HK1137762B - 1, 4-benzothiepin-1,1-dioxide derivatives which are substituted with benzyl groups, method for producing drugs containing said compounds and use thereof - Google Patents

Description

1, 4-Benzothia-1, 1-dioxide derivatives substituted by benzyl, method for the production thereof, medicaments containing said compounds and the use thereof

The invention relates to 1, 4-benzothiepins substituted by benzyl groups-1, 1-dioxide derivatives and their physiologically tolerated salts.

1, 4-Benzothia compounds of similar structure have been described previously1, 1-dioxide derivatives (US 5,994,391).

The invention is based on the following objectives: other compounds are provided which exhibit hypolipidemic effects.

The present invention therefore relates to compounds of formula I and pharmaceutically acceptable salts thereof,

wherein the meaning is:

XO、NH、CH₂or a bond;

R1(C₁-C₆) -an alkyl group;

r2, R2 ', R3, R3', R4, R4 ', R5, R5' are independently of one another H, Cl, Br, I, OH, - (CH)₂)-OH、CF₃、NO₂、N₃、CN、S(O)_p-R6、O-S(O)_p-R6、(C₁-C₆) alkylene-S (O)_p-R6、(C₁-C₆) alkylene-O-S (O)_p-R6、COOH、COO(C₁-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, O- (C)₁-C₆) -alkyl, wherein one, more than one or all of the hydrogens of the alkyl group may be replaced by fluoro; phenyl, - (CH)₂) -phenyl, - (CH)₂)_n-phenyl, O- (CH)₂)_m-phenyl, - (CH)₂)-O-(CH₂)_m-phenyl, wherein the phenyl ring may be substituted one to three times by: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

Wherein at least one of the radicals R2, R2 ', R3, R3', R4, R4 ', R5, R5' always has the following meaning: -O- (CH)₂)_m-phenyl or- (CH)₂)-O-(CH₂)_m-phenyl, wherein the phenyl ring may be substituted one to three times by: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

R6 H、OH、(C₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂；

n 2、3、4、5、6；

m 1、2、3、4、5、6；

p 0、1、2。

Preferred are compounds of formula I as defined below, wherein the meanings are:

X NH；

R1 (C₁-C₆) -an alkyl group;

r2, R2 ', R3, R3', R4, R4 ', R5, R5' are independently of one another H, Cl, Br, I, OH, - (CH)₂)-OH、CF₃、NO₂、N₃、CN、S(O)_p-R6、O-S(O)_p-R6、(C₁-C₆) alkylene-S (O)_p-R6、(C₁-C₆) alkylene-O-S (O)_p-R6、COOH、COO(C₁-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, O- (C)₁-C₆) -alkyl, wherein one, more than one or all of the hydrogens of the alkyl group may be replaced by fluoro;

phenyl, - (CH)₂) -phenyl, - (CH)₂)_n-phenyl, O- (CH)₂)_m-phenyl, - (CH)₂)-O-(CH₂)_m-phenyl, wherein the phenyl ring may be substituted one to three times by: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

Wherein at least one of the radicals R2, R2 ', R3, R3', R4, R4 ', R5, R5' always has the following meaning: s (O)_p-R6、O-S(O)_p-R6、(C₁-C₆) alkylene-S (O)_p-R6 or (C)₁-C₆) alkylene-O-S (O)_p-R6, and the other having the following meaning: -O- (CH)₂)_m-phenyl or- (CH)₂)-O-(CH₂)_m-phenyl, wherein the phenyl ring may be substituted one to three times by: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

R6 H、OH、(C₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂；

n 2、3、4、5、6；

m 1、2、3、4、5、6；

p 0、1、2。

Particular preference is given to compounds of the formula I and their pharmaceutically acceptable salts, as defined below, wherein the meanings are:

X NH；

R1 (C₁-C₆) -an alkyl group;

R2 OH；

R2′ H；

r3, R3 ', R4, R4 ', R5 and R5 ' are independently H, Cl, Br, I, OH, - (CH)₂)-OH、CF₃、NO₂、N₃、CN、S(O)_p-R6、O-S(O)_p-R6、(C₁-C₆) alkylene-S (O)_p-R6、(C₁-C₆) alkylene-O-S (O)_p-R6、COOH、COO(C₁-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, O- (C)₁-C₆) -alkyl, wherein one, more than one or all of the hydrogens of the alkyl group may be replaced by fluoro;

phenyl, - (CH)₂) -phenyl, - (CH)₂)_n-phenyl, O- (CH)₂)_m-phenyl, - (CH)₂)-O-(CH₂)_m-phenyl, wherein the phenyl ring may be substituted one to three times by: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

Wherein at least one of the radicals R3, R3 ', R4, R4 ', R5, R5 ' always has the following meaning: (S (O)_p-R6、O-S(O)_p-R6、(C₁-C₆) alkylene-S (O)_p-R6 or (C)₁-C₆) alkylene-O-S (O)_p-R6, and the other having the following meaning: -O- (CH)₂)_m-phenyl or- (CH)₂)-O-(CH₂)_m-phenyl, wherein the phenyl ring may be substituted one to three times by: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

R6 H、OH、(C₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂；

n 2、3、4、5、6；

m 1、2、3、4、5、6；

p 0、1、2。

Also particularly preferred are compounds of formula I and pharmaceutically acceptable salts thereof, as defined below, wherein the meanings are:

X NH；

R1 (C₁-C₆) -an alkyl group;

R2 OH；

R2′ H；

r3, R3 ', R4, R4 ', R5 and R5 ' are independently H, Cl, Br, I, OH, - (CH)₂)-OH、CF₃、NO₂、N₃、CN、S(O)_p-R6、O-S(O)_p-R6、 (C₁-C₆) alkylene-S (O)_p-R6、(C₁-C₆) alkylene-O-S (O)_p-R6、COOH、COO(C₁-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, O- (C)₁-C₆) -alkyl, wherein one, more than one or all of the hydrogens of the alkyl group may be replaced by fluoro;

phenyl, - (CH)₂) -phenyl, - (CH)₂)_n-phenyl, O- (CH)₂)_m-phenyl, - (CH)₂)-O-(CH₂)_m-phenyl, wherein the phenyl ring may be substituted one to three times by: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

Wherein at least one of the radicals R3, R3 ', R4, R4 ', R5, R5 ' always has the following meaning: (C)₁-C₆) alkylene-O-S (O)_p-R6, and the other having the following meaning: -O- (CH)₂)_m-phenyl, wherein the phenyl ring may be substituted one to three times by: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

R6 H、OH、(C₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂；

n 2、3、4、5、6；

m 1、2、3、4、5、6；

p 0、1、2。

Also particularly preferred are compounds of formula I and pharmaceutically acceptable salts thereof, as defined below, wherein the meanings are:

X NH；

R1 (C₁-C₆) -an alkyl group;

