JP2006527215A5

JP2006527215A5 -

Info

Publication number: JP2006527215A5
Application number: JP2006515710A
Authority: JP
Filing date: 2004-06-10
Publication date: 2007-07-12

Claims

Compounds of general formula (I), as well as their diastereomers, enantiomers or tautomers (including mixtures thereof), their pharmaceutically acceptable salts, their pharmaceutically acceptable Solvates or polymorphs:

Where
R ¹ and R ² are independently hydrogen, hydroxy, sulfanyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C Selected from _3-8 -heterocyclyl and C _3-10 -cycloalkyl, each hydroxy, sulfanyl, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, hetero Aryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl are independently hydroxy, sulfanyl, oxo, halogen, amino, sulfo, perhalomethyl, perhalomethoxy, C _1-6 -alkyl, C ₁ Optionally substituted with one or more substituents selected from _-6 -alkoxy, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl Well ;
R ³ , R ⁴ , and R ⁵ are independently hydrogen, hydroxy, sulfinyl, fluoro, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C Selected from _3-8 -heterocyclyl and C _3-10 -cycloalkyl, each hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _{3- 8} -heterocyclyl, and C _3-10 -cycloalkyl are independently hydroxy, sulfinyl, oxo, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C Each optionally substituted with one or more substituents selected from _3-8 -heterocyclyl, and C _3-10 -cycloalkyl, each hydroxy, sulfanyl, amino, sulfo, C _1-6 -alkyl, C _{2- 6} -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl are independently hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl, and Optionally substituted with one or more substituents selected from perhalomethoxy;
The compound is
Methyl-phenyl-carbamic acid 4- [3- (4-chlorophenyl) -ureido] -phenyl ester,
Methyl-phenyl-carbamic acid 4- (cyclohexanecarbonyl-amino) -phenyl ester,
Methyl-phenyl-carbamic acid 4- (2-cyclohexyl-acetylamino) -phenyl ester,
cis / trans-methyl-phenyl-carbamic acid 4-[(4-tert-butyl-cyclohexanecarbonyl) -amino] -phenyl ester,
cis-methyl-phenyl-carbamic acid 4-[(4-tert-butyl-cyclohexanecarbonyl) -amino] -phenyl ester,
trans-methyl-phenyl-carbamic acid 4-[(4-tert-butyl-cyclohexanecarbonyl) -amino] -phenyl ester,
Methyl-phenyl-carbamic acid 4- (3,3-dimethyl-butyrylamino) -phenyl ester,
Methyl-phenyl-carbamic acid 4-[(6-chloro-pyridine-3-carbonyl) -amino] -phenyl ester,
Methyl-phenyl-carbamic acid 4-[(6-chloro-pyridine-3-carbonyl) -amino] -phenyl ester,
Methyl-phenyl-carbamic acid 4-[(pyridine-2-carbonyl) -amino] -phenyl ester methyl-phenyl-carbamic acid 4-[(pyridine-3-carbonyl) -amino] -phenyl ester,
Methyl-phenyl-carbamic acid 4- (2-phenoxy-acetylamino) -phenyl ester,
Methyl-phenyl-carbamic acid 4-[(pyridine-2-carbonyl) -amino] -phenyl ester,
Methyl-phenyl-carbamic acid 4- [methyl- (thiophene-2-carbonyl) -amino] -phenyl ester,
Methyl-phenyl-carbamic acid 4-butyrylamino-phenyl ester,
Methyl-phenyl-carbamic acid 4- [2- (3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl) -acetylamino] -phenyl ester,
Methyl-phenyl-carbamic acid 4-{[4- (methyl-phenyl-carbamoyloxy) -2-oxo-1,2-dihydro-quinoline-3-carbonyl] -amino} -phenyl ester, and methyl-phenyl-carbamine Acid 4-[(4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carbonyl) -amino] -phenyl ester,
This is not a condition.

R ³ is hydrogen, A compound according to claim 1.

R ³ is hydroxy, sulfinyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, substituted C _1-6 -alkyl, or substituted 2. A compound according to claim 1 selected from Ci- ₆ -alkoxy.

