JP2004217648A - Agent for controlling weight gain - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a drug for bring about an excellent effect on controlling weight gain, and further a drug which does not allow a patient to gain weight even by administration of a PPARγagonistic substance effective for the therapy of diabetes and other diseases. <P>SOLUTION: This agent for controlling weight gain comprises a compound having an angiotensin II antagonism, its prodrug or its salt. The drug brings about an excellent effect on controlling weight gain. Further, the drug can control weight gain to be derived from a PPARγagonistic substance effective for the therapy of diabetes, and the like. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

  The present invention relates to a weight gain inhibitor, particularly a weight gain inhibitor derived from a PPARγ agonist-like agent, which is useful in treating diabetes and the like.

Suppressing weight gain due to weight gain is not only undesired cosmetically, but also a major health risk leading to the development of lifestyle-related diseases such as diabetes, hypertension and hyperlipidemia Is thought to be important in controlling the incidence of lifestyle-related diseases. However, in order to control weight gain, it is natural that sufficient exercise and an unbalanced diet are important, but at present it is not possible to respond adequately, and appropriate weight is controlled. The reality is that it is hard to find a way.
On the other hand, weight gain of patients suffering from lifestyle-related diseases such as diabetes, hypertension and hyperlipidemia often induces exacerbation of such diseases. Weight gain can be caused not only by dietary intake, but also by the administration of drugs for lifestyle-related diseases.Inhibiting weight gain in patients can be associated with diabetes, hypertension, and hyperlipidemia. It is also important in treating lifestyle-related diseases such as.

  It is known that an insulin sensitizer (eg, troglitazone, pioglitazone, rosiglitazone, etc.), which is known as an excellent therapeutic agent for diabetes, has a PPARγ agonistic action (for example, Non-Patent Document 1). However, although these drugs are effective for the treatment of diabetes, some of them have been found to increase the weight of patients by their administration (Patent Document 1, Non-Patent Document 2). Such drug-induced weight gain is one of the effects that diabetics want to avoid as much as possible. Obesity works for exacerbation of diabetes.

Compounds having angiotensin II antagonistic activity have excellent therapeutic effects on hypertension, heart disease, stroke, renal disease, circulatory system diseases such as arteriosclerosis, for example, Patent Document 2, Patent Document 3, etc. It is described in. Further, a medicine comprising a combination of a compound having an angiotensin II antagonistic action and a compound having an insulin sensitivity enhancing action can significantly reduce the dose when each active ingredient is used alone. As a result, as compared with the case where each is used alone, it is possible to suppress the occurrence of side effects of the drug, and to prevent or treat angiotensin II-mediated diseases, especially arteriosclerosis with arteriosclerosis or hypertension complications. Patent Document 4 describes that it is advantageously used as an agent for preventing or treating hypertension.
Patent Document 2 describes obesity, which is one of metabolic and nutritional disorders, as a target disease of a compound having an angiotensin II antagonistic activity. However, a compound having an angiotensin II antagonistic activity is known to be obese (including obesity). ) Has not been reported to suppress body weight gain (particularly body weight gain from PPARγ agonist-like agents) regardless of whether the condition has been reached.

International Publication No. WO 93/03724 pamphlet JP-A-5-271228 JP 2001-316296 A JP-A-9-323940 Journal of Pharmacology and Experimental Therapeutics, 284, 751-759 (1998) Diabetes, 47, suppl. 1, A18, No. 69, 1998

An object of the present invention is to provide a drug having an excellent effect of suppressing weight gain.
Another object of the present invention is to provide a drug that does not increase the weight of a patient even when a therapeutically effective PPARγ agonist substance is administered in the treatment of diabetes and other diseases.

（式中、Ｒ^１は陰イオンを形成しうる基またはそれに変じうる基を示し、Ｘはフェニレン基とフェニル基が直接または原子鎖２以下のスペーサーを介して結合していることを示し、ｎは１または２を示し、環Ａはさらに置換基を有していてもよいベンゼン環を示し、Ｒ^２は陰イオンを形成しうる基またはそれに変じうる基を示し、Ｒ^３はヘテロ原子を介して結合していてもよく、置換基を有していてもよい炭化水素残基を示す）で表される化合物である前記（１）記載の剤、
（１２）アンギオテンシンII拮抗作用を有する化合物が２−エトキシ−１−［［２'−（５−オキソ−２，５−ジヒドロ−１，２，４−オキサジアゾール−３−イル）ビフェニル−４−イル］メチル］−１Ｈ−ベンズイミダゾール−７−カルボン酸である前記（１）記載の剤、
（１３）アンギオテンシンII拮抗作用を有する化合物またはその塩がロサルタン、ロサルタンカリウム、エプロサルタン、カンデサルタン シレキセチル、カンデサルタン、バルサルタン、テルミサルタン、イルベサルタン、オルメサルタン、オルメサルタン・メドキソミルまたはタソサルタンである前記（１）記載の剤、
（１４）哺乳動物に有効量のアンギオテンシンII拮抗作用を有する化合物、そのプロドラッグまたはその塩を投与することを特徴とする哺乳動物の体重増加の抑制方法、
（１５）体重増加抑制剤の製造のための、アンギオテンシンII拮抗作用を有する化合物、そのプロドラッグまたはその塩の使用、
などに関する。 The present inventors have for the first time reported that a compound having an angiotensin II antagonistic activity, a prodrug thereof, or a salt thereof (hereinafter, may be simply referred to as a “compound having angiotensin II antagonistic activity”) may suppress weight gain for the first time. After finding out, the present invention has been completed.
That is, the present invention
(1) a compound having an angiotensin II antagonistic activity, a prodrug or a salt thereof, which suppresses weight gain;
(2) The agent according to the above (1), wherein the weight gain is weight gain before obesity.
(3) The agent according to the above (1), wherein the weight gain is weight gain of an obese patient.
(4) the agent according to the above (3), wherein the obesity is obesity accompanied by diabetes;
(5) The agent according to (4), further comprising a combination of a PPARγ agonist-like substance,
(6) The agent according to the above (1), wherein the weight gain is weight gain derived from a PPARγ agonist-like substance.
(7) The agent according to the above (6), which suppresses weight gain derived from a PPARγ agonist-like substance to about 80% or less.
(8) the agent according to the above (1), wherein the compound having an angiotensin II antagonistic action is a non-peptidic compound;
(9) The agent according to the above (1), wherein the compound having an angiotensin II antagonistic action is a compound having an oxygen atom in the molecule.
(10) The agent according to the above (1), wherein the compound having an angiotensin II antagonistic activity is a compound having an ether bond or a carbonyl group in the molecule.
(11) The compound having an angiotensin II antagonistic activity is represented by the formula (I)

(Wherein, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atom chain of 2 or less; Represents 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group convertible thereto, and R ³ represents a hetero atom. (1) a compound represented by the following formula (1):
(12) The compound having an angiotensin II antagonistic action is 2-ethoxy-1-[[2 ′-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4 -Yl] methyl] -1H-benzimidazole-7-carboxylic acid, the agent according to the above (1),
(13) The agent according to the above (1), wherein the compound having an angiotensin II antagonistic activity or a salt thereof is losartan, losartan potassium, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, olmesartan medoxomil or tasosartan,
(14) a method for suppressing weight gain in a mammal, comprising administering to the mammal an effective amount of a compound having an angiotensin II antagonistic activity, a prodrug thereof, or a salt thereof;
(15) use of a compound having an angiotensin II antagonistic activity, a prodrug thereof, or a salt thereof for the production of a weight gain inhibitor;
And so on.

The term “angiotensin II antagonism” in the present invention inhibits the binding of angiotensin II to the angiotensin II receptor on the cell membrane competitively or non-competitively. It is known that such a compound having an angiotensin II antagonistic action has an action of attenuating the strong vasoconstriction action and vascular smooth muscle growth action induced by angiotensin II, and alleviating the symptoms of hypertension.
The compound having an angiotensin II antagonistic activity used in the present invention may be either peptide or non-peptide. For example, a compound having a non-peptide antagonistic effect, which has an advantage of a long action time, is preferred. As the compound having an angiotensin II antagonistic action, a compound having an oxygen atom in the molecule is preferable, and a compound having an ether bond or a carbonyl group (the carbonyl group may form a hydroxyl group by resonance) is preferable. Is preferable, and a compound having an ether bond or a ketone derivative is more preferable, and an ether derivative is particularly preferable.
As the non-peptide compound having angiotensin II antagonistic activity, imidazole derivatives are disclosed in JP-A-56-71073, JP-A-56-71074, JP-A-57-98270, and JP-A-58-157768. And US Pat. Nos. 4,355,040 and 4,340,598, and EP-253310, EP-291969, EP-324377, EP-403158, WO-91002777, JP-A-63-23868 and JP-A-63-23868. Japanese Unexamined Patent Publication No. 1-117876 discloses an improved imidazole derivative, and US Pat. No. 5,183,899, EP-323841, EP-409332 and JP-A-1-2877071 disclose pyrrole, pyrazole and triazole derivatives. And USP , 880, 804, EP-0392317, EP-0399732, EP-0400835, EP-425921, EP-59136 and JP-A-3-63264 disclose a benzimidazole derivative, and EP-399731 and the like disclose an azaindene derivative. EP-407342 and the like disclose pyrimidone derivatives, EP-411766 and the like disclose quinazoline derivatives, EP-430300 and the like disclose xanthine derivatives, and EP-434038 and the like contain a condensed imidazole derivative. EP-444473 and the like disclose pyrimidinedione derivatives, EP-443568 and the like disclose thienopyridone derivatives, and furthermore EP-445811, EP-483683, EP-518033, EP-520423, Heterocyclic compounds are disclosed in EP-588299, EP-603712 and the like. In addition, Journal of Medicinal Chemistry (Journal of Medicinal Chemistry, Vol. 39, No. 3, 625-656, 1996) describes typical compounds among these. As the compound having non-peptide angiotensin II antagonistic activity, in addition to the compounds described in the above-mentioned known documents, any non-peptide compound having an angiotensin II antagonistic activity may be used. Losartan (DuP753), Losartan potassium, Eprosartan (SK & F108566), Candesartan cilexetil (TCV-116), Valsartan (CGP-48933), Telmisartan (Telmisartan (BIBR277)) Irbesartan (SR47436), Tasosartan (ANA-756), olmesartan medoxomil, and metabolically active substances thereof (such as candesartan and olmesartan) are preferably used.

