U.S. patent application number 12/824702 was filed with the patent office on 2010-10-14 for quinazolinone t-type calcium channel antagonists.
This patent application is currently assigned to Merck. Invention is credited to James C. Barrow, Rowena V. Cube, Phung Le Ngo, Kenneth E. Rittle, Zhiqiang Yang, Steven D. Young.
Application Number | 20100261741 12/824702 |
Document ID | / |
Family ID | 36992208 |
Filed Date | 2010-10-14 |
United States Patent
Application |
20100261741 |
Kind Code |
A1 |
Barrow; James C. ; et
al. |
October 14, 2010 |
Quinazolinone T-Type Calcium Channel Antagonists
Abstract
The present invention is directed to quinazolinone compounds
which are antagonists of T-type calcium channels, and which are
useful in the treatment or prevention of disorders and diseases in
which T-type calcium channels are involved. The invention is also
directed to pharmaceutical compositions comprising these compounds
and the use of these compounds and compositions in the prevention
or treatment of such diseases in which T-type calcium channels are
involved.
Inventors: |
Barrow; James C.;
(Harleysville, PA) ; Cube; Rowena V.;
(Harleysville, PA) ; Ngo; Phung Le; (Lansdale,
PA) ; Rittle; Kenneth E.; (Green Lane, PA) ;
Yang; Zhiqiang; (Harleysville, PA) ; Young; Steven
D.; (Harleysville, PA) |
Correspondence
Address: |
MERCK
P O BOX 2000
RAHWAY
NJ
07065-0907
US
|
Assignee: |
Merck
Rahway
NJ
|
Family ID: |
36992208 |
Appl. No.: |
12/824702 |
Filed: |
June 28, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11886053 |
Sep 7, 2007 |
7745452 |
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PCT/US2006/008177 |
Mar 8, 2006 |
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12824702 |
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60659954 |
Mar 9, 2005 |
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Current U.S.
Class: |
514/266.31 ;
514/266.3; 544/286 |
Current CPC
Class: |
A61P 25/02 20180101;
A61P 25/20 20180101; A61P 29/00 20180101; A61P 25/22 20180101; A61P
25/14 20180101; A61P 43/00 20180101; A61P 25/24 20180101; A61P
25/04 20180101; A61P 25/18 20180101; A61P 25/16 20180101; C07D
401/06 20130101; A61P 25/08 20180101; C07D 239/82 20130101; A61P
25/00 20180101; A61P 25/28 20180101; A61P 25/30 20180101; C07D
405/06 20130101 |
Class at
Publication: |
514/266.31 ;
544/286; 514/266.3 |
International
Class: |
A61K 31/517 20060101
A61K031/517; C07D 239/82 20060101 C07D239/82; A61P 25/08 20060101
A61P025/08; A61P 25/16 20060101 A61P025/16; A61P 25/18 20060101
A61P025/18; A61P 25/22 20060101 A61P025/22; A61P 25/24 20060101
A61P025/24; A61P 25/30 20060101 A61P025/30; C07D 239/80 20060101
C07D239/80 |
Claims
1-29. (canceled)
30. A compound of the formula I: ##STR00099## wherein: X.sup.1,
X.sup.2 and X.sup.3 are independently selected from the group
consisting of: (1) hydrogen, (2) fluoro, (3) chloro, and (4) bromo;
R.sup.1 is phenyl, C.sub.1-6alkyl, or C.sub.3-6cycloalkyl, which is
unsubstituted or substituted with a substituent selected from the
group consisting of: (1) halogen, (2) C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl or phenyl, (3)
--OC.sub.1-6alkyl, which is unsubstituted or substituted with
halogen, hydroxyl or phenyl, (4) --CN, (5) --NR.sup.5R.sup.6,
wherein R.sup.5 and R.sup.6 are independently selected from
hydrogen, C.sub.1-6alkyl and C.sub.1-6alkyl-phenyl, and (6)
--S(O).sub.nC.sub.1-6alkyl, wherein n is 0, 1 or 2; R.sup.2 is
C.sub.1-6alkyl, C.sub.3-6cycloalkyl, phenyl, C.sub.2-6alkenyl, or
C.sub.2-6alkynyl, which is unsubstituted or substituted with one or
more substituents selected from the group consisting of: (1)
fluoro, (2) chloro, (3) --OC.sub.1-6alkyl, which is unsubstituted
or substituted with halogen, hydroxyl or phenyl, (4)
--S(O).sub.nC.sub.1-6alkyl, (5) --OH, (6) .dbd.O, (7) --CHO, (8)
--CO.sub.2--C.sub.1-6alkyl, (9) C.sub.3-6cycloalkyl, (10) dioxanyl,
and (11) phenyl, which is unsubstituted or substituted with
halogen, hydroxyl, C.sub.1-6alkyl or --O--C.sub.1-6alkyl; R.sup.3
is C.sub.1-6alkyl which is substituted with one or more fluoro, and
which is optionally substituted with an additional substituent
selected from the group consisting of: (1) C.sub.1-6alkyl, (2)
C.sub.3-6cycloalkyl, (3) phenyl, and (4) pyridyl; or a
pharmaceutically acceptable salt thereof.
31. The compound of claim 30 wherein X.sup.1 is selected from the
group consisting of: (1) fluoro, (2) chloro, and (3) bromo; X.sup.2
is selected from the group consisting of: (1) fluoro, (2) chloro,
and X.sup.3 is hydrogen.
32. The compound of claim 30 wherein R.sup.1 is phenyl or
cyclopropyl, which is unsubstituted or substituted with a
substituent selected from the group consisting of: (1) fluoro, (2)
chloro, (3) CH.sub.3, (4) CF.sub.3, (5) OCF.sub.3, (6) OCH.sub.3,
and (7) --N(CH.sub.3).sub.2.
33. The compound of claim 32 wherein R.sup.1 is cyclopropyl.
34. The compound of claim 32 wherein R.sup.1 is phenyl.
35. The compound of claim 32 wherein R.sup.1 is
para-fluorophenyl.
36. The compound of claim 30 wherein R.sup.2 is selected from the
group consisting of: (1) CH.sub.2CH.sub.3, (2)
CH.sub.2CH.sub.2CH.sub.3, (3) cyclopropyl, (4) CF.sub.3, (5)
CH.sub.2CF.sub.3, (6) CH.sub.2CHF.sub.2, (7)
CH.sub.2C(CH.sub.3).sub.3, (8) CH.sub.2CH.dbd.CH.sub.2, (9)
C.dbd.CH.sub.2(CH.sub.3), (10) CH.sub.2C.ident.CCH.sub.3, (11)
--CO.sub.2--CH.sub.3, (12) CH.sub.2OCH.sub.2CH.sub.3, (13)
CH.sub.2CH.sub.2CH.sub.2CH.sub.3, (14) CH.sub.2CH.sub.2-dioxanyl,
and (15) CH.sub.2C(CH.sub.3).sub.2-phenyl.
37. The compound of claim 30 wherein R.sup.3 is selected from the
group consisting of: (1) CF.sub.3, (2) CF.sub.2H, (3)
CH.sub.2CF.sub.3, (4) CH.sub.2CHF.sub.2, (5) CH.sub.2CH.sub.2F, (6)
CH.sub.2CF.sub.2CH.sub.3, (6) CH.sub.2CF.sub.2CF.sub.3, (7)
CH.sub.2CF.sub.2-phenyl, and (8) CH.sub.2CF.sub.2-pyridyl.
38. The compound of claim 37 wherein R.sup.3 is CH.sub.2CF.sub.3 or
CH.sub.2CHF.sub.2.
39. A compound which is selected from the group consisting of:
4-Ethyl-6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin--
2(1H)-one;
4-Ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one;
4-Allyl-6-chloro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one;
4-Allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihy-
droquinazolin-2(1H)-one;
4-Ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihy-
droquinazolin-2(1H)-one;
6-Chloro-4-ethyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroqu-
inazolin-2(1H)-one;
6-Chloro-4-ethyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroqu-
inazolin-2(1H)-one;
6-Chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dih-
ydroquinazolin-2(1H)-one;
6-Chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydr-
o-quinazolin-2(1H)-one;
6-Chloro-4-(fluorophenyl)-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,-
4-dihydroquinazolin-2(1H)-one;
6-Chloro-4-ethyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-
-quinazolin2(1H)-one;
6-Chloro-4-allyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-
-quinazolin-2(1H)-one;
6-Chloro-4-propyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydr-
o-quinazolin-2(1H)-one;
4-Butyl-6-chloro-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-
quinazolin-2(1H)-one;
6-Chloro-4-cyclopropyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-d-
ihydro-quinazolin-2(1H)-one;
6-Chloro-4-(cyclopropylethynyl)-3-(2,2,2-trifluoroethyl)-4-(trifluorometh-
yl)-3,4-dihydroquinazolin-2((1H)-one;
6-Chloro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin--
2(1H)-one;
6-Chloro-4-ethyl-4-(4-methoxyphenyl)-3-(2,2,2-trifluoroethyl)-3-
,4-dihydroquinazolin-2(1H)-one;
6-Chloro-4-ethyl-4-(3-methoxyphenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinazolin-2(1H)-one;
6-Chloro-4-ethyl-4-(4-methylphenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one;
6-Chloro-4-ethyl-4-(3-methylphenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one;
6-Chloro-4-ethyl-4-(3-chlorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one;
6-Chloro-4-ethyl-4-(3-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one;
6-Chloro-4-ethyl-4-(4-chlorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one;
6-Chloro-4-ethyl-4-(4-dimethylaminophenyl)-3-(2,2,2-trifluoroethyl)-3,4-d-
ihydroquinazolin-2(1H)-one;
6-Chloro-4-ethyl-4-(2-methoxyphenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinazolin-2(1H)-one;
6-Fluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin--
2(1H)-one;
6-Chloro-4-ethyl-4-(3,4-difluorophenyl)-3-(2,2,2-trifluoroethyl-
)-3,4-dihydroquinazolin-2(1H)-one;
6-Fluoro-4-ethyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1-
H)-one;
6-Fluoro-4-butyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazo-
lin-2(1H)-one;
6-Fluoro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one;
6-Chloro-4-methoxymethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroqui-
nazolin-2(1H)-one;
6-Chloro-4-ethoxymethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquin-
azolin-2(1H)-one;
4-Ethyl-4-(4-fluoro-phenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazoli-
n-2(1H)-one;
6-Fluoro-4-allyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin--
2(1H)-one;
6-Fluoro-4-(2,2-dimethylpropyl)-4-phenyl-3-(2,2,2-trifluoroethy-
l)-3,4-dihydroquinazolin-2(1H)-one;
6-Fluoro-4-(2-phenyl-2-methylpropyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,-
4-dihydroquinazolin-2(1H)-one;
6-Fluoro-4-ethyl-4-phenyl-3-(2-fluoroethyl)-3,4-dihydroquinazolin-2(1H)-o-
ne;
6-Fluoro-4-butyl-4-phenyl-3-(2-fluoroethyl)-3,4-dihydroquinazolin-2(1H-
)-one;
6-Fluoro-4-ethyl-4-phenyl-3-(2,2,3,3,3-pentafluoropropyl)-3,4-dihyd-
roquinazolin-2(1H)-one;
6-Fluoro-4-butyl-4-phenyl-3-(2,2,3,3,3-pentafluoropropyl)-3,4-dihydroquin-
azolin-2(1H)-one;
6-Fluoro-4-ethyl-4-phenyl-3-(2,2-difluoropropyl)-3,4-dihydroquinazolin-2(-
1H)-one;
6-Fluoro-4-butyl-4-phenyl-3-(2,2-difluoropropyl)-3,4-dihydroquina-
zolin-2(1H)-one;
6-Fluoro-4-pentyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(-
1H)-one;
5-fluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroqui-
nazolin-2(1H)-one;
6-Chloro-5-fluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroqu-
inazolin-2(1H)-one;
6-Fluoro-4-(1-propynyl)-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazo-
lin-2(1H)-one;
3-(2,2-Difluoroethyl)-4-[2-(1,3-dioxan-2-yl)ethyl]-6-fluoro-4-phenyl-3,4--
dihydroquinazolin-2(1H)-one;
6-Fluoro-4-(2-propenyl)-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazo-
lin-2(1H)-one;
6-Fluoro-4-butyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1-
H)-one;
6-Fluoro-4-ethyl-4-(4-thiomethylphenyl)-3-(2,2,2-trifluoroethyl)-3-
,4-dihydroquinazolin-2(1H)-one;
6-Fluoro-4-cyclopropyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazol-
in-2(1H)-one;
3-(2,2-difluoroethyl)-6-fluoro-4-phenyl-4-(phenylethynyl)-3,4-dihydroquin-
azolin-2(1H)-one;
6-Chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2-difluoroethyl)-3,4-dihydroquin-
azolin-2(1H)-one;
6-Fluoro-4,4-diphenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-o-
ne;
3-(2,2-difluoroethyl)-4-(2-ethylbutyl)-6-fluoro-4-phenyl-3,4-dihydroqu-
inazolin-2(1H)-one;
3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-phenylethyl)-3,4-dihydroquin-
azolin-2(1H)-one;
3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-(4-chlorophenyl)ethyl)-3,4-d-
ihydroquinazolin-2(1H)-one;
3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-(3-chlorophenyl)ethyl)-3,4-d-
ihydroquinazolin-2(1H)-one;
3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-(4-fluorophenyl)ethyl)-3,4-d-
ihydroquinazolin-2(1H)-one;
3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-(4-methoxyphenyl)ethyl)-3,4--
dihydroquinazolin-2(1H)-one;
3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-(3-methoxyphenyl)ethyl)-3,4--
dihydroquinazolin-2(1H)-one;
5-Fluoro-4-cyclopropyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquina-
zolin-2(1H)-one;
6-Fluoro-4-methyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-
-2(1H)-one;
6-Fluoro-4-propyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-
-2(1H)-one;
6-Fluoro-4-cyclopropyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquina-
zolin-2(1H)-one;
6-Fluoro-4-cyclopropyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-di-
hydroquinazolin-2(1H)-one;
6-Chloro-4-cyclopropyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-di-
hydroquinazolin-2(1H)-one;
6-Chloro-4-cyclopropyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquina-
zolin-2(1H)-one;
5,6-Difluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazo-
lin-2(1H)-one;
6-Chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2-difluoroethyl)-3,4-dihydroquin-
azolin-2(1H)-one;
5,8-Difluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazo-
lin-2(1H)-one;
5,8-Difluoro-4-methyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinaz-
olin-2(1H)-one;
5,8-Difluoro-4-ethyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-
-2(1H)-one;
6-Fluoro-4-cyclopropylmethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydr-
oquinazolin-2(1H)-one;
5-fluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin--
2(1H)-one;
6-Chloro-4-(3-propenyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-d-
ihydroquinazolin-2(1H)-one;
6-Chloro-4-cyclopropylmethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)--
3,4-dihydroquinazolin-2(1H)-one;
6-Chloro-4-cyclopropylmethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydr-
oquinazolin-2(1H)-one;
5,6-difluoro-4-propyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinaz-
olin-2(1H)-one;
6-Chloro-4-ethyl-4-(3-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroqu-
inazolin-2(1H)-one;
6-Chloro-4-(3-formylmethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinazolin-2(1H)-one;
6-Chloro-4-(3-hydroxyethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinazolin-2(1H)-one;
6-Chloro-4-(methoxycarbonyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydr-
oquinazolin-2(1H)-one;
6-Chloro-4-cyclopropyl-4-(3,4-difluorophenyl)-3-(2,2,2-trifluoroethyl)-3,-
4-dihydroquinazolin-2(1H)-one;
4-[2-(Benzylamino)ethyl]-6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-d-
ihydroquinazolin-2(1H)-one;
6-Chloro-4-(3-propenyl)-4-(3,4-difluorophenyl)-3-(2,2,2-trifluoroethyl)-3-
,4-dihydroquinazolin-2(1H)-one;
6-Chloro-4-propyl-4-(3,4-difluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dih-
ydroquinazolin-2(1H)-one;
6-Chloro-4-(2,2-difluoroethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihy-
droquinazolin-2(1H)-one;
6-Chloro-4-(2-fluoroethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one;
5,6-Difluoro-4-cyclopropylmethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroeth-
yl)-3,4-dihydroquinazolin-2(1H)-one;
6-Chloro-4-(2-ethoxyethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one;
6-Chloro-4-(2-methoxyethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinazolin-2(1H)-one;
6-Chloro-4-propyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-
-2(1H)-one;
5,6-Difluoro-4-(2-fluoroethyl)-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl-
)-3,4-dihydroquinazolin-2(1H)-one;
6-Chloro-4-(2hydroxyethyl)-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,-
4-dihydroquinazolin-2(1H)-one;
6-Chloro-4-(2,2-difluoroethyl)-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl-
)-3,4-dihydroquinazolin-2(1H)-one;
6-Chloro-4-(2-fluoroethyl)-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,-
4-dihydroquinazolin-2(1H)-one;
6-Chloro-4-(3-propenyl)-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-d-
ihydroquinazolin-2(1H)-one;
6-Chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroqui-
nazolin-2(1H)-one;
6-Chloro-4-cyclopropyl-4-ethyl-3-(2-fluoroethyl)-3,4-dihydroquinazolin-2(-
1H)-one;
4-Butyl-6-chloro-4-cyclopropyl-3-(2,2,2-trifluoroethyl)-3,4-dihyd-
roquinazolin-2(1H)-one;
4-Butyl-6-chloro-4-cyclopropyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazoli-
n-2(1H)-one; and
4-Butyl-6-chloro-4-cyclopropyl-3-(2-fluoroethyl)-3,4-dihydroquinazolin-2(-
1H)-one; or a pharmaceutically acceptable salt thereof.
40. The compound of claim 39 which is selected from the group
consisting of:
4-Ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazo-
lin-2(1H)-one; and
6-Chloro-4-cyclopropyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-d-
ihydro-quinazolin-2(1H)-one; or a pharmaceutically acceptable salt
thereof.
41. The compound of claim 40 which is
4-Ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin--
2(1H)-one, or a pharmaceutically acceptable salt thereof.
42. The compound of claim 40 which is
6-Chloro-4-cyclopropyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-d-
ihydro-quinazolin-2(1H)-one, or a pharmaceutically acceptable salt
thereof.