The compound according to any one of claims 1 to 4, wherein R ² is hydrogen.

The compound according to any one of claims 1 to 4, wherein R ¹ is selected from the following group:

The compound according to any one of claims 1 to 4, wherein R ¹ is an amino group, a substituted amino group, or a disubstituted amino group.

R ⁴ is droxy, sulfinyl, amino, halogen, sulfo, C _1-6 -alkyl, C _1-6 -alkoxy, C _2-6 -alkenyl, aryl, substituted C _1-6 -alkyl, or substituted 12. A compound according to any one of claims 1 to 11 selected from _C1-6 -alkoxy.

R ⁴ is attached to a phenyl moiety at the para position, the compound according to any one of claims 1 to 12.

R ⁴ is attached to a phenyl moiety of the meta-position A compound according to any one of claims 1 to 12.

R ⁴ is hydrogen, A compound according to any one of claims 1 to 12.

R ⁵ is hydrogen A compound according to any one of claims 1 to 14.

Where
R ¹ is independently hydroxy, sulfinyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10- Each phenyl, optionally substituted by one or more substituents selected from one or more substituents selected from cycloalkyl, each hydroxy, sulfanyl, amino, sulfo, C _1-6- Alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl are independently hydroxy, sulfinyl, oxo, halogen, amino, sulfo, C _{1- 6} - alkyl, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - heterocyclyl, and C _3-10 - may be substituted with one or more substituents selected from cycloalkyl, S hydroxy, sulfanyl, amino, sulfo, C _1-6 - alkyl, C _2-6 - alkenyl, aryl, heteroaryl, C _3-8 - heterocyclyl and C _3-10 - cycloalkyl is, independently, hydroxy Optionally substituted with one or more substituents selected from:, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl, and perhalomethoxy;
R ² , R ³ , R ⁴ , and R ⁵ are hydrogen.

Where
R ¹ is independently hydroxy, sulfinyl, halogen, amino, sulfo, C _1-6 -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10- Each phenyl, optionally substituted by one or more substituents selected from one or more substituents selected from cycloalkyl, each hydroxy, sulfanyl, amino, sulfo, C _1-6- Alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl are independently hydroxy, sulfinyl, oxo, halogen, amino, sulfo, C _1- Optionally substituted with one or more substituents selected from ₆ -alkyl, C _2-6 -alkenyl, aryl, heteroaryl, C _3-8 -heterocyclyl, and C _3-10 -cycloalkyl;
R ² , R ³ , R ⁴ , and R ⁵ are hydrogen.

In the formula
RX is C _3-8 -heterocyclyl, and C _3-8 -heterocyclyl is independently selected from hydroxy, sulfanyl, oxo, halogen, amino, C _1-6 -alkyl, perhalomethyl, and perhalomethoxy Optionally substituted with one or more substituents;
R ² , R ³ , R ⁴ , and R ⁵ are hydrogen.

20. A compound according to any one of claims 1 to 19 having one free -COOH group.

Having one free -NH ₂ group, the compound according to any one of claims 1 to 19.

R ¹ is an amino group, substituted amino group, or a disubstituted amino group, the compound according to any one of claims 1 to 19.

20. A compound according to any one of claims 1 to 19 having one free amino group, a substituted amino group, or a disubstituted amino group.

24. A compound according to any one of claims 1 to 23 having one substituted or unsubstituted pyridine ring.

25. A compound according to any one of claims 1 to 24, wherein the molar weight of the compound is in the range of 282D to 650D.

26. A compound according to any one of claims 1 to 25, wherein the molar weight of the compound is less than 650D.

27. A compound according to any one of claims 1 to 26, wherein ACD LogP is in the range of 1.0 to 3.0.

27. A compound according to any one of claims 1 to 26, wherein ACD LogD is in the range of 0.8 to 2.0.

27. A compound according to any one of claims 1 to 26, wherein ACD LogP is in the range of 1.0 to 4.0.

27. A compound according to any one of claims 1 to 26, wherein ACD LogD is in the range of 0.8 to 3.0.

31. A compound according to any one of claims 1 to 30, wherein the number of H-bond donors is 1, 2 or 3.

32. The compound according to any one of claims 1 to 31, wherein the number of H-bond acceptors is 4, 5, or 6.

33. A compound according to any one of claims 1-32, wherein the number of rotatable bonds of the compound is in the range of 4-8.

