# US 7,407,954 B2 · Thieno-(1,3)-oxazin-4-ones with lipase inhibiting activity

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- Number: US 7,407,954 B2
- Document ID: US7407954B2
- Status: Granted
- Kind: B2
- Application number: 10/488,045
- Filed: 2002-08-23
- Published: 2005-04-07
- Granted: 2008-08-05
- Earliest claimed: 2001-08-30
- Assignees: Alizyme Therapeutics Limited
- Inventors: Harold Francis Hodson; Christopher Robert Dunk; Richard Michael John Palmer; Dale Robert Mitchell; Véronique Birault; Russell George Hunt
- Web page: https://patentgrep.com/patent/US7407954B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- 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 9/00: Drugs for disorders of the cardiovascular system
- 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 25/00: Drugs for disorders of the nervous system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 498/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The use of a compound comprising formula (I), or a salt, ester, amide or prodrug thereof in the treatment of obesity and related disorders. The invention also relates to novel compounds within formula (I), to processes for preparing them and pharmaceutical compositions containing them. In formula (I): A is an optionally substituted thienyl moiety, Y is O, S, or NR2, R1 is a branched or unbranched alkyl (optionally interrupted by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or a substituted derivative of any of the foregoing groups and R2 is hydrogen or a group as defined for R1.

## Claims

### Claim 1

A compound of formula (Ia)
or a pharmaceutically acceptable salt or ester thereof;
wherein A is a thiophenyl moiety that is optionally substituted with one or more of alkyl, aryl, halo, alkoxy, haloalkyl, aryloxy, amino, heteroaryl, or arylalkyl;
Y is O, S or NR2, wherein R2 is hydrogen or an alkyl group having 1 to 6 carbon atoms;
and R1 is
an unbranched alkyl group having from 6 to 25 carbon atoms, a branched alkyl group having from 6 to 25 carbon atoms, an arylalkyl group wherein the alkyl moiety has from 4 to 12 carbon atoms;
or
a phenyl group substituted with one or more optionally substituted phenyloxy, phenylthio, SO-phenyl, SO2-phenyl, alkylphenyl, CO-phenyl, CO2-phenyl, CONR16-phenyl, NR16CO-phenyl or NR16-phenyl groups, wherein R16 is hydrogen or an alkyl group having from 1 to 4 carbon atoms, and wherein the phenyloxy, phenylthio, SO-phenyl, SO2-phenyl, alkylphenyl, CO-phenyl, CO2-phenyl, CONR16-phenyl, NR16CO-phenyl or NR16-phenyl groups are optionally substituted with one or more of halo, cyano, nitro, alkyl, alkylhalo, alkoxy, aryl, alkylaryl, aryloxy, amino, hydroxy or heteroaryl;
or
a phenyl group substituted with one or more of halo, NR6R7, OR6, SR6, COR6, CO2R6, nitro, cyano, aryl, hetereoaryl, alkyl aryl, alkyl, haloalkyl or alkoxy with the proviso that said compound is not 5-methyl-2-(4-methoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one, 6-pentyl-2-(4-chlorophenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one or 6-pentyl-2-(4-methoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one.

### Claim 2 (depends on 1)

The compound of claim 1 wherein the compound is of formula IIa
and pharmaceutically acceptable salts or esters thereof;
wherein group A is as defined in claim 1 for formula (Ia);
Y is as defined in claim 1 for formula (Ia);
and R20 is phenyloxy, phenylthio, SO-phenyl, SO2-phenyl, alkylphenyl, CO-phenyl, CO2-phenyl, CONR6-phenyl, NR6CO-phenyl or NR6-phenyl, optionally substituted with one or more of halo, cyano, alkyl, alkylhalo, alkoxy, aryl, alkylaryl, aryloxy, amino, hydroxy or heteroaryl.