R2 OH；

R2′ H；

R5′ (C₁-C₆) alkylene-O-S (O)₂-R6；

R3, R3 ', R4, R4' and R5 are each independently H, Cl, Br, I, OH, - (CH)₂)-OH、CF₃、NO₂、N₃、CN、S(O)_p-R6、O-S(O)_p-R6、(C₁-C₆) alkylene-S (O)_p-R6、(C₁-C₆) alkylene-O-S (O)_p-R6、COOH、COO(C₁-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, O- (C)₁-C₆) -alkyl, wherein one, more than one or all of the hydrogens of the alkyl group may be replaced by fluoro;

phenyl, - (CH)₂) -phenyl, - (CH)₂)_n-phenyl, O- (CH)₂)_m-phenyl, - (CH)₂)-O-(CH₂)_m-phenyl, wherein the phenyl ring may be substituted one to three times by: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

Wherein at least one of the radicals R3, R3 ', R4, R4 ', R5, R5 ' always has the following meaning: -O- (CH)₂)_m-phenyl, wherein the phenyl ring may be substituted one to three times by: F. cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂；

R6 H、OH、(C₁-C₆) -alkyl, NH₂、NH(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂；

n 2、3、4、5、6；

m 1、2、3、4、5、6。

Preference is also given to compounds of the formula I in which one, two or three of the radicals R2, R2 ', R3, R3', R4, R4 ', R5, R5' are OH.

Preferred compounds of the formula I in one embodiment are those in which the group X is O.

Preferred compounds of the formula I in one embodiment are those in which the group X is NH.

Preferred compounds of the formula I in one embodiment are those in which the radical X is CH₂Those of (a).

Preferred compounds of the formula I in one embodiment are those in which the radical R1 is butyl.

Preferred compounds of the formula I in one embodiment are those in which the radical R1 is ethyl.

Preferred compounds of the formula I in one embodiment are those in which the radical R2 is OH.

Preferred compounds of the formula I in one embodiment are those in which at least one of the radicals R2, R2 ', R3, R3', R4, R4 ', R5 or R5' is-O-benzyl.

Preferred compounds of the formula I in one embodiment are those in which the radical R3 is-O-benzyl.

Preferred compounds of the formula I in one embodiment are those in which the radical R4 is OH or OSO₂Those of OH.

Preferred compounds of the formula I in one embodiment are those in which the radical R4 is OH.

Preferred compounds of the formula I in one embodiment are those in which at least one of the radicals R2, R2 ', R3, R3', R4, R4 ', R5 or R5' is CH₂OSO₂Those of OH.

Preferred compounds of the formula I in one embodiment are those in which at least one of the radicals R5 or R5' is CH₂OH or CH₂Those of O benzyl.

Preferred compounds of the formula I in one embodiment are those in which at least one of the radicals R5 or R5' is CH₂OSO₂Those of OH.

Preferred compounds of formula I in one embodiment are those wherein R5 is CH₂OSO₂Those of OH.

Preferred compounds of formula I in one embodiment are those wherein R5 is CH₂OSO₂OH and R5' are those of H.

Preferred compounds of formula I in one embodiment are those wherein R1 is ethyl and R5 is CH₂OSO₂Those of OH.

Preferred compounds of formula I in one embodiment are those wherein the structure of formula I is as shown below:

if a group or substituent can occur more than once in a compound of the formula I, they can each have the meanings indicated independently of one another and can be identical or different.

The alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene groups in the radicals R1, R2, R2 ', R3, R3', R4, R4 ', R5, R5' and R6 may be straight-chain or branched.

The present invention relates to compounds of formula I in their tautomeric, racemic mixture, stereoisomeric mixture, pure stereoisomer, diastereomeric mixture, pure diastereomeric form. The mixture is separated, for example, by chromatographic methods.

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

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

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

All references hereinafter to "compounds of formula I" refer to compounds of formula I as described herein, as well as their salts and solvates as described herein.

Alkyl groups refer to straight or branched hydrocarbon chains having up to 8 carbon atoms, such as methyl, ethyl, isopropyl, tert-butyl, hexyl, heptyl, octyl. The alkyl group may be substituted one or more times as described above.

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

The amount of a compound of the invention required to achieve a 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. The daily dose is generally in the range 0.3mg to 100mg (usually 3mg to 50mg) per day per kilogram body weight, for example 3-10 mg/kg/day. The intravenous dose may be, for example, from 0.3mg to 1.0mg/kg and may suitably be administered as an infusion of from 10ng to 100 ng/kg/min. Infusion solutions suitable for these purposes may contain, for example, from 0.1ng to 10mg, usually from 1ng to 10mg per ml. A single dose may contain, for example, from 1mg to 10g of active ingredient. Thus, ampoules for injection may contain, for example, from 1mg to 100mg, and single-dose preparations which can be administered orally, such as tablets or capsules, may contain, for example, from 1.0 to 1000mg, usually from 10 to 600 mg. For the treatment of the above conditions, the compounds of formula I may be used as the compounds themselves, but they are preferably in the form of a pharmaceutical composition containing an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and not deleterious 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, e.g. a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances, including other compounds of formula I, may also be present. The pharmaceutical compositions of the present invention may be prepared by any of the known pharmaceutical methods which essentially comprise admixing the ingredients with pharmacologically acceptable carriers and/or excipients.

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 in each case depends 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 coatings resistant to gastric juices include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Pharmaceutical preparations suitable for oral administration may be presented as discrete unit forms, such as capsules, cachets, suckable tablets (suckable tablets) or tablets, wherein each unit form contains a defined amount of a compound of formula I; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions may be prepared by any suitable pharmaceutical process which comprises the step of bringing into contact the active ingredient with the carrier (which may contain one or more additional ingredients). In general, the compositions may be prepared by the following method: the active ingredient is homogeneously and homogeneously mixed with the liquid and/or finely divided solid carrier, after which the product is shaped, if necessary. Thus, for example, tablets may be prepared by compressing or moulding the compound, powder or granules, optionally together with one or more additional ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, glidant, inert diluent, and/or surfactant/dispersant(s). Molded tablets may be made by molding in a suitable machine a powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for oral (sublingual) administration include suckable tablets containing a compound of formula I in combination with a flavoring agent, usually 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, but may also be administered by subcutaneous, intramuscular or intradermal injection. These formulations can preferably be prepared by mixing the compound with water and sterilizing and isotonicizing the resulting solution with blood. The injectable compositions of the invention generally contain from 0.1 to 5% by weight of active compound.

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

Pharmaceutical compositions suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, sprays, aerosols or oils. Carriers which may be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The concentration of the active ingredient is generally from 0.1 to 15%, for example from 0.5 to 2% by weight of the composition.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal application may be in the form of a single patch suitable for prolonged intimate contact with the epidermis of a patient. Such patches suitably contain the active ingredient in an aqueous solution, buffered as appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. Suitable active ingredient concentrations are about 1% to 35%, preferably about 3% to 15%. It is particularly possible to have the active ingredient released by electrotransport or iontophoresis, as, for example, in Pharmaceutical Research, 2 (6): 318 (1986).

