JPH01146895A - Griseolic acid diester derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1>, R<2> are H, hydroxyl which may be protected; R<3>, R<4> are H, or incorporate to represent a single bond; R<5>, R<6> are formula II, formula III (R<7>, R<9> are 1-10C chain alkyl, 3-10C cycloalkyl; R<8>, R<10> are H, 3-10C cycloalkyl)]. EXAMPLE:8',9'-dipivaloyloxymethyl griseolate. USE:Therapeutic agent for glaucoma. It has an excellent action to reduce intraocular pressure. PREPARATION:In the first step, the starting substance of formula IV is allowed to react with so esterification agent of formula V (X is halogen, acetoxy), in the presence of an acid acceptor (preferably 1,8-diazabicyclo[5.4.0]undec-7-ene), preferably at room temperature to give compounds of formula VI and formula VII. The product of formula VI or VII is allowed to react with an esterification agent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Objective] (Industrial Application Field) The present invention relates to a novel griseolic acid diester derivative having an excellent intraocular pressure lowering effect.

(Prior art) As a griseolic acid diester derivative,
Publication No. 0-94992 and Japanese Unexamined Patent Publication No. 61-100593
The following compounds described in the above publication are known.

(In the above formula, R1 and R= have the same meanings as above, and R"
and R6' represents a methyl group or a diphenylmethyl group.

) However, these compounds do not have an intraocular pressure-lowering effect.

(The problem that the invention seeks to solve) The inventors have
As a result of many years of intensive research into the synthesis of griseolic acid derivatives that have an intraocular pressure-lowering effect and their pharmacological activities, we have discovered a novel methyl ester derivative, f, a, yu, which has a different structure from known ester derivatives. Eyuuga 2. . Yuchi 7. The present invention was completed based on the discovery that a derivative in which the group is modified with a xolenic ring or a substituted carbonyloxy group has a good effect on lowering intraocular pressure and can be an excellent therapeutic agent for glaucoma.

[Structure] The novel griseolic acid diester derivative of the present invention has the following structure: [In the formula, R1 and R2 are the same or different and represent a hydrogen atom or an optionally protected hydroxyl group, and R3 and R4 are the same and represent a hydrogen atom. or R3 and R4 together represent a single bond, R5 and RG are the same or different, and have the general formula R'-COOCH(R8)-(II), R
'-0COOCH(R'')-(I I I ) or (wherein R7 and R9 are the same or different, a straight or branched alkyl group having 1 to 10 carbon atoms, or cycloalkyl group, R8 and R'' are
The same or different represents a hydrogen atom, a linear or branched alkyl group having 1 to 10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon atoms, and R11 is a hydrogen atom, a straight chain or branched alkyl group having 1 to 10 carbon atoms, and R11 is
straight or branched chain alkyl group, carbon number 3 to 10
represents a cycloalkyl group or an aryl group having 6 to 1 o carbon atoms. ). ].

In the above general formula (I), R1 and R'! The ``protecting group'' component of the ``optionally protected hydroxyl group'' defined in - indicates a protecting group in the reaction and a protecting group for prodrug formation when administered to a living body, such as formyl. Alkylcarbonyl groups such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl, tridecanoyl, valmitoyl, stearoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl Halogenated alkylcarbonyl group, lower alkoxyalkylcarbonyl group such as methoxyacetyl, (E)-2-
Aliphatic acyl groups such as unsaturated alkylcarbonyl groups such as methyl-2-butenoyl; arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, 2
- Halogenated arylcarbonyl groups such as bromobenzoyl, 4-chlorobenzoyl, lower alkylated arylcarbonyl groups such as 2,4.6-trimethylbenzoyl, 4-toluoyl, and lower alkoxylated arylcarbonyl groups such as 4-anisoyl. 4-nitrobenzoyl, nitrated arylcarbonyl groups such as 2-nitrobenzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl, arylated arylcarbonyl groups such as 4-phenylbenzoyl Aromatic acyl groups such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-yl Tetrahydropyranyl or tetrahydrothiopyranyl groups such as 4-yl; tetrahydrofuranyl or tetrahydrothiofuranyl groups such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tri-lower alkylsilyl groups such as t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl; 1 to 2 such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl; Silyl groups such as tri-lower alkylsilyl groups substituted with a, aryl groups; methoxymethyl, 1,1-dimethyl-1-methoxymethyl,
Lower alkoxymethyl groups such as ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, 2,
2. Alkoxymethyl groups such as halogenated lower alkoxymethyl such as 2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl; 1-ethoxyethyl, 1
- lower alkoxylated ethyl groups such as methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2,2.
a halogenated ethyl group such as 2-trichloroethyl, 2
Substituted ethyl groups such as arylzelenylated ethyl groups such as -(phenylzelenyl)ethyl; benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, Lower alkyl groups substituted with 1 to 3 aryl groups such as 9-anthrylmethyl, 4-methylbenzyl, 2.4.6-trimethylbenzyl, 3,4.5-trimethylbenzyl, 4-methoxybenzyl , 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-
aralkyl groups such as lower alkyl groups substituted with 1 to 3 aryl groups whose aryl ring is substituted with nitro, halogen, or cyano groups; methoxycarbonyl; , ethoxycarbonyl, t-butoxycarbonyl, lower alkoxycarbonyl groups such as isobutoxycarbonyl, lower substituted with halogen or tri-lower alkylsilyl groups such as 2.2.2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl Alkoxycarbonyl groups such as alkoxycarbonyl groups;
Alkenyloxycarbonyl groups such as vinyloxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3
, 4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, an aralkyloxycarbonyl group whose aryl ring may be substituted with one or two lower alkoxy or nitro groups; Protecting groups in such reactions and protecting groups that are easily hydrolyzed in vivo for prodrug formation when administered to living organisms, such as pivaoyloxymethyloxycarbonyl, are preferably aliphatic acyl groups and aromatic It is a group acyl group.

