Oxazole compounds useful as PGE2 agonists and antagonists

Details Oxazole compounds useful as PGE2 agonists and antagonists Oxazole compounds useful as PGE2 agonists and antagonists

2000-03-08

2001-06-12

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S374000, C548S203000, C548S204000, C548S205000, C548S235000, C548S236000

Reexamination Certificate

active

06245790

ABSTRACT:

This application is a 371 of PCT/JP98/02398 filed Jun. 1, 1998.
TECHNICAL FIELD
This invention relates to azole compounds and its salts which are useful as a medicament.
BACKGROUND ART
Some azole compounds are known, for example, in WO 95/17393, WO 95/24393 and WO 97/03973.
DISCLOSURE OF INVENTION
This invention relates to azole compounds. More particularly, this invention relates to azole compounds and its salts 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 azole compounds and its salts.
Another object of this invention is to provide processes for production of the azole compounds or its salts.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, said azole compounds or its salts.
Still further object of this invention is to provide use of the azole compounds and its salts for manufacture of medicaments for treating or preventing PGE
2
mediated diseases.
The azole compounds of this invention can be represented by the following formula (I):
wherein R
1
is lower alkyl substituted with hydroxy, protected carboxy or carboxy; carboxy; protected carboxy; carbamoyl; a heterocyclic group; cyano; hydroxy; halo(lower)alkylsulfonyloxy; lower alkoxy optionally substituted with hydroxy or carbamoyl; aryl substituted with carboxy, protected carboxy, carbamoyl or a heterocyclic group; or amino optionally substituted with protected carboxy or lower alkylsulfonyl,
R
2
is hydrogen or lower alkyl,
R
3
is aryl optionally substituted with halogen,
R
4
is aryl optionally substituted with halogen,
Q is
 [in which —A
1
— is a single bond or lower alkylene,
 is cyclo(C
5
-C
9
)alkene, cyclo(C
3
-C
9
)alkane, bicyclo(C
6
-C
9
)alkene or bicyclo(C
5
-C
9
)alkane, and —A
3
— is a single bond or lower alkylene], and
X is O, NH or S.
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 its salt 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 azole compounds (I) or its salt can be prepared by the processes which are illustrated in the following scheme.
wherein R
1
, R
2
, R
3
, R
4
4
, —A
1
—,
 —A
3
—, Q and X are each as defined above,
R
a
1
is lower alkoxy,
R
b
1
is halo(lower)alkylsulfonyloxy,
R
c
1
is protected carboxy,
R
d
1
is carboxy,
R
e
1
is carbamoyl,
R
f
1
is lower alkoxy substituted with carbamoyl,
R
5
is lower alkoxy substituted with carboxy or protected carboxy,
 is cyclo(C
5
-C
9
)alkene or bicyclo(C
6
-C
9
)alkene,
 is cyclo(C
5
-C
9
)alkane or bicyclo(C
6
-C
9
)alkane, and
 is cyclo(C
5
-C
9
)alkane or bicyclo(C
6
-C
9
)alkane, each of which is substituted with hydroxy.
The starting compounds (II-1) and (II-2) or their salts can be prepared according to a similar method described in WO 95/17393 or the following process.
wherein R
1
, R
2
, R
3
, R
4
, —A
1
—,
 —A
3
—,
 and X are each as defined above,
R
5
is hydrogen or lower alkyl,
R
6
is hydrogen or lower alkyl,
 is cyclo(C
5
-C
9
)alkane or bicyclo(C
6
-C
9
)alkane, each of which has two hydroxy groups at adjacent carbon atoms, and
 is cyclo(C
5
-C
9
)alkane or bicyclo(C
6
-C
9
)alkane, each of which has epoxy group at adjacent carbon atoms.
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.
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 term “halo(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 alkylene” may include straight or branched one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene, preferably one having 1 to 3 carbon atom(s), more preferably methylene.
Suitable “cyclo(C
3
-C
9
)alkane” may include cyclopropane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, or the like preferably one having 5 to 7 carbon atoms.
Suitable “cyclo(C
5
-C
9
)alkene” may include cyclopentene, cyclohexene, cycloheptene, cyclooctene, or the like, preferably one having 5 to 7 carbon atoms.
Suitable “bicyclo(C
5
-C
9
)alkane” may include bicycloheptane (e.g., bicyclo[2.2.1]heptane, etc.), bicyclooctene (e.g., bicyclo[3.2.1]octane, etc.), or the like.
Suitable “bicyclo(C
6
-C
9
)alkene” may include bicycloheptene (e.g., bicyclo[2.2.1. ]hept-2-ene, etc.), bicyclooctene (e.g., bicyclo[3.2.1]oct-2-ene, etc.), or the like.
Suitable “aryl” may include phenyl, lower alkylphenyl (e.g., tolyl, ethylphenyl, propylphenyl, etc.), naphthyl or the like.
Suitable “heterocyclic group” may include one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic group, and preferable one may be heterocyclic group such as 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), or the like, more preferably tetrazolyl.
Suitable “lower alkoxy” may include methoxy, ethoxy propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, or the like preferably methoxy.
Suitable “protected carboxy” may include esterified carboxy or the like.
Suitable example of the ester moiety of an esterified carboxy may be the ones such as lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.) which may have at least one suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl [e.g., acetoxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, etc.], halo(lower)alkyl (e.g., 2-iodoethyl, 2,2,2-trichloroethyl, etc.); lower alkenyl (e.g., vinyl, allyl, etc.); lower alkynyl (e.g., ethynyl, propynyl, etc.); ar(lower)alkyl which may have at least one suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, etc.); aryl which may have at least one suitable substituent(s) (e.g., phenyl, tolyl, 4-chlorophenyl, tert-butylphenyl, xylyl, mesityl, cumenyl, etc.); phthalidyl; or the like.
Suitable “halo” group in the term of “halo(lower)alkylsulfonyl” may include fluoro, chloro, bromo, iodo, or the like.
Suitable “halo(lower)alkylsulfonyloxy” may include trifluoromethanesulfonyloxy, or the like.
Preferred embodiments of the azole compounds (I) are as follows:
R
1
is lower alkyl substituted with carboxy; carboxy; protected carboxy; carbamoyl; a heterocyclic group; lower alkoxy substituted with carbamoyl; aryl substituted with carboxy, carbamoyl or a heterocyclic group; or amino optionally substituted with lower alkylsulfonyl (more preferably lower alkyl substituted with

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