U.S. patent application number 14/968013 was filed with the patent office on 2016-11-10 for tricyclic pyrazole sulphonamide compounds and methods of making and using same.
The applicant listed for this patent is Zafgen, Inc.. Invention is credited to Susan M. Cramp, Hazel J. Dyke, Thomas D. Pallin, Robert Zahler.
Application Number | 20160324865 14/968013 |
Document ID | / |
Family ID | 46085253 |
Filed Date | 2016-11-10 |
United States Patent
Application |
20160324865 |
Kind Code |
A1 |
Cramp; Susan M. ; et
al. |
November 10, 2016 |
TRICYCLIC PYRAZOLE SULPHONAMIDE COMPOUNDS AND METHODS OF MAKING AND
USING SAME
Abstract
The invention provides tricyclic sulfonamide compounds and their
use in treating medical disorders, such as obesity. Pharmaceutical
compositions and methods of making various tricyclic compounds are
provided. The compounds are contemplated to have activity against
methionyl aminopeptidase 2.
Inventors: |
Cramp; Susan M.; (Harlow,
GB) ; Dyke; Hazel J.; (Harlow, GB) ; Pallin;
Thomas D.; (Harlow, GB) ; Zahler; Robert;
(Pennington, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Zafgen, Inc. |
Boston |
MA |
US |
|
|
Family ID: |
46085253 |
Appl. No.: |
14/968013 |
Filed: |
December 14, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14116029 |
Nov 6, 2013 |
9242997 |
|
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PCT/US12/36793 |
May 7, 2012 |
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14968013 |
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61483275 |
May 6, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0053 20130101;
C07D 498/14 20130101; A61P 43/00 20180101; A61K 31/5383 20130101;
A61P 3/04 20180101; C07D 471/04 20130101; A61K 31/4745 20130101;
C07D 498/04 20130101 |
International
Class: |
A61K 31/5383 20060101
A61K031/5383; A61K 9/00 20060101 A61K009/00; A61K 31/4745 20060101
A61K031/4745 |
Claims
1. A method of treating and/or controlling obesity, comprising
administering to a patient in need thereof an effective amount of a
tricyclic compound represented by: ##STR00047## wherein: D.sup.1
and D.sup.2 are each 5-7 membered heterocyclic or heteroaromatic
rings in which one of the two atoms in common between rings B and D
is nitrogen and the other is carbon; X.sup.1 is selected from the
group consisting of: *--C(R.sup.D1R.sup.D2)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--.sup.#, *--N--C(R.sup.C2)--.sup.#,
*--W.sup.1--C(R.sup.D5R.sup.D6)--.sup.#, *--W.sup.1--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(O)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(O)--.sup.#; wherein the * and #
denote the attachment points of X.sup.1 in Formula I; X.sup.2 is
selected from the group consisting of:
*--C(R.sup.D1R.sup.D2)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--.sup.#, *--N--C(R.sup.C2)--.sup.#,
*--C(R.sup.C1).dbd.N--.sup.#,
*--W.sup.1--C(R.sup.D5R.sup.D6)--.sup.#, *--W.sup.1--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(O)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--W.sup.2--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--W.sup.2--C(O)--.sup.#; wherein the * and
.sup.# indicate the attachment points of X.sup.2 in Formula II; Y
is selected from CH or N; B.sup.1 or B.sup.2 rings are each
optionally be substituted by one or more fluorine atoms on any of
the available carbon atoms; W.sup.1 is selected from the group
consisting of: O or N(R.sup.N1); W.sup.2 is selected from the group
consisting of: O or N(R.sup.N2); A is a ring selected from the
group consisting of: phenyl, a 5-6 membered heteroaryl having 1, 2
or 3 heteroatoms each selected from S, N or O, and a 4-7 membered
heterocycle having 1, 2 or 3 heteroatoms each selected from N or O;
R.sup.A1 is selected, independently for each occurrence, from the
group consisting of: hydrogen, hydroxyl, cyano, halogen,
C.sub.1-4alkyl or C.sub.1-3alkoxy; wherein C.sub.1-4alkyl, or
C.sub.1-3alkoxy may be optionally substituted by one or more
fluorines; n is 1 or 2; R.sup.A2 is selected from the group
consisting of: hydrogen, R.sup.iR.sup.jN--, heterocyclyl,
heterocyclyloxy, heterocyclyl-(NR.sup.a)--; wherein said
heterocyclyl may optionally be substituted by one or more
substituents selected from R.sup.g and wherein if said heterocyclyl
contains a --NH moiety that nitrogen may optionally be substituted
by one or more groups R.sup.h; or R.sup.A2 is selected from the
group consisting of: C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6 cycloalkyl, C.sub.1-6alkoxy,
C.sub.3-6alkenyloxy, C.sub.3-6alkynyloxy, C.sub.3-6cycloalkoxy,
C.sub.1-6alkyl-S(O).sub.w-- (wherein w is 0, 1 or 2),
C.sub.1-6alkyl-N(R.sup.a)--, C.sub.1-6alkyl-N(R.sup.a)-carbonyl-,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)--SO.sub.2--,
C.sub.1-6alkyl-SO.sub.2--N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--, C.sub.1-6
alkylcarbonyl-N(R.sup.a)--C.sub.1-6alkyl-,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-C.sub.1-6alkyl-,
C.sub.1-4alkoxyC.sub.1-6alkyl-; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkoxy, C.sub.3-6alkenyloxy, C.sub.1-6alkynyloxy,
C.sub.3-6cycloalkoxy, C.sub.1-6alkyl-S(O).sub.w-- (wherein w is 0,
1 or 2), C.sub.1-6alkyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)--SO.sub.2-,
C.sub.1-6alkyl-SO.sub.2--N(R.sup.a)--,
C.sub.1-6alkykoxycarbonyl-N(R.sup.a)C,
C.sub.1-6alkylcarbonyl-N(R.sup.a)C.sub.1-6alkyl-,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-C.sub.1-6alkyl-,
C.sub.1-6alkoxy-C.sub.1-6alkyl may optionally be substituted by
R.sup.P, phenyl, phenoxy, heteroaryl, heteroaryloxy,
heteroaryl-(NR.sup.a)--, heterocyclyl, heterocyclyloxy or
heterocyclyl-N(R.sup.a)--; wherein said heteroaryl or phenyl may
optionally be substituted with one or more substituents selected
from R.sup.f; wherein said heterocyclyl may optionally be
substituted by one or more substituents selected from R.sup.g; and
wherein if said heterocyclyl contains a --NH moiety that nitrogen
may optionally be substituted by one or more groups R.sup.h;
R.sup.D1 and R.sup.D2 are each independently selected from the
group consisting of: hydrogen, fluorine, hydroxyl, C.sub.1-2alkyl
or C.sub.1-2alkoxy; wherein the C.sub.1-2alkyl and C.sub.1-2alkoxy
may optionally be substituted by one or more fluorine atoms or a
group selected from cyano or hydroxyl; R.sup.D3 and R.sup.D4 are
each independently selected from the group consisting of: hydrogen,
fluorine, hydroxyl, cyano, C.sub.1-3alkyl or C.sub.1-3alkoxy;
wherein the C.sub.1-3alkyl and C.sub.1-3alkoxy may optionally be
substituted by one or more fluorine atoms or a group selected from
cyano, hydroxyl or N(R.sup.aR.sup.b); R.sup.D5 and R.sup.D6 are
each independently selected from the group consisting of: hydrogen,
fluorine, hydroxyl, cyano, C.sub.1-2alkyl or C.sub.1-2alkoxy;
wherein the C.sub.1-2alkyl and C.sub.1-2alkoxy may optionally be
substituted by one or more fluorine atoms or a group selected from
cyano, hydroxyl or N(R.sup.aR.sup.b), R.sup.C1 is selected from the
group consisting of: hydrogen, halogen, C.sub.1-2alkyl or
C.sub.1-2alkoxy; wherein the C.sub.1-2alkyl or C.sub.1-2alkoxy may
optionally be substituted by one or more fluorine atoms; R.sup.C2
is selected from the group consisting of: hydrogen, halogen,
hydroxyl, cyano, C.sub.1-2alkyl or C.sub.1-2alkoxy; wherein the
C.sub.1-2alkyl and C.sub.1-2alkoxy may optionally be substituted by
one or more fluorine atoms or a group selected from cyano, hydroxyl
or N(R.sup.aR.sup.b); R.sup.N1 is selected from the group
consisting of: hydrogen or C.sub.1-2alkyl; R.sup.N2 is selected
from the group consisting of: hydrogen, C.sub.1-3alkyl or
C.sub.1-2alkylcarbonyl; wherein the C.sub.1-3alkyl and
C.sub.1-2alkylcarbonyl may optionally be substituted by one or more
fluorine atoms or a group selected from cyano, hydroxyl or
N(R.sup.aR.sup.b); R.sup.a and R.sup.b are independently selected,
for each occurrence, from the group consisting of: hydrogen and
C.sub.1-3alkyl; wherein C.sub.1-3alkyl may optionally be
substituted by one or more substituents selected from: fluorine,
cyano, oxo and hydroxyl; or R.sup.a and R.sup.b, together with the
nitrogen to which they are attached, form a 4-6 membered
heterocyclic ring which may have an additional heteroatom selected
from O, S, or N; and wherein the 4-6 membered heterocyclic ring may
optionally be substituted on carbon by one or more substituents
selected from the group consisting of: fluorine, cyano, oxo or
hydroxyl; R.sup.f is independently selected, for each occurrence,
from the group consisting of: R.sup.P, hydrogen, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy,
C.sub.1-6alkyl-S(O).sub.w-(wherein w is 0, 1 or 2),
C.sub.1-6alkylcarbonyl-N(R.sup.a)--;
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--; and wherein C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-4alkoxy, C.sub.1-4alkyl-S(O).sub.w--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--, C.sub.1
alkoxycarbonyl-N(R.sup.a)-- may be optionally substituted by one or
more substituents selected from R.sup.P; R.sup.g is independently
selected for each occurrence from the group consisting of: R.sup.P,
hydrogen, oxo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy, C.sub.1-6alkyl-S(O).sub.w--
(wherein w is 0, 1 or 2), C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkoxy, C.sub.1-6-alkyl-S(O).sub.w--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)-- may be optionally substituted
by one or more substituents selected from R.sup.P; R.sup.h is
independently selected for each occurrence from the group
consisting of: hydrogen, C.sub.1-6alkyl, C.sub.3-6alkenyl,
C.sub.3-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkyl-S(O).sub.2--,
C.sub.1-6alkoxycarbonyl-, R.sup.iR.sup.jN-carbonyl-,
R.sup.iR.sup.jN--SO.sub.2--; wherein C.sub.1-6alkyl, C-alkenyl,
C-alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkyl-S(O).sub.2--,
C.sub.1-6alkylcarbonyl- may optionally be substituted by one or
more substituents selected from R.sup.P; R.sup.i and R.sup.j, are
selected independently for each occurrence from the group
consisting of: hydrogen, C.sub.1-4alkyl and C.sub.3-6cycloalkyl;
wherein C.sub.1-4alkyl and C.sub.3-6cycloalkyl may be optionally
substituted by one or more substituents selected from fluorine,
hydroxyl, cyano, R.sup.aR.sup.bN--, R.sup.aR.sup.b-carbonyl-,
C.sub.1-3alkoxy; or R.sup.i and R.sup.j taken together with the
nitrogen to which they are attached form a 4-7 membered
heterocyclic ring which may have an additional heteroatom selected
from O, S, or N, optionally substituted on carbon by one or more
substituents selected from the group consisting of: fluorine,
hydroxyl, oxo, cyano, C.sub.1-6alkyl, C.sub.1-6alkoxy,
R.sup.aR.sup.bN--, R.sup.aR.sup.bN--SO.sub.2-,
R.sup.aR.sup.bN-carbonyl-; and wherein said C.sub.1-6alkyl or
C.sub.1-6alkoxy may optionally be substituted by fluorine, hydroxyl
or cyano; and optionally substituted on nitrogen by one or more
substituents selected from the group consisting of: C.sub.1-6alkyl,
R.sup.aR.sup.bN-carbonyl-; and wherein said C.sub.1-6alkyl may be
optionally substituted by fluorine, hydroxyl, cyano; R.sup.P is
independently selected, for each occurrence, from the group
consisting of: halogen, hydroxyl, cyano, C.sub.1-6alkoxy,
R.sup.iR.sup.jN--, R.sup.iR.sup.jN-carbonyl-,
R.sup.iR.sup.jN--SO.sub.2--, R.sup.iR.sup.jN-carbonyl-N(R.sup.a)--;
and pharmaceutically acceptable salts, stereoisomers, esters and
prodrugs thereof.
2. The method of claim 1, wherein X.sup.1 is selected from the
group consisting of:
*--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1)C(R.sup.C2)--.sup.#,
*--O--C(R.sup.D5R.sup.D6)--.sup.#,*--N(R.sup.N1)--C(R.sup.D5R.sup.D6)--.s-
up.#, *--C(R.sup.D1R.sup.D2)--C(O)--.sup.#,
*--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)-- and
*--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#;
wherein the * and .sup.# indicate the attachment points of X.sup.1
as indicated in Formula I.
3. The method of claim 1, wherein X.sup.1 is selected from the
group consisting of: *--CH.sub.2CH.sub.2--.sup.# and
*--CH.dbd.CH--.sup.#; wherein the * and # indicate the attachment
points of X.sup.1 as indicated in Formula I.
4. The method of claim 1, wherein X.sup.2 is selected from the
group consisting of:
*--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--, *--N--C(R.sup.C2)--.sup.#,
*--O--C(R.sup.D5R.sup.D6)--.sup.#,
*--N(R.sup.N1)--C(R.sup.D5R.sup.D6)--.sup.#,
*--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)-- and
*--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#;
wherein the * and .sup.# indicate the attachment points of X.sup.2
as indicated in Formula II.
5. The method of claim 4, wherein X.sup.2 is selected from the
group consisting of: *--CH.sub.2CH.sub.2--.sup.#,
*--CH.dbd.CH--.sup.#, *--O--CH.sub.2--.sup.#,
*--NH--CH.sub.2--.sup.# and *--O--CH.sub.2--CH.sub.2--.sup.#;
wherein the * and .sup.# indicate the attachment points of X.sup.1
as indicated in Formula II.
6. The method of claim 4, wherein R.sup.D1, R.sup.D2, R.sup.C1 and
R.sup.N1 are independently selected for each occurrence from the
group consisting of hydrogen and methyl.
7. The method of claim 4, wherein R.sup.D1, R.sup.D2, R.sup.C1 and
R.sup.N1 are hydrogen.
8. The method of claim 1, wherein R.sup.D3, R.sup.D4, R.sup.D5 and
R.sup.D6 are independently selected for each occurrence from the
group consisting of hydrogen, fluorine, cyano, or
C.sub.1-2alkyl.
9. The method of claim 8, wherein R.sup.D3, R.sup.D4, R.sup.D5 and
R.sup.D6 are hydrogen.
10. The method of claim 1, wherein R.sup.C2 is selected from the
group consisting of hydrogen, halogen, cyano or C.sub.1-2alkyl.
11. The method of claim 1, wherein R.sup.C2 is hydrogen.
12. The method of claim 1, wherein R.sup.N2 is selected from the
group consisting of hydrogen and C.sub.1-2alkyl.
13. The method of claim 12, wherein R.sup.N2 is hydrogen.
14. The method of claim 1, wherein Y is N.
15. The method of claim 1, wherein the compound is selected from
the group consisting of: ##STR00048## wherein A, R.sup.A1, n and
R.sup.A2 are defined above.
16. The method of claim 15, wherein A is phenyl.
17. A method of treating and/or controlling obesity, comprising
administering to a patient in need thereof an effective amount of a
tricyclic compound represented by: ##STR00049## wherein X.sup.1 is
selected from the group consisting of:
*--C(R.sup.D1R.sup.D2)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--.sup.#, *--N--C(R.sup.C2)--.sup.#,
*--W.sup.1--C(R.sup.D5R.sup.D6)--.sup.#, *--W.sup.1--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(O)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(O)--.sup.#; wherein the * and #
denote the attachment points of X.sup.1 in Formula I; X.sup.2 is
selected from the group consisting of:
*--C(R.sup.D1R.sup.D2)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D6R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--.sup.#, *--N--C(R.sup.C2)--.sup.#,
*--C(R.sup.C1).dbd.N--.sup.#,
*--W.sup.1--C(R.sup.D5R.sup.D6)--.sup.#, *--W.sup.1--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2) C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(O)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--W.sup.2--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--W.sup.2--C(O)--.sup.#; wherein the * and #
indicate the attachment points of X.sup.2 in Formula II; W.sup.1 is
selected from the group consisting of: O or N(R.sup.N1); W.sup.2 is
selected from the group consisting of: O or N(R.sup.N2); R.sup.A1
is selected, independently for each occurrence, from the group
consisting of: hydrogen, hydroxyl, cyano, halogen, C.sub.1-4alkyl
or C.sub.1-3alkoxy; wherein C.sub.1-4alkyl, or C.sub.1-3alkoxy may
be optionally substituted by one or more fluorines; n is 1 or 2;
R.sup.A2 is selected from the group consisting of: hydrogen,
R.sup.iR.sup.jN--, heterocyclyl, heterocyclyloxy,
heterocyclyl-(NR.sup.a)--; wherein said heterocyclyl may optionally
be substituted by one or more substituents selected from R.sup.g
and wherein if said heterocyclyl contains a --NH moiety that
nitrogen may optionally be substituted by one or more groups
R.sup.h; or R.sup.A2 is selected from the group consisting of:
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6cycloalkyl, C.sub.1-6alkoxy, C.sub.1-6alkenyloxy,
C.sub.1-6alkynyloxy, C.sub.1-6cycloalkoxy,
C.sub.1-6alkyl-S(O).sub.w-- (wherein w is 0, 1 or 2),
C.sub.1-6alkyl-N(R.sup.a)--, C.sub.1-6alkyl-N(R.sup.a)-carbonyl-,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)--SO.sub.2--,
C.sub.1-6-alkyl-SO.sub.2--N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--, C.sub.1-6
alkylcarbonyl-N(R.sup.a)--C.sub.1-6alkyl-,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-C.sub.1-6alkyl-,
C.sub.1-6alkoxyC.sub.1-6alkyl-; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6cycloalkyl,
C.sub.1-6alkoxy, C.sub.3-6alkenyloxy, C.sub.1-6alkynyloxy,
C.sub.1-6cycloalkoxy, C.sub.1-6alkyl-S(O).sub.w--,
C.sub.1-6alkyl-N(R.sup.a)--, C.sub.1-4alkyl-N(R.sup.a)-carbonyl-,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a))-carbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)--SO.sub.2--,
C.sub.1-6alkyl-SO.sub.2--N(R.sup.a)--, C.sub.1-6
alkoxycarbonyl-N(R.sup.a)--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)C.sub.1-6alkyl-,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-C.sub.1-6alkyl-, C.sub.1-6
alkoxy-C.sub.1-6alkyl may optionally be substituted by R.sup.P,
phenyl, phenoxy, heteroaryl, heteroaryloxy,
heteroaryl-(NR.sup.a)--, heterocyclyl, heterocyclyloxy or
heterocyclyl-N(R.sup.a)--; wherein said heteroaryl or phenyl may
optionally be substituted with one or more substituents selected
from R.sup.f; wherein said heterocyclyl may optionally be
substituted by one or more substituents selected from R.sup.g; and
wherein if said heterocyclyl contains a --NH moiety that nitrogen
may optionally be substituted by one or more groups R.sup.h;
R.sup.D1 and R.sup.D2 are each independently selected from the
group consisting of: hydrogen, fluorine, hydroxyl, C.sub.1-2alkyl
or C.sub.1-2alkoxy; wherein the C.sub.1-2alkyl and C.sub.1-2alkoxy
may optionally be substituted by one or more fluorine atoms or a
group selected from cyano or hydroxyl; R.sup.D3 and R.sup.D4 are
each independently selected from the group consisting of: hydrogen,
fluorine, hydroxyl, cyano, C.sub.1-3alkyl or C.sub.1-3alkoxy;
wherein the C.sub.1-3 alkyl and C.sub.1-3 alkoxy may optionally be
substituted by one or more fluorine atoms or a group selected from
cyano, hydroxyl or N(R.sup.aR.sup.b); R.sup.D5 and R.sup.D6 are
each independently selected from the group consisting of: hydrogen,
fluorine, hydroxyl, cyano, C.sub.1-2alkyl or C.sub.1-2alkoxy;
wherein the C.sub.1-2alkyl and C.sub.1-2alkoxy may optionally be
substituted by one or more fluorine atoms or a group selected from
cyano, hydroxyl or N(R.sup.aR.sup.b), R.sup.C1 is selected from the
group consisting of: hydrogen, halogen, C.sub.1-2alkyl or
C.sub.1-2alkoxy; wherein the C.sub.1-2alkyl or C.sub.1-2alkoxy may
optionally be substituted by one or more fluorine atoms; R.sup.C2
is selected from the group consisting of: hydrogen, halogen,
hydroxyl, cyano, C.sub.1-2alkyl or C.sub.1-2alkoxy; wherein the
C.sub.1-2alkyl and C.sub.1-2alkoxy may optionally be substituted by
one or more fluorine atoms or a group selected from cyano, hydroxyl
or N(R.sup.aR.sup.b); R.sup.N1 is selected from the group
consisting of: hydrogen or C.sub.1-2alkyl; R.sup.N2 is selected
from the group consisting of: hydrogen, C.sub.1-3alkyl or
C.sub.1-2alkylcarbonyl; wherein the C.sub.1-3alkyl and
C.sub.1-2alkylcarbonyl may optionally be substituted by one or more
fluorine atoms or a group selected from cyano, hydroxyl or
N(R.sup.aR.sup.b); R.sup.a and R.sup.b are independently selected,
for each occurrence, from the group consisting of: hydrogen and
C.sub.1-3alkyl; wherein C.sub.1-3alkyl may optionally be
substituted by one or more substituents selected from: fluorine,
cyano, oxo and hydroxyl; or R.sup.a and R.sup.b, together with the
nitrogen to which they are attached, may form a 4-6 membered
heterocyclic ring which may have an additional heteroatom selected
from O, S, or N; and wherein the 4-6 membered heterocyclic ring may
optionally be substituted on carbon by one or more substituents
selected from the group consisting of: fluorine, cyano, oxo or
hydroxyl; R.sup.f is independently selected, for each occurrence,
from the group consisting of: R.sup.P, hydrogen, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy,
C.sub.1-6alkyl-S(O).sub.w-(wherein w is 0, 1 or 2),
C.sub.1-6alkylcarbonyl-N(R.sup.a)--;
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--; and wherein C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy, C.sub.1-6alkyl-S(O).sub.w--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)-- may be optionally substituted
by one or more substituents selected from R.sup.P; R.sup.g is
independently selected for each occurrence from the group
consisting of: R.sup.P, hydrogen, oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkoxy, C.sub.1-6alkyl-S(O).sub.w-- (wherein w is 0, 1 or
2), C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkoxy, C.sub.1-6alkyl-S(O).sub.w,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--, C.sub.1-6
alkoxycarbonyl-N(R.sup.a)-- may be optionally substituted by one or
more substituents selected from R.sup.P; R.sup.h is independently
selected for each occurrence from the group consisting of:
hydrogen, C.sub.1-6alkyl, C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkyl-S(O).sub.2--,
C.sub.1-4alkoxycarbonyl-, R.sup.iR.sup.jN-carbonyl-,
R.sup.iR.sup.jN--SO.sub.2--; wherein C.sub.1-6alkyl,
C.sub.3-6alkenyl, C.sub.3-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-4alkyl-S(O).sub.2--, C.sub.1-6alkylcarbonyl- may optionally
be substituted by one or more substituents selected from R.sup.P;
R.sup.i and R.sup.j, are selected independently for each occurrence
from the group consisting of: hydrogen, C.sub.1-4alkyl and
C.sub.3-6cycloalkyl; wherein C.sub.1-4alkyl and C.sub.3-6cycloalkyl
may be optionally substituted by one or more substituents selected
from fluorine, hydroxyl, cyano, R.sup.aR.sup.bN--,
R.sup.aR.sup.bN-carbonyl-, C.sub.1-3alkoxy; or R.sup.i and R.sup.j
taken together with the nitrogen to which they are attached form a
4-7 membered heterocyclic ring which may have an additional
heteroatom selected from O, S, or N, optionally substituted on
carbon by one or more substituents selected from the group
consisting of: fluorine, hydroxyl, oxo, cyano, C.sub.1-6alkyl,
C.sub.1-4alkoxy, R.sup.aR.sup.bN--, R.sup.aR.sup.bN--SO.sub.2-,
R.sup.aR.sup.bN-carbonyl-; and wherein said C.sub.1-6alkyl or
C.sub.1-6alkoxy may optionally be substituted by fluorine, hydroxyl
or cyano; and optionally substituted on nitrogen by one or more
substituents selected from the group consisting of: C.sub.1-6alkyl,
R.sup.aR.sup.bN-carbonyl-; and wherein said C.sub.1-6alkyl may be
optionally substituted by fluorine, hydroxyl, cyano; R.sup.P is
independently selected, for each occurrence, from the group
consisting of: halogen, hydroxyl, cyano, C.sub.1-6alkoxy,
R.sup.iR.sup.jN--, R.sup.iR.sup.jN-carbonyl-,
R.sup.iR.sup.jN--SO.sub.2--, R.sup.iR.sup.jN-carbonyl-N(R.sup.a)--;
and pharmaceutically acceptable salts, stereoisomers, esters and
prodrugs thereof.
18. The method of claim 17, wherein R.sup.A1 is selected from the
group consisting of hydrogen, halogen, C.sub.1-2alkyl,
C.sub.1-2alkoxy; wherein C.sub.1-2alkyl may optionally be
substituted by one or more fluorines.
19. The method of claim 17, wherein R.sup.A1 is selected from
hydrogen or fluorine.
