JP2682353B2 - Oral pharmaceutical composition and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a formula (I) having an anti-AII action, which is useful for hypertension, congestive heart failure and the like.

Embedded image (In the formula, ring W represents an optionally substituted nitrogen-containing heterocyclic residue, R ³ represents a group capable of forming an anion or a group capable of being converted into an anion, X represents a phenylene group and a phenyl group directly or Oral pharmaceutical composition comprising a compound represented by a bond having a chain of 2 or less atomic chains and n is an integer of 1 or 2 and a low melting point oily substance, and a compound thereof. Regarding manufacturing method.

[0002]

2. Description of the Related Art Angiotensin II (AII) receptor antagonists (AII) are used as therapeutic agents for hypertension following angiotensin I converting enzyme (ACE) inhibitors in the treatment of hypertension.
IIA) is drawing attention. Compounds of formula (I), for example benzimidazole-7-carboxylic acid or its derivatives having a strong anti-AII action (EP Publication 0425921 and EP Publication 0459136).
It is considered that the above-mentioned publication has the following advantages over ACE inhibitors. 1) It is known that there is an AII generation system other than ACE, but benzimidazole-7-carboxylic acid or its derivative also suppresses this ACE-independent action of AII. It may have a stronger and more effective antihypertensive effect.
2) Since benzimidazole-7-carboxylic acid or its derivative does not have the effect of enhancing the action of bradykinin found in ACE inhibitors, it is unlikely to cause the side effect of cough.

[0003]

However, a compound represented by the formula (I) having an anti-AII action which is useful as a therapeutic drug for hypertension, such as benzimidazole-7-carboxylic acid or a derivative thereof, is , It is stable to temperature, humidity, and light in the solid state by itself, but when tableted with a formulation containing other ingredients, the pressure and friction applied during granulation or pressure molding in the manufacturing process It has been found that crystal distortion may occur due to heat, etc., and the daily decrease in content is accelerated. Anti-A
The compound represented by the formula (I) having II action (hereinafter, also referred to as an active ingredient) is being researched and developed as a therapeutic drug for hypertension as described above, while being formulated. The problem with respect to the stability of is not yet fully solved. In particular, benzimidazole-
A technique capable of sufficiently suppressing the daily decomposition of the active ingredient associated with the case where the 7-carboxylic acid or its derivative is manufactured into a solid preparation such as a tablet, and improving the stability of the active ingredient in the preparation, which can be used practically Is not yet obtained. The object of the present invention is thus to provide a stabilized formulation of a compound of formula (I) having an anti-AII effect. Furthermore, such stabilization does not depend on the methods that have led to an increase in the cost of the drug product, such as increased drug loading and extremely low water content, which have been performed conventionally, and is sufficiently practical in terms of cost. There is a certain stabilization. Furthermore, it is also an object of the present invention to prolong the product quality assurance period and enhance the product value by stabilizing such a formulation.

[0004]

In view of the above-mentioned circumstances, the present inventors have proposed a general-purpose stabilizing method for stabilizing a compound-containing preparation of formula (I) having an anti-AII action. Various means were tried, but no sufficiently practical stabilizing effect was found in any of the preparations. The present inventors further conducted various studies, and surprisingly, when a low-melting oily substance was added to a compound-containing preparation represented by the formula (I) having an anti-AII action, the active ingredient was remarkably decomposed. It was found that a stable formulation can be obtained by suppressing the above-mentioned problems, and further studies were conducted to complete the present invention. That is, the present invention provides (1) Formula (I) having an anti-AII action.

Embedded image (In the formula, ring W represents an optionally substituted nitrogen-containing heterocyclic residue, R ³ represents a group capable of forming an anion or a group capable of being converted into an anion, X represents a phenylene group and a phenyl group directly or A pharmaceutical composition for oral administration comprising a compound represented by the formula (2), which is bound through a spacer having an atomic chain of 2 or less, and n represents an integer of 1 or 2, and a low-melting oily substance, and (2) Formula (I) having anti-AII action

Embedded image (In the formula, ring W represents an optionally substituted nitrogen-containing heterocyclic residue, R ³ represents a group capable of forming an anion or a group capable of being converted into an anion, X represents a phenylene group and a phenyl group directly or Orally characterized by being bonded via a spacer having an atomic chain of 2 or less, and n is an integer of 1 or 2) The present invention relates to a method for producing a pharmaceutical composition for use.

In the above general formula (I), a group capable of forming an anion as R ³ (group having a hydrogen atom capable of being protonated) or a group capable of being converted into it is N, S,
Examples thereof include a 5- to 7-membered (preferably 5 to 6-membered) monocyclic optionally substituted heterocyclic residue containing one or two or more of O or a group capable of being transformed therein in vivo. Examples thereof include carboxyl, tetrazolyl, trifluoromethanesulfonic acid amide (—NHSO ₂ CF ₃ ), phosphoric acid, sulfonic acid, cyano, lower (C _1-4 ) alkoxycarbonyl, and the like, even if these groups are substituted. It may be protected with a lower alkyl group or an acyl group, etc., under biological or physiological conditions (for example, in-vivo reaction such as oxidation, reduction or hydrolysis by in-vivo enzyme), or chemically. Any group capable of forming an anion or a group capable of changing into an anion may be used. Further, R ³ is —NH or —O as a proton donor such as an oxadiazole ring or a thiadiazole ring.
It may be a group having an H group and a carbonyl group, a thiocarbonyl group or a sulfinyl group as a proton acceptor at the same time. R ³ is an optionally substituted lower (C _1-4 ) alkyl (eg, methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or an acyl group (eg. , Lower (C _2-5 ) alkanoyl, benzoyl, etc.)
A tetrazolyl or a carboxyl group (preferably a tetrazolyl group) which may be protected with is preferable. R
The substitution position of ³ may be any of ortho, meta and para positions, but the ortho position is preferable. X has a phenylene group and a phenyl group which are adjacent to each other directly or in an atomic chain
It is shown that they are bound (preferably direct binding) via the following spacers, and the spacer having an atomic chain of 2 or less is a divalent chain in which the number of atoms constituting the linear portion is 1 or 2. Any of them may be included and may have a side chain. Specifically, lower (C _1-4 ) alkylene, —CO—,
-O-, -S-, -NH-, -CO-NH-, -OC
_{H 2 -, - S-CH} 2 -, - CH = CH- , and the like. n represents an integer of 1 or 2 (preferably 1). A formula represented by the above R ³ , X and n