Other active ingredients suitable for the combination product are:

all antidiabetics mentioned in Rote Liste 2006 (chapter 12); all weight loss substances/appetite suppressants mentioned in Rote list 2006 (chapter 1); all lipid lowering substances mentioned in Rote Liste 2006 (chapter 58). They can be combined with the compounds of the formula I according to the invention, in particular for synergistic enhancement of the action. The active compound combinations can be administered by separate administration of the active ingredients to the patient or in the form of a combination in which a plurality of active ingredients are present in one pharmaceutical preparation. Most of the active ingredients listed below are disclosed in the USP dictionary of USAN and the International Drug Names (International Drug Names), US pharmacopoeia, Rockville 2001.

Antidiabetic agents include insulin and insulin derivatives, e.g.(see www.lantus.com) or HMR 1964 or(insulin detemir) or those described in WO2005005477 (Novonordisk, Inc.), rapid acting insulins (see US6,221,633), inhalable insulins such asOr Oral insulin such as IN-105(Nobex) or Oral-lyn^TM(Jerex biotech Inc.), GLP-1 derivatives such as exenatide, liraglutide, or those described in: WO98/08871, WO2005027978, WO2006037811 or WO2006037810 from Novo Nordisk A/S, WO 01/04156 from Zealand, WO 00/34331 from Bofu-Yipusheng (Beaufour-Ipsen), pramlintide acetate (Symlin; Anlin (Amylin) pharmaceuticals), and also orally active hypoglycemic active ingredients.

The orally active hypoglycemic active ingredients preferably comprise:

a sulfonylurea compound which is a compound of the formula,

(ii) a biguanide compound(s),

meglitinides (meglitinides),

(ii) oxadiazacyclo-pentane diones,

the thiazolidinediones are selected from the group consisting of thiazolidinediones,

an inhibitor of a glycosidase enzyme, wherein the glycosidase enzyme is selected from the group consisting of a glycosidase enzyme,

an inhibitor of a glycogen phosphorylase enzyme, which is capable of inhibiting glycogen phosphorylase activity,

an antagonist of the activity of glucagon is disclosed,

an activator of the enzyme glucokinase and a compound of the enzyme glucokinase,

a fructose-1, 6-bisphosphatase inhibitor,

glucose transporter 4(GLUT4) modulators,

inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT),

a GLP-1 agonist,

potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 of noh and noded (Novo Nordisk a/S) or WO2006045799 (Solvay),

inhibitors of dipeptidyl peptidase IV (DPP-IV),

an insulin sensitizer is provided,

inhibitors of liver enzymes that have been implicated in the stimulation of gluconeogenesis and/or glycogenolysis,

glucose uptake modulators, glucose turnover modulators, and glucose reabsorption modulators,

an inhibitor of 11 beta-HSD 1,

inhibitors of protein tyrosine phosphatase 1B (PTP1B),

sodium-dependent glucose transporter 1 or 2(SGLT1, SGLT2) modulators,

compounds which alter lipid metabolism, for example with antihyperlipidemic and antilipidemic (antilipidemic) active ingredients,

a compound that reduces the intake of food,

the compound that increases the heat production is,

PPAR and RXR modulators, and

active ingredients that act on the ATP-dependent potassium channel of 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 or L-659699.

In one embodiment of the invention, the compounds of the formula I are administered in combination with cholesterol absorption inhibitors, for example ezetimibe, tiquinan, pamabrin, FM-VP4 (sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech, Inc., WO2005042692, WO2005005453), MD-0727 (microbiology (Microbia) Inc., WO2005021497, WO2005021495) or compounds described in: WO2002066464 (japan gourmet corporation (Kotobuki Pharmaceutical Co. ltd.)), WO2005044256 or WO2005062824 (Merck & Co.)) or WO2005061451 and WO2005061452 (AstraZeneca AB) and WO2006017257 (funomix (Phenomix)) or WO2005033100 (lipion Biotechnology AG)).

In one embodiment of the invention, the compounds of the formula I are reacted with Vytorin^TM(fixed combination of ezetimibe and simvastatin) in combination.

In one embodiment of the invention, the compound of formula I is administered in fixed combination with ezetimibe and fenofibrate.

In another embodiment of the present invention, the compound of formula I is administered in fixed combination with fenofibrate and rosuvastatin.

In one embodiment of the invention, the compound of formula I is administered in combination with ISIS-301012, an antisense oligonucleotide capable of modulating the apolipoprotein B gene.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR γ agonist, for example rosiglitazone, pioglitazone, JTT-501, Gl 262570, R-483 or CS-011 (rivoglitazone).

In one embodiment of the invention, the compounds of the formula I are reacted with compact^TM(fixed combination of pioglitazone hydrochloride with metformin hydrochloride).

In one embodiment of the invention, the compound of formula I is reacted with duetact^TM(fixed combination of pioglitazone hydrochloride and glimepiride).

In one embodiment of the invention, the compounds of the formula I and(fixed combination of rosiglitazone maleate and metformin hydrochloride).

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR α agonist, e.g., GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945.

In one embodiment of the invention, the compounds of formula I are administered in combination with a mixed PPAR α/γ agonist, such as, for example, nateglinide (navaglitazar), LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847 or those described in: PCT/US00/11833, PCT/US 00/11490, DE10142734.4 or in J.P. Berger et al, TRENDS in pharmaceutical Sciences 28(5), 244-.

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR delta agonist, for example GW-501516.

In one embodiment of the invention, the compounds of formula I are administered in combination with metaglidasen (Metadalsen) or with MBX-2044 or other partial PPAR γ agonists/antagonists.

In another embodiment of the invention, the compounds of formula I are administered in combination with an AMP-activated protein kinase (AMPK) activator, such as those described in A-769662 or US 20050038068.

In one embodiment of the invention, the compounds of formula I are administered in combination with a fibrate, such as fenofibrate, clofibrate or bezafibrate.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, for example those described in Enptapi, BMS-201038, R-103757 or WO2005085226, WO2005121091, WO 2006010423.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, for example Tochester (torcetrapib) or JTT-705 or those described in WO2006002342, WO2006010422, WO 2006012093.

In one embodiment of the invention, the compounds of the formula I are administered in combination with bile acid absorption inhibitors (see, for example, US6,245,744, US6,221,897 or WO00/61568), such as those described in HMR 1741 or in DE 102005033099.1 and DE 102005033100.9.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid absorbent, such as cholestyramine or colesevelam.

In one embodiment of the invention, the compounds of formula I are administered in combination with an LDL receptor inducing agent (see US6,342,512), such as those described in HMR1171, HMR1586 or WO 2005097738.

In one embodiment of the invention, the compounds of the formula I and(omega-3 fatty acids; highly concentrated ethyl esters of eicosapentaenoic acid and docosahexaenoic acid).

In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, for example avasimibe or SMP-797.

In one embodiment of the invention, the compounds of formula I are administered in combination with an antioxidant, such as OPC-14117, probucol, tocopherol, ascorbic acid, beta-carotene or selenium.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a vitamin, for example vitamin B6 or vitamin B12.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase modulator, for example, ambrolipine (ibrolipim) (NO-1886).

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

In one embodiment of the invention, the compound of formula I is administered in combination with a squalene synthase inhibitor, for example BMS-188494 or as described in WO 2005077907.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein (a) antagonist, for example gemcabene (gecapene) (CI-1027).