（式中、Ｒ^１は陰イオンを形成しうる基またはそれに変じうる基を示し、Ｘはフェニレン基とフェニル基が直接または原子鎖２以下のスペーサーを介して結合していることを示し、ｎは１または２の整数を示し、環Ａはさらに置換基を有していてもよいベンゼン環を示し、Ｒ^２は陰イオンを形成しうる基またはそれに変じうる基を示し、Ｒ^３はヘテロ原子を介して結合していてもよく、置換基を有していてもよい炭化水素残基（好ましくは、置換基を有していてもよく、酸素原子を介して結合する炭化水素残基）を示す）で表されるベンズイミダゾール誘導体またはその塩などが好ましく用いられる。
前記式（Ｉ）中、Ｒ^１としての陰イオンを形成しうる基（プロトンとして遊離しうる水素原子を有する基）としては、例えば、（１）カルボキシル基、（２）テトラゾリル基、（３）トリフルオロメタンスルホン酸アミド基（−ＮＨＳＯ_２ＣＦ_３）、（４）リン酸基、（５）スルホン酸基、（６）Ｎ，Ｓ，Ｏのうちの１個または２個以上を含む５〜７員（好ましくは５〜６員）の単環状の置換されていてもよい複素環残基などが挙げられる。 Further, examples of the non-peptidic compound having an angiotensin II antagonistic activity include, for example,
Formula (I):

(Wherein, R ¹ represents a group capable of forming an anion or a group capable of forming an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atom chain of 2 or less; Represents an integer of 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group capable of forming an anion, and R ³ represents a hetero atom. And a hydrocarbon residue which may have a substituent (preferably a hydrocarbon residue which may have a substituent and binds through an oxygen atom). Benzimidazole derivatives or their salts, etc. are preferably used.
In the formula (I), examples of the group capable of forming an anion as R ¹ (a group having a hydrogen atom that can be released as a proton) include (1) a carboxyl group, (2) a tetrazolyl group, and (3) trifluoromethanesulfonic acid amide group _{(-NHSO 2} CF 3), (4) a phosphate group, (5) a sulfonic acid group, (6) 5-7 containing N, S, one or more than two of O And a 5-membered (preferably 5- to 6-membered) monocyclic optionally substituted heterocyclic residue.

などが挙げられ、また、Ｒ^１で表される複素環残基と該複素環残基が結合するフェニル基との結合は、前記式中ｇが−ＮＨ−などを示す場合、前記したような炭素−炭素結合だけでなく、複数個存在する窒素原子の１つを介して結合していてもよい。例えば、Ｒ^１が

前記式中、ｇは−ＣＨ_２−，−ＮＨ−，−Ｏ−または−Ｓ（Ｏ）ｍ−を示し、＞＝Ｚ，＞＝Ｚ’および＞＝Ｚ’’はそれぞれカルボニル基，チオカルボニル基または酸化されていてもよい硫黄原子（例、Ｓ，Ｓ（Ｏ），Ｓ（Ｏ)_２など）（好ましくはカルボニルまたはチオカルボニル基、さらに好ましくはカルボニル基）を示し、ｍは０，１または２の整数を示す。 Examples of the “5 to 7-membered (preferably 5 to 6-membered) monocyclic optionally substituted heterocyclic residue containing one or more of N, S, and O” include, for example, ,

And the bond between the heterocyclic residue represented by R ¹ and the phenyl group to which the heterocyclic residue is bonded is as described above when g represents —NH— or the like. Not only a carbon-carbon bond but also a bond via one of a plurality of nitrogen atoms may be present. For example, if R ¹ is

In the above formula, g is _{-CH 2 -, - NH -,} - O- or -S (O) m- are shown,> = Z,> = Z 'and> = Z''are each a carbonyl group, a thiocarbonyl Represents a group or a sulfur atom which may be oxidized (eg, S, S (O), S (O) ₂ etc.) (preferably a carbonyl or thiocarbonyl group, more preferably a carbonyl group), and m is 0, 1 Or an integer of 2.

〔式中、ｉは−Ｏ−または−Ｓ−を示し、ｊは＞＝Ｏ，＞＝Ｓまたは＞＝Ｓ（Ｏ）mを示し、ｍは前記と同意義を示す〕で表される基（なかでも、２，５−ジヒドロ−５−オキソ−１，２，４−オキサジアゾール−３−イル、２，５−ジヒドロ−５−チオキソ−１，２，４−オキサジアゾール−３−イル、２，５−ジヒドロ−５−オキソ−１，２，４−チアジアゾール−３−イル、とりわけ、２，５−ジヒドロ−５−オキソ−１，２，４−オキサジアゾール−３−イル）が好ましい。 Examples of the heterocyclic residue represented by R ¹ include —NH— and —OH groups as a proton donor such as an oxadiazolone ring, an oxadiazolothione ring or a thiadiazolone ring, and a carbonyl group as a proton acceptor. And a group having a thiocarbonyl group or a sulfinyl group at the same time. Further, the heterocyclic residue represented by R ¹ may form a condensed ring by bonding cyclic substituents. The preferred heterocyclic residue represented by R ^1, 5 or 6-membered ring Further, a 5-membered ring residue is preferable.
The heterocyclic residue represented by R ¹ has the formula:

Wherein i represents -O- or -S-, j represents> = O,> = S or> = S (O) m, and m has the same meaning as described above. (Among them, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-thioxo-1,2,4-oxadiazole-3- Yl, 2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl, especially 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) Is preferred.

のようなａ’，ｂ’およびｃ’の３つの互変異性体が存在するが式：

で示される複素環残基は前記のａ’，ｂ’およびｃ’のすべてを含むものである。 The heterocyclic residue (R ¹ ) has a tautomer as shown below. For example,

There are three tautomers of a ', b' and c 'such as

Is a heterocyclic residue containing all of the aforementioned a ′, b ′ and c ′.

The group capable of forming an anion as R ¹ is, at a substitutable position, an optionally substituted lower (C _1-4 ) alkyl group or an acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl Etc.).
Examples of the optionally substituted lower (C _1-4 ) alkyl group include (1) a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy and the like. A lower (C _1-4 ) alkyl group _optionally substituted with 1 to 3 phenyl groups (eg, methyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, etc.); (C _1-4 ) alkoxy-lower (C _1-4 ) alkyl group (eg, methoxymethyl, ethoxymethyl, etc.), (3) Formula —CH (R ⁴ ) —OCOR ⁵ [wherein R ⁴ is (a Hydrogen), (b) 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 And (c) a linear or branched lower alkenyl group having 2 to 6 carbon atoms or (d) a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.); ⁵ is (a) 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, n- Pentyl, isopentyl, neopentyl, etc.), (b) a linear or branched lower alkenyl group having 2-6 carbon atoms, (c) a cycloalkyl group having 3-8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) ) or an optionally substituted aryl group (e.g., halogen atom, nitro, lower _{(C 1-4)} alkyl, lower _{(C 1-4)} also have an alkoxy A lower alkyl group having 1 to 3 carbon atoms (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.) substituted with a phenyl or naphthyl group, and (d) cycloalkyl having 3 to 8 carbon atoms. Or substituted with an optionally substituted aryl group (eg, a phenyl or naphthyl group optionally having a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc.) A lower alkenyl group having 2 to 3 carbon atoms (eg, one having alkenyl moiety such as vinyl such as cinnamyl, propenyl, allyl, and isopropenyl); (e) an optionally substituted aryl group (eg, phenyl) , P-tolyl, naphthyl and other halogen atoms, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy And a (f) linear 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., (g) a linear or branched lower alkenyloxy group having 2 to 8 carbon atoms (eg, allyloxy) , Isobutenyloxy, etc.), (h) cycloalkyloxy group having 3-8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), (i) cycloalkyl having 3-8 carbon atoms (eg, cyclopentyl, cyclohexyl) , Cycloheptyl, etc.) or an optionally substituted aryl group (eg, a halogen atom, nitro, C 1-3 lower alkoxy group (eg, benzyloxy, phenethyloxy) substituted by a (C _1-4 ) alkyl, a phenyl or naphthyl group which may have a lower (C _1-4 ) alkoxy, etc. Methoxy, ethoxy, n-propoxy, isopropoxy and the like having an alkoxy moiety such as cyclopentylmethoxy and cyclohexylmethoxy), (j) cycloalkyl having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl and the like) Or substituted with an optionally substituted aryl group (eg, a phenyl or naphthyl group optionally having a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc.) C 2-3 lower alkenyloxy group (eg, vinyloxy such as cinnamyloxy, Ropenirokishi, aryloxy, such as those having alkenyloxy part such as isopropenyl b alkoxy) or (k) optionally substituted aryloxy group (e.g., phenoxy, p- nitrophenoxy, halogen atom such as naphthoxy, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy and the like, which may have a phenoxy or naphthoxy group).
The group capable of forming an anion as R ¹ is the above-mentioned optionally substituted lower (C _1-4 ) alkyl group or acyl group (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.) In addition to the protecting groups such as, for example, at the substitutable position, a lower (C _1-4 ) alkyl group which may be substituted (as exemplified as the protecting group of the group capable of forming an anion as R ¹ described above) The same as the “optionally substituted lower (C _1-4 ) alkyl group”), a halogen atom, nitro, cyano, lower (C _1-4 ) alkoxy, one or two lower (C _{1) -4} ) It may have a substituent such as amino which may be substituted with alkyl.

