U.S. patent application number 12/008696 was filed with the patent office on 2009-02-26 for piperazine derivatives and methods of use.
Invention is credited to Ben C. Askew, Kaustav Biswas, Jennifer N. Chau, Jian J. Chen, Derin C. D'Amico, Christopher H. Fotsch, Nianhe Han, Scott Harried, Aiwen Li, Qingyian Liu, Thomas Nguyen, Nobuku Nishimura, Rana Nomak, Tanya Peterkin, Wenyuan Qian, Babak Riahi, Kevin Yang, Chester Chenguang Yuan, Jiawang Zhu.
Application Number | 20090054460 12/008696 |
Document ID | / |
Family ID | 34710016 |
Filed Date | 2009-02-26 |
United States Patent
Application |
20090054460 |
Kind Code |
A1 |
Chen; Jian J. ; et
al. |
February 26, 2009 |
Piperazine derivatives and methods of use
Abstract
Selected compounds are effective for treatment of pain and
diseases, such as inflammation mediated diseases. The invention
encompasses novel compounds, analogs, prodrugs and pharmaceutically
acceptable derivatives thereof, pharmaceutical compositions and
methods for prophylaxis and treatment of diseases and other
maladies or conditions involving pain, inflammation, and the like.
The subject invention also relates to processes for making such
compounds as well as to intermediates useful in such processes.
Inventors: |
Chen; Jian J.; (Camarillo,
CA) ; Askew; Ben C.; (Marshfield, MA) ;
Biswas; Kaustav; (Calabasas, CA) ; Chau; Jennifer
N.; (Santa Ana, CA) ; D'Amico; Derin C.;
(Newbury Park, CA) ; Harried; Scott; (Woodland
Hills, CA) ; Nguyen; Thomas; (Thousand Oaks, CA)
; Qian; Wenyuan; (Camarillo, CA) ; Zhu;
Jiawang; (Thousand Oaks, CA) ; Fotsch; Christopher
H.; (Thousand Oaks, CA) ; Li; Aiwen; (Westlake
Village, CA) ; Liu; Qingyian; (Camarillo, CA)
; Nishimura; Nobuku; (West Hills, CA) ; Peterkin;
Tanya; (Woodland Hills, CA) ; Riahi; Babak;
(Woodland Hills, CA) ; Yuan; Chester Chenguang;
(Newbury Park, CA) ; Han; Nianhe; (Thousand Oaks,
CA) ; Nomak; Rana; (Istanbul, TR) ; Yang;
Kevin; (San Gabriel, CA) |
Correspondence
Address: |
AMGEN INC.
1120 VETERANS BOULEVARD
SOUTH SAN FRANCISCO
CA
94080
US
|
Family ID: |
34710016 |
Appl. No.: |
12/008696 |
Filed: |
January 11, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10874086 |
Jun 21, 2004 |
7393852 |
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12008696 |
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60480303 |
Jun 20, 2003 |
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Current U.S.
Class: |
514/255.02 ;
544/383 |
Current CPC
Class: |
A61P 1/16 20180101; C07D
405/14 20130101; A61P 39/02 20180101; C07D 409/12 20130101; A61P
31/22 20180101; A61P 11/00 20180101; A61P 25/00 20180101; A61P
37/08 20180101; A61P 35/04 20180101; A61P 27/06 20180101; A61P
25/04 20180101; A61P 41/00 20180101; A61P 29/00 20180101; C07D
401/12 20130101; A61P 11/06 20180101; A61P 1/18 20180101; A61P
17/02 20180101; A61P 35/00 20180101; A61P 17/00 20180101; A61P
25/06 20180101; A61P 27/16 20180101; A61P 25/28 20180101; A61P
13/12 20180101; A61P 17/06 20180101; A61P 3/10 20180101; A61P 17/16
20180101; A61P 9/14 20180101; C07D 405/12 20130101; A61P 13/10
20180101; A61P 21/00 20180101; A61P 13/02 20180101; A61P 25/08
20180101; A61P 27/02 20180101; C07D 241/08 20130101; A61P 31/04
20180101; C07D 413/14 20130101; A61P 17/04 20180101; A61P 31/18
20180101; A61P 9/00 20180101; A61P 9/10 20180101; C07D 245/02
20130101; C07D 409/14 20130101; A61P 19/02 20180101; A61P 7/10
20180101; A61P 1/04 20180101; A61P 11/02 20180101; A61P 25/32
20180101; C07D 403/12 20130101; A61P 31/12 20180101; C07D 243/08
20130101; A61P 43/00 20180101 |
Class at
Publication: |
514/255.02 ;
544/383 |
International
Class: |
A61K 31/495 20060101
A61K031/495; C07D 241/04 20060101 C07D241/04 |
Claims
1-117. (canceled)
118. A compound of Formula I ##STR00109## wherein q is 1; wherein t
is 1; wherein X is selected from NH; wherein R is selected from: a)
1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl,
indan-1-yl or indan-2-yl substituted with one to three basic
moieties, and optionally substituted with one to three groups
independently selected from halo, hydroxyl, cyano, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, and b) 1,2,3,4-tetrahydronaphth-1-yl,
1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl or indan-2-yl optionally
substituted with one to three groups independently selected from
halo, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; wherein R.sup.1 is selected from H,
C.sub.1-4-alkyl, substituted C.sub.1-4-alkyl, aryl and substituted
aryl; wherein R.sup.2 is selected from arylalkenyl, aryl, and
heterocyclyl selected from thienyl, quinolinyl, isoquinolinyl,
3-pyridyl, thiazol-4-yl, 4-imidazolyl, benzofuryl, benzoxadiazolyl,
benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, isoxazolthienyl,
benzothienyl, thieno[3,2-c]pyridinyl, and tetrahydroisoquinolinyl,
wherein R.sup.2 is optionally substituted with one to five groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; wherein R.sup.3, R.sup.3a, R.sup.4,
R.sup.4a, R.sup.5 and R.sup.5a are independently selected from H,
C.sub.1-3 alkyl and substituted C.sub.1-3 alkyl; or wherein R.sup.3
and R.sup.3a together form oxo, or R.sup.4 and R.sup.4a together
form oxo, or R.sup.5 and R.sup.5a together form oxo; wherein
R.sup.8 and R.sup.8'independently are H or selected from lower
alkyl, aryl and heteroaryl, each of which is optionally substituted
with one, two or three groups independently selected from lower
alkyl, halogen, lower alkoxy, hydroxy, amino, mono- or
dialkylamino, and trifluoromethyl; wherein R.sup.x is selected from
H, (C.sub.1-C.sub.3)haloalkyl, and (C.sub.1-C.sub.3)alkyl; and
wherein each substituted alkyl, substituted aryl, heteroaryl,
substituted heteroaryl, substituted cycloalkyl and substituted
saturated or partially saturated heterocyclyl is substituted with
one to three groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, (C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)haloalkyl, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8', or pharmaceutically acceptable salts
thereof; provided the basic substiuent is not 2-pyridyl, 3-pyridyl
or 2-oxo-piperaziny-4-ylmethyl.
119. Compound of claim 118 wherein R is selected from
1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl,
indan-1-yl or indan-2-yl substituted with one to two basic
moieties, and optionally substituted with one to three groups
independently selected from halo, hydroxyl, cyano, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl.
120. Compound of claim 118 wherein R.sup.1 is H or methyl.
121. Compound of claim 118 wherein R.sup.2 is selected from
phenyl-(C.sub.2-4)-alkenyl, phenyl, naphthyl, 5-membered nitrogen
containing heteroaryl, 5-membered sulfur containing heteroaryl,
6-membered nitrogen containing heteroaryl, 9-membered heterocyclyl,
and 10-membered heterocyclyl.
122. Compound of claim 118 wherein R.sup.2 is selected from
phenyl-CH.dbd.CH--, tetrahydronaphthyl, naphtho[2,3-d]dioxolyl,
benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl,
2-thienyl, isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl,
naphthyl, phenyl, 3-pyridinyl, tetrahydroisoquinolinyl, quinolinyl
and isoquinolinyl; wherein R.sup.2 is optionally substituted with
one to five groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, (C.sub.1-C.sub.6)alkylamino, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8',
--NR.sup.8C(O)R.sup.8', (C.sub.1-C.sub.6)alkyl, substituted
(C.sub.1-C.sub.6)alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl,
substituted saturated or partially saturated heterocyclyl and
unsubstituted saturated or partially saturated heterocyclyl,
wherein each substituted (C.sub.1-C.sub.6)alkyl, substituted aryl
substituted heteroaryl and substituted saturated or partially
saturated heterocyclyl is optionally substituted with one to three
groups independently selected from halo, --NH.sub.2, hydroxyl,
cyano, (C.sub.1-C.sub.4)alkylamino, (C.sub.1-C.sub.4)haloalkyl,
oxo, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, di(C.sub.1-C.sub.4)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'.
123. Compound of claim 122 wherein R.sup.2 is selected from
phenyl-CH.dbd.CH--, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl,
thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and
5-isoquinolyl; and wherein R.sup.2 is optionally substituted.
124. Compound of claim 118 wherein R.sup.2 is selected from
2,4,6-trimethylphenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl,
4-chloro-3-methylphenyl, 3-trifluoromethylphenyl,
4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-methoxyphenyl,
4-methylphenyl, 4-chlorophenyl and 4-tert-butylphenyl.
125. Compound of claim 118 wherein the basic substituent on R is
selected from amino, cycloalkylamino(C.sub.1-C.sub.6)alkyl,
cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy-C.sub.1-6-alkoxy,
amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-4-alkylamino-C.sub.2-6-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-6-alkenyl,
heterocyclyl-(C.sub.1-C.sub.6)alkylamino(C.sub.2-C.sub.6)alkyl, 5-6
membered heterocyclyloxy, 5-6 membered nitrogen-containing
heterocyclyl and 5-8 membered nitrogen-containing
heterocyclyl-alkyl; and wherein each of said basic substituents is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano, --CF.sub.3,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'.
126. The compound of claim 125 wherein the basic substituent on R
is selected from amino, mono-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
di-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
mono-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl,
di-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-4-alkenyl, optionally
substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8
membered nitrogen-containing heterocyclyl-C.sub.1-4-alkyl.
127. The compound of claim 126 wherein the basic substituent on R
is selected from amino, aminomethyl, isopropylaminomethyl,
t-butylaminomethyl, 2-t-butylaminoethyl,
2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl,
1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl,
N-isobutyl-aminomethyl, N-isobutyl-aminoethyl,
(2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl,
N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl,
N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl,
N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropyl-aminomethyl,
N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl,
N,N-diethyl-aminomethyl, N,N-di(t-butyl)-aminomethyl,
cyclopropylaminomethyl, cyclopropylaminoethyl,
cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl,
cyclobutylaminomethyl, cyclobutylaminoethyl,
cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl,
4,5-dihydro-imidazolyl, 1-piperidinylmethyl,
4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,
3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,
4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)-piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl.
128. The compound of claim 118 wherein R.sup.3 and R.sup.3a
together form oxo; wherein R.sup.4 and R.sup.4a are independently
selected from H and C.sub.1-3 alkyl; and wherein R.sup.5 and
R.sup.5a are independently H.
129. The compound of claim 118 wherein R.sup.8 and R.sup.8'
independently are H or selected from lower alkyl, aryl and
heteroaryl, each of which is optionally substituted with one, two
or three groups independently selected from lower alkyl, halogen,
lower alkoxy, hydroxy, amino, mono-alkylamino, dialkylamino, and
trifluoromethyl.
130. Compound of claim 118 wherein R.sup.x is H, methyl or
trifluoromethyl.
131. The compound of claim 118 having the structure II:
##STR00110## wherein X is NH; wherein R is selected from is
selected from 1,2,3,4-tetrahydronaphth-1-yl,
1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl or indan-2-yl substituted
with one to three basic moieties, and optionally substituted with
one to three groups independently selected from halo, hydroxyl,
cyano, oxo, (C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein R.sup.1 is selected from H,
C.sub.1-4-alkyl, substituted C.sub.1-4-alkyl, aryl and substituted
aryl; wherein R.sup.2 is selected from arylalkenyl, aryl, and
heterocyclyl selected from thienyl, quinolinyl, isoquinolinyl,
3-pyridyl, thiazol-4-yl, 4-imidazolyl, benzofuryl, benzoxadiazolyl,
benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, isoxazolthienyl,
benzothienyl, thieno[3,2-c]pyridinyl, and tetrahydroisoquinolinyl,
wherein R.sup.2 is optionally substituted with one to five groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; wherein R.sup.3, R.sup.3a, R.sup.4,
R.sup.4a, R.sup.5 and R.sup.5a are independently selected from H,
C.sub.1-3 alkyl, and substituted alkyl; or wherein R.sup.3 and
R.sup.3a together form oxo, or R.sup.4 and R.sup.4a together form
oxo, or R.sup.5 and R.sup.5a together form oxo; wherein R.sup.8 and
R.sup.8' independently are H or selected from lower alkyl, aryl and
heteroaryl, each of which is optionally substituted with one, two
or three groups independently selected from lower alkyl, halogen,
lower alkoxy, hydroxy, amino, mono- or dialkylamino, and
trifluoromethyl; wherein R.sup.x is selected from H,
(C.sub.1-C.sub.3)haloalkyl, and (C.sub.1-C.sub.3)alkyl; and wherein
each substituted alkyl, substituted aryl, heteroaryl, substituted
heteroaryl, substituted cycloalkyl and substituted saturated or
partially saturated heterocyclyl is substituted with one to three
groups independently selected from halo, --NH.sub.2, hydroxyl,
cyano, (C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl,
oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8', or pharmaceutically acceptable salts
thereof; provided the basic substiuent is not 2-pyridyl, 3-pyridyl
or 2-oxo-piperaziny-4-ylmethyl.
132. Compound of claim 131 wherein R is selected from
1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl,
indan-1-yl or indan-2-yl substituted with one to two basic
moieties, and optionally substituted with one to three groups
independently selected from halo, hydroxyl, cyano, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl.
133. Compound of claim 132 wherein R is selected from
1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl,
indan-1-yl or indan-2-yl; substituted with a basic moiety,
optionally substituted with chloro.
134. Compound of claim 131 wherein R.sup.1 is H or methyl.
135. Compound of claim 131 wherein R.sup.2 is selected from
phenyl-CH.dbd.CH--, tetrahydronaphthyl, naphtho[2,3-d]dioxolyl,
benzofuranyl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl,
1H-pyrazolyl, thienyl, isoxazolthienyl, benzothienyl,
thieno[3,2-c]pyridinyl, naphthyl, phenyl, pyridinyl,
tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl; wherein
R.sup.2 is optionally substituted with one to five groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.4)alkylamino, (C.sub.1-C.sub.4)haloalkyl, oxo,
(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, di(C.sub.1-C.sub.4)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'.
136. Compound of claim 131 wherein the basic substituent on R is
selected from amino, cycloalkylamino(C.sub.1-C.sub.6)alkyl,
cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy-C.sub.1-6-alkoxy,
amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-4-alkylamino-C.sub.2-6-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-6-alkenyl,
heterocyclyl-(C.sub.1-C.sub.6)alkylamino(C.sub.2-C.sub.6)alkyl, 5-6
membered heterocyclyloxy, 5-6 membered nitrogen-containing
heterocyclyl and 5-7 membered nitrogen-containing
heterocyclyl-alkyl; and wherein each of said basic substituents is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano, --CF.sub.3,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'.
137. The compound of claim 131 wherein the basic substituent on R
is selected from amino, aminomethyl, isopropylaminomethyl,
t-butylaminomethyl, 2-t-butylaminoethyl,
2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl,
1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl,
N-isobutyl-aminomethyl, N-isobutyl-aminoethyl,
(2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl,
N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl,
N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl,
N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl,
N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl,
N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl,
cyclopropylaminomethyl, cyclopropylaminoethyl,
cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl,
cyclobutylaminomethyl, cyclobutylaminoethyl,
cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl,
4,5-dihydro-imidazolyl, 1-piperidinylmethyl,
4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,
3-hydroxypiperidin-1-ylmethyl, 4-hydroxy-piperidin-1-ylmethyl,
4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl.
138. The compound of claim 131 wherein R.sup.3 and R.sup.3a
together form oxo; wherein R.sup.4 and R.sup.4a are independently
selected from H, and C.sub.1-3 alkyl; wherein R.sup.5 and R.sup.5a
are independently H.
139. Compound of claim 131 wherein R.sup.8 and R.sup.8'
independently are H or selected from lower alkyl, aryl and
heteroaryl, each of which is optionally substituted with one, two
or three groups independently selected from lower alkyl, halogen,
lower alkoxy, hydroxy, amino, mono-alkylamino, dialkylamino, and
trifluoromethyl.
140. Compound of claim 131 wherein R.sup.x is selected from H,
methyl and trifluoromethyl.
141. A compound of Formula III: ##STR00111## wherein R is selected
from 1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl,
indan-1-yl and indan-2-yl substituted with one to two basic
moieties, and optionally substituted with one to three groups
independently selected from halo, hydroxyl, cyano, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl, substituted heteroaryl,
substituted cycloalkyl and substituted saturated or partially
saturated heterocyclyl is substituted with one to three groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; wherein R.sup.1 is selected from H, and
C.sub.1-2-alkyl; wherein R.sup.2 is selected from arylalkenyl,
aryl, and heterocyclyl selected from thienyl, quinolinyl,
isoquinolinyl, 3-pyridyl, thiazol-4-yl, 4-imidazolyl, benzofuryl,
benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl,
isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, and
tetrahydroisoquinolinyl, wherein R.sup.2 is optionally substituted
with one to five groups independently selected from halo,
--NH.sub.2, hydroxyl, cyano, (C.sub.1-C.sub.6)alkylamino, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8',
--NR.sup.8C(O)R.sup.8', (C.sub.1-C.sub.6)alkyl, substituted
(C.sub.1-C.sub.6)alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl,
substituted saturated or partially saturated heterocyclyl and
unsubstituted saturated or partially saturated heterocyclyl,
wherein each substituted (C.sub.1-C.sub.6)alkyl, substituted aryl
substituted heteroaryl and substituted saturated or partially
saturated heterocyclyl is optionally substituted with one to three
groups independently selected from halo, --NH.sub.2, hydroxyl,
cyano, (C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl,
oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8, and
--NR.sup.8C(O)R.sup.8'; and wherein R.sup.8 and R.sup.8'
independently are H or selected from lower alkyl, aryl and
heteroaryl, each of which is optionally substituted with one, two
or three groups independently selected from lower alkyl, halogen,
lower alkoxy, hydroxy, amino, mono- or dialkylamino, and
trifluoromethyl; or pharmaceutically acceptable salts thereof;
provided the basic substiuent is not 2-pyridyl, 3-pyridyl or
2-oxo-piperaziny-4-ylmethyl.
142. The compound of claim 141 wherein R is selected from
1,2,3,4-tetrahydronaphth-1-yl, 1,2,3,4-tetrahydronaphth-2-yl,
indan-1-yl or indan-2-yl; substituted with a basic moiety,
optionally substituted with chloro.
143. The compound of claim 141 wherein each R.sup.2 is selected
from phenyl-CH.dbd.CH--, tetrahydronaphthyl,
naphtho[2,3-d]dioxolyl, benzofuranyl, benzoxadiazolyl,
benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, thienyl,
isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl,
phenyl, pyridinyl, tetrahydroisoquinolinyl, quinolinyl and
isoquinolinyl; wherein R.sup.2 is optionally substituted with one
to five groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, --CF.sub.3, (C.sub.1-C.sub.6)alkylamino, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8',
--NR.sup.8C(O)R.sup.8', (C.sub.1-C.sub.6)alkyl, substituted
(C.sub.1-C.sub.6)alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl,
substituted saturated or partially saturated heterocyclyl and
unsubstituted saturated or partially saturated heterocyclyl;
wherein each substituted (C.sub.1-C.sub.6)alkyl, substituted aryl,
substituted heteroaryl, substituted cycloalkyl and substituted
saturated or partially saturated heterocyclyl is substituted with
one to three groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, (C.sub.1-C.sub.6)alkylamino,
halo(C.sub.1-C.sub.6)alkyl, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; wherein R.sup.1 is selected from H and
C.sub.1-2-alkyl; wherein the basic substituent on R is selected
from amino, cycloalkylamino(C.sub.1-C.sub.6)alkyl,
cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy-C.sub.1-6-alkoxy,
amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-4-alkylamino-C.sub.2-6-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-6-alkenyl,
heterocyclyl-(C.sub.1-C.sub.6)alkylamino(C.sub.2-C.sub.6)alkyl, 5-6
membered heterocyclyloxy, 5-6 membered nitrogen-containing
heterocyclyl and 5-7 membered nitrogen-containing
heterocyclyl-alkyl; and wherein each of said basic substituents is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano, --CF.sub.3,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.4)alkylamino, (C.sub.1-C.sub.4)haloalkyl, oxo,
(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, di(C.sub.1-C.sub.4)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'.
144. The compound of claim 143 wherein R.sup.2 is selected from
phenyl-CH.dbd.CH--, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl,
thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and
5-isoquinolyl wherein each R.sup.2 is optionally substituted;
wherein R.sup.1 is H; and wherein the basic substituent on R is
selected from amino, mono-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
di-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
mono-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl,
di-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-4-alkenyl, optionally
substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8
membered nitrogen-containing heterocyclyl-C.sub.1-4-alkyl.
145. The compound of claim 141 wherein the basic substituent on R
is selected from amino, aminomethyl, isopropylaminomethyl,
t-butylaminomethyl, 2-t-butylaminoethyl,
2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl,
1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl,
N-isobutyl-aminomethyl, N-isobutyl-aminoethyl,
(2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl,
N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl,
N-iso-butyl-N-methyl-aminomethyl, N-t-butyl-N-ethylaminomethyl,
N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl,
N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl,
N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl,
cyclopropylaminomethyl, cyclopropylaminoethyl,
cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl,
cyclobutylaminomethyl, cyclobutylaminoethyl,
cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl,
4,5-dihydro-imidazolyl, 1-piperidinylmethyl,
4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,
3-hydroxypiperidin-1-ylmethyl, 4-hydroxy-piperidin-1-ylmethyl,
4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl.
146. The compound of claim 118 or pharmaceutically acceptable salts
thereof selected from:
2-((2R,S)-1-((5-chloro-1-benzothien-2-yl)sulfonyl)-3-oxo-2-piperazinyl)-N-
-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide-
;
2-((2R,S)-1-((5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl)-3-oxo-2-pipe-
razinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-
-naphthalenyl)acetamide;
2-((2R,S)-1-((5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl)-3-oxo-2-piper-
azinyl)-N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthal-
enyl)acetamide;
2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-pipera-
zinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)a-
cetamide;
2-((2R,S)-1-((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-
-2-piperazinyl)-N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetra-
hydro-1-naphthalenyl)acetamide;
2-((2R,S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)-N--
((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-3-oxo-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)-N--
((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide;
2-((2R,S)-1-((3-bromo-5-chloro-2-thienyl)sulfonyl)-3-oxo-2-piperazinyl)-N-
-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide-
;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphth-
alenyl)-2-((2R,S)-3-oxo-1-((4-(pentafluoroethyl)phenyl)sulfonyl)-2-piperaz-
inyl)acetamide;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphtha-
lenyl)-2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2--
piperazinyl)acetamide;
N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalen-
yl)-2-((2S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piper-
azinyl)acetamide;
N-((1R)-6-(((2,2-dimethylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphth-
alenyl)-2-((2R,S)-1-((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-
-piperazinyl)acetamide;
N-((1R)-6-(hydroxymethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R,S)-1--
((4-methyl-3-(trifluoromethyl)phenyl)sulfonyl)-3-oxo-2-piperazinyl)acetami-
de;
N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-(-
(2R,S)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1,2,3,4-tetrahydro-1--
naphthalenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)a-
cetamide;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro--
1-naphthalenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfony-
l)-2-piperazinyl)acetamide;
N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalen-
yl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperaz-
inyl)acetamide;
N-((1R)-6-(((cyclopropylmethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphtha-
lenyl)-2-((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-pipe-
razinyl)acetamide;
N-((1R)-6-(((1-methylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthaleny-
l)-2-((2R,
S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperaz-
inyl)acetamide;
N-((1R)-6-((cyclobutylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2--
((2R,S)-3-oxo-1-((4-((trifluoromethyl)oxy)phenyl)sulfonyl)-2-piperazinyl)a-
cetamide;
N-((1R)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro--
1-naphthalenyl)-2-((2R,
S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-(((2-methylpropyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalen-
yl)-2-((2R,
S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)acetamide;
N-((1R)-6-((cyclopentylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-
-((2R,S)-3-oxo-1-((4-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)aceta-
mide;
N-((1R)-6-(1-(1-piperidinylmethyl)ethenyl)-1,2,3,4-tetrahydro-1-naph-
thalenyl)-2-((2R,S)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2-piperazinyl)-
acetamide; and
2-((R)-3-oxo-1-(4-(trifluoromethyl)phenylsulfonyl)piperazin-2-yl)-N--((R)-
-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide.
147. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound according to claim 118.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/480,303, filed Jun. 20, 2003, which is hereby
incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention is in the field of pharmaceutical agents and
specifically relates to compounds, compositions, uses and methods
for treating inflammation-related disorders, including pain.
BACKGROUND OF THE INVENTION
[0003] More than two million people in the United States alone are
incapacitated by chronic pain on any given day (T. Jessell & D.
Kelly, Pain and Analgesia in PRINCIPLES OF NEURAL SCIENCE, third
edition (E. Kandel, J. Schwartz, T. Jessell, eds., (1991)).
Unfortunately, current treatments for pain are only partially
effective, and many cause lifestyle altering, debilitating, and/or
dangerous side effects. For example, non-steroidal
anti-inflammatory drugs ("NSAIDs") such as aspirin, ibuprofen, and
indomethacin are moderately effective against inflammatory pain but
they are also renally toxic, and high doses tend to cause
gastrointestinal irritation, ulceration, bleeding, increased
cardiovascular risk, and confusion. Patients treated with opioids
frequently experience confusion and constipation, and long-term
opioid use is associated with tolerance and dependence. Local
anesthetics such as lidocaine and mixelitine simultaneously inhibit
pain and cause loss of normal sensation. In addition, when used
systemically local anesthetics are associated with adverse
cardiovascular effects. Thus, there is currently an unmet need in
the treatment of chronic pain.
[0004] Pain is a perception based on signals received from the
environment and transmitted and interpreted by the nervous system
(for review, see M. Millan, Prog. Neurobiol. 57:1-164 (1999)).
Noxious stimuli such as heat and touch cause specialized sensory
receptors in the skin to send signals to the central nervous system
("CNS"). This process is called nociception, and the peripheral
sensory neurons that mediate it are nociceptors. Depending on the
strength of the signal from the nociceptor(s) and the abstraction
and elaboration of that signal by the CNS, a person may or may not
experience a noxious stimulus as painful. When one's perception of
pain is properly calibrated to the intensity of the stimulus, pain
serves its intended protective function. However, certain types of
tissue damage cause a phenomenon, known as hyperalgesia or
pronociception, in which relatively innocuous stimuli are perceived
as intensely painful because the person's pain thresholds have been
lowered. Both inflammation and nerve damage can induce
hyperalgesia. Thus, persons afflicted with inflammatory conditions,
such as sunburn, osteoarthritis, colitis, carditis, dermatitis,
myositis, neuritis, inflammatory bowel disease, collagen vascular
diseases (which include rheumatoid arthritis and lupus) and the
like, often experience enhanced sensations of pain. Similarly,
trauma, surgery, amputation, abscess, causalgia, collagen vascular
diseases, demyelinating diseases, trigeminal neuralgia, cancer,
chronic alcoholism, stroke, thalamic pain syndrome, diabetes,
herpes infections, acquired immune deficiency syndrome ("AIDS"),
toxins and chemotherapy cause nerve injuries that result in
pain.
[0005] As the mechanisms by which nociceptors transduce external
signals under normal and hyperalgesic conditions' become better
understood, processes implicated in hyperalgesia can be targeted to
inhibit the lowering of the pain threshold and thereby lessen the
amount of pain experienced.
[0006] Bradykinin (BK) and the related peptide, kallidin (Lys-BK)
mediate the physiological actions of kinins on the cardiovascular
and renal systems. However, the active peptides, BK and kallidin,
are quickly degraded by peptidases in the plasma and other
biological fluids and by those released from a variety of cells, so
that the half-life of BK in plasma is reported to be approximately
17 seconds (1). BK and kallidin are rapidly metabolized in the body
by carboxypeptidase N, which removes the carboxyterminal arginine
residue to generate des-Arg BK or des-Arg kallidin.
Des-Arg-kallidin is among the predominant kinins in man and mediate
the pathophysiological actions of kinins in man. In addition to
being a very potent proinflammatory peptide, des-Arg-BK or
des-Arg-kallidin is known to induce vasodilation, vascular
permeability, and bronchoconstriction (for review, see Regoli and
Barabe, Pharmacological Rev, 32(1), 1-46 (1980)). In addition,
des-Arg-BK and des-Arg-kallidin appear to be particularly important
mediators of inflammation and inflammatory pain as well as being
involved in the maintenance thereof. There is also a considerable
body of evidence implicating the overproduction of des-Arg-kallidin
in conditions in which pain is a prominent feature such as septic
shock, arthritis, angina, and migraine.
[0007] The membrane receptors that mediate the pleiotropic actions
of kinins are of two distinct classes, designated B1 and B2. Both
classes of receptors have been cloned and sequenced from a variety
of species, including man (Menke, et al, J. Biol. Chem. 269,
21583-21586 (1994); Hess et al, Biochem. Biophys. Res. Commun. 184,
260-268 (1992)). They are typical G protein coupled receptors
having seven putative membrane spanning regions. In various
tissues, BK receptors are coupled to every known second messenger.
B2 receptors, which have a higher affinity for BK, appear to be the
most prevalent form of bradykinin receptor. Essentially all normal
physiological responses and many pathophysio-logical responses to
bradykinin are mediated by B2 receptors.
[0008] B1 receptors, on the other hand, have a higher affinity for
des-Arg-BK compared with BK, whereas des-Arg-BK is inactive at B2
receptors. In addition, B1 receptors are not normally expressed in
most tissues. Their expression is induced upon injury or tissue
damage as well as in certain kinds of chronic inflammation or
systemic insult (F. Marceau, et al., Immunopharmacology, 30, 1-26
(1995)). Furthermore, responses mediated by B1 receptors are
up-regulated from a null level following administration of
bacterial lipopolysaccharide (LPS) or inflammatory cytokines in
rabbits, rats, and pigs.
[0009] The pain-inducing properties of kinins coupled with the
inducible expression of B1 receptors make the B1 receptor an
interesting target in the development of anti-inflammatory,
antinociceptive, antihyperalgesic and analgesic agents that may be
directed specifically at injured tissues with minimal actions in
normal tissues.
[0010] Certain compounds have been described as bradykinin
antagonists. WO 03/07958, published 30 Jan. 2003, describes
tetrahydroquinoxalines. Dihydroquinoxalinones are described in a
JACS communication.
[0011] Piperazine-2,3,5-triones are described in Tet. Lett., 40,
7557-7560 (1999). European application 641779, published 8 Mar.
1995, describes 3,6-dioxopiperazines as platelet aggregation
inhibitors.
[0012] Clearly, there is a need for new, safe and effective
treatments for inflammation and pain. Such agents are provided in
the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0013] A class of compounds useful in treating inflammation and
pain is defined by Formula I
##STR00001## [0014] wherein q is 0-3; [0015] wherein t is 0-2;
[0016] wherein X is selected from NH, S, O and NR.sup.a; wherein
R.sup.a is selected form alkyl, substituted alkyl, --C(O)R.sup.8,
--CO.sub.2R.sup.8, --C(O)NR.sup.8R.sup.8', --SO.sub.2R.sup.8 and
--SO.sub.2NR.sup.8R.sup.8'; provided R.sup.3 and R.sup.3a or
R.sup.4 and R.sup.4a together do not form oxo if R.sup.a is
--C(O)R.sup.8, --CO.sub.2R.sup.8, --C(O)NR.sup.8R.sup.8',
--SO.sub.2R.sup.8 or --SO.sub.2NR.sup.8R.sup.8; [0017] wherein R is
selected from [0018] a) 9-11 membered fused bicyclic carbocyclic or
heterocyclic ring substituted with one to three basic moieties, and
optionally substituted with one to three groups independently
selected from halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, [0019] b) 4-7 membered carbocyclic ring
substituted with one to three basic moieties, and optionally
substituted with one to three groups independently selected from
halo, hydroxyl, cyano, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, [0020] c) 4-7 membered heterocyclic ring
substituted with one to three basic moieties, and optionally
substituted with one to three groups independently selected from
halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)N.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, [0021] d) arylalkyl substituted with one to
three basic moieties, and optionally substituted with one to three
groups independently selected from halo, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, [0022] e) 5-6 membered heterocyclylalkyl
substituted with one to three basic moieties, and optionally
substituted with one to three groups independently selected from
halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, [0023] f) 5-7 membered cycloalkyl, [0024]
g) 4-7 membered carbocyclic or heterocyclic ring optionally
substituted with one to three groups independently selected from
halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, [0025] h) diphenylmethyl, and [0026] i)
9-11 membered fused bicyclic carbocyclic or heterocyclic ring
optionally substituted with one to three groups independently
selected from halo, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; [0027] wherein R.sup.1 is selected from H,
C.sub.1-4-alkyl, substituted C.sub.1-4-alkyl, aryl and substituted
aryl; [0028] alternatively R and R.sup.1 together with the nitrogen
atom to which they are attached form a 5-8 membered heterocyclyl
ring, optionally containing 1-2 additional heteroatoms, fused to a
phenyl group, further substituted with a basic moiety; [0029]
wherein R.sup.2 is selected from arylalkenyl, aryl, and
heterocyclyl selected from thienyl, quinolinyl, isoquinolinyl,
3-pyridyl, thiazol-4-yl, 4-imidazolyl, benzofuryl, benzoxadiazolyl,
benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, isoxazolthienyl,
benzothienyl, thieno[3,2-c]pyridinyl, and tetrahydroisoquinolinyl,
wherein R.sup.2 is optionally substituted with one to five groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; [0030] wherein R.sup.3, R.sup.3a, R.sup.4,
R.sup.4a, R.sup.5 and R.sup.5a are independently selected from H,
C.sub.1-3 alkyl and substituted C.sub.1-3 alkyl; [0031] or wherein
R.sup.3 and R.sup.3a together form oxo, or R.sup.4 and R.sup.4a
together form oxo, or R.sup.5 and R.sup.5a together form oxo;
[0032] wherein R.sup.8 and R.sup.8' independently are H or selected
from lower alkyl, aryl and heteroaryl, each of which is optionally
substituted with one, two or three groups independently selected
from lower alkyl, halogen, lower alkoxy, hydroxy, amino, mono- or
dialkylamino, and trifluoromethyl; [0033] wherein R.sup.x is
selected from H, (C.sub.1-C.sub.3)haloalkyl, and
(C.sub.1-C.sub.3)alkyl; and [0034] wherein each substituted alkyl,
substituted aryl, heteroaryl, substituted heteroaryl, substituted
cycloalkyl and substituted saturated or partially saturated
heterocyclyl is substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8', [0035] and pharmaceutically acceptable
derivatives thereof; [0036] provided R is not cycloheptyl when
R.sup.1 is H, R.sup.2 is 4-methylphenyl, R.sup.3 and R.sup.3a
together form oxo, R.sup.5 and R.sup.5a are both H, and when
R.sup.4 and R.sup.4a are both methyl; further provided R is not
cycloheptyl when R.sup.1 is H, R.sup.2 is 2,4,6-trimethylphenyl,
R.sup.3 and R.sup.3a together form oxo, and R.sup.4, R.sup.4a,
R.sup.5 and R.sup.5a are H; and further provided the basic
substiuent is not 2-pyridyl, 3-pyridyl or
2-oxo-piperaziny-4-ylmethyl.
[0037] The invention also relates to compounds of Formula I wherein
q is 1-2; and wherein t is 1. It also relates to compounds wherein
q is 1, in conjunction with any of the above or below
embodiments.
[0038] The invention also relates to compounds of Formula I wherein
X is selected from NH and NR.sup.a; and wherein R.sup.a is
(C.sub.1-3)alkyl or Boc, in conjunction with any of the above or
below embodiments.
[0039] The invention also relates to compounds of Formula I wherein
X is NH, in conjunction with any of the above or below
embodiments.
[0040] The invention also relates to compounds of Formula I wherein
R is selected from 9-11 membered fused bicyclic carbocyclic or
heterocyclic ring substituted with one to two basic moieties, and
optionally substituted with one to three groups independently
selected from halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, in conjunction with any of the above or
below embodiments.
[0041] The invention also relates to compounds of Formula I wherein
R is a partially unsaturated carbocyclic ring, such as
1,2,3,4-tetrahydronaphthyl or indanyl, substituted with a basic
moiety, optionally substituted with chloro, in conjunction with any
of the above or below embodiments.
[0042] The invention also relates to compounds of Formula I wherein
R is selected from 1,2,3,4-tetrahydronaphth-1-yl,
1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl,
substituted with a basic moiety, optionally substituted with
chloro, in conjunction with any of the above or below
embodiments.
[0043] The invention also relates to compounds of Formula I wherein
R is partially unsaturated heterocyclyl, such as chroman and
2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl, substituted with a
basic moiety, optionally substituted with chloro, in conjunction
with any of the above or below embodiments.
[0044] The invention also relates to compounds of Formula I wherein
R is chroman-4-yl, or
2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl, substituted with a
basic moiety, optionally substituted with chloro, in conjunction
with any of the above or below embodiments.
[0045] The invention also relates to compounds of Formula I wherein
R is selected from phenyl and 5-6 membered heteroaryl; wherein R is
substituted with one to two basic moieties, and optionally
substituted with one to three groups independently selected from
halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, in conjunction with any of the above or
below embodiments.
[0046] The invention also relates to compounds of Formula I wherein
R is phenyl substituted with a basic moiety selected from
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-4-alkylamino-C.sub.2-6-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-6-alkenyl, and
heterocyclyl-(C.sub.1-C.sub.6)alkylamino(C.sub.2-C.sub.6)alkyl, in
conjunction with any of the above or below embodiments.
[0047] The invention also relates to compounds of Formula I wherein
R is selected from 3-((piperidin-1-ylethyl)aminomethyl)phenyl and
4-imidazolin-2-ylphenyl, in conjunction with any of the above or
below embodiments.
[0048] The invention also relates to compounds of Formula I wherein
R is phenyl-(C.sub.1-3)-alkyl substituted with a basic moiety, such
as 4-(imidazolin-2-yl)phenylmethyl, 4-(imidazolin-2-yl)phenylethyl
and 4-(imidazolin-2-yl)phenylpropyl, in conjunction with any of the
above or below embodiments.
[0049] The invention also relates to compounds of Formula I wherein
R.sup.1 is H or methyl, in conjunction with any of the above or
below embodiments.
[0050] The invention also relates to compounds of Formula I wherein
R.sup.2 is selected from phenyl-(C.sub.2-4)-alkenyl, phenyl,
naphthyl, 5-membered nitrogen containing heteroaryl, 5-membered
sulfur containing heteroaryl, 6-membered nitrogen containing
heteroaryl, 9-membered heterocyclyl, and 10-membered heterocyclyl;
in conjunction with any of the above or below embodiments.
[0051] The invention also relates to compounds of Formula I wherein
R.sup.2 is selected from phenyl-CH.dbd.CH--, tetrahydronaphthyl,
naphtho[2,3-d]dioxolyl, benzofuranyl, benzoxadiazolyl,
benzothiadiazolyl, benzothiazolyl, 2-thienyl, isoxazolthienyl,
benzothienyl, thieno[3,2-c]pyridinyl, naphthyl, phenyl,
3-pyridinyl, tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl;
wherein R.sup.2 is optionally substituted with one to five groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.4)alkylamino, (C.sub.1-C.sub.4)haloalkyl, oxo,
(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, di(C.sub.1-C.sub.4)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; in conjunction with any of the above or
below embodiments.