In one embodiment of the invention, the compounds of formula I are administered in combination with a GPR109A agonist (HM74A receptor agonist), e.g. nicotinic acid or extended release nicotinic acid in combination with MK-0524A or those described in WO2006045565, WO2006045564, WO2006069242 described below.

In another embodiment of the invention, the compounds of formula I are administered in combination with a GPR116 agonist, such as those described in WO2006067531, WO 2006067532.

In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, for example orlistat or Cetilistat (Cetilistat) (ATL-962).

In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.

In one embodiment, the compounds of the formula I are administered in combination with sulfonylureas, for example tolbutamide, glyburide, glipizide or glimepiride.

In one embodiment, the compounds of formula I are administered in combination with an agent that increases insulin secretion, such as KCP-265(WO 2003097064).

In one embodiment, the compound of formula I is administered in combination with a glucose-dependent insulinotropic receptor (GDIR) agonist, e.g., APD-668.

In another embodiment, the compounds of formula I are administered in combination with a biguanide, for example metformin.

In another embodiment, the compounds of the formula I are administered in combination with meglitinides (meglitinides), for example repaglinide or nateglinide.

In one embodiment, the compounds of formula I are administered in combination with thiazolidinediones, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds described in WO 97/41097 by the regdy's research Foundation, in particular 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy ] phenyl ] methyl ] -2, 4-thiazolidinedione.

In one embodiment, the compounds of the formula I are administered in combination with an α -glucosidase inhibitor, for example miglitol or acarbose.

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

In one embodiment, the compounds of formula I are administered in combination with more than one of the above-mentioned compounds, for example with sulphonylurea and metformin, sulphonylurea and acarbose, repaglinide and metformin, insulin and sulphonylurea. Insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

In one embodiment, the compounds of formula I are administered in combination with a glycogen phosphorylase inhibitor, such as PSN-357 or FR-258900 or those described in the following references: WO2003084922, WO2004007455, WO2005073229-31 or WO 2005067932.

In one embodiment, the compounds of formula I are administered in combination with a glucagon receptor antagonist, such as A-770077, NNC-25-2504, or such as those in WO2004100875 or WO 2005065680.

In one embodiment, the compounds of formula I are administered in combination with a glucokinase activator, such as LY-2121260(WO2004063179), PSN-105, PSN-110, GKA-50 or such as those described in WO2004072031, WO2004072066, WO2005080360, WO2005044801, WO2006016194, WO 2006058923.

In one embodiment, the compounds of formula I are administered in combination with a gluconeogenesis inhibitor, e.g., FR-225654.

In one embodiment, the compounds of the formula I are administered in combination with fructose-1, 6-bisphosphatase (FBPase) inhibitors, such as those described in CS-917(MB-06322) or MB-07803 or WO 2006023515.

In one embodiment, the compounds of formula I are administered in combination with a glucose transporter 4(GLUT4) modulator, such as KST-48(D. -O.Lee et al: Arzneim. -Forsch. drug Res.54(12), 835 (2004)).

In one embodiment, the compounds of formula I are administered in combination with glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors, such as those described in WO 2004101528.

In one embodiment, the compound of formula I is administered in combination with a dipeptidyl peptidase IV (DPP-IV) inhibitor, such as vildagliptin (LAF-237), sitagliptin (MK-0431), saxagliptin (BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X, KRP-104, DP-893, or those described in: WO2003074500, WO2003106456, WO200450658, WO2005058901, WO2005012312, WO2005/012308, WO2006039325, WO2006058064, PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002, PCT/EP2005/008004, PCT/EP2005/008283, DE 102005012874.2 or DE 102005012873.4.

In one embodiment, the compound of formula I is reacted with Januvia^TM(fixed association of sitagliptin phosphate with metformin hydrochloride).

In one embodiment, the compounds of formula I are administered in combination with an inhibitor of 11- β -hydroxysteroid dehydrogenase 1(11 β -HSD1), such as BVT-2733, JNJ-25918646, INCB-13739 or such as those described in the following references: WO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251, WO2004056744, WO2004058730, WO2004065351, WO 200408989380, WO2004089470-71, WO 2004089898989896, WO2005016877, WO2005097759, WO2006010546, WO2006012227, WO2006012173, WO2006017542, WO 20060804, WO 200606040329, WO2006051662, WO 20060603448750, WO 20060952, WO 200604948331, WO 20060606060506066109, WO 2006060606066109, WO 2006060606060606631, WO 200606060606066109.

In one embodiment, the compounds of formula I are administered in combination with a protein tyrosine phosphatase 1B (PTP1B) inhibitor, such as those described in the following references: WO200119830-31, WO200117516, WO2004506446, WO2005012295, WO2005116003, PCT/EP2005/005311, PCT/EP2005/005321, PCT/EP2005/007151, PCT/EP2005/01294 or DE 102004060542.4.

In one embodiment, the compounds of formula I are administered in combination with sodium-dependent glucose transporter 1 or 2(SGLT1, SGLT2) modulators, such as KGA-2727, T-1095, SGL-0010, AVE 2268 and SAR 7226 or such as those described in the following references: WO2004007517, WO200452903, WO200452902, PCT/EP2005/005959, WO2005085237, JP2004359630, WO2005121161, WO2006018150, WO2006035796, WO2006062224, WO2006058597 or a.l. handlen, Expert opin. ther. patents (2005)15(11), 1531-ion 1540.

In one embodiment, the compounds of formula I are administered in combination with a GPR40 modulator.

In one embodiment, the compounds of formula I are administered in combination with a GPR119b modulator, such as those described in WO 2004041274.

In one embodiment, the compounds of formula I are administered in combination with a GPR119 modulator, such as those described in WO2005061489 (PSN-632408).

In one embodiment, the compounds of formula I are administered in combination with Hormone Sensitive Lipase (HSL) inhibitors, such as those described in WO 2005073199.

In one embodiment, the compounds of formula I are administered in combination with acetyl-CoA carboxylase (ACC) inhibitors, such as those described in WO199946262, WO200372197, WO2003072197, WO2005044814, WO2005108370, JP 2006131559.

In one embodiment, the compounds of the formula I are administered in combination with an inhibitor of phosphoenolpyruvate carboxykinase (PEPCK), such as those described in WO 2004074288.

In one embodiment, the compound of formula I is administered in combination with a glycogen synthase kinase 3 β (GSK-3 β) inhibitor, such as those described in US2005222220, WO2005085230, PCT/EP2005/005346, WO2003078403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997, US 2005026983, WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727 or WO 2004046117.

In one embodiment, the compounds of formula I are administered in combination with a protein kinase C β (PKC β) inhibitor, such as rubberistaurin.

In one embodiment, the compounds of formula I are administered in combination with an endothelin A receptor antagonist, such as avosentan (Avermentan) (SPP-301).

In one embodiment, the compounds of formula I are administered in combination with an "I- κ B kinase" inhibitor (IKK inhibitor), such as those described in WO2001000610, WO2001030774, WO2004022553 or WO 2005097129.

In one embodiment, the compounds of formula I are administered in combination with a glucocorticoid receptor modulator, such as those described in WO 2005090336.

