JP2003012686A - Pyrazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pyrazole derivative useful as an agent for the prevention and/or treatment of diabetes or its pharmacologically permissible salt. SOLUTION: The pyrazole derivative is expressed by general formula (I) [R<1> is H, a substituted or unsubstituted lower alkyl or a substituted or unsubstituted lower alkoxy; R<4> is a substituted or unsubstituted lower alkyl or a substituted or unsubstituted lower alkoxy; R<2> is gluconopyranosyl group (the hydroxy group in the gluconopyranosyl group may be protected); and R<3> is a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group]. The invention further relates to a pharmacologically permissible salt of the derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pyrazole derivative having a hypoglycemic effect and useful as an agent for preventing and / or treating diabetes.

[0002]

2. Description of the Related Art Diabetes is characterized by hyperglycemia caused by metabolic abnormality centered on glucose metabolism due to insufficient secretion of insulin or decreased sensitivity of the target cells. Further, if hyperglycemia lasts for a long period of time, serious complications occur in various organs and nerves such as nephropathy, retinopathy, and neuropathy, mainly due to vascular disorders. Therefore, in the treatment of diabetes, it is extremely important to control the blood sugar level and maintain it at a normal value, and means for that purpose have been studied for a long time.

[0003] Among diabetes, in a disease type that develops slowly and does not necessarily require insulin treatment for life support (non-insulin dependent diabetes mellitus: NIDDM), blood glucose level can be controlled by a combination of exercise therapy and drugs, An insulin secretagogue, which is a type of oral hypoglycemic agent, is widely used clinically. However, all of the currently available insulin secretagogues promote insulin secretion independent of blood glucose level, so that a wrong dose may cause severe hypoglycemia, or the blood glucose level cannot be controlled sufficiently. There are some points that are not always satisfactory.

On the other hand, glucose toxicity theory (Gl) in which hyperglycemia itself is involved in the onset and progression of diabetes
ucose Toxicity Theory was proposed, and it was reported that chronic hyperglycemia lowers insulin secretory ability and insulin sensitivity, and causes further blood glucose elevation [Diabetologia, Vol. 13, Vol. 610 (1990), etc.]. Therefore, it is said that diabetes can be prevented and treated if the vicious circle can be broken by correcting hyperglycemia.

As one of the methods, it is considered that excess sugar is directly excreted in the urine as urine sugar to normalize the blood glucose level. For example, phlorizin inhibits the reabsorption of sugar in the kidney by inhibiting the Na ⁺ -glucose cotransporter [sodium-glucose cotransporter (SGLT)], which is present only in the chorion of the intestine and kidney, It is possible to lower the blood glucose level by promoting excretion of (SGLT inhibitory action). Based on this action, phlorizin is subcutaneously administered daily to diabetic animals to correct hyperglycemia,
It has been confirmed that keeping the blood sugar level normal for a long time can improve and normalize the condition of diabetic animals [Journal of Clinical Investigation (J.C.
lin. Invest. ), 79, 1510 (1987), 80, 1037, (198).
7), Vol. 87, p. 561 (1991), etc.].
However, when phlorizin is orally administered, phlorizin is inactivated by a hydrolysis reaction, and the aglycone part (phloretin) produced by hydrolysis causes a side effect such as an inhibitory action of a facilitative diffusion type sugar transport carrier (GLUT). It has been reported that [stroke (S
14), page 388 (1983).
Year)].

On the other hand, in Japanese Patent Laid-Open No. 10-237089, S
Disclosed is a 4'-lower alkylpropiophenone derivative which has a GLT inhibitory action and reduces the side effect such as the inactivation by the hydrolysis reaction found in phlorizin and the inhibitory action of GLUT. Also, US Pat.
No. 825, US Pat. No. 5,194,435, US Pat. No. 5,264,451, and US Pat. No. 5,274,111 show that the compound represented by the following general formula (A) exhibits a hypoglycemic action. Is disclosed.

[0007]

[Chemical 6] (In the formula, R ^1A represents a hydrogen atom or the like, R ^2A represents a hydrogen atom or lower alkyl, R ^3A represents an aryl or the like, R ^4A
Represents lower alkyl, perfluoromethyl or lower alkoxy) Note that the action of these compounds is based on the SGLT inhibitory action, Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 39, p. 3920. (1996).

Further, WO01 / 16147 discloses that the compound represented by the following general formula (B) exhibits SGLT inhibitory action and hypoglycemic action.

[0009]

[Chemical 7] (In the formula, R ^1B represents a hydrogen atom or the like, one of Q ^B and T ^B is β-D-glucopyranosyl, the other is lower alkyl or halo lower alkyl, and R ^2B is a hydrogen atom or lower alkyl. , Lower alkoxy or lower alkylthio, etc.)

[0010]

An object of the present invention is to provide a pyrazole derivative or a pharmacologically acceptable salt thereof which has a hypoglycemic effect and is useful as an agent for preventing and / or treating diabetes.

[0011]

The present invention relates to the following (1) to (21). (1) General formula (I)

[Chemical 8] [In the formula, R ¹ represents a hydrogen atom, a substituted or unsubstituted lower alkyl, or a substituted or unsubstituted lower alkoxy, and R ⁴ represents a substituted or unsubstituted lower alkyl or a substituted or unsubstituted lower alkoxy, R ² is the general formula (II)

[0012]

[Chemical 9] (In the formula, R^Five, R⁶, R⁷And R⁸Are the same or different
Represents a hydrogen atom or a hydroxyl-protecting group),
(I) R^Five, R⁶, R⁷And R⁸At least one of
When it is a protecting group for a hydroxyl group, and R^Five, R⁶, R⁷Oh
And R⁸Is a hydrogen atom, and R¹Is substituted lower alkyl
Or a substituted or unsubstituted lower alkoxy
Come, R³Is substituted or unsubstituted aryl or substituted
Or an unsubstituted aromatic heterocyclic group, (ii) R^Five,
R⁶, R⁷And R⁸Is a hydrogen atom, and R ¹Is hydrogen
When it is a child or lower alkyl, R³Is also para substitution
Or unsubstituted lower alkylsulfinylaryl,
La-substituted or unsubstituted lower alkylsulfonyl ants
And substituted aryl (provided that the substituted aryl is in the para position)
Have no substituents) or substitutions or
Which represents an unsubstituted aromatic heterocyclic group]
Derivatives or pharmaceutically acceptable salts thereof.

(2) General formula (I)

[Chemical 10] [In the formula, R ¹ represents a hydrogen atom, a substituted or unsubstituted lower alkyl, or a substituted or unsubstituted lower alkoxy, and R ⁴ represents a substituted or unsubstituted lower alkyl or a substituted or unsubstituted lower alkoxy, R ² is the general formula (II)

[0014]

[Chemical 11] (In the formula, R^Five, R⁶, R⁷And R⁸Are the same or different
Represents a hydrogen atom or a hydroxyl-protecting group),
(I) R^Five, R⁶, R⁷And R⁸At least one of
When it is a protecting group for a hydroxyl group, and R^Five, R⁶, R⁷Oh
And R⁸Is a hydrogen atom, and R¹Is substituted lower alkyl
Or a substituted or unsubstituted lower alkoxy
Come, R³Is substituted or unsubstituted aryl or substituted
Or an unsubstituted aromatic heterocyclic group, (ii) R^Five,
R⁶, R⁷And R⁸Is a hydrogen atom, and R ¹Is hydrogen
When it is a child or lower alkyl, R³Is replaced or
Unsubstituted lower alkylsulfinylaryl, substituted if
Or unsubstituted lower alkylsulfonylaryl or
Represents a substituted or unsubstituted aromatic heterocyclic group]
A pyrazole derivative or a pharmaceutically acceptable salt thereof.