43. A pharmaceutical composition which comprises an inert carrier
and a compound of claim 30, or a pharmaceutically acceptable salt
thereof.
44. A pharmaceutical composition which comprises an inert carrier
and a compound of claim 39, or a pharmaceutically acceptable salt
thereof.
45. A method for the treatment of a disorder or disease in which
T-type calcium channels are involved which comprises administering
to a mammalian patient in need of such treatment an effective
amount of the compound of claim 30 or a pharmaceutically acceptable
salt thereof.
46. The method of claim 45 wherein said disorder or disease is
selected from the group consisting of: epilepsy; pain; neuropathic
pain; movement disorder; Parkinson's disease; essential tremor;
cognitive disorder; decreased cognition; decreased memory
retention; psychosis; schizophrenia; sleep disorder; insomnia;
decreased quality of sleep; increased time to sleep onset;
decreased REM sleep; decreased slow-wave sleep; increased
fragmentation of sleep patterns; decreased sleep maintenance;
increased wake after sleep onset; decreased total sleep time; hot
flashes; fibromyalgia; mood disorder; anxiety disorder; and
substance withdrawal.
Description
BACKGROUND OF THE INVENTION
[0001] Plasma membrane calcium channels are members of a diverse
superfamily of voltage gated channel proteins. Calcium channels are
membrane-spanning, multi-subunit proteins that allow controlled
entry of Ca2+ ions into cells from the extracellular fluid.
Excitable cells throughout the animal kingdom, and at least some
bacterial, fungal and plant cells, possess one or more types of
calcium channel. Nearly all "excitable" cells in animals, such as
neurons of the central nervous system (CNS), peripheral nerve cells
and muscle cells, including those of skeletal muscles, cardiac
muscles, and venous and arterial smooth muscles, have
voltage-dependent calcium channels
[0002] Multiple types of calcium channels have been identified in
mammalian cells from various tissues, including skeletal muscle,
cardiac muscle, lung, smooth muscle and brain. A major type of this
family are the L-type calcium channels, whose function is inhibited
by the familiar classes of calcium channel blockers
(dihydropyridines such as nifedipine, phenylalkylamines such as
verapamil, and benzothiazepines such as diltiazem). Additional
classes of plasma membrane calcium channels are referred to as T,
N, P, Q and R.
[0003] The "T-type" (or "low voltage-activated") calcium channels
are so named because their openings are of briefer duration
(T=transient) than the longer (L=long-lasting) openings of the
L-type calcium channels. The L, N, P and Q-type channels activate
at more positive potentials (high voltage activated) and display
diverse kinetics and voltage-dependent properties. There are three
subtypes of T-type calcium channels that have been molecularly,
pharmacologically, and electrophysiologically identified from
various warm blooded animals including rat [J. Biol. Chem. 276(6)
3999-4011 (2001); Eur J Neurosci 11(12):4171-8 (1999); reviewed in
Cell Mol Life Sci 56(7-8):660-9 (1999)]. These subtypes have been
termed .alpha.1G, .alpha.1H, and .alpha.1I. The molecular
properties of these channels demonstrate that the amino acid
sequences are between 60-70% identical. The electrophysiological
characterization of these individual subtypes has revealed
differences in their voltage-dependent activation, inactivation,
deactivation and steady-state inactivation levels and their
selectivities to various ions such as barium (J Biol. Chem. 276(6)
3999-4011 (2001)). Pharmacologically, these subtypes also have
differing sensitivities to blockade by ionic nickel. These channel
subtypes are also expressed in various forms due to their ability
to undergo various splicing events during their assembly (J Biol.
Chem. 276(6) 3999-4011 (2001)).
[0004] T-type calcium channels have been implicated in pathologies
related to various diseases and disorders, including epilepsy,
essential tremor, pain, neuropathic pain, schizophrenia,
Parkinson's disease, depression, anxiety, sleep disorders, sleep
disturbances, psychosis, schizophreniac, cardiac arrhythmia,
hypertension, certain types of cancer, diabetes, infertility and
sexual dysfunction (J Neuroscience, 14, 5485 (1994); Drugs Future
30(6), 573-580 (2005); EMBO J, 24, 315-324 (2005)). The known
therapeutic regimens for such treating such diseases and disorders
suffer from numerous problems. Accordingly, a more physiological
way to treat these diseases and disorders would be highly
desirable.
SUMMARY OF THE INVENTION
[0005] The present invention is directed to quinazolinone compounds
which are antagonists of T-type calcium channels, and which are
useful in the treatment or prevention of neurological and
psychiatric disorders and diseases in which T-type calcium channels
are involved. The invention is also directed to pharmaceutical
compositions comprising these compounds and the use of these
compounds and compositions in the prevention or treatment of such
diseases in which T-type calcium channels are involved.
DETAILED DESCRIPTION OF THE INVENTION
[0006] The present invention is directed to compounds of the
formula I:
##STR00001##
wherein: X.sup.1, X.sup.2 and X.sup.3 are independently selected
from the group consisting of:
[0007] (1) hydrogen,
[0008] (2) fluoro,
[0009] (3) chloro, and
[0010] (4) bromo;
R.sup.1 is phenyl, C.sub.1-6alkyl, or C.sub.3-6cycloalkyl, which is
unsubstituted or substituted with a substituent selected from the
group consisting of: [0011] (1) halogen, [0012] (2) C.sub.1-6alkyl,
which is unsubstituted or substituted with halogen, hydroxyl or
phenyl, [0013] (3) --OC.sub.1-6 alkyl, which is unsubstituted or
substituted with halogen, hydroxyl or phenyl, [0014] (4) --CN,
[0015] (5) --NR.sup.5R.sup.6, wherein R.sup.5 and R.sup.6 are
independently selected from hydrogen, C.sub.1-6alkyl and
C.sub.1-6alkyl-phenyl, and [0016] (6) --S(O).sub.nC.sub.1-6alkyl,
wherein n is 0, 1 or 2; R.sup.2 is C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, phenyl, C.sub.2-6alkenyl, or C.sub.2-6alkynyl,
which is unsubstituted or substituted with one or more substituents
selected from the group consisting of: [0017] (1) fluoro, [0018]
(2) chloro, [0019] (3) --OC.sub.1-6alkyl, which is unsubstituted or
substituted with halogen, hydroxyl or phenyl, [0020] (4)
--S(O).sub.nC.sub.1-6alkyl, [0021] (5) --OH, [0022] (6) .dbd.O,
[0023] (7) --CHO, [0024] (8) --CO.sub.2--C.sub.1-6alkyl, [0025] (9)
C.sub.3-6cycloalkyl, [0026] (10) dioxanyl, and [0027] (11) phenyl,
which is unsubstituted or substituted with halogen, hydroxyl,
C.sub.1-6alkyl or --O--C.sub.1-6alkyl; R.sup.3 is C.sub.1-6alkyl
which is substituted with one or more fluoro, and which is
optionally substituted with an additional substituent selected from
the group consisting of
[0028] (1) C.sub.1-6alkyl,
[0029] (2) C.sub.3-6cycloalkyl,
[0030] (3) phenyl, and
[0031] (4) pyridyl;
and pharmaceutically acceptable salts thereof and individual
diastereomers thereof.
[0032] An embodiment of the present invention includes compounds
wherein X.sup.1 is selected from the group consisting of:
[0033] (1) fluoro,
[0034] (2) chloro, and
[0035] (3) bromo;
X.sup.2 is selected from the group consisting of:
[0036] (1) fluoro,
[0037] (2) chloro, and
X.sup.3 is hydrogen.
[0038] An embodiment of the present invention includes compounds
wherein X.sup.1 is fluoro, X.sup.2 is hydrogen and X.sup.3 is
hydrogen.
[0039] An embodiment of the present invention includes compounds
wherein X.sup.1 is fluoro, X.sup.2 is fluoro and X.sup.3 is
hydrogen.
[0040] An embodiment of the present invention includes compounds
wherein X.sup.1 is 6-fluoro, X.sup.2 is hydrogen and X.sup.3 is
hydrogen.
[0041] An embodiment of the present invention includes compounds
wherein X.sup.1 is 6-fluoro, X.sup.2 is 5-fluoro and X.sup.3 is
hydrogen
[0042] An embodiment of the present invention includes compounds
wherein X.sup.1 is chloro, X.sup.2 is hydrogen and X.sup.3 is
hydrogen.
[0043] An embodiment of the present invention includes compounds
wherein X.sup.1 is chloro, X.sup.2 is fluoro and X.sup.3 is
hydrogen.
[0044] An embodiment of the present invention includes compounds
wherein X.sup.1 is 6-chloro, X.sup.2 is hydrogen and X.sup.3 is
hydrogen.
[0045] An embodiment of the present invention includes compounds
wherein X.sup.1 is 6-chloro, X.sup.2 is 5-fluoro and X.sup.3 is
hydrogen
[0046] An embodiment of the present invention includes compounds
wherein R.sup.1 is phenyl or cyclopropyl, which is unsubstituted or
substituted with a substituent selected from the group consisting
of:
[0047] (1) fluoro,
[0048] (2) chloro,
[0049] (3) CH.sub.3,
[0050] (4) CF.sub.3,
[0051] (5) OCF.sub.3,
[0052] (6) OCH.sub.3, and
[0053] (7) --N(CH.sub.3).sub.2.
[0054] An embodiment of the present invention includes compounds
wherein R.sup.1 is phenyl, which is unsubstituted or substituted
with fluoro, methyl or methoxy.
[0055] An embodiment of the present invention includes compounds
wherein R.sup.1 is phenyl.
[0056] An embodiment of the present invention includes compounds
wherein R.sup.1 is para-fluorophenyl.
[0057] An embodiment of the present invention includes compounds
wherein R.sup.1 is cyclopropyl.
[0058] An embodiment of the present invention includes compounds
wherein R.sup.2 is selected from the group consisting of:
[0059] (1) CH.sub.2CH.sub.3,
[0060] (2) CH.sub.2CH.sub.2CH.sub.3,
[0061] (3) cyclopropyl,
[0062] (4) CF.sub.3,
[0063] (5) CH.sub.2CF.sub.3,
[0064] (6) CH.sub.2CHF.sub.2,
[0065] (7) CH.sub.2C(CH.sub.3).sub.3,
[0066] (8) CH.sub.2CH.dbd.CH.sub.2,
[0067] (9) C.dbd.CH.sub.2(CH.sub.3),
[0068] (10) CH.sub.2C.dbd.CCH.sub.3,
[0069] (11) --CO.sub.2--CH.sub.3,
[0070] (12) CH.sub.2OCH.sub.2CH.sub.3,
[0071] (13) CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
[0072] (14) CH.sub.2CH.sub.2-dioxanyl, and
[0073] (15) CH.sub.2C(CH.sub.3).sub.2-phenyl.
[0074] An embodiment of the present invention includes compounds
wherein R.sup.2 is CH.sub.2CH.sub.3, An embodiment of the present
invention includes compounds wherein R.sup.2 is
CH.sub.2CH.sub.2CH.sub.3. An embodiment of the present invention
includes compounds wherein R.sup.2 is CF.sub.3.
[0075] An embodiment of the present invention includes compounds
wherein R.sup.3 is selected from the group consisting of:
[0076] (1) CF.sub.3,
[0077] (2) CF.sub.2H,
[0078] (3) CH.sub.2CF.sub.3,
[0079] (4) CH.sub.2CHF.sub.2,
[0080] (5) CH.sub.2CH.sub.2F,
[0081] (6) CH.sub.2CF.sub.2CH.sub.3,
[0082] (6) CH.sub.2CF.sub.2CF.sub.3,
[0083] (7) CH.sub.2CF.sub.2-phenyl, and
[0084] (8) CH.sub.2CF.sub.2-pyridyl.
[0085] An embodiment of the present invention includes compounds
wherein R.sup.3 is CH.sub.2CF.sub.3. An embodiment of the present
invention includes compounds wherein R.sup.3 is
CH.sub.2CHF.sub.2.
[0086] Specific embodiments of the present invention include a
compound which is selected from the group consisting of the subject
compounds of the Examples herein or a pharmaceutically acceptable
salt thereof.
[0087] The compounds of the present invention may contain one or
more asymmetric centers and can thus occur as racemates and racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. Additional asymmetric centers may be
present depending upon the nature of the various substituents on
the molecule. Each such asymmetric center will independently
produce two optical isomers and it is intended that all of the
possible optical isomers and diastereomers in mixtures and as pure
or partially purified compounds are included within the ambit of
this invention. The present invention is meant to comprehend all
such isomeric forms of these compounds.
[0088] The independent syntheses of these diastereomers or their
chromatographic separations may be achieved as known in the art by
appropriate modification of the methodology disclosed herein. Their
absolute stereochemistry may be determined by the x-ray
crystallography of crystalline products or crystalline
intermediates which are derivatized, if necessary, with a reagent
containing an asymmetric center of known absolute
configuration.
[0089] If desired, racemic mixtures of the compounds may be
separated so that the individual enantiomers are isolated. The
separation can be carried out by methods well known in the art,
such as the coupling of a racemic mixture of compounds to an
enantiomerically pure compound to form a diastereomeric mixture,
followed by separation of the individual diastereomers by standard
methods, such as fractional crystallization or chromatography. The
coupling reaction is often the formation of salts using an
enantiomerically pure acid or base. The diasteromeric derivatives
may then be converted to the pure enantiomers by cleavage of the
added chiral residue. The racemic mixture of the compounds can also
be separated directly by chromatographic methods utilizing chiral
stationary phases, which methods are well known in the art.
[0090] Alternatively, any enantiomer of a compound may be obtained
by stereoselective synthesis using optically pure starting
materials or reagents of known configuration by methods well known
in the art.
[0091] As appreciated by those of skill in the art, halo or halogen
as used herein are intended to include fluoro, chloro, bromo and
iodo. Similarly, C.sub.1-6, as in C.sub.1-6alkyl is defined to
identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear
or branched arrangement, such that C.sub.1-6alkyl specifically
includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tert-butyl, pentyl, and hexyl. A group which is designated as being
independently substituted with substituents may be independently
substituted with multiple numbers of such substituents.
[0092] The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids
including inorganic or organic bases and inorganic or organic
acids. Salts derived from inorganic bases include aluminum,
ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,
manganic salts, manganous, potassium, sodium, zinc, and the like.
Particularly preferred are the ammonium, calcium, magnesium,
potassium, and sodium salts. Salts in the solid form may exist in
more than one crystal structure, and may also be in the form of
hydrates. Salts derived from pharmaceutically acceptable organic
non-toxic bases include salts of primary, secondary, and tertiary
amines, substituted amines including naturally occurring
substituted amines, cyclic amines, and basic ion exchange resins,
such as arginine, betaine, caffeine, choline,
N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,
2-dimethylaminoethanol, ethanolamine, ethylenediamine,
N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine, and the like.
[0093] When the compound of the present invention is basic, salts
may be prepared from pharmaceutically acceptable non-toxic acids,
including inorganic and organic acids. Such acids include acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid, and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
fumaric, and tartaric acids. It will be understood that, as used
herein, references to the compounds of Formula I are meant to also
include the pharmaceutically acceptable salts.
[0094] Exemplifying the invention is the use of the compounds
disclosed in the Examples and herein. Specific compounds within the
present invention include a compound which selected from the group
consisting of the compounds disclosed in the following Examples and
pharmaceutically acceptable salts thereof and individual
diastereomers thereof.
[0095] The subject compounds are useful in a method of antagonizing
T-type calcium channel activity in a patient such as a mammal in
need of such inhibition comprising the administration of an
effective amount of the compound. The present invention is directed
to the use of the compounds disclosed herein as antagonists of
T-type calcium channels activity. In addition to primates,
especially humans, a variety of other mammals can be treated
according to the method of the present invention.
[0096] The present invention is further directed to a method for
the manufacture of a medicament for antagonizing T-type calcium
channels activity or treating the disorders and diseases noted
herein in humans and animals comprising combining a compound of the
present invention with a pharmaceutical carrier or diluent.
[0097] The subject treated in the present methods is generally a
mammal, preferably a human being, male or female. The term
"therapeutically effective amount" means the amount of the subject
compound that will elicit the biological or medical response of a
tissue, system, animal or human that is being sought by the
researcher, veterinarian, medical doctor or other clinician. It is
recognized that one skilled in the art may affect the neurological
and psychiatric disorders by treating a patient presently afflicted
with the disorders or by prophylactically treating a patient
afflicted with the disorders with an effective amount of the
compound of the present invention. As used herein, the terms
"treatment" and "treating" refer to all processes wherein there may
be a slowing, interrupting, arresting, controlling, or stopping of
the progression of the neurological and psychiatric disorders
described herein, but does not necessarily indicate a total
elimination of all disorder symptoms, as well as the prophylactic
therapy of the mentioned conditions, particularly in a patient who
is predisposed to such disease or disorder. The terms
"administration of" and or "administering a" compound should be
understood to mean providing a compound of the invention or a
prodrug of a compound of the invention to the individual in need
thereof.
[0098] The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts. Such term in relation to pharmaceutical
composition, is intended to encompass a product comprising the
active ingredient(s), and the inert ingredient(s) that make up the
carrier, as well as any product which results, directly or
indirectly, from combination, complexation or aggregation of any
two or more of the ingredients, or from dissociation of one or more
of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients. Accordingly, the
pharmaceutical compositions of the present invention encompass any
composition made by admixing a compound of the present invention
and a pharmaceutically acceptable carrier. By "pharmaceutically
acceptable" it is meant the carrier, diluent or excipient must be
compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof.
[0099] The utility of the compounds in accordance with the present
invention as T-type calcium channel antagonists may be readily
determined without undue experimentation by methodology well known
in the art, including the "FLIPR Ca.sup.2+ Flux Assay" and the
"T-type Calcium (Ca.sup.2+) Antagonist Voltage-Clamp Assay"
[described by Xia, et al., Assay and Drug Development Tech., 1(5),
637-645 (2003)]. In a typical experiment ion channel function from
HEK 293 cells expressing the T-type channel alpha-1G, H, or I (CaV
3.1, 3.2, 3.3) is recorded to determine the activity of compounds
in blocking the calcium current mediated by the T-type channel
alpha-1G, H, or I (CaV 3.1, 3.2, 3.3). In this T-type calcium
(Ca.sup.2+) antagonist voltage-clamp assay calcium currents are
elicited from the resting state of the human alpha-1G, H, or I (CaV
3.1, 3.2, 3.3) calcium channel as follows. Sequence information for
T-type (Low-voltage activated) calcium channels are fully disclosed
in e.g., U.S. Pat. No. 5,618,720, U.S. Pat. No. 5,686,241, U.S.
