JP2007515441A - Glucopyranosyloxy substituted aromatic compounds, medicaments containing said compounds, their use and methods for their production - Google Patents

Abstract

（式中、Ｒ¹〜Ｒ⁶及びＲ^7a、Ｒ^7b及びＲ^7cは、請求項１に記載されたものである）のグルコピラノシロキシ置換芳香族化合物に関する。本発明は、また、前記アロメートの互変体、立体異性体、混合物及び塩、特には、無機又は有機酸を含み及び有益な薬理学的特性、特にはナトリウム依存性グルコース共輸送体ＳＧＬＴ２への阻害作用を有する生理学的に相溶性塩に関する。本発明は、更に、疾患、特には代謝疾患、例えば糖尿病の治療、及び前記化合物の製造に関する。The present invention is directed to general formula (I):

(Wherein R ^{1 to} R ⁶ and R ^7a , R ^7b and R ^7c are those described in claim 1). The present invention also includes tautomers, stereoisomers, mixtures and salts of said aromates, especially inorganic or organic acids, and inhibition of beneficial pharmacological properties, particularly sodium-dependent glucose cotransporter SGLT2. Physiologically compatible salts with action. The invention further relates to the treatment of diseases, in particular metabolic diseases such as diabetes, and the preparation of said compounds.

Description

Detailed Description of the Invention

（Ｒ¹〜Ｒ⁶及びＲ^7a、Ｒ^7b及びＲ^7cは、後述に定義するようなものである）のグルコピラノシロキシ置換芳香族基、その互変体、その立体異性体、それらの混合物及びそれらの塩に関する。本発明は、また、本発明の一般式（Ｉ）の化合物を含む医薬組成物及び代謝疾患の治療のための医薬組成物を製造するための本発明の化合物の使用に関する。医薬組成物及び本発明の化合物の製造方法もまた本発明の対象である。
文献において、ナトリウム依存性グルコース共輸送体ＳＧＬＴ２に阻害作用を有する化合物が、疾患、特に糖尿病の治療のために提案されている。
グルコピラノシロキシ置換芳香族基及びそれらの製造及びそれらのＳＧＬＴ２阻害剤としての起こり得る活性は、発行されたWO 01/68660、WO 01/74834、WO 02/28872、WO 02/44192、WO 02/64606、WO 03/11880及びWO 03/80635に知られている。 The present invention is directed to general formula (I):

(R ^{1 to} R ⁶ and R ^7a , R ^7b and R ^7c are as defined below), glucopyranosyloxy-substituted aromatic groups, tautomers, stereoisomers, mixtures thereof and Relates to their salts. The invention also relates to pharmaceutical compositions comprising a compound of general formula (I) according to the invention and to the use of the compounds according to the invention for preparing a pharmaceutical composition for the treatment of metabolic diseases. Pharmaceutical compositions and methods for preparing the compounds of the present invention are also subjects of the present invention.
In the literature, compounds having an inhibitory action on the sodium-dependent glucose cotransporter SGLT2 have been proposed for the treatment of diseases, in particular diabetes.
The glucopyranosyloxy substituted aromatic groups and their preparation and their possible activity as SGLT2 inhibitors are described in published WO 01/68660, WO 01/74834, WO 02/28872, WO 02/44192, WO 02 / 64606, WO 03/11880 and WO 03/80635.

Objects of the invention The object of the present invention is to find new glucopyranosyloxy substituted aromatic groups, in particular those which are active with respect to the sodium-dependent glucose cotransporter SGLT, in particular SGLT2. It is a further object of the present invention to have an enhanced and / or better drug for the sodium-dependent glucose cotransporter SGLT2 in vitro and / or in vivo compared to known structurally similar compounds The discovery of glucopyranosyloxy substituted aromatic groups with physical or pharmacokinetic properties.
A further object of the present invention is to provide a novel pharmaceutical composition suitable for the prevention and / or treatment of metabolic diseases, particularly diabetes.
The present invention also provides a method for producing the compounds of the present invention.
Other objects of the present invention will become apparent to those skilled in the art directly from the foregoing and following description.

（式中、Ｒ¹は、Ｃ_2-6アルキニル、テトラヒドロフラン−３−イルオキシ、テトラヒドロピラン−３−イルオキシ、テトラヒドロピラン−４−イルオキシ、テトラヒドロフラニル−Ｃ_1-3アルキルオキシ又はテトラヒドロピラニル−Ｃ_1-3アルキルオキシを示し、又は、 Subject of the invention In a first aspect, the present invention provides:
A glucopyranosyloxy-substituted aromatic group of general formula (I), its tautomers, its stereoisomers, mixtures thereof and salts thereof:

Wherein R ¹ is C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 alkyloxy or tetrahydropyranyl-C _{1 -3} represents alkyloxy, or

R ³ is C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 alkyloxy and tetrahydropyranyl-C _1-3 alkyloxy. When selected from the group consisting of
R ¹ is also hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, a methyl group substituted with 1 to 3 fluorine atoms, or an ethyl group substituted with 1 to 5 fluorine atoms. , C _1-4 alkoxy, a methoxy group substituted with 1 to 3 fluorine atoms, an ethoxy group substituted with 1 to 5 fluorine atoms, hydrogen or C _1- substituted with a C _1-3 alkoxy group ₄ alkyl group, hydrogen or C _2-4 alkoxy group substituted by C _1-3 alkoxy group, C _2-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _{May be 3-6} cycloalkoxy, C _3-6 cycloalkyl-C _1-3 alkoxy, hydroxy, amino or cyano, and R ² is hydrogen, fluorine, chlorine, methyl, 1 to 3 fluorine atoms And methyl or methoxy substituted with R ³ is, C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl -C _1-3 alkyloxy or tetrahydropyranyl -C _1-3 alkyloxy Indicate or

R ¹ is C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 alkyloxy and tetrahydropyranyl-C _1-3 alkyloxy When selected from the group consisting of
R ³ is also hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkylidenemethyl, C _1-6 alkoxy, C _3-6 cycloalkyloxy, C _3-6 cycloalkyl-C _1-3 alkoxy, aryl, aryl-C _1-3 alkyl, heteroaryl, heteroaryl-C _1-3 alkyl, aryloxy, aryl-C _{1 -3} alkyloxy, methyl or methoxy group substituted by 1 to 3 fluorine atoms, C _2-4 alkyl or C _2-4 alkoxy group substituted by 1 to 5 fluorine atoms, substituted by cyano group C _1-4 alkyl groups, hydroxy or C _1-3 alkyloxy C _1-4 alkyl group substituted by a group, cyano, carboxy, C _1-3 alkylcarbonyl, aminocarbonyl, (C _1-3 alkylamino Carbonyl, di - (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C _1-3 alkyl ) -Piperazin-1-ylcarbonyl, nitro, amino, C _1-3 alkylamino, di- (C _1-3 alkyl) amino, (C _1-4 alkyl) carbonylamino, C _1-4 alkylsulfonylamino, aryl shows sulfonylamino, aryl -C _1-3 alkylsulfonylamino, C _1-4 alkylsulfanyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, alkylsulfenyl, an arylsulfinyl or arylsulfonyl,

R ⁴ and R ⁵ may be the same or different and are hydrogen, fluorine, chlorine, bromine, C _1-3 alkyl, C _1-3 alkoxy, methyl substituted by 1 to 3 fluorine atoms Or R ⁶ , R ^7a , R ^7b , R ^7c independently of one another, hydrogen, (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- Selected from (C _1-3 alkyl) carbonyl,
The aryl groups described in the above group definitions independently of one another represent phenyl or naphthyl groups which may be mono- or disubstituted by R _h , and the substituents may be the same or different. Well, and R _h represents fluorine, chlorine, bromine, iodine, C _1-3 alkyl, difluoromethyl, trifluoromethyl, C _1-3 alkoxy, difluoromethoxy, trifluoromethoxy or cyano,
Heteroaryl groups described in the above group definitions include pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl groups,
Or a pyrrolyl, furanyl, thienyl, imidazolyl or pyridyl group, wherein one or two methine groups are replaced by nitrogen atoms,
Or indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, wherein 1 to 3 methine groups are replaced by nitrogen atoms,
The heteroaryl group may be mono- or disubstituted by R _h , the substituents may be the same or different, and R _h is as defined above,
Unless otherwise stated, the alkyl group may be straight or branched.

