U.S. patent application number 11/508467 was filed with the patent office on 2007-04-26 for alpha2c adrenoreceptor agonists.
This patent application is currently assigned to Schering Corporation and Pharmacopeia Drug Discovery, Inc.. Invention is credited to Robert G. Aslanian, Purakkattle Biju, Christopher W. Boyce, Manuel de Lera Ruiz, Lisa Guise-Zawacki, Chia-Yu Huang, Bo Liang, Rong-Qiang Liu, Ruiyan Liu, Pietro Mangiaracina, Kevin D. McCormick, Neng-Yang Shih, Younong Yu.
Application Number | 20070093477 11/508467 |
Document ID | / |
Family ID | 37668030 |
Filed Date | 2007-04-26 |
United States Patent
Application |
20070093477 |
Kind Code |
A1 |
McCormick; Kevin D. ; et
al. |
April 26, 2007 |
Alpha2C adrenoreceptor agonists
Abstract
In its many embodiments, the present invention relates to a
novel class of phenylmorpholine and phenylthiomorpholine compounds
useful as .alpha.2C adrenergic receptor agonists, pharmaceutical
compositions containing the compounds, and methods of treatment,
prevention, inhibition, or amelioration of one or more diseases
associated with the .alpha.2C adrenergic receptor agonists using
such compounds or pharmaceutical compositions.
Inventors: |
McCormick; Kevin D.;
(Basking Ridge, NJ) ; Boyce; Christopher W.;
(Flemington, NJ) ; Shih; Neng-Yang; (Warren,
NJ) ; Aslanian; Robert G.; (Rockaway, NJ) ;
Mangiaracina; Pietro; (Monsey, NY) ; de Lera Ruiz;
Manuel; (Branchburg, NJ) ; Yu; Younong; (East
Brunswick, NJ) ; Biju; Purakkattle; (Piscataway,
NJ) ; Huang; Chia-Yu; (West Windsor, NJ) ;
Liang; Bo; (Lawrenceville, NJ) ; Liu; Ruiyan;
(Yardley, PA) ; Liu; Rong-Qiang; (Kendall Park,
NJ) ; Guise-Zawacki; Lisa; (Yardley, PA) |
Correspondence
Address: |
SCHERING-PLOUGH CORPORATION;PATENT DEPARTMENT (K-6-1, 1990)
2000 GALLOPING HILL ROAD
KENILWORTH
NJ
07033-0530
US
|
Assignee: |
Schering Corporation and
Pharmacopeia Drug Discovery, Inc.
|
Family ID: |
37668030 |
Appl. No.: |
11/508467 |
Filed: |
August 23, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60711453 |
Aug 25, 2005 |
|
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|
Current U.S.
Class: |
514/224.2 ;
514/230.5; 514/249; 544/105; 544/353; 544/51 |
Current CPC
Class: |
A61P 13/00 20180101;
A61P 27/06 20180101; A61P 11/02 20180101; A61P 37/08 20180101; A61P
25/04 20180101; C07D 471/04 20130101; C07D 413/14 20130101; A61P
9/10 20180101; A61P 25/24 20180101; A61P 43/00 20180101; C07D
417/06 20130101; C07D 413/06 20130101; A61P 25/00 20180101; A61P
11/00 20180101; A61P 1/12 20180101; A61P 9/04 20180101; A61P 29/00
20180101; A61P 25/18 20180101; C07D 413/04 20130101; C07D 403/06
20130101; A61P 9/00 20180101; A61P 25/06 20180101; A61P 25/22
20180101; C07D 487/04 20130101; C07D 498/04 20130101; A61P 13/02
20180101 |
Class at
Publication: |
514/224.2 ;
514/230.5; 514/249; 544/105; 544/353; 544/051 |
International
Class: |
A61K 31/5415 20060101
A61K031/5415; A61K 31/538 20060101 A61K031/538; A61K 31/498
20060101 A61K031/498; C07D 413/02 20060101 C07D413/02; C07D 417/02
20060101 C07D417/02 |
Claims
1. A compound represented by the structural formula: ##STR329## or
a pharmaceutically acceptable salt or solvate of said compound,
wherein: A is a 5-membered heterocyclic ring containing 1-3
heteroatoms, and is substituted with at least one R.sup.5; X is
--O--, --S(O).sub.p--, or --N(R.sup.6)--; J.sup.1, J.sup.2,
J.sup.3, and J.sup.4 are independently --N--, --N(O)-- or
--C(R.sup.2)--, provided that 0-3 of J.sup.1, J.sup.2, J.sup.3 and
J.sup.4 are --N--; R.sup.2 is independently selected from the group
consisting of H, --OH, halo, --CN, --NO.sub.2,
--(CH.sub.2).sub.qYR.sup.7, --(CH.sub.2).sub.qNR.sup.7YR.sup.7',
--(CH.sub.2).sub.qOYR.sup.7,
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, --P(.dbd.O)R.sup.8.sub.2, and
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, and heterocyclyl groups optionally
substituted with at least one R.sup.5; Y is selected from the group
consisting of a bond, --C(.dbd.O)--, --C(.dbd.O)NR.sup.7--,
C(.dbd.O)O--, --C(.dbd.NR.sup.7)--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, --C(.dbd.NR.sup.7)NR.sup.7O--,
--S(O).sub.p--, SO.sub.2NR.sup.7--, and --C(S)NR.sup.7--; R.sup.3
is independently selected from the group consisting of H and
(.dbd.O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups
optionally substituted with at least one R.sup.5, provided that
when n is 3 or 4, no more than 2 of the R.sup.3 groups may be
(.dbd.O); R.sup.4 is independently selected from the group
consisting of H and CN and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups optionally substituted with at least one R.sup.5; R.sup.5 is
independently selected from the group consisting of H, halo, --OH,
--CN, --NO.sub.2,--NR.sup.7R.sup.7', --SR.sup.7, and alkyl, alkoxy,
alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,
aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--NR.sup.7R.sup.7', and --SR.sup.7 substituents; R.sup.6 is
independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --SR.sup.7 substituents, and
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.8 and
--SO.sub.2NR.sup.7R.sup.7'; R.sup.7 is independently selected from
the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; R.sup.7' is independently selected from the group
consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11 substituents; or
R.sup.7 and R.sup.7' together with the nitrogen atom to which they
are attached form a 3- to 8-membered heterocyclyl, heterocyclenyl
or heteroaryl ring having, in addition to the N atom, 1 or 2
additional hetero atoms selected from the group consisting of O, N,
--N(R.sup.9)-- and S, wherein said rings are optionally substituted
by 1 to 5 independently selected R.sup.5 moieties, R.sup.8 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; R.sup.9 is
independently selected from the group consisting of H,
--C(O)--R.sup.10, --C(O)--OR.sup.10, and --S(O).sub.p--OR.sup.10
and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl groups, each of which is optionally
substituted with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; and R.sup.10 is
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl
groups, each of which is optionally substituted with at least one
of halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--SR.sup.11 substituents; R.sup.11 is a moiety independently
selected from the group consisting of H, alkyl, alkoxy, alkenyl,
alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy,
arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl; m is 1-5; n is 1-3; p is 0-2; q is 0-6; and w is
0-4. with the following provisos: (a) if J.sup.1-J.sup.4 are each
--C(H)--, n is 1, m is 1, R.sup.4 is H, A is 3H-imidazol-4-yl, and
X is --N(R.sup.6)--, then R.sup.6 is not --C(.dbd.O)-naphthyl; (b)
if J.sup.1-J.sup.4 are each --C(H)--, n is 1, m is 1, R.sup.4 is H,
A is 1H-imidazol-4-yl, and X is --N(R.sup.6)--, then R.sup.6 is not
--S(O.sub.2)-naphthyl; and (c) if J.sup.1, J.sup.2, and J.sup.4 are
each --C(H)--, J.sup.3 is --C(Br)--, n is 2, m is 1, R.sup.3 is
3-benzyl, R.sup.4 is H, A is 1H-imidazol-4-yl, and X is
--N(R.sup.6)--, then R.sup.6 is not --C(O.sub.2)benzyl.
2. The compound of claim 1, wherein: J.sup.1-J.sup.4 are each
--C(R.sup.2)--; A is a 5-membered heterocyclic ring containing 1-3
heteroatoms, and is substituted with at least one R.sup.5; X is
--O--, --S(O).sub.p--, or --N(R.sup.6)--; R.sup.2 is independently
selected from the group consisting of H, --OH, halo, --CN,
--NO.sub.2, --(CH.sub.2).sub.qYR.sup.7,
--(CH.sub.2).sub.qNR.sup.7YR.sup.7', --(CH.sub.2).sub.qOYR.sup.7,
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)N(R.sup.7R.sup.7').sub.2, --P(.dbd.O)R.sup.7R.sup.7',
and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, and heterocyclyl groups optionally
substituted with at least one R.sup.5; Y is selected from the group
consisting of a bond, --C(.dbd.O)--, --C(.dbd.O)NR.sup.7--,
--C(.dbd.O)O--, --C(.dbd.NR.sup.7)--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, --C(.dbd.N)R.sup.7)NR.sup.7O--,
--S(O).sub.p--, --SO.sub.2NR.sup.7--, --C(S)NR.sup.7--; R.sup.3 is
independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5; R.sup.4 is independently selected from
the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups optionally substituted with at least one R.sup.5; R.sup.5 is
independently selected from the group consisting of H, halo, --OH,
--CN, --NO.sub.2, --NR.sup.7R.sup.7', --SR.sup.7, and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --S(O).sub.pR.sup.7
substituents; R.sup.6 is independently selected from the group
consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each
of which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --NR.sup.7R.sup.7', and --SR.sup.7 substituents,
and --C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7 and
--SO.sub.2NR.sup.7R.sup.7'; R.sup.7is independently selected from
the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; R.sup.7' is independently selected from the group
consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11 substituents; or
R.sup.7 and R.sup.7' together with the nitrogen atom together form
a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl ring
having, in addition to the N atom, 1 or 2 additional hetero atoms
selected from the group consisting of O, N, --N(R.sup.9)-- and S,
wherein said rings are optionally substituted by 1 to 5
independently selected R.sup.5 moieties, R.sup.8 is independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl
groups, each of which is optionally substituted with at least one
of halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--SR.sup.11 substituents; R.sup.9 is independently selected from
the group consisting of H, --C(O)--R.sup.10, --C(O)--OR.sup.10, and
--S(O).sub.p--OR.sup.10 and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; and R.sup.10 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
and heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; R.sup.11 is a
moiety independently selected from the group consisting of H,
alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl; m is 1 or 2; n is 1 or 2; p is
0-2; q is 0-3; and w is 0-4.
3. The compound of claim 2, wherein A is imidazolyl.
4. The compound of claim 2, wherein X is --O--.
5. The compound of claim 2, wherein X is --N(R.sup.6)--.
6. A compound represented by the structural formula: ##STR330## or
a pharmaceutically acceptable salt or solvate of said compound,
wherein: X is --O--, --S(O).sub.p--, or --N(R.sup.6)--; J.sup.1,
J.sup.2, J.sup.3, and J.sup.4 are independently --N--or
--C(R.sup.2)--, provided that 0-3 of J.sup.1, J.sup.2, J.sup.3 and
J.sup.4 are --N--; R.sup.2 is independently selected from the group
consisting of H, --OH, halo, --CN, --NO.sub.2,
--(CH.sub.2).sub.qYR.sup.7, --(CH.sub.2).sub.qNR.sup.7YR.sup.7',
--(CH.sub.2).sub.qOYR.sup.7,
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, --P(.dbd.O)R.sup.8.sub.2, and
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, and heterocyclyl groups optionally
substituted with at least one R.sup.5; Y is selected from the group
consisting of a bond, --C(.dbd.O)--, --C(.dbd.O)NR.sup.7--,
--C(.dbd.O)O--, --C(.dbd.N)R.sup.7)--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, --C(.dbd.NR.sup.7)NR.sup.7O--,
--S(O).sub.p--, --SO.sub.2NR.sup.7--, and --C(S)NR.sup.7--; R.sup.3
is independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5; R.sup.4 is independently selected from
the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups optionally substituted with at least one R.sup.5; R.sup.5 is
independently selected from the group consisting of H, halo, --OH,
--CN, --NO.sub.2,--NR.sup.7R.sup.7', --SR.sup.7, and alkyl, alkoxy,
alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,
aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--NR.sup.7R.sup.7', and --SR.sup.7 substituents; R.sup.6 is
independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --SR.sup.7 substituents, and
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7 and
--SO.sub.2NR.sup.7R.sup.7'; R.sup.7 is independently selected from
the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; R.sup.7' is independently selected from the group
consisting of selected from the group consisting of H and alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; or R.sup.7 and
R.sup.7' together with the nitrogen atom to which they are attached
form a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl
ring having, in addition to the N atom, 1 or 2 additional hetero
atoms selected from the group consisting of O, N, --N(R.sup.9)--
and S, wherein said rings are optionally substituted by 1 to 5
independently selected R.sup.5 moieties, R.sup.8 is independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl
groups, each of which is optionally substituted with at least one
of halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--SR.sup.11 substituents; R.sup.9 is independently selected from
the group consisting of H, --C(O)--R.sup.10, --C(O)--OR.sup.10, and
--S(O).sub.p--OR.sup.10 and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; and R.sup.10 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
and heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; R.sup.11 is a
moiety independently selected from the group consisting of H,
alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl; m is 1-5; n is 1-3; p is 0-2;
q is 0-6; z is 0-3; and w is 0-4, with the following provisos: (a)
if J.sup.1-J.sup.4 are each --C(H)--, n is 1, m is 1, R.sup.4 is H,
A is 3H-imidazol-4-yl, and X is --N(R.sup.6)--, then R.sup.6 is not
--C(.dbd.O)-naphthyl; (b) if J.sup.1-J.sup.4 are each --C(H)--, n
is 1, m is 1, R.sup.4 is H, A is 1H-imidazol-4-yl, and X is
--N(R.sup.6)--, then R.sup.6 is not --S(O.sub.2)-naphthyl; and (c)
if J.sup.1, J.sup.2, and J.sup.4 are each --C(H)--, J.sup.3 is
--C(Br)--, n is 2, m is 1, R.sup.3 is 3-benzyl, R.sup.4 is H, and X
is --N(R.sup.6)--, then R.sup.6 is not --C(O.sub.2)benzyl.
7. A compound represented by the structural formula: ##STR331## or
a pharmaceutically acceptable salt or solvate of said compound,
wherein: R.sup.1 is selected from the group consisting of H, --OH,
halo, --CN, --NO.sub.2, --SR.sup.7--(CH.sub.2).sub.qYR.sup.7,
--(CH.sub.2).sub.qNR.sup.7YR.sup.7', --(CH.sub.2).sub.qOYR.sup.7,
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, --P(.dbd.O)R.sup.8.sub.2., and
alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5; X is --O--, --S(O).sub.p--, or
--N(R.sup.6)--; Y is selected from the group consisting of a bond,
--C(.dbd.O)--, --C(.dbd.O)NR.sup.7--, --C(.dbd.O)O--,
--C(.dbd.NR.sup.7)--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, --C(.dbd.NR.sup.7)NR.sup.7O--,
--S(O).sub.p--, --SO.sub.2NR.sup.7--, and --C(S)NR.sup.7--; R.sup.3
is independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5; R.sup.4 is independently selected from
the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups optionally substituted with at least one R.sup.5; R.sup.5 is
independently selected from the group consisting of H, halo, --OH,
--CN, --NO.sub.2, --NR.sup.7R.sup.7', --SR.sup.7, and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --SR.sup.7 substituents;
R.sup.6 is independently selected from the group consisting of H
and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --N(R.sup.7).sub.2, and --SR.sup.7 substituents, and
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7 and
--SO.sub.2NR.sup.7R.sup.7'; R.sup.7 is independently selected from
the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; R.sup.7' is independently selected from the group
consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11 substituents; or
R.sup.7 and R.sup.7' together with the nitrogen atom to which they
are attached form a 3- to 8-membered heterocyclyl, heterocyclenyl
or heteroaryl ring having, in addition to the N atom, 1 or 2
additional hetero atoms selected from the group consisting of O, N,
--N(R.sup.9)-- and S, wherein said rings are optionally substituted
by 1 to 5 independently selected R.sup.5 moieties, R.sup.8 is
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; R.sup.9 is
independently selected from the group consisting of H,
--C(O)--R.sup.10, --C(O)--OR.sup.10, and --S(O).sub.p--OR.sup.10
and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl groups, each of which is optionally
substituted with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; and R.sup.10 is
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl
groups, each of which is optionally substituted with at least one
of halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--SR.sup.11 substituents; R.sup.11 is a moiety independently
selected from the group consisting of H, --CN, alkyl, alkoxy,
alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,
aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl; m is 1-5; n is 1-3; p is 0-2; q is 0-6; z is
0-3; and w is 0-4, with the following provisos: (a) if n is 1, m is
1, R.sup.4 is H, and X is --N(R.sup.6)--, then R.sup.6 is not
--C(.dbd.O)-naphthyl; and (b) if n is 1, m is 1, R.sup.4 is H, and
X is --N(R.sup.6)--, then R.sup.6 is not --S(O.sub.2)-naphthyl. (c)
if R.sup.1 is Br, n is 2, m is 1, R.sup.3 is 3-benzyl, R.sup.4 is
H, A is 1H-imidazol-4-yl, and X is --N(R.sup.6)--, then R.sup.6 is
not --C(O.sub.2)benzyl.
8. The compound of claim 7 wherein X is --O--, n is 1, m is 1, and
R.sup.4 is H.
9. The compound of claim 7, wherein X is --N(R.sup.6)--, n is 1, m
is 1, and R.sup.4 is H.
10. A compound represented by the structural formula: ##STR332## or
a pharmaceutically acceptable salt or solvate of said compound,
wherein: R.sup.1 is selected from the group consisting of H, --OH,
halo, --CN, --NO.sub.2, --SR.sup.7--(CH.sub.2).sub.qYR.sup.7,
--(CH.sub.2).sub.qNR.sup.7YR.sup.7', --(CH.sub.2).sub.qOYR.sup.7,
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, --P(.dbd.O)R.sup.8.sub.2, and
alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5; X is --O--, --S(O).sub.p--, or
--N(R.sup.6)--; J.sup.1, J.sup.2, and J.sup.4 are independently
--N-- or --C(R.sup.2)--, provided that 0-3 of J.sup.1, J.sup.2, and
J.sup.4 are --N--; R.sup.2 is independently selected from the group
consisting of H, --OH, halo, --CN, --NO.sub.2,
--(CH.sub.2).sub.qYR.sup.7, --(CH.sub.2).sub.qNR.sup.7YR.sup.7',
--(CH.sub.2).sub.qOYR.sup.7,
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, --P(.dbd.O)R.sup.8.sub.2, and
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, and heterocyclyl groups optionally
substituted with at least one R.sup.5; Y is selected from the group
consisting of a bond, --C(.dbd.O)--, --C(.dbd.O)NR.sup.7--,
C(.dbd.O)O--, --C(.dbd.NR.sup.7)--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, --C(.dbd.NR.sup.7)NR.sup.7O--,
--S(O).sub.p--, SO.sub.2NR.sup.7--, and --C(S)NR.sup.7--; R.sup.3
is independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5; R.sup.4 is independently selected from
the group consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy,
alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl,
heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl
groups optionally substituted with at least one R.sup.5; R.sup.5 is
independently selected from the group consisting of H, halo, --OH,
--CN, --NO.sub.2, --NR.sup.7R.sup.7', --S(O).sub.pR.sup.7, and
alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --S(O).sub.pR.sup.7
substituents; R.sup.6 is independently selected from the group
consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups, each
of which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --NR.sup.7R.sup.7', and --SR.sup.7 substituents,
and --C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7 and
--SO.sub.2NR.sup.7R.sup.7'; R.sup.7is independently selected from
the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; R.sup.7' is independently selected from the group
consisting of selected from the group consisting of H and alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; or R.sup.7 and
R.sup.7' together with the nitrogen atom together form a 3- to
8-membered heterocyclyl, heterocyclenyl or heteroaryl ring having,
in addition to the N atom, 1 or 2 additional hetero atoms selected
from the group consisting of O, N, --N(R.sup.9)-- and S, wherein
said rings are optionally substituted by 1 to 5 independently
selected R.sup.5 moieties, R.sup.8 is independently selected from
the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11 substituents;
R.sup.9 is independently selected from the group consisting of H,
--C(O)--R.sup.10, --C(O)--OR.sup.10, and --S(O).sub.p--OR.sup.10
and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl groups, each of which is optionally
substituted with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; and R.sup.10 is
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl
groups, each of which is optionally substituted with at least one
of halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--SR.sup.11 substituents; R.sup.11 is a moiety independently
selected from the group consisting of H, alkyl, alkoxy, alkenyl,
alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl, aryloxy,
arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl; m is 1-5; n is 1-3; p is 0-2; q is 0-6; z is
0-3; and w is 0-4, with the following provisos: (a) if J.sup.1,
J.sup.2, and J.sup.4 are each --C(H)--, R.sup.1 is H, n is 1, m is
1, R.sup.4 is H, and X is --N(R.sup.6)--, then R.sup.6 is not
--C(.dbd.O)-naphthyl; (b) if J.sup.1, J.sup.2, and j.sup.4 are each
--C(H)--, R.sup.1 is H, n is 1, m is 1, R.sup.4 is H, and X is
--N(R.sup.6)--, then R.sup.6 is not --S(O.sub.2)-naphthyl; and (c)
if J.sup.1, J.sup.2, and J.sup.4 are each --C(H)--, R.sup.1 is Br,
n is 2, m is 1, R.sup.3 is 3-benzyl, R.sup.4 is H, and X is
--N(R.sup.6)--, then R.sup.6 is not --C(O.sub.2)benzyl.
11. The compound of claim 10, wherein X is --O--, n is 1, m is 1,
and R.sup.4 is H.
12. The compound of claim 10, wherein X is --N(R.sup.6)--, n is 1,
m is 1, and R.sup.4 is H.
13. The compound of claim 10, wherein R.sup.1 is selected from the
group consisting of --(CH.sub.2).sub.qYR.sup.7,
--(CH.sub.2).sub.qNR.sup.7YR.sup.7', --(CH.sub.2).sub.qOYR.sup.7,
and --(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7'.