Embedded image as

Embedded image Is preferably represented by

Typical examples of the nitrogen-containing heterocyclic residue represented by ring W are shown below. In the following formula, R
¹ represents hydrogen or an optionally substituted hydrocarbon residue, Y represents a bond, -O-, -S (O) m- (in the formula, m represents 0, 1 or 2) or -N. (R ⁴ )-(in the formula,
R ⁴ represents hydrogen or an optionally substituted alkyl group). Among them, R ¹ is lower (C _1-5 ) alkyl optionally substituted by a hydroxyl group, amino group, halogen or lower (C _1-4 ) alkoxy group (preferably lower (C _2-3 ) alkyl). Is preferred, Y is a bond, -O
—, —S— or —N (R ⁴ ) — (wherein R ⁴ represents hydrogen or lower (C _1-4 ) alkyl) is preferred. For example, formula (III)

Embedded image (In the formula, a and e constituting a heterocyclic residue each independently represent one or two optionally substituted carbon or hetero atoms, and d and f represent each independently a single substituted carbon or hetero atom. And b and c independently of one another represent one optionally substituted carbon or nitrogen atom)

[0007]

Embedded image

Embedded image (Wherein, h is _{-CH 2 -,> = O,} > = S,> S- (O)
m, —N (R ⁴ ) — or —O—, m represents 0, 1 or 2, R ⁴ is hydrogen or an optionally substituted alkyl group (preferably hydrogen or lower (C _1-4) ) Alkyl)). Further, for example, the formula (IV)

Embedded image (Wherein, a and b constituting a heterocyclic residue each independently represent one or two optionally substituted carbons or heteroatoms, and c represents one optionally substituted carbon Or a hetero atom).

Embedded image (In the formula, A represents an aromatic hydrocarbon residue or a heterocyclic residue which may be substituted and may contain a hetero atom (preferably, an aromatic hydrocarbon residue such as phenyl); And h ′ are —CH ₂ —,> = O,> =
S,> S- (O) m , -N (R 4) - indicates and -O-,
m and R ⁴ have the same meanings as described above), but are not limited thereto. The heterocyclic residue represented by the above formula (III) is substituted with a group represented by R ² in addition to the group represented by Y-R ¹ (for example, a group capable of forming an anion or a group capable of changing to it). It may have been done. The substitution position of R ² is preferably the position of the f atom in the formula (III). Examples of the group capable of forming an anion as R ² or a group capable of changing to an anion include carboxyl which may be esterified or amidated, tetrazolyl,
Trifluoromethanesulfonic acid amide (-NHSO ₂ C
F ₃ ), phosphoric acid, sulfonic acid, etc., and these groups may be protected by a lower alkyl group which may be substituted or an acyl group. Any group capable of forming an anion or a group capable of being converted into an anion by an in-vivo reaction such as oxidation, reduction or hydrolysis by an enzyme in the body).

Examples of the optionally esterified or amidated carboxyl as R ² include, for example, the formula —CO
-D [wherein D is a hydroxyl group, optionally substituted amino (for example, amino, N-lower (C _1-4 ) alkylamino, N, N-di-lower (C _1-4 ) alkylamino, etc.) Or an optionally substituted alkoxy group {eg, a hydroxyl group of an alkyl moiety, an optionally substituted amino (eg, amino, dimethylamino, diethylamino, piperidino, morpholino, etc.), halogen, lower (C _1-6 ) alkoxy, lower (C _1-6) alkylthio or optionally substituted Jiokisoreniru (e.g., 5-methyl-2-oxo-1,3-dioxolen-4-yl, etc.) may be substituted with a lower (C _{1- 6} ) an alkoxy group or a formula -O
—CH (R ⁶ ) —OCOR ⁵ [wherein R ⁶ is hydrogen, a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) , Isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), a linear or branched lower alkenyl group having 2 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, R ⁵ represents a linear or branched lower alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, etc.). -Butyl, n-pentyl, isopentyl, neopentyl, etc.), a linear or branched lower alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentene) , Cyclohexyl, cycloheptyl, etc.), cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or C 1-3 having an aryl group such as optionally substituted phenyl. It may be substituted with a lower alkyl group (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), a cycloalkyl having 3 to 8 carbon atoms or an aryl group such as optionally substituted phenyl. A lower alkenyl group having 2 to 3 carbon atoms (eg, those having an alkenyl moiety such as vinyl, propenyl, allyl, isopropenyl such as cinnamyl), an aryl group such as phenyl which may be substituted (eg, phenyl, p -Trill,
Naphthyl), a straight-chain or branched lower alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n- Pentyloxy, isopentyloxy, neopentyloxy, etc.),
A linear or branched lower alkenyloxy group having 2 to 8 carbon atoms (eg, allyloxy, isobutenyloxy, etc.), a cycloalkyloxy group having 3 to 8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), C3-C8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or C1-C3 lower alkoxy group substituted with an optionally substituted aryl group such as phenyl (eg, benzyloxy, phenethyloxy) , Cyclopentylmethyloxy, cyclohexylmethyloxy and other methoxy, ethoxy, n-propoxy, isopropoxy and other alkoxy moieties), C3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or Replaced Optionally substituted lower alkenyloxy group having 2-3 carbon atoms with an aryl group such as phenyl (eg, those having an alkenyloxy moiety such as vinyloxy, cinnamyloxy, propenyloxy, aryloxy, isopropenyloxy, etc.), substituted Optionally an aryloxy group such as phenoxy (eg, phenoxy, p
-Nitrophenoxy, naphthoxy, etc.)], etc.]], and the like.
In addition, the substituent as R ² is a group capable of forming an anion or a group capable of changing it (eg, alkyl (eg, lower (C
_1-4 ) Alkyl etc.) or acyl (eg lower (C _2-5 ) alkanoyl, optionally substituted benzoyl etc.) tetrazolyl, trifluoromethanesulfonic acid amide, phosphoric acid or sulfonic acid Etc.). Examples of the substituent R ² include —COOH and salts thereof, —COOMe, and —COOE.
t, -COOtBu, -COOPr, pivaloyloxymethoxycarbonyl, 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-
1,3-dioxolen-4-ylmethoxycarbonyl,
Acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, 1- (ethoxycarponyloxy) ethoxycarbonyl, 1- (acetyloxy) ethoxycarbonyl, 1- (isobutyryloxy) ethoxycarbonyl , Cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl and the like.
Examples of such a group include anion (eg, COO ⁻ , its derivative) under biological or physiological conditions (for example, in-vivo reaction such as oxidation / reduction or hydrolysis by in-vivo enzyme) or chemically. Etc.) can be formed, or any group that can be changed to that group. R
² may be a carboxyl group or a prodrug thereof. R ² may be one which can be converted into an anion biologically or chemically in vivo.