[0052] The invention also relates to compounds of Formula I wherein
R.sup.2 is selected from phenyl-CH.dbd.CH--, tetrahydronaphthyl,
2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl,
3-pyridyl, 8-quinolyl and 5-isoquinolyl; and wherein R.sup.2 is
optionally substituted; preferably with one or two groups
independently selected from methyl, chloro, methoxy, --OCF.sub.3 or
--CF.sub.3; such as 2,4,6-trimethylphenyl, 3,4-dichlorophenyl,
3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl,
3-trifluoromethylphenyl, 4-trifluoromethylphenyl,
4-trifluoromethoxyphenyl, 4-methoxyphenyl, 4-methylphenyl,
4-chlorophenyl and 4-tert-butylphenyl; in conjunction with any of
the above or below embodiments.
[0053] The invention also relates to compounds of Formula I wherein
the basic moieties on R are independently selected from amino,
cycloalkylamino(C.sub.1-C.sub.6)alkyl,
cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy-C.sub.1-6-alkoxy,
amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-4-alkylamino-C.sub.2-6-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-6-alkenyl,
heterocyclyl-(C.sub.1-C.sub.6)alkylamino(C.sub.2-C.sub.6)alkyl, 5-6
membered heterocyclyloxy, 4-6 membered nitrogen-containing
heterocyclyl and 5-7 membered nitrogen-containing
heterocyclyl-alkyl; and wherein each of said basic substituents is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano, --CF.sub.3,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8, in conjunction with any of the above or
below embodiments.
[0054] The invention also relates to compounds of Formula I wherein
the basic moieties on R are independently selected from amino,
mono-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
di-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
mono-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl,
di-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-4-alkenyl, optionally
substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8
membered nitrogen-containing heterocyclyl-C.sub.1-4-alkyl, in
conjunction with any of the above or below embodiments.
[0055] The invention also relates to compounds of Formula I wherein
the basic moieties on R are independently selected from amino,
aminomethyl, isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl,
1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl,
1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl, in conjunction with any of the
above or below embodiments.
[0056] The invention also relates to compounds of Formula I wherein
R.sup.3 and R.sup.3a together form oxo; wherein R.sup.4 and
R.sup.4a are independently selected from H and C.sub.1-3 alkyl; and
wherein R.sup.5 and R.sup.5a are independently H, in conjunction
with any of the above or below embodiments.
[0057] Alternatively, the invention also relates to compounds
wherein R.sup.3 and R.sup.3a together form oxo; wherein R.sup.4 and
R.sup.4a are independently selected from H and methyl; and wherein
R.sup.5 and R.sup.5a are independently H, in conjunction with any
of the above or below embodiments.
[0058] The invention also relates to compounds wherein R.sup.8 and
R.sup.8' independently are H or selected from lower alkyl, aryl and
heteroaryl, each of which is optionally substituted with one, two
or three groups independently selected from lower alkyl, halogen,
lower alkoxy, hydroxy, amino, mono-alkylamino, dialkylamino, and
trifluoromethyl; in conjunction with any of the above or below
embodiments.
[0059] The invention also relates to compounds of Formula I R.sup.x
is H, methyl or trifluoromethyl, such as H; in conjunction with any
of the above or below embodiments.
[0060] The invention also relates to compounds of Formula II
##STR00002## [0061] wherein X is selected from NH, S, O and
NR.sup.a; [0062] wherein R.sup.a is selected form alkyl,
substituted alkyl, --C(O)R.sup.8, --CO.sub.2R.sup.8,
--C(O)NR.sup.8R.sup.8', --SO.sub.2R.sup.8 and
--SO.sub.2NR.sup.8R.sup.8'; provided R.sup.3 and R.sup.3a or
R.sup.4 and R.sup.4a together do not form oxo if R.sup.a is
--C(O)R.sup.8, --CO.sub.2R.sup.8, --C(O)NR.sup.8R.sup.8',
--SO.sub.2R.sup.8 or --SO.sub.2NR.sup.8R.sup.8'; [0063] wherein R
is selected from [0064] a) 9-11 membered fused bicyclic carbocyclic
or heterocyclic ring substituted with one to three basic moieties,
and optionally substituted with one to three groups independently
selected from halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, [0065] b) phenyl substituted with one to
three basic moieties, and optionally substituted with one to three
groups independently selected from halo, hydroxyl, cyano, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, [0066] c) 5-6 membered heteroaryl
substituted with one to three basic moieties, and optionally
substituted with one to three groups independently selected from
halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, [0067] d) arylalkyl substituted with one to
three basic moieties, and optionally substituted with one to three
groups independently selected from halo, hydroxyl, cyano, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, and [0068] e) 5-6 membered heteroarylalkyl
substituted with one to three basic moieties, and optionally
substituted with one to three groups independently selected from
halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; [0069] wherein R.sup.1 is selected from H,
C.sub.1-4-alkyl, substituted C.sub.1-4-alkyl, aryl and substituted
aryl; [0070] alternatively R and R.sup.1 together with the nitrogen
atom to which they are attached form a 5-8 membered heterocyclyl
ring fused to a phenyl ring, optionally containing 1-2 additional
heteroatoms, further substituted with a basic moiety; [0071]
wherein R.sup.2 is selected from arylalkenyl, aryl, and
heterocyclyl selected from thienyl, quinolinyl, isoquinolinyl,
3-pyridyl, thiazol-4-yl, 4-imidazolyl, benzofuryl, benzoxadiazolyl,
benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, isoxazolthienyl,
benzothienyl, thieno[3,2-c]pyridinyl, and tetrahydroisoquinolinyl,
wherein R.sup.2 is optionally substituted with one to five groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; [0072] wherein R.sup.3, R.sup.3a, R.sup.4,
R.sup.4a, R.sup.5 and R.sup.5a are independently selected from H,
C.sub.1-3 alkyl, and substituted alkyl; [0073] or wherein R.sup.3
and R.sup.3a together form oxo, or R.sup.4 and R.sup.4a together
form oxo, or R.sup.5 and R.sup.5a together form oxo; [0074] wherein
R.sup.8 and R.sup.8' independently are H or selected from lower
alkyl, aryl and heteroaryl, each of which is optionally substituted
with one, two or three groups independently selected from lower
alkyl, halogen, lower alkoxy, hydroxy, amino, mono- or
dialkylamino, and trifluoromethyl; [0075] wherein R.sup.x is
selected from H, (C.sub.1-C.sub.3)haloalkyl, and
(C.sub.1-C.sub.3)alkyl; and [0076] wherein each substituted alkyl,
substituted aryl, heteroaryl, substituted heteroaryl, substituted
cycloalkyl and substituted saturated or partially saturated
heterocyclyl is substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8', and pharmaceutically acceptable derivatives
thereof; [0077] provided the basic substiuent is not 2-pyridyl,
3-pyridyl or 2-oxo-piperaziny-4-ylmethyl.
[0078] The invention also relates to compounds of Formula II
wherein X is selected from NH and NR.sup.a; and wherein R.sup.a is
(C.sub.1-3)alkyl or Boc; in conjunction with any of the above or
below embodiments.
[0079] The invention also relates to compounds of Formula II
wherein X is NH; in conjunction with any of the above or below
embodiments.
[0080] The invention also relates to compounds of Formula II
wherein R is selected from 9-11 membered fused bicyclic carbocyclic
or heterocyclic ring substituted with one to two basic moieties,
and optionally substituted with one to three groups independently
selected from halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8,
--COOR.sup.8, --C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; in conjunction with any of the above or
below embodiments.
[0081] The invention also relates to compounds of Formula II
wherein R is a partially unsaturated carbocyclic ring, such as
1,2,3,4-tetrahydronaphthyl or indanyl; substituted with a basic
moiety, optionally substituted with chloro; in conjunction with any
of the above or below embodiments.
[0082] The invention also relates to compounds of Formula II
wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl,
1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl;
substituted with a basic moiety, optionally substituted with
chloro; in conjunction with any of the above or below
embodiments.
[0083] The invention also relates to compounds of Formula II
wherein R is partially unsaturated heterocyclyl, such as chroman
and 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl; substituted with a
basic moiety, optionally substituted with chloro; in conjunction
with any of the above or below embodiments.
[0084] The invention also relates to compounds of Formula II
wherein R is chroman-4-yl, or
2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl; substituted with a
basic moiety, optionally substituted with chloro; in conjunction
with any of the above or below embodiments.
[0085] The invention also relates to compounds of Formula II
wherein R is selected from phenyl and 5-6 membered heteroaryl;
wherein R is substituted with one to two basic moieties, and
optionally substituted with one to three groups independently
selected from halo, hydroxyl, cyano, oxo, (C.sub.1-C.sub.6)alkoxy,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8',
--NR.sup.8C(O)R.sup.8', (C.sub.1-C.sub.6)alkyl, substituted
(C.sub.1-C.sub.6)alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl,
substituted saturated or partially saturated heterocyclyl and
unsubstituted saturated or partially saturated heterocyclyl; in
conjunction with any of the above or below embodiments.
[0086] The invention also relates to compounds of Formula II
wherein R is phenyl substituted with a basic moiety selected from
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-4-alkylamino-C.sub.2-6-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-6-alkenyl, and
heterocyclyl-(C.sub.1-C.sub.6)alkylamino(C.sub.2-C.sub.6)alky; in
conjunction with any of the above or below embodiments.
[0087] The invention also relates to compounds of Formula II
wherein R is selected from
3-((piperidin-1-ylethyl)aminomethyl)phenyl and
4-imidazolin-2-ylphenyl; in conjunction with any of the above or
below embodiments.
[0088] The invention also relates to compounds of Formula II
wherein R is phenyl-(C.sub.1-3)-alkyl substituted with a basic
moiety, such as 4-(imidazolin-2-yl)phenylmethyl,
4-(imidazolin-2-yl)phenylethyl and 4-(imidazolin-2-yl)phenylpropyl;
in conjunction with any of the above or below embodiments.
[0089] The invention also relates to compounds of Formula II
wherein R.sup.1 is H or methyl; in conjunction with any of the
above or below embodiments.
[0090] The invention also relates to compounds of Formula I wherein
R.sup.2 is selected from phenyl-(C.sub.2-4)-alkenyl, phenyl,
naphthyl, 5-membered nitrogen containing heteroaryl, 5-membered
sulfur containing heteroaryl, 6-membered nitrogen containing
heteroaryl, 9-membered heterocyclyl, and 10-membered heterocyclyl;
in conjunction with any of the above or below embodiments.
[0091] The invention also relates to compounds of Formula I wherein
R.sup.2 is selected from phenyl-CH.dbd.CH--, tetrahydronaphthyl,
naphtho[2,3-d]dioxolyl, benzofuranyl, benzoxadiazolyl,
benzothiadiazolyl, benzothiazolyl, 2-thienyl, isoxazolthienyl,
benzothienyl, thieno[3,2-c]pyridinyl, naphthyl, phenyl,
3-pyridinyl, tetrahydroisoquinolinyl, quinolinyl and isoquinolinyl;
wherein R.sup.2 is optionally substituted with one to five groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.4)alkylamino, (C.sub.1-C.sub.4)haloalkyl, oxo,
(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, di(C.sub.1-C.sub.4)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; in conjunction with any of the above or
below embodiments.
[0092] The invention also relates to compounds of Formula I wherein
R.sup.2 is selected from phenyl-CH.dbd.CH--, tetrahydronaphthyl,
2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl,
3-pyridyl, 8-quinolyl and 5-isoquinolyl; and wherein R.sup.2 is
optionally substituted; preferably with one or two groups
independently selected from methyl, chloro, methoxy, --OCF.sub.3 or
--CF.sub.3; such as 2,4,6-trimethylphenyl, 3,4-dichlorophenyl,
3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl,
3-trifluoromethylphenyl, 4-trifluoromethylphenyl,
4-trifluoromethoxyphenyl, 4-methoxyphenyl, 4-methylphenyl,
4-chlorophenyl and 4-tert-butylphenyl; in conjunction with any of
the above or below embodiments.
[0093] The invention also relates to compounds of Formula II
wherein the basic moieties on R are independently selected from
amino, cycloalkylamino(C.sub.1-C.sub.6)alkyl,
cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy-C.sub.1-6-alkoxy,
amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-4-alkylamino-C.sub.2-6-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-6-alkenyl,
heterocyclyl-(C.sub.1-C.sub.6)alkylamino (C.sub.2-C.sub.6)alkyl,
5-6 membered heterocyclyloxy, 5-6 membered nitrogen-containing
heterocyclyl and 5-7 membered nitrogen-containing
heterocyclyl-alkyl; and wherein each of said basic substituents is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano, --CF.sub.3,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; in conjunction with any of the above or
below embodiments.
[0094] The invention also relates to compounds of Formula II
wherein the basic moieties on R are independently selected from
amino, mono-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
di-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
mono-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl,
di-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-4-alkenyl, optionally
substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8
membered nitrogen-containing heterocyclyl-C.sub.1-4-alkyl; in
conjunction with any of the above or below embodiments.
[0095] The invention also relates to compounds of Formula II
wherein the basic moieties on R are independently selected from
amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl,
1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl,
1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl; in conjunction with any of the
above or below embodiments.
[0096] The invention also relates to compounds of Formula II
wherein R.sup.3 and R.sup.3a together form oxo; wherein R.sup.4 and
R.sup.4a are independently selected from H and C.sub.1-3 alkyl; and
wherein R.sup.5 and R.sup.5a are independently H; in conjunction
with any of the above or below embodiments.
[0097] Alternatively, the invention also relates to compounds
wherein R.sup.3 and R.sup.3a together form oxo; wherein R.sup.4 and
R.sup.4a are independently selected from H and methyl; and wherein
R.sup.5 and R.sup.5a are independently H; in conjunction with any
of the above or below embodiments.
[0098] The invention also relates to compounds wherein R.sup.8 and
R.sup.8' independently are H or selected from lower alkyl, aryl and
heteroaryl, each of which is optionally substituted with one, two
or three groups independently selected from lower alkyl, halogen,
lower alkoxy, hydroxy, amino, mono-alkylamino, dialkylamino, and
trifluoromethyl; in conjunction with any of the above or below
embodiments.
[0099] The invention also relates to compounds of Formula II
R.sup.x is H, methyl or trifluoromethyl, such as H; in conjunction
with any of the above or below embodiments.
[0100] The invention also relates to compounds of Formula III
##STR00003## [0101] wherein R is a 9-11 membered fused bicyclic
carbocyclic or heterocyclic ring substituted with one to two basic
moieties, and optionally substituted with one to three groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; [0102] wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl, substituted heteroaryl,
substituted cycloalkyl and substituted saturated or partially
saturated heterocyclyl is substituted with one to three groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; [0103] wherein R.sup.1 is selected from H,
and C.sub.1-2-alkyl; [0104] wherein R.sup.2 is selected from
arylalkenyl, aryl, and heterocyclyl selected from thienyl,
quinolinyl, isoquinolinyl, 3-pyridyl, thiazol-4-yl, 4-imidazolyl,
benzofuryl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl,
1H-pyrazolyl, isoxazolthienyl, benzothienyl,
thieno[3,2-c]pyridinyl, and tetrahydroisoquinolinyl, wherein
R.sup.2 is optionally substituted with one to five groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; and
[0105] wherein R.sup.8 and R.sup.8' independently are H or selected
from lower alkyl, aryl and heteroaryl, each of which is optionally
substituted with one, two or three groups independently selected
from lower alkyl, halogen, lower alkoxy, hydroxy, amino, mono- or
dialkylamino, and trifluoromethyl; and pharmaceutically acceptable
derivatives thereof; provided the basic substiuent is not
2-pyridyl, 3-pyridyl or 2-oxo-piperaziny-4-ylmethyl.
[0106] The invention also relates to compounds of Formula III
[0107] wherein R is a partially unsaturated carbocyclic ring, such
as 1,2,3,4-tetrahydronaphthyl or indanyl.
[0108] The invention also relates to compounds of Formula III
[0109] wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl,
1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl.
[0110] The invention also relates to compounds of Formula III
wherein R is partially unsaturated heterocyclyl, such as chroman
and 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl; substituted with a
basic moiety, optionally substituted with chloro; in conjunction
with any of the above or below embodiments.
[0111] The invention also relates to compounds of Formula III
wherein R is chroman-4-yl, or
2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl; substituted with a
basic moiety, optionally substituted with chloro; in conjunction
with any of the above or below embodiments.
[0112] The invention also relates to compounds wherein each R.sup.2
is selected from phenyl-CH.dbd.CH--, tetrahydronaphthyl,
naphtho[2,3-d]dioxolyl, benzofuranyl, benzoxadiazolyl,
benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, thienyl,
isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl,
phenyl, pyridinyl, tetrahydroisoquinolinyl, quinolinyl and
isoquinolinyl; wherein R.sup.2 is optionally substituted with one
to five groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, --CF.sub.3, (C.sub.1-C.sub.6)alkylamino, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8',
--NR.sup.8C(O)R.sup.8', (C.sub.1-C.sub.6)alkyl, substituted
(C.sub.1-C.sub.6)alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl,
substituted saturated or partially saturated heterocyclyl and
unsubstituted saturated or partially saturated heterocyclyl;
wherein each substituted (C.sub.1-C.sub.6)alkyl, substituted aryl,
substituted heteroaryl, substituted cycloalkyl and substituted
saturated or partially saturated heterocyclyl is substituted with
one to three groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, (C.sub.1-C.sub.6)alkylamino,
halo(C.sub.1-C.sub.6)alkyl, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; wherein R.sup.1 is selected from H and
C.sub.1-2-alkyl; wherein the basic substituent on R is selected
from amino, cycloalkylamino(C.sub.1-C.sub.6)alkyl,
cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy-C.sub.1-6-alkoxy,
amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-4-alkylamino-C.sub.2-6-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-6-alkenyl,
heterocyclyl-(C.sub.1-C.sub.6)alkylamino(C.sub.2-C.sub.6)alkyl, 5-6
membered heterocyclyloxy, 5-6 membered nitrogen-containing
heterocyclyl and 5-7 membered nitrogen-containing
heterocyclyl-alkyl; and wherein each of said basic substituents is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano, --CF.sub.3,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.4)alkylamino, (C.sub.1-C.sub.4)haloalkyl, oxo,
(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, di(C.sub.1-C.sub.4)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; in conjunction with any of the above or
below embodiments.
[0113] The invention also relates to compounds wherein R.sup.2 is
selected from phenyl-CH.dbd.CH--, tetrahydronaphthyl,
2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl,
3-pyridyl, 8-quinolyl and 5-isoquinolyl; wherein each R.sup.2 is
said optionally substituted; wherein R.sup.a is H; and wherein the
basic substituent on R is selected from amino,
mono-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
di-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
mono-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl,
di-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-4-alkenyl, optionally
substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8
membered nitrogen-containing heterocyclyl-C.sub.1-4-alkyl; in
conjunction with any of the above or below embodiments.
[0114] The invention also relates to compounds of Formula III
wherein the basic moieties on R are independently selected from
amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl,
1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl,
1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl; in conjunction with any of the
above or below embodiments.
[0115] The invention also relates to compounds of Formula IV
##STR00004## [0116] wherein the C ring is a 4- to 7-membered
saturated carbocyclic or heterocyclic moiety; optionally
substituted with halo, --NH.sub.2, hydroxyl, cyano, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; [0117] wherein R' is
[0117] ##STR00005## [0118] wherein R.sup.1 is independently
selected from H and C.sub.1-2-alkyl; [0119] wherein R.sup.2 is
selected from arylalkenyl, aryl, and heterocyclyl selected from
thienyl, quinolinyl, isoquinolinyl, 3-pyridyl, thiazol-4-yl,
4-imidazolyl, benzofuryl, benzoxadiazolyl, benzothiadiazolyl,
benzothiazolyl, 1H-pyrazolyl, isoxazolthienyl, benzothienyl,
thieno[3,2-c]pyridinyl, and tetrahydroisoquinolinyl, wherein
R.sup.2 is optionally substituted with one to five groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
--CF.sub.3, (C.sub.1-C.sub.6)alkylamino, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8',
--NR.sup.8C(O)R.sup.8', (C.sub.1-C.sub.6)alkyl, substituted
(C.sub.1-C.sub.6)alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl,
substituted saturated or partially saturated heterocyclyl and
unsubstituted saturated or partially saturated heterocyclyl; [0120]
wherein each substituted (C.sub.1-C.sub.6)alkyl, substituted aryl,
substituted heteroaryl, substituted cycloalkyl and substituted
saturated or partially saturated heterocyclyl is substituted with
one to three groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, (C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)haloalkyl, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8', --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; [0121] wherein R.sup.8 and R.sup.8'
independently are H or selected from lower alkyl, aryl and
heteroaryl, each of which is optionally substituted with one, two
or three groups independently selected from lower alkyl, halogen,
lower alkoxy, hydroxy, amino, mono- or dialkylamino, and
trifluoromethyl; and [0122] wherein R.sup.9, R.sup.10 and R.sup.11
are the same or different and represent H, halo, --NH.sub.2,
hydroxyl, cyano, --CF.sub.3, (C.sub.1-C.sub.6)alkylamino, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8',
--NR.sup.8C(O)R.sup.8', a basic moiety, (C.sub.1-C.sub.6)alkyl,
substituted (C.sub.1-C.sub.6)alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, cycloalkyl, substituted
cycloalkyl, substituted saturated or partially saturated
heterocyclyl and unsubstituted saturated or partially saturated
heterocyclyl; [0123] wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl, substituted heteroaryl,
substituted cycloalkyl and substituted saturated or partially
saturated heterocyclyl is substituted with one to three groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; [0124] provided at least one of R.sup.9,
R.sup.10 and R.sup.11 is a basic moiety; further provided the basic
substiuent is not 2-pyridyl, 3-pyridyl or
2-oxo-piperaziny-4-ylmethyl; and pharmaceutically acceptable
derivatives thereof.
[0125] The invention also relates to compounds of Formula IV [0126]
wherein R.sup.9 and R.sup.11 are H; and wherein R.sup.10 is
selected from amino, aminomethyl, isopropylaminomethyl,
t-butylaminomethyl, 2-t-butylaminoethyl,
2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl,
1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl,
N-isobutyl-aminomethyl, N-isobutyl-aminoethyl,
(2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl,
N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl,
N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl,
N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl,
N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl,
N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl,
cyclopropylaminomethyl, cyclopropylaminoethyl,
cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl,
cyclobutylaminomethyl, cyclobutylaminoethyl,
cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl,
4,5-dihydro-imidazolyl, 1-piperidinylmethyl,
4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,
3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,
4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl.
[0127] The invention also relates to compounds of Formula IV
wherein R.sup.10 and R.sup.11 are H; and wherein R.sup.9 is
selected from amino, aminomethyl, isopropylaminomethyl,
t-butylaminomethyl, 2-t-butylaminoethyl,
2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl,
1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl,
N-isobutyl-aminomethyl, N-isobutyl-aminoethyl,
(2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl,
N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl,
N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl,
N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl,
N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl,
N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl,
cyclopropylaminomethyl, cyclopropylaminoethyl,
cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl,
cyclobutylaminomethyl, cyclobutylaminoethyl,
cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl,
4,5-dihydro-imidazolyl, 1-piperidinylmethyl,
4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,
3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,
4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl; in conjunction with any of the
above or below embodiments.
[0128] The invention also relates to compounds of Formula IV
wherein R.sup.9 and R.sup.10 are H; and wherein R.sup.11 is
selected from amino, aminomethyl, isopropylaminomethyl,
t-butylaminomethyl, 2-t-butylaminoethyl,
2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl,
1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl,
N-isobutyl-aminomethyl, N-isobutyl-aminoethyl,
(2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl,
N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl,
N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl,
N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl,
N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl,
N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl,
cyclopropylaminomethyl, cyclopropylaminoethyl,
cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl,
cyclobutylaminomethyl, cyclobutylaminoethyl,
cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl,
4,5-dihydro-imidazolyl, 1-piperidinylmethyl,
4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,
3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,
4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl; in conjunction with any of the
above or below embodiments.
[0129] The invention also relates to compounds of Formula IV
wherein the C ring is selected from
##STR00006##
wherein R.sup.b is independently selected from R', H and
C.sub.1-2-alkyl; wherein R.sup.y is selected from halo, hydroxyl,
cyano, oxo, (C.sub.1-C.sub.4)alkoxy, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.4)alkyl, substituted (C.sub.1-C.sub.4)alkyl, phenyl,
substituted phenyl, 5-6 membered heteroaryl, substituted 5-6
membered heteroaryl, C.sub.3-6-cycloalkyl, substituted
C.sub.3-6-cycloalkyl, substituted saturated or partially saturated
5-6 membered heterocyclyl and unsubstituted saturated or partially
saturated 5-6 membered heterocyclyl; and wherein R'' is R' when
R.sup.b is hydrogen or C.sub.1-2alkyl, or R'' is hydrogen when
R.sup.b is R'; in conjunction with any of the above or below
embodiments.
[0130] The invention also relates to compounds of Formula IV
wherein R.sup.2 is selected from phenyl-CH.dbd.CH--,
tetrahydronaphthyl, naphtho[2,3-d]dioxol-6-yl, 1-benzofur-2-yl,
2,1,3-benzoxadiazol-4-yl, 2,1,3-benzothiadiazol-4-yl,
1,3-benzothiazol-2-yl, 1H-pyrazol-4-yl, thien-2-yl,
5-isoxazolthien-2-yl, benzothien-2-yl, thieno[3,2-c]pyridin-2-yl,
2-naphthyl, phenyl, 3-pyridyl, tetrahydroisoquinolyl, 8-quinolyl
and 5-isoquinolyl; wherein R.sup.2 is selected from
phenyl-CH.dbd.CH--, tetrahydronaphthyl, 2,1,3-benzoxadiazol-4-yl,
thien-2-yl, 2-naphthyl, phenyl, 3-pyridyl, 8-quinolyl and
5-isoquinolyl; wherein each R.sup.2 is optionally substituted with
one to five groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, --CF.sub.3, (C.sub.1-C.sub.6)alkylamino, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8',
--NR.sup.8C(O)R.sup.8', (C.sub.1-C.sub.6)alkyl, substituted
(C.sub.1-C.sub.6)alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl,
substituted saturated or partially saturated heterocyclyl and
unsubstituted saturated or partially saturated heterocyclyl;
wherein each substituted (C.sub.1-C.sub.6)alkyl, substituted aryl,
substituted heteroaryl, substituted cycloalkyl and substituted
saturated or partially saturated heterocyclyl is substituted with
one to three groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, (C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)haloalkyl, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; in conjunction with any of the above or
below embodiments.
[0131] The invention also relates to compounds of Formula IV
wherein R.sup.2 is selected from 2-naphthyl, 1-naphthyl, phenyl,
3-chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl,
3,4-dichlorophenyl, 2,4,6-trichlorophenyl, 3-fluorophenyl,
3-methoxyphenyl, 4-methoxyphenyl, 3-biphenyl,
3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl,
3-trifluoromethylphenyl, 4-trifluoromethylphenyl,
4-trifluoromethoxyphenyl, 3-methylphenyl, 2,1,3-benzoxadiazol-4-yl,
thien-2-yl, 3-pyridyl, 8-quinolyl and 5-isoquinolyl; in conjunction
with any of the above or below embodiments.
[0132] The invention also relates to compounds of Formula IV
wherein R.sup.1 is H; in conjunction with any of the above or below
embodiments.
[0133] The invention also relates to compounds of Formula IV
wherein R.sup.2 is 2-naphthyl; in conjunction with any of the above
or below embodiments.
[0134] The invention also relates to compounds of Formula IV
wherein R.sup.2 is 3,4-dichlorophenyl; in conjunction with any of
the above or below embodiments.
[0135] The invention also relates to compounds of Formula IV
wherein R.sup.2 is 3-trifluoromethylphenyl; in conjunction with any
of the above or below embodiments.
[0136] The invention also relates to compounds of Formula V
##STR00007##
wherein R.sup.2 is selected from naphthyl, phenyl, thienyl,
heterocyclyl selected from thienyl, benzoxadiazolyl, quinolinyl and
isoquinolinyl, and wherein each is optionally substituted with one
to three substituents selected from chloro, fluoro, methoxy,
methyl, trifluoromethyl and phenyl; [0137] wherein R.sup.7 is
selected from amino-(CH.sub.2).sub.p--, mono(C.sub.1-4)
alkylamino-(CH.sub.2).sub.p--,
di(C.sub.1-4)alkylamino-(CH.sub.2).sub.p--,
amino-(C.sub.2-4)-alkenyl,
(C.sub.1-4)alkylamino-(C.sub.2-4)-alkenyl,
di(C.sub.1-4)alkylamino-(C.sub.2-4)-alkenyl, 5-7 membered
nitrogen-containing heterocyclyl-(C.sub.2-4)-alkenyl, 5-7 membered
nitrogen-containing heterocyclyl and 5-7 membered
nitrogen-containing heterocyclyl-(CH.sub.2).sub.p-- optionally
substituted with one to three groups independently selected from
halo, --NH.sub.2, hydroxyl, cyano, --CF.sub.3,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8', .dbd.NCN,
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl, substituted heteroaryl,
substituted cycloalkyl and substituted saturated or partially
saturated heterocyclyl is substituted with one to three groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; [0138] wherein p is 0-2; [0139] wherein
R.sup.7 is at position 6, 7 or 8; and [0140] wherein R.sup.8 and
R.sup.8' independently are H or selected from lower alkyl, aryl and
heteroaryl, each of which is optionally substituted with one, two
or three groups independently selected from lower alkyl, halogen,
lower alkoxy, hydroxy, amino, mono- or dialkylamino, and
trifluoromethyl; and pharmaceutically acceptable derivatives
thereof; [0141] provided R.sup.7 is not 2-pyridyl, 3-pyridyl or
2-oxo-piperaziny-4-ylmethyl.
[0142] The invention also relates to compounds of Formula V wherein
R.sup.7 is selected from amino, aminomethyl, isopropylaminomethyl,
t-butylaminomethyl, 2-t-butylaminoethyl,
2-tert-butylamino-1-methyl-ethyl, 1-tert-butylaminoethyl,
1-(tert-butylamino-methyl)-vinyl, 1-(piperidin-1-ylmethyl)-vinyl,
N-isobutyl-aminomethyl, N-isobutyl-aminoethyl,
(2,2-dimethyl)propylaminomethyl, N-isopropyl-N-ethylaminomethyl,
N-isopropyl-N-methylaminomethyl, N-t-butyl-N-methylaminomethyl,
N-iso-butyl-N-methylaminomethyl, N-t-butyl-N-ethylaminomethyl,
N-isobutyl-N-methylaminomethyl, N-t-butyl-N-isopropylaminomethyl,
N,N-di(isopropyl)aminomethyl, N,N-dimethylaminomethyl,
N,N-diethylaminomethyl, N,N-di(t-butyl)-aminomethyl,
cyclopropylaminomethyl, cyclopropylaminoethyl,
cyclopropylmethylaminomethyl, cyclopropylmethylaminoethyl,
cyclobutylaminomethyl, cyclobutylaminoethyl,
cyclobutylmethylaminomethyl, cyclobutylmethylaminoethyl,
4,5-dihydro-imidazolyl, 1-piperidinylmethyl,
4-fluoropiperidin-1-ylmethyl, 4,4-difluoropiperidin-1-ylmethyl,
3-hydroxypiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,
4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl; in conjunction with any of the
above or below embodiments.
[0143] The invention also relates to compounds of Formula V wherein
R.sup.7 is at position 7; in conjunction with any of the above or
below embodiments.
[0144] The invention also relates to compounds of Formula V wherein
R.sup.2 is 2-naphthyl, 3,4-dichlorophenyl or
3-trifluoromethylphenyl; in conjunction with any of the above or
below embodiments.
[0145] The invention also relates to compounds of Formula VI
##STR00008## [0146] wherein R is a 9-11 membered fused bicyclic
carbocyclic or heterocyclic ring substituted with one to three
basic moieties, and optionally substituted with one to two groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl; [0147] wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl, substituted heteroaryl,
substituted cycloalkyl and substituted saturated or partially
saturated heterocyclyl is substituted with one to three groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; [0148] wherein R.sup.1 is selected from H,
and C.sub.1-2-alkyl; [0149] wherein R.sup.2 is selected from
arylalkenyl, aryl, and heterocyclyl selected from thienyl,
quinolinyl, isoquinolinyl, 3-pyridyl, thiazol-4-yl, 4-imidazolyl,
benzofuryl, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl,
1H-pyrazolyl, isoxazolthienyl, benzothienyl,
thieno[3,2-c]pyridinyl, and tetrahydroisoquinolinyl, wherein
R.sup.2 is optionally substituted with one to five groups
independently selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.6)alkylamino, (C.sub.1-C.sub.6)haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; and [0150] wherein R.sup.8 and R.sup.8'
independently are H or selected from lower alkyl, aryl and
heteroaryl, each of which is optionally substituted with one, two
or three groups independently selected from lower alkyl, halogen,
lower alkoxy, hydroxy, amino, mono- or dialkylamino, and
trifluoromethyl; and pharmaceutically acceptable derivatives
thereof; [0151] provided the basic substiuent is not 2-pyridyl,
3-pyridyl or 2-oxo-piperaziny-4-ylmethyl.
[0152] The invention also relates to compounds of Formula VI
wherein R is a partially unsaturated carbocyclic ring, such as
1,2,3,4-tetrahydronaphthyl or indanyl; substituted with a basic
moiety, optionally substituted with chloro; in conjunction with any
of the above or below embodiments.
[0153] The invention also relates to compounds of Formula VI
wherein R is selected from 1,2,3,4-tetrahydronaphth-1-yl,
1,2,3,4-tetrahydronaphth-2-yl, indan-1-yl and indan-2-yl;
substituted with a basic moiety, optionally substituted with
chloro; in conjunction with any of the above or below
embodiments.
[0154] The invention also relates to compounds of Formula VI
wherein R is partially unsaturated heterocyclyl, such as chroman
and 2,2-dioxo-3,4-dihydro-1H-2,1-benzothiaziny; substituted with a
basic moiety, optionally substituted with chloro; in conjunction
with any of the above or below embodiments.
[0155] The invention also relates to compounds of Formula VI
wherein R is chroman-4-yl, or
2,2-dioxo-3,4-dihydro-1H-2,1-benzothiazin-4-yl; substituted with a
basic moiety, optionally substituted with chloro; in conjunction
with any of the above or below embodiments.
[0156] The invention also relates to compounds wherein each R.sup.2
is selected from phenyl-CH.dbd.CH--, tetrahydronaphthyl,
naphtho[2,3-d]dioxolyl, benzofuranyl, benzoxadiazolyl,
benzothiadiazolyl, benzothiazolyl, 1H-pyrazolyl, thienyl,
isoxazolthienyl, benzothienyl, thieno[3,2-c]pyridinyl, naphthyl,
phenyl, pyridinyl, tetrahydroisoquinolinyl, quinolinyl and
isoquinolinyl; wherein R.sup.2 is optionally substituted with one
to five groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, --CF.sub.3, (C.sub.1-C.sub.6)alkylamino, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8',
--NR.sup.8C(O)R.sup.8', (C.sub.1-C.sub.6)alkyl, substituted
(C.sub.1-C.sub.6)alkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, cycloalkyl, substituted cycloalkyl,
substituted saturated or partially saturated heterocyclyl and
unsubstituted saturated or partially saturated heterocyclyl;
wherein each substituted (C.sub.1-C.sub.6)alkyl, substituted aryl,
substituted heteroaryl, substituted cycloalkyl and substituted
saturated or partially saturated heterocyclyl is substituted with
one to three groups independently selected from halo, --NH.sub.2,
hydroxyl, cyano, (C.sub.1-C.sub.6)alkylamino,
halo(C.sub.1-C.sub.6)alkyl, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; wherein R.sup.1 is selected from H and
C.sub.1-2-alkyl; wherein the basic substituent on R is selected
from amino, cycloalkylamino(C.sub.1-C.sub.6)alkyl,
cycloalkyl(C.sub.1-C.sub.6) alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy,
C.sub.1-6-alkylamino-C.sub.1-6-alkoxy-C.sub.1-6-alkoxy,
amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
C.sub.1-4-alkylamino-C.sub.2-6-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-6-alkenyl,
heterocyclyl-(C.sub.1-C.sub.6)alkylamino(C.sub.2-C.sub.6)alkyl, 5-6
membered heterocyclyloxy, 5-6 membered nitrogen-containing
heterocyclyl and 5-7 membered nitrogen-containing
heterocyclyl-alkyl; and wherein each of said basic substituents is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano, --CF.sub.3,
(C.sub.1-C.sub.6)alkylamino, oxo, (C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8',
(C.sub.1-C.sub.6)alkyl, substituted (C.sub.1-C.sub.6)alkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl,
substituted cycloalkyl, substituted saturated or partially
saturated heterocyclyl and unsubstituted saturated or partially
saturated heterocyclyl, wherein each substituted
(C.sub.1-C.sub.6)alkyl, substituted aryl substituted heteroaryl and
substituted saturated or partially saturated heterocyclyl is
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, hydroxyl, cyano,
(C.sub.1-C.sub.4)alkylamino, (C.sub.1-C.sub.4)haloalkyl, oxo,
(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkynyl, di(C.sub.1-C.sub.4)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'; in conjunction with any of the above or
below embodiments.
[0157] The invention also relates to compounds wherein R.sup.2 is
selected from phenyl-CH.dbd.CH--, tetrahydronaphthyl,
2,1,3-benzoxadiazol-4-yl, thien-2-yl, 2-naphthyl, phenyl,
3-pyridyl, 8-quinolyl and 5-isoquinolyl; wherein each R.sup.2 is
said optionally substituted; wherein R.sup.a is H; and wherein the
basic substituent on R is selected from amino,
mono-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
di-C.sub.1-4-alkylamino-C.sub.1-4-alkyl,
mono-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl,
di-C.sub.1-4-alkylamino-C.sub.2-4-alkenyl, 5-8 membered
nitrogen-containing heterocyclyl-C.sub.2-4-alkenyl, optionally
substituted 5-6 membered nitrogen-containing heterocyclyl and 5-8
membered nitrogen-containing heterocyclyl-C.sub.1-4-alkyl; in
conjunction with any of the above or below embodiments.
[0158] The invention also relates to compounds of Formula VI
wherein the basic moieties on R are independently selected from
amino, aminomethyl, isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl,
1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl,
1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl; in conjunction with any of the
above or below embodiments.
[0159] A family of specific compounds of particular interest within
Formula I consists of compounds and pharmaceutically-acceptable
salts thereof as follows: [0160]
2-[3-Oxo-1-(2,4,6-trimethylbenzenesulfonyl)-piperizin-2(R,S)-yl]-N-(1,2,3-
,4-tetrahydronaphthalen-1-yl)-acetamide; [0161]
N-((1R)-6-(((1,1-Dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphtha-
lenyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamid-
e; [0162]
2-[3-Oxo-1-(toluene-4-sulfonyl)piperizin-2-yl]-N-(6-piperidin-1--
ylmethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide; [0163]
N-7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(toluene-4-
-sulfonyl)-piperazin-2-yl]-acetamide; [0164]
N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(4-methox-
y-benzenesulfonyl)-piperazin-2-yl]-acetamide; [0165]
N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(4-chloro-
-benzenesulfonyl)-piperazin-2-yl]-acetamide; [0166]
N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(3-triflu-
oromethyl-benzenesulfonyl)-piperazin-2-yl]-acetamide; [0167]
N-((4R)-2,2-dimethyl-7-(2-piperidinyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2-
R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
[0168]
2-((2R,S)-5,5-dimethyl-3-oxo-1-((2,4,6-trimethylphenyl)sulfonyl)-2-pipera-
zinyl)-N-(1,2,3,4-tetrahydro-1-naphthalenyl)acetamide; [0169]
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-[5,5--
dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S)-yl]-ac-
etamide [0170]
N-((1R,S)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-napht-
halenyl)-2-((2R,S)-5,5-dimethyl-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piper-
azinyl)acetamide; [0171]
2-[5,5-Dimethyl-3-oxo-1-(toluene-4-sulfonyl)-piperizin-2(R,S)-yl]-N-(6-pi-
peridin-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-1(R)-yl)-acetamide;
and [0172]
N-((4R)-6-Chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro--
2H-chromen-4-yl)-2-((2R,S)-5,5-dimethyl-3-oxo-1-((2,4,6-trimethylphenyl)su-
lfonyl)-2-piperazinyl)acetamide.