The compounds of general formula (I) according to the invention and their physiologically acceptable salts have valuable pharmacological properties, in particular an inhibitory action on the sodium-dependent glucose cotransporter SGLT, in particular SGLT2. Further compounds of the invention may have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT1. Compared to a possible inhibitory effect on SGLT1, the compounds of the invention preferably selectively inhibit SGLT2.
The invention also relates to physiologically acceptable salts of the compounds of the invention with inorganic or organic acids.
The invention therefore also relates to the use of the compounds of the invention, including physiologically acceptable salts, as pharmaceutical compositions.
The invention also relates to a pharmaceutical composition comprising at least one compound of the invention or a physiologically acceptable salt of the invention, optionally together with one or more inert carriers and / or diluents.
A further subject of the present invention is at least the present invention for producing a pharmaceutical composition suitable for the treatment or prevention of diseases or conditions that can be affected by inhibiting the sodium-dependent glucose transporter SGLT, in particular SGLT2. The use of one compound or a physiologically acceptable salt of such a compound.

（式中、式中、Ｒ⁶、Ｒ^7a、Ｒ^7b及びＲ^7cが前述に定義したようなものであるが水素を表さず、Ｚ¹が脱離基を示す）の化合物を、一般式（ＩＩＩ）： The invention also relates to the use of at least one compound of the invention or one of their physiologically acceptable salts for the manufacture of a pharmaceutical composition suitable for the treatment of metabolic diseases.
The invention also relates to at least one compound of the invention or one of their physiologically acceptable salts for the manufacture of a pharmaceutical composition for inhibiting the sodium-dependent glucose transporter SGLT, in particular SGLT2. Concerning the use of two.
The present invention further relates to a process for the preparation of the pharmaceutical composition according to the invention, characterized in that the compound according to the invention is introduced into one or more inert carriers and / or diluents by non-chemical methods.
The present invention also provides
a) To prepare compounds of general formula (I) (wherein R ⁶ , R ^7a , R ^7b and R ^7c are as defined above but do not represent hydrogen) Formula (II):

A compound of the general formula: wherein R ⁶ , R ^7a , R ^7b and R ^7c are as defined above but do not represent hydrogen and Z ¹ represents a leaving group. (III):

（Ｒ¹〜Ｒ⁵は、前述に記載した意味を有する）の化合物と反応させ、又は
ｂ）一般式（Ｉ）（式中、Ｒ⁶、Ｒ^7a、Ｒ^7b及びＲ^7cが水素を表す）の化合物を製造するために、一般式（Ｉ）（Ｒ⁶及びＲ^7a、Ｒ^7b、Ｒ^7cが前述に定義したようなものであるが、水素を表さない）を加水分解し、及び
工程ｂ）を行った後、所望なら、そのようにして得られた一般式（Ｉ）の化合物（Ｒ⁶は水素原子を示す）を、一般式（Ｉ）の対応するアシル化合物へのアシル化により転化し、及び／又は
必要なら、上記反応の間に使用された保護基を再び開裂し及び／又は
所望なら、そのようにして得られた一般式（Ｉ）の化合物をその立体異性体にし及び／又は
そのようにして得られた一般式（Ｉ）の化合物を、それらの塩に、特には医薬用途のために生理学的に許容可能なそれらの塩に転化することを特徴とする、
本発明の一般式（Ｉ）の化合物を製造する方法に関する。

(R ^{1 to} R ⁵ have the meanings described above) or b) General formula (I) (wherein R ⁶ , R ^7a , R ^7b and R ^7c represent hydrogen) Hydrolyzing the general formula (I) (wherein R ⁶ and R ^7a , R ^7b , R ^7c are as defined above, but do not represent hydrogen) to produce the compound of After carrying out b), if desired, the compound of general formula (I) so obtained (R ⁶ represents a hydrogen atom) can be converted by acylation to the corresponding acyl compound of general formula (I), if desired. Converted and / or, if necessary, again cleaving the protecting groups used during the above reaction and / or, if desired, the compounds of general formula (I) thus obtained are made into their stereoisomers and / Or the compounds of the general formula (I) thus obtained into their salts, in particular physiologically for pharmaceutical use. Characterized by conversion to their pharmaceutically acceptable salts,
The present invention relates to a process for producing the compound of general formula (I) of the present invention.

DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, groups, balances and substituents, particularly R ^{1 to} R ⁶ and R ^7a , R ^7b , R ^7c are as defined above and below.
If the balance, substituents or groups appear several times in the compound, they may have the same or different meanings.
The term aryl used above and below denotes, for example, in the radicals R ³ , R ⁶ , R ^7a , R ^7b , R ^7c and R ^7d preferably phenyl. According to the general definition and unless otherwise stated, aryl groups, in particular phenyl groups, may be mono- or disubstituted by the same or different groups R _h .
The term heteroaryl used above and below denotes, for example, in the radical R ³ preferably pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl. In accordance with the general definition and unless otherwise stated, heteroaryl groups may be mono- or disubstituted by the same or different groups R _h .
The compounds of the invention may be described in the first embodiment of the invention by the general formula (I) and include tautomers, stereoisomers, mixtures thereof and salts thereof, wherein
R ¹ is C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 alkyloxy or tetrahydropyranyl-C _1-3 alkyloxy Indicate
The other groups R ^{2 to} R ⁶ and R ^7a , R ^7b , R ^7c are as defined above.

According to this embodiment, the preferred meaning of the radical R ¹ is ethynyl, 2-propyn-1-yl, 2-butyn-1-yl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, Tetrahydrofuranylmethyloxy and tetrahydropyranylmethyloxy. The most particularly preferred meanings are ethynyl, tetrahydrofuran-3-yloxy and tetrahydropyran-4-yloxy, especially ethynyl.
According to this embodiment, the preferred meaning of the radical R ³ is hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, Methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, methylsulfanyl, 2-methyl-1-propene-1- Yl, cyclopropylidenemethyl, ethynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy, tetrahydropyranylmethylo Shi, phenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl. Particularly preferred meanings are ethynyl, tetrahydrofuran-3-yloxy, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, especially ethynyl, tetrahydrofuran-3-yloxy and methoxy.

According to this embodiment, preferred meanings of the radical R ⁴ are hydrogen and fluorine, in particular hydrogen.
In a second embodiment of the invention, the compounds of the invention may be described by the general formula (I), including tautomers, stereoisomers, mixtures thereof and salts thereof, wherein
R ¹ is hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, a methyl group substituted with 1 to 3 fluorine atoms, an ethyl group substituted with 1 to 5 fluorine atoms, C _{1 -4} alkoxy, a methoxy group substituted with 1 to 3 fluorine atoms, an ethoxy group substituted with 1 to 5 fluorine atoms, a C _1-4 alkyl group substituted with hydrogen or a C _1-3 alkoxy group C _2-4 alkoxy group substituted by hydrogen or C _1-3 alkoxy group, C _2-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _3-6 Represents cycloalkoxy, C _3-6 cycloalkyl-C _1-3 alkoxy, hydroxy, amino or cyano, and also C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4 -Yloxy, tetrahydrofuranyl-C _1-3 alkyloxy or tetrahydropyranyl-C _1-3 alkyloxy,
R ³ is C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 alkyloxy and tetrahydropyranyl-C _1-3 alkyloxy. And other groups, in particular R ² and R ^{4 to} R ⁶ and R ^7a , R ^7b , R ^7c have the above-mentioned meanings.