R ² is represented by the formula —CO—D [in the formula,
D is a hydroxyl group or an alkyl moiety having a hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy (eg, acetyloxy, pivaloyloxy, etc.), 1-lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy). , Ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.) or lower (C _1-4 ) alkoxy-substituted lower (C
_1-4 ) represents an alkoxy group] is preferable.
Further, the heterocyclic residue represented by the formula (III) may further have a substituent other than the groups represented by Y-R ¹ and R ² , for example, halogen (eg, F, Cl, Br, etc.), cyano, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ).
Alkoxy, optionally substituted amino group (eg, amino, N-lower (C _1-4 ) alkylamino (eg, methylamino, etc.), N, N-dilower (C _1-4 ) alkylamino (eg, , Dimethylamino, etc.), N-arylamino (eg, phenylamino, etc.), alicyclic amino (eg, morpholino, piperidino, piperazino, N-phenylpiperazino, etc.), formula —CO-D ′ [formula Wherein D'is a hydroxyl group or an alkyl group having a hydroxyl group, lower (C _1-4 ) alkoxy, lower (C _2-6 ) alkanoyloxy (eg, acetyloxy, pivaloyloxy, etc.) or 1-lower (C _1-6 ) alkoxy. Lower (C _1-4 ) ar _optionally substituted with carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.) Or a tetrazolyl optionally protected by a group represented by the formula: or a lower (C _1-4 ) alkyl or acyl (eg, lower (C _2-5 ) alkanoyl, optionally substituted benzoyl, etc.), Examples thereof include trifluoromethanesulfonic acid amide, phosphoric acid and sulfonic acid, and lower (C _1-4 ) alkyl, halogen and the like are preferable. One or two of these substituents may be simultaneously substituted at any position of the ring. The fused heterocycle represented by the formula (III) includes

Embedded image (Wherein, Y—R ¹ and R ² have the same meanings as described above) and the like, and a compound having a benzimidazole, thiimidazole, or imidazopyridine (particularly benzimidazole, thiimidazole) skeleton is preferable.

Among the compounds represented by the above formula (I),

Embedded image [In the formula, ring A represents a benzene ring which may further have a substituent in addition to the group represented by R ² , R ¹ represents hydrogen or an optionally substituted hydrocarbon residue, and R ³ Represents a group capable of forming an anion or a group capable of converting into a group,
X shows that the phenylene group and phenyl group are bonded directly or via a chain of atoms of 2 or less spacer, R ²
Represents a carboxyl group which may be esterified,
Y is a bond, -O-, -S (O) m- (where m is 0,
1 or 2) or -N (R ⁴ )-(in the formula, R ⁴ represents hydrogen or an optionally substituted alkyl group), and n represents an integer of 1 or 2] Compounds or salts thereof, more specifically EP Publication No. 042
Among the benzimidazole-7-carboxylic acids or derivatives thereof described in JP 5921 or EP 0459136, any crystallized substance may be used, among which R in the general formula (I) ¹ is a hydroxyl group,
Amino groups, are (preferably, lower (C _2-3) alkyl) substituted lower (C _1-5) alkyl optionally substituted with halogen or lower (C _1-4) alkoxy group indicates, R ² is the formula -
CO-D [wherein D is a hydroxyl group or an alkyl moiety is a hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy (eg, acetyloxy, pivaloyloxy, etc.), 1-lower (C _1-6 ) alkoxycarbonyl Oxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.)
Or a lower (C _1-4) which may lower substituted with alkoxy (C _1-4) represents a group represented by an alkoxy, ring A is further halogen (eg besides the group represented by R ^2, F, Cl, Br, etc.), lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, nitro, formula —CO—
D ′ [wherein D ′ is a hydroxyl group or an alkyl moiety is a hydroxyl group, lower (C _1-4 ) alkoxy, lower (C _2-6 ) alkanoyloxy (eg, acetyloxy, pivaloyloxy, etc.) or 1-lower (C _{1 -6} ) represents a lower (C _1-4 ) alkoxy optionally substituted by alkoxycarbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.)], or a lower (C _1-4 ) benzene ring optionally having a substituent such as amino optionally substituted by alkyl (preferably a substituent such as lower (C _1-4 ) alkyl, halogen) (more preferably a formula) represents a benzene ring) which has no substituent in addition to the group represented by R ^2, Y represents a bond, -O -, - S- or -N (R ⁴⁾ - [wherein , R ⁴ is hydrogen or a lower (C _1-4)
It indicates an alkyl], R ³ is a lower optionally substituted (C _1-4) alkyl (e.g., methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p- methoxybenzyl, p- nitrobenzyl, etc.) Or an acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.)
Compound (I ′) in which tetrazolyl or carboxyl group (preferably tetrazolyl group) which may be protected by is represented, n is 1 and X is a bond is preferable.

