U.S. patent application number 13/908566 was filed with the patent office on 2013-10-03 for substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis.
The applicant listed for this patent is BAYER INTELLECTUAL PROPERTY GmbH. Invention is credited to Ann BULLION, Ann-Marie CAMPBELL, Martin HENTEMANN, Martin MICHELS, Aniko REDMAN, Ronald ROWLEY, William SCOTT, Jill WOOD.
Application Number | 20130261113 13/908566 |
Document ID | / |
Family ID | 39492563 |
Filed Date | 2013-10-03 |
United States Patent
Application |
20130261113 |
Kind Code |
A1 |
HENTEMANN; Martin ; et
al. |
October 3, 2013 |
SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINAZOLINE DERIVATIVES USEFUL
FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED
WITH ANGIOGENESIS
Abstract
This invention relates to novel
2,3-dihydroimidazo[1,2-c]quinazoline compounds, pharmaceutical
compositions containing such compounds and the use of those
compounds or compositions for phosphotidylinositol-3-kinase (PI3K)
inhibition and treating diseases associated with
phosphotidylinositol-3-kinase (PI3K) activity, in particular
treating hyper-proliferative and/or angiogenesis disorders, as a
sole agent or in combination with other active ingredients.
Inventors: |
HENTEMANN; Martin; (Hamden,
CT) ; WOOD; Jill; (North Haven, CT) ; SCOTT;
William; (PEEKSWILL, NY) ; MICHELS; Martin;
(Koln, DE) ; CAMPBELL; Ann-Marie; (Monroe, CT)
; BULLION; Ann; (Milford, CT) ; ROWLEY;
Ronald; (New Hope, PA) ; REDMAN; Aniko;
(Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BAYER INTELLECTUAL PROPERTY GmbH |
Monheim |
|
DE |
|
|
Family ID: |
39492563 |
Appl. No.: |
13/908566 |
Filed: |
June 3, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12517875 |
Dec 20, 2010 |
8466283 |
|
|
PCT/US2007/024985 |
Dec 5, 2007 |
|
|
|
13908566 |
|
|
|
|
Current U.S.
Class: |
514/232.5 ;
435/184; 514/233.2; 514/252.16; 514/267; 544/115; 544/250;
544/80 |
Current CPC
Class: |
A61K 31/5377 20130101;
A61P 13/12 20180101; A61P 27/02 20180101; A61P 9/00 20180101; A61P
29/00 20180101; A61P 27/06 20180101; A61K 31/519 20130101; A61P
25/00 20180101; A61P 9/12 20180101; A61P 35/00 20180101; A01N 43/90
20130101; A61P 9/10 20180101; C07D 487/04 20130101; A61P 19/02
20180101; A61P 17/06 20180101; A61P 37/06 20180101; A61P 35/02
20180101; A61P 37/02 20180101; A61P 11/00 20180101; A61P 25/28
20180101; A61P 7/02 20180101; A61P 3/10 20180101; A61P 9/04
20180101; A61P 3/00 20180101 |
Class at
Publication: |
514/232.5 ;
544/115; 514/233.2; 544/250; 514/267; 544/80; 514/252.16;
435/184 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/519 20060101 A61K031/519; C07D 487/04
20060101 C07D487/04 |
Claims
1. A compound having the formula: ##STR00155## or a physiologically
acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:
R.sup.1 is
--(CH.sub.2).sub.n--(CHR.sup.4)--(CH.sub.2).sub.m--N(R.sup.5)(R.sup.5');
R.sup.2 is a heteroaryl optionally substituted with 1, 2 or 3
R.sup.6 groups; R.sup.3 is alkyl or cycloalkyl; R.sup.4 is
hydrogen, hydroxy or alkoxy and R.sup.5 and R.sup.5' may be the
same or different and are independently, hydrogen, alkyl,
cycloalkylalklyl, or alkoxyalkyl or R.sup.5 and R.sup.5' may be
taken together with the nitrogen atom to which they are bound to
form a 3-7 membered nitrogen containing heterocyclic ring
optionally containing at least one additional heteroatom selected
from oxygen, nitrogen or sulfur and which may be optionally
substituted with 1 or more R.sup.6' groups, or R.sup.4 and R.sup.5
may be taken together with the atoms to which they are bound to
form a 5-6 membered nitrogen containing heterocyclic ring
optionally containing 1 or more nitrogen, oxygen or sulfur atoms
and which may be optionally substituted with 1 or more R.sup.6'
groups; each occurrence of R.sup.6 may be the same or different and
is independently halogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalklyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclic ring, heterocyclylalkyl, alkyl-OR.sup.7,
alkyl-SR.sup.7, alkyl-N(R.sup.7)(R.sup.7'), alkyl-COR.sup.7, --CN,
--COOR.sup.7, --CON(R.sup.7)(R.sup.7'), --OR.sup.7, --SR.sup.7,
--N(R.sup.7)(R.sup.7'), or --NR.sup.7COR.sup.7 each of which may be
optionally substituted with 1 or more R.sup.8 groups; each
occurrence of R.sup.6' may be the same or different and is
independently alkyl, cycloalkylalklyl, or alkyl-OR.sup.7; each
occurrence of R.sup.7 and R.sup.7' may be the same or different and
is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,
heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl; each
occurrence of R.sup.8 is independently nitro, hydroxy, cyano,
formyl, acetyl, halogen, amino, alkyl, alkoxy, alkenyl, alkynyl,
cycloalkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl,
heteroaryl, heterocyclic ring, heterocyclylalkyl, or
heteroarylalkyl; n is an integer from 1-4 and m is an integer from
0-4 with the proviso that when when R.sup.4 and R.sup.5 are taken
together with the atoms to which they are bound to form a 3-7
membered nitrogen containing ring, n+m 4.
2. The compound of claim 1, wherein R.sup.2 is a nitrogen
containing heteroaryl optionally substituted with 1, 2 or 3 R.sup.6
groups.
3. The compound of claim 1, wherein R.sup.5 and R.sup.5' are
independently alkyl.
4. The compound of claim 1, wherein R.sup.5 and R.sup.5' are taken
together with the nitrogen atom to which they are bound to form a
5-6 membered nitrogen containing heterocyclic ring containing at
least one additional heteroatom selected from oxygen, nitrogen or
sulfur and which may be optionally substituted with 1 or more
R.sup.6' groups.
5. The compound of claim 1, wherein R.sup.4 is hydroxy.
6. The compound of claim 1, wherein R.sup.4 and R.sup.5 are taken
together with the atoms to which they are bound to form a 5-6
membered nitrogen containing heterocyclic ring optionally
containing 1 or more nitrogen, oxygen or sulfur atoms and which may
be optionally substituted with 1 or more R.sup.6' groups.
7. The compound of claim 1, wherein R.sup.3 is methyl.
8. The compound of claim 1, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan
or thiophene, optionally substituted with 1, 2 or 3 R.sup.6
groups.
9. The compound of claim 2, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,
optionally substituted with 1, 2 or 3 R.sup.6 groups.
10. The compound of claim 1, having the formula: ##STR00156##
11. The compound of claim 10, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan
or thiophene, optionally substituted with 1, 2 or 3 R.sup.6
groups.
12. The compound of claim 11, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,
optionally substituted with 1, 2 or 3 R.sup.6 groups.
13. The compound of claim 1 having the formula: ##STR00157##
14. The compound of claim 13, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan
or thiophene, optionally substituted with 1, 2 or 3 R.sup.6
groups.
15. The compound of claim 14, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,
optionally substituted with 1, 2 or 3 R.sup.6 groups.
16. The compound of claim 1 having the formula: ##STR00158##
17. The compound of claim 16, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan
or thiophene, optionally substituted with 1, 2 or 3 R.sup.6
groups.
18. The compound of claim 17, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,
optionally substituted with 1, 2 or 3 R.sup.6 groups.
19. The compound of claim 1 having the formula: ##STR00159##
20. The compound of claim 19, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan
or thiophene, optionally substituted with 1, 2 or 3 R.sup.6
groups.
21. The compound of claim 20, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,
optionally substituted with 1, 2 or 3 R.sup.6 groups.
22. The compound of claim 19 wherein R.sup.5' is alkyl.
23. The compound of claim 1 having the formula: ##STR00160##
24. The compound of claim 23, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan
or thiophene, optionally substituted with 1, 2 or 3 R.sup.6
groups.
25. The compound of claim 24, wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole or thiazole,
optionally substituted with 1, 2 or 3 R.sup.6 groups.
26. The compound of claim 23 wherein R.sup.5' is alkyl.
27. Compounds according to any one of the preceding claims, namely:
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]pyrimidine-5-carboxamide;
N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydr-
oimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydr-
oimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-1,3-thiazole-5-carboxamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]isonicotinamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide;
N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl}nicotinamide;
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}pyrimidine-5-carboxamide;
N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinaz-
olin-5-yl}nicotinamide 1-oxide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]pyrimidine-5-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide;
6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-
imidazo[1,2-c]quinazolin-5-yl]nicotinamide;
N-[8-(2-hydroxy-3-morpholin-4-ylpropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl]nicotinamide;
N-{7-methoxy-8-[3-(3-methylmorpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl}nicotinamide;
N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-(8-{2-[4-(cyclobutylmethyl)morpholin-2-yl]ethoxy}-7-methoxy-2,3-dihydro-
imidazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-(7-methoxy-8-{2-[4-(2-methoxyethyl)morpholin-2-yl]ethoxy}-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-{8-[(4-ethylmorpholin-2-yl)methoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]-
quinazolin-5-yl}nicotinamide;
N-(7-methoxy-8-{[4-(2-methoxyethyl)morpholin-2-yl]methoxy}-2,3-dihydroimi-
dazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-{7-methoxy-8-[(4-methylmorpholin-2-yl)methoxy]-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl}nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]pyrimidine-4-carboxamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]pyrimidine-4-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-1-methyl-1H-imidazole-4-carboxamide;
rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-di-
hydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;
rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-di-
hydroimidazo[1,2-c]quinazolin-5-yl)-6-methylnicotinamide;
rel-6-acetamido-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-me-
thoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-1-methyl-1H-imidazole-5-carboxamide;
6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-2-methylnicotinamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-4-methylpyrimidine-5-carboxamide;
6-amino-5-bromo-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimida-
zo[1,2-c]quinazolin-5-yl]nicotinamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-1,3-oxazole-5-carboxamide;
N-[7-methoxy-8-(morpholin-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazoli-
n-5-yl]nicotinamide;
2-{[2-(dimethylamino)ethyl]amino}-N-{8-[3-(dimethylamino)propoxy]-7-metho-
xy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;
2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2--
c]quinazolin-5-yl}-1,3-thiazole-5-carboxamide;
rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methox-
y-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;
rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methox-
y-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
2-[(2-hydroxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-di-
hydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-[(3-methoxypropyl)amino]pyrimidine-5-carboxamide;
2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2--
c]quinazolin-5-yl}pyrimidine-5-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-[(3-morpholin-4-ylpropyl)amino]pyrimidine-5-carboxamide;
2-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-di-
hydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;
2-{[2-(dimethylamino)ethyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy-
)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;
6-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2--
c]quinazolin-5-yl}nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-pyrrolidin-1-ylpyrimidine-5-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-morpholin-4-ylpyrimidine-5-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-piperazin-1-ylnicotinamide hydrochloride;
6-[(3S)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)--
2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide hydrochloride
hydrate;
6-[(3R)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-yl-
propoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide
hydrochloride;
6-[(4-fluorobenzyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-di-
hydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;
6-[(2-furylmethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dih-
ydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;
6-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-di-
hydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-(1H-pyrrol-1-yl)nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-morpholin-4-ylnicotinamide;
N-{7-methoxy-8-[3-(methylamino)propoxy]-2,3-dihydroimidazo[1,2-c]quinazol-
in-5-yl}nicotinamide;
6-[(2,2-dimethylpropanoyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-
-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;
6-[(cyclopropylcarbonyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2-
,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-(2,2,2-trifluoroethoxy)nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-(trifluoromethyl)nicotinamide;
6-(isobutyrylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroi-
midazo[1,2-c]quinazolin-5-yl]nicotinamide;
N-{7-methoxy-8-[3-(4-methylpiperazin-1-yl)propoxy]-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl}nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-{[(methylamino)carbonyl]amino}-1,3-thiazole-4-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-{[(methylamino)carbonyl]amino}nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-(methylamino)-1,3-thiazole-4-carboxamide;
N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazol-
in-5-yl]nicotinamide;
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}-6-methylnicotinamide;
6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropo-
xy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-pyrrolidin-1-ylnicotinamide;
6-(dimethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimi-
dazo[1,2-c]quinazolin-5-yl]nicotinamide;
N-[7-methoxy-8-(3-piperidin-1-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]nicotinamide;
N-[7-methoxy-8-(2-pyrrolidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]nicotinamide;
N-[7-methoxy-8-(2-pipendin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazoli-
n-5-yl]nicotinamide;
6-{[(ethylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)--
2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;
6-fluoro-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2--
c]quinazolin-5-yl]nicotinamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-1,3-oxazole-4-carboxamide;
2-(ethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidaz-
o[1,2-c]quinazolin-5-yl]-1,3-thiazole-4-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]pyrazine-2-carboxamide;
N-[8-(2-aminoethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]n-
icotinamide;
6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]isonicotinamide;
N-{8-[3-(diethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}nicotinamide;
N-{8-[2-(diisopropylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-yl}nicotinamide;
N-{8-[2-(diethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazol-
in-5-yl}nicotinamide;
N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinaz-
olin-5-yl}nicotinamide;
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-(methylamino)pyrimidine-5-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-(methylthio)pyrimidine-5-carboxamide;
N-[8-(3-aminopropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-
nicotinamide trifluoroacetate;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]thiophene-2-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;
2-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl]pyrimidine-5-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-3-furamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]thiophene-3-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-methyl-1,3-thiazole-4-carboxamide;
6-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl]nicotinamide;
5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl]nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-methylnicotinamide;
6-(acetylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimida-
zo[1,2-c]quinazolin-5-yl]nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]nicotinamide; or a physiologically acceptable salt,
solvate, hydrate or stereoisomer thereof.
28. Compounds according to any one of the claims 1-26, namely:
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-methylnicotinamide;
5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl]nicotinamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide;
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}nicotinamide;
N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinaz-
olin-5-yl}nicotinamide;
6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropo-
xy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide;
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide;
N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazol-
in-5-yl]nicotinamide;
rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methox-
y-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methox-
y-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]pyrimidine-5-carboxamide;
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}pyrimidine-5-carboxamide;
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]pyrimidine-5-carboxamide; or a physiologically acceptable
salt, solvate, hydrate or stereoisomer thereof.
29. A pharmaceutical composition comprising a compound according to
claim 1 or a physiologically acceptable salt, solvate, hydrate or
stereoisomer thereof and a pharmaceutically acceptable diluent or
carrier.
30. The pharmaceutical composition of claim 29 wherein the compound
is present in a therapeutically effective amount.
31. The pharmaceutical composition of claim 29 further comprising
at least one further active compound.
32. The pharmaceutical composition of claim 29, wherein the further
active compound is an anti-hyper-proliferative, anti-inflammatory,
analgesic, immunoregulatory, diuretic, anti-arrhythmic,
anti-hypercholesterolemic, anti-diabetic, anti-dyslipidemia,
anti-diabetic or antiviral agent.
33. The pharmaceutical composition of claim 32, wherein the further
active compound is gemcitabine, paclitaxel, cisplatin, carboplatin,
sodium butyrate, 5-FU, doxirubicin, tamoxifen, etoposide,
trastumazab, gefitinib, intron A, rapamycin, 17-AAG, U0126,
insulin, an insulin derivative, a PPAR ligand, a sulfonylurea drug,
an .alpha.-glucosidase inhibitor, a biguanide, a PTP-1B inhibitor,
a DPP-IV inhibitor, a 11-beta-HSD inhibitor, GLP-1, a GLP-1
derivative, GIP, a GIP derivative, PACAP, a PACAP derivative,
secretin, secretin derivative, aldesleukin, alendronic acid,
alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine,
aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole,
anzmet, aranesp, arglabin, arsenic trioxide, aromasin,
5-azacytidine, azathioprine, BCG or tice BCG, bestatin,
betamethasone acetate, betamethasone sodium phosphate, bexarotene,
bleomycin sulfate, broxuridine, bortezomib, busulfan, calcitonin,
campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin,
cerubidine, chlorambucil, cisplatin, cladribine, cladribine,
clodronic acid, cyclophosphamide, cytarabine, dacarbazine,
dactinomycin, DaunoXome, decadron, decadron phosphate, delestrogen,
denileukin diftitox, depo-medrol, deslorelin, dexrazoxane,
diethylstilbestrol, diflucan, docetaxel, doxifluridine,
doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend,
epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace,
estradiol, estramustine phosphate sodium, ethinyl estradiol,
ethyol, etidronic acid, etopophos, etoposide, fadrozole, farston,
filgrastim, finasteride, fligrastim, floxuridine, fluconazole,
fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil
(5-FU), fluoxymesterone, flutamide, formestane, fosteabine,
fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab,
gleevec, gliadel, goserelin, granisetron HCl, histrelin, hycamtin,
hydrocortone, eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab
tiuxetan, idarubicin, ifosfamide, interferon alpha,
interferon-alpha 2, interferon alfa-2A, interferon alfa-2B,
interferon alfa-n1, interferon alfa-n3, interferon beta, interferon
gamma-1a, interleukin-2, intron A, iressa, irinotecan, kytril,
lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide
acetate, levamisole, levofolinic acid calcium salt, levothroid,
levoxyl, lomustine, lonidamine, marinol, mechlorethamine,
mecobalamin, medroxyprogesterone acetate, megestrol acetate,
melphalan, menest, 6-mercaptopurine, Mesna, methotrexate, metvix,
miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone,
Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen,
nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron
HCl, orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase,
Pegasys, pentostatin, picibanil, pilocarpine HCl, pirarubicin,
plicamycin, porfimer sodium, prednimustine, prednisolone,
prednisone, premarin, procarbazine, procrit, raltitrexed, rebif,
rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen,
sandostatin, sargramostim, semustine, sizofiran, sobuzoxane,
solu-medrol, sparfosic acid, stem-cell therapy, streptozocin,
strontium-89 chloride, synthroid, tamoxifen, tamsulosin,
tasonermin, tastolactone, taxotere, teceleukin, temozolomide,
teniposide, testosterone propionate, testred, thioguanine,
thiotepa, thyrotropin, tiludronic acid, topotecan, toremifene,
tositumomab, trastuzumab, treosulfan, tretinoin, trexall,
trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin
pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine,
vincristine, vindesine, vinorelbine, virulizin, zinecard,
zinostatin stimalamer, zofran, ABI-007, acolbifene, actimmune,
affinitak, aminopterin, arzoxifene, asoprisnil, atamestane,
atrasentan, BAY 43-9006 (sorafenib), avastin, CCI-779, CDC-501,
celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine,
DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin,
eflornithine, exatecan, fenretinide, histamine dihydrochloride,
histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid,
interferon gamma, intron-PEG, ixabepilone, keyhole limpet
hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafarnib,
miproxifene, minodronate, MS-209, liposomal MTP-PE, MX-6,
nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen,
onco-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium,
PN-401, QS-21, quazepam, R-1549, raloxifene, ranpirnase,
13-cis-retinoic acid, satraplatin, seocalcitol, T-138067, tarceva,
taxoprexin, thymosin alpha 1, tiazofurine, tipifarnib,
tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar,
vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic
acid or combinations thereof.
34. A packaged pharmaceutical composition comprising a container,
the pharmaceutical composition of claim 29 and instructions for
using the pharmaceutical composition to treat a disease or
condition in a mammal.
35. A method of inhibiting phosphotidylinositol-3-kinase in cells
comprising contacting a cell with one or more compounds of claim
1.
36. A method of treating a disorder mediated by
phosphotidylinositol-3-kinase inhibition in a mammal comprising
administering to a mammal in need thereof, a therapeutically
effective amount of one or more compounds of claim 1.
37. The method of claim 36, wherein the disorder mediated by
phosphotidylinosito-3-kinase is an angiogenic disorder, an
inflammatory disorder, an autoimmune disorder, a cardiovascular
disorder, a neurodegenerative disorder, a metabolic disorder, a
nociceptive disorder, an ophthalmic disorder, a pulmonary disorder,
or a renal disorder.
38. The method of claim 37, wherein the cardiovascular disorder is
thrombosis, pulmonary hypertension, cardiac hypertophy,
atherosclerosis or heart failure.
39. The method of claim 37, wherein the inflammatory disorder is
COPD.
40. The method of claim 37, wherein the angiogenic disorder
diabetic retinopathy, ischemic retinal-vein occlusion, retinopathy
of prematurity, macular degeneration, neovascular glaucoma,
psoriasis, retrolental fibroplasias, angiofibroma, inflammation,
rheumatoid arthritis, restenosis, in-stent restenosis, or vascular
graft restenosis.
41. A method of treating a hyperproliferative disorder in a mammal
comprising administering to a mammal in need thereof, a
therapeutically effective amount of one or more compounds of claim
1.
42. The method of claim 41, wherein the hyperproliferative disorder
is cancer.
43. The method of claim 42, wherein the cancer is a cancer of the
breast, respiratory tract, brain, reproductive organs, digestive
tract, urinary tract, eye, liver, skin, head and neck, thyroid,
parathyroid or a distant metastasis of a solid tumor.
44. The method of claim 42 wherein the cancer is a lymphoma,
sarcoma, or leukemia.
Description
FIELD OF THE INVENTION
[0001] This invention relates to novel
2,3-dihydroimidazo[1,2-c]quinazoline compounds, pharmaceutical
compositions containing such compounds and the use of those
compounds or compositions for phosphotidylinositol-3-kinase (PI3K)
inhibition and treating diseases associated with
phosphotidylinositol-3-kinase (PI3K) activity, in particular
treating hyper-proliferative and/or angiogenesis disorders, as a
sole agent or in combination with other active ingredients.
BACKGROUND OF THE INVENTION
[0002] In the last decade the concept of developing anti-cancer
medications which target abnormally active protein kinases has led
to a number of successes. In addition to the actions of protein
kinases, lipid kinases also play an important role in generating
critical regulatory second messengers. The PI3K family of lipid
kinases generates 3'-phosphoinositides that bind to and activate a
variety of cellular targets, initiating a wide range of signal
transduction cascades (Vanhaesebroeck et al., 2001; Toker, 2002;
Pendaries et al., 2003; Downes et al., 2005). These cascades
ultimately induce changes in multiple cellular processes, including
cell proliferation, cell survival, differentiation, vesicle
trafficking, migration, and chemotaxis.
[0003] PI3Ks can be divided into three distinct classes based upon
differences in both structure, and substrate preference. While
members of the Class II family of PI3Ks have been implicated in the
regulation of tumor growth (Brown and Shepard, 2001; Traer et al.,
2006), the bulk of research has focused on the Class I enzymes and
their role in cancer (Vivanco And Sawyers, 2002; Workman, 2004,
Chen et al., 2005; Hennessey et al., 2005; Stauffer et al., 2005;
Stephens et al., 2005; Cully et al., 2006).
[0004] Class I PI3Ks have traditionally been divided into two
distinct sub-classes based upon differences in protein subunit
composition. The Class I.sub.A PI3Ks are comprised of a catalytic
p110 catalytic subunit (p110.alpha., .beta. or .delta.)
heterodimerized with a member of the p85 regulatory subunit family.
In contrast, the Class I.sub.B PI3K catalytic subunit (p110.gamma.)
heterodimerizes with a distinct p101 regulatory subunit (reviewed
by Vanhaesebroeck and Waterfield, 1999; Funaki et al., 2000; Katso
et al., 2001). The C-terminal region of these proteins contains a
catalytic domain that possesses distant homology to protein
kinases. The PI3K.gamma. structure is similar to Class I.sub.A
p110s, but lacks the N-terminal p85 binding site (Domin and
Waterfield, 1997). Though similar in overall structure, the
homology between catalytic p110 subunits is low to moderate. The
highest homology between the PI3K isoforms is in the kinase pocket
of the kinase domain.
[0005] The Class I.sub.A PI3K isoforms associate with activated
receptor tyrosine kinases (RTKs) (including PDGFR, EGFR, VEGFR,
IGF1-R, c-KIT, CSF-R and Met), or with tyrosine phosphorylated
adapter proteins (such as Grb2, Cbl, IRS-1 or Gab1), via their p85
regulatory subunits resulting in stimulation of the lipid kinase
activity. Activation of the lipid kinase activity of the p110.beta.
and p110.gamma. isoforms has been shown to occur in response to
binding to activated forms of the ras Oncogene (Kodaki et al,
1994). In fact, the oncogenic activity of these isoforms may
require binding to ras (Kang et al., 2006). In contrast, the
p110.alpha. and p110.delta. isoforms exhibit oncogenic activity
independent of ras binding, through constitutive activation of
Akt.
[0006] Class I PI3Ks catalyze the conversion of PI(4,5)P2 [PIP2] to
PI(3,4,5)P3 [PIP3]. The production of PIP.sub.3 by PI3K affects
multiple signaling processes that regulate and coordinate the
biological end points of cell proliferation, cell survival,
differentiation and cell migration. PIP.sub.3 is bound by
Pleckstrin-Homology (PH) domain-containing proteins, including the
phosphoinositide-dependent kinase, PDK1 and the Akt proto-oncogene
product, localizing these proteins in regions of active signal
transduction and also contributing directly to their activation
(Klippel et al., 1997; Fleming et al., 2000; Itoh and Takenawa,
2002; Lemmon, 2003). This co-localization of PDK1 with Akt
facilitates the phosphorylation and activation of Akt.
Carboxy-terminal phosphorylation of Akt on Ser.sup.473 promotes
phosphorylation of Thr.sup.308 in the Akt activation loop (Chan and
Tsichlis, 2001; Hodgekinson et al., 2002; Scheid et al., 2002;
Hresko et al., 2003). Once active, Akt phosphorylates and regulates
multiple regulatory kinases of pathways that directly influence
cell cycle progression and cell survival.
[0007] Many of the effects of Akt activation are mediated via its
negative regulation of pathways which impact cell survival and
which are commonly dysregulated in cancer. Akt promotes tumor cell
survival by regulating components of the apoptotic and cell cycle
machinery. Akt is one of several kinases that phosphorylate and
inactivate pro-apoptotic BAD proteins (del Paso et al., 1997;
Pastorino et al., 1999). Akt may also promote cell survival through
blocking cytochrome C-dependent caspase activation by
phosphorylating Caspase 9 on Ser.sup.196 (Cardone et al.,
1998).
[0008] Akt impacts gene transcription on several levels. The
Akt-mediated phosphorylation of the MDM2 E3 ubiquitin ligase on
Ser.sup.166 and Ser.sup.186 facilitates the nuclear import of MDM2
and the formation and activation of the ubiquitin ligase complex.
Nuclear MDM2 targets the p53 tumor suppressor for degradation, a
process that can be blocked by LY294002 (Yap et al., 2000; Ogarawa
et al., 2002). Downregulation of p53 by MDM2 negatively impacts the
transcription of p53-regulated pro-apoptotic genes (e.g. Bax, Fas,
PUMA and DR5), the cell cycle inhibitor, p21.sup.Cip1, and the PTEN
tumor suppressor (Momand et al., 2000; Hupp et al., 2000; Mayo et
al., 2002; Su et al., 2003). Similarly, the Akt-mediated
phosphorylation of the Forkhead transcription factors FKHR, FKHRL
and AFX (Kops et al., 1999; Tang et al., 1999), facilitates their
binding to 14-3-3 proteins and export from the cell nucleus to the
cytosol (Brunet et al., 1999). This functional inactivation of
Forkhead activity also impacts pro-apoptotic and pro-angiogenic
gene transcription including the transcription of Fas ligand
(Ciechomska et al., 2003) Bim, a pro-apoptotic Bcl-2 family member
(Dijkers et al., 2000), and the Angiopoietin-1 (Ang-1) antagonist,
Ang-2 (Daly et al., 2004). Forkhead transcription factors regulate
the expression of the cyclin-dependent kinase (Cdk) inhibitor
p27.sup.KiP1. Indeed, PI3K inhibitors have been demonstrated to
induce p27.sup.Kip1 expression resulting in Cdk1 inhibition, cell
cycle arrest and apoptosis (Dijkers et al., 2000). Akt is also
reported to phosphorylate p21.sup.Cip1on Thr.sup.145 and
p27.sup.KiP1 on Thr.sup.157 facilitating their association with
14-3-3 proteins, resulting in nuclear export and cytoplasmic
retention, preventing their inhibition of nuclear Cdks (Zhou et
al., 2001; Motti et al., 2004; Sekimoto et al., 2004). In addition
to these effects, Akt phosphorylates IKK (Romashkova and Makarov,
1999), leading to the phosphorylation and degradation of I.kappa.B
and subsequent nuclear translocation of NF.kappa.B, resulting in
the expression of survival genes such as IAP and Bcl-X.sub.L.
