Process for preparing 6-substituted-1-(2H)-isoquinolinones and intermediate compound
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.
1 . 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
R 1 is H, a C 1 -C 6 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;
R 2 is —OH or L 1 , 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 (CF 3 SO 3 —);
R 3 is —OH or L 2 , 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 (CF 3 SO 3 —); and
R 4 is selected from the group consisting of —OH, —O—, p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (—SO 3 CF 3 ).
2 . The process of claim 1 , wherein the C 1 -C 6 alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl;
wherein n is 1, 2, or 3;
wherein L 1 is selected from the group consisting of chloride (—Cl), bromide (—Br), iodide (—I), p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (CF 3 SO 3 —); and
wherein L 2 is selected from the group consisting of chloride (—Cl), bromide (—Br), iodide (—I), p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (CF 3 SO 3 —).
3 . The process of claim 1 , wherein R 1 is 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;
wherein n is 2 or 3;
wherein R 2 is L 1 and R 3 is —OH, or R 2 is —OH and R 3 is L 2 ;
wherein L 1 is selected from the group consisting of chloride (—Cl), bromide (—Br), iodide (—I), p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (CF 3 SO 3 —); and
wherein L 2 is selected from the group consisting of chloride (—Cl), bromide (—Br), iodide (—I), p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (CF 3 SO 3 —).
4 . The process of claim 1 , wherein R 1 is a tert-butyloxycarbonyl (BOC) group; n is 3; and
wherein R 2 is methanesulfonate (-OMs); or
wherein R 2 is —OH; and wherein L 2 is chloride (—Cl), bromide (—Br), or iodide (—I).
5 . The process of claim 1 , wherein step A is carried out from about 0° C. to about 150° C.; and wherein step B is carried out from about −10° C. to about 50° C. or from about 25° C. to about 150° C.
6 . The process of claim 1 , wherein 1 to 5 molar equivalents of the compound of formula (II) or a pharmaceutically acceptable salt thereof relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof are used in step A.
7 . The process of claim 1 , wherein step A is carried out in the presence of a base and a first solvent; and wherein step B is carried out in the presence of an oxidizing agent and a second solvent.
8 . The process of claim 7 , wherein 1 to 5 molar equivalents of the compound of formula (II) or a pharmaceutically acceptable salt thereof relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof are used in step A, and wherein 1 to 7 molar equivalents of base relative to the compound of formula (III) or a pharmaceutically acceptable salt thereof are used in step A.
9 . The process of claim 7 , wherein 1 to 10 molar b equivalents of oxidizing agent relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof are used in step B.
10 . The process of claim 1 , wherein step A is carried out in the presence of a base and a first solvent; and wherein step B is carried out in the presence of an oxidizing agent, a catalyst, and a second solvent.
11 . The process of claim 10 , wherein 1 to 10 molar equivalents of oxidizing agent relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof are used in step B, and wherein 0.001 to 1 molar equivalents of catalyst relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof are used in step B.
12 . The process of claim 1 , wherein step A is carried out in the presence of a base and a first solvent; and wherein step B is carried out in the presence of an oxidizing agent, a catalyst, a base, and a second solvent.
13 . The process of claim 12 , wherein 1 to 10 molar equivalents of oxidizing agent relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof are used in step B, wherein 0.001 to 1 molar equivalents of catalyst relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof are used in step B, and wherein 1 to 10 molar equivalents of base relative to the compound of formula (IV) or a pharmaceutically acceptable salt thereof are used in step B.
14 . 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
R 1 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
R 4 is selected from the group consisting of-OH,-O, p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (CF 3 SO 3 -).
15 . The process of claim 14 , wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a lactam form and/or in a lactim form.
16 . The process of claim 14 , wherein R 1 is H; a C1-C6 alkyl group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl; or a protecting group selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl) diphenylmethylene (methoxytrityl, MMT) group, a tert-buyloxycarbonyl (BOC) group, and a p-toluenesulfonyl (tosyl, Ts) group;
wherein n is 1, 2, or 3; and
R 4 is selected from the group consisting of-OH,-O, p-toluenesulfonate (-OTs), methanesulfonate (-OMs), and trifluoromethanesulfonate (CF 3 SO 3 -).
