HK1080482B

HK1080482B - Novel thiophenylglycoside derivatives, methods for production thereof, medicaments comprising said compounds and use thereof

Info

Publication number: HK1080482B
Application number: HK06100362.4A
Authority: HK
Inventors: Heiner Glombik; Wendelin Frick; Hubert Heuer; Werner Kramer; Harm Brummerhop; Oliver Plettenburg
Original assignee: Sanofi-Aventis Deutschland Gmbh
Priority date: 2002-07-11
Filing date: 2003-06-27
Publication date: 2009-01-02

Description

novel thienyl glycoside derivatives, method for the production thereof, medicaments containing said compounds and the use thereof

The invention relates to substituted thiophen glycoside derivatives, their physiologically tolerated salts and physiologically functional derivatives.

The antirheumatic drug tenidap (. beta. -D-glucopyranosyluronic acid, 5- [ (Z) - [1- (amino-carbonyl) -5-chloro-1, 2-dihydro-2-oxo-3H-indol-3-ylidenehydroxymethyl-3-thienyl ] (H.G.Fouda et al, CA: 1997: 165448) is known, and furthermore, 3-amino-2-benzoyl-5-glucopyranosylaminothiophene compounds are known (J.Fuentes et al, Tetrahedron Asymmetry, 1998, 9, 2517-.

The object of the present invention is to provide a novel compound which can be used for the prevention and treatment of type I and type II diabetes.

Accordingly, the present invention relates to compounds of formula I

Wherein

R1 and R2 are hydrogen, F, Cl, Br, I, OH and NO₂、CN、COOH、CO(C₁-C₆) -alkyl, COO (C)₁-C₆) Alkyl, CONH₂、CONH(C₁-C₆) Alkyl, CON [ (C)₁-C₆) -alkyl radical]₂、(C₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl, (C)₁-C₆) Alkoxy, HO- (C)₁-C₈) Alkyl radicals, (C)₁-C₆) -alkoxy- (C)₁-C₆) Alkyl, phenyl, benzyl, (C)₁-C₄) -alkylcarbonyl, wherein one, more than one or all hydrogens on alkyl and alkoxy groups may be replaced by fluorine;

SO₂-NH₂、SO₂NH(C₁-C₆) Alkyl, SO₂N[(C₁-C₆) -alkyl radical]₂、S-(C₁-C₆) Alkyl, S- (CH)₂)_o-phenyl, SO- (C)₁-C₆) Alkyl, SO- (CH)₂)_o-phenyl, SO₂-(C₁-C₆) Alkyl, SO₂-(CH₂)_o-phenyl, wherein o may be 0-6 and phenyl may be substituted up to two times by: F. cl, Br, OH, CF₃、NO₂、CN、OCF₃、(C₁-C₆) -alkoxy, (C)₁-C₆) -alkyl, NH₂；

NH₂、NH-(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、NH(C₁-C₇) -acyl, phenyl, O- (CH)₂)_o-phenyl, wherein o may be 0-6, and wherein the phenyl ring may be substituted 1-3 times with: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、(C₁-C₆) -alkoxy, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

A is (C)₀-C₁₅) Alkylene, wherein one or more carbon atoms in the alkylene may be replaced independently of each other by: -O-, - (C ═ O) -, -CH ═ CH-, -C ≡ C-, -S-, -CH (oh) -, -CHF-, -CF-, -oh ≡ CH-, -oh-)₂-、-(S＝O)-、-(SO₂)-、-N((C₁-C₆) -alkyl) -, -N ((C)₁-C₆) -alkylphenyl) -or-NH-;

n is 0 to 4;

cyc1 is a 3-to 7-membered saturated, partially saturated, or unsaturated ring, in which one carbon atom may be replaced by O or S;

r3, R4 and R5 are hydrogen, F, Cl, Br, I, OH and NO₂、CN、COOH、COO(C₁-C₆) Alkyl, CO (C)₁-C₄) Alkyl, CONH₂、CONH(C₁-C₆) Alkyl, CON [ (C)₁-C₆) -alkyl radical]₂、(C₁-C₈) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl, (C)₁-C₁₂) Alkoxy, HO- (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy- (C)₁-C₆) -alkyl, wherein one, more than one or all hydrogens on alkyl and alkoxy may be replaced by fluorine;

NH₂、NH-(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、NH(C₁-C₇) -acyl, phenyl, (CH)₂)_o-phenyl, O- (CH)₂)_o-phenyl, wherein o may be 0-6, and wherein the phenyl ring may be substituted 1-3 times with: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、(C₁-C₈) -alkoxy, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

Or

R3 and R4 together with the carbon atom to which they are attached are a 5-to 7-membered saturated, partially or fully unsaturated ring Cyc2, wherein the carbon atoms in 1 or 2 of the rings may also be replaced by N, O or S, and Cyc2 may optionally be substituted by: (C)₁-C₆) Alkyl radicals, (C)₂-C₅) -alkenyl, (C)₂-C₅) Alkynyl, where, in each case, there is one CH₂The groups may be replaced by O, or by the following groups: H. f, Cl, OH, CF₃、NO₂、CN、COO(C₁-C₄) Alkyl, CONH₂、CONH(C₁-C₄) Alkyl radical, OCF₃(ii) a And is

R5 is hydrogen;

and pharmaceutically acceptable salts thereof.

Preferred compounds of formula I are those wherein a is attached at the 2-position of the thienyl ring.

Further preferred are compounds of formula I wherein,

r1 and R2 are hydrogen, F, Cl, Br, I, OH and NO₂、CN、COOH、CO(C₁-C₆) -alkyl, COO (C)₁-C₆) Alkyl, CONH₂、CONH(C₁-C₆) Alkyl, CON [ (C)₁-C₆) -alkyl radical]₂、(C₁-C₈) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl, (C)₁-C₆) Alkoxy, HO- (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy- (C)₁-C₆) Alkyl, phenyl, benzyl, (C)₁-C₄) -alkylcarbonyl, SO- (C)₁-C₆) -alkyl, wherein one, more than one or all hydrogens on alkyl and alkoxy may be replaced by fluorine;

n is 2 or 3;

cyc1 is a 5-or 6-membered saturated, partially saturated, or unsaturated ring, in which one carbon atom may be replaced by O or S;

r3, R4 and R5 are hydrogen, F, Cl, Br, I, OH and NO₂、CN、COOH、COO(C₁-C₆) Alkyl, CO (C)₁-C₄) Alkyl, CONH₂、CONH(C₁-C₆) Alkyl, CON [ (C)₁-C₆) -alkyl radical]₂、(C₁-C₈) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl, (C)₁-C₁₂) Alkoxy, HO- (C)₁-C₆) Alkyl radicals, (C)₁-C₆) -alkoxy- (C)₁-C₆) Alkyl radicals, (C)₁-C₄) -alkylphenyl, (C)₁-C₄) Alkoxy-phenyl, S- (C)₁-C₆) Alkyl, SO- (C)₁-C₆) -alkyl, wherein one, more than one or all hydrogens on alkyl and alkoxy may be replaced by fluorine;

or

R3 and R4 together with the carbon atom to which they are attached are a 5-to 7-membered saturated, partially or fully unsaturated ring Cyc2, wherein the carbon atoms in 1 or 2 of the rings may also be replaced by N, O or S, and Cyc2 may optionally be substituted by: (C)₁-C₆) Alkyl radicals, (C)₂-C₅) -alkenyl, (C)₂-C₅) Alkynyl, where, in each case, there is one CH₂The radical may be replaced by O, orSubstituted with the following groups: H. f, Cl, OH, CF₃、NO₂、CN、COO(C₁-C₄) Alkyl, CONH₂、CONH(C₁-C₄) Alkyl radical, OCF₃(ii) a And is

R5 is hydrogen.

Particular preference is given to compounds of the formula I in which

R1 and R2 are hydrogen and (C)₁-C₆) Alkyl radicals, (C)₁-C₄) Alkoxy, HO- (C)₁-C₄) Alkyl radicals, (C)₁-C₄) -alkoxy- (C)₁-C₄) Alkyl, F, Cl, CF₃、OCF₃、OCH₂CF₃、(C₁-C₄) -alkyl-CF₂Phenyl, benzyl and (C)₁-C₄) -alkylcarbonyl, (C)₂-C₄) -alkenyl, (C)₂-C₄) -alkynyl, COO (C)₁-C₄) -an alkyl group;

a is-CH ═ CH-CH₂-or (C)₁-C₄) Alkylene, in which one or two CH₂The groups may be replaced by: - (C ═ O) -, -CH ═ CH-, -CH (OH) -, -NH-, -CHF-, -CF₂-、-O-；

n is 2 or 3;

cyc1 is an unsaturated ring in which one carbon atom may be replaced by O or S;

r3, R4 and R5 are hydrogen, F, Cl, Br, I and NO₂、OH、CN、(C₁-C₆) Alkyl radicals, (C)₁-C₈) Alkoxy, OCF₃、OCH₂CF₃、S-(C₁-C₄) Alkyl, COOH, HO- (C)₁-C₄)-

Alkyl, (C)₁-C₄) -alkoxy- (C)₁-C₄) Alkyl radicals, (C)₁-C₂) -alkylphenyl, (C)₁-C₂) -alkoxyphenyl, or

R3 and R4 together are-CH-O-, -CH-S-, -O- (CH)₂)_p-O-, wherein p ═ 1 or 2, -O-CF₂-O-, -CH-, and

r5 is hydrogen.

Particularly preferred are compounds of formula I wherein R2 is hydrogen.

More preferred are compounds of formula I wherein,

r1 is hydrogen, CF₃、(C₁-C₄) -an alkyl group, a phenyl group,

r2 is a hydrogen atom or a salt thereof,

a is-CH₂-、-C₂H₄-、-C₃H₆-、-CH(OH)-、-(C＝O)-、-C H＝CH-、-CH＝CH-CH₂-、-CO-CH₂-CH₂-or-CO-NH-CH₂-；

n is 2 or 3;

cyc1 is an unsaturated ring in which one carbon atom may be replaced with S;

r3, R4 and R5 are hydrogen, F, Cl, I and NO₂、OH、CN、(C₁-C₆) Alkyl radicals, (C)₁-C₈) Alkoxy, O-CH₂-phenyl, OCF₃、S-CH₃COOH or

R3 and R4 taken together are-CH-O-, -O- (CH)₂)_p-O-, wherein p ═ 1 or 2, -O-CF₂-O-, -CH-, and

r5 is hydrogen.