The "straight chain or branched alkyl group having 1 to 10 carbon atoms" defined in R7, R8, R9, R'' and R'' include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl. , t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3.3-dimethylbutyl, 2 , 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 2
-ethylbutyl, heptyl, 1-methylhexyl, 2-
Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,
4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylbutyl, 2-ethylhexyl, 5,5-
dimethylhexyl, nonyl, 3-methyloctyl, 4-
Methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6
, 6-dimethylhebutyl, decyl, 1-methylnonyl,
Examples include 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3.7-dimethyloctyl, and 7.7-dimethyloctyl, preferably straight or branched chains having 1 to 6 carbon atoms. It is an alkyl group.

R7, R8, R9, R'' and R'' were defined.

As a "cycloalkyl group having 3 to 10 carbon atoms",
For example, it represents a 3- to 10-membered saturated cyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl, preferably a 5- to 7-membered saturated cyclic hydrocarbon group.

"Aryl group having 6 to 10 carbon atoms" defined by "R"
Examples thereof include 6- to 10-membered cyclic aromatic hydrocarbon groups such as phenyl and naphthyl.

Preferably it is a 6-membered cyclic aromatic hydrocarbon group.

Compound (I) of the present invention can be made into a salt, and such salts are preferably salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide. Inorganic acid salts such as hydrohalides, nitrates, perchlorates, sulfates, and phosphates, and lower alkylsulfonates such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates.

Examples include arylsulfonates such as benzenesulfonate and p-toluenesulfonate, and organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, and maleate. .

Compound (I) of the present invention has an asymmetric carbon in the molecule and exists in stereoisomers each having an S configuration and an R configuration. included in

In compound (I), suitable compounds include (1)
Compound (2) where R' and R2 are the same or different and are a hydrogen atom or a hydroxyl group optionally protected with an aliphatic acyl group or an aromatic acyl group (2) R' and R2 are the same or different and are a hydrogen atom or a compound that is a hydroxyl group'(3) R3 and R4 are the same and represent a hydrogen atom, or R
Compound (4) R3 in which 3 and R4 together form a single bond
and R4 together represent a single bond (5) R5 and R6 are the same, and the general formula is R'-COOCR(R8)-(I I ), R
'-0COOCH(R'')-(III) The compound (fly) R' is a straight or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms. A compound (7) where R8 is a hydrogen atom or a straight chain or branched alkyl group having 1 to 6 carbon atoms (8) Rθ is a hydrogen atom or a straight chain or branched alkyl group having 1 to 3 carbon atoms Compound (9) R' is a branched alkyl group Compound (10) R'' is a linear or branched alkyl group having 1 to 6 carbon atoms Compound (11) R10 which is a straight chain or branched chain alkyl group of
is a hydrogen atom or a straight chain or branched chain alkyl group having 1 to 3 carbon atoms (12) R" is a phenyl group, a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, or a carbon Compounds having 5 to 7 cycloalkyl groups (
13) A compound in which R'' is a straight or branched alkyl group having 1 to 6 carbon atoms (14) A compound in which R'' and R= are the same or different and are a hydrogen atom or an aliphatic acyl group or a hydroxyl group which may be protected by an aromatic acyl group, R3 and R4 are the same and represent a hydrogen atom, or R3 and R4 together represent a single bond,
R5 and RG are the same, and the general formula R'-COOCH (R8
)-(I I ), R9-0COOCI((R”°')
-(III) versus P1-affected H2- -rr-0 (IV), and R7 is a straight or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms; , R8 is a hydrogen atom or a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, R9 is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, and Rlo
is a hydrogen atom or a straight chain or branched alkyl group having 1 to 6 carbon atoms, and R'' is a phenyl group, a straight chain or branched alkyl group having 1 to 6 carbon atoms, or a straight chain or branched alkyl group having 5 to 6 carbon atoms. Compound (15) R'', which is a 7 cycloalkyl group, and R2 are the same or different and are a hydrogen atom or a hydroxyl group, R3 and R4 together represent a single bond, and R5 and R
6 are the same, general formula R'-COOCH(R")-(I I ), R'
−0COOCH(R”)−(I I I ), and R
7 is a straight or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms, and R
8 is a hydrogen atom or a straight chain or branched alkyl group having 1 to 3 carbon atoms, R9 is a straight chain or branched alkyl group having 1 to 6 carbon atoms, and R10 is a hydrogen atom or a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms, and compounds in which R'' is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms.

