Carboxylic acids and acylsulfonamides, compositions...

Details Carboxylic acids and acylsulfonamides, compositions... Carboxylic acids and acylsulfonamides, compositions...

1999-03-10

2001-06-05

Gerstl, Robert (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S604000, C549S065000, C562S400000, C562S466000, C562S490000, C564S091000

Reexamination Certificate

active

06242493

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to compounds which are useful for treating or preventing prostaglandin mediated diseases, methods of treatment and pharmaceutical compositions containing such compounds. The compounds are structurally different from conventional 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, and in addition inhibit hormone-induced uterine contractions. Moreover, the compounds have anti-cancer effects.
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.
SUMMARY OF THE INVENTION
The present invention relates to compounds represented by formula I:
as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein:
HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from O, S(O)
n
and N(O)
m
wherein m is 0 or 1 and n is 0, 1 or 2;
A is a one or two atom moiety and is selected from the group consisting of: —W—, —C(O)—, —C(R
7
)
2
—W—, —W—C(R
7
)
2
—, —CR
7
(OR
20
)—, —C(R
7
)
2
—, —C(R
7
)
2
—C(OR
20
)R
7
—, —C(R
7
)
2
—C(R
7
)
2
— or —CR
7
═CR
7
—, wherein W represents O, S(O)
n
or NR
17
, with n as previously defined and R
17
as defined below;
X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from O, S(O)
n
and N(O)
m
, and optionally substituted with R
14
and R
15
, and A and B are attached to the aryl or heteroaryl group ortho relative to each other;
Y represents O, S(O)
n
, NR
17
, a bond or —CR
18
═CR
18
—;
B represents —(C(R
18
)
2
)
p
—Y—(C(R
18
)
2
)
q
— wherein p and q are independently 0-3, such that when Y represents O, S(O)
n
, NR
17
or —CR
18
═CR
18
—, p+q=0-6, and when Y represents a bond, p+q is 1-6;
Z is OH or NHS
2
R
19
;
R
1
R
2
and R
3
independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(R
a
)
4-9
, —(C(R
4
)
2
)
p
SR
5
, —(C(R
4
)
2
)
p
OR
8
, —(C(R
4
)
2
)
p
N(R
6
)
2
, CN, NO
2
, —(C(R
4
)
2
)
p
C(R
7
)
3
, —CO
2
R
9
, —CON(R
6
)
2
or —(C(R
4
)
2
)
p
S(O)
n
R
10
, wherein n and p are as previously defined;
each R
4
is independently H, F, CF
3
or lower alkyl, or two R
4
groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from O, S(O)
n
or N(O)
m
;
each R
5
is independently lower alkyl, lower alkenyl, lower alkynyl, CF
3
, lower alkyl-HET, lower alkenyl-HET or —(C(R
18
)
2
)
p
Ph(R
11
)
0-2
;
each R
6
is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF
3
, Ph, Bn and when two R
6
groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, optionally containing an additional heteroatom selected from O, S(O)
n
or N(O)
m
;
each R
7
is independently H, F, CF
3
or lower alkyl, and when two R
7
groups are presents, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from O, S(O)
n
and N(O)
m
;
each R
8
represents H or R
5
;
each R
9
is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn;
each R
10
is independently lower alkyl, lower alkenyl, lower alkynyl, CF
3
, Ph(R
11
)
0-3
, CH
2
Ph(R
11
)
0-3
or N(R
6
)
2
;
each R
11
is independently lower alkyl, SR
20
, OR
20
, N(R
6
)
2
, —CO
2
R
12
, —CON(R
6
)
2
, —C(O)R
12
, CN, CF
3
, NO
2
or halogen;
each R
12
is independently H, lower alkyl or benzyl;
each R
13
is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R
6
)
2
, CO
2
R
12
, CN, CF
3
or NO
2
;
R
14
and R
15
are independently lower alkyl, halogen, CF
3
, OR
16
, S(O)
n
R
16
or C(R
16
)
2
OR
17
;
each R
16
is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF
3
;
each R
17
is independently H, lower alkyl or Bn;
each R
18
is independently H, F or lower alkyl, and when two R
18
groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from O, S(O)
n
or N;
each R
19
is lower alkyl, lower alkenyl, lower alkynyl, CF
3
, HET(R
a
)
4-9
, lower alkyl-HET(R
a
)
4-9
or lower alkenyl-HET(R
a
)
4-9
;
each R
20
is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF
3
or Ph(R
13
)
2
and
each R
a
is independently selected from the group consisting of: H, OH, halo, CN, NO
2
, amino, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
1-6
alkoxy, C
2-6
alkenyloxy, C
2-6
alkynyloxy, C
1-6
alkylamino, di-C
1-6
alkylamino, CF
3
, C(O)C
1-6
alkyl, C(O)C
2-6
alkenyl, C(O) C
2-6
alkynyl, CO
2
H, CO
2
C
1-6
alkyl, CO
2
C
2-6
alkenyl, and CO
2
C
2-6
alkynyl,
said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C
1-6
alkoxy, C
2-6
alkenyloxy, C
2-6
alkynyloxy, CF
3
, C(O)C
1-6
alkyl, C(O)C
2-6
alkenyl, C(O)C
2-6
alkynyl, CO
2
H, CO
2
C
1-6
alkyl, CO
2
C
2-6
alkenyl, CO
2
C
2-6
alkynyl, NH
2
, NHC
1-6
alkyl and N(C
1-6
alkyl)
2
.
Pharmaceutical compositions are also included which are comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier
A method of treating or preventing a prostaglandin mediated disease is also included which is comprised of administering to a mammalian patient in need thereof, a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to carboxylic acids and acylsulfonamides, which are ligands at prostaglandin receptors, as well as a method for treating or preventing a prostaglandin mediated disease comprising administering to a patient in need of such a treatment of an amount of compound of Formula I which is effective for treating or preventing a prostaglandin mediated disease.
The invention described in this patent application is described using the following definitions unless otherwise indicated.
HET represents a 5-12 membered aromatic ring system containing 0-3 heteroatoms selected from O, S(O)
n
and N wherein n is 0, 1 or 2. HET may be substituted with up to three substituents on the aromatic ring system, R
1
, R
2
and R
3
. “Aromatic ring systems” as used herein includes aryl and heteroaryl groups such as benzene, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, triazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole, 1,2-methylenedioxybenzene and pyrrole.
HET
2
is a subset of HET and represents a member selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl.
Aryl refers to aromatic 6-10 membered groups having 1-2 rings and alternating (resonating) double bonds. Examples include phenyl, biphenyl and naphthyl.
Heteroaryl refers to aromatic 5-12 membered groups having alternating (resonating) double bonds and containing from 1-4

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