In particular, in the general formula (I), R ¹ represents ethyl, R ² represents 1- (cyclohexyloxycarbonyloxy) ethoxycarbonyl, and ring A is a substituent other than the group represented by formula R ^2. A benzene ring not having Y, Y represents —O—, R ³ represents tetrazolyl, n represents 1, and X represents a bond, that is, (±) -1- (cyclohexyloxycarbonyl). (Oxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate (hereinafter referred to as compound (V). The following structural formula) is preferably used. Any crystal form may be used, but in the case of the compound (V), especially EP
The stable C-type crystal described in Experimental Example 1 of JP-A-0459136 is desirable.

Embedded image Among the compounds of formula (I) having anti-AII action, those which are crystalline and have a melting point of 100 to 200 ° C., especially 130 to 180 ° C. are conveniently used in terms of stability.

The low melting point oily substance used in the present invention is an oily substance having a melting point of about 20 to 90 ° C., preferably 20 to 60 ° C.
Any substance may be used as long as it does not adversely affect the active ingredient. In producing the oral pharmaceutical composition of the present invention, the low-melting oily substance is more uniformly compoundable with the active ingredient than the high-melting oily substance, and as a result, decomposition of the active ingredient is suppressed. In addition, a more stable oral pharmaceutical composition can be obtained. The low melting point oily substance may be soluble or insoluble in water. Here, examples of the low-melting oil-and-fat substance soluble in water include alkylene oxide polymers described below. Examples of the low melting point oily substance used in the present invention include hydrocarbons, higher fatty acids, higher alcohols, fatty acid esters of polyhydric alcohols, higher alcohol ethers of polyhydric alcohols, alkylene oxide polymers or copolymers, and the like. However, among them, fatty acid esters of polyhydric alcohols, higher alcohol ethers of polyhydric alcohols, polymers or copolymers of alkylene oxides, and particularly alkylene oxide polymers are preferably used. Examples of hydrocarbons include n-heptadecane, n-octadecane, n-nonadecane, n-eicosane, n
N-alkanes having 17 to 50 carbon atoms such as heneicosane, n-docosane, n-tricosane, n-tetracosane, n-pentacosane, n-triacontane, n-pentatriacontane, n-tetracontane, n-pentacontane And mixtures thereof (Petrolatum, paraffin wax, microcrystalline wax, etc.) and the like. Examples of higher fatty acids include capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, and mixtures thereof,
Examples include higher fatty acids collected from natural fats and oils.

Examples of higher alcohols include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, aralkyl alcohol and mixtures thereof, and higher alcohols extracted from natural oils. Examples of fatty acid esters of polyhydric alcohols include alcohols having two or more hydroxyl groups in the molecule (for example, alkylene glycols such as ethylene glycol and propylene glycol, polyethylene glycol, polypropylene glycol or polyalkylene glycols such as copolymers thereof, sorbitol, Intramolecular dehydration compounds of sorbitol such as sugars such as sucrose and flynose, 1,5-sorbitan, 1,4-sorbitol, 3,6-sorbitan, glycerin, diethanolamine, pentaerythritol, etc. and fatty acids (eg acetic acid, propione) Acid, butyric acid, pelargonic acid, capric acid, undecyl acid, lauric acid, tridecyl acid, myristic acid, pentadecyl acid, palmitic acid, heptadecyl acid, stearic acid, nonadecanoic acid, undecylenic acid, oleic acid, elaidic acid, sodium Bin acid, linoleic acid, linolenic acid, arachidonic acid, esters with stearic or roll acid), specifically, for example, sorbitan monostearate, sorbitan tristearate,
Molecular weight of sorbitan monooleate, sorbitan sesquioleate, sorbitan monopalmitate, 400-9
00 sorbitan fatty acid ester, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tripalmitate, etc. polyoxyalkylene sorbitan fatty acid ester having a molecular weight of 1000 to 1500, polyoxyethylene sorbitol hexastearate, Polyoxyethylene sorbitol hexaoleate, polyoxyethylene sorbitol tristearate, polyoxyethylene sorbitol tetralaurate and other polyoxyalkylene sorbitol fatty acid esters, polyoxyethylene sorbitol beeswax derivative and other polyoxyalkylene sorbitol beeswax derivatives, poly Polyoxyalkylene lanolin derivatives such as oxyethylene lanolin derivatives, propylene glycol Monopalmitate, propylene glycol monostearate, propylene glycol dilaurate, propylene glycol dimyristate, propylene glycol dipalmitate, propylene glycol distearate, etc. Propylene glycol fatty acid ester having a molecular weight of 200 to 700, ethylene glycol monolaurate, ethylene Glycol palmitate, ethylene glycol margarate, ethylene glycol stearate, ethylene glycol dilaurate, ethylene glycol dimyristate, ethylene glycol dipalmitate, ethylene glycol dimer gallate and other alkylene glycol fatty acid esters such as ethylene glycol fatty acid ester having a molecular weight of 500 to 1200 , Polyoxyethylene castor oil derivative, etc., molecular weight 3500-400 Polyoxyalkylene castor oil derivatives, polyoxyethylene stearates, polyoxyethylene oleate, polyoxyethylene palmitate, polyoxyethylene linoleate, molecular weight 190
0 to 2200 polyoxyalkylene fatty acid ester,
Glycerin monoacetate, glycerin monopropionate, glycerin monostearate, glycerin monooleate, glycerin monopalmitate, glycerin monolinoleate, etc. Examples include palmitate, sucrose monostearate, sucrose trimyristate, sucrose tripalmitate, sucrose tristearate and other sucrose fatty acid esters having a molecular weight of 400 to 1300.