More preferred are compounds of formula I wherein,

a is-CH₂-or-CH₂-CH₂-, or

Cyc1 is phenyl, or

Cyc1 is thienyl.

Particular mention may be made of compounds of the formula I in which

Cyc1 is monosubstituted, or

Cyc1 is para-substituted, or

Cyc1 is meta-substituted.

The invention also relates to compounds of formula I in the form of racemates, racemic mixtures and pure enantiomers as well as diastereomers and mixtures thereof.

The alkyl groups in the substituents R1, R2, R3, R4 and R5, including alkoxy, alkenyl and alkynyl groups, may be straight-chain or branched groups.

The sugar residues in the compounds of formula I may be the alpha and beta forms of the L-or D-sugar, for example, allose, altrose, glucose, mannose, gulose, idose, galactose, talose. Preferred sugars which may be mentioned are: beta-glucose, beta-galactose, beta-allose and beta-mannose, with beta-glucose, beta-allose and beta-mannose being particularly preferred, and beta-glucose being very particularly preferred.

Pharmaceutically acceptable salts are particularly suitable for pharmaceutical applications because of their higher solubility compared to the starting or base compound. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and salts of organic acids, such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable base salts are ammonium salts, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. magnesium and calcium salts), tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine salts.

Salts with a non-pharmaceutically acceptable anion, such as trifluoroacetate, are also within the scope of the invention and are useful as intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic uses, such as in vitro applications.

The term "physiologically functional derivative" is intended to mean any physiologically tolerable derivative of a compound of formula I according to the invention, for example an ester which, upon administration to a mammal such as a human, can form (directly or indirectly) a compound of formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of the compounds of the invention, for example as described by H.Okada et al, chem.pharm.Bull.1994, 42, 57-61. The prodrugs can be metabolized in vivo to provide the compounds of the invention. These prodrugs may or may not be active themselves.

The compounds of the invention may also exist in different polymorphic forms, for example amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the present invention are within the scope of the present invention and are a further aspect of the invention.

Hereinafter, "compounds of formula I" are all meant to refer to the compounds of formula I above as well as salts, solvates and physiologically functional derivatives thereof.

The amount of a compound of formula I required to achieve the desired biological effect will depend on a variety of factors, such as the particular compound selected, the intended use, the mode of administration, and the clinical condition of the patient. Generally, the daily dose will be in the range of 0.3mg to 100mg (typically 3mg to 50mg) per day per kg of body weight, for example 3 to 10 mg/kg/day. The intravenous dose may be, for example, from 0.3mg to 1.0mg/kg, and the dose may conveniently be administered as an infusion of from 10ng to 100 ng/kg/min. Infusion solutions suitable for this purpose may, for example, contain 0.1ng-10mg, typically 1ng-10 mg/ml. A single dose may, for example, contain from 1mg to 10g of active compound. Thus, ampoules for injection may, for example, contain from 1mg to 100mg, and single-dose preparations for oral administration, such as tablets or capsules, may, for example, contain from 1.0mg to 1000mg, typically from 10 to 600 mg. For the treatment of the above-mentioned disorders, although the compounds of the formula I can be used as such, they are preferably present in the form of pharmaceutical compositions together with acceptable carriers. The carrier should obviously be acceptable, i.e. compatible with the other components of the composition and not harmful to the health of the patient. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may also be present, including other compounds of formula I. The pharmaceutical composition of the present invention can be prepared by a known pharmaceutical method, which essentially comprises mixing with a pharmaceutically acceptable carrier and/or excipient.

The pharmaceutical compositions of the invention are those suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration will depend in each case on the nature and severity of the condition being treated and on the nature of the compound of formula I used in each case. Coated formulations and coated sustained release formulations are also within the scope of the invention. Acid and gastric juice resistant formulations are preferred. Suitable gastro-resistant coatings include cellulose acetate phthalate, polyethylene acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutical compounds suitable for oral administration may be presented as discrete units such as capsules, cachets, inhalation tablets or tablets, each containing a specified amount of a compound of formula I; powder or granules; such as solutions or suspensions in aqueous or non-aqueous liquids; or for example an oil-in-water or water-in-oil emulsion. As noted above, these compositions may be prepared using any suitable pharmaceutical method which includes the step of bringing into contact the active ingredient and the carrier, which may consist of one or more other ingredients. Generally, the compositions are prepared by homogeneously and homogeneously mixing the active ingredient in a liquid and/or finely divided solid carrier, after which the product is shaped if desired. Thus, for example, a tablet may be formed by compressing or molding a powder or granules of the compound with the appropriate other ingredient or ingredients. Compressed tablets may be prepared by compressing in a suitable apparatus the compound in a free-flowing form such as a powder or granules, for example, with a binder, glidant, inert diluent, and/or one or more surface active/dispersing agents as appropriate. Molded tablets may be made by molding the powdered compound moistened with an inert liquid diluent in a suitable apparatus.

Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges comprising a compound of formula I and a flavouring agent, typically sucrose and acacia or tragacanth; and lozenges comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administration preferably comprise sterile aqueous preparations of a compound of formula I, which are preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, although administration may also take place subcutaneously, intramuscularly or intradermally. These formulations can preferably be prepared by mixing the compound with water and rendering the resulting solution sterile and isotonic with blood. Generally, the injectable compositions of the present invention contain 0.1 to 5% by weight of the active compound.

Pharmaceutical compositions suitable for rectal administration are preferably presented as single dose suppositories. These compositions may be prepared by mixing a compound of formula I with one or more conventional solid excipients, such as cocoa butter, and molding the resulting mixture.

Pharmaceutical compositions suitable for topical application to the skin are preferably present as ointments, creams, lotions, ointments, sprays, aerosols or oils. Carriers which may be used are petrolatum, lanolin, polyethylene glycols, alcohols and mixtures of two or more of these substances. The concentration of the active ingredient is generally 1.0 to 15% by weight, for example 0.5 to 2% by weight, of the composition.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal use may be presented as individual ointments which are adapted for intimate contact with the epidermis of the patient over an extended period of time. The pastes generally contain the active compound in an aqueous solution which is suitably buffered, dissolved and/or dispersed in a binder or dispersed in a polymer. Suitable concentrations of the active ingredient are about 1% to 35%, preferably about 3% to 15%. As a particular possibility, the active compound can be, for example, in accordance with Pharmaceutical Research, 2 (6): 318(1986), by electrotransport or iontophoresis delivery.

Furthermore, the present invention relates to a process for the preparation of compounds of formula I, obtainable according to the following reaction schemes A, B, C, D and E:

the method A comprises the following steps:

CsCO for compounds of formula A wherein R1 and R2 have the meanings indicated above₃Or another suitable base, is deprotonated in DMF and then reacted with benzyl bromide to form the compound of formula B.

Compound B is dissolved in a mixture of methanol, tetrahydrofuran and water and converted to the compound of formula C by reaction with lithium hydroxide.

Compound C is converted to compound D with N, O-dimethylhydroxylamine using propanephosphonic anhydride or another suitable activating reagent for the formation of the amide bond.

Compound D and an organometallic compound of formula E (wherein M is Li, MgCl, MgBr and Cyc1, Cyc2, n, R3, R4, R5 have the same meaning as above) are dissolved together in tetrahydrofuran, and a Lewis Acid (LA), preferably tin tetrachloride or aluminum trichloride, is added under ice cooling to convert into a compound of formula F.

To remove the benzyl ether, compound F can be dissolved in dichloromethane and reacted with BBr₃Dimethyl sulfide complex, or dissolving compound F in methanol and reacting with hydrogenStirring with palladium on carbon under an atmosphere to obtain the compound of formula G.

Compound G is converted to a compound of formula H using 4, 5-diacetoxy-6-acetoxymethyl-2-bromo-tetrahydropyran-3-yl acetate and potassium carbonate in a mixture of dichloromethane and water.

Compound H is first reacted with sodium borohydride in a mixture of methanol and tetrahydrofuran and then converted to the compound of formula J in ethanol in the presence of palladium on carbon under a hydrogen atmosphere, or compound H is dissolved in acetonitrile and directly converted to the compound of formula J in a mixture of sodium cyanoborohydride and trimethylchlorosilane.

Compound J is dissolved in methanol and reacted with sodium methoxide to give the compound of formula K.

The compounds of examples 51-54 were synthesized using this method.

The method B comprises the following steps:

a compound of formula L wherein R1 and R2 have the meanings as described above is dissolved in dichloromethane and reacted with a compound of formula M wherein Cyc1, Cyc2, N, R3, R4, and R5 have the same meanings as described above under ice cooling to give a compound of formula N.

Dissolving Compound N in dichloromethane, and reacting with BBr₃-dimethyl sulfide complex, in this way obtaining the compound of formula Q.

Compound G was converted to the compound of formula H using 4, 5-diacetoxy-6-acetoxymethyl-2-bromo-tetrahydropyran-3-yl acetate and potassium carbonate in a mixture of dichloromethane and water.

The compounds of examples 7-34 were synthesized using this method.

The method C comprises the following steps:

compounds of formula L, wherein R1 and R2 have the above meanings, are dissolved in DMF and phosphoryl chloride is added to form compounds of formula P.

Dissolving Compound P in dichloromethane with BBr₃-dimethyl sulfide complex, in this way obtaining the compound of formula Q.

Compound Q is converted to a compound of formula R using 4, 5-diacetoxy-6-acetoxymethyl-2-bromo-tetrahydropyran-3-yl acetate and potassium carbonate in a mixture of dichloromethane and water.

Compound R was dissolved in dioxane and converted to the compound of formula S using methyltriphenylphosphonium bromide and potassium carbonate.

Compound S is converted to a compound of formula U using a compound of formula T (wherein A, Cyc1, Cyc2, n, R3, R4, R5 have the same meaning as above) in dichloromethane in the presence of the ruthenium catalyst tricyclohexylphosphine- [1, 3-bis (2, 4, 6-trimethylphenyl) -4, 5-dihydroimidazol-2-ylidene ] [ benzylidene ] ruthenium (IV) dichloride.

