Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-10-06
2001-05-29
Berch, Mark L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S360000
Reexamination Certificate
active
06239125
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to azetidinone derivatives having activity against herpes infections. More specifically, the invention relates to azetidin-2-one derivatives exhibiting antiherpes activity, to pharmaceutical compositions comprising the derivatives, and methods of using the derivatives to inhibit the replication of herpes virus and to treat herpes infections.
BACKGROUND OF THE INVENTION
Herpes viruses inflict a wide range of diseases against humans and animals. For instance, herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), are responsible for cold sores and genital lesions, respectively; varicella zoster virus (VZV) causes chicken pox and shingles; and the human cytomegalovirus (HCMV) is a leading cause of opportunistic infections in immunosuppressed individuals.
Over the past two decades, a class of compounds known as the purine and pyrimidine nucleoside analogs has received the most attention by investigators in the search for new therapeutic agents for treatment of herpes virus infections. As a result, several nucleoside analogs have been developed as antiviral agents. The most successful to date is acyclovir which is the agent of choice for treating genital HSV infections. Another nucleoside analog, ganciclovir, has been used with some success in treating HCMV infections.
Nevertheless, in spite of some significant advances, the need for effective, safe therapeutic agents for treating herpes viral infections continues to exist. For a review of current therapeutic agents in this area, see R. E. Boeheme et al., Annual Reports in Medicinal Chemistry, 1995, 30, 139.
Azetidin-2-one derivatives have been reported in the literature as having variety of biological activities; mainly antibacterial, anti-inflammatory, anti-degenerative, etc. However, azetidin-2-one derivatives have not been reported to be antiviral agents against herpes viruses.
The following references disclose azetidin-2-ones having biological activity:
S. K. Shah et al., European patent application 0,199,630, Oct. 29, 1986,
S. K. Shah et al., European patent application 0,377,549, Oct. 18, 1989,
P. L. Durette and M. Maccoss, U.S. Pat. No. 5,100,880, Mar. 31, 1992,
P. L. Durette and M. Maccoss, U.S. Pat. No. 5,104,862, Apr. 14, 1992,
W. K. Hagmann et al.,
Bioorg. Med. Chem. Lett
. 1992, 2, 681,
W. K. Hagmann et al.,
J. Med. Chem
. 1993, 36, 771,
J. B. Doherty et al., U.S. Pat. No. 5,229,381, issued Jul. 20, 1993,
S. K. Shah et al.,
Bioorg. Med. Chem. Lett
. 1993, 3, 2295,
G. Crawley, PCT patent WO 95/02579, published Jan. 26, 1995,
P. E. Finke et al.,
J. Med.Chem
. 1995, 38, 2449, and K. Kobayashi et al., Japanese patent application 07242624, published Sep. 19, 1995
; Chem. Abstr
. 1996, 124, 29520.
SUMMARY OF THE INVENTION
The present application discloses a group of azetidin-2-one derivatives particularly active against cytomegalovirus. This activity coupled with a wide margin of safety, renders these derivatives desirable agents for combating herpes infections.
The present azetidin-2-one derivatives are distinguished from the prior art compounds in that they possess different chemical structures and biological activities.
The azetidin-2-one derivatives are represented by formula 1:
wherein Y is S or O;
R
1
is C
1-6
alkyl optionally substituted with NHC(O)—R
8
or C(O)—R
8
wherein R
8
is a C
1-6
alkyl, O—C
1-6
alkyl, NH—C
1-6
alkyl, (C
0-4
alkyl)aryl or (C
0-4
alkyl)Het, wherein Het represents a five or six-membered, monovalent heterocyclic ring containing a heteroatom selected from the group consisting of N, O, or S;
(C
0-6
alkyl)aryl, wherein said aromatic ring is optionally substituted with halo, C
1-6
alkyl, O—C
1-6
alkyl or NH-R
9
wherein R
9
is:
C
1-6
alkyl, C
6-10
aryl, Het, or an acyl of formula C(O)-R
10
wherein R
10
is a C
1-6
alkyl, O—C
1-6
alkyl, NH—C
1-6
alkyl, (C
0-4
alkyl)aryl or (C
0-4
alkyl)Het;
(C
0-6
