JPH02255A - Octahydronaphthalene-substituted oxime derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Object of the Invention] Industrial Field of Application The present invention relates to octahydronaphthalene-substituted oxime derivatives having cholesterol synthesis inhibiting action.

Conventional technology Conventionally, a compound having an inhibitory effect on cholesterol synthesis (in the formula:
R represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a lower alkyl group), lower alkyl esters thereof, pharmacologically acceptable salts thereof, and lactones thereof are known (Japanese Unexamined Patent Application Publication No. 1983-1993) -55443
issue).

Problems to be Solved by the Invention As a result of intensive studies on the chemical modification of the octahydronaphthalene derivative (1), the present inventors have discovered a compound that has stronger cholesterol synthesis inhibitory activity than the octahydronaphthalene derivative (1). After this discovery, the present invention was completed.

[Structure of the invention]

The present invention is based on the general formula (wherein R represents a hydrogen atom, a methyl group, or a hydroxyl group, and X is the same or different as a substituent, and
m halogen atom, hydroxy group, C alkyl-substituted hydroxy group% C2-5 aliphatic acyl-substituted hydroxy group,
An alkyl group having 1 to 104 vAt or 3 carbon atoms, which may have an amino group, a carboxyl group, or a carboxyl group protected with a sil group-protecting group.
The alkenyl group having 1 to 10 atoms or X has 1 to 4 halogen atoms, which are the same or different as substituents,
Hydroxy group"h C1-4 alkyl-substituted hydroxy group% C2-5 aliphatic acyl-substituted hydroxy group, amino group, carboxyl group, carboxyl group protected with a carboxyl protecting group, Cl-5 alkyl group or halo r) A cycloalkyl group having 3 to 10 carbon atoms, which may have a C1-5 alkyl group, and a cycloalkyl group having 6 to 10 carbon atoms.
an aryl group having 7 to 12 carbon atoms; a 5- to 6-membered unsaturated heterocyclic group containing 1 to 3 oxygen, sulfur, or/and nitrogen atoms;
It represents a 5- to 6-membered saturated heterocyclic group containing t- to 3 oxygen, sulfur, or/and nitrogen atoms. A is a single bond; or 1 to 4 halogen atoms, the same or different as substituents, hydroxy group% C1-4 alkyl-substituted hydroxy group, C aryl-substituted hydroxy group, C7-9
Aralkyl-substituted hydroxy group, C2-5 aliphatic acyl-substituted hydroxy group, C7-15 aromatic acyl-substituted hydroxy group, amino group, mono- or di-01-4-alkyl-substituted amino group, mono- or di-C4-147 lyl-substituted amino group , mono- or di-C7-, aralkyl-substituted amino group, C2-5 aliphatic acyl-substituted amino group, C7-
15 Aromatic acyl-substituted amino group, alkylene group having 1 to 10 gAt- carbon atoms, alkenylene group having 3 to 10 carbon atoms, which may have a xyl group or a carboxyl group protected with a carboxyl group-protecting group , represents an alkadienylene group having 5 to 10 carbon atoms or an alkynylene group having 3 to 10 carbon atoms.

Y is a hydrogen atom; or 1 to 4 halogen atoms, the same or different as substituents, a hydroxy group, Cl-
4-alkyl-substituted hydroxy group, C6-14 aryl-substituted hydroxy group, C7-g aralkyl-substituted hydroxy group,
C2-5 aliphatic acyl-substituted hydroxy group, C7-15 aromatic acyl-substituted hydroxy group, mercapto group, Cl-4
Alkyl-substituted mercapto group, C6-14 aryl-substituted mercazoto group'h C7-? Aralkyl-substituted mercapto group, amino group, mono- or di-C1-4 alkyl-substituted amino group, mono- or di-C6-147 lyl-substituted amino group, mono- or di-C7-, aralkyl-substituted amino group, C2,s aliphatic acyl-substituted amino group , C7-15
Aromatic acyl-substituted amino group, nitro group, cyano group, carboxyl group, carboxyl group protected with xyl group, C1-5 alkyl group, halogeno Cl-5 alkyl group, hydroxy C4-5 alkyl group group or C2-
An aryl group having 6 to 14 carbon atoms which may have a 3-aliphatic acyl-substituted hydroxy C1-5 alkyl group, a cycloalkyl group having 3 to 10 carbon atoms, 1 to 3 oxygen, sulfur or / and a 5- to 6-membered ring unsaturated heterocyclic group containing a nitrogen atom, 1 to 3 oxygen, sulfur or/and a 5- to 6-membered ring saturated heterocyclic group containing a nitrogen atom, or a 5- to 6-membered ring saturated heterocyclic group containing 1 to 3 oxygen atoms , represents a fused heterocyclic group containing sulfur or/and nitrogen atoms. However, R is a hydrogen atom and a methyl group, X is a 1-methylpropyl group, and the group -A-Y is a hydrogen atom and an alkyl group. An octahydronaphthalene-substituted oxime consisting of an ester, a pharmacologically acceptable salt thereof, and a lactone having the formula (wherein R, X, A, Y and the group -A-Y have the same meanings as described above) Regarding derivatives.

In the general formulas (1) and (II), when X is an alkyl group, for example, methyl, ethyl, propyl, l
-Methylethyl, butyl, 1-ethylpropyl, 2-methylzolopyl, 1,1-dimethylethyl, pentyl, 1
-Methylbutyl, 2-methylbutyl, 3-methylbutyl, 1.1-diethylpropyl, 2.2-diethylpropyl, 1.2-diethylpropyl, 1-ethylpropyl,
hexyl, 1-methylpentyl, 2-methylpentyl,
1.1-dimethylbutyl, 1.3-dimethyl1 tyl, 1
-ethylbutyl, 2-ethylbutyl, 1-methyl-1-
Ethylpropyl, heethyl, 1-methyl-1-xfkf
fl, 2-methyl-2-ethylbutyl, ol/fl, l-
Methylheptyl, 2-ethylhexyl, 1,1.3.3
- straight-chain or branched alkyl groups having 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms, such as tetramethyltutyl, nonyl, decyl, and 3,7-dimethyloctyl; can.

When X is an alkenyl group, for example l-gropenyl,
2-f lovenyl, 2-butenyl, 3-butenyl, 2-/
Thiru-2-propenyl, 2-pentenyl, 3-benzonyl, 4-hexenyl, 5-hebutenyl, 2-octenyl, 4-octenyl, 2-nonenyl, 3-nonenyl, 4-
Straight chain or branched carbon atoms such as nonenyl, 3-decenyl, 5-decenyl having 3 to 10 carbon atoms, preferably 3
Examples include alkenyl groups having from 7 to 7 atoms.

When X is a cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Examples include monocyclic or polycyclic cycloalkyl radicals having 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, such as cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

When X is an aryl group, examples thereof include aryl groups having 6 to 10 carbon atoms, preferably phenyl, such as phenyl, 1-naphthyl, and 2-naphthyl.

When X is an aralkyl group, for example, benzyl, 1-methylbenzyl, phenethyl, 3-phenylpropyl,
1.1-1'methylbenzyl, 4-7enylbutyl, 1
- has 7 to 12 carbon atoms, preferably 7 to 9 carbon atoms, such as methyl-3-phenylpropyl, 5-phenylpentyl, 6-7 enylhexyl, and the alkyl moiety has 1 to 6 carbon atoms. , preferably 1 to 3, more preferably 1 to 2, and the aryl moiety includes an aralkyl group having 6 to 10 carbon atoms, preferably phenyl.

When X is a heterocyclic group, for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-teazolyl, 4
-Thiazolyl, l-pyrrolyl, 2-pyrrolyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 5-pyrimisonyl, 2-pyranyl, 4-pyranyl, 3-ynoxasilyl, 5-ynoxasilyl, 2-oxasilyl or a 5- to 6-membered unsaturated heterocyclic group containing 1 to 3 oxygen, sulfur or/and nitrogen atoms such as 5-oxasilyl, or for example 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 1-pyrrolidinyl, 3-pyrrolidinyl, 2-piperazyl, piperidino, 2-piperidyl, morpholino, 3-morpholinyl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 1,4-dioxane-
2-il.

1,3-dioxan-4-yl, 1,3-dioxane-
Mention may be made of 5- to 6-membered saturated heterocyclic groups containing 1 to 3 oxygen, sulfur or/and nitrogen atoms, such as 5-yl, preferably 1 to 2 oxygen, sulfur or/and It is a nitrogen-containing 5- to 6-membered unsaturated bicyclic group.

When X is an alkyl group or an alkenyl group, these groups may have the same or different substituents of 1 to 4, preferably 1 to 2, and such substituents include For example, ■ Halogen atoms such as chlorine, bromine, and fluorine; ■ Hydroxy groups: ■ C7,4 alkyl-substituted hydroxy groups such as methoxy and ethoxy; ■ C2-5 aliphatic groups such as acetoxy, clobionyloxy, and butyryloxy. Acyl-substituted hydroxy group: ■ Amino group; ■ Car is xyl group; ■ Methoxycar-nyl, ethoxycarbonyl, t-1
Lower allyl radicals such as toxiccargonyl? 7-ralkyloxycar such as nyl, benzyloxycar is nyl, diphenylmethoxycarbonyl, 4-nitrobenzyloxycar is nyl, 2-nitrobenzyloxycar is nil? Lower alkenyl or halognoalkenyloxycargonyl such as nyl, allyloxycarbonyl, 2-chloroallyloxycargonyl>2.2.2-trichloroethyloxycarbonyl, 2.2.2-) lituromoethyloxycargonyl lower halogenoalkyloxycar-nyl%2-()17methylsilyl)ethyloxycar-nyl, etc. 'normal cal material protected with a xyl group protecting group; etc. .

Among these substituents, preferred are a halodane atom; a hydroxyl group; a C2-5 aliphatic acyl-substituted hydroxy group; , optimally a halodane atom; Cal is a xyl group;

When X is a cycloalkyl group, aryl group, aralkyl group or heterocyclic group, these groups may have 1 to 4, preferably 1 to 2, substituents that are the same or different. Examples of such substituents include: ■ Halogen atoms such as chlorine, bromine, and fluorine; ■ and doxoxy groups; ■ C1-4 alkyl substitutions and doxy groups such as methoxy and ethoxy; 0 acetoxy, probionyloxy, and butyryloxy. C2-5 aliphatic acyl-substituted hydroxy group such as; ■ Amino group; ■ Car is xyl group; ■ Methoxycar-nyl, ethoxycar-nyl, t-1
A lower alkoxycar such as el, benzyloxycar, nyl, diphenylmethoxycar, nyl, 4-nitrobenzyloxycar, nyl, aralkyloxycar-nyl, allyloxy, 2-nitrobenzyloxycar, etc. Is lower alkenyl, such as car being nyl or 2-chloroallyloxycar being nyl, harodanoalkenyloxycar? Lower halogenoalkyloxy male such as L52e2s2-to9'chloroethyloxycargonyl, 2.2.2-) litulomoethyloxycargonyl is Ordinary Cal protected with a xyl protecting group: ■ C4,5 alkyl groups such as methyl, ethyl, chloro, isopropyl, ethyl, pentyl; ■ Halogeno c such as trifluoromethyl, -5 alkyl group; etc.

Among these substituents, preferred are a four-dimensional atom; a hydroxy group: a C1 di-, alkyl-substituted hydroxy group; a C2-5 aliphatic acyl-substituted hydroxy group; a C1-5 alkyl group; a halogeno C1-5 alkyl group; The most preferred is a halodane atom: a halo C1-5 alkyl group.

Next, when A is a divalent saturated acyclic hydrocarbon group, for example, methylene, ethylidene, ethylene, l-methylethylene, trimethylene, 1,2-dimethylethylene, 1-ethylethylene, l-methyltrimethylene, 2-methyltrimethylene, tetramethylene, 1-7"lopylethylene, l-ethyl-2-/-ruethylene, l-ethyltrimethylene, 2-ethyltrimethylene, 1,3-dimethyltrimethylene, l-methyltetramethylene , 2-methyltetramethylene, pentamethylene, 1-butylethylene,
1-Methyl-2-propylethylene, 1,2-diethylethylene, l-methyl-1-f lobylethylene, 2-propyltriethylene, l-ethyl-3-methyltrimethylene, l-ethyltetramethylene, 2 -ethyltetramethylene, 1,3-dimethyltetramethylene, 1-methyl(ntamethylene, 2-methyl(ntamethylene, 3-methylpent/'F-lene, hexamethylene, 1-pentylethylene, 1-butyl-2-methylethylene) , l-ethyl-2-propylethylene, 1-1 tiltrimethylene,
2-1 methyltrimethylene, 1,3-diethyltrimethylene, 1-methyl-3-propyltriethylene, l-propyltetramethylene, 2-propyltetramethylene, l
-ethyl-4-methyltetramethylene, 3-ethyl-1
-methyltetramethylene, 1-ditylpentamethylene,
3-ethylpentamethylene, 1,3-dimethylpentamethylene, l-methylhexamethylene, 3-methylhexamethylene, hexamethylene, l-hexylethylene, 1
-Methyl-2-pentylethylene, 1-butyl-2-ethylethylene, 1,2-dipropylethylene, l-pentyltrimethylene, 2-pentyltrimethylene, 1-butyl-3-methyltrimethylene, l-butyl -2-methyltrimethylene, 1-ethyl-3-propyltriethylene, 1,2-dimethyl-3-propyltrimethylene, 1
-1-methyltetramethylene, 1-methyl-4-f lobiltetramethylene, l-globilpentamethylene, 3-globilbentamethylene, 2-ethyl-4-methylpentamethylene, 1-ethylhexamethylene, 3- Linear or branched chain carbon atoms such as ethylhexamethylene, 1,3-dimethylhexamethylene, 1-methylhegetamethylene, 4-methylhebutamethylene, octamethylene or 2,6-dimethyloctamethylene. An alkylene group having 10 atoms, preferably 1 to 5 atoms, and which may have two valences of the same or different carbon atoms, can be mentioned.

When A is a divalent unsaturated acyclic hydrocarbon group, e.g. t
2-7" lopeylene, 2-methyl-2-f lopenylene, 2-1 tenylene, 3-1 tenylene, 2-pentenylene, 4-pentenylene, 2-methyl-2-1 tenylene, 2
-hexenylene, 2-hebutenylene, 3-methyl-2-
Hexenylene, 3-ethyl-2-pentenylene, 2-methyl-3-hexenylene, 2-octenylene, 4-octenylene, 3-methyl-2-hebutenylene, 3.5-dimethyl-2-hexenylene, 2-nonelene , 3-methyl-2-octenylene, 3.5-dimethyl-3-hebutenylene, 2-7"senylene' with a straight or branched chain carbon number such as 3,7-dimethe-2-octenylene 3 to 10 pieces, preferably 3 to 7 pieces, optimally 3 pieces
an alkenylene group having from 5 to 5 atoms, and in which the two valences may be the same or different carbon atoms; for example, 2,4-pentamethylene, 2,4-hexamethylene, 4-methyl-
214--e entadienylene, 2.4-hebutadienylene, 2.6-hebutadienylene, 3-methyl-2,4-
Hexamethylene, 2,6-octadienylene, 3-methyl-2,6-hebutadienylene, 2-methyl-2,4-
Hebutadienylene, 2,8-nonadienylene, 3-methyl-2,6-octadienylene, 2,6-zocasienylene, 2.9-7'cadienylene"ffi tad 3.7
- linear or branched carbon atoms such as dimethyl-2,6-octadienylene with 5 to 10 carbon atoms, preferably 5
Alkadielene groups in which the valences of the two atoms may be the same or different carbon atoms: examples include 2-globinylene, 2-:' f-ethylene, 2-penthelene, 2-hexyene, 4- Methyl-2 penthiene,
Go to 2-! Straight-chain or branched chain carbon atoms such as thiene, 3-octhiene, or 4-decylene with 3 to 1 carbon atoms
Examples include alkynylene groups having 0 atoms, preferably 3 to 5 atoms, and in which the two valences may be the same or different carbon atoms.