Pat. No. 5,710,250,U.S. Pat. No. 5,726,035, U.S. Pat. No.
5,792,846, U.S. Pat. No. 5,846,757, U.S. Pat. No. 5,851,824, U.S.
Pat. No. 5,874,236, U.S. Pat. No. 5,876,958, U.S. Pat. No.
6,013,474, U.S. Pat. No. 6,057,114, U.S. Pat. No. 6,096,514, WO
99/28342, and J. Neuroscience, 19(6):1912-1921 (1999). Cells
expressing the T-type channels were grown in growth media which
comprised: DMEM, 10% Tetsystem approved FBS (Clontech Laboratories
Inc.), 100 microgram/ml Penicillin/Streptomycin, 2 mM L-Glutamine,
150 microgram/ml Zeocin, 5 microgram/ml Blasticidin. T-channel
expression was induced by exposing the cells to 2 mM Tetracycline
for 24 hrs. Glass pipettes are pulled to a tip diameter of 1-2
micrometer on a pipette puller. The pipettes are filled with the
intracellular solution and a chloridized silver wire is inserted
along its length, which is then connected to the headstage of the
voltage-clamp amplifier. Trypsinization buffer was 0.05% Trypsin,
0.53 mM EDTA. The extracellular recording solution consists of
(mM): 130 mM NaCl, 4 mM KCl, 1 mM MgCl.sub.2, 2 mM CaCl.sub.2, 20
mM HEPES, 30 Glucose, pH 7.4. The internal solution consists of
(mM): 125 CsCl, 10 TEA-Cl, 10 HEPES, 8 NaCl, 0.06 CaCl.sub.2, 0.6
EGTA, 4 ATP-Mg, 0.3 GTP; 135 mM CsMeSO.sub.3, 1 MgCl.sub.2, 10
CsCl, 5 EGTA, 10 HEPES, pH 7.4; or 135 mM CsCl, 2 MgCl.sub.2, 3
MgATP, 2 Na.sub.2ATP, 1 Na.sub.2GTP, 5 EGTA, 10 HEPES, pH 7.4. Upon
insertion of the pipette tip into the bath, the series resistance
is noted (acceptable range is between 1-4 megaohm). The junction
potential between the pipette and bath solutions is zeroed on the
amplifier. The cell is then patched, the patch broken, and, after
compensation for series resistance (>=80%), the voltage protocol
is applied while recording the whole cell Ca2+ current response.
Voltage protocols: (1) -80 mV holding potential every 20 seconds
pulse to -20 mV for 70 msec duration; the effectiveness of the drug
in inhibiting the current mediated by the channel is measured
directly from measuring the reduction in peak current amplitude
initiated by the voltage shift from -80 mV to -20 mV; (2) -100 mV
holding potential every 15 seconds pulse to -20 mV for 70 msec
duration; the effectiveness of the drug in inhibiting the current
mediated by the channel is measured directly from measuring the
reduction in peak current amplitude initiated by the shift in
potential from -100 mV to -20 mV. The difference in block at the
two holding potentials was used to determine the effect of drug at
differing levels of inactivation induced by the level of resting
state potential of the cells. After obtaining control baseline
calcium currents, extracellular solutions containing increasing
concentrations of a test compound are washed on. Once steady state
inhibition at a given compound concentration is reached, a higher
concentration of compound is applied. % inhibition of the peak
inward control Ca2+ current during the depolarizing step to -20 mV
is plotted as a function of compound concentration.
[0100] The intrinsic T-type calcium channel antagonist activity of
a compound which may be used in the present invention may be
determined by these assays. In particular, the compounds of the
following examples had activity in antagonizing the T-type calcium
channel in the aforementioned assays, generally with an IC.sub.50
of less than about 10 .mu.M. Preferred compounds within the present
invention had activity in antagonizing the T-type calcium channel
in the aforementioned assays with an IC.sub.50 of less than about 1
.mu.M. Such a result is indicative of the intrinsic activity of the
compounds in use as antagonists of T-type calcium channel
activity.
[0101] With respect to the compounds disclosed in WO93/04047, WO
2004/035000, and DE 4320347 the present compounds exhibit
unexpected properties, such as with respect to duration of action
and/or metabolism, such as increased metabolic stability, enhanced
oral bioavailability or absorption, and/or decreased drug-drug
interactions.
[0102] T-type calcium channels have been implicated in a wide range
of biological functions. This has suggested a potential role for
these receptors in a variety of disease processes in humans or
other species. The compounds of the present invention have utility
in treating, preventing, ameliorating, controlling or reducing the
risk of a variety of neurological and psychiatric disorders
associated with calcium channels, including one or more of the
following conditions or diseases: movement disorders, including
akinesias and akinetic-rigid syndromes (including Parkinson's
disease, drug-induced parkinsonism, postencephalitic parkinsonism,
progressive supranuclear palsy, multiple system atrophy,
corticobasal degeneration, parkinsonism-ALS dementia complex and
basal ganglia calcification), chronic fatigue syndrome, fatigue,
including Parkinson's fatigue, multiple sclerosis fatigue, fatigue
caused by a sleep disorder or a circadian rhythm disorder,
medication-induced parkinsonism (such as neuroleptic-induced
parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced
acute dystonia, neuroleptic-induced acute akathisia,
neuroleptic-induced tardive dyskinesia and medication-induced
postural tremor), Gilles de la Tourette's syndrome, seizure
disorders, epilepsy, and dyskinesias [including tremor (such as
rest tremor, essential tremor, postural tremor and intention
tremor), chorea (such as Sydenham's chorea, Huntington's disease,
benign hereditary chorea, neuroacanthocytosis, symptomatic chorea,
drug-induced chorea and hemiballism), myoclonus (including
generalised myoclonus and focal myoclonus), tics (including simple
tics, complex tics and symptomatic tics), restless leg syndrome and
dystonia (including generalised dystonia such as iodiopathic
dystonia, drug-induced dystonia, symptomatic dystonia and paroxymal
dystonia, and focal dystonia such as blepharospasm, oromandibular
dystonia, spasmodic dysphonia, spasmodic torticollis, axial
dystonia, dystonic writer's cramp and hemiplegic dystonia); heart
disease, abnormal heart rhythms and arrythmias, myocardial
infarction, congestive heart failure, coronary heart disease,
sudden death, stroke, sexual and reproductive dysfunction, such as
impaired fertility, infertility, diseases or disorders where
abnormal oscillatory activity occurs in the brain, including
depression, migraine, neuropathic pain, Parkinson's disease,
psychosis and schizophrenia, as well as diseases or disorders where
there is abnormal coupling of activity, particularly through the
thalamus; enhancing cognitive function; enhancing memory;
increasing memory retention; increasing trained performance;
increasing immune response; increasing immune function; hot
flashes; night sweats; extending life span; schizophrenia;
muscle-related disorders that are controlled by the
excitation/relaxation rhythms imposed by the neural system such as
cardiac rhythm and other disorders of the cardiovascular system;
conditions related to proliferation of cells such as vasodilation
or vasorestriction and blood pressure; cancer; cardiac arrhythmia;
hypertension; congestive heart failure; conditions of the
genital/urinary system; disorders of sexual function and fertility;
adequacy of renal function; responsivity to anesthetics; sleep
disorders, sleep disturbances, including enhancing sleep quality,
improving sleep quality, increasing sleep efficiency, augmenting
sleep maintenance; increasing the value which is calculated from
the time that a subject sleeps divided by the time that a subject
is attempting to sleep; improving sleep initiation; decreasing
sleep latency or onset (the time it takes to fall asleep);
decreasing difficulties in falling asleep; increasing sleep
continuity; decreasing the number of awakenings during sleep;
decreasing intermittent wakings during sleep; decreasing nocturnal
arousals; decreasing the time spent awake following the initial
onset of sleep; increasing the total amount of sleep; reducing the
fragmentation of sleep; altering the timing, frequency or duration
of REM sleep bouts; altering the timing, frequency or duration of
slow wave (i.e. stages 3 or 4) sleep bouts; increasing the amount
and percentage of stage 2 sleep; promoting slow wave sleep;
enhancing EEG-delta activity during sleep; increasing the amount of
Delta sleep early in the sleep cycle, increasing REM sleep late in
the sleep cycle; decreasing nocturnal arousals, especially early
morning awakenings; increasing daytime alertness; reducing daytime
drowsiness; treating or reducing excessive daytime sleepiness;
increasing satisfaction with the intensity of sleep; increasing
sleep maintenance; idiopathic insomnia; sleep problems; insomnia,
hypersomnia, idiopathic hypersomnia, repeatability hypersomnia,
intrinsic hypersomnia, narcolepsy, interrupted sleep, sleep apnea,
obstructive sleep apnea, wakefulness, nocturnal myoclonus, REM
sleep interruptions, jet-lag, shift workers' sleep disturbances,
dyssomnias, night terror, insomnias associated with depression,
emotional/mood disorders, Alzheimer's disease or cognitive
impairment, as well as sleep walking and enuresis, and sleep
disorders which accompany aging; Alzheimer's sundowning; conditions
associated with circadian rhythmicity as well as mental and
physical disorders associated with travel across time zones and
with rotating shift-work schedules, conditions due to drugs which
cause reductions in REM sleep as a side effect; fibromyalgia;
syndromes which are manifested by non-restorative sleep and muscle
pain or sleep apnea which is associated with respiratory
disturbances during sleep; conditions which result from a
diminished quality of sleep; mood disorders, such as depression or
more particularly depressive disorders, for example, single
episodic or recurrent major depressive disorders and dysthymic
disorders, or bipolar disorders, for example, bipolar I disorder,
bipolar II disorder and cyclothymic disorder, mood disorders due to
a general medical condition, and substance-induced mood disorders;
anxiety disorders including acute stress disorder, agoraphobia,
generalized anxiety disorder, obsessive-compulsive disorder, panic
attack, panic disorder, post-traumatic stress disorder, separation
anxiety disorder, social phobia, specific phobia, substance-induced
anxiety disorder and anxiety due to a general medical condition;
acute neurological and psychiatric disorders such as cerebral
deficits subsequent to cardiac bypass surgery and grafting, stroke,
ischemic stroke, cerebral ischemia, spinal cord trauma, head
trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal
damage; Huntington's Chorea; amyotrophic lateral sclerosis;
multiple sclerosis; ocular damage; retinopathy; cognitive
disorders; idiopathic and drug-induced Parkinson's disease;
muscular spasms and disorders associated with muscular spasticity
including tremors, epilepsy, convulsions; cognitive disorders
including dementia (associated with Alzheimer's disease, ischemia,
trauma, vascular problems or stroke, HIV disease, Parkinson's
disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob
disease, perinatal hypoxia, other general medical conditions or
substance abuse); delirium, anmestic disorders or age related
cognitive decline; schizophrenia or psychosis including
schizophrenia (paranoid, disorganized, catatonic or
undifferentiated), schizophreniform disorder, schizoaffective
disorder, delusional disorder, brief psychotic disorder, shared
psychotic disorder, psychotic disorder due to a general medical
condition and substance-induced psychotic disorder;
substance-related disorders and addictive behaviors (including
substance-induced delirium, persisting dementia, persisting
anmestic disorder, psychotic disorder or anxiety disorder;
tolerance, dependence or withdrawal from substances including
alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants,
nicotine, opioids, phencyclidine, sedatives, hypnotics or
anxiolytics); attention deficit/hyperactivity disorder (ADHD);
conduct disorder; migraine (including migraine headache); urinary
incontinence; substance tolerance, substance withdrawal (including,
substances such as opiates, nicotine, tobacco products, alcohol,
benzodiazepines, cocaine, sedatives, hypnotics, etc.); psychosis;
schizophrenia; anxiety (including generalized anxiety disorder,
panic disorder, and obsessive compulsive disorder); mood disorders
(including depression, mania, bipolar disorders); trigeminal
neuralgia; hearing loss; tinnitus; neuronal damage including ocular
damage; retinopathy; macular degeneration of the eye; emesis; brain
edema; pain, including acute and chronic pain states, severe pain,
intractable pain, inflammatory pain, neuropathic pain,
post-traumatic pain, bone and joint pain (osteoarthritis),
repetitive motion pain, dental pain, cancer pain, myofascial pain
(muscular injury, fibromyalgia), perioperative pain (general
surgery, gynecological), chronic pain, neuropathic pain,
post-traumatic pain, trigeminal neuralgia, migraine and migraine
headache.
[0103] Thus, in preferred embodiments the present invention
provides methods for: treating, controlling, ameliorating or
reducing the risk of epilepsy, including absence epilepsy; treating
or controlling Parkinson's disease; treating essential tremor;
treating or controlling pain, including neuropathic pain; enhancing
the quality of sleep; augmenting sleep maintenance; increasing REM
sleep; increasing slow wave sleep; decreasing fragmentation of
sleep patterns; treating insomnia; enhancing cognition; increasing
memory retention; treating or controlling depression; treating or
controlling psychosis; or treating, controlling, ameliorating or
reducing the risk of schizophrenia, in a mammalian patient in need
thereof which comprises administering to the patient a
therapeutically effective amount of the compound of the present
invention.
[0104] The subject compounds are further useful in a method for the
prevention, treatment, control, amelioration, or reducation of risk
of the diseases, disorders and conditions noted herein.
[0105] The dosage of active ingredient in the compositions of this
invention may be varied, however, it is necessary that the amount
of the active ingredient be such that a suitable dosage form is
obtained. The active ingredient may be administered to patients
(animals and human) in need of such treatment in dosages that will
provide optimal pharmaceutical efficacy. The selected dosage
depends upon the desired therapeutic effect, on the route of
administration, and on the duration of the treatment. The dose will
vary from patient to patient depending upon the nature and severity
of disease, the patient's weight, special diets then being followed
by a patient, concurrent medication, and other factors which those
skilled in the art will recognize. Generally, dosage levels of
between 0.0001 to 10 mg/kg. of body weight daily are administered
to the patient, e.g., humans and elderly humans, to obtain
effective antagonism of T-type calcium channel. The dosage range
will generally be about 0.5 mg to 1.0 g. per patient per day which
may be administered in single or multiple doses. Preferably, the
dosage range will be about 0.5 mg to 500 mg per patient per day;
more preferably about 0.5 mg to 200 mg per patient per day; and
even more preferably about 5 mg to 50 mg per patient per day.
Pharmaceutical compositions of the present invention may be
provided in a solid dosage formulation preferably comprising about
0.5 mg to 500 mg active ingredient, more preferably comprising
about 1 mg to 250 mg active ingredient. The pharmaceutical
composition is preferably provided in a solid dosage formulation
comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or
250 mg active ingredient. For oral administration, the compositions
are preferably provided in the form of tablets containing 1.0 to
1000 milligrams of the active ingredient, particularly 1, 5, 10,
15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,
800, 900, and 1000 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
The compounds may be administered on a regimen of 1 to 4 times per
day, preferably once or twice per day.
[0106] The compounds of the present invention may be used in
combination with one or more other drugs in the treatment,
prevention, control, amelioration, or reduction of risk of diseases
or conditions for which compounds of the present invention or the
other drugs may have utility, where the combination of the drugs
together are safer or more effective than either drug alone. Such
other drug(s) may be administered, by a route and in an amount
commonly used therefor, contemporaneously or sequentially with a
compound of the present invention. When a compound of the present
invention is used contemporaneously with one or more other drugs, a
pharmaceutical composition in unit dosage form containing such
other drugs and the compound of the present invention is preferred.
However, the combination therapy may also includes therapies in
which the compound of the present invention and one or more other
drugs are administered on different overlapping schedules. It is
also contemplated that when used in combination with one or more
other active ingredients, the compounds of the present invention
and the other active ingredients may be used in lower doses than
when each is used singly. Accordingly, the pharmaceutical
compositions of the present invention include those that contain
one or more other active ingredients, in addition to a compound of
the present invention. The above combinations include combinations
of a compound of the present invention not only with one other
active compound, but also with two or more other active
compounds.
[0107] Likewise, compounds of the present invention may be used in
combination with other drugs that are used in the prevention,
treatment, control, amelioration, or reduction of risk of the
diseases or conditions for which compounds of the present invention
are useful. Such other drugs may be administered, by a route and in
an amount commonly used therefor, contemporaneously or sequentially
with a compound of the present invention. When a compound of the
present invention is used contemporaneously with one or more other
drugs, a pharmaceutical composition containing such other drugs in
addition to the compound of the present invention is preferred.
Accordingly, the pharmaceutical compositions of the present
invention include those that also contain one or more other active
ingredients, in addition to a compound of the present
invention.
[0108] The weight ratio of the compound of the compound of the
present invention to the second active ingredient may be varied and
will depend upon the effective dose of each ingredient. Generally,
an effective dose of each will be used. Thus, for example, when a
compound of the present invention is combined with another agent,
the weight ratio of the compound of the present invention to the
other agent will generally range from about 1000:1 to about 1:1000,
preferably about 200:1 to about 1:200. Combinations of a compound
of the present invention and other active ingredients will
generally also be within the aforementioned range, but in each
case, an effective dose of each active ingredient should be used.
In such combinations the compound of the present invention and
other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of
other agent(s).
[0109] The compounds of the present invention may be employed in
combination with an anti-seizure agent such as carbamazepine,
clonazepam, divalproex, ethosuximide, felbamate, fosphenyloin,
gabapentin, lamotrigine, levetiracetam, lorazepam, midazolam,
oxcarbazepine, phenobarbital, phenyloin, primidone, tiagabine,
topiramate, valproate, vigabatrin or zonisamide. In another
embodiment, the subject compound may be employed in combination
with acetophenazine, alentemol, benzhexyl, bromocriptine,
biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,
fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with
benserazide, levodopa with carbidopa, lisuride, loxapine,
mesoridazine, molindolone, naxagolide, olanzapine, pergolide,
perphenazine, pimozide, pramipexole, risperidone, sulpiride,
tetrabenazine, trihexyphenidyl, thioridazine, thiothixene,
trifluoperazine or valproic acid.
