Process for preparing 6-substituted-1-(2H)-isoquinolinones and intermediate compound
AssigneeValo Health, Inc.
InventorsPar Holmberg, Sumit Kumar, Matthew James Wathier, Huimin Zhai, Christophe Benelli, Xavier Bon, Boris Camuzat-Dedenis, Fabien Rodier
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Abstract
The invention relates to substituted 6-substituted isoquinoline oxide compounds of formula (V) and to a process for making them. The compounds of formula (V) can be used as intermediates for making 6-substituted-1-(2H)-isoquinolinone compounds of formula (I) The compounds of formula (I) are inhibitors of the enzyme Rho-kinase, or can be used as intermediates in the preparation of further inhibitors of the Rho-kinase enzyme.
Claims27
A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof
- comprising:
- i) a step A, reacting a compound of formula (II) or a pharmaceutically acceptable salt thereof
- with a compound of formula (III) or a pharmaceutically acceptable salt thereof
- to produce a compound of formula (IV) or a pharmaceutically acceptable salt thereof
- ii) a step B, reacting a compound of formula (IV) or a pharmaceutically acceptable salt thereof
- to produce a compound of formula (V) or a pharmaceutically acceptable salt thereof
- iii) a step C, reacting the compound of formula (V) or the pharmaceutically acceptable salt thereof
- in the presence of an electrophilic reagent, a solvent, and a buffer to produce the compound of formula (I) or the pharmaceutically acceptable salt thereof
- wherein
- R1 is H, a C1-C6 alkyl group, or a protecting group that inhibits a nitrogen atom to which the protecting group is attached from reacting with other molecules during a chemical reaction and is selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl)diphenylmethylene (methoxytrityl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group;
- n is 1, 2, 3, or 4;
- R2 is —OH or L1, a leaving group that is capable of being substituted by a nucleophile and is selected from the group consisting of fluoride (—F), chloride (—Cl), bromide (—Br), iodide (—I), p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (CF3SO3—);
- R3 is —OH or L2, a leaving group that is capable of being substituted by a nucleophile;
- and is selected form the group consisting of fluoride (—F), chloride (—Cl), bromide (—Br), iodide (—I), p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (CF3SO3—);
- and
- R4 is selected from the group consisting of —OH, —O—, p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (—SO3CF3).
A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof comprising reacting a compound of formula (V) or a pharmaceutically acceptable salt thereof
- in the presence of an electrophilic reagent to produce the compound of formula (I) or the pharmaceutically acceptable salt thereof
- wherein
- R1 is H, a C1-C6 alkyl group, or a protecting group selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl) diphenylmethylene (methoxytrityl, MMT) group, a tert-butyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group;
- nis 1, 2, 3, or 4;
- and
- R4 is selected from the group consisting of-OH,-O, p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (CF3SO3-).
Dependencies are inferred from the claim text.