2. The compound of claim 1, selected from the group consisting of:
Methyl-phenyl-carbamic acid 5- (4-piperidin-1-yl-benzoylamino) -phenyl ester,
Methyl-phenyl-carbamic acid 5- [4- (2-methyl-piperidin-1-yl) -benzoylamino] -phenyl ester,
Methyl-phenyl-carbamic acid 5- [4- (3-methyl-piperidin-1-yl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 5- [4- (4-methyl-piperidin-1-yl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (2-ethyl-piperidin-1-yl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (4,4-dimethyl-piperidin-1-yl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (2,6-dimethyl-piperidin-1-yl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (2,4,6-trimethyl-piperidin-1-yl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- (4-piperidin-1-ylmethyl-benzoylamino) -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (2-methyl-piperidin-1-ylmethyl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (3-methyl-piperidin-1-ylmethyl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (4-methyl-piperidin-1-ylmethyl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (2-ethyl-piperidin-1-ylmethyl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (2,6-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (4,4-dimethyl-piperidin-1-ylmethyl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 4- [4- (2,4,6-trimethyl-piperidin-1-ylmethyl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 5- [4- (2-piperidin-1-yl-ethyl) -benzoylamino] -phenyl ester,
Til-phenyl-carbamic acid 5- {4- [2- (2-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -phenyl ester,
Til-phenyl-carbamic acid 5- {4- [2- (3-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -phenyl ester,
Til-phenyl-carbamic acid 5- {4- [2- (4-methyl-piperidin-1-yl) -ethyl] -benzoylamino} -phenyl ester,
Til-phenyl-carbamic acid 5- {4- [2- (2-ethyl-piperidin-1-yl) -ethyl] -benzoylamino} -phenyl ester,
Til-phenyl-carbamic acid 5- {4- [2- (4,4-dimethyl-piperidin-1-yl) -ethyl] -benzoylamino} -phenyl ester,
Til-phenyl-carbamic acid 5- {4- [2- (2,6-dimethyl-piperidin-1-yl) -ethyl] -benzoylamino} -phenyl ester,
Tyl-phenyl-carbamic acid 5- {4- [2- (2,4,6-trimethyl-piperidin-1-yl) -ethyl] -benzoylamino} -phenyl ester.

35. A pharmaceutical composition comprising a compound according to any one of claims 1-34 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.

36. The composition of claim 35, wherein the composition is in unit dosage form, from about 0.05 to about 2000 mg, preferably from about 0.1 to about 500 mg, and more preferably from about 1.0 to about 100 mg. 35. A composition comprising the compound according to any one of 1 to 34 or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for use as a medicament for inhibiting hormone-sensitive lipase lipolytic activity against triacylglycerol, diacylglycerol, cholesterol acyl ester, or steroid acyl ester, comprising a pharmaceutically acceptable carrier or dilution A composition comprising the compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof together with a liquid.

38. A pharmaceutical composition according to any one of claims 35 to 37, for oral administration.

38. A pharmaceutical composition according to any one of claims 35 to 37 for nasal, transdermal, pulmonary, or parenteral administration.

35. Use of a compound according to any one of claims 1-34 for the preparation of a pharmaceutical composition.

35. Use of a compound according to any one of claims 1-34 for inhibition of hormone sensitive lipase.

35. A method according to any one of claims 1 to 34 for the preparation of a pharmaceutical composition for the inhibition of the lipolytic activity of hormone-sensitive lipase against triacylglycerol, diacylglycerol, cholesterol acyl ester or steroid acyl ester. Use of the compound.