20. The method of claim 17, wherein R.sup.A2 is selected from the
group consisting of hydrogen, R.sup.iR.sup.jN, heterocyclyl,
C.sub.1-6alkyl, C.sub.3-6 alkenyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkoxy; wherein said heterocyclyl may optionally be
substituted by one or more groups R.sup.g, and wherein if said
heterocyclyl contains a --NH moiety, that nitrogen may optionally
be substituted by on or more groups R.sup.h; and wherein said
C.sub.1-6alkyl, C.sub.3-6alkenyl, C.sub.3-6 cycloalkyl and
C.sub.1-6alkoxy may optionally be substituted by one or more groups
R.sup.P.
21. The method of claim 17 wherein R.sup.A2 is selected from the
group consisting of 3-(N,N-diethylamino)propyl,
3-(pyrrolidin-1-yl)propyl, (Z)-3-(N,N-diethylamino)prop-1-enyl,
(Z)-3-(azetidin-1-yl)prop-1-enyl and
(Z)-3-(pyrrolidin-1-yl)prop-1-enyl.
22. A method of treating and/or controlling obesity, comprising
administering to a patient in need thereof an effective amount of a
compound selected from the group consisting of:
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-pyrazo-
lo[5,1-a]isoquinoline-7-carboxylic acid;
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-ben-
zo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylic acid;
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-di-
hydropyrazolo[5,1-a]isoquinoline-7-carboxylic acid;
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-5-o-
xa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylic acid and
pharmaceutically acceptable salts, stereoisomers, esters and
prodrugs thereof.
23.-25. (canceled)
26. The method of claim 1, wherein the patient is a human.
27. The method of claim 1, wherein the patient is a cat or dog.
28. The method of claim 1, wherein the patient has a body mass
index greater than or equal to about 30 kg/m.sup.2 before the
administration.
29. The method of claim 1, wherein the compound is administered
orally.
30.-34. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/116,029, filed Nov. 6, 2013, which is a
national stage filing under U.S.C. .sctn.371 of PCT/US2012/036793,
filed May 7, 2012, which claims priority to U.S. Provisional Patent
Application No. 61/483,275 filed May 6, 2011, all of which are
hereby incorporated by reference in their entirety.
BACKGROUND
[0002] Over 1.1 billion people worldwide are reported to be
overweight. Obesity is estimated to affect over 90 million people
in the United States alone. Twenty-five percent of the population
in the United States over the age of twenty is considered
clinically obese. While being overweight or obese presents problems
(for example restriction of mobility, discomfort in tight spaces
such as theater or airplane seats, social difficulties, etc.),
these conditions, in particular clinical obesity, affect other
aspects of health, i.e., diseases and other adverse health
conditions associated with, exacerbated by, or precipitated by
being overweight or obese. The estimated mortality from
obesity-related conditions in the United States is over 300,000
annually (O'Brien et al. Amer J Surgery (2002) 184:4S-8S; and Hill
et al. (1998) Science, 280:1371).
[0003] There is no curative treatment for being overweight or
obese. Traditional pharmacotherapies for treating an overweight or
obese subject, such as serotonin and noradrenergic re-uptake
inhibitors, noradrenergic re-uptake inhibitors, selective serotonin
re-uptake inhibitors, intestinal lipase inhibitors, or surgeries
such as stomach stapling or gastric banding, have been shown to
provide minimal short-term benefits or significant rates of
relapse, and have further shown harmful side-effects to
patients.
[0004] MetAP2 encodes a protein that functions at least in part by
enzymatically removing the amino terminal methionine residue from
certain newly translated proteins such as
glyceraldehyde-3-phosphate dehydrogenase (Warder et al. (2008) J
Proteome Res 7:4807). Increased expression of the MetAP2 gene has
been historically associated with various forms of cancer.
Molecules inhibiting the enzymatic activity of MetAP2 have been
identified and have been explored for their utility in the
treatment of various tumor types (Wang et al. (2003) Cancer Res.
63:7861) and infectious diseases such as microsporidiosis,
leishmaniasis, and malaria (Zhang et al. (2002) J. Biomed. Sci.
9:34). Notably, inhibition of MetAP2 activity in obese and
obese-diabetic animals leads to a reduction in body weight in part
by increasing the oxidation of fat and in part by reducing the
consumption of food (Rupnick et al. (2002) Proc. Natl. Acad. Sci.
USA 99:10730).
[0005] Such MetAP2 inhibitors may be useful as well for patients
with excess adiposity and conditions related to adiposity including
type 2 diabetes, hepatic steatosis, and cardiovascular disease (via
e.g. ameliorating insulin resistance, reducing hepatic lipid
content, and reducing cardiac workload). Accordingly, compounds
capable of modulating MetAP2 are needed to address the treatment of
obesity and related diseases as well as other ailments favorably
responsive to MetAP2 modulator treatment.
SUMMARY
[0006] The invention provides, for example, compounds which may be
modulators of MetAP2, and their use as medicinal agents, processes
for their preparation, and pharmaceutical compositions containing
them as an active ingredient both alone or in combination with
other agents, as well as provides for their use as medicaments
and/or in the manufacture of medicaments for the inhibition of
MetAP2 activity in warm-blooded animals such as humans. In
particular this invention relates to compounds useful for the
treatment of obesity, type 2 diabetes, and other obesity-associated
conditions. Also provided are pharmaceutical compositions
comprising at least one disclosed compound and a pharmaceutically
acceptable carrier.
[0007] In an embodiment, provided herein are compounds represented
by formula I and II:
##STR00001##
or pharmaceutically acceptable salts, stereoisomers, esters or
prodrugs thereof, where A, B.sup.1, B.sup.2, D.sup.1, D.sup.2,
R.sup.A1, R.sup.A2, Y, X.sup.1, X.sup.2 and n are as defined
herein.
DETAILED DESCRIPTION
[0008] The features and other details of the disclosure will now be
more particularly described. Before further description of the
present invention, certain terms employed in the specification,
examples and appended claims are collected here. These definitions
should be read in light of the remainder of the disclosure and as
understood by a person of skill in the art. Unless defined
otherwise, all technical and scientific terms used herein have the
same meaning as commonly understood by a person of ordinary skill
in the art.
DEFINITIONS
[0009] "Treating" includes any effect, e.g., lessening, reducing,
modulating, or eliminating, that results in the improvement of the
condition, disease, disorder and the like.
[0010] The term "alkenyl" as used herein refers to an unsaturated
straight or branched hydrocarbon having at least one carbon-carbon
double bond. Exemplary alkenyl groups include, but are not limited
to, a straight or branched group of 2-6 or 3-4 carbon atoms,
referred to herein as C.sub.2-6alkenyl, and C.sub.3-4alkenyl,
respectively. Exemplary alkenyl groups include, but are not limited
to, vinyl, allyl, butenyl, pentenyl, etc.
[0011] The term "alkoxy" as used herein refers to a straight or
branched alkyl group attached to oxygen (alkyl-O--). Exemplary
alkoxy groups include, but are not limited to, alkoxy groups of 1-6
or 2-6 carbon atoms, referred to herein as C.sub.1-6alkoxy, and
C.sub.2-6alkoxy, respectively. Exemplary alkoxy groups include, but
are not limited to methoxy, ethoxy, isopropoxy, etc.
[0012] The term "alkoxyalkyl" as used herein refers to a straight
or branched alkyl group attached to oxygen, attached to a second
straight or branched alkyl group (alkyl-O-alkyl-). Exemplary
alkoxyalkyl groups include, but are not limited to, alkoxyalkyl
groups in which each of the alkyl groups independently contains 1-6
carbon atoms, referred to herein as C.sub.1-6alkoxy-C.sub.1-6alkyl.
Exemplary alkoxyalkyl groups include, but are not limited to
methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, 2-methoxypropyl,
ethoxymethyl, 2-isopropoxyethyl etc.
[0013] The term "alkyoxycarbonyl" as used herein refers to a
straight or branched alkyl group attached to oxygen, attached to a
carbonyl group (alkyl-O--C(O)--). Exemplary alkoxycarbonyl groups
include, but are not limited to, alkoxycarbonyl groups of 1-6
carbon atoms, referred to herein as C.sub.1-6alkoxycarbonyl.
Exemplary alkoxycarbonyl groups include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.
[0014] The term "alkenyloxy" used herein refers to a straight or
branched alkenyl group attached to oxygen (alkenyl-O--). Exemplar)
alkenyloxy groups include, but are not limited to, groups with an
alkenyl group of 3-6 carbon atoms, referred to herein as
C.sub.3-6alkenyloxy. Exemplary "alkenyloxy" groups include, but are
not limited to allyloxy, butenyloxy, etc.
[0015] The term "alkynyloxy" used herein refers to a straight or
branched alkynyl group attached to oxygen (alkynyl-O). Exemplary
alkynyloxy groups include, but are not limited to, groups with an
alkynyl group of 3-6 carbon atoms, referred to herein as
C.sub.3-6alkynyloxy. Exemplary alkynyloxy groups include, but are
not limited to, propynyloxy, butynyloxy, etc.
[0016] The term "alkyl" as used herein refers to a saturated
straight or branched hydrocarbon. Exemplary alkyl groups include,
but are not limited to, straight or branched hydrocarbons of 1-6,
1-4, or 1-3 carbon atoms, referred to herein as C.sub.1-6alkyl,
C.sub.1-4alkyl, and C.sub.1-3 alkyl, respectively. Exemplary alkyl
groups include, but are not limited to, methyl, ethyl, propyl,
isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl,
3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl,
3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl,
3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl,
pentyl, isopentyl, neopentyl, hexyl, etc.
[0017] The term "alkylcarbonyl" as used herein refers to a straight
or branched alkyl group attached to a carbonyl group
(alkyl-C(O)--). Exemplary alkylcarbonyl groups include, but are not
limited to, alkylcarbonyl groups of 1-6 atoms, referred to herein
as C.sub.1-6alkylcarbonyl groups. Exemplary alkylcarbonyl groups
include, but are not limited to, acetyl, propanoyl, isopropanoyl,
butanoyl, etc.
[0018] The term "alkynyl" as used herein refers to an unsaturated
straight or branched hydrocarbon having at least one carbon-carbon
triple bond. Exemplary alkynyl groups include, but are not limited
to, straight or branched groups of 2-6, or 3-6 carbon atoms,
referred to herein as C.sub.2-6alkynyl, and C.sub.3-6alkynyl,
respectively. Exemplary alkynyl groups include, but are not limited
to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl,
etc.
[0019] The term "carbonyl" as used herein refers to the radical
--C(O)--.
[0020] The term "cyano" as used herein refers to the radical
--CN.
[0021] The term "cycloalkoxy" as used herein refers to a cycloalkyl
group attached to oxygen (cycloalkyl-O--). Exemplary cycloalkoxy
groups include, but are not limited to, cycloalkoxy groups of 3-6
carbon atoms, referred to herein as C.sub.3-6cycloalkoxy groups.
Exemplary cycloalkoxy groups include, but are not limited to,
cyclopropoxy, cyclobutoxy, cyclohexyloxy, etc
[0022] The terms "cycloalkyl" or a "carbocyclic group" as used
herein refers to a saturated or partially unsaturated hydrocarbon
group of, for example, 3-6, or 4-6 carbons, referred to herein as
C.sub.3-6cycloalkyl or C.sub.4-6cycloalkyl, respectively. Exemplary
cycloalkyl groups include, but are not limited to, cyclohexyl,
cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.
[0023] The terms "halo" or "halogen" as used herein refer to F, Cl,
Br, or I.
[0024] The terms "heteroaryl" or "heteroaromatic group" as used
herein refers to a monocyclic aromatic 5-6 membered ring system
containing one or more heteroatoms, for example one to three
heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible,
said heteroaryl ring may be linked to the adjacent radical though
carbon or nitrogen. Examples of heteroaryl rings include but are
not limited to furan, thiophene, pyrrole, thiazole, oxazole,
isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or
pyrimidine etc.
[0025] The terms "heterocyclyl" or "heterocyclic group" are
art-recognized and refer to saturated or partially unsaturated 4-7
membered ring structures, whose ring structures include one to
three heteroatoms, such as nitrogen, oxygen, and sulfur. Where
possible, heterocyclyl rings may be linked to the adjacent radical
through carbon or nitrogen. Examples of heterocyclyl groups
include, but are not limited to, pyrrolidine, piperidine,
morpholine, thiomorpholine, piperazine, oxetane, azetidine,
tetrahydrofuran or dihydrofuran etc.
[0026] The term "heterocyclyloxy" as used herein refers to a
heterocyclyl group attached to oxygen (heterocyclyl-O--).
[0027] The term "heteroaryloxy" as used herein refers to a
heteroaryl group attached to oxygen (heteroaryl-O--).
[0028] The terms "hydroxy" and "hydroxyl" as used herein refers to
the radical --OH.
[0029] The term "oxo" as used herein refers to the radical
.dbd.O.
[0030] "Pharmaceutically or pharmacologically acceptable" include
molecular entities and compositions that do not produce an adverse,
allergic or other untoward reaction when administered to an animal,
or a human, as appropriate. For human administration, preparations
should meet sterility, pyrogenicity, and general safety and purity
standards as required by FDA Office of Biologics standards.
[0031] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" as used herein refers to
any and all solvents, dispersion media, coatings, isotonic and
absorption delaying agents, and the like, that are compatible with
pharmaceutical administration. The use of such media and agents for
pharmaceutically active substances is well known in the art. The
compositions may also contain other active compounds providing
supplemental, additional, or enhanced therapeutic functions.
[0032] The term "pharmaceutical composition" as used herein refers
to a composition comprising at least one compound as disclosed
herein formulated together with one or more pharmaceutically
acceptable carriers.
[0033] "Individual," "patient," or "subject" are used
interchangeably and include any animal, including mammals,
preferably mice, rats, other rodents, rabbits, dogs, cats, swine,
cattle, sheep, horses, or primates, and most preferably humans. The
compounds of the invention can be administered to a mammal, such as
a human, but can also be administered to other mammals such as an
animal in need of veterinary treatment, e.g., domestic animals
(e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep,
pigs, horses, and the like) and laboratory animals (e.g., rats,
mice, guinea pigs, and the like). The mammal treated in the methods
of the invention is desirably a mammal in which treatment of
obesity or weight loss is desired. "Modulation" includes antagonism
(e.g., inhibition), agonism, partial antagonism and/or partial
agonism.
[0034] In the present specification, the term "therapeutically
effective amount" means the amount of the subject compound that
will elicit the biological or medical response of a tissue, system
or animal, (e.g. mammal or human) that is being sought by the
researcher, veterinarian, medical doctor or other clinician. The
compounds of the invention are administered in therapeutically
effective amounts to treat a disease. Alternatively, a
therapeutically effective amount of a compound is the quantity
required to achieve a desired therapeutic and/or prophylactic
effect, such as an amount which results in weight loss.
[0035] The term "pharmaceutically acceptable salt(s)" as used
herein refers to salts of acidic or basic groups that may be
present in compounds used in the compositions. Compounds included
in the present compositions that are basic in nature are capable of
forming a wide variety of salts with various inorganic and organic
acids. The acids that may be used to prepare pharmaceutically
acceptable acid addition salts of such basic compounds are those
that form non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable anions, including, but not limited to,
malate, oxalate, chloride, bromide, iodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, isonicotinate, acetate,
lactate, salicylate, citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds
included in the present compositions that are acidic in nature are
capable of forming base salts with various pharmacologically
acceptable cations. Examples of such salts include alkali metal or
alkaline earth metal salts, particularly calcium, magnesium,
sodium, lithium, zinc, potassium, and iron salts. Compounds
included in the present compositions that include a basic or acidic
moiety may also form pharmaceutically acceptable salts with various
amino acids. The compounds of the disclosure may contain both
acidic and basic groups; for example, one amino and one carboxylic
acid group. In such a case, the compound can exist as an acid
addition salt, a zwitterion, or a base salt.
[0036] The compounds of the disclosure may contain one or more
chiral centers and, therefore, exist as stereoisomers. The term
"stereoisomers" when used herein consist of all enantiomers or
diastereomers. These compounds may be designated by the symbols
"(+)," "(-)," "R" or "S," depending on the configuration of
substituents around the stereogenic carbon atom, but the skilled
artisan will recognize that a structure may denote a chiral center
implicitly. The present invention encompasses various stereoisomers
of these compounds and mixtures thereof. Mixtures of enantiomers or
diastereomers may be designated "(.+-.)" in nomenclature, but the
skilled artisan will recognize that a structure may denote a chiral
center implicitly.
[0037] The compounds of the disclosure may contain one or more
double bonds and, therefore, exist as geometric isomers resulting
from the arrangement of substituents around a carbon-carbon double
bond. The symbol denotes a bond that may be a single, double or
triple bond as described herein. Substituents around a
carbon-carbon double bond are designated as being in the "Z" or "E"
configuration wherein the terms "Z" and "E" are used in accordance
with IUPAC standards. Unless otherwise specified, structures
depicting double bonds encompass both the "E" and "Z" isomers.
Substituents around a carbon-carbon double bond alternatively can
be referred to as "cis" or "trans," where "cis" represents
substituents on the same side of the double bond and "trans"
represents substituents on opposite sides of the double bond.
[0038] Compounds of the disclosure may contain a carbocyclic or
heterocyclic ring and therefore, exist as geometric isomers
resulting from the arrangement of substituents around the ring. The
arrangement of substituents around a carbocyclic or heterocyclic
ring are designated as being in the "Z" or "E" configuration
wherein the terms "Z" and "E" are used in accordance with IUPAC
standards. Unless otherwise specified, structures depicting
carbocyclic or heterocyclic rings encompass both "Z" and "E"
isomers. Substituents around a carbocyclic or heterocyclic rings
may also be referred to as "cis" or "trans", where the term "cis"
represents substituents on the same side of the plane of the ring
and the term "trans" represents substituents on opposite sides of
the plane of the ring. Mixtures of compounds wherein the
substituents are disposed on both the same and opposite sides of
plane of the ring are designated "cis/trans."
[0039] Individual enantiomers and diasteriomers of compounds of the
present invention can be prepared synthetically from commercially
available starting materials that contain asymmetric or stereogenic
centers, or by preparation of racemic mixtures followed by
resolution methods well known to those of ordinary skill in the
art. These methods of resolution are exemplified by (1) attachment
of a mixture of enantiomers to a chiral auxiliary, separation of
the resulting mixture of diastereomers by recrystallization or
chromatography and liberation of the optically pure product from
the auxiliary, (2) salt formation employing an optically active
resolving agent, (3) direct separation of the mixture of optical
enantiomers on chiral liquid chromatographic columns or (4) kinetic
resolution using stereoselective chemical or enzymatic reagents.
Racemic mixtures can also be resolved into their component
enantiomers by well known methods, such as chiral-phase liquid
chromatography or crystallizing the compound in a chiral solvent.
Stereoselective syntheses, a chemical or enzymatic reaction in
which a single reactant forms an unequal mixture of stereoisomers
during the creation of a new stereocenter or during the
transformation of a pre-existing one, are well known in the art.
Stereoselective syntheses encompass both enantio- and
diastereoselective transformations, and may involve the use of
chiral auxiliaries. For examples, see Carreira and Kvaemo, Classics
in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
[0040] The compounds disclosed herein can exist in solvated as well
as unsolvated forms with pharmaceutically acceptable solvents such
as water, ethanol, and the like, and it is intended that the
invention embrace both solvated and unsolvated forms. In one
embodiment, the compound is amorphous. In one embodiment, the
compound is a single polymorph. In another embodiment, the compound
is a mixture of polymorphs. In another embodiment, the compound is
in a crystalline form.
[0041] The invention also embraces isotopically labeled compounds
of the invention which are identical to those recited herein,
except 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, sulfur, 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. For example, a compound of
the invention may have one or more H atom replaced with
deuterium.
[0042] Certain isotopically-labeled disclosed compounds (e.g.,
those labeled with .sup.3H 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 labeled compounds of the invention can
generally be prepared by following procedures analogous to those
disclosed in the examples herein by substituting an isotopically
labeled reagent for a non-isotopically labeled reagent.
[0043] The term "prodrug" refers to compounds that are transformed
in vivo to yield a disclosed compound or a pharmaceutically
acceptable salt, hydrate or solvate of the compound. The
transformation may occur by various mechanisms (such as by
esterase, amidase, phosphatase, oxidative and or reductive
metabolism) in various locations (such as in the intestinal lumen
or upon transit of the intestine, blood or liver). Prodrugs are
well known in the art (for example, see Rautio, Kumpulainen, et al.
Nature Reviews Drug Discovery 2008, 7, 255). For example, if a
compound of the invention 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 (C.sub.1-8)alkyl, (C.sub.2-12)alkylcarbonyloxymethyl,
1-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms,
1-methyl-1-(alkylcarbonyloxy)-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.1-2)alkylamino(C.sub.2-3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-2)alkyl,
N,N-di(C.sub.1-2)alkylcarbamoyl-(C.sub.1-2)alkyl and piperidino-,
pyrrolidino- or morpholino(C.sub.2-3)alkyl.
[0044] Similarly, if a compound of the invention 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 (C.sub.1-6)alkylcarbonyloxymethyl,
1-((C.sub.1-6)alkylcarbonyloxy)ethyl,
1-methyl-1-((C.sub.1-6)alkylcarbonyloxy)ethyl
(C.sub.1-6)alkoxycarbonyloxymethyl,
N--(C.sub.1-6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-6)alkylcarbonyl, .alpha.-amino(C.sub.1-4)alkylcarbonyl,
arylalkylcarbonyl and .alpha.-aminoalkylcarbonyl, or
.alpha.-aminoalkylcarbonyl-.alpha.-aminoalkylcarbonyl, where each
.alpha.-aminoalkylcarbonyl group is independently selected from the
naturally occurring L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-6)alkyl).sub.2 or glycosyl (the radical resulting
from the removal of a hydroxyl group of the hemiacetal form of a
carbohydrate).
[0045] If a compound of the invention incorporates an amine
functional group, a prodrug can be formed, for example, by creation
of an amide or carbamate, an N-alkylcarbonyloxyalkyl derivative, an
(oxodioxolenyl)methyl derivative, an N-Mannich base, imine or
enamine. In addition, a secondary amine can be metabolically
cleaved to generate a bioactive primary amine, or a tertiary amine
can metabolically cleaved to generate a bioactive primary or
secondary amine. For examples, see Simplicio, et al., Molecules
2008, 13, 519 and references therein.