[0009] The PI3K/Akt pathway is also linked to the suppression of
apoptosis through the JNK and p38.sup.MAPK MAP Kinases that are
associated with the induction of apoptosis. Akt is postulated to
suppress JNK and p38.sup.MAPK signaling through the phosphorylation
and inhibition of two JNK/p38 regulatory kinases, Apoptosis
Signal-regulating Kinase 1 (ASK1) (Kim et al., 2001: Liao and Hung,
2003; Yuan et al., 2003), and Mixed Lineage Kinase 3 (MLK3)
(Lopez-Ilasaca et al., 1997; Barthwal et al., 2003; Figueroa et
al., 2003;). The induction of p38.sup.MAPK activity is observed in
tumors treated with cytotoxic agents and is required for those
agents to induce cell death (reviewed by Olson and Hallahan, 2004).
Thus, inhibitors of the PI3K pathway may promote the activities of
co-administered cytotoxic drugs.
[0010] An additional role for PI3K/Akt signaling involves the
regulation of cell cycle progression through modulation of Glycogen
Synthase Kinase 3 (GSK3) activity. GSK3 activity is elevated in
quiescent cells, where it phosphorylates cyclin D.sub.1 on
Ser.sup.286, targeting the protein for ubiquitination and
degradation (Diehl et al., 1998) and blocking entry into S-phase.
Akt inhibits GSK3 activity through phosphorylation on Ser.sup.9
(Cross et al., 1995). This results in the elevation of Cyclin
D.sub.1 levels which promotes cell cycle progression. Inhibition of
GSK3 activity also impacts cell proliferation through activation of
the wnt/beta-catenin signaling pathway (Abbosh and Nephew, 2005;
Naito et al., 2005; Wilker et al., 2005; Kim et al., 2006;
Segrelles et al., 2006). Akt mediated phosphorylation of GSK3
results in stabilization and nuclear localization of the
beta-catenin protein, which in turn leads to increased expression
of c-myc and cyclin D1, targets of the beta-catenin/Tcf
pathway.
[0011] Although PI3K signaling is utilized by many of the signal
transduction networks associated with both oncogenes and tumor
suppressors, PI3K and its activity have been linked directly to
cancer. Overexpression of both the p110.alpha. and p110.beta.
isoforms has been observed in bladder and colon tumors and cell
lines, and overexpression generally correlates with increased PI3K
activity (Benistant et al., 2000). Overexpression of
p110.alpha..quadrature..quadrature. has also been reported in
ovarian and cervical tumors and tumor cell lines, as well as in
squamous cell lung carcinomas. The overexpression of p110.alpha. in
cervical and ovarian tumor lines is associated with increased PI3K
activity (Shayesteh et al., 1999; Ma et al., 2000). Elevated PI3K
activity has been observed in colorectal carcinomas (Phillips et
al., 1998) and increased expression has been observed in breast
carcinomas (Gershtein et al., 1999).
[0012] Over the last few years, somatic mutations in the gene
encoding p110.alpha. (PIK3CA) have been identified in numerous
cancers. The data collected to date suggests that PIK3CA is mutated
in approximately 32% of colorectal cancers (Samuels et al., 2004;
Ikenoue et al., 2005), 18-40% of breast cancers (Bachman et al.,
2004; Campbell et al., 2004; Levine et al., 2005; Saal et al.,
2005; Wu et al., 2005), 27% of glioblastomas (Samuels et al., 2004;
Hartmann et al., 2005, Gallia et al., 2006), 25% of gastric cancers
(Byun et al., 2003; Samuels et al., 2004; Li et al., 2005), 36% of
hepatocellular carcinomas (Lee et al., 2005), 4-12% of ovarian
cancers (Levine et al., 2005; Wang et al., 2005), 4% of lung
cancers (Samuels et al., 2004; Whyte and Holbeck, 2006), and up to
40% of endometrial cancers (Oda et al., 2005). PIK3CA mutations
have been reported in oligodendroma, astrocytoma, medulloblastoma,
and thyroid tumors as well (Broderick et al., 2004; Garcia-Rostan
et al., 2005). Based upon the observed high frequency of mutation,
PIK3CA is one of the two most frequently mutated genes associated
with cancer, the other being K-ras. More than 80% of the PIK3CA
mutations cluster within two regions of the protein, the helical
(E545K) and catalytic (H1047R) domains. Biochemical analysis and
protein expression studies have demonstrated that both mutations
lead to increased constitutive p110.alpha. catalytic activity and
are in fact, oncogenic (Bader et al., 2006; Kang et al., 2005;
Samuels et al., 2005; Samuels and Ericson, 2006). Recently, it has
been reported that PIK3CA knockout mouse embryo fibroblasts are
deficient in signaling downstream from various growth factor
receptors (IGF-1, Insulin, PDGF, EGF), and are resistant to
transformation by a variety of oncogenic RTKs (IGFR, wild-type EGFR
and somatic activating mutants of EGFR, Her2/Neu)(Zhao et al.,
2006).
[0013] Functional studies of PI3K in vivo have demonstrated that
siRNA-mediated downregulation of p110.beta. inhibits both Akt
phosphorylation and HeLa cell tumor growth in nude mice (Czauderna
et al., 2003). In similar experiments, siRNA-mediated
downregulation of p110.beta. was also shown to inhibit the growth
of malignant glioma cells in vitro and in vivo (Pu et al., 2006).
Inhibition of PI3K function by dominant-negative p85 regulatory
subunits can block mitogenesis and cell transformation (Huang et
al., 1996; Rahimi et al., 1996). Several somatic mutations in the
genes encoding the p85.alpha. and p85.beta. regulatory subunits of
PI3K that result in elevated lipid kinase activity have been
identified in a number of cancer cells as well (Janssen et al.,
1998; Jimenez et al., 1998; Philp et al., 2001; Jucker et al.,
2002; Shekar et al., 2005). Neutralizing PI3K antibodies also block
mitogenesis and can induce apoptosis in vitro (Roche et al., 1994:
Roche et al., 1998; Benistant et al., 2000). In vivo
proof-of-principle studies using the PI3K inhibitors LY294002 and
wortmannin, demonstrate that inhibition of PI3K signaling slows
tumor growth in vivo (Powis et al., 1994; Shultz et al., 1995;
Semba et al., 2002; Ihle et al., 2004).
[0014] Overexpression of Class I PI3K activity, or stimulation of
their lipid kinase activities, is associated with resistance to
both targeted (such as imatinib and tratsuzumab) and cytotoxic
chemotherapeutic approaches, as well as radiation therapy (West et
al., 2002; Gupta et al., 2003; Osaki et al., 2004; Nagata et al.,
2004; Gottschalk et al., 2005; Kim et al., 2005). Activation of
PI3K has also been shown to lead to expression of multidrug
resistant protein-1 (MRP-1) in prostate cancer cells and the
subsequent induction of resistance to chemotherapy (Lee et al.,
2004).
[0015] The importance of PI3K signaling in tumorigenesis is further
underscored by the findings that the PTEN tumor suppressor, a
PI(3)P phosphatase, is among the most commonly inactivated genes in
human cancers (Li et al., 1997, Steck et al., 1997; Ali et al.,
1999; Ishii et al., 1999). PTEN dephosphorylates PI(3,4,5)P3 to
PI(4,5)P2 thereby antagonizing PI3K-dependent signaling. Cells
containing functionally inactive PTEN have elevated levels of
PIP.sub.3, high levels of activity of PI3K signaling (Haas-Kogan et
al., 1998; Myers et al., 1998; Taylor et al., 2000), increased
proliferative potential, and decreased sensitivity to pro-apoptotic
stimuli (Stambolic et al., 1998). Reconstitution of a functional
PTEN suppresses PI3K signaling (Taylor et al., 2000), inhibits cell
growth and re-sensitizes cells to pro-apoptotic stimuli (Myers et
al., 1998; Zhao et al., 2004). Similarly, restoration of PTEN
function in tumors lacking functional PTEN inhibits tumor growth in
vivo (Stahl et al., 2003; Su et al., 2003; Tanaka and Grossman,
2003) and sensitizes cells to cytotoxic agents (Tanaka and
Grossman, 2003).
[0016] The class I family of PI3Ks clearly plays an important role
in the regulation of multiple signal transduction pathways that
promote cell survival and cell proliferation, and activation of
their lipid kinase activity contributes significantly to the
development of human malignancies. Furthermore, inhibition of PI3K
may potentially circumvent the cellular mechanisms that underlie
resistance to chemotherapeutic agents. A potent inhibitor of Class
I PI3K activities would therefore have the potential not only to
inhibit tumor growth but to also sensitize tumor cells to
pro-apoptotic stimuli in vivo.
[0017] Signal transduction pathways originating from
chemoattractant receptors are considered to be important targets in
controlling leukocyte motility in inflammatory diseases. Leukocyte
trafficking is controlled by chemoattractant factors that activate
heterotrimeric GPCRs and thereby trigger a variety of downstream
intracellular events. Signal transduction along one of these
pathways that results in mobilization of free Ca.sup.2+,
cytoskelatal reorganization, and directional movement depends on
lipid-dervied second messengers producted by PI3K activity (Wymann
et al., 2000; Stein and Waterfield, 2000).
[0018] PI3K.gamma. modulates baseline cAMP levels and controls
contractility in cells. Recent research indicates that alterations
in baseline cAMP levels contributes to the increased contractility
in mutant mice. This research, therefore, shows that PI3K.gamma.
inhibitors would afford potential treatments for congestive heart
failure, ischemia, pulmonary hypertension, renal failure, cardiac
hypertrophy, atherosclerosis, thromboembolism, and diabetes.
[0019] PI3K inhibitors would be expected to block signal
transduction from GPCRs and block the activation of various immune
cells, leading to a broad anti-inflammatory profile with potential
for the treatment of inflammatory and immunoregulatory diseases,
including asthma, atopic dermatitis, rhinitis, allergic diseases,
chronic obstructive pulmonary disease (COPD), septic shock, joint
diseases, autoimmune pathologies such as rheumatoid arthritis and
Graves' disease, diabetes, cancer, myocardial contractility
disorders, thromboembolism, and atherosclerosis.
[0020] PI3K inhibitor compounds and compositions described herein,
including salts, metabolites, solvates, solvates of salts,
hydrates, and stereoisomeric forms thereof, exhibit
anti-proliferative activity and are thus useful to prevent or treat
the disorders associated with hyper-proliferation.
DESCRIPTION OF THE INVENTION
[0021] One embodiment of this invention encompasses a compound
having the formula (I):
##STR00001##
or a physiologically acceptable salt, solvate, hydrate or
stereoisomer thereof, wherein: [0022] R.sup.1 is
--(CH.sub.2).sub.n--(CHR.sup.4)--(CH.sub.2).sub.m--N(R.sup.5)(R.sup.5');
[0023] R.sup.2 is a heteroaryl optionally substituted with 1, 2 or
3 R.sup.6 groups; [0024] R.sup.3 is alkyl or cycloalkyl; [0025]
R.sup.4 is hydrogen, hydroxy or alkoxy and R.sup.5 and R.sup.5' may
be the same or different and are independently, hydrogen, alkyl,
cycloalkylalklyl, or alkoxyalkyl or R.sup.5 and R.sup.5' may be
taken together with the nitrogen atom to which they are bound to
form a 3-7 membered nitrogen containing heterocyclic ring
optionally containing at least one additional heteroatom selected
from oxygen, nitrogen or sulfur and which may be optionally
substituted with 1 or more R.sup.6' groups, or R.sup.4 and R.sup.5
may be taken together with the atoms to which they are bound to
form a 5-6 membered nitrogen containing heterocyclic ring
optionally containing 1 or more nitrogen, oxygen or sulfur atoms
and which may be optionally substituted with 1 or more R.sup.6'
groups; each occurrence of R.sup.6 may be the same or different and
is independently halogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalklyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclic ring, heterocyclylalkyl, alkyl-OR.sup.7,
alkyl-SR.sup.7, alkyl-N(R.sup.7)(R.sup.7'), alkyl-COR.sup.7, --CN,
--COOR.sup.7, --CON(R.sup.7)(R.sup.7'), --OR.sup.7, --SR.sup.7,
--N(R.sup.7)(R.sup.7'), or --NR.sup.7COR.sup.7 each of which may be
optionally substituted with 1 or more R.sup.8 groups; each
occurrence of R.sup.6' may be the same or different and is
independently alkyl, cycloalkylalklyl, or alkyl-OR.sup.7; each
occurrence of R.sup.7 and R.sup.7' may be the same or different and
is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl, heteroaryl,
heterocyclic ring, heterocyclylalkyl, or heteroarylalkyl; each
occurrence of R.sup.8 is independently nitro, hydroxy, cyano,
formyl, acetyl, halogen, amino, alkyl, alkoxy, alkenyl, alkynyl,
cycloalkyl, cycloalkylalklyl, cycloalkenyl, aryl, arylalkyl,
heteroaryl, heterocyclic ring, heterocyclylalkyl, or
heteroarylalkyl; n is an integer from 1-4 and m is an integer from
0-4 with the proviso that when R.sup.4 and R.sup.5 are taken
together with the atoms to which they are bound to form a 5-6
membered nitrogen containing ring, n+m.ltoreq.4.
[0026] In a preferred embodiment, the invention encompasses the
compound of Formula (I), wherein R.sup.2 is a nitrogen containing
heteroaryl optionally substituted with 1, 2 or 3 R.sup.6
groups.
[0027] In another preferred embodiment, the invention encompasses
the compound of Formula (I), wherein R.sup.5 and R.sup.5' are
independently alkyl;
[0028] In still another preferred embodiment, the invention
encompasses the compound of Formula (I), wherein R.sup.5 and
R.sup.5' are taken together with the nitrogen atom to which they
are bound to form a 5-6 membered nitrogen containing heterocyclic
ring containing at least one additional heteroatom selected from
oxygen, nitrogen or sulfur and which may be optionally substituted
with 1 or more R.sup.6' groups.
[0029] In yet another preferred embodiment, the invention
encompasses the compound of Formula (I), wherein R.sup.4 is
hydroxy.
[0030] In another preferred embodiment, the invention encompasses
the compound of Formula (I), wherein R.sup.4 and R.sup.5 are taken
together with the atoms to which they are bound to form a 5-6
membered nitrogen containing heterocyclic ring optionally
containing 1 or more nitrogen, oxygen or sulfur atoms and which may
be optionally substituted with 1 or more R.sup.6 groups.
[0031] In yet another preferred embodiment, the invention
encompasses the compound of Formula (I), wherein R.sup.3 is
methyl.
[0032] In still another preferred embodiment, the invention
encompasses the compound of Formula (I), wherein R.sup.2 is
pyridine, pyridazine, pyrimidine, pyrazine, pyrole, oxazole,
thiazole, furan or thiophene, optionally substituted with 1, 2 or 3
R.sup.6 groups; more preferably pyridine, pyridazine, pyrimidine,
pyrazine, pyrole, oxazole or thiazole, optionally substituted with
1, 2 or 3 R.sup.6 groups.
[0033] In a distinct embodiment, the invention encompasses a
compound of formula (Ia)
##STR00002##
or a physiologically acceptable salt, solvate, hydrate or
stereoisomer thereof, wherein R.sup.2 is as defined above.
[0034] In another distinct embodiment, the invention encompasses a
compound of formula (Ib)
##STR00003##
or a physiologically acceptable salt, solvate, hydrate or
stereoisomer thereof, wherein R.sup.2 is as defined above.
[0035] In still another distinct embodiment, the invention
encompasses a compound of formula (Ic)
##STR00004##
or a physiologically acceptable salt, solvate, hydrate or
stereoisomer thereof, wherein R.sup.2 is as defined above.
[0036] In yet another distinct embodiment, the invention
encompasses a compound of the formula (Id):
##STR00005## [0037] or a physiologically acceptable salt, solvate,
hydrate or stereoisomer thereof, [0038] wherein R.sup.2 and R.sup.4
are as defined above.
[0039] In yet another distinct embodiment, the invention
encompasses a compound of the formula (Ie):
##STR00006## [0040] or a physiologically acceptable salt, solvate,
hydrate or stereoisomer thereof, wherein R.sup.2 and R.sup.4 are as
defined above.
[0041] In a preferred embodiment, the invention encompasses a
compound of formula (I)-(V), wherein R.sup.2 is pyridine,
pyridazine, pyrimidine, pyrazine, pyrole, oxazole, thiazole, furan
or thiophene, optionally substituted with 1, 2 or 3 R.sup.6 groups;
more preferrably wherein R.sup.2 is pyridine, pyridazine,
pyrimidine, pyrazine, pyrole, oxazole or thiazole, optionally
substituted with 1, 2 or 3 R.sup.6 groups.
[0042] In still another preferred embodiment, the invention
encompasses a compound having the formula: [0043]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]pyrimidine-5-carboxamide; [0044]
N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydr-
oimidazo[1,2-c]quinazolin-5-yl)nicotinamide; [0045]
N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydr-
oimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;
[0046]
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidaz-
o[1,2-c]quinazolin-5-yl]-1,3-thiazole-5-carboxamide; [0047]
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]isonicotinamide; [0048]
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamide; [0049]
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide; [0050]
N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl}nicotinamide; [0051]
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}pyrimidine-5-carboxamide; [0052]
N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide; [0053]
N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide; [0054]
N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinaz-
olin-5-yl}nicotinamide 1-oxide; [0055]
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]pyrimidine-5-carboxamide; [0056]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide; [0057]
6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-
imidazo[1,2-c]quinazolin-5-yl]nicotinamide; [0058]
N-[8-(2-hydroxy-3-morpholin-4-ylpropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl]nicotinamide; [0059]
N-{7-methoxy-8-[3-(3-methylmorpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl}nicotinamide; [0060]
N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide; [0061]
N-(8-{2-[4-(cyclobutylmethyl)morpholin-2-yl]ethoxy}-7-methoxy-2,3-dihydro-
imidazo[1,2-c]quinazolin-5-yl)nicotinamide; [0062]
N-(7-methoxy-8-{2-[4-(2-methoxyethyl)morpholin-2-yl]ethoxy}-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide; [0063]
N-{8-[(4-ethylmorpholin-2-yl)methoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]-
quinazolin-5-yl}nicotinamide; [0064]
N-(7-methoxy-8-{[4-(2-methoxyethyl)morpholin-2-yl]methoxy}-2,3-dihydroimi-
dazo[1,2-c]quinazolin-5-yl)nicotinamide; [0065]
N-{7-methoxy-8-[(4-methylmorpholin-2-yl)methoxy]-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl}nicotinamide; [0066]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]pyrimidine-4-carboxamide; [0067]
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]pyrimidine-4-carboxamide; [0068]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-1-methyl-1H-imidazole-4-carboxamide; [0069]
rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-di-
hydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide; [0070]
rel-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-di-
hydroimidazo[1,2-c]quinazolin-5-yl)-6-methylnicotinamide; [0071]
rel-6-acetamido-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-me-
thoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide; [0072]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-1-methyl-1H-imidazole-5-carboxamide; [0073]
6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-2-methylnicotinamide; [0074]
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-4-methylpyrimidine-5-carboxamide; [0075]
6-amino-5-bromo-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimida-
zo[1,2-c]quinazolin-5-yl]nicotinamide; [0076]
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-1,3-oxazole-5-carboxamide; [0077]
N-[7-methoxy-8-(morpholin-2-ylmethoxy)-2,3-dihydroimidazo[1,2-c]quinazoli-
n-5-yl]nicotinamide; [0078]
2-{[2-(dimethylamino)ethyl]amino}-N-{8-[3-(dimethylamino)propoxy]-7-metho-
xy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide;
[0079]
2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimida-
zo[1,2-c]quinazolin-5-yl}-1,3-thiazole-5-carboxamide; [0080]
rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methox-
y-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;
[0081]
rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-
-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide;
[0082]
2-[(2-hydroxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-di-
hydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide; [0083]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-[(3-methoxypropyl)amino]pyrimidine-5-carboxamide;
[0084]
2-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2--
c]quinazolin-5-yl}pyrimidine-5-carboxamide; [0085]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-[(3-morpholin-4-ylpropyl)amino]pyrimidine-5-carboxamide;
[0086]
2-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-
-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;
[0087]
2-{[2-(dimethylamino)ethyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy-
)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide;
[0088]
6-amino-N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimida-
zo[1,2-c]quinazolin-5-yl}nicotinamide; [0089]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-pyrrolidin-1-ylpyrimidine-5-carboxamide; [0090]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxamide;
[0091]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-morpholin-4-ylpyrimidine-5-carboxamide; [0092]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-piperazin-1-ylnicotinamide hydrochloride; [0093]
6-[(3S)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)--
2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide hydrochloride
hydrate; [0094]
6-[(3R)-3-aminopyrrolidin-1-yl]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)--
2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide
hydrochloride; [0095]
6-[(4-fluorobenzyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-
-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide; [0096]
6-[(2-furylmethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dih-
ydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide; [0097]
6-[(2-methoxyethyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-di-
hydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide; [0098]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-(1H-pyrrol-1-yl)nicotinamide; [0099]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-morpholin-4-ylnicotinamide; [0100]
N-{7-methoxy-8-[3-(methylamino)propoxy]-2,3-dihydroimidazo[1,2-c]quinazol-
in-5-yl}nicotinamide; [0101]
6-[(2,2-dimethylpropanoyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-
-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide; [0102]
6-[(cyclopropylcarbonyl)amino]-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2-
,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide [0103]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-(2,2,2-trifluoroethoxy)nicotinamide; [0104]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-(trifluoromethyl)nicotinamide; [0105]
6-(isobutyrylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroi-
midazo[1,2-c]quinazolin-5-yl]nicotinamide; [0106]
N-{7-methoxy-8-[3-(4-methylpiperazin-1-yl)propoxy]-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl}nicotinamide; [0107]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-{[(methylamino)carbonyl]amino}-1,3-thiazole-4-carboxamide;
[0108]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]-
quinazolin-5-yl]-6-{[(methylamino)carbonyl]amino}nicotinamide;
[0109]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-(methylamino)-1,3-thiazole-4-carboxamide; [0110]
N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazol-
in-5-yl]nicotinamide; [0111]
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide; [0112]
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}-6-methylnicotinamide; [0113]
6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropo-
xy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide; [0114]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-pyrrolidin-1-ylnicotinamide; [0115]
6-(dimethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimi-
dazo[1,2-c]quinazolin-5-yl]nicotinamide; [0116]
N-[7-methoxy-8-(3-pipendin-1-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazol-
in-5-yl]nicotinamide; [0117]
N-[7-methoxy-8-(2-pyrrolidin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]nicotinamide; [0118]
N-[7-methoxy-8-(2-pipendin-1-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazoli-
n-5-yl]nicotinamide; [0119]
6-{[(ethylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)--
2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide; [0120]
6-fluoro-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2--
c]quinazolin-5-yl]nicotinamide; [0121]
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-1,3-oxazole-4-carboxamide; [0122]
2-(ethylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidaz-
o[1,2-c]quinazolin-5-yl]-1,3-thiazole-4-carboxamide; [0123]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]pyrazine-2-carboxamide; [0124]
N-[8-(2-aminoethoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]n-
icotinamide; [0125]
6-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]nicotinamide; [0126]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]isonicotinamide; [0127]
N-{8-[3-(diethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}nicotinamide; [0128]
N-{8-[2-(diisopropylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-yl}nicotinamide; [0129]
N-{8-[2-(diethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazol-
in-5-yl}nicotinamide; [0130]
N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinaz-
olin-5-yl}nicotinamide; [0131]
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}nicotinamide; [0132]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-(methylamino)pyrimidine-5-carboxamide; [0133]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-(methylthio)pyrimidine-5-carboxamide; [0134]
N-[8-(3-aminopropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]-
nicotinamide trifluoroacetate; [0135]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]thiophene-2-carboxamide; [0136]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide; [0137]
2-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl]pyrimidine-5-carboxamide; [0138]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-3-furamide; [0139]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]thiophene-3-carboxamide; [0140]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2-methyl-1,3-thiazole-4-carboxamide; [0141]
6-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl]nicotinamide; [0142]
5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl]nicotinamide; [0143]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-methylnicotinamide; [0144]
6-(acetylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimida-
zo[1,2-c]quinazolin-5-yl]nicotinamide; [0145]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]nicotinamide; or a physiologically acceptable salt,
solvate, hydrate or stereoisomer thereof.
[0146] In a preferred embodiment, the invention encompasses a
compound having the formula: [0147]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]nicotinamide; [0148]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-methylnicotinamide; [0149]
5-methoxy-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-
-c]quinazolin-5-yl]nicotinamide; [0150]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-2,4-dimethyl-1,3-thiazole-5-carboxamide; [0151]
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}nicotinamide; [0152]
N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinaz-
olin-5-yl}nicotinamide; [0153]
6-{[(isopropylamino)carbonyl]amino}-N-[7-methoxy-8-(3-morpholin-4-ylpropo-
xy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide; [0154]
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}-2,4-dimethyl-1,3-thiazole-5-carboxamide; [0155]
N-[7-methoxy-8-(2-morpholin-4-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazol-
in-5-yl]nicotinamide; [0156]
rel-6-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methox-
y-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide; [0157]
rel-2-amino-N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methox-
y-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide;
[0158]
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidaz-
o[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide; [0159]
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}pyrimidine-5-carboxamide; [0160]
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]pyrimidine-5-carboxamide; or a physiologically acceptable
salt, solvate, hydrate or stereoisomer thereof.
[0161] Where there is a discrepancy between the chemical name and
the chemical structure depicted, the chemical structure depicted
takes precedence over the chemical name given.
[0162] Without being bound by theory or mechanism, the compounds of
the present invention display surprising activity for the
inhibition of phosphatidylinositol-3-kinase and chemical and
structural stability over those compounds of the prior art. It is
believed that this surprising activity is based on the chemical
structure of the compounds, in particular the basicity of the
compounds as a result of R.sup.1 being amino optionally substituted
with R.sup.5 and R.sup.5'. Further, the appropriate choice of
R.sup.3 and R.sup.2 provide the necessary activity against the
appropriate isoforms to allow for activity in vivo.
DEFINITIONS
[0163] The term `alkyl` refers to a straight or branched
hydrocarbon chain radical consisting solely of carbon and hydrogen
atoms, containing solely of carbon and hydrogen atoms, containing
no unsaturation, having from one to eight carbon atoms, and which
is attached to the rest of the molecule by a single bond, such as
illustratively, methyl, ethyl, n-propyl 1-methylethyl (isopropyl),
n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term
"alkenyl" refers to an aliphatic hydrocarbon group containing a
carbon-carbon double bond and which may be a straight or branched
or branched chain having about 2 to about 10 carbon atoms, e.g.,
ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-and butenyl.
[0164] The term "alkynyl" refers to a straight or branched chain
hydrocarbonyl radicals having at least one carbon-carbon triple
bond, and having in the range of about 2 up to 12 carbon atoms
(with radicals having in the range of about 2 up to 10 carbon atoms
presently being preferred) e.g., ethynyl.
[0165] The term "alkoxy" denotes an alkyl group as defined herein
attached via oxygen linkage to the rest of the molecule.
Representative examples of those groups are methoxy and ethoxy.
[0166] The term "alkoxyakyl" denotes an alkoxy group as defined
herein attached via oxygen linkage to an alkyl group which is then
attached to the main structure at any carbon from alkyl group that
results in the creation of a stable structure the rest of the
molecule. Representative examples of those groups are
--CH.sub.2OCH.sub.3, --CH.sub.2OC.sub.2H.sub.5.
[0167] The term "cycloalkyl" denotes a non-aromatic mono or
multicyclic ring system of about 3 to 12 carbon atoms such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples of
multicyclic cycloalkyl groups include perhydronapththyl, adamantyl
and norbornyl groups bridged cyclic group or sprirobicyclic groups
e.g sprio (4,4) non-2-yl.
[0168] The term "cycloalkylalkyl" refers to cyclic ring-containing
radicals containing in the range of about 3 up to 8 carbon atoms
directly attached to alkyl group which is then also attached to the
main structure at any carbon from the alkyl group that results in
the creation of a stable structure such as cyclopropylmethyl,
cyclobuyylethyl, cyclopentylethyl.
[0169] The term "aryl" refers to aromatic radicals having in the
range of 6 up to 14 carbon atoms such as phenyl, naphthyl,
tetrahydronapthyl, indanyl, biphenyl.
