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1. CA2509249 - PROCEDE RELATIF A L'ELABORATION DE COMPOSES AMINOCYANOPYRIDINE TRICYCLIQUES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]
WHAT IS CLAIMED IS:
1. A method of making a tricyclic aminocyanopyridine MK-2 inhibiting compound, the method comprising: reacting a substituted benzaldehyde having the structure: with a tricarbonitrile having the structure: to form an aminocyanopyridine compound having the structure: wherein:
Z is selected from the group consisting of -OH, -SH, and -NR a Y;
R a is selected from the group consisting of alkyl, aryl, and heteroaryl;
Y is a protecting group for nitrogen that is selected from the group consisting of benzyl, allyl, alkyl carbamates and benzyl carbamate;
G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, it is unsubstituted; when G is sulfur, it is either unsubstituted or is substituted with one or two oxo groups;
when G is nitrogen, is it substituted with C1-C4 alkyl;
R b is selected from the group consisting of furyl and -NH-R2;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties; and
R5, R6, R7 and R8 are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, halo, alkyl, alkenyl, alkylyl, arylalkyl, alkylaryl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylamino, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, alkylcarboxyalkoxy, pyrrolidylethoxy, hydroxyalkoxy, and alkylcarboxy, where R6 and R7 are such that they optionally join to form a six membered heterocyclic ring.
2. The method according to claim 1, wherein:
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties;
R5 is selected from the group consisting of hydrogen, alkoxy, halo, alkyl, alkenyl, alkylyl, arylalkyl, or alkylaryl;
R6 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, amino; alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylalkyl, alkylaryl, or arylamino;
R7 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, and alkylcarboxyalkoxy; where the R6 and R7 groups can join to form a six membered heterocyclic ring; and
R8 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxyalkoxy, pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl.
3. The method according to claim 1, wherein the reacting step comprises heating the substituted benzaldehyde and the tricarbonitrile in a mixture of ethanol and acetic acid.
4. The method according to claim 3, wherein the mixture is heated to reflux temperature at atmospheric pressure.
5. The method according to claim 4, further comprising recovering the aminocyanopyridine compound.
6. The method according to claim 5, wherein the recovering step comprises concentrating the reaction product of the substituted benzaldehyde and the tricarbonitrile under vacuum; mixing the concentrated reaction product with trifluoroacetic acid; adding triethylsilane to the mixture of concentrated reaction product and trifluoroacetic acid; adding dichloromethane to the mixture of concentrated reaction product and trifluoroacetic acid; and collecting solids comprising the aminocyanopyridine compound.
7. The method according to claim 6, wherein the triethylsilane is added to the concentrated reaction product while the mixture is being stirred at 0°C for about 1 hour.
8. The method according to claim 6, wherein the solids are collected-by filtration-and further comprising washing the solids with dichloromethane and ether.
9. The method according to claim 1, wherein the substituted benzaldehyde comprises salicaldehyde and the tricarbonitrile comprises 2amino-1-propene-1,1,3-tricarbonitrile.
10, The method according to claim 1, wherein Y comprises tertbutylcarbamate.