According to this embodiment, the preferred meaning of R ¹ is hydrogen, fluorine, chlorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or cyano, particularly preferably hydrogen, fluorine, methyl or cyano, most Particularly preferred is hydrogen.
According to this embodiment, preferred meanings for R ³ are ethynyl and tetrahydrofuran-3-yloxy.
According to this second embodiment, preferred meanings for R ⁴ are hydrogen and fluorine, in particular hydrogen.
The following description refers to compounds of formula (I), in particular the first and second embodiments described above.
In accordance with the present invention, particularly preferred compounds according to the first and second embodiments, the following formulas (Ia), (Ib), (Ic) and (Id), in particular (Ia), (Ib) and (Ic) ) Can be represented by:

According to an alternative to the above embodiments, other preferred compounds have the phenyl group bearing the substituent R ³ have at least one other substituent R ⁴ and / or R ⁵ that is not hydrogen. According to this alternative, particularly preferred compounds are those having the substituent R ⁴ which is fluorine.
The phenyl group having the substituent R ³ is preferably at most monofluorinated.
Preferred meanings of the group R ⁵ are hydrogen and fluorine, in particular hydrogen.
Preferred meanings of the radical R ² according to the invention are hydrogen, fluorine and methyl, in particular hydrogen and methyl.
According to the invention, the group R ⁵ is preferably hydrogen, (C _1-8 alkyl) oxycarbonyl or C _1-8 alkylcarbonyl, in particular hydrogen or (C _1-6 alkyl) oxycarbonyl, particularly preferably hydrogen, Methoxycarbonyl or ethoxycarbonyl, most preferably hydrogen or methoxycarbonyl.
The substituents R ^7a , R ^7b , R ^7c are, independently of one another, preferably hydrogen, (C _1-8 alkyl) oxycarbonyl, (C _1-8 alkyl) carbonyl, benzoyl, in particular hydrogen, (C _{1 -6} alkyl) oxycarbonyl, (C _1-8 alkyl) carbonyl, particularly preferably hydrogen, methoxycarbonyl, ethoxycarbonyl, methylcarbonyl or ethylcarbonyl. Most particularly preferably R ^7a , R ^7b and R ^7c represent hydrogen.

R ⁶ , R ^7a , R ^7b and R ^7c are meanings according to the invention other than hydrogen, for example compounds of general formula (I) having C _1-8 alkylcarbonyl, preferably R ^7a , R ^7b and Suitable as intermediate in the synthesis of compounds of formula (I) in which R ^7c represents hydrogen.
Particularly preferred compounds of the general formula (I) are
(A) 1- (β-D-glucopyranosyloxy) -2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -benzene,
(B) selected from the group consisting of 1- (β-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) -benzene and derivatives thereof, wherein R ⁶ has a meaning other than hydrogen according to the present invention. And in particular R ⁶ represents ethoxycarbonyl or methoxycarbonyl, including its stereoisomers and mixtures thereof.
Some terms used above and below to describe compounds according to the present invention are more closely defined.
The term halogen denotes an atom selected from the group consisting of F, Cl, Br and I, in particular F, Cl and Br.

The term C _1-n alkyl, _{where n} can have a value from 1 to 18, refers to a saturated, branched or unbranched hydrocarbon group having _{1 to n} C atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl and the like. Can be mentioned.
The term C2 _- nalkynyl, where _n has a value of 3-6, refers to a branched or unbranched hydrocarbon group having _{2 to n} C atoms and a C≡C double bond. Examples of such groups are ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, Examples include 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
The term C _1-n alkoxy denotes a C _1-n alkyl-O group wherein C _1-n alkyl is as defined above. Examples of such groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy, Examples include isohexoxy.

The term C _1-n alkylcarbonyl denotes a C _1-n alkyl-C (═O) group, wherein C _1-n alkyl is as defined above. Examples of such groups are methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, Neopentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl and the like can be mentioned.
The term C _3-n cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group having _{3 to n} C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo [3.2.1] octyl, spiro [4.5] decyl, norpinyl ), Norbonyl, norcaryl, adamantyl and the like. Preferably, the term C _3-7 cycloalkyl denotes a saturated monocyclic group.
The term C _3-n cycloalkylcarbonyl denotes a C _3-n cycloalkyl-C (═O) group, wherein C _3-n cycloalkyl is as defined above.

（Ｒ⁶及びＲ^7a、Ｒ^7b、Ｒ^7cが前述に定義したようなものであるが水素を表さず、及びＺ¹が、脱離基、例えばハロゲン原子、例えばフッ素、塩素又は臭素原子又はアシロキシ基、例えばアセチロキシ又はトリクロロアセチミドイルオキシを示す）の化合物を、一般式（ＩＩＩ）：

（Ｒ¹〜Ｒ⁵は特定の意味を有する）の化合物と反応させる。 The styles used above and below where the bond of the substituent in the phenyl group is shown towards the center of the phenyl ring, unless otherwise stated, this substituent is attached to the free position of the phenyl ring having an H atom. Show you get.
The compounds of the present invention can be obtained using synthetic methods known in principle. Preferably, the compound is obtained by the method of the invention described in more detail below.
a) To prepare compounds of general formula (I) in which R ⁶ , R ^7a , R ^7b , R ^7c are as defined above but do not show a hydrogen atom,
General formula (II):

(R ⁶ and R ^7a , R ^7b , R ^7c are as defined above but do not represent hydrogen and Z ¹ is a leaving group such as a halogen atom such as a fluorine, chlorine or bromine atom or Compounds of an acyloxy group, such as acetyloxy or trichloroacetimidoyloxy, are represented by the general formula (III):

(R ^{1 to} R ⁵ have specific meanings) and are reacted.

The reaction is usually carried out in a solvent such as methylene chloride, chloroform, acetonitrile, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidinone, optionally with a base such as potassium carbonate, cesium carbonate, sodium hydride. Or -60-120 ° C. in the presence of potassium tert-butoxide or a silver compound such as silver (I) oxide, silver (I) carbonate or silver (I) trifluoroacetate or a catalyst such as boron trifluoride ether At a temperature of The reaction can also be carried out, for example, in a phase transfer system such as sodium hydroxide / methylene chloride / benzyl-triethylammonium bromide while simultaneously cleaving other protecting groups such as the trimethylsilyl group on the ethynyl group.
b) To prepare compounds of general formula (I) in which R ⁶ , R ^7a , R ^7b and R ^7c represent hydrogen:
A compound of general formula (I) (wherein R ⁶ , R ^7a , R ^7b and R ^7c are as defined above but does not represent hydrogen) with water or a lower alcohol such as methanol or ethanol React.

The reaction is usually carried out in water, a lower alcohol such as methanol or ethanol or an aqueous solvent mixture such as methanol / tetrahydrofuran in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide. It is carried out at a temperature of -20 to 60 ° C. In this reaction, other protecting groups such as the trimethylsilyl group on ethynyl can be cleaved simultaneously.
When a compound of general formula (I) is obtained according to the invention, wherein R ⁶ represents a hydrogen atom, this is achieved by acylation, for example in the presence of pyridine, collidine, triethylamine or N-ethyl-diisopropylamine. By acylation below, a compound in which R ⁶ represents a (C _1-18 alkyl) carbonyl group, a (C _1-18 alkyl) oxycarbonyl group, an arylcarbonyl group or an aryl- (C _1-3 alkyl) carbonyl group is obtained. Can be converted. Suitable acylating agents can in particular be the corresponding activated acyl derivatives, such as acid chlorides or anhydrides.
In the reactions described above, the reactive groups present, for example ethynyl, hydroxy, amino, alkylamino or imino groups, may be protected during the reaction by usual protecting groups, which are cleaved again after the reaction. The
For example, the protecting group for the ethynyl group may be a trimethylsilyl group.
For example, the protecting group for a hydroxy group may be a trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl group.
A protecting group for an amino, alkylamino or imino group is, for example, a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group. Also good.

