Methods of chemical synthesis of substituted 10H-phenothiazine-3,7-diamine compounds

Patent metadata

Field	Value
Publication number	US-10323010-B2
Application number	US-201615746338-A
Country	US
Kind code	B2
Filing date	Jul 20, 2016
Priority date	Jul 20, 2015
Publication date	Jun 18, 2019
Grant date	Jun 18, 2019

Abstract

The present invention pertains generally to the field of chemical synthesis, and more particularly to methods of chemical synthesis which include the step of preparing a substituted 10H-phenothiazine-3,7-diamine compound of Formula (1) by a step of selective alkylation by reductive amination, in which the corresponding unsubstituted diamine of Formula (4) is reacted with aldehyde/ketone, under reductive amination conditions. The present invention also relates to such methods which incorporate additional subsequent and/or preceding steps, for example, to prepare compounds of Formulae (2) and (3) from compounds of Formula (1), and to prepare compounds of Formula (4) from, for example, compounds of Formulae (5), (6), (7), (8), and (9). Compounds of Formula (1), Formula (2), and Formula (3) are useful, for example, in the treatment of diseases of protein aggregation, such as Alzheimer's disease.

First claim

The invention claimed is:

1. A method of synthesis of a compound of Formula (1):

comprising the step of:
reductive amination, in which a compound of Formula (4):

is reacted with aldehyde/ketone and a reductive amination agent,
under reductive amination conditions,
to give the corresponding compound of Formula (1),
wherein a carbonyl group, (O═)C<, of the aldehyde/ketone gives rise to a corresponding nitrogen substituent, —CH<;
wherein:
R 1A is independently a substituent with one point of attachment, wherein the attachment is via a —CH< group; and
R 1B is independently H or a substituent with one point of attachment, wherein the attachment is via a —CH< group;
or
R 1A and R 1B , taken together, form a substituent with two points of attachment, wherein each of the attachments is via a —CH< group;
R 2A is independently a substituent with one point of attachment, wherein the attachment is via a —CH< group; and
R 2B is independently H or a substituent with one point of attachment, wherein the attachment is via a —CH< group;
or
R 2A and R 2B , taken together, form a substituent with two points of attachment, wherein each of the attachments is via a —CH< group;

and wherein:
R 3 is independently —H, —R T3 , —R T3H , —F, —Cl, —Br, —I, —OH, —OR T3 , —NH 2 , —NHR T3 , NR T3 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or C(═O)OR T3 ; wherein each —R T3 is a C 1-10 alkyl group and R T3H is a C 1-10 haloalkyl group; and
R 4 is independently —H, —R T4 , —R T4H , —F, —Cl, —Br, —I, —OH, —OR T4 , —NH 2 , —NHR T4 , —NR T4 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or —C(═O)OR T4 ; wherein each —R T4 is a C 1-10 alkyl group and R T4H is a C 1-10 haloalkyl group;

and wherein:
R 5 is

independently —H, —R T5 , —R T5H , —F, —Cl, —Br, —I, —OH, —OR T5 , —NH 2 , —NHR T5 , —NR T5 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or —C(═O)OR T5 ; wherein each —R T5 is a C 1-10 alkyl group and R T5H is a C 1-10 haloalkyl group; and
R 6 is

independently —H, —R T6 , —R T6H , —F, —Cl, —Br, —I, —OH, —OR T6 , —NH 2 , —NHR T6 , —NR T6 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or —C(═O)OR T6 ; wherein each —R T6 is a C 1-10 alkyl group and R T6H is a C 1-10 haloalkyl group;
and wherein:
R 7 is

independently —H, —R T7 , —R T7H , —F, —Cl, —Br, —I, —OH, —OR T7 , —NH 2 , —NHR T7 , —NR T7 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or —C(═O)OR T7 ; wherein each —R T7 is a C 1-10 alkyl group and R T7H is a C 1-10 haloalkyl group; and
R 8 is

independently —H, —R T8 , —R T8H , —F, —Cl, —Br, —I, —OH, —OR T8 , —NH 2 , NHR T8 , —NR T8 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or —C(═O)OR T8 ; wherein each —R T8 is a C 1-10 alkyl group and R T8H is a C 1-10 haloalkyl group,;
R 4 is

independently —H, —R T4 , —R T4H , —F, —Cl, —Br, —I, —OH, —OR T4 , —NH 2 , —NHR T4 , —NR T4 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or —C(═O)OR T4 ; wherein each —R T4 is a C 1-10 alkyl group and R T4H is a C 1-10 haloalkyl group;
and wherein:
R 5 is

independently —H, —R T5 , —R T5H , —F, —Cl, —Br, —I, —OH, —OR T5 , —NH 2 , —NHR T5 , —NR T5 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or —C(═O)OR T5 ; wherein each —R T5 is a C 1-10 alkyl group and R T5H is a C 1-10 haloalkyl group; and
R 6 is

independently —H, —R T6 , —R T6H , —F, —Cl, —Br, —I, —OH, —OR T6 , —NH 2 , —NHR T6 , —NR T6 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or —C(═O)OR T6 ; wherein each —R T6 is a C 1-10 alkyl group and R T6H is a C 1-10 haloalkyl group;
and wherein:
R 7 is

independently —H, —R T7 , —R T7H , —F, —Cl, —Br, —I, —OH, —OR T7 , —NH 2 , —NHR T7 , —NR T7 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or —C(═O)OR T7 ; wherein each —R T7 is a C 1-10 alkyl group and R T7H is a C 1-10 haloalkyl group; and
R 8 is

independently —H, —R T8 , —R T8H , —F, —Cl, —Br, —I, —OH, —OR T8 , —NH 2 , —NHR T8 , —NR T8 2 , pyrrolidino, piperidino, morpholino, —C(═O)OH, or —C(═O)OR T8 ; wherein each —R T8 is a C 1-10 alkyl group and R T8H is a C 1-10 haloalkyl group.