I. Tricycic Compounds
[0046] In certain embodiments, the present invention provides
compounds of Formula I and Formula II:
##STR00002##
[0047] wherein:
[0048] D.sup.1 and D.sup.2 may each be 5-7 membered heterocyclic or
heteroaromatic rings in which one of the two atoms in common
between rings B and D is nitrogen and the other is carbon;
[0049] X.sup.1 may be selected from the group consisting of:
*--C(R.sup.D1R.sup.D2)--,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--.sup.#,
*--N.dbd.C(R.sup.C2)--.sup.#,
*--W.sup.1C(R.sup.D5R.sup.D6)--.sup.#, *--W.sup.1C(O).sup.#,
*--C(R.sup.D1R.sup.D2)--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(O)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(O)--.sup.#; wherein the * and *
denote the attachment points of X.sup.1 in Formula I;
[0050] X.sup.2 may be selected from the group consisting of:
*--C(R.sup.D1R.sup.D2)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--.sup.#,
*--N.dbd.C(R.sup.C2)--.sup.#, *--C(R.sup.C1).dbd.N--.sup.#,
*--W.sup.1--C(R.sup.D5R.sup.D6)--.sup.#, *--W.sup.1--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(O)C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--W.sup.2--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--W.sup.2--C(O)--.sup.#; wherein the * and
.sup.# indicate the attachment points of X.sup.2 in Formula II;
[0051] Y may be selected from CH or N;
[0052] B.sup.1 or B.sup.2 rings may each optionally be substituted
by one or more fluorine atoms on any of the available carbon
atoms;
[0053] W.sup.1 may be selected from the group consisting of: O or
N(R.sup.N1);
[0054] W.sup.2 may be selected from the group consisting of: O or
N(R.sup.N2);
[0055] A may be a ring selected from the group consisting of:
phenyl, a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms each
selected from S, N or O, and a 4-7 membered heterocycle having 1, 2
or 3 heteroatoms each selected from N or O:
[0056] R.sup.A1 may be selected, independently for each occurrence,
from the group consisting of: hydrogen, hydroxyl, cyano, halogen,
C.sub.1-4alkyl or C.sub.1-3alkoxy; wherein C.sub.1-4alkyl, or
C.sub.1-3alkoxy may be optionally substituted by one or more
fluorines;
[0057] n may be 1 or 2;
[0058] R.sup.A2 may be selected from the group consisting of:
hydrogen, R.sup.iR.sup.jN--, heterocyclyl, heterocyclyloxy,
heterocyclyl-(NR.sup.a)--; wherein said heterocyclyl may optionally
be substituted by one or more substituents selected from R.sup.g
and wherein if said heterocyclyl contains a --NH moiety that
nitrogen may optionally be substituted by one or more groups
R.sup.h; or
[0059] R.sup.A2 may be selected from the group consisting of:
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy, C.sub.3-6alkenyloxy,
C.sub.3-6alkynyloxy, C.sub.3-6cycloalkoxy,
C.sub.1-6alkyl-S(O).sub.w-(wherein w is 0, 1 or 2),
C.sub.1-6alkyl-N(R.sup.a), C.sub.1-6alkyl-N(R.sup.a)-carbonyl-,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6-alkyl-N(R.sup.a)-carbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)--SO.sub.2--,
C.sub.1-6alkyl-SO.sub.2--N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--C.sub.1-6alkyl-,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-C.sub.1-6 alkyl-,
C.sub.1-6alkoxyC.sub.1-6alkyl-; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6
alkoxy, C.sub.3-6alkenyloxy, C.sub.3-6alkynyloxy,
C.sub.3-6cycloalkoxy, C.sub.1-6alkyl-S(O).sub.w-- (wherein w is 0,
1 or 2), C.sub.1-6alkyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)--SO.sub.2--,
C.sub.1-6alkyl-SO.sub.2--N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)C.sub.1-6alkyl-,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-C.sub.1-6alkyl-,
C.sub.1-6alkoxy-C.sub.1-6alkyl may optionally be substituted by
R.sup.P, phenyl, phenoxy, heteroaryl, heteroaryloxy,
heteroaryl-(NR.sup.a)--, heterocyclyl, heterocyclyloxy or
heterocyclyl-N(R.sup.a)--; wherein said heteroaryl or phenyl may
optionally be substituted with one or more substituents selected
from R.sup.f; wherein said heterocyclyl may optionally be
substituted by one or more substituents selected from R.sup.g; and
wherein if said heterocyclyl contains a --NH moiety that nitrogen
may optionally be substituted by one or more groups R.sup.h;
[0060] R.sup.D1 and R.sup.D2 may be each independently selected
from the group consisting of: hydrogen, fluorine, hydroxyl,
C.sub.1-2alkyl or C.sub.1-2alkoxy; wherein the C.sub.1-2alkyl and
C.sub.1-2alkoxy may optionally be substituted by one or more
fluorine atoms or a group selected from cyano or hydroxyl;
[0061] R.sup.D3 and R.sup.D4 may be each independently selected
from the group consisting of: hydrogen, fluorine, hydroxyl, cyano,
C.sub.1-3alkyl or C.sub.1-3alkoxy; wherein the C.sub.1-3alkyl and
C.sub.1-3 alkoxy may optionally be substituted by one or more
fluorine atoms or a group selected from cyano, hydroxyl or
N(R.sup.aR.sup.b);
[0062] R.sup.D1 and R.sup.D6 may be each independently selected
from the group consisting of: hydrogen, fluorine, hydroxyl, cyano,
C.sub.1-2alkyl or C.sub.1-2alkoxy; wherein the C.sub.1-2alkyl and
C.sub.1-2alkoxy may optionally be substituted by one or more
fluorine atoms or a group selected from cyano, hydroxyl or
N(R.sup.aR.sup.b),
[0063] R.sup.C1 may be selected from the group consisting of:
hydrogen, halogen, C.sub.1-2alkyl or C.sub.1-2alkoxy; wherein the
C.sub.1-2alkyl or C.sub.1-2alkoxy may optionally be substituted by
one or more fluorine atoms;
[0064] R.sup.C2 may be selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, C.sub.1-2alkyl or
C.sub.1-2alkoxy; wherein the C.sub.1-2alkyl and C.sub.1-2alkoxy may
optionally be substituted by one or more fluorine atoms or a group
selected from cyano, hydroxyl or N(R.sup.aR.sup.b);
[0065] R.sup.N1 may be selected from the group consisting of:
hydrogen or C.sub.1-2alkyl;
[0066] R.sup.N2 may be selected from the group consisting of:
hydrogen, C.sub.1-3alkyl or C.sub.1-2 alkylcarbonyl; wherein the
C.sub.1-3alkyl and C.sub.1-2alkylcarbonyl may optionally be
substituted by one or more fluorine atoms or a group selected from
cyano, hydroxyl or N(R.sup.aR.sup.b);
[0067] R.sup.a and R.sup.b may be independently selected, for each
occurrence, from the group consisting of: hydrogen and
C.sub.1-3alkyl; wherein C.sub.1-3alkyl may optionally be
substituted by one or more substituents selected from: fluorine,
cyano, oxo and hydroxyl:
[0068] or R.sup.a and R.sup.b, together with the nitrogen to which
they are attached, may form a 4-6 membered heterocyclic ring which
may have an additional heteroatom selected from O, S, or N; and
wherein the 4-6 membered heterocyclic ring may optionally be
substituted on carbon by one or more substituents selected from the
group consisting of: fluorine, cyano, oxo or hydroxyl;
[0069] R.sup.f may be independently selected, for each occurrence,
from the group consisting of: R.sup.P, hydrogen, C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy, C.sub.1-6 alkyl-S(O).sub.w--
(wherein w is 0, 1 or 2), C.sub.1-6alkylcarbonyl-N(R.sup.a)--;
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--; and wherein C.sub.1-6alkyl,
C.sub.3-6-cycloalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy, C.sub.1-6 alkyl-S(O).sub.w--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)-- may be optionally substituted
by one or more substituents selected from R.sup.P;
[0070] R.sup.g may be independently selected for each occurrence
from the group consisting of: R.sup.P, hydrogen, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy,
C.sub.1-6alkyl-S(O).sub.w-(wherein w is 0, 1 or 2),
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkoxy, C.sub.1-6alkyl-S(O).sub.w--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)-- may be optionally substituted
by one or more substituents selected from R.sup.P;
[0071] R.sup.h may be independently selected for each occurrence
from the group consisting of: hydrogen, C.sub.1-6alkyl,
C.sub.3-6alkenyl, C.sub.3-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkyl-S(O).sub.2--, C.sub.1-6alkoxycarbonyl-,
R.sup.iR.sup.jN-carbonyl-, R.sup.iR.sup.jN--SO.sub.2--; wherein
C.sub.1-6alkyl, C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkyl-S(O).sub.2--,
C.sub.1-6alkylcarbonyl- may optionally be substituted by one or
more substituents selected from R.sup.P;
[0072] R.sup.i and R.sup.j may be selected independently for each
occurrence from the group consisting of: hydrogen, C.sub.1-4alkyl
and C.sub.3-6cycloalkyl; wherein C.sub.1-4alkyl and
C.sub.3-6cycloalkyl may be optionally substituted by one or more
substituents selected from fluorine, hydroxyl, cyano,
R.sup.aR.sup.bN--, R.sup.aR.sup.bN-carbonyl-, C.sub.1-3alkoxy;
[0073] or R.sup.i and R.sup.j taken together with the nitrogen to
which they are attached may form a 4-7 membered heterocyclic ring
which may have an additional heteroatom selected from O, S, or N,
optionally substituted on carbon by one or more substituents
selected from the group consisting of: fluorine, hydroxyl, oxo,
cyano, C.sub.1-6alkyl, C.sub.1-6alkoxy. R.sup.aR.sup.bN--,
R.sup.aR.sup.bN--SO.sub.2--, R.sup.aR.sup.bN-carbonyl-; and wherein
said C.sub.1-6alkyl or C.sub.1-6alkoxy may optionally be
substituted by fluorine, hydroxyl or cyano; and optionally
substituted on nitrogen by one or more substituents selected from
the group consisting of: C.sub.1-6alkyl, R.sup.aR.sup.bN-carbonyl-;
and wherein said C.sub.1-6alkyl may be optionally substituted by
fluorine, hydroxyl, cyano;
[0074] R.sup.P may be independently selected, for each occurrence,
from the group consisting of: halogen, hydroxyl, cyano,
C.sub.1-6alkoxy, R.sup.iR.sup.jN--, R.sup.iR.sup.jN-carbonyl-,
R.sup.iR.sup.jN--SO.sub.2--,
R.sup.iR.sup.jN-carbonyl-N(R.sup.a)--;
[0075] and pharmaceutically acceptable salts, stereoisomers, esters
and prodrugs thereof.
[0076] In some embodiments, X.sup.1 may be selected from the group
consisting of *--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--.sup.#,
*--O--C(R.sup.D5R.sup.D6)--.sup.#,
*--N(R.sup.N1)--C(R.sup.D5R.sup.D6).sup.#, *
--C(R.sup.D1R.sup.D2)--C(O)--.sup.#,
*--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.# and
*--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#;
wherein the * and .sup.# indicate the attachment points of X.sup.1
as indicated in Formula I. Exemplary X.sup.1 moities may be
selected from the group consisting of: *--CH.sub.2CH.sub.2--.sup.#
and *--CH.dbd.CH--.sup.#; wherein the * and .sup.# indicate the
attachment points of X.sup.1 as indicated in Formula I.
[0077] In some embodiments, X.sup.2 may be selected from the group
consisting of: *--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--.sup.#,
*--N.dbd.C(R.sup.C2)--.sup.#, *--O--C(R.sup.D5R.sup.D6)--.sup.#,
*--N(R.sup.N1)--C(R.sup.D5R.sup.D6)--.sup.#,
*--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.# and
*--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#;
wherein the * and .sup.# indicate the attachment points of X.sup.2
as indicated in Formula II. Exemplary X.sup.2 moities may be
selected from the group consisting of: *--CH.sub.2CH.sub.2--.sup.#,
*--CH.dbd.CH--.sup.#, *--O--CH.sub.2--.sup.#,
*--NH--CH.sub.2--.sup.# and *--O--CH.sub.2--CH.sub.2--.sup.#;
wherein the * and .sup.# indicate the attachment points of X.sup.2
as indicated in Formula II.
[0078] In one embodiment, R.sup.D1, R.sup.D2, R.sup.C1 and R.sup.N1
be independently selected for each occurrence from the group
consisting of hydrogen and methyl. For example, R.sup.D1, R.sup.D2,
R.sup.C1 and R.sup.N1 may be hydrogen.
[0079] In certain embodiments, R.sup.D3, R.sup.D4, R.sup.D5 and
R.sup.D6 may be independently selected for each occurrence from the
group consisting hydrogen, fluorine, cyano, or C.sub.1-2alkyl. For
example, R.sup.D3, R.sup.D4, R.sup.D5 and R.sup.D6 may be
hydrogen.
[0080] In an embodiment, R.sup.c2 may be selected from the group
consisting of hydrogen, halogen, cyano or C.sub.1-2alkyl. For
example, R.sup.C2 may be hydrogen.
[0081] In an embodiment, R.sup.N2 may be selected from the group
consisting of hydrogen and C.sub.1-2alkyl. For example, R.sup.N2
may be hydrogen.
[0082] In some embodiments, Y may be N.
[0083] Provided herein, for example, are tricyclic compounds
represented by formulas Ia, Ib, Ic, IIa, IIb, IIc, IId and IIe:
##STR00003##
wherein A, R.sup.A1, n and R.sup.A2 are defined above. For example,
A may be phenyl.
[0084] Also provided herein is a compound represented by Formula
III, Formula IV and Formula V:
##STR00004##
[0085] wherein
[0086] X.sup.1 may be selected from the group consisting of:
*--C(R.sup.D1R.sup.D2)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--.sup.#,
*--N.dbd.C(R.sup.C2)--.sup.#,
*--W.sup.1--C(R.sup.D5R.sup.D6)--.sup.#, *--W.sup.1--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(O)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(O)--.sup.#; wherein the * and
.sup.# denote the attachment points of X.sup.1 in Formula I;
[0087] X.sup.2 may be selected from the group consisting of:
*--C(R.sup.D1R.sup.D2)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.C1).dbd.C(R.sup.C2)--.sup.#,
*--N.dbd.C(R.sup.C2)--.sup.#, *--C(R.sup.C1).dbd.N--.sup.#,
*--W.sup.1--C(R.sup.D5R.sup.D6)--.sup.#, *--W.sup.1--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.sup.#,
*--W.sup.1--C(O)--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--W.sup.1--C(R.sup.D3R.sup.D4)--C(O)--.sup.#,
*--C(R.sup.D1R.sup.D2)--W.sup.2--C(R.sup.D5R.sup.D6)--.sup.#,
*--C(R.sup.D1R.sup.D2)--W.sup.2--C(O)--.sup.#; wherein the * and
.sup.# indicate the attachment points of X.sup.2 in Formula II;
[0088] W.sup.1 may be selected from the group consisting of: O or
N(R.sup.N1);
[0089] W.sup.2 may be selected from the group consisting of: O or
N(R.sup.N2);
[0090] R.sup.A1 may be selected, independently for each occurrence,
from the group consisting of: hydrogen, hydroxyl, cyano, halogen,
C.sub.1-4alkyl or C.sub.1-3alkoxy; wherein C.sub.1-4alkyl, or
C.sub.1-3alkoxy may be optionally substituted by one or more
fluorines;
[0091] n may be 1 or 2:
[0092] R.sup.A2 may be selected from the group consisting of:
hydrogen, R.sup.iR.sup.jN--, heterocyclyl, heterocyclyloxy,
heterocyclyl-(NR.sup.a)--; wherein said heterocyclyl may optionally
be substituted by one or more substituents selected from R.sup.g
and wherein if said heterocyclyl contains a --NH moiety that
nitrogen may optionally be substituted by one or more groups
R.sup.h; or
[0093] R.sup.A2 may be selected from the group consisting of:
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy, C.sub.3-6alkenyloxy,
C.sub.3-6alkynyloxy, C.sub.3-6cycloalkoxy,
C.sub.1-6alkyl-S(O).sub.w-(wherein w is 0, 1 or 2),
C.sub.1-6alkyl-N(R.sup.a)--, C.sub.1-6alkyl-N(R.sup.a)-carbonyl-,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)--SO.sub.2-,
C.sub.1-6alkyl-SO.sub.2--N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--C.sub.1-6alkyl-,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-C.sub.1-6alkyl-,
C.sub.1-6alkoxyC.sub.1-6alkyl-; wherein C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6cycloalkyl,
C.sub.1-6alkoxy, C.sub.3-6alkenyloxy, C.sub.3-6alkynyloxy,
C.sub.3-6cycloalkoxy, C.sub.1-6alkyl-S(O).sub.w--,
C.sub.1-6alkyl-N(R.sup.a)--, C.sub.1-6alkyl-N(R.sup.a)-carbonyl-,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-N(R.sup.a)--,
C.sub.1-6alkyl-N(R.sup.a)--SO.sub.2-,
C.sub.1-6alkyl-SO.sub.2--N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)C.sub.1-6alkyl-,
C.sub.1-6alkyl-N(R.sup.a)-carbonyl-C.sub.1-6alkyl-,
C.sub.1-6alkoxy-C.sub.1-6alkyl may optionally be substituted by
R.sup.P, phenyl, phenoxy, heteroaryl, heteroaryloxy,
heteroaryl-(NR.sup.a)--, heterocyclyl, heterocyclyloxy or
heterocyclyl-N(R.sup.a)--; wherein said heteroaryl or phenyl may
optionally be substituted with one or more substituents selected
from R.sup.f; wherein said heterocyclyl may optionally be
substituted by one or more substituents selected from R.sup.g; and
wherein if said heterocyclyl contains a --NH moiety that nitrogen
may optionally be substituted by one or more groups R.sup.h;
[0094] R.sup.D1 and R.sup.D2 may be each independently selected
from the group consisting of: hydrogen, fluorine, hydroxyl,
C.sub.1-2alkyl or C.sub.1-2alkoxy; wherein the C.sub.1-2alkyl and
C.sub.1-2alkoxy may optionally be substituted by one or more
fluorine atoms or a group selected from cyano or hydroxyl;
[0095] R.sup.D3 and R.sup.D4 may be each independently selected
from the group consisting of: hydrogen, fluorine, hydroxyl, cyano,
C.sub.1-3alkyl or C.sub.1-3alkoxy; wherein the C.sub.1-3alkyl and
C.sub.1-3 alkoxy may optionally be substituted by one or more
fluorine atoms or a group selected from cyano, hydroxyl or
N(R.sup.aR.sup.b);
[0096] R.sup.D5 and R.sup.D6 may be each independently selected
from the group consisting of: hydrogen, fluorine, hydroxyl, cyano,
C.sub.1-2alkyl or C.sub.1-2alkoxy; wherein the C.sub.1-2alkyl and
C.sub.1-2alkoxy may optionally be substituted by one or more
fluorine atoms or a group selected from cyano, hydroxyl or
N(R.sup.aR.sup.b),
[0097] R.sup.C1 may be selected from the group consisting of:
hydrogen, halogen, C.sub.1-2alkyl or C.sub.1-2alkoxy; wherein the
C.sub.1-2alkyl or C.sub.1-2alkoxy may optionally be substituted by
one or more fluorine atoms:
[0098] R.sup.C2 may be selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, C.sub.1-2alkyl or
C.sub.1-2alkoxy; wherein the C.sub.1-2alkyl and C.sub.1-2alkoxy may
optionally be substituted by one or more fluorine atoms or a group
selected from cyano, hydroxyl or N(R.sup.aR.sup.b);
[0099] R.sup.N1 may be selected from the group consisting of:
hydrogen or C.sub.1-2alkyl;
[0100] R.sup.N2 may be selected from the group consisting of:
hydrogen, C.sub.1-3alkyl or C.sub.1-2alkylcarbonyl; wherein the
C.sub.1-3alkyl and C.sub.1-2alkylcarbonyl may optionally be
substituted by one or more fluorine atoms or a group selected from
cyano, hydroxyl or N(R.sup.aR.sup.b);
[0101] R.sup.a and R.sup.b may be independently selected, for each
occurrence, from the group consisting of: hydrogen and
C.sub.1-3alkyl; wherein C.sub.1-3alkyl may optionally be
substituted by one or more substituents selected from: fluorine,
cyano, oxo and hydroxyl;
[0102] or R.sup.a and R.sup.b, together with the nitrogen to which
they are attached, may form a 4-6 membered heterocyclic ring which
may have an additional heteroatom selected from O, S, or N; and
wherein the 4-6 membered heterocyclic ring may optionally be
substituted on carbon by one or more substituents selected from the
group consisting of: fluorine, cyano, oxo or hydroxyl;
[0103] R.sup.f may be independently selected, for each occurrence,
from the group consisting of: R.sup.P, hydrogen, C.sub.1-6alkyl,
C.sub.3-4cycloalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy, C.sub.1-6 alkyl-S(O).sub.w--
(wherein w is 0, 1 or 2), C.sub.1-6alkylcarbonyl-N(R.sup.a)--;
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--; and wherein C.sub.1-6alkyl,
C.sub.3-6cycloalkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy, C.sub.1-6 alkyl-S(O).sub.w--,
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)-- may be optionally substituted
by one or more substituents selected from R.sup.P;
[0104] R.sup.g may be independently selected for each occurrence
from the group consisting of: R.sup.P, hydrogen, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkoxy,
C.sub.1-6alkyl-S(O).sub.w-(wherein w is 0, 1 or 2),
C.sub.1-6alkylcarbonyl-N(R.sup.a)--,
C.sub.1-6alkoxycarbonyl-N(R.sup.a)--; wherein C.sub.1-6 alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkoxy, C.sub.1-6alkyl-S(O).sub.w--, C.sub.1-6
alkylcarbonyl-N(R.sup.a)--, C.sub.1-6alkoxycarbonyl-N(R.sup.a)--
may be optionally substituted by one or more substituents selected
from R.sup.P;
[0105] R.sup.h may be independently selected for each occurrence
from the group consisting of: hydrogen, C.sub.1-6alkyl,
C.sub.3-6alkenyl, C.sub.3-6alkynyl, C.sub.3-6-cycloalkyl,
C.sub.1-6alkyl-S(O).sub.2--, C.sub.1-6alkoxycarbonyl-,
R.sup.iR.sup.jN-carbonyl-, R.sup.iR.sup.jN--SO.sub.2--; wherein
C.sub.1-6alkyl, C.sub.3-6alkenyl, C.sub.3-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkyl-S(O).sub.2--,
C.sub.1-6alkylcarbonyl- may optionally be substituted by one or
more substituents selected from R.sup.P;
[0106] R.sup.i and R.sup.j, may be selected independently for each
occurrence from the group consisting of: hydrogen, C.sub.1-4alkyl
and C.sub.3-6cycloalkyl; wherein C.sub.1-4alkyl and
C.sub.3-6cycloalkyl may be optionally substituted by one or more
substituents selected from fluorine, hydroxyl, cyano.
R.sup.aR.sup.bN--, R.sup.aR.sup.bN-carbonyl-, C.sub.1-3alkoxy:
[0107] or R.sup.i and R.sup.j taken together with the nitrogen to
which they are attached may form a 4-7 membered heterocyclic ring
which may have an additional heteroatom selected from O, S, or N,
optionally substituted on carbon by one or more substituents
selected from the group consisting of: fluorine, hydroxyl, oxo,
cyano, C.sub.1-6alkyl, C.sub.1-6-alkoxy, R.sup.aR.sup.bN--,
R.sup.aR.sup.bN--SO.sub.2--, R.sup.aR.sup.bN-carbonyl-; and wherein
said C.sub.1-6alkyl or C.sub.1-6alkoxy may optionally be
substituted by fluorine, hydroxyl or cyano; and optionally
substituted on nitrogen by one or more substituents selected from
the group consisting of: C.sub.1-6alkyl, R.sup.aR.sup.bN-carbonyl-;
and wherein said C.sub.1-6alkyl may be optionally substituted by
fluorine, hydroxyl, cyano;
[0108] R.sup.P may be independently selected, for each occurrence,
from the group consisting of: halogen, hydroxyl, cyano,
C.sub.1-6alkoxy, R.sup.iR.sup.jN--, R.sup.iR.sup.jN-carbonyl-,
R.sup.iR.sup.jN--SO.sub.2--,
R.sup.iR.sup.jN-carbonyl-N(R.sup.a)--;
[0109] and pharmaceutically acceptable salts, stereoisomers, esters
and prodrugs thereof.
[0110] In certain embodiments, R.sup.A1 of the tricyclic compounds
of Formula III, Formula IV and Formula V may be selected from the
group consisting of hydrogen, halogen, C.sub.1-2alkyl,
C.sub.1-2alkoxy; wherein C.sub.1-2alkyl may optionally be
substituted by one or more fluorines. For example, R.sup.A1 may be
hydrogen or fluorine.
[0111] In another embodiment, R.sup.A2 of the tricyclic compounds
of Formula III, Formula IV and Formula V may be selected from the
group consisting hydrogen, R.sup.iR.sup.jN, heterocyclyl,
C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkoxy; wherein said heterocyclyl may optionally be
substituted by one or more groups R.sup.g, and wherein if said
heterocyclyl contains a --NH moiety, that nitrogen may optionally
be substituted by on or more groups R.sup.h; and wherein said
C.sub.1-6alkyl, C.sub.3-6alkenyl, C.sub.3-6cycloalkyl and
C.sub.1-6alkoxy may optionally be substituted by one or more groups
R.sup.P. For example, R.sup.A2 may be selected from the group
consisting of 3-(N,N-diethylamino)propyl,
3-(pyrrolidin-1-yl)propyl, (Z)-3-(N,N-diethylamino)prop-1-enyl,
(Z)-3-(azetidin-1-yl)prop-1-enyl and
(Z)-3-(pyrrolidin-1-yl)prop-1-enyl.
[0112] Also provided herein are compounds that may be selected from
the group consisting of:
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-pyrazo-
lo[5,1-a]isoquinoline-7-carboxylic acid;
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-ben-
zo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylic acid;
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-di-
hydropyrazolo[5,1-a]isoquinoline-7-carboxylic acid;
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-4H-5--
oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylic acid and
pharmaceutically acceptable salts, stereoisomers, esters and
prodrugs thereof.
[0113] Procedures for making compounds described herein are
provided below with reference to Schemes 1-7. In the reactions
described below, it may be necessary to protect reactive functional
groups (such as hydroxyl, amino, thio or carboxyl groups) to avoid
their unwanted participation in the reactions. The incorporation of
such groups, and the methods required to introduce and remove them
are known to those skilled in the art (for example, see Greene,
Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). The
deprotection step may be the final step in the synthesis such that
the removal of protecting groups affords compounds of Formula I and
II, as disclosed herein, or as exemplified in, for example, General
formula I or II, below. Starting materials used in the following
schemes can be purchased or prepared by methods described in the
chemical literature, or by adaptations thereof, using methods known
by those skilled in the art. The order in which the steps are
performed can vary depending on the groups introduced and the
reagents used, but would be apparent to those skilled in the
art.
[0114] A general strategy used to prepare tricyclic compounds of
General formula I is depicted in Scheme 1. In Scheme 1, the group
G' is a suitably protected carboxylic acid, such as a methyl- or
tert-butyl carboxylate or is a functional group that may be readily
converted into a carboxylic acid, such as a nitrile or aldehyde.
The group G is a sulfonamide group, or a functional group that may
be subsequently converted into a sulfonamide group such as a
suitably protected aniline. The tricyclic system may be assembled
by first attaching an appropriately substituted pyrazole or pyrrole
intermediate 1B' to the substituted phenyl ring 1A to give the
intermediate 1B. The linker X' may then be formed by an
intramolecular reaction between the groups R.sup.2 and R.sup.4 to
give the intermediate 1C. Compounds of Formula I can be prepared
from intermediate 1C by removal of any protecting groups.
Alternatively, further modifications may be made to 1C, such as
modifications at G, before the removal of any protecting groups to
give compounds of General formula I. Specific steps in the
synthetic process are described in more detail below.
##STR00005##
[0115] In Scheme 1, Step (i), compounds of structure 1A may be
coupled with compounds of structure 1B' under a range of conditions
known to those skilled in the art to give compounds of structure
1B. It will be recognized by those skilled the art that several
steps may be required to prepare the intermediates and that
protecting groups may be required.
[0116] For example, compounds of structure 1A in which R.sup.1 is
an appropriate group (such as a halide or a triflate) may be
coupled with an appropriately substituted pyrazole or pyrrole 1B'
in which R.sup.3 is a boronic acid or ester, in the presence of a
palladium catalyst (such as palladium acetate, palladium chloride
dppf or tris-(dibenzylideneacetone)dipalladium) optionally in the
presence of a phosphine (such as triphenyl phosphine or
tri-tert-butylphosphonium tetrafluoroborate) and a base (such as
cesium carbonate) in a solvent (such as THF, dioxane or water or
mixtures thereof) at a temperature between room temperature and the
reflux temperature of the solvent or by irradiation in the
microwave at a temperature between 120 and 180.degree. C.