[0110] In another embodiment, the compounds of the present
invention may be employed in combination with levodopa (with or
without a selective extracerebral decarboxylase inhibitor such as
carbidopa or benserazide), anticholinergics such as biperiden
(optionally as its hydrochloride or lactate salt) and
trihexyphenidyl(benzhexyl)hydrochloride, COMT inhibitors such as
entacapone, MOA-B inhibitors, antioxidants, Ata adenosine receptor
antagonists, cholinergic agonists, serotonin receptor antagonists
and dopamine receptor agonists such as alentemol, bromocriptine,
fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It
will be appreciated that the dopamine agonist may be in the form of
a pharmaceutically acceptable salt, for example, alentemol
hydrobromide, bromocriptine mesylate, fenoldopam mesylate,
naxagolide hydrochloride and pergolide mesylate. Lisuride and
pramipexol are commonly used in a non-salt form.
[0111] In another embodiment, the compounds of the present
invention may be employed in combination with a compound from the
phenothiazine, thioxanthene, heterocyclic dibenzazepine,
butyrophenone, diphenylbutylpiperidine and indolone classes of
neuroleptic agent. Suitable examples of phenothiazines include
chlorpromazine, mesoridazine, thioridazine, acetophenazine,
fluphenazine, perphenazine and trifluoperazine. Suitable examples
of thioxanthenes include chlorprothixene and thiothixene. An
example of a dibenzazepine is clozapine. An example of a
butyrophenone is haloperidol. An example of a
diphenylbutylpiperidine is pimozide. An example of an indolone is
molindolone. Other neuroleptic agents include loxapine, sulpiride
and risperidone. It will be appreciated that the neuroleptic agents
when used in combination with the subject compound may be in the
form of a pharmaceutically acceptable salt, for example,
chlorpromazine hydrochloride, mesoridazine besylate, thioridazine
hydrochloride, acetophenazine maleate, fluphenazine hydrochloride,
flurphenazine enathate, fluphenazine decanoate, trifluoperazine
hydrochloride, thiothixene hydrochloride, haloperidol decanoate,
loxapine succinate and molindone hydrochloride. Perphenazine,
chlorprothixene, clozapine, haloperidol, pimozide and risperidone
are commonly used in a non-salt form.
[0112] In another embodiment, the compounds of the present
invention may be employed in combination with an opiate agonist, a
lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a
cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an
interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA
antagonist, an inhibitor of nitric oxide or an inhibitor of the
synthesis of nitric oxide, a non-steroidal antiinflammatory agent,
or a cytokine-suppressing antiinflammatory agent, for example with
a compound such as acetaminophen, asprin, codiene, fentanyl,
ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin,
piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap,
and the like. Similarly, the subject compound may be administered
with a pain reliever; a potentiator such as caffeine, an
H2-antagonist, simethicone, aluminum or magnesium hydroxide; a
decongestant such as phenylephrine, phenylpropanolamine,
pseudophedrine, oxymetazoline, ephinephrine, naphazoline,
xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an
antiitussive such as codeine, hydrocodone, caramiphen,
carbetapentane, or dextramethorphan; a diuretic; and a sedating or
non-sedating antihistamine. In another embodiment, the subject
compound may be employed in combination with an L-type calcium
channel antagonist, such as amlodipine.
[0113] In another embodiment, the compounds of the present
invention may be administered in combination with compounds which
are known in the art to be useful for enhancing sleep quality and
preventing and treating sleep disorders and sleep disturbances,
including e.g., sedatives, hypnotics, anxiolytics, antipsychotics,
antianxiety agents, antihistamines, benzodiazepines, barbiturates,
cyclopyrrolones, GABA agonists, 511T-2 antagonists including 5HT-2A
antagonists and 5HT-2A/2C antagonists, histamine antagonists
including histamine H3 antagonists, histamine H3 inverse agonists,
imidazopyridines, minor tranquilizers, melatonin agonists and
antagonists, melatonergic agents, other orexin antagonists, orexin
agonists, prokineticin agonists and antagonists,
pyrazolopyrimidines, other T-type calcium channel antagonists,
triazolopyridines, and the like, such as: adinazolam, allobarbital,
alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,
armodafinil, APD-125, bentazepam, benzoctamine, brotizolam,
bupropion, busprione, butabarbital, butalbital, capromorelin,
capuride, carbocloral, chloral betaine, chloral hydrate,
chlordiazepoxide, clomipramine, clonazepam, cloperidone,
clorazepate, clorethate, clozapine, conazepam, cyprazepam,
desipramine, dexclamol, diazepam, dichloralphenazone, divalproex,
diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam,
eszopiclone, ethchlorynol, etomidate, fenobam, flunitrazepam,
flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol,
glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,
indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,
MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,
methaqualone, methyprylon, midaflur, midazolam, modafinil,
nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline,
oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,
perphenazine, phenelzine, phenobarbital, prazepam, promethazine,
propofol, protriptyline, quazepam, ramelteon, reclazepam,
roletamide, secobarbital, sertraline, suproclone, TAIL-375,
temazepam, thioridazine, tiagabine, tracazolate, tranylcypromaine,
trazodone, triazolam, trepipam, tricetamide, triclofos,
trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine,
zaleplon, zolazepam, zopiclone, zolpidem, and salts thereof, and
combinations thereof, and the like, or the compound of the present
invention may be administered in conjunction with the use of
physical methods such as with light therapy or electrical
stimulation.
[0114] In another embodiment, the compounds of the present
invention may be employed in combination with an anti-depressant or
anti-anxiety agent, including norepinephrine reuptake inhibitors
(including tertiary amine tricyclics and secondary amine
tricyclics), selective serotonin reuptake inhibitors (SSRIs),
monoamine oxidase inhibitors (MAOIs), reversible inhibitors of
monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake
inhibitors (SNRIs), corticotropin releasing factor (CRF)
antagonists, .alpha.-adrenoreceptor antagonists, neurokinin-1
receptor antagonists, atypical anti-depressants, benzodiazepines,
5-HT.sub.1A agonists or antagonists, especially 5-HT.sub.1A partial
agonists, and corticotropin releasing factor (CRF) antagonists.
Specific agents include: amitriptyline, clomipramine, doxepin,
imipramine and trimipramine; amoxapine, desipramine, maprotiline,
nortriptyline and protriptyline; fluoxetine, fluvoxamine,
paroxetine and sertraline; isocarboxazid, phenelzine,
tranylcypromine and selegiline; moclobemide: venlafaxine;
aprepitant; bupropion, lithium, nefazodone, trazodone and
viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate,
diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone,
flesinoxan, gepirone and ipsapirone, and pharmaceutically
acceptable salts thereof.
[0115] In another embodiment, the compounds of the present
invention may be employed in combination with anti-Alzheimer's
agents; beta-secretase inhibitors; gamma-secretase inhibitors;
growth hormone secretagogues; recombinant growth hormone; HMG-CoA
reductase inhibitors; NSAID's including ibuprofen; vitamin E;
anti-amyloid antibodies; CB-1 receptor antagonists or CB-1 receptor
inverse agonists; antibiotics such as doxycycline and rifampin;
N-methyl-D-aspartate (NMDA) receptor antagonists, such as
memantine; cholinesterase inhibitors such as galantamine,
rivastigmine, donepezil, and tacrine; growth hormone secretagogues
such as ibutamoren, ibutamoren mesylate, and capromorelin;
histamine H.sub.3 antagonists; AMPA agonists; PDE IV inhibitors;
GABA.sub.A inverse agonists; or neuronal nicotinic agonists.
[0116] The compounds of the present invention may be administered
by oral, parenteral (e.g., intramuscular, intraperitoneal,
intravenous, ICV, intracisternal injection or infusion,
subcutaneous injection, or implant), by inhalation spray, nasal,
vaginal, rectal, sublingual, or topical routes of administration
and may be formulated, alone or together, in suitable dosage unit
formulations containing conventional non-toxic pharmaceutically
acceptable carriers, adjuvants and vehicles appropriate for each
route of administration. In addition to the treatment of
warm-blooded animals such as mice, rats, horses, cattle, sheep,
dogs, cats, monkeys, etc., the compounds of the invention are
effective for use in humans.
[0117] The pharmaceutical compositions for the administration of
the compounds of this invention may conveniently be presented in
dosage unit form and may be prepared by any of the methods well
known in the art of pharmacy. All methods include the step of
bringing the active ingredient into association with the carrier
which constitutes one or more accessory ingredients. In general,
the pharmaceutical compositions are prepared by uniformly and
intimately bringing the active ingredient into association with a
liquid carrier or a finely divided solid carrier or both, and then,
if necessary, shaping the product into the desired formulation. In
the pharmaceutical composition the active object compound is
included in an amount sufficient to produce the desired effect upon
the process or condition of diseases. As used herein, the term
"composition" is intended to encompass a product comprising the
specified ingredients in the specified amounts, as well as any
product which results, directly or indirectly, from combination of
the specified ingredients in the specified amounts.
[0118] Pharmaceutical compositions intended for oral use may be
prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
may contain one or more agents selected from the group consisting
of sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients
which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example starch, gelatin or
acacia, and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. Compositions for oral use may also be
presented as hard gelatin capsules wherein the active ingredient is
mixed with an inert solid diluent, for example, calcium carbonate,
calcium phosphate or kaolin, or as soft gelatin capsules wherein
the active ingredient is mixed with water or an oil medium, for
example peanut oil, liquid paraffin, or olive oil. Aqueous
suspensions contain the active materials in admixture with
excipients suitable for the manufacture of aqueous suspensions.
Oily suspensions may be formulated by suspending the active
ingredient in a suitable oil. Oil-in-water emulsions may also be
employed. Dispersible powders and granules suitable for preparation
of an aqueous suspension by the addition of water provide the
active ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Pharmaceutical
compositions of the present compounds may be in the form of a
sterile injectable aqueous or oleagenous suspension. The compounds
of the present invention may also be administered in the form of
suppositories for rectal administration. For topical use, creams,
ointments, jellies, solutions or suspensions, etc., containing the
compounds of the present invention may be employed. The compounds
of the present invention may also be formulated for administered by
inhalation. The compounds of the present invention may also be
administered by a transdermal patch by methods known in the
art.
[0119] Several methods for preparing the compounds of this
invention are illustrated in the following Schemes and Examples.
Starting materials are made according to procedures known in the
art or as illustrated herein. The following abbreviations are used
herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl; Ar: aryl; Ph:
phenyl; Bn: benzyl; BuLi: butyllithium; Piv: pivaloyl; Ac: acetyl;
THF: tetrahydrofuran; DMSO: dimethylsulfoxide; EDC:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide; Boc: tert-butyloxy
carbonyl; Et.sub.3N: triethylamine; DCM: dichloromethane; DCE:
dichloroethane; DME: dimethoxyethane; DEA: diethylamine; DAST:
diethylaminosulfur trifluoride; EtMgBr: ethylamgnesium bromide;
BSA: bovine serum albumin; TFA: trifluoracetic acid; DMF:
N,N-dimethylformamide; SOCl.sub.2: thionyl chloride; CDI: carbonyl
diimidazole; rt: room temperature; HPLC: high performance liquid
chromatography. The compounds of the present invention can be
prepared in a variety of fashions.
##STR00002##
[0120] Treatment of an appropriately substituted 2-amino carboxylic
acid 1-1 with N,O-dimethylhydroxylamine and a coupling reagent such
as EDC gives the Weinreb amide 1-2. Addition of an organometallic
reagent gives ketone 1-3 which can alternatively be prepared by
addition of an organometallic reagent to an appropriately
substituted nitrile 1-4. The ketone 1-3 can be elaborated to the
imidazole adduct 1-5 with CDT. Treatment with the desired primary
amine gives 1-6 (which can exist as mixture of the cyclized
4-hydroxyquinazolinone and the uncyclized keto-urea) which can be
dehydrated to 1-7 and reacted with another organometallic to give
compounds 1-8.
##STR00003##
[0121] Another general method for preparation of
hydroxyquinazolinone intermediate 1-6 is shown in Scheme 2.
Protection of an appropriately substituted aniline 2-1 with
pivaloyl chloride followed by directed ortho-metallation and
trapping with an ester gives ketone 2-3. The pivaloyl group is
removed with HCl and treatment of the resulting amino-ketone 2-4
with triphosgene and an appropriately substituted amine gives 1-6
(which can exist as mixture of the cyclized 4-hydroxyquinazolinone
and the uncyclized keto-urea).
[0122] In some cases the final product may be further modified, for
example, by manipulation of substituents. These manipulations may
include, but are not limited to, reduction, oxidation,
organometallic cross-coupling, alkylation, acylation, and
hydrolysis reactions which are commonly known to those skilled in
the art. In some cases the order of carrying out the foregoing
reaction schemes may be varied to facilitate the reaction or to
avoid unwanted reaction products. The following examples are
provided so that the invention might be more fully understood.
These examples are illustrative only and should not be construed as
limiting the invention in any way.
Example 1
##STR00004##
[0123]
N-(2-benzoyl-4-chlorophenyl)-1H-imidazole-1-carboxamide(3-2)
[0124] To a solution of 2-amino-5-chlorobenzophenone (40 g, 1727
mmol) in CH.sub.2Cl.sub.2 (175 mL) was added carbonyldiimidazole
(30.8 g, 189.9 mmol). The reaction was heated to 45.degree. C. for
16 h resulting in a white precipitate. The reaction was cooled in
an ice bath and the precipitate collected by vacuum filtration and
dried to give 39.3 g (69.9%) of
N-(2-benzoyl-4-chlorophenyl)-1H-imidazole-1-carboxamide as a white
solid. 1H NMR (CDCl.sub.3, 400 MHz) 8.66 (s, 1H); 7.46 (m, 4H);
7.25 (s, 1H); 7.19 (d, J=6.96 Hz, 2H); 7.15 (s, 1H); 6.94 (m, 2H);
6.76 (d, J=2.29 Hz, 1H). MS (Electrospray): m/z 348.0 (M+Na).
6-chloro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-
-2(1H)-one (3-3)
[0125] To a suspension of
N-(2-benzoyl-4-chlorophenyl)-1H-imidazole-1-carboxamide (39.3 g,
120.5 mmol) in THF (200 mL) was added 2,2,2-trifluoroethylamine
(14.0 g, 141.0 mmol). The reaction was heated to 50.degree. C. for
16 h. A second portion of 2,2,2-trifluoroethylamine (3.6 gm, 36.4
mmol) was added and warming continued at 50.degree. C. for 3 h. The
reaction was cooled to ambient temperature and concentrated in
vacuo. The light yellow oil was partitioned between n-butyl
chloride (500 mL) and aqueous 10% citric acid (300 mL) with
vigorous stirring. The resulting precipitate was collected by
vacuum filtration and placed under vacuum alongside P.sub.2O.sub.5
for 16 h to give 35.4 g (82.4%) of
6-chloro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazoli-
n-2(1H)-one as an off-white solid. .sup.1H NMR (CDCl.sub.3, 400
MHz) 8.41 (brs, 1H); 7.47 (d, J=8.06 Hz, 2H); 7.36 (m, 3H); 7.27
(m, 1H); 7.21 (dd, J=2.26 Hz and 8.52 Hz, 1H); 6.76 (d, J=8.52 Hz,
1H); 4.37 (m, 1H); 3.55 (m, 1H); 3.25 (s, 1H). MS (Electrospray):
m/z 357.0 (M+H).
4-ethyl-6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2-
(1H)-one (3-4)
[0126] To a -20.degree. C. solution of
6-chloro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazoli-
n-2(1H)-one (5.5 g, 15 mmol) in THF (50 mL) was added triethylamine
(10.7 mL, 77 mmol) and then thionyl chloride (1.2 mL, 17 mmol) was
added dropwise. After 20 min, 1M ethylmagnesium bromide in THF (46
mL, 46 mmol) was added over 10 min. and the reaction mixture warmed
to 0.degree. C. After an additional 30 min at 0.degree. C., the
reaction was quenched by pouring into a well stirred mixture of 300
mL EtOAc and 200 mL water which was acidified with 1N HCl solution.
The layers were mixed and separated and the organic layer washed
with 200 mL brine and filtered to remove unreacted starting
material. The filtrate was concentrated in vacuo. Purification by
normal phase chromatography (120 g silica gel cartridge, 10-75%
EtOAc/hexanes) provided
4-ethyl-6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin--
2(1H)-one. 1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.73 (s, NH); 7.39
(m, 3H); 7.35 (m, 2H); 7.09 (dd, 1H, J=8.43 and 2.2 Hz); 6.70 (d,
1H, J=8.43 Hz); 6.49 (d, 1H, J=2.38 Hz); 3.92 (dq, 1H, J=9.52 and
15.9 Hz); 3.47 (dq, 1H, J=8.61 and 17 Hz); 2.41 (dq, 1H, J=7.14 and
14.29 Hz); 2.28 (dq, 1H, J=7.14 and 14.28 Hz); 0.91 (t, J=7.14 Hz,
3H); MS (Electrospray): m/z 369.2 (M+H)
Example 2
##STR00005##
[0127] 2-amino-5-fluoro-N-methoxy-N-methylbenzamide(4-2)
[0128] To a 0.degree. C. mixture of diisopropylethylamine (34.36
mL, 197.25 mmol) and O,N-dimethyl-hydroxylamine hydrochloride
(19.24 g, 197.25 mmol) in CHCl.sub.3 (300 mL) was added
2-amino-5-fluorobenzoic acid (25.50 g, 164.38 mmol) followed by EDC
(31.51 g, 164.38 mmol). The reaction was stirred from 0.degree. C.
to ambient temperature over 2 h and then diluted with
CH.sub.2Cl.sub.2 (100 mL), washed with saturated sodium bicarbonate
solution (100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. Purification by normal phase
chromatography (3-8% MeOH/CH.sub.2Cl.sub.2) yielded
2-amino-5-fluoro-N-methoxy-N-methylbenzamide as a yellow oil. 1H
NMR (CDCl.sub.3, 400 MHz) 7.12 (m, 1H, ArH); 6.93 (m, 1H, ArH);
6.65 (m, 1H, ArH); 3.63 (s, 3H, CH.sub.3); 3.35 (s, 3H, CH.sub.3);
MS (Electrospray): m/z 199.1 (M.sup.+H).
(2-amino-5-fluorophenyl)(phenyl)methanone (4-3)
[0129] To a -78.degree. C. solution of
2-amino-5-fluoro-N-methoxy-N-methylbenzamide in THF (100 mL) was
added 1M phenylmagnesium bromide in THF (124.12 mL, 124.12 mmol).