The protecting group used is optionally acid then, for example by hydrolysis, in an aqueous solvent, for example water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, for example trifluoroacetic acid, 0 to 0 in the presence of hydrochloric acid or sulfuric acid, or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or aproticly, for example in the presence of iodotrimethylsilane. Cleavage at a temperature of 120 ° C, preferably 10 to 100 ° C.
The trimethylsilyl group is cleaved in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide, for example in water, aqueous solvent mixtures or lower alcohols such as methanol or ethanol.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is advantageously used, for example, hydrolytically, for example with hydrogen, in the presence of a catalyst, for example palladium / charcoal, in a suitable solvent, for example In methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with addition of an acid, for example hydrochloric acid, at an ambient temperature of 0-100 ° C., preferably 20-60 ° C., preferably 1-7 bar, preferably Cleavage at a hydrogen pressure of 3-5 bar. The 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.

The tert-butyl or tert-butoxycarbonyl group is preferably treated by treatment with an acid, for example trifluoroacetic acid or hydrochloric acid, or with iodotrimethylsilane and optionally a solvent, for example methylene chloride, dioxane, methanol or diethyl ether. Is cleaved by.
The trifluoroacetyl group is preferably treated with an acid, for example hydrochloric acid, optionally in the presence of a solvent, for example acetic acid, at a temperature of 50-120 ° C. or with sodium hydroxide solution. Cleavage by treatment at a temperature of 0-50 ° C., optionally in the presence of a solvent such as tetrahydrofuran or methanol.
Furthermore, the resulting compounds of general formula (I) can be resolved into their enantiomers and / or diastereomers as described above. Thus, for example, cis / trans mixtures can be resolved into their cis and trans isomers, and compounds having at least one optically active carbon atom can be separated into their enantiomers.
Thus, for example, cis / trans mixtures can be resolved into their cis and trans isomers by chromatography, and the resulting compounds of general formula (I) produced as racemates can be optically counteracted by methods known per se. (Cf. Allinger NL and Eliel EL in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971), and compounds of general formula (I) having at least two asymmetric carbon atoms are Based on the physico-chemical differences of the compounds, they can be resolved into their diastereomers using methods known per se, for example by chromatography and / or fractional crystallization, and when these compounds are obtained in racemic form They can then be resolved into enantiomers as described above.

Enantiomers are preferably obtained by column separation in a chiral phase or by recrystallization from an optically active solvent or by salts or derivatives such as racemates, in particular acids and activated derivatives or their alcohols. Reacting with an optically active substance forming an amide or ester and separating the diastereomeric mixture of the salts or derivatives so obtained, for example on the basis of their solubility differences, while Free enantiomers can be released from pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in normal use are, for example, D- and L-forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. is there. The optically active alcohol may be, for example, (+) or (−)-menthol and the optically active acyl group in the amide is, for example, (+)-or (−)-menthyloxycarbonyl. It may be.
Furthermore, the compounds of formula (I) can be converted into their salts, in particular into physiologically acceptable salts with inorganic or organic acids for pharmaceutical use. Acids that can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Furthermore, the resulting compound can be converted into a mixture, for example an amino acid, in particular a 1: 1 or 1: 2 mixture with an α-amino acid, for example proline or phenylalanine, which has particularly favorable properties, for example highly crystalline. Can have a degree.
The compounds of the general formulas (II) to (V) used as starting materials are partly known from the literature or may be obtained by methods known from the literature, optionally with additional inclusion of protecting groups be able to.
The compounds of the invention can advantageously be obtained also by the methods described in the examples below, which are also known from the literature to those skilled in the art, for example, in particular WO 01/68660, WO It can be combined with the methods described in 01/74834, WO 02/28872, WO 02/44192, WO 02/64606, WO 03/11880 and WO 03/80635.
As already mentioned, the compounds of general formula (I) according to the invention and their physiologically acceptable salts are useful in pharmacological properties, in particular in the sodium-dependent glucose transporter SGLT, preferably SGLT2. Has an inhibitory effect.
The biological properties of the new compounds can be studied as follows:

The ability of a substance to inhibit SGLT-2 activity can be demonstrated in tests that set up a CHO cell line (ATCC No. CCL61) or alternatively a HEK293 cell line (ATCC No. CRL-1573), which is stable. Transfected with the expression vector pZeoSV (Invitrogen, EMBL accession number L36849), which contains the cDNA for the coding sequence of human sodium glucose transporter 2 (Genbank Acc. No. NM_003041) (CHO-hSGLT2 or HEK-hSGLT2 ). These cell lines, ¹⁴ C-labeled α- methyl - transport to the interior of cells in glucopyranoside ⁽¹⁴ C-AMG, Amersham) sodium-dependent way.
The SGLT-2 assay is performed as follows:
CHO-hSGLT2 cells were cultured in Ham's F12 medium (BioWhittaker) with 10% fetal calf serum and 250 μg / ml zeocin (Invitrogen), and HEK293-hSGLT2 cells were cultured with 10% fetal calf serum and 250 μg. Incubate in DMEM medium with / ml zeocin (Invitrogen). Cells are detached from culture flasks by washing twice with PBS and then treating with trypsin / EDTA. After addition of cell culture medium, the cells are centrifuged, resuspended in culture medium and counted in a Casy cell counter. Then 40,000 cells per well were seeded into white, 96-well plates coated with poly-D-lysine and incubated overnight at 37 ° C., 5% CO ₂ . Cells are washed twice with 250 μl assay buffer (Hanks Balanced Salt Solution, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl ₂ , 1.2 mM MgSO ₄ and 10 mM HEPES (pH 7.4), 50 μg / ml gentamicin). 250 μl of assay buffer and 5 μl of test compound are then added to each well and the plate is incubated for an additional 15 minutes in the incubator. 5 μl of 10% DMSO is used as a negative control. The reaction is started by adding 5 μl of ¹⁴ C-AMG (0.05 μCi) to each well. After 2 hours incubation at 37 ° C. with 5% CO ₂ , the cells are washed again with 250 μl PBS (20 ° C.) and then lysed by the addition of 25 μl 0.1 N NaOH (5 min, 37 ° C.). 200 μl of MicroScint20 (Packard) is added to each well and incubation is continued for an additional 20 minutes at 37 ° C. Following this incubation, the radioactivity of absorbed ¹⁴ C-AMG is measured using a ¹⁴ C scintillation program at Topcount (Packard).

To determine selectivity for human SGLT1, a similar test is set up in which cDNA for hSGLT1 (Genbank Acc. No. NM000343) is expressed in CHO-K1 or HEK293 cells instead of hSGLT2 cDNA.
The compounds of general formula (I) according to the invention can have an EC50 value of, for example, less than 1000 nM, in particular less than 50 nM.
In view of their ability to inhibit SGLT activity, the compounds of general formula (I) according to the invention and their corresponding pharmaceutically acceptable salts are theoretically able to inhibit SGLT activity, in particular SGLT-2 activity. Suitable for the treatment and / or prophylactic treatment of all conditions or diseases that can be affected by Thus, the compounds of the present invention are particularly useful for diseases, especially metabolic diseases or conditions such as type 1 and type 2 diabetes, diabetic complications (eg retinopathy, nephropathy or neuropathy, diabetic foot, ulcer, Macrovascular disorders), metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolic disorders, insulin resistance, metabolic syndrome, dyslipidaemias of different origin, atherosclerosis and related Suitable for the prevention or treatment of diseases, obesity, hypertension, chronic heart failure, edema and hyperuricemia. These substances are also suitable for preventing β-cell degeneration, eg pancreatic β-cell necrosis or apoptosis. The substance is also suitable for improving or restoring pancreatic cell function, and also increases the number and size of pancreatic β cells. The compounds of the invention can also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.

