U.S. patent application number 12/211510 was filed with the patent office on 2009-01-29 for benzamide derivatives useful as histone deacetylase inhibitors.
This patent application is currently assigned to ASTRAZENECA AB. Invention is credited to Craig Anthony Roberts, Elaine Sophie Elizabeth Stokes, Michael James Waring.
Application Number | 20090029991 12/211510 |
Document ID | / |
Family ID | 29252435 |
Filed Date | 2009-01-29 |
United States Patent
Application |
20090029991 |
Kind Code |
A1 |
Stokes; Elaine Sophie Elizabeth ;
et al. |
January 29, 2009 |
BENZAMIDE DERIVATIVES USEFUL AS HISTONE DEACETYLASE INHIBITORS
Abstract
The invention concerns a compound of the formula (I)
##STR00001## wherein Ring A is heterocyclyl; m is 0-4 and each
R.sup.1 is a group such as hydroxy, halo, trifluoromethyl and
cyano; R.sup.2 is halo and n is 0-2; and each R.sup.4 is a group
such as hydroxy, halo, trifluoromethyl and cyano; p is 0-4; and
R.sup.3 is amino or hydroxy; or pharmaceutically-acceptable salts
or in-vivo-hydrolysable ester or amide thereof, processes for their
preparation, pharmaceutical compositions containing them and their
use in the treatment of diseases or medical conditions mediated by
histone deacetylase.
Inventors: |
Stokes; Elaine Sophie
Elizabeth; (Macclesfield, GB) ; Roberts; Craig
Anthony; (Macclesfield, GB) ; Waring; Michael
James; (Macclesfield, GB) |
Correspondence
Address: |
ASTRAZENECA R&D BOSTON
35 GATEHOUSE DRIVE
WALTHAM
MA
02451-1215
US
|
Assignee: |
ASTRAZENECA AB
Sodertalje
SE
|
Family ID: |
29252435 |
Appl. No.: |
12/211510 |
Filed: |
September 16, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10509941 |
Oct 1, 2004 |
|
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PCT/GB03/01442 |
Apr 2, 2003 |
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12211510 |
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Current U.S.
Class: |
514/234.2 ;
514/260.1; 544/122; 544/278 |
Current CPC
Class: |
C07D 213/74 20130101;
C07D 277/30 20130101; C07D 401/04 20130101; C07D 241/20 20130101;
C07D 417/06 20130101; C07D 215/12 20130101; A61P 35/00 20180101;
C07D 213/56 20130101; C07D 401/06 20130101; C07D 251/18 20130101;
C07D 403/12 20130101; C07D 409/04 20130101; C07D 495/04 20130101;
C07D 211/34 20130101; C07D 307/54 20130101; C07D 277/24 20130101;
C07D 487/04 20130101; C07D 237/08 20130101; A61P 43/00 20180101;
C07D 295/155 20130101; C07D 405/06 20130101; A61P 7/06 20180101;
A61P 25/14 20180101; C07D 239/26 20130101; C07D 239/42
20130101 |
Class at
Publication: |
514/234.2 ;
544/278; 514/260.1; 544/122 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 495/04 20060101 C07D495/04; A61K 31/519 20060101
A61K031/519 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 5, 2002 |
GB |
0207863.2 |
Dec 21, 2002 |
GB |
0229930.3 |
Claims
1. A compound of the formula (I): ##STR00117## wherein: Ring A is
piperidinyl, wherein nitrogen within the piperidinyl ring can be
optionally substituted by K; R.sup.1 is a substituent on carbon and
is selected from halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2-amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl, aryl, aryloxy,
arylC.sub.1-6alkyl, heterocyclic group, (heterocyclic
group)C.sub.1-6alkyl, or a group (B-E-); wherein R.sup.1, including
group (B-E-), may be optionally substituted on carbon by one or
more W; and wherein if said heterocyclic group contains an --NH--
moiety that nitrogen may be optionally substituted by J; W is halo,
nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2-amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl, or a group (B'-E'-); wherein
W, including group (B'-E'-), may be optionally substituted on
carbon by one or more Y; Y and Z are independently selected from
halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2-amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl or
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; G, J and K are independently
selected from C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.1-8alkanoyl,
C.sub.1-8alkylsulphonyl, C.sub.1-8alkoxycarbonyl, carbamoyl,
N--(C.sub.1-8alkyl)carbamoyl, N,N--(C.sub.1-8alkyl)carbamoyl,
benzyloxycarbonyl, benzoyl, phenylsulphonyl, aryl,
arylC.sub.1-6alkyl or (heterocyclic group)C.sub.1-6alkyl; wherein
G, J and K may be optionally substituted on carbon by one or more
Q; and wherein if said heterocyclic group contains an --NH-- moiety
that nitrogen may be optionally substituted by hydrogen or
C.sub.1-6alkyl; Q is halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2-amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
C.sub.1-6alkoxycarbonylamino, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl, aryl, aryloxy, aryl
C.sub.1-6alkyl, arylC.sub.1-6alkoxy, heterocyclic group,
(heterocyclic group)C.sub.1-6alkyl, (heterocyclic
group)C.sub.1-6alkoxy, or a group (B''-E''-); wherein Q, including
group (B''-E''-), may be optionally substituted on carbon by one or
more Z; B, B' and B'' are independently selected from
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-6alkyl, aryl,
arylC.sub.1-6alkyl, heterocyclic group, (heterocyclic
group)C.sub.1-6alkyl, phenyl or phenylC.sub.1-6alkyl; wherein B, B'
and B'' may be optionally substituted on carbon by one or more D;
and wherein if said heterocyclic group contains an --NH-- moiety
that nitrogen may be optionally substituted by a group selected
from G; E, E' and E'' are independently selected from
--N(R.sup.a)--, --O--, --C(O)O--, --OC(O)--, --C(O)--,
--N(R.sup.a)C(O)--, --N(R.sup.a)C(O)N(R.sup.b)--,
--N(R.sup.a)C(O)O--, --OC(O)N(R.sup.a)--, --C(O)N(R.sup.a)--,
--S(O).sub.r--, --SO.sub.2N(R.sup.a)--, --N(R.sup.a)SO.sub.2--;
wherein R.sup.a and R.sup.b are independently selected from
hydrogen or C.sub.1-6alkyl optionally substituted by one or more F
and r is 0-2; D and F are independently selected from halo, nitro,
cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2-amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl or
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl; m is 0, 1, 2, 3 or 4;
wherein the values of R.sup.1 may be the same or different; R.sup.2
is halo; n is 0, 1 or 2; wherein the values of R.sup.2 may be the
same or different; R.sup.3 is amino or hydroxy; R.sup.4 is halo,
nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, amino,
carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-3alkyl,
C.sub.2-3alkenyl, C.sub.2-3alkynyl, C.sub.1-3alkoxy,
C.sub.1-3alkanoyl, C.sub.1-3alkanoyloxy, N--(C.sub.1-3alkyl)amino,
N,N--(C.sub.1-3alkyl).sub.2-amino, C.sub.1-3alkanoylamino,
N--(C.sub.1-3alkyl)carbamoyl,
N,N--(C.sub.1-3alkyl).sub.2-carbamoyl, C.sub.1-3alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-3alkoxycarbonyl,
N--(C.sub.1-3alkyl)sulphamoyl,
N,N--(C.sub.1-3alkyl).sub.2sulphamoyl; p is 0, 1 or 2; wherein the
values of R.sup.4 may be the same or different; or a
pharmaceutically acceptable salt thereof.
2. A compound of the formula (I) according to claim 1 wherein:
R.sup.1 is a substituent on carbon and is selected from halo,
amino, C.sub.1-6alkyl, C.sub.1-6alkoxy, N--(C.sub.1-6alkyl)amino,
aryl, aryloxy, arylC.sub.1-6alkyl, heterocyclic group,
(heterocyclic group)C.sub.1-6alkyl, or a group (B-E-); wherein
R.sup.1, including group (B-E-), may be optionally substituted on
carbon by one or more W; and wherein if said heterocyclic group
contains an --NH-- moiety that nitrogen may be optionally
substituted by J; W is hydroxy, mercapto, C.sub.1-6alkyl,
C.sub.1-6alkoxy, N,N--(C.sub.1-6alkyl).sub.2-amino or a group
(B'-E'-); wherein W, including group (B'-E'-), may be optionally
substituted on carbon by one or more Y; Y and Z are independently
selected from halo, nitro, cyano, hydroxy, C.sub.1-6alkoxy,
N,N--(C.sub.1-6alkyl).sub.2-amino or C.sub.1-6alkanoylamino; G, J
and K are independently selected from C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.1-8alkanoyl, aryl, arylC.sub.1-6alkyl or
(heterocyclic group)C.sub.1-6alkyl; wherein G, J and K may be
optionally substituted on carbon by one or more Q; and wherein if
said heterocyclic group contains an --NH-- moiety that nitrogen may
be optionally substituted by hydrogen or C.sub.1-6alkyl; Q is
cyano, hydroxy, C.sub.1-6alkoxy, C.sub.1-6alkanoyloxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkoxycarbonylamino, aryl,
aryloxy or a group (B''-E''-); wherein Q, including group
(B''-E''-), may be optionally substituted on carbon by one or more
Z; B, B' and B'' are independently selected from C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, aryl, arylC.sub.1-6alkyl,
heterocyclic group, (heterocyclic group)C.sub.1-6alkyl, phenyl or
phenylC.sub.1-6alkyl; wherein B, B' and B'' may be optionally
substituted on carbon by one or more D; and wherein if said
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from G; E, E' and E''
are independently selected from --N(R.sup.a)--, --O--, --C(O)O--,
--OC(O)--, --C(O)--, --N(R.sup.a)C(O)--,
--N(R.sup.a)C(O)N(R.sup.b)--, --N(R.sup.a)C(O)O--,
--OC(O)N(R.sup.a)--, --C(O)N(R.sup.a)--, --S(O).sub.r--,
--SO.sub.2N(R.sup.a)--, --N(R.sup.a)SO.sub.2--; wherein R.sup.a and
R.sup.b are independently selected from hydrogen or C.sub.1-6alkyl
optionally substituted by one or more F and r is 0-2; D and F are
independently selected from halo, C.sub.1-6alkoxy or
N,N--(C.sub.1-6alkyl).sub.2-amino.
3. A compound of the formula (I) according to claim 1 wherein m is
1.
4. A compound of the formula (I) according to claim 1 wherein
R.sup.2 is fluoro and n is 0 or 1.
5. A compound of the formula (I) according to claim 1 wherein
R.sup.3 is amino.
6. A compound of the formula (I) according to claim 1 wherein p is
0.
7. A compound of formula (I) according to claim 1 wherein: Ring A
is piperidinyl, wherein nitrogen within the piperidinyl ring can be
optionally substituted by K; R.sup.1 is a substituent on carbon and
is selected from halo, amino, C.sub.1-6alkyl, C.sub.1-6alkoxy,
N--(C.sub.1-6alkyl)amino, aryl, aryloxy, arylC.sub.1-6alkyl,
heterocyclic group, (heterocyclic group)C.sub.1-6alkyl, or a group
(B-E-); wherein R.sup.1, including group (B-E-), may be optionally
substituted on carbon by one or more W; and wherein if said
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by J; W is hydroxy, mercapto,
C.sub.1-6alkyl, C.sub.1-6alkoxy, N,N--(C.sub.1-6alkyl).sub.2-amino
or a group (B'-E'-); wherein W, including group (B'-E'-), may be
optionally substituted on carbon by one or more Y; Y and Z are
independently selected from halo, nitro, cyano, hydroxy,
C.sub.1-6alkoxy, N,N--(C.sub.1-6alkyl).sub.2-amino or
C.sub.1-6alkanoylamino; G, J and K are independently selected from
C.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.1-8alkanoyl, aryl,
arylC.sub.1-6alkyl or (heterocyclic group)C.sub.1-6alkyl; wherein
G, J and K may be optionally substituted on carbon by one or more
Q; and wherein if said heterocyclic group contains an --NH-- moiety
that nitrogen may be optionally substituted by hydrogen or
C.sub.1-6alkyl; Q is cyano, hydroxy, C.sub.1-6alkoxy,
C.sub.1-6alkanoyloxy, C.sub.1-6alkoxycarbonyl,
C.sub.1-6alkoxycarbonylamino, aryl, aryloxy or a group (B''-E''-);
wherein Q, including group (B''-E''-), may be optionally
substituted on carbon by one or more Z; B, B' and B'' are
independently selected from C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, aryl, arylC.sub.1-6alkyl,
heterocyclic group, (heterocyclic group)C.sub.1-6alkyl, phenyl or
phenylC.sub.1-6alkyl; wherein B, B' and B'' may be optionally
substituted on carbon by one or more D; and wherein if said
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from G; E, E' and E''
are independently selected from --N(R.sup.a)--, --O--, --C(O)O--,
--OC(O)--, --C(O)--, --N(R.sup.a)C(O)--,
--N(R.sup.a)C(O)N(R.sup.a)--, --N(R.sup.a)C(O)O--,
--OC(O)N(R.sup.a)--, --C(O)N(R.sup.a)--, --S(O).sub.r--,
--SO.sub.2N(R.sup.a)--, --N(R.sup.a)SO.sub.2--; wherein R.sup.a and
R.sup.b are independently selected from hydrogen or C.sub.1-6alkyl
optionally substituted by one or more F and r is 0-2; D and F are
independently selected from halo, C.sub.1-6alkoxy or
N,N--(C.sub.1-6alkyl).sub.2-amino; m is 0, 1, 2, 3 or 4; wherein
the values of R.sup.1 may be the same or different; R.sup.2 is
fluoro or chloro; n is 0, 1 or 2, wherein the values of R.sup.2 may
be the same or different; R.sup.3 is amino or hydroxy; R.sup.4 is
halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy,
amino, carboxy or carbamoyl; p is 0, 1 or 2, wherein the values of
R.sup.4 may be the same or different; or a pharmaceutically
acceptable salt thereof.
8. A compound of formula (I) according to claim 1 wherein: Ring A
piperidinyl, wherein nitrogen within the piperidinyl ring can be
optionally substituted by K; R.sup.1 is a substituent on carbon and
is selected from fluoro, chloro, amino, methyl, ethyl, propyl,
methoxy, N-methylamino, N-ethylamino, N-propylamino, N-butylamino,
phenyl, naphthylethyl, piperazin-1-yl, piperidin-1-yl,
piperidin-4-yl, 2-(thiomethyl)-pyrimidin-4-yl,
tetrahydrofuran-2-ylmethyl, tetrahydropyran-2-ylmethyl,
1,2,5-thiadiazol-3-ylethyl, piperidin-1-ylmethyl,
pyridin-2-ylmethyl, or a group (B-E-); wherein R.sup.1, including
group (B-E-), may be optionally substituted on carbon by one or
more W; and wherein if said heterocyclic group contains an --NH--
moiety that nitrogen may be optionally substituted by J; W is
hydroxy, methyl, ethyl, ethoxy, N,N-(diethyl)amino,
N,N-(dibutyl)amino, or a group (B'-E'-); wherein W, including group
(B'-E'-), may be optionally substituted on carbon by one or more Y;
Y and Z are independently selected from fluoro, chloro, bromo,
nitro, cyano, hydroxy, methoxy, N,N-(dimethyl)amino or
methylcarbonylamino; G, J and K are independently selected from
methyl, ethyl, propyl, pentyl, 2-methylbutyl, butyl, acetyl,
benzyl, 3-(pyrrol-1-yl)propyl or pyrrolidin-2-one-(5S)-methyl;
wherein G, J and K may be optionally substituted on carbon by one
or more Q; and wherein if said heterocyclic group contains an
--NH-- moiety that nitrogen may be optionally substituted by
hydrogen or methyl; Q is cyano, hydroxy, methoxy, ethoxy,
methylcarbonyloxy, methoxycarbonyl, t-butoxycarbonylamino, phenyl
or a group (B''-E''-); wherein Q, including group (B''-E''-), may
be optionally substituted on carbon by one or more Z; B, B' and B''
are independently selected from methyl, ethyl, propyl, cyclohexyl,
phenyl, benzyl, 1,2,3,4-tetrahydroquinolinyl, 3-morpholinopropyl,
2-morpholinoethyl, 2-pyrrolidin-1-ylethyl, 3-morpholinopropyl,
3-(4-methylpiperazin-1-yl)propyl, 2-piperidin-1-ylethyl,
3-piperidin-1-ylpropyl, pyridin-3-ylmethyl or imidazol-1-ylpropyl;
wherein B, B' and B'' may be optionally substituted on carbon by
one or more D; and wherein if said heterocyclic group contains an
--NH-- moiety that nitrogen may be optionally substituted by a
group selected from G; E, E' and E'' are independently selected
from --N(R.sup.a)--, --O--, --C(O)--, --NHC(O)--,
--N(R.sup.a)C(O)O--; wherein R.sup.a is hydrogen or methyl
optionally substituted by one or more F; D and F are independently
selected from fluoro, methoxy or ethoxy; m is 0, 1, or 2; wherein
the values of R.sup.1 may be the same or different; R.sup.2 is
fluoro; n is 0 or 1; R.sup.3 is amino; R.sup.4 is halo; p is 0, 1
or 2, wherein the values of R.sup.4 may be the same or different;
or a pharmaceutically acceptable salt thereof.
9. A process for preparing a compound of formula (I) or a
pharmaceutically acceptable salt thereof, according to claim 1,
which process comprises of: (a) the reaction of a compound of the
formula (II) ##STR00118## wherein X is a reactive group, with a
compound of the formula (III) ##STR00119## wherein L.sup.1 and
L.sup.2 are ligands; (b) the reaction of a compound of the formula
(IV) ##STR00120## wherein L.sup.1 and L.sup.2 are ligands, with a
compound of the formula (V) ##STR00121## wherein X is a reactive
group; or (c) the reaction, in the presence of
4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium
chloride, of a compound of the formula (VI) ##STR00122## with a
compound of the formula (VII) ##STR00123## and thereafter if
necessary: i) converting a compound of the formula (I) into another
compound of the formula (I); and/or ii) removing any protecting
groups.
10. A pharmaceutical composition which comprises a compound of the
formula (I), or a pharmaceutically acceptable salt thereof,
according to claim 1 in association with a
pharmaceutically-acceptable diluent or carrier.
11. A method of treating cancer in a warm-blooded animal in need of
such treatment which comprises administering to said animal an
effective amount of a compound of the formula (I), or a
pharmaceutically acceptable salt thereof, according to claim 1.
12. A compound of formula (I) according to claim 1 wherein m is 0,
1 or 2; wherein the values of R.sup.1 are the same or different, n
is 0; R.sup.3 is amino and p is 0.
Description
[0001] This is a continuation of U.S. Nonprovisional application
Ser. No. 10/509,941 filed 1 Oct. 2004 which is a 35 USC 371
Application of International Application No PCT/GB03/01442 filed 2
Apr. 2003 which claims priority to United Kingdom Application No.
0207863.2 filed 5 Apr. 2002 and United Kingdom Application No.
0229930.3 filed 21 Dec. 2002.
[0002] This invention relates to benzamide derivatives, or
pharmaceutically acceptable salts or in vivo hydrolysable esters or
amides thereof. These benzamide derivatives possess histone
deacetylase (HDAC) inhibitory activity and accordingly have value
in the treatment of disease states associated with cancer (Marks et
al., Nature Reviews, 1, 194-202, (2001)), cystic fibrosis (Li, S.
et al, J. Biol. Chem., 274, 7803-7815, (1999)), Huntingdons chorea
(Steffan, J. S. et al., Nature, 413, 739-743, (2001)) and sickle
cell anaemia (Gabbianelli, M. et al., Blood, 95, 3555-3561,
(2000)), and accordingly are useful in methods of treatment of a
warm-blooded animal, such as man. The invention also relates to
processes for the manufacture of said benzamide derivatives, to
pharmaceutical compositions containing them and to their use in the
manufacture of medicaments to inhibit HDAC in a warm-blooded
animal, such as man.
[0003] In the eukaryotic cell, DNA is compacted to prevent
transcription factor accessibility. When the cell is activated this
compact DNA is made available to DNA-binding proteins, thereby
allowing the induction of gene transcription (Beato, M., J. Med.
Chem., 74, 711-724 (1996); Wolffe, A. P., Nature, 387, 16-17
(1997)). Nuclear DNA associates with histones to form a complex
known as chromatin. The core histones, termed H2A, H2B, H3 and H4
surrounded by 146 base pairs of DNA form the fundamental unit of
chromatin, the nucleosome. The N-terminal tails of the core
histones contain lysines that are sites for post-transcriptional
acetylation. Acetylation neutralizes the potential of the side
chain to form a positive charge on the lysine side chain, and is
thought to impact chromatin structure.
[0004] Histone Deacetylases (HDACs) are zinc-containing enzymes
which catalyse the removal of acetyl groups from the
.epsilon.-amino termini of lysine residues clustered near the amino
terminus of nucleosomal histones. HDACs may be divided into two
classes, the first (HDAC 1, 2, 3 and 8) represented by yeast
Rpd3-like proteins, and the second (HDAC 4, 5, 6, 7, 9 and 10)
represented by yeast Hda1-like proteins. The reversible process of
acetylation is important in transcriptional regulation and
cell-cycle progression. HDAC deregulation has been associated with
several cancers and HDAC inhibitors, such as Trichostatin A (a
natural product isolated from Streptomyces hygroscopicus), have
been shown to exhibit significant anti-tumour effects and
inhibition of cell-growth (Meinke, P. T., Current Medicinal
Chemistry, 8, 211-235 (2001)). Yoshida et al, Exper. Cell Res.,
177, 122-131 (1988) teaches that Trichostatin A causes arrest of
rat fibroblasts at the G1 and G2 phases of the cell cycle, thereby
implicating HDAC in cell cycle regulation. Furthermore,
Trichostatin A has been shown to induce terminal differentiation,
inhibit cell growth, and prevent the formation of tumours in mice
(Finnin et al., Nature, 401, 188-193 (1999)).
[0005] To date only a few inhibitors of HDAC are known in the art.
There is thus a need to identify additional HDAC inhibitors.