In another embodiment, the compounds of formula I are administered in combination with:

CART modulators (see, "Cocaine-amphetamine-regulated transcription affects energy metabolism, anxiety, and gastric emptying in mice" (Cocaine-amphetamine-regulated transcript fluorescence sensing reagent, anxiety and gastric emptying in mice), Asakawa, A. et al, Hormonne and Metabolic Research (2001), 33(9), 554-);

NPY antagonists such as naphthalene-1-sulfonic acid {4- [ (4-aminoquinazolin-2-ylamino) methyl ] cyclohexylmethyl } amide hydrochloride (CGP 71683A);

NPY-5 receptor antagonists, such as L-152804, S-2367 or such as those described in WO 2006001318;

peptide YY3-36 (PYY3-36) or similar compounds, such as CJC-1682 (PYY3-36 conjugated to human serum albumin via Cys 34), CJC-1643(PYY3-36 derivatives which bind to serum albumin in vivo) or those described in WO 2005080424;

CB1R (cannabinoid receptor 1) antagonists (e.g. rimonabant, SR147778, SLV-319, AVE-1625, MK-0364 or salts thereof, or those described, for example, in EP 065654, WO 00/15609, WO2001/64632, WO2001/64633, WO2001/64634, WO02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO200170700, WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO 2003023023027069, US6,509,367, WO200132663, WO2003086288, WO2003087037, WO 2004048348348348317, WO2004058145, WO 20020020084930, WO 20084943, WO 200402404040404040404040744, WO 2004023123120, WO 2004024040672004020040200406720040200408720040200402004020040200402004087200402004020040200402006046, WO 20060779, WO 20020060679, WO 200200500200200500200200200500200200500200200606746, WO 20060200602006020060200606646, WO 20060200602006020060200606620060200606660, WO 20060200602006020060200602006046, WO 200602006020060200602006046, WO 20060200602006066200606646,839, WO 200200200200602006020020020020060200602006020060200602006020060200602006020060200606620060200602006066200200602006046,839, WO 2002002002002006020020020020020060677, WO 2002002002002002002002002006067200200200200606720020020020060672002002002002002006020060200602006020060200;

MC4 agonists (e.g., 1-amino-1, 2, 3, 4-tetrahydronaphthalene-2-carboxylic acid [2- (3 a-benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxoethyl ] amide; (WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141 or those described in: WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391, WO2004112793, WO 20050222014, US20050176728, US20050164914, US20050124636, US20050130988, US20040167201, WO2004005324, WO2004037797, WO2005042516, WO2005040109, WO2005030797, US20040224901, WO200501921, WO200509184, WO2005000339, EP1460069, WO2005047253, WO2005047251, EP1538159, WO2004072076, WO2004072077 or WO 2006021655-57;

orexin receptor antagonists (e.g., 1- (2-methylbenzoxazol-6-yl) -3- [1, 5] naphthyridin-4-ylurea hydrochloride (SB-334867-A) or those described in, for example, WO200196302, WO200185693, WO2004085403, WO2005075458, or WO 2006067224);

histamine H3 receptor agonists (e.g. 3-cyclohexyl-1- (4, 4-dimethyl-1, 4, 6, 7-tetrahydroimidazo [4, 5-c ] pyridin-5-yl) -propan-1-one oxalate (WO 00/63208) or those described in WO200064884, WO 2005082893);

CRF antagonists (e.g., [ 2-methyl-9- (2, 4, 6-trimethylphenyl) -9H-1, 3, 9-triazafluoren-4-yl ] dipropylamine (WO 00/66585));

CRF BP antagonists (e.g., urocortin);

urocortin (urocortin) agonists;

β 3 adrenoceptor agonists such as 1- (4-chloro-3-methanesulfonylmethylphenyl) -2- [2- (2, 3-dimethyl-1H-indol-6-yloxy) ethylamino ] ethanol hydrochloride (WO 01/83451)); or Solabetron (GW-427353) or N-5984(KRP-204) or those described in JP 2006111553;

MSH (melanocyte stimulating hormone) agonists;

MCH (melanin concentrating hormone) receptor antagonists (e.g. NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 or those described in WO2003/15769, WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO2004039780, WO2003033476, WO 2002002006245, WO2002089729, WO2002002744, WO2003004027, FR2868780, WO 2000446, WO2006038680, WO 2006060144293, WO 2006044174);

CCK-A agonists (e.g. {2- [4- (4-chloro-2, 5-dimethoxyphenyl) -5- (2-cyclohexylethyl) -thiazol-2-ylcarbamoyl ] -5, 7-dimethylindol-1-yl } acetic acid trifluoroacetate (WO 99/15525), SR-146131(WO 0244150) or SSR-125180) or those described in WO 2001603514);

serotonin reuptake inhibitors (e.g., dexfenfluramine);

mixed serotonergic-and noradrenergic compounds (e.g., WO 00/71549);

5-HT receptor agonists, such as 1- (3-ethylbenzofuran-7-yl) piperazine oxalate (WO 01/09111);

5-HT2C receptor agonists (e.g., lorcaserin hydrochloride (APD-356), BVT-933 or those described in WO200077010, WO20077001-02, WO2005019180, WO2003064423, WO200242304 or WO 2005082859);

5-HT6 receptor antagonists, such as those described in WO 2005058858;

bombesin receptor agonists (BRS-3 agonists);

galanin (galanin) receptor antagonists;

growth hormone (e.g., human growth hormone or AOD-9604);

a growth hormone releasing compound (6-benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3, 4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695));

growth hormone secretagogue receptor antagonists (ghrelin antagonists) such as those described in a-778193 or WO 2005030734;

TRH agonists (see, e.g., EP 0462884);

uncoupling protein 2 or 3 modulators;

leptin agonists (see, e.g., Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. "Leptin agonists used as a potential pathway for the treatment of obesity" (Leptin agonists as a potential approach to obesity.) Drugs of Future (2001), 26(9), 873-);

DA agonists (bromocriptine or Doprexin (Doprexin));

lipase/amylase inhibitors (e.g., WO 00/40569);

diacylglycerol O-acyltransferase (DGAT) inhibitors, such as BAY-74-4113 or those described in: US2004/0224997, WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492, WO2005013907, WO2006004200, WO2006019020, WO 2006064189;

fatty Acid Synthase (FAS) inhibitors, such as those described in C75 or WO 2004005277;

oxyntomodulin;

oleoyl-estrone; or

Thyroid hormone receptor agonists, such as those described in KB-2115 or the following references: WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421 or WO 2005092316.

In one embodiment, the additional active ingredient is varenicline tartrate (varenicline), a partial agonist of the α 4- β 2 nicotinic acetylcholine receptor.

In one embodiment, the additional active ingredient is trodusquesine (trosquinamine).

In one embodiment, the additional active ingredient is a SIRT1 enzyme modulator, a member of the human sirtuin family of enzymes.

In one embodiment, the additional active ingredient is leptin; see, e.g., "prospects for therapeutic use of leptin" (Perspectives in therapeutic use of leptin), Salvador, Javier; Gomez-Ambrosi, Javier; fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-.

In one embodiment, the additional active ingredient is dextroamphetamine or amphetamine.