In particular, the compounds of the invention (including their physiologically acceptable salts) are suitable for the prevention or treatment of diabetes, in particular type 1 and type 2 diabetes and / or diabetic complications.
The dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound being administered, the patient, the nature and gravity of the disease or condition and the method and frequency of administration. And should be determined for the patient's physician. For convenience, the dosage may be 1-100 mg by intravenous route, preferably 1-30 mg, 1-1000 mg by oral route, preferably 1-100 mg, and in each case may be administered 1 to 4 times a day. . For this purpose, the compounds of the formula (I) prepared according to the invention are optionally combined with other active substances, one or more inert conventional carriers and / or diluents such as corn starch. , Lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose Or it can be formulated with fatty substances such as hard fat or suitable mixtures thereof to produce conventional galenic formulations such as plain and coated tablets, capsules, powders, suspensions or suppositories.

  The compounds according to the invention can also be used in combination with other active substances, in particular for the treatment and / or prevention of the diseases and conditions mentioned above. Other active agents suitable for such a combination may, for example, allow the therapeutic effect of the SGLT antagonist of the present invention and / or reduce the dosage of the SGLT antagonist of the present invention in connection with one of the above suggestions. Includes what is possible. Suitable therapeutic agents for such combinations include, for example, antidiabetics such as metformin, sulfonylureas (eg, glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (eg, rosiglitazone, pioglitazone), PPAR-γ- Agonists (eg, GI262570) and antagonists, PPAR-γ / α modulators (eg, KRP297), α-glucosidase inhibitors (eg, acarbose, voglibose), DPPIV inhibitors (eg, LAF237, MK-431), α2-antagonists, Insulin and insulin analogues, GLP-1 and GLP-1 analogues (eg exedin-4) or amylin. The list also includes inhibitors of protein tyrosine phosphatase 1, substances that affect disordered glucose production in the liver, such as inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon Receptor antagonists and inhibitors of pyruvate dehydrokinase, glycogen synthase kinase or phosphoenolpyruvate carboxykinase, lipid reducing agents such as HMG-CoA-reductase inhibitors (eg simvastatin, atorvastatin), fibrates (eg bezafibrat , Fenofibrat), nicotinic acid and their derivatives, PPAR-α agonists, PPAR-δ agonists, ACAT inhibitors (abashimibe) or choleste To treat roll absorption inhibitors such as ezetimibe, bile acid binding substances such as cholestyramine, ileac bile acid transporters, HDL-elevating compounds such as CETP inhibitors or ABC1 modulators or obesity Active substances such as sibutramine or tetrahydrolipostatin, dexfenfluramine, axoquine, antagonists of cannabinoid 1 receptors, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β3-agonists such as SB-418790 Or an agonist of AD-9777 and 5HT2c receptor.

Further, drugs that affect hypertension, chronic heart failure or atherosclerosis, such as A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists, centrally acting antihypertensive agents, Combinations with alpha-2-adrenergic receptor antagonists, neutral endopeptidase inhibitors, platelet aggregation inhibitors and others or combinations thereof are suitable. Examples of angiotensin II receptor antagonists are candesartan cilexetil, losartan potassium, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671 GA-0113, RU-64276, EMD-90423, BR-9701, and the like. Angiotensin II receptor antagonists are preferably used for the treatment or prevention of hypertension and diabetic complications and are often combined with diuretics such as hydrochlorothiazide.
Combinations with uric acid synthesis inhibitors or uric acid excretion agents are suitable for the treatment or prevention of ventilation.
Combinations with GABA-receptor antagonists, Na channel blockers, topiramats, protein-kinase C inhibitors, glycation end product inhibitors or aldose reductase inhibitors can be used for the treatment or prevention of diabetic complications.

The dose for the combination partner is usually from 1/5 of the normally recommended minimum dose to 1/1 of the normally recommended dose.
Thus, in another aspect, the present invention inhibits the sodium-dependent glucose transporter SGLT, at least one of the active substances mentioned above as a combination partner with the compounds of the invention or physiologically acceptable salts of such compounds. It relates to the use for producing a pharmaceutical composition suitable for the treatment or prevention of diseases or conditions that can be affected by They are preferably metabolic diseases, in particular one of the diseases or conditions mentioned above, most particularly diabetes or diabetic complications.
The use of the compounds according to the invention or their physiologically acceptable salts in combination with other active substances can be carried out simultaneously or at different times, but in particular within a short time. If they are administered simultaneously, the two active ingredients are given to the patient together; whereas if they are used at different times, the two active ingredients are equal to or less than 12 hours, However, it is given to the patient within a period equal to or less than 6 hours.
Accordingly, in another aspect, the invention relates to a pharmaceutical composition, which comprises at least one of the compounds of the invention or the active substance mentioned above as a physiologically acceptable salt and combination partner of such compounds, optionally Contains one or more inert carriers and / or diluents.

Thus, for example, a pharmaceutical composition of the invention comprises a combination of a compound of formula (I) of the invention or a physiologically acceptable salt of such a compound and at least one angiotensin II receptor antagonist, optionally 1 or With two or more inert carriers and / or diluents.
The compounds of the invention or their physiologically acceptable salts and the additional active ingredients to be combined with them may both be present together in one formulation, for example in tablets or capsules, Or it may be present separately in one same or different formulation, for example as a so-called kit of parts.
In the text above or below, the H atom or hydroxyl group is not explicitly shown in the structural formula in each case. The following examples are intended to illustrate the invention and not to limit it.

４−（（Ｒ）−テトラヒドロフラン−３−イルオキシ）−ブロモベンゼン Preparation of starting compounds:
Example I

4-((R) -tetrahydrofuran-3-yloxy) -bromobenzene

10 g 4-bromophenol are stirred with 21 g ((S) -tetrahydrofuran-3-yl) p-toluenesulfonate in 100 ml dimethylformamide in the presence of 11.98 g potassium carbonate for 32 hours at 60 ° C. And then purifying by chromatographic purification.
Yield: 13.7 g (97% theory)
Rf value: 0.80 (aluminum oxide; cyclohexane / ethyl acetate = 2: 1)
The following compounds were prepared as in Example 1:
(1) 4-((S) -Tetrahydrofuran-3-yloxy) -bromobenzene mass spectrum: m / z = 242/244 [M ⁺ ]

Example II

(2-Benzyloxy-phenyl)-[4-((R) -tetrahydrofuran-3-yloxy) phenyl] -methanol

5.17 ml of 1.6 M butyllithium solution (in hexane) was added dropwise at 78 ° C. to a solution of 2.0 g of 4-((R) -tetrahydrofuran-3-yloxy) -bromobenzene in 10 ml of tetrahydrofuran and further. Stir for 1 hour at -78 ° C. Then 1.75 g 2-benzyloxybenzaldehyde dissolved in 5 ml tetrahydrofuran was added dropwise and the mixture was stirred for 2 hours at -78 ° C. After heating to ambient temperature, it was stirred for 1 hour. After aqueous working up and extraction with ethyl acetate, the organic phase was dried and evaporated down. The residue was purified by chromatography through a silica gel column with cyclohexane / ethyl acetate (8: 2-1: 1).
Yield: 2.6 g (84% theory)
R _f value: 0.25 (silica gel, cyclohexane / ethyl acetate = 3: 1)
The following compounds were prepared analogously to Example II:
(1) (2-Benzyloxyphenyl)-[4-((S) -tetrahydrofuran-3-yloxy) phenyl] -methanol mass spectrum (ESI ⁺ ): m / z = 394 [M + NH ₄ ] ⁺
(2) (2-Benzyloxy-4-fluorophenyl)-[4-((R) -tetrahydrofuran-3-yloxy) phenyl] -methanol mass spectrum (ESI ⁺ ): m / z = 417 [M + Na] ⁺
(3) (2-Benzyloxy-6-methoxyphenyl)-[4-((R) -tetrahydrofuran-3-yloxy) phenyl] -methanol mass spectrum (ESI ⁺ ): m / z = 424 [M + NH ₄ ] ⁺