In the above formula, a group capable of forming an anion as R ¹ (a group having a hydrogen atom which can be released as a proton) is converted under a biological or physiological condition (for example, oxidation by an in vivo enzyme or the like). , A group capable of forming an anion by a biological reaction such as reduction or hydrolysis) (so-called prodrug), or a cyano, N-hydroxycarbamimidoyl group (-C (= N—OH) —NH ₂ ) or (1) a carboxyl group, (2) a tetrazolyl group, and (3) each protected with an optionally substituted lower (C _1-4 ) alkyl group or an acyl group. trifluoromethanesulfonic acid amide group _{(-NHSO 2} CF 3), (4) a phosphate group, (5) a sulfonic acid group, (6) 5-7 containing N, S, one or more than two of O Member (good A group (preferably a 5- to 6-membered) monocyclic optionally substituted heterocyclic residue which can be converted to a group capable of forming an anion represented by R ¹ by a chemical reaction ( (A so-called synthetic intermediate).

As R ¹ , an optionally substituted lower (C _1-4 ) alkyl (eg, methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or an acyl group (eg, Carboxyl, tetrazolyl or 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl (preferably, lower (C _2-5 ) alkanoyl, benzoyl, etc.) , Tetrazolyl) or cyano, N-hydroxycarbamimidoyl (preferably cyano), and particularly preferably cyano.

In the above formula, X represents that an adjacent phenylene group and a phenyl group are bonded directly or via a spacer having an atomic chain of 2 or less (preferably a direct bond). Any divalent chain having 1 or 2 atoms constituting the moiety may be used, and may have a side chain. Specifically, lower (C _1-4 ) alkylene having 1 or 2 atoms constituting a straight chain portion, —CO—, —O—, —S—, —NH—, —CO—NH—, — _{O-CH 2 -, - S} -CH 2 -, - CH = CH- , and the like.
In the above formula, n represents an integer of 1 or 2 (preferably 1).

In the formula, ring A represents a benzene ring which may further have a substituent other than a substituent R ^2, examples of the substituent, for example, (1) halogen (e.g., F, Cl, Br, etc.) , (2) cyano, (3) nitro, (4) optionally substituted lower (C _1-4 ) alkyl, (5) lower (C _1-4 ) alkoxy, (6) optionally substituted Amino group (eg, amino, N-lower (C _1-4 ) alkylamino (eg, methylamino, etc.), N, N-di-lower (C _1-4 ) alkylamino (eg, dimethylamino, etc.), N- Arylamino (eg, phenylamino, etc.), alicyclic amino (eg, morpholino, piberidino, piperazino, N-phenylpiperazino, etc.), (7) Formula -CO-D 'wherein D' is hydroxyl or alkyl moiety is a hydroxyl group, a lower _{(C 1-4)} Al Alkoxy, lower _{(C 2-6)} alkanoyloxy (e.g., acetoxy, etc. pivaloyloxy), a lower _{(C 1-6)} alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, etc.) or a lower _{(C 3-6)} A lower (C _1-4 ) alkoxy optionally substituted with cycloalkoxycarbonyloxy (eg, cyclohexyloxycarbonyloxy, etc.), or (8) an optionally substituted lower (C _{1 -4)} alkyl (wherein the R "optionally substituted lower (C _1-4 alkyl groups exemplified as the protecting group of the group capable of forming an anion as _^1)" include those similar to) Or tetra optionally protected by acyl (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.) Examples include zolyl, trifluoromethanesulfonic acid amide group, phosphoric acid group and sulfonic acid group.
These substituents, at substitutable position on the benzene ring one or two may be simultaneously substituted. The preferred substituents having ring A is further than substituent R ^2, which may be substituted lower _{(C 1-4)} alkyl (eg, a hydroxyl group, a carboxyl group, such as optionally substituted lower _{(C 1-4} optionally substituted by halogen) alkyl, etc.), are preferred, such as halogen, rings a other than the substituent ^{R 2} More preferably, it has no substituent.

In the above formula, examples of the group capable of forming an anion as R ² (a group having a hydrogen atom that can be released as a proton) include (1) a carboxyl group which may be esterified or amidated, and (2) ) tetrazolyl group, (3) trifluoromethanesulfonic acid amide group _{(-NHSO 2} CF 3), (4) a phosphate group, (5) and a sulfonic acid group. these groups lower optionally substituted An alkyl group (the same as the “optionally substituted lower (C _1-4 ) alkyl group” exemplified as the protecting group for the group capable of forming an anion as R ¹ ) or acyl Groups (eg, lower (C _2-5 ) alkanoyl, benzoyl, etc.), and may be protected under biological or physiological conditions (eg, oxidation, reduction by in vivo enzymes, etc.). Or an in vivo reaction such as hydrolysis), or any group capable of chemically forming an anion or a group capable of changing to an anion.

Examples of the carboxyl that may be esterified or amidated as R ² include, for example, a compound of the formula —CO—D wherein D is (1) a hydroxyl group, (2) an optionally substituted amino (eg, amino, N-lower (C _1-4 ) alkylamino, N, N-di-lower (C _1-4 ) alkylamino, etc.) or (3) optionally substituted alkoxy {eg, (i) the alkyl moiety is a hydroxyl group, Optionally substituted amino (eg, amino, N-lower (C _1-4 ) alkylamino, N, N-di-lower (C _1-4 ) alkylamino, piperidino, morpholino, etc.), halogen, lower (C _1-6) alkoxy, lower _{(C 1-6)} alkylthio, lower _{(C 3-8)} cycloalkoxy or an optionally substituted Jiokisoreniru (e.g., 5-methyl-2-oxo-1,3-di Kisoren 4-yl, etc.) may be substituted with a lower _{(C 1-6)} alkoxy group, or, (ii) formula ^{-O-CH (R 6) -OCOR} 7 wherein, ^{R 6} is (a) Hydrogen, (b) 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), (c) a linear or branched lower alkenyl group having 2 to 6 carbon atoms or (d) a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), R ⁷ is (a) 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, n -Pentyl (B) a linear or branched lower alkenyl group having 2 to 6 carbon atoms, (c) a cycloalkyl group having 3 to 8 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or Substituted with an optionally substituted aryl group (eg, a phenyl or naphthyl group optionally having a halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc.); A lower alkyl group having 1 to 3 carbon atoms (eg, benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), (d) a cycloalkyl having 3 to 8 carbon atoms or an aryl group which may be substituted (eg, a halogen atom, nitro, lower _{(C 1-4)} alkyl, lower _{(C 1-4)} have an alkoxy A lower alkenyl group having 2 to 3 carbon atoms (e.g., a phenyl or naphthyl group or the like) having a alkenyl moiety such as vinyl, propenyl, allyl, or isopropenyl such as cinnamyl; A phenyl, which may have an optionally substituted aryl group (eg, a halogen atom such as phenyl, p-tolyl, naphthyl, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy); Naphthyl group), (f) a linear 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.), and (g) a linear or branched lower alkenyl having 2 to 8 carbon atoms. Xy group (eg, allyloxy, isobutenyloxy, etc.), (h) cycloalkyloxy group having 3-8 carbon atoms (eg, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), (i) cycloalkyl having 3-8 carbon atoms (Eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (eg, halogen atom, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc. A lower alkoxy group having 1 to 3 carbon atoms substituted with a phenyl or naphthyl group (eg, methoxy such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, ethoxy, n-propoxy, isopropoxy, etc.) ), (J) 3-8 carbon atoms Cycloalkyl Yes (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (e.g., halogen atom, nitro, lower _{(C 1-4)} alkyl, lower _{(C 1-4)} alkoxy, etc. Or a lower alkenyloxy group having 2 to 3 carbon atoms (eg, a alkenyloxy group such as vinyloxy such as cinnamyloxy, propenyloxy, allyloxy, isopropenyloxy) substituted with a phenyl or naphthyl group which may be substituted, or k) having an optionally substituted aryloxy group (eg, a halogen atom such as phenoxy, p-nitrophenoxy, naphthoxy, nitro, lower (C _1-4 ) alkyl, lower (C _1-4 ) alkoxy, etc.) Phenoxy or naphthoxy group, etc.) And the like are shown below].