The reaction was stirred from -78.degree. C. to ambient temperature
over 3.5 h and then cooled again to -78.degree. C. Additional 1M
phenylmagnesium bromide in THF (62.06 mL, 62.06 mmol) was added and
the reaction stirred at -78.degree. C. for another hour. The
reaction was then diluted with CH.sub.2Cl.sub.2 (500 mL) and
quenched with saturated ammonium chloride solution (300 mL). The
layers were separated and the organic one washed with brine (300
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. Purification by normal phase chromatography (3-8%
MeOH/CH.sub.2Cl.sub.2) yielded
(2-amino-5-fluorophenyl)(phenyl)methanone as a yellow solid. 1H NMR
(CDCl.sub.3, 400 MHz) 7.63 (m, 2H, ArH); 7.55 (m, 1H, ArH); 7.47
(m, 211, ArH); 7.15 (m, 1H, ArH); 7.08 (m, 1H, ArH); 6.70 (m, 1H,
ArH); 5.91 (s, NH.sub.2); MS (Electrospray): m/z 216.1
(M.sup.+H).
N-(2-benzoyl-4-fluorophenyl)-1H-imidazole-1-carboxamide(4-4)
[0130] To a solution of (2-amino-5-fluorophenyl)(phenyl)methanone
(6.60 g, 30.67 mmol) in CH.sub.2Cl.sub.2 (60 mL) was added
carbonyldiimidazole (6.96 g, 42.93 mmol). The reaction was heated
to 45.degree. C. After 16 h at 45.degree. C., the reaction was
cooled to ambient temperature and the precipitate isolated by
vacuum filtration and washed with fresh CH.sub.2Cl.sub.2 to give
N-(2-benzoyl-4-fluorophenyl)-1H-imidazole-1-carboxamide as a white
solid. 1H NMR (CDCl.sub.3, 400 MHz) 8.91 (s, NH); 7.47 (m, 3H,
ArH); 7.25 (m, 1H, ArH); 7.18 (m, 4H, ArH); 6.99 (m, 1H, ArH); 6.95
(s, 1H, ArH); 6.53 (m, 1H, ArH); MS (Electrospray): m/z 332.1
(M.sup.+Na).
6-fluoro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-
-2(1H)-one (4-5)
[0131] To a suspension of
N-(2-benzoyl-4-fluorophenyl)-1H-imidazole-1-carboxamide (30.00 g,
97.00 mmol) in THF (300 mL) was added 2,2,2-trifluoroethylamine
(11.53 g, 116.39 mmol). The reaction was heated to 50.degree. C.
After 19 h at 50.degree. C., the reaction was cooled to ambient
temperature. Butyl chloride (500 mL) and 10% citric acid (250 mL)
were added and the reaction stirred vigorously for 40 min. The
precipitate was then isolated by vacuum filtration and placed under
vacuum alongside P.sub.2O.sub.5 for 16 h to give
6-fluoro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazoli-
n-2(1H)-one as a yellow solid. 1H NMR (CDCl.sub.3, 400 MHz) 8.59
(s, NH); d (7.47, J=6.96 Hz, 2H, ArH); 7.36 (m, 3H, ArH); 6.99 (m,
2H, ArH); 6.79 (m, 1H, ArH); 4.39 (m, 1H, CH.sub.2); 3.56 (m, 1H,
CH.sub.2); 3.23 (s, OH); MS (Electrospray): m/z 363.0
(M.sup.+Na).
(-)-4-ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazol-
in-2(1H)-one (4-6)
[0132] To a -15.degree. C. solution of
6-fluoro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazoli-
n-2(1H)-one (3.00 g, 8.82 mmol) in THF (40 mL) was added
triethylamine (6.14 mL, 44.08 mmol). The reaction was stirred for a
couple of minutes and then thionyl chloride (0.68 mL, 9.26 mmol)
was added dropwise. After 25 min, 1M ethylmagnesium bromide in THF
(27.33 mL, 27.33 mmol) was added over 10 min. After an additional
30 min at -15.degree. C., the reaction was quenched with saturated
ammonium chloride solution (60 mL) and extracted with
CH.sub.2Cl.sub.2 (120 mL.times.2). The combined organics were
washed with brine (60 mL), dried over dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. Purification by normal phase
chromatography (0-70% EtOAc/hexanes) followed by chiral reverse
phase chromatography (ChiralPak AD packing, 10-60% iPrOH/hexanes
with DEA modifier) yielded a yellow residue that was taken up in a
minimal amount of CH.sub.2Cl.sub.2, diluted with hexanes, and then
concentrated in vacuo to give
(-)-4-ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydr-
oquinazolin-2(1H)-one. 1H NMR (CDCl.sub.3, 400 MHz) 8.26 (s, NH);
7.38 (m, 5H, ArH); 6.85 (m, 1H, ArH); 6.70 (m, 1H, ArH); 6.25 (m,
1H, ArH); 3.92 (m, 1H, CH.sub.2); 3.48 (m, 1H, CH.sub.2); 2.35 (m,
2H, CH.sub.2); 0.91 (t, J=6.87 Hz, 3H, CH.sub.3); MS
(Electrospray): m/z 353.1292 (M.sup.+H);
[.alpha.].sub.D=-41.8.degree. (c0.11, MeOH). For the
(+)-enantiomer, [.alpha.].sub.D=+41.1.degree. (c0.12, MeOH).
Example 3
##STR00006##
[0133] (2-Amino-5-chlorophenyl)(4-fluorophenyl)methanone (5-1)
[0134] To a 0.degree. C. solution of 1.0M 4-fluorophenylmagnesium
bromide in THF (196.6 mL, 196.6 mmol) was added a THF solution (100
mL) of 2-amino-5-chlorobenzonitrile (10.0 gm, 65.5 mmol) over 0.5
h. The ice bath was removed and the reaction stirred at ambient
temperature for 17 h. The brown solution was cooled in an ice bath,
treated with a drop wise addition of aqueous 1N HCl (300 mL) and
extracted with ether (2.times.250 mL). The combined organic
extracts were washed with aqueous 1N HCl (100 mL), water
(2.times.150 ml), saturated aqueous sodium bicarbonate (150 ml),
brine (100 mL), dried over MgSO.sub.4, filtered, concentrated in
vacuo to 30 mL and diluted with 60 mL hexane. The resulting
precipitate was filtered to give
(2-amino-5-chlorophenyl)(4-fluorophenyl)methanone as a yellow
solid. 1H NMR (CDCl.sub.3, 400 MHz) 7.67 (m, 2H); 7.37 (d, J=2.38
Hz, 1H); 7.25 (m, 1H); 7.16 (m, 2H); 6.70 (d, J=8.79 Hz, 1H); 5.99
(s). MS (Electrospray): m/z 250.1 (M+H).
N-[4-chloro-2-(4-fluorobenzoyl)phenyl]-1H-imidazole-1-carboxamide(5-2)
[0135] To a solution of (2-amino-5-chlorophenyl)(phenyl)methanone
(50.1 g, 200.7 mmol) in CH.sub.2Cl.sub.2 (500 mL) was added
carbonyldiimidazole (35.8 g, 220.7 mmol). The reaction was heated
to 45.degree. C. for 16 h. Additional carbonyldiimidazole (9.8 g,
60.2 mmol) was added and heating continued at 45.degree. C. for 6
h. The reaction was concentrated in vacuo and the crude foam
partitioned between methyl-tert-butylether (400 mL) and water (100
mL) with vigorous stirring. The resulting precipitate was collected
by vacuum filtration and washed with fresh water, followed by
methyl-tert-butylether and heptane to give
N-[4-chloro-2-(4-fluorobenzoyl)phenyl]-1H-imidazole-1-carboxamide
as an off-white solid. 1H NMR (d.sub.6-DMSO, 400 MHz) 11.06 (s);
7.58 (m, 1H); 7.36 (m, 3H); 7.23 (m, 2H); 7.08 (m, 3H); 6.74 (s,
1H). MS (Electrospray): m/z 366.0 (M+Na).
6-chloro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinazolin-2(1H)-one (5-3)
[0136] To a suspension of
N-[4-chloro-2-(4-fluorobenzoyl)phenyl]-1H-imidazole-1-carboxamide
(63.0 g, 183.3 mmol) in THF (315 mL) was added
2,2,2-trifluoroethylamine (24.5 g, 247.4 mmol). The reaction was
heated to 50.degree. C. After 19 h at 50.degree. C., the reaction
was cooled to ambient temperature and concentrated in vacuo. The
light yellow oil was partitioned between n-butyl chloride (110 mL)
and aqueous 10% citric acid (60 mL) with vigorous stirring. The
resulting precipitate was collected by vacuum filtration and placed
under vacuum alongside P.sub.2O.sub.5 for 16 h to give
6-chloro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-d-
ihydroquinazolin-2(1H)-one as an off-white solid. 1H NMR
(d.sub.6-DMSO, 400 MHz) 10.32 (s); 7.73 (s, 1H); 7.41 (m, 2H); 7.27
(dd, J=2.38 Hz and 8.61 Hz, 1H); 7.20 (m, 2H); 6.97 (d, J=2.38 Hz,
1H); 6.92 (d, J=8.61 Hz, 1H); 4.13 (m, 1H); 3.64 (m, 1H); 3.32 (s).
MS (Electrospray): m/z 357.1 (M+H--H.sub.2O).
6-chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroqu-
inazolin-2(1H)-one (5-4)
[0137] To a -15.degree. C. solution of
6-chloro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydr-
oquinazolin-2(1H)-one (6.20 g, 16.5 mmol) in anhydrous toluene (60
mL) was added triethylamine (11.5 mL, 82.7 mmol). The reaction was
stirred for 5 min and then thionyl chloride (1.27 mL, 17.4 mmol)
was added dropwise maintaining the temperature <-5.degree. C.
After 15 min, 1M ethylmagnesium bromide in THF (51.3 mL, 51.3 mmol)
was added over 35 min maintaining the temperature <-5.degree. C.
The reaction was warmed from -15.degree. C. to 0.degree. C. over 30
min and then poured into a vigorously stirred mixture of aqueous
10% citric acid (30 mL), ice (30 g), and ethyl acetate (50 mL). The
aqueous phase was extracted with ethyl acetate (3.times.50 mL). The
combined organics were washed with water (50 mL), brine (60 mL),
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
Purification by normal phase chromatography (0-25% EtOAc/hexanes)
gave a crude light yellow oil. Crystallization of the oil from
hexane gave racemic
6-chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one as an off-white solid. 1H NMR (CDCl.sub.3, 400
MHz) 8.19 (s, NH); 7.39 (m, 2H, ArH); 7.09 (m, 3H, ArH); 6.68 (d,
J=8.51 Hz, 1H, ArH); 6.46 (d, J=2.11 Hz, 1H, ArH); 3.84 (m, 1H,
CH.sub.2); 3.56 (m, 1H, CH.sub.2); 2.40 (m, 1H, CH.sub.2); 2.22 (m,
1H, CH.sub.2); 0.90 (t, J=7.15 Hz, 3H, CH.sub.3); MS
(Electrospray): m/z 387.1 (M.sup.+H). Racemic
6-chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4--
dihydroquinazolin-2(1H)-one (2.76 g) was resolved using chiral
reverse phase chromatography (ChiralPak AD packing, 10-30%
iPrOH/hexanes with DEA modifier at 1.0 mL/L). The enantiomers were
obtained as crystalline solids from hexane to give (+) compound as
Peak 1 and (-) compound as Peak 2. Data for Peak 2: 1H NMR
(CDCl.sub.3, 400 MHz) 8.69 (s, NH); 7.39 (m, 2H, ArH); 7.09 (m,
311, ArH); 6.70 (d, J=8.60 Hz, 1H, ArH); 6.45 (d, J=2.20 Hz, 1H,
ArH); 3.81 (m, 1H, CH.sub.2); 3.59 (m, 1H, CH.sub.2); 2.40 (m, 1H,
CH.sub.2); 2.22 (m, 1H, CH.sub.2); 0.90 (t, J=7.14 Hz, 3H,
CH.sub.3); MS (Electrospray): m/z 387.0894 (M.sup.PH);
[.alpha.].sub.D=-8.5.degree. (c0.0024, CH.sub.2Cl.sub.2). Data for
Peak 1, the (+)-enantiomer, [.alpha.].sub.D=+ 7.9.degree. (c0.0027,
CH.sub.2Cl.sub.2).
Example 4
4-Allyl-6-chloro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroqu-
inazolin-2(1H)-one
[0138] To a -40.degree. C. solution of
6-chloro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydr-
oquinazolin-2(1H)-one (21.2 g, 56.6 mmol) in anhydrous THF (170 mL)
was added triethylamine (39.4 mL, 283 mmol). The reaction was
stirred for 5 min and then thionyl chloride (4.4 mL, 59.4 mmol) was
added drop wise maintaining the temperature <-20.degree. C.
After 25 min, 1.0M allylmagnesium bromide in THF (170 mL, 170 mmol)
was added over 35 min maintaining the temperature <-10.degree.
C. The reaction was stirred <-5.degree. C. over 30 min and then
poured into a vigorously stirred mixture of aqueous 10% citric acid
(150 mL), ice (50 g), and ethyl acetate (200 mL). The aqueous phase
was extracted with ethyl acetate (3.times.100 mL). The combined
organics were washed with water (100 mL), brine (100 mL), dried
over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to give
a crude brown oil. The oil was dissolved in methylene chloride (100
mL) and stirred 1 hr. The resulting precipitate was collected by
vacuum filtration and dried under vacuum for 16 h to give racemic
4-allyl-6-chloro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4--
dihydroquinazolin-2(1H)-one as an off-white solid. 1H NMR
(d.sub.6-DMSO, 400 MHz) 9.98 (s, 1H); 7.46 (m, 2H); 7.21 (m, 3H);
6.83 (d, J=8.61 Hz, 1H); 6.54 (d, J=2.01 Hz, 1H); 5.47 (m, 1H);
5.10 (m, 2H); 4.03 (m, 1H); 3.73 (m, 1H); 3.29 (m, 1H); 3.01 (m,
1H). MS (Electrospray): m/z 399.0 (M+H).
Example 5
(-)6-Chloro-4-(4-fluorophenyl)-4-propyl-3-(2,2,2-trifluoroethyl)-3,4-dihyd-
roquinazolin-2(1H)-one
[0139] To a solution of
4-allyl-6-chloro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one (22.1 g, 55.4 mmol) in ethyl acetate (450 mL)
and under a nitrogen atmosphere was added 10% palladium on carbon
(224 mg). A balloon of hydrogen was bubbled into the stirring
mixture. The reaction was then stirred over night under an
atmosphere of hydrogen. The reaction was purged with nitrogen,
filtered through a pad of celite and the filtrate concentrated in
vacuo to give 22.3 gm (100%) of
(.+-.)-6-chloro-4-(4-fluorophenyl)-4-propyl-3-(2,2,2-trifluoroethyl)-3,4--
dihydroquinazolin-2(1H)-one as a white solid. Further purification
by chiral chromatography (ChiralPak AD packing, 30% iPrOH/heptane
with DEA modifier at 1.0 mL/L) followed by crystallization from
hexanes provided individual enantiomers of
6-chloro-4-(4-fluorophenyl)-4-propyl-3-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinazolin-2(1H)-one (Peak 1 and Peak 2). Data for Peak 2: 1H NMR
(d.sub.6-DMSO, 400 MHz) .delta. 10.02 (s, 1H); 7.43 (m, 2H); 7.20
(m, 3H); 6.84 (d, J=8.61 Hz, 1H); 6.59 (d, J=2.19 Hz, 1H); 3.80 (q,
J=9.34 Hz, 2H); 2.33 (m, 2H); 1.24 (m, 1H); 0.94 (m, 1H); 0.89 (t,
J=6.87 Hz, 3H). Exact Mass (Electrospray, M+H): Calc'd, 401.1039;
Found, 401.1040. [.alpha.].sub.D=-6.7.degree. (c0.0045, MeOH).
Optical rotation for Peak 1: [a].sub.D=+5.2.degree. (c0.0062,
MeOH).
Example 6
##STR00007##
[0140] N-(3,4-Difluorophenyl)-2,2-dimethylpropanamide(6-2)
[0141] To a 0.degree. C. solution of 5.250 g (40.663 mmol)
3,4-difluoroanailine in 75 ml dichloromethane was added 5.487 mL
(44.729 mmol) pivaloyl chloride and 6.8 mL (48.796 mmol)
triethylamine. After stirring 1 h from 0.degree. C. to room
temperature, the reaction mixture was diluted with
CH.sub.2Cl.sub.2, washed with water and brine. The organic layer
was dried over NaSO.sub.4, filtered and concentrated in vacuo to
afforded N-(3,4-difluorophenyl)-2,2-dimethylpropanamide. .sup.1H
NMR (CDCl.sub.3, 400 MHz) .delta. 7.68-7.63 (m, 1H, ArH); 7.09-7.06
(m, 2H, ArH); 1.31 (s, 9H, O.dbd.C(CH.sub.3).sub.3). ES
MS+1=214.1.
(6-amino-2,3-difluorophenyl)(4-fluorophenyl)methanone (6-4)
[0142] To a -78.degree. C. solution of 2.5 g (11.724 mmol)
N-(3,4-difluorophenyl)-2,2-dimethylpropanamide in 39 ml anhydrous
THF was added drop wise over 15 mins 18 mL (28.136 mmol) n-BuLi
(1.6M solution in cyclohexanes). After 1 hr at -78.degree. C., 4 mL
(26.966 mmol) ethyl 4-fluorobenzoate was added dropwise and the
reaction mixture stirred from -78.degree. C. to rt. After 45 mins,
the reaction mixture was cooled to 0 C and quenched with saturated
ammonium chloride and poured into a 1:1 mixture of ether:water and
warmed to room temperature. The organic phase was isolated, washed
with brine, dried over MgSO.sub.4, filtered, and concentrated in
vacuo to yield
N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide(6-3).
A solution of 3.5 g (10.706 mmol)
N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-2,2-dimethylpropanamide
in 43 mL 6N HCl and 8.6 mL DME was heated to 100.degree. C. After
24 h at 100.degree. C., the reaction mixture was cooled to room
temperature and sodium carbonate was added until reaction mixture
was basic. The reactions was diluted with water, extracted three
times with ether, and washed with brine. The organic layer was
dried over MgSO.sub.4, filtered and concentrated in vacuo.
