Method of treatment using phenyl and biaryl derivatives as...

Details Method of treatment using phenyl and biaryl derivatives as... Method of treatment using phenyl and biaryl derivatives as...

2001-04-24

2003-09-30

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S517000, C514S532000, C514S539000, C560S008000, C560S011000, C560S021000, C560S055000, C560S059000, C560S102000, C544S333000, C544S335000, C546S152000, C546S192000, C548S304400, C549S229000, C549S240000

Reexamination Certificate

active

06627656

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to methods for treating prostaglandin mediated diseases. More particularly, the compounds are antagonists of the pain and inflammatory effects of E-type prostaglandins. Additionally preferred compounds are included.
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.
In The American Physiological Society (1994, 267, R289-R-294), studies suggest that PGE2-induced hyperthermia in the rat is mediated predominantly through the EP1 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 as being useful in the treatment of prostaglandin mediated diseases.
SUMMARY OF THE INVENTION
A method of treating or preventing a prostaglandin E mediated disease is described which comprises administering to a mammalian patient in need of such treatment or prevention a compound of formula I:
wherein:
R is a group Ar as defined hereinafter;
R
1
is hydrogen, hydroxy, C
1-6
alkyl, C
1-6
alkoxy, X(CH
2
)
p
Ar, or a methylenedioxy group attached to two adjacent ring carbon atoms;
R
2
is —(CH
2
)
x
C(O)N(R
4
)S(O)
y
R
5
, —(CH
2
)
x
S(O)
y
N(R
4
)C(O)R
5
, —(CH
2
)
x
C(O)N(R
4
)C(O)R
5
, —(CH
2
)
x
S(O)
y
N(R
4
)S(O)
y
R
5
, —(CH
2
)
x
CO
2
R
4
, or tetrazol-5-yl optionally substituted by C
1-6
alkyl;
R
3
is X(CH
2
)
p
Ar or X(CH
2
)
p
R
4
or a group of formula (a):
Ar is a group of formula (b) or (c):
 or Ar is naphthyl, indolyl, pyridyl, thienyl, furyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thriazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidinyl, all of which may be unsubstituted or substituted by one or more R
7
or R
8
groups;
A is C═O or (C(R
4
)
2
)
m
;
each B is independently —CH
2
— or —O—;
R
4
is hydrogen or C
1-6
alkyl;
R
5
is hydrogen or C
1-10
alkyl or Ar, both of which may be unsubstituted or substituted by one or two Cl, F, Br, hydroxy, XC
1-5
alkyl, C
1-5
alkyl, NO
2
, tetrazol-5-yl optionally substituted by C
1-6
alkyl, or R
5
is N(R
4
)
2
;
R
6
is hydrogen, R
10
, CO
2
R
11
, CO
2
C(R
10
)
2
O(CO)XR
11
, PO
3
(R
11
)
2
, SO
2
NR
11
R
10
, NR
11
SO
2
R
10
, CONR
11
SO
2
R
10
, SO
3
R
11
, S(O)
q
R
11
, S(O)
q
N(R
11
)C(O)R
10
, S(O)
q
N(R
11
)S(O)
q
R
10
, C(O)N(R
11
)C(O)R
10
, N(R
11
)C(O)R
10
, N(R
11
)
2
, N(R
11
)C(O)NR
11
, P(O)(OR
11
)R
11
, CN, —CO
2
(CH
2
)
m
C(O)N(R
4
)
2
, C(R
10
)
2
N(R
11
)
2
, C(O)N(R
4
)
2
, OR
4
or tetrazolyl optionally substituted by C1-6 alkyl;
R
7
and R
9
are independently hydrogen, R
10
, OH, C
1-8
alkoxy, S(O)
q
R
10
, N(R
4
)
2
, Br, F, I, Cl, CF
3
, NO
2
, NHCOR
4
, R
12
CO
2
R
11
, —X—R
13
—Y, —X(CR
4
)
p
OR
4
, S(CH
2
)
p
CO
2
H, (CH
2
)
p
X—R
13
, —X(CH
2
)
p
CONR
11
SO
2
R
10
, (CH
2
)
p
XCONR
11
SO
2
R
10
or X(CH
2
)
p
R
6
wherein each methylene group within —X(CH
2
)
q
R
6
may be unsubstituted or substituted by one or two —(CH
2
)
p
Ar groups;
R
8
is hydrogen, R
10
, OH, C
1-5
alkoxy, S(O)
q
R
10
, N(R
4
)
2
, Br, F, I, Cl or NHCOR
4
wherein the C
1-5