R ² is preferably carboxyl which may be esterified, and specific examples thereof include, for example, -COOH and salts thereof, -COOMe, -COOEt, -COOTBu, -COOPr, pivaloyloxymethoxycarbonyl, -(Cyclohexyloxycarbonyloxy) ethoxycarbonyl, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethoxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n-butylyloxymethoxycarbonyl, isobutylyloxy Methoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 1- (acetoxy) ethoxycarbonyl, 1- (isobutylyloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoy Under biological or physiological conditions (for example, in vivo reactions such as oxidation / reduction or hydrolysis by in vivo enzymes), such as ruoxymethoxycarbonyl, cinnamyloxycarbonyl, and cyclopentylcarbonyloxymethoxycarbonyl. Or any group capable of chemically forming an anion (eg, COO ⁻ , a derivative thereof, etc.) or a group capable of changing the same, and may be a carboxyl group or a prodrug thereof. .

R ² is a group represented by the formula —CO—D wherein D is (1) a hydroxyl group or (2) an alkyl moiety is a hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy (eg, acetooxy, pivaloyloxy, etc.) ), Lower (C _3-8 ) cycloalkanoyloxy, lower (C _1-6 ) alkoxycarbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, etc.), lower (C _3-8 ) cycloalkoxycarbonyloxy (example) and cyclohexyloxycarbonyloxy), a group represented by lower _{(C 1-4)} an alkoxy or a lower _{(C 3-8)} be substituted with a cycloalkoxy optionally substituted lower _{(C 1-4)} alkoxy] is preferably (preferably methyl or ethyl) Among these lower _{(C 1-4)} alkyl esterified with Carboxyl is preferable.

In the above formula, the “hydrocarbon residue” in the “hydrocarbon residue which may be bonded via a hetero atom and has a substituent” represented by R ³ includes, for example, (1) alkyl Group, (2) alkenyl group, (3) alkynyl group, (4) cycloalkyl group, (5) aryl group, (6) aralkyl group and the like. Among them, alkyl group, alkenyl group and cycloalkyl group are preferred. preferable.
The alkyl group of the above (1) may be a lower alkyl group having about 1 to 8 carbon atoms, which may be linear or branched. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl, hexyl, heptyl, octyl and the like.
The alkenyl group of the above (2) is a lower alkenyl group having about 2 to 8 carbon atoms and may be linear or branched. For example, vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl, 2-butenyl, Octenyl and the like.
The alkynyl group of the above (3) is a lower alkynyl group having about 2 to 8 carbon atoms, which may be linear or branched. For example, ethynyl, 2-propynyl, 2-butynyl, 2-pentynyl, 2-pentynyl, Octynyl and the like.
Examples of the cycloalkyl group (4) include lower cycloalkyl having about 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The above-mentioned alkyl group, alkenyl group, alkynyl group or cycloalkyl group is a hydroxyl group, an amino group which may be substituted (eg, amino, N-lower (C _1-4 ) alkylamino, N, N-di-lower (C _1-4 ) alkylamino), halogen, lower (C _1-4 ) alkoxy group, lower (C _1-4 ) alkylthio group and the like.
Examples of the aralkyl group of (5) include phenyl-lower (C _1-4 ) alkyl such as benzyl and phenethyl, and examples of the aryl group of (6) include phenyl.

The aralkyl group or aryl group described above may be, for example, halogen (eg, F, Cl, Br, etc.), nitro, or an optionally substituted amino group (eg, amino, N-lower) at any position on the benzene ring. (C _1-4 ) alkylamino, N, N-dilower (C _1-4 ) alkylamino, etc., lower (C _1-4 ) alkoxy (eg, methoxy, ethoxy, etc.), lower (C _1-4 ) It may have alkylthio (eg, methylthio, ethylthio, etc.), lower (C _1-4 ) alkyl (eg, methyl, ethyl, etc.) and the like.
Among the above, the “hydrocarbon residue” in the “hydrocarbon residue which may be bonded via a hetero atom and has a substituent” represented by R ³ may be substituted A good alkyl or alkenyl group (eg, a hydroxyl group, an amino group, a lower (C _1-5 ) alkyl or a lower (C _2-5 ) alkenyl group which may be substituted with a halogen or a lower (C _1-4 ) alkoxy group, etc. ) Is preferred, and lower (C _1-5 ) alkyl (more preferably, ethyl) is particularly preferred.
The “hetero atom” in the “hydrocarbon residue which may be bonded via a hetero atom and has a substituent” represented by R ³ includes —O—, —S (O) _m — [ m represents an integer of 0 to 2], -NR '-[R' represents a hydrogen atom or lower (C _1-4 ) alkyl], and -O- is particularly preferred.
Wherein among which also, as ^{R 3} _{is, -O -, - S (O} ) m - [m to 0 not indicating the integer 2 or -NR '- [R' is a hydrogen atom or a lower _{(C 1-4} ) may be bonded via an alkyl, hydroxyl, amino, halogen and lower (C _1-4) which may lower substituted with a substituent selected from alkoxy groups (C _1-5) Alkyl or lower (C _2-5 ) alkenyl groups are preferred, and lower (C _1-5 ) alkyl or lower (C _1-5 ) alkoxy (more preferably ethoxy) is particularly preferred.

（式中、Ｒ^１は（１）カルボキシル基、（２）テトラゾリル基または（３）式：

〔式中、ｉは−Ｏ−または−Ｓ−を示し、ｊは＞＝Ｏ，＞＝Ｓまたは＞＝Ｓ（Ｏ）mを示し、ｍは前記と同意義を示す〕で表される基を示し、環Ａは置換基Ｒ^２以外に置換されていてもよい低級（Ｃ_１−４）アルキル（例、水酸基、カルボキシル基，ハロゲンなどで置換されていてもよい低級（Ｃ_１−４）アルキルなど）またはハロゲンで置換されていてもよいベンゼン環（好ましくは、置換基Ｒ^２以外に置換基を有さないベンゼン環）を示し、Ｒ^２は式−ＣＯ−Ｄ〔式中、Ｄは（１）水酸基または（２）アルキル部分が水酸基、アミノ、ハロゲン、低級（Ｃ_２−６）アルカノイルオキシ（例、アセトオキシ，ピバロイルオキシなど）、低級（Ｃ_３−８）シクロアルカノイルオキシ、低級（Ｃ_１−６）アルコキシカルボニルオキシ（例、メトキシカルボニルオキシ，エトキシカルボニルオキシなど）、低級（Ｃ_３−８）シクロアルコキシカルボニロキシ（例、シクロヘキシルオキシカルボニルオキシなど）、低級（Ｃ_１−４）アルコキシまたは低級（Ｃ_３−８）シクロアルコキシで置換されていてもよい低級（Ｃ_１−４）アルコキシを示す〕で表わされる基を示し、
Ｒ^３は−Ｏ−、−Ｓ（Ｏ）_ｍ−［ｍは０ないし２の整数を示す］または−ＮＲ’−［Ｒ’は水素原子または低級（Ｃ_１−４）アルキルを示す］を介して結合していてもよく、水酸基、アミノ基、ハロゲンおよび低級（Ｃ_１−４）アルコキシ基から選ばれる置換基で置換されていてもよい低級（Ｃ_１−５）アルキルまたは低級（Ｃ_２−５）アルケニル基（好ましくは、低級（Ｃ_１−５）アルキルまたは低級（Ｃ_１−５）アルコキシ；より好ましくは、エトキシ）を示す。〕で表されるベンズイミダゾール−７−カルボン酸誘導体またはその薬理学的に許容されうる塩などが好ましく、とりわけ、２−エトキシ−１−［［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル］ベンズイミダゾール−７−カルボン酸〔Candesartan〕、１−（シクロヘキシルオキシカルボニルオキシ）エチル ２−エトキシ−１−［［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル］ベンズイミダゾール−７−カルボキシラート〔Candesartan cilexetil〕、ピバロイルオキシメチル ２−エトキシ−１−［［２’−（１Ｈ−テトラゾール−５−イル）ビフェニル−４−イル］メチル］ベンズイミダゾール−７−カルボキシラート、２−エトキシ−１−［［２’−（２，５−ジヒドロ−５−オキソ−１，２，４−オキサジアゾール−３−イル）ビフェニル−４−イル］メチル］ベンズイミダゾール−７−カルボン酸またはその塩などが好ましい。
前記したアンギオテンシンII拮抗作用を有する化合物の中でも２−エトキシ−１−［［２’−（２，５−ジヒドロ−５−オキソ−１，２，４−オキサジアゾール−３−イル）ビフェニル−４−イル］メチル］ベンズイミダゾール−７−カルボン酸（以下、化合物Ａと略称する場合がある。）またはその塩が特に好ましい。
前記したベンズイミダゾール誘導体は、例えば、ＥＰ−４２５９２１、ＥＰ−４５９１３６、ＥＰ−５５３８７９、ＥＰ−５７８１２５、ＥＰ−５２０４２３、ＥＰ−６６８２７２などに記載の公知の方法又はそれに準じた方法などにより合成することが可能である。また、Candesartan cilexetil を用いる場合には、ＥＰ−４５９１３６に記載された安定なＣ型結晶を用いるのがよい。 Among the compounds having angiotensin II antagonism represented by the formula (I), a compound represented by the formula (I ′):