[0006] Accordingly, the present invention provides a compound of
the formula (I):
##STR00002##
wherein:
[0007] Ring A is a heterocyclyl, wherein if said heterocyclyl
contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from K;
[0008] R.sup.1 is a substituent on carbon and is selected from
halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy,
amino, carboxy, carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxy,
C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2-amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl, aryl, aryloxy,
arylC.sub.1-6alkyl, heterocyclic group, (heterocyclic
group)C.sub.1-6alkyl, or a group (B-E-); wherein R.sup.1, including
group (B-E-), may be optionally substituted on carbon by one or
more W; and wherein if said heterocyclic group contains an --NH--
moiety that nitrogen may be optionally substituted by J;
[0009] W is halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2-amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl, or a group (B'-E'-); wherein
W, including group (B'-E'-), may be optionally substituted on
carbon by one or more Y;
[0010] Y and Z are independently selected from halo, nitro, cyano,
hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2-amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl or
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl;
[0011] G, J and K are independently selected from C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.1-8alkanoyl, C.sub.1-8alkylsulphonyl,
C.sub.1-8alkoxycarbonyl, carbamoyl, N--(C.sub.1-8alkyl)carbamoyl,
N,N--(C.sub.1-8alkyl)carbamoyl, benzyloxycarbonyl, benzoyl,
phenylsulphonyl, aryl, arylC.sub.1-6alkyl or (heterocyclic
group)C.sub.1-6alkyl; wherein G, J and K may be optionally
substituted on carbon by one or more Q; and wherein if said
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by hydrogen or C.sub.1-6alkyl;
[0012] Q is halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2-amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
C.sub.1-6alkoxycarbonylamino, N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl, aryl, aryloxy, aryl
C.sub.1-6alkyl, arylC.sub.1-6alkoxy, heterocyclic group,
(heterocyclic group)C.sub.1-6alkyl, (heterocyclic
group)C.sub.1-6alkoxy, or a group (B''-E''-); wherein Q, including
group (B''-E''-), may be optionally substituted on carbon by one or
more Z;
[0013] B, B' and B'' are independently selected from
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-6alkyl, aryl,
arylC.sub.1-6alkyl, heterocyclic group, (heterocyclic
group)C.sub.1-6alkyl, phenyl or phenylC.sub.1-6alkyl; wherein B, B'
and B'' may be optionally substituted on carbon by one or more D;
and wherein if said heterocyclic group contains an --NH-- moiety
that nitrogen may be optionally substituted by a group selected
from G;
[0014] E, E' and E'' are independently selected from
--N(R.sup.a)--, --O--, --C(O)O--, --OC(O)--, --C(O)--,
--N(R.sup.a)C(O)--, --N(R.sup.a)C(O)N(R.sup.b)--,
--N(R.sup.a)C(O)O--, --OC(O)N(R.sup.a)--, --C(O)N(R.sup.a)--,
--S(O).sub.r--, --SO.sub.2N(R.sup.a)--, --N(R.sup.a)SO.sub.2--;
wherein R.sup.a and R.sup.b are independently selected from
hydrogen or C.sub.1-6alkyl optionally substituted by one or more F
and r is 0-2;
[0015] D and F are independently selected from halo, nitro, cyano,
hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2-amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl or
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl;
[0016] m is 0, 1, 2, 3 or 4; wherein the values of R.sup.1 may be
the same or different;
[0017] R.sup.2 is halo;
[0018] n is 0, 1 or 2; wherein the values of R.sup.2 may be the
same or different;
[0019] R.sup.3 is amino or hydroxy;
[0020] R.sup.4 is halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-3alkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.1-3alkoxy, C.sub.1-3alkanoyl, C.sub.1-3alkanoyloxy,
N--(C.sub.1-3alkyl)amino, N,N--(C.sub.1-3alkyl).sub.2-amino,
C.sub.1-3alkanoylamino, N--(C.sub.1-3alkyl)carbamoyl,
N,N--(C.sub.1-3alkyl).sub.2-carbamoyl, C.sub.1-3alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-3alkoxycarbonyl,
N--(C.sub.1-3alkyl)sulphamoyl,
N,N--(C.sub.1-3alkyl).sub.2sulphamoyl;
[0021] p is 0, 1 or 2; wherein the values of R.sup.4 may be the
same or different;
[0022] or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide thereof, with the proviso that said
compound is not
N-(2-amino-6-hydroxyphenyl)-4-(1-methylhomopiperazin-4-yl)benzamide;
N-(2-amino-6-methylphenyl)-4-(1-methylhomopiperazin-4-yl)benzamide;
N-(2-aminophenyl)-4-(1-t-butoxycarbonylhomopiperazin-4-yl)benzamide;
or N-(2-aminophenyl)-4-(1-methylhomopiperazin-4-yl)benzamide.
[0023] According to a further aspect of the present invention,
there is provided a compound of the formula (I) wherein:
[0024] Ring A is a heterocyclyl;
[0025] R.sup.1 is halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkanoyl, C.sub.1-6alkanoyloxy,
N--(C.sub.1-6alkyl)amino, N,N--(C.sub.1-6alkyl).sub.2-amino,
C.sub.1-6alkanoylamino, N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a,
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl,
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl or a group (B-E-);
wherein,
[0026] B is selected from C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, phenyl, heterocyclyl,
phenylC.sub.1-6alkyl or heterocyclylC.sub.1-6alkyl; wherein B may
be optionally substituted on carbon by one or more D; and wherein
if said heterocyclyl contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from G;
[0027] E is --N(R.sup.a)--, --O--, --C(O)O--, --OC(O)--, --C(O)--,
--N(R.sup.a)C(O)--, --C(O)N(R.sup.a)--, --S(O).sub.r--,
--SO.sub.2N(R.sup.a)--, --N(R.sup.a)SO.sub.2--; wherein R.sup.a is
hydrogen or C.sub.1-6alkyl optionally substituted by one or more D
and r is 0-2;
[0028] D is independently selected from halo, nitro, cyano,
hydroxy, trifluoromethyl, trifluoromethoxy, amino, carboxy,
carbamoyl, mercapto, sulphamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkanoyl,
C.sub.1-6alkanoyloxy, N--(C.sub.1-6alkyl)amino,
N,N--(C.sub.1-6alkyl).sub.2-amino, C.sub.1-6alkanoylamino,
N--(C.sub.1-6alkyl)carbamoyl,
N,N--(C.sub.1-6alkyl).sub.2-carbamoyl, C.sub.1-6alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-6alkoxycarbonyl,
N--(C.sub.1-6alkyl)sulphamoyl and
N,N--(C.sub.1-6alkyl).sub.2sulphamoyl;
[0029] G is selected from C.sub.1-4alkyl, C.sub.1-4alkanoyl,
C.sub.1-4alkylsulphonyl, C.sub.1-4alkoxycarbonyl, carbamoyl,
N--(C.sub.1-4alkyl)carbamoyl, N,N--(C.sub.1-4alkyl)carbamoyl,
benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
[0030] m is 0, 1, 2, 3 or 4; wherein the values of R.sup.1 may be
the same or different;
[0031] R.sup.2 is halo;
[0032] n is 0, 1 or 2; wherein the values of R.sup.2 may be the
same or different;
[0033] R.sup.3 is amino or hydroxy;
[0034] R.sup.4 is halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C.sub.1-3alkyl, C.sub.2-3alkenyl, C.sub.2-3alkynyl,
C.sub.1-3alkoxy, C.sub.1-3alkanoyl, C.sub.1-3alkanoyloxy,
N--(C.sub.1-3alkyl)amino, N,N--(C.sub.1-3alkyl).sub.2-amino,
C.sub.1-3alkanoylamino, N--(C.sub.1-3alkyl)carbamoyl,
N,N--(C.sub.1-3alkyl).sub.2-carbamoyl, C.sub.1-3alkylS(O).sub.a
wherein a is 0 to 2, C.sub.1-3alkoxycarbonyl,
N--(C.sub.1-3alkyl)sulphamoyl,
N,N--(C.sub.1-3alkyl).sub.2sulphamoyl;
[0035] p is 0, 1 or 2; wherein the values of R.sup.4 may be the
same or different;
[0036] or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide thereof, with the proviso that said
compound is not
N-(2-amino-6-hydroxyphenyl)-4-(1-methylhomopiperazin-4-yl)lbenzamide;
N-(2-amino-6-methylphenyl)-4-(1-methylhomopiperazin-4-yl)lbenzamide;
N-(2-aminophenyl)-4-(1-t-butoxycarbonylhomopiperazin-4-yl)lbenzamide;
or N-(2-aminophenyl)-4-(1-methylhomopiperazin-4-yl)lbenzamide.
[0037] In this specification the term "alkyl" includes both
straight and branched chain alkyl groups. For example,
"C.sub.1-8alkyl" and "C.sub.1-6alkyl" includes methyl, ethyl,
propyl, isopropyl, pentyl, hexyl, heptyl, and t-butyl. However,
references to individual alkyl groups such as `propyl` are specific
for the straight-chained version only and references to individual
branched chain alkyl groups such as `isopropyl` are specific for
the branched chain version only. The term "halo" refers to fluoro,
chloro, bromo and iodo.
[0038] Where optional substituents are chosen from "one or more"
groups it is to be understood that this definition includes all
substituents being chosen from one of the specified groups or the
substituents being chosen from two or more of the specified
groups.
[0039] A "heterocyclyl" is a saturated, partially saturated or
unsaturated, mono or bicyclic ring containing 3-12 atoms of which
at least one atom is chosen from nitrogen, sulphur or oxygen, which
may, unless otherwise specified, be carbon or nitrogen linked,
wherein a ring sulphur atom may be optionally oxidised to form the
S-oxide(s). Preferably a "heterocyclyl" is a saturated, partially
saturated or unsaturated, monocyclic ring containing 5 or 6 atoms
of which at least one atom is chosen from nitrogen, sulphur or
oxygen or a 8-10 membered bicyclic ring which may, unless otherwise
specified, be carbon or nitrogen linked, wherein a ring sulphur
atom may be optionally oxidised to form S-oxide(s). Examples and
suitable values of the term "heterocyclyl" are thiazolidinyl,
pyrrolidinyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl,
2-azabicyclo[2.2.1]heptyl, morpholinyl, tetrahydrofuranyl, furanyl,
tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl,
1,3-dioxolanyl, homopiperazinyl, thienyl, pyrrolyl, pyrazolyl,
oxadiazolyl, tetrazolyl, oxazolyl, thienopyrimidinyl,
thienopyridinyl, thieno[3,2-d]pyrimidinyl, 1,3,5-triazinyl,
purinyl, 1,2,3,4-tetrahydroquinolinyl, benzimidazolyl,
benzthiazolyl, benzoxazolyl, benzothienyl, benzofuranyl, indazolyl,
quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl,
napthyridinyl, benzotriazolyl, pyrrolothienyl, imidazothienyl,
isoxazolyl, imidazolyl, thiadiazolyl, isothiazolyl,
1,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, indolyl, pyrimidyl,
thiazolyl, pyrazinyl, pyridazinyl, pyridyl,-quinolyl, quinazolinyl,
and 1-isoquinolinyl.
[0040] A "heterocyclic group" is a saturated, partially saturated
or unsaturated, mono or bicyclic ring containing 3-12 atoms of
which at least one atom is chosen from nitrogen, sulphur or oxygen,
which may, unless otherwise specified, be carbon or nitrogen
linked, wherein a CH.sub.2 group can optionally be replaced by a
C(O), and wherein a ring sulphur atom may be optionally oxidised to
form the S-oxide(s). Preferably a "heterocyclic group" is a
saturated, partially saturated or unsaturated, monocyclic ring
containing 5 or 6 atoms of which at least one atom is chosen from
nitrogen, sulphur or oxygen or a 9 or 10 membered bicyclic ring
which may, unless otherwise specified, be carbon or nitrogen
linked, wherein a CH.sub.2 group can optionally be replaced by a
C(O), and wherein a ring sulphur atom may be optionally oxidised to
form S-oxide(s). Examples and suitable values of the term
"heterocyclic group" are pyrrolidinyl, 2-pyrrolidonyl
2,5-dioxopyrrolidinyl, 2,4-dioxoimidazolidinyl,
2-oxo-1,3,4-triazolinyl, oxazolidinyl, 2-oxazolidonyl,
5,6-dihydro-uracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl,
2-azabicyclo[2.2.1]heptyl, morpholinyl, 2-oxotetrahydrofuranyl,
tetrahydrofuranyl, furanyl, tetrahydropyranyl, piperidinyl,
piperazinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl,
1,3-dioxolanyl, homopiperazinyl, thiophenyl, thienopyridinyl,
thienopyrimidinyl, thieno[3,2-d]pyrimidinyl, 1,3,5-triazinyl,
purinyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,
tetrahydroisoquinolinyl, imidazolyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl,
indazolyl, quinazolinyl, cinnolinyl, phthalazinyl, quinoxalinyl,
napthyridinyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl,
thiadiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
pyranyl, indolyl, isoindolyl, pyrimidinyl, thiazolyl, pyrazolyl,
3-pyrrolinyl, pyrazinyl, pyridazinyl, pyridinyl, pyridonyl,
pyrimidonyl and 1-isoquinolinyl.
[0041] An "aryl" group is, for example, phenyl, indenyl, indanyl,
naphthyl, tetrahydronaphthyl or fluorenyl, preferably phenyl.
[0042] An example of "C.sub.1-6alkanoyloxy" is acetoxy. Examples of
"C.sub.1-8alkoxycarbonyl", "C.sub.1-6alkoxycarbonyl" and
C.sub.1-4alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, n-
and t-butoxycarbonyl. Examples of C.sub.2-6alkynyl are ethynyl and
2-propynyl. Examples of "C.sub.1-6alkoxy" include methoxy, ethoxy
and propoxy. Examples of "C.sub.1-6alkanoylamino" and
C.sub.1-3alkanoylamino include formamido, acetamido and
propionylamino. Examples of "C.sub.1-6alkylS(O).sub.a wherein a is
0 to 2" include C.sub.1-4alkylsulphonyl, C.sub.1-3alkylS(O).sub.3,
methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and
ethylsulphonyl. Examples of "C.sub.1-8alkanoyl",
"C.sub.1-6alkanoyl" and C.sub.1-4alkanoyl include
C.sub.1-3alkanoyl, propionyl and acetyl. Examples of
"N--C.sub.1-6alkylamino" and N--(C.sub.1-3alkyl)amino include
methylamino and ethylamino. Examples of
"N,N--(C.sub.1-6alkyl).sub.2-amino" and
N,N--(C.sub.1-2alkyl).sub.2-amino include di-N-methylamino,
di-(N-ethyl)amino, di-(N-butyl)amino and N-ethyl-N-methylamino.
Examples of "C.sub.2-8alkenyl" are C.sub.2-6alkenyl and
C.sub.2-3alkenyl, and include vinyl, allyl, and 1-propenyl.
Examples of "N--(C.sub.1-8alkyl)sulphamoyl" and
"N--(C.sub.1-6alkyl)sulphamoyl" are N--(C.sub.1-3alkyl)sulphamoyl,
N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of
"N--(C.sub.1-6alkyl).sub.2sulphamoyl" are
N,N--(C.sub.1-3alkyl).sub.2sulphamoyl, N,N-(dimethyl)sulphamoyl and
N-(methyl)-N-(ethyl)sulphamoyl. Examples of
"N--(C.sub.1-8alkyl)carbamoyl" and "N--(C.sub.1-6alkyl)carbamoyl"
are N--(C.sub.1-4alkyl)carbamoyl, N--(C.sub.1-3alkyl)carbamoyl,
methylaminocarbonyl, and ethylaminocarbonyl. Examples of
"N,N--(C.sub.1-8alkyl).sub.2-carbamoyl" and
"N,N--(C.sub.1-6alkyl).sub.2-carbamoyl" are
N,N--(C.sub.1-4alkyl)carbamoyl,
N,N--(C.sub.1-2alkyl).sub.2-carbamoyl, dimethylaminocarbonyl and
methylethylaminocarbonyl. Examples of "(heterocyclic
group)C.sub.1-6alkyl" include piperidin-1-ylmethyl,
piperidin-1-ylethyl, piperidin-1-ylpropyl, pyridylmethyl,
3-morpholinopropyl, 2-morpholinoethyl and 2-pyrimid-2-ylethyl.
Examples of "(heterocyclic group)C.sub.1-6alkoxy" include
(heterocyclic group)methoxy, (heterocyclic group)ethoxy and
(heterocyclic group)propoxy. Examples of "arylC.sub.1-6alkyl"
include benzyl, 2-phenylethyl, 2-phenylpropyl and 3-phenylpropyl
Examples of "aryloxy" include phenoxy and naphthyloxy. Examples of
"C.sub.3-8cycloalkyl" include cyclopropyl and cyclohexyl. Examples
of "C.sub.3-8cycloalkylC.sub.1-6alkyl" include cyclopropylmethyl
and 2-cyclohexylpropyl. Examples of "C.sub.1-6alkoxycarbonylamino"
include methoxycarbonylamino and t-butoxycarbonylamino.
[0043] Within this specification composite terms are used to
describe groups comprising more that one functionality such as
arylC.sub.1-6alkyl. Such terms are to be interpreted as is
understood by a person skilled in the art. For example
arylC.sub.1-6alkyl comprises C.sub.1-6alkyl substituted by aryl and
such a group includes benzyl, 2-phenylethyl, 2-phenylpropyl and
3-phenylpropyl.
[0044] A suitable pharmaceutically acceptable salt of a compound of
the invention is, for example, an acid-addition salt of a compound
of the invention which is sufficiently basic, for example, an
acid-addition salt with, for example, an inorganic or organic acid,
for example acetic, hydrochloric, hydrobromic, sulphuric,
phosphoric, trifluoroacetic, citric or maleic acid. In addition a
suitable pharmaceutically acceptable salt of a compound of the
invention which is sufficiently acidic is an alkali metal salt, for
example a sodium or potassium salt, an alkaline earth metal salt,
for example a calcium or magnesium salt, an ammonium salt or a salt
with an organic base which affords a physiologically-acceptable
cation, for example a salt with methylamine, dimethylamine,
trimethylamine, piperidine, morpholine or
tris-(2-hydroxyethyl)amine.
[0045] The compounds of the formula (I) may be administered in the
form of an in vivo hydrolysable ester or in vivo hydrolysable amide
of a compound of the formula (I).
[0046] An in vivo hydrolysable ester of a compound of the formula
(I) containing carboxy or hydroxy group is, for example, a
pharmaceutically acceptable ester which is hydrolysed in the human
or animal body to produce the parent acid or alcohol. Suitable
pharmaceutically acceptable esters for carboxy include
C.sub.1-6alkoxymethyl esters for example methoxymethyl,
C.sub.1-6alkanoyloxymethyl esters for example pivaloyloxymethyl,
phthalidyl esters, C.sub.3-8cycloalkoxycarbonyloxyC.sub.1-6alkyl
esters for example 1-cyclohexylcarbonyloxyethyl;
1,3-dioxolen-2-onylmethyl esters for example
5-methyl-1,3-dioxolen-2-onylmethyl; and
C.sub.1-6alkoxycarbonyloxyethyl esters for example
1-methoxycarbonyloxyethyl and may be formed at any carboxy group in
the compounds of this invention.
[0047] An in vivo hydrolysable ester of a compound of the formula
(I) containing a hydroxy group includes inorganic esters such as
phosphate esters and .alpha.-acyloxyalkyl ethers and related
compounds which as a result of the in vivo hydrolysis of the ester
breakdown to give the parent hydroxy group. Examples of
.alpha.-acyloxyalkyl ethers include acetoxymethoxy and
2,2-dimethylpropionyloxy-methoxy. A selection of in vivo
hydrolysable ester forming groups for hydroxy include alkanoyl,
benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,
alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl
and N--(N,N-dialkylaminoethyl)-N-alkylcarbamoyl (to give
carbamates), N,N-dialkylaminoacetyl and carboxyacetyl. Examples of
substituents on benzoyl include morpholino and piperazino linked
from a ring nitrogen atom via a methylene group to the 3- or
4-position of the benzoyl ring.
[0048] A suitable value for an in vivo hydrolysable amide of a
compound of the formula (I) containing a carboxy group is, for
example, a N--C.sub.1-6alkyl or N,N-di-C.sub.1-6alkyl amide such as
N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or
N,N-diethyl amide.
[0049] Some compounds of the formula (I) may have chiral centres
and/or geometric isomeric centres (E- and Z-isomers), and it is to
be understood that the invention encompasses all such optical,
diastereoisomers and geometric isomers that possess HDAC inhibitory
activity.
[0050] The invention relates to any and all tautomeric forms of the
compounds of the formula (I) that possess HDAC inhibitory
activity.
[0051] Further values of Ring A, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, m, n and p are as follows. Such values may be used where
appropriate with any of the definitions, claims or embodiments
defined hereinbefore or hereinafter.
[0052] Ring A is a pyridyl, quinolyl, indolyl, pyrimidinyl,
morpholinyl, piperidinyl, piperazinyl, pyradazinyl, pyrazinyl,
thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl,
triazinyl, oxazolyl, pyrazolyl, or furanyl; wherein if Ring A
contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from K.
[0053] Ring A is pyridin-4-yl, pyridin-3-yl, pyridin-2-yl,
quinolin-8-yl, pyrimidin-6-yl, pyrimidin-5-yl, pyrimidin-4-yl,
morpholin-4-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl,
piperazin-4-yl, pyridazin-5-yl, pyrazin-6-yl, thiazol-2-yl,
thien-2-yl, thieno[3,2-d]pyrimidinyl, thieno[3,2b]pyrimidinyl,
thieno[3,2b]pyridinyl, purin-6-yl or triazin-6-yl; wherein if Ring
A contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from K.
[0054] Ring A is a pyridyl, quinolyl, pyrimidyl, morpholinyl,
piperidinyl, piperazinyl, pyradazinyl, pyrazinyl, thiazyl or
furanyl.
[0055] Ring A is a pyridin-4-yl, pyridin-3-yl, pyridin-2-yl,
quinoline-8-yl, pyradizin-2-yl, furan-3-yl, morpholinyl,
thiazol-2-yl, pyrimidin-6-yl, piperidin-4-yl or piperazin-4-yl.
[0056] Ring A is pyridin-4-yl, pyridin-3-yl, quinoline-8-yl,
piperidin-4-yl or piperazin-4-yl.
[0057] R.sup.1 is a substituent on carbon and is selected from
halo, amino, C.sub.1-6alkyl, C.sub.1-6alkoxy,
N--(C.sub.1-6alkyl)amino, aryl, aryloxy, arylC.sub.1-6alkyl,
heterocyclic group, (heterocyclic group)C.sub.1-6alkyl, or a group
(B-E-); wherein R.sup.1, including group (B-E-), may be optionally
substituted on carbon by one or more W; and wherein if said
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by J;
[0058] W is hydroxy, mercapto, C.sub.1-6alkyl, C.sub.1-6alkoxy,
N,N--(C.sub.1-6alkyl).sub.2-amino or a group (B'-E'-); wherein W,
including group (B'-E'-), may be optionally substituted on carbon
by one or more Y;
[0059] Y and Z are independently selected from halo, nitro, cyano,
hydroxy, C.sub.1-6alkoxy, N,N--(C.sub.1-6alkyl).sub.2-amino or
C.sub.1-6alkanoylamino;
[0060] G, J and K are independently selected from C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.1-8alkanoyl, aryl, arylC.sub.1-6alkyl or
(heterocyclic group)C.sub.1-6alkyl; wherein G, J and K may be
optionally substituted on carbon by one or more Q; and wherein if
said heterocyclic group contains an --NH-- moiety that nitrogen may
be optionally substituted by hydrogen or C.sub.1-6alkyl;
[0061] Q is cyano, hydroxy, C.sub.1-6alkoxy, C.sub.1-6alkanoyloxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkoxycarbonylamino, aryl,
aryloxy or a group (B''-E''-); wherein Q, including group
(B''-E''-), may be optionally substituted on carbon by one or more
Z;
[0062] B, B' and B'' are independently selected from
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-6alkyl, aryl,
arylC.sub.1-6alkyl, heterocyclic group, (heterocyclic
group)C.sub.1-6alkyl, phenyl or phenylC.sub.1-6alkyl; wherein B, B'
and B'' may be optionally substituted on carbon by one or more D;
and wherein if said heterocyclic group contains an --NH-- moiety
that nitrogen may be optionally substituted by a group selected
from G;
[0063] E, E' and E'' are independently selected from
--N(R.sup.a)--, --O--, --C(O)O--, --OC(O)--, --C(O)--,
--N(R.sup.a)C(O)--, --N(R.sup.a)C(O)N(R.sup.b)--,
--N(R.sup.a)C(O)O--, --OC(O)N(R.sup.a)--, --C(O)N(R.sup.a)--,
--S(O).sub.r--, --SO.sub.2N(R.sup.a)--, --N(R.sup.a)SO.sub.2--;
wherein R.sup.a and R.sup.b are independently selected from
hydrogen or C.sub.1-6alkyl optionally substituted by one or more F
and r is 0-2;
[0064] D and F are independently selected from halo,
C.sub.1-6alkoxy or N,N--(C.sub.1-6alkyl).sub.2-amino.
