A novel compound of the formula:

The present invention relates to novel oxazole derivatives which are useful for prophylaxis and therapy of diabetes.
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.
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 R1 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 R1 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 R1 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 an aromatic mono-cyclic heterocyclic groups such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, and an aromatic condensed heterocyclic groups such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolidinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and 1,2,4-triazolo[4,3-b]pyridazinyl.
Preferred examples of the non-aromatic heterocyclic group include oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and pyrrolidinyl.
Examples of the halogen atom include fluorine, chlorine, bromine and iodine. More preferably are fluorine and bromine.
The optionally substituted amino group may be an amino group (xe2x80x94NH2) which may be mono- or di-substituted with, for example, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an acyl group having 1 to 10 carbon atoms (e.g. formyl, C1-9 alkyl-carbonyl such as acetyl) or an aromatic group having 6 to 12 carbon atoms (e.g. C6-12 aryl such as phenyl). The substituted amino group includes, for example, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, acetylamino, propionylamino, benzoylamino, phenylamino and N-methyl-N-phenylamino.
The acyl moiety of the optionally substituted acyl group may be an acyl group having 1 to 13 carbon atoms, including, for example, a formyl group, and a group to be formed by bonding between an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, a cycloalkenyl group having 3 to 10 carbon atoms or an aromatic group from 6 to 12 carbon atoms and a carbonyl group (e.g., C1-10 alkyl-carbonyl such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl; C3-10 cycloalkyl-carbonyl such as cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl; C2-10 alkenyl-carbonyl such as crotonyl; C3-10 cycloalkenyl-carbonyl such as 2-cyclohexenecarbonyl; C6-10 aryl-carbonyl such as benzoyl, nicotinoyl). The substituent of the substituted acyl group may include, for example, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom (e.g., chlorine, fluorine, bromine), a nitro group, a hydroxy group and an amino group.
The substituted hydroxy group of the optionally substituted hydroxy group includes, for example, an alkoxy group, an alkenyloxy group, an aralkyloxy group, an acyloxy group, an aryloxy group, an alkylsulfonyloxy group and an arylsulfonyloxy group.
Preferred examples of the alkoxy group are alkoxy groups having 1 to 10 carbon atoms such as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy and cyclohexyloxy.
Preferred examples of the alkenyloxy group are alkenyloxy groups having 2 to 10 carbon atoms such as, for example, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy and 2-cyclohexenylmethoxy.
Preferred examples of the aralkyloxy group include aralkyloxy groups having 7 to 10 carbon atoms, for example, phenyl-C1-4 alkyloxy group (e.g., benzyloxy, phenethyloxy).
Preferred examples of the acyloxy group include acyloxy groups having 2 to 13 carbon atoms, more preferably alkanoyloxy groups having 2 to 4 carbon atoms (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy).
Preferred examples of the aryloxy group are aryloxy groups having 6 to 14 carbon atoms such as, for example, phenoxy and naphthyloxy. The aryloxy group may have 1 or 2 substituents such as, for example, a halogen atom (e.g., chlorine, fluorine, bromine), or an alkoxy group having 1 to 4 carbon atoms. The substituted aryloxy group includes, for example, 4-chlorophenoxy and 2-methoxyphenoxy.
Preferred examples of the alkylsulfonyloxy group are alkylsulfonyloxy groups having 1 to 10 carbon atoms such as, for example, methylsulfonyloxy and ethylsulfonyloxy.
Preferred examples of the arylsulfonyloxy are arylsulfonyloxy groups having 6 to 12 carbon atoms (which may be substituted by a C1-6 alkyl) such as, for example, phenylsulfonyl, 4-methylsulfonyl.
The substituted thiol group (substituted mercapto group) of the optionally substituted thiol group (optionally substituted mercapto group) includes, for example, an alkylthio group, an arylthio group, a heteroarylthio group, an aralkylthio group, a heteroarylalkylthio group and an acylthio group.
Preferred examples of the alkylthio group are alkylthio groups having 1 to 10 carbon atoms such as, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, t-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio.
Preferred examples of the arylthio group are arylthio groups having 6 to 14 carbon atoms which may be substituted by a C1-6 alkyl group such as, for example, phenylthio, 4-phenylthio and naphthylthio.
The heteroarylthio group includes, for example, thiol groups substituted by any of the above-mentioned aromatic heterocyclic groups. Preferable examples of them are 2-pyridylthio, 3-pyridylthio, 2-imidazolylthio and 1,2,4-triazol-5-ylthio.
Preferred examples of the aralkylthio group are aralkylthio groups having 7 to 10 carbon atoms such as, for example, phenyl-C1-4 alkylthio groups (e.g., benzylthio, phenethylthio).
The heteroarylalkylthio group includes, for example, alkylthio groups substituted by any of the above-mentioned aromatic heterocyclic group. The alkylthio moiety of the heteroarylaklylthio group are the same as the above-mentioned alkylthio group. Preferred examples of the heteroarylalkylthio group include pyridyl-C1-4 alkylthio groups (e.g., 2-pyridylmethylthio, 3-pyridylmethylthio).
Preferred examples of the acylthio group are acylthio groups having 2 to 13 carbon atoms, more preferably alkanoylthio groups having 2 to 4 carbon atoms (e.g., acetylthio, propionylthio, butyrylthio, isobutytylthio).
The esterified carboxy group of the optionally esterified or amidated carboxy group includes, for example, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group and a heteroarylalkyloxycarbonyl.
Preferred examples of the alkoxycarbonyl group are alkoxycarbonyl groups having 2 to 5 carbon atoms such as, for example, C1-4 alkoxy-carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl).
Preferred examples of the aralkyloxycarbonyl group are aralkyloxycarbonyl groups having 8 to 10 carbon atoms such as, for example, C7-9 aralkyloxy-carbonyl (e.g. benzyloxycarbonyl).
Preferred examples of the aryloxycarbonyl group are aryloxycarbonyl groups having 7 to 15 carbon atoms such as for example, C6-14 aryloxy-carbonyl (e.g. phenoxycarbonyl and p-tolyloxycarbonyl).
The heteroarylalkyloxycarbonyl group includes, for example, alkyloxycarbonyl groups substituted with any of the above-mentioned aromatic heterocyclic groups. The alkyloxycarbonyl moiety of the heteroarylalkyloxycarbonyl are the same as the above-mentioned alkoxycarbonyl. Preferred examples of the heteroarylalkyloxycarbonyl group include pyridyl-C1-4 alkoxy-carbonyl groups (e.g., 2-pyridylmethoxycarbonyl, 3-pyridylmethoxycarbonyl).
The amidated carboxyl group of the optionally esterified or amidated carboxyl group includes, for example, a group of formula: xe2x80x94CON(R5)(R6), wherein R5 and R6 may be the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted heterocyclic group. The hydrocarbon groups of the optionally substituted hydrocarbon group represented by R5 or R6 includes, for example, an aliphatic hydrocarbon group, an alicyclic hydrocarbon group and an aryl group, which have been referred to hereinabove as the examples of the substituent for the heterocyclic group of R1 or A. The substituted hydroxy group of the optionally substituted hydroxy group represented by R5 or R6 may be the substituted hydroxy group of R1 or A. The heterocyclic group of the optionally substituted heterocyclic group represented by R5 or R6 may be an aromatic heterocyclic group which is referred to hereinabove as the examples of the substituent for the heterocyclic group of R1 or A. Regarding the substituents of R5 or R6, the group may be substituted by 1 to 3 substituents selected from a halogen atom (e.g., chlorine, fluorine, bromine, iodine), an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms.
In the formula (I), an alicyclic hydrocarbon group, an aryl group, an aromatic heterocyclic group or a non-aromatic heterocyclic group for the substituent on the heterocyclic group may be substituted by one or more, preferably 1 to 3 suitable substituents. Such substituents include, for example, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 14 carbon atoms (e.g., phenyl, naphthyl), an aromatic heterocyclic group (e.g., thienyl, furyl, pyridyl, oxazolyl, thiazolyl), a non-aromatic heterocyclic group (e.g., tetrahydrofuryl, morpholino, piperidino, pyrrolidino, piperazino), an aralkyl group having 7 to 9 carbon atoms (e.g. benzyl), an amino group, an N-mono(C1-4)alkylamino group, an N,N-di(C1-4)alkylamino group, an acylamino group having 2 to 8 carbon atoms (e.g., C1-7 alkyl-carbonylamino such as acetylamino, propionylamino; benzoylamino), an amidino group, an acyl group having 2 to 8 carbon atoms (e.g., C1-7 alkyl-carbonyl such as acetyl, benzoyl), a carbamoyl group, an N-mono(C1-4)alkylcarbamoyl group, an N,N-di(C1-4)alkylcarbamoyl group, a sulfamoyl group, an N-mono(C1-4)alkylsulfamoyl group, an N,N-di(C1-4)alkylsulfamoyl group, a carboxy group, an alkoxycarbonyl group having 2 to 8 carbon atoms, a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an alkenyloxy group having 2 to 5 carbon atoms, a cycloalkyloxy group having 3 to 7 carbon atoms, an aralkyloxy group having 7 to 9 carbon atoms (e.g. benzyloxy), an aryloxy group having 6 to 14 carbon atoms (e.g., phenyloxy, naphthyloxy), a mercapto group, an alkylthio group having 1 to 4 carbon atoms, an aralkylthio group having 7 to 9 carbon atoms (e.g. benzylthio), an arylthio group having 6 to 14 carbon atoms (e.g., phenylthio, naphthylthio), a sulfo group, a cyano group, an azido group, a nitro group, a nitroso group and a halogen atom (e.g., fluorine, chlorine, bromine, iodine).
In the formula (I), as the halogen atom, the optionally substituted hydroxy group, the optionally substituted thiol group and the optionally substituted amino group represented by R1, are those that are mentioned hereinabove as the examples of the substituents for the heterocyclic group represented by R1 or A.
In the formula (I), R1 is preferably an optionally substituted heterocyclic group.
In the formula (I), as the optionally substituted acyl group, the optionally substituted hydroxy group, and the optionally esterified or amidated carboxy group represented by A are those that are mentioned hereinabove as the examples of the substituents for the heterocyclic group represented by R1 or A.