(3) The general formula (II) is replaced by the general formula (II
a)

[Chemical 12]

(Where R is^Five, R⁶, R⁷And R⁸Is that
Which is the same as the above), and the above (1) or (2)
The pyrazole derivatives listed above or their pharmacologically acceptable
salt. (4) R^Five, R⁶, R⁷And R⁸Is a hydrogen atom
The pyrazole derivative according to any one of (1) to (3)
Or a pharmacologically acceptable salt thereof. (5) Whether the hydroxyl-protecting group is (i) an acyl group,
Or (ii) two protecting groups together-CQ¹Q²(C
H₂)_n-(In the formula, n represents an integer of 0 to 6, and Q ¹and
Q²Are the same or different and also a hydrogen atom, halogen,
Or unsubstituted lower alkyl, substituted or unsubstituted low alkyl
Represents a primary alkoxy or a substituted or unsubstituted aryl
Above) to form —PO (OH) — or —CO—
The pyrazole derivative according to any one of (1) to (3)
Or a pharmacologically acceptable salt thereof.

(6) The pyrazole derivative or the pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), wherein the hydroxyl-protecting group is an acyl group. (7) (i) R ⁵ is an acyl group, and R ⁶ , R ⁷ and R ^{8 are}
Is a hydrogen atom, (ii) R ⁵ and R ⁶ are the same or different and are acyl groups, R ⁷ and R ⁸ are hydrogen atoms, and (iii) R ⁷
Is an acyl group, R ⁵ , R ⁶ and R ⁸ are hydrogen atoms, or (iv) R ⁸ is an acyl group and R ⁵ , R ⁶ and R ⁷ are hydrogen atoms (1) to (3). 4. The pyrazole derivative or the pharmaceutically acceptable salt thereof according to any of 1.

(8) The pyrazole derivative according to any one of (5) to (7) above, wherein the acyl group is lower alkanoyl, lower alkoxycarbonyl, lower alkoxy lower alkanoyl or lower alkoxy lower alkoxycarbonyl, or a pharmacological agent thereof. Acceptable salt. (9) Two protecting groups together form -CQ ¹ Q ² (C
H _{2) n} - (In the formula, n, Q ¹ and Q ² each have the same meanings as defined above), - PO (OH) - or -CO- in any one of (1) to (3) to form a The pyrazole derivative described above or a pharmaceutically acceptable salt thereof.

(10) R ⁷ and R ⁸ together are-
_{^{CQ 1 Q 2 (CH 2)}} n - ( wherein, Q ¹ and Q ² each have the same meanings as defined above), - PO (OH) - or -CO-
The pyrazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3) above, which forms (11) The pyrazole derivative or the pharmacology thereof according to the above (5), (9) or (10), wherein Q ¹ and Q ² are the same or different and each is a hydrogen atom, substituted or unsubstituted lower alkyl or lower alkoxy. Acceptable salt.

(12) The pyrazole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (11) above, wherein R ³ is a substituted or unsubstituted aryl. (13) The pyrazole derivative according to any one of (1) to (11) above, wherein R ³ is a substituted or unsubstituted lower alkylsulfinylaryl or a substituted or unsubstituted lower alkylsulfonylaryl, or a pharmaceutically acceptable salt thereof. Salt.

(14) The above (1) to (1) in which R ¹ is a hydrogen atom and R ⁴ is a substituted or unsubstituted lower alkyl.
The pyrazole derivative according to any of 3) or a pharmaceutically acceptable salt thereof. (15) The above (1), wherein R ⁴ is trifluoromethyl
The pyrazole derivative according to any one of (14) or a pharmaceutically acceptable salt thereof.

(16) A medicament containing the pyrazole derivative or the pharmaceutically acceptable salt thereof according to any of (1) to (15) above as an active ingredient. (17) A therapeutic agent for diabetes containing the pyrazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (15) as an active ingredient. (18) A preventive agent for diabetes, which comprises the pyrazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (15) as an active ingredient.

(19) A preventive and / or therapeutic agent for diabetic complications, which comprises, as an active ingredient, the pyrazole derivative or the pharmaceutically acceptable salt thereof described in any of (1) to (15) above. (20) A hypoglycemic agent containing the pyrazole derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (15) as an active ingredient.

(21) An SGLT inhibitor containing the pyrazole derivative or the pharmaceutically acceptable salt thereof described in any of (1) to (15) above as an active ingredient. From another point of view, the present invention provides a) for the manufacture of the above medicament,
Use of a pyrazole derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof, (b) a method for treating diabetes, which comprises a pyrazole derivative represented by the general formula (I) or a pharmacological salt thereof Which comprises administering a therapeutically effective amount of a pharmaceutically acceptable salt to mammals including humans, and c) a method of lowering blood glucose level, which comprises a pyrazole derivative represented by the general formula (I) or pharmacology thereof. Relates to a method comprising the step of administering to a mammal, including a human, an effective amount of a pharmaceutically acceptable salt.

Hereinafter, the compound represented by the general formula (I) is referred to as a compound (I). The same applies to compounds having other formula numbers.

[0026]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of each group of the general formula (I), the (a) hydroxyl group-protecting group is a conventional one which can be easily removed by a conventional method such as acid treatment, hydrolysis or reduction. Hydroxyl protecting groups [eg Protective Groups in Organic Synthesis (Protecti
ve Groups in Organic Synt
hesis), written by TW Greene,
John Wiley & Sons, In
c. ) (1981), etc.]. Specifically, for example, (i) tri-lower alkylsilyl (for example, t
ert-butyldimethylsilyl, triisopropylsilyl, trimethylsilyl, etc.), lower alkoxy lower alkyl (eg, methoxymethyl, methoxyethyl, etc.), trimethylsilylethyl, benzyloxymethyl, etc. (i
i) an acyl group (said acyl group is an acyl group is as defined above) and the like to be described later, also is (iii) 2 one protecting group together, for example, _{^{-CQ 1 Q 2 (CH 2)}} n - (Where n,
Q ¹ and Q ² have the same meanings as described above), -PO
You may form (OH)-, -CO-, etc. However, the hydroxyl-protecting group is not limited to these, and has a function of deprotecting to give a hydroxyl group after administration into the living body, a function of facilitating absorption into the living body or administration into the living body, or a lipid. Any compound having a function of increasing solubility or water solubility can be preferably used.

(B) The lower alkyl portion of lower alkyl, lower alkoxy, lower alkylsulfinylaryl, lower alkylsulfonylaryl, lower alkanoyl, lower alkoxy lower alkanoyl, lower alkoxycarbonyl and lower alkoxy lower alkoxycarbonyl has 1 carbon atom (s). ~ 6 straight or branched chain, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, te
Examples thereof include rt-butyl, n-pentyl, neopentyl, n-hexyl and the like.

The alkylene part of (c) lower alkoxy lower alkanoyl and lower alkoxy lower alkoxycarbonyl has the same meaning as the above lower alkyl with one hydrogen atom removed. (D) The aryl moiety of aryl, lower alkylsulfinylaryl and lower alkylsulfonylaryl includes, for example, an aromatic group consisting of a monocyclic ring or two or more condensed rings, and specifically, the number of ring-constituting carbon atoms. Is preferably about 6 to 14 and examples thereof include phenyl, naphthyl, indenyl and the like.