The higher alcohol ethers of polyhydric alcohols include polyhydric alcohols (those listed as alcohol components of fatty acid esters of polyhydric alcohols) and higher fatty acid alcohols (for example, cetyl alcohol, stearyl alcohol, oleyl alcohol, octyl alcohol, Decyl alcohol), specifically polyoxyethylene lauryl alcohol ether, polyoxyethylene cetyl alcohol ether, polyoxyethylene stearyl alcohol ether, polyoxyethylene oleyl alcohol ether, polyoxyethylene octyl alcohol ether, polyoxyethylene Polyoxyethylene higher alcohol ethers such as decyl alcohol ether, polyoxypropylene polyoxyethylene cetyl alcohol ether Polyoxypropylene polyoxyethylene higher grades such as ter, polyoxypropylene polyoxyethylene stearyl alcohol ether, polyoxypropylene polyoxyethylene oleyl alcohol ether, polyoxypropylene polyoxyethylene octyl alcohol ether, polyoxypropylene polyoxyethylene lauryl alcohol ether Alcohol ether is often used.

As the alkylene oxide polymer, those having a molecular weight of 1,000 to 10,000 (eg, polyethylene glycol 6000) are used. Examples of the alkylene oxide include ethylene oxide, propylene oxide, trimethylene oxide, tetrahydrofuran and the like (preferably ethylene oxide). As the alkylene oxide copolymer, a copolymer of two or more of the above alkylene oxides having a molecular weight of 1,000 to 10,000 is used.
These low melting point oily substances may be used alone or in combination of two or more kinds. These low-melting oily substances are added to the active ingredient in solid or liquid form. INDUSTRIAL APPLICABILITY The present invention is more conveniently applied to a solid formulation (granule, tablet, etc., preferably tablet) produced by molding (granulation, pressure molding, etc.).

In producing the solidifying agent of the present invention,
It is usually carried out by mixing the low melting point oily substance as described above with the active ingredient and then molding. As a compounding method for these, generally used are compounding methods such as mixing, kneading, kneading, sieving and stirring. For example, a low melting point oily substance may be added directly to the active ingredient and mixed (powder added), or a solvent may be added and mixed, and kneading, granulating and drying may be carried out by a conventional method. Alternatively, the low-melting oily substance may be dissolved in a suitable solvent, then uniformly mixed with the active ingredient, and kneaded, granulated, and dried (liquid addition) by a conventional method. Further, the low melting point oil-and-fat substance-containing liquid and the active ingredient-containing liquid may be separately sprayed and mixed into powder such as an excipient. As a suitable solvent in the case of liquid addition, for example, water, dimethylformamide, acetone, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, methylene chloride, trichloroethane and the like which do not adversely affect the active ingredient are used. After completion of the blending, a tablet containing the active ingredient can be produced by using a known pressure molding means. However, pressure molding is compression into a desired shape under pressure, and most commonly means, for example, tableting. Addition of these low-melting oil-and-fat substances reduces the distortion of crystals during kneading, granulation, and pressure molding, and further, the moldability is improved, which requires less pressure. It is believed that In addition, in the method for producing the composition of the present application, various additives used for the solidifying agent can be added in appropriate steps. For example, crystalline cellulose (eg, Avicel PH 101 (manufactured by Asahi Kasei)), carboxymethylcellulose calcium, cornstarch, wheat starch, lactose, sucrose, glucose, calcium sulfate, calcium phosphate, excipients such as sodium chloride, gum arabic, gelatin, Methyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose (hereinafter,
Sometimes referred to as HPC. ), Binder such as hydroxypropylmethyl cellulose, magnesium stearate, talc, synthetic aluminum silicate, sodium lauryl sulfate, boric acid, magnesium oxide, paraffin and other lubricants, colorants, flavoring agents, and flavoring agents. May be.
When a crystalline substance such as compound (V) having a low specific gravity is used as an active ingredient, it is preferable to disperse the substance in advance in a concentrated liquid containing a binder such as HPC and water. desirable. Furthermore, the composition of the present invention may be a coated tablet.