### Claim 3 (depends on 1)

The compound of claim 1 selected from the group consisting of:
2-Phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-Butyloxy-4H-thieno-[2,3-d][1,3]oxazin-4-one
5-Methyl-2-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
5,6-Dimethyl-2-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
5-Phenyl-2-phenylamino-4H-thieno[3,2-d][1,3]oxazin-4-one
2-(4-(3-Trifluoromethyl-phenoxy)phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one
5-(1,1-Dimethylethyl)-2-phenylamino-4H-thieno[3,2-d][1,3]oxazin-4-one
6-Methyl-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Phenoxy)phenylamino-4H-thieno[3,2-d][1,3]oxazin-4-one
2-(4-Phenylmethyl)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Benzoyl)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Methyl-2-(4-phenoxy)phenoxy-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-(4-Trifluoromethyl-phenoxy)phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-(3-Trifluoromethyl-phenoxy)phenoxy)-4H-thieno[3,2-d][1,3]oxazin-4-one
2-(4-Phenylthio) phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
5,6-Dimethyl-2-(4-phenoxy)phenoxy-4H-thieno [2,3-d][1,3]oxazin-4-one
2-Dodecylamino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one
2-N-Dodecyl-N-methylamino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one
2-Dodecylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-Dodecylthio-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-N-(1-Methylethyl)-N-phenylamino)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Phenylsulfonyl) phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Phenylcarbamoyl) phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-(4-Chlorophenoxy)-phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-(4-Methylphenoxy)-phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Cyanophenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Cyanophenyl)amino-6-propyl-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Cyanophenyl)amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Phenylmethyl-2-(4-cyanophenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Cyanophenyl)amino-6-dodecyl-4H-thieno [2,3-d][1,3] oxazin-4-one
6-Methyl-2-(4-phenylbutyl) amino-4H-thieno [2,3-d][1,3] oxazin-4-one
2-(2-Chloroethyl)amino-6-methyl-4H-thieno [2,3-d][1,3] oxazin-4-one
2-(Hept-6-enyl)amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(5-Methoxycarbonylpentyl) amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one
2-Phenylamino-5,6,7,8-tetrahydro-4H-benzothieno[2,3-d][1,3]oxazin-4-one
2-(4-Phenoxy)phenylamino-4H-thieno-[3,4-d][1,3]oxazin-4-one
2-(4-(4-Trifluoromethylphenoxy)phenylamino)-4H-thieno[3,2-d][1,3]oxazin-4-one
2-(4-Cyanophenyl)amino-4H-thieno[3,2-d][1,3]oxazin-4-one
2-Dodecylamino-4H-thieno[3,2-d][1,3]oxazin-4-one
2-(5-Methylhexyl)amino-4H-thieno[3,2-d][1,3]oxazin-4-one
5-Methyl-2-(4-phenoxy)phenylamino-4H-thieno[3,2-d][1,3]oxazin-4-one
6-Propyl-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-Hexadecylamino-6-methyl-4H-thieno-[2,3-d][1,3]oxazin-4-one
6-Chloro-2-(4-phenoxy)phenylamino-4H-thieno [2,3-d][1,3]oxazin-4-one
6-Dodecyl-2-(4-phenoxy)phenylamino-4H-thieno [2,3-d][1,3]oxazin-4-one
6-Phenylmethyl-2-(4-phenoxy)phenylamino-4H-thieno [2,3-d][1,3]oxazin-4-one
6-(4-Phenoxyphenylamino)-7-oxa-9-thia-1,5-diazafluoren-8-one
2(5,5,5-Trifluoropentyl)amino-4H-thieno [2,3-d][1,3]oxazin-4-one
2-Eicosylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-Octadecylamino-4H-thieno [2,3-d][1,3]oxazin-4-one
2-Hexadecyloxy-4H-thieno [2,3-d][1,3]oxazin-4-one
2-(12-Nitrododecyl)-amino-4H-thieno [2,3-d][1,3]oxazin-4-one
2-(12-Phenyldodecyl)-amino-4H-thieno [2,3-d][1,3]oxazin-4-one
2-(12-(Pyrid-2-yl)dodecyl)-amino-4H-thieno [2,3-d][1,3]oxazin-4-one
2-Octylamino-4H-thieno [2,3-d][1,3]oxazin-4-one
2-(8-Phenyloctyl)amino-4H-thieno [2,3-d][1,3]oxazin-4-one
2-(4-Phenylsulfinyl)-phenylamino-4H-thieno [2,3-d][1,3]oxazin-4-one
2-(4-Phenoxycarbonyl)-phenylamino-4H-thieno [2,3-d][1,3]oxazin-4-one
2(4-(4-Methoxyphenoxy)-phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one
2(4-(4-Dimethylaminophenoxy)-phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one
2(4-(4-Hydroxyphenoxy)-phenylamino)-4H-thieno[2,3-d][1,3]oxazin-4-one
2(3-Phenoxy)-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2(2-Phenoxy)-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(3-Cyanophenyl)amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Chlorophenyl)amino-6-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Aminophenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Hydroxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Methoxycarbonylphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Trifluoromethylphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-N-(4-Phenoxy)phenyl-N-ethylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-N-(4-Phenoxy)phenyl-N-1-methylethylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Cyclopropyl-2-(4-phenoxy)-phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Phenoxy)phenyl-thio-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Phenoxy)phenylamino-6-trifluoromethyl-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Methoxy-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Phenoxy-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Methyl-2-(4-methoxyphenyl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one
2-(4-Phenoxy)phenylamino-6-propyl-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Cyano-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Chloro-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Methyl-2-(4-phenoxy)phenylthio-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Methyl-2-(4-phenoxy)phenoxy-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Methyl-2-(4-phenoxy)phenoxy-4H-thieno[3,2-d][1,3]oxazin-4-one
7-Methyl-2-(4-phenoxy)phenylamino-4H-thieno[3,4-d][1,3]oxazin-4-one
5-Methyl-2-(4-phenoxy)phenylamino-4H-thieno[3,4-d][1,3]oxazin-4-one
6-Methyl-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one
6-Methyl-2-(3-methylisoxazol-5-yl)amino-4H-thieno[2,3-d][1,3]oxazin-4-one.