Compound U is dissolved in methanol and reacted with sodium methoxide to give the compound of formula X.

Alternatively, compound U can also be converted to a compound of formula V in methanol under a hydrogen atmosphere and in the presence of palladium on carbon.

Compound V is dissolved in methanol and reacted with sodium methoxide to give the compound of formula W.

Alternatively, W may be obtained by subjecting X to hydrogenolysis. This was done by treatment in methanol in the presence of palladium on carbon under hydrogen atmosphere.

Examples 36-50 were synthesized using this method.

The method D comprises the following steps:

compounds of formula a, wherein R1 and R2 have the meanings as indicated above, are dissolved in a mixture of methanol, tetrahydrofuran and water and converted into compounds of formula Y by reaction with lithium hydroxide.

Compound Y and a compound of formula Z (wherein A, Cyc1, Cyc2, n, R3, R4, R5 have the meanings as described above) are dissolved together in tetrahydrofuran and the compound is converted to compound AA with propylphosphinic anhydride or another suitable activating reagent for the formation of amide bonds under ice cooling.

Compound AA is converted to a compound of formula BB using 4, 5-diacetoxy-6-acetoxymethyl-2-bromo-tetrahydropyran-3-yl acetate and potassium carbonate in a mixture of dichloromethane and water.

Compound BB is dissolved in methanol and reacted with sodium methoxide to form the compound of formula K.

The compounds of examples 55-58 were synthesized using this method.

The method E comprises the following steps:

compound DD is converted to a compound of formula EE using 4, 5-diacetoxy-6-acetoxymethyl-2-bromo-tetrahydropyran-3-yl acetate and potassium carbonate in a mixture of dichloromethane and water.

Compound EE was dissolved in methanol and a solution of sodium methoxide in methanol was added. Compounds of formula FF wherein A, Cyc1, Cyc2, n, R3, R4, R5 have the meaning as described above are added to obtain compounds of formula GG.

Compound GG is converted to a compound of formula HH in methanol under a hydrogen atmosphere in the presence of palladium on carbon.

The compounds of examples 1-6 were synthesized using this method.

Other compounds of formula I may be prepared accordingly or by known methods.

The compounds of formula (I) may also be administered in combination with other active ingredients.

The following are other active compounds suitable for use in the combined preparation:

all antidiabetic drugs mentioned in Rote Liste 2001, chapter 12. They can be combined with the compounds of the formula I according to the invention, in particular for synergistically increasing the effect. The combination of active ingredients can be administered to a patient by administering the active ingredients separately or in the form of a combined preparation containing several active ingredients in a single pharmaceutical preparation. Most of the following active ingredients are disclosed in the USP dictionary, US pharmacopoeia, Rockville 2001, USAN and International Drug Names. Antidiabetic agents include insulin and insulin derivatives, e.g.(seewww. lantus.com) Or HMR 1964, fast-acting insulin like (see US 6,221,633), GLP-1-derivatives, such as those disclosed in WO 98/08871 by Novo Nordisk a/S, and orally active hypoglycemic active compounds.

Orally active hypoglycemic compounds preferably include sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glycosidase inhibitors, glucagon antagonists, GLP-1 agonists, calcium channel openers, such as those disclosed by Novo Nordisk A/S in WO 97/26265 and WO99/03861, insulin sensitizers, liver enzyme inhibitors involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds that alter lipid metabolism, such as antihyperlipidemic and hypolipidemic active ingredients, compounds that reduce food intake, PPAR and PXR agonists, and active ingredients that act on the ATP-dependent potassium channels of the beta cells.

In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA-reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, Rosuvastatin (Rosuvastatin).

In one embodiment of the invention, the compounds of formula I are administered in combination with a cholesterol absorption inhibitor, e.g. ezetimibe, tiquinazine, pamabrin.

In one embodiment of the invention, the compound of formula I is administered in combination with a PPAR γ agonist, such as rosiglitazone, pioglitazone, JTT-501, GI 262570.

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR α agonist, e.g., GW 9578, GW 7647.

In one embodiment of the invention, the compounds of formula I are administered in combination with a mixed PPAR α/γ agonist, for example GW 1536, AVE 8042, AVE 8134 or AVE 0847, or as described in WO00/64888, WO 00/64876, or DE 10142734.4.

In one embodiment of the invention, the compound of formula I is administered in combination with a fibrate, e.g., fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, the compound of formula I is administered in combination with an MTP inhibitor, such as Implidapide, BMS-201038 or R-103757.

In one embodiment of the invention, the compound of formula I is administered in combination with a bile acid absorption inhibitor (see, e.g., US 6,245,744 or US 6,221,897), such as HMR 1741.

In one embodiment of the invention, the compound of formula I is administered in combination with a CETP inhibitor, such as JTT-705.

In one embodiment of the invention, the compound of formula I is administered in combination with a polymeric bile acid adsorbent, such as cholestyramine and Colesevelam.

In one embodiment of the invention, the compound of formula I is administered in combination with an LDL-receptor inducing agent (see US 6,342,512), such as HMR1171, HMR 1586.

In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor, such as avasimibe (avasimibe).

In one embodiment of the invention, the compound of formula I is administered in combination with an antioxidant, such as OPC-14117.

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein lipase inhibitor, e.g., NO-1886.

In one embodiment of the invention, the compound of formula I is administered in combination with an ATP-citrate lyase inhibitor, such as SB-204990.

In one embodiment of the invention, the compound of formula I is administered in combination with a squalene synthetase inhibitor, e.g., BMS-188494.

In one embodiment of the invention, the compound of formula I is administered in combination with a lipoprotein (a) antagonist, such as CI-1027 or niacin.

In one embodiment of the invention, the compound of formula I is administered in combination with a lipase inhibitor, e.g. orlistat.

In one embodiment of the invention, the compound of formula I is administered in combination with insulin

In one embodiment of the invention, the compounds of formula I are administered in combination with a sulfonylurea, for example tolbutamide, glibenclamide, glipizide or glimepiride.

In one embodiment of the invention, the compound of formula I is administered in combination with a biguanide, for example metformin.

In yet another embodiment, the compound of formula I is administered in combination with a meglitinide, such as repaglinide.

In another embodiment, the compound of formula I is administered in combination with a thiazolidinedione, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097(dr. reddy's Research Foundation), in particular 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxo-2-quinazolinyl) methoxy ] -phenyl ] methyl ] -2, 4-thiazolidinedione.

In one embodiment, the compound of formula I is administered in combination with an α -glucosidase inhibitor, such as miglitol or acarbose.

In one embodiment, the compounds of formula I are administered in combination with an active ingredient that acts on the ATP-dependent potassium channel of beta cells, such as tolbutamide, glyburide, glipizide, glimepiride or repaglinide.

In one embodiment, the compound of formula I is administered in combination with more than one of the above compounds, for example in combination with sulfonylureas and metformin, with sulfonylureas and acarbose, with repaglinide and metformin, with insulin and sulfonylureas, with insulin and metformin, with insulin and troglitazone, with insulin and lovastatin, and the like.

In another embodiment, compounds of formula I are useful in combination with CART modulators (see "cocaine-amphetamine regulated transcription affects energy metabolism, anxiety and gastric emptying in mice," Asakawa, A et al, M.: Hormone and Metabolic Research (2001), 33(9), 554-, 3-c ] pyridin-5-yl) -1- (4-chloro-phenyl) -2-oxoethyl ] -amide; (WO 01/91752)), Orexin (Orexin) antagonists (e.g. 1- (2-methyl-benzooxazol-6-yl) -3- [1, 5] naphthyridin-4-ylurea hydrochloride (SB-334867-a)), H3-agonists (3-cyclohexyl-1- (4, 4-dimethyl-1, 4, 6, 7-tetrahydroimidazo [4, 5-c ] pyridin-5-yl) -propan-1-one oxalate (WO 00/63208)); TNF-agonists, CRF-antagonists (e.g., [ 2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-1, 3, 9-triaza-fluoren-4-yl ] -dipropylamine (WO 00/66585)), CRF BP-antagonists (e.g., Urocortin), Urocortin-agonists, β 3-agonists (e.g., 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2, 3-dimethyl-1H-indol-6-yloxy) -ethylamino ] -ethanol hydrochloride (WO 01/83451)), MSH (melanocyte stimulating hormone) agonists, CCK-a agonists (e.g., {2- [4- (4-chloro-2, 5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl ] -5, 7-dimethyl-indol-1-yl } -acetic acid trifluoroacetate (WO 99/15525)), 5-hydroxytryptamine reuptake inhibitors (e.g., dexfenfluramine), mixed 5-hydroxytryptamine compounds and noradrenergic compounds (e.g., WO 00/71549), 5 HT-agonists such as 1- (3-ethyl-benzofuran-7-yl) -piperazine oxalate (WO 01/09111), bombesin-agonists, galanin (galanin) antagonists, growth hormones (e.g., human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2-diisopropylamino-ethyl) -piperazine oxalate (WO 01/09111) Carbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), a TRH-agonist (see, e.g., EP 0462884), a uncoupling protein 2-or 3-modulator, a leptin (leptin) agonist (see, e.g., Lee, Daniel w.; leingung, Matthew c.; Rozhavskaya-Arena, Marina; grasso, patricia. leptin agonists are potential approaches to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-.

In one embodiment of the invention, the other active compound is leptin; see, e.g., "leptin promising for therapeutic applications", Salvador, Javier; Gomez-Ambrosi, Javier; fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-.

In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine

In one embodiment, the other active ingredient is sibutramine.

In one embodiment, the other active ingredient is orlistat

In one embodiment, the other active ingredient is mazindol or phentermine.

In one embodiment, the compound of formula I is administered in combination with an edible fibrous material, preferably an insoluble edible fibrous material (see, e.g., references to(Zunft HJ et al, carob pulp preparations for the treatment of hypercholesterolemia, ADVANCES IN THERAPY (9-10 months 2001), 18(5), 230-6). Caromax is a peptide derived from Nutrinova, Nutrition Specialties&FoodIngredients GmbH，Industriepark65926 fenkfurt/Main). Andthe combination can be administered by either administering a single formulation or separately administering a compound of formula I andto be implemented.It may also be administered in the form of a food, for example, taken in a bread product or a milkbreakfast bar.