Example III

2- [4-((R) -Tetrahydrofuran-3-yloxybenzyl] -phenol

Prepared from 1.97 g of the compound of Example II by catalytic hydrogenation in methanol in the presence of 0.4 g of palladium on activated carbon (10% Pd) at ambient temperature.
R _f value: 0.52 (silica gel, cyclohexane / succinethyl = 2: 1)
Mass spectrum (ESI ⁻ ): m / z = 269 [M−H] ⁻
The following compounds were prepared analogously to Example III:
(1) 2- [4-((S) -Tetrahydrofuran-3-yloxy) benzyl] -phenol mass spectrum (ESI ⁺ ): m / z = 271 [M + H] ⁺
(2) 2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -4-fluorophenol mass spectrum (ESI ⁻ ): m / z = 287 [M−H] ⁻
(3) 2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -6-methoxyphenol mass spectrum (ESI ⁺ ): m / z = 301 [M + H] ⁺

Example IV

1- (2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) -2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -benzene

例ＶＩの化合物とベンジル−トリエチルアンモニウム臭化物の存在下で反応。
Ｒｆ値：０．３０（シリカゲル；シクロヘキサン／酢酸エチル＝２：１）
質量スペクトル（ＥＳＩ⁺）：ｍ／ｚ＝５５６［Ｍ＋ＮＨ₄］⁺ 500 mg 2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -phenol, 820 mg 2,3,4,6-tetra-O-acetyl-α-glucopyranosyl bromide, 2 ml 1M Sodium hydroxide solution and 5 ml of chloroform were stirred for 16 hours at ambient temperature. Another 400 mg of 2,3,4,6-tetra-O-acetyl-α-glucopyranosyl bromide, 1 ml of 1M sodium hydroxide solution and 5 ml of methylene chloride are added and the mixture is added for 2.5 days. Stir. The organic phase was separated off, washed with water, dried and evaporated. The crude product was purified by chromatography on a silica gel column with a cyclohexane / ethyl acetate gradient (7: 3 to 1: 1).
Yield: 440 mg (40% theory)
Rf value: 0.10 (silica gel; cyclohexane / ethyl acetate = 2: 1)
Mass spectrum (ESI ⁺ ): m / z = 618 [M + NH ₄ ] ⁺
The following compounds were prepared analogously to Example IV:
(1) 1- (2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) -benzene

Reaction with the compound of Example VI in the presence of benzyl-triethylammonium bromide.
Rf value: 0.30 (silica gel; cyclohexane / ethyl acetate = 2: 1)
Mass spectrum (ESI ⁺ ): m / z = 556 [M + NH ₄ ] ⁺

(2) 1- (2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) -2- [4-((S) -tetrahydrofuran-3-yloxy) benzyl] -benzene Rf value: 0.50 (silica gel; cyclohexane / ethyl acetate = 1: 1)
Mass spectrum (ESI ⁺ ): m / z = 618 [M + NH ₄ ] ⁺
(3) 1- (2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) -2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -4 -Fluorobenzene mass spectrum (ESI ⁺ ): m / z = 636 [M + NH ₄ ] ⁺
(4) 1- (2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy) -2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -6 -Methoxybenzene mass spectrum (ESI ⁺ ): m / z = 648 [M + NH ₄ ] ⁺

Example V

2- (4-Bromobenzyl) -phenol

Sodium phenoxide (from 4.0 g phenol and 1.7 g 60% sodium hydride (in paraffin oil)) is reacted with 10.27 g 4-bromobenzyl chloride in toluene at the reflux temperature and the reaction mixture is Prepared by purification by chromatography on a silica gel column with cyclohexane / ethyl acetate (8: 2 to 1: 1).
Yield: 1.8 g (16% theory)
Rf value: 0.40 (silica gel; cyclohexane / ethyl acetate = 4: 1)
Mass spectrum (ESI ⁻ ): m / z = 261/263 [M−H] ⁻

Example VI

2- [4- (2-Trimethylsilyl-ethynyl) benzyl] -phenol

1.6 g 2- (4-bromobenzyl) -phenol in the presence of 1.03 ml trimethylsilylacetylene, 86 mg bis (triphenylphosphine) -palladium (II) chloride and 23 mg copper (I) iodide Prepared by reacting in a microwave oven at 100 ° C. in 5 ml of triethylamine and purifying the reaction mixture by chromatography on a silica gel column with cyclohexane / ethyl acetate (9: 1-7: 3).
Rf value: 0.62 (silica gel; cyclohexane / ethyl acetate = 4: 1)
Mass spectrum (ESI ⁺ ): m / z = 281 [M + H] ⁺

１−（β−Ｄ−グルコピラノシロキシ）−２−［４−（（Ｒ）−テトラヒドロフラン−３−イルオキシ）ベンジル］−ベンゼン Final compound production
Example 1

1- (β-D-glucopyranosyloxy) -2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -benzene

Ｒｆ値：０．５５（シリカゲル、塩化メチレン／メタノール＝６：１）
質量スペクトル（ＥＳＩ⁺）：ｍ／ｚ＝３８８［Ｍ＋ＮＨ₄］⁺ 400 mg of 1- (2,3,4,6-tetra-O-β-D-glucopolanosiloxy) -2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -benzene The solution in a mixture of 5 ml methanol and 5 ml tetrahydrofuran was cooled in an ice bath and combined with 3.02 ml 1M aqueous lithium hydroxide solution and stirred for 1 hour. The reaction mixture was combined with 5 ml of water and extracted with ethyl acetate. The organic phase was separated off, washed with saturated saline, dried and evaporated.
Yield: 190 mg (65% theory)
Rf value: 0.23 (silica gel; methylene chloride / methanol = 9: 1)
Mass spectrum (ESI ⁺ ): m / z = 433 [M + H] ⁺
The following compounds were obtained analogously to Example 1:
(1) 1- (β-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) -benzene

Rf value: 0.55 (silica gel, methylene chloride / methanol = 6: 1)
Mass spectrum (ESI ⁺ ): m / z = 388 [M + NH ₄ ] ⁺

融点：１３４〜１３５℃ (2) 1- (β-D-glucopyranosyloxy) -2- [4-((S) -tetrahydrofuran-3-yloxy) benzyl] -benzene

Melting point: 134-135 ° C

融点：１４５〜１４７℃ (3) 1- (β-D-glucopyranosyloxy) -2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -4-fluorobenzene

Melting point: 145-147 ° C

質量スペクトル（ＥＳＩ⁺）：ｍ／ｚ＝４８０［Ｍ＋ＮＨ₄］⁺ (4) 1- (β-D-glucopyranosyloxy) -2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -6-methoxybenzene

Mass spectrum (ESI ⁺ ): m / z = 480 [M + NH ₄ ] ⁺

１−（６−Ｏ−メトキシカルボニル−β−Ｄ−グルコピラノシロキシ）−２−（４−エチニルベンジル）−ベンゼン
０．５ｍｌの２，４，６−コリジン中の１００ｍｇの１−（β−Ｄ−グルコピラノシロキシ）−２−（４−エチニルベンジル）−ベンゼンを０．０２６ｍｌのメチルクロロホルメートと氷浴中で組み合わせ及び次いで１６時間周囲温度で攪拌した。５ｍｌの０．１Ｎ塩酸を反応混合物に添加し、それをその後１０ｍｌの酢酸エチルで抽出した。有機相を分離除去し、飽和生理食塩水で洗浄し、及び蒸発させた。残留物を８ｍｌのジエチルエーテル／石油エーテル（１：１）と共に攪拌し、固体を吸引ろ過し及び４０℃で乾燥した。
収量：７３．５ｍｇ（６３％理論）
質量スペクトル（ＥＳＩ⁺）：ｍ／ｚ＝４２９［Ｍ＋Ｈ］⁺
以下の化合物を実施例２と同様に得た：
（１）１−（６−Ｏ−メトキシカルボニル−β−Ｄ−グルコピラノシロキシ）−２−［４−（（Ｒ）−テトラヒドロフラン−３−イルオキシ）ベンジル］−ベンゼン