11, A method of making a tricyclic aminocyanopyridine MK-2 inhibiting compound, the method comprising: reacting a substituted benzaldehyde having the structure: with a tricarbonitrile having the structure: to form an aminocyanopyridine compound having the structure: wherein:
Z is selected from the group consisting of -OH, -SH, and -NR a Y;
R a is selected from the group consisting of alkyl, aryl, and heteroaryl;
Y is a protecting group for nitrogen that is selected from the group consisting of benzyl, allyl, alkyl carbamates and benzyl carbamate;
G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, it is unsubstituted; when G is sulfur, it is either unsubstituted or is substituted with one or two oxo groups; when G is nitrogen, it is substituted with C1-C4 alkyl;
R b is selected from the group consisting of furyl and -NH-R2;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties; and
R5, R6, R7 and R8 are each independently selected from the group consisting of: hydrogen, hydroxy, amino, halo, nitro, branched or unbranched C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C1-C6 alkoxy, hydroxy C1-C6 alkyl, hydroxy C1-C6 alkoxy, C1-C6 alkoxy C1 C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C2-C6 alkenoxy, branched or unbranched amino C1-C6 alkyl, diamino C2-C6 alkyl, C1 C6 alkylamino C1-C6 alkyl, C1-C6 alkylamino, di-( C1-C6 alkyl)amino, C1-C4 alkoxyarylamino, C1-C4 alkoxyalkylamino, amino C1-C6 alkoxy, di-(C1-C4 alkylamino, C2-C6 alkoxy, di-(C1-C6 alkyl)amino C1-C6 alkyl, C1-C6 alkylamino C1 -C6 alkoxy, halo C1-C6 alkoxy, dihalo C1-C6 alkoxy, trihalo C1 C6 alkoxy, cyano C1-C6 alkyl, dicyano C1-C6 alkyl, cyano C1-C6 alkoxy, dicyano C1-C6 alkoxy, carbamyl C1-C4 alkoxy, heterocyclyl C1-C4 alkoxy, heteroaryrl C1-C4 alkoxy, sulfo, sulfamyl, C1-C4 alkylaminosulfonyl, hydroxy
C1-C4 alkylaminosulfonyl; di-(C1-C4-alkyl)aminosulfonyl,-C1-C4-alkylthio, C1 C4 alkylsulfonyl, C1-C4 alkylsulfinyl,
aryl, aryl C1-C6 alkyl, heterocyclyl C1-C6 alkyl, heteroaryl C1-C6 alkyl, heterocyclyl C1-C6 alkoxy, heteroaryl C1-C6 alkoxy, aryl C1-C6 alkoxy, where the aryl ring can be substituted or unsubstituted, and, if substituted, the substituent group is selected from one or more of the group consisting of C1-C6 alkyl, halo, amino, and C1-C6 alkoxy, substituted or unsubstituted C3-C6 cyclyl, C3-C6 heterocyclyl, and, if substituted, the substituent group is selected from one or more of the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, amino, and where the
C3-C6 heterocyclyl ring contains O, S, or N, branched or unbranched C1-C6 alkoxycarbonyl C1-C6 alkoxy, and carboxy, carboxy C1-C6 alkoxy, carboxy C1-C6 alkyl, hydroxy C1-C4 alkoxycarbonyl, C1-C4 alkoxycarbonyl.
12. The method according to claim 11, wherein:
R1 is selected from the group consisting of hydrogen, branched or unbranched alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, arylalkyl, carboxy, carboxyalkyl, hydroxyalkyl, alkylcarboxy, aryl, amino, aminoalkyl, alkylamino, halo, alkylaminoalkyl, alkoxy, alkoxyalkyl, monocyclyl, bicyclyl, polycyclyl, and heterocyclyl;
R2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl;
R3 is selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties;
R4 is selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, where substituents, if any, comprise halo moieties;
R5 is selected from the group consisting of hydrogen, alkoxy, halo, -alkyl,-alkenyl, alkylyl; arylalkyl, or alkylaryl;
R6 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino,
alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylalkyl, alkylaryl, or arylamino;
R7 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, and alkylcarboxyalkoxy; where the R6 and R7 groups can join to form a six membered heterocyclic ring;
R8 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclylalkoxy, carboxyalkoxy, pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl; and
G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, R9 and R10 are absent; when G is sulfur, each of R9 and R10 is optionally absent or is oxo; when G is nitrogen, R9 is absent, and R10 is C1-C4-alkyl.
13. The method according to claim 11, wherein:
R1 is selected from the group consisting of hydrogen, ethyl, dimethylaminoethyl, butyl, propyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl;
R2 is selected from the group consisting of hydrogen, hydroxyethyl, propyl, ethyl, methyl, 4-methoxyphenyl, ethoxyethyl, aminoethyl, phenylmethyl, dimethylaminoethyl, phthaloaminoethyl, butyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl;
R3 is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl.