Representative compounds of the present invention include, for example, the compounds listed in Tables 1 to 3, but the present invention is not limited to these compounds.

When R5=R6=R7-COOCH(R8)- Compound R1R2R"9R4R' R8 number 10HOH single bond CH3-CH3- 20HOH single bond CHgCHz-CH3-30HOH
Single bond CH3(CHS, -H-40HOH Single bond C
H3 (CHz) knee CH3-50HOH single bond (
CH3)zCH-H-60HOl (single bond (CH3)
zCH-CH3-70HOH single bond (CHz)zCH
-CH3CH knee 80HOH single bond CH3(CH,)
, -H- compound R1R''R-', R4R7R8 number 90HOH single bond CHa(CH:)z-CH3-10
0HOH single bond CH, (CHsa-CH3CH knee 1
1 0HOH single bond (CH3)2CHCH:! -H
-120HOH single bond (CH3):ICHCH:! −
CH3-130HOH single bond (Clh): CHCh-
CH3CH knee 140HOH single bond (CH3)3C-
H-150HOH single bond (CH3)3C-CH3-1
60HOH single bond (CHa)3C-CH3CH2-1
70HH single bond (CH3)3C-H-180HH single bond (CH3)3C-CH3-19HOH single bond (C
H3) 3C-H-20HOH single bond (CH3):IC
-CH3-210HOHH(CH3)3C-H- 220HOHH(CH3hC-CHz-230HOHH
(CHahC-CH3CH knee 240HOH single bond C
Ha(CH:)4-H-Compound R' R” R
3, R4R7R8 number 250HOH single bond CH, (CH4- CH3-
260HOH single bond CH3 (CHs-H-270H
OH single bond CHa(CH:)s-CH3-280HO
H single bond CHa(CH:)s-CH? CH knee 290
HOH single bond CH3(CHs-CH, (CHs.-
300HOH single bond cyclohexyl-H-310H
OH single bond cycloha, xyl-CH3-320HO
H single bond CHa (CHz)? -CH3-330HOH
Single bond CHg (Ch)? -CH3CH2-340HO
H single bond CH, (CHsu8-H-350HOH single bond CH3(CHz)a-CH3-360HOH single bond
CH3-CHg (CI(=) 5-370HOH single bond CHyoCHz-CH3(CHa7-Table 1 R'=R'=R9-OCOOCH(R")- Compound R"R'LR?,R4R9R" Number 380HOH single bond CH3-H- 390HOH single bond CHa, CH, -H-400HO
H single bond cHgcH=-CH3-410HOH single bond CH, (CH,), -H-420HOH single bond CH
3(CHz)z-CH3-430HOH single bond CH3
(CH:) Knee CH3CH Knee 440HOH single bond (C1h): CH-H-450HOH single bond (CH
3) 2CH-CH3-460HOH single bond (CH3)
:ICH-CHgCH2-470HH single bond (CH3
):CH-CH3-480HH single bond (CH3)1C
H-CHxCIh-49' OHHH(Clh):C
H-CH3-50HOH single bond (CHx)zCH-C
H3-Scheme table compound number R” R' R3, R4R11510H
OH single bond CH3- 52HOH single bond CH3- 530HH single bond CH3- 540HOHHCHa- 550HOHHCH yo CH, - 560HOH single bond CH3CH2-570HOH
Single bond CH3(CH2-58 0HOH
Single bond CHa(CH,), -590HOH Single bond CH3(CH:)4-60 0
HOH single bond cyclohexyl-610HO
H single bond Phenyl-620HH single bond
Phenyl- Among the above-mentioned exemplified compounds, preferred compounds include 2°3; 4.5, 6, 8, 9. II, 12
,14,15,16,17,18,19,22,25,
27,30°31.35,41,42,44,45,4
6, 47, 49, 51, 52, 53, 54, 55 and 5
6 compounds can be mentioned.

Furthermore, suitable compounds include 8,9,11,12,1
4,15,16゜17,18.19.22,31.45
, 46, 47, 49, 51, 55 and 56 can be produced by the method described below.

[6] In the above formula, R1, R2, R3, R4, R5 and R6 have the same meanings as above, and R'' is methylidene, ethylidene,
A lower alkylidene group such as isopropylidene; a protecting group for a dihydroxy group such as an aralkylidene group such as benzylidene or an alkoxyethylidene group such as methoxyethylidene or ethoxyethylidene, preferably impropylidene. .