It is to be understood that various suitable combinations of a compound of the present invention with one or more of the above compounds and, if desired, with one or more other pharmaceutically active substances are considered to be within the scope of the present invention.

The examples which follow are intended to illustrate the invention without limiting it.

Table 1: a compound of formula I

Ex.	R1，R2	A (2-position bonded to thienyl)	Cyc1	R3，R4，R5	MS
Ex.	R1，R2	A (2-position bonded to thienyl)	Cyc1	R3，R4，R5	MS	1	H，H	-CO-CH-CH-	Ph	4-O-CH，H，H	ok
2	H，H	-CO-CH-CH-	Ph	3-O-(CH)-O-4，H	ok	1	H，H	-CO-CH-CH-	Ph	4-O-CH，H，H	ok
2	H，H	-CO-CH-CH-	Ph	3-O-(CH)-O-4，H	ok	3	H，H	-CO-CH-CH-	Ph	3-O-CH-O-4，H	ok
4	H，H	-CO-CH-CH-	Ph	3-CH＝CH-O-4，H	ok	3	H，H	-CO-CH-CH-	Ph	3-O-CH-O-4，H	ok
4	H，H	-CO-CH-CH-	Ph	3-CH＝CH-O-4，H	ok	5	H，H	-CO-CH-CH-	3-thiophenes	H，H，H	ok
6	H，H	-CO-CH-CH-	2-thiophenes	H，H，H	ok	5	H，H	-CO-CH-CH-	3-thiophenes	H，H，H	ok
6	H，H	-CO-CH-CH-	2-thiophenes	H，H，H	ok	7	H，H	-CH-	Ph	4-O-CH，H，H	ok
8	H，H	-CO-	Ph	4-O-CH，H，H	ok	7	H，H	-CH-	Ph	4-O-CH，H，H	ok
8	H，H	-CO-	Ph	4-O-CH，H，H	ok	9	H，H	-CH-	Ph	H，H，H	ok
10	H，H	-CH(OH)-	Ph	H，H，H	ok	9	H，H	-CH-	Ph	H，H，H	ok
10	H，H	-CH(OH)-	Ph	H，H，H	ok	11	H，H	-CH-	Ph	4-O-CH，H，H	ok
12	H，H	-CH-	Ph	3-O-CH，4-O-CH，H	ok	11	H，H	-CH-	Ph	4-O-CH，H，H	ok
12	H，H	-CH-	Ph	3-O-CH，4-O-CH，H	ok	13	H，H	-CH-	Ph	4-O-CH，H，H	ok
14	H，H	-CH-	Ph	4-F，H，H	ok	13	H，H	-CH-	Ph	4-O-CH，H，H	ok
14	H，H	-CH-	Ph	4-F，H，H	ok	15	H，H	-CH-	Ph	4-I，H，H	ok
16	H，H	-CH-	Ph	4-NO，H，H	ok	15	H，H	-CH-	Ph	4-I，H，H	ok
16	H，H	-CH-	Ph	4-NO，H，H	ok	17	H，H	-CH-	Ph	4-CH，H，H	ok
18	H，H	-CH-	Ph	3-CH，H，H	ok	17	H，H	-CH-	Ph	4-CH，H，H	ok
18	H，H	-CH-	Ph	3-CH，H，H	ok	19	H，H	-CH-	Ph	2-CH，H，H	ok
20	H，H	-CH-	Ph	4-CH，H，H	ok	19	H，H	-CH-	Ph	2-CH，H，H	ok
20	H，H	-CH-	Ph	4-CH，H，H	ok	21	H，H	-CH-	Ph	3-CH，4-O-CH，5-CH	ok
22	H，H	-CH-	Ph	3-O-CF-O-4，H	ok	21	H，H	-CH-	Ph	3-CH，4-O-CH，5-CH	ok
22	H，H	-CH-	Ph	3-O-CF-O-4，H	ok	23	H，H	-CH-	Ph	4-CH，H，H	ok
24	H，H	-CH-	Ph	4-C(CH)，H，H	ok	23	H，H	-CH-	Ph	4-CH，H，H	ok
24	H，H	-CH-	Ph	4-C(CH)，H，H	ok	25	H，H	-CH-	Ph	4-OH，H，H	ok
26	H，H	-CH-	Ph	4-O-CH-Ph，H，H	ok	25	H，H	-CH-	Ph	4-OH，H，H	ok
26	H，H	-CH-	Ph	4-O-CH-Ph，H，H	ok	27	H，H	-CH-	3-thiophenes	H，H，H	ok
28	H，H	-CH-	2-thiophenes	4-CH＝CH-CH＝CH-5，H	ok	27	H，H	-CH-	3-thiophenes	H，H，H	ok

29	H，H	-CH-	Ph	3-O-CH，H，H	ok
29	H，H	-CH-	Ph	3-O-CH，H，H	ok	30	H，H	-CH-	Ph	4-CN，H，H	ok
31	H，H	-CH-	Ph	3-O-CH-O-4H，H，H	ok	30	H，H	-CH-	Ph	4-CN，H，H	ok
31	H，H	-CH-	Ph	3-O-CH-O-4H，H，H	ok	32	H，H	-CH-	Ph	4-S-CH，H，H	ok
33	H，H	-CH-	Ph	4-O-CH，H，H	ok	32	H，H	-CH-	Ph	4-S-CH，H，H	ok
33	H，H	-CH-	Ph	4-O-CH，H，H	ok	34	H，H	-CH-	Ph	4-OCF，H，H	ok
35	H，H	-CH-	Ph	4-COOH，H，H	ok	34	H，H	-CH-	Ph	4-OCF，H，H	ok
35	H，H	-CH-	Ph	4-COOH，H，H	ok	36	H H	-CH-CH-	Ph	4-O-CH，H，H	ok
37	H，H	-CH＝CH-	Ph	4-O-CH，H，H	ok	36	H H	-CH-CH-	Ph	4-O-CH，H，H	ok
37	H，H	-CH＝CH-	Ph	4-O-CH，H，H	ok	38	H，H	-CH＝CH-	Ph	4-F，H，H	ok
39	H，H	-CH＝CH-	Ph	4-Cl，H，H	ok	38	H，H	-CH＝CH-	Ph	4-F，H，H	ok
39	H，H	-CH＝CH-	Ph	4-Cl，H，H	ok	40	H，H	-CH＝CH-	Ph	4-O-CH，H，H	ok
41	H，H	-CH＝CH-	Ph	4-CH，H，H	ok	40	H，H	-CH＝CH-	Ph	4-O-CH，H，H	ok
41	H，H	-CH＝CH-	Ph	4-CH，H，H	ok	42	H，H	-CH＝CH-	Ph	4-OH，H，H	ok
43	H，H	-CH-CH-	Ph	4-F，H，H	ok	42	H，H	-CH＝CH-	Ph	4-OH，H，H	ok
43	H，H	-CH-CH-	Ph	4-F，H，H	ok	44	H，H	-CH-CH-	Ph	4-Cl，H，H	ok
45	H，H	-CH-CH-	Ph	4-O-CH，H，H	ok	44	H，H	-CH-CH-	Ph	4-Cl，H，H	ok
45	H，H	-CH-CH-	Ph	4-O-CH，H，H	ok	46	H，H	-CH-CH-	Ph	4-CH，H，H	ok
47	H，H	-CH-CH-	Ph	4-OH，H，H	ok	46	H，H	-CH-CH-	Ph	4-CH，H，H	ok
47	H，H	-CH-CH-	Ph	4-OH，H，H	ok	48	H，H	-CH＝CH-CH-	Ph	4-O-CH，H，H	ok
49	H，H	-CH-CH-CH-	Ph	4-O-CH，H，H	ok	48	H，H	-CH＝CH-CH-	Ph	4-O-CH，H，H	ok
49	H，H	-CH-CH-CH-	Ph	4-O-CH，H，H	ok	50	H，H	-CH＝CH-CH-	Ph	3-O-CH-O-4，H	ok
51	5-CH(CH)，H	-CH-	Ph	4-O-CH，H，H	ok	50	H，H	-CH＝CH-CH-	Ph	3-O-CH-O-4，H	ok
51	5-CH(CH)，H	-CH-	Ph	4-O-CH，H，H	ok	52	5-Ph，H	-CH-	Ph	4-O-CH，H，H	ok
53	5-CH，H	-CH-	Ph	4-O-CH，H，H	ok	52	5-Ph，H	-CH-	Ph	4-O-CH，H，H	ok
53	5-CH，H	-CH-	Ph	4-O-CH，H，H	ok	54	5-CF，H	-CH-	Ph	4-O-CH，H，H	ok
55	H，H	-CO-NH-CH-	Ph	H，H，H	ok	54	5-CF，H	-CH-	Ph	4-O-CH，H，H	ok
55	H，H	-CO-NH-CH-	Ph	H，H，H	ok	56	H，H	-CO-NH-CH-	Ph	4-O-CH，H，H	ok
57	H，H	-CO-NH-CH-	Ph	3-O-CH-O-4，H	ok	56	H，H	-CO-NH-CH-	Ph	4-O-CH，H，H	ok
57	H，H	-CO-NH-CH-	Ph	3-O-CH-O-4，H	ok	58	H，H	-CO-NH-CH-	Ph	4-O-CF，H，H	ok

^＊The information "MS is ok" means that the mass spectrum or HPLC/MS is determined and the molecular peak M +1 (MH) is detected in this spectrum⁺) And/or M +18 (MNH)₄ ⁺) Andor M +23 (MNa)⁺)。

The compounds of formula I are characterized by a beneficial effect on sugar metabolism; in particular, they can lower blood glucose levels and are suitable for the treatment of type I and type II diabetes. The compounds can therefore be used alone or in combination with other hypoglycemic active ingredients (antidiabetics).

The compounds of formula I are also suitable for the treatment of late-stage injuries to diabetes, such as nephropathy, retinopathy, neuropathy and syndrome X, obesity, myocardial infarction, peripheral arterial occlusive disease, thrombosis, arteriosclerosis, inflammatory diseases, immune diseases, autoimmune diseases (such as AIDS), asthma, osteoporosis, cancer, psoriasis, alzheimer's disease, schizophrenia and infectious diseases, preferably for the treatment of type I and type II diabetes, and for the prevention and treatment of late-stage injuries, syndrome X and obesity caused by diabetes.