(Wherein R ¹ represents (1) a carboxyl group, (2) a tetrazolyl group, or (3) a formula:

Wherein i represents -O- or -S-, j represents> = O,> = S or> = S (O) m, and m has the same meaning as described above. Wherein ring A is a lower (C _1-4 ) alkyl which may be substituted other than the substituent R ² (eg, a lower (C _1-4 ) which may be substituted by a hydroxyl group, a carboxyl group, a halogen, etc. Alkyl or the like, or a benzene ring optionally substituted by halogen (preferably a benzene ring having no substituent other than the substituent R ² ), wherein R ² is a group represented by the formula —CO—D [where D is (1) hydroxyl group or (2) alkyl moiety is hydroxyl group, amino, halogen, lower (C _2-6 ) alkanoyloxy (eg, acetooxy, pivaloyloxy, etc.), lower (C _3-8 ) cycloalkanoyloxy, lower (C _{1) -6)} alkoxycarbonyloxy ( , Methoxycarbonyloxy, such as ethoxycarbonyloxy), lower _{(C 3-8)} cycloalkyl alkoxycarbonyl Niro alkoxy (e.g., such as cyclohexyloxycarbonyloxy), lower _{(C 1-4)} alkoxy or lower _{(C 3-8)} cycloalkyl Represents a lower (C _1-4 ) alkoxy optionally substituted with alkoxy].
R ³ represents —O—, —S (O) _m — [m represents an integer of 0 to 2] or —NR ′ — [R ′ represents a hydrogen atom or lower (C _1-4 ) alkyl]. (C _1-5 ) alkyl or lower (C ₂₋ ) which may be substituted with a substituent selected from a hydroxyl group, an amino group, a halogen and a lower (C _1-4 ) alkoxy group. ₅ ) an alkenyl group (preferably lower (C _1-5 ) alkyl or lower (C _1-5 ) alkoxy; more preferably ethoxy). A benzimidazole-7-carboxylic acid derivative or a pharmacologically acceptable salt thereof, and particularly, 2-ethoxy-1-[[2 ′-(1H-tetrazol-5-yl) biphenyl] -4-yl] methyl] benzimidazole-7-carboxylic acid [Candesartan], 1- (cyclohexyloxycarbonyloxy) ethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4 -Yl] methyl] benzimidazole-7-carboxylate [Candesartan cilexetil], pivaloyloxymethyl 2-ethoxy-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] Benzimidazole-7-carboxylate, 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2 And 4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid or a salt thereof.
Among the aforementioned compounds having angiotensin II antagonistic activity, 2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4] -Yl] methyl] benzimidazole-7-carboxylic acid (hereinafter sometimes abbreviated as compound A) or a salt thereof is particularly preferred.
The above-mentioned benzimidazole derivative can be synthesized by a known method described in, for example, EP-425921, EP-455136, EP-553879, EP-578125, EP-520423, EP-668272, or a method analogous thereto. It is possible. When Candesartan cilexetil is used, it is preferable to use a stable C-type crystal described in EP-59136.

The compound having an angiotensin II antagonistic activity or a prodrug thereof used in the present invention may be itself or a pharmacologically acceptable salt. Such salts include, when the compound having an angiotensin II antagonistic action has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, zinc). , Iron, transition metals such as copper) and organic bases (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, organic amines such as N, N′-dibenzylethylenediamine, Salts with basic amino acids such as arginine, lysine and ornithine).
When the compound having an angiotensin II antagonistic action has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid) , Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), and salts with acidic amino acids such as aspartic acid and glutamic acid. No.

A compound having an angiotensin II antagonistic action used in the present invention [hereinafter, may be referred to as an AII antagonistic compound. A prodrug is a compound which is converted into an AII antagonistic compound by a reaction with an enzyme or stomach acid or the like under physiological conditions in a living body, that is, a compound which is enzymatically oxidized, reduced, hydrolyzed, etc. to be converted to an AII antagonistic compound, It refers to a compound that undergoes hydrolysis or the like by stomach acid or the like to change to an AII antagonist compound. Examples of the prodrug of the AII antagonistic compound include compounds in which the amino group of the AII antagonistic compound is acylated, alkylated, and phosphorylated (eg, the amino group of the AII antagonistic compound is eicosanoylated, alanylated, pentylaminocarbonylated, (5 -Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); AII antagonistic compounds Compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of an AII antagonist is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethyl) Carbonylated compounds, etc.); The carboxyl group of a compound in which a ruboxyl group is esterified or amidated (eg, an AII antagonistic compound) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxy Carbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonyloxyethyl esterification, methylamidated compound, etc.); And the like. These compounds can be produced from AII antagonist compounds by a method known per se.
In addition, prodrugs of AII antagonist compounds can be converted into AII antagonist compounds under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals”, Vol. 7, pages 163 to 198, Molecular Design. You may.
Further, the AII antagonist compound may be any of a hydrate and a non-hydrate.

The PPARγ agonist-like substance used in the present invention may be any substance as long as it is an agonist for PPARγ, and may be any substance that exhibits the same action.
As the PPARγ agonist-like substance, for example, a substance showing a clear PPARγ agonist-like action at a concentration of 10 μM or less in vitro is preferable.
Preferred examples of PPARγ agonist-like agents include troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, PGJ ₂ , GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011 , FK-614 and the like.

  In the present invention, the compound having an angiotensin II antagonistic action and the PPARγ agonist-like substance are not limited to the above examples, and any substance can be used as long as it has such an action. Further, they may further have a PPARα function regulating action (agonist or antagonist action).

  The agent of the present invention may be a combination of a compound having an angiotensin II antagonism and a PPARγ agonist-like substance. As such a preferable combination, for example, the insulin sensitizer having the PPARγ agonistic action ( Examples include troglitazone, rosiglitazone, englitazone, ciglitazone, pioglitazone, etc.) and compound A.

As an insulin sensitizer having a PPARγ agonistic action, for example, troglitazone has been reported on a weight increasing effect in type 2 diabetes patients (Diabetes, 47, suppl. 1, A18, No. 69, 1998). Weight gain in diabetic patients can lead to the development of edema and swelling, which can be a serious problem in treating diabetes as exacerbations can cause serious cardiovascular disease such as cardiac hypertrophy.
Therefore, by using a compound such as Compound A, which itself has both an angiotensin II antagonistic action and an insulin resistance improving property, it is possible to avoid the use of an insulin sensitizer which causes weight gain, or to improve insulin resistance. It is possible to significantly reduce the dosage of the agent itself. When used in combination with an insulin sensitizer, the onset or possibility of weight gain can be significantly reduced as compared with the case where the insulin sensitizer is used alone, and exacerbation of diabetes symptoms can be avoided. So very useful.

The dose of the agent of the present invention may be within the range of the effective amount of each substance.
For example, the dose of a compound having an angiotensin II antagonistic activity when orally administered to an adult diabetic patient (body weight 60 kg) varies depending on the administration subject, administration route, target disease, symptoms, etc., but is usually about once. 0.001 to about 500 mg, preferably about 0.1 to about 100 mg, more preferably about 2.5 to about 60 mg, and it is desirable to administer this amount once to three times a day.
The dose of the PPARγ agonist-like substance to a diabetic patient is about 0.1 to about 600 mg / day, preferably about 0.5 to about 240 mg / day, more preferably about 1.0 to about 100 mg / day. It is about. These amounts may be administered once a day or may be administered in two or three divided doses.
The administration ratio of the compound having an angiotensin II antagonism to the PPARγ agonist-like substance (PPARγ agonist-like substance / compound having angiotensin II antagonism) is about 0.002 to about 60,000, preferably about 0.005 to about 60,000. 2400, more preferably about 0.02 to about 40, even more preferably about 0.4 to about 8.
The weight gain inhibitor of the present invention (hereinafter may be simply referred to as “agent of the present invention”) has low toxicity and is used as it is or by mixing with a pharmacologically acceptable carrier by a method known per se. The pharmaceutical composition is used as a preventive / therapeutic agent for various diseases described below for mammals (eg, human, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.). be able to.

Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations, and solvents in liquid preparations , A solubilizing agent, a suspending agent, an isotonic agent, a buffer, a soothing agent and the like. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.
Preferred examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, Pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate and the like can be mentioned.
Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Preferred examples of the binder include, for example, pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, and hydroxypropylcellulose. Hydroxypropyl methylcellulose, polyvinylpyrrolidone and the like can be mentioned.
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose.
Preferred examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
Preferred examples of the dissolution aid include, for example, polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and acetic acid. Sodium and the like.
Preferred examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
Preferred examples of the tonicity agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate.
Preferred examples of the soothing agent include benzyl alcohol and the like.
Preferable examples of the preservative include, for example, p-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Suitable examples of the antioxidant include, for example, sulfite, ascorbate and the like.
Preferable examples of the colorant include, for example, water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blues 1 and 2), and water-insoluble lakes. Dyes (eg, the aluminum salt of the water-soluble edible tar dye, etc.), natural dyes (eg, β-carotene, chlorophyll, red bengal, etc.) and the like can be mentioned.
Preferable examples of the sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

  Examples of the dosage form of the pharmaceutical composition include oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, suspensions, and sustained-release preparations; , Subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, intravitreal injections, etc.), infusions, external preparations (eg, nasal administration preparations, transdermal preparations, ointments, etc.) Preparations (eg, rectal suppositories, vaginal suppositories, etc.), pellets, drops and the like, and these can be safely orally or parenterally administered, respectively.