Purification by flash chromatography (1.times.14 cm silica gel,
linear gradient 0-20% EtOAc:hexane) afforded
(6-amino-2,3-difluorophenyl)(4-fluorophenyl)methanone. .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 7.85-7.80 (m, 2H, ArH); 7.17-7.11 (m,
3H, ArH); 6.47 (ddd, J=2.01 Hz, 3.66 Hz, 9.16 Hz, 1H, ArH); 4.84
(br s, 2H, ArNH.sub.2). ES MS+1=252.1.
N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N'-(2,2,2-trifluoroethyl)urea
(open form) and
5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-di-
hydroquinazolin-2(1H)-one (closed form) (6-5)
[0143] To a 0.degree. C. solution of 0.85 g (2.89 mmol) triphosgene
in 0.5 ml ether was slowly added a solution of 2.2 g (8.76 mmol)
(6-amino-2,3-difluorophenyl)(4-fluorophenyl)methanone and 1.221 mL
(8.758 mmol) triethylamine in 17.5 mL ether. After 1 h at 0.degree.
C., a solution of 0.7 mL (8.758 mmol) trifluoroethylamine and 1.221
mL (8.758 mmol) triethylamine in 17.5 mL ether was added quickly to
the reaction mixture. The mixture was warmed to room temperature
and after 5 h at room temperature, the reaction mixture was diluted
with EtOAc, washed with saturated NaHCO.sub.3 solution and brine.
The organic layer was dried over NaSO.sub.4, filtered and
concentrated in vacuo. Added CH.sub.2Cl.sub.2 and isolated 0.740 g
of white ppt. Concentrate filtrate and purify by flash
chromatography (1.times.14 cm silica gel, linear gradient 0-50%
EtOAc:hexane) afforded 0.7490 g. Isolated a total of 1.461 g (44%)
of a 2:1.6 mixture of
N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N'-(2,2,2-trifluoroethyl)urea
(close form) and
5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-di-
hydroquinazolin-2(1H)-one (open form). Closed form .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 8.50 (br s, 1H, ArNHC.dbd.O); 7.50
(dd, J=5.31 Hz, 8.79 Hz, 2H, ArH); 7.13 (q, J=8.97 Hz, 17.03 Hz,
1H, ArH); 7.06 (t, J=8.61 Hz, 2H, ArH); 6.60-6.57 (m, 1H, ArH);
4.33-4.23 (m, 1H, NCH.sub.2CF.sub.3); 3.56-3.44 (m, 1H,
NCH.sub.2CF.sub.3). Open form .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.34 (br s, 0.8H, ArNHC.dbd.O); 7.98-7.95 (m, 0.8H, ArH);
7.84 (td, J=1.65 Hz, 5.49 Hz, 1.6H, ArH); 7.35 (q, J=9.15 Hz, 18.31
Hz, 0.8H, ArH); 7.18 (t, J=8.42 Hz, 0.8H, ArH), 5.26 (br s, 0.8H,
0=CNHCH.sub.2CF.sub.3); 3.94-384 (m, 1.6H, NCH.sub.2CF.sub.3).
4-Allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihyd-
roquinazolin-2(1H)-one (6-6)
[0144] To a solution of 5.0 g (13.289 mmol)
N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]N'-(2,2,2-trifluoroethyl)urea
(open form) and
5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-di-
hydroquinazolin-2(1H)-one (closed form) in 25 ml THF was added
9.261 mL (66.443 mmol) triethylamine. After 1 h at 80.degree. C.,
the reaction mixture was cooled to -78.degree. C. To this solution
was added 0.969 mL (13.289 mmol) thionyl chloride. After 30 mins at
-78.degree. C., 45 mL (41.195 mmol) allylmagnesium bromide (1.0M
solution in dibutyl ether) was added dropwise. After 30 minutes at
-78.degree. C., the reaction mixture was quenched with saturated
NH.sub.4Cl and warmed to room temperature. The reaction mixture was
extracted three times with EtOAc and washed with brine. The organic
layer was dried over NaSO.sub.4, filtered and concentrated in
vacuo. Purification by flash chromatography (1.times.14 cm silica
gel, linear gradient 0-35% EtOAc:hexane) afforded
4-allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihy-
droquinazolin-2(1H)-one. 1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.46
(br s, 1H, ArNHC.dbd.O); 7.42-7.40 (m, 2H, ArH); 7.10-7.00 (m, 3H,
ArH); 6.44 (m, 1H, ArH); 5.73-5.66 (m, 1H, CH2CH.dbd.CH2);
5.13-5.09 (m, 2H, CH2CH.dbd.CH2); 3.73 (m, 2H, NCH2CF3); 3.15 (m,
2H, CH2CH.dbd.CH2). HRMS (ES) exact mass calcd for
C.sub.19H.sub.14F.sub.6N.sub.2O: 401.1083, Found: 401.1075.
Example 7
[5,6-Difluoro-4-(4-fluorophenyl)-2-oxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-te-
trahydroquinazolin-4-yl]acetaldehyde
[0145] To a -78.degree. C. solution of 2.6 g (6.495 mmol)
4-allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihy-
droquinazolin-2(1H)-one in 25 ml MeOH was bubbled ozone. After 15
mins at -78.degree. C., the ozone was removed and the reaction
mixture was quenched with 4.8 mL (64.946 mmol) dimethyl sulfide.
After stirring at room temperature overnight, the reaction mixture
was diluted with EtOAc and washed three times with water and brine.
The organic layer was dried over NaSO.sub.4, filtered and
concentrated in vacuo. Afforded
[5,6-difluoro-4-(4-fluorophenyl)-2-oxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-t-
etrahydroquinazolin-4-yl]acetaldehyde. 1H NMR (CDCl.sub.3, 400 MHz)
.delta. 9.79 (s, 1H, O.dbd.CH); 8.61 (br s, 1H, ArNHC.dbd.O);
7.38-7.27 (m, 211, ArH); 7.15-7.03 (m, 3H, ArH); 6.57-6.53 (m, 1H,
ArH); 4.08 (m, 1H, C); 3.72 (dd, 1H, J=17.4 Hz, CH2C.dbd.O); 3.50
(dd, 1H J=1.28 Hz, 17.58 Hz, CH2C.dbd.O); 3.32 (m, 1H, CH2C.dbd.O).
ES MS+1=403.1.
Example 8
4-(2,2-Difluoroethyl)-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroet-
hyl)-3,4-dihydroquinazolin-2(1H)-one (6-7)
[0146] To a 0.degree. C. solution of 2.4 g (5.966 mmol)
[5,6-difluoro-4-(4-fluorophenyl)-2-oxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-t-
etrahydroquinazolin-4-yl]acetaldehyde in 15 ml CH.sub.2Cl.sub.2 was
added 2.192 mL (17.897 mmol) DAST reagent. After 30 min at
0.degree. C., the reaction mixture was poured onto ice and warmed
to room temperature. The reaction mixture was extracted three times
with CH.sub.2Cl.sub.2 and washed with brine. The organic layer was
dried over NaSO.sub.4, filtered and concentrated in vacuo.
Purification by flash chromatography (1.times.14 cm silica gel,
linear gradient 0-40% EtOAc:hexane) afforded
4-(2,2-difluoroethyl)-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroe-
thyl)-3,4-dihydroquinazolin-2(1H)-one. Chiral separation (ChiralPak
AD, 5 cm.times.50 cm, 20.mu., 1:1 Hexanes/EtOH, modifier: DEA 1
mL/L, Flow: 50 mL/min, 30 mins) afforded the second peak off chiral
column. 1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.87 (s, 1H,
ArNHC.dbd.O); 7.39-7.35 (m, 2H, ArH); 7.14-7.07 (m, 3H, ArH);
6.59-6.55 (m, 1H, ArH); 6.03 (t, 0.25H, J=4.22 Hz, CH2CHF2); 5.89
(t, 0.50H J=4.40 Hz, CH2CHF2); 5.76 (t, 0.25H, CH2CHF2); 3.82 (m,
1H, NCH2CF3); 3.63 (m, 1H, NCH2CF3); 3.10 (m, 1H, CH2CHF2); 2.93
(m, 1H, CH2CHF2). HRMS (ES) exact mass calcd for
C.sub.18H.sub.12F.sub.8N.sub.2O: 425.0895, Found: 425.0880.
Example 9
4-Ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihyd-
roquinazolin-2(1H)-one
[0147] To a solution of 1.5 g (3.987 mmol)
N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N'-(2,2,2-trifluoroethyl)urea
(open form) and
5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-di-
hydroquinazolin-2(1H)-one (closed form) in 8 ml THF was added 2.0
mL (19.933 mmol) triethylamine. After 1 h at 80.degree. C., the
reaction mixture was cooled to -78.degree. C. To this solution was
added 0.498 mL (4.186 mmol) thionyl chloride. After 30 minutes at
-78.degree. C., 5 mL (12.358 mmol) ethylmagnesium bromide (3.0M
solution in diethyl ether) was added dropwise. After 1 h at
-78.degree. C., the reaction mixture was quenched with saturated
NH.sub.4Cl and warmed to room temperature. The reaction mixture was
extracted three times with EtOAc and washed with brine. The organic
layer was dried over NaSO.sub.4, filtered and concentrated in
vacuo. Purification by flash chromatography (1.times.14 cm silica
gel, linear gradient 0-50% EtOAc:hexane) afforded
4-ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihy-
droquinazolin-2(1H)-one. Chiral Separation (ChiralPak AD column, 5
cm.times.50 cm, 20 k, 10-40% ethanol/hexane, modifier: DEA 1 mL/L,
60 mins) afforded 350 mg of the second isomer.
[.alpha.].sup.23.sub.D+0.464.degree. (c=1.23, CH.sub.2Cl.sub.2);
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.70 (br s, 1H,
ArNHC.dbd.O); 7.40 (dd, 2H, J=5.13 Hz, 8.79 Hz, ArH); 7.09-7.00 (m,
3H, ArCH); 6.53-6.50 (m, 1H, ArH); 3.84 (m, 1H, NCH.sub.2CF.sub.3);
3.50 (m, 1H, NCH.sub.2CF.sub.3); 2.56 (m, 1H, CH.sub.2CH.sub.3);
2.36 (m, 1H, CH.sub.2CH.sub.3); 0.943 (t, 3H, J=7.14 Hz,
CH.sub.2CH.sub.3). HRMS (ES) exact mass calcd for
C.sub.18H.sub.14F.sub.6N.sub.2O 389.1083, Found: 389.1063
Example 10
##STR00008##
[0148] Tert-butyl
{2-[(4-bromophenyl)(hydroxy)methyl]-4-chlorophenyl}carbamate
(7-2)
[0149] To a -78.degree. C. solution of tert-butyl
(4-chlorophenyl)carbamate (3.0 g, 13.2 mmol) in 100 ml of THF was
added TMEDA (1.53 g, 13.2 mmol) followed by sec-BuLi (21 ml, 32.9
mmol) slowly and dropwise via syringe. The reaction mixture turns
bright yellow after about half the s-BuLi was added. The reaction
mixture was allowed to stir for 15 min at -78.degree. C. then
allowed to warm to about -20.degree. C. (tip of flask in dry-ice
bath) for 1 hr, then the reaction mixture was cooled to -78.degree.
C. again. The reaction mixture was in now a dull yellow/orange,
slightly heterogeneous and 4-bromobenzaldehyde was added dropwise,
and stirred for 30 min at -78.degree. C. The reaction mixture was
quenched with 100 ml. sat NH.sub.4Cl (pink fades to yellow),
extracted with 150 ml of ether, washed with brine, dried over
MgSO.sub.4, filtered and concentrated. The crude product was
purified by silica gel chromatography using 5-30% EtOAc/hex as the
eluent to provide tert-butyl
{2-[(4-bromophenyl)(hydroxy)methyl]-4-chlorophenyl}carbamate as a
yellow solid. .sup.1H NMR: (400 MHz, CDCl.sub.3) .delta. 7.72 (d,
J=8.4 Hz, 1H), 7.48 (d, J=8.4, 1H), 7.40-7.50 (m, 1H), 7.27 (s,
1H), 7.26 (d, J=8.8 Hz, 2H), 7.02 (d, J=2.0 Hz, 1H), 5.81 (s, 1H),
4.70-4.90 (m, 1H), 1.43 (s, 9H).
tert-butyl[2-(4-bromobenzoyl)-4-chlorophenyl]carbamate (7-3)
[0150] To a solution of tert-butyl
{2-[(4-bromophenyl)(hydroxy)methyl]-4-chlorophenyl}carbamate (10 g,
25 mmol) in 100 ml CH.sub.2Cl.sub.2, was added MnO.sub.2 (10 g, 125
mmol) and the mixture was heated to 35.degree. C. for 48 hours.
Filtration and concentration gave
tert-butyl[2-(4-bromobenzoyl)-4-chlorophenyl]carbamate as a yellow
solid. .sup.1H NMR: (400 MHz, CDCl.sub.3) .delta. 9.77 (s, 1H),
8.39 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz,
2H), 7.49 (dd, J=8.8, 2.0 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 1.51 (s,
9H).
N-[4-chloro-2-(4-bromobenzoyl)phenyl]-1H-imidazole-1-carboxamide(7-4)
[0151] To a solution of
tert-butyl[2-(4-bromobenzoyl)-4-chlorophenyl]carbamate (10 g, 25
mmol) in MeOH (50 mL) at 25.degree. C. was added 2 M HCl-MeOH (100
ml), and the reaction mixture stirred for 4 h. The organic layer
was evaporated, then the residue was partitioned between
CH.sub.2Cl.sub.2 (300 ml) and water (200 ml). The organic layer was
washed with 10% Na.sub.2CO.sub.3 (to pH=9) and brine, dried over
Na.sub.2SO.sub.4 and evaporated to give 7.5 g (98% yield)
(2-amino-5-chlorophenyl)(4-bromophenyl)methanone. To a solution of
(2-amino-5-chlorophenyl)(4-bromophenyl)methanone (13 g, 42 mmol) in
500 ml CH.sub.2Cl.sub.2 was added solid carbonyldiimidazole (15.7
g, 96 mmol) portionwise. The resulting yellow solution was allowed
to stir at 40.degree. C. for 16 hrs, concentrated to give a yellow
foam. The foam was treated with 30 ml of ether and 20 ml of water
with vigorous stirring resulting in a solid precipitate. After
filtration, the cake was recrystallized from CH.sub.2Cl.sub.2/Ether
(1:5) to give
N-[4-chloro-2-(4-bromobenzoyl)phenyl]-1H-imidazole-1-carboxamide as
a yellow solid. .sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta. 11.05
(s, 1H), 7.69 (d, J=8.4Hz, 2H), 7.55 (dd, J=8.4, 1.6 Hz, 1H), 7.33
(s, 1H), 6.98.about.7.10 (m, 5H), 6.71 (d, J=2.0 Hz, 1H).
6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroq-
uinazolin-2(1H)-one (7-5)
[0152] To a solution of
N-[4-chloro-2-(4-bromobenzoyl)phenyl]-1H-imidazole-1-carboxamide
(4.0 g, 9.9 mmol) in THF (20 mL) was added
2,2,2-trifluoroethylamine (1.1 g, 10.9 mmol). The reaction was
heated to 50.degree. C. After 19 h at 50.degree. C., the reaction
was cooled to ambient temperature and concentrated in vacuo. The
light yellow foam was partitioned between n-butyl chloride (15 mL)
and aqueous 10% citric acid (15 mL) with vigorous stirring. The
resulting precipitate was collected by vacuum filtration to give
6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinazolin-2(1H)-one as a white solid. 1H NMR (CDCl.sub.3, 500 MHz)
.delta. 7.98 (s, 1H); 7.50 (br d, 2H, J=8.79 Hz); 7.34 (br d, 211,
J=8.79 Hz); 7.22 (m, 2H); 6.97 (dd, J=1.46 and 7.57 Hz, 1H); 4.35
(dq, 1H, J=8.78 and 16 Hz); 3.53 (dq, 1H, J=8.55 and 17 Hz); 3.22
(s, 1H). MS (Electrospray): m/z M+Na, Br=79, 457.0
6-Chloro-4-ethyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroqui-
nazolin-2(1H)-one
[0153] To a -18.degree. C. solution of
6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinazolin-2(1H)-one (1 g, 2.3 mmol) in anhydrous THF (10 mL) was
added triethylamine (1.6 mL, 11 mmol). The reaction was stirred for
5 min and then thionyl chloride (0.18 mL, 2.5 mmol) was added
dropwise. After 10 min, 1M ethylmagnesium bromide in THF (9 mL, 9
mmol) was added. The reaction mixture was warmed from -18.degree.
C. to 0.degree. C. and allowed to stir for 30 min and then quenched
with 15 mL 1N aqueous HCl and extracted with 50 mL ethyl acetate.
The organic layer was washed with brine (60 mL), dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Purification by
normal phase chromatography (90 g silica gel cartridge, linear
gradient 10-70% EtOAc/hexanes) gave
6-chloro-4-ethyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroqu-
inazolin-2(1H)-one as an off-white solid. 1H NMR (CDCl.sub.3, 500
MHz) .delta. 8.41 (s, NH); 7.53 (br d, 2H, J=8.79 Hz); 7.28 (br d,
2H, J=8.54 Hz); 7.11 (dd, 1H, J=8.54 and 2.19 Hz); 6.69 (d, 1H,
J=8.55 Hz); 6.46 (d, 1H, J=2.20 Hz); 3.87 (dq, 1H, J=9.28 and 16
Hz); 3.52 (dq, 1H, J=8.30 and 17 Hz); 2.39 (dq, 1H, J=7.08 and 14
Hz); 2.22 (dq, 1H, J=7.08 and 14 Hz); 0.90 (t, J=7.08 Hz, 3H); MS
(Electrospray): m/z 447.1 (M.sup.+H, Br=79).