[0117] Alternatively, compounds of structure 1A, in which R.sup.1
is an appropriate group (such as a halide or a triflate), may be
coupled with an appropriately substituted pyrazole or pyrrole 1B',
in which R.sup.3 is a trialkyl stannane, in the presence of a
palladium catalyst (such as palladium acetate, palladium chloride
dppf or iris-(dibenzilideneacetone)dipalladium) optionally in the
presence of a phosphine (such as triphenyl phosphine or
tri-tert-butylphosphonium tetrafluoroborate) and a base (such as
cesium carbonate) in a solvent (such as THF or dioxane) at a
temperature between room temperature and the reflux temperature of
the solvent, or by irradiation in the microwave at a temperature
between 120 and 180.degree. C.
[0118] Alternatively, compounds of structure 1A, in which R.sup.1
is a boronic acid or ester, may be coupled with compounds of
structure 1B', in which R.sup.3 is a halide (such as a bromide of
iodide), in the presence of a palladium catalyst (such as palladium
acetate, palladium chloride dppf or
tris-(dibenzylideneacetone)dipalladium), optionally in the presence
of a phosphine (such as triphenyl phosphine or
tri-tert-butylphosphonium tetrafluoroborate) and a base (such as
cesium carbonate) in a solvent (such as THF, dioxane or water or
mixtures thereof) at a temperature between room temperature and the
reflux temperature of the solvent, or by irradiation in the
microwave at a temperature between 120 and 180.degree. C.
[0119] Alternatively, compounds of structure 1A, in which R.sup.1
is a trialkyl stannane, may be coupled with compounds of structure
1B', in which R.sup.3 is a halide (such as a bromide or iodide), in
the presence of a palladium catalyst (such as palladium acetate,
palladium chloride dppf or tris-(dibenzylideneacetone)dipalladium),
optionally in the presence of a phosphine (such as triphenyl
phosphine or tri-tert-butylphosphonium tetrafluoroborate) and a
base (such as cesium carbonate) in a solvent (such as THF or
dioxane) at a temperature between room temperature and the reflux
temperature of the solvent or by irradiation in the microwave at a
temperature between 120 and 180.degree. C.
[0120] Alternatively, compounds of structure 1A, in which R1 is a
halide (such as a bromide or iodide), may be coupled with a pyrrole
of structure 1B', in which Y is carbon and R.sup.3 is H, in the
presence of an oxidising agent (such as oxygen or phenyl
iodosoacetate) in the presence of a palladium catalyst (such as
palladium acetate) in a solvent (such as acetic acid) at a
temperature between room temperature and the reflux temperature of
the solvent.
[0121] Compounds of structure 1B, in which Y is N, may
alternatively be prepared according to Scheme 2, in which the
pyrazole ring is prepared by reacting an appropriately substituted
hydrazine with 1,3-dicarbonyl compound or equivalent.
##STR00006##
[0122] In Scheme 2, Step (i), compounds of structure 2A may be
treated with N,N-dimethylformamide dimethyl acetal or Bredereck's
reagent (tert-butoxy-bis(N,N-dimethylamino)methane), optionally in
a solvent (such as DCM or toluene) at a temperature between room
temperature and the reflux temperature of the solvent to give
compounds of structure 2B.
[0123] Alternatively, in Scheme 2, Step (ii), compounds of
structure 2A may be treated with a base (such as sodium hydride or
lithium diisopropylamide) in a solvent (such as THF) followed by
treatment with an alkyl formate (such as methyl formate or ethyl
formate) at a temperature between room temperature and the reflux
temperature of the solvent to give compounds of structure 2C.
[0124] In Scheme 2. Step (iii) or Step (iv), compounds of structure
2B or 2C may be converted to compounds of structure 1B by reaction
with hydrazine hydrate or an appropriately substituted hydrazine
(R.sup.4NHNH.sub.2) in a solvent (such as DCM, methanol, ethanol or
toluene) optionally in the presence of acetic acid and sodium
acetate or hydrochloric acid.
[0125] In Scheme 1, Step (ii) the groups R.sup.2 and R.sup.4 of
compound 1B can be coupled together to give the group X'. R.sup.2
or R.sup.4 may have been masked by protecting groups during the
earlier steps, and may require deprotection before the group X' can
be formed. For example, if R.sup.2 is a nitro group, that group may
be reduced, for example using hydrogen in the presence of a
suitable catalyst (such as palladium on a solid support, such as
carbon); or by treatment with an inorganic reducing agent (such as
tin (II) chloride in DMF) to give an amino group. For example, if
R.sup.2 or R.sup.4 is a hydroxyalkyl group, that group may be
treated with an oxidising agent (such as Jones reagent or manganese
dioxide) to give an aldehyde; or with a different oxidising agent
(such as potassium permanganate) to give a carboxylic acid. For
example, if R.sup.2 or R.sup.4 is an aldehyde, that group may be
treated with an oxidising agent (such as potassium permanganate) to
give a carboxylic acid or with a reducing agent (such as sodium
borohydride) to give an alcohol. For example, if R.sup.2 or R.sup.4
is a ketone, that group may be treated with a reducing agent (such
as sodium borohydride) to give a secondary alcohol. For example, if
R.sup.2 or R.sup.4 is a carboxylic acid or ester, that group may be
treated with a reducing agent (such as lithium aluminium hydride)
to give an alcohol. For example, if R.sup.2 or R.sup.4 is an alkene
group, that group may be treated with a borane (such as
9-borobicyclononane) followed by oxidation with, for example,
hydrogen peroxide, to give a primary or secondary alcohol.
[0126] The formation of the X' linker may be carried out in a
number of ways known to those skilled in the art. Several steps may
be necessary to generate the required intermediates and protecting
groups may be required.
[0127] In Scheme 1, Step (ii), if R.sup.2 is an alkyl group
attached to a leaving group, for example --C(R.sup.D1R.sup.D2)-L,
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)-L or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)-L
wherein L is a leaving group (such as a halogen, tosylate or
mesylate) and R.sup.4 is H, then 1B may be treated with a base
(such as pyridine, potassium carbonate or sodium hydride) in a
solvent (such as DCM, THF or toluene) at a temperature between room
temperature and the reflux temperature of the solvent to give a
compound of structure 1C, wherein X' is --C(R.sup.D1R.sup.D2)--,
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)-- or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0128] Alternatively if R.sup.2 is a hydroxyalkyl group, for
example --C(R.sup.D1R.sup.D2)--OH,
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--OH or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--OH
and R.sup.4 is H, then 1B may be treated with a dehydrating agent
(such as diisopropyl azodicarboxylate) in the presence of a
phosphine, (such as triphenylphosphine), to give a compound of
structure 1C, wherein X.sup.1 is --C(R.sup.D1R.sup.D2),
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)-- or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0129] Alternatively, if R.sup.2 is a vinyl group
(--CH.dbd.CH.sub.2) and R.sup.4 is H, 1B may be treated with a
peroxide (such as 3-chloroperbenzoic acid) optionally in the
presence of a catalyst (such as
N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino
manganese (III) chloride and N-methyl morpholine-N-oxide) in a
solvent (such as DCM) at a temperature between room temperature and
the reflux temperature of the solvent, to give a compound of
structure 1C, wherein X' is --CH(OH)--CH.sub.2--.
[0130] Compounds of structure 1C, in which X' is
--CH(OH)--CH.sub.2--, may be modified to provide further compounds
of structure 1C. For example, by treatment with methane sulfonyl
chloride and a base (such as triethylamine or pyridine) in a
solvent (such as DCM) at a temperature between room temperature and
the reflux temperature of the solvent to give compounds of
structure 1C, wherein X' is --CH.dbd.CH--.
[0131] Additionally, compounds of structure 1C, in which X' is
--CH.dbd.CH--, may be reduced to compounds in which X' is
--CH.sub.2--CH.sub.2-- by hydrogenation in the presence of a
catalyst (such as palladium hydroxide on a solid support, such as
carbon) in a solvent (such as dioxane) optionally in the presence
of an acid (such as acetic acid) at a temperature between room
temperature and 100.degree. C. and a hydrogen pressure between
atmospheric pressure and 100 bars.
[0132] Alternatively, compounds of structure 1B in which R.sup.2 is
a vinyl group (--CH.dbd.CH.sub.2) and R.sup.4 is an alkenyl group,
(for example an allyl group, --CH.sub.2--CH.dbd.CH.sub.2), may
undergo ring closing metathesis on treatment with a metal catalyst
(such as Grubbs catalyst) in a solvent (such as DCM) at a
temperature between room temperature and the reflux temperature of
the solvent to give an intermediate in which X' is
--CH.dbd.CH--CH.sub.2--. Hydrogenation of this intermediate in the
presence of a catalyst (such as palladium or palladium hydroxide on
a solid support, such as carbon) in a solvent (such as ethanol or
dioxane), optionally in the presence of an acid (such as acetic
acid), at a temperature between room temperature and 50.degree. C.,
and at a hydrogen pressure between atmospheric pressure and 5 bars,
to give a compound of structure 1C in which X' is
--CH.sub.2--CH.sub.2--CH.sub.2--.
[0133] Alternatively, compounds of structure 1B, in which R.sup.2
is NH.sub.2 and R.sup.4 is H, may be treated with an ortho ester
(such as triethyl orthoformate or triethyl orthoacetate) in a
solvent (such as ethanol) and in the presence of an acid (such as
4-toluenesulfonic acid), at a temperature between room temperature
and the reflux temperature of the solvent to give a compound of
structure 1C, in which X' is --N.dbd.C(R.sup.C2)--.
[0134] Alternatively, compounds of structure 1B, in which R.sup.2
is an amino group (--NH(R.sup.N1)) and R.sup.4 is H, may be treated
with an aldehyde or ketone (such as formaldehyde or acetone) in a
solvent (such as ethanol) and optionally in the presence of an acid
catalyst (such as 4-toluenesulfonic acid) at a temperature between
room temperature and the reflux temperature of the solvent, to give
a compound of structure 1C in which X' is
--N(R.sup.N1)--C(R.sup.D5R.sup.D6)--.
[0135] Alternatively, compounds of structure 1B in which R.sup.2 is
an amino group (--NH(R.sup.N1)) and R.sup.4 is an alkyl group
substituted by a leaving group, such as --C(R.sup.D5R.sup.D6)-L or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a
leaving group (such as a halide, mesylate or tosylate), may be
treated with a base (such as pyridine or triethylamine) in a
solvent (such as DCM or toluene) at a temperature between room
temperature and the reflux temperature of the solvent, to give
compounds of structure 1C in which X' is
--N(R.sup.N1)--C(R.sup.D5R.sup.D6)-- or
--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0136] Alternatively, compounds of structure 1B, in which R.sup.2
is an amino group (--NH(R.sup.N1)) and R.sup.4 is H, may be
converted to compounds of structure 1C, in which X' is
--N(R.sup.N1)--C(O)--, by treatment with an appropriate reagent
(such as phosgene, triphosgene or carbonyl-diimidazole) in a
solvent (such as DCM or toluene) and in the presence of a base
(such as pyridine or triethylamine), optionally in the presence of
a catalyst (such as 4-dimethylaminopyridine) at a temperature
between room temperature and the reflux temperature of the
solvent.
[0137] Alternatively, compounds of structure 1B, in which R.sup.2
is an amino group (--NH(R.sup.N1)) and R.sup.4 is an alkyl group
substituted by a carboxylic acid (--C(R.sup.D5R.sup.D6)CO.sub.2H),
can be treated with a dehydrating agent (such as
dicyclohexylcarbodiimide) to form 1C, where X' is
--N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0138] Alternatively, if R.sup.2 is an amino group (--NH(R.sup.N1))
and R.sup.4 is an alkyl group substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)CO.sub.2H), the carboxylic acid can be
converted to an activated ester (for example by treatment with HATU
and a base such as diisopropylethylamine or pyridine, or by
treatment with TBTU in the presence of N-methylmorpholine) and the
activated ester can be treated with further base to form 1C in
which X' is --N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0139] Alternatively, a compound of structure 1B, in which R.sup.2
is an amino group (--NH(R.sup.N1)) and R.sup.4 is an appropriate
pyrazole or pyrrole protecting group (such as
tetrahydropyran-2-yl), may be converted to other compounds of
structure 1B in which R.sup.2 is N(R.sup.N1)--C(O)--CH.sub.2-L
wherein L is a leaving group (such as a halide, for example a
chloride or bromide), by treatment with a haloacetyl halide (such
as chloroacetyl chloride or bromoacetyl bromide) in a solvent (such
as THF or DCM) in the presence of a base (such as triethylamine or
pyridine. The protecting group may be removed under conditions
known to those skilled in the art (for example, if the protecting
group is a tetrahydropyran-2-yl group, by treatment with hydrogen
chloride in methanol) to give the intermediate of structure 1B in
which R.sup.2 is --N(R.sup.N1)--C(O)--CH.sub.2-L and R.sup.4 is H.
Treatment of this intermediate with a base (such as pyridine,
potassium carbonate or sodium hydride) in a solvent (such as DCM,
THF or toluene), at a temperature between room temperature and the
reflux temperature of the solvent, will give a compound of
structure 1C wherein X' is --N(R.sup.N1)--C(O)--CH.sub.2--.
[0140] Alternatively, compounds of structure 1B, in which R.sup.2
is OH and R.sup.4 is H, may be treated with an aldehyde or ketone
(such as formaldehyde or acetone), in a solvent (such as ethanol or
toluene), optionally in the presence of an acid catalyst (such as
4-toluenesulfonic acid), at a temperature between room temperature
and the reflux temperature of the solvent, to give a compound of
structure 1C in which X' is --O--C(R.sup.D5R.sup.D6)--.
[0141] Alternatively, compounds of structure 1B in which R.sup.2 is
OH and R.sup.4 is a hydroxyalkyl group, for example
--C(R.sup.D5R.sup.D6)--OH or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)--OH, may be treated with
a dehydrating agent (such as diisopropyl azodicarboxylate), in the
presence of a phosphine, (such as triphenylphosphine), to give a
compound of structure 1C in which X' is --O--C(R.sup.D5R.sup.D6)--
or --O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0142] Alternatively, compounds of structure 1B, in which R.sup.2
is OH and R.sup.4 is an alkyl group substituted by a leaving group,
for example --C(R.sup.D5R.sup.D6)-L or
C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a leaving
group (such as a chloride or mesylate), may be treated with a base
(such as potassium carbonate or sodium hydride) in a solvent (such
as THF or DMF) at a temperature between room temperature and the
reflux temperature of the solvent, to give a compound of structure
1C in which X' is --O--C(R.sup.D5R.sup.D6)-- or
--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0143] Alternatively, compounds of structure 1B, in which R.sup.2
is fluorine and R.sup.4 is a hydroxyalkyl group, for example
--C(R.sup.D5R.sup.D6)--OH or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)--OH, may be treated with
a base (such as sodium hydride or potassium tert-butoxide) in a
solvent (such as THF or DMF) at a temperature between room
temperature and the reflux temperature of the solvent, to give a
compound of structure 1C in which X' is --O--C(R.sup.D5R.sup.D6)--
or --O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0144] Alternatively, compounds of structure 1B, in which R.sup.2
is OH and R.sup.4 is H may be treated with an appropriate reagent
(such as phosgene, triphosgene or carbonyl-diimidazole) in a
solvent (such as THF, DCM or toluene) and in the presence of a base
(such as potassium carbonate or sodium hydride) at a temperature
between room temperature and the reflux temperature of the solvent
to give compounds of structure 1C in which X' is --O--C(O)--.
[0145] Alternatively, compounds of structure 1B, in which R.sup.2
is OH and R.sup.4 is an alkyl group substituted by a carboxylic
acid (--C(R.sup.D5R.sup.D6)CO.sub.2H), can be treated with a
dehydrating agent (such as dicyclohexylcarbodiimide) to form 1C,
where X' is --O--C(O)--C(R.sup.D5R.sup.D6)--.
[0146] Alternatively, if R.sup.2 is OH and R.sup.4 is an alkyl
group substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)CO.sub.2H), the carboxylic acid can be
converted to an activated ester (for example by treatment with HATU
and a base such as diisopropylethylamine or pyridine, or by
treatment with TBTU in the presence of N-methylmorpholine) and the
activated ester can be treated with further base to form 1C in
which X' is --O--C(O)--C(R.sup.D5R.sup.D6)--.
[0147] Alternatively, a compound of structure 1B, in which R.sup.2
is OH and R.sup.4 is an appropriate pyrazole or pyrrole protecting
group (such as tetrahydropyran-2-yl), may be converted to other
compounds of structure 1B, in which R.sup.2 is O--C(O)--CH.sub.2-L,
wherein L is a leaving group (such as a halide, for example a
chloride or bromide), by treatment with a haloacetyl halide (such
as chloroacetyl chloride or bromoacetyl bromide) in a solvent (such
as THF or DCM) in the presence of a base (such as triethylamine or
pyridine). The protecting group may be removed under conditions
known to those skilled in the art (for example, if the protecting
group is a tetrahydropyran-2-yl group, by treatment with hydrogen
chloride in methanol) to give the intermediate of structure 1B in
which R.sup.2 is --O--C(O)--CH.sub.2-L and R.sup.4 is H. Treatment
of this intermediate with a base (such as pyridine, potassium
carbonate or sodium hydride) in a solvent (such as DCM, THF or
toluene) at a temperature between room temperature and the reflux
temperature of the solvent, will give a compound of structure 1C
wherein X' is --O--C(O)--CH.sub.2--.
[0148] Alternatively, compounds of structure 1B, in which R.sup.2
is an alkyl group attached to a carboxylic acid, for example
--C(R.sup.D1R.sup.D2)--CO.sub.2H or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--CO.sub.2H and R.sup.4
is H, can be treated with a dehydrating agent (such as
dicyclohexylcarbodiimide) in a solvent (such as DCM) to give a
compound of structure 1C in which X' is
--C(R.sup.D1R.sup.D2)--C(O)-- or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.
[0149] Alternatively, if R.sup.2 is an alkyl group substituted by a
carboxylic acid, for example --C(R.sup.D1R.sup.D2)--CO.sub.2H or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--CO.sub.2H, and R.sup.4
is H, the carboxylic acid can be converted to an activated ester
(for example by treatment with HATU and a base such as
diisopropylethylamine or pyridine, or by treatment with TBTU in the
presence of N-methylmorpholine) and the activated ester can be
treated with further base to form to give a compound of structure
1C in which X' is --C(R.sup.D1R.sup.D2)--C(O)-- or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.
[0150] Alternatively, if R.sup.2 is an alkoxy group substituted by
a carboxylic acid (--O--C(R.sup.D3R.sup.D4)--CO.sub.2H) or an
aminoalkyl group substituted by a carboxylic acid
(--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--CO.sub.2H), and R.sup.4 is H,
1B may be treated with a dehydrating agent (such as
dicyclohexylcarbodiimide) in a solvent (such as DCM) to give a
compound of structure 1C in which X' is
--O--C(R.sup.D3R.sup.D4)--C(O)-- or
--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(O)--.
[0151] Compounds of structure 1C (from Scheme 1) may alternatively
be prepared as shown in Scheme 3. Compounds of structure 1A may be
converted to intermediates of structure 3A by first forming the X'
linker and then cyclisation to give the tricyclic core 1C.
##STR00007##
[0152] For example, in Scheme 3, Step (i), if R.sup.2 is an alkyl
group attached to a leaving group, for example
--C(R.sup.D1R.sup.D2)-L, C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)-L
or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)-L,
wherein L is a leaving group (such as a halogen, tosylate or
mesylate) and R.sup.4 is H, then 1A and 1B' may be combined and
treated with a base (such as pyridine, potassium carbonate or
sodium hydride) in a solvent (such as DCM, THF or toluene) at a
temperature between room temperature and the reflux temperature of
the solvent, to give a compound of structure 3A wherein X' is
--C(R.sup.D1R.sup.D2)--,
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)-- or
--C(R.sup.D1R.sup.D2)
C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0153] Alternatively, in Scheme 3, Step (i), if R.sup.2 is a
hydroxyalkyl group, for example --C(R.sup.D1R.sup.D2)--OH,
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--OH or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--OH
and R.sup.4 is H, then 1A and 1B' may be combined in the presence
of a dehydrating agent (such as diisopropyl azodicarboxylate) in
the presence of a phosphine, (such as triphenylphosphine), to give
a compound of structure 3A wherein X' is --C(R.sup.D1R.sup.D2)--,
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)-- or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(R.sup.D4R.sup.D6)--.
[0154] Alternatively, in Scheme 3, Step (i), compounds of structure
1A in which R.sup.2 is an amino group (--NH(R.sup.N1)) may be
combined with compounds of structure 1B' in which R.sup.4 is an
alkyl group substituted by a leaving group, such as
--C(R.sup.D5R.sup.D6)-L or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a
leaving group (such as a chloride or mesylate), and treated with a
base (such as pyridine or triethylamine) in a solvent (such as DCM
or toluene) at a temperature between room temperature and the
reflux temperature of the solvent, to give compounds of structure
3A in which X' is --N(R.sup.N1)--C(R.sup.D5R.sup.D6)-- or
--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0155] Alternatively, in Scheme 3 Step (i), compounds of structure
1A, in which R.sup.2 is an amino group (--NH(R.sup.N1)), may be
combined with compounds of structure 1B', in which R.sup.4 is H,
and treated with an appropriate reagent (such as phosgene,
triphosgene or carbonyl-diimidazole) in a solvent (such as DCM or
toluene) and in the presence of a base (such as pyridine or
triethylamine), optionally in the presence of a catalyst (such as
4-dimethylaminopyridine) at a temperature between room temperature
and the reflux temperature of the solvent to give compounds of
structure 3A in which X' is --N(R.sup.N1)--C(O)--.
[0156] Alternatively, in Scheme 3, Step (i), compounds of structure
1A, in which R.sup.2 is an amino group (--NH(R.sup.N1)), may be
treated with compounds of structure 1B' in which R.sup.4 is an
alkyl group substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)CO.sub.2H), in the presence of a dehydrating
agent (such as dicyclohexylcarbodiimide) to give compounds of
structure 3A, in which X' is
--N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0157] Alternatively, in Scheme 3, Step (i), compounds of structure
1B', in which R.sup.4 is an alkyl group substituted by a carboxylic
acid, for example --C(R.sup.D5R.sup.D6)--CO.sub.2H, may be
converted to an activated ester (for example by treatment with HATU
and a base such as diisopropylethylamine or pyridine, or by
treatment with TBTU in the presence of N-methylmorpholine). This
activated ester may then be combined with compounds of structure
1A, in which R.sup.2 is an amino group (--NH(R.sup.N1)), in the
presence of a base (such as diisopropylethylamine or pyridine), to
give a compound of structure 3A in which X' is
--N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0158] Alternatively, in Scheme 3, Step (i), a compound of
structure 1A, in which R.sup.2 is an amino group (--NH(R.sup.N1)),
may be converted to other compounds of structure 1A, in which
R.sup.2 is --N(R.sup.N1)--C(O)--CH.sub.2-L, wherein L is a leaving
group (such as a halide, for example a chloride or bromide), by
treatment with a haloacetyl halide (such as chloroacetyl chloride
or bromoacetyl bromide), in a solvent (such as THF or DCM) in the
presence of a base (such as triethylamine or pyridine). This
intermediate may be treated with a compound of structure 1B', in
which R.sup.4 is H, in the presence of a base (such as pyridine,
potassium carbonate or sodium hydride) in a solvent (such as DCM,
THF or toluene), at a temperature between room temperature and the
reflux temperature of the solvent, to give a compound of structure
3A wherein X' is --N(R.sup.N1)--C(O)--CH.sub.2--.
[0159] Alternatively, in Scheme 3, Step (i), compounds of structure
1A, in which R.sup.2 is OH, may be combined with compounds of
structure 1B', in which R.sup.4 is a hydroxyalkyl group, for
example --C(R.sup.D5R.sup.D6)--OH or
--C(R.sup.D1R.sup.D6)--C(R.sup.D3R.sup.D4)--OH, in the presence of
a dehydrating agent (such as diisopropyl azodicarboxylate) and a
phosphine, (such as triphenylphosphine) to give a compound of
structure 3A in which X' is --O--C(R.sup.D5R.sup.D6)-- or
--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0160] Alternatively, in Scheme 3, Step (i), compounds of structure
1A, in which R.sup.2 is OH, may be combined with compounds of
structure 1B', in which R.sup.4 is an alkyl group substituted by a
leaving group, for example --C(R.sup.D5R.sup.D6)-L or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a
leaving group (such as a halide or sulfonate, for example a
mesylate), in the presence of a base (such as potassium carbonate
or sodium hydride) in a solvent (such as THF or DMF), at a
temperature between room temperature and the reflux temperature of
the solvent, to give a compound of structure 3A in which X' is
--O--C(R.sup.D5R.sup.D6)-- or
--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0161] Alternatively, compounds of structure 1A, in which R.sup.2
is OH, may be combined with compounds of structure 1B', in which
R.sup.4 is H, and treated with an appropriate reagent (such as
phosgene, triphosgene or carbonyl-diimidazole) in a solvent (such
as THF, DCM or toluene) and in the presence of a base (such as
potassium carbonate or sodium hydride) at a temperature between
room temperature and the reflux temperature of the solvent, to give
a compound of structure 3A in which X' is --O--C(O)--.
[0162] Alternatively, in Scheme 3. Step (i), compounds of structure
1A, in which R.sup.2 is OH, may be treated with compounds of
structure 1B' in which R.sup.4 is an alkyl group substituted by a
carboxylic acid (--C(R.sup.D5R.sup.D6)CO.sub.2H), in the presence
of a dehydrating agent (such as dicyclohexylcarbodiimide) to give
compounds of structure 3A, where X' is
--O--C(O)--C(R.sup.D5R.sup.D6)--.
[0163] Alternatively, in Scheme 3, Step (i), compounds of structure
1B', in which R.sup.4 is an alkyl group substituted by a carboxylic
acid, for example --C(R.sup.D5R.sup.D6)CO.sub.2H, may be converted
to the corresponding activated ester (for example by treatment with
HATU and a base such as diisopropylethylamine or pyridine, or by
treatment with TBTU in the presence of N-methylmorpholine). This
activated ester may then be combined with compounds of structure
1A, in which R.sup.2 is OH, in the presence of a base (such as
diisopropylethylamine or pyridine) to give a compound of structure
3A, in which X' is --O--C(O)--C(R.sup.D5R.sup.D6)--.