14. A compound selected from the group consisting of: ##STR333##
##STR334## ##STR335## ##STR336## ##STR337## ##STR338## ##STR339##
##STR340## ##STR341## ##STR342## ##STR343## ##STR344## ##STR345##
##STR346## ##STR347## ##STR348## ##STR349## ##STR350## ##STR351##
##STR352## ##STR353## or a pharmaceutically acceptable salt or
solvate thereof.
15. A pharmaceutical composition comprising at least one compound
of claim 1, or a pharmaceutically acceptable salt or solvate
thereof and at least one pharmaceutically acceptable carrier,
adjuvant or vehicle.
16. A pharmaceutical composition comprising at least one compound
of claim 14, or a pharmaceutically acceptable salt or solvate
thereof and at least one pharmaceutically acceptable carrier,
adjuvant or vehicle.
17. The pharmaceutical composition of claim 15, further comprising
one or more additional therapeutic agents.
18. The pharmaceutical composition of claim 16, further comprising
one or more additional therapeutic agents.
19. The pharmaceutical composition of claim 17, wherein said
additional therapeutic agents are selected from the group
consisting of anti-inflammatory steroids, PDE-4 inhibitors,
anti-muscarinic agents, cromolyn sodium, H.sub.1 receptor
antagonists, 5-HT.sub.1, agonists, NSAIDs, angiotensin-converting
enzyme inhibitors, angiotensin II receptor agonists,
.beta.-blockers, .beta.-agonists, leukotriene antagonists,
diuretics, aldosterone antagonists, ionotropic agents, natriuretic
peptides, pain management agents, anti-anxiety agents,
anti-migraine agents, and therapeutic agents suitable for treating
heart conditions, psychotic disorders, and glaucoma.
20. The pharmaceutical composition of claim 18, wherein said
additional therapeutic agents are selected from the group
consisting of steroids, PDE-4 inhibitors, anti-muscarinic agents,
cromolyn sodium, H.sub.1 receptor antagonists, 5-HT.sub.1 agonists,
NSAIDs, angiotensin-converting enzyme inhibitors, angiotensin II
receptor agonists, .beta.-blockers, .beta.-agonists, leukotriene
antagonists, diuretics, aldosterone antagonists, ionotropic agents,
natriuretic peptides, pain management agents, anti-anxiety agents,
anti-migraine agents, and therapeutic agents suitable for treating
heart conditions, psychotic disorders, and glaucoma.
21. A method for selectively stimulating .alpha.2C adrenergic
receptors in a cell in need thereof, comprising contacting said
cell with a therapeutically effective amount of at least one
compound of formula I: ##STR354## or a pharmaceutically acceptable
salt or solvate of said compound, wherein: A is a 5-membered
heterocyclic ring containing 1-3 heteroatoms, and is substituted
with at least one R.sup.5; X is --O--, --S(O).sub.p--, or
--N(R.sup.6)--; J.sup.1, J.sup.2, J.sup.3, and J.sup.4 are
independently --N--, --N(O)-- or --C(R.sup.2)--, provided that 0-3
of J.sup.1, J.sup.2, J.sup.3 and J.sup.4 are --N--; R.sup.2 is
independently selected from the group consisting of H, --OH, halo,
--CN, --NO.sub.2, --(CH.sub.2).sub.qYR.sup.7,
--(CH.sub.2).sub.qNR.sup.7YR.sup.7', --(CH.sub.2).sub.qOYR.sup.7,
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, --P(.dbd.O)R.sup.8.sub.2, and
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, and heterocyclyl groups optionally
substituted with at least one R.sup.5; Y is selected from the group
consisting of a bond, --C(.dbd.O)--, --C(.dbd.O)NR.sup.7--,
--C(.dbd.O)O--, --C(.dbd.N)R.sup.7)--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, --C(.dbd.NR.sup.7)NR.sup.7O--,
--S(O).sub.p--, --SO.sub.2NR.sup.7--, and --C(S)NR.sup.7--; R.sup.3
is independently selected from the group consisting of H and
(.dbd.O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups
optionally substituted with at least one R.sup.5, provided that
when n is 3 or 4, no more than 2 of the R.sup.3 groups may be
(.dbd.O); R.sup.4 is independently selected from the group
consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups
optionally substituted with at least one R.sup.5; R.sup.5 is
independently selected from the group consisting of H, halo, --OH,
--CN, --NO.sub.2,--NR.sup.7R.sup.7'--SR.sup.7, and alkyl, alkoxy,
alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,
aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--NR.sup.7R.sup.7', and --SR.sup.7 substituents; R.sup.6 is
independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --SR.sup.7 substituents, and
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7 and
--SO.sub.2NR.sup.7R.sup.7'; R.sup.7 is independently selected from
the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; R.sup.7' is independently selected from the group
consisting of selected from the group consisting of H and alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; or R.sup.7 and
R.sup.7' together with the nitrogen atom to which they are attached
form a 3- to 8-membered heterocyclyl, heterocyclenyl or heteroaryl
ring having, in addition to the N atom, 1 or 2 additional hetero
atoms selected from the group consisting of O, N, --N(R.sup.9)--
and S, wherein said rings are optionally substituted by 1 to 5
independently selected R.sup.5 moieties, R.sup.8 is independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl
groups, each of which is optionally substituted with at least one
of halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--SR.sup.11 substituents; R.sup.9 is independently selected from
the group consisting of H, --C(O)--R.sup.10, --C(O)--OR.sup.10, and
--S(O).sub.p--OR.sup.10 and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; and R.sup.10 is selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl,
and heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; R.sup.11 is a
moiety independently selected from the group consisting of H, --CN,
alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl; m is 1-5; n is 1-3; p is 0-2;
q is 0-6; and w is 0-4.
22. A method for treating one or more conditions associated with
.alpha.2C adrenergic receptors, comprising administering to a
mammal in need of such treatment at least one compound of formula
I: ##STR355## or a pharmaceutically acceptable salt or solvate of
said compound, wherein: A is a 5-membered heterocyclic ring
containing 1-3 heteroatoms, and is substituted with at least one
R.sup.5; X is --O--, --S(O).sub.p--, or --N(R.sup.6)--; J.sup.1,
J.sup.2, J.sup.3, and J.sup.4 are independently --N--, --N(O)-- or
--C(R.sup.2)--, provided that 0-3 of J.sup.1, J.sup.2, J.sup.3 and
J.sup.4 are --N--; R.sup.2 is independently selected from the group
consisting of H, --OH, halo, --CN, --NO.sub.2,
--(CH.sub.2).sub.qYR.sup.7, --(CH.sub.2).sub.qNR.sup.7YR.sup.7',
--(CH.sub.2).sub.qOYR.sup.7,
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, --P(.dbd.O)R.sup.8.sub.2, and
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, and heterocyclyl groups optionally
substituted with at least one R.sup.5; Y is selected from the group
consisting of a bond, --C(.dbd.O)--, --C(.dbd.O)NR.sup.7--,
--C(.dbd.O)O--, --C(.dbd.N)R.sup.7)--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, --C(.dbd.NR.sup.7)NR.sup.7O--,
--S(O).sub.p--, --SO.sub.2NR.sup.7--, and --C(S)NR.sup.7--; R.sup.3
is independently selected from the group consisting of H and
(.dbd.O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups
optionally substituted with at least one R.sup.5, provided that
when n is 3 or 4, no more than 2 of the R.sup.3 groups may be
(.dbd.O); R.sup.4 is independently selected from the group
consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups
optionally substituted with at least one R.sup.5; R.sup.5 is
independently selected from the group consisting of H, halo, --OH,
--CN, --NO.sub.2,--NR.sup.7R.sup.7', --SR.sup.7, and alkyl, alkoxy,
alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,
aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--NR.sup.7R.sup.7', and --SR.sup.7 substituents; R.sup.6 is
independently selected from the group consisting of H and alkyl,
alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy,
aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --SR.sup.7 substituents, and
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7 and
--SO.sub.2NR.sup.7R.sup.7'; R.sup.7 is independently selected from
the group consisting of H and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; R.sup.7' is independently selected from the group
consisting of selected from the group consisting of H and alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; or R.sup.7 and
R.sup.7' together with the nitrogen atom together form a 3- to
8-membered heterocyclyl, heterocyclenyl or heteroaryl ring having,
in addition to the N atom, 1 or 2 additional hetero atoms selected
from the group consisting of O, N, --N(R.sup.9)-- and S, wherein
said rings are optionally substituted by 1 to 5 independently
selected R.sup.5 moieties, R.sup.8 is independently selected from
the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
arylalkyl, heteroaryl, and heteroarylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11 substituents;
R.sup.9 is independently selected from the group consisting of H,
--C(O)--R.sup.10, --C(O)--OR.sup.10, and --S(O).sub.p--OR.sup.10
and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl groups, each of which is optionally
substituted with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; and R.sup.10 is
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl
groups, each of which is optionally substituted with at least one
of halo, --OH, --CN, --NO.sub.2, --N(R.sup.11).sub.2, and
--SR.sup.11 substituents; R.sup.11 is a moiety independently
selected from the group consisting of H, --CN. alkyl, alkoxy,
alkenyl, alkenyloxy, alkynyl, cycloalkyl, cycloalkoxy, aryl,
aryloxy, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and
heterocyclylalkyl; m is 1-5; n is 1-3; p is 0-2; q is 0-6; and w is
0-4.
23. The method of claim 22, wherein J.sup.1-J.sup.4 are each
--C(R.sup.2)--, n is 1, A is imidazolyl, and X is --O--.
24. The method of claim 22, wherein J.sup.1-J.sup.4 are each
--C(H)--, n is 1, A is imidazolyl, and X is --O--.
25. The method of claim 22, wherein J.sup.1-J.sup.4 are each
--C(R.sup.2)--, n is 1, A is imidazolyl, and X is
--N(R.sup.6)--.
26. The method of claim 22, wherein J.sup.1-J.sup.4 are each
--C(R.sup.2)--, n is 1, A is imidazolyl, and X is
--S(O).sub.p--.
27. A method for treating one or more conditions associated with
.alpha.2C adrenergic receptors, comprising administering to a
mammal in need of such treatment a compound of claim 14 or a
pharmaceutically acceptable salt or solvate thereof.
28. The method of claim 22, wherein the conditions are selected
from the group consisting of allergic rhinitis, congestion, pain,
diarrhea, glaucoma, congestive heart failure, cardiac ischemia,
manic disorders, depression, anxiety, migraine, stress-induced
urinary incontinence, neuronal damage from ischemia and
schizophrenia.
29. The method of claim 22, wherein the conditions are selected
from the group consisting of allergic rhinitis, congestion, pain,
diarrhea, glaucoma, congestive heart failure, cardiac ischemia,
manic disorders, depression, anxiety, and schizophrenia.
30. The method of claim 28, wherein the condition is
congestion.
31. The method of claim 29, wherein the condition is
congestion.
32. The method of claim 30, wherein the congestion is associated
with perennial allergic rhinitis, seasonal allergic rhinitis,
non-allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa,
sinusitis, acute rhinosinusitis, or chronic rhinosinusitis.
33. The method of claim 30, wherein the congestion is caused by
polyps or is virally induced.
34. The method of claim 31, wherein the congestion is associated
with perennial allergic rhinitis, seasonal allergic rhinitis,
non-allergic rhinitis, vasomotor rhinitis, rhinitis medicamentosa,
sinusitis, acute rhinosinusitis, or chronic rhinosinusitis.
35. The method of claim 31, wherein the congestion is caused by
polyps or is virally induced.
36. The method of claim 28, wherein the condition is pain.
37. The method of claim 36, wherein the pain is associated with
neuropathy, inflammation, arthritis or diabetes.
38. The method of claim 24, wherein the condition is pain.
39. The method of claim 38, wherein the pain is associated with
neuropathy, inflammation, arthritis or diabetes.
40. A compound of claim 1, in isolated and purified form.
41. A compound of claim 1 having the formula: ##STR356##
42. A compound of claim 1 having the formula: ##STR357##
43. A compound of claim 1 having the formula: ##STR358##
44. A compound of claim 1 having the formula: ##STR359##
45. A compound of claim 1 having the formula: ##STR360##
46. A method for the treatment of congestion in a mammal in need
thereof which comprises administering to a mammal an effective dose
of at least one compound having adrenergic activity wherein said
compound is a functionally selective agonist of the .alpha.2c
receptor.
47. The method of claim 46, wherein the functionally selective
agonist of the .alpha.2c receptor has an efficacy that is greater
than or equal to 30% E.sub.max when assayed in the GTP.gamma.S
assay.
48. A method for the treatment of congestion in a mammal in need
thereof without modifying the blood pressure at a therapeutic
dosewhich comprises administering to the mammal an effective dose
of at least one compound having adrenergic activity wherein said
compound is a functionally selective agonist of the .alpha.2c
receptor.
Description
RELATED APPLICATIONS
[0001] This application claims priority to provisional application
U.S. Ser. No. 60/711,453, filed on Aug. 25, 2005, herein
incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to phenylmorpholine and
phenylthiomorpholine compounds useful as .alpha.2C adrenergic
receptor agonists, pharmaceutical compositions containing the
compounds, and methods of treatment and prevention using the
compounds and compositions to treat disease states such as
congestion (including nasal congestion), migraine, congestive heart
failure, cardiac ischemia, pain, glaucoma, and psychotic disorders
without substantial adverse side effects associated with .alpha.2A
receptor agonist treatments.
BACKGROUND OF THE INVENTION
[0003] The initial classification of adrenergic receptors into
.alpha.- and .beta.-families was first described by Ahlquist in
1948 (Ahlquist RP, "A Study of the Adrenergic Receptors," Am. J.
Physiol. 153:586-600 (1948)). Functionally, the .alpha.-adrenergic
receptors were shown to be associated with most of the excitatory
functions (vasoconstriction, stimulation of the uterus and pupil
dilation) and B-adrenergic receptors were implicated in
vasodilation, bronchodilation and myocardial stimulation (Lands et
al., "Differentiation of Receptor Systems Activated by
Sympathomimetic amines," Nature 214:597-598 (1967)). Since this
early work, .alpha.-adrenergic receptors have been subdivided into
.alpha.1- and .alpha.2-adrenergic receptors. Cloning and expression
of .alpha.-adrenergic receptors have confirmed the presence of
multiple subtypes of both .alpha.1-(.alpha.1A, .alpha.1B,
.alpha.1D) and .alpha.2-(.alpha.2A, .alpha.2B, .alpha.2C)
adrenergic receptors (Michel et al., "Classification of
.alpha..sub.1-Adrenoceptor Subtypes," Naunyn-Schmiedeberg's Arch.
Pharmacol, 352:1-10 (1995); Macdonald et al., "Gene
Targeting--Homing in on .alpha..sub.2-Adrenoceptor-Subtype
Function," TIPS, 18:211-219 (1997)).
[0004] Current therapeutic uses of .alpha.2 adrenergic receptor
drugs involve the ability of those drugs to mediate many of the
physiological actions of the endogenous catecholamines. There are
many drugs that act on these receptors to control hypertension,
intraocular pressure, eye reddening and nasal congestion and induce
analgesia and anesthesia.
[0005] .alpha.2 adrenergic receptors can be found in the rostral
ventrolateral medulla, and are known to respond to the
neurotransmitter norepinephrine and the antihypertensive drug
clonidine to decrease sympathetic outflow and reduce arterial blood
pressure (Bousquet et al., "Role of the Ventral Surface of the
Brain Stem in the Hypothesive Action of Clonidine," Eur. J.
Pharmacol., 34:151-156 (1975); Bousquet et al., "Imidazoline
Receptors: From Basic Concepts to Recent Developments," 26:S1-S6
(1995)). Clonidine and other imidazolines also bind to imidazoline
receptors (formerly called imidazoline-guanidinium receptive sites
or IGRS) (Bousquet et al., "Imidazoline Receptors: From Basic
Concepts to Recent Developments," 26:S1-S6 (1995)). Some
researchers have speculated that the central and peripheral effects
of imidazolines as hypotensive agents may be related to imidazoline
receptors (Bousquet et al., "Imidazoline Receptors: From Basic
Concepts to Recent Developments," 26:S1-S6 (1995); Reis et al.,
"The Imidazoline Receptor: Pharmacology, Functions, Ligands, and
Relevance to Biology and Medicine," Ann. N.Y. Acad. Sci., 763:1-703
(1995).
[0006] Compounds which have adrenergic activity are well known in
the art, and are described in numerous patents and scientific
publications. The two main families of adrenergic receptor are
termed alpha adrenergic receptors and beta adrenergic receptors in
the art, and each of these two families is known to have subtypes,
which are designated by letters of the alphabet, such as .alpha.2A,
.alpha.2B, and .alpha.2C. It is generally known that adrenergic
activity is useful for treating animals of the mammalian species,
including humans, for curing or alleviating the symptoms and
conditions of numerous diseases and conditions. In other words, it
is generally accepted in the art that pharmaceutical compositions
having an adrenergic compound or compounds as the active ingredient
are useful for treating, among other things, glaucoma, chronic
pain, migraines, heart failure, and psychotic disorders. It is also
known that compounds having adrenergic activity, such as .alpha.2A
agonists, may be associated with undesirable side effects. Examples
of such side effects include hyper-and hypotension, sedation,
locomotor activity, and body temperature variations.
[0007] It has been discovered in accordance with the present
invention that adrenergic compounds that act selectively, and
preferably even specifically, as agonists of the .alpha.2C or the
.alpha.2B/.alpha.2C (hereinafter referred to as .alpha.2C or
.alpha.2B/2C) receptor subtypes in preference over the .alpha.2A
receptor subtype, with adrenergic compounds that are functionally
selective agonists of the .alpha.2C receptor subtype in preference
over the .alpha.2A receptor subtype and .alpha.2B/2C receptor
subtype, possess desirable therapeutic properties associated with
adrenergic receptors but without having one or more undesirable
side effects such as changes in blood pressure (e.g., a
hypertensive or hypotensive effect) or sedation. For the purposes
of this present invention, a compound is defined to be an active
agonist of the .alpha.2C receptor subtype if the compound's
efficacy at the .alpha.2C receptor is .gtoreq.30% E.sub.max
(GTP.gamma.S assay). A compound is a functionally selective agonist
of the .alpha.2C receptor subtype over the .alpha.2A receptor
subtype if the compound's efficacy at the .alpha.2C receptor is
.gtoreq.30% E.sub.max (GTP.gamma.S assay) and its efficacy at the
.alpha.2A receptor is .gtoreq.30% E.sub.max (GTP.gamma.S
assay).
[0008] There is a need for new compounds, formulations, treatments
and therapies to treat diseases and disorders associated with
.alpha.2C adrenergic receptors. Furthermore, there is a need to
develop compounds that are functionally selective for the .alpha.2C
receptor subtype with respect to the .alpha.2A receptor subtype or
the .alpha.2B/.alpha.2C receptor subtype. It is, therefore, an
object of this invention to provide compounds useful in the
treatment or prevention or amelioration of such diseases and
disorders.
SUMMARY OF THE INVENTION
[0009] In its many embodiments, the present invention provides a
novel class of heterocyclic compounds as active or functionally
selective .alpha.2C adrenergic receptor agonists or metabolites,
stereoisomers (e.g., enantiomers or diasteromers) salts, solvates
or polymorphs thereof, methods of preparing such compounds,
pharmaceutical compositions comprising one or more such compounds,
methods of preparing pharmaceutical formulations comprising one or
more such compounds, and methods of treatment, prevention,
inhibition or amelioration of one or more conditions associated
with .alpha.2C receptors using such compounds or pharmaceutical
compositions.
[0010] In one aspect, the present application discloses a compound,
or pharmaceutically acceptable salts or metabolites, solvates or
polymorphs of said compound, said compound having the general
structure shown in Formula I: ##STR1## or a pharmaceutically
acceptable salt or metabolite, solvate or polymorph of said
compound, wherein:
[0011] A is a 5-membered heterocyclic ring containing 1-3
heteroatoms, and is substituted with at least one R.sup.5;
[0012] X is --O--, --S(O).sub.p--, or --N(R.sup.6)--;
[0013] J.sup.1, J.sup.2, J.sup.3, and J.sup.4 are independently
--N--, --N(O)-- or --C(R.sup.2)--, provided that 0-3 of J.sup.1,
J.sup.2, J.sup.3 and J.sup.4 are --N--;
[0014] R.sup.2 is independently selected from the group consisting
of H, --OH, halo, --CN, --NO.sub.2, --(CH.sub.2).sub.qYR.sup.7,
--(CH.sub.2).sub.qNR.sup.7YR.sup.7', --(CH.sub.2).sub.qOYR.sup.7,
--(CH.sub.2).sub.qON.dbd.CR.sup.7RE.sup.7',
--P(.dbd.O)(OR.sup.7)(OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, --P(.dbd.O)R.sup.8.sub.2, and
alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, and heterocyclyl groups optionally
substituted with at least one R.sup.5;
[0015] Y is selected from the group consisting of a bond,
--C(.dbd.O)--, --C(.dbd.O)NR.sup.7--, C(.dbd.O)O--,
--C(.dbd.N)R.sup.7)--, --C(.dbd.NOR.sup.7)--,
--C(.dbd.NR.sup.7)NR.sup.7--, --C(.dbd.NR.sup.7)NR.sup.7O--,
--S(O).sub.p--, SO.sub.2NR.sup.7--, and --C(S)NR.sup.7--;
[0016] R.sup.3 is independently selected from the group consisting
of H and (.dbd.O), and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl groups
optionally substituted with at least one R.sup.5, provided that
when n is 3 or 4, no more than 2 of the R.sup.3 groups may be
(.dbd.O);
[0017] R.sup.4 is independently selected from the group consisting
of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5;
[0018] R.sup.5 is independently selected from the group consisting
of H, halo, --OH, --CN, --NO.sub.2,--NR.sup.7R.sup.7', --SR.sup.7,
and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --S(O).sub.pR.sup.7
substituents;
[0019] R.sup.6 is independently selected from the group consisting
of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups, each of which is
optionally substituted with at least one of halo, --OH, --CN,
--NO.sub.2, --NR.sup.7R.sup.7', and --SR.sup.7 substituents, and
--C(.dbd.O)R.sup.7, --C(.dbd.O)OR.sup.7,
--C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7 and
--SO.sub.2NR.sup.7R.sup.7';
[0020] R.sup.7 is independently selected from the group consisting
of H and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl groups, each of which is optionally
substituted with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents;
[0021] R.sup.7' is independently selected from the group consisting
of H and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl groups, each of which is optionally
substituted with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents; or [0022]
R.sup.7 and R.sup.7' together with the nitrogen atom to which they
are attached form a 3- to 8-membered heterocyclyl, heterocyclenyl
or heteroaryl ring having, in addition to the N atom, 1 or 2
additional hetero atoms selected from the group consisting of O, N,
--N(R.sup.9)-- and S, wherein said rings are optionally substituted
by 1 to 5 independently selected R.sup.5 moieties,
[0023] R.sup.8 is independently selected from the group consisting
of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,
heteroaryl, and heteroarylalkyl groups, each of which is optionally
substituted with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents;
[0024] R.sup.9 is independently selected from the group consisting
of H, --C(O)--R.sup.10, --C(O)--OR.sup.10, and
--S(O).sub.p--OR.sup.10 and alkyl, alkenyl, alkynyl, cycloalkyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups, each of
which is optionally substituted with at least one of halo, --OH,
--CN, --NO.sub.2, --N(R.sup.11).sub.2, and --SR.sup.11
substituents; and
[0025] R.sup.10 is selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl groups, each of which is optionally substituted
with at least one of halo, --OH, --CN, --NO.sub.2,
--N(R.sup.11).sub.2, and --SR.sup.11 substituents;
[0026] R.sup.11 is a moiety independently selected from the group
consisting of H and alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl,
cycloalkyl, cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl,
heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
[0027] m is 1-5;
[0028] n is 1-3;
[0029] p is 0-2;
[0030] q is 0-6; and
[0031] w is 0-4.