Indications
[0173] The present invention also provides methods of using the
compounds in for the treatment of a disorder such as acute pain,
dental pain, back pain, lower back pain, pain from trauma, surgical
pain, pain resulting from amputation or abscess, causalgia,
fibromyalgia, demyelinating diseases, trigeminal neuralgia, cancer,
chronic alcoholism, stroke, thalamic pain syndrome, diabetes,
acquired immune deficiency syndrome ("AIDS"), toxins and
chemotherapy, general headache, migraine, cluster headache,
mixed-vascular and non-vascular syndromes, tension headache,
general inflammation, arthritis, rheumatic diseases, lupus,
osteoarthritis, inflammatory bowel disorders, inflammatory eye
disorders, inflammatory or unstable bladder disorders, psoriasis,
skin complaints with inflammatory components, sunburn, carditis,
dermatitis, myositis, neuritis, collagen vascular diseases, chronic
inflammatory conditions, inflammatory pain and associated
hyperalgesia and allodynia, neuropathic pain and associated
hyperalgesia and allodynia, diabetic neuropathy pain,
sympathetically maintained pain, deafferentation syndromes, asthma,
vasomotor or allergic rhinitis, epithelial tissue damage or
dysfunction, herpes simplex, post-herpetic neuralgia, disturbances
of visceral motility at respiratory, genitourinary,
gastrointestinal or vascular regions, wounds, burns, allergic skin
reactions, pruritis, vitiligo, general gastrointestinal disorders,
colitis, inflammatory bowel disease, gastric ulceration, duodenal
ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy,
septic shock, and bronchial disorders.
[0174] The invention also provides for the use of the compounds of
the present invention for the prevention or for the treatment of a
disorder such as acute pain, dental pain, back pain, lower back
pain, pain from trauma, surgical pain, pain resulting from
amputation or abscess, causalgia, fibromyalgia, demyelinating
diseases, trigeminal neuralgia, cancer, chronic alcoholism, stroke,
thalamic pain syndrome, diabetes, acquired immune deficiency
syndrome ("AIDS"), toxins and chemotherapy, general headache,
migraine, cluster headache, mixed-vascular and non-vascular
syndromes, tension headache, general inflammation, arthritis,
rheumatic diseases, lupus, osteoarthritis, inflammatory bowel
disorders, inflammatory eye disorders, inflammatory or unstable
bladder disorders, psoriasis, skin complaints with inflammatory
components, sunburn, carditis, dermatitis, myositis, neuritis,
collagen vascular diseases, chronic inflammatory conditions,
inflammatory pain and associated hyperalgesia and allodynia,
neuropathic pain and associated hyperalgesia and allodynia,
diabetic neuropathy pain, sympathetically maintained pain,
deafferentation syndromes, asthma, vasomotor or allergic rhinitis,
epithelial tissue damage or dysfunction, herpes simplex,
post-herpetic neuralgia, disturbances of visceral motility at
respiratory, genitourinary, gastrointestinal or vascular regions,
wounds, burns, allergic skin reactions, pruritis, vitiligo, general
gastrointestinal disorders, colitis, inflammatory bowel disease,
gastric ulceration, duodenal ulcers, thalamic pain syndrome,
diabetes, toxins and chemotherapy, septic shock, and bronchial
disorders.
[0175] Accordingly, the present invention also relates to the use
of one or more of the compounds of the present invention in the
manufacture of a medicament for the treatment of a disorder such as
acute pain, dental pain, back pain, lower back pain, pain from
trauma, surgical pain, pain resulting from amputation or abscess,
causalgia, fibromyalgia, demyelinating diseases, trigeminal
neuralgia, cancer, chronic alcoholism, stroke, thalamic pain
syndrome, diabetes, acquired immune deficiency syndrome ("AIDS"),
toxins and chemotherapy, general headache, migraine, cluster
headache, mixed-vascular and non-vascular syndromes, tension
headache, general inflammation, arthritis, rheumatic diseases,
lupus, osteoarthritis, inflammatory bowel disorders, inflammatory
eye disorders, inflammatory or unstable bladder disorders,
psoriasis, skin complaints with inflammatory components, sunburn,
carditis, dermatitis, myositis, neuritis, collagen vascular
diseases, chronic inflammatory conditions, inflammatory pain and
associated hyperalgesia and allodynia, neuropathic pain and
associated hyperalgesia and allodynia, diabetic neuropathy pain,
sympathetically maintained pain, deafferentation syndromes, asthma,
vasomotor or allergic rhinitis, epithelial tissue damage or
dysfunction, herpes simplex, post-herpetic neuralgia, disturbances
of visceral motility at respiratory, genitourinary,
gastrointestinal or vascular regions, wounds, burns, allergic skin
reactions, pruritis, vitiligo, general gastrointestinal disorders,
colitis, inflammatory bowel disease, gastric ulceration, duodenal
ulcers, thalamic pain syndrome, diabetes, toxins and chemotherapy,
septic shock, and bronchial disorders.
[0176] The compounds of this invention may also act as inhibitors
of other receptors or kinases, and thus be effective in the
treatment of diseases associated with other protein kinases.
[0177] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of companion animals,
exotic animals and farm animals, including mammals, rodents, and
the like. More preferred animals include horses, dogs, and
cats.
DEFINITIONS
[0178] The phrase "therapeutically-effective" is intended to
qualify the amount of each agent, which will achieve the goal of
improvement in disorder severity and the frequency of incidence
over treatment of each agent by itself, while avoiding adverse side
effects typically associated with alternative therapies. For
example, effective pain therapeutic agents relieve the pain
sensation of the patient. Alternatively, effective therapeutic
agents for the treatment of inflammation minimize the damage from
the inflammation, and the like.
[0179] The term "treatment" includes therapeutic treatment as well
as prophylactic treatment (either preventing the onset of disorders
altogether or delaying the onset of a pre-clinically evident stage
of disorders in individuals).
[0180] The term "H" denotes a single hydrogen atom. This radical
may be attached, for example, to an oxygen atom to form a hydroxyl
radical.
[0181] Where the term "alkyl" is used, either alone or within other
terms such as "haloalkyl", "cyanoalkyl" and "alkylamino", it
embraces linear or branched radicals having one to about twenty
carbon atoms or, preferably, one to about twelve carbon atoms, or
as otherwise indicated. More preferred alkyl radicals are "lower
alkyl" radicals having one to about six carbon atoms. Examples of
such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the
like. Even more preferred are lower alkyl radicals having one to
four carbon atoms. The term "alkyl" also includes divalent radicals
such as methylenyl and ethyleneyl.
[0182] The term "alkenyl" embraces linear or branched radicals
having at least one carbon-carbon double bond of two to about
twenty carbon atoms or, preferably, two to about twelve carbon
atoms, or as otherwise indicated. More preferred alkenyl radicals
are "lower alkenyl" radicals having two to about four carbon atoms.
Examples of alkenyl radicals include ethenyl, 2-propenyl, allyl,
butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower
alkenyl", embrace radicals having "cis" and "trans" orientations,
or alternatively, "E" and "Z" orientations.
[0183] The term "alkynyl" embraces linear or branched radicals
having at least one carbon-carbon triple bond of two to about
twenty carbon atoms or, preferably, two to about twelve carbon
atoms, or as otherwise indicated. More preferred alkynyl radicals
are "lower alkynyl" radicals having two to about four carbon atoms.
Examples of alkynyl radicals include ethynyl, 2-propynyl, and
4-methylbutynyl.
[0184] The term "halo" means halogens such as fluorine, chlorine,
bromine or iodine atoms.
[0185] The term "haloalkyl" embraces radicals wherein any one or
more of the alkyl carbon atoms is substituted with halo as defined
above. Specifically embraced are monohaloalkyl, dihaloalkyl and
polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl
radical, for one example, may have either an iodo, bromo, chloro or
fluoro atom within the radical. Dihalo and polyhaloalkyl radicals
may have two or more of the same halo atoms or a combination of
different halo radicals. "Lower haloalkyl" embraces radicals having
1-6 carbon atoms. Even more preferred are lower haloalkyl radicals
having one to three carbon atoms. Examples of haloalkyl radicals
include fluoromethyl, difluoromethyl, trifluoromethyl,
chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
"Perfluoroalkyl" means alkyl radicals having all hydrogen atoms
replaced with fluoro atoms. Examples include trifluoromethyl and
pentafluoroethyl.
[0186] The term "hydroxyalkyl" embraces linear or branched alkyl
radicals having one to about ten carbon atoms any one of which may
be substituted with one or more hydroxyl radicals. More preferred
hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one
to six carbon atoms and one or more hydroxyl radicals. Examples of
such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,
hydroxybutyl and hydroxyhexyl. Even more preferred are lower
hydroxyalkyl radicals having one to three carbon atoms.
[0187] The term "alkoxy" embrace linear or branched oxy-containing
radicals each having alkyl portions of one to about ten carbon
atoms. More preferred alkoxy radicals are "lower alkoxy" radicals
having one to six carbon atoms. Examples of such radicals include
methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Even more
preferred are lower alkoxy radicals having one to three carbon
atoms. The "alkoxy" radicals may be further substituted with one or
more halo atoms, such as fluoro, chloro or bromo, to provide
"haloalkoxy" radicals. Even more preferred are lower haloalkoxy
radicals having one to three carbon atoms. Examples of such
radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,
trifluoroethoxy, fluoroethoxy, and fluoropropoxy.
[0188] The term "alkoxyalkyl" embraces linear or branched alkyl
radicals having one to about ten carbon atoms any one of which may
be substituted with one or more alkoxyl radicals. More preferred
alkoxyalkyl radicals are "lower alkoxyalkyl" radicals respectively
having one to six carbon atoms. Examples of such radicals include
methoxymethyl, methoxyethyl, and the like. Even more preferred are
lower alkoxyalkyl radicals respectively having one to three carbon
atoms alkyl radicals.
[0189] The term "aryl", alone or in combination, means a
carbocyclic aromatic system containing one or two rings wherein
such rings may be attached together in a pendent manner or may be
fused. The term "aryl" embraces aromatic radicals such as phenyl,
naphthyl, tetrahydronaphthyl, indane and biphenyl. More preferred
aryl is phenyl. Said "aryl" group may have 1 to 3 substituents such
as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy,
and lower alkylamino. Benzodioxolyl is considered aryl.
[0190] The term "heterocyclyl" embraces saturated, partially
saturated and unsaturated heteroatom-containing ring radicals,
where the heteroatoms may be selected from nitrogen, sulfur and
oxygen. It does not include rings containing --O--O-- or --S--S--
portions. Said "heterocyclyl" group may have 1 to 3 substituents
such as hydroxyl, halo, haloalkyl, cyano, lower alkyl, lower
aralkyl, oxo, lower alkoxy, amino, and lower alkylamino.
[0191] Examples of saturated heterocyclic radicals include
saturated 3 to 8-membered heteromonocyclic group containing 1 to 4
nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino,
piperazinyl]; saturated 3 to 8-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
morpholinyl]; saturated 3 to 8-membered heteromonocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
thiazolidinyl]. Examples of partially saturated heterocyclyl
radicals include dihydrothiophene, dihydropyran, dihydrofuran and
dihydrothiazole.
[0192] Examples of unsaturated heterocyclic radicals, also termed
"heteroaryl" radicals, include unsaturated 5 to 6 membered
heteromonocyclyl groups containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridinyl,
3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,
2H-1,2,3-triazolyl]; unsaturated 3 to 6-membered heteromonocyclic
group containing an oxygen atom, for example, pyranyl, 2-furyanl,
3-furyanl, etc.; unsaturated 5 to 6-membered heteromonocyclic group
containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.;
unsaturated 5- to 6-membered heteromonocyclic group containing 1 to
2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,
isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3
nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].
[0193] The term also embraces radicals where heterocyclic radicals
are fused/condensed with aryl radicals: unsaturated condensed
heterocyclic group containing 1 to 5 nitrogen atoms, for example,
indolinyl, isoindolinyl, indolizinyl, benzimidazolyl, quinolinyl,
isoquinolinyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl
[e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed
heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated
condensed heterocyclic group containing 1 to 2 sulfur atoms and 1
to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl].
[0194] The term also includes bridged, spiro and oxo-containing
heterocyclic rings, such as 1,4-dioxa-8-aza-spiro[4.5]decyl,
phthalimidyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, and
(1-aza-bicyclo[2.2.2]oct-3-yl).
[0195] Preferred heterocyclic radicals include five to ten membered
fused or unfused radicals. More preferred examples of heteroaryl
radicals include quinolinyl, isoquinolinyl, imidazolyl, pyridinyl,
thienyl, thiazolyl, oxazolyl, furanyl, and pyrazinyl. Even more
preferred heteroaryl radicals are 5- or 6-membered heteroaryl,
containing one or two heteroatoms selected from sulfur, nitrogen
and oxygen, selected from thienyl, furanyl, pyrrolyl, thiazolyl,
oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
pyridinyl, piperidinyl and pyrazinyl.
[0196] The term "sulfonyl", whether used alone or linked to other
terms such as alkylsulfonyl, denotes respectively divalent radicals
--SO.sub.2--.
[0197] The terms "sulfamyl," "aminosulfonyl" and "sulfonamidyl,"
whether alone or used with terms such as "N-alkylaminosulfonyl",
"N-arylaminosulfonyl", "N,N-dialkylaminosulfonyl" and
"N-alkyl-N-arylaminosulfonyl", denotes a sulfonyl radical
substituted with an amine radical, forming a sulfonamide
(--SO.sub.2NH.sub.2).
[0198] The term "cycloalkylaminoalkyl" includes
"N-cycloalkylaminoalkyl" and "N,N-dicycloalkylaminoalkyl" where
alkyl radicals are independently substituted, respectively, with
one cycloalkyl radical, or two cycloalkyl radicals. More preferred
cycloalkylaminoalkyl radicals are "lower cycloalkylaminoalkyl"
radicals having alkyl radicals with one to six carbon atoms. Even
more preferred are lower cycloalkylaminoalkyl radicals having alkyl
radicals with one to three carbon atoms. Examples of such lower
alkylaminosulfonyl radicals include N-cyclohexylaminomethyl, and
N-cyclopentylaminoethyl.
[0199] The term "cycloalkyl-alkylaminoalkyl" embraces cycloalkyl
radicals as described above, attached to an alkylaminoalkyl
radical. More preferred are lower cycloalkyl-alkylaminoalkyl
radicals independently having alkyl radicals of one to three carbon
atoms.
[0200] The term "N-arylaminoalkyl" denotes alkyl radicals
substituted with an aryl radical. More preferred arylaminoalkyl
radicals are "lower N-arylaminoalkyl" radicals having alkyl
radicals of one to six carbon atoms. Even more preferred are
phenylaminoalkyl radicals having one to three carbon atoms.
Examples of such radicals include N-phenylaminomethyl and
N-phenylaminoethyl.
[0201] The term "aralkylaminoalkyl" embraces aralkyl radicals as
described above, attached to an aminoalkyl radical. More preferred
are lower arylalkylaminoalkyl radicals independently having alkyl
radicals of one to three carbon atoms.
[0202] The term "heterocyclylaminoalkyl" embraces heterocyclyl
radicals as described above, attached to an aminoalkyl radical.
[0203] The term "heteroarylalkylaminoalkyl" embraces
heteroarylalkyl radicals as described above, attached to an
aminoalkyl radical. More preferred are lower
heteroarylalkylaminoalkyl radicals having, independently, alkyl
radicals of one to three carbon atoms.
[0204] The terms "carboxy" or "carboxyl", whether used alone or
with other terms, such as "carboxyalkyl", denotes --CO.sub.2H.
[0205] The term "carbonyl", whether used alone or with other terms,
such as "aminocarbonyl", denotes --(C.dbd.O)--.
[0206] The terms "alkylcarbonyl" denotes carbonyl radicals which
have been substituted with an alkyl radical. More preferred are
"lower alkylcarbonyl" having lower alkyl radicals as described
above attached to a carbonyl radical.
[0207] The terms "arylcarbonyl" denotes carbonyl radicals
substituted with an aryl radical. More preferred are "optionally
substituted phenylcarbonyl" radicals.
[0208] The terms "cycloalkylcarbonyl" denotes carbonyl radicals
substituted with an cycloalkyl radical. More preferred are
"optionally substituted cycloalkylcarbonyl" radicals, even more
preferably containing C.sub.3-6 cycloalkyl.
[0209] The terms "heterocyclylcarbonyl" denotes carbonyl radicals
substituted with an heterocyclyl radical. More preferred are
"optionally substituted 5-6 membered heterocyclylcarbonyl"
radicals.
[0210] The term "aminocarbonyl" when used by itself or with other
terms such as "aminocarbonylalkyl", "N-alkylaminocarbonyl",
"N-arylaminocarbonyl", "N,N-dialkylaminocarbonyl",
"N-alkyl-N-arylaminocarbonyl", "N-alkyl-N-hydroxyaminocarbonyl" and
"N-alkyl-N-hydroxyaminocarbonylalkyl", denotes an amide group of
the formula H.sub.2NC(.dbd.O)--.
[0211] The terms "N-alkylaminocarbonyl" and
"N,N-dialkylaminocarbonyl" denote aminocarbonyl radicals which have
been substituted with one alkyl radical and independently with two
alkyl radicals, respectively. More preferred are "lower
alkylaminocarbonyl" having lower alkyl radicals as described above
attached to an aminocarbonyl radical.
[0212] The terms "N-arylaminocarbonyl" and
"N-alkyl-N-arylaminocarbonyl" denote aminocarbonyl radicals
substituted, respectively, with one aryl radical, or one alkyl and
one aryl radical.
[0213] The term "aminoalkyl" embraces linear or branched alkyl
radicals having one to about ten carbon atoms any one of which may
be substituted with one or more amino radicals. More preferred
aminoalkyl radicals are "lower aminoalkyl" radicals having one to
six carbon atoms and one or more amino radicals. Examples of such
radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl
and aminohexyl. Even more preferred are lower aminoalkyl radicals
having one to three carbon atoms.
[0214] The term "alkylaminoalkyl" embraces aminoalkyl radicals
having the nitrogen atom independently substituted with an alkyl
radical. More preferred alkylaminoalkyl radicals are "lower
alkylaminoalkyl" radicals having alkyl radicals of one to six
carbon atoms. Even more preferred are lower alkylaminoalkyl
radicals having alkyl radicals of one to three carbon atoms.
Suitable alkylaminoalkyl radicals may be mono or dialkyl
substituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl,
N,N-diethylaminomethyl and the like.
[0215] The term "heterocyclylalkyl" embraces
heterocyclic-substituted alkyl radicals. More preferred
heterocyclylalkyl radicals are "5- or 6-membered heteroarylalkyl"
radicals having alkyl portions of one to six carbon atoms and a 5-
or 6-membered heteroaryl radical. Even more preferred are lower
heteroarylalkyl radicals having alkyl portions of one to three
carbon atoms. Examples include such radicals as pyridinylmethyl and
thienylmethyl.
[0216] The term "aralkyl" embraces aryl-substituted alkyl radicals.
Preferable aralkyl radicals are "lower aralkyl" radicals having
aryl radicals attached to alkyl radicals having one to six carbon
atoms. Even more preferred are lower aralkyl radicals phenyl
attached to alkyl portions having one to three carbon atoms.
Examples of such radicals include benzyl, diphenylmethyl and
phenylethyl. The aryl in said aralkyl may be additionally
substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.
[0217] The term "arylalkenyl" embraces aryl-substituted alkenyl
radicals. Preferable arylalkenyl radicals are "lower arylalkenyl"
radicals having aryl radicals attached to alkenyl radicals having
two to six carbon atoms. Examples of such radicals include
phenylethenyl. The aryl in said arylalkenyl may be additionally
substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.
[0218] The term "alkylthio" embraces radicals containing a linear
or branched alkyl radical, of one to ten carbon atoms, attached to
a divalent sulfur atom. Even more preferred are lower alkylthio
radicals having one to three carbon atoms. An example of
"alkylthio" is methylthio, (CH.sub.3S--).
[0219] The term "haloalkylthio" embraces radicals containing a
haloalkyl radical, of one to ten carbon atoms, attached to a
divalent sulfur atom. Even more preferred are lower haloalkylthio
radicals having one to three carbon atoms. An example of
"haloalkylthio" is trifluoromethylthio.
[0220] The term "alkylsulfinyl" embraces radicals containing a
linear or branched alkyl radical, of one to ten carbon atoms,
attached to a divalent --S(.dbd.O)-- atom. More preferred are lower
alkylsulfinyl radicals having one to three carbon atoms.
[0221] The term "arylsulfinyl" embraces radicals containing an aryl
radical, attached to a divalent --S(.dbd.O)-- atom. Even more
preferred are optionally substituted phenylsulfinyl radicals.
[0222] The term "haloalkylsulfinyl" embraces radicals containing a
haloalkyl radical, of one to ten carbon atoms, attached to a
divalent --S(.dbd.O)-- atom. Even more preferred are lower
haloalkylsulfinyl radicals having one to three carbon atoms.
[0223] The term "alkylamino" denotes amino groups which have been
substituted with one alkyl radical and with two alkyl radicals,
including terms "N-alkylamino" and "N,N-dialkylamino". More
preferred alkylamino radicals are "lower alkylamino" radicals
having one or two alkyl radicals of one to six carbon atoms,
attached to a nitrogen atom. Even more preferred are lower
alkylamino radicals having one to three carbon atoms. Suitable
"alkylamino" may be mono or dialkylamino such as N-methylamino,
N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.
[0224] The term "arylamino" denotes amino groups which have been
substituted with one or two aryl radicals, such as N-phenylamino.
The "arylamino" radicals may be further substituted on the aryl
ring portion of the radical.
[0225] The term "heteroarylamino" denotes amino groups which have
been substituted with one or two heteroaryl radicals, such as
N-thienylamino. The "heteroarylamino" radicals may be further
substituted on the heteroaryl ring portion of the radical.
[0226] The term "aralkylamino" denotes amino groups which have been
substituted with one or two aralkyl radicals. More preferred are
phenyl-C.sub.1-C.sub.3-alkylamino radicals, such as N-benzylamino.
The "aralkylamino" radicals may be further substituted on the aryl
ring portion of the radical.
[0227] The term "alkylaminoalkylamino" denotes alkylamino groups
which have been substituted with one or two alkylamino radicals.
More preferred are
C.sub.1-C.sub.3-alkylamino-C.sub.1-C.sub.3-alkylamino radicals.
[0228] The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals
substituted with alkylaminoalkoxy radicals. More preferred
alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy"
radicals independently having alkoxy radicals of one to six carbon
atoms. Even more preferred are lower alkylaminoalkoxyalkoxy
radicals having alkyl radicals of one to three carbon atoms.
Suitable alkylaminoalkoxyalkoxy radicals may be mono or dialkyl
substituted, such as N-methylaminoethoxymethoxy,
N,N-dimethylaminoethoxymethoxy, N,N-diethylaminomethoxymethoxy, and
the like.
[0229] The term "alkylaminoalkoxy" embraces alkoxy radicals
substituted with alkylamino radicals. More preferred
alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals
having alkoxy radicals of one to six carbon atoms. Even more
preferred are lower alkylaminoalkoxy radicals having alkyl radicals
of one to three carbon atoms. Suitable alkylaminoalkoxy radicals
may be mono or dialkyl substituted, such as N-methylaminoethoxy,
N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy and the like.
[0230] The term "aminoalkoxy" embraces alkoxy radicals substituted
with an amino radical. More preferred aminoalkoxy radicals are
"lower aminoalkoxy" radicals having alkoxy radicals of one to six
carbon atoms. Suitable aminoalkoxy radicals may be aminoethoxy,
aminomethoxy, aminopropoxy and the like.
[0231] The terms "N-aralkyl-N-alkylamino" and "N-alkyl-N-arylamino"
denote amino groups which have been substituted with one aralkyl
and one alkyl radical, or one aryl and one alkyl radical,
respectively, to an amino group.
[0232] The term "arylthio" embraces aryl radicals of six to ten
carbon atoms, attached to a divalent sulfur atom. An example of
"arylthio" is phenylthio.
[0233] The term "aralkylthio" embraces aralkyl radicals as
described above, attached to a divalent sulfur atom. More preferred
are phenyl-C.sub.1-C.sub.3-alkylthio radicals. An example of
"aralkylthio" is benzylthio.
[0234] The term "aryloxy" embraces optionally substituted aryl
radicals, as defined above, attached to an oxygen atom. Examples of
such radicals include phenoxy.
[0235] The term "aralkoxy" embraces oxy-containing aralkyl radicals
attached through an oxygen atom to other radicals. More preferred
aralkoxy radicals are "lower aralkoxy" radicals having optionally
substituted phenyl radicals attached to lower alkoxy radical as
described above.
[0236] The term "heterocyclyloxy" embraces optionally substituted
heterocyclyl radicals, as defined above, attached to an oxygen
atom. Examples of such radicals include piperidyloxy.
[0237] The term "heterocyclylalkoxy" embraces oxy-containing
heterocyclylalkyl radicals attached through an oxygen atom to other
radicals. More preferred heterocyclylalkoxy radicals are "lower
heteroarylalkoxy" radicals having optionally substituted heteroaryl
radicals attached to lower alkoxy radical as described above.
[0238] The term "heterocyclyloxyalkyl" embraces heteroaryl radicals
attached through an ether oxygen atom to an alkyl radical. More
preferred heterocyclyloxyalkyl radicals are "lower
heteroaryloxyalkyl" radicals having optionally substituted
heteroaryl radicals attached to an --O--C.sub.1-6 alkyl
radical.
[0239] The term "cycloalkyl" includes saturated carbocyclic groups.
Preferred cycloalkyl groups include C.sub.3-C.sub.6 rings. More
preferred compounds include cyclopentyl, cyclopropyl, and
cyclohexyl.
[0240] The term "cycloalkenyl" includes carbocyclic groups have one
or more carbon-carbon double bonds. "Cycloalkenyl" and
"cycloalkyldienyl" compounds are included. Preferred cycloalkenyl
groups include C.sub.3-C.sub.6 rings. More preferred compounds
include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl
and cycloheptadienyl.
[0241] The term "basic moiety" or "basic moieties" means a chemical
moiety that has a measured or calculated pK.sub.a of from about 7
to about 13. The term also can include a chemical moiety that is
protonable, to some extent, between a pH range of from about 7 to
about 10. Examples of basic moieties include, but are not limited
to, amino, cycloalkylamino(C.sub.1-C.sub.6)alkyl,
cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl amino(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy-
, amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.4)alkylamino-(C.sub.2-C.sub.6)alkenyl, 4-8-membered
nitrogen-containing heterocyclyl(C.sub.2-C.sub.6)alkenyl,
heterocyclyl(C.sub.1-C.sub.6)amino(C.sub.2-C.sub.6)alkyl, 5-6
membered heterocyclyloxy, 5-6 membered nitrogen-containing
heterocyclyl and 5-7 membered nitrogen-containing
heterocyclyl-alkyl; more specifically amino,
cycloalkylamino(C.sub.1-C.sub.6)alkyl, cycloalkyl(C.sub.1-C.sub.6)
alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl amino(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy-
, amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.4)alkylamino-(C.sub.2-C.sub.6)alkenyl, 5-8-membered
nitrogen-containing heterocyclyl(C.sub.2-C.sub.6)alkenyl,
heterocyclyl(C.sub.1-C.sub.6)amino(C.sub.2-C.sub.6)alkyl, 5-6
membered heterocyclyloxy, 5-6 membered nitrogen-containing
heterocyclyl and 5-7 membered nitrogen-containing
heterocyclyl(C.sub.1-C.sub.6)alkyl; and more specifically, amino,
aminomethyl, isopropylaminomethyl, t-butylaminomethyl,
2-t-butylaminoethyl, 2-tert-butylamino-1-methyl-ethyl,
1-tert-butylaminoethyl, 1-(tert-butylamino-methyl)-vinyl,
1-(piperidin-1-ylmethyl)-vinyl, N-isobutyl-aminomethyl,
N-isobutyl-aminoethyl, (2,2-dimethyl)propylaminomethyl,
N-isopropyl-N-ethylaminomethyl, N-isopropyl-N-methylaminomethyl,
N-t-butyl-N-methylaminomethyl, N-iso-butyl-N-methylaminomethyl,
N-t-butyl-N-ethylaminomethyl, N-isobutyl-N-methylaminomethyl,
N-t-butyl-N-isopropylaminomethyl, N,N-di(isopropyl)aminomethyl,
N,N-dimethylaminomethyl, N,N-diethylaminomethyl,
N,N-di(t-butyl)-aminomethyl, cyclopropylaminomethyl,
cyclopropylaminoethyl, cyclopropylmethylaminomethyl,
cyclopropylmethylaminoethyl, cyclobutylaminomethyl,
cyclobutylaminoethyl, cyclobutylmethylaminomethyl,
cyclobutylmethylaminoethyl, 4,5-dihydro-imidazolyl,
1-piperidinylmethyl, 4-fluoropiperidin-1-ylmethyl,
4,4-difluoropiperidin-1-ylmethyl, 3-hydroxypiperidin-1-ylmethyl,
4-hydroxypiperidin-1-ylmethyl, 4-(piperidin-1-yl)piperidinylmethyl,
4-(dimethylamino)piperidin-1-ylmethyl,
2,6-dimethylpiperidin-1-ylmethyl, 4-morpholinylmethyl,
1-pyrrolidinylmethyl, 2-methylpyrrolidin-1-ylmethyl,
2,5-dimethylpyrrolidin-1-ylmethyl, piperazin-1-ylmethyl,
azocan-1-ylmethyl, azepan-1-ylmethyl,
(7-azabicyclo[2.2.1]hept-7-yl)methyl,
(1,3,3-trimethyl-6-azaicyclo[3.2.1]oct-6-yl)methyl, 2-piperidinyl
and 4-methylpiperazin-1-ylmethyl. Each basic moiety can be
optionally substituted with one to three groups independently
selected from halo, --NH.sub.2, --OH, --CN, --CF.sub.3,
(C.sub.1-C.sub.6)alkylamino, haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxyalkyl,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
di(C.sub.1-C.sub.6)alkylamino, --C(O)R.sup.8, --COOR.sup.8,
--C(O)NR.sup.8R.sup.8', --NR.sup.8C(O)R.sup.8', .dbd.NCN; and
(C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, cycloalkyl and
heterocyclyl, each of which is optionally substituted with one to
three groups independently selected from halo, --NH.sub.2, --OH,
--CN, --CF.sub.3, (C.sub.1-C.sub.6)alkylamino, haloalkyl, oxo,
(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxyalkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, di(C.sub.1-C.sub.6)alkylamino,
--C(O)R.sup.8, --COOR.sup.8, --C(O)NR.sup.8R.sup.8', and
--NR.sup.8C(O)R.sup.8'. In one embodiment, the basic moiety is
selected from cycloalkylamino(C.sub.1-C.sub.6)alkyl,
cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl amino(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy-
, amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.4)alkylamino-(C.sub.2-C.sub.6)alkenyl, 4-8-membered
nitrogen-containing heterocyclyl(C.sub.2-C.sub.6)alkenyl,
heterocyclyl(C.sub.1-C.sub.6)amino(C.sub.2-C.sub.6)alkyl, 5-6
membered heterocyclyloxy, 5-6 membered nitrogen-containing
heterocyclyl and 5-7 membered nitrogen-containing
heterocyclyl-alkyl. In another embodiment, the basic moiety is
selected from cycloalkylamino(C.sub.1-C.sub.6)alkyl,
cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
heterocyclylamino(C.sub.1-C.sub.6)alkyl,
heterocyclyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
arylamino(C.sub.1-C.sub.6)alkyl,
aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl amino(C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)alkylamino-(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkox-
y, amino(C.sub.1-C.sub.6)alkoxy, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.4)alkylamino-(C.sub.2-C.sub.6)alkenyl, 4-8-membered
nitrogen-containing heterocyclyl(C.sub.2-C.sub.6)alkenyl,
heterocyclyl(C.sub.1-C.sub.6)amino(C.sub.2-C.sub.6)alkyl, 5-6
membered heterocyclyloxy, 5-6 membered nitrogen-containing
heterocyclyl and 5-7 membered nitrogen-containing
heterocyclyl-alkyl any of which are substituted by COOR.sub.8,
halo, C.sub.1-6alkyl or cycloalkyl.
[0242] The term "comprising" is meant to be open ended, including
the indicated component but not excluding other elements.
[0243] The specification and claims contain listing of species
using the language "selected from . . . and . . . " and "is . . .
or . . . " (sometimes referred to as Markush groups). When this
language is used in this application, unless otherwise stated it is
meant to include the group as a whole, or any single members
thereof, or any subgroups thereof. The use of this language is
merely for shorthand purposes and is not meant in any way to limit
the removal of individual elements or subgroups from the genus.
[0244] The present invention preferably includes compounds that
antagonize bradykinin 1.
[0245] The present invention also comprises the use of a compound
of the invention, or pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for the treatment either acutely or
chronically of pain or an inflammation mediated disease state,
including those described previously. The compounds of the present
invention are also useful in the manufacture of an
anti-inflammatory medicament. The compounds of the present
invention are also useful in the manufacture of a medicament to
attenuate or prevent disorders through inhibition of bradykinin 1.
The compounds of the present invention are also useful in the
manufacture of a medicament to treat pain.
[0246] The present invention comprises a pharmaceutical composition
comprising a therapeutically-effective amount of a compound of
Formulas I-VI in association with at least one
pharmaceutically-acceptable carrier, adjuvant or diluent.
Combinations
[0247] While the compounds of the invention can be administered as
the sole active pharmaceutical agent, they can also be used in
combination with one or more compounds of the invention or other
agents. When administered as a combination, the therapeutic agents
can be formulated as separate compositions that are administered at
the same time or sequentially at different times, or the
therapeutic agents can be given as a single composition.
[0248] The phrase "co-therapy" (or "combination-therapy"), in
defining use of a compound of the present invention and another
pharmaceutical agent, is intended to embrace administration of each
agent in a sequential manner in a regimen that will provide
beneficial effects of the drug combination, and is intended as well
to embrace co-administration of these agents in a substantially
simultaneous manner, such as in a single capsule having a fixed
ratio of these active agents or in multiple, separate capsules for
each agent.
[0249] The present compounds may also be used in combination
therapies with opioids and other anti-pain analgesics, including
narcotic analgesics, Mu receptor antagonists, Kappa receptor
antagonists, non-narcotic (i.e. non-addictive) analgesics,
monoamine uptake inhibitors, adenosine regulating agents,
cannabinoid derivatives, Substance P antagonists, neurokinin-1
receptor antagonists, COX-2 inhibitors such as celecoxib,
rofecoxib, valdecoxib, parecoxib, and darecoxib, NSAID's, and
sodium channel blockers, among others. More preferred would be
combinations with compounds selected from morphine, meperidine,
codeine, pentazocine, buprenorphine, butorphanol, dezocine,
meptazinol, hydrocodone, oxycodone, methadone,
tetrahydrocannibinol, pregabalin, Tramadol [(+) enantiomer], DuP
747, Dynorphine A, Enadoline, RP-60180, HN-11608, E-2078,
ICI-204448, acetominophen (paracetamol), propoxyphene, nalbuphine,
E-4018, filenadol, mirtentanil, amitriptyline, DuP631, Tramadol
[(-) enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP-1683,
GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742,
SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, and CP-99,994.
[0250] Alternatively, the present compounds may also be used in
co-therapies with other treatments for inflammation, e.g. steroids,
NSAIDs, iNOS inhibitors, p38 inhibitors, TNF inhibitors,
5-lipoxygenase inhibitors, LTB.sub.4 receptor antagonists and
LTA.sub.4 hydrolase inhibitors.
[0251] The present invention comprises a process for the
preparation of a compound of Formula I-VI.
[0252] Compounds of the present invention can possess, in general,
one or more asymmetric carbon atoms and are thus capable of
existing in the form of optical isomers as well as in the form of
racemic or non-racemic mixtures thereof. Unless otherwise
indicated, the compounds of the present invention, as depicted or
named, may exist as the racemate, a single enantiomer, or any
uneven (i.e. non 50/50) mixture of enantiomers, and are all
included in the family of compounds in Formula I-VI. The optical
isomers can be obtained by resolution of the racemic mixtures
according to conventional processes, e.g., by formation of
diastereoisomeric salts, by treatment with an optically active acid
or base. Examples of appropriate acids are tartaric,
diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and
camphorsulfonic acid and then separation of the mixture of
diastereoisomers by crystallization followed by liberation of the
optically active bases from these salts. A different process for
separation of optical isomers involves the use of a chiral
chromatography column, such as, for example, a CHIRAL-AGP column,
optimally chosen to maximize the separation of the enantiomers.
Still another available method involves synthesis of covalent
diastereoisomeric molecules by reacting compounds of the invention
with an optically pure acid in an activated form or an optically
pure isocyanate. The synthesized diastereoisomers can be separated
by conventional means such as chromatography, distillation,
crystallization or sublimation, and then hydrolyzed to deliver the
enantiomerically pure compound. The optically active compounds of
the invention can likewise be obtained by using optically active
starting materials. These isomers may be in the form of a free
acid, a free base, an ester or a salt. Preferred compounds of the
invention have an R configuration at the amide bond for example
##STR00009##
[0253] Compounds of the present invention can possess, in general,
tautomeric forms, including any enolate anions, which are included
in the family of compounds in Formula I-VI.
[0254] Also included in the family of compounds of Formula I-VI are
the pharmaceutically-acceptable salts thereof. The term
"pharmaceutically-acceptable salts" embraces salts commonly used to
form alkali metal salts and to form addition salts of free acids or
free bases. The nature of the salt is not critical, provided that
it is pharmaceutically-acceptable. Suitable
pharmaceutically-acceptable acid addition salts of compounds of
Formula I-VI may be prepared from an inorganic acid or from an
organic acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric
acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, arylaliphatic, heterocyclic carboxylic
and sulfonic classes of organic acids, example of which are formic,
acetic, adipic, butyric, propionic, succinic, glycolic, gluconic,
lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,
fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic
(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic,
pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic,
cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,
glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,
nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,
persulfuric, 2-phenylpropionic, picric, pivalic propionic,
succinic, tartaric, thiocyanic, mesylic, undecanoic, stearic,
algenic, .beta.-hydroxybutyric, salicylic, galactaric and
galacturonic acid. Suitable pharmaceutically-acceptable base
addition salts of compounds of Formula I-VI include metallic salts,
such as salts made from aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc, or salts made from organic bases
including primary, secondary and tertiary amines, substituted
amines including cyclic amines, such as caffeine, arginine,
diethylamine, N-ethyl piperidine, histidine, glucamine,
isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine,
piperidine, triethylamine, trimethylamine. All of these salts may
be prepared by conventional means from the corresponding compound
of the invention by reacting, for example, the appropriate acid or
base with the compound of Formula I-VI.
[0255] Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl, and butyl chloride, bromides and iodides;
dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides, and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0256] Examples of acids that may be employed to from
pharmaceutically acceptable acid addition salts include such
inorganic acids as HCl, H.sub.2SO.sub.4 and H.sub.3PO.sub.4 and
such organic acids as oxalic acid, maleic acid, succinic acid and
citric acid. Other examples include salts with alkali metals or
alkaline earth metals, such as sodium, potassium, calcium or
magnesium or with organic bases.
General Synthetic Procedures
[0257] The compounds of the invention can be synthesized according
to the following procedures of Schemes 1-20, wherein the
substituents are as defined for Formulas I-VI, above, except where
further noted.
##STR00010##
[0258] Compounds of Formula I may be prepared in a convergent
manner as described in Scheme 1. Acids 1 are coupled with the
substituted amine 2 using standard peptide coupling conditions,
such as with HOBT, EDC, and DIEA in a solvent, such as
CH.sub.2Cl.sub.2, and reacted at RT, to afford the substituted
amide 3. The acids 1 are commercially available or may be prepared
by literature methods (for example by the method described by
Dieter et. al. Liebigs Annalen/Recueil 4, 699-706; 1997).
Similarly, substituted amine 2 are either commercially available,
can be prepared via literature methods, or may be prepared
following literature methods described for analogous compounds.
Some of these methods are illustrated in the subsequent schemes.
Alternatively, substituted amide 3 is an intermediate to the
compounds of Formula I. Protected acetamide 3 is deprotected and
reacted with an active sulfonyl compound, such as a substituted
sulfonyl chloride, in the presence of base, preferably an organic
base such as DIEA, in a solvent such as CH.sub.2Cl.sub.2 to form
the substituted sulfonyl compounds 4.
