Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-04
2001-04-03
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S363000, C514S383000, C514S445000, C514S464000, C514S469000, C514S568000, C514S576000, C514S601000, C514S602000, C514S604000, C514S605000, C546S172000, C546S174000, C548S132000, C548S252000, C549S077000, C549S469000, C549S447000, C562S041000, C562S508000, C562S510000, C562S586000, C562S567000, C564S080000, C564S087000, C564S084000, C564S091000, C564S099000
Reexamination Certificate
active
06211197
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to compounds and methods for treating prostaglandin mediated diseases, and certain pharmaceutical compositions thereof. More particularly, the compounds of the invention are structurally different from 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, have anti-inflammatory, antipyretic and analgesic properties similar to a conventional non-steroidal anti-inflammatory drug, and in addition, inhibit hormone-induced uterine contractions and have anti-cancer effects. These compounds have a diminished ability to induce some of the mechanism-based side effects of NSAIDs which are indiscriminate cyclooxygenase inhibitors. In particular, the compounds 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.
PCT application nos WO 96/06822 (Mar. 7, 1996), WO 96/11902 (Apr. 25, 1996), WO 97/00863 (Jan. 9, 1997), WO 97/00864 (Jan. 9, 1997), WO 96/03380 (Feb. 8, 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 further defined keto-dihydro ring;
D is phenyl, 5- or 6-membered heteroaryl;
R
1
is COOH, carboxyalkyl, tetrazolyl(alkyl);
R
3
is H or alkyl, and
Z is an alkylene bridge containing 0-1 nitrogen atom or a further defined unsaturated bridge.
Compound Ia is one of the compounds specifically claimed.
SUMMARY OF THE INVENTION
The present invention relates to compounds represented by formula II:
Ar
1
—W—Ar
2
—X—Q II
as well as pharmaceutically acceptable salts and hydrates thereof, wherein:
Ar
1
is an aryl or heteroaryl group, optionally substituted with R
1
or R
3
;
R
1
is Y
m
—R
2
, Y
m
—Ar
3
, halogen, N(R
5
)
2
, CN, NO
2
, C(R
6
)
3
, CON(R
5
)
2
, S(O)
n
R
7
or OH;
Y represents a linker between R
2
or Ar
3
and Ar
1
containing 0-4 carbon atoms and not more than one heteroatom selected from O, N and S, said linker optionally containing CO, S(O)
n
, —C═C— or an acetylenic group, and said linker being optionally substituted by R
2
;
m is 0 or 1;
n is 0,or 2;
R
2
represents H, F, CHF
2
, CF
3
, lower alkyl or hydroxyC
1-6
alkyl, or two R
2
groups may be joined together and represent a carbocyclic ring of up to six members, said ring containing not more than one heteroatom selected from O, N and S;
Ar
3
represents an aryl or heteroaryl group, optionally substituted with R
3
;
R
3
is R
4
, halogen, haloC
1-6
alkyl, N(Rr)
2
, CN, NO
2
, C(R
6
)
3
, CON(R
5
)
2
, OR
4
, SR
4
or S(O)
n
R
7
;
R
4
is H, lower alkyl, lower alkenyl, lower alkynyl, CHF
2
or CF
3
;
R
5
is R
4
, Ph or Bn, or two R
5
groups in combination with the atom to which they are attached represent a ring of up to 6 members containing carbon atoms and up to 2 heteroatoms selected from O, N and S;
R
6
is H, F, CF
3
or lower alkyl, or two R
6
groups may be taken together and represent a ring of up to 6 members containing carbon atoms and 0-2 heteroatoms selected from O, N and S;
R
7
is lower alkyl, lower alkenyl, lower alkynyl, CHF
2
, CF
3
, N(R
5
)
2
, Ph(R
8
)
2
or CH
2
Ph(R
8
)
2
;
R
8
is R
4
, OR
4
, SR
4
or halogen
W represents a 3-6 membered linking group containing 0 to 2 heteroatoms selected from O, N and S, said linking group optionally containing CO, S(O)
n
, C═C or an acetylenic group, and optionally being substituted with R
9
;
R
9
is R
2
, lower alkenyl, lower alkynyl, OR
4
or SR
4
;
Ar
2
represents an aryl or heteroaryl group, optionally ubstituted with R
3
;
R
10
represents R
4
, halogen, N(R
5
)
2
, CN, NO
2
, C(R
6
)
3
, OR
4
, SR
4
or S(O)
n
R
7
;
X represents a linker which is attached to Ar
2
ortho to the attachment of W, said linker containing 0-4 carbon atoms and not more than one heteroatom selected from O, N and S, said linker further optionally containing CO, S(O)
n
, C═C or an acetylenic group, and said linker being optionally substituted with R
11
;
R
11
is R
9
;
Q represents a member selected from the group consisting of: CO
2
H, tetrazole, SO
3
H, hydroxamic acid, CONHSO
2
R
12
and SO
2
NHCOR
12
;
R
12
represents a member selected from the group consisting of: CF
3
, lower alkyl, lower alkenyl, lower alkynyl and ZAr
4
, wherein Z is an optional linker containing 0-4 carbon atoms, optionally substituted with R
13
;
R
13
is R
9
;
Ar
4
is an aryl or heteroaryl group optionally substituted with R
14
, and
R
14
is R
10
or NHCOMe.