[0032] The compounds of Formula I can be useful as .alpha.2C
adrenergic receptor agonists, and can be useful in the treatment
and prevention of allergic rhinitis, all types of congestion
(including, but not limited to nasal congestion), migraine,
congestive heart failure, cardiac ischemia, glaucoma, and psychotic
disorders. Further, the compounds of Formula I can be useful in the
treatment of pain (both chronic and acute), such as pain that is
caused by inflammation, neuropathy, arthritis (including rheumatoid
arthritis, diabetes (e.g., diabetes mellitus or diabetes insipidus)
or pain of an unknown origin. Other pain that can be treated is
nociceptive pain and pain that is visceral in origin or pain that
is secondary to inflammation or nerve damage in other diseases.
Other utilities for the inventive compounds could include
stress-induced urinary incontinence and neuronal damage from
ischemia.
[0033] Alternatively, the present invention provides for a method
for the treatment of congestion in a mammal in need thereof which
comprises administering to a mammal an effective dose of at least
one compound having adrenergic activity wherein said compound is a
functionally selective agonist of the .alpha.2c receptor.
[0034] A further embodiment of the present invention is a method
for the treatment of congestion in a mammal in need thereof which
comprises administering to a mammal an effective dose of at least
one compound having adrenergic activity wherein said compound is a
selective agonist of the .alpha.2c adrenergic receptor, wherein the
functional selective agonist of the .alpha.2c receptor has an
efficacy that is greated than or equal to 30% E.sub.max when
assayed in the GTP.gamma.S assay.
[0035] Another embodiment of the present invention is a method for
the treatment of congestion in a mammal in need thereof without
modifying the systemic blood pressure at therapeutic doses which
comprises administering to the mammal an effective dose of at least
one compound having adrenergic activity wherein said compound is a
functionally selective agonist of the .alpha.2c receptor.
DETAILED DESCRIPTION
[0036] In an embodiment, the present invention discloses certain
heterocyclic compounds which are represented by structural Formula
I, or a pharmaceutically acceptable salt or solvate thereof,
wherein the various moieties are as described above.
[0037] In another embodiment, if J.sup.1-J.sup.4 are each --C(H)--,
n is 1, m is 1, R.sup.4 is H, A is 1H-imidazol-4-yl, and X is
--N(R.sup.6)--, then R.sup.6 is not --C(.dbd.O)-naphthyl.
[0038] In another embodiment, if J.sup.1-J.sup.4 are each --C(H)--,
n is 1, m is 1, R.sup.4 is H, A is 1H-imidazol-4-yl, and X is
--N(R.sup.6)--, then R.sup.6 is not --S(O.sub.2)-naphthyl.
[0039] In another embodiment, if J.sup.1, J.sup.2, and J.sup.4 are
each --C(H)--, J.sup.3 is --C(Br)--, n is 2, m is 1, R.sup.3 is
3-benzyl, R.sup.4 is H, A is 1H-imidazol-4-yl, and X is
--N(R.sup.6)--, then R.sup.6 is not --C(O.sub.2)benzyl.
[0040] In another embodiment, J.sup.1-J.sup.4 are each
--C(R.sup.2)--, n is 1, A is imidazolyl, and X is --O--.
[0041] In another embodiment, J.sup.1-J.sup.4 are each --C(H)--, n
is 1, A is imidazolyl, and X is --O--.
[0042] In another embodiment, J.sup.1-J.sup.4 are each
--C(R.sup.2)--, n is 1, A is imidazolyl, and X is
--N(R.sup.6)--.
[0043] In another embodiment, J.sup.1-J.sup.4 are each
--C(R.sup.2)--, n is 1, A is imidazolyl, and X is
--S(O).sub.p--.
[0044] In another embodiment, R.sup.2 is independently selected
from H, --OH, halo, --CN, --NO.sub.2, --(CH.sub.2).sub.qYR.sup.7,
--(CH.sub.2).sub.qNR.sup.7YR.sup.7', --(CH.sub.2).sub.qOYR.sup.7,
--(CH.sub.2).sub.qON.dbd.CR.sup.7R.sup.7', --P(.dbd.O)(OR.sup.7)
(OR.sup.7'), --P(.dbd.O)(NR.sup.7R.sup.7').sub.2,
--P(.dbd.O)R.sup.8.sub.2, alkyl, alkoxy and polyhaloalkoxy.
[0045] In another embodiment, R.sup.3 is independently selected
from H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5.
[0046] In another embodiment, R.sup.3 is independently selected
from H, alkyl and haloalkyl.
[0047] In another embodiment, R.sup.4 is independently selected
from H, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5.
[0048] In another embodiment, R.sup.4 is independently selected
from H, alkyl, allyl, and haloalkyl.
[0049] In another embodiment, R.sup.5 is independently selected
from H, halo, --NR.sup.7R.sup.7', SR.sup.7, alkyl, and alkoxy.
[0050] In another embodiment, R.sup.6 is independently selected
from H, alkyl, haloalkyl, cycloalkyl, --C(.dbd.O)R.sup.7,
--C(.dbd.O)OR.sup.7, --C(.dbd.O)NR.sup.7R.sup.7', --SO.sub.2R.sup.7
and --SO.sub.2NR.sup.7R.sup.7'.
[0051] In another embodiment, R.sup.7 is independently chosen from
H, alkyl, haloalkyl, cycloalkyl, aryl, and heteroaryl.
[0052] In another embodiment, R.sup.7' is independently chosen from
H, alkyl, haloalkyl, cycloalkyl, aryl, and heteroaryl.
[0053] In another embodiment, R.sup.7 and R.sup.7' together with
the N atom to which they are attached form a aziridine, azetidine,
pyrrole, pyrrolidine, piperidine, piperazine or morpholine ring,
each of which are optionally substituted by R.sup.5.
[0054] In another embodiment, R.sup.8 is independently chosen from
alkyl, haloalkyl, cycloalkyl, aryl, and heteroaryl.
[0055] In another embodiment, m is 1 or 2.
[0056] In another embodiment, n is 1 or 2.
[0057] In another embodiment, n is 1.
[0058] In another embodiment, q is 0, 1, 2, or 3.
[0059] In another embodiment, the present invention discloses
compounds which are represented by structural formulae II-V or a
pharmaceutically acceptable salt, solvate or ester thereof, wherein
the various moieties are as described above: ##STR2##
[0060] wherein z is 0-3 and R.sup.1 is selected from the group
consisting of H, --OH, halo, --CN, --NO.sub.2, --SR.sup.7,
--(CH.sub.2).sub.qYR.sup.7, --(CH.sub.2).sub.qNR.sup.7YR.sup.7',
--(CH.sub.2).sub.qOYR.sup.7, --(CH.sub.2).sub.qON.dbd.C
NR.sup.7R.sup.7', --P(.dbd.O)(OR.sup.7) (OR.sup.7'),
--P(.dbd.O)(NR.sup.7R.sup.7').sub.2, --P(.dbd.O)R.sup.8.sub.2 and
alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, cycloalkyl,
cycloalkoxy, aryl, aryloxy, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl, and heterocyclylalkyl groups optionally substituted
with at least one R.sup.5.
[0061] An inventive group of compounds is shown in below: ##STR3##
##STR4## ##STR5## ##STR6## ##STR7## ##STR8## ##STR9## ##STR10##
##STR11## ##STR12## ##STR13## ##STR14## ##STR15## ##STR16##
##STR17##
[0062] As used above, and throughout this disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following meanings:
[0063] "Patient" includes both human and animals.
[0064] "Mammal" means humans and other mammalian animals.
[0065] "Congestion" refers to all type of congestion including, but
not limited to, congestion associated with perennial allergic
rhinitis, seasonal allergic rhinitis, non-allergic rhinitis,
vasomotor rhinitis, rhinitis medicamentosa, sinusitis, acute
rhinosinusitis, or chronic rhinosinusitis or when the congestion is
caused by polyps or is virally induced, such as congestion
associated with the common cold.
[0066] "Alkyl" means an aliphatic hydrocarbon group which may be
straight or branched and comprising about 1 to about 20 carbon
atoms in the chain. Preferred alkyl groups contain about 1 to about
12 carbon atoms in the chain. More preferred alkyl groups contain
about 1 to about 6 carbon atoms in the chain. Branched means that
one or more lower alkyl groups such as methyl, ethyl or propyl, are
attached to a linear alkyl chain. "Lower alkyl" means a group
having about 1 to about 6 carbon atoms in the chain which may be
straight or branched. The term "substituted alkyl" means that the
alkyl group may be substituted by one or more substituents which
may be the same or different, each substituent being independently
selected from the group consisting of halo, alkyl, aryl,
cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, --NH(alkyl),
--NH(cycloalkyl), --N(alkyl).sub.2, carboxy and --C(O)O-alkyl.
Non-limiting examples of suitable alkyl groups include methyl,
ethyl, n-propyl, isopropyl and t-butyl.
[0067] "Alkynyl" means an aliphatic hydrocarbon group containing at
least one carbon-carbon triple bond and which may be straight or
branched and comprising about 2 to about 15 carbon atoms in the
chain. Preferred alkynyl groups have about 2 to about 12 carbon
atoms in the chain; and more preferably about 2 to about 4 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl, are attached to a linear
alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon
atoms in the chain which may be straight or branched. Non-limiting
examples of suitable alkynyl groups include ethynyl, propynyl,
2-butynyl and 3-methylbutynyl. The term "substituted alkynyl" means
that the alkynyl group may be substituted by one or more
substituents which may be the same or different, each substituent
being independently selected from the group consisting of alkyl,
aryl and cycloalkyl.
[0068] "Aryl" means an aromatic monocyclic or multicyclic ring
system comprising about 6 to about 14 carbon atoms, preferably
about 6 to about 10 carbon atoms. The aryl group can be optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Non-limiting
examples of suitable aryl groups include phenyl and naphthyl.
[0069] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system comprising about 5 to about 14 ring atoms, preferably
about 5 to about 10 ring atoms, in which one or more of the ring
atoms is an element other than carbon, for example nitrogen, oxygen
or sulfur, alone or in combination. Preferred heteroaryls contain
about 5 to about 6 ring atoms. The "heteroaryl" can be optionally
substituted by one or more "ring system substituents" which may be
the same or different, and are as defined herein. The prefix aza,
oxa or thia before the heteroaryl root name means that at least a
nitrogen, oxygen or sulfur atom respectively, is present as a ring
atom. A nitrogen atom of a heteroaryl can be optionally oxidized to
the corresponding N-oxide. Non-limiting examples of suitable
heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,
pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl,
pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,
1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,
phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,
benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,
quinolinyl, imidazolyl, thienopyridyl, quinazolinyl,
thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,
benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.
[0070] "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which
the aryl and alkyl are as previously described. Preferred aralkyls
comprise a lower alkyl group. Non-limiting examples of suitable
aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl.
The bond to the parent moiety is through the alkyl.
[0071] "Alkylaryl" means an alkyl-aryl- group in which the alkyl
and aryl are as previously described. Preferred alkylaryls comprise
a lower alkyl group. Non-limiting example of a suitable alkylaryl
group is tolyl. The bond to the parent moiety is through the
aryl.
[0072] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system comprising about 3 to about 10 carbon atoms, preferably
about 5 to about 10 carbon atoms. Preferred cycloalkyl rings
contain about 5 to about 7 ring atoms. The cycloalkyl can be
optionally substituted with one or more "ring system substituents"
which may be the same or different, and are as defined above.
Non-limiting examples of suitable monocyclic cycloalkyls include
cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
Non-limiting examples of suitable multicyclic cycloalkyls include
1-decalinyl, norbornyl, adamantyl and the like.
[0073] "Halogen" and "Halo" mean fluorine, chlorine, bromine, or
iodine. Preferred are fluorine, chlorine or bromine, and more
preferred are fluorine and chlorine.
[0074] "Ring system substituent" means a substituent attached to an
aromatic or non-aromatic ring system which, for example, replaces
an available hydrogen on the ring system. Ring system substituents
may be the same or different, each being independently selected
from the group consisting of aryl, heteroaryl, aralkyl, alkylaryl,
heteroaralkyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy,
aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,
alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,
heterocyclyl, Y.sub.1Y.sub.2N--, Y.sub.1Y.sub.2N-alkyl-,
Y.sub.1Y.sub.2NC(O)-- and Y.sub.1Y.sub.2NSO.sub.2--, wherein
Y.sub.1. and Y.sub.2 may be the same or different and are
independently selected from the group consisting of hydrogen,
alkyl, aryl, and aralkyl.
[0075] "Heterocyclyl" means a non-aromatic saturated monocyclic or
multicyclic ring system comprising about 3 to about 10 ring atoms,
preferably about 5 to about 10 ring atoms, in which one or more of
the atoms in the ring system is an element other than carbon, for
example nitrogen, oxygen or sulfur, alone or in combination. There
are no adjacent oxygen and/or sulfur atoms present in the ring
system. Preferred heterocyclyls contain about 5 to about 6 ring
atoms. The prefix aza, oxa or thia before the heterocyclyl root
name means that at least a nitrogen, oxygen or sulfur atom
respectively is present as a ring atom. Any --NH in a heterocyclyl
ring may exist protected such as, for example, as an --N(Boc),
--N(CBz), --N(Tos) group and the like; such protected moieties are
also considered part of this invention. The heterocyclyl can be
optionally substituted by one or more "ring system substituents"
which may be the same or different, and are as defined herein. The
nitrogen or sulfur atom of the heterocyclyl can be optionally
oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Non-limiting examples of suitable monocyclic heterocyclyl rings
include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, and the like.
[0076] It should be noted that in heterocyclyl ring systems of this
invention, there are no hydroxyl groups on carbon atoms adjacent to
a N, O or S, as well as there are no N or S groups on carbon
adjacent to another heteroatom. Thus, for example, in the ring:
##STR18## there is no --OH attached directly to carbons marked 2
and 5.
[0077] "Alkynylalkyl" means an alkynyl-alkyl- group in which the
alkynyl and alkyl are as previously described. Preferred
alkynylalkyls contain a lower alkynyl and a lower alkyl group. The
bond to the parent moiety is through the alkyl. Non-limiting
examples of suitable alkynylalkyl groups include
propargylmethyl.
[0078] "Heteroaralkyl" means a heteroaryl-alkyl- group in which the
heteroaryl and alkyl are as previously described. Preferred
heteroaralkyls contain a lower alkyl group. Non-limiting examples
of suitable aralkyl groups include pyridylmethyl, and
quinolin-3-ylmethyl. The bond to the parent moiety is through the
alkyl.
[0079] "Heterocyclylalkyl" means a heterocyclyl-alkyl group in
which the heterocyclyl and the alkyl are as previously described.
Preferred heterocyclylalkyls contain a lower alkyl group,
Non-limiting examples of suitable heterocyclylalkyl groups include
piperidylmethyl, piperidylethyl, pyrrolidylmethyl,
morpholinylpropyl, piperazinylethyl, azindylmethyl, azetidylethyl,
oxiranylpropyl and the like. The bond to the parent moiety is
through the alkyl group.
[0080] "Heterocyclenyl" (or "heterocycloalkeneyl") means a
non-aromatic monocyclic or multicyclic ring system comprising about
3 to about 10 ring atoms, preferably about 5 to about 10 ring
atoms, in which one or more of the atoms in the ring system is an
element other than carbon, for example nitrogen, oxygen or sulfur
atom, alone or in combination, and which contains at least one
carbon-carbon double bond or carbon-nitrogen double bond. There are
no adjacent oxygen and/or sulfur atoms present in the ring system.
Preferred heterocyclenyl rings contain about 5 to about 6 ring
atoms. The prefix aza, oxa or thia before the heterocyclenyl root
name means that at least a nitrogen, oxygen or sulfur atom
respectively is present as a ring atom. The heterocyclenyl can be
optionally substituted by one or more ring system substituents,
wherein "ring system substituent" is as defined above. The nitrogen
or sulfur atom of the heterocyclenyl can be optionally oxidized to
the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting
examples of suitable monocyclic azaheterocyclenyl groups include
1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl,
1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidyl,
2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the
like. Non-limiting examples of suitable oxaheterocyclenyl groups
include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl,
and the like. Non-limiting example of a suitable multicyclic
oxaheterocyclenyl group is 7-oxabicyclo[2.2.1 ]heptenyl.
Non-limiting examples of suitable monocyclic thiaheterocyclenyl
rings include dihydrothiophenyl, dihydrothiopyranyl, and the
like.
[0081] "Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Non-limiting examples of suitable hydroxyalkyl groups include
hydroxymethyl and 2-hydroxyethyl.
[0082] "Acyl" means an organic acid group in which the --OH of the
carboxyl group is replaced by some other substituent. Suitable
non-limiting examples include H--C(O)--, alkyl-C(O)--,
cycloalkyl-C(O)--, heterocyclyl-C(O)--, and heteroaryl-C(O)--
groups in which the various groups are as previously described. The
bond to the parent moiety is through the carbonyl. Preferred acyls
contain a lower alkyl. Non-limiting examples of suitable acyl
groups include formyl, acetyl and propanoyl.
[0083] "Aroyl" means an aryl-C(O)-- group in which the aryl group
is as previously described. The bond to the parent moiety is
through the carbonyl. Non-limiting examples of suitable groups
include benzoyl and 1-naphthoyl.
[0084] "Alkoxy" means an alkyl-O-- group in which the alkyl group
is as previously described. Non-limiting examples of suitable
alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and
n-butoxy. The bond to the parent moiety is through the ether
oxygen.
[0085] "Aryloxy" means an aryl-O-- group in which the aryl group is
as previously described. Non-limiting examples of suitable aryloxy
groups include phenoxy and naphthoxy. The bond to the parent moiety
is through the ether oxygen.
[0086] "Aralkyloxy" means an aralkyl-O-- group in which the aralkyl
group is as previously described. Non-limiting examples of suitable
aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
The bond to the parent moiety is through the ether oxygen.
[0087] "Alkylthio" means an alkyl-S-- group in which the alkyl
group is as previously described. Non-limiting examples of suitable
alkylthio groups include methylthio and ethylthio. The bond to the
parent moiety is through the sulfur.
[0088] "Arylthio" means an aryl-S-- group in which the aryl group
is as previously described. Non-limiting examples of suitable
arylthio groups include phenylthio and naphthylthio. The bond to
the parent moiety is through the sulfur.
[0089] "Aralkylthio" means an aralkyl-S-- group in which the
aralkyl group is as previously described. Non-limiting example of a
suitable aralkylthio group is benzylthio. The bond to the parent
moiety is through the sulfur.
[0090] "Alkoxycarbonyl" means an alkyl-O--CO-- group. Non-limiting
examples of suitable alkoxycarbonyl groups include methoxycarbonyl
and ethoxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0091] "Aryloxycarbonyl" means an aryl-O--C(O)-- group.
Non-limiting examples of suitable aryloxycarbonyl groups include
phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent
moiety is through the carbonyl.
[0092] "Aralkoxycarbonyl" means an aralkyl-O--C(O)-- group.
Non-limiting example of a suitable aralkoxycarbonyl group is
benzyloxycarbonyl. The bond to the parent moiety is through the
carbonyl.
[0093] "Alkylsulfonyl" means an alkyl-S(O.sub.2)-- group. Preferred
groups are those in which the alkyl group is lower alkyl. The bond
to the parent moiety is through the sulfonyl.
[0094] "Arylsulfonyl" means an aryl-S(O.sub.2)-- group. The bond to
the parent moiety is through the sulfonyl.
[0095] The term "substituted" means that one or more hydrogens on
the designated atom is replaced with a selection from the indicated
group, provided that the designated atom's normal valency under the
existing circumstances is not exceeded, and that the substitution
results in a stable compound. Combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds. By "stable compound" or "stable structure" is
meant a compound that is sufficiently robust to survive isolation
to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0096] It is noted that carbons of formula I can be replaced with
1-3 silicon atoms, provided all valency requirements are
satisfied.
[0097] The term "optionally substituted" means optional
substitution with the specified groups, radicals or moieties.
[0098] It should also be noted that any heteroatom with unsatisfied
valences in the text, schemes, examples and Tables herein is
assumed to have the hydrogen atom to satisfy the valences.
[0099] When a functional group in a compound is termed "protected",
this means that the group is in modified form to preclude undesired
side reactions at the protected site when the compound is subjected
to a reaction. Suitable protecting groups will be recognized by
those with ordinary skill in the art as well as by reference to
standard textbooks such as, for example, T. W. Greene et al,
Protective Groups in organic Synthesis (1991), Wiley, New York.
[0100] When any variable (e.g., aryl, heterocycle, R.sup.2, etc.)
occurs more than one time in any constituent or formula, its
definition on each occurrence is independent of its definition at
every other occurrence.