Part A: For the above TJI, 1 equivalent of the starting compound (1) of the general formula R'-COOCR (R8)-X (I
I), R'-0COOCH(R")-X (
I I I ) or (wherein, R7, R8, R9, R''
and R11 have the same meanings as above, and X is a halogen atom such as chlorine, bromine, or iodine, 7acetoxy, an alkylcarbonyloxy group such as propionyloxy, chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy, Aliphatic groups such as halogenated alkylcarbonyloxy groups such as fluoroacetyloxy, lower alkoxyalkylcarbonyloxy groups such as methoxyacetyloxy, and unsaturated alkylcarbonyloxy groups such as (E)-2-methyl-2-butenoyloxy. Acyloxy group; arylcarbonyloxy group such as benzoyloxy, 2-bromobenzoyloxy, 4-
Halogenated arylcarbonyloxy groups such as chlorobenzoyloxy, lower alkylated arylcarbonyloxy groups such as 2.4.6-trimethylbenzoyloxy, 4-toluoyloxy, and lower alkoxylated groups such as 4-anisoyloxy. arylcarbonyloxy group,
Aromatic acyloxy groups such as nitrated arylcarbonyloxy groups such as 4-nitrobenzoyloxy and 2-nitrobenzoyloxy; trihalogenomethyloxy groups such as trichloromethyloxy; lower acyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy Alkanesulfonyloxy group; Halogeno lower alkanesulfonyloxy group such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; Leaving group such as arylsulfonyloxy group such as benzenesulfonyloxy and P-toluenesulfonyloxy. ) in a step of reacting the esterifying reagent shown in (2) and optionally removing the protecting group for the hydroxyl group of R1 or R2 to produce an 8'-monoester (2) and a 9'-monoester (3). be.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide or nitriles such as acetonitrile; and mixed solvents of the above-mentioned solvents can be mentioned.

The deoxidizing agent used is not particularly limited as long as it is used as a deoxidizing agent in normal reactions, but triethylamine, diisopropylethylamine,
N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, ■
.

5-diazabicyclo[4,3,0]non-5-ene, 1
．． 4-Diazabicyclo[2,2,2]octane, 1°8
-diazabicyclo[5,4,0]undec-7-ene (
Organic bases such as DBU) can be added, with DBU being particularly preferred.

The leaving group X of the esterification reagent is preferably a halogen atom such as chlorine, bromine, or iodine, and particularly preferably an iodine atom.

The reaction temperature is 0°C to 100°C, preferably 20°C to 70°C, and particularly preferably room temperature.

The reaction time varies mainly depending on the reaction temperature, the raw material compound or the solvent used, and the type of deoxidizing agent, but is usually from 1 hour to 4 days.

The step of deprotecting the desired hydroxyl protecting group varies depending on the type of protecting group, but is generally carried out as follows by methods well known in the art.

When a tri-lower alkylsilyl group is used as a protecting group for a hydroxyl group, it is usually removed by treatment with a compound that generates a fluorine anion, such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferred. Although the reaction temperature and reaction time are not particularly limited, the reaction is usually carried out at room temperature for 10 to 18 hours.

When the hydroxyl protecting group is an aralkyloxycarbonyl group or an aralkyl group, it can usually be removed by contacting with a reducing agent. For example, this can be achieved by carrying out catalytic reduction at room temperature using a catalyst such as palladium on carbon, platinum, or Raney nickel. The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, A mixed solvent of a fatty acid such as acetic acid or an organic solvent thereof and water is suitable. The reaction temperature and reaction time vary depending on the starting materials and reducing agent used, but are usually at 0°C to room temperature.
The duration ranges from 5 minutes to 12 hours.

It can also be removed by treating metal lithium or sodium in liquid ammonia or in an alcohol such as methanol or ethanol at -78°C to -20°C.

Additionally, alkylsilyl halides such as aluminum chloride-sodium iodide or trimethylsilyl iodide can be used for removal. The reaction is carried out in the presence of a solvent, and the reaction solvent used is not particularly limited as long as it does not participate in this reaction, but preferably nitriles such as acetonitrile, methylene chloride, chloroform, etc. Halogenated hydrocarbons or mixed solvents thereof are used. The reaction temperature varies depending on the starting materials, etc., but is usually 0°C to 50°C.

In addition, when the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

When the hydroxyl protecting group is an aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group, it can be removed by treatment with a base in the presence of a solvent. The base is not particularly limited as long as it does not affect other parts of the compound, but preferably metal alcoholades such as sodium methoxide, alkali metals such as aqueous ammonia, sodium carbonate, and potassium carbonate. It is carried out using carbonates, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or concentrated ammonia-methanol.