These divalent saturated or unsaturated acyclic hydrocarbon groups are the same or different and have 1 to 4, preferably 1 to 2
Examples of such substituents include ■ halogen atoms such as chlorine, bromine, and fluorine; ■ hydroxyl groups; ■ C1-4 alkyl substitutions such as methoxy and ethoxy. Hydroxy group; ■ Phenoxy, l-naphthyloxy, 2-7teroxy, 4-tolyloxy, 4-hydroxyphenoxy,
4-chlorophenoxy, 4-fluorophenoxy, 4-
Methoxyphenoxy, 4-carxyphenoxy, 4-
C4-147 aryl-substituted hydroxy group such as methoxycarbonylphenoxy, 4-aminophenoxy (aryl moiety is the same or different, preferably 1 to sms)
to 3 C1-4 alkyl, hydroxy, halogen, Cl-4 flukoxy, car may be substituted with xyl, protected nine car M xyl, amino); ■ benzyloxy, phenethyloxy, 4-methyl Penzyloxy, 4-hydroxybenzyloxy, 4-ropenzyloxy, 4-methoxybenzyloxy, 4-cal-
oxybenzyloxy, 4-methoxy is a C7-, aralkyl-substituted hydroxy group of nylbenzyloxy, 4-7minopenzyloxy (the aryl moiety is the same or different, 1 to 5, preferably 1 to 3 C1) −
. Alkyl, hydroxy, halogen% C1-4 alkoxy, car-xyl, protected car-xyl, amino may be substituted): ■ C2-3 fatty acids such as acetoxy, zolo-onyloxy, 1-tyryloxy Group acyl-substituted hydroxy group: ■ Benzoyloxy, 1-natutoyloxy, 2-naphthoyloxy, 4-methylbenzoyloxy, 2-hydroxybenzoyloxy, 4-hydroxybenzoyloxy, 4-chlorobenzoyloxy, 4-methoxybenzo , yloxy, 4-cal is xybenzoyloxy,
4-Methoxylic? C7-1I such as 2-nylbenzoyloxy, 4-aminobenzoyloxy! I aromatic acyl-substituted hydroxy group (aryl moiety is the same or different, 1 to 5, preferably 1 to 3, C1-4 alkyl, hydroxy, halogen% C1-4 alkoxy,
carboxyl, protected car may be substituted with xyl, at-); ■ aζ-no group; ■ mono- or di-C1-4 alkyl-substituted amino groups such as methylamino, dimethylamino, diethylamino; [Phase] Phenylamino, 1-naphthylamino, 2-7teramino, 4-tolylamino, 4-hydroxyphenylamino, 4-chlorophenylamino, 4-methoxyphenylamino, 4-cal? xyphenylamino, 4-
Methoxycar is a mono- or di-aryl-substituted amino group such as nylphenylamino or 4-7 minophenylamino (the aryl moiety is the same or different and has 1 to 5, preferably 1 to 3 C -4 alkyl,
Hydroxy, halogen% Cl-4 may be substituted with flukoxy, carboxyl, protected carboxyl, amino): ■ Benzylamino, phenethylamino, 4-methylbenzylamino, 4-hydroxybenzylamino, 4-chlorobenzylamino , 4-methoxybenzylamino, 4
A mono- or di-C7-, aralkyl-substituted amino group such as -car is xybenzylamino, 4-methoxycar is nylbenzylamino, 4-aminobenzylamino (the aryl moiety is the same or different and has 1 to 5, preferably 1 to 5) (Optionally substituted with 3 C4-4 alkyl, hydroxy, halogeno, C1-4 alkoxy, carboxyl, protected carboxyl, amino): @ acetamide, delpionamide, p? + C2-5 aliphatic acyl-substituted amino groups such as fluamino: ■ Benzamide, naphthoylamide, 4-methylbenzamide, 4-hydroxybenzamide, 4-chlorobenzamide, 4-methylbenzamide, 4-cartoxybenzamide, 4-methoxybenzamide is nylbenzamide,
C7-15 aromatic acyl-substituted amino group such as 4-aminobenzamide (aryl moieties may be the same or different)
5 to 5, preferably 1 to 3, C1-4 alkyl, hydroxy, halogen, Cl-4 alkoxy, carboxyl, protected car may be substituted with xyl, amino); carboxyl group; methoxycar is lower alkoxycargonyl, benzyloxycarbonyl, diphenylmethoxycargonyl, diphenylmethoxycargonyl,
Aralkyloxycar is nyl such as 4-nitrobenzyloxycarnonyl, 2-nitrobenzyloxycarnonyl, lower alkenyl or halogenoalkenyloxycargenyl such as allyloxycarnonyl, 2-chloroallyloxycargenyl, 2 .2e2-) 1) /Rotetraethyloxycar♂yl, 2.2.2-) Lipromoethyloxycar? A lower halogenoalkyl oxycar such as nyl is nil, 2-()! Examples include xyl group protected by a normal carboxyl protecting group such as J methylsilyl) ethyloxycarbonyl.

Of these substituents, preferably 7% a) f atom; hydroxy group: C1-4 alkyl-substituted hydroxy group; C aryl-substituted hydroxy group (
The number of aryl parts is 1 to 3, the same or different (DCl
−. optionally substituted with alkyl, hydroxy, halogeno, Cl-4 alkoxy, carboxyl, protected carboxyl, amino); C2-3 aliphatic acyl substituted hydroxy group; amino group; mono- or di-C1-4 alkyl substituted amino Group; C2-5 aliphatic acyl-substituted amino group: C7-15 aromatic acyl-substituted amino group (the aryl moiety is the same or different and has 1 to 3 C1-4 alkyl, hydroxy, halogen, 1-4 alkoxy, cal (optionally substituted with xyl, protected carboxyl, or amino): Car is a xyl group; Car protected with a carboxyl group protecting group is a xyl group; More preferably, a halokun atom: a hydroxy group: ” 1-4 alkyl-substituted hydroxy group; amino group; mono- or di-C1-. Alkyl-substituted amino group: ``2-5 aliphatic acyl-substituted amino group:'', and optimally human a+C group: C1-4 alkyl-substituted hydroxy group;

Next, when Y is an aryl group, for example phenyl, l
- Aryl groups having 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, such as naphthyl, 2-naphthyl, anthracenyl or phenanthrenyl.

When Y is a cycloalkyl group, for example, cyclodecyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, vinyl, etc. 3 to 10 carbon atoms, preferably 3 to 8, such as lunyl and menthyl
cycloalkyl groups, preferably 5 to 7 agglomerated or polycyclic cycloalkyl groups.

When Y is a heterocyclic group, for example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4
-thiazolyl, 1-pyrrolyl, 2-virolyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 5-pyrimidinyl, 2-pyranyl, 4-pyranyl, 3-yneoxasilyl, 5-isoxasilyl, 2-oxasilyl or 5- to 6-membered ring unsaturated W containing 1 to 3 oxygen, sulfur or/and nitrogen atoms, such as 5-oxasilyl!
Cyclic groups; for example, 2-tetrahydro-7lyl, 3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, l-pyrrolidinyl, 3-pyrrolidinyl,
2-piperazyl, piperidino, 2-piperidyl, morpholino, 3-morpholinyl, 2-tetrahydropyranyl,
4-tetrahydropyranyl, 1,4-dioxane-2-
a 5- to 6-membered saturated heterocyclic group containing 1 to 3 oxygen, sulfur or/and nitrogen atoms, such as yl, 1,3-dioxan-4-yl or 1,3-dioxan-5-yl; For example, 2-benzofuranyl, 2-2H-chromenyl, 2-benzothienyl, 2-indolinyl, 3-indolinyl, 2-dihydrobenzo75yl, 2-rioromael, 1,4-benzodioxan-2-yl, 4- More than 1 to 3 oxygen atoms of quinolyl or 1-isoquinolyl,
Mention may be made of fused heterocyclic groups containing sulfur or/and nitrogen atoms. These heterocyclic groups are preferably 5- to 6-membered unsaturated, saturated, and fused heterocyclic groups containing 1 to 2 oxygen or/and nitrogen atoms, and optimally 1 to 2 It is a 5- to 6-membered saturated and unsaturated heterocyclic group containing oxygen and/or nitrogen atoms.

When Y is an aryl group, cycloalkyl group or heterocyclic group, these groups are the same or different and 1 to 4
, preferably 1 to 2 substituents, such as: ■ halodane atom such as chlorine, bromine, and fluorine; ■ silica group in hydro; ■ methoxy, ethoxy Cl-4 alkyl substituted hydroxy groups such as; 0 phenoxy, 1-su7tyloxy, 2-naphthyloxy, 4-tolyloxy, 4-hydroxyphenoxy,
4-chlorophenoxy.

4-fluorophenoxy, 2-methoxyphenoxy, 4
- methoxydiphenoxy, 4-calgexyphenoxy,
C4-147 aryl-substituted hydroxy group such as 4-methoxycal/nylphenoxy, 4-aminophenoxy (1 to 5, preferably 1 to 3 aryl moieties are the same or different), C1-4 alkyl, hydroxy, halogen ” 1-4 alkoxy, cargocycl, protected and optionally substituted with cargoxyl, amino): ■ Benzyloxy, phenethyloxy, 4-methylbenzyloxy, 4-hydroxybenzyloxy, 4-chlorobenzyloxy, 4- methoxybenzyloxy, 4
-car-xybenzyloxy, 4-methoxycar is more like nylbenzyloxy, 4-aminobenzyloxy
7-, Aral-substituted hydroxy group (1 to 5 aryl moieties are the same or different, preferably 1 to 3,
C1-4 alkyl, hydroxy, halogen" 1-4
alkoxy, carboxyl, protected carboxyl,
(may be substituted with amino); ■ 7 C2-5 aliphatic acyl it-substituted hydroxy groups such as acetoxy, propionyloxy, butyryloxy; ■ benzoyloxy, 1-natutoyloxy, 2-sutoyloxy, 4-methylbenzoyloxy, 2-hydroxybenzyloxy.

C7 such as 4-hydroxybenzoyloxy, 4-chlorobenzoyloxy, 4-methoxypenzyloxy, 4-caloxybenzoyloxy, 4-methoxycarpenzoyloxy, 4-aminobenzoyloxy
-15 aromatic acyl-substituted hydroxy group (aryl moieties are the same or different, 1 to 5, preferably 1 to 3, C4-4 alkyl, hydroxy, halogen, C,
Alko inside, Cal NdP sil, protected cal is xyl, amine ft! ); ■ Mercapto group: ■ C7-4 alkyl-substituted mercapto group such as methylthio, ethylthio; [Phase] Phenylthio, l-7tylthio, 2-s7tylthio, 4-tolylthio, 4-hydro C aryl-substituted mercapto groups such as quinphenylthio, 4-chlorophenylthio, 4-methoxyphenylthio, 4-car-xyphenylthio, 4-methoxycartnylphenylthio, 4-7 minophenylthio (aryl moieties may be the same or different) 1 to 5, preferably 1 to 3, C1-4
Alkyl, hydroxy, halogen% C1-4 alkoxy, cal may be substituted with xyl, preserved carboxyl, amino); ■ Benzylthio, phenethylthio, 4-methylbenzylthio, 4-hydroxybenzylthio, 4 -/Lolobenzylthio, 4-methoxybenzylthio, 4-cartoxypennorthio, 4-methoxycarbonylpennorfyF
, 4-aminobenzylthio, a C7-9 aralkyl-substituted mercapto group (the ring moiety is the same or different, 1 to 5, preferably 1 to 3 (fi, +7) C1-
4 alkyl, hydroxy, halogen, Cl-4 flukoxy, Cal may be substituted with xyl, protected car may be substituted with xyl, amino]; @ Amino group; ■ Mono or such as methylamino, dimethylamino, diethylamino -C3-4alkyl substituted amino group; ■ Phenylamino, l-7tylamino, 2-naphthylamino, 2-tolylamino, 4-tolylamino, 4-
Hydroxyphenylamino, 4-chlorophenylamino, 4-methoxyphenylamino, 4-cal? xyphenylamino, 4-methoxycal is nylphenylamino, 4
- Mono- or di-C aryl-substituted amino group such as aquinophenylamino (aryl moiety is the same or different, 1 to 5, preferably 1 to 3, C3-4 alkyl, hydroxy, halogen) [Phase] Pennolamino, 7enethylamino, 4-methylpendylamino, 4-hydroxybenzylamino, 4
- mono- or di-C7-9 aralkyl-substituted amino groups such as chlorobenzylamino, 4-methoxybenzylamino, 4-car-xybenzylamino, 4-methoxycargenylpendylamino, 4-7 minopendylamino (
The aryl moiety may be substituted with 1 to 5, preferably 1 to 3, C1-4 furkyl, hydroxy, halogen, c, -4 alkoxy, carboxyl, protected carboxyl, amino, the same or different. );[
phase] Acetamide, propionamide, bu'? +3
C2-5 aliphatic acyl-substituted amino groups such as ruamino; ■ benzamide, naphthoylamide, 4-methylbenzamide, 4-hydroxypenzamide, 4-chlorotetrabenzamide, 4-methoxybenzamide, 4-caloxybenzamide, 4- Methoxylic? C7-15 aromatic acyl-substituted amino group such as nylbenzamide, 4-aminobenzamide (the aryl moiety is the same or different and has 1 to 5, preferably 1 to 3 Cl-4 alkyl, 1-droxy, haHf) "1-4 alkoxy, calgexyl, protected and nine car may be substituted with middle syl, amino); [Phase] Nitro group; ■ Cyano group; 0 car is xyl group; ■ Methoxy car is nyl, ethoxy car is nyl .

Lower alkoxycarginyl such as t-butoxycar-nyl, benzyloxycarbonyl, diphenylmethoxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-
Aralkyloxycargonyl such as nitrobenzyloxycar-nyl, allyloxycar-nyl, ha-alkenyl or haloalkenyloxycargenyl such as 2-chloroallyloxycar-nyl, 2.2.2-trichloroethyl- Lower halogenoalkyloxycargonyl, such as 2.2.2-)ribromoethyloxycargonyl, and ordinary carboxyl group carriers such as 2-()limethylsilyl)ethyloxycargonyl. Cl-5 is an alkyl group such as methyl, ethyl, globyl, butyl, pentyl;
5-alkyl group; [Phase] HydroxyCl-5-alkyl group such as hydroxymethyl, hydroxyethyl; [Phase] Acetoxymethyl, l- and 2-fa pionyloxyethyl, 5-butyryloxypentyl, etc. and a C2-5 aliphatic acyl-substituted hydroxy C1-5 alkyl group.