The pharmaceutical composition can be produced by a method commonly used in the technical field of formulation, for example, a method described in the Japanese Pharmacopoeia and the like. Hereinafter, a specific method for producing the preparation will be described in detail.
For example, oral preparations include, as active ingredients, excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.), binders (eg, pregelatinized starch, Arabic starch, etc.) Rubber, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added and compression-molded, then, if necessary, taste masking, enteric coating Alternatively, it is produced by coating with a coating base by a method known per se for the purpose of durability.
Examples of the coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained release film coating base.
As the sugar-coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
Examples of the water-soluble film coating base include cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), Rohm Pharma Co., Ltd.], synthetic polymers such as polyvinylpyrrolidone, and polysaccharides such as pullulan.
Examples of the enteric film coating base include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name); Acrylic polymers such as Rohm Pharma Co., Ltd., methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.] and methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co.]; Natural products such as shellac are exemplified.
Examples of the sustained-release film coating base include cellulosic polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS (Eudragit RS (trade name), Rohm Pharma Co., Ltd.); ethyl acrylate / methyl methacrylate copolymer suspension Acrylic polymers such as suspensions (Eudragit NE (trade name), Rohm Pharma Co., Ltd.) and the like.
The above-mentioned coating bases may be used by mixing two or more kinds thereof at an appropriate ratio. Further, at the time of coating, a light-shielding agent such as titanium oxide, iron sesquioxide and the like may be used.
Injectables contain an active ingredient as a dispersant (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), a preservative (eg, methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol, Phenol, etc.), isotonic agents (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.) and aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.) or oily solvents (eg, , Olive oil, sesame oil, cottonseed oil, vegetable oils such as corn oil, propylene glycol and the like). At this time, if necessary, additives such as a solubilizing agent (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used.

  The content of the compound having an angiotensin II antagonistic activity in the pharmaceutical composition is usually about 0.01 to about 99.9% by weight, preferably about 0.1 to about 50% by weight, based on the whole preparation.

As described above, a compound having an angiotensin II antagonistic action, represented by compound A, has an action of suppressing weight gain, and thus can be used as a weight gain inhibitor for mammals. The mammal to be applied may be any animal that wants to avoid weight gain, may be an animal genetically at risk of weight gain, or may have diabetes, hypertension and / or hyperlipidemia. It may be an animal suffering from a lifestyle-related disease. Weight gain may be due to excessive dietary intake or dietary habits lacking nutritional balance, or may be weight gain due to the prophylactic or therapeutic agent for lifestyle-related diseases. The weight gain may be weight gain before obesity or weight gain of an obese patient. Here, obesity means that the BMI (body mass index: body weight (kg) ÷ [height (m)] ² ) is 25 or more (according to the standards of the Japan Obesity Society) in Japanese and 30 or more in Westerners. (According to WHO standards).
The agent of the present invention is preferably used as an agent for suppressing weight gain in obese patients with diabetes. Examples thereof include insulin resistance and impaired glucose tolerance; non-insulin-dependent diabetes mellitus, type II diabetes, and II associated with insulin resistance. Diabetes, such as type II diabetes, type II diabetes with impaired glucose tolerance; hyperinsulinemia; hypertension with insulin resistance, hypertension with impaired glucose tolerance, hypertension with diabetes (eg, type II diabetes, etc.), Hypertension with hyperinsulinemia, insulin resistance associated with hypertension, impaired glucose tolerance as a complication of hypertension, diabetes associated with hypertension, hyperinsulinemia associated with hypertension, diabetic complications [E.g., microangiopathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, Infections (eg, respiratory infections, urinary tract infections, gastrointestinal infections, soft tissue infections, lower limb infections, etc.), diabetic gangrene, xerostomia, decreased hearing, diabetic cerebrovascular disease, Diabetic peripheral circulation disorder, diabetic hypertension, etc.], diabetic cachexia, diabetic nephropathy, and various other complications.

Diseases to which the compound having angiotensin II antagonistic activity as a physiologically active compound is applied include, by the contraction and proliferation of blood vessels expressed through angiotensin II receptor and organ damage, by the presence of angiotensin II, or by the presence of angiotensin II. Factors that are induced when present include diseases that develop or are promoted to develop.
Such diseases include, for example, hypertension, abnormal circadian blood pressure, heart diseases (cardiac hypertrophy, chronic heart failure including acute heart failure and congestion, cardiomyopathy, angina pectoris, myocarditis, arrhythmia, tachycardia, myocardial infarction, etc. ), Cerebrovascular disorder (asymptomatic cerebrovascular disorder, transient ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.), cerebral edema, cerebral circulatory disorder, recurrence of cerebrovascular disorder and Sequelae (neurological symptoms, psychiatric symptoms, subjective symptoms, impaired daily living, etc.), ischemic peripheral circulatory disorders, myocardial ischemia, venous insufficiency, progression of heart failure after myocardial infarction, renal disease (nephritis, glomerulonephritis, glomeruli) Sclerosis, renal failure, thrombotic microangiopathy, dialysis complications, organ damage including nephropathy due to radiation, etc., arteriosclerosis including atherosclerosis (aneurysm, coronary atherosclerosis, cerebral atherosclerosis, peripheral Arteriosclerosis), vascular thickening, in Vascular hypertrophy or occlusion and organ damage after intervention (percutaneous coronary angioplasty, stenting, coronary artery endoscopy, intravascular ultrasound, coronary thrombolysis, etc.), vascular reocclusion / restenosis after bypass surgery, Erythrocytosis, hypertension, organ damage, vascular hypertrophy after transplantation, rejection after transplantation, eye disease (glaucoma, ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, other circulation Organ diseases (deep vein thrombosis, obstructive peripheral circulatory disorders, obstructive atherosclerosis, obstructive thrombotic vasculitis, ischemic cerebral circulatory disorders, Raynaud's disease, Berger's disease, etc.), metabolic and nutritional disorders (obesity, Hyperlipidemia, hypercholesterolemia, hyperuricemia, hyperkalemia, hypernatremia, etc., neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.), During ~ Neurological disorders (disorders such as cerebral hemorrhage and cerebral infarction and their sequelae and complications, head trauma, spinal cord injury, brain edema, sensory dysfunction, sensory dysfunction, autonomic dysfunction, autonomic dysfunction, multiple sclerosis, etc. ), Dementia, memory impairment, consciousness impairment, amnesia, anxiety, tension, discomfort, mental disorders (depression, epilepsy, alcoholism, etc.), inflammatory disorders (rheumatoid arthritis, osteoarthritis, Arthritis such as rheumatic myelitis and periosteitis; inflammation after surgery and trauma; remission of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory bowel disease such as Crohn's disease and ulcerative colitis; Meningitis; Inflammatory eye diseases; Inflammatory lung diseases such as pneumonia, silicosis, pulmonary sarcoidosis, tuberculosis, etc., allergic diseases (allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis, etc.), Chronic obstructive pulmonary disease, interstitial pneumonia, carinii pneumonia, collagen disease (eg, systemic lupus erythematosus, scleroderma, polyarteritis, etc.), liver disease (hepatitis including chronic, cirrhosis, etc.), portal hypertension , Gastrointestinal disorders (gastritis, gastric ulcer, gastric cancer, post-gastric surgery disorders, dyspepsia, esophageal ulcer, pancreatitis, colon polyps, cholelithiasis, hemorrhoids disease, esophageal and gastric varices rupture, etc.), blood and hematopoietic disorders (red blood cells) Hyperplasia, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation, multiple myelosis, etc., bone disease (eg, fracture, refracture, osteoporosis, osteomalacia, bone Petchet disease, stiffness) Destruction of joint tissues in myelitis myelitis, rheumatoid arthritis, knee osteoarthritis and similar diseases, solid tumors, tumors (melanoma, malignant lymphoma, gastrointestinal (eg, gastric, intestinal, etc.) cancers, etc.) , Cancer and associated cachexia, cancer Transfer, endocrine disorders (Addison's disease, Cushing's syndrome, pheochromocytoma, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, urinary and male genital disorders (cystitis, prostatic hyperplasia, prostate cancer, sexually transmitted diseases, etc.), Gynecological disorders (menopause, pregnancy poisoning, endometriosis, uterine fibroids, ovarian disease, mammary gland disease, sexually transmitted diseases, etc.), diseases caused by environmental and occupational factors (radiation damage, damage caused by ultraviolet rays, infrared rays, laser beams, Takayama Disease), respiratory diseases (cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis / pulmonary embolism, etc.), infectious diseases (cytomegalovirus, influenza virus, herpes virus, etc., viral infections, rickettsial infections, bacteria) Infectious diseases, etc., Toxemia (sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxin shock syndrome, etc.) , Otolaryngology disease (Mennell syndrome, tinnitus, taste disorder, dizziness, balance disorder, dysphagia, etc.), skin disease (keloid, hemangioma, psoriasis, etc.), dialysis hypotension, myasthenia gravis, chronic fatigue syndrome, etc. Diseases.

