Oxazole derivatives, their production and use

Details Oxazole derivatives, their production and use Oxazole derivatives, their production and use

1998-08-25

2001-01-23

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C348S146000, C348S183000, C348S226100, C348S236000

Reexamination Certificate

active

06177452

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel oxazole derivatives which are useful for prophylaxis and therapy of diabetes.
BACKGROUND ART
As agents for diabetes, heretofore, various biguanide compounds and sulfonylurea compounds have been used. However, biguanide compounds are not used at present, because these compounds induce undesirable side effects, such as lactic acidosis. Though having an excellent blood sugar-depressing effect, sulfonylurea compounds require care in use since they often induce grave hypoglycemia. Oxazole derivatives having a blood sugar-depressing effect and a sugar tolerance-improving effect are described in, for example, EP-92239, JP59-190979 and EP-382199.
The object of the present invention is to provide novel compounds which have an insulin secretion-promoting effect and a blood sugar-depressing effect, which are useful in agents for diabetes and which have low toxicity.
DISCLOSURE OF INVENTION
The novel oxazole derivatives represented by the following formula (I) have been found to possess an excellent blood sugar-depressing effect and insulin secretion-promoting effect. On the basis of this finding, we have completed the present invention.
Specifically, the present invention provides a compound of the following general formula (I):
wherein R
1
represents a halogen atom, or an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group; A represents an optionally substituted acyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, or an optionally esterified or amidated carboxy group; B represents an optionally substituted aromatic group; Y represents a divalent aliphatic hydrocarbon group, or a salt thereof, and a pharmaceutical composition comprising the compound (I) or a pharmaceutically acceptable salt as an active ingredient.
In the formula (I), the heterocyclic group of the optionally substituted heterocyclic group represented by R
1
or A may be a 5- or 6-membered ring having 1 to 4 atoms selected from N, O and S as the ring-constituting atoms other than carbon atom(s), or a condensed ring thereof. The condensed ring includes, for example, condensed rings comprising the 5- or 6-membered ring as condensed with any of a 6-membered ring having 1 or 2 nitrogen(s), a benzene ring or a 5-membered ring having one sulfur.
Typical examples of the heterocyclic group include aromatic heterocyclic groups such as pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g. 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g. 2-pyrazinyl), pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), isoxazolyl, isothiazolyl, thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), 1,2,4-oxadiazolyl (e.g. 1,2,4-oxadiazol-5-yl), 1,2,4-triazolyl (e.g. 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl), 1,2,3-triazolyl (e.g. 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl), benzimidazolyl (e.g. benzimidazol-1-yl, benzimidazol-2-yl), indolyl (e.g. indol-1-yl, indol-3-yl), 1H-indazolyl (e.g. 1H-indazol-1-yl), 1H-pyrrolo[2,3-b]pyrazinyl (e.g. 1H-pyrrolo[2,3-b]pyrazin-1-yl), 1H-pyrrolo[2,3-b]pyridyl (e.g. 1H-pyrrolo[2,3-b]pyridin-1-yl), 1H-imidazo[4,5-b]pyridyl (e.g. 1H-imidazo[4,5-b]pyridin-1-yl), 1H-imidazo[4,5-c]pyridyl (e.g. 1H-imidazo[4,5-c]pyridin-1-yl) and 1H-imidazo[4,5-b]pyrazinyl (e.g. 1H-imidazo[4,5-b]pyrazin-1-yl), and non-aromatic heterocyclic groups such as pyrrolidinyl (e.g. 1-pyrrolidinyl), piperidinyl (e.g. piperidino), morpholinyl (e.g. morpholino), piperazinyl (e.g. 1-piperazinyl), hexamethyleneiminyl (e.g. hexamethyleneimin-1-yl), oxazolidinyl (e.g. oxazolidin-3-yl), thiazolidinyl (e.g. thiazolidin-3-yl, thiazolidin-2-yl), imidazolidinyl (e.g. imidazolidin-3-yl), imidazolinyl (e.g. imidazolin-1-yl, imidazolin-2-yl), oxazolinyl (e.g. oxazolin-2-yl), thiazolinyl (e.g. thiazolin-2-yl), and oxazinyl (e.g. oxazin-2-yl).
Preferred examples of the heterocyclic group are an azolyl group (e.g. pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl), an azolinyl group (e.g. imidazolinyl, oxazolinyl, thiazolinyl), an azolidinyl group (e.g. pyrrolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl).
The heterocyclic group represented by R
1
or A may have 1 to 3 substituents at its substitutable positions. The substituents include, for example, an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group, a non-aromatic heterocyclic group, a halogen atom, a nitro group, an optionally substituted amino group, an optionally substituted acyl group, an optionally substituted hydroxy group, an optionally substituted thiol group, an optionally esterified or amidated carboxy group and oxo group.
Examples of an azolidinyl group substituted by 1 or 2 oxo group(s) are 2-oxoimidazolidinyl (e.g. 2-oxoimidazolidin-1-yl), 2,4-dioxoimidazolidinyl (e.g. 2,4-dioxoimidazolidin-3-yl), 2,4-dioxooxazolidinyl (e.g. 2,4-dioxooxazolidin-3-yl) or 2,4-dioxothiazolidinyl (e.g. 2,4-dioxothiazolidin-3-yl).
The aliphatic hydrocarbon group may be a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms such as, for example, an alkyl group, an alkenyl group and an alkynyl group.
Preferred examples of the alkyl group are alkyl groups having 1 to 10 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, hexyl, pentyl, octyl, nonyl and decyl.
Preferred examples of the alkenyl group are alkenyl groups having 2 to 10 carbon atoms such as, for example, vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
Preferred examples of the alkynyl group are alkynyl groups having 2 to 10 carbon atoms such as, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
The alicyclic hydrocarbon group may be a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms such as, for example, a cycloalkyl group, a cycloalkenyl group and a cycloalkadienyl group.
Preferred examples of the cycloalkyl group are cycloalkyl groups having 3 to 10 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl.
Preferred examples of the cycloalkenyl group are cycloalkenyl groups having 3 to 10 carbon atoms such as, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl.
Preferred examples of the cycloalkadienyl group are cycloalkadienyl groups having 4 to 10 carbon atoms such as, for example, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl and 2,5-cyclohexadien-1-yl.
The aryl group stands for a mono-cyclic or condensed poly-cyclic aromatic hydrocarbon group, and preferred examples of them are aryl groups having 6 to 14 carbon atoms such as, for example, phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl. More preferable are phenyl, 1-naphthyl and 2-naphthyl.
Preferred examples of the aromatic heterocyclic group include

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