Regulating plasma levels of free fatty acids, glycerol, LDL-cholesterol, HDL cholesterol, insulin, and / or glucose; and / or
Intracellular triacylglycerol and cholesterol ester reservoirs (adjusting intracellular levels of fatty acids, fatty acid esters such as diacylglycerol, phosphatidic acid, long chain acyl CoA, and citric acid or malonyl CoA; and / or
Increasing insulin sensitivity in adipose tissue, skeletal muscle, liver, or pancreatic beta cells; and / or
Regulating insulin secretion from pancreatic beta cells,
35. Use of a compound according to any one of claims 1-34 for the preparation of a pharmaceutical composition for the treatment or prevention of any disorder for which it is desirable.

The disorders include insulin resistance, type 1 diabetes, type 2 diabetes, metabolic X syndrome, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, atheroschlerosis, hypertension, lipoprotein metabolism 44. Use according to claim 43, selected from the group consisting of abnormalities, and any combination thereof.

35. Use of a compound according to any one of claims 1-34 for the preparation of a pharmaceutical composition for the treatment and / or prevention of dyslipidemia.

35. Use of a compound according to any one of claims 1-34 for the preparation of a pharmaceutical composition for the treatment and / or prevention of hyperlipidemia.

35. Use of a compound according to any one of claims 1-34 for the preparation of a pharmaceutical composition for the treatment and / or prevention of hyperglycemia.

For reducing HbA _1c, use of a compound according to any one of claims 1 to 34.

35. Use of a compound according to any one of claims 1-34 for the preparation of a pharmaceutical composition for the treatment and / or prevention of type 2 diabetes.

35. Use of a compound according to any one of claims 1-34 for the preparation of a pharmaceutical composition for the treatment and / or prevention of impaired glucose tolerance.

35. Use of a compound according to any one of claims 1 to 34 for the preparation of a pharmaceutical composition for the treatment and / or prevention of metabolic X syndrome.

Use of a compound according to any one of claims 1-34 for the preparation of a pharmaceutical composition for the treatment and / or prevention of atheroschlerosis.

35. Use of a compound according to any one of claims 1-34 for the preparation of a pharmaceutical composition for delaying the progression from impaired glucose tolerance to type 2 diabetes.

35. Use of a compound according to any one of claims 1-34 for the preparation of a pharmaceutical composition for delaying the progression from non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes.

56. Use according to any one of claims 40 to 55, wherein a further antidiabetic, antiobesity, antihypertensive or appetite regulating drug is used.

56. Use according to any one of claims 40 to 55, wherein metformin is also used.

A process for the preparation of a compound according to any one of claims 1-34 or a pharmaceutically acceptable salt thereof, wherein a suitable carbamoylating reagent in a solvent and a suitable pharmaceutically suitable salt according to the following P1 reaction scheme: Causing an alcohol reaction;

Isolating the disubstituted carbamate product.

Said carbamoylation reagent:

But,

58. The method of claim 57, wherein the method is selected from the group consisting of:

59. A method according to any one of claims 57 to 58, wherein the solvent is selected from the group consisting of tetrahydrofuran, dimethylformamide, and N-methylpyrrolidone.

60. The method of any one of claims 57 to 59, wherein the base is selected from the group consisting of triethylamine, N, N-diisopropyl-N-ethylamine, and DABCO.

A method for the preparation of a compound according to any one of claims 1 to 34, wherein a suitable acylating reagent and a suitable amine in a solvent in the presence of a base according to the following P2 reaction scheme: Processing;

Isolating the disubstituted carbamate.

62. The method of claim 61, wherein Lv is Cl.

63. The method of any one of claims 61-62, wherein the solvent is selected from the group consisting of diethyl ether, tetrahydrofuran, and dichloromethane.

64. A method according to any one of claims 61 to 63, wherein the base is selected from the group consisting of trimethylamine, triethylamine, ethyl-diisopropyl-amine, and 1,4-diazabicyclo [2.2.2] octane.

Wherein the base is present as a functional group in one or both of the substituents R ³ and R ^4, thus forming an acidic H-Lv and salts The method according to any one of claims 61 to 64.