[0170] The term "arylalkyl" refers to an aryl group as defined
herein directly bonded to an alkyl group as defined herein which is
then attached to the main structure at any carbon from alkyl group
that results in the creation of a stable structure the rest of the
molecule. e.g., --CH.sub.2C.sub.6H.sub.5,
--C.sub.2H.sub.5C.sub.6H.sub.5.
[0171] The term "heterocyclic ring" refers to a stable 3- to 15
membered ring radical which consists of carbon atoms and from one
to five heteroatoms selected from the group consisting of nitrogen,
phosphorus, oxygen and sulfur. For purposes of this invention, the
heterocyclic ring radical may be a monocyclic, bicyclic or
tricyclic ring system, which may include fused, bridged or spiro
ring systems, and the nitrogen, phosphorus, carbon, oxygen or
sulfur atoms in the heterocyclic ring radical may be optionally
oxidized to various oxidation states. In addition, the nitrogen
atom may be optionally quaternized; and the ring radical may be
partially or fully saturated (i.e., heteroaromatic or heteroaryl
aromatic). Examples of such heterocyclic ring radicals include, but
are not limited to, azetidinyl, acridinyl, benzodioxolyl,
benzodioxanyl, benzofurnyl, carbazolyl cinnolinyl dioxolanyl,
indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl,
purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
tetrazoyl, imidazolyl tetrahydroisouinolyl, piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,
2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,
pyrazinyl, pyrimidinyl pyridazinyl, oxazolyl oxazolinyl
oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl,
morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl,
quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl,
isoindolinyl, octahydroindolyl, octahydroisoindolyl quinolyl,
isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl,
benzopyranyl, benzothiazolyl, benzooxazolyl, furyl,
tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl,
thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinyl sulfone,
dioxaphospholanyl, oxadiazolyl, chromanyl, isochromanyl.
[0172] The term "heteroaryl" refers to heterocyclic ring radical as
defined herein which are aromatic. The heteroaryl ring radical may
be attached to the main structure at any heteroatom or carbon atom
that results in the creation of a stable structure.
[0173] The heterocyclic ring radical may be attached to the main
structure at any heteroatom or carbon atom that results in the
creation of a stable structure.
[0174] The term "heteroarylalkyl" refers to heteroaryl ring radical
as defined herein directly bonded to alkyl group. The
heteroarylalkyl radical may be attached to the main structure at
any carbon atom from alkyl group that results in the creation of a
stable structure.
[0175] The term "heterocyclyl" refers to a heterocylic ring radical
as defined herein. The heterocylyl ring radical may be attached to
the main structure at any heteroatom or carbon atom that results in
the creation of a stable structure.
[0176] The term "heterocyclylalkyl" refers to a heterocylic ring
radical as defined herein directly bonded to alkyl group. The
heterocyclylalkyl radical may be attached to the main structure at
carbon atom in the alkyl group that results in the creation of a
stable structure.
[0177] The term "carbonyl" refers to an oxygen atom bound to a
carbon atom of the molecule by a double bond.
[0178] The term "halogen" refers to radicals of fluorine, chlorine,
bromine and iodine.
[0179] Where the plural form of the word compounds, salts,
polymorphs, hydrates, solvates and the like, is used herein, this
is taken to mean also a single compound, salt, polymorph, isomer,
hydrate, solvate or the like.
[0180] The compounds of this invention may contain one or more
asymmetric centers, depending upon the location and nature of the
various substituents desired. Asymmetric carbon atoms may be
present in the (R) or (S) configuration, resulting in racemic
mixtures in the case of a single asymmetric center, and
diastereomeric mixtures in the case of multiple asymmetric centers.
In certain instances, asymmetry may also be present due to
restricted rotation about a given bond, for example, the central
bond adjoining two substituted aromatic rings of the specified
compounds. Substituents on a ring may also be present in either cis
or trans form. It is intended that all such configurations
(including enantiomers and diastereomers), are included within the
scope of the present invention. Preferred compounds are those,
which produce the more desirable biological activity. Separated,
pure or partially purified isomers and stereoisomers or racemic or
diastereomeric mixtures of the compounds of this invention are also
included within the scope of the present invention. The
purification and the separation of such materials can be
accomplished by standard techniques known in the art.
[0181] The present invention also relates to useful forms of the
compounds as disclosed herein, such as pharmaceutically acceptable
salts, co-precipitates, metabolites, hydrates, solvates and
prodrugs of all the compounds of examples. The term
"pharmaceutically acceptable salt" refers to a relatively
non-toxic, inorganic or organic acid addition salt of a compound of
the present invention. For example, see S. M. Berge, et al.
"Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.
Pharmaceutically acceptable salts include those obtained by
reacting the main compound, functioning as a base, with an
inorganic or organic acid to form a salt, for example, salts of
hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic
acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic
acid and citric acid. Pharmaceutically acceptable salts also
include those in which the main compound functions as an acid and
is reacted with an appropriate base to form, e.g., sodium,
potassium, calcium, magnesium, ammonium, and chorine salts. Those
skilled in the art will further recognize that acid addition salts
of the claimed compounds may be prepared by reaction of the
compounds with the appropriate inorganic or organic acid via any of
a number of known methods. Alternatively, alkali and alkaline earth
metal salts of acidic compounds of the invention are prepared by
reacting the compounds of the invention with the appropriate base
via a variety of known methods.
[0182] Representative salts of the compounds of this invention
include the conventional non-toxic salts and the quaternary
ammonium salts which are formed, for example, from inorganic or
organic acids or bases by means well known in the art. For example,
such acid addition salts include acetate, adipate, alginate,
ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate,
butyrate, citrate, camphorate, camphorsulfonate, cinnamate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide,
2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,
picrate, pivalate, propionate, succinate, sulfonate, sulfate,
tartrate, thiocyanate, tosylate, and undecanoate.
[0183] Base salts include alkali metal salts such as potassium and
sodium salts, alkaline earth metal salts such as calcium and
magnesium salts, and ammonium salts with organic bases such as
dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic
nitrogen containing groups may be quaternized with such agents as
lower alkyl halides such as methyl, ethyl, propyl, or butyl
chlorides, bromides and iodides; dialkyl sulfates like dimethyl,
diethyl, dibutyl sulfate, or diamyl sulfates, long chain halides
such as decyl, lauryl, myristyl and strearyl chlorides, bromides
and iodides, aralkyl halides like benzyl and phenethyl bromides and
others.
[0184] A solvate for the purpose of this invention is a complex of
a solvent and a compound of the invention in the solid state.
Exemplary solvates would include, but are not limited to, complexes
of a compound of the invention with ethanol or methanol. Hydrates
are a specific form of solvate wherein the solvent is water.
Pharmaceutical Compositions of the Compounds of the Invention
[0185] This invention also relates to pharmaceutical compositions
containing one or more compounds of the present invention. These
compositions can be utilized to achieve the desired pharmacological
effect by administration to a patient in need thereof. A patient,
for the purpose of this invention, is a mammal, including a human,
in need of treatment for the particular condition or disease.
Therefore, the present invention includes pharmaceutical
compositions that are comprised of a pharmaceutically acceptable
carrier and a pharmaceutically effective amount of a compound, or
salt thereof, of the present invention. A pharmaceutically
acceptable carrier is preferably a carrier that is relatively
non-toxic and innocuous to a patient at concentrations consistent
with effective activity of the active ingredient so that any side
effects ascribable to the carrier do not vitiate the beneficial
effects of the active ingredient. A pharmaceutically effective
amount of compound is preferably that amount which produces a
result or exerts an influence on the particular condition being
treated. The compounds of the present invention can be administered
with pharmaceutically-acceptable carriers well known in the art
using any effective conventional dosage unit forms, including
immediate, slow and timed release preparations, orally,
parenterally, topically, nasally, ophthalmically, optically,
sublingually, rectally, vaginally, and the like.
[0186] For oral administration, the compounds can be formulated
into solid or liquid preparations such as capsules, pills, tablets,
troches, lozenges, melts, powders, solutions, suspensions, or
emulsions, and may be prepared according to methods known to the
art for the manufacture of pharmaceutical compositions. The solid
unit dosage forms can be a capsule that can be of the ordinary
hard- or soft-shelled gelatin type containing, for example,
surfactants, lubricants, and inert fillers such as lactose,
sucrose, calcium phosphate, and corn starch.
[0187] In another embodiment, the compounds of this invention may
be tableted with conventional tablet bases such as lactose, sucrose
and cornstarch in combination with binders such as acacia, corn
starch or gelatin, disintegrating agents intended to assist the
break-up and dissolution of the tablet following administration
such as potato starch, alginic acid, corn starch, and guar gum, gum
tragacanth, acacia, lubricants intended to improve the flow of
tablet granulation and to prevent the adhesion of tablet material
to the surfaces of the tablet dies and punches, for example talc,
stearic acid, or magnesium, calcium or zinc stearate, dyes,
coloring agents, and flavoring agents such as peppermint, oil of
wintergreen, or cherry flavoring, intended to enhance the aesthetic
qualities of the tablets and make them more acceptable to the
patient. Suitable excipients for use in oral liquid dosage forms
include dicalcium phosphate and diluents such as water and
alcohols, for example, ethanol, benzyl alcohol, and polyethylene
alcohols, either with or without the addition of a pharmaceutically
acceptable surfactant, suspending agent or emulsifying agent.
Various other materials may be present as coatings or to otherwise
modify the physical form of the dosage unit. For instance tablets,
pills or capsules may be coated with shellac, sugar or both.
[0188] Dispersible powders and granules are suitable for the
preparation of an aqueous suspension. They provide the active
ingredient in admixture with a dispersing or wetting agent, a
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example those
sweetening, flavoring and coloring agents described above, may also
be present.
[0189] The pharmaceutical compositions of this invention may also
be in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil such as liquid paraffin or a mixture of vegetable
oils. Suitable emulsifying agents may be (1) naturally occurring
gums such as gum acacia and gum tragacanth, (2) naturally occurring
phosphatides such as soy bean and lecithin, (3) esters or partial
esters derived form fatty acids and hexitol anhydrides, for
example, sorbitan monooleate, (4) condensation products of said
partial esters with ethylene oxide, for example, polyoxyethylene
sorbitan monooleate. The emulsions may also contain sweetening and
flavoring agents.
[0190] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil such as, for example, arachis oil,
olive oil, sesame oil or coconut oil, or in a mineral oil such as
liquid paraffin. The oily suspensions may contain a thickening
agent such as, for example, beeswax, hard paraffin, or cetyl
alcohol. The suspensions may also contain one or more
preservatives, for example, ethyl or n-propyl p-hydroxybenzoate;
one or more coloring agents; one or more flavoring agents; and one
or more sweetening agents such as sucrose or saccharin.
[0191] Syrups and elixirs may be formulated with sweetening agents
such as, for example, glycerol, propylene glycol, sorbitol or
sucrose. Such formulations may also contain a demulcent, and
preservative, such as methyl and propyl parabens and flavoring and
coloring agents.
[0192] The compounds of this invention may also be administered
parenterally, that is, subcutaneously, intravenously,
intraocularly, intrasynovially, intramuscularly, or
interperitoneally, as injectable dosages of the compound in
preferably a physiologically acceptable diluent with a
pharmaceutical carrier which can be a sterile liquid or mixture of
liquids such as water, saline, aqueous dextrose and related sugar
solutions, an alcohol such as ethanol, isopropanol, or hexadecyl
alcohol, glycols such as propylene glycol or polyethylene glycol,
glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol,
ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a
fatty acid ester or, a fatty acid glyceride, or an acetylated fatty
acid glyceride, with or without the addition of a pharmaceutically
acceptable surfactant such as a soap or a detergent, suspending
agent such as pectin, carbomers, methycellulose,
hydroxypropylmethylcellulose, or carboxymethylcellulose, or
emulsifying agent and other pharmaceutical adjuvants.
[0193] Illustrative of oils which can be used in the parenteral
formulations of this invention are those of petroleum, animal,
vegetable, or synthetic origin, for example, peanut oil, soybean
oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum
and mineral oil. Suitable fatty acids include oleic acid, stearic
acid, isostearic acid and myristic acid. Suitable fatty acid esters
are, for example, ethyl oleate and isopropyl myristate. Suitable
soaps include fatty acid alkali metal, ammonium, and
triethanolamine salts and suitable detergents include cationic
detergents, for example dimethyl dialkyl ammonium halides, alkyl
pyridinium halides, and alkylamine acetates; anionic detergents,
for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin,
ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic
detergents, for example, fatty amine oxides, fatty acid
alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene
oxide or propylene oxide copolymers; and amphoteric detergents, for
example, alkyl-beta-aminopropionates, and 2-alkylimidazoline
quarternary ammonium salts, as well as mixtures.
[0194] The parenteral compositions of this invention will typically
contain from about 0.5% to about 25% by weight of the active
ingredient in solution. Preservatives and buffers may also be used
advantageously. In order to minimize or eliminate irritation at the
site of injection, such compositions may contain a non-ionic
surfactant having a hydrophile-lipophile balance (HLB) preferably
of from about 12 to about 17. The quantity of surfactant in such
formulation preferably ranges from about 5% to about 15% by weight.
The surfactant can be a single component having the above HLB or
can be a mixture of two or more components having the desired
HLB.
[0195] Illustrative of surfactants used in parenteral formulations
are the class of polyethylene sorbitan fatty acid esters, for
example, sorbitan monooleate and the high molecular weight adducts
of ethylene oxide with a hydrophobic base, formed by the
condensation of propylene oxide with propylene glycol.
[0196] The pharmaceutical compositions may be in the form of
sterile injectable aqueous suspensions. Such suspensions may be
formulated according to known methods using suitable dispersing or
wetting agents and suspending agents such as, for example, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethyl-cellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents which may be a naturally occurring phosphatide such
as lecithin, a condensation product of an alkylene oxide with a
fatty acid, for example, polyoxyethylene stearate, a condensation
product of ethylene oxide with a long chain aliphatic alcohol, for
example, heptadeca-ethyleneoxycetanol, a condensation product of
ethylene oxide with a partial ester derived form a fatty acid and a
hexitol such as polyoxyethylene sorbitol monooleate, or a
condensation product of an ethylene oxide with a partial ester
derived from a fatty acid and a hexitol anhydride, for example
polyoxyethylene sorbitan monooleate.
[0197] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent. Diluents and solvents that may be
employed are, for example, water, Ringer's solution, isotonic
sodium chloride solutions and isotonic glucose solutions. In
addition, sterile fixed oils are conventionally employed as
solvents or suspending media. For this purpose, any bland, fixed
oil may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid can be used in the
preparation of injectables.
[0198] A composition of the invention may also be administered in
the form of suppositories for rectal administration of the drug.
These compositions can be prepared by mixing the drug with a
suitable non-irritation excipient which is solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum to release the drug. Such materials
are, for example, cocoa butter and polyethylene glycol.
[0199] Another formulation employed in the methods of the present
invention employs transdermal delivery devices ("patches"). Such
transdermal patches may be used to provide continuous or
discontinuous infusion of the compounds of the present invention in
controlled amounts. The construction and use of transdermal patches
for the delivery of pharmaceutical agents is well known in the art
(see, e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991,
incorporated herein by reference). Such patches may be constructed
for continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[0200] Controlled release formulations for parenteral
administration include liposomal, polymeric microsphere and
polymeric gel formulations that are known in the art.
[0201] It may be desirable or necessary to introduce the
pharmaceutical composition to the patient via a mechanical delivery
device. The construction and use of mechanical delivery devices for
the delivery of pharmaceutical agents is well known in the art.
Direct techniques for, for example, administering a drug directly
to the brain usually involve placement of a drug delivery catheter
into the patient's ventricular system to bypass the blood-brain
barrier. One such implantable delivery system, used for the
transport of agents to specific anatomical regions of the body, is
described in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991.
[0202] The compositions of the invention can also contain other
conventional pharmaceutically acceptable compounding ingredients,
generally referred to as carriers or diluents, as necessary or
desired. Conventional procedures for preparing such compositions in
appropriate dosage forms can be utilized. Such ingredients and
procedures include those described in the following references,
each of which is incorporated herein by reference: Powell, M. F. et
al, "Compendium of Excipients for Parenteral Formulations" PDA
Journal of Pharmaceutical Science & Technology 1998, 52(5),
238-311; Strickley, R. G "Parenteral Formulations of Small Molecule
Therapeutics Marketed in the United States (1999)-Part-1" PDA
Journal of Pharmaceutical Science & Technology 1999, 53(6),
324-349; and Nema, S. et al, "Excipients and Their Use in
Injectable Products" PDA Journal of Pharmaceutical Science &
Technology 1997, 51(4), 166-171.
[0203] Commonly used pharmaceutical ingredients that can be used as
appropriate to formulate the composition for its intended route of
administration include:
acidifying agents (examples include but are not limited to acetic
acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);
alkalinizing agents (examples include but are not limited to
ammonia solution, ammonium carbonate, diethanolamine,
monoethanolamine, potassium hydroxide, sodium borate, sodium
carbonate, sodium hydroxide, triethanolamine, trolamine);
adsorbents (examples include but are not limited to powdered
cellulose and activated charcoal); aerosol propellants (examples
include but are not limited to carbon dioxide, CCl.sub.2F.sub.2,
F.sub.2ClC--CClF.sub.2 and CClF.sub.3) air displacement agents
(examples include but are not limited to nitrogen and argon);
antifungal preservatives (examples include but are not limited to
benzoic acid, butylparaben, ethylparaben, methylparaben,
propylparaben, sodium benzoate); antimicrobial preservatives
(examples include but are not limited to benzalkonium chloride,
benzethonium chloride, benzyl alcohol, cetylpyridinium chloride,
chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate
and thimerosal); antioxidants (examples include but are not limited
to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole,
butylated hydroxytoluene, hypophosphorus acid, monothioglycerol,
propyl gallate, sodium ascorbate, sodium bisulfite, sodium
formaldehyde sulfoxylate, sodium metabisulfite); binding materials
(examples include but are not limited to block polymers, natural
and synthetic rubber, polyacrylates, polyurethanes, silicones,
polysiloxanes and styrene-butadiene copolymers); buffering agents
(examples include but are not limited to potassium metaphosphate,
dipotassium phosphate, sodium acetate, sodium citrate anhydrous and
sodium citrate dihydrate) carrying agents (examples include but are
not limited to acacia syrup, aromatic syrup, aromatic elixir,
cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral
oil, peanut oil, sesame oil, bacteriostatic sodium chloride
injection and bacteriostatic water for injection) chelating agents
(examples include but are not limited to edetate disodium and
edetic acid) colorants (examples include but are not limited to
FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6,
FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5,
D&C Red No. 8, caramel and ferric oxide red); clarifying agents
(examples include but are not limited to bentonite); emulsifying
agents (examples include but are not limited to acacia,
cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin,
sorbitan monooleate, polyoxyethylene 50 monostearate);
encapsulating agents (examples include but are not limited to
gelatin and cellulose acetate phthalate) flavorants (examples
include but are not limited to anise oil, cinnamon oil, cocoa,
menthol, orange oil, peppermint oil and vanillin); humectants
(examples include but are not limited to glycerol, propylene glycol
and sorbitol); levigating agents (examples include but are not
limited to mineral oil and glycerin); oils (examples include but
are not limited to arachis oil, mineral oil, olive oil, peanut oil,
sesame oil and vegetable oil); ointment bases (examples include but
are not limited to lanolin, hydrophilic ointment, polyethylene
glycol ointment, petrolatum, hydrophilic petrolatum, white
ointment, yellow ointment, and rose water ointment); penetration
enhancers (transdermal delivery) (examples include but are not
limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent
alcohols, saturated or unsaturated fatty alcohols, saturated or
unsaturated fatty esters, saturated or unsaturated dicarboxylic
acids, essential oils, phosphatidyl derivatives, cephalin,
terpenes, amides, ethers, ketones and ureas) plasticizers (examples
include but are not limited to diethyl phthalate and glycerol);
solvents (examples include but are not limited to ethanol, corn
oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic
acid, peanut oil, purified water, water for injection, sterile
water for injection and sterile water for irrigation); stiffening
agents (examples include but are not limited to cetyl alcohol,
cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol,
white wax and yellow wax); suppository bases (examples include but
are not limited to cocoa butter and polyethylene glycols
(mixtures)); surfactants (examples include but are not limited to
benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80,
sodium lauryl sulfate and sorbitan mono-palmitate); suspending
agents (examples include but are not limited to agar, bentonite,
carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin,
methylcellulose, tragacanth and veegum); sweetening agents
(examples include but are not limited to aspartame, dextrose,
glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol
and sucrose); tablet anti-adherents (examples include but are not
limited to magnesium stearate and talc); tablet binders (examples
include but are not limited to acacia, alginic acid,
carboxymethylcellulose sodium, compressible sugar, ethylcellulose,
gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl
pyrrolidone, and pregelatinized starch);
[0204] tablet and capsule diluents (examples include but are not
limited to dibasic calcium phosphate, kaolin, lactose, mannitol,
microcrystalline cellulose, powdered cellulose, precipitated
calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and
starch);
tablet coating agents (examples include but are not limited to
liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, methylcellulose, ethylcellulose,
cellulose acetate phthalate and shellac); tablet direct compression
excipients (examples include but are not limited to dibasic calcium
phosphate); tablet disintegrants (examples include but are not
limited to alginic acid, carboxymethylcellulose calcium,
microcrystalline cellulose, polacrillin potassium, cross-linked
polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and
starch); tablet glidants (examples include but are not limited to
colloidal silica, corn starch and talc); tablet lubricants
(examples include but are not limited to calcium stearate,
magnesium stearate, mineral oil, stearic acid and zinc stearate);
tablet/capsule opaquants (examples include but are not limited to
titanium dioxide); tablet polishing agents (examples include but
are not limited to carnuba wax and white wax); thickening agents
(examples include but are not limited to beeswax, cetyl alcohol and
paraffin); tonicity agents (examples include but are not limited to
dextrose and sodium chloride); viscosity increasing agents
(examples include but are not limited to alginic acid, bentonite,
carbomers, carboxymethylcellulose sodium, methylcellulose,
polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting
agents (examples include but are not limited to heptadecaethylene
oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene
sorbitol monooleate, and polyoxyethylene stearate).
[0205] Pharmaceutical compositions according to the present
invention can be illustrated as follows:
Sterile IV Solution: A 5 mg/mL solution of the desired compound of
this invention can be made using sterile, injectable water, and the
pH is adjusted if necessary. The solution is diluted for
administration to 1-2 mg/mL with sterile 5% dextrose and is
administered as an IV infusion over about 60 minutes. Lyophilized
powder for IV administration: A sterile preparation can be prepared
with (i) 100-1000 mg of the desired compound of this invention as a
lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii)
300-3000 mg Dextran 40. The formulation is reconstituted with
sterile, injectable saline or dextrose 5% to a concentration of 10
to 20 mg/mL, which is further diluted with saline or dextrose 5% to
0.2-0.4 mg/mL, and is administered either IV bolus or by IV
infusion over 15-60 minutes. Intramuscular suspension: The
following solution or suspension can be prepared, for intramuscular
injection: 50 mg/mL of the desired, water-insoluble compound of
this invention 5 mg/mL sodium carboxymethylcellulose 4 mg/mL TWEEN
80 9 mg/mL sodium chloride 9 mg/mL benzyl alcohol Hard Shell
Capsules: A large number of unit capsules are prepared by filling
standard two-piece hard galantine capsules each with 100 mg of
powdered active ingredient, 150 mg of lactose, 50 mg of cellulose
and 6 mg of magnesium stearate. Soft Gelatin Capsules: A mixture of
active ingredient in a digestible oil such as soybean oil,
cottonseed oil or olive oil is prepared and injected by means of a
positive displacement pump into molten gelatin to form soft gelatin
capsules containing 100 mg of the active ingredient. The capsules
are washed and dried. The active ingredient can be dissolved in a
mixture of polyethylene glycol, glycerin and sorbitol to prepare a
water miscible medicine mix. Tablets: A large number of tablets are
prepared by conventional procedures so that the dosage unit is 100
mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg
of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg.
of starch, and 98.8 mg of lactose. Appropriate aqueous and
non-aqueous coatings may be applied to increase palatability,
improve elegance and stability or delay absorption. Immediate
Release Tablets/Capsules: These are solid oral dosage forms made by
conventional and novel processes. These units are taken orally
without water for immediate dissolution and delivery of the
medication. The active ingredient is mixed in a liquid containing
ingredient such as sugar, gelatin, pectin and sweeteners. These
liquids are solidified into solid tablets or caplets by freeze
drying and solid state extraction techniques. The drug compounds
may be compressed with viscoelastic and thermoelastic sugars and
polymers or effervescent components to produce porous matrices
intended for immediate release, without the need of water.
Method of Treating Hyper-Proliferative Disorders
[0206] The present invention relates to a method for using the
compounds of the present invention and compositions thereof, to
treat mammalian hyper-proliferative disorders. Compounds can be
utilized to inhibit, block, reduce, decrease, etc., cell
proliferation and/or cell division, and/or produce apoptosis. This
method comprises administering to a mammal in need thereof,
including a human, an amount of a compound of this invention, or a
pharmaceutically acceptable salt, isomer, polymorph, metabolite,
hydrate, solvate or ester thereof; etc. which is effective to treat
the disorder. Hyper-proliferative disorders include but are not
limited, e.g., psoriasis, keloids, and other hyperplasias affecting
the skin, benign prostate hyperplasia (BPH), solid tumors, such as
cancers of the breast, respiratory tract, brain, reproductive
organs, digestive tract, urinary tract, eye, liver, skin, head and
neck, thyroid, parathyroid and their distant metastases. Those
disorders also include lymphomas, sarcomas, and leukemias.
[0207] Examples of breast cancer include, but are not limited to
invasive ductal carcinoma, invasive lobular carcinoma, ductal
carcinoma in situ, and lobular carcinoma in situ.
[0208] Examples of cancers of the respiratory tract include, but
are not limited to small-cell and non-small-cell lung carcinoma, as
well as bronchial adenoma and pleuropulmonary blastoma.
[0209] Examples of brain cancers include, but are not limited to
brain stem and hypophtalmic glioma, cerebellar and cerebral
astrocytoma, medulloblastoma, ependymoma, as well as
neuroectodermal and pineal tumor.
[0210] Tumors of the male reproductive organs include, but are not
limited to prostate and testicular cancer. Tumors of the female
reproductive organs include, but are not limited to endometrial,
cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma
of the uterus.
[0211] Tumors of the digestive tract include, but are not limited
to anal, colon, colorectal, esophageal, gallbladder, gastric,
pancreatic, rectal, small-intestine, and salivary gland
cancers.
[0212] Tumors of the urinary tract include, but are not limited to
bladder, penile, kidney, renal pelvis, ureter, urethral and human
papillary renal cancers.
[0213] Eye cancers include, but are not limited to intraocular
melanoma and retinoblastoma.
[0214] Examples of liver cancers include, but are not limited to
hepatocellular carcinoma (liver cell carcinomas with or without
fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct
carcinoma), and mixed hepatocellular cholangiocarcinoma.
[0215] Skin cancers include, but are not limited to squamous cell
carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin
cancer, and non-melanoma skin cancer.
[0216] Head-and-neck cancers include, but are not limited to
laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer,
lip and oral cavity cancer and squamous cell. Lymphomas include,
but are not limited to AIDS-related lymphoma, non-Hodgkin's
lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's
disease, and lymphoma of the central nervous system.
[0217] Sarcomas include, but are not limited to sarcoma of the soft
tissue, osteosarcoma, malignant fibrous histiocytoma,
lymphosarcoma, and rhabdomyosarcoma.
[0218] Leukemias include, but are not limited to acute myeloid
leukemia, acute lymphoblastic leukemia, chronic lymphocytic
leukemia, chronic myelogenous leukemia, and hairy cell
leukemia.
[0219] These disorders have been well characterized in humans, but
also exist with a similar etiology in other mammals, and can be
treated by administering pharmaceutical compositions of the present
invention.
[0220] The term "treating" or "treatment" as stated throughout this
document is used conventionally, e.g., the management or care of a
subject for the purpose of combating, alleviating, reducing,
relieving, improving the condition of, etc., of a disease or
disorder, such as a carcinoma.
Methods of Treating Kinase Disorders
[0221] The present invention also provides methods for the
treatment of disorders associated with aberrant kinase activity
(such as tyrosine kinase activity), including,
phosphotidylinositol-3-kinase.
[0222] Effective amounts of compounds of the present invention can
be used to treat disorders, including angiogenic disorders, such as
cancer; inflammatory disorders (including but not limited to
Chronic obstructive pulmonary disorder (COPD)), autoimmune
disorders, cardiovascular disorders (including but not limited to
thrombosis, pulmonary hypertension, cardiac hypertophy,
atherosclerosis or heart failure), neurodegenerative disorders,
metabolic disorders, nociceptive disorders, ophthalmic disorders,
pulmonary disorders, or renal disorders. Nonetheless, such cancers
and other diseases can be treated with compounds of the present
invention, regardless of the mechanism of action and/or the
relationship between the kinase and the disorder.