[0065] R.sup.1 is a substituent on carbon and is selected from
fluoro, chloro, amino, methyl, ethyl, propyl, methoxy,
N-methylamino, N-ethylamino, N-propylamino, N-butylamino, phenyl,
naphthylethyl, piperizin-1-yl, piperidin-1-yl, piperidin-4-yl,
2-(thiomethyl)-pyrimidin-4-yl, tetrahydrofuran-2-ylmethyl,
tetrahydropyran-2-ylmethyl, 1,2,5-thiadiazol-3-ylethyl,
piperidin-1-ylmethyl, pyridin-2-ylmethyl, or a group (B-E-);
wherein R.sup.1, including group (B-E-), may be optionally
substituted on carbon by one or more W; and wherein if said
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by J;
[0066] W is hydroxy, methyl, ethyl, ethoxy, N,N-(diethyl)amino,
N,N-(dibutyl)amino, or a group (B'-E'-); wherein W, including group
(B'-E'-), may be optionally substituted on carbon by one or more
Y;
[0067] Y and Z are independently selected from fluoro, chloro,
bromo, nitro, cyano hydroxy, methoxy, N,N-(dimethyl)amino or
methylcarbonylamino;
[0068] G, J and K are independently selected from methyl, ethyl,
propyl, pentyl, 2-methylbutyl, butyl, acetyl, benzyl,
3-(pyrrol-1-yl)propyl or pyrrolidin-2-one-(5S)-methyl; wherein G, J
and K may be optionally substituted on carbon by one or more Q; and
wherein if said heterocyclic group contains an --NH-- moiety that
nitrogen may be optionally substituted by hydrogen or methyl;
[0069] Q is cyano, hydroxy, methoxy, ethoxy, methylcarbonyloxy,
methoxycarbonyl, t-butoxycarbonylamino, phenyl or a group
(B''-E''-); wherein Q, including group (B''-E''-), may be
optionally substituted on carbon by one or more Z;
[0070] B, B' and B'' are independently selected from methyl, ethyl,
propyl, cyclohexyl, phenyl, benzyl, 1,2,3,4-tetrahydroquinolinyl,
3-morpholinopropyl, 2-morpholinoethyl, 2-pyrrolidin-1-ylethyl,
3-morpholinopropyl, 3-(4-methylpiperazin-1-yl)propyl,
2-piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, pyridin-3-ylmethyl
or imidazol-1-ylpropyl; wherein B, B' and B'' may be optionally
substituted on carbon by one or more D; and wherein if said
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from G;
[0071] E, E' and E'' are independently selected from
--N(R.sup.a)--, --O--, --C(O)--, --NHC(O)--, --N(R.sup.a)C(O)O--;
wherein R.sup.a is hydrogen or methyl optionally substituted by one
or more F;
[0072] D and F are independently selected from fluoro, methoxy or
ethoxy.
[0073] R.sup.1 is fluoro, chloro, amino, methyl, methoxy,
3-morpholin-4-ylpropylamino, (3-morpholin-4-yl)ethylamino, acetyl,
benzyl, methoxycarbonylmethyl, 2-pyrrolidin-1-ylethoxy,
3-morpholinopropoxy, N-(2-fluorophenyl)propanamide,
4-(diethylamino)phenylcarbonylmethyl,
3-(4-methylpiperazin-1-yl)propylamino, 2-piperidin-1-ylethylamino,
2-[N,N-(diethyl)amino]ethylamino, pyridin-3-ylmethylamino,
3-piperidin-1-ylpropylamino, imidazol-1-ylpropylamino,
3-methoxypropylamino, 3-morpholinopropylamino, piperazin-1-yl,
N-ethylamino, 4-methylpiperazin-1-yl, 1-(3-phenoxy)propyl,
1-(3-cyanophenyl)methyl, 1-(4-cyanophenyl)methyl,
tetrahydrofuran-2-ylmethyl, 1-(3-benzyloxy)propyl, 3-methoxybenzyl,
2,3-dihydroxypropyl, 2-(methylcarbonyloxy)ethyl,
3-(pyrrol-1-yl)propyl, 1-[3-(2-methoxyethoxy)]propyl,
2-(4-acetamidophenyoxy)ethyl, 2-(t-butoxycarbonylamino)ethyl,
2-(t-butoxycarbonylamino)propyl, 2-[(2-methoxyphenyl)oxy]ethyl,
(1,2,3,4-tetrahydroquinolin-1-yl)acetyl,
2-[N-(2-fluorophenyl)ylacetamide]ethyl, methoxycarbonylmethyl,
2-(ethoxy)ethyl, 4-methylpent-3-enyl, tetrahydropyran-2-ylmethyl,
1-(2S)-2-methylbutyl, 4-(benzyloxy)butyl,
2-[4-(nitro)phenoxy)]ethyl, 2-[N,N-(dibutyl)amino]ethylamino,
3-[(N-methyl-N-phenyl)amino]propylamino,
N-3-[2-(dimethylamino)ethoxy]propylamino,
2-[4-(acetamido)phenoxy]ethyl, 2-[4-(hydroxyphenoxy)]ethyl,
1,2,5-thiadiazol-3-ylethyl, piperidin-1-ylmethyl,
2-[4-(chloro)phenoxy]ethyl, pyrrolidin-2-one-(5S)-methyl,
phenylaminocarbonyloxymethyl, cyclohexylaminocarbonyloxymethyl,
2-(thiomethyl)-pyrimidin-4-yl or pyridin-2-ylmethyl.
[0074] R.sup.1 is halo, amino, C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-3alkanoyloxy, N--(C.sub.1-3alkyl)amino,
N,N--(C.sub.1-3alkyl).sub.2-amino, C.sub.1-3alkanoylamino,
N--(C.sub.1-3alkyl)carbamoyl,
N,N--(C.sub.1-3alkyl).sub.2-carbamoyl.
[0075] R.sup.1 is halo, amino, C.sub.1-6alkyl or
C.sub.1-6alkoxy.
[0076] R.sup.1 is halo, amino, methyl or methoxy.
[0077] m is 0, 1, 2, 3 or 4; wherein the values of R.sup.1 may be
the same or different.
[0078] m is 0, 1, or 2; wherein the values of R.sup.1 may be the
same or different.
[0079] m is 0 or 1.
[0080] m is 0.
[0081] m is 1.
[0082] R.sup.2 is halo.
[0083] R.sup.2 is fluoro or chloro.
[0084] R.sup.2 is fluoro.
[0085] n is 0, 1 or 2, wherein the values of R.sup.2 may be the
same or different.
[0086] n is 0 or 1.
[0087] n is 0.
[0088] n is 1.
[0089] R.sup.3 is amino or hydroxy.
[0090] R.sup.3 is amino.
[0091] R.sup.3 is hydroxy.
[0092] R.sup.4 is halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy or carbamoyl.
[0093] R.sup.4 is halo, cyano, trifluoromethyl or
trifluoromethoxy.
[0094] R.sup.4 is halo.
[0095] p is 0, 1 or 2, wherein the values of R.sup.4 may be the
same or different.
[0096] p is 0 or 1.
[0097] p is 0.
[0098] p is 1.
[0099] Therefore in an additional aspect of the invention there is
provided a compound of formula (I) (as depicted above) wherein:
[0100] Ring A is a pyridyl, quinolyl, indolyl, pyrimidinyl,
morpholinyl, piperidinyl, piperazinyl, pyradazinyl, pyrazinyl,
thiazolyl, thienyl, thienopyrimidinyl, thienopyridinyl, purinyl,
triazinyl, oxazolyl, pyrazolyl, or furanyl; wherein if Ring A
contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from K;
[0101] R.sup.1 is a substituent on carbon and is selected from
halo, amino, C.sub.1-6alkyl, C.sub.1-6alkoxy,
N--(C.sub.1-6alkyl)amino, aryl, aryloxy, arylC.sub.1-6alkyl,
heterocyclic group, (heterocyclic group)C.sub.1-6alkyl, or a group
(B-E-); wherein R.sup.1, including group (B-E-), may be optionally
substituted on carbon by one or more W; and wherein if said
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by J;
[0102] W is hydroxy, mercapto, C.sub.1-6alkyl, C.sub.1-6alkoxy,
N,N--(C.sub.1-6alkyl).sub.2-amino or a group (B'-E'-); wherein W,
including group (B'-E'-), may be optionally substituted on carbon
by one or more Y;
[0103] Y and Z are independently selected from halo, nitro, cyano,
hydroxy, C.sub.1-6alkoxy, N,N--(C.sub.1-6alkyl).sub.2-amino or
C.sub.1-6alkanoylamino;
[0104] G, J and K are independently selected from C.sub.1-8alkyl,
C.sub.2-8alkenyl, C.sub.1-8alkanoyl, aryl, arylC.sub.1-6alkyl or
(heterocyclic group)C.sub.1-6alkyl; wherein G, J and K may be
optionally substituted on carbon by one or more Q; and wherein if
said heterocyclic group contains an --NH-- moiety that nitrogen may
be optionally substituted by hydrogen or C.sub.1-6alkyl;
[0105] Q is cyano, hydroxy, C.sub.1-6alkoxy, C.sub.1-6alkanoyloxy,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkoxycarbonylamino, aryl,
aryloxy or a group (B''-E''-); wherein Q, including group
(B''-E''-), may be optionally substituted on carbon by one or more
Z;
[0106] B, B' and B'' are independently selected from
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-6alkyl, aryl,
arylC.sub.1-6alkyl, heterocyclic group, (heterocyclic
group)C.sub.1-6alkyl, phenyl or phenylC.sub.1-6alkyl; wherein B, B'
and B'' may be optionally substituted on carbon by one or more D;
and wherein if said heterocyclic group contains an --NH-- moiety
that nitrogen may be optionally substituted by a group selected
from G;
[0107] E, E' and E'' are independently selected from
--N(R.sup.a)--, --O--, --C(O)O--, --OC(O)--, --C(O)--,
--N(R.sup.a)C(O)--, --N(R.sup.a)C(O)N(R.sup.a)--,
--N(R.sup.a)C(O)O--, --OC(O)N(R.sup.a)--, --C(O)N(R.sup.a)--,
--S(O).sub.r--, --SO.sub.2N(R.sup.a)--, --N(R.sup.a)SO.sub.2--;
wherein R.sup.a and R.sup.b are independently selected from
hydrogen or C.sub.1-6alkyl optionally substituted by one or more F
and r is 0-2;
[0108] D and F are independently selected from halo,
C.sub.1-6alkoxy or N,N--(C.sub.1-6alkyl).sub.2-amino;
[0109] m is 0, 1, 2, 3 or 4; wherein the values of R.sup.1 may be
the same or different;
[0110] R.sup.2 is fluoro or chloro;
[0111] n is 0, 1 or 2, wherein the values of R.sup.2 may be the
same or different;
[0112] R.sup.3 is amino or hydroxy;
[0113] R.sup.4 is halo, nitro, cyano, hydroxy, trifluoromethyl,
trifluoromethoxy, amino, carboxy or carbamoyl;
[0114] p is 0, 1 or 2, wherein the values of R.sup.4 may be the
same or different;
[0115] or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide thereof.
[0116] Therefore in an additional aspect of the invention there is
provided a compound of formula (I) (as depicted above) wherein:
[0117] Ring A is pyridin-4-yl, pyridin-3-yl, pyridin-2-yl,
quinolin-8-yl, pyrimidin-6-yl, pyrimidin-5-yl, pyrimidin-4-yl,
morpholin-4-yl, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl,
piperazin-4-yl, pyridazin-5-yl, pyrazin-6-yl, thiazol-2-yl,
thien-2-yl, thieno[3,2-d]pyrimidinyl, thieno[3,2b]pyrimidinyl,
thieno[3,2b]pyridinyl, purin-6-yl or triazin-6-yl; wherein if Ring
A contains an --NH-- moiety that nitrogen may be optionally
substituted by a group selected from K;
[0118] R.sup.1 is a substituent on carbon and is selected from
fluoro, chloro, amino, methyl, ethyl, propyl, methoxy,
N-methylamino, N-ethylamino, N-propylamino, N-butylamino, phenyl,
naphthylethyl, piperazin-1-yl, piperidin-1-yl, piperidin-4-yl,
2-(thiomethyl)-pyrimidin-4-yl, tetrahydrofuran-2-ylmethyl,
tetrahydropyran-2-ylmethyl, 1,2,5-thiadiazol-3-ylethyl,
piperidin-1-ylmethyl, pyridin-2-ylmethyl, or a group (B-E-);
wherein R.sup.1, including group (B-E-), may be optionally
substituted on carbon by one or more W; and wherein if said
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by J;
[0119] W is hydroxy, methyl, ethyl, ethoxy, N,N-(diethyl)amino,
N,N-(dibutyl)amino, or a group (B'-E'-); wherein W, including group
(B'-E'-), may be optionally substituted on carbon by one or more
Y;
[0120] Y and Z are independently selected from fluoro, chloro,
bromo, nitro, cyano, hydroxy, methoxy, N,N-(dimethyl)amino or
methylcarbonylamino;
[0121] G, J and K are independently selected from methyl, ethyl,
propyl, pentyl, 2-methylbutyl, butyl, acetyl, benzyl,
3-(pyrrol-1-yl)propyl or pyrrolidin-2-one-(5S)-methyl; wherein G, J
and K may be optionally substituted on carbon by one or more Q; and
wherein if said heterocyclic group contains an --NH-- moiety that
nitrogen may be optionally substituted by hydrogen or methyl;
[0122] Q is cyano, hydroxy, methoxy, ethoxy, methylcarbonyloxy,
methoxycarbonyl, t-butoxycarbonylamino, phenyl or a group
(B''-E''-); wherein Q, including group (B''-E''-), may be
optionally substituted on carbon by one or more Z;
[0123] B, B' and B'' are independently selected from methyl, ethyl,
propyl, cyclohexyl, phenyl, benzyl, 1,2,3,4-tetrahydroquinolinyl,
3-morpholinopropyl, 2-morpholinoethyl, 2-pyrrolidin-1-ylethyl,
3-morpholinopropyl, 3-(4-methylpiperazin-1-yl)propyl,
2-piperidin-1-ylethyl, 3-piperidin-1-ylpropyl, pyridin-3-ylmethyl
or imidazol-1-ylpropyl; wherein B, B' and B'' may be optionally
substituted on carbon by one or more D; and wherein if said
heterocyclic group contains an --NH-- moiety that nitrogen may be
optionally substituted by a group selected from G;
[0124] E, E' and E'' are independently selected from
--N(R.sup.a)--, --O--, --C(O)--, --NHC(O)--, --N(R.sup.a)C(O)O--;
wherein R.sup.a is hydrogen or methyl optionally substituted by one
or more F;
[0125] D and F are independently selected from fluoro, methoxy or
ethoxy;
[0126] m is 0, 1, or 2; wherein the values of R.sup.1 may be the
same or different;
[0127] R.sup.2 is fluoro;
[0128] n is 0 or 1;
[0129] R.sup.3 is amino;
[0130] R.sup.4 is halo;
[0131] p is 0, 1 or 2, wherein the values of R.sup.4 may be the
same or different;
[0132] or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide thereof.
[0133] In another aspect of the invention, preferred compounds of
the invention are any one of the Examples, or a pharmaceutically
acceptable salt or an in vivo hydrolysable ester or amide
thereof.
[0134] In another aspect of the invention there is provided a
compound of the formula (I) or a or a pharmaceutically acceptable
salt thereof.
[0135] Another aspect of the present invention provides a process
for preparing a compound of formula (I) or a pharmaceutically
acceptable salt or an in vivo hydrolysable ester thereof which
process (wherein Ring A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, m, n
and p are, unless otherwise specified, as defined in formula (I))
comprises of:
(a) The reaction of a compound of the formula (II)
##STR00003##
wherein X is a reactive group, with a compound of the formula
(III)
##STR00004##
wherein L.sup.1 and L.sup.2 are ligands; (b) The reaction of a
compound of the formula (IV)
##STR00005##
wherein L.sup.1 and L.sup.2 are ligands, with a compound of the
formula (V)
##STR00006##
wherein X is a reactive group; or (c) The reaction, in the presence
of 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium
chloride, of a compound of the formula (VI)
##STR00007##
with a compound of the formula (VII)
##STR00008##
and thereafter if necessary: i) converting a compound of the
formula (I) into another compound of the formula (I); and/or ii)
removing any protecting groups.
[0136] A suitable base for process (a), (b) or (c) is, for example,
an organic amine base such as, for example, pyridine, 2,6-lutidine,
collidine, 4-dimethylaminopyridine, triethylamine, morpholine,
N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for
example, an alkali or alkaline earth metal carbonate or hydroxide,
for example sodium carbonate, potassium carbonate, calcium
carbonate, sodium hydroxide or potassium hydroxide, or, for
example, an alkali metal hydride, for example sodium hydride, or a
metal alkoxide such as sodium ethoxide.
[0137] A suitable reactive group X is, for example, a halo, alkoxy,
aryloxy or sulphonyloxy group, for example a chloro, bromo,
methoxy, phenoxy, methanesulphonyloxy, trifluoromethanesulphonyloxy
or toluene-4-sulphonyloxy group. The reactions are conveniently
carried out in the presence of a suitable inert solvent or diluent,
for example an alkanol or ester such as methanol, ethanol,
isopropanol or ethyl acetate, a halogenated solvent such as
methylene chloride, chloroform or carbon tetrachloride, an ether
such as tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxan, an
aromatic solvent such as toluene, or a dipolar aprotic solvent such
as N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one or dimethylsulphoxide. The reactions are
conveniently carried out at a temperature in the range, for
example, 10 to 250.degree. C., preferably in the range 40 to
80.degree. C.;
[0138] A suitable value for the ligands L.sup.1 and L.sup.2 which
are present on the boron atom include, for example, a hydroxy,
(1-4C)alkoxy or (1-6C)alkyl ligand, for example a hydroxy, methoxy,
ethoxy, propoxy, isopropoxy, butoxy, methyl, ethyl, propyl,
isopropyl or butyl ligand. Alternatively the ligands L.sup.1 and
L.sup.2 may be linked such that, together with the boron atom to
which they are attached, they form a ring. For example, L.sup.1 and
L.sup.2 together may define an oxy-(2-4C)alkylene-oxy group, for
example an oxyethyleneoxy or oxytrimethyleneoxy group such that,
together with the boron atom to which they are attached, they form
a cyclic boronic acid ester group;
[0139] A suitable catalyst for process (a) or (b) includes, for
example, a metallic catalyst such as a palladium(0), palladium(II),
nickel(0) or nickel(II) catalyst, for example
tetrakis(triphenylphosphine)palladium(0), palladium(II) chloride,
palladium(II) bromide, bis(triphenylphosphine)palladium(II)
chloride, tetrakis(triphenylphosphine)nickel(0), nickel(II)
chloride, nickel(II) bromide or bis(triphenylphosphine)nickel(II)
chloride. In addition a free radical initiator may conveniently be
added, for example an azo compound such as
azo(bisisobutyronitrile);
[0140] It will be appreciated that certain of the various ring
substituents in the compounds of the present invention may be
introduced by standard aromatic substitution reactions or generated
by conventional functional group modifications either prior to or
immediately following the processes mentioned above, and as such
are included in the process aspect of the invention. Such reactions
and modifications include, for example, introduction of a
substituent by means of an aromatic substitution reaction,
reduction of substituents, alkylation of substituents and oxidation
of substituents. The reagents and reaction conditions for such
procedures are well known in the chemical art. Particular examples
of aromatic substitution reactions include the introduction of a
nitro group using concentrated nitric acid, the introduction of an
acyl group using, for example, an acyl halide and Lewis acid (such
as aluminium trichloride) under Friedel Crafts conditions; the
introduction of an alkyl group using an alkyl halide and Lewis acid
(such as aluminium trichloride) under Friedel Crafts conditions;
and the introduction of a halo group. Particular examples of
modifications include the reduction of a nitro group to an amino
group by for example, catalytic hydrogenation with a nickel
catalyst or treatment with iron in the presence of hydrochloric
acid with heating; oxidation of alkylthio to alkylsulphinyl or
alkylsulphonyl.
[0141] It will also be appreciated that in some of the reactions
mentioned herein it may be necessary/desirable to protect any
sensitive groups in the compounds. The instances where protection
is necessary or desirable and suitable methods for protection are
known to those skilled in the art. Conventional protecting groups
may be used in accordance with standard practice (for illustration
see T. W. Green, Protective Groups in Organic Synthesis, John Wiley
and Sons, 1991). Thus, if reactants include groups such as amino,
carboxy or hydroxy it may be desirable to protect the group in some
of the reactions mentioned herein.
[0142] A suitable protecting group for an amino or alkylamino group
is, for example, an acyl group, for example an alkanoyl group such
as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl,
ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl
group, for example benzyloxycarbonyl, or an aroyl group, for
example benzoyl. The deprotection conditions for the above
protecting groups necessarily vary with the choice of protecting
group. Thus, for example, an acyl group such as an alkanoyl or
alkoxycarbonyl group or an aroyl group may be removed for example,
by hydrolysis with a suitable base such as an alkali metal
hydroxide, for example lithium or sodium hydroxide. Alternatively
an acyl group such as a t-butoxycarbonyl group may be removed, for
example, by treatment with a suitable acid as hydrochloric,
sulphuric or phosphoric acid or trifluoroacetic acid and an
arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be
removed, for example, by hydrogenation over a catalyst such as
palladium-on-carbon, or by treatment with a Lewis acid for example
boron tris(trifluoroacetate). A suitable alternative protecting
group for a primary amino group is, for example, a phthaloyl group
which may be removed by treatment with an alkylamine, for example
dimethylaminopropylamine, or with hydrazine.
[0143] A suitable protecting group for a hydroxy group is, for
example, an acyl group, for example an alkanoyl group such as
acetyl, an aroyl group, for example benzoyl, or an arylmethyl
group, for example benzyl. The deprotection conditions for the
above protecting groups will necessarily vary with the choice of
protecting group. Thus, for example, an acyl group such as an
alkanoyl or an aroyl group may be removed, for example, by
hydrolysis with a suitable base such as an alkali metal hydroxide,
for example lithium or sodium hydroxide. Alternatively an
arylmethyl group such as a benzyl group may be removed, for
example, by hydrogenation over a catalyst such as
palladium-on-carbon.
[0144] A suitable protecting group for a carboxy group is, for
example, an esterifying group, for example a methyl or an ethyl
group which may be removed, for example, by hydrolysis with a base
such as sodium hydroxide, or for example a t-butyl group which may
be removed, for example, by treatment with an acid, for example an
organic acid such as trifluoroacetic acid, or for example a benzyl
group which may be removed, for example, by hydrogenation over a
catalyst such as palladium-on-carbon.