Among these substituents, preferred are halogen atom; hydroxy group: C1, alkyl-substituted hydroxy group; 1-4 alkoxy, car may be substituted with xyl, protected car may be substituted with xyl, amino) C1-4 alkyl, hydroxy, halo % C1'
-4 alkoxy, car-xyl, protected cal may be substituted with xyl, amino): C2-5 aliphatic acyl-substituted hydroxy group: C7-16 aromatic acyl-substituted hydro group (aryl part is The same or different 1 to 3 C1-4 alkyl, hydroxy, ha
f, C1-4 alkoxy, car may be substituted with xyl, protected car may be substituted with xyl, amino); mercapto group: C1-a alkyl-substituted mercapto group; amino group; mono- or di-C1-4 alkyl Substituted amino group; C2-5 aliphatic acyl-substituted amino group: nitro group; cyano group; Cal is a xyl group; Cal is a xyl group protected by a protecting group for the xyl group: C1-5 alkyl group; /%
or / C, -s alkyl group; hydroxy C1-
1s alkyl group; C2-5 aliphatic acyl-substituted hydrocarbon C1-5 alkyl group; atom, more preferably a halogeno atom; hydroxy group: C1-4 alkyl-substituted hydroxy group; C aryl-substituted hydroxy group (aryl moiety are the same or different and 1 to 3 C1-4 alkyl, hydroxy, halogeno% C1-4 alkoxy, car may be substituted with xyl, protected caro may be substituted with xyl, amino): C7-garalkyl Substituted hydroxy group (aryl moiety is the same or different and has 1 to 3 Cl-4 alkyl, hydroxy, halogeno I C1-
4 alkoxy 7, car is xyl, protected car may be substituted with xyl, amino); amino group; mono- or di-C1-4 alkyl-substituted amino group; C2-5
Aliphatic acyl-substituted amino group; nitro group; cyano group; Cal is xyl group; Cal protected by a protecting group for xyl group is xyl group: C, -, alkyl group; halogeno C4-5
Alkyl group; Hydroxy C1-5 Alkyl group: C2-
5 aliphatic acyl-substituted hydroxy C1-5 alkyl group; a) f7 atom: hydroxy group; C1-a alkyl-substituted hydroxy group; amino group: mono- or di-C1-4
Alkyl-substituted amino group: C2-5 aliphatic acyl-substituted amino group; nitro group; C1-5 alkyl group: C1-5 alkyl group;

Next, Cal? having the general formula (1)? Examples of esters of phosphoric acid include alkyl esters of methyl, ethyl, globil, isogumivir, butyl, isobutyl, and pentylnato; aralkyl esters of benzyl, phenethyl, and the like.

Preferred are methyl, ethyl and benzyl.

Examples of pharmacologically acceptable salts of carganic acid having the general formula (1) include metal salts, amino acid salts, and amine salts. Examples of metal salts include alkali metal salts such as aluminum and potassium, alkaline earth metal salts such as calcium and magnesium, and aluminum salts, iron salts, zinc salts, copper salts, etc.

Kel salt and cobalt salt are rejected, but among these,
Alkali metal salts, alkaline earth metal salts and aluminum salts are preferred, and sodium, potassium, calcium and aluminum salts are most preferred. Preferred amino acid salts include basic amino acids such as arginine, lysine, histidine, α, γ-diaminobutyric acid, and ornithine. Suitable amine salts include t-octylamine, dibenzylamine, dicyclohexylamine, morpholine, D-phenylglycine alkyl ester, and D-glucosamine.

In the calgenic acid having the general formula (1), its ester, and its pharmacologically acceptable salt, and the lactone having the general formula (J), (1) preferably, R is a hydrogen atom, a methyl group, or a hydroxyl group. represents a group, and X is unsubstituted or the same or different as a substituent and 1
to 4 halodane atoms, hydroxyl group, 1-4 alkyl-substituted hydroxy group, C2-5 aliphatic acyl-substituted hydroxy group, amino group, carboxyl group protected with a xyl group or carboxyl group an alkyl group having 1 to 10 carbon atoms or an alkenyl group having 3 to 10 carbon atoms, or X is unsubstituted or is the same or different as fIt, and has 1 to 4 hero r: / atoms, hydroxy group, Cl-4 alkyl-substituted hydroxy group, C2-5 aliphatic acyl-substituted hydroxy group, amino group, carboxyl group, carboxyl group protected with a carboxyl group protecting group % C1-5 alkyl group or C2-5 A cycloalkyl group having 3 to 10 carbon atoms, a phenyl group, an aralkyl group having 7 to 9 carbon atoms, or 5 to 6 carbon atoms containing 1 to 2 oxygen, sulfur, or/and nitrogen atoms.
1-4 alkyl-substituted hydroxy group, which represents a ring-membered unsaturated heterocyclic group;
C aryl-substituted hydroxy group (aryl moiety is the same or different and has 1 to 3 C1-4 alkyl, hydroxy, halogen% C1-4 flukoxy, cargexyl, protected cal is xyl, amino and fiL'!!j4 "2-5 aliphatic acyl substituted hydroxy group, amino group, mono- or di-C alkyl f! substituted ami7 group" 2-5 aliphatic acyl [substituted amino group, C aromatic acyl amino group (The aryl moiety is the same or different and has 1 to 3 Cl-4 alkyl, hydroxy, halogen, C1, flukoxy, cargoxyl.

(The preserved cal may be substituted with xyl or amino), carmexyl group'! ! Cal is protected with a xyl group protecting group and Cal has a xyl group and has a carbon number of 1 to 1
Alkylene group having 0 carbon atoms, alkenylene group having 3 to 10 carbon atoms, alcafenylene group having 5 to 10 carbon atoms 2iI! ; Case or carbon number 3 to 511iii
Indicates an alkynylene group having 1.

Y is the same or different and has 1 to 2 halogen atoms, hydroxy groups,
C1-. Argyl flit substituted hydroxy group, c7 aryl substituted hydro Φshifi (aryl moiety is the same or different and has 1 to 3 Cl-4 alkyl, hydroxy) 10
``1-4 flukoxy, cal may be substituted with xyl, protected car-xyl, amino), C7
-, aralkyl-substituted hydroxy group (aryl moiety is the same or different and 1 to 3 C1-4 alkyl, hydroxy, halogen% C1-4 flukoxy, cal is substituted with xyl, protected cal-xyl, amino) good).

C2-5 aliphatic acyl-substituted human axy group "y-ts aromatic acyl-substituted hydrofushi group The aryl moiety is the same or different and has 1 to 3 C4-4 alkyl, hydroxy, halyn, C1-4 alkoxy, Carboxyl, protected carol may be substituted with xyl, amino), mercapto group% C1-4 alkyl-substituted mercapto group, amino group, mono- or di-C1-4 alkyl-substituted amino group"2-5 fatty group acyl-substituted acyl group, nitro group, cyano group, car-xyl group, carboxyl group where car is protected with a xyl group protecting group % C1-8 alkyl group,
Halogen C1-5 alcohol, human CIJ? C1-,
an aryl group having 6 to 10 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms; 1 to 2 same or different halogen atoms and hydroxyl groups as substituents % C1-
4-alkyl-substituted human axy group, C4-147 aryl-substituted hydroxy group (the aryl moiety is the same or different and contains 1 to 3 c, -4-alkyl, hydroxy, heggun)
1-4 alkoxy, car is xyl, protected car may be substituted with xyl, amino), C2-5 aliphatic acyl-substituted hydroxy group, ami7 group, mono- or di-C1-. Alkyl-substituted amino group s C2-5 aliphatic acyl-substituted, amino group, C7-15 aromatic acyl-substituted amino group (aryl moiety is the same or different and has 1 to 3 cl-4 alkyl, hydroxy, hacln) 1 -4
flukoxy, cargoxil, protected nine cargoxyl,
optionally substituted with amino), a carboxyl group or a carboxyl group protected with a xyl group-protecting group, an alkyl group having 1 to 10 carbon atoms, and an alkyl group having 3 to 10 carbon atoms; an alkenylene group having 5 to 10 carbon atoms, or an alkynylene group having 3 to 5 carbon atoms, and Y is unsubstituted or the same or different as a substituent;
to 2 halogen atoms, hydroxy group "1-4 alkyl-substituted hydroxy group, C6-147 aryl-substituted hydroxy group (aryl part is usually - or differently, 1 to 3 C1-4 alkyl, hydroxy, halogen% C1-4
Alkoxy, carboxyl, protected carxyl,
C7-9 aralkyl-substituted hydroxy Mi (where the ring moiety is the same or different and has 1 to 3 Cl-4 alkyl, hydroxy, halogen, C1=7 is koxy, carboxyl, (Optionally substituted with protected carxyl or amino)” 2
-5 aliphatic acyl-substituted hydroxy group; , protected car-xyl, optionally substituted with amino), mercapto group % C1-4 alkyl-substituted mercapto group, amino group, mono- or di-C1-4 alkyl-substituted amino group % C2-5 fat extension Acyl-substituted amino group, nitro group,
Cyano group, Cal is xyl group, Cal protected by carboxyl group is xyl group, C1-5 alkyl group, HaΩ
Dano Ct-s alkyl group, hydroxy C1-5 alkyl group or C2-5 aliphatic acyl substituted hydroxy C1-5
A 5- to 6-membered ring containing 1 to 3 oxygen, sulfur or/and hydrogen atoms with an alkyl group, unsaturated, saturated or! ! Substituted heterocyclic group; ■ A is unsubstituted or has 1 to 2 same or different halogen atoms or hydroxy groups as substituents % C1-
4 alkyl-substituted drooxy group, C aryl-substituted hydroxy group (aryl moiety is the same or different and has 1 to 3 C1-4 alkyl, hydroxy, halogen% C1-4
Alkoxy, car♂xyl, protected cal is xyl,
(optionally substituted with amino), C2-5 aliphatic acyl-substituted hydroxy group, amino group, mono- or di-C1
-4 Alkyl-substituted amino group, C aliphatic acyl-substituted amino group" 7-15 Aromatic acyl-substituted amino group (Aryl moiety is the same or different and has 1 to 3 C1-4 alkyl, hydroxy, C1r-n%C ?-4 flukoxy, car is xyl, protected car may be substituted with xyl, amino), carbon number 3, car has a xyl group or a carboxyl group protected with a carboxyl group protecting group
Alkenylene group having 5 to 10 carbon atoms, 5 to 10 carbon atoms
or an alkadiene group having 3 to 10 carbon atoms
It shows an alkynyl 7 group having 41i.

Y is a hydrogen atom; It is a compound that shows

(2) More preferably, R represents a hydrogen atom, a methyl group, or a hydroxy group, and X is unsubstituted or the same or different as a substituent, and 1
to 2 halogen atoms, hydroxy group% C2-5 aliphatic acyl-substituted hydroxy group, Cal is a xyl group, or Cal is a xyl group protected by a xyl group; alkyl having from al to 10 carbon atoms; group or alkenyl group having 3 to 10 carbon atoms or Acyl-substituted hydroxy group.

Indicates a 7-chloroalkyl group having 3 to 7 carbon atoms and having a C alkyl group or a halodane Cl-5 alkyl group, and (2) A is a single bond, 6 or unsubstituted, or the substituents are the same or different. 1 to 2 halogen atoms, hydroxy group" 1-4 alkyl substituted hydroxy group,
Amino group, mono- or di-C1-4 alkyl-substituted amino group or 02-5 aliphatic acyl-substituted amino group, alkylene group having 1 to 5 carbon atoms, 3 to 5 carbon atoms
represents an alkenylene group having 1 or an alkadiene group having 5 to 8 carbon atoms, and Y is unsubstituted or the same or different as a substituent,
to 2 halogen atoms, human o -? 7 fi-
CI-a alkyl-substituted hydroxy group, C aryl-substituted hydroxy group (aryl moiety is the same or different and has 1 to 3 C1-4 alkyl, hydroxy, 80r/%
Ct-4 alkoxy, Cal is xyl, protected Cal? optionally substituted with syl or amino), C7-9
Aralkyl-substituted hydroxy group (aryl moiety may be substituted with 1 to 3 C1-4 alkyl, hydroxy, halogen% C1-4 flukoxy, carboxyl, protected carboxyl, amino)
, amino group, mono- or di-C1-4 alkyl substituted amino group% C2-5 aliphatic acyl-substituted amino group, nitro group, cyano group, carboxyl group, carxyl group protected with a carxyl group protecting group , C alkyl group, halogeno Ct-s alkyl group, hydroxy C1-5 alkyl group or C2-5 aliphatic acyl-substituted hydroxy C1-5 alkyl group having 6 to 10 carbon atoms IJ-
cycloalkyl group having 5 to 7 carbon atoms;
4 alkyl-substituted hydroxy group, amino group, mono or no Cl-4 alkyl-substituted amino group or 7' (is C2-5
represents an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 3 to 5 carbon atoms, or an alkachenylene group having 5 to 8 carbon atoms, and Y is unsubstituted or Same or different as substitutes 1
to 2 noro r7 atoms, hydroxy l c, -4 alkyl substituted hydroxy group, C4-147 aryl substituted hydroxy group (aryl moieties are the same or different, l to 3
01-4 alkyl, human c2-? 7% a f
* C1-4 furukokikku, cal may be substituted with xyl, protected cal may be substituted with kyl, amino), C7
-9aralkyl substituted hydroxy! (The aryl moiety may be the same or different and have 1 to 3 01-4 alcohols, human a
KiV, /SQl'7. C1-4 alkoxy, carboxyl, protected car? (optionally substituted with amino), an amino group, mono- or di-C1-. Cal? xyl group, C1-
5 alkyl group, 7% a) fnoC1-5 alkyl group,
Hydrogenyl Cl-5 alkyl group or C2-5 fatty acyl-substituted human C1dP with C1-5 alkyl group
-2 oxygen atoms are/and a 5- to 6-membered unsaturated, saturated or fused heterocyclic group containing a nitrogen atom; (i) A is unsubstituted or the same or different substituents are 1 to 2 halodane; Atom, hydroxy group% C1-
4-alkyl-substituted human a-oxy group.

An alkenylene group having 3 to 10 carbon atoms, or an alkadiene group having 5 to 10 carbon atoms, having an amino group, a mono- or di-Cl-4 alkyl-substituted amine group, or a C2-5 aliphatic acyl-substituted amino group. This is a compound in which an ethylene group is represented, and Y is a hydrogen atom.

(3) Optimally, R represents a hydrogen atom, and X is unsubstituted or the same or different as a substituent, and 1
to 2 halogen atoms or carbon atoms having a xyl group wLl to an alkyl group having 7 carbon atoms;
to 5 alkenyl groups or X is f! AfI
jL represents a cycloalkyl group having 3 to 7 carbon atoms, which is the same or different and has 1 to 2111 halogen atoms or a haloC1-5 alkyl group, and (i) A is a single bond, or Unsubstituted or an alkylene group having 1 to 5 carbon atoms or having 1 to 2 hydrocarbon groups or Cl-4 alkyl-substituted hydroxy groups, which are the same or different, or having 3 to 5 carbon atoms as substituted components. Indicates an alkenylene group having , and Y is a device'? 1 to 2 halodane atoms, hydroxy groups, the same or different as l & or tit
1-4 alkyl-substituted human axy group, amine group, mono- or di-C1-4 alkyl-substituted amino group, C2-5 aliphatic acyl amino group, nitro group, C1-5 alkyl group, helog/C,- .