[0223] The phrase "aberrant kinase activity" or "aberrant tyrosine
kinase activity," includes any abnormal expression or activity of
the gene encoding the kinase or of the polypeptide it encodes.
Examples of such aberrant activity, include, but are not limited
to, over-expression of the gene or polypeptide; gene amplification;
mutations which produce constitutively-active or hyperactive kinase
activity; gene mutations, deletions, substitutions, additions,
etc.
[0224] The present invention also provides for methods of
inhibiting a kinase activity, especially of
phosphotidylinositol-3-kinase, comprising administering an
effective amount of a compound of the present invention, including
salts, polymorphs, metabolites, hyrates, solvates, prodrugs (e.g.:
esters) thereof, and diastereoisomeric forms thereof. Kinase
activity can be inhibited in cells (e.g., in vitro), or in the
cells of a mammalian subject, especially a human patient in need of
treatment.
Methods of Treating Angiogenic Disorders
[0225] The present invention also provides methods of treating
disorders and diseases associated with excessive and/or abnormal
angiogenesis.
[0226] Inappropriate and ectopic expression of angiogenesis can be
deleterious to an organism. A number of pathological conditions are
associated with the growth of extraneous blood vessels. These
include, e.g., diabetic retinopathy, ischemic retinal-vein
occlusion, and retinopathy of prematurity (Aiello et al. New Engl.
J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638),
age-related macular degeneration (AMD; see, Lopez et al. Invest.
Opththalmol. Vis. Sci. 1996, 37, 855), neovascular glaucoma,
psoriasis, retrolental fibroplasias, angiofibroma, inflammation,
rheumatoid arthritis (RA), restenosis, in-stent restenosis,
vascular graft restenosis, etc. In addition, the increased blood
supply associated with cancerous and neoplastic tissue, encourages
growth, leading to rapid tumor enlargement and metastasis.
Moreover, the growth of new blood and lymph vessels in a tumor
provides an escape route for renegade cells, encouraging metastasis
and the consequence spread of the cancer. Thus, compounds of the
present invention can be utilized to treat and/or prevent any of
the aforementioned angiogenesis disorders, e.g., by inhibiting
and/or reducing blood vessel formation; by inhibiting, blocking,
reducing, decreasing, etc. endothelial cell proliferation or other
types involved in angiogenesis, as well as causing cell death or
apoptosis of such cell types.
Dose and Administration
[0227] Based upon standard laboratory techniques known to evaluate
compounds useful for the treatment of hyper-proliferative disorders
and angiogenic disorders, by standard toxicity tests and by
standard pharmacological assays for the determination of treatment
of the conditions identified above in mammals, and by comparison of
these results with the results of known medicaments that are used
to treat these conditions, the effective dosage of the compounds of
this invention can readily be determined for treatment of each
desired indication. The amount of the active ingredient to be
administered in the treatment of one of these conditions can vary
widely according to such considerations as the particular compound
and dosage unit employed, the mode of administration, the period of
treatment, the age and sex of the patient treated, and the nature
and extent of the condition treated.
[0228] The total amount of the active ingredient to be administered
will generally range from about 0.001 mg/kg to about 200 mg/kg body
weight per day, and preferably from about 0.01 mg/kg to about 20
mg/kg body weight per day. Clinically useful dosing schedules will
range from one to three times a day dosing to once every four weeks
dosing. In addition, "drug holidays" in which a patient is not
dosed with a drug for a certain period of time, may be beneficial
to the overall balance between pharmacological effect and
tolerability. A unit dosage may contain from about 0.5 mg to about
1500 mg of active ingredient, and can be administered one or more
times per day or less than once a day. The average daily dosage for
administration by injection, including intravenous, intramuscular,
subcutaneous and parenteral injections, and use of infusion
techniques will preferably be from 0.01 to 200 mg/kg of total body
weight. The average daily rectal dosage regimen will preferably be
from 0.01 to 200 mg/kg of total body weight. The average daily
vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of
total body weight. The average daily topical dosage regimen will
preferably be from 0.1 to 200 mg administered between one to four
times daily. The transdermal concentration will preferably be that
required to maintain a daily dose of from 0.01 to 200 mg/kg. The
average daily inhalation dosage regimen will preferably be from
0.01 to 100 mg/kg of total body weight.
[0229] Of course the specific initial and continuing dosage regimen
for each patient will vary according to the nature and severity of
the condition as determined by the attending diagnostician, the
activity of the specific compound employed, the age and general
condition of the patient, time of administration, route of
administration, rate of excretion of the drug, drug combinations,
and the like. The desired mode of treatment and number of doses of
a compound of the present invention or a pharmaceutically
acceptable salt or ester or composition thereof can be ascertained
by those skilled in the art using conventional treatment tests.
Combination Therapies
[0230] The compounds of this invention can be administered as the
sole pharmaceutical agent or in combination with one or more other
pharmaceutical agents where the combination causes no unacceptable
adverse effects. For example, the compounds of this invention can
be combined with known anti-hyper-proliferative, antiinflammatory,
analgesic, immunoregulatory, diuretic, antiarrhytmic,
anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or
antiviral agents, and the like, as well as with admixtures and
combinations thereof.
[0231] The additional pharmaceutical agent can be aldesleukin,
alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim,
aloxi, altretamine, aminoglutethimide, amifostine, amrubicin,
amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic
trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice BCG,
bestatin, betamethasone acetate, betamethasone sodium phosphate,
bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan,
calcitonin, campath, capecitabine, carboplatin, casodex, cefesone,
celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine,
cladribine, clodronic acid, cyclophosphamide, cytarabine,
dacarbazine, dactinomycin, DaunoXome, decadron, decadron phosphate,
delestrogen, denileukin diftitox, depo-medrol, deslorelin,
dexrazoxane, diethylstilbestrol, diflucan, docetaxel,
doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek,
ellence, emend, epirubicin, epoetin alfa, epogen, eptaplatin,
ergamisol, estrace, estradiol, estramustine phosphate sodium,
ethinyl estradiol, ethyol, etidronic acid, etopophos, etoposide,
fadrozole, farston, filgrastim, finasteride, fligrastim,
floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine
monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide,
formestane, fosteabine, fotemustine, fulvestrant, gammagard,
gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron
HCl, histrelin, hycamtin, hydrocortone,
eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan,
idarubicin, ifosfamide, interferon alpha, interferon-alpha 2,
interferon alfa-2A, interferon alfa-2B, interferon alfa-n1,
interferon alfa-n3, interferon beta, interferon gamma-1a,
interleukin-2, intron A, iressa, irinotecan, kytril, lentinan
sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate,
levamisole, levofolinic acid calcium salt, levothroid, levoxyl,
lomustine, lonidamine, marinol, mechlorethamine, mecobalamin,
medroxyprogesterone acetate, megestrol acetate, melphalan, menest,
6-mercaptopurine, Mesna, methotrexate, metvix, miltefosine,
minocycline, mitomycin C, mitotane, mitoxantrone, Modrenal, Myocet,
nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex,
NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred,
oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys,
pentostatin, picibanil, pilocarpine HCl, pirarubicin, plicamycin,
porfimer sodium, prednimustine, prednisolone, prednisone, premarin,
procarbazine, procrit, raltitrexed, rebif, rhenium-186 etidronate,
rituximab, roferon-A, romurtide, salagen, sandostatin,
sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol,
sparfosic acid, stem-cell therapy, streptozocin, strontium-89
chloride, synthroid, tamoxifen, tamsulosin, tasonermin,
tastolactone, taxotere, teceleukin, temozolomide, teniposide,
testosterone propionate, testred, thioguanine, thiotepa,
thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab,
trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine,
trimetrexate, triptorelin acetate, triptorelin pamoate, UFT,
uridine, valrubicin, vesnarinone, vinblastine, vincristine,
vindesine, vinorelbine, virulizin, zinecard, zinostatin stimalamer,
zofran, ABI-007, acolbifene, actimmune, affinitak, aminopterin,
arzoxifene, asoprisnil, atamestane, atrasentan, BAY 43-9006
(sorafenib), avastin, CCI-779, CDC-501, celebrex, cetuximab,
crisnatol, cyproterone acetate, decitabine, DN-101,
doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine,
exatecan, fenretinide, histamine dihydrochloride, histrelin
hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon
gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin,
L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene,
minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin,
nemorubicin, neovastat, nolatrexed, oblimersen, onco-TCS, osidem,
paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21,
quazepam, R-1549, raloxifene, ranpirnase, 13-cis -retinoic acid,
satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin
alpha 1, tiazofurine, tipifarnib, tirapazamine, TLK-286,
toremifene, TransMID-107R, valspodar, vapreotide, vatalanib,
verteporfin, vinflunine, Z-100, zoledronic acid or combinations
thereof.
[0232] The additional pharmaceutical agent can also be gemcitabine,
paclitaxel, cisplatin, carboplatin, sodium butyrate, 5-FU,
doxirubicin, tamoxifen, etoposide, trastumazab, gefitinib, intron
A, rapamycin, 17-AAG, U0126, insulin, an insulin derivative, a PPAR
ligand, a sulfonylurea drug, an .alpha.-glucosidase inhibitor, a
biguanide, a PTP-1B inhibitor, a DPP-IV inhibitor, a 11-beta-HSD
inhibitor, GLP-1, a GLP-1 derivative, GIP, a GIP derivative, PACAP,
a PACAP derivative, secretin or a secretin derivative.
[0233] Optional anti-hyper-proliferative agents which can be added
to the composition include but are not limited to compounds listed
on the cancer chemotherapy drug regimens in the 11th Edition of the
Merck Index, (1996), which is hereby incorporated by reference,
such as asparaginase, bleomycin, carboplatin, carmustine,
chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine,
dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine),
epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine,
hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine,
mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin
C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen,
streptozocin, tamoxifen, thioguanine, topotecan, vinblastine,
vincristine, and vindesine.
[0234] Other anti-hyper-proliferative agents suitable for use with
the composition of the invention include but are not limited to
those compounds acknowledged to be used in the treatment of
neoplastic diseases in Goodman and Gilman's The Pharmacological
Basis of Therapeutics (Ninth Edition), editor Molinoff et al.,
publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby
incorporated by reference, such as aminoglutethimide,
L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan,
diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel,
erythrohydroxynonyl adenine, ethinyl estradiol,
5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate,
fludarabine phosphate, fluoxymesterone, flutamide,
hydroxyprogesterone caproate, idarubicin, interferon,
medroxyprogesterone acetate, megestrol acetate, melphalan,
mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate
(PALA), plicamycin, semustine, teniposide, testosterone propionate,
thiotepa, trimethylmelamine, uridine, and vinorelbine.
[0235] Other anti-hyper-proliferative agents suitable for use with
the composition of the invention include but are not limited to
other anti-cancer agents such as epothilone and its derivatives,
irinotecan, raloxifen and topotecan.
[0236] Generally, the use of cytotoxic and/or cytostatic agents in
combination with a compound or composition of the present invention
will serve to:
(1) yield better efficacy in reducing the growth of a tumor or even
eliminate the tumor as compared to administration of either agent
alone, (2) provide for the administration of lesser amounts of the
administered chemo-therapeutic agents, (3) provide for a
chemotherapeutic treatment that is well tolerated in the patient
with fewer deleterious pharmacological complications than observed
with single agent chemotherapies and certain other combined
therapies, (4) provide for treating a broader spectrum of different
cancer types in mammals, especially humans, (5) provide for a
higher response rate among treated patients, (6) provide for a
longer survival time among treated patients compared to standard
chemotherapy treatments, (7) provide a longer time for tumor
progression, and/or (8) yield efficacy and tolerability results at
least as good as those of the agents used alone, compared to known
instances where other cancer agent combinations produce
antagonistic effects.
EXPERIMENTAL
Abbreviations and Acronyms
[0237] A comprehensive list of the abbreviations used by organic
chemists of ordinary skill in the art appears in The ACS Style
Guide (third edition) or the Guidelines for Authors for the Journal
of Organic Chemistry. The abbreviations contained in said lists,
and all abbreviations utilized by organic chemists of ordinary
skill in the art are hereby incorporated by reference. For purposes
of this invention, the chemical elements are identified in
accordance with the Periodic Table of the Elements, CAS version,
Handbook of Chemistry and Physics, 67th Ed., 1986-87.
[0238] More specifically, when the following abbreviations are used
throughout this disclosure, they have the following meanings:
[0239] acac acetylacetonate [0240] Ac.sub.2O acetic anhydride
[0241] AcO (or OAc) acetate [0242] anhyd anhydrous [0243] aq
aqueous [0244] Ar aryl [0245] atm atmosphere [0246] 9-BBN
9-borabicyclo[3.3.1]nonyl [0247] BINAP
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [0248] Bn benzyl [0249]
bp boiling point [0250] br s broad singlet [0251] Bz benzoyl [0252]
BOC tert-butoxycarbonyl [0253] n-BuOH n-butanol [0254] t-BuOH
tert-butanol [0255] t-BuOK potassium tert-butoxide [0256] C Celsius
[0257] calcd calculated [0258] CAN ceric ammonium nitrate [0259]
Cbz carbobenzyloxy [0260] CDI carbonyl diimidazole [0261]
CD.sub.3OD methanol-d.sub.4 [0262] Celite.RTM. diatomaceous earth
filter agent, Celite.RTM. Corp. [0263] CI-MS chemical ionization
mass spectroscopy [0264] .sup.13C NMR carbon-13 nuclear magnetic
resonance [0265] m-CPBA meta-chloroperoxybenzoic acid [0266] d
doublet [0267] dd doublet of doublets [0268] DABCO
1,4-diazabicyclo[2.2.2]octane [0269] DBU
1,8-diazabicyclo[5.4.0]undec-7-ene [0270] DCC
N,N'-dicyclohexylcarbodiimide [0271] DCM dichloromethane [0272]
DEAD diethyl azodicarboxylate [0273] dec decomposition [0274] DIA
diisopropylamine [0275] DIBAL diisobutylaluminum hydride [0276]
DMAP 4-(N,N-dimethylamino)pyridine [0277] DME 1,2-dimethoxyethane
[0278] DMF N,N-dimethylformamide [0279] DMSO dimethylsulfoxide
[0280] E entgegen (configuration) [0281] EDCI or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide [0282] EDCI.HCl
hydrochloride [0283] ee enantiomeric excess [0284] EI electron
impact [0285] ELSD evaporative light scattering detector [0286]
equiv equivalent [0287] ES-MS electrospray mass spectroscopy [0288]
EtOAc ethyl acetate [0289] EtOH ethanol (100%) [0290] EtSH
ethanethiol [0291] Et.sub.2O diethyl ether [0292] Et.sub.3N
triethylamine [0293] Fmoc 9-fluorenylmethoxycarbonyl [0294] GC gas
chromatography [0295] GC-MS gas chromatography-mass spectroscopy
[0296] h hour, hours [0297] hex hexanes, or hexane [0298] .sup.1H
NMR proton nuclear magnetic resonance [0299] HMPA
hexamethylphosphoramide [0300] HMPT hexamethylphosphoric triamide
[0301] HOBT hydroxybenzotriazole [0302] HPLC high performance
liquid chromatography [0303] insol insoluble [0304] IPA
isopropylamine [0305] iPrOH isopropylalcohol [0306] IR infrared
[0307] J coupling constant (NMR spectroscopy) [0308] L liter [0309]
LAH lithium aluminum hydride [0310] LC liquid chromatography
[0311] LC-MS liquid chromatography-mass spectrometry [0312] LDA
lithium diisopropylamide [0313] M mol L.sup.-1 (molar) [0314] m
multiplet [0315] m meta [0316] MeCN acetonitrile [0317] MeOH
methanol [0318] MHz megahertz [0319] min minute, minutes [0320]
microliter [0321] mL milliliter [0322] .mu.M micromolar [0323] mol
mole [0324] mp melting point [0325] MS mass spectrum, mass
spectrometry [0326] Ms methanesulfonyl [0327] m/z mass-to-charge
ratio [0328] N equiv L.sup.-1 (normal) [0329] NBS
N-bromosuccinimide [0330] nM nanomolar NMM 4-methylmorpholine
[0331] NMR Nuclear Magnetic Resonance [0332] o ortho [0333] obsd
observed [0334] p para [0335] p page [0336] pp pages [0337]
PdCl.sub.2dppf [1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium(II) [0338] Pd(OAc).sub.2 palladium acetate [0339]
pH negative logarithm of hydrogen ion concentration [0340] Ph
phenyl [0341] pK negative logarithm of equilibrium constant [0342]
pK.sub.a negative logarithm of equilibrium constant for association
[0343] PPA poly(phosphoric acid) [0344] PS-DIEA Polystyrene-bound
diisopropylethylamine [0345] PyBOP
benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate [0346] q quartet [0347] rac racemic [0348] R
rectus (configurational) [0349] R.sub.f retardation factor (TLC)
[0350] RT retention time (HPLC) [0351] rt room temperature [0352] s
singlet [0353] S sinister (configurational) [0354] t triplet [0355]
TBDMS, TBP tert-butyldimethylsilyl [0356] TBDPS, TPS
tert-butyldiphenylsilyl [0357] TEA triethylamine [0358] THF
tetrahydrofuran [0359] Tf trifluoromethanesulfonyl (triflyl) [0360]
TFA trifluoroacetic acid [0361] TFFH
Fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate
[0362] TLC thin layer chromatography [0363] TMAD
N,N,N',N'-tetramethylethylenediamine [0364] TMSCl trimethylsilyl
chloride [0365] Ts p-toluenesulfonyl [0366] v/v volume to volume
ratio [0367] w/v weight to volume ratio [0368] w/w weight to weight
ratio [0369] Z zusammen (configuration)
[0370] The percentage yields reported in the following examples are
based on the starting component that was used in the lowest molar
amount. Air and moisture sensitive liquids and solutions were
transferred via syringe or cannula, and introduced into reaction
vessels through rubber septa. Commercial grade reagents and
solvents were used without further purification. The term
"concentrated under reduced pressure" refers to use of a Buchi
rotary evaporator at approximately 15 mm of Hg. All temperatures
are reported uncorrected in degrees Celsius (.degree. C.). Thin
layer chromatography (TLC) was performed on pre-coated glass-backed
silica gel 60 A F-254 250 .mu.m plates.
[0371] The structures of compounds of this invention were confirmed
using one or more of the following procedures.
NMR
[0372] NMR spectra were acquired for each compound and were
consistent with the structures shown.
[0373] Routine one-dimensional NMR spectroscopy was performed on
either 300 or 400 MHz Varian.RTM. Mercury-plus spectrometers. The
samples were dissolved in deuterated solvents. Chemical shifts were
recorded on the ppm scale and were referenced to the appropriate
solvent signals, such as 2.49 ppm for DMSO-d6, 1.93 ppm for CD3CN,
3.30 ppm for CD3OD, 5.32 ppm for CD2Cl2 and 7.26 ppm for CDCl3 for
1H spectra.
GC/MS
[0374] Electron impact mass spectra (EI-MS) were obtained with a
Hewlett Packard 5973 mass spectrometer equipped Hewlett Packard
6890 Gas Chromatograph with a J & W HP-5 column (0.25 uM
coating; 30 m.times.0.32 mm). The ion source was maintained at
250.degree. C. and spectra were scanned from 50-550 amu at 0.34 sec
per scan.
LC/MS
[0375] Unless otherwise noted, all retention times are obtained
from the LC/MS and correspond to the molecular ion. High pressure
liquid chromatography-electrospray mass spectra (LC/MS) were
obtained using one of the following:
Method A (LCQ)
[0376] Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a
variable wavelength detector set at 254 nm, a Waters Sunfire C18
column (2.1.times.30 mm, 3.5 .quadrature.m), a Gilson autosampler
and a Finnigan LCQ ion trap mass spectrometer with electrospray
ionization. Spectra were scanned from 120-1200 amu using a variable
ion time according to the number of ions in the source. The eluents
were A: 2% acetonitrile in water with 0.02% TFA, and B: 2% water in
acetonirile with 0.018% TFA. Gradient elution from 10% B to 95% B
over 3.5 minutes at a flow rate of 1.0 mL/min was used with an
initial hold of 0.5 minutes and a final hold at 95% B of 0.5
minutes. Total run time was 6.5 minutes.
Method B (LCQ5)
[0377] Agilent 1100 HPLC system. The Agilent 1100 HPLC system was
equipped with an Agilent 1100 autosampler, quaternary pump, a
variable wavelength detector set at 254 nm. The HPLC column used
was a Waters Sunfire C-18 column (2.1.times.30 mm, 3.5 .mu.m). The
HPLC eluent was directly coupled without splitting to a Finnigan
LCQ DECA ion trap mass spectrometer with electrospray ionization.
Spectra were scanned from 140-1200 amu using a variable ion time
according to the number of ions in the source using positive ion
mode. The eluents were A: 2% acetonitrile in water with 0.02% TFA,
and B: 2% water in acetonirile with 0.02% TFA. Gradient elution
from 10% B to 90% B over 3.0 minutes at a flow rate of 1.0 mL/min
was used with an initial hold of 1.0 minutes and a final hold at
95% B of 1.0 minutes. Total run time was 7.0 minutes.
Method C (LTQ)
[0378] Agilent 1100 HPLC system. The Agilent 1100 HPLC system was
equipped with an Agilent 1100 autosampler, quaternary pump, and a
diode array. The HPLC column used was a Waters Sunfire C18 column
(2.1.times.30 mm, 3.5 .mu.m). The HPLC eluent was directly coupled
with a 1:4 split to a Finnigan LTQ ion trap mass spectrometer with
electrospray ionization. Spectra were scanned from 50-800 amu using
a variable ion time according to the number of ions in the source
using positive or negative ion mode. The eluents were A: water with
0.1 formic acid, and B: acetonitrile with 0.1% formic acid.
Gradient elution from 10% B to 90% B over 3.0 minutes at a flowrate
of 1.0 mL/min was used with an initial hold of 2.0 minutes and a
final hold at 95% B of 1.0 minutes. Total run time was 8.0
minutes.
Method D
[0379] Gilson HPLC system equipped with a variable wavelength
detector set at 254 nm, a YMC pro C-18 column (2.times.23 mm,
120A), and a Finnigan LCQ ion trap mass spectrometer with
electrospray ionization. Spectra were scanned from 120-1200 amu
using a variable ion time according to the number of ions in the
source. The eluants were A: 2% acetonitrile in water with 0.02% TFA
and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution
from 10% B to 95% over 3.5 minutes at a flow rate of 1.0 mL/min was
used with an initial hold of 0.5 minutes and a final hold at 95% B
of 0.5 minutes. Total run time was 6.5 minutes.
Method E
[0380] Agilent 1100 HPLC system. The Agilent 1100 HPLC system was
equipped with an Agilent 1100 autosampler, quaternary pump, and a
diode array. The HPLC column used was a Waters Sunfire
(2.1.times.30 mm, 3.5 .mu.m). The HPLC eluent was directly coupled
with a 1:4 split to a Finnigan LTQ ion trap mass spectrometer with
electrospray ionization. Spectra were scanned from 50-1000 amu
using a variable ion time according to the number of ions in the
source in either positive or negative ion mode. The eluents were A:
water with 0.1 formic acid, and B: acetonirile with 0.1% formic
acid. Gradient elution from 10% B to 90% B over 3.0 minutes at a
flow rate of 1.0 mL/min was used with an initial hold of 2.0
minutes and a final hold at 95% B of 1.0 minutes. Total run time
was 8.0 minutes.
Preparative HPLC:
[0381] Preparative HPLC was carried out in reversed phase mode,
typically using a Gilson HPLC system equipped with two Gilson 322
pumps, a Gilson 215 Autosampler, a Gilson diode array detector, and
a C-18 column (e.g. YMC Pro 20.times.150 mm, 120 A). Gradient
elution was used with solvent A as water with 0.1% TFA, and solvent
B as acetonitrile with 0.1% TFA. Following injection onto the
column as a solution, the compound was typically eluted with a
mixed solvent gradient, such as 10-90% Solvent B in Solvent A over
15 minutes with flow rate of 25 mL/min. The fraction(s) containing
the desired product were collected by UV monitoring at 254 or 220
nm.
Preparative MPLC:
[0382] Preparative medium pressure liquid chromatography (MPLC) was
carried out by standard silica gel "flash chromatography"
techniques (e.g., Still, W. C. et al. J. Org. Chem. 1978, 43,
2923-5), or by using silica gel cartridges and devices such as the
Biotage Flash systems. A variety of eluting solvents were used, as
described in the experimental protocols.
General Preparative Methods
[0383] The particular process to be utilized in the preparation of
the compounds used in this embodiment of the invention depends upon
the specific compound desired. Such factors as the selection of the
specific substituents play a role in the path to be followed in the
preparation of the specific compounds of this invention. Those
factors are readily recognized by one of ordinary skill in the
art.
[0384] The compounds of the invention may be prepared by use of
known chemical reactions and procedures. Nevertheless, the
following general preparative methods are presented to aid the
reader in synthesizing the compounds of the present invention, with
more detailed particular examples being presented below in the
experimental section describing the working examples.
[0385] The compounds of the invention can be made according to
conventional chemical methods, and/or as disclosed below, from
starting materials which are either commercially available or
producible according to routine, conventional chemical methods.
General methods for the preparation of the compounds are given
below, and the preparation of representative compounds is
specifically illustrated in examples.
[0386] Synthetic transformations that may be employed in the
synthesis of compounds of this invention and in the synthesis of
intermediates involved in the synthesis of compounds of this
invention are known by or accessible to one skilled in the art.
Collections of synthetic transformations may be found in
compilations, such as: [0387] J. March. Advanced Organic Chemistry,
4th ed.; John Wiley: New York (1992) R. C. Larock. Comprehensive
Organic Transformations, 2nd ed.; Wiley-VCH: New York (1999) [0388]
F. A. Carey; R. J. Sundberg. Advanced Organic Chemistry, 2nd ed.;
Plenum Press: New York (1984) [0389] T. W. Greene; P. G. M. Wuts.
Protective Groups in Organic Synthesis, 3rd ed.; John Wiley: New
York (1999) [0390] L. S. Hegedus. Transition Metals in the
Synthesis of Complex Organic Molecules, 2nd ed.; University Science
Books: Mill Valley, Calif. (1994) [0391] L. A. Paquette, Ed. The
Encyclopedia of Reagents for Organic Synthesis; John Wiley: New
York (1994) [0392] A. R. Katritzky; O. Meth-Cohn; C. W. Rees, Eds.
Comprehensive Organic Functional Group Transformations; Pergamon
Press: Oxford, UK (1995) [0393] G. Wilkinson; F. G A. Stone; E. W.
Abel, Eds. Comprehensive Organometallic Chemistry; Pergamon Press:
Oxford, UK (1982) [0394] B. M. Trost; I. Fleming. Comprehensive
Organic Synthesis; Pergamon Press: Oxford, UK (1991) [0395] A. R.
Katritzky; C. W. Rees Eds. Comprehensive Heterocylic Chemistry;
Pergamon Press: Oxford, UK (1984) [0396] A. R. Katritzky; C. W.
Rees; E. F. V. Scriven, Eds. Comprehensive Heterocylic Chemistry
II; Pergamon Press: Oxford, UK (1996) [0397] C. Hansch; P. G.
Sammes; J. B. Taylor, Eds. Comprehensive Medicinal Chemistry:
Pergamon Press: Oxford, UK (1990).
[0398] In addition, recurring reviews of synthetic methodology and
related topics include Organic Reactions; John Wiley: New York;
Organic Syntheses; John Wiley: New York; Reagents for Organic
Synthesis: John Wiley: New York; The Total Synthesis of Natural
Products; John Wiley: New York; The Organic Chemistry of Drug
Synthesis; John Wiley: New York; Annual Reports in Organic
Synthesis; Academic Press: San Diego Calif.; and Methoden der
Organischen Chemie (Houben-Weyl); Thieme: Stuttgart, Germany.
Furthermore, databases of synthetic transformations include
Chemical Abstracts, which may be searched using either CAS OnLine
or SciFinder, Handbuch der Organischen Chemie (Beilstein), which
may be searched using SpotFire, and REACCS.
