Oxazole compounds as prostaglandin e2 agonists or antagonists

Details Oxazole compounds as prostaglandin e2 agonists or antagonists Oxazole compounds as prostaglandin e2 agonists or antagonists

2001-04-20

2002-08-20

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S471000

Reexamination Certificate

active

06437146

ABSTRACT:

TECHNICAL FIELD
This invention relates to prostaglandin E
2
agonist or antagonist such as oxazole compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some oxazole compounds are known, for example, in WO 95/17393, WO 95/24393 and WO 97/03973.
DISCLOSURE OF INVENTION
This invention relates to oxazole compounds. More particularly, this invention relates to oxazole compounds and pharmaceutically acceptable salts thereof which are useful as prostaglandin E
2
(hereinafter described as PGE
2
) agonist or antagonists.
Accordingly, one object of this invention is to provide new and useful oxazole compounds and pharmaceutically acceptable salts thereof.
Another object of this invention is to provide processes for preparing of the oxazole compounds or pharmaceutically acceptable salts thereof.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, said oxazole compounds or pharmaceutically acceptable salts thereof.
A still further object of this invention is to provide use of the oxazole compounds and pharmaceutically acceptable salts thereof for the manufacture of medicaments for treating or preventing PGE
2
mediated diseases.
A still more further object of this invention is to provide use of prostaglandin E
2
antagonist (especially, EP4 receptor blocker) such as oxazole compounds and pharmaceutically acceptable salts thereof for the manufacture of medicaments for treating or preventing mesangial proliferative glomerulonephritis.
The oxazole compounds of this invention can be represented by the following formula (I):
wherein
R
1
is aryl which may be substituted with halogen(s),
R
2
is aryl which may be substituted with halogen(s),
X is single bond
 or SO
2
,
R
3
and R
4
are independently hydrogen or suitable substituent,
(wherein X is
 neither R
3
nor R
4
is hydrogen),
R
3
and R
4
may be linked together to form
 is N-containing heterocyclic group which may be substituted with one or more suitable substituent(s),
R
5
is
(1) hydrogen,
(2) hydroxy,
(3) carboxy, or
(4) protected carboxy,
A
1
is lower alkylene or single bond,
 is cyclo(C
3
-C
9
)alkane or cyclo(C
5
-C
9
)alkene,
or a pro-drug thereof, or a pharmaceutically acceptable salt thereof.
The compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers. Furthermore certain compounds of formula (I) which contain alkenyl groups may exist as cis- or trans-isomers. In each instance, the invention includes both mixtures and separate individual isomers.
The compounds of the formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
The compound of the formula (I) and a salt thereof can be in a form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.
Also included in the scope of invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies, and any form of the crystal of the compound (I).
According to the present invention, the oxazole compounds (I) or a pharmaceutically acceptable salt thereof can be prepared by the following Processes 1 to 5.
wherein
R
1
is aryl which may be substituted with halogen(s),
R
2
is aryl which may be substituted with halogen(s),
X is single bond
 or SO
2
,
R
3
and R
4
are independently hydrogen or suitable substituent,
(wherein X is
 neither R
3
nor R
4
is hydrogen),
R
3
and R
4
may be linked together to form
 is N-containing heterocyclic group which may be substituted with one or more suitable substituent(s),
R
4a
is acyl which may be substituted with aryl,
R
5
is
(1) hydrogen,
(2) hydroxy,
(3) carboxy, or
(4) protected carboxy,
R
6
is acyl or hydroxy,
R
7
is lower alkyl, ar(lower)alkyl or aryl,
A
1
is lower alkylene or single bond,
 is cyclo(C
3
-C
9
)alkane or cyclo(C
5
-C
9
)alkene,
The starting compounds (II) or a salt thereof can be prepared according to a similar method described in WO 95/17393, below-mentioned Preparations, and the like.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.
Suitable “aryl” and aryl moiety in the terms “ar(lower)alkyl”, “aryloxy”, “ar(lower)alkenyl”, “arylsulfonyl”, “ar(lower)arylsulfonyl”, “ar(lower)alkylsulfonyl”, and “aryl oxysulfonyl” may include phenyl, lower alkylphenyl (e.g., tolyl, ethylphenyl, propylphenyl, etc.), naphthyl or the like.
Suitable “halogen” may include fluorine, chlorine, bromine, or iodine.
The term “lower” is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.
Suitable “lower alkyl” and lower alkyl moiety in the terms “lower alkylamino”, “ar(lower)alkyl”, “carboxy(lower)alkyl”, “hydroxy(lower)alkyl”, “ar(lower)alkylsulfonyl”, and lower alkylsulfonyl may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl or the like, preferably one having 1 to 4 carbon atom(s).
Suitable “lower alkylamino” may include mono- or di-(lower)alkylamino, such as methylamino, dimethylamino, ethylamino, diethylamino, or the like.
Suitable “lower alkoxy” and lower alkoxy moiety in the term “hydroxy(lower)alkoxy” may include methoxy, ethoxy propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, or the like, preferably methoxy.
Suitable “heterocyclic group” may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom. And especially preferable heterocyclic ring containing nitrogen may be ones such as
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidinyl, pyrazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g., 1H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.,;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azacycloheptyl, azacyclooctyl, perhydroazepinyl, etc.,;
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, 2,3-dihydroindolyl, isoindolyl, indolinyl, indazolyl, isoindolinyl, indolizinyl, benzimidazolyl, quinolyl, 1,2,3,4-tetrahydroquinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl,etc.,), dihydrotriazolopyridazinyl, etc.,;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 2,5-oxadiazolyl, etc.,), etc.,
saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholino, etc.,;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.,;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, thiepinyl, etc.,;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl), etc.,;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.,;
unsaturat

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