An alkyl group or a 17-alkyl group having 6 to 10 carbon atoms having a hydroxy C1-5 alkyl group or a cycloalkyl group having 5 to 7 carbon atoms; ■ A is unsubstituted or the same as a substituent; or different carbon w! having 1 to 2 hydroxy groups or C7-4 alkyl-substituted hydroxy groups! The alkylene group tfc having 1 to 5 L represents an alkenylene group having 3 to 5 carbon atoms, and Y is unsubstituted or the same or different as a substituent and 1
to 2 halogen atoms, hydroxyl group, 1-4 alkyl substitution, do-a-oxy group, amino group, mono- or di-C
1-4 alkyl-substituted amino group, 2-5 aliphatic acyl-substituted amino group, 2) Ofi% Ct-s alkyl group, halogeno CI-5 alkyl group or hydroxy C1-5 alkyl group. A 5- to 6-membered unsaturated or saturated heterocyclic group having oxygen or/and nitrogen atoms; (1) A is unsubstituted or the same or different substituents are 1 to 2 hydroxy groups or Cl-4 alkyl-substituted hydroxy groups; is an alkenylene ME having 3 to 7 carbon atoms or an alkadiene group having 5 to 8 carbon atoms, and Y is a hydrogen atom;

Examples of the carbic acid having the above-mentioned hole (1), its ester and pharmacologically acceptable salt thereof, and the lactone having the above-mentioned hole (■) obtained by the present invention include the compounds described below. I can do it.

In the above compound table, exemplified compound number 1 is preferred.

6, 11.17, 18.22.37.39.45°47
．． 54.60.61.64,65,120°122.1
23,124,126,127,128°129.13
0,131,132 and 134, more preferably compounds with Exemplified Compound No. 1.18°39.54,60.61 and 64.

In addition, in the carboxylic acid having the general formula (1), its ester, and its pharmacologically acceptable salt, as well as the lactone body having the general formula (n), an optical isomer based on an asymmetric carbon and an oxime moiety () -No-A-Y)
Although syn-anti stereoisomers exist and all of these isomers are represented by a single formula, this is not intended to limit the scope of the present description.

The object compound of the present invention has the effect of lowering blood lipids by inhibiting cholesterol synthesis, and can be used in medicine, for example, as a therapeutic agent for hyperlipidemia and a preventive agent for arteriosclerosis.

These compounds can be administered orally or parenterally in the form of capsules, tablets, injections and the like. The dosage varies depending on age, symptoms, body weight, etc., but it is usually administered to adults at about 0.5 to 500 doses per day, divided into 2 to 4 doses. However, larger amounts can be used if desired.

According to the present invention, the carboxylic acid having the above-mentioned hole (1), its ester and its pharmacologically acceptable salt, and the lactone body having the above-mentioned hole (II) are produced by the method described below. be able to.

-A-ON -A-ON In the formula, R, show.

In ζ, 17 represents a hydrogen atom or a protecting group for a hydroxy group.

R4 represents a hydrogen atom, a hydrogen atom, a radical, and a radical. R5 represents a hydrogen atom or a 3-protecting group for a hydroxy group.

In addition, in the compound having the above-mentioned - pattern hole (1), a compound in which R is a hydrogen atom is disclosed in, for example, JP-A-50-1'556.
90, JP-A No. 56-51992, compounds in which R is a methyl group are described, for example, in JP-A-55-111790, R
Compounds in which is a human tetraxyl group are disclosed in, for example, JP-A-57-50
No. 894, JP-A-57-67575, JP-A-57-1
No. 55995, JP-A-58-10572, JP-A-58
-89191.

In the compound having the above-mentioned hole (mV) t-, R5
Compounds in which R4 and R are both hydrogen atoms are described, for example, in JP-A-51-136885 and JP-A-57-83290, and compounds in which R5 is a methyl group and both R4 and R5 are hydrogen atoms are described in, for example, Japanese Patent Publication No. 55-139396
listed in the number. , In the compound having the above-mentioned -Moonhole (V), R5 is a hydrogen atom, a methyl group or a hydroxy group, X is a 1-methylpropyl group, and R is a hydrogen atom. It is the same as the compound having III), and there are nine types described above. Compounds in which X is other than l-methylbutyryl group are described in, for example, JP-A-56-122375, JP-A-56-
138181, JP-A-59-175450, JP-A-62-174040, and JP-A-62-190094.

In the compound having the above-mentioned hole (M), R3 is a hydrogen atom or a methyl group, X is a 1-methylpropyl group, and R is a hydrogen atom or a protecting group for a hydroxy group. The compound is disclosed in JP-A-56-150037 and JP-A-58-
No. 55443.

In the compound having the above-mentioned hole (■), R is a hydrogen atom or a methyl group υ, and R and R are both a hydrogen atom or a protecting group for a hydroxyl group.
It is described in No. 43.

The first step is a step of producing a compound having the above-mentioned -pattern (fV), which involves (1) a reaction to remove the 2-methylbutyryl group from the compound having the -part (III) t-;
It consists of a reaction that optionally protects a hydroxyl group.

In the reaction (2) for removing the 2-methylbutyryl group, the compound having the -pattern (III) is contacted with an excess of 2 equivalents or more of an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc. This is achieved by letting The reaction is carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction, and examples include water; alcohols such as methanol, ethanol, propatool, and ethylene glycol; ethers such as tetrahydrofuran and dioxane; or water and Examples include mixed solvents with these organic solvents. The reaction temperature is room temperature to 100°C, preferably 60°C to
The temperature is 100°C. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 3 hours to 48 hours, preferably 5 hours.
hours to 24 hours.

In this reaction, most of the lactone moieties are ring-opened simultaneously with the removal of the 2-methylbutyryl group, forming an alkali metal salt of the alkali metal hydroxide used in the reaction for removing the 2-methylbutyryl group. Therefore, in this reaction, a ring-opened type carboxylic acid metal salt may be used as a starting compound instead of the lactone type having the above-mentioned compound (1). Although subsequent reactions may be carried out in the form of a ring-opened carboxylic acid metal salt, the subsequent reactions are preferably carried out in a lactone form.

Lactonization is carried out by the following reaction. That is, the reaction mixture obtained in the above reaction is cooled, and then an inorganic acid such as hydrochloric acid or sulfuric acid is added to adjust the pi to about 3, and then extracted with an organic solvent that is immiscible with water. Suitable examples include organic acid esters such as ethyl acetate; aromatic hydrocarbons such as benzene and toluene; ethers such as diethyl ether; and halogenated hydrocarbons such as methylene chloride and chloroform. are ethyl acetate, benzene, and methylene chloride.The solvent is distilled off from the obtained extract to obtain a ring-opened carboxylic acid form.The nine carboxylic acid form obtained after lactonization is directly purified without purification. This is achieved by contacting with an acid in the presence of a solvent or by hot dehydration. When lactonization is carried out by contacting with an acid, the carboxylic acid is converted into an ester of an organic acid such as ethyl acetate: In the presence of a solvent such as a halogenated hydrocarbon such as methylene chloride; a nitrile such as acetonitrile, Example 1-1') by contacting with an acid such as lifluoroacetic acid, p-toluenesulfonic acid. .

The reaction temperature is usually θ°C to 100°C, preferably room temperature to 60°C.
It is ℃. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 30 minutes to 10 hours, preferably 1 hour to 5 hours. After the reaction is complete, the lactone is recovered from the reaction mixture in a conventional manner. For example, if a water-immiscible solvent is used as the reaction solvent, add an aqueous solution of sodium hydrogen carbonate to remove the 2-methylbutyryl group.
-Methylbutyric acid and the catalytic acid are washed away, then washed with water, and then the solvent is distilled off from the reaction mixture. Or, if a water-miscible solvent is used as the reaction solvent, add hydrogen carbonate to neutralize it, then distill off the solvent from the reaction mixture, and do not mix the resulting residue with water again. The product is obtained by dissolving it in an organic solvent, washing with water to remove 2-methylbutyryl acid produced in the reaction for removing the 2-methylbutyryl group, and the catalyst acid, and then distilling off the solvent from the reaction mixture. Next, rough
When the conversion is carried out by hot dehydration, the carboxylic acid is refluxed in an aromatic hydrocarbon solvent such as toluene or benzene using a Dean-Stark apparatus, and water is continuously dehydrated. This is done by separating. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 2 hours to 8 hours, preferably 3 hours to 5 hours.

After the reaction is complete, the lactone is recovered from the reaction mixture in a conventional manner. For example, it can be obtained by cooling the reaction mixture, adding an aqueous sodium hydrogen carbonate solution to wash and remove 2-methylbutyryl group-removal reaction and removing the 2-methylbutyryl group, and then distilling off the solvent from the reaction mixture. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or column chromatography.

Next, the reaction (2) to protect the hydroxyl group, if desired, is accomplished by reacting the compound obtained in the above reaction from which the 2-methylbutyryl group has been removed with a compound that forms a hydroxyl-protecting group. Examples of compounds that form a protecting group for hydroxyl groups include trimethylsilyl chloride, dimethyl-1-
Silyl compounds such as butylsilyl chloride, diphenyl-1-butylsilyl chloride, dihydrobyran, dihydrothiobilane, dihydrothiophene, 4-metho IF
-/-Heterocyclic compounds such as 5.6-dihydro(2H)bilane; unsaturated compounds such as ethyl vinyl ether and methoxy-1-cyclohexene; and the like. If a silyl compound is used, the reaction may be carried out using an organic base such as triethylamine, dimethylaminopyridine, imidazole, pyridine or lithium sulfide (Li,
8) in the presence of a sulfide compound such as 8).

When using heterocyclic compounds or unsaturated compounds, the reaction is carried out with small amounts of acids, such as inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous oxychloride, p-)luenesulfonic acid, trifluoroacetic acid, picric acid, benzene. Any reaction carried out in the presence of an organic acid such as a sulfonic acid is preferably carried out in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not participate in the reaction; for example, ethers such as tetrahydrofuran; nitriles such as acetonitrile; chloroform, dihydrogenated hydrocarbons such as methylene chloride, dimethyl Mention may be made of dialkylformamide a such as formamide. In particular, when using a silyl compound, pyridine, triethylamine, etc. are also used as a solvent.

The reaction temperature is not particularly limited in any case, but is usually θ
It is suitably carried out at about ℃ to room temperature. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 30 minutes to 8 hours.

After the reaction is complete, the target compound is collected from the reaction mixture in a conventional manner. For example, water is added to the reaction mixture and then an organic solvent that is immiscible with water is added for extraction.

It is obtained by washing the extract with water and distilling off the solvent from the extract. The obtained target compound can be prepared by conventional methods if necessary.
Further purification can be carried out, for example, by recrystallization, reprecipitation, or chromatography. In this step, any hydroxyl group can be selectively protected by selecting a compound that forms a hydroxyl-protecting group.

The second step is a step of producing a compound having the above-mentioned -Moonhole (V) t-, and introducing an It is a reaction to This step is a desired step. That is, when X is, for example, a l-methylbutyryl group, if there is no hydroxyl-protecting group, this step is not particularly necessary since it is the same as the compound having the above-mentioned -pattern (II).

Therefore, this step is a reaction in which X is substituted with a group other than 1-methylpropyl group in the compound having the above-mentioned -ill. The reaction is carried out using a compound having the above-mentioned Coon (IV) (wherein R4 is a hydrogen atom) (R5 and R2 are preferably hydroxyl protecting groups =>t- an organic acid having the formula X -Coon or an acid anhydride thereof) or by contacting with a reactive derivative such as an acid halide, using an organic acid [?] 1 to 3 equivalents of a condensing agent such as N,N-dicyclohexylcarbodiimide and optionally 4- It is carried out in the presence of 1/10 to 3/10 equivalents of an organic base such as dimethylaminopyridine, 4-pyrrolidinopyridine, 4-hydroxybenztriazole.

The reaction is preferably carried out in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not participate in the reaction; for example, amines such as pyridine and triethylamine; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran and dioxane. ; dialkyl formamides such as dimethylformamide; and dialkyl sulfoxides such as dimethyl sulfoxide. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 5 hours to 48 hours.

When an acid anhydride or an acid halide is used, the above-mentioned compound may be added in the presence of 1/10 to 2/10 equivalent of an organic base such as 4-dimethylaminopyridine, 4-pyrrolidinopyridine, or 4-hydroxypenztriazole, if necessary. - Monka (I)
1 equivalent of the compound having V) is reacted with 3 to 5 equivalents of the acid anhydride or acid halide. The reaction is preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction; for example, amines such as pyridine and triethylamine; halogenated hydrocarbons such as methylene chloride and chloroform; and tetrahydrofuran and dioxane. I can give you ethers. The reaction temperature is usually 0°C to 100°C. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 3 hours to 24 hours. After the reaction is completed, the target compound is collected from the reaction mixture by a conventional method. For example, it can be obtained by adding a water-immiscible organic solvent to the reaction mixture for extraction, washing the extract with an acidic aqueous solution and then with water, and then distilling off the solvent from the extract. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation or column chromatography.

The third step is a step of producing a compound having the above-mentioned -Vintage (Vl)'t-, and is achieved by oxidizing the compound having the -Vintage (V)'t-. The reaction is carried out by bringing an oxidizing agent into contact with the compound having the above-mentioned hole (V) in the presence of a solvent. The oxidizing agents used in this reaction are chromic anhydride and pyridine (Collins reagent).
, a complex of chromic anhydride and an organic base such as pyridinium dichromate, pyridinium chlorochromate, or chromic anhydride-sulfuric acid (Jones reagent), but chromic anhydride-pyridine is preferred.

The reaction is carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction; for example, halogenated hydrocarbons such as methylene chloride, dichloroethane, and chloroform; dialkylformamides such as dimethylformamide; and dimethylacetamide. Examples include dialkylacetamides. The reaction temperature is -10°C to 50°C, preferably 0°C to room temperature. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 1 hour to 48 hours, preferably 8 hours to
It is 16 hours.

Alternatively, the compound having the above-mentioned hole (M) is the above-mentioned -
It can also be obtained by sequentially subjecting a compound having a hole (V) to epoxidation, diolization and oxidation reactions. This reaction is shown in the diagram below.

The first step is an epoxidation reaction using an organic peracid, which is achieved by bringing the compound having the above-mentioned hole (V) into contact with the organic peracid in the presence of a solvent. The organic peracids used include, for example, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, perphthalic acid, etc., with m-chloroperbenzoic acid being preferred. The reaction is preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in the reaction, and examples include aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform; and ethyl acetate. Examples include organic acid esters. The reaction temperature is usually -20'C to 50C.

The zero reaction time, which is preferably 0° C. to Murataki, varies depending on the reaction reagent, reaction temperature, etc., but is usually 1 hour to 10 hours, preferably 3 hours to 6 hours.

g2 stage t! This is a conversion reaction of a z-poxy compound (a) to a dihydroxy compound (b). In the conversion reaction, after the epoxidation reaction is completed, the obtained epoxy compound (&) is brought into contact with an acidic aqueous solution (for example, hydrochloric acid or sulfuric acid) without being isolated from the reaction mixture, and then brought into contact with an aqueous sodium bicarbonate solution. This is accomplished by distilling off the solvent from the reaction mixture after washing with water.

The third step is the addition of the dihydroxy compound (b) to the above-mentioned hole (V
The conversion reaction to a compound having l) is achieved by oxidizing the dihydroxy compound (b). The reaction is carried out under the same conditions as in the above-mentioned reaction in which the compound having the -pattern (V) is brought into contact with an oxidizing agent.

Alternatively, preferably in the presence of a solvent, an organic active halogen compound such as N-bromoacetamide, N-chlorosuccinimide, N-bromphthalimide; dimethylsulfoxide-dicyclohexylcarbodiimide, dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide Fluoroacetic anhydride, dimethylsulfoxide-pyridine-sulfuric anhydride, and the like are also used as oxidizing agents. When dimethyl sulfoxide-dicyclohexylcarbodiimide is used, an acid catalyst such as phosphoric acid or trifluoroacetic acid is used; when dimethyl sulfoxide-oxalyl chloride, dimethyl sulfoxide-trifluoroacetic anhydride, or dimethyl sulfoxide-pyridine-sulfuric anhydride is used, triethylamine is used. A base catalyst of tertiary alkylamines such as tertiary alkylamines is used according to conventional methods. The reaction is preferably carried out in the presence of a solvent.