[0101] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0102] Prodrugs and solvates of the compounds of the invention are
also contemplated herein. The term "prodrug", as employed herein,
denotes a compound that is a drug precursor which, upon
administration to a subject, undergoes chemical conversion by
metabolic or chemical processes to yield a compound of formula I or
a salt and/or solvate thereof. A discussion of prodrugs is provided
in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems
(1987) Volume 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed.,
American Pharmaceutical Association and Pergamon Press, both of
which are incorporated herein by reference thereto.
[0103] For example, if a compound of Formula (I) or a
pharmaceutically acceptable salt, hydrate or solvate of the
compound contains a carboxylic acid functional group, a prodrug can
comprise an ester formed by the replacement of the hydrogen atom of
the acid group with a group such as, for example,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.12)alkanoyloxymethyl,
1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,
1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,
1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon
atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon
atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di (C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl, and
the like.
[0104] Similarly, if a compound of Formula (I) contains an alcohol
functional group, a prodrug can be formed by the replacement of the
hydrogen atom of the alcohol group with a group such as, for
example, (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxycarbonyloxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each .alpha.-aminoacyl
group is independently selected from the naturally occurring
L-amino acids, --P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate), and the like.
[0105] If a compound of Formula I incorporates a --NH-- functional
group, such as a in a primary or secondary amine or in a
nitrogen-containing heterocycle, such as imidazole or piperazine
ring, a prodrug can be formed by the replacement of a hydrogen atom
in the amine group with a group such as, for example, R-carbonyl,
RO-carbonyl, NRR'-carbonyl where R and R' are each independently
(C.sub.1-C.sub.10)alkyl, (C.sub.3-C.sub.7) cycloalkyl, benzyl, or
R-carbonyl is a natural .alpha.-aminoacyl or natural
.alpha.-aminoacyl, --C(OH)C(O)OY.sup.1 wherein Y.sup.1 is H,
(C.sub.1-C.sub.6)alkyl or benzyl, --C(OY.sup.2)Y.sup.3 wherein
Y.sup.2 is (C.sub.1-C.sub.4) alkyl and y.sup.3 is
(C.sub.1-C.sub.6)alkyl, carboxy (C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.4)alkyl or mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylaminoalkyl, --C(Y.sup.4)Y.sup.5
wherein y.sup.4 is H or methyl and Y.sup.5 is mono-N-- or
di-N,N--(C.sub.1-C.sub.6)alkylamino morpholino, piperidin-1-yl or
pyrrolidin-1-yl, and the like.
[0106] "Effective amount" or "therapeutically effective amount" is
meant to describe an amount of compound or a composition of the
present invention effective in producing the desired therapeutic,
ameliorative, inhibitory or preventative effect.
[0107] "Capsule" is meant to describe a special container or
enclosure made of methyl cellulose, polyvinyl alcohols, or
denatured gelatins or starch for holding or containing compositions
comprising the active ingredients. Hard shell capsules are
typically made of blends of relatively high gel strength bone and
pork skin gelatins. The capsule itself may contain small amounts of
dyes, opaquing agents, plasticizers and preservatives.
[0108] "Tablet" is meant to describe a compressed or molded solid
dosage form containing the active ingredients with suitable
diluents. The tablet can be prepared by compression of mixtures or
granulations obtained by wet granulation, dry granulation or by
compaction.
[0109] "Oral gels" is meant to describe to the active ingredients
dispersed or solubilized in a hydrophillic semi-solid matrix.
[0110] "Powders for constitution" refers to powder blends
containing the active ingredients and suitable diluents which can
be suspended in water or juices.
[0111] "Diluent" refers to substances that usually make up the
major portion of the composition or dosage form. Suitable diluents
include sugars such as lactose, sucrose, mannitol and sorbitol;
starches derived from wheat, corn, rice and potato; and celluloses
such as microcrystalline cellulose. The amount of diluent in the
composition can range from about 10 to about 90% by weight of the
total composition, preferably from about 25 to about 75%, more
preferably from about 30 to about 60% by weight, even more
preferably from about 12 to about 60%.
[0112] "Disintegrants" refers to materials added to the composition
to help it break apart (disintegrate) and release the medicaments.
Suitable disintegrants include starches; "cold water soluble"
modified starches such as sodium carboxymethyl starch; natural and
synthetic gums such as locust bean, karaya, guar, tragacanth and
agar; cellulose derivatives such as methylcellulose and sodium
carboxymethylcellulose; microcrystalline celluloses and
cross-linked microcrystalline celluloses such as sodium
croscarmellose; alginates such as alginic acid and sodium alginate;
clays such as bentonites; and effervescent mixtures. The amount of
disintegrant in the composition can range from about 2 to about 15%
by weight of the composition, more preferably from about 4 to about
10% by weight.
[0113] "Binders" refers to substances that bind or "glue" powders
together and make them cohesive by forming granules, thus serving
as the "adhesive" in the formulation. Binders add cohesive strength
already available in the diluent or bulking agent. Suitable binders
include sugars such as sucrose; starches derived from wheat, corn
rice and potato; natural gums such as acacia, gelatin and
tragacanth; derivatives of seaweed such as alginic acid, sodium
alginate and ammonium calcium alginate; cellulosic materials such
as methylcellulose and sodium carboxymethylcellulose and
hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics
such as magnesium aluminum silicate. The amount of binder in the
composition can range from about 2 to about 20% by weight of the
composition, more preferably from about 3 to about 10% by weight,
even more preferably from about 3 to about 6% by weight.
[0114] "Lubricant" is meant to describe a substance added to the
dosage form to enable the tablet, granules, etc. after it has been
compressed, to release from the mold or die by reducing friction or
wear. Suitable lubricants include metallic stearates such as
magnesium stearate, calcium stearate or potassium stearate; stearic
acid; high melting point waxes; and water soluble lubricants such
as sodium chloride, sodium benzoate, sodium acetate, sodium oleate,
polyethylene glycols and d'l-leucine. Lubricants are usually added
at the very last step before compression, since they must be
present on the surfaces of the granules and in between them and the
parts of the tablet press. The amount of lubricant in the
composition can range from about 0.2 to about 5% by weight of the
composition, preferably from about 0.5 to about 2%, more preferably
from about 0.3 to about 1.5% by weight.
[0115] "Glidents" means materials that prevent caking and improve
the flow characteristics of granulations, so that flow is smooth
and uniform. Suitable glidents include silicon dioxide and talc.
The amount of glident in the composition can range from about 0.1%
to about 5% by weight of the total composition, preferably from
about 0.5 to about 2% by weight.
[0116] "Coloring agents" refers to excipients that provide
coloration to the composition or the dosage form. Such excipients
can include food grade dyes and food grade dyes adsorbed onto a
suitable adsorbent such as clay or aluminum oxide. The amount of
the coloring agent can vary from about 0.1 to about 5% by weight of
the composition, preferably from about 0.1 to about 1%.
[0117] "Bioavailability" refers to the rate and extent to which the
active drug ingredient or therapeutic moiety is absorbed into the
systemic circulation from an administered dosage form as compared
to a standard or control. Conventional methods for preparing
tablets are known. Such methods include dry methods such as direct
compression and compression of granulation produced by compaction,
or wet methods or other special procedures. Conventional methods
for making other forms for administration such as, for example,
capsules, suppositories and the like are also well known.
[0118] The compounds of Formula I can form salts which are also
within the scope of this invention. Reference to a compound of
Formula I herein is understood to include reference to salts
thereof, unless otherwise indicated. The term "salt(s)", as
employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or
organic bases. In addition, when a compound of Formula III contains
both a basic moiety, such as, but not limited to a pyridine or
imidazole, and an acidic moiety, such as, but not limited to a
carboxylic acid, zwitterions ("inner salts") may be formed and are
included within the term "salt(s)" as used herein. Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are
preferred, although other salts are also useful. Salts of the
compounds of the Formula I may be formed, for example, by reacting
a compound of Formula I with an amount of acid or base, such as an
equivalent amount, in a medium such as one in which the salt
precipitates or in an aqueous medium followed by
lyophilization.
[0119] Exemplary acid addition salts include acetates, ascorbates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, fumarates,
hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates,
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates,) and the like. Additionally, acids which are generally
considered suitable for the formation of pharmaceutically useful
salts from basic pharmaceutical compounds are discussed, for
example, by S. Berge et al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1-19; P. Gould, Intemational J. of Pharmaceutics
(1986) 33 201-217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their
website). These disclosures are incorporated herein by reference
thereto.
[0120] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, salts with organic
bases (for example, organic amines) such as dicyclohexylamines,
t-butyl amines, and salts with amino acids such as arginine, lysine
and the like. Basic nitrogen-containing groups may be quarternized
with agents such as lower alkyl halides (e.g. methyl, ethyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g.
decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides (e.g. benzyl and phenethyl bromides), and
others.
[0121] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the invention
and all acid and base salts are considered equivalent to the free
forms of the corresponding compounds for purposes of the
invention.
[0122] Compounds of Formula I, and salts, solvates and prodrugs
thereof, may exist in their tautomeric form (for example, as an
amide or imino ether). All such tautomeric forms are contemplated
herein as part of the present invention.
[0123] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates and prodrugs of the compounds as well as the
salts and solvates of the prodrugs), such as those which may exist
due to asymmetric carbons or sulfurs on various substituents,
including enantiomeric forms (which may exist even in the absence
of asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
invention. For example, if a compound of Formula (I) incorporates a
double bond or a fused ring, both the cis- and trans-forms, as well
as mixtures, are embraced within the scope of the invention.
Individual stereoisomers of the compounds of the invention may, for
example, be substantially free of other isomers, or may be admixed,
for example, as racemates or with all other, or other selected,
stereoisomers. The chiral centers of the present invention can have
the S or R configuration as defined by the IUPAC 1974
Recommendations. The use of the terms "salt", "solvate" "prodrug"
and the like, is intended to equally apply to the salt, solvate and
prodrug of enantiomers, stereoisomers, rotamers, tautomers,
racemates or prodrugs of the inventive compounds.
[0124] Diasteromeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as, for example, by chromatography and/or fractional
crystallization. Enantiomers can be separated by converting the
enantiomeric mixture into a diasteromeric mixture by reaction with
an appropriate optically active compound (e.g., chiral auxiliary
such as a chiral alcohol or Mosher's acid chloride), separating the
diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. Also, some of
the compounds of Formula (I) may be atropisomers (e.g., substituted
biaryls) and are considered as part of this invention. Enantiomers
can also be separated by use of chiral HPLC column.
[0125] Polymorphic forms of the compounds of formula I, and of the
salts, solvates and prodrugs of the compounds of formula I, are
intended to be included in the present invention
[0126] The present invention also embraces isotopically-labelled
compounds of the present invention which are identical to those
recited herein, but for the fact that one or more atoms are
replaced by an atom having an atomic mass or mass number different
from the atomic mass or mass number usually found in nature.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorus, fluorine and chlorine, such as .sup.2H, .sup.3H,
.sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P,
.sup.32P, .sup.35S, .sup.18F, and .sup.36Cl, respectively.
[0127] Certain isotopically-labelled compounds of Formula (I)
(e.g., those labeled with .sup.3H, .sup.11C and .sup.14C) are
useful in compound and/or substrate tissue distribution assays.
Tritiated (i.e., .sup.3H) and carbon-14 (i.e., .sup.14C) isotopes
are particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium (i.e., .sup.2H) may afford certain therapeutic advantages
resulting from greater metabolic stability (e.g., increased in vivo
half-life or reduced dosage requirements) and hence may be
preferred in some circumstances. Isotopically labelled compounds of
Formula (I) can generally be prepared by following procedures
analogous to those disclosed in the Schemes and/or in the Examples
hereinbelow, by substituting an appropriate isotopically labelled
reagent for a non-isotopically labelled reagent.
[0128] The compounds according to the invention have
pharmacological properties; in particular, the compounds of Formula
I can be useful as .alpha.2C adrenoreceptor agonists.
[0129] A preferred dosage is about 0.001 to 500 mg/kg of body
weight/day of the compound of Formula I. An especially preferred
dosage is about 0.01 to 25 mg/kg of body weight/day of a compound
of Formula I, or a pharmaceutically acceptable salt or solvate of
said compound.
[0130] The compounds of this invention may also be useful in
combination (administered together or sequentially) with one or
more therapeutic agents such as, for example, steroids, PDE-4
inhibitors, anti-muscarinic agents, cromolyn sodium, H.sub.1
receptor antagonists, 5-HT.sub.1 agonists, NSAIDs,
angiotensin-converting enzyme inhibitors, angiotensin II receptor
agonists, .beta.-blockers, .beta.-agonists (including both short
and long acting), leukotriene antagonists, diuretics, aldosterone
antagonists, ionotropic agents, natriuretic peptides, pain
management/analgesic agents, anti-anxiety agents, anti-migraine
agents, and therapeutic agents suitable for treating heart
conditions, psychotic disorders, and glaucoma.
[0131] Suitable steroids include prednisolone, fluticasone
(including all esters such as the propionate or furoate esters),
triamcinolone, beclomethasone, mometasone (including any ester form
such as mometasone furoate), budasamine, ciclesonide,
betamethasone, dexamethasone, prednisone, flunisolide, and
cortisone.
[0132] Suitable PDE-4 inhibitors include roflumilast, theophylline,
rolipram, piclamilast, cilomilast, and CDP-840.
[0133] Suitable antiimuscarinic agents include ipratropium bromide
and tiatropium bromide.
[0134] Suitable H.sub.1 antagonists include astemizole, azatadine,
azelastine, acrivastine, brompheniramine, cetirizine,
chlorpheniramine, clemastine, cyclizine, carebastine,
cyproheptadine, carbinoxamine, descarboethoxyloratidine,
diphenhydramine, doxylamine, dimethindene, ebastine, epinastine,
efletirizeine, fexofenadine, hydroxyzine, ketotifen, loratidine,
levocabastine, meclizine, fexofenadine, hydroxyzine, ketotifen,
loratadine, levocabastine, meclizine, mizolastine, mequitazine,
mianserin, noberastine, norastemizole, picumast, pyrilamine,
promethazine, terfenadine, tripelennamine, temelastine,
trimeprazine or triprolidine.
[0135] Suitable anti-inflammatory agents include aspirin,
diclofenac, diflunisal, etodolac, flurbiprofen, ibuprofen,
indomethacin, ketoprofen, ketorolac, nabumetone, naproxen,
oxaprozin, piroxicam, sulindac, and tolmetin.
[0136] Suitable aldosterone antagonists include spironolactone.
[0137] Suitable ionotropic agents include digitalis.
[0138] Suitable angiotensin II receptor agonists include irbesartan
and losartan.
[0139] Suitable diuretics include spironolactone, methyclothiazide,
bumetanide, torsemide, hydroflumethiazide, trichlormethiazide,
hydroclorothiazide, triamterene, ethacrynic acid, methyclothiazide,
hydrochlorothiazide, benzthiazide, hydrochlorothiazide,
quinethazone, hydrochlorothiazide, chlorthalidone, furosemide,
indapamide, hydroclorothiazide, triamterene, trichlormethiazide,
hydrochlorothiazide, amiloride HCl, amiloride HCl, metolazone,
trichlormethiazide, bendroflumethiazide, hydrochlorothiazide,
polythiazide, hydroflumethiazide, chlorthalidone, and
metolazone.
[0140] Suitable pain management/analgesic agents include Celecoxib,
amitriptyline, ibuprofen, naproxen, gabapentin, tramadol,
rofecoxib, oxycodone HCl, acetaminophenoxycodone HCl,
carbamazepine, diclofenac, diclofenac, etodolac, fenoprofen
calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen,
ketorolac tromethamine, mefenamic acid, meloxicam, nabumetone,
naproxen, oxaprozin, piroxicam, sulindac, tolmetin sodium,
valdecoxib, diclofenac/misoprostol, oxycontin, vicodin, darvocet,
morphine sulfate, dilaudid, stadol, stadol NS, acetaminophen with
codeine, acetaminophen with codeine #4, Lidoderm.RTM. patches, and
percocet.
[0141] Suitable .beta.-blockers include acebutolol, atenolol,
atenolol/chlorthalidone, betaxolol, bisoprolol fumarate,
bisoprolol/HCTZ, labetolol, metoprolol tartrate, nadolol, pindolol,
propranolol, propranolol/HCTZ, sotalol, and timolol.
[0142] Suitable .beta.-agonists include dobutamine, ritodrine,
salbutamol, levalbuterol, metaproternol, formoterol, fenoterol,
bambuterol, brocaterol, clenbuterol, terbutaline, tulobuterol,
epinephrine, isoprenalin, and hexoprenalin.
[0143] Suitable leukotriene antagonists include levamisole.
[0144] Suitable anti-migraine agents include rovatriptan succinate,
naratriptan HCl, rizatriptan benzoate, sumatriptan succinate,
zolmitriptan, almotriptan malate, methysergide maleate,
dihydroergotamine mesylate, ergotamine tartrate, ergotamine
tartrate/caffeine, Fioricet.RTM., Fiorninal.RTM., Depakene.RTM.,
and Depakote.RTM..
[0145] Suitable anti-anxiety and anti-depressant agents include
amitriptyline HCl, bupropion HCl, citalopram hydrobromide,
clomipramine HCl, desipramine, fluoxetine, fluvoxamine maleate,
maprotiline HCl, mirtazapine, nefazodone HCl, nortriptyline,
paroxetine HCl, protriptyline HCl, sertraline HCl, doxepin, and
trimipramine maleate.
[0146] Suitable angiotensin converting enzyme inhibitors include
Captopril, enalapril, enalapril/HCTZ, lisinopril, lisinopriVHCTZ,
and Aceon.RTM..
[0147] The pharmacological properties of the compounds of this
invention may be confirmed by a number of pharmacological assays.
The exemplified pharmacological assays which are described later
have been carried out with the compounds according to the invention
and their salts.
[0148] This invention is also directed to pharmaceutical
compositions which comprise at least one compound of Formula I, or
a pharmaceutically acceptable salt or solvate of said compound and
at least one pharmaceutically acceptable carrier.
[0149] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 95 percent active ingredient. Suitable solid
carriers are known in the art, e.g., magnesium carbonate, magnesium
stearate, talc, sugar or lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration. Examples of pharmaceutically acceptable carriers
and methods of manufacture for various compositions may be found in
A. Gennaro (ed.), Remington's Pharmaceutical Sciences, .sub.18th
Edition, (1990), Mack Publishing Co., Easton, Pa.
[0150] Liquid form preparations include solutions, suspensions and
emulsions. As an example may be mentioned water or water-propylene
glycol solutions for parenteral injection or addition of sweeteners
and opacifiers for oral solutions, suspensions and emulsions.
Liquid form preparations may also include solutions for intranasal
administration.
[0151] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g. nitrogen.
[0152] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0153] The compounds of the invention may also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0154] The compounds of this invention may also be delivered
subcutaneously.
[0155] Preferably the compound is administered orally.
[0156] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0157] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 1 mg to about 100
mg, preferably from about 1 mg to about 50 mg, more preferably from
about 1 mg to about 25 mg, according to the particular
application.
[0158] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage regimen for a
particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day as required.
[0159] The amount and frequency of administration of the compounds
of the invention and/or the pharmaceutically acceptable salts
thereof will be regulated according to the judgment of the
attending clinician considering such factors as age, condition and
size of the patient as well as severity of the symptoms being
treated. A typical recommended daily dosage regimen for oral
administration can range from about 1 mg/day to about 500 mg/day,
preferably 1 mg/day to 200 mg/day, in two to four divided
doses.
[0160] Another aspect of this invention is a kit comprising a
therapeutically effective amount of at least one compound of
Formula I, or a pharmaceutically acceptable salt or solvate of said
compound and a pharmaceutically acceptable carrier, vehicle or
diluent.
[0161] Yet another aspect of this invention is a kit comprising an
amount of at least one compound of Formula I, or a pharmaceutically
acceptable salt or solvate of said compound and an amount of at
least one therapeutic agent listed above, wherein the amounts of
the two or more ingredients result in desired therapeutic
effect.
[0162] The invention disclosed herein is exemplified by the
following preparations and examples which should not be construed
to limit the scope of the disclosure. Alternative mechanistic
pathways and analogous structures will be apparent to those skilled
in the art.
[0163] Where NMR data are presented, .sup.1H spectra were obtained
on either a Varian VXR-200 (200 MHz, .sup.1H), Varian Gemini-300
(300 MHz), Varian Mercury VX-400 (400 MHz), or Bruker-Biospin
AV-500 (500 MHz), and are reported as ppm with number of protons
and multiplicities indicated parenthetically. Where LC/MS data are
presented, analyses was performed using an Applied Biosystems
API-100 mass spectrometer and C18 column, 10-95%
CH.sub.3CN--H.sub.2O (with 0.05% TFA) gradient. The observed parent
ion is given.
[0164] The following solvents and reagents may be referred to by
their abbreviations in parenthesis: [0165] Me=methyl; Et=ethyl;
Pr=propyl; Bu=butyl; Ph=phenyl, and Ac=acetyl [0166]
.mu.l=microliters [0167] AcOEt or EtOAc=ethyl acetate [0168] AcOH
or HOAc=acetic acid [0169] ACN=acetonitrile [0170] atm=atmosphere
[0171] Boc or BOC=tert-butoxycarbonyl [0172] DCE=dichloroethane
[0173] DCM or CH.sub.2Cl.sub.2: dichloromethane: [0174]
DIPEA=diisopropylethylamine [0175] DMAP=4-dimethylaminopyridine
[0176] DMF=dimethylformamide [0177] DMS=dimethylsulfide [0178]
DMSO=dimethyl sulfoxide [0179]
EDCl=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide [0180]
Fmoc=9-fluorenylmethoxycarbonyl [0181] g=grams [0182] h=hour [0183]
hal=halogen [0184] HOBt=1-hydroxybenzotriazole [0185] LAH=lithium
aluminum hydride [0186] LCMS=liquid chromatography mass
spectrometry [0187] min=minute [0188] mg=milligrams [0189]
mL=milliliters [0190] mmol=millimoles [0191]
MCPBA=3-chloroperoxybenzoic acid [0192] MeOH=methanol [0193]
MS=mass spectrometry [0194] NMR=nuclear magnetic resonance
spectroscopy [0195] RT or rt=room temperature (ambient, about
25.degree. C.) [0196] TEA or Et.sub.3N=triethylamine [0197]
TFA=trifluoroacetic acid [0198] THF=tetrahydrofuran [0199] TLC=thin
layer chromatography [0200] TMS=trimethylsilyl [0201]
Tr=triphenylmethyl
EXAMPLES
[0202] The compounds of this invention can be prepared as generally
described in Schemes 1 and 2, and the following examples. Scheme 1
shows an approach in which S1 and S2 are joined together. Examples
of these approaches include reaction of S1 with an electrophilic S2
compound, where R' is a carboxaldehyde (coupling by reductive
amination), carboxylic acid (amide coupling) or halide (coupling by
alkylation). ##STR19## Scheme 2 discloses a general approach for
synthesizing S1, whereby an appropriately substituted aniline S4
can be converted to S1 through a single or multistep ring
cyclization approach. ##STR20##
[0203] Compounds of formula S3 can be prepared by the general
methods outlined above. Specifically exemplified compounds were
prepared from S4 or S1 fragments as described in the examples below
or from starting materials known in the art.