##STR00007## ##STR00008##
[0399] In Reaction Scheme 1, vanillin acetate can be converted to
intermediate (III) via nitration conditions such as neat fuming
nitric acid or nitric acid in the presence of another strong acid
such as sulfuric acid. Hydrolysis of the acetate in intermediate
(III) would be expected in the presence of bases such as sodium
hydroxide, lithium hydroxide, or potassium hydroxide in a protic
solvent such as methanol. Protection of intermediate (IV) to
generate compounds of Formula (V) could be accomplished by standard
methods (Greene, T. W.; Wuts, P. G. M.; Protective Groups in
Organic Synthesis; Wiley & Sons: New York, 1999). Conversion of
compounds of formula (V) to those of formula (VI) can be achieved
using ammonia in the presence of iodine in an aprotic solvent such
as THF or dioxane. Reduction of the nitro group in formula (VI)
could be accomplished using iron in acetic acid or hydrogen gas in
the presence of a suitable palladium, platinum or nickel catalyst.
Conversion of compounds of formula (VII) to the imidazoline of
formula (VIII) is best accomplished using ethylenediamine in the
presence of a catalyst such as elemental sulfur with heating. The
cyclization of compounds of formula (VIII) to those of formula (IX)
is accomplished using cyanogen bromide in the presence of an amine
base such as triethylamine, diisopropylethylamine, or pyridine in a
halogenated solvent such as DCM or dichloroethane. Removal of the
protecting group in formula (IX) will be dependent on the group
selected and can be accomplished by standard methods (Greene, T.
W.; Wuts, P. G. M.; Protective Groups in Organic Synthesis; Wiley
& Sons: New York, 1999). Alkylation of the phenol in formula
(X) can be achieved using a base such as cesium carbonate, sodium
hydride, or potassium t-butoxide in a polar aprotic solvent such as
DMF or DMSO with introduction of a side chain bearing an
appropriate leaving group such as a halide, or a sulfonate group.
Lastly, amides of formula (I) can be formed using activated esters
such as acid chlorides and anhydrides or alternatively formed using
carboxylic acids and appropriate coupling agents such as PYBOP,
DCC, or EDCI in polar aprotic solvents.
##STR00009## ##STR00010##
[0400] In Reaction Scheme 2, a compound of formula (IV), prepared
as described above, can be converted to a structure of formula
(XII) using ammonia in the presence of iodine in an aprotic solvent
such as THF or dioxane. Alkylation of the phenol in formula (XII)
can be achieved using a base such as cesium carbonate, sodium
hydride, or potassium t-butoxide in a polar aprotic solvent such as
DMF or DMSO with introduction of a side chain bearing an
appropriate leaving group such as a halide, or a sulfonate group.
Reduction of the nitro group in formula (XIII) could be
accomplished using iron in acetic acid or hydrogen gas in the
presence of a suitable palladium, platinum or nickel catalyst.
Conversion of compounds of formula (XIV) to the imidazoline of
formula (XV) is best accomplished using ethylenediamine in the
presence of a catalyst such as elemental sulfur with heating. The
cyclization of compounds of formula (XV) to those of formula (XVI)
is accomplished using cyanogen bromide in the presence of an amine
base such as triethylamine, diisopropylethylamine, or pyridine in a
halogenated solvent such as DCM or dichloroethane. Lastly, amides
of formula (I) can be formed using activated esters such as acid
chlorides and anhydrides or alternatively formed using carboxylic
acids and appropriate coupling agents such as PYBOP, DCC, or EDCI
in polar aprotic solvents.
##STR00011##
[0401] In Reaction Scheme 3, a compound of formula (X), prepared as
described above, can be converted to amide (XVI) using activated
esters such as acid chlorides and anhydrides or alternatively
formed using carboxylic acids and appropriate coupling agents such
as PYBOP, DCC, or EDCI in polar aprotic solvents. This could then
be converted to compounds of formula (I) using a base such as
cesium carbonate, sodium hydride, or potassium t-butoxide in a
polar aprotic solvent such as DMF or DMSO with introduction of a
side chain bearing an appropriate leaving group such as a halide,
or a sulfonate group.
##STR00012##
[0402] In Reaction Scheme 4, a compound of formula (IX), prepared
as described above, can be converted to amide (XVII) using
activated esters such as acid chlorides and anhydrides or
alternatively formed using carboxylic acids and appropriate
coupling agents such as PYBOP, DCC, or EDCI in polar aprotic
solvents. Removal of the protecting group in formula (XVII) will be
dependent on the group selected and can be accomplished by standard
methods (Greene, T. W.; Wuts, P. G. M.; Protective Groups in
Organic Synthesis; Wiley & Sons: New York, 1999). Alkylation of
the phenol in formula (XVI) can be achieved using a base such as
cesium carbonate, sodium hydride, or potassium t-butoxide in a
polar aprotic solvent such as DMF or DMSO with introduction of a
side chain bearing an appropriate leaving group such as a halide,
or a sulfonate group.
##STR00013##
[0403] In Reaction Scheme 5, a compound of formula XVIII can be
converted to the bis chloride compound of formula XIX using
chlorinating agents such as POCl.sub.3 or COCl.sub.2 in aprotic
solvents. The chloride thus obtained can be converted to
imidazolines of formula XXI through reaction with appropriate
quantities of ethanolamine or a suitably protected substitute,
followed by activation with a suitable activating agent such as a
sulfonyl chloride, PPh.sub.3, or an halogenating agent such as
SOCl.sub.2. Chloride XXI can be converted to amine XXII through the
use of any source of nucleophilic amine such as ammonia,
phthalimide, or protected amines such as benzyl amine. in a polar
solvent such as DMF or DMSO. Formation of the phenol depicted in
formula X can be accomplished through deprotection of the methyl
ether using any of the conditions outlined in the literature
(Greene, T. W.; Wuts, P. G. M.; Protective Groups in Organic
Synthesis; Wiley & Sons: New York, 1999).
[0404] In order that this invention may be better understood, the
following examples are set forth. These examples are for the
purpose of illustration only, and are not to be construed as
limiting the scope of the invention in any manner. All publications
mentioned herein are incorporated by reference in their
entirety.
INTERMEDIATES
Intermediate A
Preparation of pyrimidine 4-carboxylic acid
##STR00014##
[0406] 4-Methylpyrimidine (1.00 g, 10.6 mmol) was diluted in water
(90 mL). Potassium permanganate (4.20 g, 26.5 mmol) and potassium
hydroxide (4.20 g, 74.8 mmol) were added, and the mixture was
heated at 75.degree. C. for 1.5 h. Ethanol was added dropwise, and
the precipitate was removed by filtration through Celite. The
filtrate was concentrated under reduced pressure, diluted in water,
and treated with a concentrated HCl solution until acidic. The
title compound precipitated as a fine powder, which was collected
by vacuum filtration and dried in a vacuum oven (770 mg, 58%):
.sup.1H NMR (DMSO-d.sub.6) .delta.: 13.92 (1H, br s), 9.35 (1H, d),
9.05 (1H, d), 7.99 (1H, dd).
Intermediate B
Preparation of 2-aminopyrimidine-5-carboxylic acid
##STR00015##
[0408] Sodium
(1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate was
prepared as described by Zhichkin et al. (Synthesis 2002, 6, p.
7720).
[0409] Sodium
(1Z)-2-(dimethoxymethyl)-3-methoxy-3-oxoprop-1-en-1-olate (1.37 g,
7.8 mmol) was diluted in DMF (12 mL), and guanidine hydrochloride
(640 mg, 6.7 mmol) was added. The mixture was stirred at
100.degree. C. for 1 h, then was cooled to rt and diluted with
water. Methyl 2-aminopyrimidine-5-carboxylate precipitated as a
light yellow solid, which was isolated by vacuum filtration (510
mg, 50%): .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.67 (s, 2H), 7.56
(br s, 2H), 3.79 (s, 3H).
[0410] Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol)
was diluted in methanol (5 mL) containing a few drops of water.
Lithium hydroxide (122 mg, 5.1 mmol) was added, and the reaction
mixture was stirred at 60.degree. C. overnight. The mixture was
concentrated under reduced pressure, then diluted in water and
adjusted to pH 4 with 1 M HCl. 2-Aminopyrimidine-5-carboxylic acid
precipitated as a white solid, which was isolated by vacuum
filtration (244 mg, 90%): .sup.1H NMR (DMSO-d.sub.6) .delta.: 12.73
(1H, br s), 8.63 (2H, s), 7.44 (2H, br s).
Intermediate C
Preparation of 4-(3-chloropropyl)morpholine hydrochloride
##STR00016##
[0412] To a solution of 1-bromo-3-chloropropane (45 g, 0.29 mol) in
toluene (100 mL) was added morpholine (38 g, 0.44 mol). The
solution was stirred at 84.degree. C. for 3 h, during which time a
precipitate formed. After cooling to rt, the precipitate was
isolated by vacuum filtration, washed with ether, and the solid was
discarded. The mother liquor was acidified with HCl (4 M in
dioxane, 72 mL, 0.29 mol), which caused the desired product to
precipitate as an HCl salt. Solvent was removed under reduced
pressure, and the resultant solid was dried to afford the title
compound (53 g, 90%): .sup.1H NMR (DMSO-d.sub.6) .delta.: 11.45
(1H, br s), 3.94-3.77 (4H, m), 3.74 (2H, t), 3.39 (2H, m), 3.15
(2H, m), 3.03 (2H, m), 2.21 (2H, m).
Intermediate D
Preparation of 2-amino-4-propylpyrimidine-5-carboxylic acid
##STR00017##
[0414] To a solution of ethyl
2-amino-4-propyllpyrimidine-5-carboxylate (1.0 g, 4.8 mmol) in MeOH
(20 mL) and THF (30 mL) was added a 2 N NaOH solution (10 mL). The
solution was stirred at room temperature overnight and then
neutralized with 1 N HCl (20 mL). It was then concentrated under
reduced pressure to 30 mL, filtered, and dried to give the desired
product which was used without further purification (0.6 g,
69%).
Intermediate E
Preparation of 6-amino-2-methylnicotinic acid
##STR00018##
[0416] A suspension of 6-amino-2-methylnicotinonitrile (1.0 g, 7.5
mmol) in an aqueous KOH solution (20%, 12 mL) was heated at the
reflux temperature for 3 days. After this time, it was cooled to
room temperature, neutralized with concentrated HCl, filtered and
dried to give the desired product which was used without further
purification (1.1 g, 96%).
Intermediate F
Preparation of tert-butyl
2-(2-hydroxyethyl)morpholine-4-carboxylate
##STR00019##
[0418] Methyl morpholin-2-yl acetate (5.0 g, 31.4 mmol) was diluted
with THF (10 mL) and water (10 mL) and treated with potassium
carbonate (4.34 g, 31.4 mmol). The thick suspension slowly went
into solution. Di-tert-butyl dicarbonate (6.85 g, 31.4 mmol) was
added and the reaction mixture was stirred at rt overnight. The
reaction mixture was then extracted with THF and EtOAc. The organic
layer was dried (MgSO.sub.4) and concentrated under reduced
pressure. The sticky oil was triturated with ether and the
resulting solid was collected by vacuum filtration (3.7 g, 45%).
The mixture was diluted in THF (20 mL) and treated with a solution
of sodium hydroxide (2 N, 5 mL) and stirred overnight. The reaction
mixture was concentrated under reduced pressure and then diluted
with water and EtOAc. The pH of the aqueous layer was adjusted to
5, and the organic layer was separated, dried (MgSO.sub.4) and
concentrated under reduced pressure. The solid (2 g, 8.15 mmol) was
then dissolved in THF (10 mL) and treated with a borane solution (1
M in THF, 16 mL, 16.4 mmol) and the mixture stirred at rt for 12 h.
The reaction mixture was then diluted with methanol (100 mL) and
stirred at rt overnight. The solution was then concentrated under
reduced pressure and then diluted with DCM. The solution was
filtered through a layer of silica to remove the borane salts, and
the filtrate was concentrated under reduced pressure to give an oil
(1.8 g, 96%): HPLC MS RT=2.22 min, MH.sup.+=232.2; .sup.1H NMR
(DMSO-d.sub.6) .delta.: 4.46 (1H, t), 3.81-3.73 (2H, m), 3.72-3.64
(1H, br d), 3.45 (2H, t), 3.40-3.29 (3H, m), 2.93-2.73 (1H, br s),
1.55-1.48 (2H, m), 1.39 (9H, s).
Intermediate G
Preparation of
2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-chloropropyl)
morpholine
##STR00020##
[0419] Step 1: Preparation of Morpholin-2-ylmethanol
trifluoroacetate
##STR00021##
[0421] A solution of tert-butyl
2-(hydroxymethyl)morpholine-4-carboxylate (1.1 g, 5.06 mmol) in DCM
(15 mL) was treated with trifluoroacetic acid (2.5 mL, 10.1 mmol)
and stirred at rt overnight. The reaction mixture was concentrated
under reduced pressure to yield a thick oil (1.1 g, 94%): NMR
(DMSO-d.sub.6) .delta.: 9.30 (1H, s), 4.95 (1H, s), 4.19-4.06 (1H,
br s), 3.93 (1H, dd), 3.76-3.63 (2H, m), 3.47-3.32 (2H, m),
3.22-3.09 (3H, m), 3.92 (1H, td), 2.76 (1H, t).
Step 2: Preparation of
2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine
##STR00022##
[0423] Morpholin-2-ylmethanol trifluoroacetate (0.7 g, 3.03 mmol)
in DCM was treated with triethylamine (1.67 mL, 12.1 mmol) and
tert-butyldimethylsilyl chloride (0.91 g, 6.06 mmol). The mixture
was stirred at rt for 2 h and then filtered. The filtrate was then
concentrated under reduced pressure and the residue was suspended
in a dilute solution of sodium hydroxide (10%, 5 mL), and the
mixture was stirred for 30 min. The mixture was then extracted with
DCM and concentrated under reduced pressure to a foam. The product
was taken to the next step without further purification: .sup.1H
NMR (DMSO-d.sub.6) .delta.: 5.40-5.14 (1H, br s), 3.69 (1H, m),
3.56-3.50 (1H, m), 3.46-3.3 (3H, m), 3.27-2.97 (1H, br s), 2.78
(1H, dd), 2.68-2.55 (2H, m), 2.35 (1H, m), 0.87-0.82 (9H, m), 0.02
(6H, s).
Step 3: Preparation of
2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-chloropropyl)morpholine
##STR00023##
[0425] A solution of
2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine (2.1 g, 9.07
mmol) in DCM (20 mL) was treated with triethylamine (3.8 mL, 27.2
mmol) and 1-chloro-3-iodopropane (1.95 mL, 18.1 mmol). The reaction
mixture was stirred at rt overnight. The reaction mixture was
concentrated under reduced pressure then purified by MPLC (ISCO, 0%
MeOH/100% DCM to 25% MeOH/75% DCM). The product was isolated as an
oil (560 mg, 20%): HPLC MS RT=2.66 min, MH.sup.+=308.4, 310.4;
.sup.1H NMR (DMSO-d.sub.6) .delta.: 3.79-3.69 (1H, m), 3.63 (2H, t)
3.59-3.52 (1H, m), 3.50-3.36 (3H, m), 2.73 (1H, d), 2.61 (1H, d),
2.35 (2H, t), 1.94 (1H, td), 1.83 (2H, qt), 1.73 (1H, t), 0.83 (9H,
s), 0.00 (6H, s).
Intermediate H
Preparation of
4-[(2-oxido-1,3,2-dioxathiolan-4-yl)methyl]morpholine
hydrochloride
##STR00024##
[0427] 3-Morpholin-4-ylpropane-1,2-diol (2.1 g, 9.07 mmol) was
dissolved in DCM (15 mL) and cooled to 0.degree. C. The cooled
solution was treated with thionyl chloride (1.81 mL, 24.8 mmol) and
then heated at the reflux temperature for 1 h. The reaction mixture
was then concentrated under reduced pressure to give a solid (2.5
g, 97%): .sup.1H NMR (DMSO-d.sub.6) .delta.: 11.4 (1H, br s),
5.64-5.55 (1H, m) 4.82 (1H, dd), 4.50 (1H, dd), 4.02-3.71 (4H, m),
3.55-3.33 (4H, m), 3.26-3.06 (2H, br s).
Intermediate I
Preparation of 6-(cyclopentylamino)nicotinic acid
##STR00025##
[0429] 6-Fluoronicotinic acid (300 mg, 2.13 mmol) and
cyclopentylamine (0.84 mL, 8.50 mmol) were combined in anhydrous
THF (5 mL) and triethylamine (0.59 mL, 4.25 mmol). The mixture was
heated at 60.degree. C. for 3 days. The mixture was concentrated
under reduced pressure, and the residue was suspended in water. The
aqueous mixture was brought to pH 3 with phosphoric acid. The
resulting precipitate was collected by vacuum filtration, washed
with water, and dried in a vacuum oven for 1 h at 50.degree. C. to
give the title compound as a solid (63 mg, 14%): HPLC MS RT=1.14
min, MH.sup.+=207.2; .sup.1H NMR (DMSO-d.sub.6) .delta.: 12.29 (1H,
broad s), 8.50 (1H, d), 7.73 (1H, dd), 7.29 (1H, d), 6.42 (1H, d),
4.16 (1H, broad s,), 1.90 (2H, m), 1.67 (2H, m), 1.53 (2H, m), 1.43
(2H, m).
EXAMPLES
Example 1
Preparation of
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]pyrimidine-5-carboxamide
##STR00026##
[0430] Step 1: Preparation of 4-formyl-2-methoxy-3-nitrophenyl
acetate
##STR00027##
[0432] Fuming nitric acid (2200 mL) under nitrogen was cooled to
0.degree. C. at which time vanillin acetate (528 g, 2.7 mol) was
added portionwise, keeping the internal temperature below
10.degree. C. After 2 h the resulting mixture was poured over ice
with stirring. The slurry was filtered and the resulting solids
were washed with water (3.times.100 mL) and air-dried. After 2 days
the solids were heated in DCM (3000 mL) until complete dissolution.
The solution was allowed to cool to room temperature while hexanes
(3000 mL) was added dropwise. The solids were filtered, washed with
hexanes (500 mL) and air dried to give the desired product (269 g,
41%): .sup.1H NMR, (DMSO-d.sub.6) .delta.: 9.90 (s, 1H), 7.94 (d,
1H), 7.75 (d, 1H), 3.87 (s, 3H), 2.40 (s, 3H).
Step 2: Preparation of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde
##STR00028##
[0434] A mixture of 4-formyl-2-methoxy-3-nitrophenyl acetate 438 g
(1.8 mol) and potassium carbonate (506 g, 3.7 mol) in MeOH (4000
mL) was stirred at room temperature for 16 h. The reaction mixture
was concentrated under reduced pressure to afford a viscous oil.
This was dissolved in water, acidified using a solution of HCl (2
N) and extracted with EtOAc. The organic layer was washed with
brine, dried (MgSO.sub.4) and filtered. The solvent was
concentrated under reduced pressure to 1/3 volume and the resulting
solids were filtered and air-dried to give the title compound (317
g, 88%): .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.69 (1H, s), 7.68
(1H, d), 7.19 (1H, d), 3.82 (3H, s).
Step 3: Preparation of
4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde
##STR00029##
[0436] 4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (155 g, 786 mmol)
was dissolved in DMF (1500 mL) and the stirred solution was treated
with potassium carbonate (217 g, 1.57 mol) followed by benzyl
bromide (161 g, 0.94 mol). After stirring for 16 h the reaction
mixture was concentrated under reduced pressure and separated
between water (2 L) and EtOAc (2 L). The organic layer was washed
with brine (3.times.2 L), dried (sodium sulfate) and concentrated
under reduced pressure. The resulting solids were triturated with
Et.sub.2O (1 L) to give the title compound (220 g, 97%): .sup.1H
NMR (DMSO-d.sub.6) .delta.: 9.77 (1H, s), 7.87 (1H, d), 7.58 (1H,
d), 7.51 (1H, m), 7.49 (1H, m), 7.39 (3H, m), 5.36 (2H, s), 3.05
(3H, s).
Step 4: Preparation of
4-(benzyloxy)-3-methoxy-2-nitrobenzonitrile
##STR00030##
[0438] Iodine (272 g, 1.1 mmol) was added to a mixture of
4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde (220 g, 766 mmol) and
ammonium hydroxide (28% solution, 3 L) dissolved in THF (5 L).
After 16 h the reaction mixture was treated with sodium sulfite (49
g, 383 mmol) and concentrated under reduced pressure to afford a
thick slurry. The slurry was filtered, washed with water (250 mL)
and dried to afford the title compound as a solid (206 g, 95%):
.sup.1H NMR (DMSO-d.sub.6) .delta.: 7.89 (1H, d), 7.59 (1H, d),
7.49 (2H, m), 7.40 (3H, m), 5.35 (2H, s), 3.91 (3H, s).
Step 5: Preparation of
2-amino-4-(benzyloxy)-3-methoxybenzonitrile
##STR00031##
[0440] A degassed solution of
4-(benzyloxy)-3-methoxy-2-nitrobenzonitrile (185 g, 651 mmol) in
glacial acetic acid (3500 mL) and water (10 mL) was cooled to
5.degree. C. and treated with iron powder (182 g, 3.25 mol). After
3 days the reaction mixture was filtered through Celite, and the
filtrate concentrated under reduced pressure. The oil, thus
obtained, was treated with brine, neutralized with a sodium
bicarbonate solution and extracted into DCM. The resulting emulsion
was filtered through Celite after which the organic layer was
separated, washed with brine, dried (sodium sulfate) and
concentrated under reduced pressure to afford the title compound as
a solid (145 g, 88%): .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.32-7.44
(5H, m), 7.15 (1H, d), 6.47 (1H, d), 5.69 (2H, s), 5.15 (2H, s),
3.68 (3H, s).
Step 6: Preparation of
3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline
##STR00032##
[0442] A mixture of 2-amino-4-(benzyloxy)-3-methoxybenzonitrile
(144 g, 566 mmol) and sulfur (55 g, 1.7 mol) in ethylenediamine
(800 mL) was degassed for 30 minutes then heated to 100.degree. C.
After 16 h the reaction mixture was cooled to room temperature and
then filtered. The filtrate was concentrated under reduced
pressure, diluted with a saturated sodium bicarbonate solution and
extracted with EtOAc. The organic layer was washed with brine,
dried (sodium sulfate), filtered and concentrated under reduced
pressure. The resulting solids were recrystallized from EtOAc and
hexanes to afford the title compound (145 g, 86%): .sup.1H NMR
(DMSO-d.sub.6) .delta.: 7.27-7.48 (5H, m), 7.14 (1H, d), 6.92 (2H,
m), 6.64 (1H, m), 6.32 (1H, d), 5.11 (2H, s), 3.67 (3H, s), 3.33
(2H, s).
Step 7: Preparation of
8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine
##STR00033##
[0444] A mixture of
3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline
(100 g, 336 mmol) and triethylamine (188 mL) in DCM (3 L) was
cooled to 0.degree. C. and treated with cyanogen bromide (78.4 g,
740 mmol). The reaction mixture was stirred and allowed to warm to
room temperature gradually. After 16 h the reaction mixture was
diluted with a solution of saturated sodium bicarbonate and
extracted with DCM. The organic layer was washed 3 times with
saturated bicarbonate solution followed by multiple washes with
brine. The organic layer was dried (sodium sulfate) and
concentrated under reduced pressure to give a semi solid (130 g
with triethylamine salt contamination): .sup.1H NMR (DMSO-d.sub.6)
.delta.: 7.30-7.48 (7H, m), 5.31 (2H, s), 4.32 (2H, m), 4.13 (2H,
m), 3.81 (3H, s).
Step 8: Preparation of
5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol
bis(trifluoroacetate)
##STR00034##
[0446]
3-(Benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline (30
g, 93 mmol) was added portionwise over 1 h to a round bottom flask
containing TFA (400 mL) precooled with an ice bath. The reaction
mixture was heated to 60.degree. C. and allowed to stir at this
temperature for 17 h at which time it was cooled to rt and the
reaction mixture concentrated under reduced pressure. The resulting
residue was taken up in DCM and hexanes and concentrated under
reduced pressure. The material thus obtained was dissolved in MeOH
and DCM (250 mL, 1:1) and concentrated under reduced pressure. The
resulting solid was dried overnight under vacuum with low heat to
give the title compound (44.7 g, >100%): .sup.1H NMR
(DMSO-d.sub.6) .delta.: 7.61 (1H, m), 6.87 (1H, m), 4.15 (2H, br
t), 4.00 (2H, m), 3.64 (3H, s).
Step 9: Preparation of
7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-
-5-amine
##STR00035##
[0448] 5-Amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol
bis(trifluoroacetate) (500 mg, 1.1 mmol) was diluted in DCM (10
mL), and triethylamine (0.75 mL, 5.4 mmol) was added. The
suspension was stirred at rt for 1.5 h, after which time
5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol
trifluoroacetate was isolated. The compound, thus prepared, (1.1
mmol) was dissolved in DMF (10 mL). Cesium carbonate (1.41 g, 4.3
mmol) and Intermediate C (218 mg, 1.1 mmol) were added, and the
mixture was stirred at 70.degree. C. for 30 min. Additional
Intermediate C (109 mg, 0.55 mmol) and cesium carbonate (350 mg,
1.1 mmol) were added, and stirring was continued for 1 h. Another
aliquot of Intermediate C (109 mg, 0.55 mmol) was added, and the
temperature was increased to 75.degree. C. After 3 h, the reaction
mixture was cooled to rt and filtered through a pad of Celite,
washing with methanol and DCM. The filtrate was concentrated under
reduced pressure, dry loaded onto silica gel, and purified by
biotage eluting with 5-10% methanol in DCM followed by 5-15%
methanolic ammonia (2.0 M, Aldrich) in DCM. The resultant oil was
triturated with a 1:1 mixture of hexanes:EtOAc (15 mL) to afford
the desired as a solid (171 mg, 44%): HPLC MS RT=1.07 min,
MH.sup.+=360.3; .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.43 (1H, d),
6.73 (3H, m), 4.03 (2H, t), 3.88 (4H, m), 3.69 (3H, s), 3.55 (4H,
m), 2.42 (2H, t), 2.35 (4H, m), 1.87 (2H, m).
Step 10: Preparation of
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]pyrimidine-5-carboxamide
##STR00036##
[0450]
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-amine (100 mg, 0.22 mol) was dissolved in DMF (5 mL), and
pyrimidine-5-carboxylic acid (41 mg, 0.33 mmol) was added. PYBOP
(173 mg, 0.33 mmol) and diisopropylethylamine (0.16 mL, 0.89 mmol)
were subsequently added, and the mixture was stirred at rt
overnight. EtOAc was added, and the precipitate was isolated by
vacuum filtration to give the title compound (12 mg, 11%): HPLC MS
RT=1.07 min, MH.sup.+=466.2; .sup.1H NMR (DMSO-d.sub.6+2 drops
TFA-d) .delta.: 9.48 (2H, s), 9.39 (1H, s), 8.05 (1H, d), 7.47 (1H,
d), 4.59 (2H, m), 4.35 (2H, br t), 4.26 (2H, m), 4.02 (3H, s), 4.00
(2H, m), 3.67 (2H, br t), 3.52 (2H, m), 3.33 (2H, m), 3.16 (2H, m),
2.27 (2H, m).
Example 2
Preparation of
N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydr-
oimidazo[1,2-c]quinazolin-5-yl) nicotinamide
##STR00037##
[0452]
8-{3-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dih-
ydroimidazo[1,2-c]quinazolin-5-amine (200 mg, 0.52 mmol) was
dissolved in DMF (2.0 mL), and nicotinic acid (76 mg, 0.62 mmol)
was added. PYBOP (322 mg, 0.62 mmol) and diisopropylethylamine
(0.33 mL, 1.55 mmol) were subsequently added, and the mixture was
stirred at room temperature overnight. EtOAc was added, and the
precipitate was isolated by vacuum filtration to give the title
compound (156 mg, 61%): HPLC MS RT=1.34 min, MH.sup.+=493.3;
.sup.1H NMR (DMSO-d.sub.6+2 drops TFA-d) .delta.: 9.53 (1H, s),
9.03 (1H, d), 9.00 (1H, d), 8.07 (1H, d), 8.01 (1H, dd), 7.49 (1H,
d), 4.58 (2H, m), 4.34 (2H, t), 4.27 (2H, m), 4.03 (3H, s), 3.81
(2H, m), 3.53 (2H, d), 3.29 (2H, m), 2.69 (2H, m), 2.27 (2H, m),
1.15 (6H, d).