In one embodiment, the further active ingredient is fenfluramine or dexfenfluramine.

In another embodiment, the additional active ingredient is sibutramine.

In one embodiment, the additional active ingredient is molindone or phentermine.

In one embodiment, the additional active ingredient is a diphenylazetidinone derivative, e.g. as described in US6,992,067 or US 7,205,290.

In one embodiment, the compounds of the formula I are admixed with a swelling agent, preferably an insoluble swelling agent (see, for example, carob @(Zunft H J; et al, carob pulp preparations for the treatment of hypercholesterolemia, ADVANCES IN THERAPY (9-10 months 2001), 18(5), 230-6); caromax is a product of Nutriova, Nutrition Specialties, Inc. dedicated to Nutrivitamin&Food Ingredients GmbH)，Industiepark 65926 the carob-containing product supplied by Frankfurt/Main). It is possible to administer the compounds of the formula I andto realize andand (4) combining.It may also be administered herein in the form of a food product, for example in the form of a bakery product or a muesli bar.

It will be understood that each suitable combination of a compound of the invention with one or more of the above compounds and optionally one or more other pharmacologically active substances is to be considered as being included within the scope of the present invention.

The examples described in detail below serve to illustrate the invention, without however limiting it.

Table 1:

examples

R1

R2，R2′

R3，R3′

R4，R4′

R5，R5′

X

1

Et

OH，H

OBn，H

OH，H

CH2OH，H

NH

2

n-Bu

OH，H

OBn，H

OH，H

CH2OH，H

NH

3

Et

OH，H

OBn，H

OH，H

CH2OBn，H

NH

4

Et

OH，H

OBn，H

OH，H

CH2OSO2OH， H

NH

5

Et

OH，H

OBn，H

OSO2OH，H

CH2OSO2OH， H

NH

6

n-Bu

OH，H

OBn，H

OH，H

CH2OSO2OH， H

NH

Et ═ ethyl, Bu ═ n-butyl, Bn ═ benzyl

The activity of the compounds was determined as follows.

Preparation and operation of in vitro IBAT inhibition assay:

1. cloning of the expression vector for human IBAT

The cDNA (complementary deoxyribonucleic acid) of human IBAT was cloned by standard methods of Molecular biology, for example as described in the laboratory Manual of Molecular Cloning, Joseph Sambrook and David Russell, and introduced into the pcDNA1 vector from Invitrogen. The insert was subsequently sequenced and showed complete identity with bases 599 to 1645 of the base sequence of human IBAT described by P.A. Dawson and deposited in GenBank sequence databases (GenBank accession No.: U10417). Bases 599 to 1645 correspond to the complete coding region of human IBAT.

2. Preparation of recombinant cell lines constitutively expressing human IBAT

The expression vector for human IBAT was introduced into CHO (Chinese hamster ovary) cells by stable transfection. To select single cell clones, 400. mu.g/ml geneticin was added to the cell culture medium (Ham's F12 medium supplemented with 10% fetal bovine serum, 100 units/ml penicillin, 100 units/ml streptomycin). By which a radiolabeled taurocholic acid (³H]TCA) the functionality of single cell clones resulting from selection was analyzed. Selection pair [2 ]³H]Cell clones with the highest uptake activity for TCA (hereinafter referred to as CHO-hIBAT) were further analyzed and cultured in the presence of 400. mu.g/ml geneticin.

3. Determination of the inhibitory Effect of the Compounds of the invention on the IBAT-dependent absorption of taurocholic acid in cells

CHO-hbat cells were seeded at a concentration of 40000 cells/well in poly-D-lysine coated 96-well plates in cell culture medium and cultured for 24 hours. The cells were then washed once with serum-free transport assay buffer (140mM choline chloride, 2mM potassium chloride, 1mM magnesium chloride, 1mM calcium chloride, 10mM HEPES/Tris, pH 7.5), followed by incubation at room temperature for 30 minutes with sodium-free transport assay buffer as a negative control or with sodium-containing transport assay buffer (140mM sodium chloride, 2mM potassium chloride, 1mM magnesium chloride, 1mM calcium chloride, 10mM HEPES/Tris, pH 7.5) as a positive control. At the same time, the assay wells were also assayed at various concentrations of the compound of interestIncubate in transport assay buffer containing sodium for 30 minutes at room temperature in the presence of substance. Starting with a 10mM stock in dimethyl sulfoxide, the test substance is suitably diluted in transport assay buffer (40. mu.l/well). Then by adding 10. mu.l/well of radiolabeled taurocholic acid (,)³H]-TCA) and unlabelled taurocholic acid. The final concentration of taurocholic acid in this assay was 10 μ M. After incubation at room temperature for 60 minutes, the reaction was stopped by adding 100. mu.l/well of sodium-free transport assay buffer (4 ℃), and each well was washed three times with sodium-free transport assay buffer. Finally, 100. mu.l of scintillation fluid was added to each well and the radioactivity absorbed in the cells was determined on a Microbeta scintillation microplate reader from Wallac, Inc.

Half maximal inhibitory effect (IC50 value, inhibitory concentration 50) of test compounds was determined in the following assay:

determination of the value of 1.0% inhibition. This is a determination in a transport assay buffer containing sodium in the absence of a substance.

Determination of the value of 2.100% inhibition. This is a determination in the absence of material in a sodium-free transport assay buffer.

3. Calculation of percent inhibition for those determinations performed in the presence of various concentrations of the compound under study. The concentration at which the compound 50% reduces the taurocholic acid absorption can then be found therefrom (IC50 value).

Table 2: biological activity

Examples	IC-50 (human IBAT) μ M
		1	0.0044
2	0.0069
		3	0.0035
4	0.0024
		5	0.0020
6	0.0107

From the data determined, it can be concluded that the compounds of formula I according to the invention are very suitable for the treatment of hyperlipidemia.

The use of the compounds of formula I for the treatment or prevention of other diseases is likewise conceivable. Examples of such diseases are:

1. disorders of fatty acid metabolism and glucose utilization

-disorders in which insulin resistance is involved

2. Diabetes, particularly type 2 diabetes, includes the prevention of its associated sequelae.

In this case, the specific aspects are

-a high blood sugar level,

-an improvement in the insulin resistance,

-an improvement in glucose tolerance,

protection of pancreatic beta cells

Prevention of macrovascular and microvascular disorders

3. Dyslipidemia and its sequelae such as atherosclerosis, coronary heart disease, cerebrovascular disorders, etc., especially (but not limited to) those characterized by one or more of the following factors:

-high plasma triglyceride concentration, high postprandial plasma triglyceride concentration,

low HDL cholesterol concentration

Low apoA lipoprotein concentration

High LDL cholesterol concentration

Low density LDL cholesterol particles

High apoB lipoprotein concentration

Desaturation index (e.g. fat in the ratio 18: 1/18: 0n-9, 16: 1/16: 0 n-7 or 18: 1n-9+ 16: 1 n-7/16: 0)

4. Various other disorders that may be associated with metabolic syndrome or syndrome X, such as:

increase in abdominal circumference

Dyslipidemias (e.g. hypertriglyceridemia and/or low HDL)