In the formula (I), A is preferably an optionally substituted heterocyclic group or an optionally substituted hydroxy group.
In the formula (I), the aromatic group of the optionally substituted aromatic group represented by B includes, for example, an aromatic hydrocarbon group and an aromatic heterocyclic group.
Preferred examples of the aromatic hydrocarbon group are aromatic hydrocarbon groups having 6 to 14 carbon atoms such as for example, C6-14 aryl group such as phenyl and naphthyl.
Preferred examples of the aromatic heterocyclic group are those that are mentioned hereinabove as the examples of the substituent for the heterocyclic group represented by R1 or A. More preferable are furyl, thienyl, pyridyl and quinolyl.
Regarding the optionally substituted aromatic group represented by B, it may be substituted by 1 to 3 substituents selected from, for example, a halogen atom, a nitro group, a cyano group, an optionally substituted alkoxy group, an optionally substituted alkyl group and an optionally substituted cycloalkyl group.
The halogen atom includes, for example, fluorine, chlorine, bromine and iodine.
Examples of the alkoxy group of the optionally substituted alkoxy group are those that are mentioned hereinabove as the examples of the substituent for the heterocyclic group represented by R1 or A. More preferable are linear or branched alkoxy groups having 1 to 6 carbon atoms.
Examples of the alkyl group of the optionally substituted alkyl group are those that are mentioned hereinabove as the examples of the substituent for the heterocyclic group represented by R1 or A. More preferable are linear or branched alkyl groups having 1 to 6 carbon atoms.
Examples of the cycloalkyl group of the optionally substituted cycloalkyl group are those that are mentioned hereinabove as the examples of the substituent for the heterocyclic group represented by R1 or A. More preferable are cycloalkyl groups having 3 to 7 carbon atoms.
Regarding the above-mentioned optionally substituted alkoxy, alkyl and cycloalkyl groups, each of these groups may be substituted by 1 to 3 substituents selected from, for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a hydroxy group and an alkoxy group having 1 to 6 carbon atoms.
The substituted alkoxy group includes, for example, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy and 1,1-difluoroethoxy.
The substituted alkyl group includes, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, 1-hydroxymethyl, methoxymethyl, ethoxymethyl, 2-methoxymethyl and 2,2-dimethoxyethyl.
In the formula (I), B is preferably an optionally substituted aromatic hydrocarbon group, and more preferably an optionally substituted phenyl group.
In the formula (I), the divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms represented by Y may be either linear or branched, and may be either saturated or unsaturated. Typical examples of the aliphatic hydrocarbon group include saturated groups such as xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94CH(C2H5)xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94 and xe2x80x94(CH2)7xe2x80x94, and unsaturated groups such as xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94C(C2H5)xe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 and xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94. Y is preferably a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, and is more preferably the saturated one. Preferred examples of Y are xe2x80x94(CH2)3xe2x80x94 and xe2x80x94(CH2)2xe2x80x94.
Preferred examples of the compound (I) of this invention are as follows.
(1) In the formula (I), R1 is an optionally substituted heterocyclic group, and a preferred example of the heterocyclic group is 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 comprising the 5- or 6-membered ring as condensed with any of a 6-membered ring having 1 or 2 nitrogen, a benzene ring or a 5-membered ring having one sulfur, and a more preferred example of the heterocyclic group is an azolyl group.
(2) In the formula (I), A is an optionally substituted heterocyclic group, preferred example of the heterocyclic group is 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 comprising the 5- or 6-membered ring as condensed with a 6-membered ring having 1 or 2 nitrogen, a benzene ring or a 5-membered ring having one sulfur, and more preferred example of the heterocyclic group is an azolyl, azolinyl or azolidinyl group.
(3) In the formula (I), the optionally substituted heterocyclic group represented by R1 and A is a 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, tetrazol-1-yl, tetrazol-5-yl, benzimidazol-1-yl, benzimidazol-2-yl, indol-1-yl, indol-3-yl, 1H-indazol-1-yl, 1H-pyrrolo[2,3-b]pyrazin-1-yl, 1H-pyrrolo[2,3-b]pyridin-1-yl, 1H-imidazo[4,5-b]pyridin-1-yl, 1H-imidazo[4,5-c]pyridin-1-yl, 1H-imidazo[4,5-b]pyrazin-1-yl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, hexamethyleneimin-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-3-yl, imidazolin-1-yl, imidazolin-2-yl, oxazolin-2-yl, thiazolin-2-yl, oxazin-2-yl, 2-oxoimidazolidin-1-yl, 2,4-dioxoimidazolidin-3-yl, 2,4-dioxooxazolidin-3-yl or 2,4-dioxothiazolidin-3-yl group which may be substituted by 1 to 3 substituents selected from the group consisting of 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 and an optionally esterified or amidated carboxy group.
(4) In the formula (I), A is an optionally substituted hydroxy group.
(5) In the formula (I), Y is a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms, and more preferable a divalent aliphatic hydrocarbon group having 2 to 4 carbon atoms.
(6) In the formula (I), R1 is (i) halogen, (ii) a imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, benzimidazolyl, pyrrolidinyl, piperidinyl, morphorinyl or hexamethyleneiminyl group which may be substituted by 1 to 3 substituents selected from the group consisting of C1-10 alkyl, C6-14 aryl and C1-10 alkylthio, (iii) a C1-10 alkoxy group, (iv) a C6-10 aryloxy group, (v) a C1-10 alkylthio group, (vi) a C6-14 arylthio which may be substituted by a C1-6 alkyl, (vii) a thiol group substituted by an imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or pyridyl group which may be substituted by a C1-6 alkyl or C6-14 aryl, (viii) a pyridyl-C1-4 alkylthio group, or (ix) an amino group which may be substituted by 1 or 2 C1-10 alkyl or C3-10 cycloalkyl;
A is (i) formyl group, (ii) an imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolidinyl, oxazolinyl, thiazolinyl, 2,4-dioxoimidazolidinyl, 2,4-dioxooxazolidinyl or 2,4-dioxothiazolidinyl group which may be substituted by a C1-10 alkyl group, (iii) hydroxy group, (iv) a C6-14 aryloxy group which may be substituted by a C1-4 alkoxy group, (v) a C1-10 alkylsulfonyloxy group, (vi) a C1-4 alkoxy-carbonyl group, (vii) a C7-9 aralkyloxy-carbonyl group, or (viii) a group of the formula: xe2x80x94CON(R5)(R6), wherein R5 and R6 are independently hydrogen atom, C1-10 alkyl which may be substituted by a halogen atom or a C1-10 alkoxy group;
B is a phenyl group which may be substituted by a halogen; Y is xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94 or xe2x80x94(CH2)6xe2x80x94.
(7) In the formula (I), R1 is an optionally substituted heterocyclic group; A is an optionally substituted heterocyclic group; and Y is a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms.
(8) In the above-mentioned (7), the heterocyclic group represented by R1 and A is an azolyl group, an azolinyl group or an azolidinyl group.
(9) In the above-mentioned (7), the heterocyclic group represented by R1 is an azolyl group, and the heterocyclic group represented by A is an azolyl group, an azolinyl group or an azolidinyl group.
(10) In the above-mentioned (7), R1 and A are independently a pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, imidazolinyl, oxazolinyl or thiazolinyl group which may be substituted by 1 to 3 substituents selected from the group consisting of C1-10 alkyl, C6-14 aryl, C1-10 alkylthio and oxo.
(11) In the above-mentioned (7), R1 is an azolyl group which may be substituted by 1 to 3 substituents selected from the group consisting of C1-10 alkyl, C6-14 aryl and C1-10 alkylthio.
(12) In the above-mentioned (11), the azolyl group is an imidazolyl, pyrazolyl, 1,2,4-triazolyl, or 1,2,3-triazolyl group.
(13) In the above-mentioned (7), A is an azolyl, azolinyl or azolidinyl group which may be substituted by 1 or 2 C1-10 alkyl or oxo.
(14) In the above-mentioned (7), A is an imidazolyl, pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, thiazolidinyl, oxazolinyl, thiazolinyl, 2,4-dioxoimidazolidinyl, 2,4-dioxooxazolidinyl or 2,4-dioxothiazolidinyl group which may be substituted by a C1-10 alkyl group.
(15) In the above-mentioned (7), B is an optionally substituted phenyl group.
(16) In the above-mentioned (7), B is a phenyl group which may be substiruted by a halogen atom.
(17) In the above-mentioned (7), Y is a divalent aliphatic hydrocarbon group having 3 to 5 carbon atoms.
(18) In the above-mentioned (7), Y is xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94 or xe2x80x94(CH2)5xe2x80x94.
(19) In the formula (I), R1 is an optionally substituted heterocyclic group; A is an optionally substituted hydroxy group; and Y is a divalent aliphatic hydrocarbon group having 1 to 7 carbon atoms.
(20) In the above-mentioned (19), the heterocyclic group represented by R1 is an azolyl group.
(21) In the above-mentioned (20), the azoyl group is a pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl or tetrazolyl group.
(22) In the above-mentioned (19), R1 is an azolyl group which may be substituted by 1 to 3 substituents selected from the group consisting of C1-10 alkyl, C6-14 aryl and C1-10 alkylthio.
(23) In the above-mentioned (22), the azolyl group is an imidazolyl, pyrazolyl, 1,2,4-triazolyl or 1,2,3-triazolyl group.
(24) In the above-mentioned (19), A is (i) a hydroxy group, (ii) a C1-10 alkoxy group, (iii) a C2-10 alkenyloxy group, (iv) a C7-10 aralkyloxy group, (v) a C2-13 acyloxy group, (vi) a C6-14 aryloxy group which may be substituted by 1 or 2 halogen or C1-4 alkoxy, or (vii) C1-10 alkylsulfonyloxy group, and more preferably a hydroxy group.
(25) In the above-mentioned (19), B is an optionally substituted phenyl group, and more preferably a phenyl group which may be substituted by a halogen.
(26) In the above-mentioned (19), Y is a divalent aliphatic hydrocarbon group having 3 to 5 carbon atoms, and more preferably xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94 or xe2x80x94(CH2)5xe2x80x94.