Examples of the (e) acyl group include lower alkanoyl [wherein the lower alkyl part of the lower alkanoyl is the same as the lower alkyl part (b) of the lower alkanoyl], lower alkoxy lower alkanoyl [of the lower alkoxy lower alkanoyl The lower alkyl part and the alkylene part are respectively synonymous with the lower alkyl part (b) and the alkylene part (c) of the lower alkoxy lower alkanoyl], lower alkoxycarbonyl [wherein the lower alkyl part of the lower alkoxycarbonyl is the same as the above lower alkoxycarbonyl]. Has the same meaning as the lower alkyl moiety (b)], lower alkoxy lower alkoxycarbonyl [wherein the lower alkyl moiety and alkylene moiety of the lower alkoxy lower alkoxycarbonyl are the above lower alkoxy lower alkoxycarbonyl Is synonymous with lower alkyl moiety (b) and the alkylene moiety (c)], the aryl portion of the arylcarbonyl [said aryl carbonyl can be mentioned the aryl (d) as synonymous] like. In addition, a residue obtained by removing a hydroxyl group in one carboxyl group from an amino acid is also included. Examples of the residue obtained by removing the hydroxyl group in one carboxyl group from the amino acid include, for example, aspartic acid, glutamic acid, glutamine, serine, sarcosine, proline, phenylalanine, leucine, isoleucine, glycine, tryptophan, cysteine, histidine, tyrosine, valine. Natural amino acids such as and the like, and a residue in which one hydroxyl group of a carboxyl group is removed from its enantiomer or racemate, and the like.

The aromatic heterocyclic group (f) includes, for example, an aromatic heterocyclic group which is monocyclic or has two or more condensed rings, and the kind and number of heteroatoms contained in the aromatic heterocyclic group. Is not particularly limited, for example, a nitrogen atom,
It may contain one or more heteroatoms selected from the group consisting of sulfur atoms and oxygen atoms. More specifically, an aromatic heterocyclic group having up to 10 ring-constituting atoms is preferable, and examples thereof include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl. , Triazinyl, indolyl,
Examples include indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl and the like.

(G) Halogen is fluorine, chlorine, bromine,
Represents each atom of iodine. (H) Substituted aryl, para-substituted lower alkylsulfinylaryl, para-substituted lower alkylsulphonylaryl, substituted lower alkylsulfinylaryl, substituted lower alkylsulphonylaryl and substituted aromatic heterocyclic groups, for example, may be the same or Differently, lower alkyl having 1 to 6 substitutions, substituted lower alkyl (substituent of substituted lower alkyl is synonymous with the substituent of substituted lower alkyl described later), lower alkoxy, substituted lower alkoxy (substituent of substituted lower alkoxy is Substituted lower-alkoxy has the same meaning as the substituent), lower alkylthio, substituted lower alkylthio (the substituted lower-alkylthio has the same meaning as the lower-substituted substituent described later), lower alkylsulfinyl, and substituted lower-alkylsulfinyl (substituted). Lower alkyl sulfi The substituent of nyl is synonymous with the substituent of substituted lower alkyl described below), lower alkylsulfonyl, substituted lower alkylsulfonyl (the substituent of substituted lower alkylsulfonyl is synonymous with the substituent of substituted lower alkyl described later), lower alkanoyl , Substituted lower alkanoyl (substituent of substituted lower alkanoyl is synonymous with substituent of substituted lower alkyl described later), mono- or di-lower alkylamino (in di-lower alkylamino, two lower alkyls may be the same or different. ), Halogen, carboxy, hydroxy, nitro, amino, cyano and the like.

As described herein, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl,
Lower alkylsulfonyl, lower alkanoyl and lower alkyl moieties of mono- or di-lower alkylamino are
It has the same meaning as the lower alkyl (b) and halogen has the same meaning as the halogen (g). (I) The substituted lower alkyl and the substituted lower alkoxy have, for example, the same or different substituents with 1 to 1 substituents.
3, lower alkoxy [wherein the lower alkyl part of the lower alkoxy is the lower alkyl part of the lower alkoxy (b)
And hydroxy, halogen [wherein the halogen has the same meaning as the above halogen (g)], lower alkoxycarbonyl [wherein the lower alkyl moiety of the lower alkoxycarbonyl is the same as the lower alkyl moiety (b) of the lower alkoxycarbonyl] And the like.

In the general formula (I), the substitution position of R ¹ is not particularly limited, and R ¹ can be substituted on any nitrogen atom on the ring. Examples of the pharmaceutically acceptable salt of compound (I) include acid addition salts such as inorganic acid salts and organic acid salts, base addition salts such as metal salts, ammonium salts and organic amine addition salts, amino acid addition salts and the like. Included. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochlorides, sulfates and phosphates, organic salts such as acetates, maleates, fumarates, tartrates and citrates. An acid salt can be given. Examples of the pharmacologically acceptable metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, as well as aluminum salt and zinc salt. You can
Examples of the pharmacologically acceptable ammonium salt include salts such as ammonium and tetramethylammonium, and examples of the pharmacologically acceptable organic amine addition salt include addition salts such as morpholine and piperidine. Can be raised. Examples of the pharmacologically acceptable amino acid addition salt include addition salts of lysine, glycine, phenylalanine and the like.

The compound (I) or a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate, and these adducts are also included in the present invention. The type of solvent that forms the solvate is not particularly limited as long as it is pharmacologically acceptable, and for example, ethanol, acetone, etc. can be used. The compound (I) has 5 or more asymmetric carbon atoms, and any of optical isomers or diastereoisomers in a pure form, any mixture of these isomers, racemate and the like are included in the present invention. . Also,
When a tautomer may exist in compound (I), it may be any tautomer, and all possible isomers and mixtures thereof are included in the present invention.

Next, a method for producing the compound (I) will be described. In the production methods shown below, when the defined group changes under the reaction conditions or is inappropriate for carrying out the method, a method commonly used in synthetic organic chemistry, such as protection or deprotection of a functional group, is used. Such as [protective
Groups in Organic Synthesis (Pro
tective Groups in Organic
Synthesis), Green (TW Green)
ne), John Wiley & Sons Incorporated (John Wiley & Son)
s, Inc. ) (1981), etc.] can be used for easy production. In addition, a person skilled in the art can obtain a compound (I) according to the production method specifically shown in the present specification, or by appropriately changing reagents or reaction raw materials, and by appropriately modifying or modifying those methods as necessary. ) Can be manufactured.

Production Method of Compound (I): Production Method 1: Compound (I) can be produced according to the following steps.

[0037]

[Chemical 13]

<In the formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as defined above, and X ² represents a leaving group. Examples of the leaving group include halogen [wherein the halogen has the same meaning as the above halogen (g)], phenylsulfonyloxy, substituted phenylsulfonyloxy (the substituent of the substituted phenylsulfonyloxy includes, for example, the same or different number of substituents) 1-3, lower alkyl [wherein the lower alkyl has the same meaning as the above lower alkyl (b)] and the like},
Lower alkylsulfonyloxy [wherein the lower alkyl moiety of the lower alkylsulfonyloxy has the same meaning as the above lower alkyl (b)], trifluoromethanesulfonyloxy, etc.> The compound (I) may be the compound (III) if necessary. It can be obtained by reacting compound (IV) in a solvent in the presence of a base and the like.