The solvent used is not particularly limited as long as it does not participate in the reaction, and when an organic active halogen compound is used, examples thereof include aqueous organic solvents such as aqueous t-butanol, aqueous acetone, and aqueous pyridine. dimethyl sulfoxide-dicyclohexylcarbodiimide,
When using dimethyl sulfoxide-oxalyl chloride, dimethyl sulfoxide-oxytote trifluoroacetic anhydride, dimethyl sulfoxide-pyridine-sulfuric anhydride, for example, dimethyl sulfoxide 7; aromatic hydrogen ash such as benzene and toluene: methylene chloride , halogenated hydrocarbons such as chloroform. The reaction temperature varies depending on the type of oxidizing agent used. For example, in the case of dimethyl sulfoxide-oxalyl chloride, dimethyl sulfoxide to trifluoroacetic anhydride, -70℃ to 40℃
, preferably from 0°C to room temperature, but in other cases from 0°C to 50°C, preferably from lo°C to 30°C. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 1.
The duration is 0 minutes to 6 hours.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is immiscible with water to a reaction mixture and extracting it, washing the extract with water, and then distilling off the solvent from the extract. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, column chromatography, etc.

The fourth process is a step of producing an oxime derivative having the above-mentioned -IK, wherein the compound having the above-mentioned -IK is brought into contact with a hydroxylamine derivative having the formula H2No-A-Y. It will be achieved.

The hydroxylamine derivative with 2H2N0-A-Y used in the reaction can be obtained commercially or from Aeta Chlmlea Aaadsmia Hungarica (Aeta Chlmlea Aaadsmia
eSai@ntlarum Hungari'ea*
) Vol. 84, p. 167 (1975) and Synthesis, p. 682 (1976). 2H2No -
The hydroxylamine derivative having A -Y is used as it is or in the form of a salt with an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid, with hydrochloride being particularly preferred.

In this step, in order to facilitate the reaction, for example, tertiary alkylamines such as triethylamine and tri-n-butylamine; aromatic amines such as pyridine and lutidine; alkali metal salts of acetate such as sodium acetate and potassium acetate; Bases such as alkali metal bicarbonate salts or alkali metal carbonate salts such as sodium bicarbonate, sodium carbonate, potassium carbonate, etc. can be present, and suitable bases include triethylamine, pyridine, and sodium acetate. can. The reaction is preferably carried out in the presence of a solvent. The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, but examples include alcohols such as methanol, ethanol, propatool, ethers such as tetrahydrofuran and dioxane, or combinations of these solvents and water. Mixed solvents can be mentioned.

Since the raw material compound (Vl) in this step has a diketone moiety, the compound having the general formula (DO''Ik) can be selectively produced by adjusting the amount of the hydroxylamine derivative as an oximating agent. That is, the amount of hydroxylamine derivative relative to the raw material compound CM) can be 1 to 1.
By using 1.2 equivalents, it can be produced selectively as the main product.

The reaction temperature is usually carried out at -10°C to 100°C,
The temperature is preferably 0°C to 50°C. The reaction time is 30 minutes to 10 hours, preferably 1 hour to 5 hours.

After the reaction is completed, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is immiscible with water to the reaction mixture, washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or column chromatography.

The fifth step is a step of producing a compound having the general formula (■), and is achieved by oxidizing the compound having the general formula (IV). The reaction is carried out under conditions similar to those described in the third step.

The sixth step is a step of producing a compound having the general formula (■), in which a compound having the general formula (■) is prepared by formula H2.
It consists of a reaction of contacting with a hydroxylamine derivative having No -A -Y and (ii) a reaction of optionally removing the protecting group when R4 is a protecting group for a hydroxy group. Any of these reactions may be performed first.

The reaction (1) of contacting with a hydroxylamine derivative having the formula H2No -A -Y is carried out under the same conditions as described in the fourth step.

The reaction for removing the protecting group when R4 is a hydroxy-protecting group as required in step (2) varies depending on the type of hydroxy-protecting group, but is generally removed by a method known in this technical field. .

When the protecting group for the hydroxy group is a tri-lower alkylsilyl group such as trimethylsilyl, dimethyl-1-butylsilyl, diphenyl-1-butylsilyl, the reaction is performed using a fluoride ion such as tetrabutylammonium fluoride, hydrofluoric acid, etc. This is accomplished by treatment with an acid such as trichloroacetic acid or trifluoroacetic acid. The solvent used is not particularly limited as long as it does not participate in the reaction, and suitable examples include ethers such as tetrahydrofuran and dioxane; and nitriles such as acetonitrile. Furthermore, when using fluoride ions, an organic acid such as acetic acid or propionic acid may be added to accelerate the reaction as desired. The reaction is suitably carried out by treating for 2 to 10 hours at 0°C to around room temperature.

In addition, the protecting group may be, for example, 2-tetrahydropyranyl, 2-
Heterocyclic groups such as tetrahydrothiopyranyl, 2-tetrahydrothienyl, 4-methoxytetrahydropyran-4-yl; catalysts in the case of alkoxy hydrocarbon groups such as l-ethoxyethyl and l-methoxycyclohexan-1-yl. This is easily achieved by contacting with a certain amount of acid. Examples of acids used include formic acid, acetic acid, and
Organic acids such as acid, butyric acid, Cheryl acid, ironic acid and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid are preferably used. The reaction is preferably carried out in the presence of a solvent. The solvent to be used is not particularly limited as long as it does not participate in the reaction; for example, water; alcohols such as methanol and ethanol; ethers such as tetrahydro7rane and dioxane; or combinations of these organic solvents and water. Mixed solvents are preferably used. The reaction is usually at room temperature ~
The reaction is preferably carried out at the reflux temperature of the solvent, particularly at room temperature. The reaction time is 1 to 5 hours. After the reaction is completed, the target compound is collected from the reaction mixture according to a conventional method. For example, adding a water-immiscible organic solvent to the reaction mixture, then washing with water,
Obtained by distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, column chromatography, etc.

The seventh step is a step of producing a compound having the above-mentioned hole (■), and a compound KX-C having the above-mentioned hole (4).
This is a reaction that introduces an o-group. The reaction is carried out under conditions similar to those described in the second step.

The eighth step is a step of producing a compound having the above-mentioned hole (plate), where R and /l or R in the compound having the above-mentioned hole (GK) are a protecting group for a human group. This is accomplished by removing the protecting group. The reaction is carried out under conditions similar to those described in the sixth step.

The ninth step is a step of producing a carboxylic acid having the above-mentioned (1) t-, an ester thereof, and a pharmacologically acceptable salt thereof, as desired; This is a process for producing ester derivatives, etc. of carboxylic acid metal salts whose lactone moieties are cleaved by using conventional hydrolysis or solvolysis conditions.

The reaction to obtain the carboxylic acid metal salt is carried out by the conventional method 11 in the hydrolysis reaction of the lactone compound having the above-mentioned hole (n).
! This will be achieved by doing the following. For example, the hydroxides and carbonates of the metals, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, etc., in a suitable solvent, such as water or an aqueous organic solvent such as aqueous alcohol, aqueous acetone, or aqueous dioxane. The target compound can be produced by contacting with the like. The amount of the alkali metal hydroxide used is normally 1-1 to 1.5 moles. The reaction is suitably carried out at around room temperature, and the time required for the reaction is 1 to 5 hours.

After the reaction is completed, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture under reduced pressure and freeze-drying it. The obtained desired compound can be further purified, if necessary, by conventional methods such as recrystallization or column chromatography.

The reaction to obtain the carboxylic acid ester derivative is carried out by the above-mentioned -Momona (1)
) is achieved by treating a lactone compound having the following in a conventional manner in a solvolysis reaction. For example, the above-
A compound having a crest (II) is treated with an acid catalyst, such as an inorganic acid such as hydrochloric acid or sulfuric acid, or a Lewis acid such as boron trifluoride.
It is obtained by contacting with an alcohol such as methanol, ethanol, n-propanol, isopropanol, etc. in the presence of an acidic ion exchange resin or the like. The reaction can be carried out using a suitable inert organic solvent, such as aromatic hydrocarbons such as benzene; ethers such as diethyl ether; halogenated hydrocarbons such as chloroform; however, alcohol itself may be used as the solvent. It is preferable to use The reaction is preferably carried out under heating, e.g.
It is carried out at boiling point. The reaction time is usually several hours. After the completion of the reaction, the target compound is collected from the reaction mixture by a conventional method.For example, when an ion exchange resin is used as a catalyst, it is obtained by separating the F and distilling off the solvent from the furnace liquid. When a Lewis acid is used, it can be obtained by distilling off the solvent after treatment such as neutralization, extraction with a suitable solvent, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization or chromatography.

Further, the obtained above-mentioned compound can be converted into the target compound by subjecting it to a salt-forming reaction, esterification reaction, etc. according to a conventional chemical method, if desired, and can be easily collected.

All of these methods are conventional methods, such as the following method.

The carboxylic acid having the general formula (1) has a pH of p) 14 or less, preferably pH 3.
-4. The acid used is not limited to organic acids or mineral acids as long as it does not affect the target compound; for example, trifluoroacetic acid,
Hydrochloric acid, sulfuric acid, etc. are preferably used.

The carboxylic acid thus obtained can be used in the following reaction after being subjected to treatments such as extraction, washing, and dehydration.

The amine salt of a carboxylic acid having the general formula (1) can be obtained by contacting an amine with the carboxylic acid in an aqueous solvent. Examples of the aqueous solvent used include water; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran; and mixed solvents of water and nitriles such as acetonitrile; preferred is aqueous acetone. The reaction is usually -7 to 8
．． 5 and is suitably carried out at a temperature below room temperature, particularly at 5 to 10°C.

The reaction is completed instantly. Alternatively, the carboxylic acid metal salt obtained above can be dissolved in an aqueous solvent, and then the desired amine mineral salt (for example, hydrochloride) can be added under the above conditions to carry out a salt exchange reaction.

The amino acid salt of carboxylic acid having the general formula (1) is
It is obtained by contacting an amino acid with the above carboxylic acid in an aqueous solvent. Examples of the aqueous solvent used include water: alcohols such as methanol and ethanol, and mixed solvents of water and ethers such as tetrahydrofuran. The reaction is usually carried out under heating, preferably around 50 to 60°C.

Alternatively, the alkyl ester of a carboxylic acid having the general formula (1) can be obtained by contacting the carboxylic acid obtained above with a diazoalkane. The reaction is usually carried out by contacting with an ethereal solution of the diazoalkane. Alternatively, it can be obtained by contacting the metal salt of carboxylic acid obtained above with an alkyl halide.

Suitable solvents to be used include dialkylformamides such as dimethylformamide, ethers such as tetrahydrofuran, dialkylsulfoxides such as dimethylsulfoxide, and ketones such as acetone.

All reactions are suitably carried out at around room temperature, but depending on the type of reaction system, they may be carried out under heating if necessary.

The target compound thus obtained can be collected, separated, and purified by appropriately combining various methods. For example, adsorption or ion exchange chromatography using various carriers such as activated carbon and silica gel, or gel filtration using a Cefdex column: r--f, ethyl acetate,
This is done by extraction using an organic solvent such as chloroform.

In particular, separation of isomers can be carried out at an appropriate time using the above-mentioned separation and purification means.

Next, the present invention will be explained in more detail with reference to Examples.

In addition, in the examples, "isoML-236A carboxylic acid"
and "isoML-236A lactone" are abbreviations for compounds represented by the following formula.

Example 1m, 1-(2-methylbutyryl)-3
, 4-dihydro-6-oxo-4-benzyloxyiminoiso ML-236A lactone (Exemplary Compound No. 1) 1
6-t-Butyldimethylsilyloxy-1-(2-methylbutyryl)-3,4-dihydro-4,6-thioxoiso ML-236A lactone (JP-A-58-55443
(See Example 1 of the issue, hereinafter referred to as "dioxo compound") 15
1 (28mM) in 150ml of ethanol, then benzyl and droxylamine hydrochloride 4.48N (2'
8mM) and then added anhydrous sodium acetate 2.765+ (3.36mM) little by little while stirring under ice-cooling.
After stirring the reaction mixture for 2 hours, water was added to the reaction mixture and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off from the extract to obtain a residue 18.611.
When fractionated and purified with hexane-3:2), 16-1-
11.9 of butyldimethylsilyloxy-1-(2-methylbutyryl)-3,4-dihydro-6-oxo-4-benzyloxyiminoiso m-5sA lactone was obtained. The above oxime compound 2.741 was dissolved in 28d of a hydrofluoric acid-acetonitrile solution (a solution in which 5d of 5゛〇-hydrofluoric acid aqueous solution was dissolved in 95WLt of acetonitrile),
The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was cooled on ice and then neutralized with a saturated aqueous solution of sodium bicarbonate.
The solvent was distilled off from the reaction mixture under reduced pressure, and ethyl acetate was added to the resulting residue for extraction. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off from the extract. The resulting residue was purified by silica gel chromatography (ethyl acetate:n-hexane-4=1) to obtain 1.46 g of the title compound as a colorless foam.

Nuclear magnetic resonance spectrum (CDCt, sδ: PPm
, 2701i1Hz) 7.36 (5H), 6.5
4 (IH, d), 5.47 (IH, s), 5.20
(2H, q) e4.66 (IHem), 4.37 (II
, br, s), 3.17゛C1ii * m) Infrared absorption spectrum CHCAS-t・1. ! D・3450.1725.1660 Example 1b・1-(2-methylbutyryl)-3,4
-Dihydro-6-oxo-4-benzyloxyiminoiso ML-236A carboxylic acid sodium salt was stirred.

After the reaction was completed, ethanol was distilled off from the reaction mixture under reduced pressure, and the mixture was then freeze-dried to obtain 530 da of the title compound as a light brown powder (hygroscopic).

Example 1a, 1-(2-methylbutyryl)-3
, 4-dihydro-6-oxo 4-benzyloxyiminoiso ML-236A carboxylic acid benzyl ester 1-(2-methylbutyryl)-3 obtained in Example 1-,
4-dihydro-6-oxo-4-benzyloxyiminoiso m-5sA lactone 525111F in ethanol 1
After dissolving 0tJK, 0. IN aqueous sodium hydroxide solution I Qitj (1 equivalent) was added at room temperature for 2 hours Example 1b
1-(2-methylbutyry)-3e4-dihydro-6-oxo-4-benzyloxyiminoiso M obtained in
L-236A carboxylic acid sodium salt 280115F in dimethylformamide 5! ! After dissolving in Lt, benzyl bromide 120115F (1.4 equivalents) was added and the
After the reaction was stirred for 0 hours, water was added to the reaction mixture, and then ethyl acetate was added for extraction.

The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off from the extract. The resulting residue was purified by silica gel chromatography (ethyl acetate:n-hexane 15:85) to yield the title compound 34.
ON#p was obtained as a pale yellow candy.

Nuclear magnetic resonance spectrum (CDC1, δ: ppm,
270MH1) 7.35 (IOH), 6.53 (IH
, d), 5.50 (IH, s).

5.20 (2H, d), 5.15 (2H, s), 4.2
6 (IH, m) = 3.79 (IH, m), 3.18 (I
H, m) Infrared absorption spectrum She Alquid, -1
:ax 3450, 1730. 1660. 1575 Example 2m, 1-(2-methylbutyryl)-3,4-
Dihydro-6-oxo-4-(4-methoxybenzyl)
Oximinoiso ML-236A lactone (Exemplary Compound No. 6) Dioxo form 5.3F (10mM) Oh! Hy-(4-methoxybenzyl)hydroxylamine hydrochloride 1.9#(
In the same manner as in Example 1a, 1.76 g of the title compound was obtained as a pale yellow candy.