The solvent used is not particularly limited as long as it is used in ordinary hydrolysis reactions, and includes water, alcohols such as methanol, ethanol, and n-propanol, and ethers such as tetrahydrofuran and dioxane. An organic solvent or a mixed solvent of water and an organic solvent is suitable. The reaction temperature and reaction time vary depending on the starting materials, the base used, etc. and are not particularly limited, but in order to suppress side reactions, they are usually at 0°C to 150°C and for 1 to 10 hours.

When the protecting group for the hydroxyl group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, or a substituted ethyl group, it can be removed by treatment with an acid in a normal solvent. The acid used is
Preferred are hydrochloric acid, acetic acid-sulfuric acid, p-toluenesulfonic acid or acetic acid. The solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; tetrahydrofurane,
Ethers such as dioxane or a mixed solvent of these organic solvents and water are suitable. The reaction temperature and reaction time vary depending on the starting materials and the type of acid used, but are usually 0°C to 50°C and 10 minutes to 18 hours.

When the protecting group for the hydroxyl group is an alkenyloxycarbonyl group, the protecting group for the hydroxyl group is usually an aliphatic acyl group,
It can be removed by treatment with a base under the same conditions as the removal reaction for aromatic acyl groups or alkoxycarbonyl groups. In the case of allyloxycarbonyl, removal using palladium and triphenylphosphine or nickel tetracarbonyl is particularly convenient and can be carried out with fewer side reactions.

After completion of the reaction, the target compound (2) or (3) of this reaction is collected from the reaction mixture according to a conventional method.

For example, adding a water-immiscible organic solvent to the reaction mixture;
After washing with water, the solvent is distilled off. If necessary, the obtained target compound can be further purified by conventional methods such as recrystallization, reprecipitation, or chromatography to obtain a single compound (2) or (3).

In the fth step, the 7'-position hydroxyl group and the 9'-position carboxyl group of the starting compound (1) are protected with a dihydroxy-protecting group in the presence or absence of a solvent and in the presence of an acid catalyst to form a compound ( This is the process of manufacturing 4). In this step, water may be removed using a dehydrating agent such as copper sulfate, sodium sulfate, or calcium carbide, or a molecular sieve, or using azeotropy.

Reagents used in the step of protecting dihydroxy groups include lower alkyl carbonyl compounds such as formaldehyde, acetaldehyde, and acetone; aryl carbonyl compounds such as benzaldehyde, or lower alkyl orthoformates such as trimethyl orthoformate and triethyl orthoformate. The ester can be an ester, preferably a lower alkylcarbonyl compound, more preferably acetone.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, halogenated hydrocarbons such as chloroform; esters such as ethyl acetate, propyl acetate; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane; methanol, ethanol, n-propanol, isopropanol, n - alcohols such as butanol, isobutanol, isoamyl alcohol; dimethylformamide,
Examples include amides such as dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide; and ketones such as acetone; when acetone is used as a protection reagent, it also serves as a solvent. Acetone is used.

The acid catalyst used is not particularly limited as long as it is used as an acid catalyst in ordinary reactions, but preferably inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, or para Examples include Brønsted acids such as organic acids such as toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid, and Lewis acids such as zinc chloride and tin tetrachloride. Organic acids are preferred, and organic acids are more preferred. is a strong organic acid.

The reaction temperature is from -10°C to 100°C, preferably from 0°C to room temperature.

The reaction time varies mainly depending on the reaction temperature, the raw material compound or the solvent used, and the type of acid catalyst, but is usually 10 minutes to 3 days.

After completion of the reaction, the target compound (4) of this reaction can be 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 chromatography, but preferably an alkali metal carbonate such as sodium carbonate or potassium carbonate; sodium hydrogen carbonate; Alkali metal bicarbonates such as potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide After neutralizing with a base that is insoluble in an organic solvent such as, filtering off insoluble matter, and distilling off the solvent, the product can be subjected to Step A-3 without any particular isolation and purification. Ru.

Step 1-Y is a step of producing compound (5) by treating compound (4) in the same manner as step A-1.

In the second step, the protecting group of the dihydroxy group of compound (5) is removed with an acid catalyst in the presence or absence of a solvent, and if desired, the hydroxyl group at the 7' position is protected, thereby forming the compound (5). 2)
This is the process of manufacturing.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, halogenated hydrocarbons such as chloroform; esters such as ethyl acetate, propyl acetate; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane; methanol, ethanol, n-propanol, isopropanol, n - alcohols such as butanol, imbutanol, isoamyl alcohol; dimethylformamide,
Amides such as dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide; and ketones such as acetone can be mentioned.

The acid catalyst used is not particularly limited as long as it is used as an acid catalyst in ordinary reactions, but preferably inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, or para Examples include Brønsted acids such as organic acids such as toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and citric acid, preferably organic acids, and more preferably trifluoroacetic acid.

The reaction temperature is from -10°C to 100°C, preferably from 0°C to room temperature.

The reaction time varies mainly depending on the reaction temperature, the raw material compound or the solvent used, and the type of acid catalyst, but is usually from 10 minutes to 1 day.

