JPWO2006001471A1 - Pharmaceutical composition for promoting glucose-responsive insulin secretion - Google Patents

Abstract

A composition comprising a compound represented by formula (I): or a salt thereof, or a physiologically hydrolyzable and acceptable ester thereof.

Description

  The present invention relates to a glucose-responsive insulin secretagogue.

  Glucose is a central substance of energy homeostasis in the living body, and insulin secretion for regulating glucose concentration plays an extremely important role in energy management of the living body. In regulating the blood glucose concentration, promoting insulin secretion in response to an increase in glucose concentration, that is, glucose-responsive insulin secretion plays an important role. When this regulatory function is impaired and insulin secretion increases, various disorders due to hypoglycemia develop. In addition, when glucose-responsive insulin secretion fails and the ability to secrete insulin in response to blood glucose concentration decreases, blood glucose concentration increases and is an important cause of metabolic diseases such as diabetes, obesity, and lipid metabolism disorders It has become.

  The main organ that secretes insulin is the pancreas, and the secretion of insulin in that organ is well-regulated under the control of Wnt signal by low-density lipoprotein receptor-related proteins, etc. However, the involvement of other factors in the insulin secretion regulatory mechanism is unclear. Hedgehog is a protein factor that plays an important role in regulating cell differentiation and morphogenesis, and its inhibitors are effective in treating epithelial cell hyperplasia, tissue fibrosis, inflammation, cancer or immune disorders Has been devised (Patent Document 1). Furthermore, it is known to play an important role in the differentiation of Langerhans islet beta cells that are responsible for insulin secretion in the pancreas (Non-patent Document 2, Non-patent Document 3, and Patent Document 2). However, the function of hedgehog in differentiated and mature cells has not yet been elucidated.

  On the other hand, since it was reported that cyclopamine is a hedgehog signal inhibitor (hereinafter also referred to as “hedgehog inhibitor” for short), research on hedgehog signals using cyclopamine has been promoted (non-patent literature). 4). The effect on insulin secretion has been examined by treating INS-1 cells, which are cell lines, with cyclopamine, and it has been reported that cyclopamine suppresses insulin secretion (Non-patent Document 2). However, unlike studies using primary cell cultures, studies using cell lines contain changes in cell function due to cell culture as artifacts, making it difficult to study physiological cell responses. It seems to be accompanied. Furthermore, in the above report, direct insulin secretion by cyclopamine treatment has been examined from various aspects, but glucose-responsive insulin secretion, which has physiological significance, has not been studied. Therefore, it was considered impossible to estimate the effect of hedgehog inhibitors on physiological insulin secretion.

Prior art document information related to the invention of the present application is shown below.
WO00074706 WO03050249 WO0126644A Fujino, T., H. Asaba, et al. (2003). "Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion." Proc Natl Acad Sci USA 100 ( 1): 229-34. Thomas, MK, N. Rastalsky, et al. (2000). "Hedgehog signaling regulation of insulin production by pancreatic beta-cells." Diabetes 49 (12): 2039-47. Kawahira, H., NH Ma, et al. (2003). "Combined activities of hedgehog signaling inhibitors regulate pancreas development." Development 130 (20): 4871-9. Incardona, JP, W. Gaffield, et al. (2000). "Cyclopamine inhibition of Sonic hedgehog signal transduction is not mediated through effects on cholesterol transport." Dev Biol 224 (2): 440-52.

  An object of the present invention is to provide a pharmaceutical composition for improving glucose-responsive insulin secretion.

  As a result of intensive studies to solve the above problems, the present inventors have found that a specific hedgehog signal inhibitor promotes glucose-responsive insulin secretion.

  In the present invention, using the primary culture of pancreatic islets of Langerhans prepared with great care to reflect physiological functions from mice, the glucose responsiveness of Compound 1 of the present invention (cyclopamine known as a hedgehog inhibitor) is used. As a result of examining insulin secretion, it was found that the compound 1 of the present invention promotes direct insulin secretion, contrary to previous reports (Thomas, Rastalsky et al. 2000). Furthermore, the action was found to be more potent in glucose-responsive insulin secretion. In order to further verify that the hedgehog inhibitor promotes glucose-responsive insulin secretion, the inventors of the present invention compound 2, which is an androgen derivative (Non-patent Document 4) that is assumed to have a hedgehog inhibitory action, As a result of studies using 3 and 4, it was found that glucose-responsive insulin secretion was promoted in these compounds, and the present invention was completed.

  That is, according to one aspect of the present invention, it relates to a method of promoting glucose-responsive insulin secretion, comprising administering a hedgehog inhibitor to a mammalian cell or animal.

  Another aspect of the present invention relates to a pharmaceutical composition for preventing / treating a disease requiring promotion of glucose-responsive insulin secretion, comprising a hedgehog signal inhibitor as an active ingredient.