Nuclear magnetic resonance spectrum (coct5 *δ: ppm
, 270MI(z)7.31(2H)-6,91(
2H)=6.55(IH-d)e5.48(IH,br
,+a)-5,13(2Hsq),4.63(IH,m
)-4,38 (IH, rn), 3.81 (3H, s),
3.16 (IH, m) infrared absorption spectrum νCHCL
3 cm-' :ax 3450.1725.1655 Example 2b, 1-(2-methylbutyryl)-3
,4-dihydro-6-oxo-4-(4-methoxybenzyl)oxyiminoiso ML-236A carboxylic acid sodium salt 1-(2-methylbutyryl)-3 obtained in Example 2a
,4-dihydro-6-oxo-4-(4-methoxybenzyl)oxyiminoisoML-236A lactone 180
9 was carried out in the same manner as in Example 1b to obtain the title compound 18.
0'Mg was obtained as a pale purple powder.

Example 3m, 1-(2-methylbutyryl)-3
,4-dihydro-6-oxo-4-(4-fluorobenzyl)oxyiminoisoML-236A lactone (Exemplary Compound No. 129) fluoropenzyl)hydroxylamine tj[[180q
(1mM) in the same manner as in Example 1m to obtain 220 da of the title compound as a colorless foam.

Nuclear magnetic resonance spectrum (cDct, e δ: ppm
, 270MHN) 7.0 to 7.3 (4H) −
6,52(I H* d ) -5,46(I H-b
r −s ) *5.15(2H,q), 4.63(
IH, m), 4.38 (IH, rn) 13.14 (
IH,m) Example 3b, 1-(2-methylbutyryl)-3
,4-dihydro-6-oxo-4-(4-fluorobenzyl)oxyiminoiso ML-236A carboxylic acid sodium salt 1-(2-methylbutyryl)-3 obtained in Example 3a
,4-dihydro-6-oxo-4-(4-fluorobenzyl)oxyiminoiso ML-236A lactone 601
The procedure was carried out in the same manner as in Example 1b using Compound 19 to obtain the title compound 57 as a light brown powder.

Example 4m, 1-(2-methylbutyryl)-3
, 4 No. 15) Force ← dioxoform 530 da (1mM) and 0-(4-nitrobenzyl)hydroxylamine jJll [2x.

The title compound 115119 was obtained as a pale yellow foam by carrying out the same procedure as in Example 1a using Da (1mM).

Nuclear magnetic resonance spectrum (CDCA3.δ: PPtfl
-270MHz)7.3~8.4(4H),s,s
g(1a,a)*5.48(IHebr,s).

5.30 (2Hes), 4.64 (IH, m), 4.3
8(1i1.m)*3.18(IH,m) Infrared absorption spectrum C:HC1,,1:3400.1
725. '1650.1530 Example 4b, 1-(
2-methylbutyryl) -3,4 dihydro 1-6-oxo-4-(4-nitrobenzyl)oxyiminoiso ML
-236A carboxylic acid sodium salt obtained in Example 4a! -(2-methylbutyryl)-3
#4-dihydro-6-oxo-4-(4-nitrobenzyl)oxyitnoiso ML-236 mulactone 8011
The title compound 8 was obtained in the same manner as in Example 1b using
0 da was obtained as a pale red powder.

Example 5a 1-(2-methylbutyryl)-3,4
-Dihydro E! -6-oxo-4-(3-)lifluoromethylbenzyl)oxyiminoiso ML-236A lactone (Exemplary Compound No. 119) Dioxo compound 53089 (1mM) and 0-(3-
Trifluorobenzyl) hydroxylamine hydrochloride 23
The title compound 410p was obtained as a colorless foam in the same manner as in Example 1m using 0il (1mM).

Nuclear magnetic resonance spectrum (CDCA3 *δ: pptn
e270MHs)7.5~7-7 (41) -
6,51(II-d)-5,48(IH-br-
s) e5.24(2H,5)=4.63(11,m)
-4,38(11,m)-3,14(IH,m) Infrared absorption spectrum CHCLsffi-1:m&X 3450, 1725. 1660 Example 5b, 1-(2-methylbutyryl)-3,
4-dihydro-6-oxo-4-(3-)lifluoromethylbenzyl)oxyiminoiso ML-236A carboxylic acid sodium salt 1-(2-methylbutyryl)-3 obtained in Example 5a
, 4-dihydro-6-oxo-4-(3-trifluoromethylbenzyl)oxyiminoiso ML-236A lactone 24011Pt- was carried out in the same manner as in Example 1b to obtain the title compound 240'IIg as a colorless powder. Ta.

Example 6m, 1-(2-methylbutyryl)-3
,4-dihydro-6-oxo-4-(2-hydroxymethylbenzyl)oximinoin ML-236A lactone (Exemplary Compound No. 11) Dioxo compound 5.311 (10mM) and 0-(2-hydroxymethylbenzyl) ) Hydroxylamine hydrochloride 1
．． The reaction was carried out in the same manner as in Example 1m using 9N (10mM) to obtain the title compound 3.7II as a pale yellow candy.

Nuclear magnetic resonance spectrum (CDct5.δ: ppm m
270 MHs) 7.4 (4H, m), 6.48 (
IH, d), 5.46 (IH, br, s).

5.31 (2H, s), 4.76 (2H, s), 4.6
3(IH,m)*4.38(IH,m), 3.12(I
H, m) Infrared absorption spectrum νCHCl, , -1=
ax 3500, 1720. 1665 Example 6b, 1-(2-methylbutyryl)-3,
4-dihydro 6-oxo 4-(2-hydroxymethylbenzyl)oxyiminoiso ML-236A carboxylic acid sodium salt 1-(2-methylbutyryl)-3 obtained in Example 6a
, 4-dihydro-6-oxo-4-(2-hydroxymethylbenzyl)oxyiminoiso ML-236A lactone 1. The title compound 980119 was obtained as a colorless powder by carrying out the same procedure as in Example 1b using Og.

Example 7m, 1-(2-methylbutyryl)-3
, 4-dihydro-6-oxo-4-(3-hydroxybenzyl)oximinoiso ML-236A lactone (Exemplary Compound No. 5) 1.6 g (3 mM) of dioxo compound and 0-(3-hydroxybenzyl)hydroxylamine hydrochloride salt 535 da (3
430 Wv of the title compound was obtained as a pale red foam.

Nuclear magnetic resonance spectrum A/ (CDCl2 sδ: pp
m, 270 MHz) 6.8-7.3 (41
) -6,55(IH-d) -5,46(IHt
br, @).

5.17 (2He () * 4.65 (IH*m
) -4,38(IH,m) -3,15(IH,m
) Infrared absorption spectrum νcHCtscrIL″1 ;a
x 3650.3400,1720. 1660.1610
Example 8m, 1-(2-methylbutyryl)-3
, 4dihydro-6-oxo-4-phenyloxyiminoiso ML-236A lactone (Exemplary Compound No. 16) Example 1a using dioquine compound 53Qs+p (1 mM) and 0-phenylhydroxylamine hydrochloride 145 (1 mM) The procedure was carried out in the same manner as above to obtain the title compound 420.times. as a colorless foam.

Nuclear magnetic resonance spectrum (CDCA3 ta: ppm,
270MHs)7.1~7.4 (5B)a 6.
70 (IH-d)-5,52(ta,br,5)-
4,63 (IH, tn) # 4.30 (IH, m)
, 3.40 (IH, m) CHCL3-1° infrared absorption spectrum νwax crIL.

3400.1725, 1660.1600 Example 8b,
1-(2-Methylbutyryl)-3,4-dihydro-6-oxo-4-phenyloxyimino°isoML
-236A carboxylic acid sodium salt 1-(2-methylbutyryl)-3,4-dihydro-6 obtained in Example 8a
-oxo-4-phenyloxyiminoiso ML-236
The same procedure as in Example 1b was carried out using A-lacto 722019 to obtain 220 da of the title compound as a colorless powder.

Example 9m, 1-(2-methylbutyryl)-3
,4-dihydro-6-oxo-4-(3-phenylpropyl)oxyiminoiso ML-236A lactone (Exemplary Compound No. 18) Dioxo compound 530 da (1mM) and 0-(3-phenylpropyl)hydroxylamine hydrochloride 190'9 (
The title compound 4soW9 was obtained as a pale yellow candy by carrying out the same procedure as in Example 1m using 1mM).

Nuclear magnetic resonance spectrum (coct, , δ: ppm
, 270 kms) 7.25 (5H) #6.53
(IH, d), 5.48 (IH, br, l').

4.64 (IH, m), 4.38 (IH, br, s
), 4.20 (2H, m) e3.08 (IH=m) Infrared absorption spectrum νCHCL3cIL-1=ax 3450.1730.1660 Example 9b, 1-(2-methylbutyryl)-3
, 4-hydro-6-o-4-(3-phenylpropyl)oxyiminoiso ML-236A carboxylic acid sodium salt obtained in Example 9a 1-(2-methylbutyryl)-3
,4-dihydro-6-oxo-4-(3-phenylpropyl)oxyiminoiso ML-236A? Chthon 16
The title compound 165IIP was obtained as a colorless powder in the same manner as in Example 1b using 0m9''i.

Example 10m, 1(2-methylbutyryl) -3,4-
Dihydro-6-oxo-4-(3-pyridylmethyl)oxyiminoiso ML-236A ychthone (Exemplary Compound No. 37) Dioxo compound 1. IJl (2mM), 0-(3-picolyl)hydroxylamine dihydrochloride 400M9 (2mM)
The reaction was carried out in the same manner as in Example 1m using anhydrous sodium acetate 5001119 (6 mM) to obtain 680 da of the title compound as a pale yellow candy.

Nuclear magnetic resonance spectrum (CDCA, , δ: ppm
#270 WnZz) 8.62 (2H), 7.72
(IM), 7.31 (IH), 6.50 (III.

d), 5.48 (IH, br, 5) s5.21 (2H
, a), 4.63 (I H* m ) a 4.38
(IHem) -3,15(IH-m) Infrared r
llt, collection I)/l/νCH"5 cm-'
:ax 3500.1725.1660.1620 Example tob
, 1-(2-methylbutyryl)-3,4-dihydro-
6-oxo-4-(3-pyridylmethyl)oxyiminoiso ML-236A carboxylic acid sodium salt 1-(2-methylbutyryl) obtained in Example 10m
-3,4-dihydro-6-oxo-4-(3-pyridylmethyl)oxyiminoiso ML-236A lactone 42
The title compound 4 was obtained in the same manner as in Example 1b using 0.
30# was obtained as a pale red powder.

Example 11m, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-furfuryloxyiminoiso ML-236A lactone (Exemplary compound number dioxo form 1.61! (3mM) and O-7/I/7lylhydroxylamine hydrochloride 450η (3mM) The reaction was carried out in the same manner as in Example 1m to obtain the title compound 1.429 as a light brown candy.

Nuclear magnetic resonance spectrum (coct3.δ: ppm e
270 MHz)7.4a(lu),s,4t(z
a), s, 5a (lu, d), s, 47 (IH-br
-m) e 5.12 (2Hsq) a 4.
64 (IHsm) -4,40 (IH=m), 3.6
1 (IH, m) infrared absorption spectrum CHCl3. ．．
-1 :ax 3450.1725.1650 Example 11b, 1-(2-methylbutyryl) -3,4
-Dihydro 6-oxo 4-furfuryloxyiminoiso ML-236A carboxylic acid sodium salt Example 11
1-(2-methylbutyryl)-3,4- obtained in m
Example 1b using dihydro-6-oxo-4-furfuryloxyiminoiso ML-236A lactone 450 da
In the same manner as above, 450 parts of the title compound were obtained as a light brown powder.

Example 11e, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-furfuryloxyiminoiso ML-236A carboxylic acid benzyl ester 1-(2-methylbutyryl) obtained in Example 11b -3,
4-dihydro-6-oxo-4-furfuryloxyiminoiso ML-236A sodium carboxylate [550j
Example 1e using 9 and benzyl bromide 240 da
In the same manner as above, 590 mg of the title compound was obtained as a light brown candy.

Nuclear magnetic resonance spectrum /I/ (CDCl3 mδ:pp
m, 270MHz) 7.45 (IH), 6.42 (2H
), 7.35 (5H), 6.54 (IH.

d), 5.48 (IH, br, 5) = 5.20 (2He
s), 5.12 (2H* q ) e 4.28 (I
H-m) -3,75 (I H-m) -3,4
5(11(,m) tlquld −1.

Infrared absorption spectrum　νr,.　　. .

3450.1730.1660 Example 11d, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-furfuryloxyiminoiso ML-236A carboxylic acid ethyl ester Example 1
1-(2-methylbutyryl)-3,4 obtained in 1b
-Dihydro-6-oxo-4-furfuryloxyiminoiso ML-236A carboxylic acid sodium salt (320 da) was dissolved in dimethylformamide (51:7), ethyl iodide (20ON9) was added, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, water was added to the reaction mixture, and then ethyl acetate was added for extraction. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off from the extract. Dissolve the resulting residue in silica gel. Purification by chromatography (ethyl acetate:n-hexane-1:1) gave the title compound 310il as a colorless candy.

Nuclear magnetic resonance spectrum (CDCL!!, a:pp
m, 270 MHz) 7.43 (IH), 6.4
2 (11), 6.38 (IH), 6.52 (IH, d)
, 5.50CIH,br,s) -5,12(2He
q).

4.27(IH=m)-4,17(2H*q)*3.8
3(II-m)-3,14(IH,m) Infrared absorption spectrum νtiquid, ff-1=ax 3500.1720.1660 Example 11, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-furfuryloxyiminoiso ML-236A carboxylic acid dicyclohexylamine salt obtained in Example 11b 7'tl-(2-methylbutyryl) -3,4-dihydro-6-oxo-4- Furfuryloxyiminoiso ML-236A carboxylic acid sodium salt was dissolved in 28011 ft of water, then made acidic by adding 101 sulfuric acid, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and after death, the solvent was distilled off from the extract to give 1-(2-methylbutyryl)-3,4-dihydro-6-oxo-4-furfuryloxy. Iminoiso ML-236A carboxylic acid 243
19 (0.46mM) was obtained as a candy. The obtained carboxylic acid was immediately dissolved in 1 m of ethyl acetate and then dissolved in dicyclo1+-/ruamine 83'9 (0,46
After adding t-mM), the solvent was distilled off. Ether was added to the obtained residue, and then the precipitated crystals were separated and washed with ether.

When the obtained crystals are recrystallized from n-hexane-ethanol, the title compound 230■ having a decomposition point of 145-146°C is obtained.
was obtained as pale yellow prismatic crystals.

Elemental analysis value C"") Calculated value as C40H62N209 C, 67, 20H, 8, 74N, 3.92 Actual value C, 66, 89H, 8, 71N, 3.92 Example 12
m, 1-(2-methylbutyryl)-3,4dihydro-
6-Oxo-4-(2-tetrahydrofurylmethyl)oxyiminoiso ML-236A lactone (Exemplary Compound No. 45) Dioxo compound 530 IIP (1mM) and 0-(2
-Tetrahydrofurylmethyl)hydroxylamine hydrochloride 155# (1 mM) was carried out in the same manner as in Example 1m to obtain the title compound 410w9 as a colorless candy.

