METHYLLACTAM RING COMPOUND AND PHARMACEUTICAL USE THEREOF
An object of the present invention is to provide a methyllactam ring compound that has an SGLT1 inhibitory activity and is useful for a drug, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising it, and pharmaceutical use thereof. A compound of Formula [I]: or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising it, and pharmaceutical use thereof is provided.
1 - 11 . (canceled)
12 . A method of preparing a compound of Formula [17]:
the method comprising a step C1-1, comprising reacting a compound of Formula [15]:
with a compound of Formula [16]:
in a solvent and in the presence of a base, wherein
L 3 is a leaving group;
P C1 and P C2 are each independently a carboxyl protecting group; and
each R 3 is independently methoxy or ethoxy.
13 . The method of claim 12 , wherein
the base of step C1-1 is selected from the group consisting of potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, potassium hexamethyldisilazane, potassium carbonate, cesium carbonate, and sodium hydride;
the solvent of step C1-1 is selected from the group consisting of an ether solvent, an alcohol solvent, and a polar solvent; and
the reacting of step C1-1 is carried out at a temperature from −78° C. to 100° C.
14 . A method of preparing compound of Formula [10]:
or salt thereof, the method comprising a step B1-4, comprising removing a P N2 group from a compound of Formula [9]:
in a solvent, wherein
each P N2 group is an amine protecting group or the two P N2 groups are combined with the nitrogen atom to which they are attached to form 2,5-dimethylpyrrole; and
L 1 is a leaving group.
15 . The method of claim 14 , wherein
the removing of step B1-4 is carried out by hydroxylamine or hydroxylamine hydrochloride;
the solvent of step B1-4 is selected from the group consisting of an alcohol, water, or a mixture thereof; and
the removing of step B1-4 is carried out at a temperature from 40° C. to 150° C.
16 . The method of claim 14 , wherein the compound of Formula [9] is obtained by a step B1-3, comprising introducing L 1 into a compound of Formula [8]:
in a solvent and in the presence of a base, wherein
each P N2 group is an amine protecting group or the two P N2 groups are combined with the nitrogen atom to which they are attached to form 2,5-dimethylpyrrole.
17 . The method of claim 16 , wherein
the base of step B1-3 is selected from the group consisting of n-butyllithium, lithium diisopropylamide, lithium hexamethyldisilazide, and lithium tetramethylpiperidide;
L 1 is iodine and is introduced by an iodizing agent selected from the group consisting of iodine, iodine monochloride, N-iodosuccinimide, and 1-chloro-2-iodoethane;
the two P N2 groups are combined with nitrogen atom to which they are attached to form 2,5-dimethylpyrrole;
the solvent of step B1-3 is selected from the group consisting of an ether solvent, a hydrocarbon solvent, or a mixture of the foregoing; and
the introducing is carried out at a temperature from −100° C. to 40° C.
18 . A compound selected from the group consisting of:
wherein
each L 1 and L 3 is independently a leaving group;
P C1 and P C2 are each independently a carboxyl protecting group;
each P N2 group is an amine protecting group or the two P N2 groups are combined with the nitrogen atom to which they are attached to form 2,5-dimethylpyrrole; and
each R 3 is independently methoxy or ethoxy.
19 . The compound of claim 18 , wherein
L 1 is chlorine, bromine, or iodine;
L 3 is chlorine or bromine;
P C1 and P C2 are each independently methyl, ethyl, tert-butyl, or benzyl; and
the two P N2 groups are combined with the nitrogen atom to which they are attached to form 2,5-dimethylpyrrole.
20 . A compound of Formula [10], or a salt thereof:
wherein
L 1 is a leaving group.
21 . The compound of claim 20 , or a salt thereof, wherein L 1 is chlorine, bromine, or iodine.