Benzoxazepine compounds, their preparation and use
View Patent ↗The invention provides a novel benzoxazepine compound of the general formula (I): wherein R 1 and R 2 are as defined in the specification; or a stereoisomer, a geometric isomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a polymorph thereof; a process for its preparation; and a pharmaceutical composition including an effective amount of the compound. The compounds are useful in the treatment of insulin resistance and clinical conditions associated therewith.
1. A compound of formula (I),
wherein:
-------- (dotted line) represents an optional bond;
R 1 is:
where:
R 3 and R 4 are, independently of each other:
hydrogen; hydroxyl; alkoxy; C 1 -C 4 alkyl; amino; or aryl;
R 5 , R 6 and R 7 are, independently of each other:
hydrogen; C 1 -C 4 alkyl; or aryl;
n is 0, 1 or 2; and
the arrows indicate the point of attachment of R 1 group;
R 2 is:
mono or bicyclic heteroaryl, containing one nitrogen and optionally another heteroatom selected from nitrogen, sulphur or oxygen;
which may be unsubstituted or substituted with R 8 , wherein R 8 is:
hydrogen; hydroxyl; alkoxy; C 1 -C 4 alkyl; halogen; amino; or aryl; and
a stereoisomer, geometric isomer or pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein
R 1 is:
where:
R 3 and R 4 are, independently of each other:
hydrogen; hydroxyl; alkoxy; C 1 -C 4 alkyl; amino; or aryl;
R 5 and R 6 are, independently of each other:
hydrogen; C 1 -C 4 alkyl; or aryl;
n is 0, 1 or 2;
the arrows indicate the point of attachment of R 1 group; and
a stereoisomer, geometric isomer or pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 , wherein:
R 1 is:
where:
R 3 and R 4 are, independently of each other:
hydroxyl or alkoxy;
R 5 is:
hydrogen; C 1 -C 4 alkyl; or aryl;
n is 0, 1 or 2;
the arrows indicate the point of attachment of R 1 group; and
a stereoisomer, geometric isomer or pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 , wherein
R 1 is:
where:
R 3 and R 4 are, independently of each other:
hydroxyl or alkoxy;
n is 0, 1 or 2;
the arrow indicates the point of attachment of R 1 group; and
a stereoisomer, geometric isomer or pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 , wherein
R 1 is:
where:
R 7 is:
hydrogen; C 1 -C 4 alkyl; or aryl;
the arrows indicate the point of attachment of R 1 group; and
a stereoisomer, geometric isomer or pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 , wherein
R 1 is:
where:
R 7 is:
hydrogen or C 1 -C 4 alkyl;
the arrow indicates the point of attachment of R 1 group; and
a stereoisomer, geometric isomer or pharmaceutically acceptable salt thereof.
7. A compound according to claim 1 , wherein:
R 2 is heteroaryl selected from:
where:
R 8 is:
hydrogen; hydroxyl; alkoxy; C 1 -C 4 alkyl; halogen; amino; or aryl;
the arrows indicate the point of attachment of R 2 group to the benzoxazepine core; and
a stereoisomer, geometric isomer, or pharmaceutically acceptable salt thereof.
8. The compound according to claim 7 , wherein
R 2 is heteroaryl selected from:
where:
R 8 is:
hydrogen; hydroxyl; alkoxy; C 1 -C 4 alkyl; halogen; amino; or aryl;
the arrows indicate the point of attachment of R 2 group to the benzoxazepine core; and
a stereoisomer, geometric isomer or pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 , wherein
R 1 is:
R 3 and R 4 are, independently of each other:
hydroxyl or alkoxy;
R 5 is:
hydrogen; C 1 -C 4 alkyl; or aryl;
n is 0, 1 or 2;
R 2 is heteroaryl selected from:
where:
R 8 is:
hydrogen; hydroxyl; alkoxy; C 1 -C 4 alkyl; halogen; amino; or aryl;
the arrows indicate the point of attachment of R 2 group to the benzoxazepine core; and
a stereoisomer, geometric isomer or pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 , wherein
R 1 is:
where:
R 7 is:
hydrogen or C 1 -C 4 alkyl;
the arrow indicates the point of attachment of R 1 group;
R 2 is heteroaryl selected from:
where:
R 8 is:
hydrogen; C 1 -C 4 alkyl; or halogen;
the arrows indicate the point of attachment of R 2 group to the benzoxazepine core; and
a stereoisomer, geometric isomer or pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 , wherein the optional double bond (--------) is absent.