3 is a graph showing glucose-responsive insulin secretion from the islets of Langerhans in Test Example 1. FIG. As a result of overnight culture of pancreatic islets of Langerhans prepared from normal mice together with 20 μM of the compound 1 of the present invention, insulin secretion from pancreatic beta cells upon stimulation with high glucose increased. The vertical axis represents the amount of insulin secretion as an average value ± standard error (N = 6). The white bar graph represents the vehicle (ethanol) treatment group, and the black bar graph represents the compound treatment group. The graph which showed glucose-responsive insulin secretion from the islets of Langerhans in Test Example 2. As a result of overnight culture of pancreatic islets of Langerhans prepared from normal mice with 30 μM of the compound 2 of the present invention, insulin secretion from pancreatic beta cells upon stimulation with high glucose increased. The vertical axis represents the amount of insulin secretion as an average value ± standard error (N = 6). The white bar graph represents the vehicle (DMSO) treatment group, and the black bar graph represents the compound treatment group. The graph which showed glucose-responsive insulin secretion from the islets of Langerhans in Test Example 3. As a result of overnight culture of pancreatic islets of Langerhans prepared from normal mice with 10 μM of the compound 3 of the present invention, insulin secretion from pancreatic beta cells upon stimulation with high glucose increased. The vertical axis represents the amount of insulin secretion as an average value ± standard error (N = 6). The white bar graph represents the vehicle (DMSO) treatment group, and the black bar graph represents the compound treatment group. The graph which showed glucose-responsive insulin secretion from the islets of Langerhans in Test Example 4. As a result of overnight culture of pancreatic islets of Langerhans prepared from normal mice with 30 μM of the compound 4 of the present invention, insulin secretion from pancreatic beta cells upon stimulation with high glucose increased. The vertical axis represents the amount of insulin secretion as an average value ± standard error (N = 6). The white bar graph represents the vehicle (DMSO) treatment group, and the black bar graph represents the compound treatment group. 6 is a graph showing glucose-responsive insulin secretion from the islets of Langerhans in Test Example 5. FIG. As a result of overnight culture of pancreatic islets of Langerhans prepared from normal mice with 1-30 μM compound 5 of the present invention, insulin secretion from pancreatic beta cells during high glucose stimulation increased in a concentration-dependent manner, and the increase was low. It was more than twice the glucose stimulation. The vertical axis represents the amount of insulin secretion as an average value ± standard error (N = 6). 0 on the horizontal axis represents a vehicle (DMSO) -treated group, and 1-30 represents a compound-treated group having the indicated concentration (μM).

  As described above, in one aspect, the present invention relates to a pharmaceutical composition for preventing / treating a disease requiring promotion of glucose-responsive insulin secretion, which comprises a hedgehog inhibitor as an active ingredient, and in another aspect, hedgehog The present invention relates to a method of promoting glucose-responsive insulin secretion by administering an inhibitor to a mammalian cell or animal.

[式（I）中 R1は水素原子、置換基を有してもよい低級アルキル基（C1-C5）、置換基を有してもよい低級アルコキシ基（C1-C5）、R9CO、sugar-O-。
ここでR9は、水素原子、置換基を有してもよい低級アルキル基（C1-C5）、置換基を有してもよい低級アルコキシ基（C1-C5）、R10(R11)N-である。
ここで、R10、R11はそれぞれ、水素原子、低級アルキル基（C1-C5）であり、
R2は水素原子、もしくは、R1が置換基を有してもよい低級アルキル基（C1-C5）の場合は置換基を有してもよい低級アルコキシ基（C1-C5）であり、
R1とR2は一緒になって、低級アルキレン基（C1-C5）、＝O、＝N-OR12でもよい。
ここでR12は、置換基を有してもよい低級アルキル基（C1-C5）であり、
R3、R4、R7はそれぞれ、水素原子、水酸基、ハロゲン原子、置換基を有してもよい低級アルキル基（C1-C5）であり、
R3とR4は結合を形成してもよい。
R7が水素原子の場合にのみ点線は結合を表しうる（すなわち、二重となる）。
R5は水素原子、置換基を有してもよい低級アルキル基（C1-C5）、置換基を有してもよい低級アルコキシ基（C1-C5）、R13CO、sugar-O-である。
ここでR9は、水素原子、置換基を有してもよい低級アルキル基（C1-C5）、置換基を有してもよい低級アルコキシ基（C1-C5）、R14(R15)N-である。
ここで、R14、R15はそれぞれ、水素原子、低級アルキル基（C1-C5）であり、
R6は水素原子、もしくは、R5が置換基を有してもよい低級アルキル基（C1-C5）の場合は置換基を有してもよい低級アルコキシ基（C1-C5）である。
R5とR6は一緒になって、低級アルキレン基（C1-C5）、＝O、＝N-OR16でもよい。
ここでR16は、置換基を有してもよい低級アルキル基（C1-C5）を示す。
R8は水素原子、置換基を有してもよい低級アルキル基（C1-C5）、置換基を有してもよい低級アルコキシ基（C1-C5）、R16COであり、
ここでR16は、水素原子、置換基を有してもよい低級アルキル基（C1-C5）、置換基を有してもよい低級アルコキシ基（C1-C5）、R17(R18)N-であり、ここで、R17、R18はそれぞれ、水素原子、低級アルキル基（C1-C5）である。
以上の中で置換基とは、水酸基、ハロゲン原子、カルボキシル基、R19(R20)N-、などを指す。
ここで、R19、R20はそれぞれ、水素原子、低級アルキル基（C1-C5）（Ra, Rb）及び（Rc, Rd）：H、OH、置換基を有していてもよい低級アルキル基 (C1〜C5)、置換低級アルコキシ基（例えば-O(CH2)nNRa1Ra2、n=1〜5ここで、R17、R18はそれぞれ、水素原子、低級アルキル基（C1-C5）である。
以上の中で置換基とは、水酸基、ハロゲン原子、カルボキシル基、R19(R20)N-、などを指す。
ここで、R19、R20はそれぞれ、水素原子、低級アルキル基（C1-C5）である。］

［式（II）中（Ra, Rb）及び（Rc, Rd）はH、OH、置換基を有していてもよい低級アルキル基 (C1〜C5)、置換低級アルコキシ基（例えば-O(CH2)nNRa1Ra2、n=1〜5, Ra1, Ra2は低級アルキル（C1〜C5）、Sugar-O-であり、または（Ra, Rb）及び（Rc, Rd）は一緒になって低級アルキレン（C1〜C5）、＝O, ＝N−ORa3, Ra3は水素、あるいは低級アルキル基（C1〜C5）である。］