[0145] The protecting groups may be removed at any convenient stage
in the synthesis using conventional techniques well known in the
chemical art.
Biological Assays
[0146] The following assays can be used to measure the effects of
the compounds of the present invention as HDAC inhibitors, as
inhibitors in vitro of pooled histone deacetylases from nuclear
extracts prepared from the human cervical cancer cell line HeLa, as
inhibitors in vitro of recombinant human HDAC1 produced in Hi5
insect cells, and as inducers in vitro of Histone H3 acetylation in
whole cells.
(a) In Vitro Enzyme Assay of Pooled Histone Deacetylases
[0147] HDAC inhibitors were screened against pooled histone
deacetylases from nuclear extracts prepared from the human cervical
cancer cell line HeLa.
[0148] The deacetylase assays were carried out in a 40 .mu.l
reaction. 2.5 .mu.g of nuclear extract diluted in 15 .mu.l of
reaction buffer (25 mM Tris HCl (pH 8), 137 mM NaCl, 2.7 mM KCl, 1
mM MgCl.sub.2) was mixed with either buffer alone (5 .mu.l) or
buffer containing compound (5 .mu.l) for 30 minutes at ambient
temperature. 25 .mu.M fluor-de-lys substrate (Biomol) diluted in 20
.mu.l of buffer was then added to the reaction and incubated for
one hour at ambient temperature. The reaction was stopped by
addition of an equal volume (40 .mu.l) fluor de lys developer
(Biomol) containing Trichostatin A at 2 .mu.M. The reaction was
allowed to develop for 30 minutes at ambient temperature and then
fluorescence measured at an excitation wavelength of 360 nM and an
emission wavelength of 465 nM. IC.sub.50 values for HDAC enzyme
inhibitors were determined by performing dose response curves with
individual compounds and determining the concentration of inhibitor
producing fifty percent decrease in the maximal signal (no
inhibitor control).
(b) In Vitro Enzyme Assay of Recombinant HDAC1
[0149] HDAC inhibitors were screened against recombinant human
HDAC1 produced in Hi5 insect cells. The enzyme was cloned with a
FLAG tag at the C-terminal of the gene and affinity purified using
Anti-FLAG M2 agarose from SIGMA (A2220).
[0150] The deacetylase assays were carried out in a 50 .mu.l
reaction. 75 ng of enzyme diluted in 15 .mu.l of reaction buffer
(25 mM Tris HCl (pH 8), 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl.sub.2)
was mixed with either buffer alone (5 .mu.l) or buffer containing
compound (10 .mu.l) for 30 minutes at ambient temperature. 50 .mu.M
fluor-de-lys substrate (Biomol) diluted in 25 .mu.l of buffer was
then added to the reaction and incubated for one hour at ambient
temperature. The reaction was stopped by addition of an equal
volume (50 .mu.l) fluor de lys developer (Biomol) containing
Trichostatin A at 2 .mu.M. The reaction was allowed to develop for
30 minutes at ambient temperature and then fluorescence measured at
an excitation wavelength of 360 nM and an emission wavelength of
465 nM. IC.sub.50 values for HDAC enzyme inhibitors were determined
by performing dose response curves with individual compounds and
determining the concentration of inhibitor producing fifty percent
decrease in the maximal signal (no inhibitor control).
(c) In Vitro Enzyme Assay of Histone Deacetylase Activity in Whole
Cells
[0151] Histone H3 acetylation in whole cells using
immunohistochemistry and analysis using the Cellomics arrayscan.
A549 cells were seeded in 96 well plates at 1.times.10.sup.4
cells/well, and allowed to adhere overnight. They were treated with
inhibitors for 24 hours and then fixed in 1.8% formaldehyde in tris
buffered saline (TBS) for one hour. Cells were permeabilized with
ice-cold methanol for 5 minutes, rinsed in TBS and then blocked in
TBS 3% low-fat dried milk for 90 minutes. Cells were then incubated
with polyclonal antibodies specific for the acetylated histone H3
(Upstate #06-599) diluted 1 in 500 in TBS 3% milk for one hour.
Cells were rinsed three times in TBS and then incubated with
fluorescein conjugated secondary antibodies (Molecular Probes
#A11008) & Hoechst 333542 (1 .mu.g/ml) (Molecular Probes
#H3570) in TBS 1% Bovine serum albumin (Sigma #B6917) for one hour.
Unbound antibody was removed by three rinses with TBS and after the
final rinse 100 .mu.l of TBS was added to the cells and the plates
sealed and analysed using the Cellomics arrayscan.
[0152] EC.sub.50 values for HDAC inhibitors were determined by
performing dose response curves with individual compounds and then
determining the concentration of inhibitor producing fifty percent
of the maximal signal (reference compound control--Trichostatin A
(Sigma)).
[0153] Although the pharmacological properties of the compounds of
the formula (I) vary with structural change as expected, in general
activity possessed by compounds of the Formula I, may be
demonstrated at the following concentrations or doses in one or
more of the above tests (a) and (b):--
[0154] Test (a): --IC.sub.50 in the range, for example, <50.0
.mu.M;
[0155] Test (b): --IC.sub.50 in the range, for example, <2.5
.mu.M;
[0156] Test (c): --EC.sub.50 in the range, for example, <9.0
.mu.M;
[0157] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a compound of
the formula (I), or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide thereof, as defined hereinbefore in
association with a pharmaceutically-acceptable diluent or
carrier.
[0158] The composition may be in a form suitable for oral
administration, for example as a tablet or capsule, for parenteral
injection (including intravenous, subcutaneous, intramuscular,
intravascular or infusion) as a sterile solution, suspension or
emulsion, for topical administration as an ointment or cream or for
rectal administration as a suppository.
[0159] In general the above compositions may be prepared in a
conventional manner using conventional excipients.
[0160] The compound of formula (I) will normally be administered to
a warm-blooded animal at a unit dose within the range 5-5000 mg per
square meter body area of the animal, i.e. approximately 0.1-100
mg/kg, and this normally provides a therapeutically-effective dose.
A unit dose form such as a tablet or capsule will usually contain,
for example 1-250 mg of active ingredient. Preferably a daily dose
in the range of 1-50 mg/kg is employed. However the daily dose will
necessarily be varied depending upon the host treated, the
particular route of administration, and the severity of the illness
being treated. Accordingly the optimum dosage may be determined by
the practitioner who is treating any particular patient.
[0161] We have found that the compounds defined in the present
invention, or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide thereof, are effective cell cycle
inhibitors (anti-cell proliferation agents), which property is
believed to arise from their HDAC inhibitory properties. We also
believe that the compounds of the present invention may be involved
in the inhibition of angiogenesis, activation of apoptosis and
differentiation. Accordingly the compounds of the present invention
are expected to be useful in the treatment of diseases or medical
conditions mediated alone or in part by HDAC enzymes, i.e. the
compounds may be used to produce a HDAC inhibitory effect in a
warm-blooded animal in need of such treatment. Thus the compounds
of the present invention provide a method for treating the
proliferation of malignant cells characterised by inhibition of
HDAC enzymes, i.e. the compounds may be used to produce an
anti-proliferative effect mediated alone or in part by the
inhibition of HDACs.
[0162] According to one aspect of the present invention there is
provided a compound of the formula (I), or a pharmaceutically
acceptable salt or in vivo hydrolysable ester or amide thereof, as
defined hereinbefore for use in a method of treatment of the human
or animal body by therapy.
[0163] Thus according to a further aspect of the invention there is
provided a compound of the formula (I), or a pharmaceutically
acceptable salt or in vivo hydrolysable ester or amide thereof, as
defined hereinbefore for use as a medicament.
[0164] According to a further aspect of the invention there is
provided the use of a compound of the formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide thereof, as defined hereinbefore in the manufacture of a
medicament for use in the production of a HDAC inhibitory effect in
a warm-blooded animal such as man.
[0165] According to a further feature of this aspect of the
invention there is provided a method for producing a HDAC
inhibitory effect in a warm-blooded animal, such as man, in need of
such treatment which comprises administering to said animal an
effective amount of a compound of the formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide thereof, as defined hereinbefore.
[0166] According to a further aspect of the invention there is
provided the use of a compound of the formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide thereof, as defined hereinbefore in the manufacture of a
medicament for use in the production of a cell cycle inhibitory
(anti-cell-proliferation) effect in a warm-blooded animal such as
man.
[0167] According to a further feature of this aspect of the
invention there is provided a method for producing a cell cycle
inhibitory (anti-cell-proliferation) effect in a warm-blooded
animal, such as man, in need of such treatment which comprises
administering to said animal an effective amount of a compound of
the formula (I), or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide thereof, as defined hereinbefore.
[0168] According to an additional feature of this aspect of the
invention there is provided a method of treating cancer in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of the formula (I), or a pharmaceutically acceptable salt
or in vivo hydrolysable ester or amide thereof, as defined
hereinbefore.
[0169] According to a further feature of the invention there is 74a
compound of the formula (I), or a pharmaceutically acceptable salt
or in vivo hydrolysable ester or amide thereof, as defined
hereinbefore in the manufacture of a medicament for use in the
treatment of cancer.
[0170] According to an additional feature of this aspect of the
invention there is provided a compound of the formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide thereof, as defined hereinbefore, for use in the treatment of
cancer.
[0171] In a further aspect of the present invention there is
provided the use of a compound of the formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide thereof, as defined hereinbefore, in the manufacture of a
medicament for use in lung cancer, colorectal cancer, breast
cancer, prostate cancer, lymphoma and leukaemia.
[0172] In a further aspect of the present invention the is provided
a method of treating lung cancer, colorectal cancer, breast cancer,
prostate cancer, lymphoma or leukaemia, in a warm-blooded animal,
such as man, in need of such treatment which comprises
administering to said animal an effective amount of a compound of
the formula (I), or a pharmaceutically acceptable salt or in vivo
hydrolysable ester or amide thereof, as defined hereinbefore.
[0173] Cancers that are amenable to treatment with the present
invention include oesophageal cancer, myeloma, hepatocellular,
pancreatic and cervical cancer, Ewings tumour, neuroblastoma,
kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer,
prostate cancer, bladder cancer, melanoma, lung cancer [including
non small cell lung cancer (NSCLC) and small cell lung cancer
(SCLC)], gastric cancer, head and neck cancer, brain cancer, renal
cancer, lymphoma and leukaemia.
[0174] There is further provided is a compound of the formula (I),
or a pharmaceutically acceptable salt or in vivo hydrolysable ester
or amide thereof, as defined hereinbefore, for use in a method of
treating inflammatory diseases, autoimmune diseases and
allergic/atopic diseases.
[0175] In particular a compound of the formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide thereof, as defined hereinbefore, is provided for use in a
method of treating inflammation of the joint (especially rheumatoid
arthritis, osteoarthritis and gout), inflammation of the
gastro-intestinal tract (especially inflammatory bowel disease,
ulcerative colitis and gastritis), inflammation of the skin
(especially psoriasis, eczema, dermatitis), multiple sclerosis,
atherosclerosis, spondyloarthropathies (ankylosing spondylitis,
psoriatic arthritis, arthritis connected to ulcerative colitis),
AIDS-related neuropathies, systemic lupus erythematosus, asthma,
chronic obstructive lung diseases, bronchitis, pleuritis, adult
respiratory distress syndrome, sepsis, and acute and chronic
hepatitis (either viral, bacterial or toxic).
[0176] Further provided is a compound of the formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide thereof, as defined hereinbefore, for use as a medicament in
the treatment of inflammatory diseases, autoimmune diseases and
allergic/atopic diseases in a warm-blooded animal such as man.
[0177] In particular a compound of the formula (I), or a
pharmaceutically acceptable salt or in vivo hydrolysable ester or
amide thereof, as defined hereinbefore, is provided for use as a
medicament in the treatment of inflammation of the joint
(especially rheumatoid arthritis, osteoarthritis and gout),
inflammation of the gastro-intestinal tract (especially
inflammatory bowel disease, ulcerative colitis and gastritis),
inflammation of the skin (especially psoriasis, eczema,
dermatitis), multiple sclerosis, atherosclerosis,
spondyloarthropathies (ankylosing spondylitis, psoriatic arthritis,
arthritis connected to ulcerative colitis), AIDS-related
neuropathies, systemic lupus erythematosus, asthma, chronic
obstructive lung diseases, bronchitis, pleuritis, adult respiratory
distress syndrome, sepsis, and acute and chronic hepatitis (either
viral, bacterial or toxic).
[0178] Further provided is the use of a compound of the formula
(I), or a pharmaceutically acceptable salt or in vivo hydrolysable
ester or amide thereof, as defined hereinbefore, in the manufacture
of a medicament for use in the treatment of inflammatory diseases,
autoimmune diseases and allergic/atopic diseases in a warm-blooded
animal such as man.
[0179] As stated above the size of the dose required for the
therapeutic or prophylactic treatment of a particular
cell-proliferation disease will necessarily be varied depending on
the host treated, the route of administration and the severity of
the illness being treated. A unit dose in the range, for example,
1-100 mg/kg, preferably 1-50 mg/kg is envisaged.
[0180] The HDAC inhibitory activity defined hereinbefore may be
applied as a sole therapy or may involve, in addition to a compound
of the invention, one or more other substances and/or treatments.
Such conjoint treatment may be achieved by way of the simultaneous,
sequential or separate administration of the individual components
of the treatment. In the field of medical oncology it is normal
practice to use a combination of different forms of treatment to
treat each patient with cancer. In medical oncology the other
component(s) of such conjoint treatment in addition to the cell
cycle inhibitory treatment defined hereinbefore may be: surgery,
radiotherapy or chemotherapy. Such chemotherapy may include one or
more of the following categories of anti-tumour agents:
(i) other cell cycle inhibitory agents that work by the same or
different mechanisms from those defined hereinbefore, for example
cyclin dependent kinase (CDK) inhibitors, in particular CDK2
inhibitors; (ii) cytostatic agents such as antioestrogens (for
example tamoxifen, toremifene, raloxifene, droloxifene,
iodoxyfene), progestogens (for example megestrol acetate),
aromatase inhibitors (for example anastrozole, letrazole, vorazole,
exemestane), antiprogestogens, antiandrogens (for example
flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH
agonists and antagonists (for example goserelin acetate,
luprolide), inhibitors of testosterone 5.alpha.-dihydroreductase
(for example finasteride), anti-invasion agents (for example
metalloproteinase inhibitors like marimastat and inhibitors of
urokinase plasminogen activator receptor function) and inhibitors
of growth factor function, (such growth factors include for example
vascular endothelial growth factor, epithelial growth factor,
platelet derived growth factor and hepatocyte growth factor such
inhibitors include growth factor antibodies, growth factor receptor
antibodies, tyrosine kinase inhibitors and serine/threonine kinase
inhibitors); (iii) antiproliferative/antineoplastic drugs and
combinations thereof, as used in medical oncology, such as
antimetabolites (for example antifolates like methotrexate,
fluoropyrimidines like 5-fluorouracil, purine and adenosine
analogues, cytosine arabinoside); antitumour antibiotics (for
example anthracyclines like doxorubicin, daunomycin, epirubicin and
idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum
derivatives (for example cisplatin, carboplatin); alkylating agents
(for example nitrogen mustard, melphalan, chlorambucil, busulphan,
cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic
agents (for example vinca alkaloids like vincrisitine and taxoids
like taxol, taxotere); topoisomerase inhibitors (for example
epipodophyllotoxins like etoposide and teniposide, amsacrine,
topotecan); (iv) antiangiogenic agents that work by different
mechanisms from those defined hereinbefore (for example receptor
tyrosine kinases like Tie-2, inhibitors of integrin .alpha.v.beta.3
function, angiostatin, razoxin, thalidomide), and including
vascular targeting agents; and (v) differentiation agents (for
example retinoic acid and vitamin D).
[0181] According to this aspect of the invention there is provided
a pharmaceutical product comprising a compound of the formula (I)
as defined hereinbefore and an additional anti-tumour substance as
defined hereinbefore for the conjoint treatment of cancer.
[0182] In addition to their use in therapeutic medicine, the
compounds of formula (I) and their pharmaceutically acceptable
salts or in vivo hydrolysable esters or amides thereof, are also
useful as pharmacological tools in the development and
standardisation of in vitro and in vivo test systems for the
evaluation of the effects of inhibitors of cell cycle activity in
laboratory animals such as cats, dogs, rabbits, monkeys, rats and
mice, as part of the search for new therapeutic agents.
[0183] For the benefit of the reader, where a pharmaceutical
composition comprising a compound of formula (I), or the use of a
compound of formula (I) as a medicament, or the use of a compound
of formula (I) in a method of treatment, or the use of a compound
of formula (I) in the manufacture of a medicament, or the use of a
compound of formula (I) in the treatment of cancer, is described
herein, it is to be understood that here, the definition of the
compound of formula (I) includes the compounds
N-(2-amino-6-hydroxyphenyl)-4-(1-methylhomopiperazin-4-yl)benzamide;
N-(2-amino-6-methylphenyl)-4-(1-methylhomopiperazin-4-yl)benzamide;
N-(2-aminophenyl)-4-(1-t-butoxycarbonylhomopiperazin-4-yl)benzamide;
and N-(2-aminophenyl)-4-(1-methylhomopiperazin-4-yl)benzamide.
[0184] The invention will now be illustrated in the following
Examples in which, generally:
[0185] (i) operations were carried out at ambient temperature, i.e.
in the range 17 to 25.degree. C. and under an atmosphere of an
inert gas such as argon unless otherwise stated;
[0186] (ii) evaporations were carried out by rotary evaporation in
vacuo and work-up procedures were carried out after removal of
residual solids by filtration;
[0187] (iii) column chromatography (by the flash procedure) and
medium pressure liquid chromatography (MPLC) were performed on
Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art.
9303) reversed-phase silica obtained from E. Merck, Darmstadt,
Germany or high pressure liquid chromatography (HPLC) was performed
on C18 reverse phase silica, for example on a Dynamax C-18 60 .ANG.
preparative reversed-phase column;
[0188] (iv) yields, where present, are not necessarily the maximum
attainable;
[0189] (v) in general, the structures of the end-products of the
Formula (I) were confirmed by nuclear magnetic resonance (NMR)
and/or mass spectral techniques; fast-atom bombardment (FAB) mass
spectral data were obtained using a Platform spectrometer and,
where appropriate, either positive ion data or negative ion data
were collected; NMR chemical shift values were measured on the
delta scale [proton magnetic resonance spectra were determined
using a Jeol JNM EX 400 spectrometer operating at a field strength
of 400 MHz, Varian Gemini 2000 spectrometer operating at a field
strength of 300 MHz or a Bruker AM300 spectrometer operating at a
field strength of 300 MHz]; the following abbreviations have been
used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad;
[0190] (vi) intermediates were not generally fully characterised
and purity was assessed by thin layer chromatographic, HPLC,
infa-red (IR) and/or NMR analysis;
[0191] (vii) melting points are uncorrected and were determined
using a Mettler SP62 automatic melting point apparatus or an
oil-bath apparatus; melting points for the end-products of the
formula (I) were determined after crystallisation from a
conventional organic solvent such as ethanol, methanol, acetone,
ether or hexane, alone or in admixture;
[0192] (viii) the following abbreviations have been used:-- [0193]
DMF N,N-dimethylformamide [0194] DMSO dimethylsulphoxide [0195] THF
tetrahydrofuran
EXAMPLE 1
N-(2-Aminophenyl)-4-pyridin-4-ylbenzamide
[0196] N-(2-t-Butoxycarbonylaminophenyl)-4-pyridin-4-ylbenzamide
(Method 1; 100 mg, 0.26 mmol), 1,4-dioxane (2 ml) and a 4M solution
of hydrogen chloride in dioxane (2 ml) were stirred at ambient
temperature for approximately 20 hours. The resultant precipitate
was collected by filtration and washed with iso-hexane and diethyl
ether and dried in vacuo to give the title compound as its
hydrochloride (43 mg, 46%); NMR Spectrum: (DMSO-d.sub.6) 7.31 (m,
2H), 7.39 (t, 1H), 7.54 (t, 1H), 8.17 (d, 2H), 8.30 (d, 2H), 8.40
(d, 2H), 8.96 (d, 2H), 10.62 (s, 1H); Mass Spectrum: M+H.sup.+
290.
EXAMPLE 2
[0197] Using an analogous procedure to that described in Example 1,
the appropriate N-(2-t-butoxycarbonylaminophenyl)-benzamide
starting material was reacted to give the compounds described in
Table 1. Unless otherwise stated, each compound was obtained as its
hydrochloride salt.
TABLE-US-00001 TABLE 1 ##STR00009## Note R.sup.1 Analytical Data SM
1 quinolin-8-yl NMR Spectrum: (DMSO-d.sub.6) 7.37 (t, Meth 2 1 H),
7.49 (t, 1 H), 7.62 (d, 1 H), 7.78 (m, 5 H), 7.93 (d, 1 H), 8.18
(d, 1 H), 8.31 (d, 2 H), 8.72 (d, 1 H), 9.04 (dd, 1 H), 10.75 (s, 1
H); Mass Spectrum: M + H.sup.+ 340. 2 pyridin-3-yl NMR Spectrum:
(DMSO-d.sub.6) 7.32 (m, Meth 3 2 H), 7.43 (d, 1 H), 7.57 (d, 1 H),
7.95 (dd, 1 H), 8.03 (d, 2 H), 8.27 (d, 2 H), 8.72 (d, 1 H), 8.83
(d, 1 H), 9.25 (s, 1 H), 10.60 (s, 1 H); Mass Spectrum: M + H.sup.+
290. 3 pyridin-2-yl NMR Spectrum: (DMSO-d.sub.6): 6.63 (t, Meth 4
Formic acid salt 1 H), 6.80 (d, 1 H), 6.98 (t, 1 H), 7.23 (d, 1 H),
7.44 (t, 1 H), 7.95 (t, 1 H), 8.13 (m, 3 H), 8.22 (d, 2 H), 8.72
(d, 1 H), 9.74 (s, 1 H); Mass Spectrum: M + H.sup.+ 290. 4
6-(methoxy)-1,2-pyrazin-3-yl NMR Spectrum: (DMSO-d.sub.6) 4.09 (s,
Meth 5 3 H), 7.32 (m, 4 H), 7.49 (m, 1 H), 8.24 (m, 5 H), 10.46 (s,
1 H); Mass Spectrum: M + H.sup.+ 321. 5 furan-3-yl NMR Spectrum:
(DMSO-d.sub.6) 7.09 (s, Meth 6 1 H), 7.25 (m, 3 H), 7.58 (d, 1 H),
7.83 (d, 3 H), 8.06 (d, 2 H), 8.33 (s, 1 H), 10.32 (s, 1 H); Mass
Spectrum: M + H.sup.+ 279. 6 2-methylpyridin-4-yl NMR Spectrum:
(DMSO-d.sub.6) 2.82 (s, Meth 7 3 H), 7.21 (m, 1 H), 7.29 (m, 2 H),
7.51 (d, 2 H), 8.20 (d, 2 H), 8.31 (m, 3 H), 8.41 (s, 1 H), 8.89
(d, 1 H), 10.51 (s, 1 H); Mass Spectrum: M + H.sup.+ 304. 7
2-fluoropyridin-4-yl NMR Spectrum: (DMSO-d.sub.6) 7.26-7.33 Meth 8
(m, 3 H), 7.49 (d, 1 H), 7.68 (s, 1 H), 7.83 (m, 1 H), 8.08 (d, 2
H), 8.23 (d, 2 H), 8.37 (d, 1 H), 10.50 (s, 1 H); Mass Spectrum: M
+ H.sup.+ 308. 8 thiazol-2-yl NMR Spectrum: (DMSO-d.sub.6) 7.39 (t,
Meth 9 1 H), 7.48 (t, 1 H), 7.56 (d, 1 H), 7.64 (d, 1 H), 7.92 (d,
1 H), 8.02 (d, 1 H), 8.13 (d, 2 H), 8.27 (d, 2 H), 10.77 (s, 1 H);
Mass Spectrum: M + H.sup.+ 296. 9 2-amino-pyrimidin-6-yl NMR
Spectrum: (DMSO-d.sub.6) 7.32 (m, Meth 10 2 H), 7.41 (m, 1 H), 7.57
(m, 2 H), 8.30 (m, 4 H), 8.51 (d, 1 H), 10.64 (s, 1 H); Mass
Spectrum: M + H.sup.+ 306. 10 pyrimidin-6-yl NMR Spectrum:
(DMSO-d.sub.6) 7.33 (m, Meth 11 3 H), 7.52 (m, 1 H), 8.25 (m, 3 H),
8.40 (d, 2 H), 8.95 (d, 1 H), 9.33 (s, 1 H), 10.52 (s, 1 H); Mass
Spectrum: M + H.sup.+ 291. 11 2-chloro-pyrimidin-6-yl NMR Spectrum:
(DMSO-d.sub.6) 7.39 (m, Meth 12 2 H), 7.46 (dd, 1 H), 7.58 (dd, 1
H), 8.30 (m, 3 H), 8.39 (d, 2 H), 8.93 (d, 1 H), 10.72 (s, 1 H);
Mass Spectrum: M + H.sup.+ 325.