12. The compound according to claim 1 , wherein the compound is selected from:
2-(4-pyridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethyl)-malonic acid dimethyl ester,
2-(4-pyridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-yl)-methylene)-malonic acid dimethyl ester,
5-(4-pyridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethyl)-thiazolidine-2,4-dione,
5-(4-pyridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethylene)-thiazolidine-2,4-dione,
5-(4-benzooxazol-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethyl)-thiazolidine-2,4-dione,
5-(4-benzooxazol-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethylene)-thiazolidine-2,4-dione,
5-(4-pyridine-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethyl)-thiazolidine-2,4-dione maleate; or
5 -(4-pyridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethylene)-thiazolidine-2,4-dione maleate; or
a stereoisomer, geometric isomer or pharmaceutically acceptable salt thereof.
13. A process for the preparation of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof,
wherein:
-------- (dotted line) represents an optional bond; and
R 1 and R 2 are as defined in claim 1 ,
which process comprises the steps of:
a) chloromethylation of compound of formula (2), wherein R 2 is as defined in claim 1 , with formaldehyde in presence of hydrochloric acid and a Lewis acid at a temperature in the range of 10° C. to 50° C. for 24 to 72 hours to give compound of formula (3), wherein R 2 is as defined in claim 1 ;
b) cyclisation of compound of formula (3), wherein R 2 is as defined in claim 1 , in the presence of potassium iodide and/or potassium fluoride, optionally in the presence of a base selected from sodium carbonate, potassium carbonate and potassium bicarbonate, in DMF, dioxane or THF, at a temperature in the range of 50° C. to 150° C. from 0.5 to 5 hours to give compound of formula (II), wherein R 2 is as defined in claim 1 ;
c) reaction of compound of formula (II) with R 1 —H, wherein R 1 is as defined in claim 1 , either (i) in the presence of a Lewis acid catalyst in a solvent selected from chloroform, carbon tetrachloride, tetrahydrofuran, ether and dioxane, or in a mixture of two or more of these solvents, in presence of pyridine, at a temperature in the range of 0° C. to ambient temperature, for 2 to 24 hours; or (ii) in the presence of piperidinium acetate in toluene, refluxed in a Dean Stark apparatus to give compound of formula (I), wherein R 1 and R 2 are as defined in claim 1 and the optional double bond is present;
d) optionally reducing the double bond of compound of formula (I) obtained in step (c) with Al-amalgam in a solvent selected from dioxane or 1,2-dimethoxyethane at a temperature in the range of −10° C. to 15° C. for 2 to 6 hours, or by catalytic hydrogenation, to give compound of formula (I), wherein R 1 and R 2 are as defined in claim 1 and ----- represents no bond;
e) optionally converting compound of formula (I) wherein R 1 and R 2 are as defined in claim 1 , into a pharmaceutically acceptable salt.
14. The process according to claim 13 , wherein the Lewis acid is zinc chloride, ferric chloride or aluminium chloride.
15. The process according to claim 13 , wherein catalytic hydrogenation is carried out in presence of gaseous hydrogen and a catalyst selected from Pd—C, Rh—C and Pt—C in a solvent selected from dioxane, acetic acid, ethyl acetate, methanol and ethanol, at a pressure between atmospheric pressure and 40 psi, at ambient temperature, for 6 to 24 hours.
16. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
17. A method for the treatment of insulin resistance or conditions associated with insulin resistance, comprising administering to a human or non-human mammal in need thereof, a therapeutically effective amount of a compound of the formula (I), as claimed in claim 1 , or a stereoisomer, geometric isomer, or pharmaceutically acceptable salt thereof, wherein the conditions associated with insulin resistance comprise type 2 diabetes mellitus, lipid and carbohydrate metabolism disorders, dyslipidemia, hyperinsulinemia, glucose intolerance, or obesity.
18. The method according to claim 17 , wherein the condition associated with insulin resistance comprises type 2 diabetes mellitus.