質量スペクトル（ＥＳＩ⁺）：ｍ／ｚ＝５０８［Ｍ＋ＮＨ₄］⁺ Example 2

1- (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) -benzene 100 mg 1- (β-in 0.5 ml 2,4,6-collidine D-glucopyranosyloxy) -2- (4-ethynylbenzyl) -benzene was combined with 0.026 ml of methyl chloroformate in an ice bath and then stirred for 16 hours at ambient temperature. 5 ml of 0.1N hydrochloric acid was added to the reaction mixture, which was then extracted with 10 ml of ethyl acetate. The organic phase was separated off, washed with saturated saline and evaporated. The residue was stirred with 8 ml of diethyl ether / petroleum ether (1: 1), the solid was filtered off with suction and dried at 40 ° C.
Yield: 73.5 mg (63% theory)
Mass spectrum (ESI ⁺ ): m / z = 429 [M + H] ⁺
The following compounds were obtained analogously to Example 2:
(1) 1- (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -benzene

Mass spectrum (ESI ⁺ ): m / z = 508 [M + NH ₄ ] ⁺

融点：１４９〜１５０℃ (2) 1- (6-O-methoxycarbonyl-β-D-glucopyranosyloxy) -2- [4-((S) -tetrahydrofuran-3-yloxy) benzyl] -benzene

Melting point: 149-150 ° C

The following compounds were also prepared analogously to other methods known from the above examples and literature:

製造方法：
活性物質、ラクトース及びスターチを一緒に混合し及びポリビニルピロリドンの水溶液で均質に湿潤させた。湿潤組成物をスクリーニングし（２．０ｍｍメッシュサイズ）及びラックタイプ乾燥機内において５０℃で乾燥した後、それを再びスクリーニングし（１．５ｍｍメッシュサイズ）及び潤滑剤を添加した。最終混合物を圧縮してタブレットを形成した。
タブレットの質量：２２０ｍｇ
直径：１０ｍｍ、２平面、両サイドでファセット(facet)され及び一方のサイドでノッチされた。 Example A
Tablet containing 100 mg of active substance
Composition :
One tablet includes:

Manufacturing method :
The active substance, lactose and starch were mixed together and homogeneously wetted with an aqueous solution of polyvinylpyrrolidone. After the wet composition was screened (2.0 mm mesh size) and dried at 50 ° C. in a rack-type dryer, it was screened again (1.5 mm mesh size) and lubricant was added. The final mixture was compressed to form tablets.
Tablet mass: 220mg
Diameter: 10 mm, two planes, faceted on both sides and notched on one side.

製造：
ラクトース、コーンスターチ及びシリカと混合した活性物質を、２０％水性ポリビニルピロリドン溶液で湿潤させ及びメッシュサイズ１．５ｍｍのスクリーンに通した。４５℃に乾燥した顆粒を同一のスクリーンに再び通し及び特定量のステアリン酸マグネシウムと混合した。タブレットを混合物から圧縮した。
タブレットの質量：３００ｍｇ
ダイ：１０ｍｍ、フラット Example B
Tablets containing 150 mg of active substance
Composition :
One tablet includes:

Manufacturing :
The active substance mixed with lactose, corn starch and silica was wetted with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules dried at 45 ° C were passed again through the same screen and mixed with a certain amount of magnesium stearate. Tablets were compressed from the mixture.
Tablet mass: 300mg
Die: 10mm, flat

製造：
活性物質を賦形剤と混合し、０．７５ｍｍのメッシュサイズを有するスクリーンに通し、及び適切な装置を用いて均質混合した。最終混合物をサイズ１硬質ゼラチンカプセルにパックした。
カプセル充填：約３２０ｍｇ
カプセルシェル：サイズ１硬質ゼラチンカプセル Example C
Hard gelatin capsule containing 150 mg of active substance
Composition :
1 capsule contains:

Manufacturing :
The active substance was mixed with excipients, passed through a screen having a mesh size of 0.75 mm and mixed homogeneously using a suitable device. The final mixture was packed into size 1 hard gelatin capsules.
Capsule filling: about 320mg
Capsule shell: Size 1 hard gelatin capsule

製造：
座薬塊を溶解した後、活性物質をその中に均質に分散させ及び溶融物を冷却金型に注入した。 Example D
Suppositories containing 150 mg of active substance
Composition :
One suppository contains:

Manufacturing :
After dissolving the suppository mass, the active substance was homogeneously dispersed therein and the melt was poured into a cooling mold.

製造：
活性物質を必要量の０．０１Ｎ ＨＣｌ中に溶解し、食塩で等張にし、無菌ろ過し、及び２ｍｌアンプルに入れた。 Example E
Ampoules containing 10 mg of active substance
Composition :

Manufacturing :
The active substance was dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and placed in a 2 ml ampoule.

製造：
活性物質を適量の０．０１Ｎ ＨＣｌ中に溶解し、食塩で等張にし、無菌ろ過し及び１０ｍｌアンプルに入れた。 Example F
Ampoules containing 50 mg of active substance
Composition :

Manufacturing :
The active substance was dissolved in an appropriate amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and placed in a 10 ml ampoule.

Claims (14)

A glucopyranosyloxy-substituted aromatic compound of the general formula (I), a tautomer thereof, a stereoisomer thereof, a mixture thereof or a salt thereof.