EXAMPLE 3
N-(2-Aminophenyl)-4-morpholinobenzamide
[0198] A solution of 1-(N-t-butoxycarbonylamino)-2-aminobenzene
(Method 17; 104 mg, 0.5 mmol) in DMF (1.6 ml) was added to
4-morpholinobenzoic acid (149 mg, 0.5 mmol) followed by
4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium
chloride (Method 18, 138 mg, 0.5 mmol) and the reaction mixture
stirred at ambient temperature for 48 hours. The solvent was
removed in vacuo and the resultant residue partitioned between
ethyl acetate and water. The organic phase was separated, then
washed with water, brine and dried over sodium sulfate then
filtered. The organic extracts were concentrated by half and a 4M
solution of hydrogen chloride in 1,4-dioxane (1 ml) added. The
reaction mixture was stirred at ambient temperature for a further
64 hours and the resultant precipitate was collected by filtration.
This solid was purified by preparative mass triggered HPLC, eluting
with an increasing gradient of acetonitrile in water (which
contains 5% (v/v) of a 1% (v/v) solution of formic acid in
methanol) to afford the title compound (17 mg, 12%); NMR Spectrum:
(DMSO-d.sub.6) 3.25 (m, 4H), 3.76 (m, 4H), 4.83 (s, 2H), 6.60 (m,
1H), 6.79 (dd, 1H), 6.96 (m, 1H), 7.01 (d, 2H), 7.16 (dd, 1H), 7.90
(d, 2H), 9.31 (brs, 1H); Mass Spectrum: M+H.sup.+ 298.
EXAMPLE 4
N-(2-Aminophenyl)-4-(1-methylpiperidin-4-yl)benzamide
[0199] N-(2-Aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 48
mg, 0.16 mmol) was stirred and dissolved in anhydrous DMF (2 ml) at
ambient temperature. Potassium carbonate (23 mg, 0.16 mmol) was
added followed by iodomethane (0.01 ml, 0.16 mmol) and the mixture
stirred for 3 hours. The reaction mixture was diluted with water
(20 ml) and extracted with ethyl acetate. The combined extracts
were washed once with brine, dried over magnesium sulfate, filtered
and the solvent evaporated to give the title compound as a
colourless solid (16 mg, 32%); NMR Spectrum: (DMSO-d.sub.6) 1.70
(m, 4H), 1.96 (m, 2H), 2.18 (s, 3H), 2.85 (m, 2H), 3.03 (m, 1H),
4.84 (b, 2H), 6.57 (m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.16 (d,
1H), 7.36 (d, 2H), 7.99 (d, 2H), 9.54 (b, 1H); Mass Spectrum:
M+H.sup.+ 310.
EXAMPLE 5
N-(2-Aminophenyl)-4-piperidin-4-ylbenzamide
[0200] A 4M solution of hydrogen chloride in dioxane (5 ml, 20
mmol) was added to a stirred solution of
N-(2-t-butoxycarbonylaminophenyl)-4-(1-t-butoxycarbonylpiperidin-4-yl)ben-
zamide (Method 15, 693 mg, 1.40 mmol) in 1,4-dioxane (5 ml) and the
mixture stirred at ambient temperature for 18 hours. The resultant
precipitate was filtered and washed with diethyl ether. The
resultant solid was dissolved in water and basified to pH 12 with
2M solution of aqueous sodium hydroxide. The resultant precipitate
was filtered, washed with water and dried in vacuo to give the
title compound (338 mg, 82%); NMR Spectrum: (DMSO-d.sub.6) 1.52 (m,
2H), 1.69 (m, 2H), 2.60 (m, 3H), 3.02 (m, 2H), 4.84 (br, 2H), 6.58
(m, 1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.16 (d, 1H), 7.34 (d, 2H),
7.89 (d, 2H), 9.53 (br, 1H); Mass Spectrum: M+H.sup.+ 296.
EXAMPLE 6
N-(2-Aminophenyl)-4-(1-methylpiperazin-4-yl)benzamide
[0201]
N-(2-t-Butoxycarbonylaminophenyl)-4-(1-methylpiperazin-4-yl)benzami-
de (Method 16, 196 mg, 0.48 mmol) was dissolved in a 1M solution of
hydrogen chloride in diethyl ether (7.2 ml, 7.2 mmol) and stirred
at ambient temperature for 24 hours. The resultant precipitate was
collected by filtration and washed with diethyl ether. To the solid
was added a 2M solution of aqueous sodium hydroxide (5 ml) and the
mixture extracted with ethyl acetate. The organic extract was dried
over magnesium sulfate, filtered and evaporated to afford the title
compound as a colourless solid (16 mg, 11%); NMR Spectrum:
(CDCl.sub.3) 2.36 (s, 3H), 2.57 (t, 4H), 3.33 (t, 4H), 3.88 (br,
2H), 6.81 (m, 2H), 6.91 (d, 2H) 7.06 (t, 1H), 7.27 (d, 1H), 7.79
(s, 1H), 7.80 (m, 2H); Mass Spectrum: M+H.sup.+ 311.
EXAMPLE 7
N-(2-Aminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]benzamide
[0202]
N-(2-Aminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]ben-
zamide trihydrochloride (Method 19, 28 mg, 0.052 mmol) was
dissolved in water (2 ml) and basified to pH 10 by the of addition
of 28% aqueous ammonium hydroxide solution (2 drops). The resultant
precipitate was collected by filtration and dried under vacuum at
40.degree. C. overnight to afford the title compound as a yellow
solid (9 mg, 40%); NMR (DMSO-d.sub.6): 1.75 (m, 2H), 2.37 (m, 6H),
3.41 (brm, 2H), 3.59 (m, 4H), 4.92 (s, 2H), 6.62 (t, 1H), 6.80 (d,
1H), 6.99 (t, 1H), 7.21 (m, 2H), 7.28 (t, 1H), 8.11 (d, 2H), 8.22
(d, 2H), 8.39 (d, 1H), 9.74 (s, 1H); Mass Spectrum: M+H.sup.+
433.
EXAMPLE 8
N-(2-Aminophenyl)-4-[2-(3-morpholinoaminoethyl)-pyrimidin-6-yl]benzamide
[0203]
N-(2-Aminophenyl)-4-[2-(3-morpholinoaminoethyl)-pyrimidin-6-yl]benz-
amide trihydrochloride (Method 24, 22 mg, 0.042 mmol) was reacted
in an analogous manner to that described for Example 7 to afford
the title compound as a pale yellow solid (12 mg, 68%); NMR
(DMSO-d.sub.6): 2.45 (m, 4H), 2.54 (m, 2H), 3.51 (m, 2H), 3.59 (m,
4H), 4.92 (s, 2H), 6.62 (t, 1H), 6.80 (d, 1H), 6.99 (t, 1H), 7.07
(t, 1H), 7.20 (d, 1H), 7.24 (d, 1H), 8.11 (d, 2H), 8.23 (d, 2H),
8.40 (d, 1H), 9.74 (s, 1H); Mass Spectrum: M+H.sup.+ 419.
EXAMPLE 9
[0204] Using an analogous procedure to that described in Example 1,
the appropriate N-(2-t-butoxycarbonylaminophenyl)benzamide starting
material was reacted to give the compounds described in Table 2.
Unless otherwise stated, each compound was obtained as its
hydrochloride salt.
TABLE-US-00002 TABLE 2 ##STR00010## Note R.sup.1 Analytical Data SM
1 ##STR00011## NMR Spectrum: (DMSO-d.sub.6)1.39 (m, 1 H), 1.70 (m,
1 H),1.79 (m, 4 H), 2.06 (m, 2 H),2.85 (m, 2 H), 3.12 (m, 2 H),3.52
(m, 2 H), 4.41 (d, 2 H), 7.33(m, 2 H), 7.41 (m, 2 H), 7.59 (m,1 H),
8.27 (d, 2 H), 8.32 (d, 2 H),8.48 (d, 1 H), 10.10 (s, 1 H),10.61
(s, 1 H); Mass Spectrum:M + H.sup.+ 431. Meth 29 2 ##STR00012## NMR
Spectrum: (DMSO-d.sub.6)2.17 (qn, 2 H) 3.42 (m, 2 H),4.33 (t, 2 H),
7.30 (m, 2 H), 7.37(m, 2 H), 7.57 (m, 1 H), 7.75(brm, 2 H), 7.85
(t, 1 H), 8.26 (s,4 H), 8.45 (d, 1 H), 9.21 (s, 1 H),10.56 (s, 1
H); Mass Spectrum:M + H.sup.+ 414. Meth 30 3 ##STR00013## NMR
Spectrum: (DMSO-d.sub.6)2.08 (m, 2 H), 2.84 (s, 3 H), 3.28(m, 2 H),
3.49 (brm, 6 H), 3.69(brm, 4 H), 7.32 (m, 2 H), 7.40(m, 2 H), 7.57
(m, 1 H), 7.74(brm, 1 H), 8.26 (d, 2 H), 8.32(m, 2 H), 8.47 (d, 1
H), 10.58 (s,1 H); Mass Spectrum: M + H.sup.+446. Meth 31 4
##STR00014## NMR Spectrum: (DMSO-d.sub.6)1.22 (t, 6 H), 1.69 (m, 2
H), 1.77(m, 2 H), 3.08 (m, 6 H), 3.50 (m,2 H), 7.33 (m, 2 H), 7.44
(m,2 H), 7.60 (m, 1 H), 7.98 (brs,1 H), 8.30 (m, 4 H), 8.48 (d,1
H), 10.12 (s, 1 H), 10.64 (s,1 H); Mass Spectrum: M + H.sup.+433.
Meth 32 5 ##STR00015## NMR Spectrum: (DMSO-d.sub.6)1.25 (t, 6 H),
3.22 (qn, 4 H), 3.30(q, 2 H), 3.80 (brm, 2 H), 7.32(m, 2 H), 7.40
(m, 2 H), 7.56 (m,1 H), 7.61 (brs, 1 H), 8.25 (d,2 H), 8.32 (d, 2
H), 8.50 (d, 1 H),10.14 (brs, 1 H), 10.57 (s, 1 H);Mass Spectrum: M
+ H.sup.+ 405. Meth 33 6 ##STR00016## NMR Spectrum:
(DMSO-d.sub.6)4.82 (s, 2 H), 7.35 (m, 2 H), 7.41(d, 1 H), 7.45 (m,
1 H), 7.59 (m,1 H), 8.02 (dd, 1 H), 8.19 (brs,1 H), 8.42 (s, 4 H),
8.48 (m, 1 H),8.58 (m, 1 H), 8.81 (d, 1 H), 8.92(s, 1 H), 10.62 (s,
1 H); MassSpectrum: M + H.sup.+ 397. Meth 34 7 ##STR00017## NMR
Spectrum: (DMSO-d.sub.6)1.41 (m, 1 H), 1.73 (m, 1 H),1.80 (m, 4 H),
2.95 (m, 2 H),3.30 (m, 2 H), 3.54 (m, 2 H),3.81 (m, 2 H), 7.30 (m,
2 H),7.35 (m, 1 H), 7.40 (d, 1 H), 7.53(d, 1 H), 7.63 (brs, 1 H),
8.24 (d,2 H), 8.31 (d, 2 H), 8.49 (d, 1 H),9.93 (brs, 1 H), 10.51
(s, 1 H);Mass Spectrum: M + H.sup.+ 417. Meth 35 8 ##STR00018## NMR
Spectrum: (DMSO-d.sub.6)1.86 (qn, 2 H), 3.26 (s, 3 H),3.45 (t, 2
H), 3.50 (brm, 2 H),7.32 (m, 2 H), 7.39 (m, 2 H),7.54 (m, 1 H),
8.24 (d, 2 H), 8.33(d, 2 H), 8.47 (d, 1 H), 10.56 (s,1 H); Mass
Spectrum: M + H.sup.+378. Meth 36 9 ##STR00019## NMR Spectrum:
(DMSO-d.sub.6)2.25 (m, 2 H) 3.08 (m, 2 H), 3.27(m, 2 H), 3.45 (d, 2
H), 3.85 (t,2 H), 3.97 (m, 2 H), 4.43 (t, 2 H),7.24 (s, 1 H), 7.36
(t, 1 H), 7.43(t, 1 H), 7.44 (d, 1 H), 7.51 (d,1 H), 7.62 (d, 1 H),
7.98 (d, 2 H),8.27 (d, 2 H), 8.29 (d, 1 H),10.67 (s, 1 H), 11.26
(s, 1 H);Mass Spectrum: M + H.sup.+ 433. Meth 37 10 ##STR00020##
NMR Spectrum: (DMSO-d.sub.6)2.76 (s, 3 H), 7.28 (m, 3 H), 7.51(d, 1
H), 7.93 (d, 1 H), 8.05 (d,2 H), 8.27 (d, 2 H), 8.75 (d, 1 H),9.17
(s, 1 H), 10.46 (s, 1 H);Mass Spectrum: M + H.sup.+ 304. Meth 38 11
##STR00021## NMR Spectrum: (DMSO-d.sub.6)1.36 (m, 1 H), 1.78-1.66
(m,5 H) 2.05 (m, 2 H), 2.86 (q, 2 H),3.13 (m, 2 H), 3.57 (m, 4
H),7.36 (m, 4 H), 7.53 (d, 1 H), 8.23(d, 2 H), 8.32 (d, 2 H), 8.37
(d,1 H), 9.78 (brs, 1 H) 10.59 (s,1 H); Mass Spectrum: M +
H.sup.+487. Meth 39 12 ##STR00022## NMR Spectrum:
(DMSO-d.sub.6)7.39 (t, 1 H), 7.45 (t, 1 H), 7.51(d, 1 H), 7.63 (d,
1 H), 7.80 (d,1 H), 8.34 (d, 2 H), 8.39 (d, 2 H),8.65 (d, 1 H),
9.35 (s, 1 H),10.77 (s, 1 H); Mass Spectrum:M + H.sup.+ 347. Meth
40 13 ##STR00023## NMR Spectrum (DMSO-d.sub.6)1.39 (m, 1 H), 1.70
(m, 1 H),1.78 (m, 4 H), 2.02 (m, 2 H),2.86 (m, 2 H), 3.08 (m, 2
H),3.42 (m, 4 H), 7.37 (m, 2 H),7.48 (d, 1 H), 7.61 (d, 1 H),
7.86(d, 2 H), 8.21 (d, 2 H), 8.81 (s,2 H), 10.17 (s, 1 H), 10.56
(s,1 H); Mass Spectrum: M + H.sup.+431. Meth 41 14 ##STR00024## NMR
Spectrum (DMSO-d.sub.6)2.03 (m, 2 H), 2.82 (t, 3 H), 3.23(t, 2 H),
3.45 (m, 6 H), 3.67 (m,4 H), 7.34 (t, 1 H), 7.42 (t, 1 H),7.50 (d,
1 H), 7.62 (d, 1 H), 7.85(d, 2 H), 8.21 (d, 2 H), 8.81 (s,2 H),
10.60 (s, 1 H); MassSpectrum: M + H.sup.+ 446. Meth 42 15
##STR00025## NMR Spectrum (DMSO-d.sub.6)2.00 (m, 2 H), 3.08 (m, 2
H),3.18 (m, 2 H), 3.43 (m, 4 H),3.87 (m 2 H), 4.00 (m, 2 H),
7.34(m, 2 H), 7.42 (d, 1 H) 7.58 (d,1 H), 7.87 (d, 2 H), 8.19 (d, 2
H),8.82 (s, 2 H), 10.46 (s, 1 H),10.82 (s, 1 H); Mass Spectrum:M +
H.sup.+ 433. Meth 43 16 ##STR00026## NMR Spectrum
(DMSO-d.sub.6)1.91 (m, 2 H), 2.05 (m, 2 H),3.13 (m, 2 H), 3.68 (m,
4 H),4.75 (t, 2 H), 7.36 (m, 2 H), 7.47(d, 1 H), 7.60 (d, 1 H),
8.00 (d,2 H), 8.26 (d, 2 H), 9.11 (s, 2 H),10.60 (s, 1 H), 10.80
(s, 1 H);Mass Spectrum: M + H.sup.+ 404. Meth 45 17 ##STR00027##
NMR Spectrum: 2.10 (m, 2 H),3.06 (m, 2 H), 3.21 (M, 2 H),3.43 (d, 2
H), 3.55 (m, 2 H), 3.84(m, 2 H), 3.94 (m, 2 H), 7.37 (m,2 H), 7.42
(m, 1 H), 7.51 (d,1 H), 7.64 (d, 1 H), 8.23 (d, 2 H),8.37 (d 2 H),
8.40 (d, 1 H),10.75, (s, 1 H), 11.10 (brs, 1 H);Mass Spectrum: M +
H.sup.+ 489. Meth 65 18 ##STR00028## NMR Spectrum:
(DMSO-d.sub.6)1.41 (m, 1 H), 1.72 (m, 1 H),1.80 (m, 4 H), 2.96 (m,
2 H),3.32 (q, 2 H), 3.57 (m, 2 H), 3.83(m, 2 H), 7.34 (m, 2 H),
7.38 (d,1 H), 7.41 (m, 1 H), 7.58 (m,1 H), 8.25 (d, 2 H), 8.35 (d,
2 H),8.39 (d, 1 H), 9.92 (s, 1 H),10.63 (s, 1 H); Mass Spectrum:M +
H.sup.+ 474. Meth 66 19 ##STR00029## NMR Spectrum:
(DMSO-d.sub.6):1.20 (m, 5 H), 1.54 (d, 1 H), 1.69(d, 2 H), 1.78 (d,
2 H), 3.30 (m,1 H), 5.28 (s, 2 H), 7.29 (d, 1 H),7.38 (t, 1 H),
7.44 (t, 1 H), 7.52(d, 1 H), 7.62 (d, 1 H), 8.00 (s,1 H), 8.10 (d,
2 H), 8.25 (d, 2 H),10.66 (s, 1 H); Mass Spectrum:M + H.sup.+ 451.
Meth 67 20 ##STR00030## NMR Spectrum: (DMSO-d.sub.6):2.59 (s, 3 H),
4.93 (s, 2 H), 6.62(t, 1 H), 6.81 (d, 1 H), 7.01 (t,1 H), 7.20 (d,
1 H), 7.75 (d, 1 H),7.84 (d, 1 H), 7.94 (d, 2 H), 8.08(d, 2 H),
8.15 (d. 1 H), 8.65 (d,1 H), 9.75 (s, 1 H); MassSpectrum: M +
H.sup.+ 419 Meth 68 21 ##STR00031## NMR Spectrum:
(DMSO-d.sub.6):7.34 (t, 1 H), 7.44 (t, 1 H), 7.60(d, 1 H), 7.70 (d,
1 H), 7.96 (m,2 H), 8.10 (d, 2 H), 8.44 (d, 2 H),8.67 (m, 1 H),
9.08 (m, 1 H),10.88 (s, 1 H); Mass Spectrum:M + H.sup.+ 346. Meth
74 22 ##STR00032## NMR Spectrum: (DMSO-d.sub.6):7.37 (m, 1 H), 7.43
(t, 1 H), 7.49(dd, 1 H), 7.61 (dd, 1 H), 7.76(d, 1 H), 8.11 (d, 1
H), 8.17 (d,2 H), 8.33 (d, 2 H), 9.21 (s, 1 H),10.73 (s, 1 H); Mass
Spectrum:M + H.sup.+ 347. Meth 75
EXAMPLE 10
[0205] Using an analogous procedure to that described in Example 1,
the appropriate N-(2-t-butoxycarbonylaminophenyl)benzamide starting
material was reacted to give the compounds described in Table 3.
Unless otherwise stated, each compound was obtained as its
hydrochloride salt.
TABLE-US-00003 TABLE 3 ##STR00033## 1 3-pyridyl NMR Spectrum:
(DMSO-d.sub.6): 7.40 (m, Meth 44 2 H), 7.50 (d, 1 H), 7.63 (d, 1
H), 7.91 (t, 1 H), 7.99 (t, 1 H), 8.18 (m, 2 H), 8.58 (d, 1 H),
8.89 (d, 1 H), 9.10 (s, 1 H), 10.76 (s, 1 H); Mass Spectrum: M +
H.sup.+ 308.
EXAMPLE 11
[0206] Using an analogous procedure to that described in Example 7,
the appropriate N-(2-aminophenyl)-benzamide hydrochloride salt
starting material was reacted to give the compounds described in
Table 4. Unless otherwise stated, each compound was obtained as its
free base.