Example 3
Preparation of
N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dihydr-
oimidazo[1,2-c]quinazolin-5-yl)-2,4-dimethyl-1,3-thiazole-5-carboxamide
##STR00038##
[0454]
8-{3-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]propoxy}-7-methoxy-2,3-dih-
ydroimidazo[1,2-c]quinazolin-5-amine (120 mg, 0.31 mmol) was
dissolved in DMF (1.5 mL), and
2,4-dimethyl-1,3-thiazole-5-carboxylic acid (58 mg, 0.37 mmol) was
added. PYBOP (193 mg, 0.37 mmol) and diisopropylethylamine (0.16
mL, 0.93 mmol) were subsequently added, and the mixture was stirred
at room temperature overnight. EtOAc was added, and the precipitate
was isolated by vacuum filtration to give the title compound (131
mg, 80%): HPLC MS RT=2.05 min, MH.sup.+=527.1; .sup.1H NMR
(DMSO-d.sub.6+2 drops TFA-d) .delta.: 8.02 (1H, d), 7.43 (1H, d),
4.38 (2H, m), 4.32 (2H, m), 4.22 (2H, m), 4.00 (3H, s), 3.81 (2H,
m), 3.53 (2H, d), 3.28 (2H, m), 2.72-2.63 (8H, m), 2.26 (2H, m),
1.13 (6H, d).
Example 4
Preparation of
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-e-
]quinazolin-5-yl]-1,3-thiazole-5-carboxamide
##STR00039##
[0456]
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-amine (250 mg, 0.70 mol) was dissolved in DMF (4 mL), and
2-amino-1,3-thiazole-5-carboxylic acid (110 mg, 0.76 mmol) was
added. PYBOP (543 mg, 1.04 mmol) and diisopropylethylamine (0.61
mL, 3.50 mmol) were subsequently added, and the mixture was stirred
at room temperature overnight. The desired product was isolated via
HPLC to give the title compound (80.0 mg, 24%): HPLC MS RT=1.03
min, MH.sup.+=486.3; .sup.1H NMR (MeOH-d.sub.4+2 drops TFA-d)
.delta.: 7.90 (1H, d), 7.79 (1H, d), 7.50-7.60 (2H, m), 3.70 (2H,
m), 3.30 (2H, d), 3.20 (2H, q), 2.10 (2H, s), 1.35 (10H, m).
Example 5
Preparation of
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-e-
]quinazolin-5-yl]isonicotinamide
##STR00040##
[0458]
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-amine (100 mg, 0.28 mol) was dissolved in DMF (3 mL), and
2-aminopyridine-4-carboxylic acid (38 mg, 0.28 mmol) was added.
PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (0.15 mL, 0.83
mmol) were subsequently added, and the mixture was stirred at rt
overnight. The mixture was purified by HPLC to give the title
compound (50 mg, 37%). LC MS RT=1.02 min, MH.sup.+=480.3. .sup.1H
NMR (DMSO-d.sub.6) .delta.: 13.25 (1H, br s), 10.15 (1H, br s),
8.42 (1H, br s), 8.08 (1H, s), 8.06 (1H, d), 7.43 (1H, d), 7.75
(1H, s), 7.50 (1H, d), 7.38 (1H, dd), 4.50 (2H, dd), 4.35 (2H, br
t), 4.27 (2H, dd), 4.01 (3H, s), 3.99 (2H, br s), 3.66 (2H, t),
3.50 (2H, d), 3.31 (2H, br t), 3.13 (2H, m), 2.25 (2H, m).
Example 6
Preparation of
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]-4-methyl-1,3-thiazole-5-carboxamide
##STR00041##
[0460]
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-amine (100 mg, 0.28 mol) was dissolved in DMF (3 mL), and
2-amino-4-methylthiazole-5-carboxylic acid (44 mg, 0.28 mmol) was
added. PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (0.15
mL, 0.83 mmol) were subsequently added, and the mixture was stirred
at rt overnight. The mixture was purified by HPLC to give the title
compound (6 mg, 4%): LC MS RT=1.06 min, MH.sup.+=500.1; .sup.1H NMR
(DMSO-d.sub.6) .delta.: 12.59 (1H, s), 7.55 (1H, d), 7.47 (1H,$),
6.98 (1H, d), 4.13 (2H, t), 3.93 (4H, m), 3.86 (3H, s), 3.55 (4H,
t), 2.47 (3H, s), 2.45 (2H, t), 2.33 (4H, m), 1.93 (2H, m).
Example 7
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]-
quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide
##STR00042##
[0462]
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-amine (100 mg, 0.28 mol) was dissolved in DMF (3 mL), and
Intermediate D (50 mg, 0.28 mmol) was added. PYBOP (217 mg, 0.42
mmol) and diisopropylethylamine (0.15 mL, 0.83 mmol) were
subsequently added, and the mixture was stirred at rt overnight.
The resulting precipitate was filtered and washed with MeOH to give
the title compound (76 mg, 52%): LC MS RT=1.64 min, MH.sup.+=523.3;
.sup.1H NMR (DMSO-d.sub.6 with 2 drops TFA-d) .delta.: 10.04 (1H,
br s), 9.14 (1H, s), 8.02 (1H, d), 7.43 (1H, d), 4.48 (2H, dd),
4.33 (2H, t), 4.21 (2H, dd), 4.01 (2H, m) 3.98 (3H, s), 3.65 (2H,
t), 3.52 (2H, d), 3.30 (2H, br t), 3.13 (4H, m), 2.24 (2H, m), 1.68
(2H, m), 0.95 (3H, t).
Example 8
Preparation of
N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl}nicotinamide
##STR00043##
[0463] Step 1: Preparation of
N-[8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicot-
inamide
##STR00044##
[0465]
8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine
(21 g, 65 mmol) and nicotinic acid (12 g, 97.7 mmol) were suspended
in DMF (240 mL). Diisopropylethylamine (33.7 g, 260.4 mmol) and
then PYBOP (51 g, 97.7 mmol) were added and the resulting mixture
stirred with overhead stirring for 3 days at ambient temperature.
At this time, the resultant precipitate was isolated by vacuum
filtration. After repeated washing with EtOAc, the material was
dried under vacuum with slight heating to yield the title compound
(27.3 g, 98%): HPLC MS RT=1.09 min, MH.sup.+=481.2; .sup.1H NMR
(DMSO-d.sub.6+2 drops TFA-d) .delta.: 9.32 (1H, s), 8.89 (1H, br
m), 8.84 (1H, d), 7.89 (1H, br m), 7.82 (1H, d), 7.37 (1H, d), 7.27
(1H, d), 7.16 (6H, m), 5.18 (2H, s), 4.36 (2H, t), 4.04 (2H, t),
3.78 (3H, s).
Step 2: Preparation of
N-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinam-
ide
##STR00045##
[0467]
N-[8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl-
]nicotinamide (20 g, 45.1 mmol) was added portionwise over 1 h to a
round bottom flask containing TFA (400 mL) precooled with an ice
bath. The reaction mixture was heated to 60.degree. C. and allowed
to stir at this temperature for 17 h at which time it was cooled to
ambient. The reaction mixture was then concentrated under reduced
pressure. The resulting residue was taken up in DCM and hexane and
concentrated under reduced pressure. The material thus obtained was
dissolved in MeOH and DCM (250 mL, 1:1) and concentrated under
reduced pressure. The resulting solids were dried overnight under
vacuum with low heat to give the title compound (17.3 g, 66%): HPLC
MS RT=1.09 min, MH.sup.+=481.2; .sup.1H NMR (DMSO-d.sub.6+2 drops
TFA-d) .delta.: 13.41 (1H, s), 12.21 (1H, br s), 9.38 (1H, s), 8.78
(1H, d), 8.53 (1H, d), 7.85 (1H, d), 7.59 (1H, m), 7.17 (1H, d),
4.54 (2H, m), 4.21 (2H, m), 3.98 (3H, s).
Step 3: Preparation of tert-Butyl
2-[2-({7-methoxy-5-[(pyridin-3-ylcarbonyl)amino]-2,3-dihydroimidazo[1,2-c-
]quinazolin-8-yl}oxy)ethyl]morpholine-4-carboxylate
##STR00046##
[0469] A solution of Intermediate F (420 mg, 1.83 mmol) in DMF (5
mL) was treated with triethylamine (340 .mu.L, 2.44 mmol) and
methanesulfonyl chloride (141 .mu.L, 1.83 mmol) and the mixture was
stirred at rt for 1.5 h. A suspension of the compound prepared in
example 8 step 2 (650 mg, 1.22 mmol) in DMF (20 mL) was treated
with cesium carbonate (2.0 g, 6.10 mmol) and stirred for 1.5 h
before adding the preformed and filtered mesylate. The reaction
mixture was stirred at 60.degree. C. overnight and then
concentrated under reduced pressure and the residue was extracted
with a solution of 20% isopropanol/80% chloroform and washed with a
saturated solution of sodium hydrogen carbonate. The organics were
dried (MgSO.sub.4) and concentrated under reduced pressure. The
residue was triturated with EtOAc and filtered to give the title
compound as a solid (850 mg, 84%): HPLC MS RT=2.48 min,
MH.sup.+=551.2; .sup.1H NMR (DMSO-d.sub.6) .delta.: 12.7 (1H, s),
9.32 (1H, dd), 8.72 (1H, dd), 8.46 (1H, dt), 7.60 (1H, d), 7.51
(1H, dd), 7.07 (1H, d), 4.23-4.19 (2H, m), 4.15-4.10 (2H, m),
4.04-4.02 (2H, m), 3.93 (3H, s), 3.91-3.78 (2H, m), 3.75-3.66 (1H,
m) 3.56-3.48 (1H, m), 3.41-3.35 (1H, td), 2.97.2.76 (1H, br s),
2.74-2.55 (1H, br s), 2.04-1.94 (1H, br m) 1.94-1.84 (1H, br m),
1.39 (9H, s).
Step 4: Preparation of
N-[7-methoxy-8-(2-morpholin-2-ylethoxy)-2,3-dihydroimidazo[1,2-c]quinazol-
in-5-yl]nicotinamide
##STR00047##
[0471] tert-Butyl
2-[2-({7-methoxy-5-[(pyridin-3-ylcarbonyl)amino]-2,3-dihydroimidazo[1,2-c-
]quinazolin-8-yl}oxy)ethyl]morpholine-4-carboxylate (650 mg, 1.44
mmol) was dissolved in trifluoroacetic acid (10 mL) and stirred at
rt for 4 h. The reaction mixture was concentrated under reduced
pressure, and the resulting oil was diluted with methanol (1 mL)
and pulled through a silica bound-NH.sub.2cartridge. The solution
was concentrated under reduced pressure to give the title compound
as a solid (45 mg, 69%): HPLC MS RT=0.21 min, MH.sup.+=451.1;
.sup.1H NMR (DMSO-d.sub.6) .delta.: 12.8-12.7 (1H, br s), 9.32 (1H,
s), 8.73 (1H, d), 8.46 (1H, d), 7.60 (1H, d), 7.54-7.49 (1H, m),
7.06 (1H, d) 4.22-3.99 (6H, m), 3.94 (3H, s), 3.78 (1H, d),
3.66-3.58 (1H, m), 3.47 (1H, t), 2.95 (1H, d), 2.82-2.65 (2H, m),
1.98-1.78 (2H, m).
Step 5: Preparation of
N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl}nicotinamide
##STR00048##
[0473]
N-[7-Methoxy-8-(2-morpholin-2-ylethoxy)-2,3-dihydroimidazo[1,2-c]qu-
inazolin-5-yl]nicotinamide trifluoroacetate (100 mg, 0.18 mol) in
THF was treated with acetaldehyde (30 .mu.L, 0.53 mmol) and stirred
for 30 min. before adding sodium triacetoxyborohydride (113 mg,
0.53 mmol) and acetic acid (13 .mu.L, 0.23 mmol). The reaction
mixture was stirred at 60 C overnight after which it was diluted
with methanol and a drop of 2 N hydrochloric acid to dissolve all
solids. The crude solution was purified by HPLC (Gilson, 5%
MeCN/95% H.sub.2O to 50% MeCN/50% H.sub.2O gradient, 0.1% TFA). The
fractions were concentrated under reduced pressure then diluted
with a minimum of methanol and pulled through a silica bound
NH.sub.2 cartridge to give the title compound as a solid (17 mg,
20%): HPLC MS RT=0.21 min, MH.sup.+=479.1; .sup.1H NMR
(DMSO-d.sub.6) .delta.: 12.75 (1H, s), 9.32 (1H, s), 8.71 (1H, d),
8.45 (1H, d), 7.59 (1H, d), 7.54-7.47 (1H, m), 7.06 (2H, d),
4.23-4.08 (3H, m), 4.06-3.98 (2H, m) 3.92 (3H, s), 3.77 (1H, d),
3.67-3.57 (1H, m), 3.46 (1H, t), 2.84 (1H, d), 2.68 (1H, d), 2.30
(2H, q), 1.99-1.79 (3H, m), 1.74 (1H, t), 0.99 (3H, t).
Example 9
Preparation of
N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl}pyrimidine-5-carboxamide
##STR00049##
[0475] Sodium hydride (865 mg, 22 mmol, 60% dispersion in mineral
oil) was diluted in DMF (35 mL).
N-(8-Hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidin-
e-5-carboxamide bis(trifluoroacetate) (1.75 g, 3.1 mmol) was added,
followed by 2-chloro-N,N-dimethylethanamine hydrochloride (890 mg,
6.2 mmol). The reaction mixture was stirred at rt until gas
evolution ceased and then was heated to 50.degree. C. for 2 h. At
this time, the mixture was cooled to rt, and an additional
equivalent of 2-chloro-N,N-dimethylethanamine hydrochloride (445
mg, 3.1 mmol) was added. The resulting reaction mixture was stirred
at 50.degree. C. overnight. After cooling to rt, the excess sodium
hydride was carefully quenched by the addition of water and the
mixture was extracted several times with DCM. The combined organic
layers were dried (sodium sulfate) and concentrated under reduced
pressure. The resultant solid was triturated with EtOAc and hexanes
to afford the title compound as a solid (710 mg, 56%): HPLC MS
RT=1.09 min, MH.sup.+=410.1; .sup.1H NMR (DMSO-d.sub.6+2 drops
TFA-d) .delta.: 9.47 (2H, s), 9.39 (1H, s), 8.12 (1H, d), 7.52 (1H,
d), 4.61 (4H, m), 4.26 (2H, m), 4.03 (3H, s), 3.67 (2H, br t), 2.93
(6H, s).
Example 10
Preparation of
N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide
##STR00050##
[0476] Step 1: Preparation of
N-(8-{3-[2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholin-4-yl]propoxy-
}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide
##STR00051##
[0478] A suspension of
N-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinam-
ide bis-trifluoroacetate (650 mg, 1.22 mmol) in DMF (20 mL) was
treated with cesium carbonate (2.0 g, 6.10 mmol) and stirred for
1.5 h before adding Intermediate G (0.56 g, 1.83 mmol) and
triethylamine (0.34 mL, 2.44 mmol). The reaction mixture was
stirred at 60.degree. C. overnight, after which time it was
concentrated under reduced pressure and the residue was extracted
with a solution of 20% isopropanol/80% chloroform and washed with a
saturated solution of sodium hydrogen carbonate. The organic layer
was dried (MgSO.sub.4) and concentrated under reduced pressure. The
residue was triturated with EtOAc and filtered to give the title
compound as a solid (260 mg, 35%): HPLC MS RT=2.36 min,
MH.sup.+=609.2; .sup.1H NMR (CD.sub.3OD-d.sub.4) .delta.: 9.24 (1H,
d), 8.60 (1H, dd), 8.48 (1H, dt), 7.53 (1H, d), 7.46 (1H, dd), 6.94
(1H, d), 4.21-4.05 (6H, m), 3.88 (1H, br d), 3.74-3.55 (4H, m),
2.95 (1H, d), 2.82 (1H, d), 2.60 (2H, t) 2.22-2.13 (1H, m), 2.05
(2H, qt), 1.94 (1H, t), 0.91 (9H, s), 0.08 (6H, s).
Step 2: Preparation of
N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide
##STR00052##
[0480]
N-(8-{3-[2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholin-4-yl]p-
ropoxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide
(260 mg, 0.43 mmol) was suspended in THF (2 mL) and treated with a
solution of tetra-n-butylammonium fluoride (1N, 0.64 mL, 0.64 mmol)
in THF. The resulting mixture was stirred at rt for 4 h and was
then diluted with water and extracted with 20% isopropanol/80%
chloroform, dried (MgSO.sub.4) and concentrated under reduced
pressure. The residue was then triturated with methanol and
filtered to give the product as a solid (100 mg, 47%): HPLC MS
RT=0.19 min, MH.sup.+=495.2; .sup.1H NMR (DMSO-d.sub.6) .delta.:
12.7 (1H, s), 9.33 (1H, dd), 8.73 (1H, dd), 8.46 (1H, dt), 7.60
(1H, d), 7.54-7.49 (1H, m), 7.06 (1H, d) 4.66 (1H, t), 4.20-4.09
(4H, m), 4.07-3.98 (2H, m) 3.93 (3H, s), 3.76 (1H, br d), 3.48 (1H,
td), 3.42-3.26 (4H, m), 2.83 (1H, d), 2.70 (1H, d), 2.47 (2H, t),
2.03-1.91 (3H, m).
Example 11
Preparation of
N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-2,3-dihydroim-
idazo[1,2-c]quinazolin-5-yl)nicotinamide
##STR00053##
[0482] Cesium carbonate (3 g, 9.37 mmol) was added to a suspension
of
N-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinam-
ide bis-trifluoroacetate (1.0 g, 1.88 mmol) in DMF (40 mL) and
stirred for 1.5 h before adding Intermediate H (0.39 g, 1.88 mmol).
After 3 h, the reaction mixture was treated with another equivalent
of Intermediate H and stirred at 60.degree. C. overnight. The
reaction mixture was concentrated under reduced pressure and the
product was extracted with a solution of 20% isopropanol/80%
chloroform and washed with a saturated solution of sodium hydrogen
carbonate. The organics were dried (MgSO.sub.4) and concentrated
under reduced pressure, and the resulting residue was triturated
with EtOAc and filtered. The solid was then purified by HPLC
(Gilson, 5% MeOH/95% H.sub.2O to 50% MeOH/50% H.sub.2O gradient,
0.1% NH.sub.4OH) to give the title compound (160 mg, 18%): HPLC MS
RT=0.19 min, MH.sup.+=495.2; .sup.1H NMR (DMSO-d.sub.6+1 drop
TFA-d) .delta.: 13.40-13.38 (1H, br s), 9.45 (1H, d), 8.90 (1H,
dd), 8.72 (1H, d), 8.06 (1H, d), 7.77 (1H, dd), 7.51 (1H, d) 4.59
(2H, t), 4.49-4.41 (1H, br s), 4.33-4.22 (4H, m), 4.06 (3H, s)
4.05-3.92 (2H, m), 3.86-3.67 (2H, m), 3.51 (2H, d), 3.43-3.13 (4H,
m).
Example 12
Preparation of
N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinaz-
olin-5-yl}nicotinamide 1-oxide
##STR00054##
[0483] Step 1: Preparation of
N-[8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicot-
inamide 1-oxide
##STR00055##
[0485] The title compound was synthesized from
8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine
as described in Example 8, step 1 (1.31 g, 95%): HPLC MS RT=2.38
min, MH.sup.+=444.1; .sup.1H NMR (DMSO-d.sub.6+2 drops TFA-d)
.delta.: 4.00 (3H, s), 4.22-4.28 (2H, m), 4.53-4.60 (2H, m), 5.42
(2H, s), 7.36-7.46 (3H, m), 7.51-7.54 (2H, m), 7.58-7.69 (2H, m),
8.04 (1H, d), 8.17 (1H, d), 8.56 (1H, d), 8.93-8.94 (1H, m).
Step 2: Preparation of
N-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinam-
ide 1-oxide bistrifluoroacetate salt
##STR00056##
[0487] The title compound was synthesized from
N-[8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicot-
inamide 1-oxide as described in Example 8, step 2 (1.41 g, 94%):
HPLC MS RT=0.35 min, MH.sup.+=354.2; .sup.1H NMR (DMSO-d.sub.6+2
drops TFA-d) .delta.: 3.97 (3H, s), 4.17-4.24 (2H, m), 4.51-4.57
(2H, m), 7.17 (1H, d), 7.66 (1H, dd), 7.88 (1H, d), 8.17 (1H, d),
8.53-8.56 (1H, m), 8.93-8.94 (1H, m).
Step 3: Preparation of
N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinaz-
olin-5-yl}nicotinamide 1-oxide
##STR00057##
[0489] The title compound was synthesized from
N-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinam-
ide 1-oxide bistrifluoroacetate salt as described in Example 9 (42
mg, 37%): HPLC MS RT=1.08 min, MH.sup.+=439.2; .sup.1H NMR
(DMSO-d.sub.6+2 drops TFA-d) .delta.: 2.19-2.25 (2H, m), 2.84 (3H,
s), 3.23-3.28 (2H, m), 4.02 (3H, s), 4.22-4.35 (4H, m), 4.54-4.61
(2H, m), 7.48 (1H, d), 7.66-7.71 (1H, m), 8.06 (1H, d), 8.19 (1H,
d), 8.57 (1H, d), 8.95 (1H, bs).
Example 13
Preparation of
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]pyrimidine-5-carboxamide
##STR00058##
[0490] Step 1: Preparation of
4-hydroxy-3-methoxy-2-nitrobenzonitrile
##STR00059##
[0492] 4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (200 g, 1.01 mol)
was dissolved in THF (2.5 L) and then ammonium hydroxide (2.5 L)
was added followed by iodine (464 g, 1.8 mol). The resulting
mixture was allowed to stir for 2 days at which time it was
concentrated under reduced pressure. The residue was acidified with
HCl (2 N) and extracted into diethyl ether. The organic layer was
washed with brine and dried (sodium sulfate) and concentrated under
reduced pressure. The residue was washed with diethyl ether and
dried under vacuum to provide the title compound (166 g, 84%):
.sup.1H NMR (DMSO-d.sub.6) .delta.: 11.91 (1H, s), 7.67 (1H, d),
7.20 (1H, d), 3.88 (3H, s)
Step 2: Preparation of
3-methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile
##STR00060##
[0494] To a solution of 4-hydroxy-3-methoxy-2-nitrobenzonitrile
(3.9 g, 20.1 mmol) in DMF (150 mL) was added cesium carbonate (19.6
g, 60.3 mmol) and Intermediate C (5.0 g, 24.8 mmol). The reaction
mixture was heated at 75.degree. C. overnight then cooled to room
temperature and filtered through a pad of silica gel and
concentrated under reduced pressure. The material thus obtained was
used without further purification
Step 3: Preparation of
2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile
##STR00061##
[0496] 3-Methoxy-4-(3-morpholin-4-ylpropoxy)-2-nitrobenzonitrile
(7.7 g, 24.1 mmol) was suspended in acetic acid (170 mL) and cooled
to 0.degree. C. Water (0.4 mL) was added, followed by iron powder
(6.7 g, 120 mmol) and the resulting mixture was stirred at room
temperature for 4 h at which time the reaction mixture was filtered
through a pad of Celite and washed with acetic acid (400 mL). The
filtrate was concentrated under reduced pressure to 100 mL and
diluted with EtOAc (200 mL) at which time potassium carbonate was
added slowly. The resulting slurry was filtered through a pad of
Celite washing with EtOAc and water. The layers were separated and
the organic layer was washed with saturated sodium bicarbonate
solution. The organic layer was separated and passed through a pad
of silica gel. The resultant solution was concentrated under
reduced pressure to provide the title compound (6.5 g, 92%):
.sup.1H NMR (DMSO-d.sub.6) .delta.: 7.13 (1H, d), 6.38 (1H, d),
5.63 (2H, br s), 4.04 (2H, t), 3.65 (3H, s), 3.55 (4H, br t), 2.41
(2H, t), 2.38 (4H, m), 1.88 (2H, quint.).
Step 4: Preparation of
6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholin-4-ylpropoxy)ani-
line
##STR00062##
[0498] To a degassed mixture of
2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile (6.5 g,
22.2 mmol) and ethylene diamine (40 mL) was added sulfur (1.8 g,
55.4 mmol). The mixture was stirred at 100.degree. C. for 3 h at
which time water was added to the reaction mixture. The precipitate
that was formed was collected and washed with water and then dried
overnight under vacuum to provide the title compound (3.2 g, 43%):
HPLC MS RT=1.25 min, MH.sup.+=335.2; .sup.1H NMR (DMSO-d.sub.6)
.delta.: 7.15 (1H, d), 6.86 (2H, br s), 6.25 (1H, d), 4.02 (2H, t),
3.66 (3H, s), 3.57 (8H, m), 2.46 (2H, t), 2.44 (4H, m), 1.89 (2H,
quint.).
Step 5: Preparation of
7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-
-5-amine
##STR00063##
[0500] Cyanogen bromide (10.9 g, 102.9 mmol) was added to a mixture
of
6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholin-4-ylpropoxy)ani-
line (17.2 g, 51.4 mmol) and TEA (15.6 g, 154.3 mmol) in DCM (200
mL) precooled to 0.degree. C. After 1 h the reaction mixture was
concentrated under reduced pressure and the resulting residue
stirred with EtOAc (300 mL) overnight at rt. The resulting slurry
was filtered to generate the title compound contaminated with
triethylamine hydrobromide (26.2 g, 71%): HPLC MS RT=0.17 min,
MH.sup.+=360.2.
Step 6: Preparation of
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c-
]quinazolin-5-yl]pyrimidine-5-carboxamide
##STR00064##
[0502]
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-amine (100 mg, 0.22 mol) was dissolved in DMF (5 mL), and
Intermediate B (46 mg, 0.33 mmol) was added. PYBOP (173 mg, 0.33
mmol) and diisopropylethylamine (0.16 mL, 0.89 mmol) were
subsequently added, and the mixture was stirred at rt overnight.
EtOAc was added, and the solids were isolated by vacuum filtration
to give the title compound (42.7 mg, 40%): HPLC MS RT=1.09 min,
MH.sup.+=481.2; .sup.1H NMR (DMSO-d.sub.6+2 drops TFA-d) .delta.:
9.01 (2H, s), 8.04 (1H, d), 7.43 (1H, d), 4.54 (2H, m), 4.34 (2H,
br t), 4.23 (2H, m), 4.04 (2H, m), 4.00 (3H, s), 3.65 (2H, br t),
3.52 (2H, m), 3.31 (2H, m), 3.18 (2H, m), 2.25 (2H, m).
Example 14
Preparation of
N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazo-
lin-5-yl]-6-(2-pyrrolidin-1-ylethyl)nicotinamide
##STR00065##
[0504]
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-amine (150 mg, 0.21 mmol) was dissolved in DMF (2 mL), and
6-(2-pyrrolidin-1-ylethyl)nicotinic acid (92 mg, 0.42 mmol) was
added. PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (73
.mu.L, 0.42 mmol) were subsequently added, and the mixture was
stirred at rt overnight. The solids that formed were isolated by
vacuum filtration and washed copiously with ethyl acetate to give
the title compound (81 mg, 69%): HPLC MS RT=1.05 min,
MH.sup.+=562.2; .sup.1H NMR (DMSO-d.sub.6+2 drops TFA-d) .delta.:
9.30 (1H, s), 8.99 (0.5H, m), 8.50 (1H, d), 8.24 (0.5H, m), 8.06
(1H, d), 7.53 (1H, d), 7.46 (1H, d), 4.55 (2H, t), 4.35 (2H, t),
4.24 (2H, t), 4.01 (3H, s), 4.00 (2H, m), 3.68 (2H, m), 3.60 (4H,
m), 3.51 (2H, m), 3.29 (4H, m), 3.11 (2H, m), 2.26 (2H, m), 2.02
(3H, m), 1.87 (3H, m).
Example 15
Preparation of
6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-
imidazo[1,2-c]quinazolin-5-yl]nicotinamide
##STR00066##
[0506]
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quin-
azolin-5-amine (150 mg, 0.21 mmol) was dissolved in DMF (2 mL), and
Intermediate I (60 mg, 0.29 mmol) was added. PYBOP (217 mg, 0.42
mmol) and diisopropylethylamine (73 .mu.L, 0.42 mmol) were
subsequently added, and the mixture was stirred at rt overnight.
The solids that formed were isolated by vacuum filtration and
washed copiously with ethyl acetate to give the title compound (80
mg, 69%): HPLC MS RT=1.74 min, MH.sup.+=548.2; .sup.1H NMR
(DMSO-d.sub.6+2 drops TFA-d) .delta.: 8.71 (1H, broad s), 8.39 (1H,
broad s), 8.03 (1H, d), 7.44 (1H, d), 7.04 (1H, broad s), 4.51 (2H,
t), 4.34 (2H, t), 4.25 (2H, t), 4.13 (1H, m), 4.03 (2H, m), 4.00
(3H, s), 3.67 (2H, t), 3.52 (2H, d), 3.32 (2H, t), 3.15 (2H, t),
2.26 (2H, m), 2.03 (2H, m), 1.72 (2H, m), 1.61 (4H, m).
[0507] By using the methods described above for Examples 1-15, and
by substituting the appropriate starting materials, Examples 16-104
found in the table below were similarly prepared.