### Claim 4 (depends on 1)

The compound of claim 1 which is 6-methyl-2-(4-phenoxy)phenylamino-4H-thieno[2,3-d][1,3]oxazin-4-one.

### Claim 5 (depends on 1)

A process for the preparation of a compound of formula (Ia) as defined in claim 1 which process comprises:
Process (A): reacting a compound of formula (IV):
with a compound of formula (V):
wherein groups A, Y and R1 are as defined in claim 1;
or:
Process (B): cyclising a compound of formula (VI):
wherein groups A, Y and R1 are as defined in claim 1 and R18 is hydrogen or C1-6alkyl;
or:
Process (C): reacting a compound of formula (VII):
with a compound of formula (VIII):
R1—YH (VIII)
wherein groups A, Y and R1 are as defined in claim 1 and Ha1 is a halide;
or:
Process (D): reacting a compound of formula (IX):
wherein group A is as defined in claim 1 and X is O, S or NH,
with a compound of formula (X):
ICH2R1 (X)
wherein group R1 is as defined in claim 1;
or:
Process (E) converting a compound of formula (Ia) into a different compound of formula (Ia) by:
(i) reduction of a compound of formula (Ia) wherein R1 or R2 or any substituent on the heterocyclic group A contains an alkenyl or alkynyl group or moiety, to the corresponding alkyl or alkenyl group or moiety; or
(ii) alkylation of a compound of formula (Ia) where one or more substituent on the heterocyclic group A represents a halogen atom.

### Claim 6 (depends on 1, 2, 3, 4)

A method for the treatment of obesity, the method comprising administering to a patient a compound of any one of claims 1 to 4.

### Claim 7 (depends on 1, 2, 3, 4)

The method for the treatment of an obesity-related disorder selected from one or more of hyperlipaemia, hyperlipidaemia, hyperglycaemia (type II diabetes), or hypertension, the method comprising administering to a patient a compound of any one of claims 1 to 4.

### Claim 8 (depends on 6)

The method of claim 6 wherein the compound inhibits a lipase enzyme involved in the metabolism or degradation of a fat.

### Claim 9 (depends on 1, 2, 3, 4)

A method for reducing levels of dioxins and polychlorinated biphenyls (PCBs) in body fat, the method comprising administering to a patient a compound as defined in any one of claims 1 to 4.

### Claim 10 (depends on 6)

The method of claim 6 wherein the patient is a human.

### Claim 11 (depends on 6)

The method of claim 6 wherein the patient is an animal.

### Claim 12 (depends on 6)

The method of claim 6 wherein the compound inhibits a lipase enzyme.