In addition, by suppressing the action of angiotensin II in the long term, it improves or suppresses the impairment or abnormality of biological functions and physiological functions that cause various diseases associated with adult diseases and aging, resulting from these Primary and secondary prevention or progression of a disease or condition can be suppressed. Such disorders or abnormalities in biological functions and physiological actions include, for example, disorders or abnormalities in the ability to automatically regulate cerebral circulation and renal circulation, circulatory disorders (peripheral, brain, microcirculation, etc.), disorders in the blood-brain barrier, salt sensitivity , Coagulation / fibrinolytic abnormalities, abnormal properties of blood and blood cell components (increased platelet aggregation, abnormal red blood cell deformability, increased white blood cell adhesion, increased blood viscosity, etc.), growth factors and cytokines (PDGF, VEGF, FGF, Interleukin, TNF-α, MCP-1 etc.) production and action, inflammatory cell production and invasion, free radical production, fat deposition, endothelial dysfunction, endothelium, cell and organ damage, edema, Morphological changes of cells such as smooth muscle (form change to such proliferating), production and hyperactivity vasoactive substance and thrombosis inducers (endothelin, such as thromboxane a _2), abnormalities such as vascular yield Abnormalities such as constriction, abnormal metabolism (abnormal serum lipids, abnormal blood glucose, etc.), abnormal proliferation of cells, angiogenesis (including abnormal angiogenesis in abnormal capillary network formation of atherosclerotic lesion outer membrane), etc. Above all, primary and secondary prevention of organ disorders associated with various diseases (eg, cerebrovascular disorders and associated organ disorders, organ disorders associated with cardiovascular diseases, organ disorders associated with diabetes, organ disorders following intervention, etc.) -It can be used as a therapeutic agent. Therefore, the agent of the present invention can also be advantageously used when a patient whose weight gain is to be suppressed has the above-mentioned disease.

In the present invention, when a compound having an angiotensin II antagonistic action is used in combination with a PPARγ agonist-like substance, it may be administered in the form of separate preparations or in the form of a single preparation as a mixture. There may be. When used in combination as separate preparations, the administration timing of each preparation is not limited, and these preparations may be simultaneously administered to the administration subject, or may be administered with a time lag. The dosage form of each preparation may be different, and as each dosage form, a dosage form usually used as a medicine is appropriately selected for each active ingredient.
When the PPARγ agonist-like substance used in combination is prepared as a separate preparation from the compound having an angiotensin II antagonistic action, the agent containing the PPARγ agonist-like substance contains a pharmacologically acceptable carrier. May be. As such a carrier, various organic or inorganic carrier substances commonly used as formulation materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents, dissolution aids, suspensions in liquid preparations It is blended as an agent, isotonic agent, buffer, soothing agent and the like. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used.
Examples of the carrier or compounding agent include the same as those described above.
The content of the PPARγ agonist-like substance in the pharmaceutical composition containing the PPARγ agonist-like substance is usually about 0.01 to about 99.9% by weight, preferably about 0.1 to about 9% by weight based on the whole preparation. 50% by weight.

The agent of the present invention is effective for suppressing weight gain observed in patients with various diseases (eg, diabetes, etc.) while taking a PPARγ agonist-like substance (eg, insulin sensitizer), and angiotensin II It is useful for the treatment / prevention of diseases related to (eg, the above-mentioned hypertension, etc.).
The agent of the present invention can suppress the increase in body weight derived from a PPARγ agonist-like substance observed in patients taking a PPARγ agonist-like substance (eg, a diabetic patient) to, for example, about 80% or less.
Diseases to which the PPARγ agonist-like substance is applied include, for example, diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, Postprandial hyperlipidemia, etc.), diabetic complications (eg, neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, etc.), impaired glucose tolerance (IGT), obesity, osteoporosis, cachexia (Eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine cachexia, cachexia due to infectious cachexia or acquired immunodeficiency syndrome), fatty liver, Hypertension, polycystic ovary syndrome, gestational diabetes, renal disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive renal sclerosis, end stage renal disease, etc.), muscular dystrophy, myocardial infarction, narrow Heart disease, cerebrovascular disease (Eg, cerebral infarction, stroke), insulin resistance syndrome, syndrome X, hyperinsulinemia, impaired perception in hyperinsulinemia, tumor (eg, leukemia, breast cancer, prostate cancer, skin cancer, etc.), irritable bowel syndrome , Acute or chronic diarrhea, visceral obesity syndrome and the like. Further, it can be used in the treatment for the purpose of improving insulin resistance, enhancing insulin sensitivity, and suppressing transition from glucose intolerance to diabetes. Further, the agent of the present invention can be used to regulate appetite and food intake in patients undergoing treatment for diabetes.

Regarding the criterion of diabetes, a new criterion was reported by the Japanese Diabetes Association in 1999.
According to this report, diabetes is defined as a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more and a 75 g oral glucose tolerance test (75 g OGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or more. And the blood sugar level (glucose concentration in venous plasma) at any time is 200 mg / dl or more. In addition, it did not correspond to the above-mentioned diabetes, and the fasting blood glucose level (glucose concentration in venous plasma) was less than 110 mg / dl, or the 2-hour value (glucose concentration in venous plasma) of 75 g oral glucose tolerance test (75 g OGTT) was 140 mg / dl. A state that is not “a state indicating less than dl” (normal type) is called a “boundary type”.

In addition, new criteria for diabetes are reported by ADA (American Diabetes Association) in 1997 and by WHO in 1998.
According to these reports, diabetes is defined as a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more and a 2-hour 75 g oral glucose tolerance test (glucose concentration in venous plasma) of 200 mg / dl. dl or more.
According to the above report, impaired glucose tolerance refers to a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl and a 2-hour value of 75 g oral glucose tolerance test (glucose concentration in venous plasma). Is 140 mg / dl or more and less than 200 mg / dl. Further, according to the report of ADA, a state in which the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, of the IFG (Impaired Fasting Glucose), a state in which the 75-hour oral glucose tolerance test 2-hour value (glucose concentration in venous plasma) is less than 140 mg / dl is referred to as IFG (Impaired Fasting Glycemia). Call.
The PPARγ agonist-like substance is also used as a preventive / therapeutic agent for diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, the agent of the present invention can also prevent progression from borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) to diabetes.

  Further, the agent of the present invention includes a drug such as a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antihypertensive agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent (hereinafter abbreviated as a concomitant drug). ) Can be used in combination. Further, the agent of the present invention itself may contain these concomitant drugs. In the present specification, unless otherwise specified, the term “combination” may be either a form in which separate drugs are administered or a form in which a single drug is combined. When used in combination as separate drugs, the administration time of the agent of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at an interval. Further, two or more concomitant drugs may be used in combination at an appropriate ratio.

  The dose of the concomitant drug can be appropriately selected based on the clinically used dose of each drug. The mixing ratio of the agent of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, and the like.

Examples of the therapeutic agent for diabetes include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast), α-glucosidase inhibitors ( Eg, voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (eg, phenformin, metformin, buformin, etc.), insulin secretagogues [eg, sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, Acetohexamide, glyclopyramide, glimepiride, glibizide, glybuzole, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium salt hydrate, GLP-1, etc.), amylin agonist (eg, plum Nchido etc.), phosphotyrosine phosphatase inhibitors (examples include vanadic acid, etc.) and the like.
Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-112, etc.), neurotrophic factors (eg, NGF , NT-3, BDNF, etc.), neurotrophic factor production promoter, PKC inhibitor (eg, LY-333531, etc.), AGE inhibitor (eg, ALT946, pimagedine, pyratoxatin, N-phenacylthiazolium bromide (ALT766) ), EXO-226, etc.), active oxygen scavengers (eg, thioctic acid, etc.), cerebral vasodilators (eg, tiapride, mexiletine, etc.).
Examples of anti-hyperlipidemic agents include statin compounds which are cholesterol synthesis inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, itavastatin or salts thereof (eg, sodium salt)), and squalene synthesis. Examples include an enzyme inhibitor or a fibrate compound having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate, etc.).
Antihypertensives include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, losartan, candesartan cilexetil, eprosartan, valsantan, telmisartan, irbesartan, tasosartan, olmesartan, etc.), calcium antagonist Agents (eg, manidipine, nifedipine, amronidipine, efonidipine, nicardipine, etc.) and the like.

Examples of the antiobesity agent include central antiobesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzolex), pancreatic lipase inhibition Drugs (eg, orlistat etc.), β3 agonists (eg, CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-19685, AZ40140, etc.), peptide appetite suppressants (Eg, leptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lynch tryp, FPL-15849, etc.) and the like.
As diuretics, for example, xanthine derivatives (eg, sodium theobromine salicylate, calcium theobromine salicylate, etc.), thiazide-based preparations (eg, ethiazide, cyclopentiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide) , Methyclothiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide , Ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, adriamycin, etc.), Examples include plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etopoxide and the like. Among them, a 5-fluorouracil derivative such as furturon or neofurturon is preferred.
Examples of the immunotherapeutic agent include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), cytokines obtained by genetic engineering techniques ( Examples include interferon, interleukin (IL), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin, etc.), and among them, IL-1, IL-2, IL-12 and the like are preferable.