alkoxy may be unsubstituted or substituted by OH, methoxy or halogen;
R
10
is hydrogen, Ar, C
1-10
alkyl, C
2-10
alkenyl, C
2-10
alkynyl, all of which may be unsubstituted or substituted by one or more OH,.CH
2
OH, N(R
4
)
2
or halogen; or R
10
is N(R
4
)
2
;
R
11
is independently hydrogen, C
1-10
alkyl, C
2-10
alkenyl or C
2-8
alkynyl, all of which may be unsubstituted or substituted by one or more OH, N(R
4
)
2
, CO
2
R
14
, halogen or XC
1-5
alkyl; or R
11
is (CH
2
)
p
Ar;
R
12
is divalent Ar, C
1-10
alkylene, C
1-10
alkylidene, C
2-10
alkenylene, C
2-10
alkynylene, all of which may be unsubstituted or substituted by one or more of OH, CH
2
OH, N(R
4
)
2
or halogen;
R
13
is a bond, C
1-10
alkylene, C
1-10
alkenylene, C
1-10
alkylidene, C
1-10
alkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one or more OH, N(R
4
)
2
, COOH or halogen;
R
14
is hydrogen, C
1-6
alkyl, C
2-6
alkenyl or C
2-7
alkynyl;
X is (CH
2
)
p
,O, NR
4
or S(O)
p
;
Y is CH
3
or X(CH
2
)
p
Ar;
q is zero, one or two;
p is an integer from 0 to 6;
m is 1, 2 or 3;
n is 1 to 4;
x is 0 to 4;
y is 1 or 2;
the dotted line signifies the optional presence of a bond such that it represents a single or double bond.
DETAILED DESCRIPTION
In one aspect of the invention, a method of treating or preventing a prostaglandin E mediated disease is described which comprises administering to a mammalian patient in need of such treatment or prevention a compound of formula I:
wherein:
R is a group Ar as defined hereinafter;
R
1
is hydrogen, hydroxy, C
1-6
alkyl, C
1-6
alkoxy, X(CH
2
)
p
Ar, or a methylenedioxy group attached to two adjacent ring carbon atoms;
R
2
is —(CH
2
)
x
C(O)N(R
4
)S(O)
y
R
5
, —(CH
2
)
x
S(O)
y
N(R
4
)C(O)R
5
, —(CH
2
)
x
C(O)N(R
4
)C(O)R
5
, —(CH
2
)
x
S(O)
y
N(R
4
)S(O)
y
R
5
, —(CH
2
)
x
CO
2
R
4
, or tetrazol-5-yl optionally substituted by C
1-6
alkyl;
R
3
is X(CH
2
)
p
Ar or X(CH
2
)
p
R
4
or a group of formula (a):
Ar is a group of formula (b) or (c):
 or Ar is naphthyl, indolyl, pyridyl, thienyl, furyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thriazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidinyl, all of which may be unsubstituted or substituted by one or more R
7
or R
8
groups;
A is C═O or (C(R
4
)
2
)
m
;
each B is independently —CH
2
— or —O—;
R
4
is hydrogen or C
1-6
alkyl;
R
5
is hydrogen or C
1-10
alkyl or Ar, both of which may be unsubstituted or substituted by one or two Cl, F, Br, hydroxy, XC
1-5
alkyl, C
1-5
alkyl, NO
2
, tetrazol-5-yl optionally substituted by C
1-6
alkyl, or R
5
is N(R
4
)
2
;
R
6
is hydrogen, R
10
, CO
2
R
11
, CO
2
C(R
10
)
2
O(CO)XR
11
, PO
3
(R
11
)
2
, SO
2
NR
11
R
10
, NR
11
SO
2
R
10
, CONR
11
SO
2
R
10
, SO
3
R
11
, S(O)
q
R
11
, S(O)
q
N(R
11
)C(O)R
10
, S(O)
q
N(R
11
)S(O)
q
R
10
, C(O)N(R
11
)C(O)R
10
, N(R
11
)C(O)R
10
, N(R
11
)
2
, N(R
11
)C(O)NR
11
, P(O)(OR
11
)R
11
, CN, —CO
2
(CH
2
)
m
C(O)N(R
4
)
2
, C(R
10
)
2
N(R
11
)
2
, C(O)N(R
4
)
2
, OR
4
or tetrazolyl optionally substituted by C1-6 alkyl;
R
7
and R
9
are independently hydrogen, R
10
, OH, C
1-8
alkoxy, S(O)
q
R
10
, N(R
4
)
2
, Br, F, I, Cl, CF
3
, NO
2
, NHCOR
4
, R
12
CO
2
R
11
, —X—R
13
—Y, —X(CR
4
)
p
OR
4
, S(CH
2
)
p
CO
2
H, (CH
2
)
p
X—R
13
, —X(CH
2
)
p
CONR
11
SO
2
R
10
, (CH
2
)
p
XCONR
11
SO
2
R
10
or X(CH
2
)
p
R
6
wherein each methylene group within —X(CH
2
)
q
R
6
may be unsubstituted or substituted by one or two —(CH
2
)
p
Ar groups;

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