Pharmaceutical compositions and methods of treatment are also included.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds represented by formula II:
Ar
1
—W—Ar
2
—X—Q II
as well as pharmaceutically acceptable salts and hydrates thereof, wherein:
Ar
1
is an aryl or heteroaryl group, optionally substituted with R
1
or R
3
;
R
1
is Y
m
—R
2
, Y
m
—Ar
3
, halogen, N(R
5
)
2
, CN, NO
2
, C(R
6
)
3
, CON(R
5
)
2
, S(O)
n
R
7
or OH;
Y represents a linker between R
2
or Ar
3
and Ar
1
containing 0-4 carbon atoms and not more than one heteroatom selected from O, N and S, said linker optionally containing CO, S(O)
n
, —C═C— or an acetylenic group, and said linker being optionally substituted by R
2
;
m is 0 or 1;
n is 0, 1 or 2;
R
2
represents H, F, CHF
2
, CF
3
, lower alkyl or hydroxyC
1-6
alkyl, or two R
2
groups may be joined together and represent a carbocyclic ring of up to six members, said ring containing not more than one heteroatom selected from O, N and S;
Ar
3
represents an aryl or heteroaryl group, optionally substituted with R
3
;
R
3
is R
4
, halogen, haloC
1-6
alkyl, N(R
5
)
2
, CN, NO
2
, C(R
6
)
3
, CON(R
5
)
2
, OR
4
, SR
4
or S(O)
n
R
7
;
R
4
is H, lower alkyl, lower alkenyl, lower alkynyl, CHF
2
or CF
3
;
R
5
is R
4
, Ph or Bn, or two R
5
groups in combination with the atom to which they are attached represent a ring of up to 6 members containing carbon atoms and up to 2 heteroatoms selected from O, N and S;
R
6
is H, F, CF
3
or lower alkyl, or two R
6
groups may be taken together and represent a ring of up to 6 members containing carbon atoms and 0-2 heteroatoms selected from O, N and S;
R
7
is lower alkyl, lower alkenyl, lower alkynyl, CHF
2
, CF
3
, N(R
5
)
2
, Ph(R
8
)
2
or CH
2
Ph(R
8
)
2
;
R
8
is R
4
, OR
4
, SR
4
or halogen
W represents a 3-6 membered linking group containing 0 to 2 heteroatoms selected from O, N and S, said linking group optionally containing CO, S(O)
n
, C═C or an acetylenic group, and optionally being substituted with R
9
;
R
9
is R
2
, lower alkenyl, lower alkynyl, OR
4
or SR
4
;
Ar
2
represents an aryl or heteroaryl group, optionally substituted with R
3
;
R
10
represents R
4
, halogen, N(R
s
)
2
, CN, NO
2
, C(R
6
)
3
, OR
4
, SR
4
or S(O)
n
R
7
;
X represents a linker which is attached to Ar
2
ortho to the attachment of W, said linker containing 0-4 carbon atoms and not more than one heteroatom selected from O, N and S, said linker further optionally containing CO, S(O)
n
, C═C or an acetylenic group, and said linker being optionally substituted with R
Belley Michel
Chauret Nathalie
Gallant Michel
Labelle Marc
Lachance Nicholas
Huang Evelyn Mei
Merck Frosst Canada & Co.
Rose David L.
Yuro Raynard
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