##STR00011##
[0259] Compounds of Formula III may be prepared as described in
Scheme 2. Piperazinyl esters 5 may be prepared by reacting
ethylenediamines with maleate diesters such as dimethyl maleate,
the resulting esters are coupled with an active sulfonyl compound,
such as a substituted sulfonyl chloride, in the presence of base,
preferably an organic base such as DIEA, in a solvent such as
CH.sub.3CN or CH.sub.2Cl.sub.2 to form the substituted sulfonyl
piperazinyl ester 6. After hydrolysis, substituted sulfonyl
piperazinyl racemic ester 7, may be resolved in to its R or S
enantimer using a chiral amine such (R)-.alpha.-methylbenzylamine
as a resolving agent. Following an acid mediated salt break, the
resulting enantiomerically pure acid is reacted with the HNRR.sup.1
using standard peptide coupling conditions, such as with HOBT, EDC,
and DIEA in a solvent, such as CH.sub.2Cl.sub.2, and reacted at RT,
to afford the substituted amide 8. The reaction is kept at a
temperature above about 0.degree. C., preferably at about RT, to
yield the compound of Formula III. In this manner, either racemic,
or R or S antipodes of the compounds of Formula III may be prepared
from racemic or R or S compound 8.
##STR00012##
[0260] (5(R)-Amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanol is
prepared by the method described in Scheme 3. (R)-methyl CBS
oxazaborolidine (in dry solvent such as toluene or dichloromethane)
is treated with borane methyl sulfide complex and
5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester
(9). The reaction is kept at a temperature below RT, preferably
below about 0.degree. C., more preferably at about -10.degree. C.,
to provide the alcohol 10. The azide 10 is formed from the alcohol
11, such as by treatment with DPPA and DBU, at a temperature above
about 0.degree. C., preferably at about RT.
[0261] Reduction of the azide 11, such as with LAH, at a
temperature above about 0.degree. C., preferably at about RT
provides the methanol 12. Similarly
(4-(R)-amino-chroman-7-yl)-methanol and
(1-(R)-amino-indan-5-yl)-methanol can be prepared.
##STR00013##
[0262] (5-Oxo-piperazin-2-yl)-acetic acids (where R.sup.4 and
R.sup.4A together form oxo) may be prepared in a convergent manner
as described in Scheme 4. Acids 13, protected for example with a
CBZ group, are homologated with magnesium monomethylmalonate to
afford the protected ester 15. The acids 12 are commercially
available or may be prepared by literature methods (for example by
the method described by Patino-Molina, R. Tetrahedron (1999) 55,
15001. Similarly, magnesium monomethylmalonate 14 may be prepared
following literature methods described in Reetz, M. T., J. Angew.
Chem. Int. Ed. Eng. (1979) 18, 72. The protected ester 15 is
deprotected, such as via hydrogenation for a CBZ group, which in
turn can be reacted with ZnCl.sub.2 to form the imine that can be
reduced, such as with NaBH.sub.3CN, to yield the
5-oxopiperazin-2-yl ester 16. Hydrolysis of the ester following
common literature conditions followed by protection of the amine
forms the acid 17.
##STR00014##
[0263] (2-Oxo-[1,4]diazepan-5-yl)-acetic acid esters (where R.sup.4
and R.sup.4A together form oxo and t is 2) may be prepared in a
manner similar to that described in Scheme 4 to give the 7 membered
version 20.
##STR00015##
[0264] 5-Oxo-[1,4]diazepan-2-yl)-acetic acid esters (where R.sup.4
and R.sup.4A together form oxo and q is 2) may be prepared in a
manner similar to that described in Scheme 4 to give a 7 membered
version 23.
##STR00016##
[0265] Amino compounds 26 are prepared from the corresponding
ketones 24 by the method described in Scheme 7. Treatment of the
ketones 24 with hydroxylamine in a solvent such as NaOAc, at a
temperature above RT, preferably above about 75.degree. C., even
more preferably at reflux, provides the oxime 25. Hydrogenation of
the oxime 25, such as in the presence of a catalyst such as Pd/C,
provides the amine 26.
##STR00017##
[0266] Alternatively, (5-oxo-[1,4]diazepan-2-yl)-acetic acid esters
(where R.sup.4 and R.sup.4A together form oxo and q is 2) 29 and
(5-oxo-piperazin-2-yl)-acetic acid esters (where R.sup.4 and
R.sup.4A together form oxo and q is 1) 31 can be synthesized
enatioselectively from chiral 3,4-diaminobuytric acid in a manner
similar to that described in Scheme 8.
##STR00018##
[0267] (3-Oxo-[1,4]diazocan-2-yl)-acetic acid 36 (where R.sup.3 and
R.sup.3A together form oxo, where R.sup.4 and R.sup.4A A are H, and
q is 3) can be synthesized enatioselectively from chiral
2-amino-succinic acid 4-benzyl ester 32 in a manner similar to that
described in Scheme 9 utilizing ring closing metathesis (RCM) to
give 8-membered versions 37. The RCM step is as described by J.
Reichwein, et al. J. Angew. Chem. Int. Ed. 1999, 38, 3684-3687.
##STR00019##
[0268] Similarly, (3-oxo-piperazin-2-yl)-acetic acid 41(where
R.sup.3 and R.sup.3A together form oxo, and q is 1) can be
synthesized enatioselectively from chiral substituted
sulfonylamino-succinic acid 4-benzyl ester in a manner similar to
that described in Scheme 10 utilizing Mitsunobu alkylation ring
closure to give 6-membered versions 41. The Mitsunobu alkylation
step is as described by S. Pikul, et al. Bioorg. Med. Chem. Lett.
(2001), 11:1009-1013.
##STR00020##
[0269] Compounds of Formula I 47 (where X is O) may be prepared in
a convergent manner as described in Scheme 1. See H. Fukawa et al.,
Chem. Pharm. Bull. (1983) 31:94-99 for preparation of ester 42.
##STR00021##
[0270] Compounds 51 (where R.sup.3 and R.sup.3A together form oxo,
where R.sup.4 and R.sup.4A are both methyl and q is 1) may be
prepared as described in Scheme 12, similar to that described in
Scheme 2. (5,5-Dimethyl-3-oxo-piperazin-2-yl)-acetic acid ethyl
ester 48 is prepared according to the procedure of Dutta and Foye
(J. Pharmaceutical Science (1990) 79:447-452). Treatment of 48 with
sulfonyl chlorides in the presence of base such as Na.sub.2CO.sub.3
or TEA, in organic solvents such as CH.sub.3CN or CH.sub.2Cl.sub.2,
at a temperature of about RT to about 80.degree. C. yielded
sulfonamides 49. Hydrolysis to the acid in the presence of bases
such as LiOH or NaOH, in the aqueous solvent such as MeOH and THF
at a temperature of about 0.degree. C. to about RT forms the acids
50. The acid 50 is coupled with appropriate amines using coupling
agents HOBt/EDCI or HATU with or without organic bases such as TEA
or DIEA at a temperature of about 0.degree. C. to about RT provides
compounds 51.
##STR00022##
[0271] Additional analogs of compounds of Formula II may be
prepared as illustrated in Schemes 13-15. Following Boc protection,
amino alcohol 12 is converted to its methyl ketone 55 by the three
step procedure depicted in Scheme 13. Protected
1-amino-6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalene 52 is
oxidized, such as with MnO.sub.2 in an organic solvent, such as
CH.sub.2Cl.sub.2, preferably at a temperature of about RT, to form
the aldehyde 53. The aldehyde is alkylated, such as with a Grignard
reagent in a solvent such as THF, at a temperature initially below
RT, preferably about -30.degree. C. and more preferably at about
-78.degree. C., then at about RT, to form the alcohol 54. The
alcohol 54 is oxidized, such as with MnO.sub.2 as previously
described, to form the protected ketone 55. The resulting ketone 56
is deprotected such as with HCl, and converted to compound 57
similar to the method described in Scheme 11.
##STR00023## ##STR00024##
[0272] Vinyl amine derivatives of compounds of Formula II may be
prepared by the methods illustrated in Scheme 14. The
6-hydroxy-1-tetralone was reacted with triflic anhydride and the
temperature was preferably maintained between 0 C and RT, to form
triflate 59. Treatment of the triflate 59 with
(R)-2-methyl-CBS-oxazaborolidine and BMS and
trifluoro-methanesulfonic acid at a temperature between 0 C and RT,
provides the alcohol 60. Alcohol 60 was converted to the azide by
addition of DBU and dppa, at a temperature between 0.degree. C. and
RT. Addition of PPh.sub.3 to the azide 61 provides the amine 62,
which can be coupled, as described above, with the appropriate acid
to form amide 63. Reaction with the amide 62 palladium(II)acetate,
dppf, base (e.g. Et.sub.3N) and allyl alcohol, heated to a
temperature above RT, preferably between about 50.degree. C. and
about 100.degree. C., more preferably at about 80.degree. C.
provides the vinyl alcohol 64. Treatment of the
1-hydroxymethyl-vinyl compound 64 with methanesulfonyl chloride
provides mesyl derivative 65, which upon treatment with an amine,
such as pyrrolidine, provides the vinyl amine 66.
[0273] Following the protocols illustrated in Schemes 15 and 16,
the tether length for all of the amino compounds of Formulas I and
II may be varied from 1-4 carbons. The protected alcohol 52 can be
activated such as by reaction with methane sulfonyl chloride. The
resulting mesylate 67 may be reacted with the lithiated dithiane
reagent 68 to afford the protected aldehyde 69. Following removal
of the Boc protecting group, such as with an ethereal HCl solution
or trifluoroacetic acid at a temperature between 0 C and 25 C, the
resulting amine is coupled to an acid 41 to afford 70. The latent
aldehyde functionality is unmasked by reaction with
Hg(ClO.sub.4).sub.2 in a solvent such as ethanol, and the resulting
aldehyde 71 is converted to compounds of Formula I by reacting with
primary or secondary amines using the reductive amination
conditions described previously. Compounds with 3 carbon tethers
are prepared by the method described in Scheme 17. The cyano-vinyl
compound 73 is prepared via treatment of the aldehyde 53 with
diethyl cyanophosphate and sodium bis(trimethylsilyl)amide at a
temperature between about -78.degree. C. and RT. Deprotection
yields the free amine 74 which can be coupled as described above,
to provide the intermediate 75. Reduction, such as with Pt
catalyzed treatment with H.sub.2 yields the aminopropyl compound 76
of the present invention, which may be further elaborated by
alkylation of the resulting primary amines using well-known
methods.
##STR00025##
##STR00026##
[0274] The aldehyde 53 can be converted to the carbonitrile 73 such
as with treatment with P(Ph).sub.3, DEAD and acetone cyanohydrin.
The nitrile 74 can be coupled with the acid, such as with HATU, EDC
and DEA. The (7-cyanomethyl-4-tetralin 75 is hydrogenated, such as
with palladium catalyst in an alcohol, e.g. MeOH, to form the alkyl
amine 76 of the present invention. The alkyl amine can be
substituted using standard methods to make the substituted amines
77(where R.sup.n is alkyl, substituted alkyl, and the like).
##STR00027##
[0275] Methods for preparing additional compounds of Formulas I and
II are illustrated in Schemes 18-20. The cyano alcohol 78 can be
treated with DMAP, base (e.g. NEt.sub.3), and PBDPSCl to form the
protected alcohol 79. The protected alcohol 79 is aminated, such as
with Me.sub.3Al, at a temperature below RT and preferably at about
0 C, to yield the amidine 80. Formation of the
5,6,7,8-tetrahydro-quinazolone 82 is achieved such as by reaction
of amidine 80 and 2-dimethylaminomethylene-cyclohexane-1,3-dione 81
at a temperature above RT, preferably above about 50 C. and more
preferably at about 80 C. 5,6,7,8-tetrahydro-quinazolone 82 is
reduced such as with NaBH.sub.4 to give the alcohol 83. The alcohol
83 is treated with DPPA and DBU to form the azide derivative which
is reduced to form the amine 84. The amine 84 is deprotected, such
as with TBAF to form the desired intermediate 85, which is
converted to compounds 86 of Formula I using methods similar to
those described above.
[0276] Tetrahydroindazole analogs of Formula I may be prepared as
depicted in Scheme 18. Hydroxyethyl hydrazine 87 is reacted with
2-dimethylamino-methylene-cyclohexane-1,3-dione 81 at a temperature
between 0 and 25.degree. C. to afford the hydroxyl ketone 87 in
high yield. Following protection of the hydroxyl moiety with a
silyl protecting group such as TBS, the ketone is reduced and the
resulting alcohol carried on to compounds of Formula I using
methods previously described in this invention.
##STR00028## ##STR00029##
[0277] Additional compounds of the present invention are depicted
in Schemes 19 and 20 and may be prepared by Palladium mediated
cross coupling reactions on the aryl trifilate or similar aryl
halides. For example, aryl trifilate 63 is reacted with the boronic
acid 93 to afford the protected amine 94. Following deprotection,
the resulting amine is converted to compounds 96 by reductive
alkylation with aldehydes or ketones. In addition to the vinal
boronic acid 93 illustrated in the above example, a variety of
commercially available or readily synthesized boronic acids or
boronate esters may be used to make similar alkyl, or biaryl
analogs. In addition, terminal alkynes or alkenes may be used is
similar palladium mediated cross coupling reactions as illustrated
in Scheme 20.
##STR00030## ##STR00031##
[0278] Compounds of the invention can be prepared as described in
Scheme 20. The protected amino bicyclic compound 97 was treated
with is alkylated, such as with vinyltributyltin in the presence of
PPh.sub.3, a base such as Et.sub.3N and a palladium catalyst, e.g.
Pd.sub.2(dba).sub.3. The reaction is maintained at a temperature
above RT, preferably in a range between about 50 C. and about 100
C., more preferably at about 80 C., more preferably in a microwave.
After deprotection, such as with TFA in the case the amine is BOC
protected, the free amine 99b can be coupled as described above.
Oxidation of the vinyl compound 101, such as with OsO4 produces
aldehyde 102. Reductive amination, such as with NaHB(OAc).sub.3 in
the presence of an amine provides compounds 103.
##STR00032## ##STR00033##
[0279] Additional analogs of any of the templates in described in
Schemes 1-20 may be prepared using the procedures analogous to
those described for above and illustrated in the examples below. In
addition elaboration of all intermediates in the above schemes to
compounds of Formula I may be accomplished using known by those
skilled in the arts of organic and medicinal chemistry.
[0280] If one or more other functional groups, for example carboxy,
hydroxy, amino, or mercapto, are or need to be protected in a
compound of Formulas I-VI, because they should not take part in the
reaction, these are such groups as are usually used in the
synthesis of peptide compounds, and also of cephalosporins and
penicillins, as well as nucleic acid derivatives and sugars.
[0281] The protecting groups may already be present in precursors
and should protect the functional groups concerned against unwanted
secondary reactions, such as acylations, etherifications,
esterifications, oxidations, solvolysis, and similar reactions. It
is a characteristic of protecting groups that they lend themselves
readily, i.e. without undesired secondary reactions, to removal,
typically by solvolysis, reduction, photolysis or also by enzyme
activity, for example under conditions analogous to physiological
conditions, and that they are not present in the end-products. The
specialist knows, or can easily establish, which protecting groups
are suitable with the reactions mentioned above and
hereinafter.
[0282] The protection of such functional groups by such protecting
groups, the protecting groups themselves, and their removal
reactions are described for example in standard reference works,
such as J. McOmie, "Protective Groups in Organic Chemistry", Plenum
Press, London and New York (1973); in T. Greene, "Protective Groups
in Organic Synthesis", Wiley, New York (1981); in "The Peptides",
Volume 3 (eds: E. Gross and J. Meienhofer), Academic Press, London
and New York (1981); in "Methoden der organischen Chemie" (Methods
of organic chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg
Thieme Verlag, Stuttgart (1974); in H. Jakubke and H. Jescheit,
"Aminosauren, Peptide, Proteine" (Amino acids, peptides, proteins),
Verlag Chemie, Weinheim, Deerfield Beach, and Basel (1982); and in
Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und
Derivate" (Chemistry of carbohydrates: monosaccharides and
derivatives), Georg Thieme Verlag, Stuttgart (1974).
[0283] In the additional process steps, carried out as desired,
functional groups of the starting compounds which should not take
part in the reaction may be present in unprotected form or may be
protected for example by one or more of the protecting groups
mentioned above under "protecting groups". The protecting groups
are then wholly or partly removed according to one of the methods
described there.
[0284] Salts of a compound of Formula I with a salt-forming group
may be prepared in a manner known per se. Acid addition salts of
compounds of Formula I may thus be obtained by treatment with an
acid or with a suitable anion exchange reagent. A salt with two
acid molecules (for example a dihalogenide of a compound of Formula
I) may also be converted into a salt with one acid molecule per
compound (for example a monohalogenide); this may be done by
heating to a melt, or for example by heating as a solid under a
high vacuum at elevated temperature, for example from
130-170.degree. C., one molecule of the acid being expelled per
molecule of a compound of Formula I.
[0285] Salts can usually be converted to free compounds, e.g. by
treating with suitable basic agents, for example with alkali metal
carbonates, alkali metal hydrogen carbonates, or alkali metal
hydroxides, typically potassium carbonate or sodium hydroxide.
[0286] All process steps described here can be carried out under
known reaction conditions, preferably under those specifically
mentioned, in the absence of or usually in the presence of solvents
or diluents, preferably such as are inert to the reagents used and
able to dissolve these, in the absence or presence of catalysts,
condensing agents or neutralizing agents, for example ion
exchangers, typically cation exchangers, for example in the H.sup.+
form, depending on the type of reaction and/or reactants at
reduced, normal, or elevated temperature, for example in the range
from about -100.degree. C. to about 190.degree. C., preferably from
about -80.degree. C. to about 150.degree. C., for example at about
-80.degree. C. to about 60.degree. C., at RT, at about -20.degree.
C. to about 40.degree. C. or at the boiling point of the solvent
used, under atmospheric pressure or in a closed vessel, where
appropriate under pressure, and/or in an inert atmosphere, for
example, under argon or nitrogen.
[0287] Salts may be present in all starting compounds and
transients, if these contain salt-forming groups. Salts may also be
present during the reaction of such compounds, provided the
reaction is not thereby disturbed.
[0288] In certain cases, typically in hydrogenation processes, it
is possible to achieve stereoselective reactions, allowing for
example easier recovery of individual isomers.
[0289] The solvents from which those can be selected which are
suitable for the reaction in question include, for example,
H.sub.2O, esters, typically lower alkyl-lower alkanoates, e.g.
EtOAc, ethers, typically aliphatic ethers, e.g. Et.sub.2O, or
cyclic ethers, e.g. THF, liquid aromatic hydrocarbons, typically
benzene or toluene, alcohols, typically MeOH, EtOH or 1-propanol,
IPA, nitrites, typically CH.sub.3CN, halogenated hydrocarbons,
typically CH.sub.2Cl.sub.2, acid amides, typically DMF, bases,
typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic
acids, typically lower alkanecarboxylic acids, e.g. HOAc,
carboxylic acid anhydrides, typically lower alkane acid anhydrides,
e.g. acetic anhydride, cyclic, linear, or branched hydrocarbons,
typically cyclohexane, hexane, or isopentane, or mixtures of these
solvents, e.g. aqueous solutions, unless otherwise stated in the
description of the process.
[0290] The invention relates also to those forms of the process in
which one starts from a compound obtainable at any stage as a
transient and carries out the missing steps, or breaks off the
process at any stage, or forms a starting material under the
reaction conditions, or uses said starting material in the form of
a reactive derivative or salt, or produces a compound obtainable by
means of the process according to the invention and processes the
said compound in situ. In the preferred embodiment, one starts from
those starting materials which lead to the compounds described
above as preferred.
[0291] The compounds of Formula I-VI, including their salts, are
also obtainable in the form of hydrates, or their crystals can
include for example the solvent used for crystallization (present
as solvates).
[0292] New starting materials and/or intermediates, as well as
processes for the preparation thereof, are likewise the subject of
this invention. In the preferred embodiment, such starting
materials are used and reaction conditions so selected as to enable
the preferred compounds to be obtained.
[0293] Starting materials of the invention, are known, are
commercially available, or can be synthesized in analogy to or
according to methods that are known in the art.
[0294] In the preparation of starting materials, existing
functional groups which do not participate in the reaction should,
if necessary, be protected. Preferred protecting groups, their
introduction and their removal are described above or in the
examples.
[0295] All remaining starting materials are known, capable of being
prepared according to known processes, or commercially obtainable;
in particular, they can be prepared using processes as described in
the examples.
[0296] The following examples contain detailed descriptions of the
methods of preparation of compounds of Formulas I-VI. These
detailed descriptions fall within the scope, and serve to
exemplify, the above-described General Synthetic Procedures which
form part of the invention. These detailed descriptions are
presented for illustrative purposes only and are not intended as a
restriction on the scope of the invention.
[0297] The compounds of this invention may contain one or more
asymmetric centers and thus occur as racemates and racemic
mixtures, scalemic mixtures, single enantiomers, individual
diastereomers and diastereomeric mixtures. All such isomeric forms
of these compounds are expressly included in the present invention.
The compounds of this invention may also be represented in multiple
tautomeric forms, for example, as illustrated below:
##STR00034##
The invention expressly includes all tautomeric forms of the
compounds described herein. The compounds may also occur in cis- or
trans- or E- or Z-double bond isomeric forms. All such isomeric
forms of such compounds are expressly included in the present
invention. All crystal forms of the compounds described herein are
expressly included in the present invention.
[0298] Substituents on ring moieties (e.g., phenyl, thienyl, etc.)
may be attached to specific atoms, whereby they are intended to be
fixed to that atom, or they may be drawn unattached to a specific
atom, whereby they are intended to be attached at any available
atom that is not already substituted by an atom other than H
(hydrogen).
[0299] The compounds of this invention may contain heterocyclic
ring systems attached to another ring system. Such heterocyclic
ring systems may be attached through a carbon atom or a heteroatom
in the ring system.
[0300] Alternatively, a compound of any of the formulas delineated
herein may be synthesized according to any of the processes
delineated herein. In the processes delineated herein, the steps
may be performed in an alternate order and may be preceded, or
followed, by additional protection/deprotection steps as necessary.
The processes may further comprise use of appropriate reaction
conditions, including inert solvents, additional reagents, such as
bases (e.g., LDA, DIEA, pyridine, K.sub.2CO.sub.3, and the like),
catalysts, and salt forms of the above. The intermediates may be
isolated or carried on in situ, with or without purification.
Purification methods are known in the art and include, for example,
crystallization, chromatography (liquid and gas phase), extraction,
distillation, trituration, reverse phase HPLC and the like.
Reactions conditions such as temperature, duration, pressure, and
atmosphere (inert gas, ambient) are known in the art and may be
adjusted as appropriate for the reaction.
[0301] As can be appreciated by the skilled artisan, the above
synthetic schemes are not intended to comprise a comprehensive list
of all means by which the compounds described and claimed in this
application may be synthesized. Further methods will be evident to
those of ordinary skill in the art. Additionally, the various
synthetic steps described above may be performed in an alternate
sequence or order to give the desired compounds. Synthetic
chemistry transformations and protecting group methodologies
(protection and deprotection) useful in synthesizing the inhibitor
compounds described herein are known in the art and include, for
example, those such as described in R. Larock, Comprehensive
Organic Transformations, VCH Publishers (1989); T. Greene and P.
Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley
and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's
Reagents for Organic Synthesis, John Wiley and Sons (1994); and L.
Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John
Wiley and Sons (1995).
[0302] The compounds of this invention may be modified by appending
appropriate functionalities to enhance selective biological
properties. Such modifications are known in the art and include
those which increase biological penetration into a given biological
compartment (e.g., blood, lymphatic system, central nervous
system), increase oral availability, increase solubility to allow
administration by injection, alter metabolism and alter rate of
excretion.
[0303] Unless otherwise noted, all materials were obtained from
commercial suppliers and used without further purification. All
parts are by weight and temperatures are in Degrees centigrade
unless otherwise indicated. All compounds showed NMR spectra
consistent with their assigned structures.
[0304] In order that the invention described herein may be more
readily understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
[0305] The following examples contain detailed descriptions of the
methods of preparation of compounds of Formulas I-VI. These
detailed descriptions fall within the scope, and serve to
exemplify, the above-described General Synthetic Procedures which
form part of the invention. These detailed descriptions are
presented for illustrative purposes only and are not intended as a
restriction on the scope of the invention.
[0306] The following abbreviations are used:
AcOH, HOAc--acetic acid CH.sub.3CN--acetonitrile NH.sub.3--ammonia
NH.sub.4Cl--ammonium chloride NH.sub.4OH--ammonium hydroxide
HATU--O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate AIBN--2,2'-azobisisobutyronitrile
(PPh.sub.3).sub.2NiBr.sub.2
bis(triphenylphosphine)nickel(II)bromide BH.sub.3--borane
BH.sub.3SMe.sub.2--borane-methyl sulfide complex
Br.sub.2--bromine
NBS--N-bromosuccinimide
[0307] CCl.sub.4--carbon tetrachloride CHCl.sub.3--chloroform
CBS--4-cyanobenzoic acid DBU--1,8-diazabicyclo[5.4.0]undec-7-ene
CH.sub.2Cl.sub.2--dichloromethane Et.sub.2O--diethyl ether
Ip.sub.2NEt, DIEA diisopropylethylamine Me.sub.2NH--dimethylamine
EDC--(3-dimethylamino-propyl)-ethyl-carbodiimide-HCl salt
DMAP--4-(dimethylamino)pyridine DMF--dimethylformamide
DMSO--dimethyl sulfoxide (also known as methyl sulfoxide)
DPPA--diphenylphosphoryl azide EtOH--ethanol EtOAc--ethyl acetate
HCO.sub.2H--formic acid g--gram h--hour HCl--hydrochloric acid
H.sub.2-- hydrogen HOAt--1-hydroxy-7-azabenzotriazole
HOBt--1-hydroxybenzotriazole IPA--isopropanol iPrOH--isopropanol
LAH--lithium aluminum hydride LDA--lithium diisopropylamide
LiOH--lithium hydroxide MgSO.sub.4--magnesium sulfate
MeOH--methanol
NMM--N-methylmorpholine
[0308] NMP--1-methyl-2-pyrrolidone mL--milliliter min--minutes
N.sub.2--nitrogen Pd/C--palladium on carbon Pd(OH).sub.2--palladium
hydroxide H.sub.3PO.sub.4--phosphoric acid
K.sub.2CO.sub.3--potassium carbonate KCN--potassium cyanide
KOH--potassium hydroxide RT--room temperature SiO.sub.2--silica
NaOAc--sodium acetate NaN.sub.3--sodium azide NaHCO.sub.3--sodium
bicarbonate NaBH.sub.4--sodium borohydride NaOH--sodium hydroxide
NaBH(OAc).sub.3--sodium triacetoxyborohydride
H.sub.2SO.sub.4--sulfuric acid SOCl.sub.2--thionyl chloride
THF--tetrahydrofuran TsCl--tosyl chloride TsOH--toluene sulfonic
acid TEA, Et.sub.3N--triethylamine TFA--trifluoroacetic acid
PPh.sub.3--triphenylphosphine H.sub.2O--water
[0309] Unless otherwise noted, all materials were obtained from
commercial suppliers and used without further purification. All
parts are by weight unless otherwise indicated. All compounds
showed NMR spectra consistent with their assigned structures.
Melting points were determined on a Buchi apparatus and are
uncorrected. Mass spectral data was determined by electrospray
ionization technique. All examples were purified to >90% purity
as determined by high-performance liquid chromatography. Unless
otherwise stated, reactions were run at RT.
Preparation I
Chroman-4-one oxime
[0310] To a mixture of 4-chromanone (10.00 g, 67.50 mmol) and
hydroxylamine hydrochloride (7.04 g, 101 mmol) in EtOH (100 mL) was
added a solution of NaOAc (16.61 g, 202.5 mmol) in H.sub.2O (30
mL). The reaction was heated to reflux for 2 h. The mixture was
cooled to RT and concentrated in vacuo. The residue was diluted
with H.sub.2O and acidified with 1N HCl. The aqueous mixture was
extracted with EtOAc until TLC analysis showed no evidence of title
compound in the aqueous layer. The combined organics were dried
with MgSO.sub.4 and concentrated in vacuo to furnish the crude
title compound which was used without further purification. MS
(APCI pos) 164 (M+H).
Preparation II
Chroman-4-ylamine
[0311] LAH (6.35 g, 167 mmol) was suspended in THF (100 mL) at
0.degree. C. A solution of chroman-4-one oxime (10.92 g, 66.92
mmol) in THF (100 mL) was added drop-wise. The mixture was heated
slowly to reflux for 4 h. The reaction was cooled to RT and added
drop-wise to a stirred saturated solution of Rochelle's salt in
H.sub.2O. The bi-phasic mixture was stirred rapidly at RT for 1 h.
The layers were separated and the aqueous layer was extracted with
EtOAc until TLC analysis of the aqueous layer showed no evidence of
the title compound. The combined organics were dried over
MgSO.sub.4 and concentrated in vacuo to furnish the crude material,
which was purified by flash column chromatography to afford the
title compound. MS (APCI pos) 150 (M+H).
Preparation III
6-bromo-chroman-4-ylamine
[0312] A solution of chroman-4-ylamine (2.550 g, 17.09 mmol) in
AcOH (50 mL) at RT was treated with Br.sub.2 (3.01 g, 0.96 mL, 18.8
mmol) drop-wise. The reaction was stirred at RT until HPLC analysis
showed complete consumption of starting material. The mixture was
diluted with H.sub.2O (100 mL) and NaOH was added until the
solution became basic. The aqueous layer was extracted with EtOAc
until TLC analysis of the aqueous layer showed no evidence of the
title compound. The combined organics were dried over MgSO.sub.4
and concentrated in vacuo to yield the crude compound, which was
purified by flash column chromatography to afford the pure title
compound. MS (APCI pos) 229 (M+H).
Preparation IV
(6-bromo-chroman-4-yl)-carbamic acid tert-butyl ester
[0313] To a RT solution of 6-bromo-chroman-4-ylamine (2.270 g,
9.952 mmol) and di-tert-butyl dicarbonate (2.606 g, 11.94 mmol) in
CH.sub.2Cl.sub.2 (50 mL) was added a solution of NaHCO.sub.3 (1.672
g, 19.90 mmol) in H.sub.2O (50 mL). The bi-phasic mixture was
rapidly stirred until complete consumption of starting material was
observed by HPLC analysis (overnight). The reaction was diluted
with EtOAc and H.sub.2O and the layers were separated. The organics
were dried with MgSO.sub.4 and concentrated in vacuo to afford the
crude title compound, which was used without further
purification.
Preparation V
(6-formyl-chroman-4-yl)-carbamic acid tert-butyl ester
[0314] (6-Bromo-chroman-4-yl)-carbamic acid tert-butyl ester (3.859
g, 11.76 mmol) was dissolved in THF (50 mL) and cooled to
-78.degree. C. n-Butyllithium (2.5 M) (11.76 mL, 29.40 mmol) was
added drop-wise to the stirred solution. The reaction was stirred
at -78.degree. C. for 30 min and DMF (4.55 mL, 58.8 mmol) was added
drop-wise and the system was slowly warmed to RT overnight. The
reaction was quenched with saturated aqueous NH.sub.4Cl solution
and extracted with EtOAc. The combined organics were dried with
MgSO.sub.4 and concentrated in vacuo to afford the crude, which was
purified by flash column chromatography to furnish the pure title
compound.
Preparation VI
6-bromo-3,4-dihydro-1H-naphthalen-2-one oxime
[0315] To a mixture of 6-bromo-3,4-dihydro-1H-naphthalen-2-one
(5.370 g, 23.86 mmol) and hydroxylamine hydrochloride (2.487 g,
35.79 mmol) in EtOH (80 mL) was added a solution of NaOAc (5.871 g,
71.57 mmol) in H.sub.2O (20 mL). The mixture was heated to reflux
for 2 h. The reaction was cooled to RT and concentrated in vacuo.
The residue was suspended in H.sub.2O and filtered. The pad was
washed with H.sub.2O (2.times.50 mL) and Et.sub.2O (2.times.50 mL)
and the solids were dried in vacuo to furnish the title compound,
which was used without further purification. MS (APCI pos) 242
(M+H).
Preparation VII
6-bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamine
[0316] A solution of BH.sub.3-THF complex (1 M) (35.9 mL, 35.9
mmol) was added drop-wise to a stirred solution of
6-bromo-3,4-dihydro-1H-naphthalen-2-one oxime (3.450 g, 14.37 mmol)
in THF (125 mL) at 0.degree. C. The mixture was warmed to RT and to
reflux for 24 h. The reaction was cooled to RT and 1 N aqueous HCl
was added carefully until the mixture was acidic and the system was
stirred until no further gas was evolved. The solution was made
basic by the addition of NaOH and the aqueous layer was extracted
with EtOAc. The combined organics were dried over MgSO.sub.4 and
concentrated in vacuo to afford the crude title compound, which was
purified by flash column chromatography to yield the title
compound. MS (APCI pos) 228 (M+H).
Preparation VIII
(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid
tert-butyl ester
[0317] Di-tert-butyl dicarbonate (1.030 g, 4.719 mmol) was added to
a stirred RT solution of
6-bromo-1,2,3,4-tetrahydro-naphthalen-2-ylamine (0.970 g, 4.290
mmol) in CH.sub.2Cl.sub.2 (100 mL). TEA (0.897 mL, 6.435 mmol) was
added to the reaction and the mixture was stirred at RT until HPLC
analysis showed complete consumption of starting material. The
reaction was diluted with CH.sub.2Cl.sub.2, washed with saturated
aqueous NaHCO.sub.3, dried over MgSO.sub.4 and concentrated in
vacuo to afford the crude material. The crude was purified by flash
column chromatography to yield the title compound. MS (APCI pos)
269 (M-t-Bu).
Preparation IX
(6-formyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid
tert-butyl ester
[0318] (6-Bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid
tert-butyl ester (1.080 g, 3.311 mmol) was dissolved in THF (30 mL)
and cooled to -78.degree. C. n-Butyllithium (2.5 M) (3.311 mL,
8.276 mmol) was added drop-wise to the stirred solution. The
reaction was stirred at -78.degree. C. for 30 min and DMF (1.282
mL, 16.55 mmol) was added drop-wise and the mixture was slowly
warmed to RT overnight. The reaction was quenched with saturated
aqueous NH.sub.4Cl solution and extracted with EtOAc. The combined
organics were dried over MgSO.sub.4 and concentrated in vacuo to
afford the crude material, which was purified by flash column
chromatography to furnish the pure title compound. MS (APCI pos)
217 (M-t-Bu).
Preparation X
(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic
acid tert-butyl ester
[0319] (6-Formyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid
tert-butyl ester (0.090 g, 0.33 mmol) was dissolved in
N,N-dimethylacetamide (10 mL). Piperidine (0.162 mL, 1.63 mmol) was
added and the mixture was stirred at RT for 30 min. NaBH(OAc).sub.3
(0.173 g, 0.817 mmol) was added in one portion and the reaction was
stirred at RT until complete consumption of starting material was
observed by HPLC analysis. The reaction was in concentrated in
vacuo and the residue was diluted with CH.sub.2Cl.sub.2 and
H.sub.2O and the aqueous layer was made basic with NaOH. The layers
were separated and the organics were dried over MgSO.sub.4 and
concentrated in vacuo to afford the crude title compound, which was
used without further purification. MS (APCI pos) 345 (M+H).
Preparation XI
6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamine
[0320]
(6-Piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbami-
c acid tert-butyl ester (0.113 g, 0.327 mmol) was suspended in
CH.sub.2Cl.sub.2 (2.5 mL) then TFA was added (2.5 mL). The reaction
was stirred at RT until complete consumption of starting material
was observed by HPLC analysis (2 h). The reaction mixture was
concentrated in vacuo to afford the crude title compound as the
bis-TFA salt, which was used without further purification. MS (APCI
pos) 245 (M+H).
Preparation XII
4-hydroxyimino-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2.lamda..sup.6-benzo[-
c][1,2]thiazine-7-carboxylic acid methyl ester
[0321] NaOAc (3.66 g, 44.5 mmol) was added to an EtOH (100 mL)
solution of
1-methyl-2,2,4-trioxo-1,2,3,4-tetrahydro-2.lamda..sup.6-benzo[c][1,2]thia-
zine-7-carboxylic acid methyl ester (4.00 g, 14.8 mmol) and
hydroxylamine hydrochloride (1.55 g, 22.3 mmol). After heating at
reflux for 4 days, it was evaporated, diluted with CH.sub.2Cl.sub.2
(400 mL), washed with H.sub.2O, dried over MgSO.sub.4, filtered,
and concentrated in vacuo. Crystallization from MeOH provided the
title compound. MS (-APCI, m/z): 283 (M-H).sup.-.
Preparation XIII
4-Amino-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2.lamda..sup.6-benzo[c][1,2]-
thiazine-7-carboxylic acid methyl ester
[0322]
4-Hydroxyimino-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2.lamda..sup.6-
-benzo[c][1,2]thiazine-7-carboxylic acid methyl ester (1.50 g, 5.28
mmol) was hydrogenated over Pd(OH).sub.2 (1.30 g, 20% on carbon,
wet) in MeOH (100 mL) for 60 h. After filtration and evaporation,
chromatography (silica, 0-3% MeOH in CH.sub.2CL.sub.2) furnished
the title compound. MS (+APCI, nm/z): 271 (M+H).sup.+, 254
(M-NH.sub.2).sup.+, MS (-APCI, m/z): 252 (M-NH.sub.4).sup.-.
Preparation XIV
5(S)-Hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid
methyl ester
[0323] To an oven-dried 2 L round-bottomed flask equipped with an
argon inlet/outlet and magnetic stirring was added (R)-methyl CBS
oxaborolidine (7.4 mL of a 1 M soln in toluene, 7.4 mmol, Aldrich).
Toluene 190 mL was added and the reaction was cooled in an ice-salt
bath (bath temp. =-10.degree. C.). BH.sub.3--SMe.sub.2 was added
(17 mL, 180 mmol, Aldrich), then
5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester
(30 g, 150 mmol, Albany Molecular) in 200 mL of THF was added over
5 h using a syringe pump. After the addition was complete, the
mixture was stirred for an additional 1 h. The mixture was poured
into an addition funnel, and the mixture was added to 200 mL of
MeOH, cooled in a ice-salt bath, over 30 min at such a rate that
the internal temp. was kept below 0.degree. C. The mixture was
concentrated in vacuo. Et.sub.2O (IL) was added, and the mixture
was washed with 1 M H.sub.3PO.sub.4 (3.times.), satd NaHCO.sub.3,
and brine (ca. 400 mL each wash). The organic layer was dried over
MgSO.sub.4, filtered and concentrated in vacuo. The residue was
dissolved in Et.sub.2O again (500 mL), and the mixture was washed
with 1 M H.sub.3PO.sub.4 (3.times.200 mL), satd NaHCO.sub.3, and
brine. After drying the organic layer over MgSO.sub.4, the mixture
was filtered and concentrated in vacuo, which gave the title
compound as a white-yellow solid. MS (+ ion ESI) m/z=207
(MH.sup.+), 189 (MH.sup.+-H.sub.2O).
Preparation XV
5(R)-Azido-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl
ester
[0324] To a 500 mL three-neck round-bottomed flask equipped with
argon inlet/outlet, thermometer, and magnetic stirring was added
5(S)-hydroxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid
methyl ester (29 g, 140 mmol) in 280 mL of toluene. The reaction
was cooled in a ice-salt bath, and DPPA (36 mL, 170 mmol, Aldrich)
was added (internal temp. =-4.degree. C.). DBU (25 mL, 170 mmol,
Aldrich) was added over 10 min at such a rate that the internal
temp. was kept below 1.degree. C. The ice in the bath was allowed
to melt, and the reaction continued for 12 h during which time the
mixture stopped stirring because a precipitate had formed. Stirring
was resumed, and the mixture was stirred at RT for another 11 h.