［上記式（III）において、Rxは置換基を有していてもよい低級アルキル（C1〜C5）,ｎは０〜２０である。］

[式（IV）中 Reは水素原子、低級アルキル基（C1―C5）、シクロアルキル基（C3―C5）、−（CH2）m-アリール基、−（CH2）m-へテロアリール基であり、
Rfは水素原子、低級アルキル基（C1―C5）、−（CH2）m-アリル基、−（CH2）m-へテロアリル基であり、
Rｈは低級アルキル基（C1―C5）、ハロゲン、−NH2、−NO2、−OH、−CN、―CF3であり、
Lは−（CH2）m、低級アルケニル基（C1―C5）、低級アルキニル基（C1―C5）、−NRｇ（CH2）m-であり、
Xは−CH−、−Ｎ−、単結合であり、
Yは−CH2−、−Ｎ（Rg）−、単結合であり、
Rgは水素原子、低級アルキル基（C1―C5）、シクロアルキル基（C4−C8）であり、
ｍは０から５の整数である。]The hedgehog inhibitor that can be used to promote insulin secretion is not particularly limited as long as it has hedgehog signal inhibitory activity, and it is an antisense that can inhibit synthesis of a low-molecular compound having hedgehog inhibitory activity, hedgehog protein. Examples include nucleic acids such as nucleic acids, polypeptides such as antibodies that can inhibit the activity of hedgehog signal protein, and the like. As a low molecular weight compound having hedgehog inhibitory activity, the compound represented by the following general formulas (I) to (IV) or a salt thereof, or physiologically hydrolyzable and acceptable The ester etc. can be mentioned.

[In the formula (I), R1 represents a hydrogen atom, a lower alkyl group (C1-C5) which may have a substituent, a lower alkoxy group (C1-C5) which may have a substituent, R9CO, sugar-O -.
Here, R9 is a hydrogen atom, a lower alkyl group (C1-C5) which may have a substituent, a lower alkoxy group (C1-C5) which may have a substituent, or R10 (R11) N-. .
Here, R10 and R11 are a hydrogen atom and a lower alkyl group (C1-C5), respectively.
R2 is a hydrogen atom or a lower alkoxy group (C1-C5) which may have a substituent when R1 is a lower alkyl group (C1-C5) which may have a substituent;
R1 and R2 together may be a lower alkylene group (C1-C5), ═O, ═N—OR12.
Here, R12 is a lower alkyl group (C1-C5) which may have a substituent,
R3, R4 and R7 are each a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group (C1-C5) which may have a substituent,
R3 and R4 may form a bond.
A dotted line can represent a bond only when R7 is a hydrogen atom (ie, double).
R5 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), R13CO, or sugar-O-.
Here, R9 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), or R14 (R15) N-. .
Here, R14 and R15 are a hydrogen atom and a lower alkyl group (C1-C5), respectively.
R6 is a hydrogen atom or a lower alkoxy group (C1-C5) which may have a substituent when R5 is a lower alkyl group (C1-C5) which may have a substituent.
R5 and R6 together may be a lower alkylene group (C1-C5), = O, = N-OR16.
Here, R16 represents a lower alkyl group (C1-C5) which may have a substituent.
R8 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), R16CO,
R16 is a hydrogen atom, a lower alkyl group (C1-C5) which may have a substituent, a lower alkoxy group (C1-C5) which may have a substituent, or R17 (R18) N-. Here, R17 and R18 are a hydrogen atom and a lower alkyl group (C1-C5), respectively.
In the above, the substituent refers to a hydroxyl group, a halogen atom, a carboxyl group, R19 (R20) N-, and the like.
Here, R19 and R20 are each a hydrogen atom, a lower alkyl group (C1-C5) (Ra, Rb) and (Rc, Rd): H, OH, and an optionally substituted lower alkyl group (C1 -C5), a substituted lower alkoxy group (for example, -O (CH2) nNRa1Ra2, n = 1-5, wherein R17 and R18 are a hydrogen atom and a lower alkyl group (C1-C5), respectively.
In the above, the substituent refers to a hydroxyl group, a halogen atom, a carboxyl group, R19 (R20) N-, and the like.
Here, R19 and R20 are a hydrogen atom and a lower alkyl group (C1-C5), respectively. ]

[In the formula (II), (Ra, Rb) and (Rc, Rd) are H, OH, an optionally substituted lower alkyl group (C1-C5), a substituted lower alkoxy group (for example, —O (CH 2 ) nNRa1Ra2, n = 1-5, Ra1, Ra2 is lower alkyl (C1-C5), Sugar-O-, or (Ra, Rb) and (Rc, Rd) together are lower alkylene (C1- C5), = O, = N-ORa3, Ra3 is hydrogen or a lower alkyl group (C1-C5).]

[In the above formula (III), Rx is an optionally substituted lower alkyl (C1-C5), and n is 0-20. ]

[In the formula (IV), Re is a hydrogen atom, a lower alkyl group (C1-C5), a cycloalkyl group (C3-C5), a-(CH2) m-aryl group, a-(CH2) m-heteroaryl group,
Rf is a hydrogen atom, a lower alkyl group (C1-C5),-(CH2) m-allyl group,-(CH2) m-heteroallyl group,
Rh is a lower alkyl group (C1-C5), halogen, -NH2, -NO2, -OH, -CN, -CF3,
L is-(CH2) m, lower alkenyl group (C1-C5), lower alkynyl group (C1-C5), -NRg (CH2) m-,
X is -CH-, -N-, a single bond,
Y is —CH 2 —, —N (Rg) —, a single bond,
Rg is a hydrogen atom, a lower alkyl group (C1-C5), a cycloalkyl group (C4-C8),
m is an integer from 0 to 5. ]

  Next, the manufacturing method of the said compound is demonstrated. In addition, in the production method shown below, when the defined group is subjected to an undesirable chemical transformation under the conditions of the implementation method, for example, the production can be performed by using means such as functional group protection and deprotection. Can be implemented. Examples of the protecting group selection and desorption operation include the method described in “Greene and Wuts,“ Protective Groups in Organic Synthesis ”(2nd edition, John Wiley & Sons 1991). What is necessary is just to use suitably according to conditions. Further, the order of reaction steps such as introduction of substituents can be changed as necessary. Various methods are conceivable as a method for producing the compound of the present invention represented by the general formula (I), which can be synthesized using ordinary organic synthesis means. Typical examples include the following methods. be able to.

  In any of the above general formulas, the “lower alkyl group (C1-C5)” means a linear or branched alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl and the like are included.

  In the present invention, the “C 1-5 alkoxy group” means an alkyloxy group having a linear or branched alkyl group having 1 to 5 carbon atoms as an alkyl moiety, and examples thereof include methoxy, ethoxy, n-propoxy, Examples include i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy and the like.