The coating can be carried out by a method known per se, and a coating agent usually used as a coating agent (eg, hydroxypropylmethylcellulose,
Hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, etc.) are used, and as a coating aid, polyethylene glycol 6000, polysorbate (eg, Tween 80, etc.), pigments such as titanium oxide, red iron oxide, etc. are used. In the oral pharmaceutical composition of the present invention obtained by blending an active ingredient with a low melting point oily substance, the low melting point oily substance is 0.5 to 15% in the composition.
%, Preferably 1 to 10% by weight, more preferably 2 to 5% by weight, and the active ingredient in the composition is
It is contained in an amount of 0.1 to 15% by weight, preferably 0.7 to 9% by weight, and more preferably 1.5 to 4% by weight. From the viewpoint of disintegration, the oral pharmaceutical composition of the present invention preferably disintegrates in an aqueous solution within 30 minutes. In this way, the oral pharmaceutical composition of the present invention obtained by blending the active ingredient with a low-melting oily substance is a stable preparation in which degradation over time due to molding is suppressed. When the pharmaceutical composition of the present invention is used to treat mammals (eg, human, dog, rabbit, rat, etc.) for hypertension, heart disease, stroke, renal disease, etc., it should be orally administered as tablets. You can The doses of the active ingredients (the formula (I) having an anti-AII effect are
The daily dose of the compound is about 1 to 50 mg, preferably about 2 to 30 mg.

[0018]

The present invention will be described in more detail with reference to the following examples, which are not intended to limit the present invention. Example 1 Polyethylene glycol 6000 was used as a low melting point oily substance according to the following formulation using a fluidized bed granulator (Powrec, FD-3S) and a compound represented by the formula (I) having an anti-AII action (effective) Ingredients), spraying an aqueous solution of hydroxypropylcellulose as a binding solution, granulating, drying and sizing, adding and mixing carboxymethylcellulose calcium and magnesium stearate, and mixing with a tablet machine (Kikusui Seisakusho Correct 19K). 0.0 mm
φ, using a flat corner punch, weight 130 mg, pressure 2.0 to
Tableted at n / cm ² . Store the tablets at 50 ° C or 40 ° C,
A daily stability test was conducted.

[0019]

[Table 1] Method

[Table 2] Daily stability test results In the stability test, after storage for each period, the content of compound (V) was measured by liquid chromatography and the residual rate was shown as a percentage. As a control, the preparation (B) to which no stabilizer (low melting point oily substance) was added was used and tested in comparison with the preparation (A) to which polyethylene glycol 6000 was added as a low melting point oily substance. As is clear from the test results, the composition of the present invention has the compound (V) as compared with the control.
Has excellent stability.

Example 2 Using a fluidized bed granulator (Glad WSG-15) and following the same formulation as in Example 1 except that polyethylene glycol 6000 as a low melting point oily substance was dissolved in water to give a compound. (V) is dispersed, sprayed on a powder consisting of lactose and corn starch, further sprayed with an aqueous solution of hydroxypropyl cellulose, granulated, dried and sized, and carboxymethyl cellulose calcium and magnesium stearate are added and mixed to give tablets. The tablet was compressed with a machine using a punch having a flat corner of 7.0 mm and a weight of 130 mg and a pressure of 2.0 ton / cm ² .

[Table 3] Daily stability test results From the test results, it can be seen that in the composition of the present invention, the compound (V) is extremely stable as compared with the control.

Example 3 A liquid obtained by dissolving polyethylene glycol 6000 as a low-melting oily substance in water using a fluidized bed granulator (Pawreck FD-5S) and the same formulation as in Example 1 except for lactose. And a cornstarch powder, and further sprayed with a liquid in which the compound (V) is dispersed in a hydroxypropylcellulose aqueous solution, granulated, dried and sized, and carboxymethylcellulose calcium and magnesium stearate are added and mixed, Tablet machine (Kikusui Seisakusho,
Tablets were compressed with Correct 19K) to a diameter of 7.0 mm and a plain surface punch with a weight of 130 mg and a pressure of 2.0 ton / cm ² . further,
According to the following water-based coating tablet formulation, water-based coating (5 m
g) Accelerator Coater 24 (Manestie, UK)
I went in.

[Table 4] Method

[Table 5] Daily stability test results From the test results, it can be seen that in the composition of the present invention, the compound (V) is extremely stable as compared with the control.

Example 4 Agitation Granulator (Pawreck, Vertical Granulator V
Compound (V) is dispersed in a liquid obtained by dissolving polyethylene glycol 6000 as a low melting point oily substance and HPC in water using G10), and this liquid is added to a powder consisting of lactose and corn starch, kneaded and dried. The powder was sized, carboxymethylcellulose calcium and magnesium stearate were added and mixed, and the mixture was tableted with a tablet machine at a weight of 130 mg and a pressure of 2.0 ton / cm ² using a punch having a flat corner.

[Table 6] Method

[Table 7] Daily stability test results From the test results, it can be seen that in the composition of the present invention, the compound (V) is extremely stable as compared with the control.

Example 5 Tablets were produced in the same manner as in Example 1 except that the type and amount of the low melting point oily substance were as shown in the following [Table 8]. A daily stability test was also conducted on these tablets in the same manner as in Example 1. The results are shown in [Table 9].

[Table 8]

[Table 9] From the above test results, it is understood that the composition of the present invention containing the low melting point oily substance has excellent content stability of the compound (V).

Example 6 Formulation Example In the same manner as in Example 1, tablets can be produced with the types and amounts of the active ingredient and the low melting point oily substance as shown in Table 10 below.

[Table 10]

[0025]

INDUSTRIAL APPLICABILITY According to the present invention, a compound represented by the formula (I) having an anti-AII action is used as an active ingredient, and a low melting point oily substance is added thereto to decompose the active ingredient. It is possible to obtain a stable oral pharmaceutical composition which has the effect of suppressing the above and maintaining a high content of the active ingredient even with the passage of time.