(27) In the formula (I), 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol or its salt, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanol or its salt, 4-(4-chlorophenyl)-5-[3-(1-imidazolyl)propyl]-2-(2-methyl-1-imidazolyl)oxazole or its salt, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepentanol or its salt, or 4-(4-chlorophenyl)-5-[4-(1-imidazolyl)butyl]-2-(2-methyl-1-imidazolyl)oxazole or its salt.
As the salts of compounds (I) of the present invention, preferred are pharmaceutically acceptable salts thereof, which include, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids. Preferred examples of the salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and also aluminum salts and ammonium salts. Preferred examples of the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N,Nxe2x80x2-dibenzylethylenediamine. Preferred examples of the salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid. Preferred examples of the salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. Preferred examples of the salts with basic amino acids include salts with arginine, lysine or ornithine; and preferred examples of the salts with acidic amino acids include salts with aspartic acid or glutamic acid. Of those salts, the most preferred are sodium salts and potassium salts.
The compounds (I) or their salts of the present invention may also be in the form of hydrates thereof.
The compounds (I) or their pharmaceutically acceptable salts of the present invention (hereinafter referred to as the compounds of the present invention) have a blood sugar lowering effect and an insulin secretion-promoting effect.
The compounds of the present invention can be used, either directly or after having been mixed with any of per-se known, pharmaceutically acceptable carriers, excipients, vehicles and others, as insulin secretion-promoting agents, agents for diabetes, agents for arteriosclerosis, antihyperlipemia, antihypertensive agents, and agents for diabetic complications (e.g., nephropathy, retinopathy, neuropathy), which are applicable to mammals (e.g., humans, mice, rats, rabbits, dogs, cats, bovines, horses, pigs, monkeys).
The compounds of the present invention are of low toxicity. For example, when the compound as obtained in Example 36, as described hereinafter, was orally administered to mice in an amount of 1 g/kg/day, there was no mortality at 5 days.
The compounds of the present invention are orally administered in any form of, for example, tablets, capsules (including soft capsules and microcapsules), powders and granules. As the case may be, however, they may also be parenterally administered for example, as injections, suppositories or pellets. The dose of the compounds of the present invention varies depending on the objects to which they are administered, the administration routes to be employed, and the conditions to which they are directed to. For example, when they are orally administered to adults, the dose thereof may be desirably from 1 to 500 mg/kg/day, preferably from 10 to 150 mg/kg/day, and it may be administered by dividing into 1 to 3 portions.
The pharmaceutical composition of the present invention can be produced by blending the compound of the invention with pharmaceutically acceptable carriers. The pharmaceutical composition may be produced according to any conventional means that are known in the field of formulations. The pharmaceutical composition may be in any form of solid preparations such as tablets, capsules, granules or powders, or liquid preparations such as syrups or injections. These can be administered to mammals such as those mentioned hereinabove, either orally or parenterally.
The pharmaceutical composition of the present invention can be used in insulin secretion-promoting agents, agents for diabetes, agents for arteriosclerosis, antihyperlipemia, antihypertensive agents, and agents for diabetic complications (e.g., nephropathy, retinopathy, neuropathy), and is used especially preferably in insulin secretion-promoting agents and agents for diabetes.
And the compound (I) of the present invention can be given, to the same object, agents for diabetes, agents for diabetic complications, antihyperlipemia or antihypertensive agents at the same time or time lag.
Examples of the agents for diabetes are insulin sensitivity-increasing agents (e.g. pioglitazone, troglitazone, BRL-49653, etc.), xcex1-glucosidase inhibitor (e.g. voglibose, acarbose, miglitol, etc.) and so on. Examples of the agents for diabetic complications are aldose reductase inhibitor (e.g. tolrestat, epalrestat, zenarestat, etc.) and so on. Examples of the antihyperlipemia are statins such as cholesterol-biosynthesis inhibitor (e.g. pravastatin, sinvastatin, lovastatin, cerivastatin, etc.), squalene synthetase inhibitor or fibrates having triglyceride lowering effect (e.g. bezafibrate, etc.). Examples of the antihypertensive agents are angiotensin converting enzyme inhibitor (e.g. captopril, enalapril, delapril, etc.), angiotensin II antagonist (e.g. losartan, candesartan, cilexetil, etc.) and so on.
The pharmaceutically acceptable carriers include various conventional, organic or inorganic carrier substances that are commonly used for formulation matter. For example, for solid preparations, employable carriers are excipients, lubricants, binders and disintegrators; and for liquid preparations, employable carriers are solvents, dissolution aids, suspending agents, isotonizing agents, buffers and analgesics. If desired, further employable carriers are any other pharmaceutical additives such as preservatives, antioxidants, colorants and sweeteners.
Preferred examples of excipients include lactose, white sugar, D-mannitol, starch, crystalline cellulose and light silicic acid anhydride.
Preferred examples of lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.
Preferred examples of binders include crystalline cellulose, white sugar, D-mannitol, trehalose, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and polyvinyl pyrrolidone.
Preferred examples of disintegrators include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium cross-carmellose and sodium carboxymethyl starch.
Preferred examples of solvents are water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and tricaprylin.
Preferred examples of dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate.
Preferred examples of suspending agents include surfactants such as stearyltriethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerol monostearate; and also hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
Preferred examples of isotonizing agents include sodium chloride, glycerin and D-mannitol.
Preferred examples of buffers include those of phosphates, acetates, carbonates or citrates.
A preferred example of analgesics is benzyl alcohol.
Preferred examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
Preferred examples of antioxidants include sulfites, and ascorbic acid.
The compounds (I) of the present invention can be produced by per-se known methods. For example, the compounds (I) of the invention can be produced by the methods mentioned hereinafter or according to these, or by the methods described in EP-92239 and JP59-190979 or according to those methods.
In the formula (I), a compound represented by the formula (I-a):
wherein R1a is a halogen atom, and the other symbols are of the same meanings as defined above, or a salt thereof can be produced by reacting a compound represented by the formula:
wherein all symbols are of the same meanings as defined above, or a salt thereof with a halogenating agent, and a compound represented by the formula (I-b):
wherein R1b is an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group, corresponding to R1, and the other symbols are of the same meanings as defined above, or a salt thereof can be produced by reacting a compound (I-a) or a salt thereof with a compound represented by the formula:
R1bxe2x80x94H
wherein all symbols are of the same meanings as defined above, or a salt thereof.
wherein R2 represents an alkyl group having 1 to 5 carbon atoms; X represents a halogen atom; and the others are of the same meanings as mentioned above.
The alkyl group having 1 to 5 carbon atoms, represented by R2 may include those having 1 to 5 carbon atoms of the examples of the alkyl group as referred to herein above for the substituent for the heterocyclic group of R1 or A.
The halogen atom represented by X includes, for example, chlorine, fluorine and bromine.
Compounds (I-1) which correspond to compounds (I) where R1 is a halogen atom and A is an esterified carboxyl group, can be produced, for example, by haloqenation of compounds (II). This reaction may be conducted generally in the presence of a halogenating agent in a solvent that does not have any influence on the reaction. If desired, an excess amount of such a halogenating agent can be used for the solvent to effect the reaction.
The halogenating agent includes, for example, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride and phosphorus tribromide. The amount of the halogenating agent to be used may be from 1 to 10 molar equivalents, preferably from 3 to 6 molar equivalents, relative to the compound (II).
The solvent that does not have any influence on the reaction includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene; pyridine; and mixed solvents of these.
The reaction temperature ranges generally from 20 to 180xc2x0 C., preferably from 50 to 130xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
The compounds (I-1) thus produced may be isolated and purified through any ordinary separating and isolating means, for example, through concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein all symbols are of the same meanings as mentioned above.
Compounds (I-3) which correspond to compounds (I) where A is a carboxyl group, can be produced, for example, by hydrolysis of compounds (I-2). This reaction may be conducted in any ordinary manner, for example, in the presence of a base or an acid in an aqueous solvent.
The aqueous solvent may be a mixed solvent comprising water and any of alcohols (methanol and ethanol), ethers (e.g. tetrahydrofuran and dioxane), dimethylsulfoxide and acetone.
The acid includes, for example, hydrochloric acid, sulfuric acid, acetic acid and hydrobromic acid. The base includes, for example, potassium carbonate, sodium carbonate, sodium methoxide, potassium hydroxide, sodium hydroxide and lithium hydroxide. It is desirable that the acid or base to be used is excess over the compound (I-2) (for example, from about 1.2 to about 5 equivalents of the base, or from about 2 to about 50 equivalents of the acid).
The reaction temperature ranges generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably from xe2x88x9210xc2x0 C. to 100xc2x0 C. The reaction time ranges from 0.1 to 20 hours.