  Furthermore, drugs that have been shown to improve cachexia in animal models and clinically, namely cyclooxygenase inhibitors (eg, indomethacin, etc.) [Cancer Research, 49, 5935-5939, 1989] ], Progesterone derivatives (eg, megesterol acetate) [Journal of Clinical Oncology, Vol. 12, 213-225, 1994], carbohydrate steroids (eg, dexamethasone, etc.), metoclopramide Drugs, tetrahydrocannabinol drugs (the literature is the same as above), fat metabolism improvers (eg, eicosapentaenoic acid, etc.) [British Journal of Cancer, Vol. 68, 314] 318, 1993], growth hormone, IG -1, or TNF-alpha is a factor which induce cachexia, LIF, IL-6, or oncostatin M, can also be used in combination with the present invention a pharmaceutical.

Preferred examples of the concomitant drug include the following.
1) insulin preparation 2) biguanide;
3) an insulin secretagogue such as a sulfonylurea agent;
4) biguanides;
5) α-glucosidase inhibitors;
6) insulin preparations and biguanides;
7) insulin preparations and α-glucosidase inhibitors;
8) insulin secretagogues such as sulfonylurea agents and biguanides;
9) an insulin secretagogue such as a sulfonylurea agent and an α-glucosidase inhibitor;
10) biguanides and α-glucosidase inhibitors;
11) an insulin sensitizer (eg, an agent for a PPARγ agonist);
12) a combination of the insulin sensitizer and the agent described in 1) to 10) above;
13) hypoglycemic agents and other diabetic complication treating agents;
14) other above agents and combinations of two or more thereof;
When the agent of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range considering the adverse effects of those agents. In particular, an insulin preparation, an insulin secretagogue such as a sulfonylurea agent, and a biguanide can be reduced from the usual dose. Therefore, side effects that may be caused by these agents can be safely prevented. In addition, the dosage of diabetic complications, antihyperlipidemics and antihypertensives can be reduced, so that the side effects that may be caused by these agents can be effectively prevented.

  The agent of the present invention has an excellent effect of suppressing weight gain. For example, it has been reported that administration of a PPARγ agonist-like substance effective for the treatment of diabetes and other diseases progresses the cure of the target disease but increases the weight of the patient. The agent can suppress weight gain of such patients.

Hereinafter, the present invention will be described in more detail with reference to Test Examples and Examples, but the present invention is not limited thereto.
The components (additives) other than the active ingredient in the formulations described in the examples may be those listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Pharmaceuticals or the Pharmaceutical Excipients Standard.

Test example 1
2-ethoxy-1-[[2 ′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxy Effect of acid (compound A) on weight gain in obese mice
1) Experimental method
Male KKA ^y mice (10 weeks old) were used as obese mice. After measuring the body weight and performing grouping, feeding of a CE-2 powder feed (control) (n = 7) and a 0.005% compound A mixed feed (n = 7) was started. After 4 days of feeding, body weight was measured to calculate the amount of weight gain. In addition, C57BL mice were used as normal controls, and CE-2 powder diet was fed for 4 days to examine whether male KKA ^y mice of the same age were obese.
The results are shown as the mean ± standard error. Student's t test was used for analysis of significance.
2) Results
The body weights of 10-week-old KKA ^y mice and C57BL mice were 41.4 ± 0.7 g and 22.9 ± 0.8 g, respectively, indicating that the weight of KKA ^y mice was significantly (p <0.01) heavier. Therefore, it was shown that KKA ^y mice at this age were obese. In the KKA ^y mice, body weight gain during the experimental period was 1.2 ± 0.2 g and 0.1 ± 0.4 g in the control group and the compound A group (approximately 6.5 mg / kg / day), respectively, and significantly increased in the compound A group. Was suppressed (p <0.05).

Test example 2
Effect of Compound A on PPARγ agonist-like substance (pioglitazone) -induced weight gain
1) Experimental method Male Wistar fatty rats (16 weeks old) were used as obese rats. After measuring the body weight and performing grouping, the drug solution suspended in a 0.5% methylcellulose solution was repeatedly orally administered once a day for 7 days repeatedly, and the body weight was measured 24 hours after the final administration. Weight gain was calculated. The results are shown as the mean ± standard error. Student's t test was used for analysis of significance.
2) Results
While the increase in body weight of the Control group is 24.4 ± 2.4 g, the increase in the PPARγ agonist-like substance administration group (pioglitazone hydrochloride: 0.5 mg / kg / day, po) is 30.8 ± 1.8 g, There was a tendency to increase (p <0.05). The weight gain of rats administered with PPARγ agonist-like substance (0.5 mg / kg / day, po) and Compound A (1 mg / kg / day, po) was 19.3 ± 2.5 g, and PPARγ agonist-like substance alone was administered. There was a significant decrease compared to the group (p <0.05).

Example 1 Capsule (1) Compound A 5 mg
(2) Lactose 115mg
(3) Microcrystalline cellulose 70mg
(4) Magnesium stearate 10mg
200mg per capsule
After mixing (1), (2) and 1/2 of (3) and (4), granulate. The remaining (4) is added thereto, and the whole is encapsulated in a gelatin capsule.

Example 2 Tablet (1) Compound A 10 mg
(2) Lactose 55mg
(3) Corn starch 150mg
(4) Microcrystalline cellulose 30mg
(5) Magnesium stearate 5mg
250mg / tablet
After mixing 2/3 of (1), (2), (3) and (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.

Example 3 Capsule (1) Compound A 5 mg
(2) Pioglitazone hydrochloride 30mg
(3) Lactose 85mg
(4) 70 mg of microcrystalline cellulose
(5) Magnesium stearate 10mg
200mg per capsule
After mixing (1), (2), (3) with 1/2 of (4) and (5), granulate. The remaining (5) is added thereto, and the whole is encapsulated in a gelatin capsule.

Example 4 Tablet (1) Compound A 10 mg
(2) Pioglitazone hydrochloride 30mg
(3) Lactose 35mg
(4) corn starch 150mg
(5) Microcrystalline cellulose 30mg
(6) Magnesium stearate 5mg
250mg / tablet
After mixing 2/3 of (1), (2), (3), (4), (5) and 1/2 of (6), granulate. The remaining (5) and (6) are added to the granules and pressed into tablets.

Example 5 Capsule (1) Candesartan cilexetil 5 mg
(2) Pioglitazone hydrochloride 30mg
(3) Lactose 90mg
(4) 70 mg of microcrystalline cellulose
(5) Magnesium stearate 10mg
200mg per capsule
After mixing (1), (2), (3) with 1/2 of (4) and (5), granulate. The remaining (5) is added thereto, and the whole is encapsulated in a gelatin capsule.

Example 6 Tablet (1) Candesartan cilexetil 10 mg
(2) Pioglitazone hydrochloride 30mg
(3) Lactose 35mg
(4) corn starch 150mg
(5) Microcrystalline cellulose 30mg
(6) Magnesium stearate 5mg
250mg / tablet
After mixing 2/3 of (1), (2), (3), (4), (5) and 1/2 of (6), granulate. The remaining (5) and (6) are added to the granules and pressed into tablets.

The agent of the present invention has an excellent effect of suppressing weight gain. For example, it has been reported that administration of a PPARγ agonist-like substance effective for the treatment of diabetes and other diseases progresses the cure of the target disease but increases the weight of the patient. The agent can suppress weight gain of such patients.

Claims (15)

An agent for suppressing weight gain, comprising a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof. The agent according to claim 1, wherein the weight gain is a weight gain before obesity. The agent according to claim 1, wherein the weight gain is weight gain of an obese patient. The agent according to claim 3, wherein the obesity is obesity accompanied by diabetes. The agent according to claim 4, further comprising a PPARγ agonist-like substance. The agent according to claim 1, wherein the weight gain is a weight gain derived from a PPARγ agonist-like substance. The agent according to claim 6, wherein the body weight gain derived from the PPARγ agonist-like substance is suppressed to about 80% or less. The agent according to claim 1, wherein the compound having an angiotensin II antagonistic action is a non-peptidic compound. The agent according to claim 1, wherein the compound having an angiotensin II antagonistic activity is a compound having an oxygen atom in the molecule. The agent according to claim 1, wherein the compound having an angiotensin II antagonistic activity is a compound having an ether bond or a carbonyl group in the molecule. The compound having an angiotensin II antagonistic activity is represented by the formula (I)

(Wherein, R ¹ represents a group capable of forming an anion or a group capable of changing to an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atom chain of 2 or less; Represents 1 or 2, ring A represents a benzene ring which may further have a substituent, R ² represents a group capable of forming an anion or a group convertible thereto, and R ³ represents a hetero atom. The compound according to claim 1, which is a compound which may be bonded to a hydrocarbon residue and may have a substituent. A compound having an angiotensin II antagonistic action is 2-ethoxy-1-[[2 ′-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] The agent according to claim 1, which is methyl] -1H-benzimidazole-7-carboxylic acid. The agent according to claim 1, wherein the compound having an angiotensin II antagonistic activity or a salt thereof is losartan, losartan potassium, eprosartan, candesartan cilexetil, candesartan, valsartan, telmisartan, irbesartan, olmesartan, olmesartan medoxomil, or tasosartan. A method for suppressing weight gain in a mammal, comprising administering to the mammal an effective amount of a compound having an angiotensin II antagonistic activity, a prodrug thereof, or a salt thereof. Use of a compound having an angiotensin II antagonistic activity, a prodrug thereof or a salt thereof for the manufacture of a weight gain inhibitor.