  In the present invention, “C1-C5 alkylene” means a linear or branched divalent alkylene group having 1 to 5 carbon atoms, such as methylene, ethylene, propylene (—CH 2 CH 2 CH 2 —, —CH (-CH3) CH2- and -CH (-CH2CH3)-, etc.), and butylene (-CH2CH2CH2CH2-, -CH (-CH3) CH2CH2-, -CH2CH (-CH3) CH2-, CH2-CH2CH (-CH3 )-, -CH (-CH2CH3) CH2-, -CH2CH (-CH2CH3)-, -CH (-CH2CH2CH3)-and -CH (-CH3) CH (-CH3)-) and the like.

In the present invention, the “cycloalkyl group (C3-C5)” means a cyclic alkyl group having 3 to 5 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and the like.
In the present invention, the “lower alkynyl group (C1-C5)” means a linear or branched alkenyl group having 1 to 5 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like are included.

In the present invention, the “lower alkenyl group (C1-C5)” means a linear or branched alkenyl group having 1 to 5 carbon atoms. For example, ethenyl (vinyl), 1-propenyl, 2-propenyl ( Allyl), propen-2-yl, 3-butenyl (homoallyl), and the like. Vinyl group, allyl group, n-butenyl group, i-butenyl group, sec-butenyl group, pentenyl group and the like are included.

  The compound represented by the general formula (I) of the present invention can be produced, for example, according to the following method, but the production method of the compound of the present invention is not limited thereto. In addition, as a raw material compound used in manufacture, you may use what is marketed, or may manufacture by a conventional method as needed.

The compound represented by the general formula (I) can be synthesized using the following compound 1 or compound 2 as a raw material.

  Compound 1 and Compound 2 can be obtained by the method described in Patent Publication WO2001 / 27135A2.

  A compound in which R8 is an optionally substituted lower alkyl group is treated with a reductive N-alkylation reaction between Compound 1 and a lower alkyl aldehyde, or with a lower alkyl halide in the presence of an organic base or an inorganic base. Can be manufactured.

  A compound in which R8 is R16CO can be produced by treating Compound 1 with R16COCl in the presence of an organic base or an inorganic base. Further, a compound in which R16 of R16CO is R17 (R18) N- can be produced by a reaction with, for example, R17N = C = O instead of R16COCl when either R17 or R18 is a hydrogen atom.

  For compounds in which R1 and R2 together form a keto group, the secondary amino group of compound 1 or compound 2 is protected with an appropriate protecting group, and then the secondary hydroxyl group is converted to a keto group under appropriate oxidation conditions. Thereafter, it can be produced by deprotection.

  For compounds in which R1 is a lower alkyl group and R2 is a hydroxyl group, the secondary amino group of compound 1 is protected with an appropriate protecting group, and then the secondary hydroxyl group is converted to a keto group under appropriate oxidation conditions, and then alkyllithium. Or a nucleophilic alkylating agent such as an alkyl Grignard reagent and finally deprotecting.

  Compounds in which R1 is a lower alkoxy group and R2 is a hydrogen atom are treated with a lower alkyl halide in the presence of an organic or inorganic base after protecting the secondary amino group of Compound 1 or Compound 2 with an appropriate protecting group. And then deprotecting.

  For compounds in which R1 is R9COO and R2 is a hydrogen atom, the secondary amino group of Compound 1 or Compound 2 is protected with an appropriate protecting group, then treated with R9COCl in the presence of an organic base or inorganic base, and then removed. It can be manufactured by protecting. In addition, when R9 of R9COO is R10 (R11) N-, when either R10 or R11 is a hydrogen atom, instead of R9COCl, for example, by reacting with R10N = C = O, deprotecting Can be manufactured.

  A compound in which R1 and R2 together form a lower alkylene group is obtained by protecting the secondary amino group of Compound 1 with an appropriate protecting group, and then converting the secondary hydroxyl group to a keto group under appropriate oxidation conditions. It can be produced by treating with a Wittig reagent and finally deprotecting.

  A compound in which R1 and R2 together form ═N—OR12 is obtained by protecting the secondary amino group of compound 1 with an appropriate protecting group, and then converting the secondary hydroxyl group to a keto group under appropriate oxidation conditions. It can then be prepared by treatment with O-alkylhydroxyamine and finally deprotection.

  For compounds in which R5 is a lower alkyl group and R6 is a hydroxyl group, the secondary amino group and secondary hydroxyl group of compound 2 are protected sequentially or simultaneously with appropriate protective groups, and then nucleophilic, such as alkyllithium and alkyl Grignard reagents. It can be prepared by treating with an alkylating agent and finally deprotecting.

  For compounds in which R5 is a lower alkoxy group and R6 is a hydrogen atom, the secondary amino group and secondary hydroxyl group of compound 2 are protected sequentially or simultaneously with an appropriate protecting group, and then the keto group is protected with sodium borohydride or the like. It can be prepared by treating with a reducing agent, then treating with a lower alkyl halide in the presence of an organic or inorganic base, and finally deprotecting.

  For compounds in which R5 is R13COO and R6 is a hydrogen atom, the secondary amino group and secondary hydroxyl group of compound 2 are protected sequentially or simultaneously with an appropriate protecting group, and then the keto group is reduced with a reducing agent such as sodium borohydride. Followed by treatment with R13COCl in the presence of an organic or inorganic base and finally deprotection. In addition, when either R14 or R15 is a hydrogen atom, a compound in which R13 of R13COO is R14 (R15) N- is reacted with, for example, R14N = C = O instead of R13COCl, and then deprotected. Can be manufactured.

  A compound in which R5 and R6 are combined to form a lower alkylene group is protected with a suitable protecting group sequentially or simultaneously with the secondary amino group and secondary hydroxyl group of compound 2, and then treated with a Wittig reagent, etc. It can be manufactured by deprotection.

  A compound in which R5 and R6 are combined to form ═N—OR16 is treated with O-alkylhydroxyamine after protecting the secondary amino group and secondary hydroxyl group of compound 2 sequentially or simultaneously with an appropriate protecting group. And then deprotecting.