[0204] The starting materials and reagents used in preparing
compounds described are either available from commercial suppliers
such as Aldrich Chemical Co. (Wisconsin, USA) and Acros Organics
Co. (New Jersey, USA) or were prepared by literature methods known
to those skilled in the art. These examples are being provided to
further illustrate the present invention. They are for illustrative
purposes only; the scope of the invention is not to be considered
limited in any way thereby.
Preparative Example 1
[0205] ##STR21##
[0206] A solution of 3,4-dihydro-2H-1,4-benzoxazine 1A (0.1 g, 0.75
mmol) in DCE (10 mL) was treated with imidazole-4-carboxaldehye 1B
(0.11 g, 1.1 mmol), NaBH(OAc).sub.3 (0.47 g, 2.2 mmol), and ACOH
(one drop) and stirred at 60.degree. C. overnight. The reaction was
then diluted with CH.sub.2Cl.sub.2, washed with saturated aqueous
NaHCO.sub.3, dried over Na.sub.2SO.sub.4, and concentrated.
Chromatography (0-4% 7 N NH.sub.3-MeOH/CH.sub.2Cl.sub.2) provided 1
as a beige solid (0.08 g, 50%). LMCS m/z 216 (MH+).
[0207] Alternatively, the title compound 1 can be synthesized by
the reaction of 1A and resin bound imidazole-4-carboxaldehye 1D as
described below: ##STR22##
[0208] Novabiochem Resin 1C (100-200 mesh, 1% DVB, 1.4 mmol/g, 5 g)
was suspended in anhydrous DMF (25 mL) and DCE (25 mL) and treated
sequentially with 1B (2 g, 21 mmol) and TEA (2.96 mL, 21 mmol). The
resin was shaken overnight and washed with DMF (3.times.), MeOH
(3.times.), and DCM (4.times.) then dried in vacuo overnight. The
resulting resin 1D (100 mg, 1.4 mmol/g, 0.14 mmol) was suspended in
DCE (4 mL) and treated with 1A (94.5 mg, 0.7 mmol) and
NaBH(OAc).sub.3 (148 mg, 0.7 mmol). The reaction was shaken
overnight and washed with DMF (3.times.), MeOH (3.times.), and DCM
(4.times.), then dried in vacuo. The resulting resin was subjected
to 30% TFA/DCM, stirred at RT for 2 h and the mixture was
concentrated under vacuum. The residue was purified by Gilson
prep-HPLC to afford compound 1 (12.3 mg).
Preparative Example 2
[0209] ##STR23##
[0210] A solution of 3,4-dihydro-2H-1,4-benzoxazine (0.52 g, 3.8
mmol) and thiophene-3-acetic acid (0.82 g, 5.7 mmol) in 1:1
CH.sub.2Cl.sub.2:DMF (20 mL) was treated with DIPEA (2.6 ml, 15
mmol), HOBt (1.29 g, 9.5 mmol), and EDCI (1.83 g, 9.5 mmol) and
stirred at 70.degree. C. overnight. The reaction was then diluted
with CH.sub.2Cl.sub.2, washed with saturated aqueous NaHCO.sub.3,
dried over Na.sub.2SO.sub.4, and concentrated. Chromatography
(0-10% 1 N NH.sub.3-MeOH/EtOAc) provided 2A as a red solid (0.54 g,
55%)
Step 2
[0211] A solution of 2A (0.094 g, 0.36 mmol) in THF (10 mL) was
treated with BH.sub.3--SMe.sub.2 (2M/THF, 0.27 mL, 0.54 mmol) and
stirred at reflux for 2 h. The reaction was concentrated and
subjected to chromatography (EtOAc) to provide 2 as a white solid
(0.040 g, 45%). LMCS m/z 246 (MH+).
Preparative Example 3
[0212] ##STR24##
[0213] A mixture of 2-amino-4-nitrophenol (3A, 25.03 g, 0.16 mol)
in 4-methyl-2-pentanone and water (420 mL, 1:1) was treated with
sodium bicarbonate (32.74 g, 0.39 mol), cooled to 0.degree. C., and
treated then with chloroacetyl chloride (15.52 mL, 0.19 mol). The
reaction mixture was heated to reflux overnight. After cooling to
RT, the mixture was concentrated under vacuum. The residue was
diluted with water (200 mL) and EtOAc (100 mL), and filtered to
give the pale gray solid 3B (26.05 g). The filtrate was separated
and the aqueous was extracted with EtOAc (3.times.100 mL). The
combined organic layers were washed with water, and dried
(MgSO.sub.4), filtered, and concentrated under vacuum to give
additional light gray solid 3B (7.7 g). The resulting solid
(quantitative yield) was used for next reaction without further
purification. ##STR25##
[0214] To compound 3B (6.76 g, 34.84 mmol) in anhydrous THF (200
mL) was added BH.sub.3--SMe.sub.2 (2.0M/THF, 35 mL, 69.68 mmol).
The mixture was heated to reflux for 2 h. After cooling to RT, the
mixture was quenched with MeOH (10 ml) and heated to reflux for
another 10 minutes. The reaction mixture was concentrated under
vacuum. Chromatography (10%-30% EtOAc/hexanes) provided 3C (6.1 g,
97% for two steps). ##STR26##
[0215] A mixture of 3C (4.35 g, 21.16 mmol) in anhydrous
dichloroethane (60 mL) was treated with imidazole-4-carboxaldehye
(1B, 2.79 g, 28.99 mmol) and AcOH (0.35 mL, 6 mmol). The mixture
was stirred at RT for 10 min and then treated with NaBH(OAc).sub.3
(15.36 g, 72.48 mmol). The reaction mixture was stirred at RT
overnight, and quenched with 2N NaOH solution, concentrated under
vacuum. The residue was diluted with water (50 mL) and extracted
with EtOAc (4.times.100 mL). The organic layer was dried
(MgSO.sub.4), filtered, and concentrated under vacuum.
Chromatography (DCM containing 1 to 5% of 7N NH.sub.3 in MeOH)
provided 3D (5.56 g, 89%). MS m/z 261 (MH+). ##STR27##
[0216] Compound 3D (5.56 g, 21.38 mmol) was dissolved in MeOH/EtOAc
(300 mL, 1:1), 10% Pd/C (1.11 g, 20% by weight) was carefully
added. The mixture was stirred at RT under a hydrogen balloon
overnight and filtered. The solvent was evaporated off under vacuum
to give a white solid 3E (5.46 g, 100%). MS m/z 231 (MH+).
##STR28##
[0217] A mixture of amine 3E (2.14 g, 9.30 mmol) in anhydrous DCM
(40 mL) was sequentially treated with TEA (3.24 mL, 23.3 mmol) and
ClCO.sub.2Me (1.43 mL, 18.6 mmol). The mixture was stirred at RT
for 2 h, and then quenched with 2N NaOH solution. The resulting
mixture was stirred for another 2 h and separated. The aqueous
layer was extracted with DCM (3.times.50 mL). The combined organic
layers were dried (MgSO.sub.4), filtered, and concentrated under
vacuum. Chromatography (DCM containing 1 to 4% of 7N NH.sub.3/MeOH)
provided 3 as a white solid (1.64 g, 61%). MS m/z 289 (MH+).
Preparative Example 4
[0218] ##STR29##
[0219] In a manner similar to Example 3, Step 5, amine 3E was
treated with TEA and AcCl to provide the compound 4. MS m/z 273
(MH+).
Preparative Example 5
[0220] ##STR30##
[0221] A solution of 3C (3 g, 16.7 mmol) in anhydrous DCM (100 mL)
was treated with Boc.sub.2O (7.27 g, 33.3 mmol), pyridine (5.39 mL,
66.7 mmol), and catalytic DMAP. The mixture was stirred at RT
overnight and concentrated under vacuum. The residue was diluted
with water (50 mL) and extracted with EtOAc (3.times.100 mL). The
combined organic layers were dried (MgSO.sub.4), concentrated and
subjected to chromatography (5-5% EtOAc/hexanes, yield: 3 g,
64%).
[0222] The resulting product was hydrogenated in a manner similar
to that found in Example 3, Step 4 to provide 5A. ##STR31##
[0223] To amine 5A (1.1 g, 4.4 mmol) in anhydrous THF (15 mL) was
added MeNCO (215 mg, 4.4 mmol). The mixture was stirred at RT
overnight and then concentrated. Chromatography (DCM containing 1
to 5% of 7N NH.sub.3/MeOH) provided 5B (890 mg, 66%). ##STR32##
[0224] Compound 5B (890 mg, 2.9 mmol) was stirred at RT in 30%
TFA/DCM (14 mL) containing three drops of Et.sub.3SiH for 1 h, and
then quenched with 2N NaOH solution. The mixture was extracted with
EtOAc (3.times.50 mL). The organic layer was dried (MgSO.sub.4),
filtered and concentrated under vacuum. The residue (5C, 600 mg)
was used in the next reaction without further purification.
##STR33##
[0225] In a manner similar to that described in Example 3 (Step 3),
compound 5C was treated with imidazole-4-carboxaldehyde (1B) to
provide title compound 5 (56% for two steps). MS m/z 288 (MH+).
[0226] Compounds 5D-5F in Table 1 below can be prepared from
compound 5A using various capping reagents as shown, followed by
Boc-deprotection and reductive alkylation as described above.
TABLE-US-00001 TABLE 1 ##STR34## Cpd Reagent R MS (MH+) 5D
Methanesulfonic anhydride/pyridine ##STR35## 309 5E ##STR36##
##STR37## 338 5F ##STR38## ##STR39## 302
Preparative Example 6
[0227] ##STR40##
[0228] To a flask with Ac.sub.2O (2.02 mL, 21.4 mmol) at 0.degree.
C. was added HCO.sub.2H (0.82 mL, 21.4 mmol) by syringe. After
stirring at 0.degree. C. for 5 min, the mixture was heated up to
55.degree. C. for 2 h, and then was cooled to 0.degree. C. again.
Amine 5A (2 g, 8.0 mmol) in anhydrous THF (100 mL) was added and
the mixture was stirred at 0.degree. C. for 30 min. The reaction
mixture was concentrated under vacuum and diluted with 2 N NaOH
solution to pH 9, extracted with EtOAc (3.times.50 mL). The organic
layer was dried (MgSO.sub.4), filtered, and concentrated under
vacuum to give a foam 6A (quantitative yield).
[0229] Alternatively, a mixture of compound 5A (17.5 g, 69.9 mmol)
in butyl formate (700 ml) was heated at 50.degree. C. for 3 h and
then left at RT overnight. The reaction mixture was then
concentrated, added to 100 ml of 0.5N NaOH, extracted with
CH.sub.2Cl.sub.2 (4.times.), dried with Na.sub.2SO.sub.4, and
concentrated. Chromatography (10%-50% EtOAc/hexane) gave 6A (9.19
g, 47%) as a light brown sticky foam. ##STR41##
[0230] A mixture of compound 6A (2.75 g, 9.88 mmol) in THF (30 ml)
was treated slowly with BH.sub.3-DMS (2.0 M/THF, 7.8 ml) and then
heated at reflux for 3 h. The reaction mixture was concentrated,
treated with K.sub.2CO.sub.3 (1.5 g) and EtOH, and then stirred
overnight at RT. The reaction mixture was filtered, concentrated,
added to H.sub.2O and extracted with CH.sub.2Cl.sub.2 (4.times.).
The combined organic layers were dried with Na.sub.2SO.sub.4,
filtered and concentrated to provide 6B as a clear oil (2.76 g).
##STR42##
[0231] A solution of 6B (2.76 g, crude) in CH.sub.2Cl.sub.2 (20 ml)
was treated slowly with MeNCO (1.0 g, 12.5 mmol) and stirred at RT
overnight. The reaction mixture was concentrated and
chromatographed (50% to 80% EtOAc/hex, 3.10 g, 98% yield from 6A).
This product (3.10 g, 9.65 mmol) was taken up in of
CH.sub.2Cl.sub.2 (80 ml) and deprotected with of TFA (11.5 ml) as
described in Example 5, Step 4 (95% yield). A mixture of the
resulting amine and aldehyde 1B (1 eq) in a minimal amount of
CH.sub.2Cl.sub.2 was treated with Ti(OiPr).sub.4 (1.3 eq). After
stirring for 2 h at RT, NaBH.sub.4 (1.2 eq) and EtOH were added.
The reaction mixture was then stirred overnight, concentrated,
treated with H.sub.2O and extracted with CH.sub.2Cl.sub.2
(4.times.). The combined organic layers were dried with
Na.sub.2SO.sub.4, filtered, concentrated and chromatographed
(silica gel, 5% MeOH/CH.sub.2Cl.sub.2 w/NH.sub.3) to provide the
title compound 6 (74% yield). MS m/z 302 (MH+). Compounds in Table
2 below can be prepared from compound 6B using the various capping
reagents as shown, followed by Boc-deprotection and reductive
alkylation as shown in Example 5. TABLE-US-00002 TABLE 2 ##STR43##
Cpd Reagent R MS (MH+) 6C TMSNCO ##STR44## 288 6D ##STR45##
##STR46## 352 6E MeCOCl /pyridine ##STR47## 303 ##STR48##
##STR49##
[0232] Compound 6F was prepared as follows: 6A was treated with
TFA, followed by reductive alkylation with
imidazole-4-carboxaldehyde (1B) as described previously in Example
5 (Step 4) and Example 3 (Step 3). MS m/z 259 (MH+). ##STR50##
[0233] In a manner similar to Example 3, Step 2, compound 6F was
reduced with BH.sub.3--SMe.sub.2 to provide 6G. MS m/z 245
(MH+).
Preparative Example 7
[0234] ##STR51##
[0235] To a suspension of compound 3D (4.8 g, 18.46 mmol) in
anhydrous DCM (200 mL) was sequentially added TrCl (5.15 g, 18.46
mmol) and TEA (7.7 mL, 55.37 mmol). The mixture was stirred at RT
overnight, and quenched with saturated NH.sub.4Cl solution. The
solution was separated and the aqueous was extracted with DCM
(3.times.100 mL). The combined organic layers were washed with
water, dried (MgSO.sub.4), filtered, and concentrated under vacuum
to give red yellowish solid 7A (9.13 g, yield: 98%). ##STR52##
[0236] To compound 7A (4.55 g, 9.06 mmol) in MeOH/EtOAc (400 mL,
1:1) in a hydrogenation bottle was added 10% Pd--C (1 g). The
reaction vessel was shaken in the Parr shaker under 50 psi hydrogen
for 4 h. Then the catalyst was filtered off through a celite bed
and washed with MeOH and EtOAc. The filtrate was concentrated under
vacuum to give white solid 7B (3.81 g, 89%). ##STR53##
[0237] Following the approach outlined in Example 6 (Steps 1-2), 7B
was treated with Ac.sub.2O/HCO.sub.2H and then reduced with
BH.sub.3--SMe.sub.2 to afford 7C. In a manner similar to that found
in Example 5 (Steps 3-4), 7C was further elaborated by treatment
with EtNCO and deprotection with TFA to provide the title compound
7. MS m/z 316 (MH+).
Preparative Example 8
[0238] ##STR54##
[0239] To compound 7C (1.5 g, 3.09 mmol) in anhydrous DCM (10 mL)
was added pyridine (0.5 mL, 6.18 mmol) and ClCO.sub.2Et (0.59 mL,
6.18 mmol) sequentially. The mixture was stirred at RT overnight,
and then quenched with saturated NH.sub.4Cl solution. The solution
was concentrated and the aqueous was extracted with EtOAc
(3.times.50 mL). The combined organic layers were washed with
brine, dried (MgSO.sub.4), filtered, and concentrated under
vacuum.
[0240] The residue was then deprotected with TFA, in a manner
described in Example 5, Step 4, to afford compound 8 (145 mg, 15%
for two steps). MS m/z 317 (MH+).
Preparative Example 9
[0241] ##STR55## The synthesis in Example 9 used starting materials
9A, 9B or 9C. Compound 9B can be synthesized from 9A by using
reduction method A or B:
[0242] Method A: To compound 9A in MeOH was added 10% Pd/C and the
mixture was stirred at RT under hydrogen balloon overnight. Then
the catalyst was filtered off through a celite bed and washed with
MeOH. The filtrate was concentrated to give compound 9B for next
reaction without further purification.
[0243] Method B: To compound 9A in EtOH was added
SnCl.sub.2-2H.sub.2O (4eq.), and the mixture was heated to reflux
for 2 h. The mixture was concentrated and poured into ice,
neutralized to pH 7 with sat. NaHCO.sub.3. Then the solid was
filter off and washed extensively with EtOAc. The filtrate was
separated and the aqueous was extracted with (3.times.). The
organic layer was dried (MgSO.sub.4), filtered and concentrated to
give compound 9B. ##STR56##
[0244] Compounds 9E-9Z (shown in Table 3) were synthesized starting
from 9A, 9B or 9C by following the procedures described in Example
3. The selective single-nitro reduction of starting material 9A13
(2,6-dinitrophenol) using Method A provided 2-amino-6-nitrophenol.
TABLE-US-00003 TABLE 3 Reduction Starting method Spectral data
Material R from 9A Cpd MS (MH+) unless noted 9A1 4-F A 9E 234 9A2
5-F A 9F 234 9A3 6-F A 9G 234 9A4 5,6-diF A 9H 252 9B1 4-Cl N.A. 9I
.sup.1H NMR(CDCl.sub.3): 7.60(s, 1H), 6.90(s, 1H), 6.75(d, 1H),
6.66(d, 1H), 6.55(dd, 1H), 4.40(s, 2H), 4.20(t, 2H), 3.40(t, 2H)
9B2 5-Cl N.A. 9J 250 9A5 6-Cl B 9K 250 9A6 4,6-diCl B 9L 284 9C1
4-Me N.A. 9M 230 9A7 3-Me A 9N 230 9B3 4-Ph N.A. 9O 292 9A8 4-Br B
9P 294 9A9 4-CF.sub.3 A 9Q 284 9A10 3-OMe A 9R 246 9A11 4-OMe A 9S
246 9B4 5-OMe N.A. 9T 246 9A12 6-OMe A 9U 246 9B5
4-SO.sub.2NH.sub.2 N.A. 9V 295 9B6 4-SO.sub.2Et N.A. 9W 308 9B7
5-NO.sub.2 N.A. 9X 261 9A13 6-NO.sub.2 A 9Y 261 9A14
4-CO.sub.2CH.sub.3 B 9Z 274
Starting material 9A10 in Table 3 was prepared as follows:
[0245] Dimethylsulfate (2.7 mL, 0.058 mmol) was added carefully to
2-nitrobenzene-1,3-diol (2.5 g, 0.232 mmol) and the mixture was
stirred vigorously while 10% NaOH solution (21 mL) was added and
the temperature was kept below 40.degree. C. After about 15 min,
the mixture was cooled and then filtered. The filtrate was
collected and acidified with 10% HCl, and extracted with ether
(3.times.25 mL). The organic layer was dried (MgSO.sub.4),
filtered, and concentrated under vacuum. Chromatography (10-30%
EtOAc/hexanes) provided 9A10 (1 g, 37%).
Starting material 9A12 in Table 3 was prepared as follows:
[0246] Fuming HNO.sub.3 (0.34 mL, 0.008 mmol) was carefully added
to a mixture of 2-methoxyphenol (0.886 mL, 0.008 mmol) in anhydrous
DCM (10 mL) at -20.degree. C. After stirring for 2 h at RT, the
mixture was concentrated under vacuum. Chromatography (10-30%
EtOAc/hexanes) provided 9A12 (400 mg, 29%) and
2-methoxy-3-nitrophenol (400 mg, 29%).
Preparative Example 10
[0247] ##STR57##
[0248] A mixture of compound 9Z (46 mg, 0.24 mmol) in anhydrous THF
(10 mL) at 0.degree. C. was carefully treated with LAH powder (18
mg, 0.48 mmol) and then stirred for 2 h at RT. The reaction was
quenched with 1N NaOH solution (2 mL), filtered and concentrated
under vacuum. Chromatography (DCM with 3 to 5% of 7N NH.sub.3-MeOH)
provided 10 (47 mg, 80%). MS m/z 246(MH+).
Preparative Example 11
[0249] ##STR58##
[0250] A mixture of 9Z (67 mg, 0.24 mmol) in MeOH (5 mL) was
treated with NaOH (15 mg, 0.38 mmol) and stirred at RT overnight.
The reaction was then neutralized with 10% HCl and concentrated
under vacuum. The residue was taken up in MeOH, stirred for 1 h,
filtered, and concentrated. Chromatography (Prep-HPLC) provided
compound 11 (21 mg, 32%). MS m/z 260(MH+).
Preparative Example 12
[0251] ##STR59##
[0252] A mixture of 6-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (9D,
1.5 g, 7.05 mmol) and CuCN (1.58 g, 17.61 mmol) in anhydrous DMF
(15 mL) was stirred at 130.degree. C. for 3 h and then at
150.degree. C. overnight. Then the mixture was cooled to RT,
quenched with water and concentrated under vacuum. The residue was
taken up in 2N NaOH and EtOAc (100 mL) and then agitated in a
sonicator for 1 h. The precipitate was filtered off and washed with
EtOAc. The filtrate and washings were combined and extracted with
EtOAc (2.times.80 mL). The organic layer was dried (MgSO.sub.4),
filtered and concentrated under vacuum to give compound 12A (1.062
g, 94%).
Step 2
[0253] In a manner similar to that found in Example 3, Step 3, 12A
was converted to the title compound 12. MS m/z 241 (MH+).