After completion of the reaction, the target compound (2) of this reaction 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 chromatography.

In the EΔYudan step, compound (2) or (3) is used as a raw material, and the same or different esterification reagent as that used in Step A-1 is used, and the process is carried out in the same manner as in Step A-1. This is a step of processing to produce the compound (6) of the present invention.

β1 Ki21]
(72-In the above formula, R'', R', R3, R4 and R5 have the same meanings as above.

Step 1 uses 1M compound (1) and a large excess of the esterification reagent, and is treated in the same manner as Step A-1 to protect the 8'-carboxy group and the 9'-carboxy group with the same group. This is a step for producing the compound (7) of the present invention.

The raw material compound of the present invention is a known compound, for example, JP-A No. 60-94992, JP-A No. 60-149.
It can be produced by the method described in JP-A No. 394, JP-A-60-246396, and JP-A-61-100593. Moreover, the esterification reagent R' of the present invention
-COOCH(RO)-X (II),
R9-0COOCH(R”)-X (I I I
) or (wherein R7, R8, R9, R'', R1l
and X have the same meanings as above. ) is produced as follows, or a commercially available reagent is used.

R7CD>(+R day CHO→R/C00C)((R8)-X (ID COXri+R1 mouth CHO→XCXC00C)-1(R1')-×+ R"OH→R
"0COOC)-1(R1)-X(III) (In the formula, R7, R8, R9, R10 and X have the same meanings as above.) That is, active derivative R7C0X of carboxylic acid R'C0OH
and aldehyde compound R8CHO in a solvent in the presence of a base according to a conventional method, compound
I) can be produced.

Phosgene derivative COX, and aldehyde compound RIOCH
O is reacted in a solvent in the presence of a base according to a conventional method,
Furthermore, compound (III) can be produced by reacting with alcohol compound R'OH according to a conventional method.

1koR31ko)-10+F? 11CHO→CH-,
CH(OH)-C(23-R”→,]
co>ku2 (wherein R'' and X have the same meanings as above) using known methods [for example, chemical
Farm Bulletin, Volume 32, Page 4316 (198
4), p. 22418 (1984), vol. 33, 4
870 (1985), the aldehyde compound R11CHO and acetaldehyde are subjected to acyloin condensation according to a conventional method, and the product is reacted with a phosgene derivative in a solvent. The methyl group of the product product is halogenated by a radical reaction with a halogen molecule according to a conventional method, and if desired, the halogen atom is replaced with an X group. The test was carried out using male New Sealant White pups (weighing approximately 2.5 kg) with no abnormalities in each group of three. The animals were kept in a breeding room at a temperature of 23° C. and a humidity of 60%, with restricted feeding and free access to water. The test substance is this compound in 50mM phosphate buffer (pH 7.0) containing 0.4% sodium chloride.
The concentration was basically 1%.

Both eyes of the rabbit were treated with an ophthalmological surface anesthetic (0.4% Benoxil:
After the eye drops were anesthetized using Santen Pharmaceutical, the intraocular pressure of both eyes was measured.
G (Pheumatonograph: Alcon)
Measured at

Then, apply the test substance to either the left or right eye (experimental eye) for 50 minutes.
%m eye drop 0.5% timolol is 30 μm), Part 6
After 0 minutes, the same amount was instilled into the eye again (twice in total).

On the other hand, no eye drops were applied to the opposite eye, which served as a control eye. After the first instillation of the test substance, 30.60.90.120.15
After 0.180 minutes, the intraocular pressure of both eyes was measured, and the actual measured values were substituted into the following formula to calculate the intraocular pressure lowering value of the test substance. Intraocular pressure drop (mm) Ig) = control intraocular pressure value - experimental intraocular pressure value) - (control intraocular pressure value immediately before the first instillation - experimental intraocular pressure value immediately before the first instillation) Find the average value of the pressure drop values and set it as 0.
The value of the test substance was calculated when the value of 5% timolol was set to 1.

state, to.

Drug Drug concentration Intraocular pressure lowering effect % Timolol ratio Glyseolic acid 1.0 -0.12 Glyseolic acid dimethyl ester 0.033 -0.01 Compound of Example 1 0.002 0,77 Compound of Example 2 0.01 0.58 Compound of Example 3 0.01 0.50 U 4 of 8
〇, 002 0.08 As mentioned above, the novel griseolic acid diester derivative of the present invention has an excellent intraocular pressure lowering effect and is not toxic, so it is useful as a therapeutic agent for glaucoma.

The compound (I) of the present invention may be administered in the form of an ophthalmic pharmaceutical composition suitable for topical administration to the eye, such as a solution, suspension, gel, ointment or solid insert. preferable. The formulations of these compositions may contain from 0.01 to 10%, especially from 0.1 to 5%, of the compound of the invention. In addition to containing the compound of the present invention as a single drug, it may also contain a β-blocker agent such as timolol maleate or a drug such as pilocarpine, which is a parasympathomimetic stimulant.