  For compounds in which R3 is a hydroxyl group and R4 is a hydrogen atom or a lower alkyl group, the secondary amino group and secondary hydroxyl group of compound 1 are protected sequentially or simultaneously with an appropriate protecting group, and then m-chloroperbenzoic acid, etc. An epoxide can be formed by treatment with an oxidizing agent, followed by treatment with a suitable reducing agent or nucleophilic alkylating agent, and finally deprotection.

  A compound in which R 3, R 4 and R 7 are simultaneously hydrogen atoms can be produced by subjecting compound 1 to catalytic hydrogenation conditions.

  For compounds in which R3 is a hydrogen atom and R4 is a hydroxyl group, the secondary amino group and secondary hydroxyl group of compound 1 or compound 2 are protected sequentially or simultaneously with an appropriate protecting group, and then the conditions for hydroboration-oxidation are used. It can manufacture by attaching | subjecting and deprotecting after that.

Compound 3 and Compound 4 can also be produced by methods described in the literature (John P. Incardona, et al., Developmental Biology, 2000, 224, 440-452.).

The compound represented by the general formula (II) can be synthesized from the compound 5 or 6 obtained by a method described in the literature (Tetrahedron, 1982, 1755.).

  In the general formula (II), a compound in which Ra is hydrogen and Rb is a lower alkyl group is obtained by protecting the hydroxyl group of compound 2 with a tri-t-butyldimethylsilyl group or the like under basic conditions, and then alkyllithium or Grignard reagent. It is obtained by treating and finally deprotecting.

  A compound in which Ra is hydrogen and Rb is an alkyloxy group can be obtained by treating compound 5 with Ra1Ra2N (CH2) nCl or the like under basic conditions. A compound in which Ra is hydrogen and Rb is O-Sugar can be obtained by treating Compound 5 with, for example, beta D-glucose pentaacetate and silver carbonate or a trifluoroborane ether complex.

  Compounds in which either (Ra, Rb) and (Rc, Rd) are lower alkylene or O-alkyl oxime are protected with the hydroxyl group of compound 5 or 6, respectively, and then reacted with Wittig reagent or O-alkylhydroxylamine. Can be synthesized. (A compound in which both (Ra, Rb) and (Rc, Rd) are lower alkylene or O-alkyloxime can be synthesized in the same manner using 4-Androstene-3,17-dione.

An example of the compound represented by the general formula (III) (compound 12) can be synthesized using compound 7 as a raw material.

  Compound 8 is obtained by treating commercially available compound 7 with alkyl halide under basic conditions. Compound 9 is similarly treated with alkyl halide and basic conditions to give compound 9. This is catalytically reduced together with a palladium catalyst in a hydrogen atmosphere to obtain the deprotected body 10. Compound 10 is reacted with 2-bromoethyl phosphorodichloridate to obtain phosphate 11. This is treated with trimethylamine to give compound 12.

  The compound represented by the above general formula (IV) can be produced by the method described in Patent Document 3 (WO0126644A) and the like.

  According to still another aspect of the present invention, there is provided a composition for preventing / treating a disease requiring promotion of glucose-responsive insulin secretion. This disease includes diabetes with impaired glycemic control, hyperlipidemia or obesity, diabetes with impaired insulin secretion, hyperlipidemia with abnormal lipid metabolism, obesity with hyperglycemia or abnormal lipid metabolism, etc. . The pharmaceutical composition of the present invention contains the above-described compounds of formulas (I) to (IV) or a pharmaceutically acceptable salt or ester thereof as an active ingredient.

  Pharmaceutically acceptable salts of the compounds represented by formulas (I) to (IV) are produced by bringing the compound into contact with an acid or base that can be used for the production of a pharmaceutical product. Examples of the salt include hydrochloride, hydrobromide, hydroiodide, sulfate, sulfonate, phosphate, phosphonate, acetate, citrate, malate, salicylate Carboxylates such as sodium salts, alkali metal salts such as potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkyls Ammonium salts such as ammonium salts are included.

  The compound according to the present invention or a pharmaceutically acceptable salt thereof has an excellent effect of promoting glucose-responsive insulin secretion, has excellent stability in the body and solubility in water, and requires glucose-responsive insulin secretion. Diseases selected from diabetes, hyperlipidemia or obesity with impaired blood glucose control, diabetes with impaired insulin secretion, hyperlipidemia with abnormal lipid metabolism, obesity with hyperglycemia or abnormal lipid metabolism It is useful as a preventive or therapeutic agent (especially a therapeutic agent). Further, the compound according to the present invention or a pharmaceutically acceptable salt thereof includes diabetes with glycemic control failure, hyperlipidemia or obesity, diabetes with insulin secretion failure, hyperlipidemia with dyslipidemia, It is useful as a prophylactic or therapeutic agent (especially therapeutic agent) for diseases selected from obesity accompanied by hyperglycemia or lipid metabolism abnormality. Furthermore, the compound of the present invention is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for diabetes accompanying insulin secretion failure.

  These methods involve pharmaceutically effective amounts of a pharmaceutical composition comprising a disclosed compound of the invention or a pharmaceutically acceptable salt thereof in need of such treatment or such disease or condition. Administering to a patient suffering from

  The pharmaceutical composition of the present invention is used for diabetes, hyperlipidemia or obesity with glycemic control failure, diabetes with impaired insulin secretion, hyperlipidemia with dyslipidemia, obesity with hyperglycemia or dyslipidemia. When used as a prophylactic or therapeutic agent for a selected disease, the method of administration is oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, Examples include intraperitoneal, intravesical, topical (ointment, gel or cream) administration and inhalation (oral or nasal spray). The dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and non-filled containers adapted to be subdivided into individual doses. Examples include oral solutions. The dosage form can also be adapted to various modes of administration including controlled release formulations such as subcutaneous implantation.

  Said formulation is manufactured by a well-known method using additives, such as an excipient | filler, a lubricant (coating agent), a binder, a disintegrating agent, a stabilizer, a corrigent, a diluent.