17 . The process of claim 14 , wherein reacting the compound of formula (V) or the pharmaceutically acceptable salt thereof to produce the compound of formula (I) or the pharmaceutically acceptable salt thereof is carried out at a temperature of from about-10° C. to about 100° C.
18 . The process of claim 14 , wherein reacting the compound of formula (V) or the pharmaceutically acceptable salt thereof to produce the compound of formula (I) or the pharmaceutically acceptable salt thereof is carried out in the presence of an electrophilic reagent, a solvent, and a base.
19 . The process of claim 18 , wherein 0.05 to 10 molar equivalents of electrophilic reagent relative to the compound of formula (V) or the pharmaceutically acceptable salt thereof are used, and wherein 0.1 to 10 molar equivalents of base relative to the compound of formula (V) or the pharmaceutically acceptable salt thereof are used.
20 . The process of claim 14 , wherein reacting the compound of formula (V) or the pharmaceutically acceptable salt thereof to produce the compound of formula (I) or the pharmaceutically acceptable salt thereof is carried out in the presence of an electrophilic reagent, a solvent, and a buffer.
21 . The process of claim 20 , wherein 0.05 to 10 molar equivalents of electrophilic reagent relative to the compound of formula (V) or the pharmaceutically acceptable salt thereof are used, and wherein 0.1 to 10 molar equivalents of buffer relative to the compound of formula (V) or the pharmaceutically acceptable salt thereof are used.
22 . The process of claim 20 , wherein the buffer is selected form the group consisting of sodium acetate-acetic acid buffer, H 3 PO 4 -Na 2 HPO 4 buffer, Na 2 HPO 4 -NaH 2 PO 4 buffer, imidazole-HCl buffer, H 3 PO 4 -triethylamine (TEA) buffer, citric acid-triethylamine (TEA) buffer, citric acid-tris (hydroxymethyl) aminomethane (TRIS) buffer, and 3-(N-morpholino)-propanesulfonic acid (MOPS)-triethylamine (TEA) buffer.
23 . The process of claim 14 , further comprising a deprotection step D of reacting a compound of formula (I) or a pharmaceutically acceptable salt thereof
wherein R 1 is a protecting agent selected from the group consisting of a trityl (triphenylmethyl, Tr) group, a (4-methoxyphenyl) diphenylmethylene (methoxytrityl, MMT) group, a tert-buyloxycarbonyl (BOC) group, and a p -toluenesulfonyl (tosyl, Ts) group; and n is 1, 2, 3, or 4;
with a deprotection reagent to produce a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R 1 is H and n is 1, 2, 3, or 4; and
wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof wherein R 1 is H is in a lactam form and/or in a lactim form.
24 . The process of claim 23 , wherein the deprotection reagent is selected from the group consisting of acyl chloride, acyl bromide, acyl iodide, acetic anhydride, formic anhydride, acetic formic anhydride, trifluoroacetic anhydride, trimethylacetic anhydride, hexanoic anhydride, benzoic anhydride, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and mixtures thereof.
25 . The process of claim 23 , wherein step D produces a monohydrochloride salt or a dihydrochloride salt of the compound of formula (I), and wherein the monohydrochoride salt or the dihydrochloride salt of the compound of formula (I) is in a lactam form and/or in a lactim form.
26 . The process of claim 14 , wherein the process produces a monohydrochloride salt or a dihydrochloride salt of the compound of formula (I), and wherein the monohydrochloride salt or the dihydrochloride salt of the compound of formula (I) is in a lactam form and/or in a lactim form.
27 . The process of claim 23 , wherein 1 to 20 molar equivalents of deprotection reagent relative to the compound of formula (I) or the pharmaceutically acceptable salt thereof wherein R 1 is a protecting group are used in step D.