Pharmaceutical formulations containing the active compositions may be conveniently admixed with non-toxic pharmaceutical inorganic or organic carriers.

Typical pharmaceutically acceptable carriers are, for example, water, lower alkanols or mixtures of water with water-miscible solvents such as alkanols, vegetable oils, polyalkylene glycols, petroleum-based sherry, ethylcellulose, oleic acid, etc. Ethyl acid, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conveniently used acceptable carriers. Pharmaceutical formulations may also contain non-toxic auxiliary substances such as emulsifiers, preservatives, wetting agents, excipients, etc., such as polyethylene glycol 200.3.
00.400 and 600, carbowax 1,000.
1,500.4,000.6,000 and 10,0
00, quaternary ammonium compounds known to have pasteurizing properties and are non-toxic in use, such as quaternary ammonium compounds, phenylmercury salts, thimerosal, methyl and propylparabens, benzyl alcohol, phenylethanol, table salt. , buffer components such as sodium borate, sodium acetate, gluconate buffers, and sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol , ethylenediaminetetraacetic acid, and the like. Furthermore, suitable ophthalmic excipients can be used as carrier media for the purposes of the present invention, including conventional phosphate buffered excipient systems, isotonic boric acid excipients, isodominant saline excipients. agents, isotonic sodium borate excipients, and the like.

Pharmaceutical formulations can also be in the form of solid inserts that remain substantially intact after administration of the drug, or biodegradable inserts that dissolve in lachrymal fluid or otherwise disintegrate.

Generally, from about 0.001 to about 50 mg, preferably from about 0.01 to about 20 mg per kg of body weight of a compound of the invention may be used. Depending on the required daily dosage, administration can be in single or multiple doses and in unit doses.

The present invention will be explained in more detail below with reference to Examples, Reference Examples, and Formulation Examples.

Addition 1 Add 100 ml of acetonitrile to 1 g of griseolic acid, and add 1,8-diazabicyclo(5
,4,0]-7-undecene was added, and then 2.56 g of iodomethyl pivalate was added under water cooling.
Stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was dissolved in 60 ml of ethyl acetate and 30 ml of diluted hydrochloric acid. After separating the ethyl acetate layer, it was washed successively with diluted hydrochloric acid, 5% aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, and the organic layer was dried over magnesium sulfate. After distilling off the solvent, silica gel chromatography (ethyl acetate:acetonitrile 2:
The product was separated and purified in step 1) and freeze-dried from benzene to obtain 970 mg (60.5%) of the target compound.

NMR spectrum δ, ppm (DMSO-d6)8
．． 30. IN,S.

8.17. IH,s (2 or 8-H); 6.54. IH
,s(1'-H): 6.08. IH, dd(2,4,4,9)(3'-H
):5.07. IH, d(2,0)(5'-H); 4
．． 63.2H,m(2' and 7'-f(); 7.39
,2H,br 5(NH:):6.20. IH, d(4
, 4) (2'-0H): 5.68-5.77.5H,
m(CH2,7'-0H); 1-17 t 3Hv
s(CH*); 1.09,3H,5(CH3).

380 mg of biloxycarbonyloxy ethyl ester griseol acid to 1.5 m of dimethyl sulfoxide
1,8-diazabicyclo(5,
After adding 0.17 ml of 4,0)-7-undecene and further adding 1 ml of acetonitrile, 1-bromoethyl isopropyloxycarboxylate was added under ice cooling, and the mixture was reacted at room temperature for 3 hours. Acetonitrile was distilled off, the residue was dissolved in 20 ml of ethyl acetate and a 3% aqueous sodium bicarbonate solution containing ice, the ethyl acetate layer was separated, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and treated with activated carbon. When the solvent was distilled off, a colorless, almost single spot of the target compound was obtained. This was separated and purified by silica gel chromatography (ethyl acetate:acetonitrile 5:2) to yield 120 mg (18.8%) of the target compound.
I got it.

NMR spectrum δ, ppm (DMSO-d6)8.
31 and 8.34. IH, each S.

8.17 and 8.18. IH, m (2 or 8-H);
6.50 and 6,51. IH, each s(1'-H); 6
．． 09 and 6.14. IH, each dd (2, 4, 5, 4)
(3'-H): 5.03 and 5.10. IH, each d(
2,4)(5'-H);4.62.2H,m(2' and 7'-H);7.38,2H,br 5(NH!ri;6.67.2H,m(CH ); 6.35 and 6.19.IH,m(2'-0H);5
．． 60.1)1. m(7'-0H);4-65~4-
83,2H9m(eH); 1.17-1.52,18H
, m (CHs).