Examples of the base include triethylamine,
Examples thereof include tertiary amines such as diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, etc., and the base is 1 to 10 equivalents relative to compound (III), preferably 2 to 5
Used in equivalent amounts. Examples of the solvent include halogenated hydrocarbons such as dichloromethane, dichloroethane, 1,1,2,2-tetrachloroethane, aromatic hydrocarbons such as toluene and xylene, acetonitrile, N, N-dimethylformamide, N, N. -Dimethylacetamide, 1-
Methyl-2-pyrrolidinone, N, N′-dimethylimidazolidin-2-one, dimethylsulfoxide and the like can be mentioned, and these can be used alone or in combination.

Compound (IV) is used in an amount of 1 to 5 equivalents, preferably 2 to 3 equivalents, relative to compound (III), the reaction is carried out at a temperature between 0 and 60 ° C., and for 1 hour to 3 days. finish. The starting compound (III) is
Of Medicinal Chemistry (J. Med. C
hem. ), 39, 3920 (1996), or in accordance therewith.

Further, with respect to a part of the compound (I) obtained by the above-mentioned production method 1, a new compound (I) can be introduced by the following production method using this as a synthetic intermediate. Production Method 2: Of Compound (I), Compound (Ib) in which R ¹ is a substituted or unsubstituted lower alkyl can be produced from Compound (Ia) in which R ¹ is a hydrogen atom according to the following steps. .

[0042]

[Chemical 14]

(In the formula, R ² , R ³ and R ⁴ have the same meanings as described above, X ¹ has the same meaning as X ² and R ^1b represents R 1
¹ represents a substituted or unsubstituted lower alkyl in the definition of ¹ ) Compound (Ib) can be obtained by reacting compound (Ia) with compound (V) in a solvent in the presence of a base and the like if necessary. it can. Examples of the base include tertiary amines such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydrogencarbonate. The base is 1 to the compound (Ia). 10 equivalents, preferably 2-5 equivalents are used.

Examples of the solvent include halogenated hydrocarbons such as dichloromethane, dichloroethane and 1,1,2,2-tetrachloroethane, aromatic hydrocarbons such as toluene and xylene, acetonitrile, N, N-dimethylformamide, and the like. N, N-dimethylacetamide, 1-methyl-
2-pyrrolidinone, N, N′-dimethylimidazolidin-2-one, dimethyl sulfoxide and the like can be mentioned, and these can be used alone or in a mixture.

The compound (V) is used in an amount of 1 to 5 equivalents, preferably 2 to 3 equivalents, relative to the compound (Ia), and the reaction is 0.
It is carried out at a temperature between -60 ° C and finishes in 1 hour to 3 days. The compound (Ia) can be obtained by the method described in the above-mentioned production method 1 or the below-mentioned production method 3, or a method analogous thereto. Production Method 3: Of Compound (I), Compound (Ia) is R
It can be produced from compound (Ic) in which ¹ is methoxymethyl according to the following steps.

[0046]

[Chemical 15]

(In the formula, R ² , R ³ and R ⁴ have the same meanings as described above, and R ^1c represents methoxymethyl.) The compound (Ia) includes the compound (Ic) in an amount of 1 to 10 equivalents,
Preferably, it can be obtained by treating in a suitable solvent in the presence of an acid such as 2 to 5 equivalents of trifluoroacetic acid, boron trifluoride / diethyl ether complex, hydrogen chloride aqueous solution and the like.

Examples of the solvent include water, acetonitrile, acetic anhydride and the like, which may be used alone or in a mixture. The reaction is carried out at a temperature between 0 and 60 ° C. and is completed in 1 hour to 3 days. The compound (Ic)
Can be obtained by the method described in the above-mentioned production method 1 or production method 2 or by modifications thereof. Production Method 4: In the compound (Ie), wherein R ³ is a substituted or unsubstituted lower alkylsulfinylaryl or a substituted or unsubstituted lower alkylsulfonylaryl, the corresponding R ³ is a lower alkylthioaryl. It can be produced from a compound (Id) or compound (VI) according to the following steps.

[0049]

[Chemical 16]

[Wherein R ¹ , R ² and R ⁴ have the same meanings as described above, R ^3e represents a substituted or unsubstituted lower alkyl [wherein the lower alkyl has the same meaning as the above lower alkyl (b),
The substituent of the substituted lower alkyl has the same meaning as the above-mentioned substituent (i) of the substituted lower alkyl, and n ^e represents 1 or 2.} The compound (Ie) is the compound (Id) or the compound (V
It can be obtained by treating I) with an oxidizing agent in a solvent.

Examples of the oxidizing agent include a monopersulfate compound, metachloroperbenzoic acid (MCPBA), aqueous hydrogen peroxide, etc., and the oxidizing agent is 0.1 to the compound (Id) or the compound (VI). It is used in an amount of 5 to 10 equivalents, preferably 0.7 to 5 equivalents. Examples of the solvent include ketones such as acetone and methyl ethyl ketone, methanol,
Examples thereof include alcohols such as ethanol, halogenated hydrocarbons such as dichloromethane and chloroform, water and the like, and these can be used alone or in a mixture.

The reaction is carried out at a temperature between 0 ° C. and room temperature and is completed in 1 to 12 hours. The compound (Id) or the compound (VI) can be obtained by the method described in the above-mentioned production method 1, production method 2 or production method 3 or a modification thereof. Production Method 5: Deprotection of compound (If) in which any one of R ⁵ , R ⁶ , R ⁷ and R ⁸ is a hydroxyl-protecting group, or R ⁵ ,
Introduction of a protective group into a compound (Ig) in which any one of R ⁶ , R ⁷ and R ⁸ is a hydrogen atom can be achieved by, for example, protecting
Groups in Organic Synthesis (Pro
tective Groups in Organic
Synthesis), Green (TW Green)
ne), John Wiley & Sons, Inc. (John Wiley & Sons,
Inc. ) (1981) or the like.

The intermediate compound and the target compound obtained in the above-mentioned production method are purified by a method commonly used in synthetic organic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography and the like. It can be isolated and purified by means. In addition, the intermediate compound can be subjected to the next reaction without being particularly purified. In the case of producing a salt of compound (I), the free form of compound (I) is dissolved or suspended in an appropriate solvent, and then an appropriate acid or base is added to form a salt, and if necessary, It may be separated and purified. It is also possible to convert the desired substance obtained in the form of a salt into the compound (I) in a free form and then to the desired salt.

Specific examples of the compound (I) obtained by the above production method are shown in Table 1.