[0164] Alternatively, compounds of structure 1A, in which R.sup.2
is OH, may be converted to other compounds of structure 1A, in
which R.sup.2 is --O--C(O)--CH.sub.2-L, wherein L is a leaving
group (such as a halide, for example a chloride or bromide), by
treatment with a haloacetyl halide (such as chloroacetyl chloride
or bromoacetyl bromide) in a solvent (such as THF or DCM), in the
presence of a base (such as triethylamine or pyridine). Treatment
of this intermediate with a compound of structure 1B', in which
R.sup.4 is H, in the presence of a base (such as pyridine,
potassium carbonate or sodium hydride) in a solvent (such as DCM,
THF or toluene) at a temperature between room temperature and the
reflux temperature of the solvent, to give a compound of structure
3A, in which X' is --O--C(O)--CH.sub.2--.
[0165] Alternatively, compounds of structure 1A, in which R.sup.2
is an alkyl group attached to a carboxylic acid, for example
--C(R.sup.D1R.sup.D2)--CO.sub.2H or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--CO.sub.2H, may be
combined with compounds of structure 1B', in which R.sup.4 is H, in
the presence of a dehydrating agent (such as
dicyclohexylcarbodiimide) in a solvent (such as DCM) to give a
compound of structure 3A, in which X' is
--C(R.sup.D1R.sup.D2)--C(O)-- or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.
[0166] Alternatively, in Scheme 3, Step (i), if R.sup.2 is an alkyl
group substituted by a carboxylic acid, for example
--C(R.sup.D1R.sup.D2)CO.sub.2H or
--C(R.sup.D1R.sup.D2)C(R.sup.D3R.sup.D4)CO.sub.2H, it may be
converted to the corresponding activated ester (for example by
treatment with HATU and a base such as diisopropylethylamine or
pyridine, or by treatment with TBTU in the presence of
N-methylmorpholine) and the activated ester can then be treated
with a compound of structure 1B', in which R.sup.4 is H in the
presence of a further base (such as diisopropylethylamine or
pyridine) to give a compound of structure 3A, in which X' is
--C(R.sup.D1R.sup.D2)--C(O)-- or
--C(R.sup.D1R.sup.D2)--C(R.sup.D3R.sup.D4)--C(O)--.
[0167] Alternatively, compounds of structure 1A, in which R.sup.2
is an alkoxy group substituted by a carboxylic acid
(--O--C(R.sup.D3R.sup.D4)--CO.sub.2H), or an aminoalkyl group
substituted by a carboxylic acid
(--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--CO.sub.2H), may be combined
with a compound of structure 1B', in which R.sup.4 is H, in the
presence of a dehydrating agent (such as dicyclohexylcarbodiimide)
in a solvent (such as DCM) to give a compound of structure 3A, in
which X' is --O--C(R.sup.D3R.sup.D4)--C(O)-- or
--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(O)--.
[0168] In Scheme 3, Step (ii), compounds of structure 3A may be
converted to compounds of structure 1C by formation of the
carbon-carbon bond. One skilled in the art will recognize that it
may be necessary to remove protecting groups and modify the groups
R.sup.1 and R.sup.3 groups in order to carry out the reaction to
form the carbon-carbon bond.
[0169] For example, compounds of structure 3A, in which either
R.sup.1 or R.sup.3 is an appropriate group (such as a halide or a
triflate) and the other group is a boronic acid or ester, may be
treated with a palladium catalyst (such as palladium acetate,
palladium chloride dppf or tris-(dibenzylideneacetone)dipalladium),
optionally in the presence of a phosphine (such as triphenyl
phosphine or tri-tert-butylphosphonium tetrafluoroborate) and a
base (such as cesium carbonate) in a solvent (such as THF, dioxane
or water or mixtures thereof) at a temperature between room
temperature and the reflux temperature of the solvent, or by
irradiation in the microwave at a temperature between 120 and
180.degree. C., to give a compound of structure 1C.
[0170] Alternatively, compounds of structure 3A, in which either
R.sup.1 or R.sup.3 is an appropriate group (such as a halide or a
triflate) and the other group is a trialkyl stannane, may be
treated with a palladium catalyst (such as palladium acetate,
palladium chloride dppf or tris-(dibenzylideneacetone)dipalladium),
optionally in the presence of a phosphine (such as triphenyl
phosphine or tri-tert-butylphosphonium tetrafluoroborate) and a
base (such as cesium carbonate) in a solvent (such as THF or
dioxane) at a temperature between room temperature and the reflux
temperature of the solvent, or by irradiation in the microwave at a
temperature between 120 and 180.degree. C., to give a compound of
structure 1C.
[0171] Alternatively, in Scheme 3, Step (ii), a compound of
structure 3A, in which R.sup.1 is an appropriate group (such as a
bromide or triflate), R.sup.3 is H and Y is carbon, may be treated
with a palladium catalyst (such as palladium acetate or
bis-triphenylphosphine palladium chloride) in the presence of a
base (such as cesium carbonate or potassium carbonate) optionally
in the presence of a phosphine (such as triphenyl phosphine) in a
solvent (such as DMF or dioxane), at a temperature between room
temperature and the reflux temperature of the solvent, or
alternatively by irradiation in the microwave at a temperature
between 120 and 180.degree. C., to give a compound of structure 1C,
in which Y is carbon.
[0172] Alternatively, compounds of structure 3A, in which R.sup.1
is a halide (such as a bromide or iodide), R.sup.3 is H and Y is
carbon, may be treated with an oxidising agent (such as oxygen or
phenyl iodosoacetate) in the presence of a palladium catalyst (such
as palladium acetate) in a solvent (such as acetic acid) at a
temperature between room temperature and the reflux temperature of
the solvent to give a compound of structure 1C in which Y is
carbon.
[0173] In Scheme 1, Step (iii), compounds of structure 1C may be
converted to compounds of General formula I by the conversion of
the group G' to a carboxylic acid. If the group G' is a carboxylic
ester (such as a methyl, tert-butyl or benzyl ester) then a variety
of reagents and conditions known to those skilled in the art can be
used to convert 1E into a compound of the General formula I. For
example, if G' is a methyl, ethyl or benzyl ester, it may be
converted to a carboxylic acid by treatment with an inorganic base
(such as lithium hydroxide or sodium hydroxide) in a solvent (such
as methanol, dioxane or water, or mixtures thereof) at a
temperature between room temperature and the reflux temperature of
the solvent, or alternatively by irradiation in the microwave at a
temperature between 120 and 180.degree. C. Alternatively, if G' is
a benzyl ester it may be converted to a carboxylic acid by
hydrogenation in the presence of a catalyst (for example, palladium
on a solid support, such as carbon) in a solvent (such as dioxane
or ethyl acetate). Alternatively, if G' is a tert-butyl ester, it
may be converted to a carboxylic acid by treatment with an acid
(such as trifluoromethanesulfonic acid or hydrogen chloride) in a
solvent (such as dichloromethane or dioxane).
[0174] Alternatively, if the group G' is a nitrile, it may be
converted into a carboxylic acid by treatment with aqueous acid
(such as a mineral acid, for example hydrochloric acid) under
appropriate conditions (such as heating, for example at reflux); or
by treatment with aqueous base (such as an aqueous hydroxide, for
example aqueous sodium hydroxide) under appropriate conditions
(such as heating, for example at reflux).
[0175] Alternatively, if the group G' is an aldehyde or a
hydroxymethyl moiety then it may be converted into a carboxylic
acid by treatment with a suitable oxidising reagent (such as
potassium permanganate or chromic acid).
[0176] A general strategy to prepare compounds of General formula 2
is shown in Scheme 4. The groups G and G' are as previously defined
in Scheme 1.
##STR00008##
[0177] In Scheme 4, a compound of structure 4A, may be coupled with
an appropriately substituted pyrrole or imidazole to form the
carbon-nitrogen bond in 4B. Formation of the X' linker would
generate the intermediate 4D. Alternatively, the X' linker may be
formed first to give the intermediate 4C which may be cyclised to
give 4D. It will be recognised by those skilled in the art that it
may be necessary to modify the groups R.sup.1, R.sup.2 and R.sup.3
in order to generate the required intermediates. In addition,
protecting groups may be required during some of the steps.
[0178] In Scheme 4, Step (i), the carbon-nitrogen bond may be
formed under a range of conditions known to those skilled in the
art. For example, compounds of structure 4A may be reacted with
compounds of structure 4B' in the presence of a palladium catalyst
(such as palladium acetate or
tris-(dibenzylideneacetone)-dipalladium) in the presence of a
phosphine (such as BINAP or tri-tert-butylphosphonium
tetrafluoroborate) and in the presence of a base (such as sodium
tert-butoxide or cesium carbonate) in a solvent (such as THF or
toluene) at a temperature between room temperature and the reflux
temperature of the solvent, or alternatively by irradiation in the
microwave at a temperature between 120 and 180.degree. C. to give
compounds of structure 4B.
[0179] Alternatively, in Scheme 4. Step (i), the carbon-nitrogen
bond may be formed by the reaction of a compound of structure 4A,
in which R.sup.1 is a suitable group (such as a halide or a
triflate), with a compound of structure 4B', in the presence of a
copper catalyst (such as copper or copper (1) iodide) in the
presence of a base (such as potassium carbonate or potassium
phosphate) optionally in the presence of an additive (such as a
crown ether, for example 18-crown-6, or a ligand, for example
1,10-phenanthroline or 1,4-diaminocyclohexane) in a solvent (such
as DMPU, DMF or toluene) at a temperature between room temperature
and the reflux temperature of the solvent, or alternatively by
irradiation in the microwave at a temperature between 120 and
180.degree. C.
[0180] In Scheme 4, Step (ii) the groups R.sup.2 and R.sup.3 of
compound 4B can be coupled together to give the group X'. R.sup.2
or R.sup.3 may have been masked by protecting groups during Step
(i), and may require deprotection before the group X' can be
formed, or alternatively, R.sup.2 and R.sup.3 may require
modification to other groups prior to the formation of the X'
linker. For example, if R.sup.2 is a nitro group, that group may be
reduced, for example using hydrogen in the presence of a suitable
catalyst (such as palladium on a solid support, such as carbon); or
by treatment with an inorganic reducing agent (such as tin (II)
chloride in DMF) to give an amino group. For example, if R.sup.2 or
R.sup.3 is a hydroxyalkyl group, that group may be treated with an
oxidising agent (such as Jones reagent or manganese dioxide) to
give an aldehyde; or with a different oxidising agent (such as
potassium permanganate) to give a carboxylic acid. For example, if
R.sup.2 or R.sup.3 is an aldehyde, that group may be treated with
an oxidising agent (such as potassium permanganate) to give a
carboxylic acid, or with a reducing agent (such as sodium
borohydride) to give an alcohol. For example, if R.sup.2 or R.sup.3
is a ketone, that group may be treated with a reducing agent (such
as sodium borohydride) to give a secondary alcohol. For example, if
R.sup.2 or R.sup.3 is a carboxylic acid or ester, that group may be
treated with a reducing agent (such as lithium aluminium hydride)
to give an alcohol. For example, if R.sup.2 or R.sup.3 is an alkene
group, that group may be treated with a borane (such as
9-borobicyclononane) followed by oxidation with, for example,
hydrogen peroxide to give a primary or secondary alcohol.
[0181] For example, compounds of structure 4B, in which R.sup.2 is
a vinyl group (--CH.dbd.CH.sub.2) and R.sup.3 is an alkenyl group,
for example an allyl group (--CH.sub.2--CH.dbd.CH.sub.2), may
undergo ring closing metathesis on treatment with a metal catalyst
(such as Grubbs catalyst) in a solvent (such as DCM) at a
temperature between room temperature and the reflux temperature of
the solvent to give an intermediate in which X' is
--CH.dbd.CH--CH.sub.2--. Hydrogentaion of this intermediate in the
presence of a catalyst (such as palladium or palladium hydroxide on
a solid support, such as carbon) in a solvent (such as ethanol or
dioxane) optionally in the presence of an acid (such as acetic
acid) to give a compound of structure 4D in which X' is
--CH.sub.2--CH.sub.2--CH.sub.2--.
[0182] Alternatively, compounds of structure 4B, in which R.sup.2
is an amino group (--NH(R.sup.N1)) and R.sup.3 is an alkyl group
substituted by a leaving group, such as --C(R.sup.D5R.sup.D6)-L or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a
leaving group (such as a chloride or a mesylate), may be treated
with a base (such as pyridine or triethylamine) in a solvent (such
as DCM or toluene) at a temperature between room temperature and
the reflux temperature of the solvent, to give compounds of
structure 4D in which X' is --N--(R.sup.N1)--C(R.sup.D5R.sup.D6)--
or --N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0183] Alternatively, compounds of structure 4B, in which R.sup.2
is an alkylamino group (--C(R.sup.D1R.sup.D2)NH(R.sup.2)) and
R.sup.3 is an alkyl group substituted by a leaving group
(--C(R.sup.D5R.sup.D6)-L, wherein L is a leaving group, such as a
chloride or a mesylate), may be treated with a base (such as
pyridine or triethylamine) in a solvent (such as DCM or toluene) at
a temperature between room temperature and the reflux temperature
of the solvent, to give compounds of structure 4D in which X' is
--C(R.sup.D1R.sup.D2)--N(R.sup.N2)--C(R.sup.D5R.sup.D6)--.
[0184] Alternatively, in Scheme 4, Step (ii), compounds of
structure 4B, in which R.sup.2 is an alkyl group substituted by a
leaving group (--C(R.sup.D1R.sup.D2)-L, wherein L is a leaving
group, such as a chloride or mesylate) and R.sup.4 is an alkylamino
group (--C(R.sup.D5R.sup.D6)--NH(R.sup.N2)), may be treated with a
base (such as pyridine or triethylamine) in a solvent (such as DCM
or toluene) at a temperature between room temperature and the
reflux temperature of the solvent to give compounds of structure 4D
in which X' is
--C(R.sup.D1R.sup.D2)--N(R.sup.N2)--C(R.sup.D5R.sup.D6)--.
[0185] Alternatively, compounds of structure 4B, in which R.sup.2
is an amino group (--NH(R.sup.N1)), and R.sup.4 is an alkyl group
substituted by a carboxylic acid, (--C(R.sup.D5R.sup.D6)CO.sub.2H),
can be treated with a dehydrating agent (such as
dicyclohexylcarbodiimide) to form 4D, where X' is
--N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0186] Alternatively, in Scheme 4, Step (ii), if R.sup.2 is an
amino group (--NH(R.sup.N1)) and R.sup.4 is an alkyl group
substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)--CO.sub.2H), the carboxylic acid can be
converted to an activated ester (for example, by treatment with
HATU and a base such as diisopropylethylamine or pyridine, or by
treatment with TBTU in the presence of N-methylmorpholine) and the
activated ester can be treated with further base to form 4D in
which X' is --N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0187] Alternatively, compounds of structure 4B, in which either
R.sup.2 or R.sup.3 is NH.sub.2 and the other group is an aldehyde
group, may be heated in a solvent (such as ethanol or toluene)
optionally in the presence of acid catalyst (for example
4-toluenesulfonic acid), to give compounds of structure 4D, in
which X' is --CH.dbd.N--, or --N.dbd.CH--.
[0188] Alternatively, compounds of structure 4B, in which R.sup.2
is OH and R.sup.3 is a hydroxyalkyl group, for example
--C(R.sup.D5R.sup.D6)--OH or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)--OH, may be treated with
a dehydrating agent (such as diisopropyl azodicarboxylate) in the
presence of a phosphine, (such as triphenylphosphine), to give
compounds of structure 4D, in which X' is
--O--C(R.sup.D5R.sup.D6)-- or
--O--C(R.sup.D5R.sup.D6)--C(R.sup.D5R.sup.D6)--.
[0189] Alternatively, compounds of structure 4B, in which R.sup.2
is OH and R.sup.3 is an alkyl group substituted by a leaving group,
for example --C(R.sup.D5R.sup.D6)-L or
C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a leaving
group (such as a chloride or a mesylate), may be treated with a
base (such as potassium carbonate or sodium hydride) in a solvent
(such as THF or DMF), at a temperature between room temperature and
the reflux temperature of the solvent, to give a compound of
structure 4D, in which X' is --O--C(R.sup.D5R.sup.D6)-- or
--O--C(R.sup.D3R.sup.D4)--C(R.sup.D6)--.
[0190] Alternatively, compounds of structure 4B, in which R.sup.2
is OH and R.sup.3 is an alkyl group substituted by a carboxylic
acid (--C(R.sup.D5R.sup.D6)--CO.sub.2H) can be treated with a
dehydrating agent (such as dicyclohexylcarbodiimide) to form 4D, in
which X' is --O--C(O)--C(R.sup.D5R.sup.D6)--.
[0191] Alternatively, if R.sup.2 is OH and R.sup.3 is an alkyl
group substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)--CO.sub.2H), the carboxylic acid can be
converted to an activated ester (for example by treatment with HATU
and a base such as diisopropylethylamine or pyridine, or by
treatment with TBTU in the presence of N-methylmorpholine), which
can be further treated with base to form 4D, in which X' is
--O--C(O)--C(R.sup.D5R.sup.D6)--.
[0192] In Scheme 4, Step (iii), the linker X' may be formed by the
reaction of an appropriately substituted intermediate 4A with an
imidazole or pyrrole intermediate 4C'. It will be recognised by
those skilled in the art that it may be necessary to have a
protecting group present on the imidazole or pyrrole nitrogen prior
to reaction and that the protecting group will need to be removed
prior to Step (iv).
[0193] For example, in Scheme 4, Step (iii), compounds of structure
4A, in which R.sup.2 is an amino group (--NH(R.sup.N1)), may be
coupled with compounds of structure 4C', in which R.sup.3 is an
alkyl group substituted by a leaving group, such as
--C(R.sup.D5R.sup.D6)-L or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a
leaving group (such as a chloride or mesylate), in the presence of
a base (such as pyridine or triethylamine) in a solvent (such as
DCM or toluene) at a temperature between room temperature and the
reflux temperature of the solvent to give compounds of structure 4C
in which X' is --N(R.sup.N1)--C(R.sup.D5R.sup.D6)-- or
--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0194] Alternatively, compounds of structure 4A, in which R.sup.2
is an amino group (--NH(R.sup.N1)), may be coupled with compounds
of structure 4C', in which R' is an alkyl group substituted by a
carboxylic acid (--C(R.sup.D5R.sup.D6)--CO.sub.2H), in the presence
of a dehydrating agent (such as dicyclohexylcarbodiimide) to form
4C, where X' is --N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6).
[0195] Alternatively, compounds of structure 4C', in which R.sup.3
is an alkyl group substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)--CO.sub.2H), may be converted to the
corresponding activated ester (for example by treatment with HATU
and a base such as diisopropylethylamine or pyridine, or by
treatment with TBTU in the presence of N-methylmorpholine) and the
activated ester may then be reacted with a compound of structure
4A, in which R.sup.2 is an amino group (--NH(R.sup.N1)) in the
presence of a base (such as diisopropylethylamine or pyridine) to
give compounds of structure 4C, in which X' is
--N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0196] Alternatively, compounds of structure 4A, in which R.sup.2
is OH, may be reacted with compounds of structure 4C', in which
R.sup.3 is a hydroxyalkyl group, for example
--C(R.sup.D5R.sup.D6)--OH or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)--OH, in the presence of
a dehydrating agent (such as diisopropyl azodicarboxylate) and a
phosphine, (such as triphenylphosphine) to give a compound of
structure 4C, in which X' is --O--C(R.sup.D5R.sup.D6)-- or
--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0197] Alternatively, in Scheme 4. Step (iii), compounds of
structure 4A, in which R.sup.2 is OH may be reacted with compounds
of structure 4C', in which R.sup.3 is an alkyl group substituted by
a leaving group, for example --C(R.sup.D5R.sup.D6)-L or
C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a leaving
group (such as a chloride or mesylate), in the presence of a base
(such as potassium carbonate or sodium hydride) in a solvent (such
as THF or DMF) at a temperature between room temperature and the
reflux temperature of the solvent to give a compound of structure
4C, in which X' is --O--C(R.sup.D5R.sup.D6)-- or
--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6).
[0198] Alternatively, compounds of structure 4A, in which R.sup.2
is OH, may be reacted with a compound of structure 4C', in which
R.sup.3 is an alkyl group substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)--CO.sub.2H), in the presence of a
dehydrating agent (such as dicyclohexylcarbodiimide) to form 4C, in
which X' is --O--C(O)--C(R.sup.D5R.sup.D6)--.
[0199] Alternatively, a compound of structure 4C', in which R.sup.3
is an alkyl group substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)--CO.sub.2H), may be converted to the
corresponding activated ester (for example by treatment with HATU
and a base such as diisopropylethylamine or pyridine, or by
treatment with TBTU in the presence of N-methylmorpholine), and the
activated ester may then be reacted with a compound of structure
4A, in which R.sup.2 is OH, in the presence of a base (such as
diisopropylethylamine or pyridine) to give a compound of structure
4C, in which X' is --N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0200] In Scheme 4, Step (iv), a compound of structure 4C may be
converted to a compound of structure 4D by formation of the
carbon-nitrogen bond. It will be recognized by those skilled in the
art that protecting groups may have been required during the
earlier steps and that these will require removal prior to Step
(iv).
[0201] In Scheme 4, Step (iv), the carbon nitrogen bond may be
formed by the treatment of 4C, in which R.sup.1 is a suitable
leaving group (such as a halide or triflate), with a palladium
catalyst (such as palladium acetate or
tris-(dibenzylideneacetone)-dipalladium) in the presence of a
phosphine (such as BINAP or tri-tert-butylphosphonium
tetrafluoroborate) and in the presence of a base (such as sodium
tert-butoxide or cesium carbonate) in a solvent (such as THF or
toluene) at a temperature between room temperature and the reflux
temperature of the solvent, or alternatively by irradiation in the
microwave at a temperature between 120 and 180.degree. C., to give
4D.
[0202] Alternatively, in Scheme 4. Step (iv), the carbon-nitrogen
bond may be formed by the treatment of 4C, in which R.sup.1 is a
suitable group (such as a halide or a triflate), with a copper
catalyst (such as copper or copper iodide) in the presence of a
base (such as potassium carbonate or potassium phosphate)
optionally in the presence of an additive (such as a crown ether,
for example 18-crown-6, or a ligand, for example
1,10-phenanthroline or 1,4-diaminocyclohexane), in a solvent (such
as DMPU, DMF or toluene) at a temperature between room temperature
and the reflux temperature of the solvent, or alternatively by
irradiation in the microwave at a temperature between 120 and
180.degree. C., to give a compound of structure 4D.
[0203] Compounds of formula 4D, in which Y is nitrogen, may
alternatively be prepared according to Scheme 5. The compounds of
structure 4A may be converted to compounds of structure 5A or 5B,
each of which may be cyclised to form compounds of structure 5C.
Conversion of compounds of structure 5C to compounds of structure
4D is well known to those skilled in the art and will be described
in detail below. It will be recognised that protecting groups may
be required during some of the steps which will require removal
prior to the additional steps.
##STR00009##
[0204] In Scheme 5, Step (i), compounds of structure 4A, in which
R.sup.1 is an amino group, may be reacted with compounds of
structure 5A', in which R.sup.4 is a leaving group (such as a
chloride), in the presence of a base (such as triethylamine or
pyridine) in a solvent (such as DCM or toluene) at a temperature
between room temperature and the reflux temperature of the
solvent.
[0205] Alternatively, in Scheme 5. Step (i), compounds of structure
5A', in which R.sup.4 is OH, may be converted to the corresponding
activated ester (for example by treatment with HATU and a base such
as diisopropylethylamine or pyridine, or by treatment with TBTU in
the presence of N-methylmorpholine) and the activated ester can
then be reacted with a compound of structure 4A, in which R.sup.1
is NH.sub.2, in the presence of a base (such as
diisopropylethylamine or pyridine) to give a compound of structure
5A.
[0206] In Scheme 5, Step (ii), compounds of structure 5A may be
converted to compounds of structure 5B by formation of the X'
linker. It will be recognised by those skilled in the art that it
may be necessary to modify the groups R.sup.2 and R.sup.3 prior to
the formation of the linker and that protecting groups present in
Step (i) may need to be removed.
[0207] For example, in Scheme 5, Step (ii), compounds of structure
5A, in which either R2 or R3 is a vinyl group (--CH.dbd.CH.sub.2)
and the other group is an alkenyl group, for example an allyl group
(--CH.sub.2--CH.dbd.CH.sub.2), may undergo ring closing metathesis
on treatment with a metal catalyst (such as Grubbs catalyst) in a
solvent (such as DCM) at a temperature between room temperature and
the reflux temperature of the solvent to give an intermediate in
which X' is --CH.dbd.CH--CH.sub.2-- or --CH.sub.2--CH.dbd.CH--.
Hydrogenation of this intermediate in the presence of a catalyst
(such as palladium or palladium hydroxide on a solid support, such
as carbon) in a solvent (such as ethanol or dioxane) optionally in
the presence of an acid (such as acetic acid) may give a compound
of structure 5B, in which X' is
--CH.sub.2--CH.sub.2--CH.sub.2--.