The activity of the compounds was tested as described below:

preparation of brush border membrane vesicles from Rabbit, rat and pig intestines

According to the so-called Mg²⁺The precipitation method prepares brush border membrane vesicles from intestinal cells of the small intestine. The small intestine was dissected and suspended in 60ml ice-cold Tris/HCl buffer (ph 7.1)/300mM mannitol, 5mM EGTA. It is diluted to 300ml with ice-cold distilled water and homogenized with Ultraturrax (18-axis, IKAWerk Staufen, FRG) at 75% maximum power for 2X 1 min while cooling in ice. After adding 3ml of 1M MgCl₂After the solution (final concentration 10mM), the mixture was left at 0 ℃ for 15 minutes. Adding Mg²⁺The cell membranes except the brush border membrane vesicles are allowed to aggregate and sediment. After centrifugation at 3000Xg (5000rpm, SS-34 rotor) for 15 minutes, the pellet was discarded and the supernatant containing the brush border membrane vesicles was centrifuged at 26700Xg (15000rpm, SS-34 rotor) for 30 minutes. The supernatant was discarded and the pellet was re-homogenized in 60ml of 12mM Tris/HCl buffer (pH7.1)/60mM mannitol, 5mM EGTA using a Potter Elvejhem homogenizer (Braun, Melsungen, 900rpm, 10 strokes). Adding0.1ml of 1M MgCl₂The solution was incubated at 0 ℃ for 15 minutes and centrifuged at 3000Xg for 15 minutes. The supernatant was then centrifuged again for 30 minutes at 46000Xg (20000rpm, SS-34 rotor). The pellet was taken up in 30ml of 20mM Tris/Hepes buffer (pH 7.4)/280mM mannitol and suspended again homogeneously by impacting 20 times in a PotterElvejhem homogenizer at 1000 rpm. After centrifugation at 48000Xg (20000rpm, SS-34 rotor) for 30 minutes, the pellet was taken up in 0.5-2ml Tris/Hepes buffer (pH 7.4)/280mM mannitol (final concentration 20mg/ml) and resuspended with a tuberculin syringe with 27 gauge needle.

Vesicles can be used directly after preparation for labeling or transport studies, or stored in 4mg aliquots in liquid nitrogen at-196 ℃.

To prepare brush border membrane vesicles from rat small intestine, 6-10 male Wistar rats (housed in Kastengrund, Aventis Pharma) were sacrificed by cervical dislocation method, and the small intestine was removed and rinsed with cold isotonic saline. The small intestine was cut and the mucosa was peeled off. The method of isolating the brush border membrane vesicles is as previously described. To remove the cytoskeletal portion, brush border membrane vesicles were prepared from rat small intestine by treatment with KSCN as a chaotropic (chaotropic) ion.

To prepare brush border membrane vesicles from rabbit small intestine, rabbits were sacrificed by intravenous injection of 0.5ml of an aqueous solution of 2.5mg tetracaine HCl, 100mg m-butramide, and 25mg mebezonium iodide. The small intestine was removed, rinsed with ice cold physiological saline, and frozen and stored in plastic bags under nitrogen at-80 ℃ for 4-12 weeks. To prepare the membrane vesicles, the frozen small intestine was thawed in a water bath at 30 ℃ and then the mucosa was peeled off. The membrane vesicles were obtained by treatment as described previously.

To prepare brush border capsules from porcine small intestine, jejunum from freshly slaughtered pigs was rinsed with ice-cooled isotonic saline and frozen in plastic bags at-80 ℃ under nitrogen. Membrane vesicles were obtained as described previously.

Preparation of brush border membrane vesicles from the renal cortex of rat kidney

By means of Biber, etcThe brush border membrane vesicles were prepared from the renal cortex of rat kidney. The kidneys were removed from 6 to 8 rats (200- & 250g) and the cortex was excised from each kidney with a layer thickness of about 1 mm. Kidneys were placed in 30ml ice-cold 12mM Tris/HCl buffer (pH 7.4)/300mM mannitol and homogenized using an Ultraturrax axis (standard 180V) for 4X 30 seconds while cooling in ice. 42ml of ice-cold distilled water was added, followed by 850. mu.l of 1M MgCl₂And (3) solution. Incubate at 0 ℃ for 15 minutes, then centrifuge at 4500rpm (Sorvall SS-34 rotor) for 15 minutes. The precipitate was discarded and the supernatant was centrifuged at 16000rpm for 30 minutes. The pellet was resuspended in 60ml of 6mM Tris/HCl buffer (pH 7.4)/150mM mannitol/2.5 mM EGTA by 10 strokes in a Potter-Elvejhem homogenizer (900rpm) and 720. mu.l of 1mM MgCl was added₂The solution was then incubated at 0 ℃ for 15 minutes. The supernatant obtained after centrifugation at 4500rpm (SS-34 rotor) for 15 minutes was centrifuged again at 16000rpm for 30 minutes. The supernatant was homogenized by 10 strokes in 60ml of 20mM Tris/Hepes buffer (pH 7.4)/280mM mannitol and the resulting suspension was centrifuged again at 20000rpm for 30 minutes. The pellet was resuspended in 20mM Tris/HCl buffer (pH 7.4)/280mM mannitol using a tuberculin syringe with a 27 gauge needle and adjusted to a protein concentration of 20 mg/ml.

Determination of glucose uptake by brush border membrane vesicles

Measurement of uptake into the brush border membrane vesicles by membrane diafiltration¹⁴C ]-labelled glucose. Mu.l of brush border membrane vesicle suspension in 10mM Tris/Hepes buffer (pH 7.4)/300mM mannitol was added to 90. mu.l of 10pM, [2 ], [ pH ], [ 300 ] at 30 ℃¹⁴C]D glucose and the relevant inhibitor at a suitable concentration (5-200. mu.M) in a solution of 10mM Tris/Hepes buffer (pH 7.4)/100mM NaCl/100 mM.

After 15 seconds of incubation, the transport process was stopped by adding 1ml of ice-cold stop buffer (10mM Tris/Hepes buffer (pH 7.4)/150mM KCl), and the vesicle suspension was immediately filtered off with suction under a vacuum of 25-35mbar using a nitrocellulose membrane filter (0.45 μm, diameter 25mM, Schleicher & Schull). The filter was washed with 5ml of ice-cold stop solution. Each measurement was performed in duplicate or triplicate. To measure uptake of the radiolabeled substrate, the membrane filter was dissolved in 4ml of a suitable scintillant (Quickszint 361, Zinsser Analytik GmbH, Frankfurtam Main) and radioactivity was determined by liquid scintillation measurement. After calibration of the instrument with standard samples and correction for any chemiluminescence present, measurements are obtained in the form of dpm (decay per minute).

IC obtained in transport assay of selected substances on brush border membrane vesicles of rabbit kidney cortex₂₅The data are based on comparing the activity of the active ingredients. (Absolute values can be species-dependent and experiment-dependent)

Example No. IC25[ mu M ]

5^＊ 13.9

6^＊ 9.9

7^＊ 1.1

9^＊ 1.4

11^＊ 1.3

13^＊ 3.5

34^＊ 1.0

43^＊ 2.2

44^＊ 0.9

45^＊ 2.9

47^＊ 1.6

50^＊ 4.7

54^＊ 1.4

56^＊ 2.8

^＊Beta-glucose form

The preparation of the examples is described in detail below, and the other compounds of the formula I are obtained in a similar manner.

Experimental part

Example 1:

3- (4-methoxy-phenyl) -1- [3- (3, 4, 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -thiophen-2-yl ] -propan-1-one

a)4, 5-diacetoxy-6-acetoxymethyl-2- (2-acetyl-thiophen-3-yloxy) -tetrahydropyran-3-yl acetate

2g of 1- (3-hydroxy-thiophen-2-yl) -ethanone are dissolved in 120ml of dichloromethane and stirred at 22 ℃ for 20 hours with 6.4g of 4, 5-diacetoxy-6-acetoxymethyl-2-bromotetrahydropyran-3-yl acetate, 1.4g of benzyltributylammonium chloride, 6.4g of potassium carbonate and 1.2ml of water. Filtering to remove insoluble components, concentrating the filtrate and subjecting the crude product mixture to column chromatography (SiO)₂Ethyl acetate/n-heptane 1: 1). The product obtained, molecular weight 472.5 (C)₂₀H₂₄O₁₁S)，MS(Cl)：473(M+H⁺)。

b)3- (4-methoxy-phenyl) -1- [3- (3, 4, 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -thiophen-2-yl ] -propenone

472mg of 4, 5-diacetoxy-6-acetoxymethyl-2- (2-acetyl-thiophen-3-yloxy) -tetrahydropyran-3-yl acetate are dissolved in 20ml of methanol and 5ml of 1N NaOCH are added₃The methanol solution of (1). 410mg of 4-methoxy-benzaldehyde are then added and the mixture is stirred at 22 ℃ for 20 hours. The mixture was neutralized with a small amount of hydrochloric acid in dilute methanol, concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol 6: 1). The product obtained, having a molecular weight of 422.5 (C)₂₀H₂₂O₈S)，MS(ESI)：423(M+H⁺)。

c)3- (4-methoxy-phenyl) -1- [3- (3, 4, 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -thiophen-2-yl ] -propan-1-one

100mg of 3- (4-methoxy-phenyl) -1- [3- (3, 45-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -thiophen-2-yl]-propenone was dissolved in 10ml ethanol and hydrogenated with about 20mg of 5% palladium on carbon, the hydrogenation was carried out in a shaking apparatus, during which slightly elevated pressure was applied (about 4 hours, TLC detection). The catalyst is filtered off, the filtrate is concentrated and the residue is purified by column chromatography (SiO)₂Dichloromethane/methanol ═ 6: 1). The product obtained, molecular weight 424.5 (C)₂₀H₂₄O₈S)，MS(ESI)：447(M+Na⁺)。

alpha-D-acetylbromoglucose was used in place of 4, 5-diacetoxy-6-acetoxymethyl-2-bromotetrahydropyran-3-yl acetate during the synthesis as described above. The glycoside of example 1 was thus obtained in the form of β -D-glucose. This also applies to all embodiments described below. However, if α -D-acetylbromogalactose is used, the glycoside is obtained in the form of β -D-galactose, if α -D-acetylbromoallose is used, the glycoside is obtained in the form of β -D-allose, or if α -D-acetylbromomannose is used, the glycoside is obtained in the form of α -D-mannose.

