Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-10-01
2001-08-21
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S455000, C540S461000
Reexamination Certificate
active
06277839
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to compounds and methods for treating prostaglandin mediated diseases, certain pharmaceutical compositions thereof, and the like. More particularly, the compounds of the invention are structurally different from nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates, and are antagonists of the pain and inflammatory effects of E-type prostaglandins.
Two review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists:
Eicosanoids: From Biotechnology to Therapeutic Applications
, Folco, Samuelsson, Maclouf, and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87. An article from
The British Journal of Pharmacology
(1994, 112, 735-740) suggests that Prostaglandin E
2
(PGE
2
) exerts allodynia through the EP
1
receptor subtype and hyperalgesia through EP
2
and EP
3
receptors in the mouse spinal cord.
Thus, selective prostaglandin ligands, agonists or antagonists, depending on which prostaglandin E receptor subtype is being considered, will have anti-inflammatory, antipyretic and analgesic properties similar to a conventional non-steroidal anti-inflammatory drug and, in addition, will inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects of NSAIDs which are indiscriminate cyclooxygenase inhibitors. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects. In
The American Physiological Society
(1994, 267, R289-R-294), studies suggest that PGE
2
-induced hyperthermia in the rat is mediated predominantly through the EP
1
receptor. World patent applications WO 96/06822 (Mar. 7, 1996), WO 96/11902 (Apr. 25, 1996) and EP 752421-A1 (Jan. 8, 1997) disclose compounds represented by Formula I as being useful in the treatment of prostaglandin mediated diseases.
wherein:
A is phenyl, naphthyl, 5- or 6-membered heteroaryl;
B is phenyl, 5- or 6-membered heteroaryl or a keto-dihydro ring;
D is phenyl, 5- or 6-membered heteroaryl;
R
1
is COOH, (CH
2
)
n
COOH, tetrazolyl(alkyl);
R
3
is H, alkyl;
Z is an alkylene bridge;
Ia is one of the compounds specifically claimed.
SUMMARY OF THE INVENTION
The present invention relates to biphenylene lactams which are ligands at the prostaglandin receptors, as well as a method for treating prostaglandin mediated diseases comprising administration to a patient in need of such a treatment of a non-toxic therapeutically effective amount of compound of Formula II, and the like.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention is a compound of structural Formula II:
or a pharmaceutically acceptable salt, crystal form, or hydrate thereof, wherein:
A and B are independently unsubstituted, monosubstituted or disubstituted ortho-benzenediyl or ortho-heteroarylenediyl wherein the substituents are selected from the group consisting of:
a) halogen,
b) C
1-5
alkyl,
c) C
1-5
alkoxy,
d) C
1-5
alkylthio,
e) nitro,
f) CN,
g) C
1-5
fluoroalkyl,
h) COOR
3
, and
i) NR
3
2
;
X is CH
2
CH
2
, CH═CH, CH
2
Y, YCH
2
, CH
2
CH
2
CH
2
, ortho-benzenediyl or ortho-heteroarylenediyl;
Y is O, S, CF
2
, or C═O;
D is unsubstituted, monosubstituted, or disubstituted benzendiyl wherein the substituents are selected from:
a) halogen,
b) C
1-5
alkyl,
c) C
1-5
alkoxy,
d) C
1-5
alkylthio,
e) nitro,
f) CN,
g) C
1-5
fluoroalkyl,
h) COOR
3
, and
i) NR
3
2
;
R is:
a) C
1-6
alkyl,
b) (CR
1
R
2
)
n
O—Ph,
c) (CR
1
R
2
)
n
O-heteroaryl,
d) O—(CR
1
R
2
)
n
Ph,
e) O—(CR
1
R
2
)
n
heteroaryl,
f) NR
3
—(CR
1
R
2
)
n
Ph,
g) NR
3
—(CR
1
R
2
)
n
heteroaryl,
h) C
2-6
alkenyl-Ph,
i) C
2-6
alkenyl-heteroaryl,
j) (CR
1
R
2
)
n
Ph, or
k) (CR
1
R
2
)
n
heteroaryl,
wherein Ph or heteroaryl is unsubstituted, monosubstituted or disubstituted with substituents selected from:
1) halogen,
2) C
1-5
alkyl,
3) C
1-5
alkoxy,
4) C
1-5
alkylthio,
5) nitro,
6) CN,
7) C
1-5
fluoroalkyl,
8) COOR
3
, and
9) NR
3
2
;
n=0, 1, 2 or 3;
R
1
and R
2
are independently hydrogen, C
1-3
alkyl, benzyl, C
1-3
fluoroalkyl, C
1-3
alkoxy,or fluorine;
R
3
is H or C
1-6
alkyl.