  Examples of excipients include starches such as starch, potato starch, and corn starch, lactose, crystalline cellulose, and calcium hydrogen phosphate.

  Examples of the coating agent include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.

  Examples of the binder include polyvinyl pyrrolidone, macrogol and the same compound as the excipient.

  Examples of the disintegrant include the same compounds as the above excipients and chemically modified starch / celluloses such as croscarmellose sodium, carboxymethyl starch sodium, and crosslinked polyvinylpyrrolidone.

  Examples of the stabilizer include paraoxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; Mention may be made of dehydroacetic acid; and sorbic acid.

  Examples of the flavoring agent include sweeteners, acidulants, and fragrances that are commonly used.

  Moreover, ethanol, phenol, chlorocresol, purified water, distilled water, or the like can be used as a solvent for producing the liquid agent.

  Examples of the surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate, lauromacrogol and the like.

The pharmaceutical composition of the present invention is used for diabetes, hyperlipidemia or obesity with glycemic control failure, diabetes with impaired insulin secretion, hyperlipidemia with dyslipidemia, obesity with hyperglycemia or dyslipidemia. When used as a prophylactic or therapeutic agent for a selected disease, the amount of the compound of the present invention or a pharmaceutically acceptable salt thereof used depends on symptoms, age, body weight, relative health status, presence of other medications, It depends on the administration method. For example, for patients (warm-blooded animals, particularly humans), generally effective amounts are as active ingredients (compounds of the invention represented by formula (I)) per kg body weight per day in the case of oral agents Preferably it is 0.1 to 1000 mg, more preferably 1 to 400 mg per kg body weight, and the daily usage is preferably in the range of 10 to 800 mg for adult patients with normal body weight. In the case of a parenteral preparation, it is preferably 0.1 to 1000 mg per kg body weight per day, more preferably 10 to 800 mg per kg body weight. It is desirable to administer this once or several times a day according to the symptoms.
In addition, all prior art documents cited in the present specification are incorporated herein by reference.

In the present invention, the following four compounds were used in the examples.
The present compound 1 (compound 1): cyclopamine The present compound 2 (compound 5): 4-Androstene-3,17-dione
The present compound 3: 3β- (2-Diethylamino-ethoxy) androstenone, hydrochloride
Compound 4 of the present invention (Compound 12, wherein Rx = Me, n = 15): 1-Hexadecyl-2-methylglycero-3-phosphorylcholine
Compound 5 of the present invention: N-[(5S) -1- (1,3-benzodioxol-5-ylmethyl) -5- (1-piperazinylcarbonyl) -3-pyrrolidinyl] -N-[(3-methoxyphenyl) methyl]- 3,3-dimethyl-Butanamide (CUR61414)

Example 1: Promoting action of Compound 1 of the present invention on glucose-responsive insulin secretion in pancreatic islets of Langerhans (1)
In order to examine the action of Compound 1 of the present invention on physiological insulin secretion, the amount of glucose-responsive insulin secretion was evaluated using a primary culture system of pancreatic islets of Langerhans.

  The primary culture system of pancreatic islets of Langerhans was prepared from 6-week-old male C57BL / 6J mice. Mice were purchased from CLEA Japan, and were raised under conditions of room temperature 25 ° C. and light / dark cycle 12 hours (light period 08: 00-20: 00). Solid CE-2 (CLEA Japan) was used as a feed, and was freely consumed with drinking water. The animals were acclimated for one week and then 20 male C57BL / 6J mice were subjected to the experiment.

The mouse was anesthetized with Nembutal and then laparotomized, the duodenal opening was clamped with Clemme, and Hanks' balanced solution (Sigma) containing 1-2 ml of 1 mg / ml collagenase (Wako Pure Chemical Industries) was injected from the common bile duct. And perfused the pancreas. The pancreas was isolated and incubated for 13 minutes at 37 ° C. for collagenase digestion. After this, the islets of Langerhans are collected under a microscope and contain 20 μM cyclopamine (Toronto Research Chemicals Inc.) or 0.2% ethanol and 10% fetal calf serum (Sigma), 100 units / ml penicillin and 100 μg / ml streptomycin (Gibco) Using RPMI 1640 medium (Gibco), the cells were cultured overnight under conditions of 5% CO ₂ and 37 ° C., and subjected to measurement of glucose-responsive insulin secretion by a batch incubation method.

Islets of Langerhans cultured overnight with RPMI 1640 are Krebs-Ringer bicarbonate buffer (KRBB, 119 mM NaCl, 4.74 mM KCl, 2.54 mM CaCl ₂ , 1.19 mM) containing 2.8 mM glucose and 0.2% bovine serum albumin (BSA, Sigma). _{KH 2 PO 4, 1.19 mM MgSO} 4, transferred to _{25 mM NaHCO 3, pH 7.4)} , and incubated 1 h before under the condition of 5% CO _2, 37 ℃. Pour KRBB containing 500 μl of 2.8 mM or 16.7 mM glucose and 0.2% BSA into a 24-well plate, add 10 pre-cultured islets of Langerhans per well, and add 5% CO ₂ at 37 ° C. Glucose stimulation was applied by culturing for a period of time. After culturing, the entire medium was collected, and 2.5 μl of the medium was quantified for insulin using the Rat Insulin [ ¹²⁵ I] Biotrak Assay System (Amersham Pharmacia Biotech).

The results are shown in FIG.
From FIG. 1, it was shown that the islets of Langerhans in the primary culture increased insulin secretion from pancreatic β cells in response to high glucose stimulation by about 5 times. Further, when cultured overnight with 20 μM of the present compound 1 (cyclopamine), insulin secretion increased by about 1.6 times in the culture with low concentration of glucose (2.8 mM) (P = 0.0017), and when stimulated with high glucose (16.7 mM), insulin secretion was accelerated about 4 times (P = 0.0002).

  This result shows that the compound 1 of the present invention, which is a hedgehog signal inhibitor, promotes insulin secretion, contrary to the previous report, and the insulin secretory ability could not be properly evaluated in studies using cell lines. It shows that. This result also shows that the compound 1 of the present invention strongly promotes glucose-responsive insulin secretion.