Continuation of the front page (56) Reference JP-A-49-71131 (JP, A) JP-A-55-87715 (JP, A) JP-A-56-40606 (JP, A) JP-A-63-99012 (JP , A) Japanese Patent Publication No. 41-14399 (JP, B1) US Patent 5294631 (US, A) European Patent 425921 (EP, B) European Patent 459136 (EP, B)

Claims (34)

(57) [Claims] [Claim 1] have a anti-AII action, crystallinity of the formula (I) ## STR1 ## (In the formula, ring W represents an optionally substituted nitrogen-containing heterocyclic residue, and R ³ has (1) a protonatable hydrogen atom.
5 containing one or more of N, S and O
A 7-membered monocyclic optionally substituted heterocyclic residue, or
Or (2) an optionally substituted lower alkyl group and
It may be protected by a group selected from an acyl group (i)
Carboxyl group, (ii) tetrazolyl group, (iii) tri
Fluoromethanesulfonic acid amide group, (iv) phosphoric acid group,
(V) sulfonic acid group, (vi) cyano group or (vii) lower
_{Represents a} (C _1-4 ) alkoxycarbonyl group , X represents that the phenylene group and the phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less, and n is 1 or 2
Represents an integer) or a salt thereof;
Fatty acid esters of higher alcohols and polyhydric alcohols
And alkylene oxide polymers or copolymers
An oral solid pharmaceutical composition comprising a spilled low melting point oily substance. 2. A have anti-AII action, crystal of formula (I) ## STR2 ## (In the formula, ring W represents an optionally substituted nitrogen-containing heterocyclic residue, and R ³ has (1) a protonatable hydrogen atom.
And, N, 1 single S and O, or 5 comprising two or more
A 7-membered monocyclic optionally substituted heterocyclic residue, or
Or (2) an optionally substituted lower alkyl group and
It may be protected by a group selected from an acyl group (i)
Carboxyl group, (ii) tetrazolyl group, (iii) tri
Fluoromethanesulfonic acid amide group, (iv) phosphoric acid group,
(V) sulfonic acid group, (vi) cyano group or (vii) lower
_{Represents a} (C _1-4 ) alkoxycarbonyl group , X represents that the phenylene group and the phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less, and n is 1 or 2
Or a salt thereof ; and 0.005 to 0.15 part by weight / part by weight of the composition of an alkylene oxide polymer, for oral solid pharmaceutical composition. 3. A crystalline formula (I) having an anti-AII action. (Wherein the ring W ¹ is represented by the formula (III): (In the formula, a and e independently represent 1 or 2 carbons or heteroatoms, d and f independently represent one carbon or heteroatom, and b and c independently of each other. Represents one carbon or nitrogen atom, R ¹ represents hydrogen or an optionally substituted hydrocarbon residue,
Y represents a bond, -O-, -S (O) m- (m represents 0, 1 or 2) or -N (R ⁴ )-(R ⁴ represents hydrogen or an optionally substituted alkyl group. (Indicated by (showing)), the nitrogen-containing heterocyclic residue represented by the formula-
In addition to the substituent represented by Y-R ^1, it may be substituted .
There lower alkyl or acyl which may be protected respectively in group (1) esterified or amidated carboxyl group which may be, (2) tetrazolyl group, (3)
Trifluoromethanesulfonic acid amide group, represented by (4) a phosphate group and (5) R ² selected from a sulfonic acid group
It may have a substituent that; R ³ may be protonated
A hydrogen atom, N, represents 1, or 5 to 7-membered monocyclic like optionally substituted double <br/> heterocyclic residues containing two or more S and O; X is phenylene Group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less, and n is 1 or 2)
Or a salt thereof; and a high-grade alcohol, a polyhydric polymer or copolymer oral solid pharmaceutical compositions containing a low melting point fat and oil-like substance selected from of alcohols fatty ester le Contact <br/> preliminary alkylene oxide. 4. The melting point of the compound represented by formula (I) is 100.
The composition according to claim 1, which is at about 200 ° C. 5. The ring W in the compound represented by formula (I) is represented by the formula (III): (In the formula, a and e independently represent 1 or 2 carbons or heteroatoms, d and f independently represent one carbon or heteroatom, and b and c independently of each other. Represents one carbon or nitrogen atom, R ¹ represents hydrogen or an optionally substituted hydrocarbon residue,
Y represents a bond, -O-, -S (O) m- (m represents 0, 1 or 2) or -N (R ⁴ )-(R ⁴ represents hydrogen or an optionally substituted alkyl group. (Indicated by (showing)), the nitrogen-containing heterocyclic residue represented by the formula-
In addition to the substituent represented by Y-R ^1, it may be substituted .
Protected by a lower alkyl group and an acyl group
(1) Esterified or amidated
Good carboxyl group, (2) tetrazolyl group, (3)
Trifluoromethanesulfonic acid amide group, (4) phosphoric acid
Represented by group and (5) R ² selected from sulfo phosphate group
The composition according to claim 1, which may have a substituent . Wherein R ² Gae esterification or amidated good carboxyl group is also optionally composition of claim 5. 7. R ³ has a protonatable hydrogen atom,
5 to 7 containing one or more of N, S and O
The composition of claim 1 wherein the monocyclic form an optionally substituted heterocyclic residue of the members. 8. The composition according to claim 1, wherein ring W in the compound represented by formula (I) is a benzimidazole ring. 9. The composition according to claim 1, wherein ring W in the compound represented by formula (I) is benzimidazole-7-carboxylic acid or a derivative thereof. 10. A ring W in a compound represented by formula (I)