TABLE-US-00001 TABLE 1 LC-MS m/z Ex Structure Method 16
##STR00067## RT = 1.13 Min MH.sup.+ = 481.4 Route 4 17 ##STR00068##
RT = 1.12 Min MH.sup.+ = 479.1 Route 4 18 ##STR00069## RT = 0.19
Min MH.sup.+ = 495.1 Route 4 19 ##STR00070## RT = 0.21 Min MH.sup.+
= 519.1 Route 4 20 ##STR00071## RT = 0.20 Min MH.sup.+ = 509.1
Route 4 21 ##STR00072## RT = 0.23 Min MH.sup.+ = 465.2 Route 4 22
##STR00073## RT = 1.12 Min MH.sup.+ = 495.3 Route 4 23 ##STR00074##
RT = 1.03 Min MH.sup.+ = 451.4 Route 4 24 ##STR00075## RT = 0.32
Min MH.sup.+ = 466.3 Route 1 25 ##STR00076## RT = 0.34 Min MH.sup.+
= 481.3 Route 1 26 ##STR00077## RT = 1.11 Min MH.sup.+ = 468.4
Route 1 27 ##STR00078## RT = 1.54 Min MH.sup.+ = 494.3 Route 1 28
##STR00079## RT = 1.23 Min MH.sup.+ = 507.2 Route 1 29 ##STR00080##
RT = 1.95 Min MH.sup.+ = 550.2 Route 1 30 ##STR00081## RT = 1.09
Min MH.sup.+ = 468.4 Route 1 31 ##STR00082## RT = 1.13 Min MH.sup.+
= 494.4 Route 1 32 ##STR00083## RT = 1.20 Min MH.sup.+ = 495.3
Route 1 33 ##STR00084## RT = 1.69 Min MH.sup.+ = 558.2 Route 1 34
##STR00085## RT = 1.05 Min MH.sup.+ = 470.3 Route 1 35 ##STR00086##
RT = 1.00 Min MH.sup.+ = 437.2 Route 4 36 ##STR00087## RT = 0.27
Min MH.sup.+ = 510.3 Route 2 37 ##STR00088## RT = 0.24 Min MH.sup.+
= 444.1 Route 1 38 ##STR00089## RT = 1.36 Min MH.sup.+ = 508.8
Route 1 39 ##STR00090## RT = 1.07 Min MH.sup.+ 508.2 Route 1 40
##STR00091## RT = 1.34 Min MH.sup.+ = 525.2 Route 2 41 ##STR00092##
RT = 1.90 Min MH.sup.+ = 553.2 Route 2 42 ##STR00093## RT = 1.17
Min MH.sup.+ = 439.1 Route 1 43 ##STR00094## RT = 1.14 Min MH.sup.+
= 608.3 Route 2 44 ##STR00095## RT = 1.66 Min MH.sup.+ = 539.2
Route 2 45 ##STR00096## RT = 1.14 Min MH.sup.+ = 552.3 Route 2 46
##STR00097## RT = 1.04 Min MH.sup.+ = 438.1 Route 1 47 ##STR00098##
RT = 0.48 Min MH.sup.+ = 535.3 Route 2 48 ##STR00099## RT = 0.33
Min MH.sup.+ = 564.3 Route 2 49 ##STR00100## RT = 1.93 Min MH.sup.+
= 551.2 Route 2 50 ##STR00101## RT = 1.03 Min MH.sup.+ = 549.1
Route 2 51 ##STR00102## RT = 0.99 Min MH.sup.+ = 549.2 Route 2 52
##STR00103## RT = 0.98 Min MH.sup.+ = 549.2 Route 2 53 ##STR00104##
RT = 1.84 Min MH.sup.+ = 588.2 Route 2 54 ##STR00105## RT = 1.48
Min MH.sup.+ = 560.2 Route 2 55 ##STR00106## RT = 1.07 Min MH.sup.+
= 538.2 Route 2 56 ##STR00107## RT = 2.10 Min MH.sup.+ = 530.1
Route 2 57 ##STR00108## RT = 1.43 Min MH.sup.+ = 550.2 Route 2 58
##STR00109## RT = 0.31 Min MH.sup.+ = 409.2 Route 4 59 ##STR00110##
RT = 2.06 Min MH.sup.+ = 564.2 Route 2 60 ##STR00111## RT = 1.90
Min MH.sup.+ = 548.2 Route 2 61 ##STR00112## RT = 2.15 Min MH.sup.+
= 563.1 Route 2 62 ##STR00113## RT = 1.94 Min MH.sup.+ = 533.1
Route 2 63 ##STR00114## RT = 1.93 Min MH.sup.+ = 550.2 Route 2 64
##STR00115## RT = 1.04 Min MH.sup.+ = 478.1 Route 4 65 ##STR00116##
RT = 1.25 Min + MH.sup.+ = 543.1 Route 2 66 ##STR00117## RT = 1.53
Min MH.sup.+ = 537.0 Route 2 67 ##STR00118## RT = 1.07 Min MH.sup.+
= 500.1 Route 2 68 ##STR00119## RT = 1.02 Min MH.sup.+ = 451 Route
4 69 ##STR00120## RT = 1.38 Min MH.sup.+ = 443.0 Route 4 70
##STR00121## RT = 1.03 Min MH.sup.+ = 423 Route 4 71 ##STR00122##
RT = 1.91 Min MH.sup.+ = 565.2 Route 2 72 ##STR00123## RT = 1.11
Min MH.sup.+ = 534.2 Route 2 73 ##STR00124## RT = 1.05 Min MH.sup.+
= 508.2 Route 2 74 ##STR00125## RT = 1.15 Min MH.sup.+ = 463.1
Route 4 75 ##STR00126## RT = 1.05 Min MH.sup.+ = 435.0 Route 4 76
##STR00127## RT = 1.09 Min MH.sup.+ = 449.0 Route 4 77 ##STR00128##
RT = 1.81 Min MH.sup.+ = 555.1 Route 2 78 ##STR00129## RT = 1.76
Min MH.sup.+ = 483.0 Route 2 79 ##STR00130## RT = 1.07 Min MH.sup.+
= 470.2 Route 2 80 ##STR00131## RT = 1.28 Min MH.sup.+ = 514.3
Route 2 81 ##STR00132## RT = 1.07 Min MH.sup.+ = 466.0 Route 2 82
##STR00133## RT = 1.89 Min MH.sup.+ = 381.4 Route 4 83 ##STR00134##
RT = 0.23 Min MH.sup.+ = 480.2 Route 1 84 ##STR00135## RT = 0.21
Min MH.sup.+ = 465 Route 2 85 ##STR00136## RT = 0.25 Min MH.sup.+ =
451.3 Route 4 86 ##STR00137## RT = 1.19 Min MH.sup.+ = 465.2 Route
4 87 ##STR00138## RT = 1.07 Min MH.sup.+ = 437.1 Route 4 88
##STR00139## RT = 1.04 Min MH.sup.+ = 423.2 Route 4 89 ##STR00140##
RT = 1.03 Min MH.sup.+ = 409.3 Route 4 90 ##STR00141## RT = 1.28
Min MH.sup.+ = 495.2 Route 2 91 ##STR00142## RT = 1.27 Min MH.sup.+
= 512.3 Route 2 92 ##STR00143## RT = 0.95 Min MH.sup.+ = 395.1
Route 4 93 ##STR00144## RT = 1.86 Min MH.sup.+ = 470.2 Route 2 94
##STR00145## RT = 1.74 Min MH.sup.+ = 499.1 Route 2 95 ##STR00146##
RT = 1.55 Min MH.sup.+ = 496.1 Route 2 96 ##STR00147## RT = 0.61
Min MH.sup.+ = 454.2 Route 2 97 ##STR00148## RT = 1.09 Min MH.sup.+
= 470.1 Route 2 98 ##STR00149## RT = 0.35 Min MH.sup.+ = 485.3
Route 2 99 ##STR00150## RT = 1.91 Min MH.sup.+ = 495.1 Route 2 100
##STR00151## RT = 1.38 Min MH.sup.+ = 495.1 Route 2 101
##STR00152## RT = 1.03 Min MH.sup.+ = 479.2 Route 4 102
##STR00153## RT = 1.60 Min MH.sup.+ = 522.1 Route 4 103
##STR00154## RT = 1.04 Min MH.sup.+ = 465.2 Route 2
Biological Evaluation
[0508] The utility of the compounds of the present invention can be
illustrated, for example, by their activity in vitro in the in
vitro tumor cell proliferation assay described below. The link
between activity in tumor cell proliferation assays in vitro and
anti-tumor activity in the clinical setting has been very well
established in the art. For example, the therapeutic utility of
taxol (Silvestrini et al. Stem Cells 1993, 11(6), 528-35), taxotere
(Bissery et al. Anti Cancer Drugs 1995, 6(3), 339), and
topoisomerase inhibitors (Edelman et al. Cancer Chemother.
Pharmacol. 1996, 37(5), 385-93) were demonstrated with the use of
in vitro tumor proliferation assays.
[0509] Demonstration of the activity of the compounds of the
present invention may be accomplished through in vitro, ex vivo,
and in vivo assays that are well known in the art. For example, to
demonstrate the activity of the compounds of the present invention,
the following assays may be used.
Biological Assays
[0510] The effects of the compounds of the present invention were
examined by the following assays.
[Determination of IC.sub.50 values of compounds in kinase assay of
PI3K.alpha.]
Chemicals and Assay Materials
[0511] Phosphatidylinositol (PtdIns) and phosphatidylserine
(PtdSer) were purchased from DOOSAN SERDARY RESEARCH LABORATORIES
(Toronto, Canada). Recombinant truncated forms (.DELTA.N 1-108) of
the human p110.alpha. and p110.alpha. subunits of PI3K with
N-terminal Hiss-Tags were expressed in S. frugiperda 9 insect
cells. Recombinant human PI3K.gamma. (full length human PI3K
p110.gamma. fused with a Hiss-tag at the C-terminus expressed in S.
frugiperda 9 insect cells) was obtained from ALEXIS BIOCHEMICALS
(#201-055-0010; San Diego, Calif.). [.gamma..sup.33P]ATP and
unlabeled ATP were purchased from AMERSHAM PHARMACIA BIOTECH
(Buckinghamshire, UK) and ROCHE DIAGNOSTICS (Mannheim, Germany),
respectively. Scintillation cocktails and MicroScint PS.TM. were
purchased from PACKARD (Meriden, Conn.). Maxisorp.TM. plates were
purchased from NALGE NUNC INTERNATIONAL K.K. (Tokyo, Japan). All
other chemicals not further specified were from WAKO PURE CHEMICALS
(Osaka, Japan).
Solid-Phase Lipid Kinase Assay
[0512] To assess inhibition of PI3K.alpha. by compounds, the
Maxisorp.TM. plates were coated with 50 .mu.L/well of a solution
containing 50 mg/ml PtdIns and 50 mg/ml PtdSer dissolved in
chloroform:ethanol (3:7). The plates were subsequently air-dried by
incubation for at least 2 hours in a fume hood. The reaction was
set up by mixing 25 mL/well of assay buffer 2.times. (100 mM
MOPSO/NaOH, 0.2 M NaCl, pH 7.0, 8 mM MgCl.sub.2, 2 mg/mL BSA (fatty
acid-free)), and 7.5 ng/well PI3K.alpha. in the lipid pre-coated
plate. 10.times. test compounds were added in 2% DMSO. The reaction
was started by adding 20 .mu.L/well of ATP mix (final 10 .mu.M ATP;
0.05 .mu.Ci/well [.gamma..sup.33P]ATP). After incubation at RT for
2 hours, the reaction was terminated by adding 50 .mu.l/well stop
solution (50 mM EDTA, pH 8.0). The plate was then washed twice with
Tris-buffered saline (TBS, pH 7.4). MicroScint PS.TM. (PACKARD)
scintillation mix was added at 100 .mu.L/well, and radioactivity
was counted using a TopCount.TM. (PACKARD) scintillation
counter.
[0513] The inhibition percent at each concentration of compound was
calculated, and IC.sub.50 values were determined from the
inhibition of curve.
[0514] The following compounds displayed an average IC.sub.50 of
less than 10 nanomolar in the p110.alpha. assay: Entries: 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 13, 16, 18, 19, 20, 22, 23, 27, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 42, 44, 45, 46, 51, 52,
54, 55, 58, 60, 63, 66, 68, 69, 71, 73, 74, 75, 76, 78, 83, 85, 87,
88, 89, 92, 94, 100, 101 and 103. The following compounds displayed
an average IC.sub.50 of between 10 nanomolar and 100 nanomolar in
this assay: Entries: 14, 15, 17, 21, 25, 26, 41, 43, 47, 49, 50,
53, 56, 57, 61, 62, 93 and 98. The following compounds displayed an
average IC.sub.50 of greater than 100 nanomolar in this assay:
Entries: 12, 24, 48 and 59.
[Isozyme Selectivity Test in PI3K]
Chemicals and Assay Materials
[0515] A recombinant truncated form (AN 1-108) of the human
p110.beta. subunit of PI3K with an N-terminal Hiss-Tag was
expressed in S. frugiperda 9 insect cells. Recombinant human
PI3K.gamma. (full length human PI3K p110.gamma. fused with a
Hiss-tag at the C-terminus expressed in S. frugiperda 9 insect
cells) was obtained from ALEXIS BIOCHEMICALS (#201-055-0010; San
Diego, Calif.).
Determination of IC.sub.50 Values of Compounds in Kinase Assays of
PI3K.beta. and PI3K.gamma.
[0516] Kinase assays using recombinant truncated p110.beta. or the
full length p110.gamma. were performed in a similar manner as
described in the part of [Determination of IC.sub.50 values of
compounds in kinase assay of PI3K.alpha.] except that these
isoforms were assayed using 7.5 ng and 25.0 ng of protein/well,
respectively.
[0517] The following compounds displayed an average IC.sub.50 of
less than 10 nanomolar in the p110.beta. assay: Entries: 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 13, 16, 18, 19, 20, 22, 23, 27, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 42, 44, 45, 46, 51, 52,
54, 55, 58, 60, 63, 66, 68, 69, 71, 73, 74, 75, 76, 78, 83, 85, 87,
88, 89, 92, 94, 100, 101 and 103. The following compounds displayed
an average IC.sub.50 of between 10 nanomolar and 100 nanomolar in
this assay: Entries: 14, 15, 17, 21, 25, 26, 41, 43, 47, 49, 50,
53, 56, 57, 61, 62, 93 and 98. The following compounds displayed an
average IC.sub.50 of greater than 100 nanomolar in this assay:
Entries: 12, 24, 48 and 59.
[Determination of IC.sub.50 Values of Compounds in Cell Based
Assays of PI3K.quadrature. Activity]
Chemicals and Assay Materials
[0518] 96-well collagen treated clear bottom/black sided Costar
plates were purchased from CORNING LIFE SCIENCES (Corning, N.Y.;
at.#3904). Gibco RPMI medium (Cat.#11875), Biosource
anti-phospho-AKT(Ser 473) antibody (Cat.#44-621G) and recombinant
IGF-1 (Cat.#PHG0074) were purchased from INVITROGEN (Carlsbad,
Calif.). The secondary donkey anti-rabbit IgG horse radish
peroxidase conjugate (Cat. #NA934V) and ECL chemiluminesence
reagent (Cat.#RPN2209) were purchased from AMERSHAM
(Buckinghamshire, UK). Cell culture tested bovine serum albumin
solution (35% in DPBS; Cat.#A7979) and all other chemicals were
purchased from SIGMA (St. Louis, Mo.). The Wallac Victor2 1420
Multilabel HTS Counter was purchased from PERKINELMER (Wellesley,
Mass.)
IGF-1 Induced AKT Phosphorylation Assay
[0519] To test inhibition of IGF-1 induced AKT phosphorylation by
compounds, A549 cells (5.times.10.sup.4 cells/well) were seeded in
100 .mu.L of 0.1% bovine serum albumin (BSA) in RPMI medium in
96-well collagen treated clear bottom/black sided plates and
incubated overnight at 37.degree. C. in a 5% CO.sub.2 incubator.
10.times. compound solution (in 0.1% BSA in RPMI) was added to the
plates and incubation at 37.degree. C. was continued for 1 hour.
All wells (except no IGF-1 controls) were then treated with 25
ng/ml IGF-1 for 10 minutes at 37.degree. C. in a 5% CO.sub.2
incubator. Following removal of the supernatants and washing with
the wells with TBS (50 mM Tris pH 8.0 containing 138 mM NaCL and 27
mM KCl), 200 .mu.L of 3.7% formaldehyde in TBS was added to each
well, and the plate was incubated at 4.degree. C. for 10 minutes.
Supernatants were once again removed and replaced with 50 .mu.L
Methanol (-20.degree. C.) and the plate incubated at 4.degree. C.
for 5 minutes. 200 .mu.L of 0.1% BSA in TBS was then added to each
well and the plate incubated at room temperature for 1/2 hour.
Supernatants were removed and 50 .mu.L of a solution comprising the
primary anti-phospho-AKT(Ser 473) antibody diluted 1:250 in TBS
containing 0.1% BSA was added to each well (except
control/background wells). The plate was then incubated for 11/2
hour at room temperature. Supernatants were removed, each well was
washed 3 times with 200 .mu.L TBS, and 100 .mu.L of a solution
containing the secondary donkey anti-rabbit IgG antibody
HRP-conjugate diluted 1:100 in TBS-T (TBS containing 0.1% triton).
Plates were then incubated for 1 hour at room temperature. After
removing the secondary antibody, each well was washed 6 times with
cold TBS-T, 100 .mu.L of ECL was added to each well, and the plate
was placed on an orbital shaker for 1 minute. The plates were then
read on a Wallac Victor2 1420 Multilabel HTS Counter using the
luminometry window (maximum light detection is measured at 428 nM).
1050 values were determined from the inhibition curve.
[0520] The following compounds displayed an average IC.sub.50 of
less than 100 nanomolar in the A549 cell assay: Entries: 2, 3, 6,
7, 8, 10, 11, 13, 16, 18, 19, 20, 21, 22, 23, 27, 28, 29, 31, 32,
33, 35, 37, 38, 39, 42, 46, 47, 52, 60, 63, 66, 68, 69, 70, 71, 74,
75, 76, 77, 83, 85, 90, 91, 94, 95, 99, 101 and 103. The following
compounds displayed an average IC.sub.50 of between 100 nanomolar
and 1000 nanomolar in this assay: Entries: 1, 4, 5, 9, 30, 34, 36,
40, 41, 45, 51, 54, 55, 57, 58, 61, 62, 64, 67, 72, 73, 78, 80, 82,
84, 86, 87, 88, 89, 93, 96, 97 and 100. The following compounds
displayed an average IC.sub.50 of greater than 1000 nanomolar in
this assay: Entries: 12, 14, 15, 24, 25, 26, 43, 44, 48, 50, 53,
56, 59, 65, 79, 81, 92 and 98.
Mouse
[0521] To evaluate the in vivo anti-tumor effect of PI3K
inhibitors, efficacy studies were conducted in the NCr athymic
female mice (Taconic, N.Y.). Human carcinoma cells of various
histological types were harvested from mid-log phase cultures using
Trypsin-EDTA (Gibco). Cells were pelleted, rinsed twice, and
resuspended in sterile HBSS (Hank's Balanced Salt Solution) to
final concentration of 2.5.times.106 cells/ml. Cells were implanted
subcutaneously (s.c.) in a 0.2 ml volume (5.times.106 cells) into
the right flank.
[0522] When tumors reached an average size of .about.100-125 mg,
the mice were randomized, and treatment initiated. Each
experimental group consisted of 10 mice and the dosing volume was
10 ml/kg body weight. Compounds were dissolved in a compatible
vehicle for both intravenous and oral administration. For
intravenous administration, mice are placed under a heat lamp to
warm for 5 minutes, then placed in a restraining device and the
tail vein injected with a sterile 27 gauge 1/2 inch needle. Oral
dosing utilizes sterile disposable feeding needles (20 gauge/11/2
inches) from Popper and Sons, New Hyde Park, N.Y. Tumor growth was
measured with electronic calipers 2-3 times a week and tumor weight
(mg) calculated according to the following formula: [length
(mm).times.width (mm)2]/2. Percent inhibition or tumor growth
inhibition (TGI) is calculated on days of measurement using the
following formula: (100-mean tumor value of treated (T)/mean tumor
of control value (C).times.100)=% T/C. Of note: the control used in
the calculations is either the "untreated control" or "vehicle",
whichever provides the most conservative representation of the
data.
Rat
[0523] To evaluate the in vivo anti-tumor effect of PI3K
inhibitors, efficacy studies were conducted in the HSD athymic
female rats (Harlan, Id.). Human carcinoma cells of various
histological types were harvested from mid-log phase cultures using
Trypsin-EDTA (Gibco). Cells were pelleted, rinsed twice, and
resuspended in sterile HBSS (Hank's Balanced Salt Solution) to
final concentration of 2.5.times.106 cells/ml. Cells were implanted
subcutaneously (s.c.) in a 0.2 ml volume (5.times.106 cells) into
the right flank. When tumors reached an average size of
.about.200-400 mg, the rats were randomized, and treatment
initiated. Each experimental group consisted of 10 nude rats.
Compounds were dissolved in a compatible vehicle for both
intravenous and oral administration. For intravenous administration
of compound, rats were warmed under a heating lamp for 5 minutes,
then placed in a restraining device, and injected intravenously via
the tail vein using a dosing volume ranging from 2 mL/kg to 5 mL/kg
with a sterile 25 gauge needle. Oral dosing utilizes sterile
disposable feeding needles (18 gauge/2 inch) from Popper and Sons,
New Hyde Park, N.Y. Tumor growth was measured with electronic
calipers 2-3 times a week and tumor weight (mg) calculated
according to the following formula: [length (mm).times.width
(mm)2]/2. Percent inhibition or tumor growth inhibition (TGI) is
calculated on days of measurement using the following formula:
(100-mean tumor value of treated (T)/mean tumor of control value
(C).times.100)=% T/C. Of note: the control used in the calculations
is either the "untreated control" or "vehicle", whichever provides
the most conservative representation of the data.
[0524] It is believed that one skilled in the art, using the
preceeding information and information available in the art, can
utilize the present invention to its fullest extent. Those skilled
in the art will recognize that the invention may be practiced with
variations on the disclosed structures, materials, compositions and
methods without departing from the spirit or scope of the invention
as it is set forth herein and such variations are regarded as
within the ambit of the invention. The compounds described in the
examples are intended to be representative of the invention, and it
will be understood that the scope of the invention is not limited
by the scope of the examples. The topic headings set forth above
are meant as guidance where certain information can be found in the
application, but are not intended to be the only source in the
application where information on such topics can be found. All
publications and patents cited above are incorporated herein by
reference.
REFERENCES
[0525] 1. Abbosh, P. H.; Nephew, K. P. Multiple signaling pathways
converge on b-catenin in thyroid cancer. Thyroid 2005, 15, 551-561.
[0526] 2. Ali, I. U.; Schriml, L. M.; Dean, M. Mutational spectra
of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase
activity. J. Natl. Cancer Inst. 1999, 91, 1922-1932. [0527] 3.
Bachman, K. E.; Argani, P.; Samuels, Y.; Silliman, N.; Ptak, J.;
Szabo, S.; Konishi, H.; Karakas, B.; Blair, B. G.; Lin, C.; Peters,
B. A.; Velculescu, V. E.; Park, B. H. The PIK3CA gene is mutated
with high frequency in human breast cancers. Cancer Biol. Therap.
2004, 3, 772-775. [0528] 4. Bader, A. G.; Kang, S.; Vogt, P. K.
Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc.
Natl. Acad. Sci. U.S.A. 2006, 103, 1475-1479. [0529] 5. Barthwal,
M. K.; Sathyanarayana, P.; Kundu, C. N.; Rana, B.; Pradeep, A.;
Sharma, C.; Woodgett, J. R.; Rana, A. Negative Regulation of Mixed
Lineage Kinase 3 by Protein Kinase B/AKT Leads to Cell Survival. J.
Biol. Chem. 2003, 278, 3897-3902. [0530] 6. Benistant, C.; Chapuis,
H.; Roche, S. A specific function for phosphatidylinositol 3-kinase
a (p85a-p110a) in cell survival and for phosphatidylinositol
3-kinase b (p85a-p110b) in de novo DNA synthesis of human colon
carcinoma cells. Oncogene 2000, 19, 5083-5090. [0531] 7. Broderick,
D. K.; Di, C.; Parrett, T. J.; Samuels, Y. R.; Cummins, J. M.;
McLendon, R. E.; Fults, D. W.; Velculescu, V. E.; Bigner, D. D.;
Yan, H. Mutations of PIK3CA in anaplastic oligodendrogliomas,
high-grade astrocytomas, and medulloblastomas. Cancer Res. 2004,
64, 5048-5050. [0532] 8. Brown, R. A.; Shepherd, P. R. Growth
factor regulation of the novel class II phosphoinositide 3-kinases.
Biochem. Soc. Trans. 2001, 29, 535-537. [0533] 9. Brunet, A.;
Bonni, A.; Zigmond, M. J.; Lin, M. Z.; Juo, P.; Hu, L. S.;
Anderson, M. J.; Arden, K. C.; Blenis, J.; Greenberg, M. E. Akt
promotes cell survival by phosphorylating and inhibiting a Forkhead
transcription factor. Cell 1999, 96, 857-868. [0534] 10. Byun,
D.-S.; Cho, K.; Ryu, B.-K.; Lee, M.-G.; Park, J.-I.; Chae, K.-S.;
Kim, H.-J.; Chi, S.-G. Frequent monoallelic deletion of PTEN and
its reciprocal association with PIK3CA amplification in gastric
carcinoma. Int. J. Cancer 2003, 104, 318-327. [0535] 11. Campbell,
I. G.; Russell, S. E.; Choong, D. Y. H.; Montgomery, K. G.;
Ciavarella, M. L.; Hooi, C. S. F.; Cristiano, B. E.; Pearson, R.
B.; Phillips, W. A. Mutation of the PIK3CA gene in ovarian and
breast cancer. Cancer Res. 2004, 64, 7678-7681. [0536] 12. Cardone,
M. H.; Roy, N.; Stennicke, H. R.; Salvesen, G. S.; Franke, T. F.;
Stanbridge, E.; Frisch, S.; Reed, J. C. Regulation of cell death
protease caspase-9 by phosphorylation. Science 1998, 282,
1318-1321. [0537] 13. Chen, Y. L.; Law, P.-Y.; Loh, H. H.
Inhibition of PI3K/Akt signaling: An emerging paradigm for targeted
cancer therapy. Curr. Med. Chem. Anticancer Agents 2005, 5,
575-589. [0538] 14. Ciechomska, I.; Pyrzynska, B.; Kazmierczak, P.;
Kaminska, B. Inhibition of Akt kinase signalling and activation of
Forkhead are indispensable for up-regulation of FasL expression in
apoptosis of glioma cells. Oncogene 2003, 22, 7617-7627. [0539] 15.
Cross, D. A. E.; Alessi, D. R.; Cohen, P.; Andjelkovich, M.;
Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin
mediated by protein kinase B. Nature 1995, 378, 785-9. [0540] 16.
Cully, M.; You, H.; Levine, A. J.; Mak, T. W. Beyond PTEN
mutations: the PI3K pathway as an integrator of multiple inputs
during tumorigenesis. Nat. Rev. Cancer 2006, 6, 184-192. [0541] 17.
Czauderna, F.; Fechtner, M.; Aygun, H.; Arnold, W.; Klippel, A.;
Giese, K.; Kaufmann, J. Functional studies of the PI(3)-kinase
signalling pathway employing synthetic and expressed siRNA. Nucleic
Acids Res. 2003, 31, 670-682. [0542] 18. del Peso, L.;
Gonzalez-Garcia, M.; Page, C.; Herrera, R.; Nunez, G.
Interleukin-3-induced phosphorylation of BAD through the protein
kinase Akt. Science 1997, 278, 687-689. [0543] 19. Diehl, J. A.;
Cheng, M.; Roussel, M. F.; Sherr, C. J. Glycogen synthase kinase-3b
regulates cyclin D1 proteolysis and subcellular localization. Genes
Dev. 1998, 12, 3499-3511. [0544] 20. Dijkers, P. F.; Medema, R. H.;
Lammers, J.-W. J.; Koenderman, L.; Coffer, P. J. Expression of the
pro-apoptotic Bcl-2 family member Bim is regulated by the Forkhead
transcription factor FKHR-L1. Curr. Biol. 2000, 10, 1201-1204.
[0545] 21. Domin, J.; Waterfield, M. D. Using structure to define
the function of phosphoinositide 3-kinase family members. FEBS
Lett. 1997, 410, 91-95. [0546] 22. Downes, C. P.; Gray, A.; Lucocq,
J. M. Probing phosphoinositide functions in signaling and membrane
trafficking. Trends Cell Biol. 2005, 15, 259-268. [0547] 23.