R4 is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl;
R5 is selected from the group consisting of hydrogen, hydroxy, methoxy, bromo, and 2-pyridomethyl;
R6 is selected from the group consisting of hydrogen, hydroxy, methoxy, amino, carboxy, diaminoethoxy, bromo, propoxy, isobutylcarboxymethoxy, dimethylamino, nitro, phenyl, chloro, pyridylmethyl, and fluoro;
R7 is selected from the group consisting of hydrogen, hydroxy, methoxy, hydroxyethoxy, ethoxyethoxy, ethoxy, aminoethoxy, morpholinoethoxy, carboxymethoxy, N-pyrrolidylethoxy, dimethylaminoethoxy, pyridylmethyl, 2-propenoxy, and isobutylcarboxymethoxy, where the R6 and R7 groups can join to form a six membered heterocyclic ring;
R8 is selected from the group consisting of hydrogen, hydroxy, fluoro, methoxy, nitro, amino, pyrrolidylethoxy, carboxymethoxy, methyl, hydroxyethoxy, aminoethoxy, 4-pyridylmethoxy, isobutyl, ethylcarboxy, dimethylaminoethoxy, carboxy, bromo, and pyrridylmethyl; and
G is selected from the group consisting of oxygen, sulfur, and nitrogen; when G is oxygen, R9 and R10 are absent; when G is sulfur, each of R9 and R10 is optionally absent or is oxo; when G is nitrogen, R9 is absent and R10 is -CH3.
14. The method according to claim 11, wherein:
R1 is selected from the group consisting of hydrogen, and C1-C2 alky;
R2 is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy C1-C2 alkyl, C1-C2 alkoxyphenyl, C1-C2 alkoxy C1-C2 alkyl, amino
C1-C2 alkyl, phenyl C1-C2 alkyl, and di C1-C2 alkylamino C1-C2 alkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, dicyano C1-C2 alkyl, and halophenyl;
R5 is selected from the group consisting of hydrogen, and hydroxy;
R6 is selected from the group consisting of hydrogen, hydroxy, C1 C3 alkoxy; amino,nitro, carboxy, diamino C1-C2-alkoxy, halo, propenoxy, iso C3 - C4 alkylcarboxy C1 - C2 alkoxy, di C1 - C2 alkylamino, and phenyl;
R7 is selected from the group consisting of hydrogen, hydroxy, C1 C3 alkoxy, hydroxy C1 - C2 alkoxy, C1 - C2 alkoxy C1 - C2 alkoxy, amino C1
- C2 alkoxy, morpholino C1 - C2 alkoxy, carboxyl C1 - C2 alkoxy, pyrrolidyl
C1 - C2 alkoxy, di C1 - C2 alkylamino C1 - C2 alkoxy, pyrrolidyl C1 - C2 alkyl, iso C3 - C4 alkylcarboxy C1 - C2 alkoxy, and 2-propenoxy, where the R6 and R7 groups can join to form a six membered heterocyclic ring;
R8 is selected from the group consisting of hydrogen, hydroxy, halo,
C1-C2 alkyl, C1-C2 alkoxy, nitro, amino, pyrrolidyl C1-C2 alkoxy, carboxy C1 C2 alkoxy, hydroxy C1-C2 alkoxy, and amino C1-C2 alkoxy; and
G is selected from the group consisting of oxygen and sulfur; when G is sulfur, each of R9 and R10 is optionally absent or is oxo; when G is oxygen, R9 and R10 are absent.
15. The method according to claim 11, wherein:
R1 is hydrogen;
R2 is selected from the group consisting of hydrogen, C1 - C3 alkyl, hydroxy G1 - C2 alkyl, C1 - C2 alkoxyphenyl, C1 - C2 alkoxy C1 - C2 alkyl, amino C1 - C2 alkyl, phenyl C1 - C2 alkyl, and di C1 - C2 alkylamino C1 - C2 alkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, and dicyano C1 - C2 alkyl.