Example 11
6-Chloro-4-ethyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroqui-
nazolin-2(1H)-one (7-6)
[0154] To a solution of 0.062 g (0.14 mmol)
6-chloro-4-ethyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroqu-
inazolin-2(1H)-one in 1 mL DMF was added 0.015 g (0.17 mmol)
copper(I) cyanide and the mixture heated in a sealed tube at
200.degree. C. for 2 hours. After cooling to room temperature, the
mixture was filtered and the resulting DMF solution purified by
preperative reverse phase chromatography (linear gradient 5 to 95%
CH.sub.3CN/H.sub.2O over 30 min, 0.05% added TFA, C18 SunFire
19.times.150 mm) to provide
6-chloro-4-ethyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroqu-
inazolin-2(1H)-one. 1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.06 (s,
NH); 7.71 (br d, 2H, J=8.24 Hz); 7.55 (br d, 2H, J=8.43 Hz); 7.14
(dd, 1H, J=8.61 and 2.20 Hz); 6.69 (d, 1H, J=8.61 Hz); 6.43 (d, 1H,
J=2.02 Hz); 3.78 (dq, 1H, J=8.97 and 18 Hz); 3.60 (dq, 1H, J=8.43
and 17 Hz); 2.44 (dq, 1H, J=7.15 and 14 Hz); 2.27 (dq, 1H, J=7.14
and 14 Hz); 0.93 (t, J=7.15 Hz, 3H); MS (Electrospray): exact mass
calculated for C.sub.i9H.sub.15ClF.sub.3N.sub.3O+H 394.0929 found
394.0937
Example 12
6-Chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihy-
droquinazolin-2(1H)-one
[0155] To a -18.degree. C. solution of
6-chloro-4-(4-bromophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydro-
quinazolin-2(1H)-one (2 g, 4.6 mmol) in anhydrous THF (20 mL) was
added triethylamine (2.6 mL, 18 mmol). The reaction was stirred for
5 min and then thionyl chloride (0.0.37 mL, 5 mmol) was added
dropwise. After 10 min, 0.5M cyclopropylmagnesium bromide in THF
(36 mL, 18 mmol) was added. The reaction mixture was warmed from
-18.degree. C. to 0.degree. C. and allowed to stir for 6 hours and
then quenched with 25 mL 1N aqueous HCl and extracted with 150 mL
ethyl acetate. The organic layer was washed with brine (100 mL),
dried over MgSO.sub.4, filtered, and concentrated in vacuo.
Purification by normal phase chromatography (120 g silica gel
cartridge, linear gradient 10-70% EtOAc/hexanes) followed by
crystallization from hexanes gave
6-chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dih-
ydroquinazolin-2(1H)-one as a green solid. 1H NMR (CDCl.sub.3, 400
MHz) .delta. 7.56 (s, NH); 7.46 (br d, 2H, J=8.61 Hz); 7.21 (dd,
1H, J=8.42 and 2.20 Hz); 7.12 (br d, 211, J=7.14 Hz); 6.85 (br m,
1H); 6.68 (d, 1H, J=8.24 Hz); 4.27 (m, 2H); 1.6 (obs, 1H); 0.77 (m,
2H); 0.19 (m, 1H); 0.09 (m, 1H); MS (Electrospray): m/z 459.0
(M.sup.PH, Br=79).
Example 13
6-Chloro-4-cyclopropyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihy-
droquinazolin-2(1H)-one
[0156] To a solution of 0.39 g (0.85 mmol)
6-chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dih-
ydroquinazolin-2(1H)-one in 2.5 mL DMF was added 0.13 g (1.4 mmol)
copper(I) cyanide and the mixture heated in a sealed tube at
190.degree. C. for 2 hours. After cooling to room temperature, the
reaction mixture was diluted with 125 mL ether, washed 2.times.100
mL water and 1.times.100 mL brine, dried over dried over
MgSO.sub.4, filtered, and concentrated in vacuo. Purification by
normal phase chromatography (40 g silica gel cartridge, linear
gradient 5-75% EtOAc/hexanes) followed by preperative chiral
chromatography (5.times.50 mm Chiralcel OD, 100% MeOH) provided the
first peak (-)
6-chloro-4-cyclopropyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dih-
ydroquinazolin-2(1H)-one. Optical rotation -83.degree. (c=0.00175
g/mL in CH.sub.2Cl.sub.2, Na lamp,) 1H NMR (CDCl.sub.3, 400 MHz)
.delta. 8.18 (s, NH); 7.64 (br d, 2H, J=7.88 Hz); 7.39 (br d, 2H,
J=6.22 Hz); 7.26 (obscured, 1H); 6.85 (br m, 1H); 6.74 (d, 1H,
J=8.24 Hz); 4.34 (m, 1H); 4.23 (br m, 1H); 1.62 (m, 1H); 0.82 (m,
2H); 0.20 (m, 1H); 0.097 (m, 1H); MS (Electrospray): exact mass
calculated for C.sub.20H.sub.15C1F.sub.3N.sub.3O+H 406.0925 found
406.0935 Collect 0.1 g second peak Optical rotation+100.degree.
(c=0.002 g/mL in CH.sub.2Cl.sub.2, Na
Example 14
##STR00009##
[0157]
N-[4-Chloro-2-(trifluoroacetyl)phenyl]-2,2-dimethyl-propanamide(8-2-
)
[0158] To a -40.degree. C. mixture of
N-(4-chlorophenyl)-2,2-dimethylpropanamide (4.0 g, 18.9 mmol) and
anhydrous tetrahydrofuran (38 ml), n-butyllithium (1.6M, 45.2 mmol)
was added under nitrogen atmosphere. The reaction was stirred for
30 minutes at -40.degree. C. and allowed to warm to 0.degree. C.
where upon the yellow homogenous mixture turned gradually darker to
a deep yellow color. After 30 minutes of stirring at 0.degree. C.,
the reaction was cooled to -40.degree. C. Ethyl trifluoroacetate
(6.1 g, 43.5 mmol) was added to the mixture and allowed to warm to
room temperature overnight. The reaction was quenched with water
(100 ml) and saturated aqueous ammonium chloride solution (80 ml).
The aqueous layer was extracted with ethyl acetate (3.times.75 ml).
Combined organic extracts were dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford a dark yellow oil. Flash
chromatography on silica gel (0-50% ethyl acetate/hexanes) afforded
N-[4-chloro-2-(trifluoroacetyl)phenyl]-2,2-dimethyl-propanamide.
.sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 11.15 (s), 8.89 (d, J=9.2
Hz, 1H), 7.92 (m, 1H), 7.65 (dd, J=2.4 and 9.2 Hz, 1H), 1.36 (s,
9H). MS (Electrospray): m/z 308.0 (M+).
1-(2-Amino-5-chlorophenyl)-2,2,2-trifluoroethanone (8-3)
[0159] 6N Hydrochloric acid (6.0M, 257 mmol) was added to
N-[4-chloro-2-(trifluoroacetyl)phenyl]-2,2-dimethylpropanamide (3.3
g, 10.7 mmol) in anhydrous dimethoxyethane (40 ml) at room
temperature and mixture was heated to reflux conditions for two
hours until no starting material was observed by LC/MS. After
cooling reaction to 0.degree. C., reaction was basified to pH 9 by
adding solid sodium bicarbonate in portions. Reaction was extracted
with ethyl acetate (3.times.150 ml), and combined organic extracts
were dried over MgSO.sub.4 and Na.sub.2SO.sub.4. After filtering
mixture, the collected filtrate was concentrated in vacuo to give a
crude yellow solid. Flash chromatography of the crude solid on
silica gel (0-25% ethyl acetate/hexanes) afforded
1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone as a yellow
solid. 1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.70 (m, 1H), 7.32 (dd,
J=2.4 and 9.2 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.46 (s, 2H). MS
(Electrospray): m/z 223.9 (M+).
6-Chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydr-
o-quinazolin-2(1H)-one (8-4)
[0160] A mixture of triethylamine (1.3 ml, 9.4 mmol) and
1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2.1 g, 9.4
mmol) in diethyl ether (18 ml) was cooled to 0.degree. C. under
nitrogen atmosphere. In a separate round bottom, triphosgene (929
mg, 3.1 mmol) in diethyl ether (11 ml) was cooled to 0.degree. C.
To the phosgene mixture at 0.degree. C. was added dropwise the
trifluoroethanone mixture. After stirring for 15 minutes, to this
reaction was added a mixture of triethylamine (1.3 ml, 9.4 mmol)
and trifluoroethylamine in diethyl ether (18 ml). The reaction
stirred for two hours at room temperature and then quenched with
water (50 ml) and washed with saturated aqueous sodium bicarbonate
solution (2.times.30 ml). The aqueous layer was extracted with
ethyl acetate (3.times.100 ml) and the combined organic extracts
were dried over Na.sub.2SO.sub.4, filtered and concentrated to give
crude material which was purified by flash chromatography on silica
gel (0-30% ethyl acetate/hexanes). This afforded
6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihyd-
roquinazolin-2(1H)-one as a yellow solid. .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 9.22 (s, 1H), 7.58 (s, 1H), 7.39 (dd, J=2.0 and
8.6 Hz, 1H), 6.84 (d, J=8.4 Hz), 4.71 (m, 1H), 4.38 (s, 1H), 4.18
(m, 1H). Exact Mass (Electrospray, M+H): Calc'd, 349.0173; Found,
349.0166.
6-Chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-
-quinazolin-2(1H)-one (8-5)
[0161] To a -78.degree. C. mixture of
6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihyd-
roquinazolin-2(1H)-one (214 mg, 0.6 mmol) and tetrahydrofuran (2.0
ml) was added triethylamine (0.4 ml, 3.1 mmol) under nitrogen
atmosphere. After stirring mixture at -78.degree. C. for 20
minutes, thionyl chloride (0.05 ml, 0.64 mmol) was added dropwise
whereupon a yellow solid precipitated in the reaction mixture
forming a thick yellow emulsion. After the emulsion was stirred at
-78.degree. C. for 30 minutes, 3.0M phenyl magnesium bromide was
added. Reaction was allowed to stir for one hour until no further
increase in desired product was observed by LC/MS. Reaction was
quenched with saturated aqueous ammonium chloride solution (10 ml)
at -78.degree. C. and mixture was allowed to warm to room
temperature. Mixture was extracted with ethyl acetate (3.times.20
ml) and combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The resulting crude oil was
purified by flash chromatography on silica gel (0-30% ethyl
acetate/hexanes) to afford an oil which was further purified by
reverse phase prep HPLC to give
6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydr-
oquinazolin-2(1H)-one as colorless oil. 1H NMR (CD.sub.3OD, 400
MHz) .delta. 7.52 (m, 5H), 7.34 (dd, J=2.4 and 8.4 Hz, 1H), 6.95
(d, J=8.4 Hz, 1H), 6.4 (m, 1H), 4.29 (m, 1H), 3.62 (m, 1H). Exact
Mass (Electrospray, M+H): Calc'd, 409.0537; Found, 409.0533.
Example 15
6-Chloro-4-(fluorophenyl)-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-
-dihydroquinazolin-2(1H)-one
[0162] Utilizing the general procedure outlined for
6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydr-
oquinazolin-2(1H)-one,
6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihyd-
roquinazolin-2(1H)-one (100 mg, 0.29 mmol) was reacted with 1.0 M
4-fluorophenyl magnesium bromide (1.0 ml, 1.0 mmol) to afford
6-chloro-4-(fluorophenyl)-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,-
4-dihydro-uinazolin-2(1H)-one as a white solid. .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. 9.50 (s, 1H), 7.51 (m, 2H), 7.29 (dd,
J=2.4 and 8.6 Hz, 1H), 7.17 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 6.53
(s, 1H), 4.43 (m, 1H), 3.52 (m, 1H). Exact Mass (Electrospray,
M+H): Calc'd, 427.0443; Found, 427.0430.
Example 16
6-Chloro-4-ethyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro--
quinazolin2(1H)-one
[0163] Utilizing the general procedure outlined for
6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydr-
oquinazolin-2(1H)-one,
6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihyd-
roquinazolin-2(1H)-one (227 mg, 0.65 mmol) was reacted with 3.0M
ethyl magnesium bromide (0.9 ml, 2.6 mmol) to afford
6-chloro-4-ethyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-
quinazolin2(1H)-one as a white solid. .sup.1H NMR (d.sub.6-DMSO,
400 MHz) .delta. 7.41 (s, 1H), 7.35 (dd, J=2.4 and 8.6 Hz, 1H),
6.88 (d, J=8.8 Hz, 1H), 4.52 (m, 1H), 4.26 (m, 1H), 2.55 (m, 1H),
2.36 (m, 1H), 0.9 (t, J=6.8 Hz, 3H). Exact Mass (Electrospray, M+H)
Calc'd, 361.0537; Found, 361.0532.
Example 17
6-Chloro-4-allyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro--
quinazolin-2(1H)-one
[0164] Utilizing the general procedure outlined for
6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydr-
oquinazolin-2(1H)-one,
6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihyd-
roquinazolin-2(1H)-one (374 mg, 1.1 mmol) was reacted with 1.0M
allyl magnesium bromide (6.4 ml, 6.4 mmol) to afford
4-allyl-6-chloro-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-
quinazolin-2(1H)-one as a colorless oil. .sup.1H NMR (CDCl.sub.3,
400 MHz) .delta. 9.88 (s, 1H), 7.29 (dd, J=2.4 and 8.6 Hz, 1H),
7.17 (s, 1H), 6.80 (d, J=8.8 Hz, 1H), 5.53 (m, 1H), 5.22 (m, 2H),
4.56 (m, 1H), 4.12 (m, 1H), 3.11 (m, 2H). MS (Electrospray): m/z
373.0 (M+).
Example 18
6-Chloro-4-propyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-
-quinazolin-2(1H)-one
[0165] A mixture of
4-allyl-6-chloro-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-
quinazolin-2(1H)-one (42 mg, 0.11 mmol), ethyl acetate (3.5 ml) and
10% Pd/C (10 mg) was placed under hydrogen atmosphere (1 atm) at
room temperature and stirred overnight. After bubbling nitrogen
through reaction mixture, the mixture was filtered through a
Celite, washing with ethyl acetate. The collected filtrate was
concentrated to give an oil which was purified by reverse phase
prep HPLC to afford
6-chloro-4-propyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydr-
oquinazolin-2(1H)-one as a white solid. .sup.1H NMR (CD.sub.3OD,
400 MHz) .delta. 7.40 (s, 1H), 7.35 (dd, J=2.4 and 8.6 Hz, 1H),
6.86 (d, J=8.8 Hz 1H), 4.45 (m, 1H), 4.27 (m, 1H), 2.47 (m, 1H),
2.17 (m, 1H), 1.23 (m, 2H), 0.96 (t, J=7.2 Hz, 3H). Exact Mass
(APCI, M+) Calc'd, 375.0644; Found, 375.0686.
Example 19
4-Butyl-6-chloro-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroq-
uinazolin-2(1H)-one
[0166] Utilizing the general procedure outlined for
6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydr-
oquinazolin-2(1H)-one,
6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihyd-
roquinazolin-2(1H)-one (100 mg, 0.3 mmol) was reacted with 1.0M
butyl magnesium chloride (1.0 ml, 1.0 mmol) to afford
4-butyl-6-chloro-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-
quinazolin-2(1H)-one as an oil. .sup.1H NMR (CD.sub.3OD, 400 MHz)
.delta. 7.41 (s, 1H), 7.35 (dd, J=2.4 and 8.4 Hz, 1H), 6.9 (d,
J=8.4 Hz, 1H), 4.55 (m, 1H), 4.29 (m, 1H), 2,50(m, 1H), 2.22 (m,
1H), 1.40 (m, 2H), 1.24 (m, 1H), 1.13 (m, 1H), 0.90 (m, 3H). Exact
Mass (Electrospray, M+H) Cal'd, 389.0850; Found, 389.0850.
Example 20
6-Chloro-4-cyclopropyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-di-
hydro-quinazolin-2(1H)-one
[0167] Utilizing the general procedure outlined for
6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydr-
oquinazolin-2(1H)-one,
6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihyd-
roquinazolin-2(1H)-one (217 mg, 0.62 mmol) was reacted with 0.5 M
cyclopropyl magnesium bromide (4.9 ml, 2.5 mmol) to afford
6-chloro-4-cyclopropyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-d-
ihydroquinazolin-2(1H)-one as an oil. .sup.1H NMR (CD.sub.3OD, 400
MHz) .delta. 7.89 (d, J=2.0 Hz, 1H), 7.36 (dd, J=2.4 and 8.6 Hz),
1H), 6.91 (dd, J=1.6 Hz and 7.6 Hz, 1H), 4.74 (m, 1H), 4.52 (m,
1H), 1.50 (m, 1H), 1.26 (m, 2H), 1.15 (m, 1H), 1.02 (m, 1H). Exact
Mass (Electrospray, M+H) Calc'd, 373.0537; Found, 373.0541.
Example 21
6-Chloro-4-(cyclopropylethynyl)-3-(2,2,2-trifluoroethyl)-4-(trifluoromethy-
l)-3,4-dihydroquinazolin-2((1H)-one
[0168] 3.0 M Ethyl magnesium bromide (0.29 ml, 0.86 mmol) was added
dropwise to a mixture of cyclopropylacetylene (0.1 ml, 1.1 mmol) in
anhydrous tetrahydrofuran (1.5 ml) at room temperature under
nitrogen atmosphere. Vigorous bubbling was observed as mixture was
allowed to stir for 40 minutes. In a separate round bottom, thionyl
chloride (0.022 ml, 0.3 mmol) was added to a -78.degree. C. mixture
of
6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihyd-
roquinazolin-2(1H)-one (100 mg, 0.29 mmol), triethylamine (0.2 ml,
1.4 mmol) and tetrahydrofuran (2.0 ml). After reaction was allowed
to stir at -78.degree. C. for 30 minutes, the cyclopropylacetylene
mixture was added. By LC/MS, less than ten percent of desired
product was observed in the reaction. An additional 3.0 equivalents
of cyclopropyl acetylene Grignard reagent was added to reaction and
stirred for 40 minutes at -78.degree. C. Reaction was quenched with
saturated aqueous ammonium chloride solution. The aqueous layer was
extracted with ethyl acetate (3.times.20 ml) and combined organic
extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give a crude oil which was purified by
flash chromatography on silica gel (0-35% ethyl acetate/hexanes).