Figueroa, C.; Tarras, S.; Taylor, J.; Vojtek, A. B. Akt2 negatively
regulates assembly of the POSH-MLK-JNK signaling complex. J. Biol.
Chem. 2003, 278, 47922-47927. [0548] 24. Fleming, I. N.; Gray, A.;
Downes, C. P. Regulation of the Rac1-specific exchange factor tiam1
involves both phosphoinositide 3-kinase-dependent and -independent
components. Biochem. J. 2000, 351, 173-182. [0549] 25. Funaki, M.;
Katagiri, H.; Inukai, K.; Kikuchi, M.; Asano, T. Structure and
function of phosphatidylinositol-3,4 kinase. Cell. Signal. 2000,
12, 135-142. [0550] 26. Gallia, G. L.; Rand, V.; Siu, I. M.;
Eberhart, C. G.; James, C. D.; Marie, S. K. N.; Oba-Shinjo, S. M.;
Carlotti, C. G.; Caballero, O. L.; Simpson, A. J. G.; Brock, M. V.;
Massion, P. P.; Carson, B. S., Sr.; Riggins, G. J. PIK3CA gene
mutations in pediatric and adult glioblastoma multiforme. Mol.
Cancer. Res. 2006, 4, 709-714. [0551] 27. Gershtein, E. S.;
Shatskaya, V. A.; Ermilova, V. D.; Kushlinsky, N. E.; Krasil'nikov,
M. A. Phosphatidylinositol 3-kinase expression in human breast
cancer. Clin. Chim. Acta 1999, 287, 59-67. [0552] 28. Gottschalk,
A. R.; Doan, A.; Nakamura, J. L.; Stokoe, D.; Haas-Kogan, D. A.
Inhibition of phosphatidylinositol-3-kinase causes increased
sensitivity to radiation through a PKB-dependent mechanism. Int. J.
Radiat. Oncol. Biol. Phys. 2005, 63, 1221-1227. [0553] 29. Gupta,
A. K.; Cerniglia, G. J.; Mick, R.; Ahmed, M. S.; Bakanauskas, V.
J.; Muschel, R. J.; McKenna, W. G. Radiation sensitization of human
cancer cells in vivo by inhibiting the activity of PI3K using
LY294002. Int. J. Radiat. Oncol. Biol. Phys. 2003, 56, 846-853.
[0554] 30. Haas-Kogan, D.; Shalev, N.; Wong, M.; Mills, G.; Yount,
G.; Stokoe, D. Protein kinase B (PKB/Akt) activity is elevated in
glioblastoma cells due to mutation of the tumor suppressor
PTEN/MMAC. Curr. Biol. 1998, 8, 1195-1198. [0555] 31. Hartmann, C.;
Bartels, G.; Gehlhaar, C.; Holtkamp, N.; von Deimling, A. PIK3CA
mutations in glioblastoma multiforme. Acta Neuropathol. 2005, 109,
639-642. [0556] 32. Hennessy, B. T.; Smith, D. L.; Ram, P. T.; Lu,
Y.; Mills, G. B. Exploiting the PI3K/AKT Pathway for Cancer Drug
Discovery. Nat. Rev. Drug Disc. 2005, 4, 988-1004. [0557] 33.
Hodgkinson, C. P.; Sale, E. M.; Sale, G. J. Characterization of
PDK2 activity against Protein Kinase B gamma. Biochemistry 2002,
41, 10351-10359. [0558] 34. Hresko, R. C.; Murata, H.; Mueckler, M.
Phosphoinositide-dependent Kinase-2 is a distinct protein kinase
enriched in a novel cytoskeletal fraction associated with adipocyte
plasma membranes. J. Biol. Chem. 2003, 278, 21615-21622. [0559] 35.
Huang, C.; Ma, W.-Y.; Dong, Z. Requirement for phosphatidylinositol
3-kinase in epidermal growth factor-induced AP-1 transactivation
and transformation in JB6 P+ cells. Mol. Cell. Biol. 1996, 16,
6427-6435. [0560] 36. Hupp, T. R.; Lane, D. P.; Ball, K. L.
Strategies for manipulating the p53 pathway in the treatment of
human cancer. Biochem. J. 2000, 352, 1-17. [0561] 37. Ihle, N. T.;
Williams, R.; Chow, S.; Chew, W.; Berggren, M. I.; Paine-Murrieta,
G.; Minion, D. J.; Halter, R. J.; Wipf, P.; Abraham, R.;
Kirkpatrick, L.; Powis, G. Molecular pharmacology and antitumor
activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase
signaling. Mol. Cancer. Therap. 2004, 3, 763-772. [0562] 38.
Ikenoue, T.; Kanai, F.; Hikiba, Y.; Obata, T.; Tanaka, Y.; Imamura,
J.; Ohta, M.; Jazag, A.; Guleng, B.; Tateishi, K.; Asaoka, Y.;
Matsumura, M.; Kawabe, T.; Omata, M. Functional analysis of PIK3CA
gene mutations in human colorectal cancer. Cancer Res. 2005, 65,
4562-4567. [0563] 39. Ishii, N.; Maier, D.; Merlo, A.; Tada, M.;
Sawamura, Y.; Diserens, A.-C.; Van Meir, E. G. Frequent
co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor
genes in human glioma cell lines. Brain Pathol. 1999, 9, 469-479.
[0564] 40. Itoh, T.; Takenawa, T. Phosphoinositide-binding domains.
Functional units for temporal and spatial regulation of
intracellular signalling. Cell. Signal. 2002, 14, 733-743. [0565]
41. Janssen, J. W. G.; Schleithoff, L.; Bartram, C. R.; Schulz, A.
S. An oncogenic fusion product of the phosphatidylinositol 3-kinase
p85b subunit and HUMORF8, a putative deubiquitinating enzyme.
Oncogene 1998, 16, 1767-1772. [0566] 42. Jimenez, C.; Jones, D. R.;
Rodriguez-Viciana, P.; Gonzalez-Garcia, A.; Leonardo, E.;
Wennstrom, S.; Von Kobbe, C.; Toran, J. L.; R.-Borlado, L.; Calvo,
V.; Copin, S. G.; Albar, J. P.; Gaspar, M. L.; Diez, E.; Marcos, M.
A. R.; Downward, J.; Martinez-A, C.; Merida, I.; Carrera, A. C.
Identification and characterization of a new oncogene derived from
the regulatory subunit of phosphoinositide 3-kinase. EMBO J. 1998,
17, 743-753. [0567] 43. Jucker, M.; Sudel, K.; Horn, S.; Sickel,
M.; Wegner, W.; Fiedler, W.; Feldman, R. A. Expression of a mutated
form of the p85a regulatory subunit of phosphatidylinositol
3-kinase in a Hodgkin's lymphoma-derived cell line (CO). Leukemia
2002, 16, 894-901. [0568] 44. Kang, S.; Bader, A. G.; Vogt, P. K.
Phosphatidylinositol 3-kinase mutations identified in human cancer
are oncogenic. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 802-807.
[0569] 45. Kang, S.; Denley, A.; Vanhaesebroeck, B.; Vogt, P. K.
Oncogenic transformation induced by the p110b, -g, and -d isoforms
of class I phosphoinositide 3-kinase. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 1289-1294. [0570] 46. Katso, R.; Okkenhaug, K.; Ahmadi,
K.; White, S.; Timms, J.; Waterfield, M. D. Cellular function of
phosphoinositide 3-kinases: implications for development, immunity,
homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 2001, 17,
615-675. [0571] 47. Kim, A. H.; Khursigara, G.; Sun, X.; Franke, T.
F.; Chao, M. V. Akt phosphorylates and negatively regulates
apoptosis signal-regulating kinase 1. Mol. Cell. Biol. 2001, 21,
893-901. [0572] 48. Kim, D.; Dan, H. C.; Park, S.; Yang, L.; Liu,
Q.; Kaneko, S.; Ning, J.; He, L.; Yang, H.; Sun, M.; Nicosia, S.
V.; Cheng, J. Q. AKT/PKB signaling mechanisms in cancer and
chemoresistance. Front. Biosci. 2005, 10, 975-987. [0573] 49.
Klippel, A.; Kavanaugh, W. M.; Pot, D.; Williams, L. T. A specific
product of phosphatidylinositol 3-kinase directly activates the
protein kinase Akt through its pleckstrin homology domain. Mol.
Cell. Biol. 1997, 17, 338-44. [0574] 50. Kodaki, T.; Woscholski,
R.; Hallberg, B.; Rodriguez-Viciana, P.; Downward, J.; Parker, P.
J. The activation of phosphatidylinositol 3-kinase by Ras. Curr.
Biol. 1994, 4, 798-806. [0575] 51. Kops, G. J. P. L.; De Ruiter, N.
D.; De Vries-Smits, A. M. M.; Powell, D. R.; Bos, J. L.; Burgering,
B. M. T. Direct control of the Forkhead transcription factor AFX by
protein kinase B. Nature 1999, 398, 630-634. [0576] 52. Lee, J. T.,
Jr.; Steelman, L. S.; McCubrey, J. A. Phosphatidylinositol
3'-Kinase Activation Leads to Multidrug Resistance Protein-1
Expression and Subsequent Chemoresistance in Advanced Prostate
Cancer Cells. Cancer Res. 2004, 64, 8397-8404. [0577] 53. Lee, J.
W.; Soung, Y. H.; Kim, S. Y.; Lee, H. W.; Park, W. S.; Nam, S. W.;
Kim, S. H.; Lee, J. Y.; Yoo, N. J.; Lee, S. H. PIK3CA gene is
frequently mutated in breast carcinomas and hepatocellular
carcinomas. Oncogene 2005, 24, 1477-1480. [0578] 54. Lemmon, M. A.
Phosphoinositide recognition domains. Traffic 2003, 4, 201-213.
[0579] 55. Levine, D. A.; Bogomolniy, F.; Yee, C. J.; Lash, A.;
Barakat, R. R.; Borgen, P. I.; Boyd, J. Frequent Mutation of the
PIK3CA Gene in Ovarian and Breast Cancers. Clin. Cancer Res. 2005,
11, 2875-2878. [0580] 56. Li, J.; Yen, C.; Liaw, D.; Podsypanina,
K.; Bose, S.; Wang, S. I.; Puc, J.; Miliaresis, C.; Rodgers, L.;
McCombie, R.; Bigner, S. H.; Giovanella, B. C.; Ittmann, M.; Tycko,
B.; Hibshoosh, H.; Wigler, M. H.; Parsons, R. PTEN, a putative
protein tyrosine phosphatase gene mutated in human brain, breast,
and prostate cancer. Science 1997, 275, 1943-1947. [0581] 57. Li,
V. S. W.; Wong, C. W.; Chan, T. L.; Chan, A. S. W.; Zhao, W.; Chu,
K.-M.; So, S.; Chen, X.; Yuen, S. T.; Leung, S. Y. Mutations of
PIK3CA in gastric adenocarcinoma. BMC Cancer 2005, 5, 29. [0582]
58. Liao, Y.; Hung, M.-C. Regulation of the activity of p38
mitogen-activated protein kinase by Akt in cancer and adenoviral
protein E1A-mediated sensitization to apoptosis. Mol. Cell. Biol.
2003, 23, 6836-6848. [0583] 59. Lopez-Ilasaca, M.; Li, W.; Uren,
A.; Yu, J.-c.; Kazlauskas, A.; Gutkind, J. S.; Heidaran, M. A.
Requirement of phosphatidylinositol-3 kinase for activation of
JNK/SAPKs by PDGF. Biochem. Biophys. Res. Commun. 1997, 232,
273-277. [0584] 60. Ma, Y.-Y.; Wei, S.-J.; Lin, Y.-C.; Lung, J.-C.;
Chang, T.-C.; Whang-Peng, J.; Liu, J. M.; Yang, D.-M.; Yang, W. K.;
Shen, C.-Y. PIK3CA as an oncogene in cervical cancer. Oncogene
2000, 19, 2739-2744. [0585] 61. Mayo, L. D.; Dixon, J. E.; Durden,
D. L.; Tonks, N. K.; Donner, D. B. PTEN protects p53 from Mdm2 and
sensitizes cancer cells to chemotherapy. J. Biol. Chem. 2002, 277,
5484-5489. [0586] 62. Momand, J.; Wu, H.-H.; Dasgupta, G.
MDM2--master regulator of the p53 tumor suppressor protein. Gene
2000, 242, 15-29. [0587] 63. Motti, M. L.; De Marco, C.; Califano,
D.; Fusco, A.; Viglietto, G. Akt-dependent T198 phosphorylation of
cyclin-dependent kinase inhibitor p27kip1 in breast cancer. Cell
Cycle 2004, 3, 1074-1080. [0588] 64. Myers, M. P.; Pass, I.; Batty,
I. H.; Van Der Kaay, J.; Stolarov, J. P.; Hemmings, B. A.; Wigler,
M. H.; Downes, C. P.; Tonks, N. K. The lipid phosphatase activity
of PTEN is critical for its tumor suppressor function. Proc. Natl.
Acad. Sci. U.S.A. 1998, 95, 13513-13518. [0589] 65. Nagata, Y.;
Lan, K.-H.; Zhou, X.; Tan, M.; Esteva, F. J.; Sahin, A. A.; Klos,
K. S.; Li, P.; Monia, B. P.; Nguyen, N. T.; Hortobagyi, G. N.;
Hung, M.-C.; Yu, D. PTEN activation contributes to tumor inhibition
by trastuzumab, and loss of PTEN predicts trastuzumab resistance in
patients. Cancer Cell 2004, 6, 117-127. [0590] 66. Naito, A. T.;
Akazawa, H.; Takano, H.; Minamino, T.; Nagai, T.; Aburatani, H.;
Komuro, I. Phosphatidylinositol 3-Kinase-Akt Pathway Plays a
Critical Role in Early Cardiomyogenesis by Regulating Canonical Wnt
Signaling. Circ. Res. 2005, 97, 144-151. [0591] 67. Oda, K.;
Stokoe, D.; Taketani, Y.; McCormick, F. High Frequency of
Coexistent Mutations of PIK3CA and PTEN Genes in Endometrial
Carcinoma. Cancer Res. 2005, 65, 10669-10673.
[0592] 68. Ogawara, Y.; Kishishita, S.; Obata, T.; Isazawa, Y.;
Suzuki, T.; Tanaka, K.; Masuyama, N.; Gotoh, Y. Akt enhances
Mdm2-mediated ubiquitination and degradation of p53. J. Biol. Chem.
2002, 277, 21843-21850. [0593] 69. Olson, J. M.; Hallahan, A. R.
p38 MAP kinase: a convergence point in cancer therapy. Trends Mol.
Med. 2004, 10, 125-129. [0594] 70. Osaki, M.; Oshimura, M.; Ito, H.
PI3K-Akt pathway: Its functions and alterations in human cancer.
Apoptosis 2004, 9, 667-676. [0595] 71. Pastorino, J. G.; Tafani,
M.; Farber, J. L. Tumor necrosis factor induces phosphorylation and
translocation of BAD through a phosphatidylinositide-3-OH
kinase-dependent pathway. J. Biol. Chem. 1999, 274, 19411-19416.
[0596] 72. Pendaries, C.; Tronchere, H.; Plantavid, M.; Payrastre,
B. Phosphoinositide signaling disorders in human diseases. FEBS
Lett. 2003, 546, 25-31. [0597] 73. Phillips, W. A.; St. Clair, F.;
Munday, A. D.; Thomas, R. J. S.; Mitchell, C. A. Increased levels
of phosphatidylinositol 3-kinase activity in colorectal tumors.
Cancer 1998, 83, 41-47. [0598] 74. Philp, A. J.; Campbell, I. G.;
Leet, C.; Vincan, E.; Rockman, S. P.; Whitehead, R. H.; Thomas, R.
J. S.; Phillips, W. A. The phosphatidylinositol 3'-kinase p85a gene
is an oncogene in human ovarian and colon tumors. Cancer Res. 2001,
61, 7426-7429. [0599] 75. Powis, G.; Bonjouklian, R.; Berggren, M.
M.; Gallegos, A.; Abraham, R.; Ashendel, C.; Zalkow, L.; Matter, W.
F.; Dodge, J. Wortmannin, a potent and selective inhibitor of
phosphatidylinositol-3-kinase. Cancer Res. 1994, 54, 2419-23.
[0600] 76. Pu, P.; Kang, C.; Zhang, Z.; Liu, X.; Jiang, H.
Downregulation of PIK3CB by siRNA suppresses malignant glioma cell
growth in vitro and in vivo. Technol. Cancer Res. Treat. 2006, 5,
271-280. [0601] 77. Rahimi, N.; Tremblay, E.; Elliott, B.
Phosphatidylinositol 3-kinase activity is required for hepatocyte
growth factor-induced mitogenic signals in epithelial cells. J.
Biol. Chem. 1996, 271, 24850-24855. [0602] 78. Roche, S.; Downward,
J.; Raynal, P.; Courtneidge, S. A. A function for
phosphatidylinositol 3-kinase b (p85a-p110b) in fibroblasts during
mitogenesis: requirement for insulin- and lysophosphatidic
acid-mediated signal transduction. Mol. Cell. Biol. 1998, 18,
7119-7129. [0603] 79. Roche, S.; Koegl, M.; Courtneidge, S. A. The
phosphatidylinositol 3-kinase a is required for DNA synthesis
induced by some, but not all, growth factors. Proc. Natl. Acad.
Sci. U.S.A. 1994, 91, 9185-9. [0604] 80. Romashkova, J. A.;
Makarov, S. S, Nf-kB is a target of Akt in anti-apoptotic PDGF
signalling. Nature 1999, 401, 86-90. [0605] 81. Saal, L. H.; Holm,
K.; Maurer, M.; Memeo, L.; Su, T.; Wang, X.; Yu, J. S.; Malmstroem,
P.-O.; Mansukhani, M.; Enoksson, J.; Hibshoosh, H.; Borg, A.;
Parsons, R. PIK3CA mutations correlate with hormone receptors, node
metastasis, and ERBB2, and are mutually exclusive with PTEN loss in
human breast carcinoma. Cancer Res. 2005, 65, 2554-2559. [0606] 82.
Samuels, Y.; Diaz, L. A., Jr.; Schmidt-Kittler, O.; Cummins, J. M.;
DeLong, L.; Cheong, I.; Rago, C.; Huso, D. L.; Lengauer, C.;
Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. Mutant PIK3CA
promotes cell growth and invasion of human cancer cells. Cancer
Cell 2005, 7, 561-573. [0607] 83. Samuels, Y.; Ericson, K.
Oncogenic PI3K and its role in cancer. Curr. Opin. Oncol. 2006, 18,
77-82. [0608] 84. Samuels, Y.; Wang, Z.; Bardelli, A.; Silliman,
N.; Ptak, J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, S. M.;
Riggins, G. J.; Willson, J. K. V.; Markowitz, S.; Kinzler, K. W.;
Vogelstein, B.; Velculescu, V. E. Brevia: High frequency of
mutations of the PIK3Ca gene in human cancers. Science 2004, 304,
554. [0609] 85. Scheid, M. P.; Marignani, P. A.; Woodgett, J. R.
Multiple phosphoinositide 3-kinase-dependent steps in activation of
protein kinase B. Mol. Cell. Biol. 2002, 22, 6247-6260. [0610] 86.
Schultz, R. M.; Merriman, R. L.; Andis, S. L.; Bonjouklian, R.;
Grindey, G. B.; Rutherford, P. G.; Gallegos, A.; Massey, K.; Powis,
G. In vitro and in vivo antitumor activity of the
phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer
Res. 1995, 15, 1135-9. [0611] 87. Segrelles, C.; Moral, M.; Lara,
M. F.; Ruiz, S.; Santos, M.; Leis, H.; Garcia-Escudero, R.;
Martinez-Cruz, A. B.; Martinez-Palacio, J.; Hernandez, P.;
Ballestin, C.; Paramio, J. M. Molecular determinants of Akt-induced
keratinocyte transformation. Oncogene 2006, 25, 1174-1185. [0612]
88. Sekimoto, T.; Fukumoto, M.; Yoneda, Y. 14-3-3 suppresses the
nuclear localization of threonine 157-phosphorylated p27Kip1. EMBO
J. 2004, 23, 1934-1942. [0613] 89. Semba, S.; Itoh, N.; Ito, M.;
Youssef, E. M.; Harada, M.; Moriya, T.; Kimura, W.; Yamakawa, M.
Down-regulation of PIK3CG catalytic subunit of phosphatidylinositol
3-OH kinase by CpG hypermethylation in human colorectal carcinoma.
Clin. Cancer Res. 2002, 8, 3824-3831. [0614] 90. Shayesteh, L.; Lu,
Y.; Kuo, W.-L.; Baldocchi, R.; Godfrey, T.; Collins, C.; Pinkel,
D.; Powell, B.; Mills, G. B.; Gray, J. W. PIK3CA is implicated as
an oncogene in ovarian cancer. Nat. Genet. 1999, 21, 99-102. [0615]
91. Shekar, S. C.; Wu, H.; Fu, Z.; Yip, S.-C.; Nagajyothi; Cahill,
S. M.; Girvin, M. E.; Backer, J. M. Mechanism of Constitutive
Phosphoinositide 3-Kinase Activation by Oncogenic Mutants of the
p85 Regulatory Subunit. J. Biol. Chem. 2005, 280, 27850-27855.
[0616] 92. Stahl, J. M.; Cheung, M.; Sharma, A.; Trivedi, N. R.;
Shanmugam, S.; Robertson, G. P. Loss of PTEN Promotes Tumor
Development in Malignant Melanoma. Cancer Res. 2003, 63, 2881-2890.
[0617] 93. Stambolic, V.; Suzuki, A.; De La Pompa, J. L.; Brothers,
G. M.; Mirtsos, C.; Sasaki, T.; Ruland, J.; Penninger, J. M.;
Siderovski, D. P.; Mak, T. W. Negative regulation of
PKB/Akt-Dependent cell survival by the tumor suppressor PTEN. Cell
1998, 95, 29-39. [0618] 94. Stauffer, F.; Holzer, P.;
Garcia-Echeverria, C. Blocking the PI3K/PKB pathway in tumor cells.
Curr. Med. Chem. Anticancer Agents 2005, 5, 449-462. [0619] 95.
Steck, P. A.; Pershouse, M. A.; Jasser, S. A.; Yung, W. K. A.; Lin,
H.; Ligon, A. H.; Langford, L. A.; Baumgard, M. L.; Hattier, T.;
Davis, T.; Frye, C.; Hu, R.; Swedlund, B.; Teng, D. H. F.;
Tavtigian, S. V. Identification of a candidate tumor suppressor
gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple
advanced cancers. Nat. Genet. 1997, 15, 356-362. [0620] 96. Stein,
R. C.; Waterfield, M. D. P13-kinase inhibition: a target for drug
development? Mol. Med. Today 2000, 6, 347-358. [0621] 97. Stephens,
L.; Williams, R.; Hawkins, P. Phosphoinositide 3-kinases as drug
targets in cancer. Curr. Opin. Pharmacol. 2005, 5, 357-365. [0622]
98. Su, J. D.; Mayo, L. D.; Donner, D. B.; Durden, D. L. PTEN and
Phosphatidylinositol 3'-Kinase Inhibitors Up-Regulate p53 and Block
Tumor-induced Angiogenesis: Evidence for an Effect on the Tumor and
Endothelial Compartment. Cancer Res. 2003, 63, 3585-3592. [0623]
99. Tanaka, M.; Grossman, H. B. In vivo gene therapy of human
bladder cancer with PTEN suppresses tumor growth, downregulates
phosphorylated Akt, and increases sensitivity to doxorubicin. Gene
Ther. 2003, 10, 1636-1642. [0624] 100. Tang, E. D.; Nunez, G.;
Barr, F. G.; Guan, K.-L. Negative regulation of the forkhead
transcription factor FKHR by Akt. J. Biol. Chem. 1999, 274,
16741-16746. [0625] 101. Taylor, V.; Wong, M.; Brandts, C.; Reilly,
L.; Dean, N. M.; Cowsert, L. M.; Moodie, S.; Stokoe, D. 5'
Phospholipid phosphatase SHIP-2 causes protein kinase B
inactivation and cell cycle arrest in glioblastoma cells. Mol.
Cell. Biol. 2000, 20, 6860-6871. [0626] 102. Toker, A.
Phosphoinositides and signal transduction. Cell. Mol. Life. Sci.
2002, 59, 761-779. [0627] 103. Traer, C. J.; Foster, F. M.;
Abraham, S. M.; Fry, M. J. Are class II phosphoinositide 3-kinases
potential targets for anticancer therapies? Bull. Cancer (Paris).
2006, 93, E53-8. [0628] 104. Vanhaesebroeck, B.; Leevers, S. J.;
Ahmadi, K.; Timms, J.; Katso, R.; Driscoll, P. C.; Woscholski, R.;
Parker, P. J.; Waterfield, M. D. Synthesis and function of
3-phosphorylated inositol lipids. Annu. Rev. Biochem. 2001, 70,
535-602. [0629] 105. Vanhaesebroeck, B.; Waterfield, M. D.
Signaling by Distinct Classes of Phosphoinositide 3-Kinases. Exp.
Cell Res. 1999, 253, 239-254.
[0630] 106. Vivanco, I.; Sawyers, C. L. The phosphatidylinositol
3-Kinase-AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2,
489-501.
[0631] 107. Wang, Y.; Helland, A.; Holm, R.; Kristensen Gunnar, B.;
Borresen-Dale, A.-L. PIK3CA mutations in advanced ovarian
carcinomas. Hum. Mutat. 2005, 25, 322. [0632] 108. West, K. A.;
Castillo, S. S.; Dennis, P. A. Activation of the PI3K/Akt pathway
and chemotherapeutic resistance. Drug Resist. Update. 2002, 5,
234-48. [0633] 109. Whyte, D. B.; Holbeck, S. L. Correlation of
PIK3Ca mutations with gene expression and drug sensitivity in
NCI-60 cell lines. Biochem. Biophys. Res. Commun. 2006, 340,
469-475. [0634] 110. Wilker, E.; Lu, J.; Rho, O.; Carbajal, S.;
Beltran, L.; DiGiovanni, J. Role of PI3K/Akt signaling in
insulin-like growth factor-1 (IGF-1) skin tumor promotion. Mol.
Carcinog. 2005, 44, 137-145. [0635] 111. Workman, P. Inhibiting the
phosphoinositide 3-kinase pathway for cancer treatment. Biochem.
Soc. Trans. 2004, 32, 393-396. [0636] 112. Wu, G.; Xing, M.; Mambo,
E.; Huang, X.; Liu, J.; Guo, Z.; Chatterjee, A.; Goldenberg, D.;
Gollin, S. M.; Sukumar, S.; Trink, B.; Sidransky, D. Somatic
mutation and gain of copy number of PIK3CA in human breast cancer.
Breast Cancer Res. 2005, 7, R609-R616. [0637] 113. Wymann, M. P.;
Sozzani, S.; Altruda, F.; Mantovani, A.; Hirsch, E. Lipids on the
move: phosphoinositide 3-kinases in leukocyte function. Immunol.
Today 2000, 21, 260-264. [0638] 114. Yap, D. B.; Hsieh, J. K.; Lu,
X. Mdm2 inhibits the apoptotic function of p53 mainly by targeting
it for degradation. J. Biol. Chem. 2000, 275, 37296-302. [0639]
115. Yuan, Z.-q.; Feldman, R. I.; Sussman, G. E.; Coppola, D.;
Nicosia, S. V.; Cheng, J. Q. AKT2 Inhibition of Cisplatin-induced
JNK/p38 and Bax Activation by Phosphorylation of ASK1: Implication
of AKT2 in Chemoresistance. J. Biol. Chem. 2003, 278, 23432-23440.
[0640] 116. Zhao, H.; Dupont, J.; Yakar, S.; Karas, M.; LeRoith, D.
PTEN inhibits cell proliferation and induces apoptosis by
downregulating cell surface IGF-IR expression in prostate cancer
cells. Oncogene 2004, 23, 786-794. [0641] 117. Zhao, J. J.; Cheng,
H.; Jia, S.; Wang, L.; Gjoerup, O. V.; Mikami, A.; Roberts, T. M.
The p110a isoform of PI3K is essential for proper growth factor
signaling and oncogenic transformation. Proc. Natl. Acad. Sci.
U.S.A. 2006, 103, 16296-300. [0642] 118. Zhou, B. P.; Liao, Y.;
Xia, W.; Spohn, B.; Lee, M.-H.; Hung, M.-C. Cytoplasmic
localization of p21 Cip1/WAF1 by Akt-induced phosphorylation in
HER-2/neu-overexpressing cells. Nat. Cell Biol. 2001, 3,
245-252.
* * * * *