# US 7,745,414 B2 · Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture

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- Number: US 7,745,414 B2
- Document ID: US7745414B2
- Status: Granted
- Kind: B2
- Application number: 11/674,839
- Filed: 2007-02-14
- Published: 2008-03-06
- Granted: 2010-06-29
- Earliest claimed: 2006-02-15
- Assignees: Boehringer Ingelheim International GmbH
- Inventors: Matthias Eckhardt; Frank Himmelsbach; Peter Eickelmann; Achim Sauer; Leo Thomas
- Web page: https://patentgrep.com/patent/US7745414B2

## CPC

- C07D 309/10: Oxygen atoms
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07H 7/04: Carbocyclic radicals
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

Glucopyranosyl-substituted benzonitrile derivatives as defined herein, including the tautomers, the stereoisomers thereof, the mixtures thereof and the salts thereof. The compounds according to the invention are suitable for the treatment of metabolic disorders.

## Claims

### Claim 1

A glucopyranosyl-substituted benzonitrile derivative selected from the list according to formula II, III, or i.2,
wherein
R3 is cyclopentyloxy, cyclobutyloxy, cyclohexyloxy, tetrahydropyran-4-yloxy, 1-acetyl-piperidin-4-yloxy or C1-3-alkyloxy, and
R′ denotes H, C1-4-alkyl, (C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, arylcarbonyl or aryl-(C1-3-alkyl)-carbonyl, wherein the alkyl or aryl groups may be mono- or polysubstituted by halogen;
R8a, R8b, R8c, R8d independently of one another denote hydrogen or an allyl group, a benzyl group, a (C1-4-alkyl)carbonyl, (C1-4-alkyl)oxycarbonyl, arylcarbonyl, aryl-(C1-3-alkyl)-carbonyl and aryl-(C1-3-alkyl)-oxycarbonyl or a RaRbRcSi group or a ketal or acetal group, particularly an alkylidene or arylalkylidene ketal or acetal group, while in each case two adjacent groups R8a, R8b, R8c, R8d may form a cyclic ketal or acetal group or a 1,2-di(C1-3-alkoxy)-1,2-di(C1-3-alkyl)-ethylene bridge, while the above-mentioned ethylene bridge forms, together with two oxygen atoms and the two associated carbon atoms of the pyranose ring, a substituted dioxane ring, particularly a 2,3-dimethyl-2,3-di(C1-3-alkoxy)- 1,4-dioxane ring, and while alkyl, allyl, aryl and/or benzyl groups may be mono- or polysubstituted by halogen or C1-3-alkoxy, and while benzyl groups may also be substituted by a di-(C1-3-alkyl)amino group; and
Ra, Rb, Rc independently of one another denote C1-4-alkyl, aryl or aryl-C1-3-alkyl, wherein the aryl or alkyl groups may be mono- or polysubstituted by halogen;
while by the aryl groups mentioned in the definition of the above groups are meant phenyl or naphthyl groups; and
Alk denotes C1-4-alkyl.

### Claim 2

A glucopyranosyl-substituted benzonitrile derivative selected from the group consisting of:
(1) 2-(4-Cyclopentyloxy-benzyl)-4-(β-D-glucopyranos- 1-yl)-benzonitrile,
(2) 2-(4-Cyclobutyloxy-benzyl)-4-(β-D-glucopyranos- 1-yl)-benzonitrile,
(3) 2-(4-Cyclohexyloxy-benzyl)-4-(β-D-glucopyranos- 1-yl)-benzonitrile,
(4) 2-[4-(Tetrahydropyran-4-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzonitrile,
(5) 2-[4-(1-Acetyl-piperidin-4-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzonitrile,
(6) 2-(4-Methoxy-benzyl)-4-(β-D-glucopyranos- 1-yl)-benzonitrile,
(7) 2-(4-Ethoxy-benzyl)-4-(β-D-glucopyranos- 1-yl)-benzonitrile,
(8) 4-(β-D-glucopyranos-1-yl)-2-(4-isopropoxy-benzyl)-benzonitrile,
or a derivative thereof wherein one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with groups selected from (C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, phenylcarbonyl and phenyl-(C1-3-alkyl)-carbonyl.

### Claim 3 (depends on 2)

Glucopyranosyl-substituted benzonitrile derivative according to claim 2, wherein the hydrogen atom of the hydroxyl group O-6 of the β-D-glucopyranosyl-group is replaced by a group selected from among (C1-8-alkyl)carbonyl, (C1-8-alkyl)oxycarbonyl and phenylcarbonyl.

### Claim 4 (depends on 2)

Pharmaceutical composition, comprising a compound according to claim 2 optionally together with one or more inert carriers and/or diluents.

### Claim 5 (depends on 2)

A method of treating diseases or conditions which can be influenced by inhibiting the sodium-dependent glucose cotransporter SGLT said method comprised of the steps of administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2, wherein said disease or condition is selected from the group consisting of type 1 and type 2 diabetes mellitus, complications of diabetes, metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, edema and hyperuricaemia.

### Claim 6 (depends on 2)

A method of treating metabolic disorders, said method comprised of the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2, wherein said metabolic disorders is selected from the group consisting of type 1 and type 2 diabetes mellitus, complications of diabetes, metabolic acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, edema and hyperuricaemia.

### Claim 7 (depends on 2)

A method of inhibiting the sodium-dependent glucose cotransporter SGLT2, said method comprised of the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2.

### Claim 8 (depends on 2)

A method of treating the degeneration of pancreatic beta cells and/or for improving the functionality of beta cells, said method comprised of the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2.

### Claim 9 (depends on 2)

A method of slowing, delaying or treating diseases or conditions attributed to abnormal accumulation of liver fat, said method comprised of the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2.

### Claim 10 (depends on 1)

A glucopyranosyl-substituted benzonitrile derivative according to claim 1, wherein R3 is methoxy, ethoxy or isopropoxy.

### Claim 11 (depends on 1)

A glucopyranosyl-substituted benzonitrile derivative according to claim 1, wherein said aryl groups are phenyl groups.