R5 is selected from the group consisting of hydrogen, and hydroxy;
R6 is selected from the group consisting of hydrogen, hydroxy, C1 C2 alkoxy, amino, carboxy, nitro, diamino C1-C2 alkoxy, halo, 2-propenoxy, iso C3-C4 alkylcarboxy C1-C2 alkoxy, di C1-C2 alkylamino, and phenyl;
R7 is selected from the group consisting of hydrogen, hydroxy, C1 C2 alkoxy, hydroxy C1-C2 alkoxy, C1-C2 alkoxy C1-C2 alkoxy, amino C1-C2 alkoxy, morpholino C1-C2 alkoxy, carboxyl C1-C2 alkoxy, pyrrolidyl C1-C2 alkoxy, di C1-C2 alkylamino C1-C2 alkoxy, pyrrolidyl C1-C2 alkyl, iso C3-C4 alkylcarboxy-C1-C2 -alkoxy, and 2-propenoxy; wherein the R6 and R7 groups can join to form a six membered heterocyclic ring;
R8 is selected from the group consisting of hydrogen, hydroxy, halo,
C1-C2 alkoxy, nitro, amino, pyrrolidyl C1-C2 alkoxy, and carboxy C1-C2 alkoxy; and
G is selected from the group consisting of oxygen and sulfur; when G is sulfur, each of R9 and R10 is optionally absent or is oxo; when G is oxygen, R9 and R10 are absent.
16. The method according to claim 11, wherein:
R1 is hydrogen;
R2 is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy C1-C2 alkyl, C1-C2 alkoxyphenyl, C1-C2 alkoxy C1-C2 alkyl, amino
C1-C2 alkyl, and phenyl C1-C2 alkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, and dicyano C1-C2 alkyl.
R5 is selected from the group consisting of hydrogen, and hydroxy;
R6 is selected from the group consisting of hydrogen, hydroxy, C1 C2 alkoxy, amino, carboxy, diamino C1-C2 alkoxy, halo, 2-propenoxy; iso
C3-C4 alkylcarboxy C1-C2 alkoxy, and di C1-C2 alkylamino;
R7 is selected from the group consisting of hydrogen, hydroxy, C1 C2 alkoxy, hydroxy C1-C2 alkoxy, C1-C2 alkoxy C1-C2 alkoxy, amino C1-C2 alkoxy, morpholino C1-C2 alkoxy, carboxyl C1-C2 alkoxy, pyrrolidyl C1-C2 alkoxy, di C1-C2 alkylamino C1-C2 alkoxy, pyrrolidyl C1-C2 alkyl, iso C3-C4 alkylcarboxy C1-C2 alkoxy, and 2-propenoxy; where the R6 and R7 groups can join to form a six membered heterocyclic ring;
R8 is selected from the group consisting of hydrogen, hydroxy, halo,
C1-C2 alkoxy, nitro, amino, and pyrrolidyl C1-C2 alkoxy; and
G is selected from the group consisting of oxygen and sulfur; when G is sulfur, each of R9 and R10 is optionally absent or is oxo; when G is oxygen, there R9 and R10 are absent.
17. The method according to claim 11, wherein:
R1 is hydrogen;
R2 is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy C1-C2 alkyl, C1-C2 alkoxyphenyl, C1-C2 alkoxy C1-G2 alkyl, and amino C1-C2 alkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, and dicyanoethyl;
R5 is selected from the group consisting of hydrogen, and hydroxy;
R6 is selected from the group consisting of hydrogen, hydroxy, C1 C2 alkoxy, amino, carboxy, diamino C1-C2 alkoxy, halo, 2-propenoxy, iso
C3-C4 alkylcarboxy C1-C2 alkoxy, and di C1-C2 alkylamino;
R7 is selected from the group consisting of hydrogen, hydroxy, C1 C2 alkoxy, hydroxy C1-C2 alkoxy, C1-C2 alkoxy C1-C2 alkoxy, amino C1-C2 alkoxy, morpholino C1-C2 alkoxy, carboxyl C1-C2 alkoxy, pyrrolidyl C1-C2 alkoxy, di C1-C2 alkylamino C1-C2 alkoxy, pyrrolidyl C1-C2 alkyl, iso C3-C4 alkylcarboxy C1-C2 alkoxy, and 2-propenoxy; where the R6 and R7 groups can join to form a six membered heterocyclic ring;
R8 is selected from the group consisting of hydrogen, hydroxy, halo, methoxy, nitro, and amino; and
G is selected from the group consisting of oxygen and sulfur; when G is sulfur, each of R9 and R10 is optionally absent or is oxo; when G is oxygen, R9 and R10 are absent,