Is of formula (II) (In the formula, ring A represents a benzene ring which may further have a substituent other than the group represented by R ^2a , R ¹ represents hydrogen or an optionally substituted hydrocarbon residue, and R ^2a represents a carboxyl group which may be esterified, Y is a bond, -O -, - S (O ) m- ( wherein, m is 0, 1 or 2) or -N (R ⁴⁾ The composition according to claim 1, which is a benzimidazole ring represented by-(R ⁴ represents hydrogen or an alkyl group which may be substituted). 11. R ^2a is of the formula —CO—D [wherein D is a hydroxyl group or an alkyl moiety is a hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy, 1-lower (C _1-6 ) alkoxy. 11. The composition according to claim 10, which is a group represented by carbonyloxy, cyclohexyloxycarbonyloxy or lower (C _1-4 ) alkoxy optionally substituted with lower (C _1-4 ) alkoxy]. 12. A compound represented by the formula (I) has the formula: (In the formula, ring A represents a benzene ring which may have a substituent in addition to the group represented by R ^2a , R ^1a represents a hydroxyl group,
Represents a lower (C _1-5 ) alkyl group optionally substituted with amino, halogen or lower (C _1-4 ) alkoxy, R ^2a represents an optionally esterified carboxyl group, and Y ^a represents a bond Hand, -O-, -S (O) m- (m represents 0, 1 or 2) or -N ( ^R4a )-( ^R4a represents hydrogen or a lower ( _C1-4 ) alkyl group) Indicates
R ^3a represents (1) carboxyl or (2) tetrazolyl, each of which may be substituted by optionally substituted lower (C _1-4 ) alkyl or acyl, and X represents a phenylene group and a phenyl group directly or as an atom. It is shown that the chains are linked through a spacer of 2 or less, and n is 1 or 2
The composition according to claim 10, which is a compound represented by 13. R ^3a is methyl, triphenylmethyl, me
Toxymethyl, ethoxymethyl, p-methoxybenz
, P-nitrobenzyl, lower (C _2-5 ) alkanoyl
And may be protected by a group selected from benzoyl
13. The composition according to claim 12, which is tetrazolyl . 14. The composition of claim 1 wherein R ³ is tetrazolyl. 15. R ³ is —NH— as a proton donor.
Group or -OH group and a carbonyl group as a proton acceptor, composition according to claim 1, wherein a group having a thiocarbonyl group or sulfinyl group. 16. The composition of claim 1 wherein R ³ is an oxadiazolyl or thiadiazolyl group. 17. R ^2a is of the formula —CO—D [wherein D is (i)
Hydroxyl group or (ii) alkyl moiety is hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy, 1-lower (C _1-6 ) alkoxycarbonyloxy, cyclohexyloxycarbonyloxy or lower (C _1-4 ) alkoxy. A lower group (represented by lower (C _1-4 ) alkoxy optionally substituted with] is represented by the formula: 18. The composition according to claim 12, wherein ring A is a benzene ring having no substituent other than the group represented by R ^2a . 19. The composition according to claim 12, wherein X is a bond. 20. The composition according to claim 12, wherein n is 1. 21. The composition according to claim 12, wherein R ^1a is lower (C _2-3 ) alkyl. 22. Y ^a is a bond, -O -, - S- or -
The composition according to claim 12, which is N (R ^4a )-(R ^4a represents hydrogen or lower (C _1-4 ) alkyl). 23. The compound represented by the formula (I) is (±) -1.
-(Cyclohexyloxycarbonyloxy) ethyl
2-ethoxy-1-[[2 '-(1H-tetrazole-
The composition according to claim 1, which is 5-yl) biphenyl-4-yl] methyl] -1H-benzimidazole-7-carboxylate. 24. The compound represented by the formula (I) is 2-butyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] benzimidazole-7.
-The composition of claim 1 which is a carboxylic acid. 25. The melting point of a low melting point oily substance is 20 to 90 ° C.
The composition according to claim 1, which is: 26. The composition according to claim 1, wherein the low melting point oily substance is a polymer of alkylene oxide. 27. Claim 2 6 composition according alkylene oxide is ethylene oxide. 28. The composition of claim 2 6, wherein to the molecular weight of the polymer of alkylene oxide 1000 10000. 29. The composition according to claim 1, which contains a low melting point oily substance in an amount of 0.5 to 15% by weight. 30. The composition according to claim 1, which contains a low melting point oily substance in an amount of 10% by weight or less . 31. A compound represented by the formula (I) is (±) -1.
-(Cyclohexyloxycarbonyloxy) ethyl
2-ethoxy-1-[[2 '-(1H-tetrazole-
The composition according to claim 1, which is 5-yl) biphenyl-4-yl] methyl] -1H-benzimidazol-7-carboxylate, and the low melting point oily substance is a polymer of alkylene oxide. 32. (±) -1- (Cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2'-
The composition according to claim 1, which is a tablet containing (1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-benzimidazol-7-carboxylate and polyethylene glycol. 33. possess anti AII activity, crystalline formula (I) embedded image (In the formula, ring W represents an optionally substituted nitrogen-containing heterocyclic residue, and R ³ has (1) a protonatable hydrogen atom.
5 containing one or more of N, S and O
A 7-membered monocyclic optionally substituted heterocyclic residue, or
Or (2) an optionally substituted lower alkyl group and
It may be protected by a group selected from an acyl group (i)
Carboxyl group, (ii) tetrazolyl group, (iii) tri
Fluoromethanesulfonic acid amide group, (iv) phosphoric acid group,
(V) sulfonic acid group, (vi) cyano group or (vii) lower
_{Represents a} (C _1-4 ) alkoxycarbonyl group , X represents that the phenylene group and the phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less, and n is 1 or 2
Compound or higher A to a salt thereof of an integer)
Rucol, fatty acid ester of polyhydric alcohol and al
A method for producing an oral solid pharmaceutical composition, which comprises blending a low melting point oily substance selected from a polymer or copolymer of xylene oxide and molding the mixture. 34. A method according to claim 3 3, wherein the molding pressure molding.