Example 13
[0254] ##STR60##
[0255] A solution of 12 (0.179 g, 0.75 mmol) in anhydrous EtOH (10
mL) was cooled to 0.degree. C. and treated with bubbling HCl gas
for 15 min. The mixture was stirred at 0.degree. C. for 30 min,
warmed to RT overnight, and concentrated. The residue was dissolved
in 2.0 M NH.sub.3-MeOH (5 mL), stirred at RT for 4 h, and then
concentrated under vacuum. Chromatography (Ranin-Prep HPLC, Waters
SunFire.TM. Prep C18 5 .mu.M, 19-100 mm column, 5-90%
CH.sub.3CN/H.sub.2O gradient) gave the compound 13 (36 mg: 19%). MS
m/z 258 (MH+).
Preparative Example 14
[0256] ##STR61##
[0257] To a suspension of KH (30% in mineral oil, washed with
hexanes, 1.2 g, 8.98 mmol) in anhydrous THF (20 mL) at 0.degree. C.
under argon was added a solution of
6-bromo-4H-benzo[1,4]oxazin-3-one (9C, 1.02 g, 4.49 mmol) in THF
(20 mL). After 15 min, the solution was cooled to -78.degree. C.,
and t-BuLi (1.7 M in pentane, 5.18 mL, 8.8 mmol) was added
dropwise. The mixture was stirred for 15 min at -78.degree. C., and
then treated with dimethyl disulfide dropwise. The solution was
warmed gradually to RT and stirred overnight. The reaction was then
quenched by sat. NH.sub.4Cl (15 mL) carefully, and filtered. The
filtrate was diluted with water and extracted with EtOAc
(3.times.50 mL). The combined organic layers were dried
(MgSO.sub.4), filtered, and concentrated. Chromatography (5-25%
EtOAc/hexanes) provided 14A (0.483 g, 55%). ##STR62##
[0258] In a manner similar to that found in Example 3, Steps 2-3,
14A was reduced with BH.sub.3--SMe.sub.2 and treated with
imidazole-4-carboxaldehyde to provide 14B. MS m/z 262(MH+).
##STR63##
[0259] To compound 14B (0.447 g, 1.71 mmol) in anhydrous DCM (10
mL) was added MCPBA (77%, 0.85 g, 3.77 mmol), and the mixture was
stirred at RT overnight. The reaction was quenched with sat.
Na.sub.2CO.sub.3 solution and the solvent was removed under vacuum.
The concentrated solution was extracted with EtOAc (3.times.10 mL).
The organic layer was dried (MgSO.sub.4), filtered, and
concentrated under vacuum. Chromatography (DCM containing 1-7% of
7N NH.sub.3-MeOH) provided the title compound 14 (67 mg, 13%, MS
m/z 294 MH+) and a mixture of 14C and 14, which was purified by
Ranin-preparative HPLC to provided 14C (39 mg, 8%, MS m/z 278
MH+).
Preparative Example 15
[0260] ##STR64##
[0261] To compound 6-bromo-4H-benzo[1,4]oxazin-3-one (9C, 500 mg,
2.2 mmol) in toluene (44 mL) was added Pd(PPh.sub.3).sub.4 (127 mg,
0.11 mmol). After stirring at RT for 30 min, boronic acid 15A (697
mg, 3.3 mmol) in EtOH (13 mL, 0.25 M) and saturated NaHCO.sub.3
solution (22 mL) were added and the solution was heated to reflux
overnight. Then the mixture was cooled to RT, and poured into
saturated NaCl solution, and concentrated under vacuum. The residue
was diluted with water and extracted with EtOAc (3.times.25 mL).
The organic layer was dried (MgSO.sub.4), filtered, and
concentrated under vacuum. Chromatography (10 to 30% EtOAc/hexanes)
provided 15B (320 mg, 46%). ##STR65##
[0262] In a manner similar to that found in Example 3, Steps 2-3,
15B was reduced with BH.sub.3--SMe.sub.2 and treated with
imidazole-4-carboxaldehyde to provide 15C. MS m/z 381 (MH+).
Step 4
[0263] A mixture of 15C (143 mg, 0.37 mmol) in 4.0M HCl-dioxane
(1.5 mL, 0.56 mmol) was stirred at RT overnight. The reaction was
neutralized with 7N NH.sub.3-MeOH and concentrated. The residue was
purified by preparative TLC (DCM containing 10% of 7N
NH.sub.3-MeOH) to provide the title compound 15 (28 mg, 26%). MS
m/z 281 (MH+).
Preparative Example 16
[0264] ##STR66##
[0265] To a stirred solution of Pd (OAc).sub.2 (3 mg, 0.0125 mmol)
and PPh.sub.3 (13 mg, 0.05 mmol) in anhydrous THF (2 mL) under
argon was added 6-bromo-4H-benzo[1,4]oxazin-3-one (9C, 57 mg, 0.25
mmol). The mixture was stirred at RT for 10 min and treated
sequentially with a solution of 3-pyridine boronic acid (62 mg, 0.5
mmol) in EtOH (1 mL) and aqueous NaHCO.sub.3 solution (2 M, 2 mL).
The mixture was heated to reflux for 2 h and then cooled to RT. The
solution was poured into saturated NaCl solution, and then
concentrated under vacuum. The residue was diluted with water (5
mL) and extracted with EtOAC (3.times.10 mL). The organic layer was
dried (MgSO.sub.4), filtered, and concentrated under vacuum.
Chromatography (10-30% EtOAc/hexanes) provided 16A (21 mg,
37%).
Steps 2-3
[0266] Compound 16A was converted to compound 16 by reduction with
BH.sub.3--SMe.sub.2 and reductive alkylation with
imidazole-4-carboxaldehyde as described in Example 3, Steps 2-3. MS
m/z 293(MH+).
Preparative Example 17
[0267] ##STR67##
[0268] A Smith process vial (2-5 mL) was charged with a stir bar,
6-bromo-4H-benzo[1,4]oxazin-3-one (9C, 23 mg, 0.1 mmol),
thiophen-3-ylboronic acid (17 mg, 0.13 mmol) and EtOH (2 mL).
Aqueous K.sub.2CO.sub.3 (1 M, 0.12 mL) and polymer-supported Pd (40
mg, 3 mol% Pd, FiberCat. 1000-D32, Pd % 4.26) were then added
sequentially. The reaction vessel was sealed and heated to
110.degree. C. for 1 h under microwave irradiation. After cooling,
the reaction mixture was transferred to a prepacked column of
Si-carbonate (2 g, 0.79 mmol/g), which had been conditioned with
MeOH/DCM (1:1). The product was eluted with MeOH/DCM (1:1,
3.times.3 mL, gravity filtration) and concentrated to give compound
17A (18 mg, 80%).
Steps 2-3
[0269] Compound 17A was converted to 17 in a manner similar to that
found in Example 3, Steps 2-3. MS m/z 298 (MH+).
Preparative Example 18
[0270] ##STR68##
[0271] A Smith process vial (20 mL) was charged with a stir bar,
compound 3A (1 g, 6.49 mmol), ethyl 2-bromo-2-methylpropanoate (1
mL, 6.81 mmol), KF (1.13 g, 19.5 mmol) and DMF (10 mL). The
reaction vessel was sealed and heated to 160.degree. C. for 1 h
under microwave irradiation. After cooling, the reaction mixture
was poured into ice-water and extracted with EtOAc (3.times.50 mL).
The organic layer was dried (MgSO.sub.4), filtered, and
concentrated under vacuum. Chromatography (10-30% EtOAc/hexanes)
gave 18A (0.245 g, 17%). ##STR69##
[0272] In a manner similar to that found in Example 3, Steps 2-3,
18A was reduced with BH.sub.3--SMe.sub.2 and reacted with
imidazole-4-carboxaldehyde to provide 18B. MS m/z 289 (MH+).
##STR70##
[0273] Following the procedure found in Example 3, Step 4, 18B was
hydrogenated to give compound 18C. In a manner similar to that
found in Example 3, Step 5, 18C was further reacted with
ClCO.sub.2Me to provide the title compound 18. MS m/z 317
(MH+).
Preparative Example 19
[0274] ##STR71##
[0275] To 2-fluorophenol (19A, 8 mL, 86.4 mmol) in anhydrous DCM
(70 mL) at 0.degree. C. was added fuming HNO.sub.3 (0.34 mL, 0.008
mmol) dropwise through an addition funnel. The mixture was warmed
to RT and stirred for 2 h, then cooled to 0.degree. C. again and
quenched with 2N NaOH solution to pH 5. The mixture was
concentrated under vacuum, diluted with water, extracted with EtOAc
(3.times.100 mL). The combined organic layer was dried
(MgSO.sub.4), filtered, and concentrated under vacuum to give
compound 19B (15.07 g, yield: 86.4%). Step 2 ##STR72##
[0276] A solution of 19B (15.07 g, 74.6 mmol) in EtOH (300 mL) was
treated with SnCl.sub.2-2H.sub.2O (50.5 g, 224 mmol) and heated to
reflux for 2 h. The mixture was concentrated, poured into ice, and
neutralized to pH 7 with 2N NaOH solution. The solid was filtered
off and washed with EtOAc (5.times.500 mL). The filtrate was
separated and the aqueous was extracted with EtOAc (3.times.100
mL). The organic layer was dried (MgSO.sub.4), filtered and
concentrated under afford 19C (12.59 g, 98%). ##STR73##
[0277] In a manner similar to that found in Example 3, Steps 1-3,
19C was reacted with chloroacetyl chloride, reduced with
BH.sub.3--SMe.sub.2, and treated with imidazole-4-carboxaldehyde to
provide compound 19D. MS m/z 279 (MH+). ##STR74##
[0278] In a manner similar to that found in Example 3, Step 4, 19D
was hydrogenated to afford compound 19E. MS m/z 249 (MH+). Compound
19E was further reacted with ClCO.sub.2Me as described in Example
3, Step 5, to provide the title compound 19. MS m/z 307 (MH+).
Preparative Example 20
[0279] ##STR75##
[0280] To 2-chloro-4,6-dinitrophenol (20A, 2 g, 9.18 mmol) in EtOH
(100 mL) was added a scoop of Raney nickel (20% by weight)
carefully. The mixture was stirred at RT under hydrogen balloon
overnight and then filtered. The solvent was evaporated off under
vacuum to give white solid 20B (1.3 g, 89%) and used directly in
the next reaction. ##STR76##
[0281] Following the procedure described in example 3, Step 1, 20B
was reacted with chloroacetyl chloride to provide 20C (5%).
Compound 20C was treated with ClCO.sub.2Me, reduced with
BH.sub.3--SMe.sub.2, and reductively alklyated in a manner similar
to that found in Example 8 and Example 3 (Steps 2-3) to afford the
title compound 20. MS m/z 323 (MH+).
Preparative Example 21
[0282] ##STR77##
[0283] To compound 21A (5 g, 30 mmol) in concentrated
H.sub.2SO.sub.4 (17 mL) was added a 1:1 mixture of fuming HNO.sub.3
and conc. H.sub.2SO.sub.4 (7 mL) over 15 min. The mixture was
stirred for additional 30 min at RT and was slowly poured into ice
water (500 mL). The mixture was filtered to collect solid and
washed with water (4.times.). The solid was placed under high
vacuum in an 80.degree. C. oil bath for 5 h to provide 21B (3.82 g,
60%). ##STR78##
[0284] In a manner similar to that found in Example 3, Steps 2-3,
21B was reduced with BH.sub.3--SMe.sub.2 and then treated with
imidazole-4-carboxaldehye to afford compound 21C. MS m/z 279 (MH+).
##STR79##
[0285] In a manner similar to that found in Example 3, Steps 4, 21C
was hydrogenated to provide compound 21D. Compound 21D was then
converted to the title compound 21 as described in Example 3, Step
5. MS m/z 307 (MH+).
Preparative Example 22
[0286] ##STR80##
[0287] Following the procedures described in Example 21 (Step 1)
and Example 3 (Steps 2-3), 22A was nitrated with HNO.sub.3, reduced
with BH.sub.3--SMe.sub.2, and reacted with
imidazle-4-carboxaldehyde to provide compound 22. MS m/z 262
(MH+).
Preparative Example 23
[0288] ##STR81##
[0289] A solution of compound 23A (330 mg, 2.2 mmol, U.S. Pat. No.
5,652,363) in DMF (4 mL) was treated with NaH (60% in mineral oil,
88 mg, 2.2 mmol) at RT. The mixture was stirred for 20 min,
followed by addition of a solution of compound 23B (0.79 g, 2.2
mmol, J. Med. Chem., 2002, 45, 533) in DMF (4 mL). The mixture was
stirred at 45.degree. C. for 3 days, and then quenched with water
and concentrated under vacuum. The residue was dissolved in EtOAc
(50 mL), washed with water (2.times.10 mL). The organic layer was
dried (Na.sub.2SO.sub.4), filtered, and concentrated under vacuum.
Chromatography (DCM with 2-3% 7 N NH.sub.3-MeOH) provided 23C (519
mg, 50%). MS m/z 473 (MH+).
Steps 2-3
[0290] In a manner similar to that found in Example 2 (Step 2) and
Example 15 (Step 4), 23C was reduced with BH.sub.2--SMe.sub.2 (18 h
at reflux) and then deprotected with HCl-dioxane (1 h at 60.degree.
C.) to provide the title compound 23. MS m/z 217 (MH+).
Preparative Example 24
[0291] ##STR82##
[0292] A stirred solution of 2-chloro-5-nitroaniline 24A (34.4 g,
0.2 mol) in absolute EtOH (200 mL) at 70.degree. C. was treated
gradually with a solution of sodium sulfide nonahydrate (48 g, 0.2
mol) and sulfur (9.6 g, 0.3 mol), which had been preheated to
melting. The mixture was refluxed for 30 min and cooled to RT. The
mixture was filtered to collect the solid, wash with water. The
solid was dried under vacuum at 100.degree. C. for 5 h. The
resulting solid was taken up in water (200 mL) and treated with
NaOH (8 g, 0.2 mol) and ClCH.sub.2COOH (18.9 g, 0.2 mol). The
mixture was then heated to reflux for 1.5 h. After cooling down,
the mixture was acidified with 10% HCl solution and filtered to
collect brown-yellow solid, and washed with water to give compound
24B (25 g, 60%). ##STR83##
[0293] Following the procedure described in Example 3, Steps 2-3,
24B was reduced with BH.sub.3--SMe.sub.2 and treated with
imidazole-4-carboxaldehyde to provide 24C. MS m/z 277 (MH+).
##STR84##
[0294] In a manner similar to that found in Example 3, Step 4, 24C
was hydrogenated to provide 24D. MS m/z 247 (MH+). Compound 24D was
further treated with ClCO.sub.2Me as described in Example 3, Step
5, to provide the title compound 24. MS m/z 305 (MH+).
Preparative Example 25
[0295] ##STR85##
[0296] Following procedures described in Example 3 (Steps 2-3),
compound 25A was subjected to reduction with BH.sub.3--SMe.sub.2
and then reductive amination with imidazole-4-carboxaldehyde to
provide compound 25B. MS m/z 232 (MH+). ##STR86##
[0297] In a manner similar to that found in Example 14, Step 4, 25B
was oxidized with MCPBA to the afford compounds 25C (MS m/z 248
MH+) and 25 (MS m/z 264 MH+).
Preparative Example 26
[0298] ##STR87##
[0299] In a manner similar to that found in Example 1,
1,2,3,4-tetrahydro-quinoxaline and imidazole-4-carboxaldehye 1B
underwent reductive amination to provide 26A. LMCS m/z 215 (MH+).
##STR88##
[0300] In a manner similar to that found in Example 3, Step 5, 26A
was converted to 26B. LMCS m/z 273 (MH+).
Step 3
[0301] Compound 26B (120 mg) was added portionwise to a stirred
slurry of LAH powder (500 mg) in Et.sub.2O (15 mL) at 0.degree. C.
The mixture was refluxed for 1 h and then cooled to 0.degree. C.
The reaction was treated sequentially with H.sub.2O (0.5 mL), 1 N
NaOH (0.5 mL), and H.sub.2O (1.5 mL). and then concentrated.
Chromatography (DCM with 2 to 5% of 7N NH.sub.3-MeOH) provided the
title compound 26. MS m/z 229(MH+). Alternatively, compounds in
this class may be synthesized by a solid phase approach as
described in the following Example 27.
Preparative Example 27
[0302] ##STR89##
[0303] A mixture of 1,2,3,4-tetrahydroquinoxaline (27A, 2 g, 14.9
mmol) in dioxane (15 mL) and water (24 mL) at 0.degree. C. was
sequentially treated with Na.sub.2CO.sub.3 (1.58 g, 14.9 mmol) and
FmocCl (3.84 g, 14.9 mmol) in dioxane (20 mL, added dropwise). The
mixture was warmed to RT gradually and stirred overnight. The
reaction mixture was diluted with water (50 mL) and extracted with
DCM (2.times.70 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4), concentrated, and subjected to chromatography
(30-40% EtOAc/hexanes, yields 0.75 g, 14%). Subsequent reaction
with resin 1D as described in Example 1 provided 27B. ##STR90##
[0304] Compound 27B (0.5 g, 1.4 mmol/g) was stirred in 30%
piperidine/DMF overnight. The resin was washed with DMF (3.times.),
MeOH (3.times.) and DCM and then dried in vacuo to provide 27C.
Resin 27C (125 mg, 1.4 mmol/g) was suspended in DCM (5 mL) and
treated with pyridine (0.283 mL, 3.5 mmol) and MeSO.sub.2Cl (0.135
mL, 1.75 mmol). The reaction was shaken overnight, then washed with
MeOH (2.times.), DMF (2.times.), DCM (2.times.), MeOH (2.times.)
and DCM (3.times.). Subsequent cleavage from the resin with TFA, as
described in Example 1, provided the title compound 27. MS m/z 293
(MH+).
[0305] Compounds in Table 4 can be prepared from Resin 27C by
reaction with the various reagents shown followed by TFA cleavage.
TABLE-US-00004 TABLE 4 ##STR91## Cpd Reagent R MS (MH+) 27D
Me.sub.2NSO.sub.2Cl/ pyridine ##STR92## 322 27E Ac.sub.2O/ pyridine
##STR93## 257 27F MeNCO ##STR94## 272
Preparative Example 28
[0306] ##STR95##
[0307] To 6-nitro-2-aminophenol (3A, 3.03 g, 19.7 mmol) in
anhydrous DCM (50 mL) was added dipyridylcarbonate (4.25 g, 19.7
mmol). The mixture was stirred at RT overnight, and then
concentrated under vacuum. Chromatography (1-6% MeOH/DCM) afforded
the solid 28A (2.77 g, 78%). ##STR96##
[0308] A solution of 28A (0.69 g, 3.83 mmol) in 2-ethoxyethanol (10
mL) was treated with KOH (0.22 g, 3.83 mmol) and stirred at RT for
1 h. The mixture was then heated to reflux and treated with
1-bromo-3-chloropropane (0.75 mL, 7.67 mmol). After refluxing for 4
h, the solution was filtered and concentrated to provide 28B, which
was taken on to Step 3 without further purification. ##STR97##
[0309] A solution of 28B in 2-ethoxyethanol and DMF (10 mL, 1:1)
was transferred into a Smith process vial (20 mL) with a stir bar,
and treated with KOH (0.86 g, 15.32 mmol). The reaction vessel was
sealed and heated to 220.degree. C. for 1 h under microwave
irradiation. After cooling, the reaction mixture was filtered and
concentrated. The residue was diluted with water and extracted with
EtOAc (3.times.10 mL). The combined organic layers were dried
(MgSO.sub.4), filtered, and concentrated under vacuum.
Chromatography (DCM containing 1-5% 7N NH.sub.3-MeOH) provided 28C
(124 mg, 17% for 2 steps). ##STR98##
[0310] In a manner similar to that found in Example 3 (Step 3), 28C
was reacted with imidazole-4-carboxyaldehyde to provide compound
28D. MS m/z 275 (MH+). ##STR99##
[0311] In a manner similar to that found in Example 3 (Step 4), 28D
was hydrogenated to afford compound 28E. MS m/z 245 (MH+).
Following the procedure found in Example 3 (Step 5), 28E was
further reacted with ClCO.sub.2Me to provide the title compound 28.
MS m/z 303 (MH+).
Preparative Example 29
[0312] ##STR100##
[0313] A mixture of 4-hydroxy-3-nitrophenylacetic acid (10 g, 51
mmol) and 4M HCl-dioxane (40 mL) in EtOH (150 mL) was refluxed for
2 h and concentrated. The residue was then taken up in 1 N NaOH (50
mL) and extracted with CH.sub.2Cl.sub.2 (8.times.). The combined
organic layers were dried over Na.sub.2SO.sub.4, and concentrated
to provide 29A (8.39 g, 73%) as a yellow oil. ##STR101##
[0314] In a manner similar to that described in Example 20 (Step 1)
and Example 3 (Step 1), 29A was hydrogenated with Raney Ni (50 psi
H.sub.2) and then cyclized with chloroacetyl chloride to provide
29B. Compound 29B could be further elaborated to the title compound
29 following the procedure detailed in Example 3 (Steps 2-3). LMCS
m/z 302 (MH+).
Preparative Example 30
[0315] ##STR102##
[0316] A stirred solution of benyzlamine (0.070 mL, 0.66 mmol) in
CH.sub.2Cl.sub.2 (10 mL) was treated dropwise with AlMe.sub.3
(2M/toluene, 0.33 mL, 0.66 mmol) at 20.degree. C. After 20 min, a
solution of 29 (0.10 g, 0.33 mmol) in CH.sub.2Cl.sub.2 (3 mL) was
added slowly. The mixture was then heated at reflux overnight and
cooled to 20.degree. C. The reaction was quenched with H.sub.2O
(0.5 mL), and stirred 1 h. The mixture was then dried with
Na.sub.2SO.sub.4, filtered, and concentrated. Chromatography (2-5%
1 N NH.sub.3-MeOH/CH.sub.2Cl.sub.2) provided 30 as a white film
(0.115 g, 96%). LMCS m/z 363 (MH+).
Preparative Example 31
[0317] ##STR103##
[0318] In a manner similar to that found in Example 26 (Step 3) and
Example 1, 29B was reduced with LAH and then treated with
imidazole-4-carboxaldehyde to provide 31A. LMCS m/z 260 (MH+).