The reaction contents were poured into a 2 L sep funnel, and the
lower dark-brown layer was removed. Water (250 mL) was added to the
remaining top layer, and the mixture was extracted with Et.sub.2O
(3.times.250 mL). The combined organic layers were washed with 1 M
H.sub.3PO.sub.4, water, satd NaHCO.sub.3, and brine. The organic
layer was dried over MgSO.sub.4, filtered and concentrated in
vacuo. Purification by silica gel chromatography (330 g Isco
Redisep.RTM. column, 1:1 hexane-CH.sub.2Cl.sub.2) of the crude
material provided the title compound. MS (+ ion ESI) m/z=232
(MH.sup.+).
Preparation XLVI
(5(R)-Amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanol
[0325] To an oven-dried, 3-neck, 2 L round-bottomed flask equipped
with argon inlet/outlet, addition funnel, thermometer, and overhead
stirring was added 700 mL of THF and LAH (470 mL of a 1 M soln in
THF, 470 mmol, Aldrich). The reaction was cooled in a ice-salt
bath, and 5-azido-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid
methyl ester (27 g, 120 mmol) in 100 mL of THF was added over ca.
30 min. The mixture was warmed to RT overnight, then cooled in an
ice-salt bath the next morning. Water (18 mL) in THF (20 mL) was
added to the reaction mixture over 4 h. Vigorous gas evolution
occurred. 5M NaOH (18 mL) was added over 30 min followed by 54 mL
of water. After stirring for an additional 1 h, the mixture was
filtered, and the filtrate was concentrated in vacuo. The residue
was reconstituted in MeOH and CH.sub.3CN, and concentrated in vacuo
again to provide the title compound as light-brown solid. MS (+ ion
ESI) m/z=161 (M-NH.sub.3).
[0326] Similarly (4-(R)-amino-chroman-7-yl)-methanol and
(1-(R)-amino-indan-5-yl)-methanol were prepared.
Preparation XVII
7-bromomethyl-6-chloro-chroman-4-one
[0327] A mixture of 6-chloro-7-methyl-chroman-4-one (20 g, 101.71
mmol), NBS (19.9 g, 111.88 mmol), and AIBN (4.17 g, 25.43 mmol) in
anhydrous CCl.sub.4 (300 mL) was heated at reflux in 24 h. The
mixture was cooled, filtered the solid. The filtrate was
concentrated and used in the next step without purification.
Preparation XVIII
7-(tert-butylamino-methyl)-6-chloro-chroman-4-one
[0328] To a stirred mixture of tert-butylamine (7.3 g, 99.78 mmol)
and Et.sub.3N (10.1 g, 99.78 mmol) in anhydrous CH.sub.2Cl.sub.2
(50 mL) was added a solution of
7-bromomethyl-6-chloro-chroman-4-one (25 g, 90.71 mmol) in
CH.sub.2Cl.sub.2 (150 mL) dropwise. Stirring was continued for 16
h. The mixture was concentrated, taken up in H.sub.2O, acidified
with 10% HCl until pH 1, and extracted with Et.sub.2O (discarded).
The acidic aqueous layer was neutralized with 5 N NaOH, and
extracted with CH.sub.2Cl.sub.2 (3.times.). The combined extracts
were dried over MgSO.sub.4, concentrated to give a yellow
solid.
Preparation XIX
7-(tert-butylamino-methyl)-6-chloro-chroman-4(S)-ol
[0329] To a stirred solution of
(1S,2S)-(+)-N-(4-toluene-sulfonyl)-1,2-diphenylethylenediamine
(0.29 g, 8.08 mmol) in i-PrOH (15 mL) was added
[RuCl.sub.2(n6-p-cymene)]2, and Et.sub.3N under argon. The mixture
was heated at 80.degree. C. for 1 h, cooled, and concentrated to
dryness. To this mixture was added a solution of
7-(tert-butylamino-methyl)-6-chloro-chroman-4-one (12 g, 44.91
mole) in anhydrous CH.sub.3CN (150 mL), followed by 5:2 formic
acid/TEA (6 mL). The reaction was stirred at RT for 24 h. The
mixture was concentrated, taken up in H.sub.2O, neutralized with
10% Na.sub.2CO.sub.3, extracted with CH.sub.2Cl.sub.2 (3.times.),
dried over MgSO.sub.4, concentrated to give a brown foam which was
stirred in hexane/ether (1:1), and filtered. The filtrate was
concentrated to give a light brown foam.
Preparation XX
4(R)-azido-6-chloro-chroman-7-ylmethyl)-tert-butylamine
[0330] To a stirred, cooled (0.degree. C.) solution of
7-(tert-butylamino-methyl)-6-chloro-chroman-4(S)-ol (11.55 g, 42.91
mmol) in anhydrous toluene (150 mL) was added DPPA (23.6 g, 85.81
mmol) dropwise in 0.5 h and DBU (13.1 g, 85.91 mmol). The mixture
was stirred at RT for 24 h. The mixture was concentrated, taken up
in H.sub.2O, extracted with CH.sub.2Cl.sub.2(3.times.), dried over
MgSO.sub.4, concentrated and purified by ISCO (3%
MeOH/CH.sub.2Cl.sub.2) to give a brown oil. MS (APCI) m/z 296
(M+2).
Preparation XXI
7-(tert-butylamino-methyl)-6-chloro-chroman-(4R)-ylamine
[0331] A mixture of
4(R)-azido-6-chloro-chroman-7-ylmethyl)-tert-butylamine (12 g,
40.73 mmol) and Ph.sub.3P (16 g, 61.09 mmol) in anhydrous THF (100
mL) was stirred at RT in 3 h. H.sub.2O (100 mL) was added and the
mixture was heated at reflux for 24 h. The mixture was cooled,
concentrated, taken up in toluene, extracted with 5N HCl. The
aqueous layer was neutralized with 10N NaOH, extracted with
CHCl.sub.3 (3.times.), dried over MgSO.sub.4, concentrated to give
a brown oil. MS (APCI) m/z 270 (M+2).
Preparation XXII
(5,5-Dimethyl-3-oxo-1-(toluene-4-sulfonyl)piperazin-2-yl)acetic
acid ethyl ester
[0332] (5,5-Dimethyl-3-oxo-piperazin-2(R,S)-yl)acetic acid ethyl
ester (2.0 g, 10 mmol, prepared according to the literature
procedure of Dutta and Foye, J. Pharmaceutical Science 1990, 79,
447-452.) was added to 4-toluenesulfonyl chloride (Aldrich, 3.5 g,
20 mmol) and Na.sub.2CO.sub.3 (3.0 g, 30 mmol) in CH.sub.3CN (40
mL). The mixture was heated at 45.degree. C. overnight. The mixture
was cooled to RT. EtOAc (200 mL) was added, and the mixture was
washed with brine (3.times.100 mL). The EtOAc solution was dried
and evaporated. The crude compound was purified by column
chromatograph (silica gel, hexane-10% EtOAc/hexane-10%
EtOAc/--CH.sub.2Cl.sub.2) to give the desired compound as a white
solid: MS (APCI+, m/z): 369 (M+1).sup.+.
[0333] The following compounds were prepared similar to that
described above from the appropriate starting materials: [0334] a)
(5,5-Dimethyl-3-oxo-1-(2,4,6-trimethylbenzene-sulfonyl)piperazin-2(R,S)-y-
l)acetic acid ethyl ester; [0335] b)
3-oxo-1-(2,4,6-trimethylbenzene-sulfonyl)piperazin-2(R,S)-yl)acetic
acid ethyl ester; and [0336] c)
3-oxo-1-(4-toluene-sulfonyl)piperazin-2(R,S)-yl)acetic acid ethyl
ester.
Preparation XXIII
(5,5-Dimethyl-3-oxo-1-(toluene-4-sulfonyl)piperazin-2(R,S)-yl)acetic
acid
[0337]
(5,5-Dimethyl-3-oxo-1-(toluene-4-sulfonyl)piperazin-2(R,S)-yl)aceti-
c acid ethyl ester (1.5 g, 4 mmol) was dissolved in 30 mL of MeOH
and 30 mL of THF. LiOH (15 mmol) in water (10 mL) was added. The
mixture was stirred at RT overnight. The mixture was concentrated,
and acidified. After 30 min the precipitate was filtered, washed
with water and dried in vacuo to give the titled compound. MS: 339
(M-1).sup.+.
[0338] The following compounds were prepared similar to that
described above from the appropriate starting materials: [0339] a)
(5,5-dimethyl-3-oxo-1-(2,4,6-trimethylbenzene-sulfonyl)piperazin-2(R,S)-y-
l)acetic acid; [0340] b)
3-oxo-1-(2,4,6-trimethylbenzene-sulfonyl)piperazin-2(R,S)-yl)acetic
acid; and [0341] c)
3-oxo-1-(4-toluene-sulfonyl)piperazin-2(R,S)-yl)acetic acid.
Preparation XXIV
[1-(4-acetylamino-benzenesulfonyl)-3-oxo-piperazin-2-yl]-acetic
acid
[0342] To a stirred solution of
[1-(4-acetylamino-benzenesulfonyl)-3-oxo-piperazin-2-yl]-acetic
acid ethyl ester (0.2 g, 0.52 mmol) in EtOH (5 mL) was added 1N
LiOH (0.52 mL, 0.52 mmol). Stirring was continued for 24 h. Dowex
1.times.8-400 (1 g), i-Pr.sub.2NEt (0.5 mL) was added and the
mixture was stirred for 2 h. The resin was filtered, washed with
MeOH/H.sub.2O (85:15, 10 mL), dried and HCO.sub.2H/H.sub.2O (9:1 10
mL) was added and the mixture was stirred for 1 h. The resin was
filtered off and washed with CH.sub.3CN/H.sub.2O (85:15). The
filtrate was concentrated to give an off-white solid. MS (APCI) m/z
356 (M+1).
[0343] The following compounds were prepared similar to that
described above from the appropriate starting materials: [0344] a)
[3-oxo-1-toluene-4-sulfonyl)-piperazin-2-yl]-acetic acid; MS (APCI)
m/z 313 (M+1). [0345] b)
[3-oxo-1-(3-trifluoromethyl-benzenesulfonyl)-piperazin-2-yl]-acetic
acid; MS (APCI) m/z 367 (M+1). [0346] c)
[1-(4-methoxy-benzenesulfonyl)-3-oxo-piperazin-2-yl]-acetic acid;
MS (APCI) m/z 329 (M+1). [0347] d)
[1-(4-chloro-benzenesulfonyl)-3-oxo-piperazin-2-yl]-acetic acid; MS
(APCI) m/z 333 (M+1).
EXAMPLE 1
##STR00035##
[0348]
N-Cycloheptyl-2-(5,5-dimethyl-3-oxo-1-(2,4,6-trimethylbenzene-sulfo-
nyl)piperazin-2(R,S)-yl)acetamide
[0349] To
(5,5-dimethyl-3-oxo-1-(2,4,6-trimethylbenzene-sulfonyl)piperazin-
-2-yl)acetic acid (0.32 g, 0.94 mmol) in DMF (3 mL) was added
cycloheptyl amine (0.5 mL), EDC (0.5 g, 2.5 mmol), and DMAP (0.3 g,
2.6 mmol). The mixture was stirred at RT overnight. TLC indicated
that the reaction was not complete. Additional EDC (0.3 g) was
added and the mixture was heated at 65.degree. C. for 1 h. The
mixture was cooled to RT. EtOAc (80 mL) was added and mixture was
washed with dilute HCl in brine. The EtOAc solution was dried and
evaporated to give the crude compound. Column chromatograph
purification (silica gel, 0-2% MeOH/CH.sub.2Cl.sub.2) gave the
titled compound. MS: 464.1 (M+1).sup.+.
EXAMPLE 2
##STR00036##
[0350]
2-[5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-
-2(R,S)-yl]-N-indan-1-yl-acetamide
[0351]
[5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2-
(R,S)-yl]-acetic acid (50 mg, 0.135 mmol) was dissolved in DMF (2.5
mL) and DIEA (0.1 mL) was added to make a solution. HATU (117 mg,
0.31 mmol) was added and after stirring for two min,
(R)-(-)-indanamine (0.1 mL) was added and the mixture was stirred
overnight. The solution was poured into EtOAc (50 mL), washed with
saturated NH.sub.4Cl (1.times.50 mL), 1 N HCl (1.times.50 mL),
saturated NaHCO.sub.3 (1.times.50 mL), and saturated brine
(1.times.50 mL). The organic layer was dried with Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo to provide a crude brown oil
(140 mg). This crude oil was purified by SiO.sub.2 column
chromatography (40 to 100% EtOAc in hexanes) to produce pure title
compound. MS (APCI pos) 484 (M+H).
EXAMPLE 3
##STR00037##
[0352]
N-Benzhydryl-2-[5,5-dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfon-
yl)-piperazin-2(R,S)-yl]-acetamide
[0353]
5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(-
R,S)-yl]-acetic acid (100 mg, 0.27 mmol) was dissolved in DMF (3
mL) and DIEA (0.2 mL) was added to make a solution. HATU (206 mg,
0.54 mmol) was added and after the reaction was stirred for two
min, aminodiphenylmethane (0.2 mL) was added and the reaction was
stirred overnight. The solution was poured into EtOAc (50 mL),
washed with saturated NH.sub.4Cl (1.times.50 mL), 1 N HCl
(1.times.50 mL), saturated NaHCO.sub.3 (1.times.50 mL), and
saturated brine (1.times.50 mL). The organic layer was dried with
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to provide
crude brown oil (355 mg). This crude oil was purified by SiO.sub.2
column chromatography (50 to 100% EtOAc in hexanes) to produce pure
title compound. MS (APCI pos) 534 (M+H).
[0354] The following compounds were prepared similar to that
described above from the appropriate starting materials:
EXAMPLE 3a
2-((2R,S)-5,5-dimethyl-3-oxo-1-((2,4,6-trimethylphenyl)sulfonyl)-2-piperaz-
inyl)-N-((1R)-5-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl)acetamide;
MS 514 (M+H)
EXAMPLE 3b
2-((2R,S)-5,5-dimethyl-3-oxo-1-((2,4,6-trimethylphenyl)sulfonyl)-2-piperaz-
inyl)-N-(1,2,3,4-tetrahydro-1-naphthalenyl)acetamide; MS 498
(M+H)
EXAMPLE 3c
2-[3-Oxo-1-(2,4,6-trimethylbenzenesulfonyl)-piperizin-2(R,S)-yl]-N-(1,2,3,-
4-tetrahydronaphthalen-1-yl)-acetamide. MS (ESI, pos. ion.) m/z:
470 (M+1).
EXAMPLE 4
##STR00038##
[0355]
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-2-
-[5,5-dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S)--
yl]-acetamide
A) Preparation of
2-[5,5-dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S-
)-yl]-N-(6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-acetamide
[0356]
[5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2-
(R,S)-yl]-acetic acid (600 mg, 1.6 mmol) and
(5(R)-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanol (290 mg,
1.6 mmol) were dried by azeotroping with anhydrous toluene
(3.times.1 mL) and dissolved in anhydrous DMF (10 mL). DIEA (0.55
mL, 3.2 mmol) and HATU (923 mg, 2.4 mmol) were added to the
reaction and stirred for 18 h at RT. The reaction was diluted with
EtOAc (30 mL), washed with dilute HCl (2.times.), 1N NaOH
(2.times.), and brine, dried over MgSO.sub.4, filtered, and
concentrated in vacuo to provide a residue which was purified by
column chromatography (SiO.sub.2, 5% MeOH in CH.sub.2Cl.sub.2) to
provide the title compound. ESMS 528.4 (M+H), 526.6 (M-H).
B) Preparation of
2-[5,5-dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S-
)-yl]-N-(6-formyl-1,2,34-tetrahydro-naphthalen-1(R)-yl)-acetamide
[0357] Manganese (IV) oxide (1.0 g, 11.5 mmol) was added to a
solution of
2-[5,5-dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S-
)-yl]-N-(6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-acetamide
(Step a, 620 mg, 1.17 mmol) in CH.sub.2Cl.sub.2 (25 mL). The
reaction was stirred for 2 h at RT, filtered through Celite.RTM.
and concentrated in vacuo to provide the title compound. ESMS 526.4
(M+H), 524.5 (M-H).
C) Preparation of
N-[6-(tert-butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-yl]-2-[5-
,5-dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2(R,S)-yl]-
-acetamide
[0358]
2-[5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-
-2(R,S)-yl]-N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-acetamide
(Step b, 550 mg, 1.0 mmol) was dissolved in 1,2-dicholoethane (10
mL) and tert-butylamine (1.5 mL). NaBH(OAc).sub.3 (1.5 g, 6.0 mmol)
was added to the reaction, and heated to 85.degree. C. in a sealed
tube for 18 h. The mixture was cooled to RT, diluted with EtOAc (25
mL), washed with sat. NaHCO.sub.3 solution (2.times.), and brine,
dried over MgSO.sub.4, filtered, and concentrated in vacuo to
provide a residue which was purified by column chromatography
(SiO.sub.2, 10% MeOH in CH.sub.2Cl.sub.2+1% NH.sub.3) to provide
the title compound. ESMS 583.4 (M+H), 581.5 (M-H).
[0359] The following compounds were prepared similar to that
described above from the appropriate starting materials:
EXAMPLE 4a
[0360]
N-((1R)-5-(((1,1-dimethylethyl)amino)methyl)-2,3-dihydro-1H-inden-1-
-yl)-2-((2R,S)-5,5-dimethyl-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazin-
yl)acetamide was made from
5,5-dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-2-yl]-ac-
etic acid and (1-(R)-amino-indan-5-yl)methanol.
EXAMPLE 4b
[0361]
N-((1R,S)-6-(((1,1-dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-
-naphthalenyl)-2-((2R,S)-5,5-dimethyl-1-((4-methylphenyl)sulfonyl)-3-oxo-2-
-piperazinyl)acetamide was made from
5-dimethyl-3-oxo-1-(4-toluene-sulfonyl)-piperazin-2-yl]-acetic acid
and
(5-(R,S)-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanol.
EXAMPLE 5
##STR00039##
[0362]
N-{6-[2-Methyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1-
(R)-yl)-2-[3-oxo-1-(toluene-4-sulfonyl)-piperazin-2(R,S)-yl]-acetamide
A) Preparation of
N-(6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-2-[3-oxo-1-(tol-
uene-4-sulfonyl)-piperazin-2 (R,S)-yl]-acetamide
[0363] To a 50 mL flask was added
3-oxo-1-(4-toluene-sulfonyl)piperazin-2 (R,S)-yl)acetic acid (312
mg, 1.0 mmol), HOBT (162 mg, 1.2 mmol) and EDC (230 mg, 1.2 mmol).
This mixture was dissolved in 2 mL of dichloroethane and 1 mL of
NMP. This solution was added dropwise to a stirred solution of
(5-(R)-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanol in 1 mL
of NMP over 20 min. After stirring overnight at RT, the solution
was diluted with EtOAc, and quenched with water. The aqueous phase
was extracted with EtOAc (10 mL.times.2). The organic layers was
combined and washed with water, sat. NaHCO.sub.3 and brine, dried
over Na.sub.2SO.sub.4 and evaporated in vacuo. Flash chromatography
(SiO.sub.2, EtOAc to MeOH/EtOAc=5% to 10% to 12%) afforded the
titled compound as a white solid.
B) Preparation of
N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-2-[3-oxo-1-(toluene-4--
sulfonyl)-piperazin-2(R,S)-yl]-acetamide
[0364] To a solution of
N-(6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-2-[3-oxo-1-(tol-
uene-4-sulfonyl)-piperazin-2(R,S)-yl]-acetamide (425 mg, 0.90 mmol)
in CH.sub.2Cl.sub.2 (10 mL) at RT was added MnO.sub.2 (392 mg, 4.51
mmol). After stirring for 1 h, another 392 mg of MnO.sub.2 was
added. After 3 h, the mixture was filtered through a Celite.RTM.
pad with the help of a mixed solvent (EtOAc/MeOH=2:1). The
resulting solution was evaporated to give the title compound.
C) Preparation of
N-{6-[2-methylpropylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-
-2-[3-oxo-1-(toluene-4-sulfonyl)-piperazin-2(R,S)-yl]-acetamide
[0365] To a solution of
N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-2-[3-oxo-1-(toluene-4--
sulfonyl)-piperazin-2(R,S)-yl]-acetamide (Step b, 646 mg, 1.38
mmol) and isobutylamine (0.69 mL, 6.89 mmol) in 12 mL of
dichloroethane was added NaBH(OAc).sub.3 (875.5 mg, 4.13 mmol).
After stirring overnight at RT, the reaction was diluted with EtOAc
and washed with sat NaHCO.sub.3 and brine. The organic phase was
dried over Na.sub.2SO.sub.4 and evaporated to dryness in vacuo.
Flash chromatography (SiO.sub.2, EtOAc to EtOAc/MeOH=100:15 to
EtOAc/NH.sub.3 in MeOH=100:10 to 100:20) afforded the title
compound as a white solid. MS: 527.3 (M+1).
[0366] The following compounds were prepared similar to that
described above from the appropriate starting materials:
##STR00040##
EXAMPLE 5a
N-((1R)-6-(((1,1-Dimethylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthal-
enyl)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide-
; white solid. MS: 527.4 (M+1).
##STR00041##
[0367] EXAMPLE 5b
N-((1R)-6-((Cyclobutylamino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-(-
(2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
white solid. MS: 525.6 (M+1).
##STR00042##
[0368] EXAMPLE 5c
N-((1R)-6-(((1-Methylethyl)amino)methyl)-1,2,3,4-tetrahydro-1-naphthalenyl-
)-2-((2R,S)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide;
white solid. MS: 513.4 (M+1).
##STR00043##
[0369] EXAMPLE 5d
2-[3-Oxo-1-(toluene-4-sulfonyl)-piperazin-2(R,S)-yl]-N-(6-piperidin-1-ylme-
thyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-acetamide. White solid.
MS: 539.7 (M+1).
##STR00044##
[0370] EXAMPLE 5e
2-[3-Oxo-1-(toluene-4-sulfonyl)-piperazin-2(R,S)-yl]-N-(6-pyrrolidin-1-ylm-
ethyl-1,2,3,4-tetrahydro-naphthalen-1(R)-yl)-acetamide. White
solid. MS: 525.4 (M+1).
##STR00045##
[0371] EXAMPLE 5f
N-{6-[2,2-dimethyl-propylamino)-methyl]-1,2,3,4-tetrahydro-naphthalen-1(R)-
-yl)-2-[3-oxo-1-(toluene-4-sulfonyl)-piperazin-2(R,S)-yl]-acetamide;_White
solid. MS: 541.4 (M+1).
EXAMPLE 6
##STR00046##
[0372]
2-[3-Oxo-1-(toluene-4-sulfonyl)piperizin-2-yl]-N-(6-piperidin-1-ylm-
ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-acetamide
A) Preparation of
5(S)-Hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0373] To a 250-mL three-necked flask containing (R)-CBS (2.9 mL,
1.0 M in toluene, 2.9 mmol, Aldrich) under N.sub.2, was added a
solution of BH.sub.3--SMe.sub.2 (4.0 g, 53 mmol, Aldrich) in
toluene (50 .mu.L) dropwise through an additional funnel. After the
addition, the solution was cooled to 0.degree. C. A solution of
5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (10 g, 58 mmol,
Rintech) in THF (180 mL) was added through an addition funnel over
a period of 1.5 h. The mixture was stirred at 0.degree. C. for
additional 30 min. A preformed mixture of MeOH (50 mL) and acetyl
chloride (0.21 mL, 2.9 mmol, Aldrich) was added dropwise to the
reaction mixture. The reaction was stirred at RT overnight. The
solvents were removed in vacuo and the residue was dissolved in HCl
(150 mL, 5%). The compound was extracted with EtOAc (3.times.250
mL). The combined organics were washed with brine (300 mL, 5%) and
dried over Na.sub.2SO.sub.4. Filtration and concentration in vacuo
afforded the title compound as a light yellow solid. MS (ESI, pos.
ion.) m/z: 174 (M+1).
B) Preparation of
5(R)-azido-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0374] To a 500-mL round-bottomed flask containing
5-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [step a, 9.9
g, 57 mmol] in THF (240 mL) at RT was added DPPA (21 g, 77 mmol,
Aldrich). The solution was cooled to 0.degree. C. and DBU (12 g, 78
mmol, Aldrich) was added slowly through a syringe. The mixture was
stirred at RT overnight. The reaction was quenched with HCl (100
mL, 10%) and THF was removed in vacuo. The residue was taken up in
water (100 mL) and the compound was extracted with CH.sub.2Cl.sub.2
(3.times.200 mL). The combined organics were washed with brine (300
mL, 5%) and dried over Na.sub.2SO.sub.4. Filtration and
concentration in vacuo followed by silica-gel chromatography (10:1
hexane:EtOAc) afforded the title compound as colorless oil.
C) Preparation of
5(R)-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
[0375] A solution of
5-azido-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [10 g, 53
mmol, step (b)] in EtOH (150 mL) was stirred at RT in the presence
of 10% Pd/C (1050 mg, Aldrich) under H.sub.2 (1 atm) for 4 h. The
reaction was passed through a pad of Celite.RTM. and the pad was
washed with MeOH (2.times.100 mL). The filtrate was concentrated in
vacuo to afford the title compound as an orange oil. MS (ESI, pos.
ion.) m/z: 173 (M+1).
D) Preparation of
5(R)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydronaphthalene--
2-carbonitrile
[0376] To a 200-mL round-bottomed flask equipped with Dean-Stark
apparatus was added
5-amino-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile [9.0 g, 52
mmol, step(c)], phthalic anhydride (8.5 g, 58 mmol, Aldrich), DIEA
(2.4 g, 19 mmol, Aldrich), and toluene (175 mL). The reaction was
heated at reflux for 3 h. After cooling to RT, the mixture was
concentrated in vacuo. The residue was taken up in HCl (150 mL,
10%) and extracted with CH.sub.2Cl.sub.2 (3.times.150 mL). The
organic phase was washed with 5% brine (2.times.70 mL), dried over
Na.sub.2SO.sub.4, filtrated, and concentrated. The solution of the
crude compound in CH.sub.2Cl.sub.2 (100 mL) sat overnight at RT and
partially precipitated out as crystalline material. Crystalline
solid was collected by filtration (2.4 g, 98% ee.). The mother
liquor was concentrated in vacuo and purification by chromatography
(silica gel, 5:1 hexane:EtOAc gave the title compound as an
off-white solid. MS (ESI, pos. ion.) m/z: 303 (M+1).
E) Preparation of
5(R)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydronaphthalene--
2-carbaldehyde
[0377] To a 100-mL round-bottomed flask containing
5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydro-naphthalene-2--
carbonitrile [0.95 g, 3.2 mmol, step d] in formic acid (11 mL,
Aldrich), was added Raney-Ni (0.95 g, 3201, Aldrich) and water (1
mL). The reaction was heated at reflux for 6 h. After cooling to
RT, the mixture was filtered through Celite and the filtrate was
concentrated in vacuo. The residue was taken up in EtOAc (50 mL),
washed with 5% brine (2.times.10 mL), and dried over
Na.sub.2SO.sub.4. Filtration and concentration in vacuo afforded
the crude compound. Purification by column chromatography over
silica gel with hexane:EtOAc (5:1) gave the title compound as a
white solid.
F) Preparation of
2-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydronaphthalene-1(R)-yl)-isoindol-
e-1,3-dione
[0378] To a 100-mL round-bottomed flask containing 5
(R)-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-
-carbaldehyde [0.54 g, 1.8 mmol, step (e)] in DMF, was added
piperidine (0.35 mL, 3.5 mmol, Aldrich), NaBH(OAc).sub.3 (0.75 g,
3.5 mmol), and glacial AcOH (12 mg, 0.2 mmol, J. T. Baker). The
reaction mixture was stirred at RT for 12 h. After removal of the
solvent in vacuo, the residue was taken up in EtOAc (50 mL) and the
resulting organic phase was washed with 5% brine (2.times.15 mL),
and dried over Na.sub.2SO.sub.4. Filtration, concentration in vacuo
afforded the title compound as a clear oil. MS (ESI, pos. ion.)
m/z: 375 (M+1).
G) Preparation of
6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalene-1(R)-ylamine
[0379] To a 100-mL round-bottomed flask containing
2-(6-piperidin-1-ylmethyl-1,2,3,4-tetrahydronaphthalene-1(R)-yl)-isoindol-
e-1,3-dione [0.63 g, 1.7 mmol, step (f)] in EtOH (10 mL), was added
hydrazine (1.3 mL, 42 mmol, Aldrich). The reaction was stirred at
RT for 2 h. After the removal of the solvent and excess hydrazine
in vacuo, the residue was taken in EtOH (15 mL) and heated at
reflux under N.sub.2 for 2 h. After cooling to RT, filtration
through a fritted-glass funnel gave the title compound as a clear
oil. MS (ESI, pos. ion.) m/z: 245 (M+1).
H) Preparation of
2-[3-oxo-1-(toluene-4-sulfonyl)piperizin-2(R,S)-yl]-N-(6-piperidin-1-ylme-
thyl-1,2,3,4-tetrahydronaphthalen-1(R)-yl)-acetamide
[0380] The coupling of
[3-oxo-1-(toluene-4-sulfonyl)piperizin-2-yl]-acetic acid and
6-piperidin-1-ylmethyl-1,2,3,4-tetrahydro-naphthalene-1-ylamine
(Step g) in the presence of HATU following the general procedure
outline in Example 3 gave the titled compound. MS (ESI, pos. ion.)
m/z: 539 (M+1).
[0381] The following compounds were prepared similar to that
described above from the appropriate starting materials:
##STR00047##
EXAMPLE 6a
2-[5,5-Dimethyl-3-oxo-1-(toluene-4-sulfonyl)-piperizin-2(R,S)-yl]-N-(6-pip-
eridin-1-ylmethyl-1,2,3,4-tetrahydronaphthalen-[(R)-yl)-acetamide.
MS (ESI, pos. ion.) m/z: 567 (M+1).
EXAMPLE 7
##STR00048##
[0382]
N-7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(tol-
uene-4-sulfonyl)-piperazin-2-yl]-acetamide
[0383] A mixture of
3-oxo-1-toluene-4-sulfonyl)-piperazin-2-yl]-acetic acid (0.050 g,
0.14 mmol), HOAt (0.025 g, 0.18 mmol), i-Pr.sub.2NEt (0.12 mL, 0.70
mmol), and EDC (0.035 g, 0.18 mmol) in anhydrous DMF (2 mL) was
stirred at RT in 24 h. The mixture was concentrated, taken up in
H.sub.2O, extracted with CH.sub.2Cl.sub.2 (3.times.), dried over
MgSO.sub.4, concentrated and purified by pre-TLC plate to give the
title compound. MS (APCI) m/z 563 (M+1). 562.20 Calc'd for
C.sub.27H.sub.35ClN.sub.4O.sub.5S.
[0384] The following compounds were prepared similar to that
described above from the appropriate starting materials:
EXAMPLE 8
##STR00049##
[0385]
2-[1-(4-Acetylamino-benzenesulfonyl)-3-oxo-piperazin-2-yl]-N-[7-(te-
rt-butylamino-methyl)-6-chloro-chroman-4-yl]-acetamide
[0386] MS (APCI) m/z 606 (M+1). 605.21 Calc'd for
C.sub.28H.sub.36ClN.sub.5O.sub.6S.
EXAMPLE 9
##STR00050##
[0387]
N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(4--
methoxy-benzenesulfonyl)-piperazin-2-yl]-acetamide
[0388] MS (APCI) m/z 579 (M+1). 578.20 Calc'd for
C.sub.27H.sub.35ClN.sub.4O.sub.6S.
EXAMPLE 10
##STR00051##
[0389]
N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(4--
chloro-benzenesulfonyl)-piperazin-2-yl]-acetamide
[0390] MS (APCI) m/z 583 (M+1). 582.15 Calc'd for
C.sub.26H.sub.32Cl.sub.2N.sub.4O.sub.5S.
EXAMPLE 11
##STR00052##
[0391]
N-[7-(tert-Butylamino-methyl)-6-chloro-chroman-4-yl]-2-[3-oxo-1-(3--
trifluoromethyl-benzenesulfonyl)-piperazin-2-yl]-acetamide
[0392] MS (APCI) m/z 617 (M+1). 616.71 Calc'd for
C.sub.27H.sub.32ClF.sub.3N.sub.4O.sub.5S.
EXAMPLE 12
##STR00053##
[0393]
N-((4R)-6-Chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2-
H-chromen-4-yl)-2-((2R,S)-5,5-dimethyl-3-oxo-1-((2,4,6-trimethylphenyl)sul-
fonyl)-2-piperazinyl)acetamide
EXAMPLE 13
##STR00054##
[0394]
N-((4R)-6-Chloro-7-(((1,1-dimethylethyl)amino)methyl)-3,4-dihydro-2-
H-chromen-4-yl)-2-((2R,S)-5,5-dimethyl-1-((4-methylphenyl)sulfonyl)-3-oxo--
2-piperazinyl)acetamide
EXAMPLE 14
##STR00055##
[0395]
N-((4R)-2,2-dimethyl-7-(2-piperidinyl)-3,4-dihydro-2H-chromen-4-yl)-
-2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide
A) Preparation of
N-(2,2-dimethyl-7-pyridin-2-yl-chroman-4R-yl)-2R-[3-oxo-1-toluene-4-sulfo-
nyl)-piperazin-2-yl]-acetamide
[0396] A mixture of
[3-oxo-1-toluene-4-sulfonyl)-piperazin-2R-yl]-acetic acid (0.41 g,
1.30 mmol), HOAt (0.30 g, 1.95 mmol), i-Pr.sub.2NEt,
[2,2,-dimethyl-7-pyridin-2R-yl-chroman-4-ylamine (0.33 g, 1.30
mmol), and EDC (0.40 g, 1.95 mmol) in anhydrous DMF (10 mL) was
stirred at RT in 24 h. The mixture was quenched by H.sub.2O, and
the solid was filtered, purified by ISCO (3%
MeOH/--CH.sub.2Cl.sub.2) to give the title compound. MS (APCI) m/z
549 (M+1).
B) Preparation of
N-((4R)-2,2-dimethyl-7-(2-piperidinyl)-3,4-dihydro-2H-chromen-4-yl)-2-((2-
R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide
[0397] A mixture of
N-(2,2-dimethyl-7-pyridin-2-yl-chroman-4R-yl)-2R-[3-oxo-1-toluene-4-sulfo-
nyl)-piperazin-2-yl]-acetamide (Step a, 0.15 g, 0.27 mmol),
PtO.sub.2 (0.20 g), and HOAc (0.1 mL) in MeOH (10 mL) was
hydrogenated at RT in 24 h. The catalyst was filtered off. The
filtrate was concentrated and purified by ISCO (15%
MeOH/CH.sub.2Cl.sub.2) to give the title compound. MS (APCI) m/z
555 (M+1).
EXAMPLE 15
##STR00056##
[0398]
N-[6-(4-Methyl-piperazin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-
R-yl]-2-[3-oxo-1-(toluene-4-sulfonyl)-piperazin-2R-yl]-acetamide
A) Preparation of
3(R)-benzyloxycarbonylamino-N-(2,2-dimethoxy-ethyl)-succinamic acid
tert-butyl ester
[0399] A mixture of D-CBz-ASP(OTBU)-OH (5 g, 15.46 mmol), HOAt
(2.72 g, 20.1 mmol), i-Pr.sub.2NEt (10 g, 77.3 mmol), amino
acetaldehyde dimethyl acetal (3.25 g, 30.92 mmol), and EDC (3.90 g,
20.1 mmol) in anhydrous CH.sub.3CN (100 mL) was stirred at RT for
24 h. The mixture was concentrated, taken up in H.sub.2O, extracted
with EtOAc (3.times.), dried over MgSO.sub.4, concentrated and
purified by ISCO (30% EtOAc/Hexane) to give a colorless oil.
B) Preparation of
2R-tert-butoxycarbonylmethyl-3-oxo-3,4-dihydro-2H-pyrazine-1-carboxylic
acid benzyl ester
[0400] A mixture of
3R-benzyloxycarbonylamino-N-(2,2-dimethoxy-ethyl)-succinamic acid
tert-butyl ester (Step a, 3.2 g, 7.80 mmol) and p-TsOH (0.13 g,
0.78 mmol) in anhydrous toluene (50 mL) was stirred at 55.degree.
C. for 1 h. The mixture was cooled, concentrated, and purified by
ISCO (20% EtOAc/Hexane) to give a colorless oil.
C) Preparation of (3-oxo-piperazin-2R-yl)-acetic acid tert-butyl
ester
[0401] A solution of
2R-tert-butoxycarbonylmethyl-3-oxo-3,4-dihydro-2H-pyrazine-1-carboxylic
acid benzyl ester (Step b, 1.7 g, 4.91 mmol) in MeOH (20 mL) was
hydrogenated at RT in 10% Pd/C (0.1 g) in 36 h. The catalyst was
filtered off, and the filtrate was concentrated and used in the
next step without further purification.
D) Preparation of
[3-oxo-1-(toluene-4-sulfonyl)-piperazin-2R-yl]acetic acid
tert-butyl ester
[0402] To a stirred, cooled (0.degree. C.) mixture of
(3-oxo-piperazin-2R-yl)-acetic acid tert-butyl ester (Step c, 1.06
g, 4.95 mmol) and Et.sub.3N (0.76 mL, 1.1 mmol) in anhydrous
CH.sub.2Cl.sub.2 (15 mL) was added p-TsCl. The mixture was stirred
at RT for 4 h, H.sub.2O was added, and layers were separated. The
organic extracts were dried over MgSO.sub.4, concentrated, and used
in the next step without further purification. MS (APCI) m/z 369
(M+1).
E) Preparation of
[3-oxo-1-toluene-4-sulfonyl)-piperazin-2R-yl]-acetic acid
[0403] To a stirred solution of
3-oxo-1-(toluene-4-sulfonyl)-piperazin-2R-yl]acetic acid tert-butyl
ester (Step d, 1.7 g, 4.62 mmol) in CH.sub.2Cl.sub.2 (20 mL) was
added 95% TFA/H.sub.2O (1 mL) and stirred for 2 h. The mixture was
concentrated, triturated in ether to give the title compound. MS
(APCI) m/z 313 (M+1).
F) Preparation of
N-(6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1R-yl)-2-[3-oxo-1-(tolue-
ne-4-sulfonyl)-piperazin-2R-yl)]-acetamide
[0404] Following the same preparation of
N-(2,2-dimethyl-7-pyridin-2-yl-chroman-4R-yl)-2R-[3-oxo-1-(toluene-4-sulf-
onyl)-piperazin-2-yl]-acetamide (Example 14) gave the title
compound. MS (APCI) m/z 472 (M+1).
G) Preparation of
N-(6-chloromethyl-1,2,3,4-tetrahydro-naphthalen-1R-yl)-2-[3-oxo-1-(toluen-
e-4-sulfonyl)-piperazin-2R-yl]-acetamide
[0405] To a stirred solution of
N-(6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1R-yl)-2-[3-oxo-1-(tolue-
ne-4-sulfonyl)-piperazin-2R-yl)]-acetamide (Step f, 0.16 g, 0.34
mmole) in anhydrous p-dioxane (5 mL) was added SOCl.sub.2 (0.13 g,
1.02 mmol). Stirring was continued for 3 h. The mixture was
concentrated to give a brown oil. MS (APCI) m/z 490 (M+1).
H) Preparation of
N-[6-(4-methyl-piperazin-1-ylmethyl)-1,2,3,4-naphthalen-1R-yl]-2-[3-oxo-1-
-(toluene-4-sulfonyl)-piperazin-2R-yl]-acetamide
[0406] To a stirred solution of
N-(6-chloromethyl-1,2,3,4-tetrahydro-naphthalen-1R-yl)-2-[3-oxo-1-(toluen-
e-4-sulfonyl)-piperazin-2R-yl]-acetamide (Step g, 0.16 g, 0.32
mmole) in anhydrous p-dioxane (2 mL) was added N-methylpiperazine
(0.08 g, 1.1 mmol). Stirring was continued for 2 h. The mixture was
concentrated, taken up in H.sub.2O, and a tan solid was filtered.
The solid was air dried and purified by prep-TLC to give a tan
solid. MS (APCI) m/z 554 (M+1).