Following the same synthetic route described above in example 1, the following exemplary materials 2-6 were prepared:

example 7

2-hydroxymethyl-6- [2- (4-methoxybenzyl) -thiophen-3-yloxy ] -tetrahydropyran-3, 4, 5-triol

Example 8:

(4-methoxy-phenyl) - [3- (3, 4, 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -5-thiophen-2-yl ] methanone

a) (4-methoxy-phenyl) - (3-methoxy-thiophen-2-yl) -methanone

2.7ml of tin tetrachloride are added to a solution of 2.3g of 3-methoxy-thiophene and 3.4g of 4-methoxybenzoyl chloride in 50ml of dichloromethane while cooling on ice. The mixture was stirred at room temperature overnight. For workup, 75ml of 2N hydrochloric acid were added and the mixture was extracted three times with dichloromethane. The combined organic phases are washed twice with 2N sodium carbonate solution and water, the solvent is removed in vacuo and the crude product is purified by column chromatography (SiO)₂Ethyl acetate/n-heptane 1: 2). The product obtained, having a molecular weight of 248.3 (C)₁₃H₁₂O₃S)，MS(CI)：249(M+H⁺)。

b) (3-hydroxy-thiophen-2-yl) - (4-methoxy-phenyl) -methanone

993mg of (4-methoxy-phenyl) - (3-methoxy-thiophen-2-yl) -methanone was dissolved in 20ml of anhydrous dichloromethane, and 7ml of boron tribromide/bis-methylsulfide complex was added. The mixture was stirred at room temperature until the reaction was complete (TLC detection). Then poured into water and extracted several times with dichloromethane. The organic phase is dried and concentrated and the residue is purified by column chromatography (SiO)₂Ethyl acetate/n-heptane ═ 1: 4). The product obtained, molecular weight 234.3 (C)₁₂H₁₀O₃S)，MS(CI)：235(M+H⁺)。

c) (4-methoxy-phenyl) - [3- (3, 4, 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -thiophen-2-yl ] -methanone ═ example 8

2.8g of (3-hydroxythien-2-yl) - (4-methoxy-phenyl) -methanone are dissolved in 350ml of dichloromethane, 12.64g are added3, 4, 5-triacetoxy-6-bromo-tetrahydropyran-2-ylmethyl acetate, 15.4g of potassium carbonate, 3.6g of benzyltributylammonium chloride and finally 3ml of water are added. The mixture was stirred vigorously at room temperature for 20 hours. After completion of the reaction, the residue was filtered and concentrated with SiO₂Filtered and eluted with ethyl acetate/heptane 1: 2. The solvent is removed, the residue is taken up in about 300ml of methanol, 35ml of 1N NaOCH are added₃The mixture was stirred at room temperature for 1 hour. This was neutralized with 7% hydrochloric acid in methanol (about 35ml), and about 100ml of a mobile phase mixture of dichloromethane/methanol/concentrated aqueous ammonia 30: 5: 0.1 was added and stirred for 5 minutes. Subsequently concentrated and the same mobile phase mixture was added to the residue to remove insoluble salts from the solution. Chromatography on silica gel gave the product having a molecular weight of 396.42 (C)₁₈H₂₀O₈S)，MS(ESI)：397(M+H⁺)，235(M+H⁺-gluc)。

d) 2-hydroxymethyl-6- [2- (4-methoxy-benzyl) -thiophen-3-yloxy ] -tetrahydropyran-3, 4, 5-triol ═

Example 7

4.1g of (4-methoxy-phenyl) - [3- (3, 4, 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -thiophen-2-yl ] -methanone are dissolved in 200ml of tetrahydrofuran +20ml of methanol, and 500mg of sodium borohydride are added. After completion of the reaction (TLC assay, dichloromethane/methanol/concentrated ammonia: 30: 5: 1; about 30-60 min); water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. 2- {2- [ hydroxy- (4-methoxy-phenyl) -methyl ] -thiophen-3-yloxy } -6-hydroxymethyl-tetrahydropyran-3, 4, 5-triol was obtained as a crude product, which was purified by filtration on silica gel.

All materials were dissolved in about 800ml of absolute ethanol and the solution was made up with argon in a shaking apparatusThe gas is saturated. Then, anhydrous palladium/carbon was added as a catalyst, and the mixture was hydrogenated at 22 ℃ under vigorous shaking and atmospheric pressure for 6 to 7 hours. After the reaction was complete, the mixture was filtered through a clear layer with suction and the solvent was removed in vacuo. The residue was purified by column chromatography (SiO)₂Dichloromethane/methanol ═ 9: 1). (TLC plate, color development with 10% sulfuric acid). The product obtained, molecular weight 382.44 (C)₁₈H₂₂O₇S)，MS(ESI)：383(M+H⁺)，221(M+H⁺-gluc)。

Alternatively, the compound can also be prepared in the following manner:

226mg of 3, 4, 5-triacetoxy-6- [2- (4-methoxy-benzyl) -thiophen-3-yloxy]-tetrahydropyran-2-yl-methyl acetate was dissolved in 4ml acetonitrile and cooled to 0 ℃ in an ice bath. 0.3ml of trimethylchlorosilane and 151mg of sodium cyanoborohydride are added, the ice bath is removed and the reaction is stirred for 2 hours. The reaction mixture is diluted with 30ml of dichloromethane, filtered over celite and the organic phase is washed with 20ml of saturated sodium bicarbonate solution and 20ml of sodium chloride solution. The residue was purified by column chromatography (SiO)₂Ethyl acetate/n-heptane 1: 2). The crude product was taken up in methanol and 1ml of sodium methoxide solution (10mg/ml in methanol) was added. The solution was stirred at 22 ℃ for 18H, after which Amberlyst15 (H) was added⁺Form) was added, diluted with 10ml of methanol and filtered. The residue is washed with 20ml of methanol, the organic phase is concentrated and the residue is purified by chromatography on silica gel. 120mg of product are obtained, having a molecular weight of 382.44 (C)₁₈H₂₂O₇S)，MS(ESI)：400(M+NH₄ ⁺)。

Preparation of (3-methoxy-thiophen-2-yl) - (4-nitro-phenyl) -methanone:

0.5ml of 3-methoxythiophene was dissolved in 50ml of dichloromethane. 968mg of 4-nitrobenzoyl chloride were added and the reaction mixture was cooled to 0 ℃ in an ice bath. Then, 696mg of aluminum trichloride was added, and the reaction mixture was stirred at 0 ℃ for 4 hours. The reaction mixture was added to 100ml of ice-water and stirred for 15 minutes, 100ml of dichloromethane was added. The organic phase is separated off, washed with 50ml of 0.5M sodium hydroxide solution and 50ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The resulting mixture was purified by column chromatography (SiO)₂Ethyl acetate/n-heptane). The product obtained has a molecular weight of 263.27 (C)₁₂H₉NO₄S)；MS(CI)：264.25(M+H⁺)。

Then, (3-methoxy-thiophen-2-yl) - (4-nitro-phenyl) -methanone was converted to the exemplary material 16 as described in example 7.

The same synthetic route was used to prepare the following exemplary materials 9-34:

note that the MS/LCMS is OK means that the molecular peak M +1 (MH) of the indicated compound is obtained⁺) And/or M +18 (MNH)₄ ⁺) And/or M +23 (MNa)⁺)。

Example 35:

4- [3- (3, 4, 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -thiophen-2-ylmethyl ] -benzoic acid

46mg of 4- [3- (3, 4, 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -thiophen-2-ylmethyl]-benzonitrile was dissolved in a mixture of 5ml methanol and 2ml 25% potassium hydroxide solution and heated at 70 ℃ for 3 hours. The solution was diluted with 10ml of water and neutralized with 2N HCl. The resulting solution was freeze-dried. The crude product was purified by column chromatography (SiO)₂Dichloromethane/methanol/acetic acid/water 8: 2: 0.1). 45mg of product are obtained, having a molecular weight of 396.42 (C)₁₈H₂₀O₈S)，MS(ESI)：414.45(M+NH₄ ⁺)。

Example 36:

2-hydroxymethyl-6- {2- [2- (4-methoxy-phenyl) -ethyl ] -thiophen-3-yloxy } -tetrahydropyran-3, 4, 5-triol

Example 37:

2-hydroxymethyl-6- {2- [2- (4-methoxy-phenyl) -vinyl ] -thiophen-3-yloxy } -tetrahydropyran-3, 4, 5-triol

a) 3-methoxy-thiophene-2-carbaldehyde

1.03ml of 3-methoxythiophene was dissolved in 2.3ml of dimethylformamide. While cooling with ice, 1.06ml of phosphorus oxychloride was added. After 1 hour, the reaction solution was added to ice, and the solution was neutralized with 5M sodium hydroxide solution. The aqueous phase is extracted three times with 25ml of ether and the combined organic phases are washed with 50ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. 840mg of product are obtained, having a molecular weight of 142.18 (C)₆H₇O₂S)。MS(ESI)：143.0(M+H⁺)。

b) 3-hydroxy-thiophene-2-carbaldehyde

200mg of 3-methoxy-thiophene-2-carbaldehyde are dissolved in 5ml of dichloromethane. 880mg of boron tribromide-dimethylsulfide complex was dissolved in 5ml of dichloromethane and added to the reaction solution. The solution was stirred for 18 hours. The reaction mixture is poured into 30ml of water and the mixture is extracted 4 times with 20ml of dichloromethane each time. The combined organic phases are washed with 30ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. 140mg of 3-hydroxy-thiophene-2-carbaldehyde are obtained, whose molecular weight is 128.15 (C)₅H₄O₂S)。MS(ESI)：129.0(M+H⁺)。

c)4, 5-diacetoxy-6-acetoxymethyl-2- (2-formyl-thiophen-3-yloxy) -tetrahydropyran-3-yl acetate