Example 2: Promoting action of Compound 2 of the present invention on glucose-responsive insulin secretion in pancreatic islets of Langerhans (2)
In order to examine the action of Compound 2 of the present invention on physiological insulin secretion, the glucose-responsive insulin secretion amount was evaluated in the same manner as in Test Example 1.

The results are shown in FIG.
From FIG. 2, by culturing overnight with the compound 2 of the present invention, the insulin secretion was not promoted in the culture at low concentration of glucose (2.8 mM), but at the time of stimulation with high glucose (16.7 mM). Insulin secretion showed a significant increase.

Example 3: Promoting action of compound 3 of the present invention on glucose-responsive insulin secretion in pancreatic islets of Langerhans (3)
In order to examine the action of Compound 3 of the present invention on physiological insulin secretion, the glucose-responsive insulin secretion amount was evaluated in the same manner as in Test Example 1.

The results are shown in FIG.
From FIG. 3, by culturing overnight with the compound 3 of the present invention, it was confirmed that insulin secretion was stimulated upon stimulation with high glucose (16.7 mM) as in the case of the compound 2 of the present invention.

Example 4: Promoting action of Compound 4 of the present invention on glucose-responsive insulin secretion in pancreatic islets of Langerhans (4)
In order to examine the action of Compound 4 of the present invention on physiological insulin secretion, the glucose-responsive insulin secretion amount was evaluated in the same manner as in Test Example 1.

The results are shown in FIG.
From FIG. 4, by culturing together with the compound 4 of the present invention overnight, as in the case of the compounds 2 and 3, promotion of insulin secretion upon stimulation with high glucose (16.7 mM) was observed.

Test Example 5: Promoting action of compound 5 of the present invention on glucose-responsive insulin secretion in pancreatic islets of Langerhans (5)
In order to examine the action of Compound 5 of the present invention on physiological insulin secretion, the glucose-responsive insulin secretion amount was evaluated in the same manner as in Test Example 1.
The results are shown in FIG.
From FIG. 5, by culturing overnight with the compound 5 of the present invention at a concentration of 30 μM, insulin secretion from pancreatic beta cells upon stimulation with high glucose (16.7 mM) increases, and the amount of increase during stimulation with low glucose ( 2.8 mM).

  According to the present invention, it is possible to treat a disease accompanied by an increase in blood glucose by promoting glucose-responsive insulin secretion using a cyclopamine derivative, an androgen derivative or the like which is a hedgehog signal inhibitor. In particular, since it is considered that promotion of glucose-responsive insulin secretion is important in diabetes accompanying insulin secretion failure, the present invention is useful for the treatment or prevention of diabetes accompanying insulin secretion failure.

Claims (14)

A method of promoting glucose-responsive insulin secretion, comprising administering a hedgehog signal inhibitor to a mammalian cell or animal. The hedgehog signal inhibitor is a compound selected from any of the following general formulas (I) to (IV) or a salt thereof, or a physiologically hydrolyzable and acceptable ester thereof: The method according to 1.

[In formula (I), R1 represents a hydrogen atom, a lower alkyl group (C1-C5) optionally having substituent (s), a lower alkoxy group (C1-C5) optionally having substituent (s), R9COO, sugar-O Where R9 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), R10 (R11) N-.
Here, R10 and R11 are a hydrogen atom and a lower alkyl group (C1-C5), respectively.
R2 is a hydrogen atom or a lower alkoxy group (C1-C5) which may have a substituent when R1 is a lower alkyl group (C1-C5) which may have a substituent;
R1 and R2 together may be a lower alkylene group (C1-C5), ═O, ═N—OR12.
Here, R12 is a lower alkyl group (C1-C5) which may have a substituent,
R3 and R4 are each a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group (C1-C5) which may have a substituent,
R3 and R4 may form a bond.
R7 is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group (C1-C5) which may have a substituent,
However, when the dotted line can represent a bond (ie, becomes double), R7 is unsubstituted.
R5 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), R13COO, sugar-O-,
Here, R9 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), or R14 (R15) N-. ,
Here, R14 and R15 are a hydrogen atom and a lower alkyl group (C1-C5), respectively.
R6 is a hydrogen atom or a lower alkoxy group (C1-C5) which may have a substituent when R5 is a lower alkyl group (C1-C5) which may have a substituent;
R5 and R6 together may be a lower alkylene group (C1-C5), = O, = N-OR16.
Here, R16 is a lower alkyl group (C1-C5) which may have a substituent,
R8 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), R16CO,
R16 is a hydrogen atom, a lower alkyl group (C1-C5) which may have a substituent, a lower alkoxy group (C1-C5) which may have a substituent, or R17 (R18) N-. ,
Here, R17 and R18 are a hydrogen atom and a lower alkyl group (C1-C5), respectively.
In the above, the substituent refers to a hydroxyl group, a halogen atom, a carboxyl group, R19 (R20) N-, and the like.
Here, R19 and R20 are a hydrogen atom and a lower alkyl group (C1-C5), respectively. ]

[In the above formula (II), (Ra, Rb) and (Rc, Rd) are H, OH, an optionally substituted lower alkyl group (C1-C5), a substituted lower alkoxy group (for example, —O (CH2) nNRa1Ra2, n = 1-5, Ra1, Ra2 is lower alkyl (C1-C5)), Sugar-O-, or (Ra, Rb) and (Rc, Rd) together are lower alkylene (C1 to C5), ═O, ═N—ORa3, and Ra3 are hydrogen or a lower alkyl group (C1 to C5). ]

[In Formula (III), Rx is optionally substituted lower alkyl (C1-C5), and n is 0-20. ]