EXAMPLE 16
##STR00057##
[0407]
3-{[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-y-
lcarbamoyl]-methyl}-4-(3-trifluoromethyl-benzenesulfonyl)-piperazine-1(R,S-
)-carboxylic acid tert-butyl ester
A) Preparation of
3(R,S)-methoxycarbonylmethyl-4-(3-trifluoromethyl-benzenesulfonyl)-pipera-
zine-carboxylic acid tert-butyl ester
[0408] To a 250-mL round-bottomed flask containing methyl
4-Boc-piperizine-2(R,S)-acetate (2.0 g, 7.7 mmol, Astatech) in THF
(5 mL), was added 3-trifluoromethylbenzenesulfonyl chloride (1.9 g,
7.7 mmol, Aldrich) and sat K.sub.2CO.sub.3 (5 mL). The reaction was
stirred at RT for 20 h. The compound was extracted with EtOAc (25
mL) and the organic phase was washed with 5% brine (2.times.5 mL),
and dried over Na.sub.2SO.sub.4. Filtration and concentration in
vacuo, followed by column chromatography over silica gel with
hexane:EtOAc (3:1) gave the title compound as a clear oil. MS (ESI,
pos. ion.) m/z: 467 (M+1).
B) Preparation of
3(R,S)-carboxymethyl-4-(3-trifluoromethyl-benzenesulfonyl)-carboxylic-car-
boxylic acid tert-butyl ester
[0409] To a 200-mL round-bottomed flask containing
3(R,S)-methoxycarnonylmethyl-4-(3-trifluoromethyl-benzenesulfonyl)-carbox-
ylic-carboxylic acid tert-butyl ester [3.0 g, 6.4 mmol, step (a)]
in THF (10 mL), was added LiOH (0.81 g, 19 mmol, Aldrich). The
reaction was stirred at RT overnight. The mixture was acidified to
pH 6 with 2 N HCl and the compound was extracted with EtOAc
(2.times.30 mL). The organic phase was washed with 5% brine
(2.times.10 mL), dried over Na.sub.2SO.sub.4. Filtration and
concentration in vacuo afforded the title compound as a white
solid. MS (ESI, pos. ion.) m/z: 453 (M+1).
C) Preparation of
3(R,S)-[6-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-[(R)-ylcarbamoyl)-me-
thyl]-4-(3-trifluoromethyl-benzenesulfonyl)-carboxylic-carboxylic
acid tert-butyl ester
[0410] To a 100-mL round-bottomed flask containing
3(R,S)-carboxymethyl-4-(3-trifluoromethyl-benzenesulfonyl)-carboxylic-car-
boxylic acid tert-butyl ester [0.30 g, 0.66 mmol, step (b)] in DMF
(8 mL), was added
5(R)-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanol (0.12 g,
0.66 mmol) HATU (0.88 g, 2.3 mmol, PerSeptive Biosystem) and DIEA
(0.40 mL, 2.3 mmol, Aldrich). The mixture was stirred at RT for 20
h. The reaction was quenched with water (10 mL) and the compound
was extracted with EtOAc (2.times.20 mL). The organic phase was
washed with 5% brine (2.times.10 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated. Purification with column chromatography
over silica gel with hexane:EtOAc (1:1) gave the title compound as
a clear oil. MS (ESI, pos. ion.) m/z: 612 (M+1).
D) Preparation of
3(R,S)-[6-formyl-1,2,3,4-tetrahydronaphthalen-1(R)-ylcarbamoyl)-methyl]-4-
-(3-trifluoromethyl-benzenesulfonyl)-carboxylic-carboxylic acid
tert-butyl ester
[0411] To a 100-mL round-bottomed flask containing
3(R,S)-[6-hydroxymethyl-1,2,3,4-tetrahydronaphthalen-1(R)-ylcarbamoyl)-me-
thyl]-4-(3-trifluoromethyl-benzenesulfonyl)-carboxylic-carboxylic
acid tert-butyl ester [0.39 g, 0.64 mmol, step (c)] in
CH.sub.2Cl.sub.2 (10 mL), was added MnO.sub.2 (0.83 g, 9.6 mmol,
Aldrich). The reaction was stirred at RT for 3 h. After filtration
through Celite.RTM., the solution was concentrated in vacuo to give
the title compound as a white powder. MS (ESI, pos. ion.) m/z: 611
(M+1).
E) Preparation of
3(R,S)-{[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-yl-
carbamoyl]-methyl}-4-(3-trifluoromethyl-benzenesulfonyl)-piperazine-1-carb-
oxylic acid tert-butyl ester
[0412] To a 50-mL reaction tube containing
3(R,S)-[6-formyl-1,2,3,4-tetrahydronaphthalen-1(R)-ylcarbamoyl)-methyl]-4-
-(3-trifluoromethyl-benzenesulfonyl)-carboxylic-carboxylic acid
tert-butyl ester [0.35 g, 0.58 mmol, step (d)] in DMF (10 mL), was
added tert-butylamine (0.61 mL, 5.8 mmol, Aldrich) and AcOH (33
.mu.L, 0.58 mmol). The reaction tube was sealed and the mixture was
stirred at 55.degree. C. for 1 h. After cooling to RT,
NaBH(OAc).sub.3 (0.35 g, 2.88 mmol, Aldrich) was added and the
mixture was stirred at RT overnight. The reaction was quenched with
5% brine (5 mL) and the compound was extracted with EtOAc
(2.times.15 mL). The organic phase was washed with 5% brine
(2.times.5 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated. Column chromatography over silica gel with
hexane:EtOAc:MeOH (5:5:1) gave the title compound as clear oil. MS
(ESI, pos. ion.) m/z: 667 (M+1).
EXAMPLE 17
##STR00058##
[0413]
N-[6-(tert-Butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-yl-
]-2-[1-(3-trifluoromethyl-benzenesulfonyl)-piperazin-2(R,S)-yl-acetamide
[0414] To a 50-mL round-bottomed flask was added
3(R,S)-{[6-(tert-butylamino-methyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-yl-
carbamoyl]-methyl}-4-(3-trifluoromethyl-benzenesulfonyl)-piperazine-1-carb-
oxylic acid tert-butyl ester (33 mg, 0.050 mmol, Example 16) and
HCl (1.5 mL, 6.0 mmol, 4.0 M in 1,4-dioxane, Aldrich) and MeOH (2
mL). The reaction was stirred at RT for 1 h. The solution was
concentrated in vacuo to give the compound as a white solid. MS
(ESI, pos. ion.) m/z: 567(M+1).
EXAMPLE 18
##STR00059##
[0415]
2-[3-Oxo-1-(toluene-4-sulfonyl)-piperazin-2-yl]-N-[6-(1-piperidin-1-
-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-[(R)-yl]-acetamide
A) Preparation of trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester
[0416] To a 1 L round-bottomed flask charged with
6-hydroxy-1-tetralone (Aldrich, 21.97 g, 0.136 mol) at 0.degree. C.
was added CH.sub.2Cl.sub.2 (500 mL) and pyridine (Aldrich, 11 mL,
0.136 mmol). Triflic anhydride (Aldrich, 23 mL, 0.136 mmol) was
added through an additional funnel over a period of 12 min. The
mixture was gradually warmed to RT and stirred at RT overnight. The
residue was diluted with water and two phases were separated. The
organic phase was washed with 1 N HCl (100 mL.times.2), sat
NaHCO.sub.3, and brine, dried over Na.sub.2SO.sub.4. After
filtration and concentration in vacuo, the crude was purified by
flash chromatography (5-11% EtOAc-hexane) to provide the title
compound as yellow oil. MS (ESI): 295 (M+H).sup.+.
B) Preparation of trifluoro-methanesulfonic acid
5(S)-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl ester
[0417] To a dry three-necked flask containing
(R)-2-methyl-CBS-oxazaborolidine (Aldrich, 1.94 mL, 1.0 M in
toluene, 1.93 mmol, 0.05 eq) under N.sub.2 was added a solution of
BH.sub.3-Me.sub.2S (Aldrich, 3.30 mL, 34.80 mmol, 0.9 eq) in
toluene (200 mL) through an addition funnel. After the addition,
the reaction was cooled to 0.degree. C. A solution of
trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (step a, 11.37 g,
38.67 mmol, 1.0 eq) in THF (180 mL) was added drop-wise through an
addition funnel. Following the addition, the reaction mixture was
stirred at RT for 40 min, then quenched with MeOH. The solvent was
removed in vacuo and the crude was diluted with H.sub.2O (50 mL).
The aqueous phase was extracted with ether (3.times.150 mL). The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The title compound was
obtained as an off-white solid by flash chromatography (16-22%
EtOAc-hexane).
C) Preparation of trifluoro-methanesulfonic acid
5(R)-azido-5,6,7,8-tetrahydro-naphthalen-2-yl ester
[0418] To a solution of trifluoro-methanesulfonic acid
5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Step b, 11.2 g,
37.9 mmol, 1.0 eq) in THF (150 .mu.L) at RT was added DPPA
(Aldrich, 11.1 mL, 51.6 mmol, 1.36 eq). The resulting mixture was
cooled to 0.degree. C. and DBU (Aldrich, 7.7 mL, 51.6 mmol, 1.36
eq) was added slowly through a syringe. The mixture was warmed to
RT and stirred over the weekend. The reaction was concentrated in
vacuo. The crude compound was dissolved in EtOAc (400 mL). The
organic layer was washed with NH.sub.4Cl (twice), H.sub.2O, and
brine, dried over Na.sub.2SO.sub.4. After filtration and
concentration in vacuo, the crude was purified by flash
chromatography (5% EtOAc-hexane) to provide the title compound.
D) Preparation of trifluoro-methanesulfonic acid
5(R)-amino-5,6,7,8-tetrahydro-naphthalen-2-yl ester
[0419] To a solution of trifluoro-methanesulfonic acid
5-azido-5,6,7,8-tetrahydro-naphthalen-2-yl ester (step c, 10.3 g,
32.1 mmol, 1.0 eq) in THF (70 mL) was added PPh.sub.3 (Aldrich, 8.4
g, 32.1 mmol, 1.0 eq), and H.sub.2O (30 mL) at 0.degree. C. The
mixture was warmed to RT and stirred overnight. 2 N HCl was added
until the mixture was acidic (pH=1-2). The mixture was extracted
with toluene (3.times.100 mL). The aqueous phase was neutralized
with 5N NaOH until the pH=12-13, extracted with Et.sub.2O
(3.times.150 mL). The ether solution was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude was
purified by flash chromatography (6% MeOH--CH.sub.2Cl.sub.2) to
provide the title compound.
E) Preparation of trifluoro-methanesulfonic acid 5
(R)-tert-butoxycarbonylamino-5,6,7,8-tetrahydro-naphthalen-2-yl
ester
[0420] To a solution of trifluoro-methanesulfonic acid 5
(R)-amino-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Step d, 2.0 g,
6.8 mmol, 1.0 eq) in CH.sub.2Cl.sub.2 (20 mL) was added Et.sub.3N
(1.9 mL, 13.6 mmol, 2.0 eq) and di-tert-butyl carbonate (Aldrich,
1.8 g, 8.1 mmol, 1.2 eq). The mixture was stirred at RT overnight,
washed with saturated NaHCO.sub.3 (2.times.20 mL) and brine, and
dried over Na.sub.2SO.sub.4. After filtration and concentration in
vacuo, the crude was purified by flash chromatography (4-10%
EtOAc-hexane) to provide the title compound as a white solid.
F) Preparation of
[6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-yl]--
carbamic acid tert-butyl ester
[0421] To a solution of trifluoro-methanesulfonic acid
5-tert-butoxycarbonylamino-5,6,7,8-tetrahydro-naphthalen-2-yl ester
(Step e, 1.89 g, 4.79 mmol, 1.0 eq) in CH.sub.3CN (25 mL) purged
with N.sub.2 was added palladium (II) acetate (Strem Chemicals, 65
mg, 0.29 mmol, 0.06 eq), 1,1'-bis(diphenylphosphino) ferrocene
(Aldrich, 0.70 g, 1.26 mmol, 0.26 eq), K.sub.2CO.sub.3 (0.99 g,
7.18 mmol, 1.5 eq) and N-allyl piperidine (Lancaster, 3.00 g, 23.96
mmol, 5.0 eq). The vessel was sealed with a septum and heated to
80.degree. C. overnight. After cooling to RT, the mixture was
diluted with H.sub.2O, and extracted with Et.sub.2O (3.times.). The
ether solution was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude was purified by flash
chromatography (14-21% EtOAc-Hexane) to provide the title compound.
MS (ESI): 371 (M+H).sup.+.
G) Preparation of
6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-ylami-
ne
[0422] To a solution of
[6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-yl]--
carbamic acid tert-butyl ester in CH.sub.2Cl.sub.2 (3 mL) was added
TFA (3 mL). The mixture was stirred at RT for 4 h, concentrated in
vacuo. The crude was neutralized with 10% Na.sub.2CO.sub.3 until
the aqueous phase was basic, then extracted with CH.sub.2Cl.sub.2
three times. The organic solution was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to provide the
title compound. MS (ESI): 271 (M+H).sup.+.
H) Preparation of
2-[3-oxo-1-(toluene-4-sulfonyl)-piperazin-2-yl]-N-[6-(1-piperidin-1-ylmet-
hyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1(R)-yl]-acetamide
[0423] To a 20 mL flask equipped with stirring was added
[3-oxo-1-(toluene-4-sulfonyl)-piperazin-2-yl]-acetic acid (104 mg,
0.33 mmol),
6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1(R-
)-ylamine (Step g, 90 mg, 0.33 mmol), EDC (Aldrich, 96 mg, 0.50
mmol), HOBt (Aldrich, 45 mg, 0.33 mmol), and CH.sub.2Cl.sub.2 (2
mL). The reaction mixture was stirred at RT overnight and diluted
with CH.sub.2Cl.sub.2 (50 mL). The organic phase was washed with
saturated NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The crude was purified by
preparative TLC in 10% MeOH--CH.sub.2Cl.sub.2 to afford the title
compound as a mixture of two diastereomers. MS (ESI): 565
(M+H).sup.+.
EXAMPLE 19
##STR00060##
[0424]
3-{[6-(1-Piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen--
1(R)-ylcarbamoyl]-methyl}-4-(3-trifluoromethyl-benzenesulfonyl)-piperazine-
-1-carboxylic acid tert-butyl ester
[0425]
3-{[6-(1-Piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen--
1(R)-ylcarbamoyl]-methyl}-4-(3-trifluoromethyl-benzenesulfonyl)-piperazine-
-1-carboxylic acid tert-butyl ester was prepared from
3-carboxymethyl-4-(3-trifluoromethyl-benzenesulfonyl)-piperazine-1-carbox-
ylic acid tert-butyl ester using essentially the same procedure
described in Example 18 yielding a light yellow solid. MS (ESI):
705 (M+H).sup.+.
EXAMPLE 20
##STR00061##
[0426]
(R)-2-(3-oxo-1-tosylpiperazin-2-yl)-N-(2-(2-(piperidin-1-yl)ethyl)--
5,6,7,8-tetrahydroquinazolin-5-yl)acetamide
A. Preparation of 3-(tert-butyldiphenyl-silyloxy)propanenitrile
[0427] To a solution of 3-hydroxypropanenitrile (7.1 g, 0.1 mol)
and DMAP (1.22 g, 0.01 mmol) in 30 mL of dry DCM at room
temperature was added NEt3 (30.3 g, 0.3 mol), followed by
tert-butyldiphenyl-silylchloride (27.5 g, 0.1 mol). A lot of white
solid appeared. After stirring at room temperature overnight, the
reaction mixture was quenched with Sat. NH4Cl solution, extracted
with DCM, dried over Na2SO4, and evaporated in vaco. Flash
chromatography (SiO2, hexane/EtOAc=100:2 to 100:5 to 100:10) gave
the title compound as a white solid.
B. Preparation 3-(tert-butyldiphenylsilyloxy)propanamidine
[0428] To a suspension of NH4Cl (5.35 g, 0.1 mol) in 60 mL of dry
benzend at 0 C was slowly added 50 mL of 2 M solution of
trimethylaluminum in toluene. After the addition was complete, the
reaction mixture was allowed to warm up to room temperature and was
stirred for 2 h until gas evolution had ceased. A solution of the
above nitrile in 20 mL of dry benzene was added to the aluminum
amide reagent and the resulting mixture was heated up to 80 C for
20 h. The reaction mixture was slowly cooled to room temperature
and then carefully poured into a slurry of 300 mL of DCM and 200 g
of silica gel. It was then filtered and washed thoroughly with
MeOH/DCM (1:2). After concentration, flash chromatography
(SiO.sub.2, EtOAc to EtOAc/MeOH=100:20 to 100:30 to EtOAc/2 m NH3
in MeOH=100:30) gave the product as a white solid.
C. Preparation of
3-(tert-butyldiphenylsilyloxy)propanamidine-2-(2-(tert-butyldiphenylsilyl-
oxy)ethyl)-7,8-dihydroquinazolin-5(6H)-one
[0429] A Solution of 3-(tert-butyldiphenylsilyloxy) propanamidine
(25 g, 77 mmol) and
2-((dimethylamino)methylene)cyclohexane-1,3-dione (12.8 g, 77 mmol)
in 400 mL of dry EtOH was heated at 80.degree. C. for 3 h. After
cooling to room temperature, the solvent was evaporated. Flash
chromatography (SiO.sub.2, EtOAc/hexane=1:1) gave the title
compound as a white solid.
D. Preparation of
2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydro-quinazolin-5-o-
l
[0430] A solution of the above ketone (2.16 g, 5 mmol) in 30 mL of
dry MeOH was treated with NaBH.sub.4 (189 mg, 5 mmol). After 5 min,
the reaction was quenched with 5 mL of Sat. NH4Cl solution. The
MeOH was evaporated and the residue was extracted with DCM, dried
over Na.sub.2SO.sub.4 and evaporated. Flash chromatography
(SiO.sub.2, DCM to EtOAc) gave the title compound as a white
solid.
E. Preparation of 5-azido-2-(2-(tert-butyldiphenyl
silyloxy)ethyl)-5,6,7,8-tetrahydroquinazoline
[0431] To a solution of the above product (2.0 g, 4.63 mmol) in 25
mL of toluene at -10.degree. C. was added DPPA (1.2 mL, 5.56 mmol).
To this stirred solution was then added DBU (0.83 mL, 5.56 mmol)
dropwise while keeping the temperature below 0.degree. C. After
stirring at room temperature for 16 h, the reaction was evaporated
to dryness and directly submitted to flash chromatography
(SiO.sub.2, hexane/DCM=1:2) to afford the azide as a white
solid.
F. Preparation of
2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5,6,7,8-tetrahydro-quinazolin-5-a-
mine
[0432] A suspension of 80 mg of Pd/C (10% w/w) in a solution of the
above azide (800 mg, 1.75 mmol) in 30 mL of EtOAc was stirred under
H.sub.2 atmosphere overnight. The reaction mixture was then
directly submitted to flash chromatograph (SiO.sub.2, EtOAc to
EtOAc/MeOH=100:15 to EtOAc/2M NH.sub.3 in MeOH=2:1) to give the
amine (570 mg, 76%) as a white solid.
G. Preparation of
2-(5-amino-5,6,7,8-tetrahydroquinazolin-2-yl)ethanol
[0433] A solution of the above product (570 mg, 1.32 mmol) in 10 mL
of THF at 0.degree. C. was treated with a 1M TBAF solution in THF
(1.56 mL, 1.56 mmol). After stirring at room temperature overnight,
the reaction mixture was directly submitted to flash chromatograph
(SiO.sub.2, EtOAc to EtOAc/MeOH=100:15 to EtOAc/2M NH.sub.3 in
MeOH=1:1) to the title compound as a white solid.
H. Preparation of
(R)--N-(2-(2-hydroxyethyl)-5,6,7,8-tetrahydroquinazolin-5-yl)-2-(3-oxo-1--
tosylpiperazin-2-yl)acetamide
[0434] A solution of (R)-2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid
(1.55 g, 5.0 mmol), crude
2-(5-amino-5,6,7,8-tetrahydroquinazolin-2-yl)ethanol (966 mg, 5.0
mmol), HOBt (676 mg, 5.0 mmol) and EDCI (959 mg, 5.0 mmol) in 2.5
mL of DMF was stirred overnight at room temperature. After
quenching with Sat. NaHCO.sub.3 solution, the reaction mixture was
extracted with EtOAc. The combined organic phase was washed brine,
dried over Na.sub.2SO.sub.4, and evaporated in vaco. Flash
chromatography (SiO.sub.2, EtOAc/MeOH=100:15 to 100:20 to 100:25 to
100:30) gave the title compound as a white solid.
I. Preparation of
(R)-2-(5-(2-(3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahydroqui-
nazolin-2-yl)ethyl methanesulfonate
[0435] To a solution of the product from the previous step (1.22 g,
2.5 mmol) in dry DCM at 0.degree. C. was added MsCl (860 mg, 7.5
mmol), followed by NEt.sub.3 (1.25 g, 12.5 mmol). After stirring at
0.degree. C. for 20 min, the reaction mixture was quenched with
sat. NaHCO.sub.3 solution, extracted with EtOAc, dried over
Na.sub.2SO.sub.4, and evaporated in vaco. Flash chromatography
(SiO.sub.2, EtOAc/MeOH=100:10 to 100:15 to 100:16 to 100:18) gave
the title compound as a white solid. MS: 566.2 (M+1).
J. Preparation of
(R)-2-(5-(2-(3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahydroqui-
nazolin-2-yl)ethyl methanesulfonate
[0436] A solution of
(R)-2-(5-(2-(3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahydroqui-
nazolin-2-yl)ethyl methanesulfonate (565 mg, 1.0 mmol) and
piperidine (170 mg, 2.0 mmol) in dry DCM at room temperature was
stirred overnight. The reaction mixture was quenched with sat.
NH.sub.4Cl solution, extracted with EtOAc, washed with water, dried
over Na.sub.2SO.sub.4, and evaporated in vaco. Flash chromatography
(SiO.sub.2, EtOAc/MeOH=100:15 to 100:20 to EtOAc/2M NH.sub.3 in
MeOH=100:15 to 100:20 to 100:30) gave the title compound as a white
solid. MS: 555.2 (M+1).
EXAMPLE 21
##STR00062##
[0437]
(R)-2-(3-oxo-1-tosylpiperazin-2-yl)-N-(1-(2-(piperidin-1-yl)ethyl)--
4,5,6,7-tetrahydro-1H-indazol-4-yl)acetamide
A. Preparation of
1-(2-hydroxyethyl)-6,7-dihydro-1H-indazol-4(5H)-one
[0438] 2-hydroxyethyl hydrazine (1.36 mL, 20 mmol) was slowly added
to an ice-cooled solution of
2-((dimethylamino)methylene)cyclohexane-1,3-dione (3.34 g) in
methanol (50 mL). After stirring at room temperature for 20 min,
the solvent was evaporated. Flash chromatography (SiO.sub.2,
EtOAc/MeOH=100:5 to 100:7 to 100:10) gave the title compound as a
white solid.
B. Preparation of
1-(2-(tert-butyldimethylsilyloxy)ethyl)-6,7-dihydro-1H-indazol-4(5H)-one
[0439] To a solution of the product from step A (14 g, 77.8 mmol)
in 100 mL of dry DCM was added NEt.sub.3 (22 mL, 155.6 mmol),
followed by TBSCl (14 g, 93.3 mmol) and DMAP (95 mg, 0.78 mmol).
After stirring at room temperature overnight, the reaction was
quenched with brine and extracted with EtOAc. Flash chromatography
(SiO.sub.2, EtOAc/hexane=1:1) gave the title compound as a white
solid.
C. Preparation of
1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-o-
l
[0440] A solution of the product of step B (21 g, 71.4 mmol) in 200
mL of dry MeOH was treated with NaBH.sub.4 (2.7 g, 71.4 mmol).
After 30 min, the reaction was quenched with 15 mL of Sat.
NH.sub.4Cl solution. The MeOH was evaporated and the residue was
extracted with EtOAc, dried over Na.sub.2SO.sub.4 and evaporated.
Flash chromatography (SiO.sub.2, EtOAc/hexane=1:1 to EtOAc) gave
the title compound as a white solid.
D. Preparation of 4-azido-1-(2-(tert-butyldimethyl
silyloxy)ethyl)-4,5,6,7-tetrahydro-1H-indazole
[0441] To a solution of the above alcohol (23 g, 77.7 mmol) in 200
mL of toluene at -10.degree. C. was added DPPA (20 mL, 93.2 mmol).
To this stirred solution was then added DBU (13.9 mL, 93.2 mmol)
dropwise while keeping the temperature below 0.degree. C. After
stirring at room temperature for 18 h, the reaction was evaporated
to dryness and directly submitted to flash chromatography
(SiO.sub.2, hexane/EtOAc=2:1 to EtOAc) to afford the title compound
as a colorless liquid, together with 12 g of recovered starting
alcohol.
E. Preparation of 1-(2-(tert-butyldimethyl
silyloxy)ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-amine
[0442] A suspension of 150 mg of Pd/C (10% w/w) in a solution of
the product from step D (2.0 g, 6.23 mmol) in 100 mL of EtOAc was
stirred under H.sub.2 atmosphere overnight. The reaction mixture
was then directly submitted to flash chromatograph (SiO.sub.2,
EtOAc to EtOAc/MeOH=100:20 to EtOAc/2M NH.sub.3 in MeOH=100:20 to
100:30 to 100:40) to give the title compound as a white solid.
F. Preparation of
(R)--N-(1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-1H-ind-
azol-4-yl)-2-(3-oxo-1-tosylpiperazin-2-yl)acetamide
[0443] A solution of (R)-2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid
(624 mg, 2.0 mmol),
1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-a-
mine (649 mg, 2.2 mmol), HOBt (297 mg, 2.2 mmol) and EDCI (422 mg,
2.2 mmol) in 1.2 mL of DMF was stirred overnight at room
temperature. After quenching with Sat. NaHCO.sub.3 solution, the
reaction mixture was extracted with EtOAc. The combined organic
phase was washed brine, dried over Na.sub.2SO.sub.4, and evaporated
in vaco. Flash chromatography (SiO.sub.2, EtOAc/MeOH=100:4 to 100:8
to 100:10 to 100:15) gave the title compound as a white solid. MS:
590.2 (M+1).
G. Preparation of
(R)--N-(1-(2-hydroxyethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl)-2-(3-oxo-1-
-tosylpiperazin-2-yl)acetamide
[0444] A solution of the product from step F (810 mg, 1.375 mmol)
in 15 mL of THF at 0.degree. C. was treated with HOAc (991 mg, 16.5
mmol) followed by a 1.0M solution of TBAF in THF (5.5 mL, 5.5
mmol). After stirring at room temperature overnight, the reaction
mixture was evaporated to dryness and was directly submitted to
flash chromatograph (SiO.sub.2, EtOAc to EtOAc/MeOH=100:15 to
100:18 to 100:20 to 100:25 to 100:30) to give the title compound as
a white solid. MS: 476.2 (M+1).
H. Preparation of
(R)-2-(4-(2-(3-oxo-1-tosylpiperazin-2-yl)acetamido)-4,5,6,7-tetrahydroind-
azol-1-yl)ethyl methanesulfonate
[0445] To a solution of the product of step G (900 mg, 1.89 mmol)
in dry DCM at 0.degree. C. was added MsCl (0.44 mL, 5.68 mmol),
followed by NEt.sub.3 (1.3 mL, 9.45 mmol). After stirring at
0.degree. C. for 15 min, the reaction mixture was quenched with
sat. NaHCO.sub.3 solution, extracted with EtOAc, dried over
Na.sub.2SO.sub.4, and evaporated in vaco. Flash chromatography
(SiO.sub.2, EtOAc/MeOH=100:12 to 100:15 to 100:18 to 100:20 to
100:25 to 100:30) gave the crude product as a white solid.
I. Preparation of
((R)-2-(3-oxo-1-tosylpiperazin-2-yl)-N-(1-(2-(piperidin-1-yl)ethyl)-4,5,6-
,7-tetrahydro-1H-indazol-4-yl)acetamide
[0446] A solution of the product of step H (220 mg, 0.4 mmol) and
piperidine (135 mg, 1.6 mmol) in dry DCM at room temperature was
stirred overnight. The reaction mixture was quenched with Sat.
NH.sub.4Cl solution, extracted with EtOAc, washed with water, dried
over Na.sub.2SO.sub.4, and evaporated in vaco. Flash chromatography
(SiO.sub.2, EtOAc/MeOH=100:15 to 100:20 to EtOAc/2M NH.sub.3 in
MeOH=100:15 to 100:20 to 100:25) gave the title compound as a white
solid. MS: 543.2 (M+1).
EXAMPLE 22
##STR00063##
[0447]
3-((5R)-5-(2-(3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrah-
ydronaphthalen-2-yl)benzamide
Preparation
of--3-((5R)-5-(2-(3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahyd-
ronaphthalen-2-yl)benzamide
[0448] To a 25 mL pressure tube was added
(R)-5-(2-(3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahydronaphth-
alen-2-yl trifluoromethanesulfonate (150 mg, 0.25 mmol),
benzamide-3-boronic acid (Frontier, 63 mg, 0.38 mmol),
tetrakis(triphenylphosphine)-palladium (0) (Aldrich, 30 mg, 0.025
mmol), Toluene (1.5 mL), EtOH (0.4 mL), and 1 M NaHCO.sub.3 (0.4
mL) at room temperature under N.sub.2. The reaction mixture was
sealed and stirred at 80.degree. C. overnight, cooled to room
temperature, and diluted with EtOAc (40 mL). The organic layer was
separated, washed with saturated NaHCO.sub.3, water and brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue was purified by silica gel chromatography to provide
the title compound. MS (ESI): 561 (M+H).sup.+.
EXAMPLE 23
##STR00064##
[0449]
N-((1R)-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1,2,3,4-tetrahy-
dronaphthalen-1-yl)-2-(3-oxo-1-tosylpiperazin-2-yl)acetamide
A. Preparation of tert-butyl
(1R)-6-(2-(hydroxymethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbama-
te
[0450] To a 150 mL sealed tube was added
(R)-5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl
trifluoromethanesulfonate (1.0 g, 3.38 mmol) followed by
(2-hydroxymethylphenyl)boronic acid (677.0 mg, 5.05 mmol),
Pd(PPh.sub.3).sub.4 (292.0 mg, 0.253 mmol), EtOH (5 mL),
NaHCO.sub.3 (1M, 5 mL) and toluene (20 mL). The resulting mixture
was capped and heated at 80.degree. C. for 20 h. The solution
mixture was partitioned between EtOAc and H.sub.2O. The organic
layer was washed with brine, dried over MgSO.sub.4, and removed
solvent. The residue was purified by chromatography on silica gel.
Elution with Hex:EtOAc mixture (80:20) gave title compound. MS m/z:
354.3 (M+H). Calc'd. for C.sub.22H.sub.27NO.sub.3-353.47.
B. Preparation of
2-((5R)-5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl)benzoic
acid
[0451] To a 100 mL round bottom flask was added (tert-butyl
(1R)-6-(2-(hydroxymethyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbama-
te (200.0 mg, 0.565 mmol) followed by CCl.sub.4 (2 mL), MeCN (2
mL), H.sub.2O (3 mL), NaIO.sub.4 (363.0 mg, 1.70 mmol), and
RuCl.sub.3 (hydrate, 6 mg, 0.0289 mmol) The resulting mixture was
capped and stirred at rt for 2 h. The solution mixture was
partitioned between EtOAc and H.sub.2O. The organic layer was
separated from the RuCl.sub.3 by passing through the celite. The
organic layer was dried over MgSO.sub.4 and removed solvent. The
residue was purified by chromatography on silica gel. Elution with
CH.sub.2Cl.sub.2:MeOH mixture (95:5) gave title compound. MS m/z:
368.4 (M+H). Calc'd. for C.sub.22H.sub.25NO.sub.4-367.45.
C. Preparation of tert-butyl
(1R)-6-(2-(chlorocarbonyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbam-
ate
[0452] To a 100 mL round bottom flask was added
2-((5R)-5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl)benzoic
acid (270.0 mg, 0.735 mmol) followed by CH.sub.2Cl.sub.2 (15 mL),
oxalyl chloride (0.7 mL, 1.5 mmol), and DMF (2 drops). The
resulting mixture was stirred at rt for 3 h. The solution mixture
was evaporated all solvent off to dryness to give title compound.
MS m/z: 386.4 (M+H). Calc'd. for
C.sub.22H.sub.24ClNO.sub.3-385.89.
D. Preparation of tert-butyl
(1R)-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1,2,3,4-tetrahydronaphth-
alen-1-ylcarbamate
[0453] To a 100 mL round bottom flask was added tert-butyl
(1R)-6-(2-(chlorocarbonyl)phenyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbam-
ate (150.0 mg, 0.388 mmol) followed by dry CH.sub.2Cl.sub.2 (15
mL), NEt.sub.3 (0.11 mL, 1.3 mmol), and acetamide (86 mg, 1.17
mmol). The resulting mixture was stirred at rt for 20 h. Removed
solvent to dryness. Added toluene (15 mL) and heated at 115.degree.
C. for 20 h. Solvent was removed. The residue was purified by
chromatography on silica gel. Elution with CH.sub.2Cl.sub.2:MeOH
mixture (95:5) gave title compound (75 mg, 48%). MS m/z: 406.2
(M+H). Calc'd. for C.sub.24H.sub.27N.sub.3O.sub.3-405.3.
E.
(1R)-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1,2,3,4-tetrahydronaph-
thalen-1-amine
[0454] To a solution of the product of step D (75 mg, 0.184 mmol)
in anhydrous ethyl acetate (100 mL) was added 20 mL of 4 N HCl in
dioxane the resulting mixture was stirred at RT for 3 h then
evaporated to afford the title compound as a colorless glass. MS
m/z: 306.2 (M+H). Calc'd. for C.sub.19H.sub.19N.sub.3O-305.3.
F. Preparation of
N-((1R)-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1,2,3,4-tetrahydronap-
hthalen-1-yl)-2-(3-oxo-1-tosylpiperazin-2-yl)acetamide
[0455] To a 100 mL round bottom flask was added
(1R)-6-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-1,2,3,4-tetrahydronaphth-
alen-1-amine (25.0 mg, 0.06 mmol), followed by
2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid (50 mg, 0.016 mmol), dry
CH.sub.2Cl.sub.2 (10 mL), HATU (12 mg, 0.03 mmol), EDCI (13 mg,
0.068 mmol) and hunig base (0.022 mL, 0.123 mmol). The resulting
mixture was stirred at rt for 20 h. Removed solvent to dryness.
Solvent was removed. The residue was purified by chromatography on
silica gel. Elution with CH.sub.2Cl.sub.2:MeOH mixture (97:3) gave
final compound. MS m/z: 600.3 (M+H). Calc'd. for
C.sub.32H.sub.33N.sub.5O.sub.5S-599.71.s
EXAMPLE 24
##STR00065##
[0456]
(R)-2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)-N-(6-(piperidin-1-ylmethyl)-
-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide
A. Preparation of Diethyl 3-(2-aminoethylamino)pentanedioate
[0457] To ethylenediamine (13.0 ml, 194 mmol) under N.sub.2 was
added diethyl glutaconate (3.40 ml, 19.2 mmol) over 5 min. After 15
min, the mixture was concentrated under reduced pressure and dried
in vacuo to yield the title compound. MS: 247.2
B. Preparation of Ethyl
2-(7-oxo-4-tosyl-1,4-diazepan-5-yl)acetate
[0458] A solution of the product of step A (1.34 g, 5.44 mmol) was
stirred in THF (30 ml) at 0*C. Bu.sub.3SnOTf (90%, 2.73 g, 5.60
mmol) in THF 8.0 ml was added dropwise over 6 min, and the mixture
was heated to reflux for 22 h. The reaction was cooled to 0*C, and
triethylamine (1.52 ml, 10.9 mmol) and dimethylaminopyridine (0.135
g, 1.11 mmol) were added followed by p-toluenesulfonyl chloride
(2.09 g, 11.0 mmol) in THF 4.0 ml. The reaction was allowed to r.t.
and after 4 h concentrated under reduced pressure. AcOEt (100 ml)
was added to the residue and washed with 0.1 N HCl aq. (100
ml.times.2), sat'd NaHCO.sub.3 aq. (100 ml.times.2) and sat'd NaCl
aq. (100 ml.times.2), dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude product was chromatographed on
silica (AcOEt.fwdarw.AcOEt/-MeOH=80/1) to yield the title compound.
MS:355.2
C. 2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)acetic acid (3)
[0459] To a solution of the product of step B (0.416 g, 1.17 mmol)
in 1,4-dioxane (24 ml) and MeOH (24 ml), 0.13 N LiOH (28 ml, 3.6
mmol) was added, and the mixture was heated to reflux for
overnight. The reaction was cooled to r.t. and AcOEt (400 ml) was
added and washed with sat'd NaCl (400 ml.times.5), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to yield
the title compound. MS: 327.1
D.
(R)-2-(7-Oxo-4-tosyl-1,4-diazepan-5-yl)-N-(6-(piperidin-1-ylmethyl)-1,2-
,3,4-tetrahydronaphthalen-1-yl)acetamide
[0460] To a mixture of 2-(7-oxo-4-tosyl-1,4-diazepan-5-yl)acetic
acid (0.115 g, 0.352 mmol),
(R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine
(0.0945 g, 0.387 mmol) and HOBt (<5% H.sub.2O, .about.0.398
mmol) in DMF (3.0 ml) was added EDCI*HCl (0.0805 g, 0.420 mmol),
and stirred overnight under N.sub.2. AcOEt (60 ml) was added and
washed with sat'd NaHCO.sub.3 aq. (60 ml.times.3) and sat'd NaCl
aq. (60 ml.times.3), dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude product was chromatographed on
silica (CH.sub.2Cl.sub.2/MeOH with 2N NH.sub.3=10/1) to yield the
title compound. MS: 553.1
EXAMPLE 25
##STR00066##
[0461]
(R)-2-(5-oxo-1-tosylpiperazin-2-yl)-N-(6-(piperidin-1-ylmethyl)-1,2-
,3,4-tetrahydronaphthalen-1-yl)acetamide
A. Preparation of Ethyl
4-(2-(benzyloxycarbonyl)acetamido)-3-oxobutanoate
[0462] 2-(2-(benzyloxycarbonyl)acetamido)acetic acid (1.0 g, 3.75
mmol) and 1,1'-carbonyldiimidazole (730 mg, 4.5 mmol, 1.2 equiv)
were stirred in THF (10 mL) at room temperature for 1 h and
subsequently cooled to -78.degree. C. In a separate oven-dried
round-bottomed flask, ethyl acetate (1.9 mL, 19.5 mmol, 5.2 equiv)
in THF (5 mL) was cooled to -78.degree. C. and treated with a
dropwise addition of Lithium bis(trimethylsilyl)amide (20 mL of a
1.0 M solution in THF, 5.3 equiv, 19.8 mmol). After 90 min, the
acid imidazolide solution was transferred to this flask via
cannula. The reaction was warmed to room temperature over 75 min,
quenched with saturated ammonium chloride solution (10 mL) and
extracted with ethyl acetate (2.times.20 mL). The combined organic
layers were dried over MgSO.sub.4, concentrated and purified on
silica gel using 80% ethyl acetate in hexane as the eluant,
affording ethyl 4-(2-(benzyloxycarbonyl)acetamido)-3-oxobutanoate.
MS: 337.2 (M+H).sup.+.
B. Preparation of Ethyl 2-(5-oxo-1-tosylpiperazin-2-yl)acetate
[0463] A solution of ethyl
4-(2-(benzyloxycarbonyl)acetamido)-3-oxobutanoate (630 mg, 1.87
mmol) in dioxane (25 mL) was treated with Pd/C (10%, 100 mg) and
stirred under an atmosphere of hydrogen at room temperature for 24
h. The catalyst was filtered through celite, the filtrate
concentrated, dissolved in 1,2-dichloroethane (25 mL), treated with
sodium cyanoborohydride (352 mg, 5.61 mmol, 3.0 equiv) and zinc
(II) chloride (3.8 mL of a 0.5 M solution in THF, 1.87 mmol, 1.0
equiv). The reaction was heated to 50.degree. C. for 2 h, cooled to
room temperature and concentrated in vacuo. The crude reaction
mixture was dissolved in 1:1 dioxane:water (40 mL) and
p-toluenesulfonyl chloride (680 mg, 3.74 mmol, 2.0 equiv) and
sodium carbonate (1.9 g, 18 mmol, 10.0 equiv) were added while
stirring at room temperature. After 4 h, the reaction was diluted
with ethyl acetate (50 mL) and washed with HCl solution (10%),
water, brine, dried over MgSO.sub.4, concentrated and purified on
silica gel using 4% methanol in methylene chloride as eluant,
affording ethyl 2-(5-oxo-1-tosylpiperazin-2-yl)acetate. MS: 341.2
(M+H).sup.+.