[0055]

[Table 1]

[0056]

[Table 2]

Next, for the pharmacological action of a typical compound (I)
This will be specifically described with reference to test examples. Test Example 1: SGLT inhibitory activity Pig proximal tubular epithelial cell line LLC-PK₁35 mm
4x10 for nourishing dishes^Fivecells / dish / 2mL
The seeds were sowed and used to be completely confluent. culture
The supernatant is aspirated and the reaction buffer at 37 ° C. [140 mmol
/ L NaCl, 2 mmol / L KCl, 1 mmol /
L CaCl₂1 mmol / L MgCl ₂・ 6H₂O,
10 mmol / L N- (2-hydroxyethyl) pipe
Radine-N'-2-ethanesulfonic acid (Hepes, Nacala
Made by Itesque, abbreviated as HEPES hereinafter), 5 mmol / L
 Tris (hydroxymethyl) aminomethane (Tris,
(Hereinafter abbreviated as Tris), pH 7.3] washed once with 2 mL
Then, add 2 mL of 37 ° C. reaction buffer, and add 10 mL.
Pre-incubated for ~ 15 minutes. 0.05 mmol / L α-
Methyl-D-glucoside (hereinafter abbreviated as AMG), 7.4
kBq [¹⁴C] AMG (Amersham, USA) and
And drug dissolved dimethyl sulfoxide (hereinafter DMSO
2.5 μL (final concentration 1 nmoL / L-10 μ)
0.5 mL of reaction buffer containing moL / L)
Incubated for 0 minutes. Aspirate the supernatant and ice-cool the phosphate buffer
(Manufactured by ICN, abbreviated as PBS below)
Stop the uptake and add 1 mL of 1moL / L NaOH
The cells were thawed by adding and standing still at room temperature for 30 minutes (thin cells).
Cell melt). 1moL / L HCl 1m to cell lysate
After neutralizing by adding L, ULTIMA was added to 1 mL of this neutralization solution.
 GOLD (Packard, Netherlands
s) Add 8 mL and add liquid scintillation counter
-Radiation at (LS6500, Beckman, USA)
The activity was measured. In addition, Na⁺AMG in the absence
When measuring the amount of uptake (Blank) of⁺
Reaction buffer with choline replaced by choline
Liquid (140 mmol / L choline chlori
de, 2 mmol / L KCl, 1 mmol / L CaC
l₂1 mmol / L MgCl₂・ 6H₂O, 10 mmo
1 / L HEPES, 5 mmol / L Tris, pH
7.3) was used. In addition, WAY-
123783 [Journal of Medicinal Chem
Streamy (J. Med. Chem.), Volume 39, Volume 3
920 (1996)].

[0058]

[Chemical 17]

The SGLT inhibitory activity was measured by using the AMG uptake amount (nmol / dish) per culture dish as an index, and the inhibition rate was calculated by the following formula. The concentration at which AMG uptake is inhibited by 50% (IC ₅₀ ) is Probi.
It was calculated by the t-method (logistic model).

[0060]

[Equation 1]

SAM: AMG uptake amount at the time of drug addition CONT: AMG uptake amount at the time of no drug addition (DMSO only addition) BLANK: AMG uptake amount in the absence of Na ^{+ The} results are shown in Table 2.

[0062]

[Table 3]

Table 2 shows that the compound of the present invention has a stronger SGLT inhibitory activity than WAY-123783 used as a comparative control. Test Example 2: GLUT1 inhibitory activity Human blood was centrifuged (300 xg, 10 minutes, 4 ° C) to sediment erythrocytes, and plasma and leukocyte layers were removed. A 10-fold amount of physiological saline was added and gently mixed, and then centrifuged again to remove the supernatant. After performing this washing operation three times, the hematocrit was diluted with a physiological saline solution to 20%.

100 μL of the erythrocyte diluted solution was dispensed into a 2 mL tube and left still for several tens of minutes in ice water. 18.5kBq D
- [6- ³ H] glucose (Amersham made, US
A) DMSO 0.2 μL (final concentration 1 n) in which 3 mmol / L D-glucose (Kanto Kagaku) and drug were dissolved
PBS 100μ containing moL / L-10μmoL / L)
L was added and mixed. After incubation in ice water for 20 seconds, 500 μmol / L phloretin (Sigma, U
(SA) and 100 μmol / L cytochalasin B (Sigma, USA), 900 μL of ice-cooled PBS was added to stop the reaction. N-dibutyl phthalate (500 μL) was added as a separating agent, and the cells were centrifuged (10000 × g, 1 minute) to sediment the blood cells and suck the aqueous layer. 1.5 mL of water was added without disturbing the n-dibutyl phthalate layer to wash the wall of the tube, and then the aqueous layer and the n-dibutyl phthalate layer were sucked. 1 v / v% TritonX-1 in the isolated blood cells
00 (Triton surfactant, Yoneyama Pharmaceutical Co., Ltd.) 100
μL was added and mixed well, and the whole amount was transferred to a vial. Further, the tube was rinsed with 100 μL of 1 v / v% Triton X-100, and the whole amount was transferred to a vial. Soluen
e-350 (Packard, Netherlands)
s) and ethanol mixed solution (mixing ratio 1: 2) 500 μL
And mix until there is no solid (hemocyte membrane),
Bleaching was performed by adding 500 μL of 30% hydrogen peroxide solution. Add 50 mL of acetic acid to neutralize, ULTIMA GOLD 1
Liquid scintillation counter (LS
Radioactivity was measured at 6500, Beckman, USA). Also, as a comparative drug, WAY-123783
Was tested.

GLUT1 activity is the glucose uptake in erythrocytes per assay tube (nmol /
Tube) was used as an index for measurement. The inhibition rate was calculated by the following formula. The concentration at which glucose uptake is inhibited by 50% (IC ₅₀ ) is the Probit method (logistic).
model).

[0066]

[Equation 2]

SAM: Glucose uptake amount when drug is added CONT: Glucose uptake amount when drug is not added (DMSO only is added) BLANK: Glucose uptake when the drug was added after adding the reaction stop solution C. BLANK: Table 3 shows the glucose uptake results when the solvent was added after the reaction stop solution was added.

[0068]

[Table 4]

According to Table 3, the compounds of the present invention show remarkable GL.
It was shown that there is no UT1 inhibitory effect. Test Example 3: Urinary glucose excretion test by intravenous administration in rats SLC SD male rats were pentobarbital sodium (Nembutal injection, Dainippon Pharmaceutical, Osaka) (50
mg / kg, i. p. ), The abdomen is opened, and a urine collection tube (PE-50, Nip) is inserted into the bladder from the bladder apex.
pon Becton Dickinson, Tokyo). When the flow rate of urine was stable, the drug solution prepared by the following method was administered through the femoral vein in a volume of 0.1 mL / 100 g body weight, and urine was collected for 2 hours after the administration. The glucose concentration in urine is AU500 / Katayama Chemical Co., Ltd.
The measurement was performed using a glucose measuring reagent for exclusive use of 550. In addition, as a comparative drug, Vehicle [10 w / v% polyethylene glycol # described in the method for preparing a drug solution below]
400 (PEG-400, Kanto Kagaku, Tokyo) only].

Preparation of drug solution: A drug solution was prepared by dissolving it in a physiological saline solution containing 10 w / v% polyethylene glycol # 400. The results are shown in Table 4.

[0071]

[Table 5]

As is clear from Table 4, the compound of the present invention showed a remarkable urinary glucose excretion promoting action upon intravenous administration to rats. Test Example 4: Urinary glucose excretion test in oral administration to rats SLC SD male rats were orally administered with a drug suspension prepared by the following method at a volume of 1.0 mL / 100 g body weight,
It was placed in a metabolic cage and urine was collected for 6 hours after the administration. In addition,
The experiment was carried out under free drinking water, and the glucose concentration in urine was measured using a glucose measuring reagent for exclusive use of AU500 / 550 manufactured by Katayama Chemical Co., Ltd. In addition, as a comparative drug, Vehicle [0.
5% methyl cellulose 400 cP (methyl ce
llulose, manufactured by Wako Pure Chemical Industries) only], WAY-123
783 and compounds described in WO01 / 16147 (B
The test was carried out using a).