[0208] Alternatively, compounds of structure 5A, in which R.sup.2
is an amino group (--NH(R.sup.N1)) and R.sup.3 is an alkyl group
substituted by a leaving group, such as --C(R.sup.D5R.sup.D6)-L or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a
leaving group (such as a chloride or mesylate), may be treated with
a base (such as pyridine or triethylamine) in a solvent (such as
DCM or toluene) at a temperature between room temperature and the
reflux temperature of the solvent, to give compounds of structure
5B, in which X' is --N(R.sup.N1)--C(R.sup.D5R.sup.D6)-- or
--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0209] Alternatively, compounds of structure 5A, in which R.sup.2
is an amino group (--NH(R.sup.N1)) and R.sup.3 is a carboxylic acid
(--CO.sub.2H) or an alkyl group substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)--CO.sub.2H), can be treated with a
dehydrating agent (such as dicyclohexylcarbodiimide) to form 5B, in
which X' is --N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0210] Alternatively, in compounds of structure 5A, in which
R.sup.2 is an amino group (--NH(R.sup.N1)) and R.sup.3 is a
carboxylic acid (--CO.sub.2H) or an alkyl group substituted by a
carboxylic acid (--C(R.sup.D5R.sup.D6)--CO.sub.2H), the carboxylic
acid can be converted to an activated ester (for example by
treatment with HATU and a base such as diisopropylethylamine or
pyridine, or by treatment with TBTU in the presence of
N-methylmorpholine) and the activated ester can be further treated
with base to form 5B, in which X' is
--N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0211] Alternatively, compounds of structure 5A, in which R.sup.2
is OH and R.sup.3 is a hydroxyalkyl group, for example
--C(R.sup.D5R.sup.D6)--OH or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)--OH, may be treated with
a dehydrating agent (such as diisopropyl azodicarboxylate) in the
presence of a phosphine, (such as triphenylphosphine) to give a
compound of structure 5B, in which X' is --O--C(R.sup.D5R.sup.D6)--
or --O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0212] Alternatively, compounds of structure 5A, in which R.sup.2
is OH and R.sup.6 is an alkyl group substituted by a leaving group,
for example --C(R.sup.D5R.sup.D6)-L or
C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a leaving
group (such as a chloride or mesylate), may be treated with a base
(such as potassium carbonate or sodium hydride) in a solvent (such
as THF or DMF) at a temperature between room temperature and the
reflux temperature of the solvent, to give a compound of structure
5B, in which X' is --O--C(R.sup.D5R.sup.D6)-- or
--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6).
[0213] Alternatively, compounds of structure 5A, in which R.sup.2
is OH and R.sup.3 is a carboxylic acid (--CO.sub.2H) or an alkyl
group substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)--CO.sub.2H), can be treated with a
dehydrating agent (such as dicyclohexylcarbodiimide) to form 5B, in
which X' is --O--C(O)--C(R.sup.D5R.sup.D6)--.
[0214] Alternatively, if R.sup.2 is OH and R.sup.3 is a carboxylic
acid (--CO.sub.2H) or an alkyl group substituted by a carboxylic
acid (--C(R.sup.D1R.sup.D2)--CO.sub.2H), the carboxylic acid can be
converted to an activated ester (for example by treatment with HATU
and a base such as diisopropylethylamine or pyridine, or by
treatment with TBTU in the presence of N-methylmorpholine) which
can then be treated with further base to form 5B, in which X' is
--O--C(O)--C(R.sup.D5R.sup.D6)--.
[0215] In Scheme 5, Step (iii), the X' linker may be formed by the
reaction of an appropriately substituted intermediate 4A with an
appropriately substituted and protected carboxylic acid derivative
5C', to give 5C. For example, compounds of structure 4A, in which
R.sup.2 is an aldehyde (--CHO), may be reacted with an appropriate
compound 5C', in which R.sup.6 is alkylidene phosphorane (for
example ethoxymethylene triphenyl phosphorane), in a solvent (such
as DCM, THF or toluene) at a temperature between room temperature
and the reflux temperature of the solvent to give a compound of
structure 5C, in which X' is --CH.dbd.CH--.
[0216] Alternatively, compounds of structure 4A, in which R.sup.2
is an aldehyde (--CHO), may be reacted with an appropriate compound
5C', in which R.sup.6 is a phosphonate (such as trimethyl
phosphonoacetate) in the presence of a base (such as sodium
hydride, potassium tert-butoxide or butyllithium) in a solvent
(such as DMF or THF) at a temperature between -78.degree. C. and
room temperature to give a compound of structure 5C, in which X' is
--CH.dbd.CH--.
[0217] A compound of structure 5C, in which X' is --CH.dbd.CH--,
may be converted to other compounds of structure 5C, in which X' is
--CH.sub.2--CH.sub.2--, by hydrogenation in the presence of a metal
catalyst (for example palladium or palladium hydroxide on a solid
support, such as carbon) in a solvent (such as methanol, ethanol or
ethyl acetate).
[0218] Alternatively, compounds of structure 4A, in which R.sup.2
is an amino group (--NH(R.sup.N1)), may be coupled with compounds
of structure 5C', in which R.sup.6 is an alkyl group substituted by
a leaving group, such as --C(R.sup.D5R.sup.D6)-L or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a
leaving group (such as a chloride or mesylate), in the presence of
a base (such as pyridine or triethylamine) in a solvent (such as
DCM or toluene) at a temperature between room temperature and the
reflux temperature of the solvent to give compounds of structure
5C, in which X' is --N(R.sup.N1)--C(R.sup.D5R.sup.D6)-- or
--N(R.sup.N1)--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0219] Alternatively, in Scheme 5, Step (iii), compounds of
structure 4A, in which R.sup.2 is an amino group (--NH(R.sup.N1)),
may be coupled with compounds of structure 5C', in which R.sup.6 is
a carboxylic acid (--CO.sub.2H) or an alkyl group substituted by a
carboxylic acid (--C(R.sup.D5R.sup.D6)CO.sub.2H), in the presence
of a dehydrating agent (such as dicyclohexylcarbodiimide) to form
5C, in which X' is --N(R.sup.N1)--C(O)-- or
--N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0220] Alternatively, a compound of structure 5C', in which R.sup.6
is a carboxylic acid (--CO.sub.2H) or an alkyl group substituted by
a carboxylic acid (--C(R.sup.D5R.sup.D6)--CO.sub.2H), may be
converted to the corresponding activated ester (for example by
treatment with HATU and a base such as diisopropylethylamine or
pyridine, or by treatment with TBTU in the presence of
N-methylmorpholine), which can then be reacted with a compound of
structure 4A in which R.sup.2 is an amino group (--NH(R.sup.N1)),
in the presence of a base (such as diisopropylethylamine or
pyridine) to give a compound of structure 5C, in which X' is
--N(R.sup.N1)--C(O)--C(R.sup.D5R.sup.D6)--.
[0221] Alternatively, in Scheme 5, Step (iii), compounds of
structure 4A, in which R.sup.2 is NH.sub.2, may be reacted with a
compound of structure 5C', in which R.sup.6 is an aldehyde group
(such as a glyoxylic acid or ester), optionally in the presence of
a drying agent (such as anhydrous sodium sulphate) in a solvent
(such as DCM or toluene) at a temperature between room temperature
and the reflux temperature of the solvent, to give compounds of
structure 5C, in which X' is --N.dbd.CH--.
[0222] Alternatively, compounds of structure 4A, in which R.sup.2
is an amino group, for example --NH(R.sup.N1), may be reacted with
a compound of structure 5C', in which R.sup.6 is a vinyl group
(such as an alkyl acrylate), in a solvent (such as acetic acid) at
a temperature between room temperature and the reflux temperature
of the solvent to give a compound of structure 5C, in which X' is
--N(R.sup.N1)--CH.sub.2--CH.sub.2--.
[0223] Alternatively, compounds of structure 4A, in which R.sup.2
is OH, may be reacted with compounds of structure 5C', in which
R.sup.6 is a hydroxyalkyl group, for example
--C(R.sup.D5R.sup.D6)--OH or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)--OH, in the presence of
a dehydrating agent (such as diisopropyl azodicarboxylate) and a
phosphine, (such as triphenylphosphine) to give a compound of
structure 5C, in which X' is --O--C(R.sup.D5R.sup.D6)-- or
--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0224] Alternatively, compounds of structure 4A, in which R.sup.2
is OH, may be reacted with compounds of structure 5C', in which
R.sup.6 is an alkyl group substituted by a leaving group, for
example --C(R.sup.D5R.sup.D6)-L or
--C(R.sup.D5R.sup.D6)--C(R.sup.D3R.sup.D4)-L, wherein L is a
leaving group (such as a chloride or mesylate), in the presence of
a base (such as potassium carbonate or sodium hydride) in a solvent
(such as THF or DMF) at a temperature between room temperature and
the reflux temperature of the solvent to give a compound of
structure 5C, in which X' is --O--C(R.sup.D5R.sup.D6)-- or
--O--C(R.sup.D3R.sup.D4)--C(R.sup.D5R.sup.D6)--.
[0225] Alternatively, compounds of structure 4A, in which R.sup.2
is OH, may be reacted with a compound of structure 5C', in which
R.sup.6 is a carboxylic acid (--CO.sub.2H) or an alkyl group
substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6)--CO.sub.2H), in the presence of a
dehydrating agent (such as dicyclohexylcarbodiimide) to form 5C, in
which X' is --O--C(O)-- or --O--C(O)--C(R.sup.D5R.sup.D6)--.
[0226] Alternatively, in Scheme 5, Step (iii), a compound of
structure 5C', in which R.sup.6 is a carboxylic acid (--CO.sub.2H)
or an alkyl group substituted by a carboxylic acid
(--C(R.sup.D5R.sup.D6) CO.sub.2H), may be converted to the
corresponding activated ester (for example by treatment with HATU
and a base such as diisopropylethylamine or pyridine, or by
treatment with TBTU in the presence of N-methylmorpholine) and the
activated ester can be reacted with a compound of structure 4A, in
which R.sup.2 is OH, in the presence of a base (such as
diisopropylethylamine or pyridine) to give a compound of structure
5C, in which X' is --O--C(O)-- or
--O--C(O)--C(R.sup.D5R.sup.D6)--.
[0227] In Scheme 5, Step (iv), compounds of structure 5C. may be
converted to compounds of structure 5B by a variety of methods
known to those skilled in the art. For example, if R.sup.1 is
NH.sub.2 and R.sup.5 is a leaving group (such as a chloride) then
5C may be treated with a base (such as triethylamine) in a solvent
(such as DCM) at a temperature between room temperature and the
reflux temperature of the solvent, to give compounds of structure
5B.
[0228] Alternatively, compounds of structure 5C, in which R.sup.1
is NH.sub.2 and R.sup.5 is OH, may be treated with a dehydrating
agent (such as dicyclohexylcarbodiimide) or an appropriate reagent
(for example HATU and a base, such as diisopropylamine or pyridine,
or TBTU in the presence of N-methylmorpholine) to give compounds of
structure 5B.
[0229] Alternatively, compounds of structure 5C, in which R.sup.1
is NH.sub.2 and R.sup.5 is an alkoxy group (such as methoxy or
ethoxy), may be heated in a solvent (such as methanol or ethanol)
to give compounds of structure 5B.
[0230] Alternatively, compounds of structure 5C, in which R.sup.1
is an appropriate group (such as a bromide or triflate) and R.sup.5
is NH.sub.2, may be heated in a solvent (such as DMF or
N-methylpyrrolidinone) in the presence of a base (such as potassium
carbonate) optionally in the presence of a catalyst (for example a
copper catalyst, such as copper (I) iodide) and an additive (such
as N,N'-dimethylethylenediamine) at a temperature between
50.degree. C. and the reflux temperature of the solvent, or
alternatively by irradiating in the microwave at a temperature
between 120 and 180.degree. C., to give a compound of structure
5B.
[0231] In Scheme 5, Step (v), compounds of structure 5B may be
converted to compounds of structure 5D by treatment with either
Lawesson's reagent in a solvent (such as toluene, THF or DMF) at a
temperature between room temperature and the reflux temperature of
the solvent, or phosphorus pentasulfide, in a solvent (such as
acetonitrile or toluene) optionally in the presence of a base (such
as triethylamine) at a temperature between room temperature and the
reflux temperature of the solvent.
[0232] In Scheme 5, Step (vi), compounds of structure 5D may be
converted to compounds of structure 5E by treatment with methyl
iodide in the presence of a base (such as potassium carbonate or
cesium carbonate) in a solvent (such as acetone or DMF) at a
temperature between room temperature and the reflux temperature of
the solvent.
[0233] Alternatively, in Scheme 5, Step (viii), compounds of
structure 5B may be converted to compounds of structure 5F by
treatment with a chlorinating agent (such as phosphorus
oxychloride) optionally in a solvent (such as toluene) at a
temperature between room temperature and the reflux temperature of
the mixture.
[0234] In Scheme 5, Step (vii) or Step (ix), compounds of structure
5E or 5F may be converted to compounds of structure 5G by reaction
with aminoacetaldehyde dimethyl acetal, optionally in the presence
of a base (such as triethylamine) in a solvent (such as ethanol or
toluene) at a temperature between room temperature and the reflux
temperature of the solvent.
[0235] In Scheme 5, Step (x), compounds of structure 5G may be
treated with an acid (such as hydrochloric acid) in a solvent (such
as methanol) at a temperature between room temperature and the
reflux temperature of the solvent, to give compounds of structure
4D.
[0236] Compounds of structure 4D, in which Y is CH, may be
alternatively prepared by aerial oxidation of the corresponding
dihydropyrrole intermediates as shown in Scheme 6.
##STR00010##
[0237] The dihydropyrrole intermediates 6A may be prepared in a
similar manner to the corresponding pyrrole intermediates as
described in Scheme 4. Oxidation by stirring in a solvent (such as
DCM) in air will provide the compounds 4D.
[0238] In Scheme 4, Step (v), compounds of structure 4D may be
converted to compounds of General formula 2 by conversion of the
group G' to a carboxylic acid. This may be carried out as described
earlier for compounds of General formula 1.
[0239] The general synthetic strategy to modify the group G is
depicted in Scheme 7. The group G may be introduced and/or modified
either before, during or after the assembly of the tricyclic ring
system. Specific steps used to assemble the sulfonamide are
described in more detail below.
##STR00011##
[0240] In Scheme 7, the asterisks denote either the presence of the
groups R.sup.1 and R.sup.2 (as shown in Scheme 1 or Scheme 4), or
the presence of the one or both of the rings of the tricyclic core,
or intermediates towards the preparation of the core (as shown in
Schemes 1-6).
[0241] In Scheme 7, Step (i), compounds of structure 7A, in which G
is a nitro group, may be converted to compounds of structure 7B by
reduction, for example by catalytic hydrogenation in the presence
of a metal catalyst (for example palladium on a solid support such
as carbon) in a solvent (such as tetrahydrofuran, methanol or
ethanol). Alternatively, compounds of structure 7A, in which G is a
nitro group, may be converted to compounds of structure 7B by
chemical reduction. For example, the reduction may be achieved
using a metal or metal salt (such as iron, zinc or tin (11)
chloride) in the presence of an acid (such as hydrochloric acid or
acetic acid).
[0242] In Scheme 7, Step (i), compounds of structure 7A, in which G
is a protected amino group, may be converted to compounds of
structure 7B by removal of the protecting groups. Protecting groups
for amines are well known to those skilled in the art and methods
for their removal are equally well known (for example, see Greene,
Wuts, Protective Groups in Organic Synthesis. 2nd Ed. (1999)). For
example, compounds of structure 7A, in which G is an amino group
protected with one or two Boc groups, may be converted to compounds
of structure 7B by treatment with an acid (such as trifluoroacetic
acid, formic acid or hydrogen chloride) in a solvent (such as
dichloromethane or dioxane).
[0243] Alternatively, in Scheme 7, Step (i), compounds of structure
7A, in which G is a pivaloyl protected amino group, may be
converted to compounds of structure 7B by treatment with an acid
(such as concentrated sulfuric acid) in a solvent (such as methanol
or water) at a temperature between room temperature and the reflux
temperature of the solvent.
[0244] In Scheme 7, Step (ii), compounds of structure 7B may be
converted to compounds of structure 7C by treatment with an
appropriate sulfonyl chloride (such as a substituted or
unsubstituted benzenesulfonyl chloride) or an activated sulfonate
ester (such as a pentafluorophenyl sulfonate ester) in the presence
of a suitable base (such as pyridine, diisopropylethylamine or
cesium carbonate) in a suitable solvent (such as dichloromethane or
dimethylformamide) at a temperature between room temperature and
the reflux temperature of the solvent.
[0245] Compounds of any of Formula I or II or, for example, General
Formula I or II as depicted above, or any of the intermediates
described in the schemes above, can be further derivatised by using
one or more standard synthetic methods known to those skilled in
the art. Such methods can involve substitution, oxidation or
reduction reactions. These methods can also be used to obtain or
modify compounds of General Formula I or any preceding
intermediates by modifying, introducing or removing appropriate
functional groups. Particular substitution approaches include
alkylation, arylation, heteroarylation, acylation, thioacylation,
halogenation, sulfonylation, nitration, formylation, hydrolysis and
coupling procedures. These procedures can be used to introduce a
functional group onto the parent molecule (such as the nitration or
sulfonylation of aromatic rings) or to couple two molecules
together (for example to couple an amine to a carboxylic acid to
afford an amide; or to form a carbon-carbon bond between two
heterocycles). For example, alcohol or phenol groups can be
converted to ether groups by coupling a phenol with an alcohol in a
solvent (such as tetrahydrofuran) in the presence of a phosphine
(such as triphenylphosphine) and a dehydrating agent (such as
diethyl, diisopropyl or dimethyl azodicarboxylate). Alternatively,
ether groups can be prepared by deprotonation of an alcohol, using
a suitable base (such as sodium hydride) followed by the addition
of an alkylating agent (such as an alkyl halide or an alkyl
sulfonate).
[0246] In another example, a primary or secondary amine can be
alkylated using a reductive alkylation procedure. For example, the
amine can be treated with an aldehyde and a borohydride (such as
sodium triacetoxyborohydride, or sodium cyanoborohydride in a
solvent (such as a halogenated hydrocarbon, for example
dichloromethane, or an alcohol, for example ethanol) and, where
necessary, in the presence of an acid (such as acetic acid).
[0247] In another example, hydroxy groups (including phenolic OH
groups) can be converted into leaving groups, such as halogen atoms
or sulfonyloxy groups (such as alkylsulfonyloxy, for example
trifluoromethanesulfonyloxy, or aryl sufonyloxy, for example
p-toluenesulfonyloxy) using conditions known to those skilled in
the art. For example, an aliphatic alcohol can be reacted with
thionyl chloride in a halogenated hydrocarbon (such as
dichloromethane) to afford the corresponding alkyl chloride. A base
(such as triethylamine) can also be used in the reaction.
[0248] In another example, ester groups can be converted to the
corresponding carboxylic acid by acid- or base-catalysed hydrolysis
depending on the nature of the ester group. Acid catalysed
hydrolysis can be achieved by treatment with an organic or
inorganic acid (such as trifluoroacetic acid in an aqueous solvent,
or a mineral acid such as hydrochloric acid in a solvent such as
dioxane). Base catalysed hydrolysis can be achieved by treatment
with an alkali metal hydroxide (such as lithium hydroxide in an
aqueous alcohol, for example methanol).
[0249] In another example, aromatic halogen substituents in the
compounds may be subjected to halogen-metal exchange by treatment
with a base (such as a lithium base, for example n-butyl or
tert-butyl lithium) optionally at a low temperature (such as
-78.degree. C.) in a solvent (such as tetrahydrofuran) and the
mixture may then be quenched with an electrophile to introduce a
desired substituent. Thus, for example, a formyl group can be
introduced by using dimethylformamide as the electrophile. Aromatic
halogen substituents can also be subjected to palladium catalysed
reactions to introduce groups such as carboxylic acids, esters,
cyano or amino substituents.
[0250] In another example, an aryl, or heteroaryl ring substituted
with an appropriate leaving group (such as a halogen or sulfonyl
ester, for example a triflate) can undergo a palladium catalysed
coupling reaction with a wide variety of substrates to form a
carbon-carbon bond. For example, a Heck reaction can be used to
couple such a ring system to an alkene (which may, or may not, be
further substituted) by treatment with an organopalladium complex
(such as tetrakis-(triphenylphosphine)palladium, palladium (II)
acetate or palladium (II) chloride) in the presence of a ligand
(such as a phosphine, for example triphenylphosphine) in the
presence of a base (such as potassium carbonate or a tertiary
amine, for example, triethylamine), in an appropriate solvent (such
as THF or DMF), at a temperature between room temperature and the
reflux temperature of the solvent. In another example, a
Sonogashira reaction can be used to couple such a ring system to an
alkyne (which may, or may not be further substituted) by treatment
with a palladium complex (such as
tetrakis-(triphenylphosphine)palladium) and a halide salt of copper
(I) (such as copper (I) iodide), in the presence of a base (such as
a potassium carbonate or a tertiary amine, for example,
triethylamine), in an appropriate solvent (such as THF or DMF), at
a temperature between room temperature and the reflux temperature
of the solvent. In another example, a Stille reaction can be used
to couple such a ring system to an alkene or alkyne, by treatment
with an organotin compound (such as an alkenyltin or alkynyltin
reagent, for example an alkenyltributylstannane) in the presence of
a palladium complex (such as
tetrakis-(triphenylphosphine)palladium(0)), optionally in the
presence of a salt (such as a copper (I) halide), in an appropriate
solvent (such as dioxane or DMF), at a temperature between room
temperature and the reflux temperature of the solvent.
[0251] Particular oxidation approaches include dehydrogenations and
aromatisation, decarboxylation and the addition of oxygen to
certain functional groups. For example, aldehyde groups can be
prepared by oxidation of the corresponding alcohol using conditions
well known to those skilled in the art. For example, an alcohol can
be treated with an oxidising agent (such as Dess-Martin
periodinane) in a solvent (such as a halogenated hydrocarbon, for
example dichloromethane). Alternative oxidising conditions can be
used, such as treatment with oxalyl chloride and an activating
amount of dimethylsulfoxide and subsequent quenching by the
addition of an amine (such as triethylamine). Such a reaction can
be carried out in an appropriate solvent (such as a halogenated
hydrocarbon, for example dichloromethane) and under appropriate
conditions (such as cooling below room temperature, for example to
-78.degree. C. followed by warming to room temperature). In another
example, sulfur atoms can be oxidised to the corresponding
sulfoxide or sulfone using an oxidising agent (such as a peroxy
acid, for example 3-chloroperoxybenzoic acid) in an inert solvent
(such as a halogenated hydrocarbon, for example dichloromethane) at
around ambient temperature.
[0252] Particular reduction approaches include the removal of
oxygen atoms from particular functional groups or saturation (or
partial saturation) of unsaturated compounds including aromatic or
heteroaromatic rings. For example, primary alcohols can be
generated from the corresponding ester or aldehyde by reduction,
using a metal hydride (such as lithium aluminium hydride or sodium
borohydride in a solvent such as methanol). Alternatively,
CH.sub.2OH groups can be generated from the corresponding
carboxylic acid by reduction, using a metal hydride (such as
lithium aluminium hydride in a solvent such as THF). In another
example, a nitro group may be reduced to an amine by catalytic
hydrogenation in the presence of a metal catalyst (such as
palladium on a solid support such as carbon) in a solvent (such as
an ether, for example THF, or an alcohol, such as methanol), or by
chemical reduction using a metal (such as zinc, tin or iron) in the
presence of an acid (such as acetic acid or hydrochloric acid). In
a further example an amine can be obtained by reduction of a
nitrile, for example by catalytic hydrogenation in the presence of
a metal catalyst (for example palladium on a solid support such as
carbon, or Raney nickel) in a solvent (such as THF) and under
suitable conditions (such as cooling to below room temperature, for
example to -78.degree. C., or heating, for example to reflux).
[0253] Salts of compounds of General Formula I can be prepared by
the reaction of a compound of General Formula I with an appropriate
acid or base in a suitable solvent, or mixture of solvents (such as
an ether, for example, diethyl ether, or an alcohol, for example
ethanol, or an aqueous solvent) using conventional procedures.
Salts of compound of General Formula I can be exchanged for other
salts using methods known to those skilled in the art, for example
by treatment using conventional ion-exchange chromatography
procedures.
[0254] Where it is desired to obtain a particular enantiomer of a
compound of General Formula I, this may be produced from a
corresponding mixture of enantiomers by employing any suitable
conventional procedure for resolving enantiomers known to those
skilled in the art. For example, diastereomeric derivatives (such
as salts) can be produced by reaction of a mixture of enantiomers
of a compound of General Formula I (such a racemate) and an
appropriate chiral compound (such as a chiral base). The
diastereomers can then be separated by any conventional means such
as crystallization or chromatography, and the desired enantiomer
recovered (such as by treatment with an acid in the instance where
the diastereomer is a salt). Alternatively, a racemic mixture of
esters can be resolved by kinetic hydrolysis using a variety of
biocatalysts (for example, see Patel Steroselective Biocatalysts,
Marcel Decker, New York 2000).
[0255] In another resolution process a racemate of compounds of
General Formula I can be separated using chiral High Performance
Liquid Chromatography. Alternatively, a particular enantiomer can
be obtained by using an appropriate chiral intermediate in one of
the processes described above. Chromatography, recrystallisation
and other conventional separation procedures may also be used with
intermediates or final products where it is desired to obtain a
particular geometric isomer of the invention.
II. Methods
[0256] Another aspect of the invention provides methods of
modulating the activity of MetAP2. Such methods comprise exposing
said receptor to a compound described herein. In some embodiments,
the compound utilized by one or more of the foregoing methods is
one of the generic, subgeneric, or specific compounds described
herein, such as a compound of Formula I, Ia, Ib, Ic, II, IIa, IIb,
IIc, IId, IIe, III, IV and V. The ability of compounds described
herein to modulate or inhibit MetAP2 can be evaluated by procedures
known in the art and/or described herein. Another aspect of the
invention provides methods of treating a disease associated with
expression or activity of MetAP2 in a patient. For example, a
contemplated method includes administering a disclosed compound in
an amount sufficient to establish inhibition of intracellular
MetAP2 effective to increase thioredoxin production in the patient
and to induce multi organ stimulation of anti-obesity processes in
the subject, for example, by administering a disclosed compound in
an amount insufficient to reduce angiogenesis in the patient.