This gave an oil which was further purified by reverse phase prep
HPLC to afford
6-chloro-4-(cyclopropylethynyl)-3-(2,2,2-trifluoroethyl)-4-(trifluorometh-
yl)-3,4-dihydroquinazolin-2((1H)-one as a white solid. .sup.1H NMR
(CD.sub.3OD, 400 MHz) .delta. 7.55 (s, 1H), 7.41 (m, 1H), 6.92 (d,
J=8.4 Hz, 1H), 4.71 (m, 1H), 4.25 (m, 1H), 1.54 (m, 1H), 0.98 (m,
2H), 0.82 (m, 2H). Exact Mass (Electrospray, M+H) Calc'd, 397.0537;
Found, 397.0515.
TABLE-US-00001 TABLE 1 The following compounds were prepared using
the foregoing methodology, but substituting the appropriately
substituted reagent, such as organometallic or amine, as described
in the foregoing examples. The requisite starting materials were
commercialy available, described in the literature or readily
synthesized by one skilled in the art of organic synthesis without
undue experimentation. parent ion STRUCTURE NAME (MH.sup.+) m/z
##STR00010## 6-CHLORO-4-ETHYL-4-PHENYL-
3-(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 369.0
##STR00011## 6-CHLORO-4-ETHYL-4-(4- FLUOROPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 387.0
##STR00012## 6-CHLORO-4-ETHYL-4-(-4- METHOXYPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 399.0
##STR00013## 6-CHLORO-4-ETHYL-4-(-3- METHOXYPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 399.0
##STR00014## 6-CHLORO-4-ETHYL-4-(4- METHYLPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 383.0
##STR00015## 6-CHLORO-4-ETHYL-4-(3- METHYLPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 383.0
##STR00016## 6-CHLORO-4-ETHYL-4-(3- CHLOROPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 403.0
##STR00017## 6-CHLORO-4-ETHYL-4-(3- FLUOROPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 387.0
##STR00018## 6-CHLORO-4-ETHYL-4-(4- CHLOROPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 403.0
##STR00019## 6-CHLORO-4-ETHYL-4-(4- DIMETHYLAMINOPHENYL)-3-
(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 412.1
##STR00020## 6-CHLORO-4-ETHYL-4-(2- METHOXYPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 399.1
##STR00021## 6-FLUORO-4-ETHYL-4-PHENYL-
3-(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 353.1
##STR00022## 6-CHLORO-4-ETHYL-4-(3,4- DIFLUOROPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 405.1
##STR00023## 6-FLUORO-4-ETHYL-4-PHENYL- 3-(2,2-DIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 335.1 ##STR00024##
6-FLUORO-4-BUTYL-4-PHENYL- 3-(2,2-DIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 363.2 ##STR00025##
6-FLUORO-4-ETHYL-4-(4- FLUOROPHENYL)-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 371.1 ##STR00026## 6-CHLORO-4-
METHOXYMETHYL-4-PHENYL- 3-(2,2,2-TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 385.1 ##STR00027##
6-CHLORO-4-ETHOXYMETHYL- 4-PHENYL-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 399.1 ##STR00028##
4-ETHYL-4-(4-FLUORO-PHENYL)- 3-(2,2,2-TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 353.1 ##STR00029##
6-FLUORO-4-ALLYL-4-PHENYL- 3-(2,2,2-TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 365.1 ##STR00030## 6-FLUORO-4-(2,2-
DIMETHYLPROPYL)-4-PHENYL- 3-(2,2,2-TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 395.2 ##STR00031##
6-FLUORO-4-(2-PHENYL-2- METHYLPROPYL)-4-PHENYL-3-
(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 457.2
##STR00032## 6-FLUORO-4-ETHYL-4-PHENYL- 3-(2-FLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 317.1 ##STR00033##
6-FLUORO-4-BUTYL-4-PHENYL- 3-(2-FLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 345.2 ##STR00034##
6-FLUORO-4-ETHYL-4-PHENYL- 3-(2,2,3,3,3- PENTAFLUOROPROPYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 403.1 ##STR00035##
6-FLUORO-4-BUTYL-4-PHENYL- 3-(2,2,3,3,3-PENTAFLUOROPROPYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 431.2 ##STR00036##
6-FLUORO-4-ETHYL-4-PHENYL- 3-(2,2-DIFLUOROPROPYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 349.2 ##STR00037##
6-FLUORO-4-BUTYL-4-PHENYL- 3-(2,2-DIFLUOROPROPYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 377.2 ##STR00038##
6-FLUORO-4-PENTYL-4-PHENYL- 3-(2,2-DIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 377.2 ##STR00039##
5-FLUORO-4-ETHYL-4-PHENYL- 3-(2,2,2-TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ON 353.1 ##STR00040##
6-CHLORO-5-FLUORO-4-ETHYL- 4-PHENYL-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 387.1 ##STR00041##
6-FLUORO-4-(1-PROPYNYL)-4- PHENYL-3-(2,2- DIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 345.1 ##STR00042##
3-(2,2-difluoroethyl)-4-[2-(1,3-
dioxan-2-yl)ethyl]-6-fluoro-4-phenyl-
3,4-dihydroquinazolin-2(1H)-one 421.3 ##STR00043##
6-FLUORO-4-(2-PROPENYL)-4- PHENYL-3-(2,2- DIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 347.1 ##STR00044##
6-FLUORO-4-BUTYL-4-PHENYL 3-(2,2-DIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 440.2 ##STR00045##
6-FLUORO-4-ETHYL-4-(4- THIOMETHYLPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 399.1
##STR00046## 6-FLUORO-4-CYCLOPROPYL-4- PHENYL-3-(2,2-
DIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 347.1 ##STR00047##
3-(2,2-difluoroethyl)-6-fluoro-4- phenyl-4-(phenylethynyl)-3,4-
dihydroquinazolin-2(1H)-one 407.1 ##STR00048##
6-CHLORO-4-ETHYL-4-(4- FLUOROPHENYL)-3-(2,2- DIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 369.1 ##STR00049##
6-FLUORO-4,4-DIPHENYL-3-(2,2- DIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 383.3 ##STR00050##
3-(2,2-difluoroethyl)-4-(2-ethylbutyl)- 6-fluoro-4-phenyl-3,4-
dihydroquinazolin-2(1H)-one 391.2 ##STR00051##
3-(2,2-difluoroethyl)-6-fluoro-4- phenyl-4-(2-phenylethyl)-3,4-
dihydroquinazolin-2(1H)-one 411.2 ##STR00052##
3-(2,2-difluoroethyl)-6-fluoro-4-
phenyl-4-(2-(4-chlorophenyl)ethyl)- 3,4-dihydroquinazolin-2(1H)-one
445.1 ##STR00053## 3-(2,2-difluoroethyl)-6-fluoro-4-
phenyl-4-(2-(3-chlorophenyl)ethyl)- 3,4-dihydroquinazolin-2(1H)-one
445.1 ##STR00054## 3-(2,2-difluoroethyl)-6-fluoro-4-
phenyl-4-(2-(4-fluorophenyl)ethyl)- 3,4-dihydroquinazolin-2(1H)-one
429.2 ##STR00055## 3-(2,2-difluoroethyl)-6-fluoro-4-
phenyl-4-(2-(4- methoxyphenyl)ethyl)-3,4-
dihydroquinazolin-2(1H)-one 441.2 ##STR00056##
3-(2,2-difluoroethyl)-6-fluoro-4- phenyl-4-(2-(3-
methoxyphenyl)ethyl)-3,4- dihydroquinazolin-2(1H)-one 441.2
##STR00057## 5-FLUORO-4-CYCLOPROPYL-4- PHENYL-3(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 365.1
##STR00058## 6-FLUORO-4-METHYL-4- PHENYL-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 339.1
##STR00059## 6-FLUORO-4-PROPYL-4-PHENYL-
3-(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 367.1
##STR00060## 6-FLUORO-4-CYCLOPROPYL-4- PHENYL-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 365.1
##STR00061## 6-FLUORO-4-CYCLOPROPYL-4- (4-FLUOROPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 383.1
##STR00062## 6-CHLORO-4-CYCLOPROPYL-4- (4-FLUOROPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 399.1
##STR00063## 6-CHLORO-4-CYCLOPROPYL-4- PHENYL-342,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 381.1
##STR00064## 5,6-DIFLUORO-4-ETHYL-4- PHENYL-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 371.1
##STR00065## 6-CHLORO-4-ETHYL-4-(4- FLUOROPHENYL)-3-(2,2-
DIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 369.1 ##STR00066##
5,8-DIFLUORO-4-ETHYL-4- PHENYL-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 371.1 ##STR00067##
5,8-DIFLUORO-4-METHYL-4- PHENYL-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 357.1 ##STR00068##
5,8-DIFLUORO-4-ETHYL-4- PHENYL-3-(2,2- DIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 353.1 ##STR00069## 6-FLUORO-4-
CYCLOPROPYLMETHYL-4- PHENYL-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 361.2 ##STR00070##
5-FLUORO-4-ETHYL-4-PHENYL- 3-(2,2,2-TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 371.1 ##STR00071##
6-CHLORO-4-(3-PROPENYL)-4- PHENYL-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 381.1 ##STR00072## 6-CHLORO-4-
CYCLOPROPYLMETHYL-4-(4- FLUOROPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 413.1
##STR00073## 6-CHLORO-4- CYCLOPROPYLMETHYL-4- PHENYL-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 395.1
##STR00074## 5,6-DIFLUORO-4-PROPYL-4- PHENYL-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 385.1
##STR00075## 6-CHLORO-4-ETHYL-4-(3- CYANOPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 394.1
##STR00076## 6-CHLORO-4-(3- FORMYLMETHYL)-4-PHENYL-3-
(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 383.1
##STR00077## 6-CHLORO-4-(3- HYDROXYETHYL)-4-PHENYL-3-
(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 385.1
##STR00078## 6-CHLORO-4- (METHOXYCARBONYL)-4- PHENYL-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 399.1
##STR00079## 6-CHLORO-4-CYCLOPROPYL-4-
(3,4-DIFLUOROPHENYL)-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 417 ##STR00080##
4[2-(benzylamino)ethyl]-6-chloro-4-
phenyl-3-(2,2,2-trifluoroethyl)-3,4- dihydroquinazolin-2(1H)-one
474.1 ##STR00081## 6-CHLORO-4-(3-PROPENYL)-4-
(3,4-DIFLUOROPHENYL)-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 417 ##STR00082##
6-CHLORO-4-PROPYL-4-(3,4- DIFLUOROPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 419 ##STR00083##
6-CHLORO-4-(2,2- DIFLUOROETHYL)-4-PHENYL-3-
(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 405
##STR00084## 6-CHLORO-4-(2- FLUOROETHYL)-4-PHENYL-3-
(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 387
##STR00085## 5,6-DIFLUORO-4- CYCLOPROPYLMETHYL-4-(4-
FLUOROPHENYL)-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 415
##STR00086## 6-CHLORO-4-(2- ETHOXYETHYL)-4-PHENYL-3-
(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 413.1
##STR00087## 6-CHLORO-4-(2- METHOXYETHYL)-4-PHENYL-3-
(2,2,2-TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 399.1
##STR00088## 6-CHLORO-4-PROPYL-4- PHENYL-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 383.1
##STR00089## 5,6-DIFLUORO-4-(2- FLUOROETHYL)-4-(4-
FLUOROPHENYL)-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 407.0 ##STR00090## 6-CHLORO-4-
(2HYDROXYETHYL)-4-(4- FLUOROPHENYL)-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 403 ##STR00091## 6-CHLORO-4-(2,2-
DIFLUOROETHYL)-4-(4- FLUOROPHENYL)-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 423.0 ##STR00092## 6-CHLORO-4-(2-
FLUOROETHYL)-4-(4- FLUOROPHENYL)-3-(2,2,2- TRIFLUOROETHYL)-3,4-
DIHYDROQUINAZOLIN-2(1H)- ONE 405 ##STR00093##
6-CHLORO-4-(3-PROPENYL)-4-(4- FLUOROPHENYL)-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN-2(1H)- ONE 399
Example 22
##STR00094##
[0169]
N-[4-chloro-2-(cyclopropylcarbonyl)phenyl]-N'-(2,2,2-trifluoroethyl-
)urea (9-2)
[0170] To a solution of 0.51 g (2.6 mmol)
(2-amino-5-chlorophenyl)(cyclopropyl)-methanone (4-1, Tetrahedron
Lett 1994, 35, 6811) in 5 mL 1,2-dichloroethane was added 0.5 g
(3.1 mmol) carbonyldiimidazole and the reaction mixture heated to
60 degrees for 18 hours. Upon cooling to room temperature, 0.3 mL
(3.9 mmol) 2,2,2-trifluoroethylamine was added and the reaction
mixture heated to 60 degrees another 18 hours. Upon cooling the
mixture was diluted with 100 mL CH.sub.2Cl.sub.2, washed with 100
mL each of 10% KHSO.sub.4, water and brine then dried over
MgSO.sub.4 and concentrated to give
N-[4-chloro-2-(cyclopropyl-carbonyl)-phenyl]-N'-(2,2,2-trifluoroethyl)ure-
a. 1H NMR (CDCl.sub.3, 400 MHz) 11.06 (s, 1H); 8.49 (d, J=8.97 Hz,
1H); 8.03 (d, J=2.39 Hz, 1H); 7.47 (dd, J=2.56 and 9.15 Hz, 1H);
5.00 (t, J=6.08 Hz, 1H); 3.93 (dq, J=6.59 and 8.97 Hz, 2H); 2.64
(tt, J=4.58 and 7.88 Hz, 1H); 1.26 (m, 2H); 1.39 (m, 2H).
Electrospray mass spectrum M+H=321.0.
6-chloro-4-cyclopropyl-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquina-
zolin-2(1H)-one (9-3)
[0171] To a 0.degree. C. solution of 0.33 g (1 mmol)
N-[4-chloro-2-(cyclopropylcarbonyl)-phenyl]-N'-(2,2,2-trifluoroethyl)urea
was added 0.091 g (2.2 mmol, 60% dispersion in mineral oil) sodium
hydride and the reaction mixture was allowed to warm to room
temperature and stir 16 hours. The reaction was quenched with 100
mL saturated aqueous NH.sub.4Cl solution and extracted with 200 mL
EtOAc. The extract was washed with 100 mL brine, dried over
MgSO.sub.4, filtered, and concentrated. Purification by automated
flash chromatography (40 g silica gel cartridge, 10-50%
EtOAc/hexanes over 15 min) afforded 223 mg starting ketone and 83
mg of
6-chloro-4-cyclopropyl-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquin-
azolin-2(1H)-one. 1H NMR (CDCl.sub.3, 400 MHz) 7.74 (s, 1H); 7.41
(d, J=2.19 Hz, 1H); 7.27 (dd, obscured by CHCl3, 1H); 6.74 (d,
J=8.42 Hz, 1H); 4.6 (m, 1H); 4.15 (m, 1H); 1.20 (m, 1H); 0.86 (m,
1H); 0.64 (m, 1H); 0.44 (m, 2H). Electrospray mass spectrum
M+H=321.0
6-chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquin-
azolin-2(1H)-one (9-4)
[0172] To a 0.degree. C. solution of 0.08 g (0.25 mmol)
6-chloro-4-cyclopropyl-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquin-
azolin-2(1H)-one in 3 mL toluene was added 0.17 mL (1.25 mmol) Et3N
and 0.018 mL (0.25 mmol) SOCl.sub.2. After 20 min at 0.degree. C. 1
mL (1 mmol, 1M solution in ether) isobutyl magnesium bromide was
added and the reaction mixture was stirred 30 minutes before an
additional 0.5 mL (0.5 mmol) isobutyl magnesium bromide was added
and the reaction mixture was allowed to warm to room temperature.
The reaction mixture was quenched with 75 mL saturated aqueous
NH.sub.4Cl solution and extracted with 100 mL EtOAc. The extract
was washed with 75 mL brine, dried over MgSO4, filtered, and
concentrated. Purification by flash chromatography (1.times.10 cm
silica gel, linear gradient 10-35% EtOAc/hexanes) followed by
preparative HPLC (YMC C18 PRO 20.times.150 mm, linear gradient
5-95% CH3CN/H2O 0.05% added TFA, over 30 min) to afford afforded
6-chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroqui-
nazolin-2(1H)-one. 1H NMR (CDCl.sub.3, 400 MHz) 8.17 (s, 1H); 7.43
(d, J=2.20 Hz, 1H); 7.15 (dd, J=2.38 and 8.61 Hz, 1H); 6.62 (d,
J=8.42 Hz, 1H); 4.50 (dq, J=15.4 and 8.61 Hz, 1H); 3.96 (dq, J=15.4
and 8.60 Hz, 1H); 1.56 (m, 1H); 1.41 (dd, J=14.8 and 5.31 Hz, 1H);
1.23 (dd, J=14.8 and 5.68 Hz, 1H); 0.88 (m, 1H); 0.80 (d, J=6.59
Hz, 3H); 0.78 (m, 1H); 0.69 (m, 2H); 0.55 (d, J=6.59 Hz, 3H). High
resolution mass spec (FT/ICR): calc M+H=361.1289, found
361.1283.
TABLE-US-00002 TABLE 2 The following compounds were prepared using
the foregoing methodology, but substituting the appropriately
substituted reagent, such as organometallic or amine, as described
in the foregoing examples. The requisite starting materials were
commercialy available, described in the literature or readily
synthesized by one skilled in the art of organic synthesis without
undue experimentation. parent ion STRUCTURE NAME (MH.sup.+) m/z
##STR00095## 6-CHLORO-4- CYCLOPROPYL-4-ETHYL-3-
(2-FLUOROETHYL)-3,4- DIHYDROQUINAZOLIN- 2(1H)-ONE 297.1
##STR00096## 4-BUTYL-6-CHLORO-4- CYCLOPROPYL-3-(2,2,2-
TRIFLUOROETHYL)-3,4- DIHYDROQUINAZOLIN- 2(1H)-ONE 361.1
##STR00097## 4-butyl-6-chloro-4-cyclopropyl-
3-(2,2-difluoroethyl)-3,4- dihydroquinazolin-2(1H)-one 343.1
##STR00098## 4-butyl-6-chloro-4-cyclopropyl- 3-(2-fluoroethyl)-3,4-
dihydroquinazolin-2(1H)-one 325.1
[0173] While the invention has been described and illustrated with
reference to certain particular embodiments thereof, those skilled
in the art will appreciate that various adaptations, changes,
modifications, substitutions, deletions, or additions of procedures
and protocols may be made without departing from the spirit and
scope of the invention.
* * * * *