TABLE-US-00004 TABLE 4 ##STR00034## Note R.sup.1 Analytical Data SM
1 ##STR00035## NMR Spectrum: (DMSO-d.sub.6) 1.74 (m,2 H), 2.42
(brm, 4 H), 3.34 (m, 4 H), 3.60(m, 4 H), 4.91 (s, 2 H), 6.62 (t, 2
H), 6.81(m, 3 H), 6.99 (t, 1 H), 7.20 (d, 1 H), 7.79(d, 2 H), 8.09
(m, 3 H), 9.72 (s, 1 H), MassSpectrum: M + H.sup.+ 432. Meth 46 2
##STR00036## NMR Spectrum: (DMSO-d.sub.6) 3.92 (s, 3 H),5.00 (brs,
2 H), 6.63 (t, 1 H), 6.82 (d, 1 H),7.01 (m, 1 H), 7.23 (d, 1 H),
8.20 (d, 2 H),8.70 (s, 1 H), 8.98 (d, 2 H), 9.06 (s, 1 H),9.82 (s,
1 H); Mass Spectrum: M + H.sup.+ 345. Meth 47 3 ##STR00037## NMR
Spectrum: (DMSO-d.sub.6) 2.84 (m,4 H), 3.61 (m, 4 H), 4.62 (s, 2
H), 6.62 (t,1 H), 6.80 (d, 1 H), 6.99 (t, 1 H), 7.21 (d,1 H), 8.09
(d, 2 H), 8.21 (d, 2 H), 8.31 (s,1 H), 8.53 (s, 1 H), 9.72 (s, 1
H); MassSpectrum: M + H.sup.+ 375. Meth 48 4 ##STR00038## NMR
Spectrum: (DMSO-d.sub.6 @ 373K)1.22 (t, 6 H) 3.43 (qn, 4 H), 4.72
(brs, 2 H),6.65 (t, 1 H), 6.83 (d, 1 H), 6.90 (m, 2 H),7.01 (t, 1
H), 7.28 (d, 1 H), 8.06 (d, 2 H),8.39 (d, 2 H), 9.44 (s, 1 H);
MassSpectrum: M + H.sup.+ 378. Meth 49 5 ##STR00039## NMR Spectrum:
(DMSO-d.sub.6) 2.26(s, 3 H), 2.43 (m, 4 H), 3.86 (m, 4 H),4.92 (s,
2 H), 6.62 (t, 1 H), 6.81 (d,1 H), 6.99 (t, 1 H), 7.20 (d, 1 H),
7.31(d, 1 H), 8.11 (d, 2 H), 8.26 (d, 2 H),8.50 (d, 1 H), 9.75 (s,
1 H); MassSpectrum: M + H.sup.+ 389. Meth 50
EXAMPLE 12
N-(2-aminophenyl)-4-[5-(piperidin-1-ylmethyl)-1,3-thiazol-2-yl]benzamide
[0207]
N-(2-t-butoxycarbonylaminophenyl)-4-[5-(piperidin-1-ylmethyl)-1,3-t-
hiazol-2-yl]benzamide (Method 51, 271 mg, 0.54 mmol) was suspended
in 1,4 dioxane (4 ml) and a 4M solution of hydrogen chloride in
1,4-dioxane (4 ml) added. The reaction mixture was stirred at
ambient temperature for 17 hours. The resultant precipitate was
collected by filtration, washed with diethyl ether and air dried to
yield the title compound as its hydrochloride salt. The crude solid
was purified using an Oasis MCX column, eluting with
methanol/dichloromethane (0-100%) then 2M ammonia in
methanol/methanol (0-20%) to give the title compound as its free
base (119 mg, 56%); NMR Spectrum: (DMSO-d.sub.6) 1.40 (m, 2H), 1.50
(m, 4H), 2.41 (m, 4H), 3.74 (s, 2H), 4.94 (s, 2H), 6.61 (t, 1H),
6.80 (d, 1H), 6.99 (t, 1H), 7.18 (d, 1H), 7.80 (s, 1H), 8.06 (d,
2H), 8.09 (d, 2H), 9.78 (s, 1H); Mass Spectrum: M+H.sup.+ 402.
EXAMPLE 13
N-(2-aminophenyl)-4-[2-({3-[2-(dimethylamino)ethoxy]propyl}amino)pyrimidin-
-4-yl]benzamide
[0208] To a solution of dimethylaminoethoxypropylamine (2.02 mg,
12.5 .mu.mol) in N,N-dimethylacetamide (125 .mu.l), was added a
solution of
N-(2-aminophenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]benzamide
(Method 62, 2.2 mg, 5 .mu.mol) in N,N-dimethylacetamide (100.mu.).
The reaction mixture was heated to 5.degree. C. and agitated for a
period of 16 hours, before being evaporated to dryness to give the
title compound; Mass Spectrum: M+H.sup.+ 435.
EXAMPLE 14
[0209] Using an analogous procedure to that described in Example
13, N-(2-aminophenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]benzamide
(Method 62) was reacted with the appropriate amine to give the
compounds described in Table 5.
TABLE-US-00005 TABLE 5 ##STR00040## Note R.sup.1 Analytical Data SM
1 ##STR00041## Mass Spectrum: M + H.sup.+ 453. CAS53485-07-7 2
##STR00042## Mass Spectrum: M + H.sup.+ 461. CAS3529-09-7
EXAMPLE 15
[0210] Using an analogous procedure to that described in Example 5,
the appropriate N-(2-aminophenyl)benzamide hydrochloride salt
starting material was reacted to give the compounds described in
Table 6. Unless otherwise stated, each compound was obtained as its
free base.
TABLE-US-00006 TABLE 6 ##STR00043## Note R.sup.1 Analytical Data SM
1 ##STR00044## NMR Spectrum: (DMSO-d.sub.6):4.93 (s, 2 H), 5.46 (s,
2 H), 6.62(t, 1 H), 6.80 (d, 1 H), 7.01 (m,2 H), 7.21 (d, 1 H),
7.32 (m, 2 H),7.50 (d, 2 H), 8.10 (m, 5 H), 9.78(s, 1 H), 9.83 (s,
1 H); MassSpectrum: M + H.sup.+ 445 Meth 70
EXAMPLE 16
N-(2-aminophenyl)-4-piperazin-1-ylbenzamide
[0211] To a solution of 4-(4-t-butoxycarbonylpiperazin-1-yl)benzoic
acid (1.0 g, 3.3 mmol) and 1-(t-butoxycarbonylamino)-2-aminobenzene
(Method 17, 0.68 g, 3.3 mmol) in DMF (10 ml) was added
4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium
chloride (1.1 g, 4.0 mmol) (Method 18). The mixture was stirred at
ambient temperature for 20 hours. The mixture was concentrated in
vacuo and the residue partitioned between water and ethyl acetate.
The organic phase was separated and the aqueous reextracted with
ethyl acetate. The combined organic extracts were dried over
magnesium sulfate and evaporated. The residue was purified by flash
chromatography (eluting with 4:1-1:1 isohexane/ethyl acetate). The
product was dissolved in 1,4-dioxane (2.5 ml) and treated with a 4M
solution of hydrogen chloride in 1,4-dioxane (2.5 ml). The mixture
was stirred at ambient temperature for 4 hours. The resulting solid
was collected by filtration, treated with a 2M aqueous solution of
sodium hydroxide and extracted with ethyl acetate. The organic
extract was dried over magnesium sulfate to afford the title
compound as a colourless solid (176 mg, 92%); NMR Spectrum:
(DMSO-d.sub.6) 2.89 (t, 4H), 3.25 (t, 4H), 4.90 (s, 2H), 6.66 (t,
1H), 6.84 (d, 1H), 7.01 (m, 3H), 7.21 (d, 1H), 7.92 (d, 2H), 9.48
(s, 1H); Mass Spectrum: M+H.sup.+ 297.
EXAMPLE 17
(RS)--N-(2-aminophenyl)-4-piperidin-3-ylbenzamide
[0212] To a solution of
N-(2-t-butoxycarbonylaminophenyl)-4-pyridin-3-ylbenzamide (2.0 g,
5.1 mmol) (Method 3) in ethanol (20 ml) was added PtO.sub.2 (200
mg) and the resulting mixture was heated at 80.degree. C. under an
atmosphere of hydrogen at 80 Bar for 16 hours. The mixture was
allowed to cool and was filtered and evaporated to afford
(RS)--N-(2-t-butoxycarbonylaminophenyl)-4-piperidin-3-ylbenzamide
(1.9 g, 94%).
[0213] To a solution of
(RS)--N-(2-t-butoxycarbonylaminophenyl)-4-piperidin-3-ylbenzamide
(1.0 g, 2.5 mmol) in 1,4-dioxane (9.5 ml) was added a solution of
hydrogen chloride (4M in 1,4-dioxane, 9.5 ml, 38 mmol) and the
mixture stirred at ambient temperature for 6 hours. The solid
formed was collected by filtration, washed with diethyl ether and
dried in vacuo. It was treated with a 2M solution of aqueous sodium
hydroxide and extracted three times with ethyl acetate. The
combined organic extracts were dried over magnesium sulfate and
evaporated to afford the product as a colourless solid (0.73 g,
99%); NMR Spectrum: (DMSO-d.sub.6) 1.71 (m, 4H), 2.61 (m, 2H), 2.75
(m, 1H), 3.03 (m, 2H), 4.92 (s, 2H), 6.65 (t, 1H), 6.83 (d, 1H),
7.02 (t, 1H), 7.23 (d, 1H), 7.42 (d, 2H), 7.96 (d, 2H), 9.61 (s,
1H); Mass Spectrum: M+H.sup.+ 296.
EXAMPLE 18
N-(2-aminophenyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide
dihydrochloride
[0214] t-Butyl
4-{4-[({2-[(t-butoxycarbonyl)amino]phenyl}amino)carbonyl]phenyl}-3,6-dihy-
dropyridine-1(2H)-carboxylate (Method 71, 62 mg, 0.13 mmol) was
stirred and dissolved in 1,4-dioxane (0.4 ml) and a 4M solution of
hydrogen chloride in 1,4-dioxane (0.4 ml) added. The reaction
mixture was stirred at ambient temperature for 24 hours. The
resultant precipitate was collected by filtration, washed with
diethyl ether and dried in vacuo at 60.degree. C. to yield the
title compound as an off white solid (34 mg, 89%); NMR Spectrum:
(DMSO-d.sub.6) 2.70 (m, 2H), 3.30 (m, 2H), 3.76 (m, 2H), 6.33 (m,
1H), 7.23 (m, 2H), 7.33 (m, 1H), 7.49 (m, 1H), 7.61 (d, 2H), 8.10
(d, 2H), 9.27 (s, 1H); Mass Spectrum: M+H.sup.+ 294.
EXAMPLE 19
N-(2-aminophenyl)-4-(1-{3-[(2-fluorophenyl)amino]-3-oxopropyl}piperidin-4--
yl)benzamide
[0215] N-(2-aminophenyl)-4-piperidine-4-ylbenzamide (Example 5, 162
mg, 0.55 mmol), potassium carbonate (153 mg, 1.1 mmol) and
(2-fluorophenyl)-3-bromopropionamide (149 mg, 0.61 mmol) in DMF (5
ml) were stirred at ambient temperature for approximately 20 hours.
The mixture was concentrated in vacuo and the residue partitioned
between water and ethyl acetate. The organic layer was separated,
dried over magnesium sulfate and evaporated. The residue was
purified by flash chromatography (eluting with 0-25%
methanol/dichloromethane to afford the product as a colourless
solid (76 mg, 30%); NMR Spectrum: (CDCl.sub.3) 1.92 (m, 4H), 2.18
(m, 1H), 2.57 (t, 2H), 2.64 (m, 2H) 2.72 (t, 2H), 3.19 (d, 2H),
3.62 (s, 2H), 6.80 (m, 2H), 7.05 (m, 4H), 7.31 (d, 1H), 7.34 (d,
2H), 7.87 (d, 2H), 8.08 (s, 1H), 8.44 (t, 1H), 11.39 (s, 1H); Mass
Spectrum: M+H.sup.+ 461.
EXAMPLE 20
4-(1-acetylpiperidin-4-yl)-N-(2-aminophenyl)benzamide
[0216] N-(2-aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 30
mg, 0.10 mmol) was stirred and dissolved in N,N-dimethylacetamide
(2 ml) and acetic anhydride (0.011 ml, 0.11 mmol) added. The
reaction was stirred at ambient temperature for 1 hour and then
partitioned between water and ethyl acetate. The organic layer was
separated, washed with brine and dried over magnesium sulfate,
filtered and evaporated to give the title compound as a colourless
solid (23 mg, 68%); NMR Spectrum: (DMSO-d.sub.6) 1.48 (m, 1H), 1.64
(m, 1H), 1.79 (m, 2H), 2.02 (s, 3H), 2.59 (m, 1H), 2.84 (m, 1H),
3.13 (m, 1H), 3.92 (d, 1H), 4.53 (d, 1H), 4.85 (s, 2H), 6.58 (m,
1H), 6.76 (d, 1H), 6.95 (m, 1H), 7.15 (d, 1H), 7.37 (d, 2H), 7.90
(d, 2H), 9.55 (s, 1H); Mass Spectrum: M+H.sup.+ 338.
EXAMPLE 21
[0217] Using an analogous procedure to that described in Example
19, N-(2-aminophenyl)-4-piperidin-4-ylbenzamide (Example 5) was
reacted to give the compounds described in Table 7.
TABLE-US-00007 TABLE 7 ##STR00045## Note R.sup.1 Analytical Data SM
1 ##STR00046## NMR Spectrum: (DMSO-d.sub.6)1.39 (s, 9 H), 1.59 (m,
2 H), 1.71(m, 2 H), 1.78 (m, 2 H), 2.02 (m,2 H), 2.34 (m, 2 H),
2.61 (m,1 H), 2.98 (m, 4 H), 4.87 (s,2 H), 6.60 (t, 1 H), 6.78 (d,
1 H),6.83 (s, 1 H), 6.97 (t, 1 H), 7.17(d, 1 H), 7.38 (d, 2 H),
7.91 (d,2 H), 9.56 (s, 1 H); MassSpectrum: M + H.sup.+ 453. 2
##STR00047## NMR Spectrum: (DMSO-d.sub.6)1.73 (m, 4 H), 2.07 (m, 2
H),2.53 (m, 1 H), 2.92 (m, 2 H),3.51 (s, 2 H), 4.85 (s, 2 H),
6.56(t, 1 H), 6.76 (d, 1 H), 6.95 (t,1 H), 7.15 (d, 1 H), 7.31 (m,7
H), 7.89 (d, 2 H), 9.53 (s, 1 H);Mass Spectrum: M + H.sup.+ 386. 3
##STR00048## NMR Spectrum: (DMSO-d.sub.6)1.73 (m, 4 H), 2.37 (m, 7
H),2.98 (t, 2 H), 3.30 (m, 2 H), 3.71(m, 1 H), 4.88 (s, 2 H), 6.60
(t,1 H), 6.78 (d, 1 H), 6.97 (t, 1 H),7.16 (d, 1 H), 7.38 (d, 2 H),
7.55(s, 1 H), 7.91 (d, 2 H), 9.58 (s,1 H); Mass Spectrum: M +
H.sup.+393. 4 ##STR00049## NMR Spectrum: (DMSO-d.sub.6)1.73 (m, 4
H), 2.18 (t, 2 H), 2.59(m, 1 H), 2.75 (t, 2 H), 3.09 (d,2 H), 3.76
(s, 3H), 4.09 (t, 2 H),4.89 (s, 2 H), 6.60 (t, 1 H), 6.79(d, 1 H),
6.89 (m, 2 H), 6.99 (m,3 H), 7.18 (d, 1 H), 7.39 (d, 2 H),7.92 (d,
2 H), 9.60 (s, 1 H);Mass Spectrum: M + H.sup.+ 446. 5 ##STR00050##
NMR Spectrum: (CDCl.sub.3) 1.88(m, 4 H), 2.29 (m, 2 H), 2.62 (m,1
H), 2.90 (t, 2 H), 3.18 (m, 2 H),3.89 (s, 2 H), 4.18 (t, 2 H),
6.86(m, 2 H), 6.96 (m, 3 H), 7.11 (t,1 H), 7.31 (m, 5 H), 7.86 (d,2
H), 7.90 (s, 1 H); MassSpectrum: M + H.sup.+ 416. 6 ##STR00051##
NMR Spectrum: (DMSO-d.sub.6)1.73 (m, 4 H), 2.00 (s, 3 H), 2.16(t, 2
H), 2.46 (m, 1 H), 2.72 (t,2 H), 3.07 (m, 2 H), 4.06 (t, 2 H),4.89
(s, 2 H), 6.59 (t, 1 H), 6.78(d, 1 H), 6.89 (d, 2 H), 6.96 (t,1 H),
7.17 (d, 1 H), 7.39 (d, 2 H),7.47 (d, 2 H), 7.91 (d, 2 H), 9.58(s,
1 H), 9.77 (s, 1 H); MassSpectrum: M + H.sup.+ 473. CAS
no57011-90-2JustusLiebigsAnn.Chem.1899,287.DE85988 7 ##STR00052##
NMR Spectrum: (DMSO-d.sub.6)1.61 (m, 2 H), 1.74 (m, 2 H),2.20 (t, 2
H), 2.67 (m, 1 H), 2.73(t, 2 H), 2.92 (m, 2 H), 3.27 (m,2 H), 3.34
(s, 2 H), 3.75 (t, 2 H),4.86 (s, 2 H), 6.60 (t, 1 H), 6.78(d, 1 H),
6.97 (t, 1 H), 7.09 (t,1 H), 7.18 (m, 3 H), 7.35 (d,2 H), 7.60 (m,
1 H), 7.91 (d,2 H), 9.55 (s, 1 H); MassSpectrum: M + H.sup.+ 470.
Method 73 8 ##STR00053## NMR Spectrum: (DMSO-d.sub.6)1.73 (m, 4 H),
2.16 (m, 2 H),2.60 (m, 1 H), 2.74 (t, 2 H), 3.07(m, 2 H), 4.10 (t,
2 H), 4.88 (s,2 H), 6.60 (t, 1 H), 6.78 (d, 1 H),6.98 (m, 3 H),
7.17 (d, 1 H),7.33 (d, 2 H), 7.39 (d, 2 H), 7.91(d, 2 H), 9.56 (s,
1 H); MassSpectrum: M + H.sup.+ 450. 9 ##STR00054## NMR Spectrum:
(DMSO-d.sub.6)1.75 (m, 4 H), 2.18 (m, 2 H),2.61 (m, 1 H), 2.96 (m,
2 H),4.86 (s, 2 H), 6.60 (t, 1 H), 6.79(d, 1 H), 6.97 (t, 1 H),
7.18 (d,1 H), 7.27 (t, 1 H), 7.39 (d, 2 H),7.48 (d, 1 H), 7.78 (t,
1 H), 7.92(d, 2 H), 8.50 (d, 1 H), 9.56 (s,1 H); Mass Spectrum: M +
H.sup.+388. 10 ##STR00055## Mass Spectrum: M + H.sup.+ 411 11
##STR00056## Mass Spectrum: M + H.sup.+ 411 12 ##STR00057## Mass
Spectrum: M + H.sup.+ 416 13 ##STR00058## Mass Spectrum: M +
H.sup.+ 439 14 ##STR00059## Mass Spectrum: M + H.sup.+ 412 15
##STR00060## Mass Spectrum: M + H.sup.+ 370 16 ##STR00061## Mass
Spectrum: M + H.sup.+ 380 17 ##STR00062## Mass Spectrum: M +
H.sup.+ 444 18 ##STR00063## Mass Spectrum: M + H.sup.+ 403 19
##STR00064## Mass Spectrum: M + H.sup.+ 382
EXAMPLE 22
N-(2-aminophenyl)-4-[1-(4-bromobenzoyl)piperidin-4-yl]benzamide
[0218] To a solution of 4-bromobenzoic acid (1.0 g, 3.3 mmol) in
DMF (5 ml) was added benzotriazolyloxytripyrollidinophosphonium
hexafluorophosphate (99 mg, 0.19 mmol) and the mixture stirred at
ambient temperature for 30 minutes.
N-(2-aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 50 mg, 0.17
mmol) was added and the mixture stirred for a further 24 hours. The
resulting solution was absorbed onto an SCX-2 column, washed with
methanol (2 column volumes) and eluted with a 2M solution of
ammonia in methanol (2 column volumes) to afford the product. This
was purified by flash chromatography (eluting with 0-20%
methanol/dichloromethane) to afford the title compound as a
colourless solid (29 mg, 18%); NMR Spectrum: (DMSO-d.sub.6) 1.70
(m, 4H), 2.60 (m, 1H), 2.91 (m, 2H), 3.31 (m, 2H), 4.89 (s, 2H),
6.60 (t, 1H), 6.78 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.43 (d,
4H), 7.67 (d, 2H), 7.93 (d, 2H), 9.60 (s, 1H); Mass Spectrum:
M+H.sup.+ 478.
EXAMPLE 23
[0219] Using an analogous procedure to that described in Example
19, (RS)--N-(2-aminophenyl)-4-piperidin-3-ylbenzamide was reacted
to give the compounds described in Table 8.
TABLE-US-00008 TABLE 8 ##STR00065## Note R.sup.1 Analytical Data SM
1 ##STR00066## NMR Spectrum: (DMSO-d.sub.6)1.47 (m, 1 H), 1.66 (m,
2 H),1.85 (m, 1 H), 2.30 (m, 2 H),2.88 (m, 3 H), 3.29 (m, 1 H),3.62
(s, 3 H), 4.87 (s, 2 H), 6.61(t, 1 H), 6.79 (d, 1 H), 6.98 (t,1 H),
7.18 (d, 1 H), 7.40 (d, 2 H),7.92 (d, 2 H), 9.57 (s, 1 H);Mass
Spectrum: M + H.sup.+ 368. 2 ##STR00067## NMR Spectrum:
(CDCl.sub.3) 1.42(m, 1 H), 1.88 (m, 3 H), 2.39 (m,3 H), 2.93 (m, 4
H), 3.67 and3.99 (m, 1 H), 3.80 (m, 2 H),6.78 (m, 2 H), 7.02 (t, 1
H), 7.28(m, 3 H), 7.72 (s, 1 H), 7.77 (d,2 H); Mass Spectrum: M +
H.sup.+380. 3 ##STR00068## NMR Spectrum: (DMSO-d.sub.6)1.48 (m, 2
H), 1.68 (m, 1 H),1.80 (m, 1 H), 1.90 (t, 2 H), 2.15(t, 1 H), 2.22
(t, 1 H), 2.72 (m,2 H), 2.82 (m, 1 H), 2.90 (s,2 H), 3.73 (m, 2 H),
4.86 (s,2 H), 6.60 (t, 1 H), 6.78 (d, 1 H),6.97 (t, 1 H), 7.14 (m,
4 H), 7.36(d, 2 H), 7.57 (m, 1 H), 7.91 (d,2 H), 9.56 (s, 1 H);
MassSpectrum: M + H.sup.+ 469. Method 73 4 ##STR00069## Mass
Spectrum: M + H.sup.+ 461 CAS no13288-06-7J. Prakt.Chem.,1881,242 5
##STR00070## Mass Spectrum: M + H.sup.+ 366 6 ##STR00071## Mass
Spectrum: M + H.sup.+ 386 7 ##STR00072## Mass Spectrum: M + H.sup.+
458 8 ##STR00073## Mass Spectrum: M + H.sup.+ 485 9 ##STR00074##
Mass Spectrum: M + H.sup.+ 432 10 ##STR00075## Mass Spectrum: M +
H.sup.+ 394 CAS no.53012-70-7J. Het.Chem.1984,1157 11 ##STR00076##
Mass Spectrum: M + H.sup.+ 466 12 ##STR00077## Mass Spectrum: M +
H.sup.+ 378 13 ##STR00078## Mass Spectrum: M + H.sup.+ 473 CAS
no57011-90-2JustusLiebigsAnn.Chem.1899,287DE85988 14 ##STR00079##
Mass Spectrum: M + H.sup.+ 368 15 ##STR00080## Mass Spectrum: M +
H.sup.+ 394
EXAMPLE 24
[0220] Using an analogous procedure to that described in Example
19, N-(2-aminophenyl)-4-piperazin-1-ylbenzamide (Example 16) was
reacted to give the compounds described in Table 9
TABLE-US-00009 TABLE 9 ##STR00081## Note R.sup.1 Analytical Data SM
1 ##STR00082## NMR Spectrum: (CDCl.sub.3) 2.62(t, 2 H), 2.78 (m, 6
H), 3.45 (m,4 H), 6.83 (m, 2 H), 7.07 (m,3 H), 7.26 (s, 1 H), 7.31
(d, 1 H),7.74 (s, 1 H), 7.84 (d, 2 H), 7.96(d, 2 H), 8.41 (t, 1 H),
11.07 (s,1 H); Mass Spectrum: M + H.sup.+462. 2 ##STR00083## NMR
Spectrum: (CDCl.sub.3) 2.74(m, 4 H), 3.29 (s, 2 H), 3.37 (m,4 H),
3.74 (s, 3 H), 6.71 (m,2 H), 6.90 (d, 2 H), 7.06 (t, 1 H),7.28 (d,
1 H), 7.77 (s, 1 H), 7.80(d, 2 H); Mass Spectrum: M + H.sup.+369. 3
##STR00084## NMR Spectrum: (CDCl.sub.3) 2.61(m, 4 H), 3.33 (m, 4
H), 3.57 (s,2 H), 6.81 (m, 4 H), 6.91 (m,2 H), 7.06 (m, 2 H), 7.34
(m,3 H), 7.72 (s, 1 H), 7.80 (d, 2 H);Mass Spectrum: M + H.sup.+
387. 4 ##STR00085## NMR Spectrum: (CDCl.sub.3) 1.21(t, 6 H), 2.77
(4 H), 3.43 (m,10 H), 3.78 (s, 2 H), 6.62 (d,2 H), 6.83 (m, 2 H),
6.93 (d,2 H), 7.07 (t, 1 H), 7.30 (d, 1 H),7.69 (s, 1 H), 7.81 (d,
2 H), 7.93(d, 2 H); Mass Spectrum: M + H.sup.+486.
Preparation of the Starting Materials
[0221] The starting materials for the above examples are either
commercially available or are readily prepared by standard methods
from known materials. For example the following reactions are
illustrations but not limitations of the preparation of some of the
starting materials used in the above reactions.