Step 3
[0319] A solution of 31A (0.20 g, 77 mmol) in 1,2-dichloroethane
(10 mL) was treated with Et.sub.3N (0.20 mL, 1.5 mmol) and MeNCO
(0.050 mL, 0.85 mmol) and stirred for 3 h at 20.degree. C. The
mixture was treated with H.sub.2O (10 mL), extracted with
CH.sub.2Cl.sub.2 (2.times.), and concentrated. The residue was
subjected to chromatography (2-5% MeOH/CH.sub.2Cl.sub.2) and then
stirred in Et.sub.2NH (5 mL) at 20.degree. C. overnight. The
mixture was concentrated, treated with 1 N NaOH, and extracted with
CH.sub.2Cl.sub.2 (3.times.). The combined organic extracts were
dried with Na.sub.2SO.sub.4, and concentrated. Chromatography (5%
MeOH/CH.sub.2Cl.sub.2) provided 31 as a white film (0.080 g, 33%).
LMCS m/z 317 (MH+).
Preparative Example 32
[0320] ##STR104##
[0321] Following the procedures found in Example 20 (Step 1) and
Example 3 (Step 1), 32A was hydrogenated with Raney Ni (50 psi
H.sub.2) and then cyclized with chloroacetyl chloride to provide
32B. ##STR105##
[0322] Following the procedure found in Example 26 (Step 3), the
nitrile and amide found in compound 32B were concomitantly reduced
with LAH. The resultant product (0.83 g, 5.1 mmol) in
CH.sub.2Cl.sub.2 (50 mL) was treated with BOC.sub.2O (1.07 g, 5.1
mmol), stirred at 20.degree. C. for 0.5 h and then concentrated.
Chromatography (20-50% EtOAc/hexanes) provided 32C as a white
sticky foam (1.19 g, 89%) ##STR106##
[0323] In a manner similar to that found in Example 1 and Example
15 (Step 4), 32C was treated with imidazole-4-carboxaldehyde and
then deprotected to afford 32D. LMCS m/z 245 (MH+). Following the
procedure described Example 3, Step 5, 32D was treated with
ClCO.sub.2Me and converted to the title compound 32. LMCS m/z 303
(MH+).
Preparative Example 33
[0324] ##STR107##
[0325] In a manner similar to that found in Example 3 (Step 1) and
Example 26 (Step 3), 2-amino-3-hydroxypyridine was cyclized with
chloroacetyl chloride and then reduced with LAH to afford 33A.
##STR108##
[0326] A solution of 33A (0.105 g 0.77 mmol) in DMF (5 mL) was
treated with KN(SiMe.sub.3).sub.2 (0.5 M/toluene, 1.8 mL, 0.93
mmol), stirred at 0.degree. C. for 20 min, and then treated with
33B (0.155 g 1.16 mmol, Tetrahedron Letters 2000, 41, 8661). The
reaction was warmed to 20.degree. C., stirred 2 h, and
concentrated. The residue was then treated with 0.5 N NaOH (10 mL)
and washed with CH.sub.2Cl.sub.2 (3.times.). The aqueous layer was
concentrated and subjected to chromatography (20-80% EtOAc/hexanes)
to provide 33 as a white solid (0.065 g, 36%). LMCS m/z 234
(MH+).
Preparative Example 34
[0327] ##STR109##
[0328] A mixture of 2-chloro-3-nitropyridine (9.4 g, 59 mmol),
glycine ethyl ester hydrochloride (10.8 g, 77 mmol), and
K.sub.2CO.sub.3 (21.3 g, 154 mmol) in toluene (100 mL) was refluxed
overnight. The mixture was then filtered, concentrated, and
subjected to chromatography (20% EtOAc/hexanes). The resulting
yellow solid was dissolved in EtOH (300 mL), treated with Raney Ni
(2 g) and hydrogenated at 40 psi H.sub.2 overnight. The mixture was
filtered, concentrated and chromatographed (2-5%
MeOH/CH.sub.2Cl.sub.2) to provide 34A (1.25 g, 14%) and
N-(3-amino-2-pyridinyl)glycine ethyl ester (8.2 g, 71%).
##STR110##
[0329] In a manner similar to that found in Example 5 (Step 1), 34A
was converted to 34B (BOC.sub.2O, DMAP and Et.sub.3N in refluxing
DCM). ##STR111##
[0330] In a manner similar to that found in Example 26 (Step 3),
34B was treated with LAH to provide 34C as a white solid (0.040 g,
48%). Following the procedure found in Example 1, 34C was then
treated with imidazole-4-carboxaldehyde to provide the title
compound 34. LMCS m/z 230 (MH+).
Preparative Example 35
[0331] ##STR112##
[0332] A solution of 34A (0.260 g, 1.74 mmol) in THF (15 mL) was
treated with Et.sub.3N (1.2 mL, 8.7 mmol) and Ac.sub.2O (0.33 mL,
3.5 mmol) and stirred overnight at 20.degree. C. The reaction was
treated diluted with H.sub.2O (10 mL) and extracted with 10%
MeOH/CH.sub.2Cl.sub.2 (3.times.). The combined organic extracts
were dried with Na.sub.2SO.sub.4 and concentrated. Chromatography
(20-50% EtOAc/hexanes) provided 35A as a white solid (0.140 g,
42%).
[0333] In a manner similar to that found in Example 26 (Step 3) and
Example 1, 35A was reduced with LAH and then treated with
imidazole-4-carboxaldehyde to provide the title compound 35. LMCS
m/z 244 (MH+).
Preparative Example 36
[0334] ##STR113##
[0335] A solution of 34A (0.200 g 1.33 mmol) in DMF (15 mL) was
treated with KN(SiMe.sub.3).sub.2 (0.5M/toluene, 3.2 mL, 0.93
mmol), stirred at 0.degree. C. for 30 min, and then treated with
CH.sub.3I (0.12 mL, 2.00 mmol). The reaction was warmed to
20.degree. C., stirred overnight, and concentrated. The residue was
then treated with 0.5 N NaOH (10 mL) and extracted with
CH.sub.2Cl.sub.2 (3.times.). The combined organic layers were
concentrated and subjected to chromatography (2-5%
MeOH/CH.sub.2Cl.sub.2) to provide 36A (0.120 g, 55%).
[0336] In a manner similar to that found in Example 26 (Step 3) and
Example 1, 36A was reduced with LAH and then reacted with
imidazole-4-carboxaldehyde to provide 36. LMCS m/z 230 (MH+).
Preparative Example 37
[0337] ##STR114##
[0338] A mixture of 3C (2 g, 11.1 mmol) in anhydrous DMF (20 mL)
was treated with 2-(1H-imidazol-4-yl)acetic acid (2 g, 17.5 mmol),
HATU (6.2 g, 16.3 mmol) and DIEA (0.4 mL, 2.3 mmol) at 25.degree.
C. The mixture was stirred at room temperature overnight and then
concentrated under vacuum. Column chromatography (DCM containing
1-6% of 7N NH.sub.3/MeOH) provided 37A (1.2 g, yield: 38%). In a
manner similar to Example 2, Step 2, compound 37A was reduced with
BH.sub.3--SMe.sub.2 to provide compound 37. MS m/z 275 (MH+).
Preparative Example 38
[0339] ##STR115##
[0340] A solution of compound 3C (14.1 g, 78 mmol) in MeCN (200 mL)
was treated with (BOC).sub.2O (20.5 g, 94 mmol) and DMAP (0.5 g)
and then refluxed overnight. The reaction mixture was concentrated
and chromatographed (10% -50% EtOAc/hexanes) to give compound 38A
(16.1 g, 74%, typically 70-90%) and recovered starting material 3C.
##STR116##
[0341] A mixture of compound 38A (16.1 g, 58 mmol) in EtOH (300 ml)
was treated with Raney Ni (.about.5 g) and hydrogenated (40 psi
H.sub.2) overnight. The reaction mixture was filtered and
concentrated.
[0342] The resulting white solid (.about.15.3 g, 61 mmol) was
suspended in anhydrous THF (200 mL) and treated slowly with
Ac.sub.2O (.about.18 mL, 173 mmol). After stirring for 2 h at
20.degree. C., the reaction mixture was concentrated in vacuo and
taken up in 25% aqueous NaOH (100 mL) and CH.sub.2Cl.sub.2. The
layers were separated. The aqueous layer was further extracted with
CH.sub.2Cl.sub.2 (3.times.). The organic layers were combined,
dried with Na.sub.2SO.sub.4, and filtered to give 38B as a gray
solid (17.6 g, quantitative yield). ##STR117##
[0343] A solution of compound 38B (21 g, 72 mmol) in THF (300 ml)
at 0.degree. C. was slowly treated with BH.sub.3-DMS (60 ml,
2M/THF) and then heated to reflux overnight. The mixture was
concentrated, treated with K.sub.2CO.sub.3 (9.9 g) and EtOH (300
mL) and then refluxed for 45 min. The reaction mixture was
filtered, concentrated, added to H.sub.2O and extracted with
CH.sub.2Cl.sub.2 (4.times.). The combined organic layers were dried
with Na.sub.2SO.sub.4, filtered and concentrated.
[0344] The resulting clear oil (21.9 g) was dissolved in anhydrous
CH.sub.2Cl.sub.2 (300 ml), treated slowly with MeNCO (.about.5 g,
86 mmol), and then stirred at RT for 30 min. The reaction mixture
was concentrated and chromatographed (50%-80% EtOAc/hexanes) to
give the product 38C as a white solid (21.65 g, 90% yield for two
steps).
Steps 6-7
[0345] A solution of compound 38C (21.65 g, 65 mmol) in of
CH.sub.2Cl.sub.2 (300 ml) was treated with TFA (100 mL) and
refluxed for 0.5 h. The reaction mixture was concentrated, treated
with 20% NaOH (150 mL) and extracted with CH.sub.2Cl.sub.2
(4.times.). The combined organic layers were dried with
Na.sub.2SO.sub.4, filtered and concentrated to give a white solid
(14.23 g, .about.93%).
[0346] The crude product (16.2 g, 68.9 mmol) was combined with
4-imidazolecarboxaldehyde (1B, 6.6 g, 68.9 mmol) and Ti(OiPr).sub.4
(25 mL, 86 mmol) in CH.sub.2Cl.sub.2 (15 ml) and stirred at RT
until the reaction mixture became clear (.about.1 h). Following the
addition of NaBH.sub.4 (3.3 g, 86 mmol) and EtOH (200 mL), the
reaction was stirred at RT overnight and concentrated. The residue
was taken up in 0.5 N NaOH and extracted with CH.sub.2Cl.sub.2
(4.times.). The combined organic layers were dried with
Na.sub.2SO.sub.4, filtered, and concentrated. Chromatography (5-10%
of 7N NH.sub.3-MeOH in CH.sub.2Cl.sub.2) provided compound 38
(14.13 g, 68%) as a white solid.
Preparative Example 39
[0347] ##STR118##
[0348] Bromine (8.0 g, 50 mmol, 2.3 eq) in anhydrous Ac.sub.2O (40
mL) was added dropwise to a solution of 1B (2.08 g, 21.7 mmol) and
NaOAc (18.7 g, 228 mmol, 10.5 eq) in anhydrous HOAc (200 mL) over a
period of 1 h at RT. The resulting mixture was stirred at RT for
2.5 h and then concentrated. The residue was partitioned between
Et.sub.2O (200 mL) and water (200 mL), the layers were separated
and the aqueous layer was extracted with Et.sub.2O (200 mL). The
combined organic phase was dried, concentrated and chromatographed
(EtOAc) to afford 5-bromo-4-formyl imidazole 39A (1.00 g, 26%) as
white crystals. ##STR119##
[0349] In a manner similar to that found in Example 1, 39A was
treated with 39B (Example 6) to afford the title compound 39. LCMS
m/z 280 (MH+).
Preparative Example 40
[0350] ##STR120##
[0351] A mixture of 6 (0.25 g, 0.83 mmol) and NaHCO.sub.3 (0.7 g,
8.3 mmol) in 1:1 THF-H.sub.2O (20 mL) was stirred vigorously for 10
min and then treated with phenyl chloroformate (PhOCOCl, 0.26 mL,
2.1 mmol). The reaction was stirred at RT for 2 h and then diluted
with EtOAc. The organic layer was isolated, dried over
Na.sub.2SO.sub.4 and concentrated. The resulting residue was
dissolved in MeOH, treated with Et.sub.3N (0.6 mL, 4.3 mmol) and
stirred overnight. The solution was concentrated and subjected to
chromatography (5-10% NH.sub.3-MeOH/EtOAc) to provide the title
compound 40 as a light yellow foam (0.2 g, 76%).
Preparative Example 41
[0352] ##STR121##
[0353] A mixture of 1A (0.2 g, 1.5 mmol) and
imidazole-4-carboxaldehyde (1B, 0.16 g, 1.6 mmol) in
CH.sub.2Cl.sub.2 (5 mL) was treated with Ti(OiPr).sub.4 (0.55 mL,
1.88 mmol), stirred at RT overnight, and then treated with
Et.sub.2AlCN (2 mL, 1M/toluene). After 18 h, EtOAc, H.sub.2O, and
celite were added. Filtration and subsequent chromatography (0-10%
of 7N NH.sub.3-MeOH in CH.sub.2Cl.sub.2) provided 41 as a yellow
solid (0.178 g, 50%). LCMS m/z 241 (MH+).
Preparative Example 42
[0354] ##STR122##
[0355] In a manner similar to that found in Example 41, a mixture
of 1A and 42A (Journal of Medicinal Chemistry, 1971, 14, 883) was
treated sequentially with Ti(OiPr).sub.4 and Et.sub.2AlCN to
provide the compound 42B. ##STR123##
[0356] A solution of 42B (0.2 g, 0.41 mmol) in 1N NH.sub.3-MeOH (50
mL) was treated with Raney Ni and hydrogenated (50 psi H.sub.2)
overnight at RT. Filtration and subsequent chromatography (0-7% of
7N NH.sub.3-MeOH in CH.sub.2Cl.sub.2) provided 42C as a yellow film
(0.15 g, 74%).
[0357] A mixture of 42C (145 mg, 0.3 mmol) in CH.sub.2Cl.sub.2 (2
mL) was treated with TFA (0.5 mL) and Et.sub.3SiH (0.05 mL). The
reaction mixture was stirred at RT overnight and then concentrated.
Chromatography (2-15% of 7 N NH.sub.3-MeOH in CH.sub.2Cl.sub.2)
provided the title compound 42 (69 mg, 95%) as a yellow oil. LCMS
m/z 245 (MH+).
Preparative Example 43
[0358] ##STR124##
[0359] In a manner similar to that described in Examples 19 and 3,
2-cyanophenol was subjected to bis-nitration with HNO.sub.3,
selective reduction with SnCl.sub.2, cyclization with chloroacetyl
chloride, and reduction with BH.sub.3-SMe.sub.2 to provide 43A.
##STR125##
[0360] A mixture of 43A (0.65 g, 3.2 mmol) and Et.sub.3N (0.9 mL,
6.3 mmol) in CH.sub.2Cl.sub.2 (60 mL) was treated with Ac.sub.2O (6
mL) and DMAP (0.15 g) and then refluxed for 2 d. The reaction was
then cooled, washed with 1N HCl (2.times.), washed with brine,
dried over Na.sub.2SO.sub.4, and concentrated. Chromatography
(10-100% of EtOAc/hexanes) provided 43B as a yellow solid (0.688 g,
88%). ##STR126##
[0361] In a manner similar to that described in Example 3 (Step 4),
43B was hydrogenated with Pd/C.
[0362] A mixture of the aniline product (0.080 g, 0.38 mmol) in 6M
HCl (0.5 mL) was treated with a solution of NaNO.sub.2 (27 mg, 0.39
mmol) at 0.degree. C. After 0.5 h, the solution was neutralized
with sat. aq. Na.sub.2CO.sub.3 and then added dropwise to solution
of CuCN (37 mg, 0.41 mmol) and NaCN (40 mg, 0.82 mmol). The
resulting mixture was stirred at 60.degree. C. overnight and then
filtered.
[0363] The brown precipitate (44 mg) was collected and then treated
with 10% aq. NaOH (0.5 mL) for 2 h at RT. The reaction was then
diluted with H.sub.2O and extracted with CH.sub.2Cl.sub.2
(3.times.). The combined organic layers were washed with brine,
dried over Na.sub.2SO.sub.4, and concentrated. Chromatography
(20-100% of EtOAc/hexanes) provided 43C as a beige solid (0.0.15
g).
[0364] In a manner similar to that described in Example 3 (Step 3),
43C was converted to the title compound 43. LCMS m/z 266 (MH+).
Preparative Example 44
[0365] ##STR127##
[0366] A solution of 4-phenylbutyl bromide (0.98 g, 4.6 mmol) and
44A (1.0 g, 4.6 mmol) in 10 mL of benzene was treated sequentially
with Bu.sub.4NHSO.sub.4 (0.16 g, 0.46 mmol) and 50% aqueous NaOH
(2.4 mL, 46 mmol, added slowly). After stirring at RT under N.sub.2
for 20 h, the solvent was removed. The reaction mixture was then
diluted with H.sub.2O, extracted with EtOAc, washed with H.sub.2O
(3.times.) and brine, dried over Na.sub.2SO.sub.4, and filtered.
The filtrate was concentrated and chromatographed (5-10%
EtOAc/hexanes) to provide 44B (0.7 g, 44%). ##STR128##
[0367] To a solution of 44B (0.2 g, 0.57 mmol) in 5 mL of
CH.sub.2Cl.sub.2 (5 mL) was added TFA (1.5 mL). After stirring at
RT for 1.5 h, the solution was cooled to 0.degree. C. and treated
with concentrated aqueous NH.sub.3 (until pH=10-11). The mixture
was extracted with CH.sub.2Cl.sub.2, dried over Na.sub.2SO.sub.4,
and filtered. The filtrate was concentrated to give an unstable
amine (0.12 g, 84%) which was immediately taken up in
CH.sub.2Cl.sub.2 (8 mL) and treated with compound 7B (0.21 g, 0.44
mmol) and Et.sub.3N (0.17 mL, 1.2 mmol). After the mixture was
cooled to -50.degree. C., triphosgene (0.04 g, 0.13 mmol) was added
to the solution. The mixture was stirred at -50.degree. C. under
N.sub.2 for 1 h, then slowly warmed up to RT, and stirred under
N.sub.2 overnight. After adding 5% aqueous NaOH (10 mL), the
products were extracted with CH.sub.2Cl.sub.2, dried over
Na.sub.2SO.sub.4, and filtered. Chromatography (2% MeOH/EtOAc)
provided 44C (0.2 g, 67%).
Step 4
[0368] A mixture of 44C (0.13 g) in 3N HCl-MeOH (8 mL) was heated
at 60.degree. C. under N.sub.2 for 1.5 h, cooled to 0.degree. C.
and neutralized with concentrated aqueous NH.sub.3. The solution
was concentrated, taken up in H.sub.2O and extracted with
CH.sub.2Cl.sub.2. The organic extract was dried over
Na.sub.2SO.sub.4, filtered and chromatographed (5% NH.sub.3-MeOH in
CH.sub.2Cl.sub.2) to give the title compound 44 (0.05 g, 62%). LCMS
m/z 506 (MH+).
Preparative Example 45
[0369] ##STR129##
[0370] A solution of 4-phenylbutanol (2.50 g, 16.6 mmol) and
1,6-dibromohexane (8.12 g, 33.2 mmol) in anhydrous THF (30 mL) was
treated slowly with NaH (1.0 g, 24.9 mmol) at RT. After refluxing
under N.sub.2 for 20 h, the mixture was cooled to RT, and quenched
with H.sub.2O. The products were extracted with ether, washed with
brine, dried over Na.sub.2SO.sub.4, and filtered. The filtrate was
concentrated and chromatographed (2% EtOAc/hexanes) to give 45A
(3.3 g, 63%). ##STR130##
[0371] To a solution of 45A (0.07 g, 0.21 mmol) and 7B (0.1 g, 0.21
mmol) in toluene (3 mL) and DMF (0.5 mL) was added DIPEA (0.07 mL,
0.42 mmol) at RT. After heating at 80.degree. C. under N.sub.2 for
20 h, the mixture was concentrated, taken up in CH.sub.2Cl.sub.2,
washed with H.sub.2O (3.times.) and brine, dried over
Na.sub.2SO.sub.4, and filtered. Chromatography (60% EtOAc/hexanes)
provided 45B (0.04 g, 27%).
[0372] In a manner similar to that described in Example 5 (Step 3)
and Example 44 (Step 4), 45B was sequentially treated with MeNCO
and HCl to provide the title compound 45. LCMS m/z 520 (MH+).
Preparative Example 46
[0373] ##STR131##
[0374] Compound 46A (from Example 38, Step 2, 250 mg, 1 mmol) was
taken up in DCE (10 mL) and treated sequentially with
2-methoxypropene (0.14 mL, 1.5 mmol), HOAc (0.06 mL, 1.1 mmol), and
NaBH(OAc).sub.3 (424 mg, 2.0 mmol). The reaction mixture was
stirred at RT overnight, quenched with 1.0 N NaOH and extracted
with CH.sub.2Cl.sub.2 (3.times.20 mL). The combined organic layers
were washed with brine, dried, and then concentrated.
Chromatography (EtOAc/hexanes) affored 46B (190 mg, 65%).
Steps 3-5
[0375] In a manner similar to that described in Example 38 (Steps
5-7), 46B was sequentially treated with MeNCO, deprotected with
TFA, and treated with 4-imdazolecarboxaldehyde to provide the title
compound 46. LCMS m/z 330 (MH+).
Preparative Example 47
[0376] ##STR132##
[0377] A mixture of 46A (500 mg, 2 mmol) in CH.sub.2Cl.sub.2 (10
mL) was sequentially treated with methoxyacetyl chloride (0.22 mL,
2.4 mmol) and TEA (0.56 mL, 4.0 mmol). The reaction mixture was
stirred at RT overnight, quenched with sat. NaHCO.sub.3, and
extracted with CH.sub.2Cl.sub.2 (2.times.20 mL). The combined
organic layers were washed with brine, dried, and concentrated.
Chromatography (EtOAc/hexanes) afforded 47A (610 mg, 95%).