[In the formula (IV), Re is a hydrogen atom, a lower alkyl group (C1-C5), a cycloalkyl group (C3-C5), a-(CH2) m-aryl group, a-(CH2) m-heteroaryl group,
Rf is a hydrogen atom, a lower alkyl group (C1-C5),-(CH2) m-allyl group,-(CH2) m-heteroallyl group,
Rh is a lower alkyl group (C1-C5), halogen, -NH2, -NO2, -OH, -CN, -CF3,
L is-(CH2) m, lower alkenyl group (C1-C5), lower alkynyl group (C1-C5), -NRg (CH2) m-,
X is -CH-, -N-, a single bond,
Y is —CH 2 —, —N (Rg) —, a single bond,
Rg is a hydrogen atom, a lower alkyl group (C1-C5), a cycloalkyl group (C4-C8),
m is an integer from 0 to 5. ] The method according to claim 1 or 2, wherein the condition requiring promotion of glucose-responsive insulin secretion is caused by a disease accompanied by glycemic control failure. The method according to claims 1 to 3, wherein the condition requiring the promotion of glucose-responsive insulin secretion is caused by a disease selected from the group consisting of diabetes, hyperlipidemia or obesity. The method according to claim 4, wherein the condition requiring promotion of glucose-responsive insulin secretion is diabetes accompanied by insulin secretion failure. The method according to claim 4, wherein the condition requiring promotion of glucose-responsive insulin secretion is hyperlipidemia accompanied by abnormal lipid metabolism. The method according to claim 4, wherein the condition requiring promotion of glucose-responsive insulin secretion is obesity accompanied by hyperglycemia or abnormal lipid metabolism. A pharmaceutical composition for preventing / treating a disease requiring promotion of glucose-responsive insulin secretion, comprising a hedgehog signal inhibitor as an active ingredient. The hedgehog signal inhibitor is a compound selected from any of the following general formulas (I) to (IV) or a salt thereof, or a physiologically hydrolyzable and acceptable ester thereof: 9. The composition according to 8.

[In formula (I), R1 represents a hydrogen atom, a lower alkyl group (C1-C5) optionally having substituent (s), a lower alkoxy group (C1-C5) optionally having substituent (s), R9COO, sugar-O Where R9 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), R10 (R11) N-.
Here, R10 and R11 are a hydrogen atom and a lower alkyl group (C1-C5), respectively.
R2 is a hydrogen atom or a lower alkoxy group (C1-C5) which may have a substituent when R1 is a lower alkyl group (C1-C5) which may have a substituent;
R1 and R2 together may be a lower alkylene group (C1-C5), ═O, ═N—OR12.
Here, R12 is a lower alkyl group (C1-C5) which may have a substituent,
R3 and R4 are each a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group (C1-C5) which may have a substituent,
R3 and R4 may form a bond.
R7 is a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group (C1-C5) which may have a substituent,
However, when the dotted line can represent a bond (ie, becomes double), R7 is unsubstituted.
R5 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), R13COO, sugar-O-,
Here, R9 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), or R14 (R15) N-. ,
Here, R14 and R15 are a hydrogen atom and a lower alkyl group (C1-C5), respectively.
R6 is a hydrogen atom or a lower alkoxy group (C1-C5) which may have a substituent when R5 is a lower alkyl group (C1-C5) which may have a substituent;
R5 and R6 together may be a lower alkylene group (C1-C5), = O, = N-OR16.
Here, R16 is a lower alkyl group (C1-C5) which may have a substituent,
R8 is a hydrogen atom, an optionally substituted lower alkyl group (C1-C5), an optionally substituted lower alkoxy group (C1-C5), R16CO,
R16 is a hydrogen atom, a lower alkyl group (C1-C5) which may have a substituent, a lower alkoxy group (C1-C5) which may have a substituent, or R17 (R18) N-. ,
Here, R17 and R18 are a hydrogen atom and a lower alkyl group (C1-C5), respectively.
In the above, the substituent refers to a hydroxyl group, a halogen atom, a carboxyl group, R19 (R20) N-, and the like.
Here, R19 and R20 are a hydrogen atom and a lower alkyl group (C1-C5), respectively. ]

[In the above formula (II), (Ra, Rb) and (Rc, Rd) are H, OH, an optionally substituted lower alkyl group (C1-C5), a substituted lower alkoxy group (for example, —O (CH2) nNRa1Ra2, n = 1-5, Ra1, Ra2 is lower alkyl (C1-C5)), Sugar-O-, or (Ra, Rb) and (Rc, Rd) together are lower alkylene (C1 to C5), ═O, ═N—ORa3, and Ra3 are hydrogen or a lower alkyl group (C1 to C5). ]

[In Formula (III), Rx is optionally substituted lower alkyl (C1-C5), and n is 0-20. ]

[In the formula (IV), Re is a hydrogen atom, a lower alkyl group (C1-C5), a cycloalkyl group (C3-C5), a-(CH2) m-aryl group, a-(CH2) m-heteroaryl group,
Rf is a hydrogen atom, a lower alkyl group (C1-C5),-(CH2) m-allyl group,-(CH2) m-heteroallyl group,
Rh is a lower alkyl group (C1-C5), halogen, -NH2, -NO2, -OH, -CN, -CF3,
L is-(CH2) m, lower alkenyl group (C1-C5), lower alkynyl group (C1-C5), -NRg (CH2) m-,
X is -CH-, -N-, a single bond,
Y is —CH 2 —, —N (Rg) —, a single bond,
Rg is a hydrogen atom, a lower alkyl group (C1-C5), a cycloalkyl group (C4-C8),
m is an integer from 0 to 5. ] The composition according to claim 8 or 9, wherein the condition requiring promotion of glucose-responsive insulin secretion is a disease accompanied by glycemic control failure. The composition according to claim 8 or 9, wherein the condition requiring promotion of glucose-responsive insulin secretion is a disease selected from the group consisting of diabetes, hyperlipidemia or obesity. 10. The composition according to claim 8 or 9, wherein the condition requiring promotion of glucose-responsive insulin secretion is diabetes accompanied by insulin secretion failure. The composition according to claim 8 or 9, wherein the condition requiring promotion of glucose-responsive insulin secretion is hyperlipidemia accompanied by abnormal lipid metabolism. The composition according to claim 8 or 9, wherein the condition requiring promotion of glucose-responsive insulin secretion is obesity accompanied by hyperglycemia or abnormal lipid metabolism.

Images