[0073]

[Chemical 18]

Preparation of drug suspension: The drug was prepared by suspending the drug in 0.5% methylcellulose 400 cP. The fifth result
Shown in the table.

[0075]

[Table 6]

As is clear from Table 5, the compound of the present invention showed a remarkable urinary glucose excretion promoting action in oral administration to rats, compared to WAY-123783 and compound (Ba) used as comparative controls. As an active ingredient of medicine,
One or more substances selected from the group consisting of compound (I) and a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof can be used. Although the above substances can be administered alone,
Usually, it is desirable to provide it in the form of a pharmaceutical composition containing the above-mentioned substance as an active ingredient and one or more additives for formulation. These medicines can be administered to humans and other mammals.

The form of the pharmaceutical composition is not particularly limited, and an appropriate form most suitable for the purpose of treatment or prevention can be selected from the dosage forms for oral administration or parenteral administration. Formulation forms suitable for oral administration include, for example, tablets, powders, granules, syrups and the like, and formulation forms suitable for parenteral administration include, for example,
Examples thereof include injections, but are not limited thereto.

Liquid preparations suitable for oral administration, for example, syrups and the like include water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, p-
It can be produced using antiseptics such as hydroxybenzoic acid esters, flavors such as strawberry flavor, peppermint and the like. Further, for the production of solid preparations such as tablets, powders and granules, for example, excipients such as lactose, glucose, sucrose and mannitol, starch, disintegrating agents such as sodium alginate, magnesium stearate, talc and the like. A lubricant, a binder such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, a surfactant such as a fatty acid ester, a plasticizer such as glycerin and the like can be used.

Injectable formulations suitable for parenteral administration preferably contain the above-mentioned substances as active ingredients in dissolved or suspended form in a sterile aqueous medium that is isotonic with the blood of the recipient. For example, in the case of an injection, a solution can be prepared using a salt solution, a glucose solution, an aqueous medium composed of a mixture of salt water and a glucose solution, or the like. These formulations for parenteral administration include one selected from glycols, oils, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. or It is also possible to add two or more auxiliary components.

The dose and frequency of administration of compound (I) are
It is desirable to increase or decrease appropriately depending on various factors such as the type and severity of disease, administration form, conditions such as patient's age and weight, presence or absence of complications, etc.
It is preferable to administer 00 mg / kg in 3 to 4 divided doses. The compound (I) or a pharmaceutically acceptable salt thereof is useful, for example, as an active ingredient of a drug, but the use of the compound (I) or a pharmaceutically acceptable salt thereof is limited to this specific use. There is no limitation.

[0081]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to the following examples. Example 1: 4-[(4-methylthiophenyl) methyl]
-3- (2,3,4,6-O-tetraacetyl-β-D
-Glucopyranosyloxy) -5-trifluoromethyl-1H-pyrazole (Compound 1) Journal of Medicinal Chemistry (J.
Med. Chem. ), 39, 3920 (199
6-years) 1,2-dihydro-4-obtained by the method described in
[(4-Methylthiophenyl) methyl] -5-trifluoromethyl-3H-pyrazol-3-one (4.00
g, 13.9 mmol) and 2,3,4,6-O-tetraacetyl-β-D-glucopyranosyl bromide (14.
78 g, 36.1 mmol) of acetonitrile (300
mL) solution in potassium carbonate (9.69 g, 70.1 mm)
ol) was added and the mixture was stirred at room temperature for 3 days. Volume of reaction solution is 1
Acetonitrile was distilled off until the ratio became / 2, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform.
The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 10: 1) to give the title compound (4.95 g,
58%). ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 1.91 (s, 3H), 2.03 (s,
3H), 2.04 (s, 3H), 2.08 (s, 3H), 2.44 (s, 3H), 3.
73 (s, 2H), 3.83 (m, 1H), 4.19 (dd, 1H, J = 12.4,
2.2 Hz), 4.27 (dd, 1H, J = 12.4, 4.3 Hz), 5.15-5.2
9 (m, 3H), 5.40 (m, 1H), 7.08 (d, 2H, J = 8.4 Hz),
7.15 (d, 2H, J = 8.4 Hz) IR (neat, cm ^-1 ): 1755, 1714, 1495, 1437, 1367, 122
8, 1134 TOF-MS: m / z 618 (M ⁺ )

Example 2: 1-Methoxymethyl-4-
[(4-Methylthiophenyl) methyl] -3- (2,
3,4,6-O-Tetraacetyl-β-D-glucopyranosyloxy) -5-trifluoromethylpyrazole (Compound 2a) and 1-methoxymethyl-4-[(4-methylthiophenyl) methyl]- 5- (2,3,4,6-
O-tetraacetyl-β-D-glucopyranosyloxy) -3-trifluoromethylpyrazole (Compound 2
b) Compound 1 obtained in Example 1 (4.84 g, 7.83 m)
chloromethyl methyl ether (1.20 mL, 15.8 mmo) in a dichloromethane (50 mL) solution.
1) and triethylamine (2.20 mL, 15.8)
mmol) was added and the mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 10: 1) to give the title compound (2.82 g, 54%) as the compound 2a and the compound 2b.
(Mixing ratio: compound 2a: compound 2b = 65: 3)
Obtained as 5). Compound 2a: ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 1.89-2.17 (m, 12H), 2.
44 (s, 3H), 3.35 (s, 3H), 3.39-3.74 (m, 1H), 3.86
(brs, 2H), 3.86-4.26 (m, 2H), 4.87-5.68 (m, 6H), 7.
02-7.20 (m, 4H) Compound 2b: ¹ H-NMR (270 MHz, CDCl ₃ ) δ 1.89-2.17 (m, 12H), 2.4
7 (s, 3H), 3.39 (s, 3H), 3.39-3.74 (m, 1H), 3.75
(brs, 2H), 3.86-4.26 (m, 2H), 4.87-5.68 (m, 6H),
7.02-7.20 (m, 4H) IR (neat, cm ^-1 ): 1754, 1585, 1494, 1440, 1403, 131
7, 1269, 1168 TOF-MS: m / z 647 (M ⁺ -CH ₃ )

Example 3: 3- (β-D-glucopyranosyloxy) -1-methoxymethyl-4-[(4-methylthiophenyl) methyl] -5-trifluoromethylpyrazole (Compound 3a) and 5 -(Β-D-glucopyranosyloxy) -1-methoxymethyl-4-[(4-methylthiophenyl) methyl] -3-trifluoromethylpyrazole (Compound 3b) Compound 2a obtained in Example 2; A mixture of compound 2b (2.03 g, 3.07 mmol) in methanol (50
(mL) solution, a 28% sodium methoxide methanol solution (2.68 g, 13.9 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Methanol was distilled off until the volume of the reaction solution was reduced to 1/2, 2 mol / L HCl aqueous solution was added to acidify the liquid property, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) and the title compound (white solid 1.
13 g, 73%) was obtained as a mixture of compound 3a and compound 3b (mixing ratio compound 3a: compound 3b = 65: 35). Compound 3a: ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 2.38 (s, 3H), 3.27 (s,
3H), 3.51-3.67 (m, 2H), 3.70-3.76 (m, 3H), 3.98-
4.92 (br, 3H), 5.22-5.41 (m, 3H), 7.00-7.12 (m, 4
H) Compound 3b: ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 2.39 (s, 3H), 3.40 (s,
3H), 3.51-3.67 (m, 2H), 3.70-3.76 (m, 1H), 3.86
(brs, 2H), 3.98-4.92 (br, 3H), 5.22-5.41 (m, 3H),
7.00-7.12 (m, 4H) IR (neat, cm ^-1 ): 1508, 1491, 1457, 1130, 1097, 106
6 TOF-MS: m / z 494 (M ⁺ )