[0257] In certain embodiments, the invention provides a method of
treating and or ameliorating obesity in a patient by administering
an effective amount of a disclosed compound. Also provided herein
are methods for inducing weight loss in a patient in need thereof.
Contemplated patients include not only humans, but other animals
such as companion animals (e.g., dogs, cats).
[0258] Other contemplated methods of treatment include method of
treating or ameliorating an obesity-related condition or
co-morbidity, by administering a compound disclosed herein to a
subject. For example, contemplated herein are methods for treating
type 2 diabetes in a patient in need thereof.
[0259] Exemplary co-morbidities include cardiac disorders,
endocrine disorders, respiratory disorders, hepatic disorders,
skeletal disorders, psychiatric disorders, metabolic disorders, and
reproductive disorders.
[0260] Exemplary cardiac disorders include hypertension,
dyslipidemia, ischemic heart disease, cardiomyopathy, cardiac
infarction, stroke, venous thromboembolic disease and pulmonary
hypertension. Exemplary endocrine disorders include type 2 diabetes
and latent autoimmune diabetes in adults. Exemplary respiratory
disorders include obesity-hyperventilation syndrome, asthma, and
obstructive sleep apnea. An exemplary hepatic disorder is
nonalcoholic fatty liver disease. Exemplary skeletal disorders
include back pain and osteoarthritis of weight-bearing joints.
Exemplary metabolic disorders include Prader-Willi Syndrome and
polycystic ovary syndrome. Exemplary reproductive disorders include
sexual dysfunction, erectile dysfunction, infertility, obstetric
complications, and fetal abnormalities. Exemplary psychiatric
disorders include weight-associated depression and anxiety.
[0261] In particular, in certain embodiments, the invention
provides a method of treating the above medical indications
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound described herein,
such as a compound of Formula I, Ia, Ib, Ic, II, IIa, Ib, IIc, IId,
IIe, III, IV and V.
[0262] Obesity or reference to "overweight" refers to an excess of
fat in proportion to lean body mass. Excess fat accumulation is
associated with increase in size (hypertrophy) as well as number
(hyperplasia) of adipose tissue cells. Obesity is variously
measured in terms of absolute weight, weight:height ratio,
distribution of subcutaneous fat, and societal and esthetic norms.
A common measure of body fat is Body Mass Index (BMI). The BMI
refers to the ratio of body weight (expressed in kilograms) to the
square of height (expressed in meters). Body mass index may be
accurately calculated using either of the formulas:
weight(kg)/height.sup.2(m.sup.2) (SI) or
703.times.weight(lb)/height.sup.2(in.sup.2) (US).
[0263] In accordance with the U.S. Centers for Disease Control and
Prevention (CDC), an overweight adult has a BMI of 25 kg/m.sup.2 to
29.9 kg/m, and an obese adult has a BMI of 30 kg/m.sup.2 or
greater. A BMI of 40 kg/m.sup.2 or greater is indicative of morbid
obesity or extreme obesity. Obesity can also refer to patients with
a waist circumference of about 102 cm for males and about 88 cm for
females. For children, the definitions of overweight and obese take
into account age and gender effects on body fat. Patients with
differing genetic background may be considered "obese" at a level
differing from the general guidelines, above.
[0264] The compounds of the present invention also are useful for
reducing the risk of secondary outcomes of obesity, such as
reducing the risk of left ventricular hypertrophy. Methods for
treating patients at risk of obesity, such as those patients who
are overweight, but not obese, e.g. with a BMI of between about 25
and 30 kg/m.sup.2, are also contemplated. In certain embodiments, a
patient is a human.
[0265] BMI does not account for the fact that excess adipose can
occur selectively in different parts of the body, and development
of adipose tissue can be more dangerous to health in some parts of
the body rather than in other parts of the body. For example,
"central obesity", typically associated with an "apple-shaped"
body, results from excess adiposity especially in the abdominal
region, including belly fat and visceral fat, and carries higher
risk of co-morbidity than "peripheral obesity", which is typically
associated with a "pear-shaped" body resulting from excess
adiposity especially on the hips. Measurement of waist/hip
circumference ratio (WHR) can be used as an indicator of central
obesity. A minimum WHR indicative of central obesity has been
variously set, and a centrally obese adult typically has a WHR of
about 0.85 or greater if female and about 0.9 or greater if
male.
[0266] Methods of determining whether a subject is overweight or
obese that account for the ratio of excess adipose tissue to lean
body mass involve obtaining a body composition of the subject. Body
composition can be obtained by measuring the thickness of
subcutaneous fat in multiple places on the body, such as the
abdominal area, the subscapular region, arms, buttocks and thighs.
These measurements are then used to estimate total body fat with a
margin of error of approximately four percentage points. Another
method is bioelectrical impedance analysis (BIA), which uses the
resistance of electrical flow through the body to estimate body
fat. Another method is using a large tank of water to measure body
buoyancy. Increased body fat will result in greater buoyancy, while
greater muscle mass will result in a tendency to sink.
[0267] In another aspect, the invention provides methods for
treating an overweight or obese subject involving determining a
level of at least one biomarker related to being overweight or
obese in the subject, and administering an effective amount of a
disclosed compound to achieve a target level in the subject.
Exemplary biomarkers include body weight, Body Mass Index (BMI),
Waist/Hip ratio WHR, plasma adipokines, and a combination of two or
more thereof.
[0268] In certain embodiments, the compound utilized by one or more
of the foregoing methods is one of the generic, subgeneric, or
specific compounds described herein, such as a compound of Formula
I, Ia, Ib, Ic, II, IIa, IIb, IIc, IId, IIe, III, IV and V.
[0269] The compounds of the invention may be administered to
patients (animals and humans) in need of such treatment in dosages
that will provide optimal pharmaceutical efficacy. It will be
appreciated that the dose required for use in any particular
application will vary from patient to patient, not only with the
particular compound or composition selected, but also with the
route of administration, the nature of the condition being treated,
the age and condition of the patient, concurrent medication or
special diets then being followed by the patient, and other factors
which those skilled in the art will recognize, with the appropriate
dosage ultimately being at the discretion of the attendant
physician. For treating clinical conditions and diseases noted
above, a compound of this invention may be administered orally,
subcutaneously, topically, parenterally, by inhalation spray or
rectally in dosage unit formulations containing conventional
non-toxic pharmaceutically acceptable carriers, adjuvants and
vehicles. Parenteral administration may include subcutaneous
injections, intravenous or intramuscular injections or infusion
techniques.
[0270] Treatment can be continued for as long or as short a period
as desired. The compositions may be administered on a regimen of,
for example, one to four or more times per day. A suitable
treatment period can be, for example, at least about one week, at
least about two weeks, at least about one month, at least about six
months, at least about 1 year, or indefinitely. A treatment period
can terminate when a desired result, for example a weight loss
target, is achieved. A treatment regimen can include a corrective
phase, during which dose sufficient to provide reduction of weight
is administered, and can be followed by a maintenance phase, during
which a e.g. a lower dose sufficient to prevent weight gain is
administered. A suitable maintenance dose is likely to be found in
the lower parts of the dose ranges provided herein, but corrective
and maintenance doses can readily be established for individual
subjects by those of skill in the art without undue
experimentation, based on the disclosure herein. Maintenance doses
can be employed to maintain body weight in subjects whose body
weight has been previously controlled by other means, including
diet and exercise, bariatric procedures such as bypass or banding
surgeries, or treatments employing other pharmacological
agents.
III. Pharmaceutical Compositions and Kits
[0271] Another aspect of the invention provides pharmaceutical
compositions comprising compounds as disclosed herein formulated
together with a pharmaceutically acceptable carrier. In particular,
the present disclosure provides pharmaceutical compositions
comprising compounds as disclosed herein formulated together with
one or more pharmaceutically acceptable carriers. These
formulations include those suitable for oral, rectal, topical,
buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal,
or intravenous) rectal, vaginal, or aerosol administration,
although the most suitable form of administration in any given case
will depend on the degree and severity of the condition being
treated and on the nature of the particular compound being used.
For example, disclosed compositions may be formulated as a unit
dose, and/or may be formulated for oral or subcutaneous
administration.
[0272] Exemplary pharmaceutical compositions of this invention may
be used in the form of a pharmaceutical preparation, for example,
in solid, semisolid or liquid form, which contains one or more of
the compound of the invention, as an active ingredient, in
admixture with an organic or inorganic carrier or excipient
suitable for external, enteral or parenteral applications. The
active ingredient may be compounded, for example, with the usual
non-toxic, pharmaceutically acceptable carriers for tablets,
pellets, capsules, suppositories, solutions, emulsions,
suspensions, and any other form suitable for use. The active object
compound is included in the pharmaceutical composition in an amount
sufficient to produce the desired effect upon the process or
condition of the disease.
[0273] For preparing solid compositions such as tablets, the
principal active ingredient may be mixed with a pharmaceutical
carrier, e.g., conventional tableting ingredients such as corn
starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium
stearate, dicalcium phosphate or gums, and other pharmaceutical
diluents, e.g., water, to form a solid preformulation composition
containing a homogeneous mixture of a compound of the invention, or
a non-toxic pharmaceutically acceptable salt thereof. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredient is dispersed evenly throughout
the composition so that the composition may be readily subdivided
into equally effective unit dosage forms such as tablets, pills and
capsules.
[0274] In solid dosage forms for oral administration (capsules,
tablets, pills, dragees, powders, granules and the like), the
subject composition is mixed with one or more pharmaceutically
acceptable carriers, such as sodium citrate or dicalcium phosphate,
and/or any of the following: (1) fillers or extenders, such as
starches, lactose, sucrose, glucose, mannitol, and/or silicic acid;
(2) binders, such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia;
(3) humectants, such as glycerol; (4) disintegrating agents, such
as agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain silicates, and sodium carbonate; (5) solution
retarding agents, such as paraffin; (6) absorption accelerators,
such as quaternary ammonium compounds; (7) wetting agents, such as,
for example, acetyl alcohol and glycerol monostearate; (8)
absorbents, such as kaolin and bentonite clay; (9) lubricants, such
a talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate, and mixtures thereof; and (10)
coloring agents. In the case of capsules, tablets and pills, the
compositions may also comprise buffering agents. Solid compositions
of a similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or
milk sugars, as well as high molecular weight polyethylene glycols
and the like.
[0275] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the subject composition moistened with an inert liquid
diluent. Tablets, and other solid dosage forms, such as dragees,
capsules, pills and granules, may optionally be scored or prepared
with coatings and shells, such as enteric coatings and other
coatings well known in the pharmaceutical-formulating art.
[0276] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. Liquid
dosage forms for oral administration include pharmaceutically
acceptable emulsions, microemulsions, solutions, suspensions,
syrups and elixirs. In addition to the subject composition, the
liquid dosage forms may contain inert diluents commonly used in the
art, such as, for example, water or other solvents, solubilizing
agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, cyclodextrins and mixtures thereof.
[0277] Suspensions, in addition to the subject composition, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0278] Formulations for rectal or vaginal administration may be
presented as a suppository, which may be prepared by mixing a
subject composition with one or more suitable non-irritating
excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a suppository wax or a salicylate, and which
is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the body cavity and release the active
agent.
[0279] Dosage forms for transdermal administration of a subject
composition include powders, sprays, ointments, pastes, creams,
lotions, gels, solutions, patches and inhalants. The active
component may be mixed under sterile conditions with a
pharmaceutically acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
[0280] The ointments, pastes, creams and gels may contain, in
addition to a subject composition, excipients, such as animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0281] Powders and sprays may contain, in addition to a subject
composition, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays may additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0282] Compositions and compounds of the present invention may
alternatively be administered by aerosol. This is accomplished by
preparing an aqueous aerosol, liposomal preparation or solid
particles containing the compound. A non-aqueous (e.g.,
fluorocarbon propellant) suspension could be used. Sonic nebulizers
may be used because they minimize exposing the agent to shear,
which may result in degradation of the compounds contained in the
subject compositions. Ordinarily, an aqueous aerosol is made by
formulating an aqueous solution or suspension of a subject
composition together with conventional pharmaceutically acceptable
carriers and stabilizers. The carriers and stabilizers vary with
the requirements of the particular subject composition, but
typically include non-ionic surfactants (Tweens, Pluronics, or
polyethylene glycol), innocuous proteins like serum albumin,
sorbitan esters, oleic acid, lecithin, amino acids such as glycine,
buffers, salts, sugars or sugar alcohols. Aerosols generally are
prepared from isotonic solutions.
[0283] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise a subject composition in
combination with one or more pharmaceutically-acceptable sterile
isotonic aqueous or non-aqueous solutions, dispersions, suspensions
or emulsions, or sterile powders which may be reconstituted into
sterile injectable solutions or dispersions just prior to use,
which may contain antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0284] Examples of suitable aqueous and non-aqueous carriers which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate and cyclodextrins. Proper fluidity may
be maintained, for example, by the use of coating materials, such
as lecithin, by the maintenance of the required particle size in
the case of dispersions, and by the use of surfactants
[0285] In another aspect, the invention provides enteral
pharmaceutical formulations including a disclosed compound and an
enteric material; and a pharmaceutically acceptable carrier or
excipient thereof. Enteric materials refer to polymers that are
substantially insoluble in the acidic environment of the stomach,
and that are predominantly soluble in intestinal fluids at specific
pHs. The small intestine is the part of the gastrointestinal tract
(gut) between the stomach and the large intestine, and includes the
duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5,
the pH of the jejunum is about 6.5 and the pH of the distal ileum
is about 7.5. Accordingly, enteric materials are not soluble, for
example, until a pH of about 5.0, of about 5.2, of about 5.4, of
about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4,
of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about
7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of
about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2,
of about 9.4, of about 9.6, of about 9.8, or of about 10.0.
Exemplary enteric materials include cellulose acetate phthalate
(CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl
acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate
succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl
methylcellulose succinate, cellulose acetate succinate, cellulose
acetate hexahydrophthalate, cellulose propionate phthalate,
cellulose acetate maleate, cellulose acetate butyrate, cellulose
acetate propionate, copolymer of methylmethacrylic acid and methyl
methacrylate, copolymer of methyl acrylate, methylmethacrylate and
methacrylic acid, copolymer of methylvinyl ether and maleic
anhydride (Gantrez ES series), ethyl
methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl
acrylate copolymer, natural resins such as zein, shellac and copal
collophorium, and several commercially available enteric dispersion
systems (e. g., Eudragit L30D55, Eudragit FS30D, Eudragit L100,
Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and
Aquateric). The solubility of each of the above materials is either
known or is readily determinable in vitro. The foregoing is a list
of possible materials, but one of skill in the art with the benefit
of the disclosure would recognize that it is not comprehensive and
that there are other enteric materials that would meet the
objectives of the present invention.
[0286] Advantageously, the invention also provides kits for use by
a e.g. a consumer in need of weight loss. Such kits include a
suitable dosage form such as those described above and instructions
describing the method of using such dosage form to mediate, reduce
or prevent inflammation. The instructions would direct the consumer
or medical personnel to administer the dosage form according to
administration modes known to those skilled in the art. Such kits
could advantageously be packaged and sold in single or multiple kit
units. An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a preferably transparent plastic material. During the packaging
process recesses are formed in the plastic foil. The recesses have
the size and shape of the tablets or capsules to be packed. Next,
the tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic foil and the sheet.
Preferably the strength of the sheet is such that the tablets or
capsules can be removed from the blister pack by manually applying
pressure on the recesses whereby an opening is formed in the sheet
at the place of the recess. The tablet or capsule can then be
removed via said opening.
[0287] It may be desirable to provide a memory aid on the kit,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen which
the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on the card,
e.g. as follows "First Week, Monday, Tuesday, . . . etc. . . .
Second Week, Monday, Tuesday, . . . " etc. Other variations of
memory aids will be readily apparent. A "daily dose" can be a
single tablet or capsule or several pills or capsules to be taken
on a given day. Also, a daily dose of a first compound can consist
of one tablet or capsule while a daily dose of the second compound
can consist of several tablets or capsules and vice versa. The
memory aid should reflect this.
[0288] Also contemplated herein are methods and compositions that
include a second active agent, or administering a second active
agent. For example, in addition to being overweight or obese, a
subject or patient can further have overweight- or obesity-related
co-morbidities, i.e., diseases and other adverse health conditions
associated with, exacerbated by, or precipitated by being
overweight or obese. Contemplated herein are disclosed compounds in
combination with at least one other agent that has previously been
shown to treat these overweight- or obesity-related conditions.
[0289] For example, Type II diabetes has been associated with
obesity. Certain complications of Type II diabetes, e.g.,
disability and premature death, can be prevented, ameliorated, or
eliminated by sustained weight loss (Astrup, A. Pub Health Nutr
(2001) 4:499-5 15). Agents administered to treat Type II diabetes
include sulfonylureas (e.g., Chlorpropamide, Glipizide, Glyburide,
Glimepiride); meglitinides (e.g., Repaglinide and Nateglinide);
biguanides (e.g., Metformin); thiazolidinediones (Rosiglitazone,
Troglitazone, and Pioglitazone); dipeptidylpeptidase-4 inhibitors
(e.g., Sitagliptin, Vildagliptin, and Saxagliptin); glucagon-like
peptide-1 mimetics (e.g., Exenatide and Liraglutide); and
alpha-glucosidase inhibitors (e.g., Acarbose and Miglitol.
[0290] Cardiac disorders and conditions, for example hypertension,
dyslipidemia, ischemic heart disease, cardiomyopathy, cardiac
infarction, stroke, venous thromboembolic disease and pulmonary
hypertension, have been linked to overweight or obesity. For
example, hypertension has been linked to obesity because excess
adipose tissue secretes substances that are acted on by the
kidneys, resulting in hypertension. Additionally, with obesity
there are generally higher amounts of insulin produced (because of
the excess adipose tissue) and this excess insulin also elevates
blood pressure. A major treatment option of hypertension is weight
loss. Agents administered to treat hypertension include
Chlorthalidone; Hydrochlorothiazide; Indapamide, Metolazone; loop
diuretics (e.g., Bumetanide, Ethacrynic acid, Furosemide, Lasix,
Torsemide); potassium-sparing agents (e.g., Amiloride
hydrochloride, benzamil, Spironolactone, and Triamterene);
peripheral agents (e.g., Reserpine); central alpha-agonists (e.g.,
Clonidine hydrochloride, Guanabenz acetate, Guanfacine
hydrochloride, and Methyldopa); alpha-blockers (e.g., Doxazosin
mesylate, Prazosin hydrochloride, and Terazosin hydrochloride);
beta-blockers (e.g., Acebutolol, Atenolol, Betaxolol, Bisoprolol
fumarate, Carteolol hydrochloride, Metoprolol tartrate, Metoprolol
succinate, Nadolol, Penbutolol sulfate, Pindolol, Propranolol
hydrochloride, and Timolol maleate); combined alpha- and
beta-blockers (e.g., Carvedilol and Labetalol hydrochloride);
direct vasodilators (e.g., Hydralazine hydrochloride and
Minoxidil); calcium antagonists (e.g., Diltiazem hydrochloride and
Verapamil hydrochloride); dihydropyridines (e.g., Amlodipine
besylate, Felodipine, Isradipine, Nicardipine, Nifedipine, and
Nisoldipine); ACE inhibitors (benazepril hydrochloride, Captopril,
Enalapril maleate, Fosinopril sodium. Lisinopril, Moexipril,
Quinapril hydrochloride, Ramipril, Trandolapril); Angiotensin II
receptor blockers (e.g., Losartan potassium, Valsartan, and
Irbesartan); Renin inhibitors (e.g., Aliskiren); and combinations
thereof. These compounds are administered in regimens and at
dosages known in the art.
[0291] Carr et al. (The Journal of Clinical Endocrinology &
Metabolism (2004) Vol. 89, No. 6 2601-2607) discusses a link
between being overweight or obese and dyslipidemia. Dyslipidemia is
typically treated with statins. Statins, HMG-CoA reductase
inhibitors, slow down production of cholesterol in a subject and/or
remove cholesterol buildup from arteries. Statins include
mevastatin, lovastatin, pravastatin, simvastatin, velostatin,
dihydrocompactin, fluvastatin, atorvastatin, dalvastatin,
carvastatin, crilvastatin, bevastatin, cefvastatin, rosuvastatin,
pitavastatin, and glenvastatin. These compounds are administered in
regimens and at dosages known in the art. Eckel (Circulation (1997)
96:3248-3250) discusses a link between being overweight or obese
and ischemic heart disease. Agents administered to treat ischemic
heart disease include statins, nitrates (e.g., Isosorbide Dinitrate
and Isosorbide Mononitrate), beta-blockers, and calcium channel
antagonists. These compounds are administered in regimens and at
dosages known in the art.
[0292] Wong et al. (Nature Clinical Practice Cardiovascular
Medicine (2007) 4:436-443) discusses a link between being
overweight or obese and cardiomyopathy. Agents administered to
treat cardiomyopathy include inotropic agents (e.g., Digoxin),
diuretics (e.g., Furosemide), ACE inhibitors, calcium antagonists,
anti-arrhythmic agents (e.g., Sotolol, Amiodarone and
Disopyramide), and beta-blockers. These compounds are administered
in regimens and at dosages known in the art. Yusef et al. (Lancet
(2005) 366(9497): 1640-1649) discusses a link between being
overweight or obese and cardiac infarction. Agents administered to
treat cardiac infarction include ACE inhibitors, Angiotensin II
receptor blockers, direct vasodilators, beta blockers,
anti-arrhythmic agents and thrombolytic agents (e.g., Alteplase,
Retaplase, Tenecteplase, Anistreplase, and Urokinase). These
compounds are administered in regimens and at dosages known in the
art.
[0293] Suk et al. (Stroke (2003) 34:1586-1592) discusses a link
between being overweight or obese and strokes. Agents administered
to treat strokes include anti-platelet agents (e.g., Aspirin,
Clopidogrel, Dipyridamole, and Ticlopidine), anticoagulant agents
(e.g., Heparin), and thrombolytic agents. Stein et al. (The
American Journal of Medicine (2005) 18(9):978-980) discusses a link
between being overweight or obese and venous thromboembolic
disease. Agents administered to treat venous thromboembolic disease
include anti-platelet agents, anticoagulant agents, and
thrombolytic agents. Sztrymf et al. (Rev Pneumol Clin (2002) 58(2):
104-10) discusses a link between being overweight or obese and
pulmonary hypertension. Agents administered to treat pulmonary
hypertension include inotropic agents, anticoagulant agents,
diuretics, potassium (e.g., K-dur), vasodilators (e.g., Nifedipine
and Diltiazem), Bosentan, Epoprostenol, and Sildenafil. Respiratory
disorders and conditions such as obesity-hypoventilation syndrome,
asthma, and obstructive sleep apnea, have been linked to being
overweight or obese. Elamin (Chest (2004) 125:1972-1974) discusses
a link between being overweight or obese and asthma. Agents
administered to treat asthma include bronchodilators,
anti-inflammatory agents, leukotriene blockers, and anti-Ige
agents. Particular asthma agents include Zafirlukast, Flunisolide,
Triamcinolone, Beclomethasone, Terbutaline, Fluticasone,
Formoterol, Beclomethasone, Salmeterol, Theophylline, and
Xopenex.
[0294] Kessler et al. (Eur Respir J (1996) 9:787-794) discusses a
link between being overweight or obese and obstructive sleep apnea.
Agents administered to treat sleep apnea include Modafinil and
amphetamines.
[0295] Hepatic disorders and conditions, such as nonalcoholic fatty
liver disease, have been linked to being overweight or obese.
Tolman et al. (Ther Clin Risk Manag (2007) 6:1153-1163) discusses a
link between being overweight or obese and nonalcoholic fatty liver
disease. Agents administered to treat nonalcoholic fatty liver
disease include antioxidants (e.g., Vitamins E and C), insulin
sensitizers (Metformin, Pioglitazone, Rosiglitazone, and Betaine),
hepatoprotectants, and lipid-lowering agents.
[0296] Skeletal disorders and conditions, such as, back pain and
osteoarthritis of weight-bearing joints, have been linked to being
overweight or obese, van Saase (J Rheumatol (1988) 15(7):
1152-1158) discusses a link between being overweight or obese and
osteoarthritis of weight-bearing joints. Agents administered to
treat osteoarthritis of weight-bearing joints include
Acetaminophen, non-steroidal anti-inflammatory agents (e.g.,
Ibuprofen, Etodolac, Oxaprozin, Naproxen, Diclofenac, and
Nabumetone), COX-2 inhibitors (e.g., Celecoxib), steroids,
supplements (e.g. glucosamine and chondroitin sulfate), and
artificial joint fluid.
[0297] Metabolic disorders and conditions, for example,
Prader-Willi Syndrome and polycystic ovary syndrome, have been
linked to being overweight or obese. Cassidy (Journal of Medical
Genetics (1997) 34:917-923) discusses a link between being
overweight or obese and Prader-Willi Syndrome. Agents administered
to treat Prader-Willi Syndrome include human growth hormone (HGH),
somatropin, and weight loss agents (e.g., Orlistat, Sibutramine,
Methamphetamine, lonamin, Phentermine. Bupropion, Diethylpropion.
Phendimetrazine, Benzphetermine, and Topamax).
[0298] Hoeger (Obstetrics and Gynecology Clinics of North America
(2001) 28(1):85-97) discusses a link between being overweight or
obese and polycystic ovary syndrome. Agents administered to treat
polycystic ovary syndrome include insulin-sensitizers, combinations
of synthetic estrogen and progesterone, Spironolactone,
Eflornithine, and Clomiphene. Reproductive disorders and conditions
such as sexual dysfunction, erectile dysfunction, infertility,
obstetric complications, and fetal abnormalities, have been linked
to being overweight or obese. Larsen et al. (Int J Obes (Lond)
(2007) 8:1189-1198) discusses a link between being overweight or
obese and sexual dysfunction. Chung et al. (Eur Urol (1999)
36(1):68-70) discusses a link between being overweight or obese and
erectile dysfunction. Agents administered to treat erectile
dysfunction include phosphodiesterase inhibitors (e.g., Tadalafil,
Sildenafil citrate, and Vardenafil), prostaglandin E analogs (e.g.,
Alprostadil), alkaloids (e.g., Yohimbine), and testosterone.