3.81g of 3-hydroxy-thiophene-2-carbaldehyde, 30.5g of (4, 5-diacetoxy-6-acetoxymethyl-2- [ 5-isopropyl-2- (4-methoxy-benzoyl) -thiophen-3-yloxy-2-carbonyl]-tetrahydropyran-3-yl) acetate, 37.0g potassium carbonate and 9.2g benzyltributylammonium chloride were dissolved in 850ml dichloromethane. 7.5ml of water were added and the reaction mixture was stirred for 60 hours. The solution was extracted with water and saturated sodium chloride solution, and the organic phase was dried over sodium sulfate and evaporated. To the brown foam formed, 60ml of ethanol: water (9: 1) were added and the fine precipitate formed was filtered off with suction. The product obtained has a molecular weight of 458.44 (C)₁₉H₂₂O₁₁S)，MS(ESI)：476(M+NH₄ ⁺)。

d)3, 4, 5-Triacetoxy-6- (2-vinyl-thiophen-3-yloxy) -tetrahydropyran-2-ylmethyl acetate

3.30g of 3, 4, 5-triacetoxy-6- (2-formyl-thiophen-3-yloxy) -tetrahydropyran-2-ylmethyl acetate were dissolved in 60ml of dioxane. 6.43g of methyltriphenylphosphonium bromide, 5.37g of potassium carbonate and 0.25ml of water were added and the solution was refluxed for 4 hours. The solution was concentrated and purified by column filtration. 2.89g of product are obtained, having a molecular weight of 456.47 (C)₂₀H₂₄O₁₀S)，MS(ESI)：479.10(M+Na⁺)；474.10(M+NH₄ ⁺)。

e)3, 4, 5-Triacetoxy-6- {2- [2- (4-methoxy-phenyl) -vinyl ] -thiophen-3-yloxy } -tetrahydro-pyran-2-ylmethyl acetate

148mg of 3, 4, 5-triacetoxy-6- (2-vinyl-thiophen-3-yloxy) -tetrahydropyran-2-ylmethyl acetate are dissolved in 2ml of dichloromethane under argon. Adding tricyclohexylphosphine- [1, 3-bis (2, 4, 6-trimethylphenyl) -4, 5-dihydroimidazol-2-ylidene][ benzylidene group]Ruthenium (IV) dichloride (23mg, dissolved in 2ml dichloromethane) and the solution heated under reflux for 8 hours. The reaction solution was concentrated and purified by column chromatography (SiO)₂Heptane/ethyl acetate 2: 1). 132mg of product are obtained, having a molecular weight of 562.60 (C)₂₇H₃₀O₁₁S)。MS(ESI)：575.20(M+Na⁺)。

f) 2-hydroxymethyl-6- {2- [2- (4-methoxy-phenyl) -vinyl ] -thiophen-3-yloxy } -tetrahydropyran-3, 4, 5-triol example 37

150mg of 3, 4, 5-triacetoxy-6- {2- [2- (4-methoxy-phenyl) -vinyl]-thien-3-yloxy } -tetrahydropyran-2-ylmethyl acetate was suspended in 10ml of anhydrous methanol. 1.0ml of NaOMe in methanol (10mg/ml) was added. The solution was stirred at 22 ℃ for 18 hours. Amberlyst15 (H) was added⁺Form) and the solution was diluted with 10ml MeOH and filtered, and the residue was washed with 20ml MeOH. The organic phase is concentrated and the residue is purified by chromatography on silica gel. 100mg of product are obtained, having a molecular weight of 394.45 (C)₁₉H₂₂O₇S)，MS(ESI)：417(M+Na⁺)；412(M+NH₄ ⁺)。

g) 2-hydroxymethyl-6- {2- [2- (4-methoxy-phenyl) -ethyl ] -thiophen-3-yloxy } -tetrahydropyran-3, 4, 5-triol example 36

50mg of 2-hydroxymethyl-6- {2- [2- (4-methoxy-phenyl) -vinyl]-thien-3-yloxy } -tetrahydropyran-3, 4, 5-triol is dissolved in 10ml of methanol. 20mg of palladium on activated carbon was added and the solution was stirred under hydrogen atmosphere for 18 hours. The catalyst was filtered off, washed with 60ml of methanol and the organic phase was concentrated. The residue was chromatographed on silica gel (ethyl acetate). 18mg of product are obtained, having a molecular weight of 396.46 (C)₁₉H₂₄O₇S)；MS(ESI)：419.05(M+Na⁺)，414.10(M+NH₄ ⁺)。

The same synthetic route was used to prepare the following exemplary materials 38-50:

Example 51:

2-hydroxymethyl-6- [ 5-isopropyl-2- (4-methoxy-benzyl) -thiophen-3-yloxy ] -tetrahydropyran-3, 4, 5-triol

a) 3-benzyloxy-5-isopropyl-thiophene-2-carboxylate

1.16g of methyl 3-hydroxy-5-isopropyl-thiophene-2-carboxylate (prepared by a well-known method in H.Fiesselmann, F.Thoma, chem.Ber.1956, 89, 1907) were dissolved in 25ml of Dimethylformamide (DMF), and 2.83g of cesium carbonate and 1.72ml of benzyl bromide were added. The reaction mixture was stirred at 22 ℃ for 72 hours. Then, 10ml of methanol was added, and after 30 minutes, 100ml of a saturated sodium bicarbonate solution and 50ml of water were added. The mixture was extracted 3 times with 70ml of ether each time. The combined organic phases were dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (SiO)₂Ethyl acetate/n-heptane ═ 1: 4). The product obtained, molecular weight 290.4 (C)₁₆H₁₈O₃S)，MS(ESI)：291(M+H⁺)。

b) 3-benzyloxy-5-isopropyl-thiophene-2-carboxylic acid

1.16g of methyl 3-benzyloxy-5-isopropyl-thiophene-2-carboxylate are dissolved in 10ml of Tetrahydrofuran (THF) and 10ml of methanol, and 1.7g of lithium hydroxide in 10ml of water are added. The reaction mixture was stirred at 22 ℃ for 72 hours. Methanol and THF were distilled off on a rotary evaporator. Under ice-cooling, the reaction mixture was adjusted to pH 4 with 2M hydrochloric acid and extracted twice with 50ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. Obtaining the productMolecular weight of 276.4 (C)₁₅H₁₈O₃S)，MS(ESI)：294(M+Na⁺)。

c) 3-benzyloxy-5-isopropyl-N-methoxy-N-methylthiophene-2-carboxamide

860mg of 3-benzyloxy-5-isopropyl-thiophene-2-carboxylic acid are dissolved in 30ml of dichloromethane, and 560mg of N, O-dimethylhydroxylamine hydrochloride and 2.3ml of triethylamine are added. After 15 minutes at 22 ℃ 2.3ml of a 50% solution of 1-propanephosphonic anhydride in acetic acid are added and the mixture is stirred for a further 18 hours at 22 ℃. The reaction mixture was washed with 2X 70ml of water and 70ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. The product obtained has a molecular weight of 319.4 (C)₁₇H₂₁NO₃S)，MS(ESI)：320(M+H⁺)。

d) (3-benzyloxy-5-isopropyl-thiophen-2-yl) - (4-methoxy-phenyl) -methanone

860mg of 3-benzyloxy-5-isopropyl-N-methoxy-N-methylthiophene-2-carboxamide are dissolved in 50ml of Tetrahydrofuran (THF) and cooled to 0 ℃ in an ice bath, and 31.3ml of a 0.5M solution of 4-methoxyphenyl magnesium bromide in tetrahydrofuran are added. After 30 minutes, the ice bath was removed and the reaction mixture was warmed to 22 ℃. After 1 hour, 70ml of saturated sodium bicarbonate solution were added to the reaction mixture, which was extracted with 2X 100ml of methyl acetate. The combined organic phases are washed with 70ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (SiO)₂Ethyl acetate/n-heptane 1: 3). The product obtained has a molecular weight of 366.5 (C)₂₂H₂₂O₃S)，MS(ESI)：367(M+H⁺)。

e) (3-hydroxy-5-isopropyl-thiophen-2-yl) - (4-methoxy-phenyl) -methanone

1.00g of (3-benzyloxy-5-isopropyl-thiophen-2-yl) - (4-methoxy-phenyl) -methanone was dissolved in 20ml of dichloromethane. To the reaction solution was added 2.73ml of a methylene chloride solution of 1M boron tribromide-dimethyl sulfide complex. The solution was stirred at 22 ℃ for 1.5 hours. The reaction mixture was poured into 50ml of water and the mixture was extracted with 2X 30ml of dichloromethane. The combined organic phases are washed with 2X 30ml of saturated sodium bicarbonate solution and 1 time with 50ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (SiO)₂Ethyl acetate/n-heptane ═ 1: 4). The product obtained has a molecular weight of 276.4 (C)₁₅H₁₆O₃S)，MS(ESI)：299(M+Na⁺)。

f) (4, 5-diacetoxy-6-acetoxymethyl-2- [ 5-isopropyl-2- (4-methoxy-benzoyl) -thiophen-3-yloxy ] -tetrahydropyran-3-yl) acetate

380mg of (3-hydroxy-5-isopropyl-thiophen-2-yl) - (4-methoxy-phenyl) -methanone, 848mg of 4, 5-diacetoxy-6-acetoxymethyl-2-bromo-tetrahydropyran-3-yl acetate, 1.43g of potassium carbonate and 71.1mg of benzyltributylammonium chloride are dissolved in 20ml of dichloromethane, and 1.20ml of water are added. The reaction mixture was stirred at 22 ℃ for 40 hours. 50ml of water are added to the reaction mixture, which is extracted with 2X 50ml of dichloromethane. The combined organic phases are washed with 50ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. Will be coarseThe product was purified by column chromatography (SiO)₂Ethyl acetate/n-heptane 1: 1). The product obtained has a molecular weight of 606.7 (C)₂₉H₃₄O₁₂S)，MS(ESI)：607(M+H⁺)。

g) (4, 5-diacetoxy-6-acetoxymethyl-2- [ 5-isopropyl-2- (4-methoxy-benzyl) -thiophen-3-yloxy ] -tetrahydropyran-3-yl) acetate