The compounds (I-3) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein R3 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; Z represents an optionally substituted heterocyclic, hydroxy, thiol or amino group; and the other symbols are of the same meanings as mentioned above.
The alkyl group having 1 to 5 carbon atoms, represented by R3 may include those having 1 to 5 carbon atoms as referred to hereinabove for the examples of the alkyl group to be the substituent for the heterocyclic group of R1 or A.
The optionally substituted heterocyclic, hydroxy, thiol or amino group which are represented by Z may include those as referred to hereinabove for the optionally substituted heterocyclic, hydroxy, thiol or amino group of R1.
Compounds (I-5) which correspond to compounds (I) where R1 is an optionally substituted heterocyclic, hydroxy, thiol or amino group, and A is an optionally esterified carboxy group, can be produced, for example, by reacting a compound (I-4) with a compound (XI). This reaction may be effected generally in the presence of a base in a solvent that does not have any influence on the reaction. Where Z is an optionally substituted amino group in the compound (XI), an excess amount of said compound (XI) can be used as the solvent.
The solvent that does not have any influence on the reaction includes, for example, alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; N,N-dimethylformamide, dimethylsulfoxide, acetone, water; and mixed solvents of these.
The base includes, for example, alkali metal salts such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate; metal hydrides such as sodium hydride; sodium ethoxide, and sodium methoxide.
The amount of the compound (XI) to be used may be generally from about 1 to about 10 molar equivalents relative to the compound (I-4). Where Z is an optionally substituted amino group in the compound (XI), the amount of the compound (XI) to be used may be generally from about 1 to about 50 molar equivalents relative to the compound (I-4).
The reaction temperature ranges generally from 20 to 180xc2x0 C., preferably from 80 to 140xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
The compounds (I-5) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein R4 represents an alkyl, aralkyl, heteroarylalkyl or acyl group; and the other symbols are of the same meanings as those mentioned above.
The alkyl, aralkyl, heteroarylalkyl or acyl group represented by R4, include the alkyl, aralkyl, heteroarylalkyl or acyl group of the alkylthio, aralkylthio, heteroarylalkylthio or acyl group that has been mentioned hereinabove for the optionally substituted thiol group of R1.
Compounds (I-6) which correspond to compounds (I) where R1 is a substituted thiol group, and A is an optionally esterified carboxy group, can be produced, for example, by reacting a compound (III) with a compound (XII). This reaction may be conducted in the presence of a base in a solvent that does not have any influence on the reaction.
The base includes, for example, alkali metal salts such as potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogencarbonate; metal hydrides such as sodium hydride; sodium methoxide, and sodium ethoxide.
The solvent that does not have any influence on the reaction includes, for example, ethers such as tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene and xylene; N,N-dimethylformamide, dimethylsulfoxide, acetone, water; and mixed solvents of these.
The amount of the compound (XII) to be used may be from about 1 to about 10 molar equivalents relative to the compound (III).
The reaction temperature ranges generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably from about 0 to about 100xc2x0 C. The reaction time ranges from 0.1 to 20 hours.
The compounds (I-6) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein Y1 represents a divalent aliphatic hydrocarbon group; and the other symbols are of the same meanings as those mentioned above.
Y1xe2x80x94CH2 represents a divalent aliphatic hydrocarbon group represented by the above-mentioned Y.
Compounds (I-8) which correspond to compounds (I) where A is a hydroxyl group, can be produced, for example, by reduction of compounds (I-7). This reaction may be conducted in any per-se known manner. Generally using a reducing agent, the reduction may be conducted in a solvent that does not have any influence on the reaction.
The reducing agent to be used includes, for example, metal hydrides such as alkali metal borohydrides (e.g., sodium borohydride, lithium borohydride), metal-hydrogen complexes (e.g. lithium aluminium hydride), organic tin compounds (e.g. triphenyl tin hydride), diborane, and substituted boranes.
The solvent that does not have any influence on the reaction includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride; ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; N,N-dimethylformamide; and mixed solvents of these. These solvents may be suitably selected, depending on the type of the reducing agent used.
The reaction temperature ranges generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably from about 0 to about 100xc2x0 C. The reaction time ranges from 0.1 to 10 hours.
The compounds (I-8) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein all symbols are of the same meanings as those mentioned above.
Compounds (I-9) which correspond to compounds (I) where A is a formyl group, can be produced, for example, by oxidation of compounds (I-8). This reaction may be conducted in any per-se known manner. The oxidation may be effected, for example, with manganese dioxide, chromic acid, dimethylsulfoxide or the like.
Where the oxidation is conducted with dimethylsulfoxide, the reaction may be conducted in the presence of an electrophilic reagent in a solvent that does not have any influence on the reaction.
The electrophilic reagent includes, for example, acetic anhydride, phosphoric anhydride, oxalyl chloride, dicyclohexylcarbodiimide and chlorine. The amount of the electrophilic reagent to be used may be generally an equimolar amount relative to dimethylsulfoxide.
The solvent that does not have any influence on the reaction includes, for example, halogenated hydrocarbons such as chloroform and dichloromethane; and aromatic hydrocarbons such as benzene, and toluene.
The amount of dimethylsulfoxide to be used may be from 1 to 5 molar equivalents, preferably from 1 to 2 molar equivalents, relative to the compound (I-8).
The reaction temperature ranges generally from xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably from about 0 to about 60xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
The compounds (I-9) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer chromatography or the like.
wherein all symbols are of the same meanings as those mentioned above.
Compounds (I-10) which correspond to compounds (I) where A is a substituted hydroxy group, can be produced, for example, by acylation of compounds (I-8). This reaction may be conducted in any per-se known manner. The acylation may be effected, for example, according to a method of directly condensing the compound (I-8) with a carboxylic acid derivative (R4CO2H), using a dehydrating agent (e.g., dicyclohexylcarbodiimide), or according to a method of suitably reacting the compound (I-8) with a reactive derivative of such a carboxylic acid derivative (R4CO2H). The reactive derivative of a carboxylic acid derivative (R4CO2H) includes, for example, acid anhydrides, acid halides (e.g., acid chlorides, acid bromides), imidazolides, and mixed acid anhydrides (e.g., anhydrides with methyl carbonate, ethyl carbonate or isobutyl carbonate).
Of these, the most simple method is to use such an acid chloride or acid anhydride, in which the intended reaction is conducted in the presence of a base in a solvent that does not have any influence on the reaction.
The base includes, for example, triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogencarbonate, potassium carbonate and sodium carbonate.
The solvent that does not have any influence on the reaction includes, for example, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethyl acetate; and tetrahydrofuran.
The amount of the acid chloride or acid anhydride to be used may be from about 1 to about 5 molar equivalents relative to the compound (I-8).
The reaction temperature ranges from about xe2x88x9230xc2x0 C. to about 100xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
The compounds (I-10) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein E represents a halogen atom or OSO2R4; Z1 represents an optionally substituted heterocyclic or hydroxy group; and the other symbols are of the same meanings as those mentioned above.
The halogen atom represented by E includes, for example, chlorine, fluorine and bromine atoms.
The optionally substituted heterocyclic or hydroxy group represented by Z1 may include the examples of the optionally substituted heterocyclic or hydroxy group as referred to hereinabove for R1.
Compounds (I-11) which correspond to the compounds (I) where A is an optionally substituted heterocyclic or hydroxy group, can be produced, for example, by condensation of a compound (IV or I-20) with a compound (XIII). This reaction may be conducted in any ordinary manner, in the presence of a base in a solvent that does not have any influence on the reaction.
The base includes, for example, alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate and potassium carbonate; amines such as pyridine, triethylamine and N,N-dimethylaniline; metal hydrides such as potassium hydride and sodium hydride; sodium methoxide, sodium ethoxide, and potassium t-butoxide. The amount of the base to be used may be preferably from 1 to 5 molar equivalents relative to the compound (IV or I-20).
The solvent that does not have any influence on the reaction includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and dioxane; ketones such as acetone and 2-butanone; halogenated hydrocarbons such as chloroform and dichloromethane; N,N-dimethylformamide, dimethylsulfoxide; and mixed solvents of these.
The reaction temperature ranges generally from xe2x88x9250xc2x0 C. to 150xc2x0 C., preferably from about xe2x88x9210xc2x0 C. to about 100xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
The compounds (I-11) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein all symbols are of the same meanings as those mentioned above.
Compounds (I-11) which correspond to the compounds (I) where A is an optionally substituted heterocyclic or hydroxy group, can be produced, for example, by condensation of a compound (I-8) with a compound (XIII). This reaction may be conducted in any ordinary manner, in the presence of an organic phosphorus compound and an electrophilic reagent in a solvent that does not have any influence on the reaction.