Insulin resistance

High coagulability

Hyperuricemia

Microalbuminemia

Thrombosis, hypercoagulability and prothrombotic stages (arteries and veins)

-hypertension

Heart failure, such as (but not limited to) myocardial infarction, hypertensive heart disease or heart failure after cardiomyopathy

5. Liver disorders and conditions associated therewith

Fatty liver

-hepatic steatosis

-non alcoholic hepatitis

-non-alcoholic steatohepatitis (NASH)

-alcoholic hepatitis

Acute fatty liver

Fatty liver of pregnancy

-drug-induced hepatitis

Iron overload disorder

-hepatic fibrosis

-cirrhosis of the liver

Hepatoma cell line

Viral hepatitis

6. Skin disorders and conditions and those associated with polyunsaturated fatty acids

-eczema

-acne

Psoriasis (psoriasis)

Keloid formation or prevention

Other diseases associated with mucosal fatty acid composition

7. Primary hypertriglyceridemia or secondary hypertriglyceridemia after the following diseases

Familial histiocytosis reticulocytosis

Lipoprotein lipase deficiency

Hyperlipoproteinemia

Apolipoprotein deficiency (e.g. apoCII or apoE deficiency)

8. Diseases or disorders associated with neoplastic cell proliferation

Benign or malignant tumors

-cancer

-neoplasia

-transfer range

-carcinogenesis

9. Diseases or disorders associated with neurological, psychiatric or immunological disorders or conditions

10. Among other disorders or conditions that may, for example, involve inflammatory responses or cell differentiation are:

atherosclerosis, such as (but not limited to) coronary arteriosclerosis, including angina or myocardial infarction, stroke, ischemic stroke and Transient Ischemic Attack (TIA)

Peripheral occlusive disease

Restenosis or reocclusion of blood vessels

Chronic inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis

-pancreatitis

Sinusitis

Other inflammatory states

Retinopathy, ischemic retinopathy

-adipose cell tumors

Adipose cell carcinoma, such as liposarcoma

Solid tumors and neoplasms, such as (but not limited to) gastrointestinal cancer, liver cancer, bile duct cancer and pancreatic cancer, endocrine tumors, lung cancer, kidney and urinary tract cancer, genital tract cancer, prostate cancer and the like

Acute and chronic myeloproliferative disorders and lymphomas

Angiogenesis

-neurodegenerative disorders

-Alzheimer's disease

Multiple sclerosis

Parkinson's disease

Erythrodermic diseases, e.g. psoriasis

Acne vulgaris

Other skin disorders and dermatological conditions modulated by PPAR

-eczema and neurodermatitis

Dermatitis, such as seborrheic dermatitis or solar dermatitis

Keratitis and keratoses, such as seborrheic keratosis, senile keratosis, actinic keratosis, photo-induced keratosis (photo-induced keratoses) or follicular keratosis

Keloid and keloid prevention

Warts, including condyloma or condyloma acuminata

Human Papillomavirus (HPV) infections such as venereal papillomata (venereal papillomata), viral warts such as molluscum contagiosum, leukoplakia mucosae

Papular dermatitis, e.g. lichen planus

Skin cancer, e.g. basal cell carcinoma, melanoma or cutaneous T-cell lymphoma

Localized benign epidermal tumors, such as keratoderma, epidermal nevi

Chilblain

-hypertension

Syndrome X

Polycystic ovarian syndrome (PCOS)

-asthma

Cystic fibrosis

-osteoarthritis

Lupus Erythematosus (LE) or inflammatory rheumatic disorders, such as rheumatoid arthritis

Vasculitis

Emaciation (cachexia)

Gout (gout)

Ischemia/reperfusion syndrome

-Acute Respiratory Distress Syndrome (ARDS)

Viral diseases and infections

Lipodystrophy and lipodystrophy states, and also for the treatment of drug side effects (e.g. side effects after the use of drugs for the treatment of HIV or tumors)

Myopathies and lipid myopathies (e.g. carnitine palmitoyl transferase I or II deficiency)

The preparation of some of the examples is described in detail below; other compounds of formula I are obtained analogously:

experimental part:

example 1

Synthesis of Compound 2:

15.0g (32.7mmol) of bromide 1(Eur. J. Med. chem, (1996)31, 557-574) were dissolved in 250ml of dimethylformamide. 7.5g of sodium azide was added, followed by stirring at room temperature for 1 hour. The reaction solution was extracted with water and ethyl acetate, and the organic phase was washed twice with saturated sodium chloride solution, filtered through a small amount of silica gel, and concentrated. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give 11.1g (81% yield) of azide 2 as a colourless oil which solidified on standing for a long period of time. TLC (n-heptane/ethyl acetate 2: 1), R_f＝0.4，C₁₉H₂₃N₃O₈(421.41)MS(M+H)⁺＝422.3。

Synthesis of Compound 2 via Glucosyl chloride alternatives

In analogy to the synthesis of glucosyl bromide, 1.5g of 2, 4, 6-tri-O-acetyl-3-O-benzyl- α -D-glucopyranosyl chloride (J.org.chem (1997), 62(9)2832-46) were reacted. In which case the reaction temperature must be raised to 60 c. 1.3g (86%) of azide 2 were obtained.

Synthesis of Compound 3

8.8g (20.9mmol) of azide 2 are dissolved in 100ml of dichloromethane and 2ml of triethylamine. 300mg of 10% palladium was addedActivated carbon and then hydrogenated at 4 bar hydrogen pressure for 1 hour. The catalyst was removed via a small amount of silica gel, which was washed with ethyl acetate. The solution was concentrated until crystallization started. A total of 6.9g of crystalline solid 3 (83% yield) was obtained. TLC (ethyl acetate), R_f＝0.2，C₁₉H₂₅NO₈(395.41)，MS(M+H)⁺＝396.3。

Synthesis of example 1

900mg of triphosgene are dissolved in 10ml of dichloromethane. A solution of 3.0g (7.6mmol) of amine 3 and 3ml of N-ethylmorpholine in 20ml of dichloromethane is added dropwise to the solution over a period of 20 minutes at room temperature. Then stirred for 1 hour, followed by the slow dropwise addition of a solution of 3.0g (7.0mmol) of aniline 4(US 5,994,391) in 20ml of dichloromethane. The reaction was complete after an additional 30 minutes (TLC detection). Washed twice with saturated sodium chloride solution, filtered through silica gel and concentrated to give 7g of crude product 5. This was dissolved in 50ml of methanol and 2ml of 1M sodium methoxide/methanol solution were added. After 30 minutes, the reaction solution was neutralized with 4ml of a 0.5 MHCL/methanol solution and concentrated. The residue was purified by flash chromatography. Yield 4.72g (93%) of example 1 as a colorless solid. TLC (dichloromethane/methanol/concentrated ammonia 30/5/1), R_f＝0.7，C₃₈H₅₁N₃O₉S(725.91)，MS(M+H)⁺＝726.38。

Example 2

Analogously to the synthesis of example 1, starting from amine 3 and di-n-butylAniline (US 5.994.391) prepared example 2 starting with triphosgene gave example 2 as a colorless solid in 90% yield. TLC (dichloromethane/methanol/concentrated ammonia 30/5/1), R_f＝0.75，C₄₀H₅₅N₃O₉S(753.96)，MS(M+H)⁺＝754.38。