alkyl)Het the carbon atoms of said Het being optionally substituted with halo, C
1-6
alkyl, O-R
9
or NH-R
9
wherein R
9
is as defined above;
or the nitrogen atom of said Het being optionally substituted with R
9
wherein R
9
is as defined above; or
R
1
is an amino acid analog or dipeptide analog of the formula:
wherein R
2
is H, C
1-10
alkyl optionally monosubstituted with (C
1-6
alkyl)thio, (C
1-6
alkyl)sulfonyl or C
6-10
aryl,
or an amide or ester group mono- or di-substituted with C
1-6
alkyl;
A is C
6-10
aryl, Het or CH—R
3
wherein R
3
is C
1-6
alkyl or (C
0-4
alkyl)aryl; and
Z is H, C
1-6
alkyl, or an acyl of formula C(O)-R
8
wherein R
8
is as defined above;
R
4
is hydrogen, lower alkyl, methoxy, ethoxy, or benzyloxy; and
R
5
is lower alkyl, lower cycloalkyl, (CH
2
)
m
—C(O)OR
6
wherein m is the integer 1 or 2 and R
6
is lower alkyl or phenyl(lower alkyl);
phenyl, phenyl monosubstituted, disubstituted or trisubstituted with a substituent selected independently from the group consisting of:
lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy and amino; phenyl(lower alkyl), phenyl(lower alkyl) monosubstituted or disubstituted on the phenyl portion thereof with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkylamino, di(lower alkyl)amino, lower acylamino, di(lower alkyl)aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl)thio, (trifluoromethyl)sulfinyl, (trifluoromethyl)sulfonyl and C(O)OR
7
wherein R
7
is lower alkyl or phenyl(lower alkyl);
Het or Het(lower alkyl) wherein Het represents an unsubstituted, monosubstituted or disubstituted five or six membered, monovalent heterocyclic ring containing one or two heteroatoms selected from the group consisting of N, O or S, wherein each substituent is selected independently from the group consisting of lower alkyl, lower alkoxy, halo and hydroxy;
5-(benzo[1,3]dioxolyl) methyl, (1(R)-1-naphthalenyl)ethyl, 2-benzothiazolyl or 2-thiazolo[4,5-b]pyridinyl; or
R
4
and R
5
together with the nitrogen atom to which they are attached form a piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, 1-(3,4-dihydro-1H-isoquinolinyl) or 2-(3,4-dihydro-1H-isoquinolinyl) or a pyrrolidino ring optionally substituted with phenyl or C(O)OCH
2
-phenyl, said phenyl ring optionally mono- or di-substituted with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkylamino, di(lower alkyl)amino, lower acylamino, di(lower alkyl)aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl)thio, (trifluoromethyl)sulfinyl, (trifluoromethyl)sulfonyl and C(O)OR
7
wherein R
7
is lower alkyl or phenyl(lower alkyl); or a therapeutically acceptable acid addition salt thereof.
Preferred compounds of the invention include compounds of formula (1) wherein Y is S or O; R
1
is C
1-6
alkyl optionally substituted with C(O)—R
8
or NHC(O)—R
8
wherein R
8
is a C
1-6
alkyl, NH—C
1-6
alkyl or phenyl;
(C
0-4
alkyl)phenyl wherein said phenyl ring is optionally substituted with halo, C
1-6
alkyl, or NH-R
9
, wherein R
9
is:
C
1-4
alkyl, phenyl or an acyl of formula C(O)—R
10
wherein R
10
is a C
1-6
alkyl, NH—C
1-6
alkyl or phenyl;
(C
0-3
alkyl)Het wherein said carbon atoms of said Het is optionally substituted with halo, C
1-6
alkyl or NH-R
9
;
or said nitrogen atom of said Het is substituted with R
9
, wherein R
9
is:
C
1-4
alkyl, phenyl or an acyl of formula C(O)—R
10
wherein R
10
is a C
1-6
alkyl, NH—C
1-6
alkyl or phenyl;
or
R
1
is an amino acid analog or dipeptide analog of formula:
wherein R
2
is H, the side chain of asparagine optionally N-alkylated, or C
1-6
alkyl optionally monosubstituted with (C
1-6
alkyl)sulfonyl or phenyl;
A is phenyl or CH—R
3
wherein R
3
is C
1-6
alkyl or (C
0-4
alkyl)phenyl; and
Z is C(O)—R
8
wherein R
8
is C
1-6
alkyl, C
1-6
alkoxy or phenyl;
R
4
is hydrogen or C
1-3
alkyl; and
R
5
is phenyl optionally substituted with a substituent selected independently from the group consisting of lower alkyl, l
Deziel Robert
Malenfant Eric
O'Meara Jeffrey
Ogilvie William W.
Berch Mark L.
Boehringer Ingelheim (Canada) Ltd.
Devlin Mary-Ellen M.
Raymond Robert P.
Stempel Alan R.
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