)alkoxycarbonyl; 3,6-dimethyl-2-(phenylethoxycarbonyl)cyclohexylcarbonyl; or a straight or branched chain 1,4-dioxoalkyl containing from five to eleven carbon atoms;
R
1
is lower alkyl, hydroxy(lower)alkyl, mercapto(lower)alkyl, methoxy(lower)alkyl, methylthio(lower)alkyl, benzyloxy(lower)alkyl, benzylthio(lower)alkyl, carboxy(lower)alkyl, lower cycloalkyl, (lower cycloalkyl)methyl, phenyl, phenylmethyl, 2-thienyl or 2-thienylmethyl;
R
2
is hydrogen, lower alkyl or phenyl(lower)alkyl;
R
3
and R
4
each independently is hydrogen or lower alkyl, or R
3
and R
4
together with the carbon atom to which they are attached form a lower cycloalkyl;
R
5
is lower alkyl, lower cycloalkyl, or (lower cycloalkyl)methyl;
W
1
, W
2
, and W
3
each independently is oxo or thioxo;
Y is
a. (1-14C)alkoxy, (3-14)alkenyloxy, CH
3
(OCH
2
CH
2
)
n
—O wherein n is the integer 1, 2 or 3, lower cycloalkyloxy, lower alkoxy monosubstituted with a lower cycloalkyl, phenoxy, phenoxy monosubstituted with hydroxy, halo, lower alkyl or lower alkoxy, phenyl(lower)alkoxy or phenyl(lower)alkoxy in which the aromatic portion thereof is substituted with hydroxy, halo, lower alkyl or lower alkoxy, or
b. NR
6
R
7
wherein R
6
is lower alkyl and R
7
is lower alkoxy, or
c. NR
6
R
7
wherein R
6
is hydrogen or lower alkyl and R
7
is (1-14C)alkyl, lower cycloalkyl, lower alkyl monosubstituted with a lower cycloalkyl; phenyl, phenyl monosubstituted with halo, lower alkyl or lower alkoxy; phenyl(lower)alkyl, phenyl(lower)alkyl in which the aromatic portion thereof is substituted with halo, lower alkyl or lower alkoxy; or (Het)-lower alkyl wherein Het represents a five or six membered heterocyclic radical containing one or two heteroatoms selected from nitrogen, oxygen or sulfur, or
d. NR
6
R
7
wherein R
6
and R
7
together with the nitrogen to which they are attached form a pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or 4-(lower alkyl)piperazino; and
Z is hydrogen; COOH; CH
2
COOH; CH
2
CH
2
COOH; CH
2
OH; 5-1H-tetrazolyl; COOR
8
wherein R
8
is lower alkyl; CONR
9
R
10
wherein R
9
and R
10
each independently is hydrogen or lower alkyl; or CON(R
11
)OH wherein R
11
is hydrogen or lower alkyl; with the provisos that (1) when X is a (1-10C)alkanoyl containing one or two carbon atoms (i.e. formyl or acetyl) then R
2
is lower alkyl or phenyl lower alkyl, and that (2) when Z is hydrogen then R
3
is hydrogen or lower alkyl and R
4
is lower alkyl or R
3
or R
4
together with the carbon atom to which they are attached form a lower cycloalkyl; or a therapeutically acceptable salt thereof.
A preferred group of the peptides of this invention is represented by formula 1 wherein X is (1-10C)alkanoyl; (1-10C)alkanoyl monosubstituted with chloro, fluoro, hydroxy or methoxy; benzoyl monosubstituted with phenyl, 2-carboxyphenyl or benzyl; phenyl(2-10C)alkanoyl; phenyl(2-10C)alkanoyl monosubstituted on the aromatic portion thereof with a substitutent selected from halo, hydroxy, lower alkyl, lower alkoxy or phenyl; phenyl(3-10C)alkenyl; (lower cycloalkyl)carbonyl; (lower cycloalkyl)carbonyl monosubstituted, disubstituted, trisubstituted or tetrasubstituted with methyl; cyclohexylcarbonyl substituted at position 2 with a phenyl-(lower)alkanoyl; 1&agr;,2&agr;,3&bgr;,6&bgr;-3,6-dimethyl-2-(phenyl-ethoxycarbonyl)cyclohexanecarbonyl or 6-methyl-2-(1-methylethyl)-1,4-dioxoheptyl; R
1
is as defined hereinabove; R
2
is hydrogen or lower alkyl; R
3
and R
4
each independently is hydrogen or lower alkyl or R
3
and R
4
together with the carbon atom to which they are joined form a lower cycloalkyl; R
5
is 1-methylethyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopentyl, cyclopentylmethyl, cyclohexyl or cyclohexylmethyl; W
1
, W
2
and W
3
are as defined hereinabove; Y is (1-14C)alkoxy, lower cycloalkyloxy, lower cycloalkylmethoxy, phenyl(lower)alkoxy, NR
6
R
7
wherein R
6
is lower alkyl and R
7
is lower alkoxy, or NR
6
R
7
wherein R
6
is hydrogen or lower alkyl and R
7
is (1-14C)alkyl, (3-14C)alkenyloxy, CH
3
—(OCH
2
CH
2
)
3
—O, lower cycloalkyl, lower cycloalkylmethyl, phenyl, phenyl monosubstituted with halo, lower alkyl or lower alkoxy, phenyl(lower)alkyl, phenyl(lower)alkyl monosubstituted with halo, lower alkyl or lower alkoxy, (Het)-lower alkyl wherein Het is a heterocyclic radical selected from 2-pyrrolyl, 2-pyridinyl, 4-pyridinyl, 2-furyl, 2-isoxazolyl and 2-thiazolyl, or NR
6
R
7
wherein R
6
and R
7
together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino or morpholino; and Z is as defined hereinabove; with the provisos that (1) when X is a (1-10C)alkanoyl containing one or two carbon atoms then R
2
is methyl, and that (2) when Z is hydrogen then R
3
is
Adams Julian
Beaulieu Pierre Louis
Deziel Robert
Moss Neil
Boehringer Ingelheim (Canada) Ltd.
Davenport Avis M.
Devlin M-E. M.
Raymond R. P.
LandOfFree
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