The organic phosphorus compound includes, for example, triphenylphosphine and tributylphosphine. The electrophilic reagent includes, for example, diethyl azodicarboxylate, diisopropyl azodicarboxylate and azodicarbonylpiperazine. The amount of the organic phosphorus compound and that of the electrophilic reagent may be preferably from 1 to 5 molar equivalents each, relative to the compound (I-8).
The solvent that does not have any influence on the reaction includes, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; N,N-dimethylformamide, dimethylsulfoxide; and mixed solvents of these.
The reaction temperature ranges generally from xe2x88x9250xc2x0 C. to 150xc2x0 C., preferably from about xe2x88x9210xc2x0 C. to about 100xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
The compounds. (I-11) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein all symbols are of the same meanings as those mentioned above.
Compounds (I-12) which correspond to the compounds (I) where A is an amidated carboxy group, can be produced, for example, by reacting a compound (I-7) with a compound (XIV).
Where R3 is an alkyl group having 1 to 5 carbon atoms in the compound (I-7), the reaction may be conducted in the presence of a solvent that does not have any influence on the reaction or in the presence of no solvent.
The solvent that does not have any influence on the reaction includes, for example, alcohols such as methanol and ethanol; aromatic hydrocarbons such as toluene and xylene; pyridine, N,N-dimethylformamide, and dimethylsulfoxide.
The amount of the compound (XIV) to be used is preferably an excess one over the compound (I-7).
The reaction temperature ranges from 20 to 200xc2x0 C., and the reaction time ranges from 0.1 to 20 hours.
Where R3 is a hydrogen atom in the compound (I-7), the reaction may be conducted according to a method of directly condensing the compound (I-7) with the compound (XIV) in the presence of a dehydrating agent (e.g., dicyclohexylcarbodiimide), or a method of suitably reacting a reactive derivative of the compound (I-7) with the compound (XIV). In this reaction, the reactive derivative of the compound (I-7) includes, for example, acid anhydrides, acid halides (e.g., acid chlorides, acid bromides), imidazolides, and mixed acid anhydrides (e.g., anhydrides with methyl carbonate, ethyl carbonate or isobutyl carbonate).
Of these, the most simple method is to use such an acid halide or mixed acid anhydride.
For example, when an acid halide is used, the reaction may be conducted in the presence of a base in a solvent that does not have any influence on the reaction.
The base includes, for example, triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogencarbonate, potassium carbonate, and sodium carbonate.
The solvent that does not have any influence on the reaction includes, for example, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethyl acetate, tetrahydrofuran, water; and mixed solvents of these.
The amount of the compound (XIV) to be used may be from about 1 to about 1.5 molar equivalents relative to the compound (I-7).
The reaction temperature ranges from about xe2x88x9230xc2x0 C. to about 100xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
On the other hand, where a mixed acid anhydride is used, the compound (I-7) is first reacted with a chlorocarbonate (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, or isobutyl chlorocarbonate) in the presence of a base (e.g., triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogencarbonate, potassium carbonate, sodium carbonate), and then reacted with the compound (XIV). The amount of the compound (XIV) to be used may be from about 1 to about 1.5 molar equivalents relative to the compound (I-7).
This reaction may be conducted in a solvent that does not have any influence on the reaction. Such an inert solvent includes, for example, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethyl acetate, tetrahydrofuran, water; and mixed solvents of these.
The reaction temperature ranges from about xe2x88x9230xc2x0 C. to about 50xc2x0 C., and the reaction time ranges from 0.5 to 20 hours.
The compounds (I-12) thus produced may be isolated and purified through any ordinary separating and isolating means, for example, through concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, trans-solvation, chromatography or the like.
wherein n represents 2 or 3; and the other symbols are of the same meanings as those mentioned above.
Compounds (I-14) which correspond to the compounds (I) where A is a heterocyclic group, can be produced, for example, through cyclization of a compound (I-13).
This reaction may be conducted in the presence of a base in a solvent that does not have any influence on the reaction.
The base includes, for example, alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate and potassium carbonate; amines such as pyridine, triethylamine and N,N-dimethylaniline; metal hydrides such as potassium hydride and sodium hydride; sodium methoxide, sodium ethoxide, and potassium t-butoxide. The amount of the base to be used may be preferably from 1 to 5 molar equivalents relative to the compound (I-13).
The solvent that does not have any influence on the reaction includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene;
ethers such as tetrahydrofuran and dioxane; ketones such as acetone and 2-butanone; halogenated hydrocarbons such as chloroform and dichloromethane; N,N-dimethylformamide, dimethylsulfoxide; and mixed solvents of these.
The reaction temperature ranges generally from xe2x88x9250xc2x0 C. to 150xc2x0 C., preferably from about xe2x88x9210xc2x0 C. to about 100xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
The compounds (I-14) thus produced may be isolated and purified through any ordinary separating and isolating means, for example, through concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, trans-solvation, chromatography or the like.
wherein R7 represents an alkyl, aralkyl, aryl or heteroarylalkyl group; and the other symbols are of the same meanings as those mentioned above.
The alkyl, aralkyl, aryl or heteroarylalkyl group to represented by R7, include the examples of the alkyl, aralkyl, aryl or heteroarylalkyl moiety of the esterified carboxy group, or that is, the alkoxycarbonyl, aralkyloxycarbonyl, aryloxycarbonyl or heteroarylalkyloxycarbonyl group, that have been mentioned hereinabove for the substituent for R1 or A.
Compounds (I-15) which correspond to the compounds (I) where A is an esterified carboxy group, can be produced, for example, by reacting a compound (I-3) with a compound (XV). This reaction may be conducted in any ordinary manner, in the presence of a base in a solvent that does not have any influence on the reaction.
The base includes, for example, alkali metal salts such as potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydrogencarbonate, potassium carbonate and sodium carbonate; metal hydrides such as sodium hydride; sodium methoxide, and sodium ethoxide.
The solvent that does not have any influence on the reaction includes, for example, ethers such as tetrahydrofuran and dioxane; ketones such as acetone and 2-butanone; N,N-dimethylformamide, dimethylsulfoxide; and mixed solvents of these.
The amount of the compound (XV) to be used may be preferably from about 1 to about 10 molar equivalents relative to the compound (I-3).
The reaction temperature ranges generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably from about 0xc2x0 C. to about 100xc2x0 C. The reaction time ranges from 0.5 to 20 hours. The compounds (I-15) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein all symbols are of the same meanings as those mentioned above.
The compound (I-16) can be produced by dehydroxylation of the compound (XVI). In this method, the compound (XVI) is directly reduced by silane, or the hydroxy group on the compound (XVI) is halogenated and further reduced. The reduction with silane is promoted by reaction with the compound (XVI) and triethylsilane or diethylsilane in trifluoro acetic acid. The halogenating agent includes, for example, thionyl chloride and phosphorus tribromide. For the reducing agent, metals such as iron, zinc are preferably used in hydrochloric acid or acetic acid.
The compounds (I-16) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extration, precipitation, recrystallization, phasic transfer, chromatography or the like.
The starting compounds(XVI) can be produced by the folowing Method N.
wherein all symbols are of the same meanings as those mentioned above.
In this method, the compound(XIX) can be produced by condensing the compound(XVII) and the compound(XVIII). This condensing reaction is the same manner as producing the compound(VII) by condensing the compound(V) and the compound(VI) as described in the Method R. Further, the compound(XX) can be produced by halogenating the compound(XIX). This halogenating reaction is the same manner as the halogenating reaction of the compound(II) as described in the Method A. The compound(XXI) can be produced by reacting with thus-obtained compound(XX) and the compound(XI). This reaction is conducted in the same manner as producing the compound(I-5) by reacting with the compound(I-4) and the compound(XI). Further, the compound(XVI) can be produced by reducing the compound(XXI). The reducting reaction is conducted in the same manner as the reacting reaction as described in the Method E.
wherein all symbols are of the same meanings as those mentioned above.
The compound(I-17) wherein A is a heterocyclic group in the compound(I) can be produced by reacting with the compound(I-9) and the compound(XXII). This reaction may be effected in any ordinary manner, for example, in the presence of a base or an acid in a solvent that does not have any influence on the reaction. The acid used in this reaction includes, for example, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and p-toluenesulfonic acid. The base used in this reaction includes, for example, sodium acetate and p-toluenesulfonyl pyridine.
The amount of the acid or the base to be used may be from about 0.1 to 2 molar equivalents relative to the compound(I-9).
The solvent that does not have any influence on the reaction includes, for example, aromatic hydrocarbons such as benzene, toluene; tetrahydrofuran; acetic acid.
The reaction temperature generally ranges from about xe2x88x9220 to 200xc2x0 C., preferably from about 0 to 150xc2x0 C. The reaction time ranges from about 0.5 to 20 hours.
The compounds (I-17) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extration, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein all symbols are of the same meanings as those mentioned above.