### Claim 13 (depends on 1, 2, 3, 4)

A pharmaceutical composition comprising the compound of any one of claims 1 to 4 in combination with a pharmaceutically acceptable carrier or diluent.

### Claim 14 (depends on 1, 2, 3, 4)

A method for the treatment of obesity or an obesity-related disorder selected from one or more of hyperlipaemia, hyperlipidaemia, hyperglycaemia (type II diabetes), or hypertension, the method comprising administering to a patient, a compound of any one of claims 1 to 4, a pharmaceutical composition comprising the compound of any one of claims 1 to 4 in combination with a pharmaceutically acceptable carrier or diluent, or a food product comprising the compound of any one of claims 1 to 4.

### Claim 15 (depends on 1, 2)

A method for inhibiting an enzyme in vitro, comprising contacting the enzyme with a compound of formula (Ia) or (IIa) as defined in claim 1 or 2, wherein the enzyme is a lipase.

### Claim 16 (depends on 1, 2)

A method for reducing fat content of animals, the method comprising administering to an animal a compound of formula (Ia) or (IIa) as defined in claim 1 or 2.

### Claim 17 (depends on 1, 2)

A method for maintaining a given weight, or for weight loss, the method comprising administering to a patient a compound of formula (Ia) or (IIa) as defined in claim 1 or 2.

### Claim 18 (depends on 2)

A process for the preparation of a compound of formula (IIa) as defined in claim 2 which process comprises:
Process (A): reacting a compound of formula (IV):
with a compound of formula (V):
wherein groups A, Y and R1 are as defined in claim 2;
or:
Process (B): cyclising a compound of formula (VI):
wherein groups A, Y and R1 are as defined in claim 2 and R18 is hydrogen or C1-6alkyl;
or:
Process (C): reacting a compound of formula (VII):
with a compound of formula (VIII):
R1—YH (VIII)
wherein groups A, Y and R1 are as defined in claim 2 and Ha1 is a halide;
or:
Process (D): reacting a compound of formula (IX):
wherein group A is as defined in claim 2 and X is O, S or NH,
with a compound of formula (X):
ICH2R1 (X)
wherein group R1 is as defined in claim 2;
or:
Process (E) converting a compound of formula (IIa) into a different compound of formula (IIa) by:
(i) reduction of a compound of formula (IIa) wherein R1 or R2 or any substituent on the heterocyclic group A contains an alkenyl or alkynyl group or moiety, to the corresponding alkyl or alkenyl group or moiety; or
(ii) alkylation of a compound of formula (IIa) where one or more substituent on the heterocyclic group A represents a halogen atom.

### Claim 19 (depends on 13)

The pharmaceutical composition of claim 13 wherein the compound is present in an amount sufficient to inhibit a lipase enzyme.

### Claim 20 (depends on 13)

The pharmaceutical composition of claim 13 wherein the compound is present in an amount sufficient to treat a condition selected from obesity or an obesity-related disorder selected from one or more of hyperlipaemia, hyperlipidaemia, hyperglycaemia (type II diabetes), or hypertension.

### Claim 21 (depends on 13)

The pharmaceutical composition of claim 13 wherein the compound is present in an amount sufficient to reduce levels of toxins in body fat.

### Claim 22 (depends on 13)

The pharmaceutical composition of claim 13 wherein the composition is formulated for administration to humans.

### Claim 23 (depends on 13)

The pharmaceutical composition of claim 13 wherein the composition is formulated for administration to animals.

### Claim 24 (depends on 1, 2, 3, 4)

A process for preparing a pharmaceutical composition comprising providing a compound of any one of claims 1 to 4; and mixing the compound with a pharmaceutically acceptable carrier or diluent.

### Claim 25 (depends on 9)

The method of claim 9 wherein the patient is a human.

### Claim 26 (depends on 9)

The method of claim 9 wherein the patient is an animal.

### Claim 27 (depends on 9)

The method of claim 9 wherein the compound inhibits a lipase enzyme.

### Claim 28 (depends on 3)

A pharmaceutically acceptable salt of a compound of claim 3.

### Claim 29 (depends on 3)

A pharmaceutically acceptable ester of a compound of claim 3.