C. Preparation of 2-(5-Oxo-1-tosylpiperazin-2-yl)acetic acid. Ethyl
2-(5-oxo-1-tosylpiperazin-2-yl)acetate
[0464] (500 mg, 1.47 mmol) in 4:1 THF:water (10 mL) was mixed with
LiOH.H.sub.2O (75 mg, 1.76 mmol, 1.2 equiv) and stirred at room
temperature for 1 h. The reaction was quenched with Dowex-50 acidic
resin, filtered and concentrated to afford
2-(5-oxo-1-tosylpiperazin-2-yl)acetic acid. MS: 313.2
(M+H).sup.+.
D. Preparation of
(R)-2-(5-oxo-1-tosylpiperazin-2-yl)-N-(6-(piperidin-1-ylmethyl)-1,2,3,4-t-
etrahydronaphthalen-1-yl)acetamide
[0465] Coupling of 2-(5-oxo-1-tosylpiperazin-2-yl)acetic acid with
(R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine
was conducted in the usual way with standard peptide coupling
reagents as exemplified previously, to afford the title compound.
MS: 539.2 (M+H).sup.+.
EXAMPLE 26
##STR00067##
[0466]
N--((R)-6-((R,S)-1-(isobutylamino)ethyl)-1,2,3,4-tetrahydronaphthal-
en-1-yl)-2-((R)-3-oxo-1-tosylpiperazin-2-yl)acetamide
Step A
Preparation of
(6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid
tert-butyl ester
[0467] A mixture of
(5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanol (2.50 g, 14.1
mmol, 1.0 eq) and di-tert-butyl dicarbonate (Aldrich, 3.69 g, 16.9
mmol, 1.2 eq) and triethylamine (Aldrich, 2.85 g, 28.2 mmol, 2.0
eq) in CH.sub.2Cl.sub.2 (60 mL) was stirred at room temperature
overnight. The reaction was quenched with H.sub.2O (100 mL) and
extracted with CH.sub.2Cl.sub.2 (100 mL.times.3). The extract phase
was washed with saturated NaCl, dried over Na.sub.2SO.sub.4,
filtered and concentrated. Flash column chromatography (silica gel,
0-35% EtOAc-Hexane) afforded the title compound as a white solid.
MS (ESI, pos. ion) m/z: 278 (M+1).
Step B
Preparation of
(6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid
tert-butyl ester
[0468] A mixture of
(6-hydroxymethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid
tert-butyl ester (3.16 g, 11.4 mmol, 1.0 eq) and MnO.sub.2
(Aldrich, 12.9 g, 148.3 mmol, 13 eq) in CH.sub.2Cl.sub.2 (110 mL)
was stirred at room temperature overnight. The reaction mixture was
allowed to pass through a pad of Celite and the pad was washed with
CH.sub.2Cl.sub.2 (100 mL.times.2). The concentration of the
filtrate afforded the title compound as a white sticky semisolid.
MS (ESI, pos. ion) m/z: 298 (M+Na).
Step C
Preparation of
[6-(1-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-carbamic
acid tert-butyl ester
[0469] To a solution of
(6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid
tert-butyl ester (2.80 g, 10.2 mmol, 1.0 eq) in THF (100 mL) at
-78.degree. C. was added a solution of MeMgBr [Aldrich, 1.4 M in
toluene/THF (3:1), 29 mL, 40.7 mmol, 4.0 eq] slowly. The reaction
mixture was stirred at -78.degree. C. for 20 min, warmed up to room
temperature and stirred at room temperature for 2 h. The reaction
was quenched with saturated NaHCO.sub.3 (120 mL), and the crude
product was extracted with EtOAc (100 mL.times.3). The extract
phase was washed with saturated NaCl, dried over Na.sub.2SO.sub.4,
filtered and concentrated. The title compound was obtained as a
white solid. MS (ESI, pos. ion) m/z: 292 (M+1).
Step D
Preparation of
(6-acetyl-1,2,34-tetrahydro-naphthalen-1-yl)-carbamic acid
tert-butyl ester
[0470] A mixture of
[6-(1-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-carbamic
acid tert-butyl ester (2.63 g, 9.04 mmol, 1.0 eq) and MnO.sub.2
(Aldrich, 10.2 g, 117.5 mmol, 13 eq) in CH.sub.2Cl.sub.2 (100 mL)
was stirred at room temperature overnight. The reaction mixture was
allowed to pass through a pad of Celite and the pad was washed with
CH.sub.2Cl.sub.2 (100 mL.times.2). The concentration of the
filtrate afforded the title compound as a white sticky semisolid.
MS (ESI, pos. ion) m/z: 290 (M+1).
Step E
Preparation of
N--((R)-6-acetyl-1,2,34-tetrahydronaphthalen-1-yl)-2-((R)-3-oxo-1-tosylpi-
perazin-2-yl)acetamide
[0471] A mixture of
(6-acetyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid
tert-butyl ester (463 mg, 1.6 mmol, 1.0 eq) in HCl/EtOAc (4.7 M, 20
mL) was stirred at room temperature for 5 h. The solvent was
removed with a rotary evaporator, and the resulting
1-(5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone hydrogen
chloride was dried in vacuo.
[0472] A mixture of
1-(5-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone hydrogen
chloride, (R)-2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid (500 mg,
1.6 mmol, 1.0 eq), EDCI (Aldrich, 552 mg, 2.88 mmol, 1.8 eq), HOBt
(Aldrich, 43 mg, 0.32 mmol, 0.2 eq) and diisobutylethylamine
(Aldrich, 416 mg, 3.2 mmol, 2.0 eq) in CH.sub.2Cl.sub.2 (20 .mu.L)
was stirred at room temperature overnight. The reaction was
quenched with 5% HCL (80 mL). The crude product was extracted with
CH.sub.2Cl.sub.2 (80 mL.times.3). The extract phase was washed with
saturated NaCl, dried over Na.sub.2SO.sub.4, filtered and
concentrated. Flash column chromatography (silica gel, 0-5%
MeOH--CH.sub.2Cl.sub.2) afforded the title compound as a white
solid. MS (ESI, pos. ion) m/z: 484 (M+1).
Step F
Preparation of
N--((R)-6-((R,S)-1-(isobutylamino)ethyl)-1,2,3,4-tetrahydronaphthalen-1-y-
l)-2-((R)-3-oxo-1-tosylpiperazin-2-yl)acetamide
[0473] A mixture of
N--((R)-6-acetyl-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-3-oxo-1-tosylp-
iperazin-2-yl)acetamide (120 mg, 0.248 mmol, 1.0 eq), isobutylamine
(Aldrich, 145 mg, 1.99 mmol, 8.0 eq), NaBH(OAc).sub.3 (Aldrich, 158
mg, 0.744 mmol, 3.0 eq) and glacial acetic acid (J, T. Baker, 30
mg, 0.496 mmol, 2.0 eq) in ClCH.sub.2CH.sub.2Cl (4 mL) was stirred
at room temperature for 3 days. The reaction was quenched with
saturated NaHCO.sub.3 (60 mL). The crude product was extracted with
CH.sub.2Cl.sub.2 (60 mL.times.3). The extract phase was washed with
saturated NaCl, dried over Na.sub.2SO.sub.4, filtered and
concentrated. Flash column chromatography (silica gel, 0-10%
MeOH--CH.sub.2Cl.sub.2) afforded the title compound as a white
solid. MS (ESI, pos. ion) m/z: 541 (M+1).
EXAMPLE 27
##STR00068##
[0474] tert-butyl
4-((R)-5-(2-((R,S)-3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahy-
dronaphthalen-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate
Preparation of tert-butyl
4-((R)-5-(2-((R,S)-3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahy-
dronaphthalen-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate
[0475] A mixture of
(R)-5-(2-(3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahydronaphth-
alen-2-yl trifluoromethanesulfonate (330 mg, 0.562 mmol, 1.0 eq),
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (ChemShop, 261 mg, 0.843 mmol, 1.5 eq) and
Pd(PPh.sub.3).sub.4 (Aldrich, 65 mg, 0.0562 mmol, 0.1 eq) in
toluene (3 mL), ethanol (0.7 mL) and aqueous NaHCO.sub.3 (1.0 M,
0.7 mL) was stirred under N.sub.2 at 80.degree. C. for 20 h. The
reaction mixture was allowed to cool down to room temperature and
diluted with saturated NaHCO.sub.3 (60 mL). The crude product was
extracted with EtOAc (60 mL.times.3). The extract phase was washed
with saturated NaCl, dried over Na.sub.2SO.sub.4, filtered and
concentrated.
[0476] The reaction was repeated under the same condition as
described above with
5-(2-((R,S)-3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahydronaph-
thalen-2-yl trifluoromethanesulfonate (900 mg, 1.53 mmol, 1.0 eq),
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (ChemShop, 710 mg, 2.3 mmol, 1.5 eq) and
Pd(PPh.sub.3).sub.4 (Aldrich, 177 mg, 0.153 mmol, 0.1 eq).
[0477] Purification of the combined product from the above two
experiments by flash column chromatography (silica gel, 0-7%
MeOH--CH.sub.2Cl.sub.2) afforded the title compound as a tan solid.
MS (ESI, pos. ion) m/z: 623 (M+1).
EXAMPLE 28
##STR00069##
[0478]
2-((R,S)-3-oxo-1-tosylpiperazin-2-yl)-N--((R)-6-(1,2,3,6-tetrahydro-
pyridin-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide
[0479] A mixture of tert-butyl
4-((R)-5-(2-((R,S)-3-oxo-1-tosylpiperazin-2-yl)acetamido)-5,6,7,8-tetrahy-
dronaphthalen-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.10 g,
1.77 mmol, 1.0 eq) in HCl/EtOAc (4.7 M, 20 mL) was stirred at room
temperature for 1 h. The reaction was quenched with saturated
NaHCO.sub.3 (100 mL). The product was extracted with
CH.sub.2Cl.sub.2 (100 mL.times.4). The extract phase was washed
with saturated NaCl, dried over Na.sub.2SO.sub.4 and filtered.
Concentration with a rotary evaporator afforded the title compound
as a yellow solid. MS (ESI, pos. ion) m/z: 523 (M+1).
EXAMPLE 29
##STR00070##
[0480]
N--((R)-6-(1-(cyclopropylmethyl)-1,2,3,6-tetrahydropyridin-4-yl)-1,-
2,3,4-tetrahydronaphthalen-1-yl)-2-((R,S)-3-oxo-1-tosylpiperazin-2-yl)acet-
amide
[0481] A mixture of
2-((R,S)-3-oxo-1-tosylpiperazin-2-yl)-N--((R)-6-(1,2,3,6-tetrahydropyridi-
n-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (97 mg, 0.19
mmol, 1.0 eq), cyclopropanecarbaldehyde (Aldrich, 20.3 mg, 0.29
mmo, 1.5 eq) and NaBH(OAc).sub.3 in ClCH.sub.2CH.sub.2Cl (2 .mu.L)
was stirred under N.sub.2 at room temperature overnight. The
reaction was quenched with saturated NaHCO.sub.3 (30 mL). The crude
product was extracted with CH.sub.2Cl.sub.2 (40 mL.times.3). The
extract phase was washed with saturated NaCl, dried over
Na.sub.2SO.sub.4, filtered and concentrated. Flash column
chromatography (silica gel, 0-10% MeOH--CH.sub.2Cl.sub.2) afforded
the title compound as a white solid. MS (ESI, pos. ion) m/z: 577
(M+1).
EXAMPLE 30
##STR00071##
[0482]
2-((R)-1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N--((R)-6-(2-
-(piperidin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide
A. Preparation of S)-tert-butyl
6-(iodomethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate
[0483] To a solution of (R)-tert-butyl
6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (415.5
mg, 1.5 mmol) in dichloromethane/ether (1:1, 30 mL) at room
temperature were added triphenylphosphine (590 mg, 2.25 mmol) and
imidazole (153 mg, 2.25 mmol). To this stirred solution was then
added iodine (571 mg, 2.25 mmol). After stirring for 20 min, the
reaction was quenched with 10% Na.sub.2S.sub.2O.sub.3 (15 mL) until
it became a clear two-phase solution. The aqueous phase was
extracted with ether. The combined organic phase was dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. Flash
chromatography (SiO.sub.2, hexane/CH.sub.2Cl.sub.2=3:1 to pure
CH.sub.2Cl.sub.2) afforded the title compound as a white solid.
B. Preparation of (R)-tert-butyl
6-(2-(1,3-dithian-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate
[0484] To a solution of 1,3-dithiane (1.01 g, 8.4 mmol) in 10 mL of
dry THF at -30.degree. C. was added dropwise 2.5M n-butyllithium in
hexane (3.36 mL, 8.4 mmol). After stirring at -20.degree. C. for
1.5 h, a solution of the iodide from the previous (542 mg, 1.4
mmole, azeotroped with benzene) in 10 mL of dry THF was added
dropwise at -20.degree. C. The reaction was stirred at -5.degree.
C. to 0.degree. C. for 1 h. It was then quenched with sat.
NH.sub.4Cl solution, extracted with EtOAc, dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. Flash
chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/hexane=1:1 to 2:1 to
CH.sub.2Cl.sub.2/EtOAc=100:3) afforded the title compound as a
white solid.
C. Preparation of
(R)-6-(2-(1,3-dithian-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine
[0485] To a solution of the above dithiane (146 mg, 0.385 mmol) in
5 mL of methanol at room temperature was added 4 N HCl in dioxane
(0.48 mL, 1.93 mmol). After stirring at room temperature for 2 h,
the reaction solution was evaporated to dryness. The residue was
treated with 0.5 mL of triethylamine and it was evaporated again in
vacuo. The crude product was azeotroped with benzene and directly
used in the next step.
D. Preparation of
N--((R)-6-((1,3-dithian-2-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-
-((R)-1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetamide
[0486] A solution of
(R)-2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetic acid
(1.98 g, 6.0 mmol), crude
(R)-6-(2-(1,3-dithian-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine
(1.8 g, 6.45 mmol), HOBt (892 mg, 6.6 mmol) and EDCI (1.265 g, 6.6
mmol) in 15 mL of DMF was stirred overnight at room temperature.
After quenching with Sat. NaHCO.sub.3 solution, the reaction
mixture was extracted with EtOAc/hexane (1:1, 200 mL.times.2). The
combined organic phase was washed brine, dried over
Na.sub.2SO.sub.4, and evaporated in vaco. Flash chromatography
(SiO.sub.2, hexane/EtOAc=2:1 to 3:2 to 1:1) gave the title compound
as a white solid. MS: 609.7 (M+1).
E. Preparation of
2-((R)-1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N--((R)-6-(2-oxoet-
hyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide
[0487] Dithiane from the above step (3.5 g, 5.56 mmol) and
CaCO.sub.3 (1.61 g, 16.08 mmol) were suspended in 60 mL of
THF/water (5:1). Then a solution of Hg(ClO.sub.4).sub.2 (4.28 g,
10.72 mmol) in 10 mL of water was added dropwise. After stirring at
room temperature for 1 h, the reaction mixture was filtered through
a silica gel pad with the help of EtOAc. The filtrate was
evaporated to dryness. Flash chromatography (SiO.sub.2,
hexane/EtOAc=3:2 to 1:2) gave the title compound as a white solid,
together with 230 mg of recovered starting material.
F. Preparation of
2-((R)-1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N--((R)-6-(2-(pipe-
ridin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide
[0488] To a solution of the product from step E (63 mg, 0.116 mmol)
and piperidine (20 mg, 0.23 mmol) in 1 mL of dichloroethane was
added sodium triacetoxyborohydride (49 mg, 0.23 mmol). After
stirring overnight at room temperature, the reaction solution was
diluted with EtOAc and washed with sat. NaHCO.sub.3 and brine. The
organic phase was dried over Na.sub.2SO.sub.4 and evaporated to
dryness in vaco. Flash chromatography (SiO.sub.2, EtOAc to
EtOAc/MeOH=100:10 to 100:12) afforded the title compound as a white
solid. MS: 573.2 (M+1).
EXAMPLE 31
##STR00072##
[0489]
R)-2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N-(6-(piperid-
in-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide
A. Preparation of (R)-tert-butyl
6-bromo-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate
[0490] To a solution of (t-Boc).sub.2O (3.28 g, 15 mmol) and
(R)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-amine (3.94 g, 15 mmol)
in DMF (10 mL) was added dropwise triethylamine (3.0 g, 30 mmol) at
0 C. After stirring 3 h at room temperature, the reaction solution
was diluted with EtOAc/Hexane (2:1), washed with water, dried over
Na.sub.2SO.sub.4 and evaporated to afford the title compound as a
white solid.
B. Preparation of (R)-tert-butyl
6-vinyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate
[0491] A mixture of the above product (1.63 g, 5 mmol),
vinyltributyltin (2.2 g, 7 mmol), tri-t-butylphosphine (101 mg, 0.5
mmol), triethylamine (1.0 g, 10 mmol) and Pd.sub.2(dba).sub.3 (229
mg, 0.25 mmol) in toluene (2 mL) was heated at 80.degree. C. in
microwave for 20 min. After cooling down to room temperature, the
reaction solution was quenched with sat. NH.sub.4Cl, extracted with
EtOAc, dried, and evaporated to dryness. Flash chromatography
(SiO.sub.2, hexane to hexane/DCM=2:1 to 1:1 to pure DCM) afforded
the title compound as a white solid.
C. Preparation of (R)-tert-butyl
6-vinyl-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate
[0492] TFA (0.7 mL, 9.07 mmol) was added dropwise to a solution of
the product from step A (620 mg, 2.27 mmol) in DCM (10 mL). After
stirring at room temperature for 4 h, the reaction mixture was
evaporated to dryness. NEt.sub.3 (1 mL) was added to the residue
and evaporated again to give the crude product, which was directly
used in the next step.
D. Preparation of
(R)-2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N-(6-vinyl-1,2,3,4-
-tetrahydronaphthalen-2-yl)acetamide
[0493] A solution of
2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)acetic acid (332
mg, 1 mmol), crude 48999-36 (190 mg, 1.1 mmol), II (135 mg, 1 mmol)
and III (191 mg, 1 mmol) in 1 mL of DMF was stirred overnight at
room temperature. After quenching with sat. NaHCO.sub.3 solution,
the reaction mixture was extracted with EtOAc. The combined organic
phase was washed brine, dried over Na.sub.2SO.sub.4, and evaporated
in vaco. Flash chromatography (SiO.sub.2, EtOAc to EtOAc/MeOH=100:3
to 100:5 to 100:6) gave the title compound as a white solid.
E. Preparation of
(R)-2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N-(6-formyl-1,2,3,-
4-tetrahydronaphthalen-2-yl)acetamide
[0494] To a solution of the product of step D. (280 mg, 0.575 mmol)
in 13 mL of a mixture solvent t-butanol/THF/water (10:2:1) was
added NMO (135 mg, 1.15 mmol), followed by OsO.sub.4 (2.5% w/w in
t-butanol, 175 mg, 0.017 mmol). After stirring overnight at room
temperature, 4 mL of pH 7.2 phosphate buffer was added, followed by
NaIO.sub.4 (615 mg, 2.875 mmol). After stirring for 5 h at room
temperature, the reaction solution was diluted with EtOAc and
washed with brine. The organic phase was dried over
Na.sub.2SO.sub.4 and evaporated to dryness in vaco. Flash
chromatography (SiO.sub.2, EtOAc/hexane=1:1) afforded the title
compound as a white solid.
Preparation of
(R)-2-(1-(4-chlorophenylsulfonyl)-3-oxopiperazin-2-yl)-N-(6-(piperidin-1--
ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide
[0495] To a solution of the product of the previous step (60 mg,
0.123 mmol) and piperidine (20 mg, 0.23 mmol) in 1 mL of
dichloroethane was added sodium triacetoxyborohydride (49 mg, 0.23
mmol). After stirring overnight at room temperature, the reaction
solution was diluted with EtOAc and washed with sat. NaHCO.sub.3
and brine. The organic phase was dried over Na.sub.2O.sub.4 and
evaporated to dryness in vaco. Flash chromatography (SiO.sub.3,
EtOAc to EtOAc/MeOH=100:15 to 100:20 to EtOAc/2.0 M NH.sub.3 in
MeOH=100:15 to 100:20) afforded the title compound as a white
solid. MS: 559.2 (M+1).
EXAMPLE 32
##STR00073##
[0496]
N--((R)-6-(3-aminopropyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-
-3-oxo-1-tosylpiperazin-2-yl)acetamide
A. Preparation of (R,E)-tert-butyl
6-(2-cyanovinyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate
[0497] To a 300 mL flame dry 3-neck round bottom flask was added
diethyl cyanophosphonate (14.86 g, 83.89 mmol) and THF (100 mL).
After cooled to 0.degree. C., sodium bis(trimethyl-silyl)amide
(72.0 mL, 71.90 mmol) was added dropwise via the addition funnel.
After stirred for 30 min at 0.degree. C., It was cooled to
-78.degree. C. followed by adding
(R)-tert-butyl-6-formyl-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate
(6.6 g, 23.97 mmol) in THF (60 mL) dropwise via the addition
funnel. It was stirred for 18 h. Acetone cyanohydrin (3.1 mL, 33.48
mmol) was then added dropwise via the addition funnel. The
resulting mixture was warmed up to rt and continued to stir for 18
h. The reaction mixture was quenched with sat. NH.sub.4Cl. Solvent
was evaporated in vacuo. The residue was extracted with EtOAc. The
organic layer was washed with H.sub.2O, brine, dried over
MgSO.sub.4 and removed solvent. The crude product was purified by
chromatography on silica gel. Elution with Hex:EtOAc mixture
(70:30) gave final compound. MS m/z: 299.12 (M+H). Calc'd. for
C.sub.18H.sub.22N.sub.2O.sub.2-298.23.
B.
(R,E)-3-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)acrylonitrile
[0498] The product from the previous step was deprotected using HCl
in dioxane to give the title compound in quantitative yield. MS
m/z: 199.12 (M+H). Calc'd. for C.sub.13H.sub.14N.sub.2-198.23.
C.
N--((R)-6-((E)-2-cyanovinyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)--
3-oxo-1-tosylpiperazin-2-yl)acetamide
[0499] To a 250 mL round bottom flask was added
(R)-2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid (2.0 g, 6.40 mmol),
followed by
(R,E)-3-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)acrylonitrile
(1.26 g, 6.40 mmol), dry CH.sub.2Cl.sub.2 (70 mL), HATU (1.2 mg,
3.20 mmol), EDCI (1.4 g, 7.04 mmol) and hunig base (2.2 mL, 12.80
mmol). The resulting mixture was stirred at rt for 20 h. Removed
solvent to dryness. The residue was purified by chromatography on
silica gel. Elution with CH.sub.2Cl.sub.2:MeOH mixture (95:5) gave
final compound (2.1 g, 66%). MS m/z: 493.3 (M+H). Calc'd. for
C.sub.26H.sub.28N.sub.4O.sub.4S-492.6.
D.
N--((R)-6-(3-aminopropyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-3-o-
xo-1-tosylpiperazin-2-yl)acetamide
[0500] To a solution of
N--((R)-6-((E)-2-cyanovinyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-3--
oxo-1-tosylpiperazin-2-yl)acetamide (1.6 g, 3.25 mmol) in
EtOH:CHCl.sub.3=20:1 solvent mixture (40 mL) was added PtO.sub.2
(221.0 mg, 0.97 mmol). It was flushed with N.sub.2 followed by
evacuating--this was done 3 times to ensure free of air and
N.sub.2. After last evacuation, H2 balloon was inserted. It was
stirred at rt under H.sub.2 for 20 h. The solvent was separated
from the catalyst by passing through celite. Solvent was then
removed to give the final product. MS m/z: 499.1 (M+H). Calc'd. for
C.sub.26H.sub.34N.sub.4O.sub.4S-498.6.
EXAMPLE 33
##STR00074##
[0501]
N--((R)-6-(3-(diisobutylamino)propyl)-1,2,3,4-tetrahydronaphthalen--
1-yl)-2-((R)-3-oxo-1-tosylpiperazin-2-yl)acetamide
[0502] To a solution of
N--((R)-6-(3-aminopropyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-3-oxo-
-1-tosylpiperazin-2-yl)acetamide (650.0 mg, 1.3 mmol) in dry DCM
(15 mL) was added isobutyraldehyde (240.0 .mu.L, 2.61 mmol) and
HOAc (2 drops). The resulting mixture was stirred at rt under
N.sub.2. After 1 h, MS showed the formation of imine;
NaBH(OAc).sub.3 (830.0 mg, 3.91 mmol) was then added. The resulting
mixture was stirred for 10 min. The reaction mixture was quenched
with sat. NaHCO.sub.3. The organic layer was dried over MgSO.sub.4
and evaporated in vacuo. The crude solid was purified by
chromatography on silica gel. Elution with DCM:MeOH(2M NH.sub.3)
mixture (95:5) gave final compound. MS m/z: 611.21 (M+H). Calc'd.
for C.sub.34H.sub.50N.sub.4O.sub.4S-610.87. Examples numbers marked
with "*" indicate the stereochemical bond in the alpha position on
the piperazinone ring is predominantly in the R configuration.
[0503] The following compounds were made using the methods
described in Examples 1-17.
TABLE-US-00001 ##STR00075## No. R.sup.2 R.sup..alpha. X MW MS data
34 5-chlorobenzo[b]thiophen-2-yl 1-piperidinyl CH.sub.2 615.215
614.7, 616.7 35 4-pentafluoroethylphenyl tert-butylamino CH.sub.2
630.675 631.1 36 3-methyl-5-chlorobenzo[b]- tert-butylamino O
619.203 619 thiophen-2-yl 37 3-methyl-5-chlorobenzo[b]-
cyclopentylamino CH.sub.2 629.24 629 thiophen-2-yl 38
3-trifluoromethyl-4- tert-butylamino CH.sub.2 594.695 595.2
methylphenyl 39 3-trifluoromethyl-4- 1-piperidinyl CH.sub.2 606.705
607.2 methylphenyl 40 3-trifluoromethyl-4- isobutylamino CH.sub.2
594.695 595.2 methylphenyl 41 3-trifluoromethyl-4- 2,2-dimethyl-
CH.sub.2 608.72 609.2 methylphenyl propylamino 42
3,5-dibromo-4-methylphenyl tert-butylamino CH.sub.2 684.49 685.1 43
3,5-diD-4-methylphenyl tert-butylamino CH.sub.2 528.71 529.2 44
3-trifluoromethyl-4- hydroxy CH.sub.2 539.57 540.2 methylphenyl 45
3-trifluoromethyl-4- tert-butylamino CH.sub.2 615.115 615.2
chlorophenyl 46 4-methylphenyl 2,2-dimethyl- CH.sub.2 540.725 541.4
propylamino 47 3-trifluoromethylphenyl piperidin-1-yl CH.sub.2
578.695 579 48 2,5-dimethyl-4-chlorophenyl 4-methylpiperazin-1-yl O
604.17 605.3 49 2,5-dimethyl-4-chlorophenyl tetrahydropyran-4- O
605.15 606.2 ylamino 50 2,5-dimethyl-4-chlorophenyl
(cyclopropylmethyl)- O 575.125 576.3 amino 51
2,5-dimethyl-4-chlorophenyl cyclopentylamino O 589.155 590.4 52
2,5-dimethyl-4-chlorophenyl cyclopentylamino CH.sub.2 587.18 588.3
53 2,5-dimethyl-4-chlorophenyl 4-methylpiperazin-1-yl CH.sub.2
602.195 603.4 54 2,5-dimethyl-4-chlorophenyl tetrahydropyran-4-
CH.sub.2 603.18 604.3 ylamino 55 2,5-dimethyl-4-chlorophenyl
(cyclopropylmethyl)- CH.sub.2 573.155 574.2 amino 56
4-trifluoromethoxyphenyl tert-butylamino CH.sub.2 596.665 597.2 57
4-trifluoromethoxyphenyl tert-butylamino O 598.64 599 58
4-trifluoromethoxyphenyl isobutylamino CH.sub.2 596.665 597.2 59
4-trifluoromethoxyphenyl (cyclopropylmethyl)- CH.sub.2 594.65 595.2
amino 60 4-trifluoromethoxyphenyl isopropylamino CH.sub.2 582.64
583.2 61 4-trifluoromethoxyphenyl cyclobutylamino CH.sub.2 594.65
595.2 62 4-trifluoromethylphenyl tert-butytamino CH.sub.2 580.67
581.2 63 4-trifluoromethylphenyl piperidin-1-yl CH.sub.2 592.68
593.3 64 4-trifluoromethylphenyl isobutylamino CH.sub.2 580.67
581.2 65 4-trifluoromethylphenyl cyclopentylamino CH.sub.2 592.68
593.3 66 4-methylphenyl tert-butylamino O 563.115 563.4, 564.4 67
4-methylphenyl 4-methylpiperazin-1-yl CH.sub.2 553.724 554.1 68
4-methylphenyl cyclopentylamino O 540.681 541.2 69
3,4-dichlorophenyl tert-butylamino CH.sub.2 609.615 609 70
3,4-dichlorophenyl tert-butylamino CH.sub.2 581.56 581 71
3,4-dichlorophenyl piperidin-1-yl CH.sub.2 593.575 593 72
3,4-dichlorophenyl 4-fluoropiperidin-1-yl CH.sub.2 611.565 611 73
3,4-dichlorophenyl pyrrolidin-1-yl CH.sub.2 579.545 579 74
3,4-dichlorophenyl isobutylamino CH.sub.2 581.56 581 75
2,5-dichlorophenyl piperidin-1-yl CH.sub.2 593.575 593 76
2,5-dimethyl-4-chlorophenyl piperidin-1-yl CH.sub.2 587.18 587 77
3-methylphenyl piperidin-1-yl CH.sub.2 538.71 539 78 2-methylphenyl
piperidin-1-yl CH.sub.2 538.71 539 79 3-chloro-4-fluorophenyl
piperidin-1-yl CH.sub.2 577.12 577 80 4-tert-butylphenyl
piperidin-1-yl CH.sub.2 580.79 581 81 2,4-dichlorophenyl
piperidin-1-yl CH.sub.2 593.58 593 82 2-chlorophenyl piperidin-1-yl
CH.sub.2 559.13 559 83 phenyl piperidin-1-yl CH.sub.2 524.68 525 84
3-trifluorophenyl piperidin-1-yl CH.sub.2 592.68 593 85
3-bromo-5-chlorothiophen-2-yl piperidin-1-yl CH.sub.2 644.05 645 86
4-methylphenyl piperidin-1-yl CH.sub.2 538.71 539.7 87
4-methylphenyl 2-(pyrrolidin-1- CH.sub.2 567.751 568.5
yl)ethylamino 88 4-methylphenyl 4-fluoropiperidin-1-yl CH.sub.2
556.699 557.2 89 4-methylphenyl morpholin-4-yl CH.sub.2 540.681
541.4 90 4-methylphenyl isopentylamino CH.sub.2 540.725 541.4 91
4-methylphenyl isopentylamino CH.sub.2 554.752 555.4 92
4-methylphenyl cyclohexylmethylamino CH.sub.2 566.765 567.4 93
4-methylphenyl 2-(2-fluorophenyl)- CH.sub.2 592.73 593.2 ethylamine
94 4-methylphenyl benzylamino CH.sub.2 560.715 561.4 95
4-methylphenyl piperidin-1-ylmethyl CH.sub.2 552.735 553.2 96
4-chlorophenyl piperidin-1-yl CH.sub.2 559.13 559.2 97
4-chlorophenyl morpholin-4-yl CH.sub.2 561.1 561.2 98
4-chlorophenyl 4-methylpiperazin-1-yl CH.sub.2 574.14 574.2 99
4-chlorophenyl 2,2-dimethyl- CH.sub.2 561.145 561.2 propylamino 100
4-chlorophenyl isobutylamino CH.sub.2 547.115 547.2 101
4-chlorophenyl benzylamino CH.sub.2 581.135 581.2 102
4-chlorophenyl 2-phenylethylamino CH.sub.2 595.16 595.2 103
4-chlorophenyl 2-(2-fluorophenyl)- CH.sub.2 613.15 613.2 ethylamino
104 4-chlorophenyl cyclobutylamino CH.sub.2 545.1 545.2 105
4-chlorophenyl 2-(pyrrolidin-1- CH.sub.2 588.17 588.2 yl)ethylamino
106 4-chlorophenyl isopentylamino CH.sub.2 561.145 561.2 107
4-chlorophenyl 4-fluoropiperidin-1-yl CH.sub.2 577.12 577.2 108
4-chlorophenyl (naphth-1-yl- CH.sub.2 631.195 631.2 methyl)amino
109 4-chlorophenyl 2-(2-methoxyphenyl)- CH.sub.2 625.185 625.2
ethylamino 110 4-chlorophenyl H CH.sub.2 491.01 491.2 111
4-methylphenyl 2-methoxyethylamino CH.sub.2 528.67 529.2 112
4-methylphenyl 2-hydroxymethylamino CH.sub.2 514.644 515.2 113
3-methyl-5-chlorothiophen-2- tert-butylamino CH.sub.2 617.23 617 yl
##STR00076## No. R.sup.2 R.sup..alpha. X MW MS data 114
3,5-dibromo-4-methylphenyl 2,2-dimethyl- CH.sub.2 698.517 699
propylamino 115 4-methylphenyl 4-fluoropiperidin-1-yl CH.sub.2
556.699 557.2 116 4-methylphenyl piperidin-1-yl O 540.681 541 117
4-methylphenyl piperidin-1-yl CH.sub.2 538.709 539.2 118
3,4-dichlorophenyl tert-butylamino O 617.979 617.2, 619.2 119
4-methylphenyl tert-butylamino O 528.67 529 120
5-chlorothiophen-2-yl 4-methylpiperazin-1-yl O 582.143 583 121
4-methylphenyl 4-methylpiperazin-1-yl O 555.696 556 122
4-chlorophenyl piperidin-1-yl CH.sub.2 559.128 559.2 123
4-chlorophenyl tert-butylamino CH.sub.2 547.117 547.2 124
4-chlorophenyl 2,2-dimethyl- CH.sub.2 561.143 561.2 propylamino 125
4-chlorophenyl 2,2-dimethyl- O 563.115 563.2 propylamino 126
4-chlorophenyl isobutylamino CH.sub.2 547.117 547.2 127
4-chlorophenyl cyclobutylamino CH.sub.2 545.101 545.2 128
4-methylphenyl tert-butylamino CH.sub.2 526.698 527.4 129
4-methylphenyl 2,2-dimethyl- CH.sub.2 540.725 541.4 propylamino 130
4-methylphenyl isobutylamino CH.sub.2 526.698 527.2 131
4-methylphenyl isopentylamino CH.sub.2 540.725 541.2 132
4-methylphenyl (S)-sec-butylamino CH.sub.2 526.698 527.2 133
4-methylphenyl 2-(pyrrolidin-1- CH.sub.2 567.751 568.2
yl)ethylamino 134 4-methylphenyl cyclohexylmethylamino CH.sub.2
566.763 567.2 135 4-methylphenyl cyclohexylamino CH.sub.2 552.736
553.2 136 4-methylphenyl (cyclopropyl- CH.sub.2 524.682 525.2
methyl)amino 137 4-methylphenyl morpholin-4-yl CH.sub.2 540.681
541.2 138 4-methylphenyl cyclopentylamino CH.sub.2 538.709 539.2
139 4-methylphenyl cyclopropylamino CH.sub.2 510.656 511.2 140
4-methylphenyl azepan-1-yl CH.sub.2 552.736 553.2 141
4-methylphenyl 3-hydroxypiperidin-1-yl CH.sub.2 554.71 555.2
##STR00077## No. R.sup.2 R.sup..alpha. X MW MS data 142
4-methylphenyl tert-butylamino CH.sub.2 526.698 527.4 143
3,5-dibromo-4-methylphenyl tert-butylamino CH.sub.2 684.49 685
##STR00078## No. R.sup.2 R.sup..alpha. X MW MS data 144
2,4,6-trimethylphenyl tert-butylamino O 591.17 591.3, 593.3 145
3,4-dichlorophenyl tert-butylamino O 617.98 617.2 146 naphth-2-yl
tert-butylamino O 599.15 599.2, 601.2 ##STR00079## No. R.sup.2
R.sup..beta. X MW MS data 147 3,4-dichlorophenyl H CH.sub.2 496.413
496 148 4-methylphenyl H SO.sub.2 491.587 492.4 The following
compounds were made using the methods described in Example 26.
##STR00080## No. R.sup.2 R.sup..beta. X MW MS data 149
4-methylphenyl (R)--CH(CH.sub.3)-- CH.sub.2 540.725 541
N(H)isobutyl 150 4-methylphenyl (R)--CH(CH.sub.3)-- CH.sub.2
552.735 N(H)cyclopentyl
[0504] The following compounds were made using the methods
described in Examples 22, 23 and 27.
TABLE-US-00002 ##STR00081## No. R.sup.2 R.sup..beta. X MW MS data
151 4-methylphenyl ##STR00082## CH.sub.2 622.783 623 152
4-methylphenyl 3,6-dihydro-2H- CH.sub.2 522.667 523 pyridin-4-yl
153 4-methylphenyl ##STR00083## CH.sub.2 576.758 577 154
4-methylphenyl ##STR00084## CH.sub.2 578.774 579 155 4-methylphenyl
##STR00085## CH.sub.2 564.747 565 156 4-methylphenyl ##STR00086##
CH.sub.2 606.82 607 157 4-methylphenyl ##STR00087## CH.sub.2
618.838 619 158 4-methylphenyl ##STR00088## CH.sub.2 612.791 613
159 4-methylphenyl pyridin-3-yl CH.sub.2 518.635 519.4 160
4-methylphenyl 3-(isobutylamino) CH.sub.2 550.72 551.3
prop-1-yn-1-yl 161 4-methylphenyl 3-cyanophenyl CH.sub.2 542.655
543.2 162 4-methylphenyl piperidin-3-yl CH.sub.2 524.68 525.3 163
4-methylphenyl pyridin-2-yl CH.sub.2 518.635 519.2 164
4-methylphenyl piperidin-2-yl CH.sub.2 524.68 525.3 165
4-methylphenyl 2-(3-methyl-1,2,4- CH.sub.2 599.71 600.5
oxadiazol-5-yl) phenyl 166 4-methylphenyl 1-(pyrrolidin-1- CH.sub.2
550.72 551 ylmethyl)ethen-1-yl 167 4-methylphenyl 3-carbamoylphenyl
CH.sub.2 560.67 561 168 4-methylphenyl 3- CH.sub.2 575.685 576
(methoxycarbonyl)- phenyl 169 4-methylphenyl 3-acetamidophenyl
CH.sub.2 574.7 575 170 4-methylphenyl 3- CH.sub.2 595.74 596
methyl- sulfonylphenyl 171 4-methylphenyl 3-(hydroxymethyl)-
CH.sub.2 547.675 548 phenyl 172 4-methylphenyl 3-(cyclobutylamino-
CH.sub.2 600.78 601 methyl)phenyl 173 4-methylphenyl
3-carboxyphenyl CH.sub.2 561.655 562 174 4-methylphenyl 3-fluoro-4-
CH.sub.2 579.645 580 carboxyphenyl 175 4-methylphenyl
3-(isobutylamino- CH.sub.2 602.795 603 methyl)phenyl 176
4-methylphenyl 3- CH.sub.2 614.805 615 (cyclopentylamino-
methyl)phenyl 177* 4-methylphenyl 1-(piperidin-1- CH.sub.2 564.747
565 ylmethyl)ethen-1-yl 178 4-methylphenyl 2- CH.sub.2 525.625
526.4 (methoxycarbonyl)- ethenyl
[0505] The following compounds were made using the methods
described in Example 25.