Dissolve 3 g of dimethylglyseolic acid in 30 ml of dimethyl sulfoxide and add 1,8-diazabicyclo(5,4
After adding 2.4 ml of ,0l-7-undecene, 7.6 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl iodide was added under water cooling, and the mixture was heated at room temperature for 4 hours. Made it react. Add 300ml of ethyl acetate and 30ml of water to the reaction solution.
After separating the organic layer, it was washed again with water, dried over magnesium sulfate, treated with activated carbon, and the solvent was distilled off. 5. The residue is separated and purified by silica gel chromatography (methylene chloride containing 4% ethanol) and crystallized from methylene chloride. : from, target compound 715
mg (15.0%) was obtained.

NMR spectrum δ, ppm (DMSO-d6)8.
33. LH,s.

8.17. LH,s(2 or 8-H); 6.52. L
H,s(1'-H); 6.10. LH, dd(2,4,5,4)(3'-H
):5.12. LH, d(2,4)(5'-H); 4
．． 59. LH, t(4,4)(2'-H); 4.64
．． IH, d(9,3)(7'-H); 7.40,2H
,br 5(NHS; 6.28.LH,d(4,4)(2'-0H):5.
64. LH, d(9,3)(7'-0H); 5.03
,21(,5(CH2,) ;4',95,2H,5(
CH2); 2,18,3H,5(CH3); 2.17,3H,5(CH3).

Dissolve 450 mg of pivaloyloxymethyl ester 7'-desoxyglyseolic acid in 2.5 ml of dimethyl sulfoxide and dissolve in a nitrogen stream. ,8-
After adding 0.22 ml of diazabicyclo(5,4,0)-7-undecene and 2 ml of acetonitrile, 410 mg of iodomethyl pivalate was added under water cooling, and the mixture was reacted at room temperature for 3 hours and then at 5° C. for 16 hours. Acetonitrile was distilled off, the residue was dissolved in 50 ml of ethyl acetate and 50 ml of 3% aqueous sodium bicarbonate solution, the ethyl acetate layer was separated, the aqueous layer was further extracted with 20 ml of ethyl acetate, the ethyl acetate layers were combined, and sulfuric acid was added. After drying with magnesium, it was treated with activated carbon and the solvent was distilled off to obtain a crystalline material with a single spot. 290mg lyophilized from benzene
(40.2%) of the target compound was obtained.

NMR spectrum δ, ppm (DMSO-d6)8
．． 29. ll-1,s.

8.18. IH,s(2 or 8-H); 6.46.
LH,s(1'-H);6.03. IH, dd(2
,4,4,9)(3'-H):5.03. IH, d(
2,4)(5'-H);4.59. LH,t(4,4
,4,9)(2'-)1):2.90. IH, d(1
7,1)(7'-H);3.30. LH,d(17,
1)(7'-H);7.39,2H,br 5(Nl
2);5.99. IH, d(3,9)(2'-0H)
;5.66-5.80.4H,m(CH2).

Compound Example 1L Compound of Example 1 0.002g Disodium Phosphate 0.716g Sodium Phosphate 0.728g Sodium Chloride
0.400 gp-methyl hydroxybenzoate 0.026 g p-hydroxyamdene, propyl fomanate 0.014. - Sterile purified water
Appropriate amount of sodium hydroxide Appropriate amount of total amount 10
An eye drop was prepared using a conventional method at a pH of 7.0.

Compound of Formulation Example IL1 and Example 2 0.002g disodium phosphate 0.500g sodium phosphate 1.100g sodium chloride
0.300g Penzathonium chloride
0.010g sterile purified water
An ophthalmic solution was prepared in a conventional manner using an appropriate amount of 100 ml and a pH of 7.0.

Formulation example 1. The compound of Example 4 was stirred at 0.002 g, disodium phosphate at 0.400 V, and sodium phosphate at 1.000 V.

Sodium chloride 0.690g10%
Benzalkonium chloride solution 100 μl sterile purified water
An ophthalmic solution was prepared in a conventional manner using an appropriate amount of 100 ml and a pH of 7.0.

Sender: Sankyo Co., Ltd. Agent: Patent attorney Shoji Kashi

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom or a hydroxyl group that may be protected. , R^3 and R^4 are the same and represent a hydrogen atom, or R^3 and R^4 together represent a single bond, R^5 and R^6 are the same or different, and the general formula R ^7-COOCH(R^8)-(II), R^9
-OCOOCH(R^1^0)-(III) or ▲ formula,
There are chemical formulas, tables, etc. ▼ (IV) (In the formula, R^7 and R^9 are the same or different, and are a straight chain or branched alkyl group having 1 to 10 carbon atoms, or a straight chain or branched alkyl group having 3 to 10 carbon atoms. represents a cycloalkyl group, and R^6 and R^1^0 are the same or different and represent a hydrogen atom, a straight or branched alkyl group having 1 to 10 carbon atoms, or a cycloalkyl group having 3 to 10 carbon atoms. Indicates an alkyl group, R^1^1
represents a straight or branched alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, or an aryl group having 6 to 10 carbon atoms. ). ] and its salts.