The compound(I-18) wherein A is a heterocyclic group in the compound(I) can be produced by reacting with the compound(XXIV) anad the compound(XXV). This reaction may be conducted in any ordinary manner in a solvent that does not have any influence on the reaction. The solvent that does not have any influence on the reaction includes, for example, alcohols such as methanol, ethanol, propanol, isopropanol; aromatic hydrocarbons such as benzene, toluene; tetrahydrofuran; N,N-dimethylformamide; pyridine; acetic acid.
The reaction temperature generally ranges from about xe2x88x9220 to 200xc2x0 C., preferably about 0 to 150xc2x0 C. The reaction time ranges from about 0.5 to 20 hours.
The compounds (I-18) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extration, precipitation, recrystallization, phasic transfer, chromatography or the like.
wherein all symbols are of the same meanings as those mentioned above.
The compound(XXIV) can be produced by dehydration of the compound(I-19). This reaction may be conducted in any ordinary manner in a solvent that does not have any influences on the reaction. The dehydrating agent includes, for example, sulfuric acid, acetic anhydride, phosphorus pentaoxide, phosphorus oxychloride. This solvent that does not have any influences on the reaction includes, for example, alcohols such as methanol, ethanol, propanol, isopropanol; aromatic hydrocarbons such as benzene, toluene; tetrahydrofuran; N,N-dimethylformamide.
The reaction temperature generally ranges from about xe2x88x9220 to 200xc2x0 C., preferably 0 to 150xc2x0 C. The reaction time ranges from about 0.5 to 20 hours.
The compounds (XXIV) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extration, precipitation, recrystallization, phasic transfer, chromatography or the like.
The starting compounds (II), (III) and (IV) to be used for the production of the compounds (I) of the invention can be produced by any per-se known methods. For example, these starting compounds can be produced by the methods mentioned hereinafter or according to these, or by the methods described in EP-92239 and JP59-190976 or according to those methods.
The starting compounds (II) for the Method A can be produced, for example, by the following method R.
wherein B1 represents an optionally substituted phenyl group; and the other symbols are of the same meanings as those mentioned above.
The substituent for the optionally substituted phenyl group represented by B1 includes, for example, an alkyl group having 1 to 4 carbon atoms (e.g., methyl), a halogen atom (e.g., chlorine), and a nitro group.
In this process, a compound (V) is first condensed with a compound (VI) to obtain a compound (VII). This reaction may be conducted in any ordinary manner, in the presence of a Lewis acid and in the presence of a solvent that does not have any influence on the reaction or in the presence of no solvent.
The Lewis acid includes, for example, aluminium chloride, titanium tetrachloride, tin tetrachloride, and boron trifluoride. The amount of the Lewis acid to be used may be preferably from 1 to 5 molar equivalents relative to the compound (V).
The solvent that does not any influence on the reaction includes, for example, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; carbon disulfide; and mixed solvents of these.
The amount of the compound (VI) to be used may be from 1 to 5 molar equivalents, preferably from 1 to 3 molar equivalents, relative to the compound (V).
The reaction temperature ranges generally from xe2x88x9220xc2x0 C. to 150xc2x0 C. preferably from about xe2x88x9210xc2x0 C. to about 80xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
Next, the compound (VII) is halogenated to obtain a compound (VIII). This reaction may be conducted in any ordinary manner, generally in the presence of a halogenating agent in a solvent that does not have any influence on the reaction.
The halogenating agent includes, for example, chlorine and bromine. The amount of the halogenating agent to be used may be preferably from 1 to 1.5 molar equivalents relative to the compound (VII).
The solvent that does not have any influence on the reaction includes, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as dichloromethane and chloroform; acetic acid; and mixed solvents of these.
The reaction temperature ranges generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably from about xe2x88x9210xc2x0 C. to about 80xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
Next, the thus-obtained compound (VIII) is suitably reacted with a salt of an organic acid in the presence of a solvent that does not have any influence on the reaction, to obtain a compound (IX).
The salt of an organic acid includes, for example, sodium formate, potassium formate, and sodium acetate. The amount of the salt may be from 1 to 20 molar equivalents, preferably from about 2 to about 10 molar equivalents, relative to the compound (VIII).
The solvent that does not have any influence on the reaction includes, for example, alcohols such as methanol and ethanol.
The reaction temperature ranges generally from 0 to 150xc2x0 C., preferably from about 30 to about 100xc2x0 C. The reaction time ranges from 1 to 50 hours.
Next, the resulting compound (IX) is reacted with a chlorocarbonate to obtain a compound (X). This reaction may be conducted in any ordinary manner, in the presence of a base in a solvent that does not have any influence on the reaction.
The base includes, for example, alkali metal salts such as potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate and potassium carbonate; and amines such as pyridine, triethylamine and N,N-dimethylaniline. The amount of the base to be used may be preferably from 2 to 5 molar equivalents relative to the compound (IX).
The solvent that does not have any influence on the reaction includes, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; N,N-dimethylformamide, dimethylsulfoxide; and mixed solvents of these.
The reaction temperature ranges generally from xe2x88x9250xc2x0 C. to 150xc2x0 C., preferably from about xe2x88x9230xc2x0 C. to about 0xc2x0 C. The reaction time ranges from 0.5 to 20 hours.
Next, the compound (X) is reacted with ammonia or its salt to obtain the intended compound (II). This reaction may be conducted generally in the presence of a solvent that does not have any influence on the reaction.
The ammonia or its salt includes, for example, ammonia gas, and ammonium acetate. For example, when such an ammonium salt is used, its amount may be from 1 to 20 molar equivalents relative to the compound (X).
The solvent that does not have any influence on the reaction includes, for example, ethers such as tetrahydrofuran and dioxane; acetic acid; and mixed solvents of these.
The reaction temperature ranges generally from 0 to 150xc2x0 C., preferably from about 50 to about 120xc2x0 C. The reaction temperature ranges from 0.5 to 20 hours.
The compounds (II) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
The starting compounds (III) for the Method D can be produced, for example, by the following method S.
wherein all symbols are of the same meanings as those mentioned above.
The compounds (III) can be produced by reacting a compound (I-1) with thiourea, thioacetic acid or its salt, in the presence of a base in a suitable solvent that does not have any influence on the reaction.
The base includes, for example, alkali metal salts such as potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium hydrogencarbonate, and potassium carbonate.
The solvent that does not have any influence on the reaction includes, for example, ethers such as tetrahydrofuran and dioxane; N,N-dimethylformamide, dimethylsulfoxide; and mixed solvents of these.
The amount of thiourea, thioacetic acid or its salt to be used may be from 1 to 20 molar equivalents, preferably from about 2 to about 10 molar equivalents, relative to the compound (I-1).
The reaction temperature ranges generally from 0 to 150xc2x0 C., preferably from about 50 to about 120xc2x0 C. The reaction time ranges from 0.1 to 20 hours.
The compounds (III) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.
The starting compounds (IV) for the Method H can be produced, for example, by the following method T.
wherein all symbols are of the same meanings as those mentioned above.
The compound (IV), wherein E is halogen, can be produced by reacting a compound (I-8) with a halogenating agent, and the compound (IV), wherein E is OSO2R4, can be produced by reacting a compound (I-8) with a sulfonylating agent.
Where a halogenating agent is used, it is preferably thionyl chloride, phosphorus tribromide or the like. In this case, produced are the compounds (IV) where E is chlorine or bromine. The amount of the halogenating agent to be used may be from about 1 to about 20 molar equivalents relative to the compound (I-8).
The reaction may be effected generally in a solvent that does not have any influence on the reaction (e.g., benzene, toluene, chloroform, dichloromethane). If desired, an excess amount of the halogenating agent may be used for the solvent.
The reaction temperature ranges generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably from about 10 to about 100xc2x0 C. The reaction time ranges 0.1 to 20 hours.
Where a sulfonylating agent is used, it is preferably mesyl chloride, tosyl chloride, benzenesulfonyl chloride or the like. In this case, produced are the compounds (I-20) where E is a mesyloxy, tosyloxy or benzenesulfonyloxy group, respectively.
The reaction may be conducted generally in the presence of a solvent that does not have any influence on the reaction, preferably in the presence of a suitable base.
The solvent that does not have any influence on the reaction includes, for example, aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as chloroform and dichloromethane; ethyl acetate, and tetrahydrofuran.
The base includes, for example, triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogencarbonate, potassium carbonate, and sodium carbonate.
The amount of the sulfonylating agent and that of the base to be used may be from about 1 to about 1.5 molar equivalents each, relative to the compound (I-8).
The reaction temperature ranges generally from xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably from about 10 to about 100xc2x0 C. The reaction time ranges from 0.1 to 20 hours.
The compounds (IV) thus produced may be isolated and purified through any ordinary separating and isolating means such as concentration, concentration under reduced pressure, solvent extraction, precipitation, recrystallization, phasic transfer, chromatography or the like.