Wherein R ¹ is C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 alkyloxy or tetrahydropyranyl-C _{1 -3} represents alkyloxy, or
R ³ is C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 alkyloxy and tetrahydropyranyl-C _1-3 alkyloxy. When selected from the group consisting of
R ¹ is also hydrogen, fluorine, chlorine, bromine, iodine, C _1-4 alkyl, a methyl group substituted with 1 to 3 fluorine atoms, or an ethyl group substituted with 1 to 5 fluorine atoms. , C _1-4 alkoxy, a methoxy group substituted with 1 to 3 fluorine atoms, an ethoxy group substituted with 1 to 5 fluorine atoms, hydrogen or C _1- substituted with a C _1-3 alkoxy group ₄ alkyl group, hydrogen or C _2-4 alkoxy group substituted by C _1-3 alkoxy group, C _2-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-3 alkyl, C _{May be 3-6} cycloalkoxy, C _3-6 cycloalkyl-C _1-3 alkoxy, hydroxy, amino or cyano, and R ² is hydrogen, fluorine, chlorine, methyl, 1 to 3 fluorine atoms And methyl or methoxy substituted with R ³ is, C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl -C _1-3 alkyloxy or tetrahydropyranyl -C _1-3 alkyloxy Or R ¹ is C _2-6 alkynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranyl-C _1-3 alkyloxy and tetrahydropyranyl-C _{1 -3} when selected from the group consisting of alkyloxy,
R ³ is also hydrogen, fluorine, chlorine, bromine, iodine, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, C _3-6 cycloalkylidenemethyl, C _1-6 alkoxy, C _3-6 cycloalkyloxy, C _3-6 cycloalkyl-C _1-3 alkoxy, aryl, aryl-C _1-3 alkyl, heteroaryl, heteroaryl-C _1-3 alkyl, aryloxy, aryl-C _{1 -3} alkyloxy, methyl or methoxy group substituted by 1 to 3 fluorine atoms, C _2-4 alkyl or C _2-4 alkoxy group substituted by 1 to 5 fluorine atoms, substituted by cyano group C _1-4 alkyl group, hydroxy or C _1-3 C _1-4 alkyl group substituted by alkyloxy, cyano, carboxy, C _1-3 alkylcarbonyl, aminocarbonyl was, (C _1-3 alkylamino) Carbonyl, di - (C _1-3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C _1-3 alkyl ) -Piperazin-1-ylcarbonyl, nitro, amino, C _1-3 alkylamino, di- (C _1-3 alkyl) amino, (C _1-4 alkyl) carbonylamino, C _1-4 alkylsulfonylamino, aryl shows sulfonylamino, aryl -C _1-3 alkylsulfonylamino, C _1-4 alkylsulfanyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, alkylsulfenyl, an arylsulfinyl or arylsulfonyl,
R ⁴ and R ⁵ may be the same or different and are hydrogen, fluorine, chlorine, bromine, C _1-3 alkyl, C _1-3 alkoxy, methyl substituted by 1 to 3 fluorine atoms Or R ⁶ , R ^7a , R ^7b , R ^7c independently of one another, hydrogen, (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- Selected from (C _1-3 alkyl) carbonyl,
The aryl groups described in the above group definitions independently of one another represent phenyl or naphthyl groups which may be mono- or disubstituted by R _h , and the substituents may be the same or different. Well, and R _h represents fluorine, chlorine, bromine, iodine, C _1-3 alkyl, difluoromethyl, trifluoromethyl, C _1-3 alkoxy, difluoromethoxy, trifluoromethoxy or cyano,
Heteroaryl groups described in the above group definitions include pyrrolyl, furanyl, thienyl, imidazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl groups,
Or a pyrrolyl, furanyl, thienyl, imidazolyl or pyridyl group, wherein one or two methine groups are replaced by nitrogen atoms,
Or indolyl, benzofuranyl, benzothiophenyl, quinolinyl or isoquinolinyl group, wherein 1 to 3 methine groups are replaced by nitrogen atoms,
The heteroaryl group may be mono- or disubstituted by R _h , the substituents may be the same or different, and R _h is as defined above,
Unless otherwise stated, the alkyl group may be linear or branched) In which R ¹ represents ethynyl or R ³ consists of ethynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy and tetrahydropyranylmethyloxy If you choose
R ¹ may also be hydrogen, fluorine, chlorine, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or cyano, and R ² represents hydrogen, fluorine or methyl ,
R ³ represents ethynyl, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethyloxy or tetrahydropyranylmethyloxy, or when R ¹ represents ethynyl,
R ³ is also hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, iso Propoxy, difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, methylsulfanyl, 2-methyl-1-propen-1-yl, cyclopropylidene May also represent methyl, phenyl, fluorophenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl Ku, and R ⁴ represents hydrogen, fluorine or methyl,
R ⁵ represents hydrogen,
R ⁶ , R ^7a , R ^7b and R ^7c are independently of each other hydrogen, (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl). ) Selected from carbonyl
A glucopyranosyloxy-substituted aromatic compound of the general formula (I) according to claim 1, its tautomer, its stereoisomer, a mixture thereof or a salt thereof. Wherein R ¹ represents ethynyl, or R ³ is selected from the group consisting of ethynyl and tetrahydrofuran-3-yloxy,
R ¹ may also further represent hydrogen, fluorine, methyl, methoxy or cyano,
R ² represents hydrogen or methyl;
R ³ represents ethynyl or tetrahydrofuran-3-yloxy, or when R ¹ is ethynyl,
R ³ may also further represent methyl, ethyl, methoxy, difluoromethyl or trifluoromethyl,
R ⁴ represents hydrogen or fluorine,
R ⁵ represents hydrogen,
R ⁶ , R ^7a , R ^7b and R ^7c are independently of each other hydrogen, (C _1-18 alkyl) carbonyl, (C _1-18 alkyl) oxycarbonyl, arylcarbonyl and aryl- (C _1-3 alkyl). ) Selected from carbonyl
A glucopyranosyloxy-substituted aromatic compound of general formula (I) according to claim 1, its stereoisomer or a mixture thereof. In which R ⁶ has the meaning of the invention other than hydrogen, and in particular R ⁶ represents ethoxycarbonyl or methoxycarbonyl,
(A) 1- (β-D-glucopyranosyloxy) -2- [4-((R) -tetrahydrofuran-3-yloxy) benzyl] -benzene,
(B) 1- (β-D-glucopyranosyloxy) -2- (4-ethynylbenzyl) -benzene and a compound of general formula (I) according to claim 1 selected from the group consisting of derivatives thereof, The tautomer, stereoisomer or mixture thereof.   A physiologically acceptable salt of an inorganic or organic acid and a compound according to at least one of claims 1 to 4.   A medicament comprising a compound according to one or more of claims 1-4 or a physiologically acceptable salt according to claim 5, optionally together with one or more inert carriers and / or diluents. Composition.   At least according to one or more of claims 1 to 4 for the manufacture of a pharmaceutical composition suitable for the treatment or prevention of diseases or conditions that may be affected by inhibiting the sodium-dependent glucose cotransporter SGLT. Use of one compound or physiologically acceptable salt according to claim 5.   Use of one or more compounds of one or more of claims 1-4 or a physiologically acceptable salt of claim 5 for the manufacture of a pharmaceutical composition suitable for the treatment or prevention of metabolic diseases.   Metabolic disorders include type 1 and type 2 diabetes, diabetic complications, metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinemia, glucose metabolic disorders, insulin resistance, metabolic syndrome, heterolipemia of different origin 9. Use according to claim 8, selected from the group consisting of infectious diseases, atherosclerosis and related diseases, obesity, hypertension, chronic heart failure, edema and hyperuricemia.   6. At least one compound according to at least one of claims 1-4 or physiologically acceptable according to claim 5 for the manufacture of a pharmaceutical composition for inhibiting the sodium-dependent glucose cotransporter SGLT. Use of salt.   At least according to at least one of claims 1 to 4 for the manufacture of a pharmaceutical composition for the prevention of pancreatic β-cell degeneration and / or for improving and / or restoring pancreatic β-cell functionality. Use of one compound or physiologically acceptable salt according to claim 5.   Use of at least one compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5 for the manufacture of diuretics and / or antihypertensives.   A compound according to at least one of claims 1 to 4 or a physiologically acceptable salt according to claim 5 is introduced into one or more inert carriers and / or diluents by non-chemical methods. The manufacturing method of the pharmaceutical composition of Claim 6 characterized by the above-mentioned. a) for preparing compounds of general formula (I) in which R ⁶ , R ^7a , R ^7b and R ^7c are as defined in claim 1 but do not represent hydrogen General formula (II):

A compound of the general formula: wherein R ⁶ , R ^7a , R ^7b and R ^7c are as defined above but do not represent hydrogen and Z ¹ represents a leaving group. (III):

(R ^{1 to} R ⁵ are as defined in claim 1) or b) general formula (I) wherein R ⁶ , R ^7a , R ^7b and R ^7c are hydrogenated. In order to produce a compound of formula (I), hydrolyzing the general formula (I) (R ⁶ and R ^7a , R ^7b , R ^7c as defined above, but not hydrogen), And, if desired, the compound of general formula (I) so obtained (R ⁶ represents a hydrogen atom) converted by acylation to the corresponding acyl compound of general formula (I), and / or If necessary, the protecting group used during the above reaction is cleaved again and / or, if desired, the compound of general formula (I) thus obtained is made into its stereoisomer and / or as such. The compounds of general formula (I) obtained are physiologically acceptable for their salts, in particular for pharmaceutical use. Characterized in that it is converted into their active salts,
The method to manufacture the compound of general formula (I) of Claims 1-4.