Nuclear magnetic resonance spectrum (CDOA, δ: ppm *
270 MHz)6.52 (IHs br-s
) e 5.48 (IHe br -s) *4.
66 (IH, m) #4.38 (111, m) #4.20
(2H#m).

3.8 (2H, m), 3.18 (IH, m) infrared absorption Schep) A/, cucz, Ca1-':ax 3450.1730.1660 Example 12b, 1-(2-methylbutyryl)- 3,4
-6-okine-4-(2-tetrahydrofurylmethyl)oxyiminoiso ML-236A carboxylic acid sodium salt obtained in Example 12m 1-(2-methylbutyryl)
-3,4-dihydro-6-oxo-4-(2-tetrahydrofurylmethyl)oxyiminoiso ML-236A Lactone 21011jF was carried out in the same manner as in Example 1b to obtain the title compound 21519 as a colorless powder. .

Example 13a, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-(2-tetrahydropyranylmethyl)oxyiminoiso ML-236A lactone (Exemplary Compound No. 47) Dioxo form 530 Wv (1mM) and 0-(2-
The reaction was carried out in the same manner as in Example 1m using 170 ml (1 mM) of tetrahydropyranylmethyl)hydroxylamine hydrochloride to obtain 380 ml of the title compound as a colorless candy.

Nuclear magnetic resonance spectrum (coct, , δ: PPfl
l-270MHx)6.52 (IH#d)
$5-48 (I H-br-s) *4-
64 (IH*re) , 4.38 (IH, m) , 4
．． 0 to 4.2 (3H, m), 3.65 (IH, 111
) e3.40 (IH, m) e3.20 (IH, m)
Aiqllid-1.

Infrared absorption spectrum -1xcIIL.

3450.1730.1660 Example 13b, 1-(2-methylbutyryl)-3e4-
Dihydro-6-oxo-4-(2-tetrahydropyranylmethyl)oxyiminoiso ML-236A carboxylic acid sodium salt 1-(2-methylbutyryl) obtained in Example 13m
-3,4-dihydro-6-oxo-4-(2-tetrahydropyranylmethyl)oxyiminoiso ML-236A
The same procedure as in Example 1b was carried out using Tukton 200# to obtain 200 da of the title compound as a colorless powder.

Example 14m, 1(2-methylbutyryl) -3,4-
Dihydro-6-oxo-4-cyclohexylmethyloxyiminoiso ML-236A lactone (Exemplary Compound No. 60) Dioxo compound 3.211 (6mM) and 0-(cyclohexylmethyl)hydroxylamine hydrochloride 1.0.
9 (6mM) in the same manner as in Example 1m to obtain 2.89 of the title compound as a colorless candy.

Nuclear magnetic resonance spectrum (CDCt, , δ: ppm
, 270 MHz) 6.54 (IH, d), 5.4
6 (IH, br, s), 4.60 (IH.

m)-4,29(IH*m)s4. oo(2H,ra)
, 3.14 (IH, m) Infrared absorption spectrum CHCt3m-1:ax 3450.1725.1660 Example 14b 1-(2-methylbutyryl) -3,
4-dihydro-6-oxo-4-cyclohexylmethyloxyiminoiso■, -236A carboxylic acid sodium salt 1-(2-methylbutyryl) obtained in Example 14m
-3,4-dihydro-6-oxo-4-cyclohexylmethyloxyiminoiso ML-236A? Chthon 1.
4JF' was carried out in the same manner as in Example 1b to obtain the title compound 1.45 If as a colorless powder.

Example 15m 1-(2-methylbutyryl)-3,
4-dihydro-6-oxo-4-(cis-4-hydroxycyclohexylmethyl)oxyiminoiso ML-23
6-lactone (Exemplary Compound No. 61) dioxo form 1.6
．． 9 (3mM) and 0-(cis-4-hydroxycyclohexylmethyl)hydroxylamine hydrochloride 550μ
(3mM) in the same manner as in Example 1m to obtain 1.32g of the title compound as a colorless candy.

Nuclear magnetic resonance spectrum v (CDCt, eδ: ppm,
270 MHz) 6.53 (IH, d), 5.4
8 (IH, br, s), 4.64 (IH.

m) , 4.39 (IH, m) , 4.07 (2H, d
), 4.03 (IH.

m) =3.16(IH,m) Infrared absorption spectrum CHCL3crIL''1:1x 3450.1725.1665 Example 15b, 1-(2-methylbutyryl) -3,4
-dihydro-6-oxo-4-(cis-4-hydroxycyclohexylmethyl)oxyiminoiso ML-236
A carboxylic acid sodium salt 1- obtained in Example 15m
(2-Methylbutyryl)-3,4-dihydro-6-oxo-4-(cis-4-hydroxycyclohexylmethyl)oxyiminoiso ML-236A Lactone 320
The title compound 33 was obtained in the same manner as in Example 1b using
0ny was obtained as a colorless powder.

Example 15a, 1(2-methylbutyryl)-3,4-
Dihydro-6-oyano-4-(cis-4-hydroxycyclohexylmethyl)oxyiminoiso ML-236A
Carboxylic acid benzyl ester obtained in Example 15b:
-(2-methylbutyryl) -3,4-dihyde c1-6
-Oxo-4-(cis-4-hydroxycyclohexylmethyl)oxyiminoiso ML-236A carboxylic acid sodium salt 200 ml and benzyl bromide 82 ml were carried out in the same manner as in Example 1a to obtain 210 ml of the title compound.
was obtained as a pale yellow candy.

Nuclear magnetic resonance spectrum (cvct3.δ: ppm,
270MHz)7.35 (5H) = 6.52
(IH-d) + 5.51 (IH-br-s
) -5,15 (2H, i), 4.28 (IH, m),
4.03 (3H, m) - 3,80 (IH, m), 3.1
3(IH,m)Aiquid-1.

Infrared absorption spectrum CxcrIL.

3500.1730.1660 Example 16m, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-(1,3-dioxane-
5-ylmethyl)oxyiminoiso ML-236A lactone (Exemplary Compound No. 54) Dioxo form 530 N (1mM) and O-(1,
The reaction was carried out in the same manner as in Example 1m using 170 Da (1 mM) of 3-diochitin-5-ylmethyl)hydroxylamine hydrochloride to obtain 380 Da of the title compound as a colorless candy.

Nuclear magnetic resonance spectrum (CDCA, , δ: ppm
*270 MHz)6.50(IH=d)C5,4
B(IHebr-s)-4,85(2H-q)=
4.66 (I H* m ) e 4.38 (i
He m ) −4,25(2Hed), 4.02(
2H, m), 3.75 (2) f, m), 3.14 (IH
-m) Infrared absorption spectrum SI L1qu1d, -1:m&x 3450.1725.1660 Example 16b, 1-(2-methylbutyryl) -3,4
1-(2-Methylbutyryl) obtained in 1-DiC draw 6-oxo-4-(1,3-dioxan-5-ylmethyl)oxyiminoiso ML-236 mucarboxylic acid sodium salt Example 16m
-3,4-dihydrolo-6-oxo4- (1,3-
dioxan-5-ylmethyl)oxyiminoisoML-
The procedure of Example 1b was repeated using 220 da of 236A lactone to obtain 220 da of the title compound as a colorless powder.

Example 17m, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-(3-methyA/-2-butenyl)oxyiminoiso ML-236A Ni'chthone (Exemplary Compound No. 64) Dioxo compound 1. III (2mM) and 0-(3-methyl-2-butenyl)hydroxylamine hydrochloride 2801
The procedure was repeated in the same manner as in Example 1m using 1 and 9 (2mM) to obtain 780 da of the title compound as a colorless candy.

Nuclear magnetic resonance spectrum (CDCA, , δ” PPII
I m 270 MHS ) 6.54 (1)! ,d)
, 5.47 (IH, br, I) C5,43 (IH.

t), 4.68 (2H, d), 4.64 (IH, n+)
, 4.38 (IH.

m), 3.15 (IH=m) Aiquid -1.

Infrared absorption spectrum　ν,.　　α　.

3450.1725.1660 Example 17b, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-(3-methyl-2-butenyl)oxyiminoiso ML-236A carboxylic acid sodium salt 1-(2-methylbutyryl) obtained in Example 17m
-3,4-dihydro-5-oxo-4-(3-methyl-
The title compound 29011P was obtained as a colorless powder in the same manner as in Example 1b using 280 da of 2-butenyl)oximinoiso ML-236A lactone.

Example 18m, 1-(2-methylbutyry#)-1e
4-dihydro-6-oxo-4-(4- to droxy-3
-methyl-2-butenyl)oxyiminoiso ML-23
6A lactone (exemplified compound number 65) dio, xo form 53
0Q (1mM) and 0-(4-hydroxy-3
-methyl-2-butenyl)hydroxylamine hydrochloride 1
The procedure was carried out in the same manner as in Example 1m using 60 Da (1mM) to obtain a marked metal article 410j'jF as a pale yellow candy.

Nuclear magnetic resonance spectrum (CDC15, δ: ppm,
270 MHz)6.53(IH=d)C5,71
(IH-4)-5,48(IH-br-s) a 4
．． 76 (2H* d) * 4.66 (I H-
m) -4,38 (IH, br, s), 4.08 (2
H, a), 3.15 (IH, m) tlquld −1
゜Infrared absorption spectrum νm0 1.

3550.1730.1660 Example 18b, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-(4-hydroac-3-
Methyl-2-butenyl)oxyiminoiso ML-236
1-obtained in A-ruboxic acid sodium salt Example 18m
(2-Methylbutyryl) -3,4-dihydro-6-oxo-4-(4-hydroxy-3-methyl-2-butenyl)oxyiminoiso ML-236A lactone 200■
The title compound 210 was prepared in the same manner as in Example 1b using
19 was obtained as a colorless powder (hygroscopic).

Example 19m, 1(2-methylbutyryl) -3,4-
Dihydro-6-oxo-4-(2-hydroxy-2-phenylethyl)oxyiminoin ML-236A lactone (Exemplary Compound No. 22) Amine hydrochloride 190 μ (1 m
The title compound 28019 was obtained as a pale yellow candy by carrying out the same procedure as in Example 1m using M).

Nuclear magnetic resonance spectrum (CDC1, δ: ppm,
270MHz) 7.40 (5H), 6.52 (IH
, d), 5.49 (IH, br, s) 5.09 (IH,
m), 4.64 (IH, m), 4.38 (II.

br, s) 14.29 (IH, m), 3.20 (IH
, m) Infrared absorption spectrum vCHCLS[-1=ax 3500.1725.1660 Example 20m, 1-(2-methylbutyryl) -3,4
-dihydro-6-oxo-4-(1-naphthylmethyl)
Oximinoiso ML-236A? Chthone (Exemplary Compound No. 34) Dioxo form 530W (1mM) and 0-(2-
Hydroxy-2-phenylethyl) todroxyl dioxo compound 530N (1mM) and 0-(1-naphthylmethyl)hydroxylamine hydrochloride 210D (1mM)
) was carried out in the same manner as in Example 1m to obtain the title compound 4.
30 μm was obtained as a pale brown foam.

Nuclear magnetic resonance spectrum (coct, , δ: ppm
, 270MHz) 7.4-8.1 (7H), ass
(xu, d)-5,66(2Heq)-5,45(IH
, 5) = 4.62 (IH, m) - 4,37 (IH, m)
-3,12(IH,m) Infrared absorption spectrum sicHCL3i1:ax 3450.1720, 1660.1590 Example 21m
, 1-(2-methylbutyryl)-3,4-dihydro-
6-oxo-4-(4-methylbenzyl)oxyiminoiso ML-236A? Chthone (Exemplary Compound No. 123
) dioxoform 3.30 fi (6,2mM) and 0
-(4-methylbenzyl)hydroxylamine tJ[t
Working as in Example 1a using J[1,181 (6.8 mM), 1.0 g of the title compound was obtained as a colorless foam.

Nuclear magnetic resonance spectrum (CDCl2.δ: PPm e
270 MHz) 7.2s (2a, d), 7. x7
(zH, d), 6.54 (ta, d).

5.47 (IH, br, 5) = 5.16 (2H, q),
4.65 (IH, m) - 4,39 (IH, m), 3.1
6 (IH, m), 2.35 (3H, s) Elemental analysis value (arrogance) Calculated value as C,, H4, O, N 0.68.9
9 H, 7, 66 N, 2.60 actual value C, 68, 6
7H, 7-59N, 2.56 Example 21b, 1-(2-
methylbutyryl) -3,4-dihydro-6-oxo-
4-(4-methylbenzyl)oxyiminoiso ML-2
36A carboxylic acid sodium salt 1-(2-methylbutyryl) obtained in Example 21m
-3,4-dihydro-6-oxo-4-(4-methylbenzyl)oxyiminoiso ML-236A lactone 18
The same procedure as in Example 1b was carried out using 0w9 to obtain 170 da of the title compound as a colorless powder.

Example 22m, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-(2,5-dimethylbenzyl)oxyiminoiso ML-236A lactone (Exemplary Compound No. 124) l5 l-(2-methylbutyryl) -3,4-dihydro-4
, 6-thioxoiso ML-236A lactone (Unexamined Japanese Patent Publication No.
6-150037, 1.1.9 (2°6 mM) (hereinafter referred to as "desilyldioxoform") was dissolved in 10+t of ethanol, and then O-(2,5-dimethylbenzyl)hydroxylamine salt was prepared. 11 salt 516 da (
2,7mM) t-add dissolved 0 reaction mixture to -20
Anhydrous sodium acetate 320Q (3.9 m
After adding M) and stirring for 2 hours, water was added to the reaction mixture, and then extracted with ethyl acetate.

The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off from the extract to obtain a residue of 1.46N.

Flood the resulting residue with silica gel.

Chromatography (ethyl acetate: n-hexane-2:
1), 450m9 of the title compound was obtained as a colorless foam.

Nuclear magnetic resonance spectrum (coct, , δ” PI) I
ns 270 MHz)7.0~7.2 (3H)
-6,55(11-d) -5,48(IH* b
r −s ) −5,20(2H,q), 4.64(I
H, m) *4.40 (IH-m) - 3,15 (IH, m
) = 2.33 (6H, s) Elemental analysis value (1) C32
Calculated value as H4sO,N C, 69, 42H, 7, 8
3N, 2.53 estimated tE C, 69, 21H, 7, 7
9N, 2.37 Example 22b, 1-(2-methylbutyryl)-3,4-dihydro-6-oxo-4-(2,5
-dimethylbenzyl)oxyiminoiso ML-236A
Carboxylic acid sodium salt obtained in Example 22m, 7'cl-(2-methylbutyryl)-3,4-dihydro-6-oxo-4-(2#5-
The title compound 100N was obtained as a colorless powder in the same manner as in Example 1b using dimethylbenzyl)oximinoino ML-236 mulactone 100N9.

Example 23m, 1-(2-methylbutyryl) -L4-
Dihydro-6-oxo-4-(2-(1-hydroxy-1-methylethyl)benzyl)oxyiminoiso ML
-236A lactone (Exemplary Compound No. 125) desilylated dioxo form 1.01 (2.4mM) and 0-(2-
(1-Hydroxy-1-methylethyl)benzylcohydroxylamine hydrochloride 51711119 (2,4mM)
The procedure was carried out in the same manner as in Example 22m using 640 da of the title compound as a colorless foam.

Nuclear magnetic resonance spectrum /I/ (CDCt, #δ”P
Pn1 m 270 MHz) 7.25-7.45 (
4H)-6,50(IH,d), 5.63(IH,m)
.

5.48 (2H=q)-4,63 (IH-m) #4.3
7 (IH-m).