Oxazole derivatives, their production and use

Abstract: A novel compound of the formula:

Abstract: wherein R1 is a halogen atom, an optionally substituted heterocyclic, hydroxy, thiol or amino group; A is an optionally substituted acyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, or an optionally esterified or amidated carboxy group; B is an optionally substituted aromatic group; Y is a divalent aliphatic hydrocarbon group, or a salt thereof, which have an excellent insulin secertion-promoting and blood sugar-depressing effect, and useful in agents for diabetes.


The present invention relates to a sol composition for forming an aerogel composite, wherein the sol composition is a sol composition with a sufficient pot life for forming an aerogel composite superior in thermal insulation and flexibility, and comprises: at least one selected from the group consisting of a silicon compound having a hydrolyzable functional group or a condensable functional group and a hydrolysis product of the silicon compound having a hydrolyzable functional group; and a silica particle having an average primary particle diameter of 5 to 300 nm or a specific surface area of 10 to 600 m2/g.

Silica aerogels are known as materials having thermal insulation with low thermal conductivity. Silica aerogels are useful as functional raw materials with superior functionality (e.g., thermal insulation), unique optical properties, unique electric properties, etc., and used for, for example, materials for electronic substrates, which utilize the property of an ultralow dielectric constant of a silica aerogel, thermal insulation materials, which utilize the high thermal insulation of a silica aerogel, and light reflective materials, which utilize the ultralow refractive index of a silica aerogel.
Supercritical drying is known as a method for producing such a silica aerogel, in which a gel compound (alcogel) obtained by hydrolyzing and polymerizing an alkoxysilane is dried under supercritical conditions for a dispersion medium (e.g., see Patent Literature 1). Supercritical drying is a method in which an alcogel and a dispersion medium (a solvent used for drying) are introduced into a high-pressure container, and a temperature and pressure equal to or higher than the critical point of the dispersion medium is applied to the dispersion medium to convert it into a supercritical fluid, thereby removing the solvent contained in the alcogel. However, supercritical drying requires a high-pressure process, and hence needs capital investment for special apparatuses or the like capable of enduring supercritical condition, as well as much time and effort.
In view of this, techniques of drying an alcogel with a versatile method without need of any high-pressure process have been proposed. A known example of such a method is a method in which monoalkyltrialkoxysilane and tetraalkoxysilane are used in combination with a specific ratio as gel materials to enhance the strength of the resulting alcogel, and the alcogel is dried under ambient pressure (e.g., see Patent Literature 2). When such ambient pressure drying is employed, however, the gel tends to shrink because of a stress caused by capillary force in the inside of the alcogel.

Sol composition, aerogel composite, support member provided with aerogel composite, and heat insulator


A magnetic buckle includes first and second buckle members. The first buckle member includes a first end and a second end adapted to engage a strap, a mounting surface, a latching aperture defined in the mounting surface, and a first magnet. A release direction extends along a longitudinal axis of the first buckle member from the first end to the second end. The second buckle member includes a joining surface adapted to be joined with the mounting surface, a latch hook adapted to engage the latching aperture extending from the joining surface, and a second magnet. The magnets pull the latch hook into engagement with the latching aperture when the joining surface is placed in proximity to the mounting surface. Engagement of the latching aperture by the latch hook prevents the second buckle member from being pulled apart from the first buckle member in a direction orthogonal to the mounting surface or against the release direction.

The invention relates generally to the field of closure devices, and more particularly, to buckles for releasably connecting two ends of one or more straps.
Buckles are used every day all over the world to releasably secure opposing ends of a belt around a user's body. Many conventional two-piece buckles have multiple moving and/or flexible parts which require two hands and significant dexterity to manipulate. Currently available magnetically-assisted buckles are no exception, as they too require appreciable fine motor skills to operate. For example, buckles with depressible release buttons, flexible arms, movable release catches can be particularly challenging to unlatch, especially with only one hand. The moving and/or flexible parts of such buckles also tend to wear out after a certain number of use cycles, requiring replacement of the worn part or the entire buckle. Accordingly, a need exists for a more durable buckle which can be operated with only one hand. What is needed then are improvements in buckles.