TABLE-US-00003 ##STR00089## MS No. R.sup.2 R.sup..beta. X MW data
179 4-methylphenyl piperidin-1- CH.sub.2 538.71 539.2 ylmethyl 180
4-methylphenyl 1-(piperidin-1- CH.sub.2 564.745 565.2
ylmethyl)ethenyl 181 3,4-dichlorophenyl piperidin-1- CH.sub.2
593.575 593.2, ylmethyl 595.2
[0506] The following compounds were made using the methods
described in Examples 32 and 33.
TABLE-US-00004 ##STR00090## MS No. R.sup.2 R.sup..beta. X MW data
182 4-methylphenyl 3-(isobutylamino)prop- CH.sub.2 554.75 555.4
1-yl 183 4-methylphenyl 3,3-bis(isobutylamino)- CH.sub.2 610.86
611.4 prop-1-yl 184 4-methylphenyl 3-((cyclopentylmethyl)- CH.sub.2
580.79 581.5 amino)prop-1-yl 185 2,5-dimethyl-4-chlorophenyl
3-aminopropyl CH.sub.2 547.115 548.3 186
2,5-dimethyl-4-chlorophenyl 3-((pyridin-4-yl- CH.sub.2 638.23 639.4
methyl)amino)prop-3-yl 187* 4-methylphenyl 3-aminopropyl CH.sub.2
498.645 499.5 188* 4-methylphenyl 3,3-bis(isobutylamino)- CH.sub.2
610.859 611.3 prop-1-yl 189* 4-methylphenyl 3-(isobutylamino)prop-
CH.sub.2 554.752 555.4 1-yl 190 2,5-dimethyl-4-chlorophenyl
3-((tetrhydro-2H-pyran- CH.sub.2 645.26 645.3
4-ylmethyl)amino)prop- 3-yl
[0507] The following compounds were made using the methods
described in Example 18.
TABLE-US-00005 ##STR00091## No. R.sup.2 R.sup..beta. X MW MS data
191 4-methylphenyl 1-(piperidin-1- CH.sub.2 564.745 565
ylmethyl)ethenyl 192 3-trifluoromethylphenyl 1-(piperidin- 1-
CH.sub.2 604.735 605 ylmethyl)ethenyl 193 4-methylphenyl
1-(piperidin-1- CH.sub.2 566.763 567 ylmethyl)ethyl 194
4-methylphenyl 1-((isobutylamino)- CH.sub.2 552.735 553
methyl)ethenyl 195 4-methylphenyl 1-((tert-butylamino)- CH.sub.2
552.735 553 methyl)ethenyl 196 4-methylphenyl 1-(((cyclopropyl-
CH.sub.2 550.72 551 methyl)amino)- methyl)ethenyl 197
4-methylphenyl 1-((cyclobutylamino)- CH.sub.2 550.72 551
methyl)ethenyl 198 4-methylphenyl 1-(azetidin-1- CH.sub.2 536.695
537 ylmethyl)ethenyl 199 4-methylphenyl 1-(4-fluoropiperidin-1-
CH.sub.2 582.735 583 ylmethyl)ethenyl 200 4-methylphenyl
1-((2,2-dimethylpropyl- CH.sub.2 566.765 567 amino)methyl)ethenyl
201* 4-methylphenyl 1-(pyrrolidin-1- CH.sub.2 550.72 551
ylmethyl)ethenyl
[0508] The following compounds were made using the methods
described in Example 30.
TABLE-US-00006 ##STR00092## MS No. R.sup.2 R.sup..beta. X MW data
202 4-chlorophenyl 2-piperidin-1-ylethyl CH.sub.2 573.155 573.2 203
4-chlorophenyl 2-(isobutylamino)ethyl CH.sub.2 561.145 561.2 204
4-chlorophenyl 2- CH.sub.2 561.145 561.2 (tert-butylamino)ethyl 205
4-chlorophenyl 2-((2,2-dimethyl- CH.sub.2 575.17 575.2
propyl)amino)ethyl 206 4-chlorophenyl 2-(cyclobutylamino)- CH.sub.2
559.13 559.2 ethyl 207 4-chlorophenyl 2-(benzylamino)ethyl CH.sub.2
595.16 595.2 208 4-chlorophenyl 2-morpholin-4-ylethyl CH.sub.2
575.125 575.1 209 4-chlorophenyl 2-pyrrolidin-1-ylethyl CH.sub.2
559.13 559.2 210 4-methylphenyl (cyclopentylamino)- CH.sub.2 538.71
539.4 methyl 211* 4-methylphenyl 2-piperidin-1-ylethyl CH.sub.2
552.736 553.2 212* 4-chlorophenyl 2-piperidin-1-ylethyl CH.sub.2
573.154 573.2
[0509] The following compounds were made using the methods
described in Example 31.
TABLE-US-00007 ##STR00093## MS No. R.sup.2 R.sup..beta. MW data 213
4-chlorophenyl piperidin-1-ylmethyl 559.13 559.2 214 4-chlorophenyl
2-((2-pyrrolidin-1- 602.195 588.2 ylethyl)amino)ethyl
[0510] The following compounds were prepared using a procedure
essentially as described above.
EXAMPLE 215
##STR00094##
[0511]
2-[5,5-Dimethyl-3-oxo-1-(2,4,6-trimethyl-benzenesulfonyl)-piperazin-
-2-yl]-N-(1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide
EXAMPLE 216
##STR00095##
[0512]
2-[3-Oxo-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-2-yl]-N-(-
1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide
EXAMPLE 217
##STR00096##
[0513]
2-[3-Oxo-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-2-yl]-N-(-
1,2,3,4-tetrahydro-naphthalen-1-yl)-acetamide
EXAMPLE 218
##STR00097##
[0514]
3-{[6-(1-Piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen--
1-ylcarbamoyl]-methyl}-4-(3-trifluoromethyl-benzenesulfonyl)-piperazine-1--
carboxylic acid tert-butyl ester
EXAMPLE 219
##STR00098##
[0515]
N-[6-(1-Piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-
-yl]-2-[1-(3-trifluoromethyl-benzenesulfonyl)-piperazin-2-yl]-acetamide
EXAMPLE 220
##STR00099##
[0516]
2-((2R)-3-oxo-1-((2,4,6-trimethylphenyl)sulfonyl)-2-piperazinyl)-N--
((1R)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide
EXAMPLE 221
##STR00100##
[0517]
N-((1R)-6-(hydroxymethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)-2-((2R-
)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)acetamide
[0518] The following examples can be made using the above examples
and generic schemes.
TABLE-US-00008 ##STR00101## R.sup.7' p piperidin-1-yl 2
(CH.sub.3).sub.2N-- 1 piperazin-1-yl 1 4-CH.sub.3-piperazin-1-yl 1
(Et.sub.2)N-- 1 (CH.sub.3)(Et)N-- 2 piperazin-1-yl 2
TABLE-US-00009 TABLE 3 ##STR00102## R.sup.7' p piperidin-1-yl 2
(CH.sub.3).sub.2N-- 1 piperazin-1-yl 1 4-CH.sub.3-piperazin-1-yl 1
(Et.sub.2)N-- 1 ##STR00103## 1 (CH.sub.3)(Et)N-- 2 piperazin-1-yl 2
##STR00104## R.sup.2 5,6,7,8-tetrahydronaphth-2-yl 2-quinolyl
phenyl 2-chlorophenyl 3-chlorophenyl 4-chlorophenyl 4-methoxyphenyl
3,5-dichlorophenyl 3-methoxyphenyl 3-fluorophenyl 3-biphenyl
4-biphenyl 3-methylphenyl 3-CF.sub.3-phenyl 2,4,6-trichlorophenyl
2,3,4-trichlorophenyl 2,4,5 -trichlorophenyl 3,4-dichlorophenyl
4-t-butylphenyl 1-naphthyl 4-methyl-1-naphthyl phenyl-ethenyl
benzo[1,2,5]oxadiazol-5-yl 5-(dimethylamino)naphth-1-yl
5-chloro-3-methylphenyl benzothiazol-2-yl
2,3,4,5,6-pentamethylphenyl 6-methoxy-2-naphthyl
3-chloro-4-methylphenyl 5-methoxy-3-methylbenzothien-2-yl
6-methoxy-3-methylbenzothien-2-yl 5 -chloro-3-methylbenzothien-2-yl
3-methylbenzothien-2-yl 2,4-dichloro-5-methylphenyl
3,5-dichloro-4-methylphenyl 2,4-dichloro-3-methylphenyl
7-methoxy-2-naphthyl 6-fluoroethoxy-2-naphthyl
3-methyl-5-trifluoromethoxybenzofur-2-yl
3-methyl-5-methoxybenzofur-2-yl 5-chloro-benzo[1,2,5]oxadiazol-4-yl
3-methyl-5-trifluoromethoxybenzothien-2-yl 6-ethoxy-2-naphthyl
2-Cl-4-CF.sub.3-phenyl 6-bromonaphthyl 3-methylbenzofur-2-yl
3-chlorobenzothien-2-yl 5-chloro-benzo[1,2,5]thiadiazol-4-yl
5-chloro-1,3-dimethyl-1H-pyrazol-4-yl 2,3-dichlorothien-5-yl
2,5-dichlorothien-3-yl 5-chloro-2-naphthyl 4-butoxyphenyl
3,5-di(trifluoromethyl)phenyl 5-(isoxazol-3-yl)thien-2-yl
2-chlorothien-5-yl 4-chloro-benzo[1,2,5]oxadiazol-7-yl
2,4-dichloro-6-methylphenyl 2,4,6-trimethylphenyl
2,5-dimethylphenyl 4-chloro-2,5-dimethylphenyl 2,5-dichlorophenyl
3,4-difluorophenyl 3-chloro-4-fluorophenyl
2-methyl-5-trifluoromethylphenyl 4-methylcyclohexyl
3,5-dimethylbenzothien-2-yl 5-fluoro-3-methylbenzothien-2-yl
5-methylbenzothien-2-yl 5-chloro-3-methylbenzofur-2-yl 3-pyridyl
##STR00105## R 3-isopropyl-7-(1-methylpiperidin-2-yl)chroman-4-yl
2,2-dimethyl-7-(1-methylpiperidin-2-yl)chroman-4-yl
7-(piperidin-2-yl)chroman-4-yl
2,2-dimethyl-7-(methylaminomethyl)chroman-4-yl
7-(dimethylaminomethyl)-1,2,3,4-tetrahydonaphth-4-yl
7-(piperidin-1-ylaminomethyl)-1,2,3,4-tetrahydonaphth-2-yl
5-(piperidin-1-yl)methylindan-1-yl
6-(4-methylpiperazin-1-yl)methylindan-1-yl
4-(piperazin-1-yl)methylindan-1-yl
2-(di-ethylarninomethyl)-5,6,7,8-tetrahydoquinolin-5-yl
2-(isopropylaminomethyl)-5,6,7,8-tetrahydoquinolin-8 -yl
2-(t-butylaminomethyl)-5,6,7,8-tetrahydoisoquinolin-8-yl
7-(morpholin-4-ylmethyl)-quinolin-4-yl
1-methyl-2-oxo-6-(piperidin-1-yl)methylindol-3-yl
7-(dimethylaminomethyl)-1,2,3,4-tetrahydonaphth-2-yl
7-(diethylaminomethyl)-4,5,6,7-tetrahydobenzofur-4-yl
7-(4-morpholinylmethyl)-4,5,6,7-tetrahydobenzothien-4-yl
7-(aminomethoxy)chroman-4-yl
4-4-(4,5-dihydro-1H-imidazol-2-yl)-phenylethyl
4-4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl 4-(aminopropyl)phenyl
4-(aminoethyl)phenyl ##STR00106## R.sup.7 piperidin-1-ylmethyl
CH.sub.3NH-methyl piperazin-1-yl-methyl
4-CH.sub.3-piperazin-1-ylmethyl (t-but)NH-methyl (Et)NH-vinyl
1-methylpiperazin-1-yl-vinyl ##STR00107## R.sup.7
piperidin-1-ylmethyl CH.sub.3NH-methyl piperazin-1-yl-methyl
4-CH.sub.3-piperazin-1-ylmethyl (t-but)NH-methyl (Et)NH-vinyl
1-methylpiperazin-1-yl-vinyl ##STR00108## R.sup.7
piperidin-1-ylmethyl CH.sub.3NH-methyl piperazin-1-yl-methyl
4-CH.sub.3-piperazin-1-ylmethyl (t-but)NH-methyl (Et)NH-vinyl
1-methylpiperazin-1-yl-vinyl
[0519] Although the pharmacological properties of the compounds of
Formula I-VI vary with structural change, in general, activity
possessed by compounds of Formula I-VI may be demonstrated in vivo.
The pharmacological properties of the compounds of this invention
may be confirmed by a number of pharmacological in vitro assays.
The exemplified pharmacological assays, which follow, have been
carried out with the compounds according to the invention and their
salts. Compounds of the present invention showed binding
IC.sub.50's of B1 at doses less than 20 .mu.M.
Biological Testing
Human Bradykinin B1 Receptor and Human B2 Receptor In Vitro Binding
Assay Supporting Methods
Preparation of Membranes Expressing Human B1 and Human B2
Bradykinin Receptor
[0520] Membranes were prepared from CHO-d'AQN cells stably
transfected with human bradykinin B1 receptor cDNA. For large-scale
production of membranes, cells were grown in 100 L suspension
culture to 1.0E8 cells/mL then harvested using the Viafuge at
continuous centrifugation of 1000 g. For pilot studies, cells were
grown in 2 L spinner culture and harvested by centrifugation (1900
g, 10 min, 4.degree. C.). The cell pellet was washed with PBS,
centrifuged (1900 g, 10 min, 4.degree. C.), then the cells
resuspended in lysis buffer (25 mM HEPES, pH 7.4, 5 mM EDTA, 5 mM
EGTA, 3 mM MgCl.sub.2, 10% (w/v) sucrose, Complete Protease
Inhibitor tablets (EDTA-free)) to a density of 14% w/v for passage
through a microfluidizer (Microfluidics 110S, 3 passes, 6,000 psi).
The resulting cell lysate was centrifuged (1900 g, 10 min,
4.degree. C.), and the crude particulate fraction isolated by
centrifugation (142,000 g, 1 h, 4.degree. C.) of the low-speed
supernatant. The resulting pellet was resuspended in 1/3 the
original lysis buffer volume, homogenized, and recentrifuged as
above. The membrane pellet was resuspended by homogenization in
storage buffer (25 mM HEPES, pH 7.4, 3 mM MgCl.sub.2, 10% (w/v)
sucrose and Complete Protease Inhibitor tablets (EDTA-free)).
Single-use aliquots were made and flash-frozen in liquid N.sub.2
prior to storage at -80.degree. C.
[0521] Membranes containing human bradykinin B2R were purchased
from Receptor Biology (now Perkin Elmer Life Sciences). They were
derived from a CHO-K1 line stably expressing the human B2 receptor
developed by Receptor Biology and subsequently purchased by Amgen.
For some studies, membranes were prepared in-house from this same
cell line using the method described for human B1 receptor
membranes, except cells were grown in roller bottles and harvested
using Cellmate.
Radioligand Binding Assay for Human B1 and Human B2 Bradykinin
Receptor
[0522] Human B1 receptor binding assay was performed in 96-well
polypropylene plates (Costar 3365) by adding 50 .mu.l
[.sup.3H]des-arg.sup.10 kallidin (NET1064; Perkin Elmer Life
Sciences) to 10 .mu.l test compound diluted in 90 .mu.l assay
buffer (24 mM TES, pH 6.8, 1 mM 1,10 o-phenanthroline, 0.3% BSA,
0.5 mM Pefabloc SC, 2 .mu.g/mL aprotinin, 5 .mu.g/mL leupeptin, and
0.7 .mu.g/mL pepstatin A). Membranes (50 .mu.l) were added last.
[.sup.3H] des-arg.sup.10 kallidin was diluted from stock into assay
buffer to yield a final concentration of -0.3 nM in the assay but
was adjusted as needed to ensure a concentration at or below the
K.sub.d determined for each batch of receptor membranes.
Nonspecific binding was defined with 2 .mu.M
des-Arg.sup.10Leu.sup.9 kallidin. Membranes were diluted in assay
buffer to yield a final concentration of 0.068 nM hB1 receptor in
the assay. Compounds were solubilized in either DMSO or ddH.sub.20,
plated into polypropylene plates (Costar 3365), then serially
diluted in either DMSO or dilution buffer (20 mM Hepes, pH 7.6,
0.1% BSA) to yield a final concentration of either 5% DMSO or no
DMSO in the assay. The assay mixture was incubated with shaking for
1 hr at RT and then filtered through GF/C plates presoaked in 0.5%
polyethyleneimine (Unifilter; Perkin Elmer Life Sciences) using a
Filtermate 96-well harvester (Perkin Elmer Life Sciences). Filter
plates were rapidly washed 6 times with 200 .mu.l ice-cold buffer
(50 mM Tris, pH 7.4), dried in a vacuum oven at 55.degree. C. for
15-20 min, backed, and 40 .mu.l per well of Microscint 20 was
added. The plates were sealed and activity read on Topcount (Perkin
Elmer Life Sciences) using a count time of 3 min per channel.
[0523] For human B2 bradykinin receptor, the same procedure was
followed with the following exceptions: [.sup.3H]bradykinin
(NET706; Perkin Elmer Life Sciences) was used at a final
concentration of .about.0.2 nM and non-specific binding was defined
with 2 .mu.M bradykinin. Human B2 receptor concentration was 0.068
nM final in the assay.
Data Analysis
[0524] Data was analyzed in XLFit with the four-parameter logistic
y=A+((B-A)/(1+((C/x) D))) and fit with the Levenburg-Marquardt
algorithm. Raw cpm were converted to percent of control values
prior to analysis (POC=((compound cpm-nonspecfic cpm)/(no-compound
cpm-nonspecific cpm)*100)). K.sub.i values were determined from the
IC.sub.50 using the Cheng-Prusoff equation and K.sub.d values
determined by direct saturation binding of the radioligands.
[0525] The compounds of examples 3b-3c, 4, 4b, 5a, 6, 6a, 7, 9-12,
and 14 have binding Ki's to the hB1 receptor at a level below 1
.mu.M. The compounds should have binding Ki's to the hB2 receptor
at a level above 1 .mu.M.
In Vitro B1-Inhibition Activity
In Vitro Assay of Human B1 Receptor Function Using Calcium Flux
[0526] Activation of the G.sub.q linked B1 receptor results in an
increase in intracellular calcium. The calcium sensitive
photoprotein aequorin can, therefore, be used as an indicator of B1
receptor activation. Aequorin is a 21-kDa photoprotein that forms a
bioluminescent complex when linked to the chromophore cofactor
coelenterazine. Following the binding of calcium to this complex,
an oxidation reaction of coelenterazine results in the production
of apoaequorin, coelenteramide, CO.sub.2, and light that can be
detected by conventional luminometry.
[0527] A stable CHO D-/hB1/Aequorin cell line was established and
the cells were maintained in suspension in spinner bottles
containing a 1:1 ratio of DMEM and HAM F12 (Gibco 11765-047), high
glucose (Gibco 11965-084), 10% Heat Inactivated Dialyzed serum
(Gibco 26300-061), 1.times. Non-Essential Amino Acids (Gibco
11140-050), 1.times. Glutamine-Pen-Strep (Gibco 10378-016), and
Hygromycin, 300 .mu.g/mL (Roche 843555). 15-24 h prior to the
luminometer assay, 25,000 cells/well (2.5E6 cells/10 mL/plate) were
plated in 96-well black-sided clear bottom assay plates (Costar
#3904).
[0528] Media was removed from the wells and replaced with 60 .mu.l
of serum free HAM's F12 with 30 mM HEPES (pH 7.5) and 15 .mu.M
coelenterazine (Coelenterazine h Luciferin #90608 from Assay
Designs). The plates were incubated for 1.5-2 h. Ten point
IC.sub.50 compound plates containing 1:3 or 1:5 dilutions of
antagonist compounds and an agonist activator plate (20 nM
des-Arg10-Kallidin final concentration, EC.sub.80) were prepared
using Ham's F12 with 30 mM HEPES, pH 7.5. Following coelenterazine
incubation, an automated flash-luminometer platform was used to
dispense the B1 antagonist compounds (dissolved in DMSO and diluted
with buffer to the desired concentration (final DMSO concentration
<1% DMSO)) to the cell plate, a CCD camera situated underneath
the cell plate took 12 images of the cell plate at 5 second
intervals to determine if there was any agonist activity with the
compounds. The hB1 agonist, des-Arg10-Kallidin, was added to the
cell plate and another 12 images were recorded to determine the
IC.sub.50 of the antagonist(s). The compounds of examples 3c, 7,
and 9-12 have binding IC.sub.50's to hB1 receptor function at a
level below 1 .mu.M.
In Vitro Assay of hB2 Receptor Function Using Calcium Flux
[0529] The intracellular calcium flux induced by hB2 receptor
activation was analyzed using an hB2 recombinant cell line (CHO-K1)
purchased from PerkinElmer (Catalog Number: RBHB2C000EA) on a
fluorometric imaging plate reader (FLIPR). The cells were cultured
in T225 flask containing Ham's F12 Nutrient Mixture (Invitrogen
Corp., Cat # 11765-047), 10% Fetal Clone II Bovine Serum (HyClone,
Cat # SH3006603), 1 mM Sodium pyruvate (100 mM stock, Invitrogen
Corp., Cat# 12454-013), and 0.4 mg/mL Geneticin (G418; 50 mg/mL
active geneticin, Invitrogen, Cat# 10131-207). Culture medium was
changed every other day. 24 h prior to the FLIPR assay, the hB2/CHO
cells were washed once with PBS (Invitrogen, Cat. #) and 10 .mu.L
of Versene (1:5000, Invitrogen, Cat# 15040-066) was added to each
flask. After 5 min incubation at 37.degree. C., Versene was removed
and cells were detached from the flask and resuspended in culture
medium. Cells were counted and 25,000 cells/well were plated in
96-well black-sided clear bottom assay plates (Costar #3904). Cells
were incubated in a 37.degree. C. CO.sub.2 incubator overnight.
[0530] The media was aspirated from the cells and replaced with
65111 of dye-loading buffer. The loading buffer was prepared by
diluting a stock solution of 0.5 mM Fluo-4 AM (Molecular Probes,
dissolved in DMSO containing 10% [w/v] pluronic acid) to a
concentration of 1 .mu.M in Clear Dulbecco's Modified Eagle Medium
(DMEM) containing 0.1% BSA, 20 mM HEPES, and 2.5 mM probenecid. The
cells were dye-loaded for 1 h at RT. The excess dye was removed by
washing the cells 2.times. with assay buffer. The assay buffer
consists of Hank's Balanced Salt Solution (HBSS) containing 20 mM
HEPES, 0.1% BSA, and 2.5 mM probenecid. After the wash cycles, a
volume of 100 .mu.L was left in each well, and the plate was ready
to be assayed in the FLIPR System. Single point (10 .mu.M final
concentration) POC antagonist compound plates or ten point
IC.sub.50 compound plates containing 1:3 or 1:5 dilutions of
antagonist compounds (dissolved in DMSO and diluted with buffer to
the desired concentration (final DMSO concentration <1% DMSO))
and an agonist activator plate (0.3 nM bradykinin final
concentration, EC.sub.80) were prepared using assay buffer. The
cell plate and the compound plates were loaded onto the FLIPR and
during the assay, fluorescence readings are taken simultaneously
from all 96 wells of the cell plate. Ten 1-second readings were
taken to establish a stable baseline for each well, then 25 .mu.L
from the B1 antagonist plate was rapidly (50 .mu.L/sec.) added. The
fluorescence signal was measured in 1-second (1 min) followed by
6-second (2 min) intervals for a total of 3 min to determine if
there is any agonist activity with the compounds. The B2 agonist,
bradykinin, was added to the cell plate and another 3 min were
recorded to determine the percent inhibition at 10 .mu.M (POC
plates) or the IC.sub.50 of the antagonist.
Cell and Tissue Based In Vitro Assays of hB1 Receptor Binding
[0531] These studies established the antagonist activity of several
compounds at the bradykinin B1 receptors in in vitro cell-based and
isolated organ assays.
[0532] 1. Rabbit endothelial cell B1-specific PGI.sub.2 secretion
Assay
[0533] 2. B1 and B2 umbilical vein Assay
In vitro B1-Inhibition Activity
[0534] The effectiveness of the compounds as inhibitors of B1
activity (i.e., B1 "neutralization") can be evaluated by measuring
the ability of each compound to block B1 stimulated CGRP and
substance P release and calcium signaling in Dorsal Root Ganglion
(DRG) neuronal cultures.
Dorsal Root Ganglion Neuronal Cultures
[0535] Dorsal root ganglia are dissected one by one under aseptic
conditions from all spinal segments of embryonic 19-day old (E19)
rats that are surgically removed from the uterus of timed-pregnant,
terminally anesthetized Sprague-Dawley rats (Charles River,
Wilmington, Mass.). DRG are collected in ice-cold L-15 media
(GibcoBRL, Grand Island, N.Y.) containing 5% heat inactivated horse
serum (GibcoBRL), and any loose connective tissue and blood vessels
are removed. The DRG are rinsed twice in Ca.sup.2+- and
Mg.sup.2+-free Dulbecco's phosphate buffered saline (DPBS), pH 7.4
(GibcoBRL). The DRG are dissociated into single cell suspension
using a papain dissociation system (Worthington Biochemical Corp.,
Freehold, N.J.). Briefly, DRG are incubated in a digestion solution
containing 20 U/mL of papain in Earle's Balanced Salt Solution
(EBSS) at 37.degree. C. for fifty minutes. Cells are dissociated by
trituration through fire-polished Pasteur pipettes in a
dissociation medium consisting of MEM/Ham's F12, 1:1, 1 mg/mL
ovomucoid inhibitor and 1 mg/mL ovalbumin, and 0.005%
deoxyribonuclease I (DNase). The dissociated cells are pelleted at
200.times.g for 5 min and re-suspended in EBSS containing 1 mg/mL
ovomucoid inhibitor, 1 mg/mL ovalbumin and 0.005% DNase. Cell
suspension is centrifuged through a gradient solution containing 10
mg/mL ovomucoid inhibitor, 10 mg/mL ovalbumin at 200.times.g for 6
min to remove cell debris, then filtered through a 88-.mu.M nylon
mesh (Fisher Scientific, Pittsburgh, Pa.) to remove any clumps.
Cell number is determined with a hemocytometer, and cells are
seeded into poly-ornithine 100 .mu.g/mL (Sigma, St. Louis, Mo.) and
mouse laminin 1 .mu.g/mL (GibcoBRL)-coated 96-well plates at
10.times.10.sup.3 cells/well in complete medium. The complete
medium consists of minimal essential medium (MEM) and Ham's F12,
1:1, penicillin (100 U/mL), streptomycin (100 .mu.g/mL), and 10%
heat inactivated horse serum (GibcoBRL). The cultures are kept at
37.degree. C., 5% CO.sub.2 and 100% humidity. For controlling the
growth of non-neuronal cells, 5-fluoro-2'-deoxyuridine (75 .mu.M)
and uridine (180 .mu.M) are included in the medium. Two hours after
plating, cells are treated with recombinant human .beta.-B1 or
recombinant rat .beta.-B1 at a concentration of 10 mg/mL (0.38 nM).
Positive controls comprising serial-diluted anti-B1 antibody
(R&D Systems, Minneapolis, Minn.) are applied to each culture
plate. Compounds are added at ten concentrations using 3.16-fold
serial dilutions. All samples are diluted in complete medium before
being added to the cultures. Incubation time is generally around 40
h prior to measurement of VR1 expression.
Measurement of VR1 Expression in DRG Neurons.
[0536] Cultures are fixed with 4% paraformaldehyde in Hanks'
balanced salt solution for 15 min, blocked with Superblock (Pierce,
Rockford, Ill.), and permeabilized with 0.25% Nonidet P-40 (Sigma)
in Tris.HCl (Sigma)-buffered saline (TBS) for 1 h at RT. Cultures
are rinsed once with TBS containing 0.1% Tween 20 (Sigma) and
incubated with rabbit anti-VR1 IgG (prepared at Amgen) for 1.5 h at
RT, followed by incubation of Eu-labeled anti-rabbit second
antibody (Wallac Oy, Turku, Finland) for 1 h at RT. Washes with TBS
(3.times.five min with slow shaking) are applied after each
antibody incubation. Enhance solution (150 mL/well, Wallac Oy) is
added to the cultures. The fluorescence signal is measured in a
time-resolved fluorometer (Wallac Oy). VR1 expression in samples
treated with the compounds is determined by comparing to a standard
curve of B1 titration from 0-1000 ng/mL. Percent inhibition
(compared to maximum possible inhibition) of B1 effect on VR1
expression in DRG neurons is determined by comparing to controls
that are not B1-treated.
In Vivo Antinociceptive Activity in Rat and Monkey Pain Models
Rat Neuropathic Pain Model
[0537] Male Sprague-Dawley rats (200 g) are anesthetized with
isoflurane inhalant anesthesia and the left lumbar spinal nerves at
the level of L5 and L6 are tightly ligated (4-0 silk suture) distal
to the dorsal root ganglion and prior to entrance into the sciatic
nerve, as first described by Kim and Chung (Kim, S. H.; Chung, J.
M. An experimental model for peripheral neuropathy produced by
segmental spinal nerve ligation in the rat. Pain 50:355-363,
(1992)). The incisions are closed and the rats are allowed to
recover. This procedure results in mechanical (tactile) allodynia
in the left hind paw as assessed by recording the pressure at which
the affected paw (ipsilateral to the site of nerve injury) was
withdrawn from graded stimuli (von Frey filaments ranging from 4.0
to 148.1 mN) applied perpendicularly to the plantar surface of the
paw (between the footpads) through wire-mesh observation cages. A
paw withdrawal threshold (PWT) was determined by sequentially
increasing and decreasing the stimulus strength and analyzing
withdrawal data using a Dixon non-parametric test, as described by
Chaplan et al. (Chaplan, S. R.; Bach, F. W.; Pogrel, J. W.; Chung,
J. M.; Yaksh, T. L. Quantitative assessment of tactile allodynia in
the rat paw. J. Neurosci. Meth., 53:55-63 (1994)).
[0538] Normal rats and sham surgery rats (nerves isolated but not
ligated) withstand at least 148.1 mN (equivalent to 15 g) of
pressure without responding. Spinal nerve ligated rats respond to
as little as 4.0 mN (equivalent to 0.41 g) of pressure on the
affected paw. Rats are included in the study only if they did not
exhibit motor dysfunction (e.g., paw dragging or dropping) and
their PWT was below 39.2 mN (equivalent to 4.0 g). At least seven
days after surgery rats are treated with compounds (usually a
screening dose of 60 mg/kg) or control diluent (PBS) once by s.c.
injection and PWT was determined each day thereafter for 7
days.
Rat CFA Inflammatory Pain Model
[0539] Male Sprague-Dawley rats (200 g) are lightly anesthetized
with isoflurane inhalant anesthesia and the left hindpaw is
injected with complete Freund's adjuvant (CFA), 0.15 mL. This
procedure results in mechanical (tactile) allodynia in the left
hind paw as assessed by recording the pressure at which the
affected paw is withdrawn from graded stimuli (von Frey filaments
ranging from 4.0 to 148.1 mN) applied perpendicularly to the
plantar surface of the paw (between the footpads) through wire-mesh
observation cages. PWT is determined by sequentially increasing and
decreasing the stimulus strength and analyzing withdrawal data
using a Dixon non-parametric test, as described by Chaplan et al.
(1994). Rats are included in the study only if they do not exhibit
motor dysfunction (e.g., paw dragging or dropping) or broken skin
and their PWT is below 39.2 mN (equivalent to 4.0 g). At least
seven days after CFA injection rats are treated with compounds
(usually a screening dose of 60 mg/kg) or control solution (PBS)
once by s.c. injection and PWT is determined each day thereafter
for 7 days. Average paw withdrawal threshold (PWT) is converted to
percent of maximum possible effect (% MPE) using the following
formula: % MPE=100*(PWT of treated rats-PWT of control
rats)/(15-PWT of control rats). Thus, the cutoff value of 15 g
(148.1 mN) is equivalent to 100% of the MPE and the control
response is equivalent to 0% MPE.
[0540] At the screening dose of 60 mg/kg, compounds in vehicle are
expected to produce an antinociceptive effect with a PD
relationship.
Green Monkey LPS Inflammation Model
[0541] The effectiveness of the compounds as inhibitors of B1
activity are evaluated in Male green monkeys (Cercopithaecus
aethiops St Kitts) challenged locally with B1 agonists essentially
as described by deBlois and Horlick (British Journal of
Pharmacology, 132:327-335 (2002), which is hereby incorporated by
reference in its entirety).
[0542] In order to determine whether compounds of the present
invention inhibit B1 induced oedema the studies described below are
conducted on male green monkeys (Cercopithaecus aethiops St Kitts)
at the Caribbean Primates Ltd. experimental farm (St Kitts, West
Indies). Procedures are reviewed and accepted by the Animal Care
Committees of the CR-CHUM (Montreal, Canada) and of Caribbean
Primates Ltd. (St Kitts, West Indies). Animals weighing 6.0.+-.0.5
kg (n=67) were anaesthetized (50 mg ketamine kg.sup.-1) and
pretreated with a single intravenous injection of LPS (90 .mu.g
kg.sup.-1) or saline (1 mL) via the saphenous vein.
Inflammation Studies
[0543] Kinin-induced oedema is evaluated by the ventral skin fold
assay (Sciberras et al., 1987). Briefly, anaesthetized monkeys were
injected with captopril (1 mg kg.sup.-1 30 min before assay). A
single subcutaneous injection of dKD, BK or the vehicle (2 mM
amastatin in 100 .mu.l Ringer's lactate) is given in the ventral
area and the increase in thickness of skin folds is monitored for
30-45 min using a calibrated caliper. The results are expressed as
the difference between the skin fold thickness before and after the
subcutaneous injection. Captopril and amastatin are used to reduce
degradation of kinins at the carboxyl- and amino-terminus,
respectively.
Antagonist Schild Analysis
[0544] The dose-response relationship for dKD (1-100 nmol)-induced
oedema is determined at 24 h post-LPS in the absence or presence of
different concentrations of antagonist. BK (30 nmol) is used as a
positive control.
Antagonst Time Course
[0545] The time course of inhibition by antagonist is determined at
4, 24 and 48 h, 72 and/or 96 h after single bolus administration.
BK (30 nmol) is used as a positive control.
Drugs
[0546] Ketamine hydrochloride, LPS, amastatin and captopril are
from Sigma (MO, U.S.A.). All peptides are from Phoenix
Pharmaceuticals (CA, U.S.A.).
Statistics
[0547] Values are presented as mean.+-.standard error of the mean
(s.e. mean). In edema studies, the pre-injection thickness of the
skin folds was subtracted from the values after subcutaneous
challenge. Curve fitting and EC.sub.50 calculations were obtained
using the Delta Graph 4.0 software for Apple Computers. Data were
compared by two-way analysis of variance followed by unpaired, one
tail Student's t-test with Bonferroni correction. P<0.05 was
considered statistically significant.
Formulations
[0548] Also embraced within this invention is a class of
pharmaceutical compositions comprising the active compounds of
Formula I-V in association with one or more non-toxic,
pharmaceutically-acceptable carriers and/or diluents and/or
adjuvants (collectively referred to herein as "carrier" materials)
and, if desired, other active ingredients. The active compounds of
the present invention may be administered by any suitable route,
preferably in the form of a pharmaceutical composition adapted to
such a route, and in a dose effective for the treatment intended.
The compounds and compositions of the present invention may, for
example, be administered orally, mucosally, topically, rectally,
pulmonarily such as by inhalation spray, or parentally including
intravascularly, intravenously, intraperitoneally, subcutaneously,
intramuscularly intrasternally and infusion techniques, in dosage
unit formulations containing conventional pharmaceutically
acceptable carriers, adjuvants, and vehicles.
[0549] The pharmaceutically active compounds of this invention can
be processed in accordance with conventional methods of pharmacy to
produce medicinal agents for administration to patients, including
humans and other mammals.
[0550] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
For example, these may contain an amount of active ingredient from
about 1 to 2000 mg, preferably from about 1 to 500 mg or 5 to 1000
mg. A suitable daily dose for a human or other mammal may vary
widely depending on the condition of the patient and other factors,
but, once again, can be determined using routine methods.
[0551] The amount of compounds which are administered and the
dosage regimen for treating a disease condition with the compounds
and/or compositions of this invention depends on a variety of
factors, including the age, weight, sex and medical condition of
the subject, the type of disease, the severity of the disease, the
route and frequency of administration, and the particular compound
employed. Thus, the dosage regimen may vary widely, but can be
determined routinely using standard methods. A daily dose of about
0.01 to 500 mg/kg, preferably between about 0.1 and about 50 mg/kg,
and more preferably about 0.1 and about 20 mg/kg body weight may be
appropriate. The daily dose can be administered in one to four
doses per day.
[0552] For therapeutic purposes, the active compounds of this
invention are ordinarily combined with one or more adjuvants
appropriate to the indicated route of administration. If
administered per os, the compounds may be admixed with lactose,
sucrose, starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium stearate,
magnesium oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose.
[0553] In the case of psoriasis and other skin conditions, it may
be preferable to apply a topical preparation of compounds of this
invention to the affected area two to four times a day.
[0554] Formulations suitable for topical administration include
liquid or semi-liquid preparations suitable for penetration through
the skin (e.g., liniments, lotions, ointments, creams, or pastes)
and drops suitable for administration to the eye, ear, or nose. A
suitable topical dose of active ingredient of a compound of the
invention is 0.1 mg to 150 mg administered one to four, preferably
one or two times daily. For topical administration, the active
ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2%
by weight of the formulation, although it may comprise as much as
10% w/w, but preferably not more than 5% w/w, and more preferably
from 0.1% to 1% of the formulation.
[0555] When formulated in an ointment, the active ingredients may
be employed with either paraffinic or a water-miscible ointment
base. Alternatively, the active ingredients may be formulated in a
cream with an oil-in-water cream base. If desired, the aqueous
phase of the cream base may include, for example at least 30% w/w
of a polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include DMSO and related analogs.
[0556] The compounds of this invention can also be administered by
a transdermal device. Preferably transdermal administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane.
[0557] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it may comprise a mixture
of at least one emulsifier with a fat or an oil or with both a fat
and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate,
glyceryl distearate alone or with a wax, or other materials well
known in the art.
[0558] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters may be used. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0559] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredients are dissolved
or suspended in suitable carrier, especially an aqueous solvent for
the active ingredients. The active ingredients are preferably
present in such formulations in a concentration of 0.5 to 20%,
advantageously 0.5 to 10% and particularly about 1.5% w/w.
[0560] Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules using one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration or by using other suitable dispersing or wetting
agents and suspending agents. The compounds may be dissolved in
water, polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, tragacanth gum, and/or various buffers. Other adjuvants
and modes of administration are well and widely known in the
pharmaceutical art. The active ingredient may also be administered
by injection as a composition with suitable carriers including
saline, dextrose, or water, or with cyclodextrin (ie. Captisol),
cosolvent solubilization (ie. propylene glycol) or micellar
solubilization (ie. Tween 80).
[0561] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed, including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[0562] For pulmonary administration, the pharmaceutical composition
may be administered in the form of an aerosol or with an inhaler
including dry powder aerosol.
[0563] Suppositories for rectal administration of the drug can be
prepared by mixing the drug with a suitable non-irritating
excipient such as cocoa butter and polyethylene glycols that are
solid at ordinary temperatures but liquid at the rectal temperature
and will therefore melt in the rectum and release the drug.
[0564] The pharmaceutical compositions may be subjected to
conventional pharmaceutical operations such as sterilization and/or
may contain conventional adjuvants, such as preservatives,
stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and
pills can additionally be prepared with enteric coatings. Such
compositions may also comprise adjuvants, such as wetting,
sweetening, flavoring, and perfuming agents.
[0565] The foregoing is merely illustrative of the invention and is
not intended to limit the invention to the disclosed compounds.
Variations and changes which are obvious to one skilled in the art
are intended to be within the scope and nature of the invention
which are defined in the appended claims.
[0566] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
[0567] No unacceptable toxological effects are expected when
compounds of the present invention are administered in accordance
with the present invention.
[0568] All mentioned references, patents, applications and
publications, are hereby incorporated by reference in their
entirety, as if here written.
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