Example 4: 3- (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -1-methoxymethyl-4-[(4-methylthiophenyl) methyl]
-5-trifluoromethylpyrazole (compound 4a) and 5- (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -1-methoxymethyl-4-[(4-
Methylthiophenyl) methyl] -3-trifluoromethylpyrazole (Compound 4b) To a 2,4,6-collidine (9 mL) solution of the mixture (846 mg, 1.71 mmol) of Compound 3a and Compound 3b obtained in Example 3 was obtained. , Methyl chloroformate (0.20m
L, 2.59 mmol) of dichloromethane (1.0 m
L) solution was added, and the mixture was added at -40 ° C for 1 hour and at room temperature for 2 hours.
Stir for hours. A 2 mol / L HCl aqueous solution was added to the reaction solution to make the solution acidic, and then extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the title compound (75
0 mg, 79%) was obtained as a mixture of compound 4a and compound 4b (mixing ratio compound 4a: compound 4b = 65: 35). Compound 4a: ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 2.45 (s, 3H), 3.34 (s,
3H), 3.42-3.68 (m, 4H), 3.79 (s, 3H), 3.85 (brs,
2H), 4.18-4.62 (m, 2H), 5.23-5.64 (m, 3H), 7.01-7.
19 (m, 4H) Compound 4b: ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 2.45 (s, 3H), 3.41 (s,
3H), 3.42-3.68 (m, 4H), 3.78 (s, 3H), 3.93 (brs,
2H), 4.18-4.62 (m, 2H), 5.23-5.64 (m, 3H), 7.01-7.
19 (m, 4H) IR (KBr, cm ^-1 ): 1490, 1441, 1392, 1302, 1275, 117
2, 1124 TOF-MS: m / z 551 (M ⁺ -H)

Example 5: 3- (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -4-[(4
-Methylthiophenyl) methyl] -5-trifluoromethyl-1H-pyrazole (Compound 5) Trifluoroacetic acid (9 mL) and water were added to the mixture (750 mg, 1.36 mmol) of compound 4a and compound 4b obtained in Example 4. (1.0 mL) was added, and at room temperature, 2
It was stirred for a day. The reaction solution was poured into ice water (50 mL) and extracted with chloroform. The organic layer was washed with saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (310 mg, 45%). Melting point: 102.5-103.5 ° C (methanol-water) ¹ H-NMR (270 MHz, DMSO-d ₆ ) δ: 2.42 (s, 3H), 3.23-
3.52 (m, 5H), 3.67 (s, 3H), 3.72 (brs, 2H), 4.16 (d
d, 1H, J = 11.2, 5.6 Hz), 4.34 (brd, 1H, J = 11.5 H
z), 5.21 (br, 1H), 5.31 (brd, 1H, J = 5.0 Hz), 5.5
0 (br, 1H), 7.02-7.19 (m, 4H) IR (KBr, cm ^-1 ): 1734, 1637, 1490, 1442, 1319, 127
4, 1136, 1066 TOF-MS: m / z 508 (M ⁺ )

Example 6: 3- (β-D-Glucopyranosyloxy) -4-[(4-methylsulfinylphenyl) methyl] -5-trifluoromethyl-1H-pyrazole (Compound 6) Reference Example 1 Compound (Ba) obtained in (22 mg, 0.0
MCPBA in a methanol (1 mL) solution of 5 mmol).
(7 mg, 0.04 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After methanol was distilled off from the reaction solution under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the title compound (5 mg, 20%). ¹ H-NMR (270 MHz, CD ₃ OD) δ: 2.76 (s, 3H), 3.29-3.3
6 (m, 3H), 3.68 (brd, 1H, J = 11.6 Hz), 3.85 (brd,
1H, J = 11.6 Hz), 3.97 (brs, 2H), 4.58 (s, 1H), 5.2
7 (m, 1H), 7.46 (d, 2H, J = 8.4 Hz), 7.60 (d, 2H,
J = 8.4 Hz) TOF-MS: m / z 465 (M ⁺ -1)

Example 7: 3- (β-D-glucopyranosyloxy) -4-[(4-methylsulfonylphenyl)
Methyl] -5-trifluoromethyl-1H-pyrazole (Compound 7) Compound (Ba) obtained in Reference Example 1 (22 mg, 0.0
5 mmol) in methanol (2 mL), MCPB
A (28 mg, 0.16 mmol) was added, and at room temperature, 2
Stir for hours. After methanol was distilled off from the reaction solution under reduced pressure, water and methanol were added to the residue to remove precipitated crystals. After concentrating the filtrate, silica gel column chromatography (chloroform: methanol = 20: 1)
The title compound (6 mg, 26%) was obtained. ¹ H-NMR (270 MHz, CD ₃ OD) δ: 3.08 (s, 3H), 3.29-3.4
0 (m, 2H), 3.58 (m, 1H), 3.66 (dd, 1H, J = 11.9,
3.8 Hz), 3.85 (d, 1H, J = 11.9 Hz), 4.00 (s, 2H),
4.58 (s, 1H), 4.85 (m, 1H), 7.48 (d, 2H, J = 8.1 H
z), 7.82 (d, 2H, J = 8.1 Hz) TOF-MS: m / z 481 (M ⁺ -1)

Reference Example 1: 3- (β-D-Glucopyranosyloxy) -4-[(4-methylthiophenyl) methyl] -5-trifluoromethyl-1H-pyrazole [Compound (Ba)] Example Compound 1 obtained in 1 (908 mg, 1.48 m
50% potassium carbonate aqueous solution (2 mL) was added to an ethanol (15 mL) solution of (mol) and stirred at room temperature for 1 hour. Concentrate the reaction mixture to 1/2 its volume and
The mixture was acidified with 1 / L HCl aqueous solution and then extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (45.7 mg, 7%) as a white solid. Melting point: 107.0 to 108.5 ° C (chloroform-diethyl ether) ¹ H-NMR (270 MHz, DMSO-d ₆ ) δ: 2.48 (s, 3H), 3.03-
3.30 (m, 6H), 3.46 (m, 1H), 3.65 (m, 1H), 3.73 (br
s, 2H), 4.53 (br, 1H), 5.01 (br, 1H), 5.10 (br, 1
H), 7.09-7.16 (m, 4H), 13.3 (br, 1H) IR (KBr, cm ^-1 ): 1497, 1460, 1331, 1257, 1126, 108
4, 1051 TOF-MS: m / z 449 (M ⁺ -H) Elemental analysis: Calculated as C ₁₈ H ₂₁ F ₃ N ₂ O ₆ S.0.8H ₂ O (%): C, 46.51; H, 4.90; N, 6.03 Found (%): C, 46.57; H, 4.99; N, 5.75

[0089]

INDUSTRIAL APPLICABILITY The present invention can provide a pyrazole derivative or a pharmacologically acceptable salt thereof which has a hypoglycemic effect and is useful as an agent for preventing and / or treating diabetes.