A subembodiment of the invention is the compound of structural Formula II as recited above, wherein:
A and B are independently unsubstituted, monosubstituted or disubstituted ortho-benzenediyl wherein the substituents are selected from the group consisting of:
a) halogen,
b) C
1-5
alkyl,
c) C
1-5
alkoxy,
d) C
1-5
alkylthio,
e) nitro,
f) CN,
g) C
1-5
fluoroalkyl,
h) COOR
3
, and
i) NR
3
2
;
X is CH
2
CH
2
, CH═CH, CH
2
Y, YCH
2
, CHCH
2
CH, ortho-benzenediyl or ortho-heteroarylenediyl;
Y is O or S;
D is unsubstituted or monosubstituted benzendiyl wherein the substituents are selected from:
a) halogen,
b) C
1-3
alkyl,
c) C
1-3
alkoxy,
d) C
1-3
alkylthio,
e) nitro,
f) CN,
g) C
1-3
fluoroalkyl,
h) COOR
3
, and
i) NR
3
2
;
R is:
a) C
1-6
alkyl,
b) (CR
1
R
2
)
n
O—Ph,
c) O—(CR
1
R
2
)
n
Ph,
d) NR
3
—(CR
1
R
2
)
n
Ph,
e) NR
3
—(CR
1
R
2
)
n
heteroaryl,
f) C
2-6
alkenyl-Ph, or
g) (CR
1
R
2
)
n
Ph,
wherein Ph or heteroaryl is unsubstituted, monosubstituted or disubstituted with substituents selected from:
1) halogen,
2) C
1-3
alkyl,
3) C
1-3
alkoxy,
4) C
1-3
alkylthio,
5) nitro,
6) CN,
7) C
1-3
fluoroalkyl,
8) COOR
3
, and
9) NR
3
2
;
n=0, 1, 2 or 3;
R
1
and R
2
are independently hydrogen, C
1-3
alkyl, C
1-3
fluoroalkyl, or C
1-3
alkoxy;
R
3
is H or C
1-6
alkyl.
A most preferred embodiment of the invention is the compound of structural Formula II above, wherein:
A and B are independently unsubstituted, monosubstituted or disubstituted ortho-benzenediyl wherein the substituents are halogen;
X is CH
2
CH
2
, CH═CH, or OCH
2
;
D is benzendiyl;
R is:
a) C
1-3
alkyl,
b) (CR
1
R
2
)
n
O—Ph,
c) O—(CR
1
R
2
)
n
Ph,
d) NR
3
—(CR
1
R
2
)
n
Ph,
e) NR
3
—(CR
1
R
2
)
n
thienyl,
f) C
2-3
alkenyl-Ph, or
g) (CR
1
R
2
)
n
Ph,
wherein Ph is unsubstituted or monosubstituted with halogen;
n=0,1, 2 or 3;
R
1
and R
2
are independently hydrogen, C
1-3
alkyl, C
1-3
fluoroalkyl, or C
1-3
alkoxy;
R
3
is H or C
1-3
alkyl.
Another embodiment of the present invention is a method for treating or preventing a prostaglandin mediated condition comprising administration to a mammalian patient in need of such a treatment of a non-toxic therapeutically effective amount of a compound of Formula II above. A preferred prostaglandin mediated condition is inflammation. Yet another embodiment of the invention is a method for treating or preventing a prostaglandin mediated condition in a mammal, comprising the administration of a non-toxic therapeutically effective amount of a compound of Formula II and a nonsteroidal anti-inflammatory drug. Preferred nonsteroidal anti-inflammatory drugs are aspirin, ibuprofen, naproxen, and ketoprofen. Another embodiment of the invention is a method for treating or preventing a prostaglandin mediated condition in a mammal, comprising the administration of a non-toxic therapeutically effective amount of a compound of Formula II as recited in claim
1
and a cyclooxygenase-2 (COX-2) selective inhibitor. Examples of such COX-2 inhibitors are disclosed in U.S. Pat. Nos. 5,474,995; 5,633,272; and 5,466,823; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691, and WO 95/0051.
Preferred prostaglandin mediated conditions are rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), Paget's disease, gout and ankylosing spondylitis, bursitis, burns inclu
Atkinson Joseph G.
Labelle Marc
Lacombe Patrick
Ruel Rejean
Billups Richard C.
Kifle Bruck
Merck Frosst Canada & Co.
Rose David L.
Yuro Raynard
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