Method 1
N-(2-t-Butoxycarbonylaminophenyl)-4-pyridin-4-ylbenzamide
[0222] N-(2-t-Butoxycarbonylaminophenyl)-4-bromobenzamide (Method
14; 136 mg, 0.33 mmol), pyridine-4-boronic acid (48 mg, 0.39 mmol),
tetrakis(triphenylphosphine) palladium (5 mg, 0.005 mmol), THF (2
ml) and a saturated aqueous solution of sodium hydrogen carbonate
(2 ml) were stirred at 55.degree. C. under an atmosphere of argon
for 96 hours. The cooled mixture was partitioned between ethyl
acetate and water. The organics were washed with brine, dried over
magnesium sulfate, filtered and evaporated, to give the title
compound (103 mg, 80%), which was used without further
purification; Mass Spectrum: M+H.sup.+ 390.
Method 2
N-(2-t-Butoxycarbonylaminophenyl)-4-quinolin-8-ylbenzamide
[0223] N-(2-t-Butoxycarbonylaminophenyl)-4-bromobenzamide (Method
14; 200 mg, 0.5 mmol), 8-quinoline boronic acid (104 mg, 0.6 mmol),
tetrakis(triphenylphosphine)palladium (8 mg, 0.007 mmol),
1,2-dimethoxyethane (3 ml) and a saturated aqueous solution of
sodium hydrogen carbonate (3 ml) were stirred at 80.degree. C.
under an atmosphere of argon for 20 hours. The mixture was allowed
to cool before being partitioned between ethyl acetate and water.
The organics were washed with brine, dried over magnesium sulfate,
filtered and evaporated. The resultant residue was purified by
flash column chromatography, eluting with methanol/dichloromethane
(0-10%), to give the title compound (201 mg, 84%); NMR Spectrum:
(DMSO-d.sub.6): 1.47 (s, 9H), 7.20 (m, 2H), 7.60 (m, 4H), 7.73 (t,
1H), 7.84 (t, 3H), 8.06 (d, 2H), 8.47 (d, 1H), 8.68 (s, 1H), 8.93
(m, 1H), 9.91 (s, 1H), Mass Spectrum: M+H.sup.+: 440.
Method 3
N-(2-t-Butoxycarbonylaminophenyl)-4-pyridin-3-ylbenzamide
[0224] The title compound was prepared using an analogous procedure
of Method 2 and used without further purification; Mass Spectrum:
M+H.sup.+ 390.
Method 4
N-(2-t-Butoxycarbonylaminophenyl)-4-pyridin-2-ylbenzamide
[0225]
N-(2-t-Butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-diox-
aborolan-2-yl)benzamide (Method 13; 132 mg, 0.3 mmol),
2-bromopyridine (40 mg, 0.25 mmol),
tetrakis(triphenylphosphine)palladium (4 mg, 0.004 mmol),
1,2-dimethyoxyethane (1.5 ml) and a saturated aqueous solution of
sodium hydrogen carbonate (1.5 ml) were stirred at 80-85.degree. C.
under an atmosphere of argon for 24 hours. The mixture was allowed
to cool before being partitioned between ethyl acetate and water.
The organics were separated, washed with brine, dried over
magnesium sulfate, filtered and evaporated to yield the title
compound (86 mg, 74%) which was used in the next reaction without
further purification; Mass Spectrum: M+H.sup.+ 390.
Method 5-12
[0226] Using an analogous procedure to that described in Method 4,
the
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide starting material was reacted with the
appropriate bromo compound to give the compounds described in Table
10. Where required, the crude residues were purified by flash
column chromatography, eluting with methanol/dichloromethane
(1:10).
TABLE-US-00010 TABLE 10 ##STR00086## Method R.sup.1 Analytical Data
SM 5 6-(methoxy)-1,2-pyrazin-3-yl NMR Spectrum: (DMSO-d.sub.6) 1.44
(s, Meth 13 9 H), 4.09 (s, 3 H), 7.14 (m, 2 H), 7.34 (d, 1 H), 7.57
(t, 2 H), 8.09 (d, 2 H), 8.22 (d, 2 H), 8.26 (d, 1 H); Mass
Spectrum: M + H.sup.+ 421. 6 furan-3-yl Mass Spectrum: (M +
H.sup.+-tBu) 323. Meth 13 7 2-methylpridin-4-yl NMR Spectrum:
(DMSO-d.sub.6) 1.46 (s, Meth 13 9 H), 2.57 (s, 3 H), 7.20 (m, 2 H),
7.59 (m, 3 H), 7.69 (s, 1 H), 7.98 (d, 2 H), 8.10 (d, 2 H), 8.56
(d, 1 H), 8.67 (s, 1 H), 9.92 (s, 1 H); Mass Spectrum: M + H.sup.+
404. 8 2-fluoropyridin-4-yl NMR Spectrum: (DMSO-d.sub.6) 1.46 (s,
Meth 13 9 H), 7.20 (m, 2 H), 7.57 (m, 2 H), 7.65 (s, 1 H), 7.81 (m,
1 H), 8.06 (d, 2 H), 8.12 (d, 2 H), 8.37 (d, 1 H), 8.68 (s, 1 H),
9.94 (s, 1 H); Mass Spectrum: (M + H.sup.+-Boc) 308. 9 thiazol-2-yl
Mass Spectrum: (M + H.sup.+-tBu) 340. Meth 13 10
2-amino-pyrimidn-6-yl Mass Spectrum: (M + Na.sup.+) 428. Meth 13 11
pyrimidin-6-yl Mass Spectrum: (M + H.sup.+-tBu) 335. Meth 13 12
2-chloro-pyrimidin-6-yl NMR Spectrum: (DMSO-d.sub.6) 1.46 (s, Meth
13 9 H), 7.23 (m, 2 H), 7.57 (t, 2 H), 8.15 (d, 2 H), 8.29 (d, 1
H), 8.38 (d, 2 H), 8.73 (br, 1 H), 8.91 (d, 1 H), 10.00 (s, 1 H);
Mass Spectrum: (M + H.sup.+-tBu) 369.
Method 13
N-(2-t-Butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola-
n-2-yl)benzamide
[0227] N-(2-t-Butoxycarbonylaminophenyl)-4-bromobenzamide (Method
14; 3.0 g, 7.7 mmol) was added to a solution of bis-pinacolato
diboron (2.3 g, 9.2 mmol),
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) chloride
(157 mg, 0.19 mmol) and potassium acetate (2.3 g, 23 mmol) in DMF
(48 ml) at 80.degree. C. under an atmosphere of argon for 20 hours.
The mixture was allowed to cool and the solvent removed in vacuo.
The residue was partitioned between ethyl acetate and water. The
organics were washed with brine, dried over magnesium sulphate and
evaporated to give the title compound (3.9 g, quantitative), which
was used without further purification; NMR Spectrum: (DMSO-d.sub.6)
1.14 (s, 6H), 1.31 (s, 9H), 1.43 (s, 6H), 7.16 (m, 2H), 7.52 (m,
2H). 7.79 (d, 2H), 7.95 (d, 2H), 8.66 (s, 1H), 9.86 (s, 1H); Mass
Spectrum: (M+H.sup.+-Boc) 383.
Method 14
N-(2-t-Butoxycarbonylaminophenyl)-4-bromobenzamide
[0228] 4-(4,6-Dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium
chloride (Method 18; 5.4 g, 19.4 mmol) was added to a solution of
4-bromobenzoic acid (3.5 g, 17.4 mmol) and
1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17; 4.3 g, 20.9
mmol) in DMF (100 ml) and stirred at ambient temperature for 20
hours. The reaction mixture was partitioned between water and ethyl
acetate. The organics were washed with a saturated aqueous solution
of sodium hydrogen carbonate, water, 1M aqueous hydrochloric acid,
water and brine, before being dried over magnesium sulfate. The
organics were then evaporated to give the title compound (7.1 g,
quantitative), which was used without further purification. NMR
Spectrum: (DMSO-d.sub.6): 1.45 (s, 9H), 7.18 (m, 2H), 7.54 (m, 2H),
7.76 (d, 2H). 7.90 (d, 2H), 8.63 (s, 1H), 9.86 (s, 1H); Mass
Spectrum: (M+H.sup.+-Boc) 291.
Method 15
N-(2-t-Butoxycarbonylaminophenyl)-4-(1-t-butoxycarbonylpiperidin-4-yl)benz-
amide
[0229] 1-(N-t-Butoxycarbonylamino)-2-aminobenzene (Method 17, 3.1
g, 14.7 mmol) was added to a stirred solution of
4-(1-t-butoxycarbonylpiperidin-4-yl)benzoic acid (4.1 g, 13.4 mmol)
in DMF (50 ml) and the mixture stirred at ambient temperature for
10 minutes.
4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium
chloride (Method 18, 4.45 g, 16.1 mmol) was added and the mixture
stirred at ambient temperature for 24 hours. The solvent was
evaporated and the residue was dissolved in ethyl acetate (100 ml)
and washed with water. The organics were dried over magnesium
sulfate, filtered and evaporated. The resultant gum was purified by
flash chromatography using 1% methanol/dichloromethane to give the
title compound as a foam (5.44 g, 82%); NMR Spectrum:
(DMSO-d.sub.6) 1.41 (s, 9H), 1.43 (s, 9H), 1.54 (m, 2H), 1.77 (m,
2H), 2.79 (m, 3H), 4.08 (m, 2H), 7.15 (m, 2H), 7.40 (d, 2H), 7.52
(m, 2H), 7.87 (d, 2H), 8.60 (br, 1H), 9.74 (br, 1H), Mass Spectrum:
(M+H.sup.+-Boc) 396.
Method 16
N-(2-t-Butoxycarbonylaminophenyl)-4-(1-methylpiperazin-4-yl)benzamide
[0230] 4-(1-Methylpiperazin-4-yl)benzoic acid (250 mg, 1.13 mmol)
and 1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17, 331 mg,
1.59 mmol) were dissolved in DMF (3 ml).
4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium
chloride (Method 18, 313 mg, 1.13 mmol) was added and the resulting
solution was stirred for 20 hours at ambient temperature. The
solution was poured into water and extracted several times with
ethyl acetate. The combined organic extracts were dried over
magnesium sulfate and evaporated. The residue was purified by flash
chromatography (eluting with 99:1.fwdarw.9:1
dichloromethane:methanol) to afford the title compound as a
colourless gum which crystallised on trituration (240 mg, 52%);
Mass Spectrum: M+H.sup.+ 411.
Method 17
1-(N-t-Butoxycarbonylamino)-2-aminobenzene
[0231] The title compound was prepared according to the literature
method described in Seto, C, T.; Mathias, J. P.; Whitesides, G. M.;
J. Am. Chem. Soc., 1993, 115, 1321-1329.
Method 18
4-(4,6-Dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium
chloride
[0232] 4-(4,6-Dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium
chloride was prepared according to the literature procedure
described in Kunishima, M., Kawachi, C., Morita, J., Terao, K.,
Iwasaki, F., Tani, S., Tetrahedron, 1999, 55, 13159-13170.
Method 19
N-(2-Aminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]benzamide
trihydrochloride
[0233]
N-(2-t-Butoxyaminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin--
6-yl]benzamide (Method 20, 64 mg, 0.120 mmol) was suspended in 1,4
dioxane (1.5 ml) and a 4M solution of hydrogen chloride in
1,4-dioxane (1 ml) added. The reaction mixture was stirred at
ambient temperature for 64 hours. The reaction mixture was diluted
with diethyl ether, and the resultant precipitate was collected by
filtration, washed with diethyl ether and air dried, to yield the
title compound (as its hydrochloride salt) as an off white solid
(62 mg, 95%); Mass Spectrum: M+H.sup.+ 433.
Method 20
N-(2-t-Butoxyaminophenyl)-4-[2-(3-morpholinoaminopropyl)-pyrimidin-6-yl]be-
nzamide
[0234]
N-(2-t-Butoxyaminophenyl)-4-(2-methylsulfonyl-pyrimidin-6-yl)benzam-
ide (Method 21, 62.5 mg, 0.133 mmol) was dissolved in a mixture of
THF (2 ml) and N,N-dimethylacetamide (2 ml) and
N-(3-aminopropyl)morpholine (60 .mu.l, 0.411 mmol) added. The
reaction mixture was heated to 50.degree. C. and stirred for 2
hours. The reaction mixture was then cooled and solvents removed
under reduced pressure. The resultant oil was purified by elution
through silica with a 5% methanol in dichloromethane, to yield the
title compound as a colourless solid (65 mg, 92%); NMR Spectrum:
(DMSO-d.sub.6) 1.45 (s, 9H), 1.74 (m, 2H), 2.37 (m, 6H), 3.40 (br,
2H), 3.59 (m, 4H), 7.20 (m, 2H), 7.23 (d, 1H), 7.34 (t, 1H), 7.57
(d, 1H), 8.08 (d, 2H), 8.26 (d, 2H), 8.40 (m, 1H), 8.72 (s, 1H),
9.94 (s, 1H); Mass Spectrum: M+H.sup.+ 534.
Method 21
N-(2-t-Butoxyaminophenyl)-4-(2-methylsulfonyl-pyrimidin-6-yl)benzamide
[0235]
N-(2-t-Butoxyaminophenyl)-4-(2-thiomethyl-pyrimidin-6-yl)benzamide
(Method 22, 140 mg, 0.32 mmol) was dissolved in methanol (8 ml) and
a small amount of ethyl acetate, followed by a solution of
Oxone.RTM. (630 mg, 1.02 mmol) in water (4 ml). The resultant
suspension was stirred at ambient temperature for 1 hour before
being partitioned between ethyl acetate and a mixture of water and
saturated sodium bicarbonate. The organic phase was separated and
the aqueous phase extracted with further aliquots of ethyl acetate.
The combined organic extracts were washed with brine and dried over
magnesium sulfate. Evaporation to dryness afforded the title
compound as an off white powder (126 mg, 84%); NMR Spectrum:
(DMSO-d.sub.6) 1.45 (s, 9H), 3.54 (s, 3H), 7.20 (m, 2H), 7.57 (t,
2H), 8.18 (d, 2H), 8.48 (d, 2H), 8.54 (s, 1H), 8.73 (s, 1H), 9.20
(d, 1H), 10.02 (s, 1H); Mass Spectrum: (M+H.sup.+-Boc) 369.
Method 22
N-(2-t-Butoxyaminophenyl)-4-(2-thiomethyl-pyrimidin-6-yl)benzamide
[0236] 4-Iodo-2-methylthiopyrimidine (Method 23, 360 mg, 1.43 mmol)
was reacted with
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13, 631 mg, 1.44 mmol) in an analogous
manner to that described in Method 4 to yield the crude title
compound. This was purified by elution through silica with a
solution of ethyl acetate in isohexane (25% to 50% (v/v)) to afford
the pure title compound as a pale yellow foam (306 mg, 49%); NMR
Spectrum: (DMSO-d.sub.6) 1.45 (s, 9H), 2.63 (s, 3H), 7.20 (m, 2H),
7.57 (t, 2H), 7.91 (d, 1H), 8.13 (d, 2H), 8.37 (d, 2H), 8.72 (s,
1H), 8.77 (d, 1H), 9.97 (s, 1H); Mass Spectrum: (M+H.sup.+-tBu)
381.
Method 23
4-Iodo-2-methylthiopyrimidine
[0237] 4-Chloro-2-methylthiopyrimidine (5 g, 31.15 mmol) was added
dropwise to a cooled 57% aqueous hydriodic acid solution (0.degree.
C.). Stirring was continued at 0.degree. C. for 30 minutes, before
warming to ambient temperature and stirring for 24 hours. Aqueous
sodium bicarbonate was then carefully added and the resultant
suspension basified to pH 9 by addition of sodium carbonate. The
mixture was extracted with ethyl acetate and the extracts dried
over magnesium sulfate and concentrated by reduced pressure. The
resultant solid was dissolved in boiling isohexane and cooled by
refrigeration overnight. The resultant solid was filtered and dried
to afford the title compound as colourless needles (5.4 g, 69%);
NMR Spectrum: (CDCl.sub.3) 2.55 (s, 3H), 7.40 (d, 1H), 7.98 (d,
1H); Mass Spectrum: M+H.sup.+ 253. Method 24
N-(2-Aminophenyl)-4-[2-(3-morpholinoaminoethyl)-pyrimidin-6-yl]benzamide
trihydrochloride
[0238]
N-(2-t-Butoxyaminophenyl)-4-[2-(3-morpholinoaminoethyl)-pyrimidin-6-
-yl]benzamide (Method 25, 59 mg, 0.113 mmol) was reacted in an
analogous manner to that described for Method 19 to yield the title
compound (as its hydrochloride salt) as a beige solid (56 mg, 94%);
Mass Spectrum: M+H.sup.+ 419.
Method 25
N-(2-t-Butoxyaminophenyl)-4-[2-(3-morpholinoaminoethyl)-pyrimidin-6-yl]ben-
zamide
[0239]
N-(2-t-Butoxyaminophenyl)-4-(2-methylsulfonyl-pyrimidin-6-yl)benzam-
ide (Method 21, 62.5 mg, 0.133 mmol) was reacted with
N-(2-aminoethyl)morpholine (60 .mu.l, 0.457 mmol) in an analogous
manner to that described in method 20 to yield the title compound
as a pale yellow solid (66 mg, 96%); NMR Spectrum: (DMSO-d.sub.6)
1.46 (s, 9H), 2.45 (brm, 4H), 3.30 (m, 2H), 3.50 (brm, 2H), 3.58
(m, 4H), 7.14 (t, 1H), 7.17 (m, 1H), 7.22 (m, 1H), 7.25 (d, 1H),
7.57 (d, 2H), 8.09 (d, 2H), 8.27 (d, 2H), 8.42 (d, 1H), 8.73 (s,
1H), 9.94 (s, 1H); Mass Spectrum: M+H.sup.+ 519.
Method 29
N-(2-t-butoxycarbonylaminophenyl)-4-{2-[(3-piperidin-1-ylpropyl)amino]pyri-
midin-4-yl}benzamide
[0240] To a 24 mm.times.150 mm pyrex tube, charged with
3-aminopropylpiperidine (73 mg, 0.51 mmol), was added a solution of
N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide
(Method 52, 85 mg, 0.20 mmol) in N,N-dimethylacetamide (4.6 ml).
The reaction mixture was then heated to 50.degree. C. and stirred
for 16 hours, before being evaporated to dryness. The resultant
residue was purified by flash chromatography, on silica (10 g),
eluting with methanol/dichloromethane (5-15%), to give the title
compound (48 mg, 45%); Mass Spectrum: M+H.sup.+ 531.
Method 30-36
[0241] Using an analogous procedure to that described in Method 29,
the
N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide
starting material (Method 52) was reacted with the appropriate
amine to give the compounds described in Table 11. Where required,
the crude residues were purified by flash column chromatography, on
silica (10 g), eluting with methanol/dichloromethane (5-15%).
TABLE-US-00011 TABLE 11 ##STR00087## Method R.sup.1 Analytical Data
SM 30 ##STR00088## Mass Spectrum: M + H.sup.+ 514. 31 ##STR00089##
Mass Spectrum: M + H.sup.+ 546. 32 ##STR00090## Mass Spectrum: M +
H.sup.+ 533. 33 ##STR00091## Mass Spectrum: M + H.sup.+ 505. 34
##STR00092## Mass Spectrum: M + H.sup.+ 497. 35 ##STR00093## Mass
Spectrum: M + H.sup.+ 517. 36 ##STR00094## Mass Spectrum: M +
H.sup.+ 478. Meth 52
Method 37
N-(2-t-butoxycarbonylaminophenyl)-4-[2-(3-morpholin-4-ylpropoxy)pyridin-4--
yl]benzamide
[0242] To a suspension of sodium hydride in tetrahydrofuran (1 ml)
was added, dropwise, via syringe, a solution of
3-N-morpholinopropanol (147 mg, 1.01 mmol). The reaction mixture
was stirred, under an argon atmosphere, for 30 minutes, then added,
via cannula, to a solution of
N-(2-t-butoxycarbonylaminophenyl)-2-fluoropyridin-4-ylbenzamide
(Method 8, 119 mg, 0.29 mmol) in tetrahydrofuran (2 ml). The
mixture was then stirred, under an argon atmosphere, for 2 hours at
ambient temperature, before being heated to 50.degree. C. and
stirred for a further 5.5 hours. The reaction mixture was allowed
to cool before being partitioned between ethyl acetate and water.
The organics were separated and aqueous extracted further with
ethyl acetate. The combined organic layers were then combined,
washed with brine, dried over magnesium sulfate, filtered and
evaporated. The resultant residue was purified by flash
chromatography, on silica (20 g), eluting with
methanol/dichloromethane (0-10%), to give the title compound (70
mg, 45%); NMR Spectrum: (DMSO-d.sub.6) 1.46 (s, 9H), 1.92 (m, 2H),
2.38 (m, 4H), 2.45 (m, 2H), 3.59 (t, 4H), 4.36 (t, 2H), 7.20 (m,
3H), 7.39 (dd, 1H), 7.57 (d, 2H), 7.97 (d, 2H), 8.08 (d, 2H), 8.26
(d, 1H), 8.67 (s, 1H), 9.91 (s, 1H); Mass Spectrum: M+H.sup.+
533.