Continued front page    (72) Inventor Hideaki Kusaka             1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture Kyowa Fermentation             Industry Research Institute, Pharmaceutical Research Institute (72) Inventor Kenichi Takeshita             1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture Kyowa Fermentation             Industry Research Institute, Pharmaceutical Research Institute (72) Inventor Yoshiko Matsumoto             1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture Kyowa Fermentation             Industry Research Institute, Pharmaceutical Research Institute (72) Inventor Masayuki Abe             1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture Kyowa Fermentation             Industry Research Institute, Pharmaceutical Research Institute (72) Inventor Yoshihisa Ota             1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture Kyowa Fermentation             Industry Research Institute, Pharmaceutical Research Institute (72) Inventor Yuji Nomoto             1188 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture Kyowa Fermentation             Industry Research Institute, Pharmaceutical Research Institute F-term (reference) 4C057 AA17 BB02 DD02 KK01                 4C086 AA01 AA02 AA03 EA11 MA01                       MA04 NA14 ZC35 ZC41

Claims (21)

[Claims] 1. The general formula (I) [Chemical 1] [In the formula, R¹Is a hydrogen atom, a substituted or unsubstituted lower
Alkyl, or substituted or unsubstituted lower alkoxy
Represent, R^FourIs a substituted or unsubstituted lower alkyl or
Represents a substituted or unsubstituted lower alkoxy, R²Is one
General formula (II) [Chemical 2] (In the formula, R^Five, R⁶, R⁷And R⁸Are the same or different
Represents a hydrogen atom or a hydroxyl-protecting group),
(I) R^Five, R⁶, R⁷And R⁸At least one of
When it is a protecting group for a hydroxyl group, and R^Five, R⁶, R⁷Oh
And R⁸Is a hydrogen atom, and R¹Is substituted lower alkyl
Or a substituted or unsubstituted lower alkoxy
Come, R³Is substituted or unsubstituted aryl or substituted
Or an unsubstituted aromatic heterocyclic group, (ii) R^Five,
R⁶, R⁷And R⁸Is a hydrogen atom, and R ¹Is hydrogen
When it is a child or lower alkyl, R³Is also para substitution
Or unsubstituted lower alkylsulfinylaryl,
La-substituted or unsubstituted lower alkylsulfonyl ants
And substituted aryl (provided that the substituted aryl is in the para position)
Have no substituents) or substitutions or
Which represents an unsubstituted aromatic heterocyclic group]
Derivatives or pharmaceutically acceptable salts thereof. 2. The general formula (I) [Chemical 3] [In the formula, R¹Is a hydrogen atom, a substituted or unsubstituted lower
Alkyl, or substituted or unsubstituted lower alkoxy
Represent, R^FourIs a substituted or unsubstituted lower alkyl or
Represents a substituted or unsubstituted lower alkoxy, R²Is one
General formula (II) [Chemical 4] (In the formula, R^Five, R⁶, R⁷And R⁸Are the same or different
Represents a hydrogen atom or a hydroxyl-protecting group),
(I) R^Five, R⁶, R⁷And R⁸At least one of
When it is a protecting group for a hydroxyl group, and R^Five, R⁶, R⁷Oh
And R⁸Is a hydrogen atom, and R¹Is substituted lower alkyl
Or a substituted or unsubstituted lower alkoxy
Come, R³Is substituted or unsubstituted aryl or substituted
Or an unsubstituted aromatic heterocyclic group, (ii) R^Five,
R⁶, R⁷And R⁸Is a hydrogen atom, and R ¹Is hydrogen
When it is a child or lower alkyl, R³Is replaced or
Unsubstituted lower alkylsulfinylaryl, substituted if
Or unsubstituted lower alkylsulfonylaryl or
Represents a substituted or unsubstituted aromatic heterocyclic group]
A pyrazole derivative or a pharmaceutically acceptable salt thereof. 3. A compound represented by the general formula (II) is represented by the general formula (IIa): (In the formula, R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as defined above.) The pyrazole derivative or the pharmaceutically acceptable salt thereof according to claim 1 or 2. 4. The pyrazole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen atoms. 5. The hydroxyl-protecting group is (i) an acyl group, or (ii) two protecting groups are taken together to form --CQ.
¹ Q ² (CH ₂ ) _n- (wherein, n represents an integer of 0 to 6,
¹ and Q ² are the same or different and each is a hydrogen atom, halogen,
A substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower alkoxy or a substituted or unsubstituted aryl), -PO (OH)-or -CO- is formed. A pyrazole derivative or a pharmaceutically acceptable salt thereof. 6. The pyrazole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the hydroxyl-protecting group is an acyl group. 7. (i) R ⁵ is an acyl group, R ⁶ , R ⁷ and R ⁸ are hydrogen atoms, (ii) R ⁵ and R ⁶ are the same or different and are acyl groups, and R ⁷ and R ⁸ is a hydrogen atom,
(Iii) R ⁷ is an acyl group, R ⁵ , R ⁶ and R ⁸ are hydrogen atoms, or (iv) R ⁸ is an acyl group, R ⁵ , R ⁶
And R ⁷ is a hydrogen atom, The pyrazole derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. 8. The pyrazole derivative according to claim 5, wherein the acyl group is lower alkanoyl, lower alkoxycarbonyl, lower alkoxy lower alkanoyl or lower alkoxy lower alkoxycarbonyl, or a pharmaceutically acceptable derivative thereof. salt. 9. The two protecting groups taken together are --CQ ¹ Q ²
(CH _{2) n} - (wherein, n, Q ¹ and Q ² each have the same meanings as defined above), - PO (OH) - or according to any one of claims 1 to 3 to form a -CO- A pyrazole derivative or a pharmaceutically acceptable salt thereof. 10. R ⁷ and R ^{8 taken} together are —CQ.
_{^{1 Q 2 (CH 2) n}} - ( wherein, Q ¹ and Q ² each have the same meanings as defined above), - PO (OH) - or according to any one of claims 1 to 3 to form a -CO- Or a pharmaceutically acceptable salt thereof. 11. The pyrazole derivative according to claim 5, 9 or 10 or a pharmacologically acceptable thereof, wherein Q ¹ and Q ² are the same or different and each is a hydrogen atom, substituted or unsubstituted lower alkyl or lower alkoxy. Salt. 12. The pyrazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is a substituted or unsubstituted aryl. 13. R ¹ is a substituted or unsubstituted lower alkylsulfinyl aryl or a substituted or unsubstituted lower alkyl sulfonylaryl.
A pyrazole derivative or a pharmaceutically acceptable salt thereof according to any one of 1. 14. The pyrazole derivative or the pharmaceutically acceptable salt thereof according to claim ¹ , wherein R ¹ is a hydrogen atom and R ⁴ is a substituted or unsubstituted lower alkyl. 15. The pyrazole derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ is trifluoromethyl. 16. A medicine comprising the pyrazole derivative according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient. 17. A therapeutic agent for diabetes containing the pyrazole derivative according to any one of claims 1 to 15 or a pharmacologically acceptable salt thereof as an active ingredient. 18. A preventive agent for diabetes which comprises the pyrazole derivative according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient. 19. A preventive and / or therapeutic agent for diabetic complications, which comprises the pyrazole derivative according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient. 20. A hypoglycemic agent containing the pyrazole derivative according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient. 21. A Na ⁺ -glucose cotransporter [sodium-glucose cotransporter (containing a pyrazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15 as an active ingredient. SGL
T)] inhibitors.