Coating media and their use in processes for producing single-layer and multi-layer coatings are described. The coating media contain an aqueous mixture comprising. I. 99-70% by weight of a mixture of PA1 II. 1-30% by weight of one or more binder vehicles (component C), which are miscible both with the binder vehicles of component A) at the storage temperature and with each other at the curing temperature of the coating media and which contain ionic groups, the charge of which is opposite to the charge of the ionic groups of component I), wherein the percentages by weight are given with respect to the weight of resin solids in each case and wherein the proportions of components I) and II) are matched to each other so that 0.5 to 70% of the number of charges of the ionic groups of I) are neutralised by the charges of the ionic groups of II), and PA1 III. customary lacquer additives and/or pigments and/or extenders, and optionally one or more customary lacquer solvents.. A) 50-100% by weight of one or more binder vehicles which at least in part contain ionic groups, PA2 B) 0-50% by weight of one or more crosslinking agents, which at least in part may contain ionic groups, for binder vehicle A), wherein the ionic groups which are present have the same charge as those of component A), and

When water-thinnable resins, particularly aqueous basecoats, are pigmented, problems generally arise in that the pigments agglomerate or settle out. In order to produce stable water-thinnable lacquers, it is necessary that the pigments are satisfactorily wetted and are ground to a suitable particle size. The latter is generally less than 10 .mu.m. When water-thinnable dispersions with a low content of solvent are used, these aqueous dispersions can be destroyed by the action of shear forces. It is therefore necessary in many cases to replace part of the binder vehicles by special binder vehicles, which are termed paste resins and in which the pigments are ground, in order to effect wetting of the pigment or additives. These pigment pastes may be solvent-containing or water-containing substances. They are subsequently mixed with the remaining water-thinnable binder vehicles and thus form the aqueous coating medium, e.g. a primer, a primer surfacer or a base lacquer.
At the same time, it is necessary that aqueous coating media are stable on storage. Therefore they must not settle out, and there should be no formation of agglomerations of binder vehicles or pigments, which impair the uniform smooth appearance of the coating on the subsequent application thereof.
Water-tinnable coating media for metallic base lacquers or binder vehicles therefor which have an anionic basis are described in EP-A-0 260 447, EP-A-0 297 576, DE-A-40 00 889 and EP-A-0 438 090, for example. Proportions of the anionic base resin or neutral melamin resins. are used here as paste resins for the grinding of pigments, for example, or special paste resins are used which contain carboxyl groups incorporated by reaction. After neutralisation and conversion of the binder vehicles into the aqueous phase, the pigments are ground. Coating media can be produced with these aqueous pigment pastes.
DE-A-40 11 633, DE-A-26 06 831 and EP-A-0 251 772 describe aqueous coating media based on cationic resins which are at least partially neutralised. These can be used as an electro-dip lacquer or as an aqueous base lacquer. The pigments are ground in a non-ionic wetting agent together with organic solvents, for example. These pigment pastes are then mixed with a binder vehicle which contains cationic groups and are subsequently diluted to form an aqueous coating medium. In addition, cationic paste resins are also described, e.g. epoxy resins containing sulphonium groups which are employed for the production of pigment pastes, which are then processed with cationic resins to form a cationic lacquer material.
The coating media which have been described hitherto therefore only comprise those with cationic or anionic binder vehicles which contain additives or paste resins comprising the same ionic groups or comprising non-ionic groups.
DE-A-38 23 731 describes aqueous, thermally curable coating media which contain at least two binder vehicles containing oppositely charged ionic groups. With these coating media it is essential that the binder vehicles which contain differently charged ionic groups are immiscible with each other at storage temperatures, i.e. below the curing temperature. Two separate resin phases are therefore present. The binder vehicles only become miscible under curing conditions, i.e. at elevated temperature. The amounts of resins have to be selected so that the numbers of different ionic groups are present in about the same order of magnitude.
EP-A-0 459 634 describes binder vehicles which contain, simultaneously, substituents which can be converted into anionic groups and substituents which can be converted into cationic groups. The anionic groups are neutralised and the binder vehicle is converted into the aqueous phase. After the addition of pigments and neutralising agents, coating media are obtained. Mixtures of resins which are neutralised differently are therefore not described. CA-A-2 017 505 describes binder vehicles for the coating of paper, which are produced by the emulsion polymerisation of monomers containing cationic groups in an aqueous solution of a polymeric dispersing agent which contains neutralised anionic groups. The dispersing agent has to be neutralised in excess with a volatile amine in order to obtain a stable emulsion. The dispersing agent is present in amounts such that salt formation occurs on heating after the paper has been coated, whereby a dry film is formed.
For water-thinnable binder vehicles which contain ionic groups and which are used in the lacquer industry, it is necessary to develop a pigment paste, the polarity of which is matched to that of the binder vehicles in each case. This results in a considerable amount of costly development work.

Aqueous coating media and their use in single-layer and multi-layer coating processes


A metrology system for measuring the magnetic properties of a magnetic recording medium layer on a device used for perpendicular recording.

Previously, in magnetic recording technology, increasingly higher data densities have been stored on disk drives using what is known as longitudinal recording techniques. As seen in FIG. 3 (Prior Art), in longitudinal recording the magnetization on the recording medium is switched between lying parallel and anti-parallel to the direction in which the write head is moving in relation to the surface. Although increases in areal densities of nearly 100 percent every year or two for the last several years have been achieved with longitudinal techniques, it is believed that the superparamagnetic limit is beginning to limit the capacities of this kind of recording. As a result, perpendicular recording is being adopted by many manufacturers to find ways to further increase areal density. In perpendicular recording, instead of "lying down" as it were, in same plane as the disk or magnetic surface, the bits are recorded "perpendicularly" in the magnetic surface. This enables much higher recording densities.
Perpendicular recording enables the use of media with higher coercivity. The write heads used to record data perpendicularly must generate much stronger magnetic fields as a result. The higher the coercivity, the more thermally stable and therefore, the less likely the medium is to succumb to superparamagnetic effect at higher than present recording densities. However, at the same time, this means that many of the conventional methods of measuring the magnetic properties of recording media may be inadequate for perpendicular recording applications, as they may not have sufficient magnetic field strength to switch the higher coercivity media.
Perpendicular recording media typically consist of at least a perpendicular recording layer and a soft magnetic underlayer (SUL). To switch magnetization in the perpendicular recording layer, a sufficient perpendicular magnetic field has to be applied. As seen in FIG. 5 (Prior Art) in a perpendicular hard disk drive, this is done with a microscopic single pole tip (SPT) write head 30 at near contact distance (of the order of 10 nanometer). In this situation, the SUL 12 functions as a magnetic flux feedback path for the SPT head, practically doubling the field of the head by the magnetic image effect.
For disk testers in line with production machines, a flying SPT head on a spin stand is not practical. At this point one needs to know the macroscopic magnetic properties such as MRT and HR for immediate process feedback. These properties need to be measured with great accuracy and repeatability (both fractions of a percent), over a large area of the disk, and it has to be done quickly (of the order of 1 disk per minute). For this purpose a macroscopic recording head is a good solution. Current art for longitudinal macroscopic disk measurement uses for example macroscopic heads of 2.5 mm wide, positioned at approximately 25-100 micrometer from the disk. The head is not actually flying, it is positioned to a predetermined distance. Typically 3 tracks are measured, an outer diameter (OD), middle diameter (MD) and inner diameter (ID) track.
For a perpendicular tester with a macroscopic SPT write head, the soft underlayer is too thin to function as a magnetic flux feedback. The soft underlayer is typically less than 1 micrometer thick and therefore can not carry the flux from a core that is orders of magnitude larger. Without the flux feedback through the SUL, the perpendicular magnetic field strength of a macroscopic perpendicular SPT head is limited, and may not be enough to even write the perpendicular media. This is particularly true as it is expected that over the coming years, coercivity will creep up in order to enhance thermal stability of ever smaller magnetic bits. Furthermore, for a macroscopic tester to function properly, it has to be able to not only switch the magnetization, but also to drive fields high enough to achieve maximum remanence, typically at least 2.2× larger than coercivity.
The principle of a macroscopic head residing altogether on one side of a disk has worked in the past for longitudinal magnetic inspection and measurement equipment. However for perpendicular testing and inspection equipment this approach yields insufficient magnetic field perpendicular to the disk.

Method and system for perpendicular magnetic media metrology


One embodiment of the invention is directed to operating, in a wireless network, a device that is designed for operation in a different wireless network. In one embodiment, a device designed to operate in a GSM wireless network may be used to communicate in a PHS wireless network.

The Personal Handyphone System (PHS) is a lightweight mobile communication system that makes use of the existing public telephone network by building upon the existing land line network. Because base stations in a PHS network have much smaller coverage radius than that of a typical cellular network and because PHS mobile units employ low-power transmitters, PHS is best suited for densely populated areas. PHS was originally deployed in Japan in the early 1990s and was intended to provide a low cost alternative to a cellular network. However, PHS was not a commercial success, as many subscribers were frustrated by the limited mobility, poor signal quality and limited ability to operate in moving vehicles.
In spite of the tepid public response in Japan, PHS has recently been deployed in other densely populated areas in Asia, in an attempt to provide a low-cost alternative to traditional wireless and landline communication networks.
However, given the lack of commercial success of PHS in Japan, hardware manufacturers have been reticent to invest large sums of money in the design and further development of PHS hardware (e.g., base station and mobile unit chipsets). Thus, it would be desirable to have wireless devices capable of operating in a PHS wireless system without the time and expense of the design and development of such devices.

Methods and apparatus for communication in a wireless system