2. A method according to claim 1 , wherein:
R 1A is —CH(R 1AX )(R 1AY ); and
R 1B is independently —H or —CH(R 1BX )(R 1BY ); or
R 1A and R 1B , taken together, form —CH 2 —R 1AB —CH 2 —;

wherein:
R 1AX is independently —H, C 1-10 alkyl, C 3-6 cycloalkyl, or C 6-10 carboaryl; and
R 1AY is independently —H, C 1-10 alkyl, C 3-6 cycloalkyl, or C 6-10 carboaryl; or
R 1AX and R 1AY , taken together, form C 4-6 alkylene;

and wherein:
R 1BX is independently —H, C 1-10 alkyl, C 3-6 cycloalkyl, or C 6-10 carboaryl; and
R 1BY is independently —H, C 1-10 alkyl, C 3-6 cycloalkyl, or C 6-10 carboaryl; or
R 1BX and R 1BY , taken together, form C 4-6 alkylene;

and wherein:
R 1AB is C 2-4 alkylene;

and wherein:
R 2A is —CH(R 2AX )(R 2AY ); and
R 2B is independently —H or —CH(R 2BX )(R 2BY ); or
R 2A and R 2B , taken together, form —CH 2 —R 2AB —CH 2 —;

wherein:
R 2AX is independently —H, C 1-10 alkyl, C 3-6 cycloalkyl, or C 6-10 carboaryl; and
R 2AY is independently —H, C 1-10 alkyl, C 3-6 cycloalkyl, or C 6-10 carboaryl; or
R 2AX and R 2AY , taken together, form C 4-6 alkylene;

and wherein:
R 2BX is independently —H, C 1-10 alkyl, C 3-6 cycloalkyl, or C 6-10 carboaryl; and
R 2BY is independently —H, C 1-10 alkyl, C 3-6 cycloalkyl, or C 6-10 carboaryl; or
R 2BX and R 2BY , taken together, form C 4-6 alkylene;

and wherein:
R 2AB is C 2-4 alkylene;

wherein:
if (a):
R 1A is —CH(R 1AX )(R 1AY ); and
R 1B is independently —H or —CH(R 1BX )(R 1BY );
R 2A is —CH(R 2AX )(R 2AY ); and
R 2B is independently —H or —CH(R 2BX )(R 2BY );

then the aldehyde/ketone comprises:
R 1AX —C(═O)—R 1AY , and
R 2AX —C(═O)—R 2AY ;

and further if R 1B is other than —H, then the aldehyde/ketone further comprises:
R 1BX —C(═O)—R 1BY ;

and further if R 2B is other than —H, then the aldehyde/ketone further comprises:
R 2BX —C(═O)—R 2BY ;

and if (b):
R 1A and R 1B , taken together, form —CH 2 —R 1AB —CH 2 —; and
R 2A and R 2B , taken together, form —CH 2 —R 2AB —CH 2 —;

then the aldehyde/ketone comprises:
(O═)CH—R 1AB —CH(═O); and
(O═)CH—R 2AB —CH(═O).

3. A method according to claim 2 , wherein:
R 1A is —CH(R 1AX )(R 1AY );
R 1B is —CH(R 1BX )(R 1BY );
R 2A is —CH(R 2AX )(R 2AY ); and
R 2B is —CH(R 2BX )(R 2BY );

and the aldehyde/ketone comprises:
R 1AX —C(═O)—R 1AY ;
R 2AX —C(═O)—R 2AY ;
R 1BX —C(═O)—R 1BY ; and
R 2BX —C(═O)—R 2BY .

4. A method according to claim 3 , wherein:
R 1A and R 2A are the same; and
R 1B and R 2B are the same.

5. A method according to claim 4 , wherein:
R 1A and R 2A are the same;
R 1B and R 2B are the same; and
R 1A and R 1B are the same.

6. A method according to claim 2 , wherein:
R 1A is —CH 3 ;
R 1B is —CH 3 ;
R 2A is —CH 3 ; and
R 2B is —CH 3 ;

and the aldehyde/ketone comprises formaldehyde.

7. A method according to claim 3 , wherein the amount of aldehyde/ketone is about 4 equivalents.

8. A method according to claim 1 , wherein:
R 3 is independently H, C 1-4 alkyl, or C 1-4 haloalkyl;
R 4 is independently H, C 1-4 alkyl, or C 1-4 haloalkyl;
R 5 is independently H, C 1-4 alkyl, o

Assignees

• Wista Lab Ltd

Inventors

• Storey John Mervyn David
• Larch Christopher Paul
• Kemp Steven John
• Clunas Scott
• Nicoll Sarah Louise
• Gibbard Helen Sarah
• Simpson Michael
• Sinclair James Peter
• Marshall Colin

Classifications

• C07D279/20 Primary

  with hydrogen atoms directly attached to the ring nitrogen atom · CPC title