Method 38
N-(2-t-butoxycarbonylaminophenyl)-4-(6-methylpyridin-3-yl)benzamide
[0243] Using an analogous procedure to that described in Method 4,
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13, 1.20 g, 2.74 mmol) was reacted with
2-methyl-5-bromopyridine (505 mg, 2.94 mmol). The crude residue was
purified by flash chromatography on silica (90 g), eluting with
ethyl acetate/isohexane (40-100%) to give the title compound (504
mg, 46%); NMR Spectrum: (DMSO-d.sub.6) 1.46 (s, 9H), 2.51 (s, 3H),
7.19 (m, 2H), 7.40 (d, 1H), 7.58 (m, 2H), 7.91 (d, 2H), 8.08, (d,
3H), 8.66 (s, 1H), 8.86 (d, 1H), 9.89 (s, 1H); Mass Spectrum:
M+H.sup.+ 404.
Method 39
N-(2-t-butoxycarbonylaminophenyl)-4-{2-[(3-piperidin-1-ylpropyl)amino]thie-
no[3,2-d]pyrimidin-4-yl}benzamide
[0244] A solution of 3-aminopropylpiperidine (60 .mu.l, 0.38 mmol)
and
N-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylsulfonyl)thieno[3,2-d]pyrim-
idin-4-yl]benzamide (Method 54, 81 mg, 0.15 mmol) in
N,N-dimethylacetamide was heated first to 50.degree. C. for 23
hours and then further heated to 75.degree. C. for a period of 16
hours. The reaction mixture was evaporated to dryness and the crude
residue purified by flash chromatography, on silica (10 g), eluting
with methanol/dichloromethane (0-15%) to give the title compound
(23 mg, 26%); Mass Spectrum: M+H.sup.+ 587.
Method 40
N-(2-t-butoxycarbonylaminophenyl)-4-thieno[3,2-d]pyrimidin-4-ylbenzamide
[0245] Using an analogous procedure to that described in Method
4,4-chlorothieno[3,2-d]pyrimidine (538 mg, 3.15 mmol) was reacted
with
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13, 1.53 g, 3.50 mmol). The crude residue
was purified by flash chromatography, on silica, eluting with ethyl
acetate/hexane (25-75%) to give the title compound (1.08 g, 69%);
NMR Spectrum: (DMSO-d.sub.6) 1.47 (s, 9H), 7.21 (m, 2H), 7.57 (t,
2H), 7.79 (d, 1H), 8.23 (d, 2H), 8.34 (d, 2H), 8.64 (d, 1H), 8.75
(s, 1H), 9.35 (s, 1H), 10.03 (s, 1H); Mass Spectrum: M+H.sup.+
447.
Method 41
N-(2-aminophenyl)-4-{2-[(3-piperidin-1-ylpropyl)amino]pyrimidin-5-yl}benza-
mide
[0246] To a solution of
N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-5-yl)benzamide
(Method 53, 80 mg, 0.19 mmol) in N,N-dimethylacetamide (3.5 ml) was
added 3-aminopropylpiperidine (108 mg 0.76 mmol). The reaction
mixture was stirred at 50.degree. C. for 20 hours, before being
allowed to cool. The reaction mixture was partitioned between water
and ethyl acetate, before being filtered under gravity, through a
Varian Chem Elut (CE1010) diatomaceous earth column. The resulting
solution was then concentrated under reduced pressure and purified
by flash column chromatography, eluting with
methanol/dichloromethane (0-20%), to give the title compound, which
was used without further purification; Mass Spectrum: M+H.sup.+
531.
Method 42-43
[0247] Using an analogous procedure to that described in method 41,
the
N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-5-yl)benzamide
(Method 53) was reacted with the appropriate amine to give the
compounds described in Table 12. Where required, the crude residues
were purified by flash column chromatography, on silica (10 g),
eluting with methanol/dichloromethane (0-20%).
TABLE-US-00012 TABLE 12 ##STR00095## Method R.sup.1 Analytical Data
SM 42 ##STR00096## Mass Spectrum: M + H.sup.+ 546 43 ##STR00097##
Mass Spectrum: M + H.sup.+ 533.
Method 44
N-(2-t-butoxycarbonylaminophenyl)-3-fluoro-4-pyridin-3-ylbenzamide
[0248] t-Butyl 2-[(4-bromo-3-fluorobenzoyl)amino]phenylcarbamate
(Method 63, 205 mg, 0.5 mmol), 3-pyridine boronic acid (74 mg, 0.6
mmol), tetrakis(triphenylphosphine) palladium (104 mg, 0.09 mmol),
1,2-dimethoxyethane (3 ml) and a saturated aqueous solution of
sodium hydrogen carbonate (3 ml) were stirred at 80.degree. C.
under an atmosphere of argon for 48 hours. The cooled mixture was
partitioned between ethyl acetate and water. The aqueous layer was
removed using Varian Chem Elut column (CE1010) and the resulting
solution was then concentrated under reduced pressure and purified
by flash column chromatography, eluting with ethyl
acetate/isohexane (25-75%), to give the title compound (186 mg,
91%). Mass Spectrum: M+H.sup.+ 408.
Method 45
N-(2-t-butoxycarbonylaminophenyl)-4-[2-(2-pyrrolidin-1-ylethoxy)pyrimidin--
5-yl]benzamide
[0249] Using an analogous procedure to that described in Method 44,
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with
5-bromo-2-(2-pyrrolidin-1-ylethoxy)pyrimidine (Method 64, 136 mg,
0.5 mmol) to give the title compound (71 mg; 28%). Mass Spectrum:
M+H.sup.+ 504.
Method 46-50
[0250] Using an analogous procedure to that described in Example 1,
the appropriate N-(2-t-butoxycarbonylaminophenyl)benzamide starting
material was reacted to give the compounds described in Table 13,
as their hydrochloride salt.
TABLE-US-00013 TABLE 13 ##STR00098## Method R.sup.1 Analytical Data
SM 46 ##STR00099## Mass Spectrum: M + H.sup.+ 432. Meth 56 47
##STR00100## Used without further purification. Meth 57 48
##STR00101## Mass Spectrum: M + H.sup.+ 375. Meth 58 49
##STR00102## Mass Spectrum: M + H.sup.+ 378 Meth 59 50 ##STR00103##
Mass Spectrum: M + H.sup.+ 389 Meth 60
Method 51
N-(2-t-butoxycarbonylaminophenyl)-4-[5-(piperidin-1-ylmethyl)-1,3-thiazol--
2-yl]benzamide
[0251] Using an analogous procedure to that described in Method 44,
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with
1-[(2-chloro-1,3-thiazol-5-yl)methyl]piperidine (108 mg, 0.5 mmol)
to give the title compound (271 mg, >100%) which was carried
through the next step; Mass Spectrum: M+H.sup.+ 493.
Method 52
N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide
[0252] Using an analogous procedure to that described in Method 4,
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13, 3.9 g, 8.9 mmol) was reacted with
2,4-dichloropyrimidine (3.06 g, 20.5 mmol). The crude residue was
purified by flash chromatography on silica, eluting with ethyl
acetate/isohexane (1:1) to give the title compound (1.2 g, 32%);
NMR Spectrum: (DMSO-d.sub.6) 1.45 (s, 9H), 7.23 (m, 2H), 7.57 (t,
2H), 8.15 (d, 2H), 8.29 (d, 1H), 8.38 (d, 2H), 8.73 (s, 1H), 8.91
(d, 1H), 10.00 (s, 1H); Mass Spectrum: M-H.sup.- 423.
Method 53
N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-5-yl)benzamide
[0253]
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-diox-
aborolan-2-yl)benzamide (Method 13, 4.0 g, 9.12 mmol),
5-bromo-2-chloropyrimidine (1.76 g, 9.12 mmol),
tetrakis(triphenylphosphine) palladium (527 mg, 0.46 mmol),
1,2-dimethoxyethane (40 ml) and a saturated aqueous solution of
sodium hydrogen carbonate (40 ml) were stirred at 80.degree. C.
under an atmosphere of argon for 18 hours. The cooled mixture was
concentrated under reduced pressure. The residue was then stirred
with ethyl acetate for 1 hour and the resultant solid collected by
suction filtration and dried to give the title compound (2.38 g;
61%); NMR Spectrum: (DMSO-d.sub.6) 1.47 (s, 9H), 7.20 (m, 2H), 7.58
(d, 2H), 8.02 (d, 2H), 8.11 (d, 2H), 8.66 (s, 1H), 9.23 (s, 2H),
10.93 (s, 1H); Mass Spectrum: M+H.sup.+-.sup.tBu 369.
Method 54
N-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylsulfonyl)thieno[3,2-d]pyrimi-
din-4-yl]benzamide
[0254] To a cooled (0.degree. C.) solution of
N-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylthio)thieno[3,2-d]pyrimidin-
-4-yl]benzamide (Method 55, 960 mg, 1.95 mg) in DMF (40 ml), was
added meta-chloroperbenzoic acid (57%, 630 mg, 2.08 mmol) and the
reaction mixture stirred, allowing warming to ambient temperature.
After 3 hours a further portion of meta-chloroperbenzoic acid (70%,
589 mg, 2.40 mmol) was added and stirring continued for 2 hours.
The reaction mixture was then carefully poured into aqueous sodium
metabisulfite solution (0.25M, 100 ml), before addition of ethyl
acetate (100 ml). The insoluble material was removed by filtration
and dried in vacuo to yield the title compound (586 mg, 57%); NMR
Spectrum: (DMSO-d.sub.6) 1.46 (s, 9H), 3.57 (s, 3H), 7.18 (t, 1H),
7.24 (t, 1H), 7.59 (m, 2H), 8.00 (d, 1H), 8.27 (d, 2H), 8.41 (d,
2H), 8.75 (s, 1H), 8.90 (d, 1H), 10.07 (s, 1H); Mass Spectrum:
M+Na.sup.+ 547.
Method 55-59
[0255] Using an analogous procedure to that described in Method 4,
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13) was reacted with the appropriate
halide to give the compounds described in Table 14. Where
appropriate compounds were filtered from reaction mixtures
following partitioning or if required, the crude residues were
purified by flash column chromatography, on silica eluting with
methanol/dichloromethane (0-20%).
TABLE-US-00014 TABLE 14 ##STR00104## Method R.sup.1 Analytical Data
SM 55 ##STR00105## NMR Spectrum: (DMSO-d.sub.6) 1.46(s, 9 H), 2.67
(s, 3 H), 7.17 (t, 1 H),7.23 (t, 1 H), 7.59 (t, 2 H), 7.65 (d,1 H),
8.22 (d, 2 H), 8.30 (d, 2 H), 8.59(d, 1 H), 8.75 (brs, 1 H), 10.03
(s,1 H); Mass Spectrum: M + H.sup.+ 493. [CAS176530-47-5] 56
##STR00106## NMR Spectrum: (DMSO-d.sub.6) 1.46(s, 9 H), 1.72 (m, 2
H), 2.37 (m, 6 H),3.33 (m, 2 H), 3.58 (t, 4 H), 6.62 (t,1 H), 6.77
(s, 1 H), 6.83 (d, 1 H), 7.19(m, 2 H), 7.56 (d, 2 H), 7.81 (d, 2
H),8.07 (m, 3 H), 8.66 (s, 1 H), 9.89 (s,1 H); Mass Spectrum: M +
H.sup.+ 532. Meth 61 57 ##STR00107## NMR Spectrum: (DMSO-d.sub.6)
1.47(s, 9 H), 3.92 (s, 3 H), 7.18 (m, 2 H),7.59 (m, 2 H), 8.18 (d,
2 H), 8.70 (s,1 H), 9.00 (d, 2 H), 9.06 (s, 1 H), 9.97(brs, 1 H);
Mass Spectrum: M + H.sup.+445. [CAS2346-74-9] 58 ##STR00108## Mass
Spectrum: M + H.sup.+-Boc 376. [CAS61655-58-1] 59 ##STR00109## Mass
Spectrum: M + H.sup.+ 479. [CAS122-34-9]
Method 60
N-(2-t-Butoxycarbonylaminophenyl)-4-[2-(4-methylpiperazin-1-yl)pyrimidin-4-
-yl]benzamide
[0256] Using an analogous procedure to that described in Method 41,
the
N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide
(Method 52, 59 mg, 0.14 mmol) was reacted with 1-methylpiperazine
(77 mg, 0.69 mmol) and residue purified by flash chromatography
eluting with methanol/dichloromethane (0-20%) to give the title
compound (48 mg, 71%); Mass Spectrum: M+H.sup.+ 489.
Method 61
4-Iodo-N-(3-morpholin-4-ylpropyl)pyridin-2-amine
[0257] A solution of 4-iodo-2-fluoropyridine (2.32 g, 10.00 mmol)
and N-(3-aminopropyl)morpholine (4.2 ml, 26.00 mmol) in
N,N-dimethylacetamide (30 ml) was heated to 100.degree. C. for 20
hours before being concentrated in vacuo, to afford the crude title
compound which was used without any further purification; Mass
Spectrum: M+H.sup.+ 348.
Method 62
N-(2-aminophenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]benzamide
[0258] Using an analogous procedure to that described in Example 1,
N-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]ben-
zamide (Method 21, 1.097 g, 2.34 mmol) was reacted to give the
title compound as its hydrochloride salt (1.01 g, 98%); NMR
Spectrum: (DMSO-d.sub.6) 3.53 (s, 3H), 7.31 (m, 3H), 7.52 (d, 1H),
8.30 (d, 2H), 8.48 (d, 2H), 8.53 (d, 1H), 9.20 (d, 1H), 10.56 (s,
1H); Mass Spectrum: M+H.sup.+ 369.
Method 63
t-Butyl 2-[(4-bromo-3-fluorobenzoyl)amino]phenylcarbamate
[0259] 1-(N-t-butoxycarbonylamino)-2-aminobenzene (Method 17, 1.25
g, 6 mmol) was reacted with 4-bromo-3-fluorobenzoic acid (1.1 g,
5.0 mmol) in an analogous manner to that described in Method 16 to
give the title compound, which was used without further
purification; Mass Spectrum: (M+H.sup.+-Boc) 311.
Method 64
5-bromo-2-(2-pyrrolidin-1-ylethoxy)pyrimidine
[0260] To a solution of N-2-hydroxyethylpyrrolidine (0.9 ml, 7.71
mmol) and 5-bromo-2-chloropyrimidine (1.2 g, 6.20 mmol), in DMF (7
ml), was added sodium hydride (60% in mineral oil, 0.35 g, 8.75
mmol). The mixture was stirred, under argon, at ambient temperature
for 1 hour, before being heated to 90.degree. C. and stirred for a
further hour. The reaction mixture was then partitioned between
ethyl acetate and water. The organics were separated, dried over
magnesium sulfate and evaporated to dryness. The resultant oil was
purified by flash chromatography on silica, eluting with an
increasing gradient of methanol in dichloromethane (which contained
1% aqueous ammonia solution, 0.88 M) to give the title compound
(640 mg, 38%); NMR Spectrum: (CDCl.sub.3) 1.76 (m, 4H), 2.39 (m,
4H), 3.90 (t, 2H), 4.48 (t, 2H), 8.50 (s, 2H); Mass Spectrum:
M+H.sup.+ 272.
Method 65-66
[0261] Using an analogous procedure to that described in Method 39,
N-(2-t-butoxycarbonylaminophenyl)-4-[2-(methylsulfonyl)thieno[3,2-d]pyrim-
idin-4-yl]benzamide (Method 54) was reacted with the appropriate
amine to give the compounds described in Table 15. The resultant
residues, where required, were purified by flash chromatography on
silica, eluting with methanol/dichloromethane (0-15%).
TABLE-US-00015 TABLE 15 ##STR00110## Method R.sup.1 Analytical Data
SM 65 ##STR00111## Used without further purification. 66
##STR00112## Mass Spectrum: M + H.sup.+ 573.
Method 67
[2-(4-{[(2-t-butoxycarbonylaminophenyl)amino]carbonyl}phenyl)-1,3-thiazol--
5-yl]methyl cyclohexylcarbamate
[0262] Using an analogous procedure to that described in Method 4,
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with
(2-chloro-1,3-thiazol-5-yl)methyl cyclohexylcarbamate (138 mg, 0.5
mmol). The crude residue was stirred in ethyl acetate for 16 hours
before being filtered, mixed with water and the aqueous removed
using a Varian Chem Elut Column (CE1010). The resulting solution
was concentrated and purified by flash chromatography on silica,
eluting with methanol/dichloromethane (0-30%) to give the title
compound; Mass Spectrum: M+H.sup.+ 551.
Method 68
N-(2-t-butoxycarbonylaminophenyl)-4-{5-[2-(methylthio)pyrimidin-4-yl]thien-
-2-yl}benzamide
[0263] Using an analogous procedure to that described in Method 4,
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with
4-(5-bromothien-2-yl)-2-(methylthio)pyrimidine (145 mg, 0.5 mmol).
The crude residue stirred in ethyl acetate/water for 1 hour before
being filtered, and the aqueous removed using a Varian Chem Elut
Column (CE1010). The resulting solution was concentrated and
recrystallised from methanol to give the title compound; Mass
Spectrum: M+H.sup.+-Boc 463.
Method 69
[2-(4-{[(2-t-butoxycarbonylaminophenyl)amino]carbonyl}phenyl)-1,3-thiazol--
5-yl]methyl phenylcarbamate
[0264] Using an analogous procedure to that described in Method 4,
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with
(2-chloro-1,3-thiazol-5-yl)methyl N-phenylcarbamate (136 mg, 0.5
mmol). The crude residue stirred in ethyl acetate/water for 16
hours before being filtered, and the aqueous removed using a Varian
Chem Elut Column (CE1010). The resulting solution was concentrated
and purified by flash chromatography on silica, eluting with
methanol/dichloromethane (0-30%) to give the title compound; Mass
Spectrum: M+H.sup.+-Boc 489.
Method 70
[2-(4-{[(2-aminophenyl)amino]carbonyl}phenyl)-1,3-thiazol-5-yl]methyl
phenylcarbamate
[0265] Using an analogous procedure to that described in Example
12, the appropriate N-(2-t-butoxycarbonylaminophenyl)benzamide
starting material was reacted to give the compound described in
Table 16, as its hydrochloride salt.
TABLE-US-00016 TABLE 16 Structure Analytical Data SM ##STR00113##
Mass Spectrum: M + H.sup.+ 445. Meth 69.sub.5
Method 71
t-Butyl
4-{4-[({2-[(t-butoxycarbonyl)amino]phenyl}amino)carbonyl]phenyl}-3-
,6-dihydropyridine-1(2H)-carboxylate
[0266] A saturated solution of sodium hydrogen carbonate (3 ml) was
added to a stirred solution of t-butyl
4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate
(Method 72, 200 mg, 0.60 mmol) in 1,2-dimethoxyethane (3 ml).
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13) (318 mg, 0.72 mmol) was added
followed by tetrakis(triphenylphosphine) palladium (100 mg, 0.09
mmol) and the mixture stirred at 80.degree. C. for 18 hours. The
cooled mixture was partitioned between ethyl acetate and water. The
organic phase was separated, then washed with water and dried over
magnesium sulfate, filtered and evaporated. The resultant residue
was purified by flash column chromatography (eluting with 0-15%
methanol in dichloromethane) to give the title compound (220 mg,
74%); NMR Spectrum: (DMSO-d.sub.6) 1.42 (s, 9H), 1.43 (s, 9H), 2.48
(m, 2H), 3.55 (m, 2H), 4.02 (m, 2H), 6.31 (s, 1H), 7.17 (m, 2H),
7.52 (m, 2H), 7.58 (d, 2H), 7.92 (d, 2H), 8.62 (s, 1H), 9.79 (s,
1H); Mass Spectrum: M+H.sup.+ 494.
Method 72
t-Butyl
4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carbo-
xylate
[0267] A 1.6 M solution of n-butyllithium in hexanes (6.9 ml, 11
mmol) was added to a stirred solution of diisopropylamine (1.5 ml,
11 mmol) in THF at -78.degree. C. and the mixture stirred for 30
minutes. A solution of t-butyl 4-oxopiperidine-1-carboxylate (2.0
g, 10 mmol) in THF was added and after 20 minutes a solution of
N-phenyl-bis(trifluoromethanesulfonimide) (3.9 g, 11 mmol) in THF
was added. The mixture was stirred at ambient temperature overnight
and the solvent evaporated. The resultant residue was partioned
between diethyl ether and a 2M solution of aqueous sodium
hydroxide, the organic layer separated, washed once with brine and
dried over magnesium sulfate, filtered and evaporated to give the
title compound (3.01 g, 83%); NMR Spectrum: (DMSO-d.sub.6) 1.48 (s,
9H), 2.44 (m, 2H), 3.63 (t, 2H), 4.04 (d, 2H), 5.76 (s, 1H).
Method 73
1-Bromoacetyl-1,2,3,4-tetrahydroquinoline
[0268] 1,2,3,4-tetrahydroquinoline (10 g, 75 mmol) was dissolved in
benzene (40 ml) and cooled to 10.degree. C. A solution of
bromoacetyl bromide (16 g, 80 mmol) in benzene (40 ml) was added
dropwise over 1 hour. The mixture was stirred for a further 15
minutes. A 2M aqueous solution of sodium hydroxide (500 ml) was
added. The organic layer was separated, washed with water (100 ml),
dried over magnesium sulfate and evaporated to afford the crude
product as an oil. This was purified by distillation under reduced
pressure followed by recrystallisation from 60-80 petroleum ether
to afford the product as a colourless solid (12.5 g, 66%). Anal.
Calc. for C.sub.11H.sub.12ONBr gives C, 52.0%; H, 4.8%; N, 5.5%;
Br, 31.4%. found C, 51.9%; 4.8%; N, 5.6%; Br 30.9%.
Method 74-75
[0269] Using an analogous procedure to that described in Method 4,
N-(2-t-Butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)benzamide (Method 13) was reacted with the requisite
chloroheterocycle to give the compounds described in Table 17
TABLE-US-00017 TABLE 17 ##STR00114## Method R.sup.1 Analytical Data
SM 74 ##STR00115## Mass Spectrum:M + H.sup.+ 446. Meth 76 75
##STR00116## NMR Spectrum:(DMSO-d.sub.6) 1.47(s, 9 H), 7.21(m, 2
H),7.58 (m, 2 H),7.78 (d,1 H), 8.12(d, 1 H),8.19 (m,4 H), 8.71(s, 1
H),9.23 (s,1 H),10.01 (s, 1 H);Mass Spectrum:M + H.sup.+ 347.
Method 76
7-chlorothieno[3,2-b]pyridine
[0270] Thieno[3,2,b]pyridin-7-ol (200 mg; 1.32 mmol) was added to
thionyl chloride (1.57 g; 13.2 mmol), followed by a drop of DMF.
The solution was stirred at 80.degree. C. for 4 hours. The cooled
solution was diluted with ethyl acetate and neutralised to pH 7
with a saturated solution of sodium hydrogen carbonate (25 ml). The
organic layer was washed with brine, dried and concentrated to
yield the title compound (112 mg; 50%); Mass Spectrum: M+H.sup.+
170.
* * * * *