3.15 (IH, m), 1.67 (3H, s), 1.6
5(3H,a) Elemental analysis value (1) l3. H4,08
Calculated value as N: 0.67.90H, 7,77N,
2.40 actual measurement value C, 67, 59H, 7, 52N, 2.
16 Example 23b, 1-(2-methylbutyryl)-3
,4-dihydro-6-oxo-4-(2-(1-hydroxy-1-methylethyl/L/)benzyl)oxyiminoiso ML-236A carboxylic acid sodium salt Example 23
1-(2-methylbutyryl)-3,4- obtained in m
Dihydro-6-okine-4-(2-(1-hydroxy-
1-Methylethyl)pencil]oxyiminoisoML-
The same procedure as in Example 1b was carried out using 110 da of 236A lactone to obtain the title compound 110 as a pale purple powder.

Example 24m, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-(2-ethoxybenzyl)oxyiminoiso ML-236A Lacto/(Exemplary Compound No. 126) Desilylated dioxo compound 1.0 g (2.4 mM) and 〇-(2-ethoxybenzyl) Example 22 using hydroxylamine hydrochloride 49019 (2,4mM)
The title compound 560W9 was obtained as a pale yellow foam.

Nuclear magnetic resonance spectrum (coct, , δ” PP'D
e 270 MHz) 6.8-7.4 (4H), 6
．． 56 (IH, d), 5.48 (IH, br, s).

5.30 (2H, i), 4.64 (IH, m), 4.3
8(IH,m)-4,07(2H=q)-3,2
0(I H* m) Elemental analysis value (Li C3□H4,0
Calculated value as 8N C, 67, 47H, 7, 61N, 2
．． 46 actual measurement value C, 67, 21H, 7, 50N, 2.2
7 Example 24b 1-(2-methylbutyryl)-3
,4-dihydro-6-oxo-4-(2-ethoxybenzyl)oxyiminoiso ML-236A carboxylic acid sodium salt 1-(2-methylbutyryN)- obtained in Example 24m
L4-dihydro-6-oxo-4-(2-ethoxybenzyl)oxyiminoiso ML-236A lactone 120
The title compound 1 was obtained in the same manner as in Example 1b using
25■ was obtained as a pale purple powder.

Example 25m, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-(4-7'toxybenzyl)oxyiminoiso ML-236A lactone (Exemplary Compound No. 127) Dioxo compound 4.0II (7.5mM) and 0-(4-
butoxybenzyl)hydroxylamine hydrochloride t, 74
The title compound 2.41 was obtained as a colorless foam in the same manner as in Example 1a using y (7°5 mM).

Nuclear magnetic resonance spectrum k (CDCjl #δ” pPm
e 270'MHz) 7.31 (2H, d), 6
．． 90 (2H, d), 6.55 (IH, d).

5.47 (IH, br, i), 5.12 (2H, q) v
4.66 (IH-m).

4.38 (IHem) = 3.96 (2H, t), 3.1
4 (IH, m) elemental analysis value C%) C, 4H4, O,
Calculated value as N c, 68-32 H, 7,93N,
2.34 actual measurements C, 68, 10H, 7, 91N, 2.
36 Example 25b, 1-(2-methylbutyryl)-3
, 4-dihydro-6-oxo-4-(4-butoxybenzyl)oxyiminoiso ML-236A carboxylic acid sodium salt 1-(2-methylbutyryl) obtained in Example 25m
-3,4-dihydro-6-oxo-4-(4-butoxybenzyl)oxyiminoiso ML-236A lactone 1
6019 was carried out in the same manner as in Example 1b to obtain the title compound 160Wv as a pale purple powder.

Example 26m, 1-(2-methylbutyryl)-3,4
-dihydro-6-oxo-4-(5-yneoxacylylmethyl)oxyiminoia ML-236A lactone (
Exemplary Compound No. 128) Example 22 using desilylated dioxo compound 1.0.9 (2,4mM) and 〇-(5-isoxa9zolylmethyl)hydroxylamine hydrochloride 360 da (2,4mM) t-
After reacting in the same manner as in m, use a Roper column (Licloprep RP-18, size B# acetonitrile:
640 da of the title compound was obtained as a pale yellow foam.

Nuclear magnetic resonance spectrum (coct, , δ” Ppnl
#270 MHz) 8.24 (IH, d), 6.
48(1)1. d), 6.32 (IH, d).

5.48 (IH, br, 5) = 5.28 (2H, @) -
4,65 (IH, m).

4.38 (IH, m) = 3.15 (IH, m) Elemental analysis value (ts) Calculated value as C2, H36N208 C, 6
2,78H, 7,02N, 5.42 actual measurement value C, 62,
50,H, 7,06N, 5.11 Example 26b, 1-(
2-Methylbutyryl) -3,4-dihydro-6-oxo-4-(5-isoxacylmethyl)oxyiminoiso ML-236A carboxylic acid sodium salt 1-(2-methylbutyryl) obtained in Example 26m
The title compound 11019 was obtained as a colorless powder in the same manner as in Example 1b using 110 da of -3,4-dihydro-6-oxo-4-(5-isoxacylylmethyl)oxyiminoisokite-236A lactone. It was done.

Example 27m, 1-(2-methylbutyry/L/)-3,
4-dihydro-6-oxo-4-(2-sulfolinoethyl)oxyiminoiso ML-236A lactone (Exemplary Compound No. 122) Dioxo compound 2.65jl (4.96mM) and 〇-(
After reacting in the same manner as in Example 1a using 2-morpholinoethyl) hydroxylamine dihydrochloride 1.3.9 (5.9 mM), silica gel Fluid 1 Chromadog 2 Fi(ethyl acetate; ethanol) was used for fractional purification. -3:1) gave the title compound 1.0611 as a colorless foam.

Nuclear magnetic resonance spectrum (cDct, , δ: ppm
, 270 MH! ) 6.53 (IH, d), 5.4
8 (IH, br, s), 4.65 (IH, m) = 4.3
~4.5 (3H-m) -3,74 (4He m
) * 3. Z 3 (I H1m) Elemental analysis value (arrogant) Calculated value as C29H4408N2 C,63,
48H, 8, 08N, 5.11 actual measurement value C = 63.22
H,7,97N-5,05 Example 27b,1-(2
-methylbutyryl) -3,4-dihydro-6-oxo-4-(2-sulfolinoethyl)oxyiminoiso ML
-236A carboxylic acid sodium salt 1-(2-methylbutyryl) obtained in Example 27m
-3,4-dihydro-6-oxo-4-(2-morpholinoethyl)oxyiminoiso ML-236A lactone 5
The title compound 565w9 was obtained as a colorless powder in the same manner as in Example 1b using 50w1i11I-.

Below is a reference example.

In addition, in the reference examples, the expressions "3-hydroxy-ML-2364 carboxylic acid" and "3-hydroxy-ML-236A lactone" are abbreviations of compounds represented by the following formula.

3-Hydroxy-ML-236A 3-Hydroxy-ML-236A carboxylic acid lactone Reference example 3-Hydroxy-ML-236B carboxylic acid sodium salt (sodium carboxylate of a compound in which R is hydroxy in the above-mentioned Monena (■)) Salt; Special Public Service 1986-136
44.6# (same as the compound described as M-4Nm salt in No. 99) was placed in a 2-hole flask, 600 IRt of 173 N aqueous sodium hydroxide was added thereto, refluxed for 3 hours, and then cooled to room temperature to form 3-hydroxy. -ML-2
A solution containing 36A carboxylic acid sodium salt was obtained.

The physical properties of 3-hydroxy-ML-236A carboxylic acid sodium salt are as follows.

1) NMR spectrum (D20.δ: ppm +
270 MHz)0.69 (3H*d)-
3,65(I H-m) -3,93(I He m
).

4.22 (IH, m), 4.34 (IH, m) C5
, 33 (IHebr-s) = 5.85 (2H, m) 2) Elemental analysis value C%) C15H2; roaNa-H2
Calculated value as O C, 56,83H, 7,68 Actual value 0.57.02 H, 7,64 Solution containing 3-hydroxy-ML-236A carboxylic acid sodium salt obtained above 1 & pH 3 with -6N hydrochloric acid , after adjusting to 0,
Saturated with sodium chloride and then extracted three times with ethyl acetate (1
．． ! MXZ times, 1. The extracts were combined, washed with 300 IILt of saturated saline, and dried over sodium sulfate to obtain a solution containing 3-hydroxy-ML-236A carboxylic acid.

The physical properties of 3-hydroxy-ML-236A carboxylic acid are as follows.

1) High performance liquid chromatography It has a retention time of 5.81 minutes under the following conditions.

Column; inner diameter 8N, length 10cIIL brim pack (
Novapak) C18 (manufactured by Waters) Mobile phase: 18 Acetonitrile 10.21) Ethylamine-phosphate buffer (pH 3,3) Flow rate: 2 i/min Detector: UV 238 nm Obtained above 93 -Hydroxy-ML-236A The solution containing carboxylic acid was concentrated under reduced pressure at 50°C to about 21%, and then 2.01111 t of trifluoroacetic acid was added and the solution was heated to 50-60°C.
It was heated for about 2 hours. After the reaction was completed, ethyl acetate 11 was added to the reaction mixture, and then washed with 10 tbsp of sodium bicarbonate aqueous solution (400mj x 1 time and 200IILt x 1), saturated saline (20017 x 2 times), and dried over sodium sulfate. The solvent was distilled off from the mixture to obtain crude crystals 18I. When the obtained crude crystals are recrystallized using a small amount of acetone, the melting point is 158-161'C.
3-Hydroxy-ML-23 as a colorless amorphous crystal with
11.7 g of 6A-)j) were obtained.

The physical properties of lactone in 3-hydroxy-ML-236 are as follows.

l) Mass spectrometry m/e = 286 (M-H2O) -268CM-
2H20) 2) Elemental analysis value (calculated value as Cl8H2605 C, 67,06H, 8,13 Actual value C, 66,89H, 7-95 NujoL-1.

3) Infrared absorption spectrum ν, □.

3430.3330.3220.17304) 'H
-NMR spectrum ((CD,)2Co-CD, 00
.

δ: ppm e 90MHz) 0.9 (3H, d), 2.65 (2H, d), 4.2 ~
4.9 (4H, m) - 5,55 (IHIm), 5.9 (
2H, m) 5) “C-NMR spectrum (CD, 0
0. δ” ppm I 22.5MHs) 14.0
．． 63.15. 65.44. 66.89. 7B,
10. 127.35°128.94. 135.89
．． 136.03. 173.446) Thin layer chromatography Rf value: 0.27 Adsorbent: Silica gel platem 5719 (manufactured by Merck & Co.) Developing solvent: Benzene:acetone:acetic acid -50:50:3 [Effects of the invention] As mentioned above, this invention The octahydronaphthalene-substituted oxime derivatives of the invention exhibit serum cholesterol lowering effects.

Specifically, cholesterol biosynthesis is inhibited in enzyme systems isolated from experimental animals and cultured cell systems by competing with its rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme-containing ductase, and also at the individual animal level. Shows strong serum cholesterol lowering effect.

Here, the measurement of inhibitory activity was performed by Shapiro CD, J, 5hap.
1ro) et al. [Analytical Bloch@mls
try) Volume 31, pp. 383-390 (1969)
] Kuroda et al.'s method with some improvements [biostain power]
Bioehlmica a
t Blophyalea Acta) 486 volumes,
70-81 (1977)].

The results are shown in Table 2.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents a hydrogen atom, a methyl group, or a hydroxy group.
It may have a halogen atom, a hydroxy group, a C_1_-_4 alkyl-substituted hydroxy group, a C_2_-_5 aliphatic acyl-substituted hydroxy group, an amino group, a carboxyl group, or a carboxyl group protected with a carboxyl group-protecting group. an alkyl group having 1 to 10 carbon atoms or an alkenyl group having 3 to 10 carbon atoms, or C_2_-_5 Aliphatic acyl-substituted hydroxy group, amino group, carboxyl group, carboxyl group protected with a carboxyl group protecting group, C_1_-_5
A cycloalkyl group having 3 to 10 carbon atoms, which may have an alkyl group or a halogeno C_1_-_5 alkyl group, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, 5-6 containing 1-3 oxygen, sulfur or/and nitrogen atoms
It represents a ring-membered unsaturated heterocyclic group or a 5- to 6-membered ring saturated heterocyclic group containing 1 to 3 oxygen, sulfur, or/and nitrogen atoms. A is a single bond; or the same or different 1 to 4 halogen atoms, hydroxy group, C_1_-_4 alkyl-substituted hydroxy group, C_6_
-_1_4 aryl substituted hydroxy group, C_7_-_9
Aralkyl-substituted hydroxy group, C_2_-_5 aliphatic acyl-substituted hydroxy group, C_7_-_1_5 aromatic acyl-substituted hydroxy group, amino group, mono- or di-C_
1_-_4-alkyl substituted amino group, mono- or di-
C_6_-_1_4 aryl-substituted amino group, mono- or di-C_7_-_9 aralkyl-substituted amino group, C_2
_-_5 aliphatic acyl-substituted amino group, C_7_-_1_
5 Aromatic acyl-substituted amino group, alkylene group having 1 to 10 carbon atoms, which may have a carboxyl group or a carboxyl group protected with a carboxyl group protecting group, alkenylene group having 3 to 10 carbon atoms , represents an alkadienylene group having 5 to 10 carbon atoms or an alkynylene group having 3 to 10 carbon atoms. Y is a hydrogen atom; or the same or different substituents are 1
~4 halogen atoms, hydroxy group, C_1_-_
4 alkyl-substituted hydroxy group, C_6_-_1_4 aryl-substituted hydroxy group, C_7_-_9 aralkyl-substituted hydroxy group, C_2_-_5 aliphatic acyl-substituted hydroxy group, C_7_-_1_5 aromatic acyl-substituted hydroxy group, mercapto group, C_1_-_4 alkyl-substituted Mercapto group, C_6_-_1_4 aryl-substituted mercapto group, C_7_-_9 aralkyl-substituted mercapto group, amino group, mono- or di-C_1_-_4 alkyl-substituted amino group, mono- or di-C_6_-_1_4 aryl-substituted amino group, mono- or di- C_7_-_9 aralkyl-substituted amino group, C_2_-_5 aliphatic acyl-substituted amino group, C_7_-_1_5 aromatic acyl-substituted amino group, nitro group, cyano group, carboxyl group, carboxyl group protected with a carboxyl group-protecting group, C_1_ −＿
5 alkyl group, halogeno C_1_-_5 alkyl group, hydroxy C_1_-_5 alkyl group or C_2_-_
5 Aliphatic acyl-substituted hydroxy C_1_-_5 An aryl group having 6 to 14 carbon atoms which may have an alkyl group, a cycloalkyl group having 3 to 10 carbon atoms, 1 to 3 oxygen, sulfur or / and a 5- to 6-membered unsaturated heterocyclic group containing a nitrogen atom, a 5- to 6-membered saturated heterocyclic group containing 1 to 3 oxygen, sulfur, or/and a nitrogen atom, or a 5- to 6-membered saturated heterocyclic group containing 1 to 3 oxygen atoms , represents a fused heterocyclic group containing sulfur or/and nitrogen atoms. However, R
is a hydrogen atom and a methyl group, X is a 1-methylpropyl group, and the group -AY is a hydrogen atom and an alkyl group except when ), their esters, and their pharmacologically acceptable salts, as well as their formulas, mathematical formulas, chemical formulas, tables, etc. An octahydronaphthalene-substituted oxime derivative consisting of a lactone having the same meaning.