630mg of (4, 5-diacetoxy-6-acetoxymethyl-2- [ 5-isopropyl-2- (4-methoxy-benzoyl) -thiophen-3-yloxy)]-tetrahydropyran-3-yl) acetate was dissolved in 30ml acetonitrile and cooled to 0 ℃ in an ice bath. 1.31ml of trimethylchlorosilane and 652mg of sodium cyanoborohydride were added, the ice bath was removed, and the reaction was stirred for 2 hours. 100ml of water are added to the reaction mixture, which is extracted with 2X 70ml of dichloromethane. The combined organic phases are washed with 50ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (SiO)₂Ethyl acetate/n-heptane 1: 1). The product obtained has a molecular weight of 592.7 (C)₂₉H₃₆O₁₁S)，MS(ESI)：593(M+H⁺)。

h) 2-hydroxymethyl-6- [ 5-isopropyl-2- (4-methoxy-benzyl) -thiophen-3-yloxy ] -tetrahydropyran-3, 4, 5-triol

450mg of (4, 5-diacetoxy-6-acetoxymethyl-2- [ 5-isopropyl-2- (4-methoxy-benzyl) -thiophen-3-yloxy)]-tetrahydropyran-3-yl) acetate was dissolved in 20ml of methanol, and 0.41ml of 30% sodium methoxide in methanol was added. The reaction mixture was stirred at 22 ℃ for 1 hour and addedAmberlyst 15(H⁺Form) was filtered and washed with 30ml of methanol. The solution was concentrated. The product obtained, molecular weight 424.5 (C)₂₁H₂₈O₇S)，MS(ESI)：447(M+Na⁺)。

The following examples 52 to 54 were prepared by the same synthetic route starting from the 3-hydroxy-thiophene-2-carboxylic acid compounds described in the following documents: H.Fiesselmann, F.Thoma, chem.Ber.1956, 89, 1907-; M.D. Mullican et al, J.Med. chem.1991, 34, 2186-; G.M. Karp et al Synthesis 2000, 1078-1080. ]:

example 55

3- (3, 4, 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -N-benzylthiophene-2-carboxamide

a) 3-hydroxy-thiophene-2-carboxylic acid

10.0g of methyl 3-hydroxy-thiophene-2-carboxylate are dissolved in a mixture of 90ml of Tetrahydrofuran (THF) and 90ml of methanol, and 25.2g of lithium hydroxide in 25ml of water are added. The reaction mixture was stirred at 22 ℃ for 18 hours and then heated at 55 ℃ for 6 hours. In a rotary evaporatorThe reaction mixture is concentrated to 50ml, acidified to pH 1 with 2M hydrochloric acid and extracted with 3 × 50ml of tert-butyl methyl ether. The combined organic phases were dried over magnesium sulfate and concentrated. The product obtained has a molecular weight of 144.2 (C)₅H₄O₃S)，MS(ESI)：145(M+H⁺)。

b) N-benzyl-3-hydroxy-thiophene-2-carboxamides

1.44g of 3-hydroxy-thiophene-2-carboxylic acid are dissolved in 100ml of dichloromethane, 2.18ml of benzylamine and 5.00ml of a 50% solution of 1-propanephosphonic anhydride in acetic acid are added. The reaction mixture was stirred at 22 ℃ for 2 hours and, after addition of 100ml of saturated sodium bicarbonate solution, extracted with 2X 100ml of dichloromethane. The combined organic phases are washed with 100ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The product obtained, molecular weight 233.3 (C)₁₂H₁₁NO₂S)，MS(ESI)：234(M+H⁺)。

c)3, 4, 5-Triacetoxy-6- (2-Benzylcarbamoyl-thiophen-3-yloxy) -tetrahydropyran-2-ylmethyl acetate

1.12g of 1.12g N-benzyl-3-hydroxy-thiophene-2-carboxamide, 3.16g of 4, 5-diacetoxy-6-acetoxymethyl-2-bromo-tetrahydropyran-3-yl acetate, 3.30g of potassium carbonate and 235mg of benzyltributylammonium chloride are dissolved in 25ml of dichloromethane, and 2.00ml of water are added. The reaction mixture was stirred at 22 ℃ for 40 hours. 50ml of saturated sodium bicarbonate solution are added to the reaction mixture, which is extracted with 2X 50ml of dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (SiO)₂Ethyl acetate-N-heptane 1: 1). The product obtained has a molecular weight of 563.6 (C)₂₆H₂₉NO₁₁S)，MS(ESI)：564(M+H⁺)。

d) N-benzyl-3- (3, 4, 5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy) -thiophene-2-carboxamide

600mg of 3, 4, 5-triacetoxy-6- (2-benzylcarbamoyl-thiophen-3-yloxy) -tetrahydropyran-2-ylmethyl acetate are dissolved in 40ml of methanol, and 1.40ml of 30% sodium methoxide solution in methanol are added. The reaction mixture was stirred at 22 ℃ for 2 hours, neutralized with 0.5M HCl in methanol and concentrated. The crude product was purified by column chromatography (SiO)₂Ethyl acetate/methanol 10: 1). The product obtained has a molecular weight of 395.4 (C)₁₈H₂₁NO₇S)，MS(ESI)：396(M+H⁺)。

The following examples 56-58 were prepared following the same synthetic route:

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof

Wherein

R1, R2 independently of one another are hydrogen, F, Cl, Br, I, OH, NO₂、CN、COOH、CO(C₁-C₆) -alkyl, COO (C)₁-C₆) Alkyl, CONH₂、CONH(C₁-C₆) -an alkyl group,

CON[(C₁-C₆) -alkyl radical]₂、(C₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₂-C₆) -alkynyl, (C)₁-C₆) Alkoxy, HO- (C)₁-C₈) Alkyl radicals, (C)₁-C₆) -alkoxy- (C)₁-C₆) -alkyl, phenyl, benzyl or (C)₁-C₄) -an alkyl-carbonyl group,

wherein one, more than one or all of the hydrogens on the alkyl or alkoxy group are optionally replaced with fluorine;

a is-CH₂-、-C₂H₄-、-C₃H₆-、-CH(OH)-、-(C＝O)-、-CH＝CH-、-CH＝CH-CH₂-、-CO-CH₂-CH₂-or-CO-NH-CH₂-；

n is 2 or 3;

cyc1 is phenyl or thienyl;

r3, R4, R5 are each independently of the others hydrogen, F, Cl, Br, I, OH, NO₂、CN、COOH、COO(C₁-C₆) Alkyl, CO (C)₁-C₄) Alkyl radicals, (C)₁-C₈) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₁-C₁₂) Alkoxy, HO- (C)₁-C₆) Alkyl or S- (C)₁-C₆) -an alkyl group,

S-(CH₂)_o-phenyl, (CH)₂)_o-phenyl or O- (CH)₂)_o-phenyl, wherein o is 0-6;

or

R3 and R4 together are-CH-O-, -CH-S-, -O- (CH)₂)_p-O-, wherein p ═ 1 or 2, -O-CF₂-O-or-CH-, and

r5 is hydrogen.

2. A compound of formula I according to claim 1, wherein a is attached in position 2 of the thienyl ring.

3. A compound of formula I according to claim 1, wherein,

r1, R2 independently of one another are hydrogen, F, Cl, Br, I, OH, NO₂、CN、COOH、CO(C₁-C₆) -alkyl, COO (C)₁-C₆) Alkyl radicals, (C)₁-C₈) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₁-C₆) Alkoxy, HO- (C)₁-C₆) -alkyl, phenyl, benzyl or (C)₁-C₄) -an alkyl-carbonyl group,

r3, R4, R5 are each independently of the others hydrogen, F, Cl, Br, I, OH, NO₂、CN、COOH、COO(C₁-C₆) Alkyl, CO (C)₁-C₄) Alkyl radicals, (C)₁-C₈) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₁-C₁₂) Alkoxy, HO- (C)₁-C₆) Alkyl radicals, (C)₁-C₄) -alkylphenyl, (C)₁-C₄) An alkoxyphenyl group or S- (C)₁-C₆) -an alkyl group,

or

r5 is hydrogen.

4. A compound of formula I according to claim 1, wherein

R1, R2 are independently of each other hydrogen, (C)₁-C₆) Alkyl radicals, (C)₁-C₄) Alkoxy, HO- (C)₁-C₄) Alkyl, F, Cl, CF₃、OCF₃、OCH₂CF₃、(C₁-C₄) -alkyl-CF₂-, phenyl, benzyl, (C)₁-C₄) -alkylcarbonyl, (C)₂-C₄) -alkenyl or COO (C)₁-C₄) -an alkyl group;

r3, R4, R5 are each independently of the others hydrogen, F, Cl, Br, I, NO₂、OH、CN、(C₁-C₆) Alkyl radicals, (C)₁-C₈) Alkoxy, OCF₃、OCH₂CF₃、S-(C₁-C₄) Alkyl, COOH, HO- (C)₁-C₄) Alkyl radicals, (C)₁-C₂) -alkylphenyl or (C)₁-C₂) -alkoxyphenyl, or R3 and R4 together are-CH-O-, -CH-S-, -O- (CH)₂)_p-O-, wherein p ═ 1 or 2, -O-CF₂-O-or-CH-, and

r5 is hydrogen.

5. A compound of formula I according to claim 1, wherein R2 is hydrogen.

6. A compound of formula I according to claim 1, wherein,

r1 is hydrogen, CF₃、(C₁-C₄) -an alkyl group or a phenyl group,

r2 is a hydrogen atom or a salt thereof,

R3, R4, R5 are each independently of the others hydrogen, F, Cl, I, NO₂、OH、CN、(C₁-C₆) Alkyl radicals, (C)₁-C₈) Alkoxy, O-CH₂-phenyl, OCF₃、S-CH₃Or COOH, or

r5 is hydrogen.

7. A compound of formula I in accordance with claim 1, wherein A is-CH₂-or-CH₂-CH₂-。

8. A compound of formula I according to claim 1, wherein Cyc1 is phenyl.

9. A compound of formula I according to claim 1, wherein Cyc1 is thienyl.

10. A compound of formula I according to claim 1, wherein Cyc1 is monosubstituted.

11. A medicament for the treatment of type I and type II diabetes or for lowering blood glucose, comprising one or more compounds according to one or more of claims 1 to 10.

12. Use of a compound according to one or more of claims 1 to 10 for the manufacture of a medicament for the treatment of type I and type II diabetes.

13. Use of a compound according to one or more of claims 1 to 10 for the manufacture of a medicament for lowering blood glucose.

14. A process for the manufacture of a medicament comprising one or more compounds as claimed in one or more of claims 1 to 10, which comprises mixing the active ingredients with a pharmaceutically acceptable carrier and converting the mixture into a form suitable for administration.