Steps 2-5
[0378] In a manner similar to that described in Example 38 (Steps
4-7), 47A was reduced with BH.sub.3--SMe.sub.e, treated with MeNCO,
deprotected with TFA, and treated with 4-imdazolecarboxaldehyde to
provide the title compound 47. LCMS m/z 346 (MH+)
Preparative Example 48
[0379] ##STR133##
[0380] A solution of 7B (140 mg, 0.3 mmol) in anhydrous
CH.sub.2Cl.sub.2 (5 mL) was treated with benzyl isocyanate (48 mg,
0.36 mmol). The reaction mixture was stirred at RT overnight and
then concentrated. Chromatography afforded 48A (130 mg, 72%).
[0381] In a manner similar to that described in Example 42 (Step
3), 48A was deprotected with with TFA and Et.sub.3SiH to provide
the title compound 48. LCMS m/z 364 (MH+).
Preparative Example 49
[0382] ##STR134##
[0383] A mixture of 7B (1.0 g, 2.12 mmol), benzyloxyacetic acid
(0.46 g, 2.75 mmol), EDCl (0.61 g, 3.18 mmol) and HOBt (0.42 g,
3.18 mmol) in DMF were stirred at RT for 1 d. The reaction was
quenched with 0.5 N aq. NaOH (50 mL) and extracted with
CH.sub.2Cl.sub.2. The combined extracts were washed with brine,
dried (Na.sub.2SO.sub.4) and concentrated. Preparative TLC
chromatography (5% NH.sub.3-MeOH in CH.sub.2Cl.sub.2) provided 49A
(0.52 g).
[0384] In a manner similar to that described in Example 42 (Step
3), 49A was deprotected with TFA and Et.sub.3SiH to provide the
title compound 49. LCMS m/z 379 (MH+).
Preparative Example 50
[0385] ##STR135##
[0386] In a manner similar to that described in Example 5 (Steps
1-2) and Example 6 (Steps 1-2), compound 28C was converted to 50A.
##STR136##
[0387] A mixture of 50A (0.247 g, 0.99 mmol) in anhydrous DCM (5
mL) was treated with carbonyldiimidazole (0.32 g, 1.97 mmol) and
Et.sub.3N (0.28 mL, 1.97 mmol) and then stirred at RT overnight.
The reaction was washed with water and extracted with DCM
(3.times.10 mL). The combined organic layer was dried (MgSO.sub.4),
filtered, and concentrated under vacuum to give compound 50B.
##STR137##
[0388] A solution of 50B was in anhydrous MeCN (5 mL) in a sealed
tube was treated with Mel (2 mL). The sealed reaction mixture was
heated to 55.degree. C. for 3 h, cooled to RT and concentrated. The
residue was dissolved in anhydrous THF (5 mL) and then treated with
MeONH.sub.2-HCl (0.25 g, 2.97 mmol) and DIEA (0.53 mL, 2.97 mmol).
After stirring at RT overnight, the reaction was quenched with
saturated NH.sub.4Cl solution and concentrated under vacuum. The
residue was diluted with water and extracted with EtOAc (3.times.10
mL). The combined organic layer was dried (MgSO.sub.4), filtered,
and concentrated under vacuum to afford crude compound 50C (279 mg,
80% for 3 steps).
[0389] In a manner similar to that found in Example 5 (Step 4) and
Example 3 (Step 3), compound 50C was deprotected and converted to
the title compound 50. MS m/z=332 (MH+).
Preparative Example 51
[0390] ##STR138##
[0391] In a manner similar to that described in Example 21 (Step
1), Example 3 (Step 2), Example 5 (Step 1) and Example 3 (Step 4),
compound 22A was sequentially nitrated, reduced with
BH.sub.3--SMe.sub.2, treated with Boc.sub.2O, and hydrogenated to
yield compound 51A.
Steps 5-7
[0392] In a manner similar to that described in Example 5 (Steps
3-5), 51A was treated with MeNCO, deprotected with TFA, and
converted to the title compound 51. MS m/z=289 (MH+).
Preparative Example 52
[0393] ##STR139##
[0394] To a solution of 51A (740 mg, 2.95 mmol) in DCM (30 ml) was
added 4-nitrophenylchloroformate (891 mg, 4.42 mmol) and pyridine
(0.48 ml, 5.90 mmol). After stirring overnight at RT, TLC indicated
consumption of the starting material. MeONH.sub.2--HCl salt (739
mg, 8.84 mmol) in anhydrous THF (10 ml) and DIEA (1.57 mL, 8.84
mmol) were then sequentially added. After stirring at RT overnight,
the reaction was quenched by water, concentrated, diluted with
water and extracted with EtOAc. The organic phase was dried
(MgSO.sub.4), filtered, and concentrated. Flash chromatography
(20-50% of EtOAc/hexanes) provided 52A (650 mg, 68%).
[0395] In a manner similar to that found in Example 5 (Step 4) and
Example 3 (Step 3), 52A was converted to 52. MS m/z=305 (MH+).
Preparative Example 53
[0396] ##STR140##
[0397] To compound 51A (100 mg, 0.40 mmol) in DCE (5 mL) was added
acetaldehyde (0.045 mL, 0.80 mmol). The mixture was stirred at RT
for 1 h and then treated with MeOH (3 mL) and NaBH.sub.4 (45.5 mg,
1.2 mmol). After stirring at RT overnight, the reaction was
quenched by 2N NaOH solution, concentrated, diluted with water and
extracted with EtOAc. The organic phase was dried (MgSO4),
filtered, and concentrated under vacuum to give a residue 53A (40
mg, 36%).
[0398] In a manner similar to that found in Example 3 (Step 5),
Example 5 (Step 4) and Example 3 (Step 3), 53A was treated with
ClCO.sub.2Me/pyridine, deprotected with TFA and converted to the
title compound 53. MS m/z=318 (MH+).
Preparative Example 54
[0399] ##STR141##
[0400] In a manner similar to that found in Example 3 (Step 2),
compound 54A (see WO 2006/020561) was reduced with
BH.sub.3--SMe.sub.2 to provide 54B.
[0401] Compound 54B was then elaborated into 54 (MS m/z=295, MH+)
as previously described in Example 3 (Step 3).
Preparative Example 55
[0402] ##STR142##
[0403] A Smith process vial was charged with a stir bar, compound
54B (0.33 g, 1.54 mmol), CuCN (0.276 g, 3.08 mmol) and DMF (3 mL).
The reaction vessel was sealed and heated to 120.degree. C. for 3 h
under microwave irradiation. After cooling, the reaction mixture
was transferred to a round bottom flask and concentrated under
vacuum. Compound 55A was obtained quantitatively by continuous
extraction with EtOAc in a Soxlet apparatus.
[0404] Compound 55A was then elaborated into 55 (MS m/z=242, MH+)
as previously described in Example 3 (Step 3).
Preparative Example 56
[0405] ##STR143##
[0406] In a manner similar to that previously described,
2-chloro-4,6-dinitrophenol was sequentially reduced with SnCl.sub.2
(Example 19, Step 2), treated with chloroacetyl chloride, reduced
with BH.sub.3--SMe.sub.2 (Example 3, Steps 1-2), protected with
Boc.sub.2O (Example 5, Step 1), and reduced again with SnCl.sub.2
to yield compound 56A. ##STR144##
[0407] To a solution of compound 56A (0.29 g, 1 mmol) in anhydrous
DCM (3 ml) was added 4-nitrophenylchloroformate (0.24 g, 1.2 mmol)
and pyridine (0.13 ml, 1.57 mmol). After stirring overnight at RT,
the reaction was quenched with sat. NH.sub.4Cl solution and
extracted with DCM. The organic phase was then concentrated. A
solution of this residue in CH.sub.3CN (5 mL) was treated with 40%
MeNH.sub.2 in H.sub.2O (20 mL) and heated in a sealed tube at
90.degree. C. overnight. The mixture was cooled, stirred at RT
overnight, and then quenched with water. The reaction was
concentrated, diluted with water and extracted with EtOAc. The
organic phase was dried (MgSO.sub.4), filtered, and concentrated to
give 56B.
[0408] As described previously in Example 5 (Step 4) and Example 3
(Step 3), 56B was deprotected and converted to 56. MS m/z=322
(MH+).
Preparative Example 57
[0409] ##STR145##
[0410] Compound 127 (0.388 g, 1.22 mmol) was dissolved in anhydrous
DCM (10 mL) and cooled to -78.degree. C. To this solution was added
1.0M BBr.sub.3 in DCM (6.1 mL) dropwise. The reaction mixture was
stirred at -78.degree. C. for 30 min and then at RT for 3 h. The
reaction was quenched with water and neutralized with 2N NaOH
solution. The mixture was separated and the aqueous phase was
extracted with DCM (3.times.10 mL). The organic phase was dried
(MgSO.sub.4), filtered, and concentrated under vacuum. The residue
was purified by flash column chromatography (DCM containing 2 to 8%
of 7N NH.sub.3 in MeOH) to afford compound 57 in 30% yield. MS
m/z=305 (MH+).
Preparative Example 58
[0411] ##STR146##
[0412] In a manner similar to that described in Example 37,
compound 58A (prepared in Example 6) and 58B (Bioconjugate
Chemistry, 13, 333-350, 2002) were reacted with HATU to provide
58C. MS m/z=572 (MH+)
Steps 2-3
[0413] A solution of 58C (720 mg, 1.3 mmol) in THF (50 mL) was
treated with BH.sub.3--SMe.sub.2 (5 mL, 2 M in THF) and heated at
80.degree. C. for 12 h. After it was cooled to 25.degree. C., MeOH
(15 mL) was added dropwise until bubbling ceased. The solvent was
removed and partitioned between EtOAc and water. The organic phase
was dried over Na.sub.2SO.sub.4 and concentrated. The crude residue
was stirred in DCM/TFA (1:3, 5 mL) at 25.degree. C. for 4 h.
Solvent was removed and the residue was partitioned between EtOAc
and water. The organic phase was dried and concentrated. Column
chromatography and preparative TLC (DCM containing 5% of 7N
NH.sub.3/MeOH) gave 58. MS m/z=316 (MH+).
Preparative Example 59
[0414] ##STR147##
[0415] In a manner similar to that described in Example 3 (Step 4
then Steps 1-2), methyl 2-hydroxy-3-nitrobenzoate was sequentially
hydrogenated, treated with chloroacetylchloride, and reduced with
BH.sub.3--SMe.sub.2 to yield compound 59A.
Step 4
[0416] Compound 59A was treated with 4-imidazolecarboxaldehyde to
afford the title compound 59 in a manner similar to that described
in Example 3 (Step 3). MS m/z=274 (MH+).
Preparative Example 60
[0417] ##STR148##
[0418] A mixture of LiBH.sub.4 (44 mg, 2 mmol) and 59A (400 mg, 2
mmol) in THF (50 mL) was stirred at RT for 4 h and then
concentrated. The residue was partitioned between EtOAc and water.
The organic phase was dried and concentrated to give 60A (300 mg,
91%).
[0419] Compound 60A was converted to 60 in a manner similar to that
described in Example 3 (Step 3). MS m/z=246 (MH+).
Preparative Example 61
[0420] ##STR149##
[0421] To 2-chloro-5-hydroxypyridine (61A) in acetone (80 mL) was
added K.sub.2CO.sub.3 (8.96 g, 65 mmol) and methylchloroacetate
(2.54 mL, 29 mmol). The mixture was heated at 60.degree. C. for 4
h. After cooling to RT, the mixture was filtered, and the solids
were washed with acetone (50 mL). The filtrate was concentrated in
vacuo to give 4.3 g intermediate (92% yield). The intermediate (4.3
g, 21.3 mmol) was dissolved in CHCl.sub.3 (75 mL) and treated with
m-chloroperbenzoic acid (4.78 g, 27.7 mmol). The resulting solution
was heated at 50.degree. C. for 4 h, then stirred at RT overnight.
The mixture was treated with sodium sulfate, filtered and
concentrated in vacuo. Flash column chromatography (5%-10% MeOH in
DCM) provided 61B (3.46 g, 75%). ##STR150##
[0422] The N-oxide 61B (1.0 g, 4.61 mmol) was dissolved in
H.sub.2SO.sub.4 (2 mL) at 0.degree. C. HNO.sub.3 (1 mL) was added
slowly over several minutes. The reaction mixture was then placed
in an oil bath heated to 40.degree. C. The temperature was slowly
raised to 75.degree. C. over 1 h and then maintained there for 2 h.
The mixture was then poured over ice and adjusted to pH 9 by the
addition of 50% NaOH. Water was removed in vacuo, and the resultant
solids were washed with MeOH to yield crude nitro pyridine N-oxide
intermediate (2.6 g). A portion of this intermediate (1.33 g, 5.3
mmol) was dissolved in MeOH (50 mL) and treated with
H.sub.2SO.sub.4 (1 mL). The mixture was heated at 70.degree. C. for
2 h and then concentrated. The residue was treated with 1N NaOH (20
mL) and EtOAc (50 mL). The solution was extracted with EtOAc
(2.times.50 mL). The combined organic extracts were dried over
sodium sulfate, filtered and concentrated in vacuo to give compound
61C (1.4 g, 100%). ##STR151##
[0423] A mixture of 61C (0.06 g, 0.23 mmol) in MeOH (2 mL) was
treated with iron powder (0.09 g, 1.61 mmol) and HOAC (0.08 mL).
The resulting solution was heated at 70.degree. C. for 4 h. The hot
solution was filtered through a pad of celite and concentrated. The
residue was taken up in MeOH (2 mL) and treated with
K.sub.2CO.sub.3 (0.073 g, 0.53 mmol). After heating at 65.degree.
C. for 2 h, the solvent was removed in vacuo and the product
purified by preparative TLC (5% MeOH in DCM) to give compound 61D
(0.032 g, 76%). ##STR152##
[0424] In a manner similar to that found in Example 3 (Step 2) and
Example 5 (Step 1), compound 61D was reduced and protected to give
compound 61E. ##STR153##
[0425] A mixture of 61E (0.250 g, 0.91 mmol), benzophenoneimine
(0.152 mL, 0.91 mmol), tris(dibenzylideneacetone dipalladium(0)
(0.004 g, 0.0045 mmol),
rac-2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene (0.004 g, 0.007
mmol), and NaOtBu (0.088 g, 0.91 mmol) in toluene (8 mL) in a
culture tube was heated in a rotating oven at 80.degree. C.
overnight. After cooling to RT, the contents were transferred to a
round-bottomed flask and treated with several scoops of silica gel.
The solvent was removed in vacuo and the product purified by flash
column chromatography (10% to 50% EtOAc-hexanes) to give 61F (0.205
g, 54%). ##STR154##
[0426] A mixture of 61F (0.205 g, 0.5 mmol) in THF (4 mL) was
treated with 15% aqueous citric acid solution (4 mL). The resulting
solution was stirred at RT overnight. Saturated aqueous NaHCO.sub.3
(5 mL) was added and the solution was extracted with EtOAc
(2.times.25 mL). The organic extracts were dried over sodium
sulfate, filtered and concentrated in vacuo. The product was
purified by flash column chromatography (10% to 50% EtOAc-hexanes)
to give 61G (0.114 g, 91%).
[0427] In a manner similar to that found in Example 3 (Step 5),
Example 5 (Step 4) and Example 3 (Step 3), compound 61G was
sequentially treated with ClCO.sub.2Me, deprotected and converted
the title compound 61. MS m/z=290 (MH+).
Preparative Example 62
[0428] ##STR155##
[0429] A slurry of 38 in anhydrous DCE (4 ml) and anhydrous THF (4
ml) was treated with anhydrous TEA (0.2 ml) followed by
benzenesulfonyl chloride (0.070 mL). After 2 h at RT, additional
benzenesulfonyl (0.2 mL) was added. The mixture was stirred for 1
h, then diluted with CH.sub.2Cl.sub.2, washed with brine, dried
(Na.sub.2SO.sub.4), and concentrated. Preparative TLC
chromatography (9% MeOH/CH.sub.2Cl.sub.2) afforded 62 (43 mg). The
following compounds were prepared following essentially the same
procedure as described above. TABLE-US-00005 MS Cpd Structure (MH+)
100 ##STR156## 230 101 ##STR157## 230 102 ##STR158## 230 103
##STR159## 216 104 ##STR160## 234 105 ##STR161## 248 106 ##STR162##
341 107 ##STR163## 327 108 ##STR164## 349 109 ##STR165## 317 110
##STR166## 329 111 ##STR167## 301 112 ##STR168## 287 113 ##STR169##
273 114 ##STR170## 288 115 ##STR171## 262 116 ##STR172## 293 117
##STR173## 217 118 ##STR174## 217 119 ##STR175## 289 120 ##STR176##
289 121 ##STR177## 241 122 ##STR178## 289 123 ##STR179## 309 124
##STR180## 312 125 ##STR181## 259 126 ##STR182## 291 127 ##STR183##
319 128 ##STR184## 303 129 ##STR185## 275 130 ##STR186## 303 131
##STR187## 306 132 ##STR188## 277 133 ##STR189## 327 134 ##STR190##
320 135 ##STR191## 321 136 ##STR192## 320 137 ##STR193## 290 138
##STR194## 245 139 ##STR195## 303 140 ##STR196## 275 141 ##STR197##
275 142 ##STR198## 354 143 ##STR199## 289 144 ##STR200## 318 145
##STR201## 300 146 ##STR202## 274 147 ##STR203## 437 148 ##STR204##
323 149 ##STR205## 229 150 ##STR206## 311 151 ##STR207## 317 152
##STR208## 276 153 ##STR209## 306 154 ##STR210## 337 155 ##STR211##
323 156 ##STR212## 287 157 ##STR213## 301 158 ##STR214## 301 159
##STR215## 331 160 ##STR216## 361 161 ##STR217## 436 162 ##STR218##
355 163 ##STR219## 331 164 ##STR220## 345 165 ##STR221## 375 166
##STR222## 419 167 ##STR223## 405 168 ##STR224## 327 169 ##STR225##
341 170 ##STR226## 332 171 ##STR227## 314 172 ##STR228## 321 173
##STR229## 321 174 ##STR230## 291 175 ##STR231## 263 176 ##STR232##
335 177 ##STR233## 277 178 ##STR234## 335 179 ##STR235## 349 180
##STR236## 349 181 ##STR237## 332 182 ##STR238## 286 183 ##STR239##
256 184 ##STR240## 314 185 ##STR241## 328 186 ##STR242## 327 187
##STR243## 376 188 ##STR244## 333 189 ##STR245## 329 190 ##STR246##
299 191 ##STR247## 357 192 ##STR248## 371 193 ##STR249## 371 194
##STR250## 385 195 ##STR251## 370 196 ##STR252## 384 197 ##STR253##
354 198 ##STR254## 339 199 ##STR255## 353 200 ##STR256## 338 201
##STR257## 352 202 ##STR258## 322 203 ##STR259## 392 204 ##STR260##
406 205 ##STR261## 406 206 ##STR262## 389 207 ##STR263## 289 208
##STR264## 333 209 ##STR265## 343 210 ##STR266## 327 211 ##STR267##
350 212 ##STR268## 380 213 ##STR269## 368 214 ##STR270## 351 215
##STR271## 390 216 ##STR272## 369 217 ##STR273## 356 218 ##STR274##
384
219 ##STR275## 355 220 ##STR276## 303 221 ##STR277## 365 222
##STR278## 289 223 ##STR279## 316 224 ##STR280## 274 225 ##STR281##
304 226 ##STR282## 303 227 ##STR283## 288 228 ##STR284## 304 229
##STR285## 324 230 ##STR286## 318 231 ##STR287## 348 232 ##STR288##
336 233 ##STR289## 337 234 ##STR290## 351 235 ##STR291## 352 236
##STR292## 350 237 ##STR293## 331 238 ##STR294## 330 239 ##STR295##
316 240 ##STR296## 317 241 ##STR297## 304 242 ##STR298## 317 243
##STR299## 318 244 ##STR300## 332 245 ##STR301## 330 246 ##STR302##
347 247 ##STR303## 328 248 ##STR304## 390 249 ##STR305## 349 250
##STR306## 381 251 ##STR307## 351 252 ##STR308## 381 253 ##STR309##
275 254 ##STR310## 277 255 ##STR311## 309 256 ##STR312## 345 257
##STR313## 331 258 ##STR314## 331 259 ##STR315## 407 260 ##STR316##
361 261 ##STR317## 247 262 ##STR318## 341 263 ##STR319## 373 264
##STR320## 345 265 ##STR321## 359 266 ##STR322## 335 267 ##STR323##
351 268 ##STR324## 365 269 ##STR325## 365 270 ##STR326## 391 271
##STR327## 317 272 ##STR328## 331
Assay:
[0430] Efficacy agonist activity values (E.sub.max, GTP.gamma.S
assay) for .alpha.2C were determined by following the general
procedure detailed by Umland et. al ("Receptor reserve analysis of
the human .alpha..sub.2c-adrenoceptor using [.sup.35S]GTP.gamma.S
and cAMP functional assays" European Journal of Pharmacology 2001,
411, 211-221). For the purposes of the present invention, a
compound is defined to be an active agonist of the .alpha.2C
receptor subtype if the compound's efficacy at the .alpha.2C
receptor is .gtoreq.30% E.sub.max (GTP.gamma.S assay). A compound
is a functionally selective agonist of the .alpha.2C receptor
subtype over the .alpha.2A receptor subtype if the compound's
efficacy at the .alpha.2C receptor is .gtoreq.30% E.sub.max
(GTP.gamma.S assay) and its efficacy at the .alpha.2A receptor is
.gtoreq.30% E.sub.max (GTP.gamma.S assay).
[0431] The following compounds were evaluated to be active or
functionally selective agonists of the .alpha.2C receptor subtype
based on the previously defined definition: 1, 3, 3D, 3E, 5, 6, 6E,
7, 8, 9E, 9G, 9I, 9K, 9L, 9M, 9N, 9P, 9Q, 9R, 9S, 12, 13, 14, 14B,
15, 19, 19D, 20, 21, 22, 24, 24D, 25B, 26, 26A, 26B, 27E, 28, 28D,
29, 30, 37, 38, 46, 51, 53, 54, 55, 57, 58, 114, 117, 124, 125,
129, 130, 132, 134, 135, 137, 139, 142, 144, 145, 148, 151, 152,
158, 159, 160, 162, 163, 164, 165, 167, 168, 169, 171, 178, 181,
218, 223, 231, 232, 235, 236, 238, 239, 240, 242, 243, 244, 245,
246, 247, 248, 249, and 250.
[0432] While the present invention has been described with in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and other variations thereof will be
apparent to those of ordinary skill in the art. All such
alternatives, modifications and variations are intended to fall
within the spirit and scope of the present invention.
* * * * *