Example 3

Synthesis of dibenzyl glucose-1-amine building Block 9:

1.36g (3.55mmol) of the benzylidene derivative 6(Terahedron Letters (1999), 40(3), 547-549) are dissolved in 35ml of dichloromethane and 7ml of triethylsilane (ABCR). After adding 1ml of boron trifluoride etherate, the reaction was allowed to proceed at room temperature for 30 minutes. The solution was then washed with saturated sodium bicarbonate solution, filtered through a small amount of silica gel and concentrated the residue was purified by flash chromatography (n-heptane/ethyl acetate) to give 1.13g (83% yield) of azide 7 as a colorless oil which solidified upon standing for a long period of time. TLC (n-heptane/ethyl acetate 1: 1), R_f＝0.4，C₂₀H₂₃N₃O₅(385.42)，MS(M+NH₄)⁺＝403.21。

Synthesis of compound 8:

1.12g (2.9mmol) of diol 7 are dissolved in 15ml of pyridine and 15ml of acetic anhydride. The solution was heated at 50 ℃ for 2 hours and then concentrated under high vacuum. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give 1.2g (88% yield) of azide 8 as a colorless oil. TLC (n-heptane/ethyl acetate 2: 1), R_f＝0.5，C₂₄H₂₇N₃O₇(469.50)，MS(M+NH₄)⁺＝487.21。

Synthesis of compound 9:

1.2g (2.55mmol) of azide 8 are dissolved in 30ml of dichloromethane and 1ml of triethylamine. 35mg of 10% palladium on activated carbon were added and then hydrogenated under a hydrogen pressure of 4 bar for 1 hour. The catalyst was removed via a small amount of silica gel, which was washed with ethyl acetate and concentrated. The residue was purified by flash chromatography (n-heptane/ethyl acetate) to give 1.07g (95% yield) of the glucose-1-amine derivative 8 as a colorless oil. TLC (ethyl acetate), R_f＝0.2，C₂₄H₂₉NO₇(443.50)，MS(M+H)⁺＝444.32。

Example 3

In analogy to the synthesis of example 1, example 3 was prepared starting from amine 9 and aniline 4(US 5.994.391) with triphosgene to obtain example 3 as colorless solid in 80% yield. TLC (dichloromethane/methanol/concentrated ammonia 100/7/1), R_f＝0.5，C₄₅H₅₇N₃O₉S(816.03)，MS(M+H)⁺＝816.48。

Examples 4 and 5

50.0g (68.9mmol) of example 1 are dissolved in 500ml of pyridine and, after addition of 17g of pyridine-sulfur trioxide complex, stirred for 30 minutes at 60 ℃. After addition of 400ml of methanol, inConcentrating in a rotary evaporator. The residue was again evaporated with 300ml methanol and then purified by flash chromatography. Yield 38.4g (68%) of example 4 as ammonium salt. TLC (dichloromethane/methanol/concentrated ammonia 30/5/1), R_f＝0.4，C₃₈H₅₁N₃O₁₂S₂×NH₃(823.00)，MS(M+H)⁺＝804.21。

As by-product, 4.0g (7%) of the disulfate salt of example 5 are obtained as the diammonium salt. TLC (dichloromethane/methanol/concentrated ammonia 30/5/1), R_f＝0.1，C₃₈H₅₁N₃O₁₅S₃×2NH₃(920.09)，MS(M +H)⁺＝886.45.

The disulfate salt is also available as the main product if twice the amount of sulfur trioxide complex is used.

Separately prepared salt of example 4

Preparation of potassium salts

8.3g of example 4 (ammonium salt) dissolved in 150ml of methanol are stirred vigorously with 200g of potassium-loaded AmberlitIR120 at room temperature for 1 hour. The ion exchange resin was then separated and washed twice with methanol. The solvent was evaporated to give 9g of crude product. This was dissolved in 40ml of methanol and washed with 150ml of ethanol. 4.5g of the potassium salt of example 4 having a melting point of 220 ℃ with degradation are crystallized at room temperature overnight. A single crystal was obtained by slowly growing crystals (over 2 days) from a solution of 2.5g of the potassium salt of example 4 in 50ml of methanol and 100ml of ethanol, with the aid of which the structure and stereochemistry of example 4 could be confirmed by the single crystal X-ray structure.

Preparation of zinc salts

1.1g of the (ammonium) salt from example 4 are dissolved in 11ml of water (yellowish clear solution) and mixed with a solution of 120mg of zinc chloride in 13ml of water. The spontaneously precipitated precipitate was stirred at room temperature for a further 2 hours and filtered with suction. Crystals of the zinc salt of example 4 (977mg, 88%) were obtained.

Preparation of calcium salts

Similar to the preparation of the zinc salt, a large amount of calcium salt precipitate was obtained after addition of a solution of 85mg calcium chloride in 13ml water, which precipitate showed difficulty in suction filtration and was hygroscopic (937mg, 85%).

Preparation of magnesium salts

Analogously to the preparation of the zinc salt, a colorless precipitate of the magnesium salt was obtained after addition of a solution of 72mg of magnesium chloride in 11ml of water, which was hygroscopic (977mg, 89%).

Example 6

Example 6 was prepared analogously to the synthesis described for example 4 starting from 105mg of example 2 to yield 67mg (65%) of the ammonium salt of example 6. TLC (dichloromethane/methanol/concentrated ammonia 30/5/1). R_f＝0.45。C₄₀H₅₅N₃O₁₂S₂×NH₃(851.06)。MS(M+H)⁺＝834.43。

Claims (12)

1. A compound of the formula and pharmaceutically acceptable salts thereof,

2. a compound as claimed in claim 1 wherein the pharmaceutically acceptable salt is an ammonium salt.

3. A compound as claimed in claim 1 wherein the pharmaceutically acceptable salt is an alkali metal or alkaline earth metal salt.

4. A compound as claimed in claim 1 wherein the pharmaceutically acceptable salt is the potassium salt.

5. A compound as claimed in claim 1 wherein the pharmaceutically acceptable salt is a zinc salt.

6. A medicament comprising a compound as claimed in any one of claims 1 to 5.

7. A medicament as claimed in claim 6, comprising one or more metal salts as further excipients.

8. Use of a compound as claimed in any one of claims 1 to 5 in the manufacture of a medicament for the treatment of a disorder of lipid metabolism.

9. A process for the preparation of a medicament comprising a compound as claimed in any one of claims 1 to 5, which process comprises mixing the active ingredient with a pharmaceutically acceptable carrier and converting the mixture into a form suitable for administration.

10. Use of a compound as claimed in any one of claims 1 to 5 in the manufacture of a medicament for the treatment of hyperlipidemia.

11. Use of a compound as claimed in any one of claims 1 to 5 in the manufacture of a medicament for use in lowering serum cholesterol levels.

12. Use of a compound as claimed in any one of claims 1 to 5 in the manufacture of a medicament for the treatment of the manifestations of arteriosclerosis.