Pasquali et al. (Hum Reprod (1997) 1:82-87) discusses a link
between being overweight or obese and infertility. Agents
administered to treat infertility include Clomiphene, Clomiphene
citrate, Bromocriptine, Gonadotropin-releasing Hormone (GnRH), GnRH
agonist, GnRH antagonist, Tamoxifen/nolvadex, gonadotropins, Human
Chorionic Gonadotropin (HCG), Human Menopausal Gonadotropin (HmG),
progesterone, recombinant follicle stimulating hormone (FSH),
Urofollitropin, Heparin, Follitropin alfa, and Follitropin
beta.
[0299] Weiss et al. (American Journal of Obstetrics and Gynecology
(2004) 190(4): 1091-1097) discusses a link between being overweight
or obese and obstetric complications. Agents administered to treat
obstetric complications include Bupivacaine hydrochloride,
Dinoprostone PGE2, Meperidine HCl,
Ferro-folic-500/iberet-folic-500, Meperidine, Methylergonovine
maleate, Ropivacaine HCl, Nalbuphine HCl, Oxymorphone HCl,
Oxytocin, Dinoprostone, Ritodrine, Scopolamine hydrobromide,
Sufentanil citrate, and Oxytocic.
[0300] Psychiatric disorders and conditions, for example,
weight-associated depression and anxiety, have been linked to being
overweight or obese. Dixson et al. (Arch Intem Med (2003)
163:2058-2065) discusses a link between being overweight or obese
and depression. Agents administered to treat depression include
serotonin reuptake inhibitors (e.g., Fluoxetine, Escitalopram,
Citalopram, Paroxetine, Sertraline, and Venlafaxine); tricyclic
antidepressants (e.g., Amitriptyline, Amoxapine, Clomipramine,
Desipramine, Dosulepin hydrochloride, Doxepin, Imipramine,
Iprindole, Lofepramine, Nortriptyline, Opipramol, Protriptyline,
and Trimipramine); monoamine oxidase inhibitors (e.g.,
Isocarboxazid, Moclobemide, Phenelzine, Tranylcypromine.
Selegiline, Rasagiline, Nialamide, Iproniazid, Iproclozide,
Toloxatone, Linezolid, Dienolide kavapyrone desmethoxyyangonin, and
Dextroamphetamine); psychostimulants (e.g., Amphetamine,
Methamphetamine, Methylphenidate, and Arecoline); antipsychotics
(e.g., Butyrophenones, Phenothiazines, Thioxanthenes, Clozapine,
Olanzapine, Risperidone, Quetiapine, Ziprasidone, Amisulpride,
Paliperidone, Symbyax, Tetrabenazine, and Cannabidiol); and mood
stabilizers (e.g., Lithium carbonate, Valproic acid, Divalproex
sodium, Sodium valproate, Lamotrigine, Carbamazepine, Gabapentin,
Oxcarbazepine, and Topiramate).
[0301] Simon et al. (Archives of General Psychiatry (2006)
63(7):824-830) discusses a link between being overweight or obese
and anxiety. Agents administered to treat anxiety include serotonin
reuptake inhibitors, mood stabilizers, benzodiazepines (e.g.,
Alprazolam, Clonazepam, Diazepam, and Lorazepam), tricyclic
antidepressants, monoamine oxidase inhibitors, and
beta-blockers.
[0302] Another aspect of the invention provides methods for
facilitating and maintaining weight loss in a subject involving
administering to the subject an amount of a disclosed compound
effective to result in weight loss in the subject; and
administering a therapeutically effective amount of a different
weight loss agent to maintain a reduced weight in the subject.
Weight loss agents include serotonin and noradrenergic re-uptake
inhibitors; noradrenergic re-uptake inhibitors; selective serotonin
re-uptake inhibitors; and intestinal lipase inhibitors. Particular
weight loss agents include orlistat, sibutramine, methamphetamine,
ionamin, phentermine, bupropion, diethylpropion, phendimetrazine,
benzphetermine, bromocriptine, lorcaserin, topiramate, or agents
acting to modulate food intake by blocking ghrelin action,
inhibiting diacylglycerol acyltransferase 1 (DGAT1) activity,
inhibiting stearoyl CoA desaturase 1 (SCD1) activity, inhibiting
neuropeptide Y receptor 1 function, activating neuropeptide Y
receptor 2 or 4 function, or inhibiting activity of sodium-glucose
cotransporters 1 or 2. These compounds are administered in regimens
and at dosages known in the art.
EXAMPLES
[0303] The compounds described herein can be prepared in a number
of ways based on the teachings contained herein and synthetic
procedures known in the art. In the description of the synthetic
methods described below, it is to be understood that all proposed
reaction conditions, including choice of solvent, reaction
atmosphere, reaction temperature, duration of the experiment and
workup procedures, can be chosen to be the conditions standard for
that reaction, unless otherwise indicated. It is understood by one
skilled in the art of organic synthesis that the functionality
present on various portions of the molecule should be compatible
with the reagents and reactions proposed. Substituents not
compatible with the reaction conditions will be apparent to one
skilled in the art, and alternate methods are therefore indicated.
The starting materials for the examples are either commercially
available or are readily prepared by standard methods from known
materials.
[0304] At least some of the compounds identified as "Intermediates"
herein are contemplated as compounds of the invention.
[0305] .sup.1H NMR spectra were recorded at ambient temperature
using a Varian Unity Inova (400 MHz) spectrometer with a triple
resonance 5 mm probe for Example compounds, and either a Bruker
Avance DRX (400 MHz) spectrometer or a Bruker Avance DPX (300 MHz)
spectrometer for Intermediate compounds. Chemical shifts are
expressed in ppm relative to tetramethylsilane. The following
abbreviations have been used: br=broad signal, s=singlet,
d=doublet, dd=double doublet, dt=double triplet, ddd=double double
doublet, t=triplet, td=triple doublet, tdd=triple double doublet,
q=quartet, m=multiplet.
[0306] Mass Spectrometry (LCMS) experiments to determine retention
times and associated mass ions were performed using the following
methods:
[0307] Method A: Experiments were performed on a Waters ZMD single
quadrapole mass spectrometer linked to a Hewlett Packard HPI 100 LC
system with a diode array detector. The spectrometer has an
electrospray source operating in positive and negative ion mode. LC
was carried out using a Luna 3 micron 30.times.4.6 mm C18 column
and a 2 mL/minute flow rate. The initial solvent system was 95%
water containing 0.1% formic acid (solvent A) and 5% acetonitrile
containing 0.1% formic acid (solvent B) for the first 0.5 minute
followed by a gradient up to 5% solvent A and 95% solvent B over
the next 4 minutes. The final solvent system was held constant for
a further 1 minute.
[0308] Method B: Experiments were performed on a Waters platform LC
quadrupole mass spectrometer linked to a Hewlett Packard HP1100 LC
system with a diode array detector. The spectrometer has an
electrospray source operating in positive and negative ion mode.
Additional detection was achieved using a Sedex 85 evaporative
light scattering device. LC was carried out using a Luna 3 micron
30.times.4.6 mm C18 column and a 2 mL/minute flow rate. The initial
solvent system was 95% water containing 0.1% formic acid (solvent
A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for
the first 0.5 minute followed by a gradient up to 5% solvent A and
95% solvent B over the next 4 minutes. The final solvent system was
held constant for a further 1 minute.
[0309] Method C: Experiments were performed on a Waters Micromass
ZQ2000 quadrapole mass spectrometer linked to a Waters Acquity UPLC
system with a PDA UV detector. The spectrometer has an electrospray
source operating in positive and negative ion mode. LC was carried
out using an Acquity BEH 1.7 micron C18 column, an Acquity BEH
Shield 1.7 micron RP18 column or an Acquity HSST 1.8 micron column.
Each column has dimensions of 100.times.2.1 mm and was maintained
at 40.degree. C. with a flow rate of 0.4 mL/minute. The initial
solvent system was 95% water containing 0.1% formic acid (solvent
A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for
the first 0.4 minute followed by a gradient up to 5% solvent A and
95% solvent B over the next 6 minutes. The final solvent system was
held constant for a further 0.8 minutes.
[0310] Microwave experiments were carried out using a Biotage
Initiator.TM., which uses a single-mode resonator and dynamic field
tuning. Temperatures from 40-250.degree. C. can be achieved, and
pressures of up to 20 bars can be reached. A facility exists to
apply air cooling during the irradiation.
[0311] H-Cube.RTM. is a continuous flow hydrogenation reactor from
ThalesNano which allows temperatures up to 100.degree. C. and
pressures up to 100 bars. Various catalysts, housed in packed
cartridges may be used and the product may be collected in
fractions.
[0312] Preparative HPLC purification was carried out using either a
C18-reverse-phase column from Genesis (C18) or a C6-phenyl column
from Phenomenex (C6-phenyl) (100.times.22.5 mm i.d. with 7 micron
particle size, UV detection at 230 or 254 nm, flow 5-15 mL/min),
eluting with gradients from 100-0 to 0-100% water/acetonitrile or
water/methanol containing 0.1% formic acid. Fractions containing
the required product (identified by LCMS analysis) were pooled, the
organic fraction was removed by evaporation, and the remaining
aqueous fraction was lyophilised, to give the product.
[0313] Compounds which required column chromatography were purified
manually or fully automatically using either a Biotage SP1.TM.
Flash Purification system with Touch Logic Control.TM. or a
Combiflash Companion, with pre-packed silica gel Isolute.RTM. SPE
cartridge, Biotage SNAP cartridge or Redisep.RTM. Rf cartridge
respectively.
[0314] Compounds have been named using Autonom2000 within
ISISDraw.
ABBREVIATIONS
DCM Dichloromethane
DMF N,N-Dimethylformamide
[0315] DMAP 4-dimethylaminopyridine
THF Tetrahydrofuran
DMSO Dimethylsulfoxide
[0316] TFA Trifluoroacetic acid
Example 1
8-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-pyrazol-
o[5,1-a]isoquinoline-7-carboxylic acid
##STR00012##
[0318] A mixture of methyl
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-pyrazo-
lo[5,1-a]isoquinoline-7-carboxylate (Intermediate 1, 0.075 g) and
lithium hydroxide (3M aqueous solution, 2 mL) in dioxane (6 mL) was
heated to 80.degree. C. for 6 hours. The resultant mixture was
cooled and concentrated in vacuo. The residue was acidified using
formic acid and then concentrated in vacuo. The residue was
partitioned between ethyl acetate and water and the organic layer
was dried (MgSO.sub.4) and filtered. The filtrate was concentrated
in vacuo and the residue was triturated with methanol. The mixture
was centrifuged and the supernatant was decanted twice. The
resultant solid was dried in vacuo overnight to give
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-p-
yrazolo[5,1-a]isoquinoline-7-carboxylic acid (0.044 g) as a
solid.
[0319] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.38 (1H, d), 8.26 (1H,
br, m), 8.17 (1H, d), 7.95 (1H, d), 7.83 (1H, br, m), 7.67 (1H, br,
d), 7.43 (1H, br, d), 7.30-7.19 (2H, m), 7.10 (1H, br, s), 6.11
(1H, br, m), 3.84 (2H, br, m), 3.10 (4H, br, m), 1.07 (6H, br,
t).
[0320] LCMS (Method C) r/t 3.48 (M+H) 497
Example 2
7-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-benz-
o[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylic acid
##STR00013##
[0322] A suspension of methyl
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-ben-
zo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 15,
0.074 g) and lithium hydroxide monohydrate (0.060 g) in dioxane (2
mL) and water (0.5 mL) was irradiated in the microwave at
130.degree. C. for 45 minutes. After cooling, the mixture was
acidified to pH3 with formic acid, diluted with ethanol and toluene
and concentrated in vacuo. The residue was triturated with a
solution of methanol in DCM (10%) and the solid was filtered off
and washed with DCM. The filtrate was concentrated in vacuo and the
residue was purified by chromatography on silica, eluting with a
mixture of methanol and DCM with a gradient of 0-6%. The resultant
solid was triturated with a mixture of ethyl acetate and ether and
the solid obtained was dried in vacuo at 60.degree. C. overnight to
give
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4-
H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylic acid (0.012 g) as
a white solid.
[0323] .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.64 (1H, m), 7.53 (1H,
d), 7.38 (2H, m), 7.24 (2H, m), 7.10 (1H, d), 6.24 (1H, t), 6.16
(1H, m), 6.00 (1H, d), 5.02 (2H, s), 3.80 (2H, br. d), 3.14 (4H,
br, d), 1.14 (6H, t).
[0324] LCMS (Method C) r/t 3.54 (M+H) 500
Example 3
8-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-dih-
ydropyrazolo[5,1-a]isoquinoline-7-carboxylic acid
##STR00014##
[0326] A mixture of methyl
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-di-
hydropyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 20,
0.057 g) and lithium hydroxide monohydrate (0.090 g) in dioxane (4
mL) and water (1 mL) was heated to 80.degree. C. for 32 hours. The
resultant mixture was concentrated in vacuo and the residue was
acidified with aqueous citric acid solution (10%) and extracted
into DCM, dried (MgSO.sub.4) and filtered. The filtrate was
concentrated in vacuo and the residue was purified by
chromatography on silica, eluting with a mixture of methanol and
DCM with a gradient of 0-15% to give
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-di-
hydropyrazolo[5,1-a]isoquinoline-7-carboxylic acid (0.020 g) as a
white solid.
[0327] .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.73 (1H, br, s), 7.53
(1H, br, d), 7.43-7.34 (3H, m), 7.29-7.19 (2H, m), 6.59 (1H, s),
6.14 (1H, br, s), 4.10 (2H, t), 3.82 (2H, br, s), 3.16 (2H, d),
3.13 (4H, br, s), 1.10 (6H, br, s).
[0328] LCMS (Method C) r/t 3.33 (M+H) 499
Example 4
7-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-5-ox-
a-3,9b-diazacyclopenta[a]naphthalene-6-carboxylic acid
##STR00015##
[0330] A mixture of methyl
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-5-o-
xa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate (Intermediate
24, 0.138 g) and lithium hydroxide monohydrate (0.421 g) in dioxane
(8 mL) and water (2 mL) was irradiated in the microwave at
135.degree. C. for 45 minutes. After cooling, the mixture was
diluted with methanol, acidified with formic acid and concentrated
in vacuo. The residue was triturated with a solution of methanol in
DCM (15%) and the solid was removed by filtration. The filtrate was
concentrated in vacuo and the residue was purified by
chromatography on silica, eluting with a mixture of methanol and
DCM with a gradient of 0-30%. The resultant gum was triturated with
ethyl acetate and the solid was collected by filtration to give
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-5-o-
xa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylic acid (0.09 g) as
a white solid.
[0331] .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.80 (1H, d), 7.70 (1H,
m), 7.53 (1H, d), 7.37 (1H, d), 7.28-7.20 (2H, m), 7.12 (1H, d),
7.07 (1H, d), 6.13 (1H, m), 5.14 (2H, s), 3.78 (2H, br, s), 3.10
(4H, br, s), 1.11 (6H, t).
[0332] LCMS (Method C) r/t 2.52 (M+H) 501
Intermediate 1
Methyl
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]--
pyrazolo[5,1-a]isoquinoline-7-carboxylate
##STR00016##
[0334] A mixture of methyl
8-(2-bromo-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinoline-7-ca-
rboxylate (Intermediate 2, 0.103 g),
tris-(dibenzylideneacetone)-dipalladium (0) (0.025 g),
tri-tert-butylphosphonium tetrafluoroborate (0.0127 g) and
N,N-diethyl-N--((Z)-1-tributylstannanylprop-1-en-3-yl)-amine
(Intermediate 3, 0.265 g) in dioxane (3 mL) was irradiated in the
microwave at 80.degree. C. for 2 hours. After cooling, the mixture
was diluted with ethyl acetate and filtered through Celite. The
filtrate was concentrated in vacuo and the residue was purified by
chromatography on silica, eluting with a mixture of methanol and
DCM with a gradient of 0-20%6 to give methyl
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-pyrazo-
lo[5,1-a]isoquinoline-7-carboxylate (0.030 g).
[0335] .sup.1H NMR (CDCl.sub.3) .delta.: 8.26 (1H, d), 8.17 (1H,
dd), 8.06 (1H, d), 7.96 (1H, s), 7.63 (1H, d), 7.40 (1H, d),
7.15-7.00 (3H, m), 6.89 (1H, s), 6.07 (1H, m), 4.05 (3H, s), 3.02
(2H, d), 2.44 (4H, q), 0.85 (6H, t).
Intermediate 2
Methyl
8-(2-bromo-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinolin-
e-7-carboxylate
##STR00017##
[0337] A mixture of methyl
8-aminopyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 6,
0.140 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.190 g) in
pyridine (4 mL) and DCM (3 mL) was stirred at room temperature
overnight. The resultant mixture was concentrated in vacuo and the
residue was purified by chromatography on silica, eluting with a
mixture of ethyl acetate and cyclohexane with a gradient of 0-60%.
The resultant glass was triturated with ether to give methyl
8-(2-bromo-4-fluorobenzenesulfonylamino]-pyrazolo[5,1-a]isoquinoline-7-ca-
rboxylate (0.103 g) as an off-white solid.
[0338] .sup.1H NMR (CDCl.sub.3) .delta.: 9.89 (1H, br, s),
8.30-8.20 (2H, m), 8.11 (1H, d), 7.97 (1H, s), 7.83 (1H, d), 7.43
(2H, m), 7.15 (1H, m), 6.93 (1H, s), 4.11 (3H, s).
Intermediate 3
N,N-Diethyl-N--((Z)-1-tributylstannanylprop-1-en-3-yl)-amine
##STR00018##
[0340] Diethylamine (19 mL) was added to a solution of
((Z)-3-bromoprop-1-enyl)-tributyl-stannane (Intermediate 4, 7.52 g)
in THF (60 mL) and the mixture was stirred for 3 hours. The
reaction mixture was evaporated to dryness and the residue was
purified by chromatography on a silica column which had been
pre-washed with 20% triethylamine in acetonitrile. The column was
eluted with a mixture of ethyl acetate and pentane with a gradient
of 0-10% to give
N,N-diethyl-N--((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (4.75
g) as an orange oil.
[0341] .sup.1H NMR (CDCl.sub.3) .delta.: 6.59 (1H, dt), 5.97 (1H,
dt), 3.08 (2H, dd), 2.53 (4H, q), 1.49 (6H, m), 1.37-1.24 (6H, m),
1.04 (6H, t), 0.92-0.89 (15H, m).
Intermediate 4
((Z)-3-Bromoprop-1-enyl)-tributylstannane
##STR00019##
[0343] A solution of triphenylphosphine (5.32 g) in DCM (60 mL) was
added to a solution of (Z)-3-tributylstannanylprop-2-en-1-ol
(Intermediate 5, 6.4 g) and carbon tetrabromide (9.18 g) in DCM (60
mL) and the mixture was stirred for 2.5 hours. The mixture was
evaporated to low volume and pentane was added. The solid was
removed by filtration and the filtrate was evaporated to dryness.
Pentane was added and the solid was again removed by filtration and
the filtrate was evaporated to dryness to give
((Z)-3-bromoprop-1-enyl)-tributylstannane (12.14 g) as an oil.
[0344] .sup.1H NMR (CDCl.sub.3) .delta.: 6.71 (1H, dt), 6.11 (1H,
d), 3.88 (2H, d), 1.52-1.50 (6H, m), 1.37-1.27 (6H, m), 0.99-0.97
(6H, m), 0.90 (9H, t).
Intermediate 5
(Z)-3-Tributylstannanylprop-2-en-1-ol
##STR00020##
[0346] Propargyl alcohol (5 mL) was added to a solution of lithium
aluminium hydride (1M in THF, 43 mL) in THF (70 mL) at -78.degree.
C. The resultant mixture was warmed to room temperature and stirred
for 18 hours. It was re-cooled to -78.degree. and a solution of
tri-n-butyl tin chloride (8.3 mL) in ether (50 mL) was added and
the mixture was stirred for 3 hours whilst gradually warming to
room temperature. The reaction mixture was cooled to -5.degree. C.
and quenched by addition of water and 15% aqueous sodium hydroxide
solution then it was allowed to warm to room temperature. Ethyl
acetate was added and the mixture was stirred for 1 hour. The
mixture was filtered through Celite and the filtrate was evaporated
to dryness. The residue was purified by chromatography on a silica
column which had been pre-washed with 20% triethylamine in
acetonitrile. The column was eluted with a mixture of ethyl acetate
and pentane with a gradient of 0-10% to give
(Z)-3-tributylstannanylprop-2-en-1-ol (5.06 g) as a clear oil.
[0347] .sup.1H NMR (CDCl.sub.3) .delta.: 6.70 (1H, dt), 6.08 (1H,
dt), 4.12 (2H, dd), 1.49 (6H, m), 1.31 (6H, m), 0.98-0.84 (15H,
m).
Intermediate 6
Methyl 8-amino-pyrazolo[5,1-a]isoquinoline-7-carboxylate
##STR00021##
[0349] TFA (3 mL) was added to a solution of methyl
8-[bis-(tert-butoxycarbonyl)amino]-pyrazolo[5,1-a]isoquinoline-7-carboxyl-
ate (Intermediate 7, 0.280 g) in DCM (3 mL) and the reaction
mixture was stirred at room temperature for 2 hours. The mixture
was stirred with saturated aqueous sodium bicarbonate solution for
30 minutes and then the organic layer was separated, dried
(MgSO.sub.4) and filtered. The filtrate was concentrated in vacuo
and the residue was purified by chromatography on silica, eluting
with a mixture of ethyl acetate and cyclohexane with a gradient of
0-100% to give methyl
8-aminopyrazolo[5,1-a]isoquinoline-7-carboxylate (0.140 g) as a
glass.
[0350] .sup.1H NMR (CDCl.sub.3) .delta.: 8.25 (1H, d), 7.96 (1H,
d), 7.91 (1H, d), 7.72 (1H, d), 6.92 (1H, d), 6.78 (1H, d),
5.87-5.4 (2H, br), 4.03 (3H, s).
Intermediate 7
Methyl
8-[bis-(tert-butoxycarbonyl)amino]-pyrazolo[5,1-a]isoquinoline-7-ca-
rboxylate
##STR00022##
[0352] Methanesulfonyl chloride (0.5 mL) was added to a solution of
methyl
8-[bis-(tert-butoxycarbonyl)amino]-6-hydroxy-5,6-dihydro-pyrarolo[5,1-a]i-
soquinoline-7-carboxylate (Intermediate 8, 0.290 g) in
triethylamine (0.7 mL) and DCM (10 mL) and the reaction mixture was
stirred at room temperature for 30 minutes. The resultant mixture
was washed with 1M aqueous hydrochloric acid and the organic layer
was separated, dried (MgSO.sub.4) and filtered. The filtrate was
concentrated in vacuo to give methyl
8-[bis-(tert-butoxycarbonyl)amino]-pyrazolo[5,1-a]isoquinoline-7-c-
arboxylate (0.280 g) as a gum.
[0353] LCMS (Method B) r/t 3.83 (M+H) 442
Intermediate 8
Methyl
8-[bis-(tert-butoxycarbonyl)amino]-6-hydroxy-5,6-dihydro-pyrazolo[5-
,1-a]isoquinoline-7-carboxylate
##STR00023##
[0355] To a cooled solution of methyl
6-[bis-(tert-butoxycarbonyl)amino]-3-(2H-pyrazol-3-yl)-2-vinylbenzoate
(Intermediate 9, 2.4 g) in anhydrous DCM (100 mL) at 0.degree. C.
was added
(S,S)-(+)--N,N'-bis(3,5-di-tert-butylsaliclidene)-1,2-cyclohexanedi-
amino manganese (III) chloride (0.280 g) and N-methylmorpholine
N-oxide (3.2 g). m-Chloroperbenzoic acid (3.8 g) was then added
portionwise and the reaction mixture was stirred at 0.degree. C.
for 20 minutes. The resultant mixture was quenched by the addition
of 2M aqueous sodium carbonate solution and the organic layer was
separated, dried (MgSO.sub.4) and filtered. The filtrate was
concentrated in vacuo and the residue was purified by
chromatography on silica, eluting with a mixture of ethyl acetate
and DCM with a gradient of 0-100%. The resultant material was
repurified by chromatography on silica, eluting with a mixture of
ethyl acetate and DCM with a gradient of 0-100% to give methyl
8-[bis-(tert-butoxycarbonyl)amino]-6-hydroxy-5,6-dihydro-pyrazolo[5,1-a]i-
soquinoline-7-carboxylate (0.290 g).
[0356] .sup.1H NMR (CDCl.sub.3) .delta.: 7.75 (1H, d), 7.59 (1H,
s), 7.27 (1H, d), 6.64 (1H, s), 5.08 (1H, br, s), 4.79 (1H, d),
4.25 (1H, d), 3.96 (3H, s), 3.39 (1H, br, s), 1.39 (18H, s).
Intermediate 9
Methyl 6-1
bis-(tert-butoxycarbonyl)aminol-3-(2H-pyrazol-3-yl)-2-vinvlbenz-
oate
##STR00024##
[0358] A mixture of methyl
6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-
-3-yl]-2-vinylbenzoate (Intermediate 10, 2.6 g) and concentrated
hydrochloric acid (3 drops) in methanol (80 mL) was stirred at room
temperature for 30 minutes. The solution was treated with saturated
aqueous sodium bicarbonate solution and the mixture was
concentrated in vacuo. The residue was partitioned between ethyl
acetate and water and the organic layer was dried (MgSO.sub.4) and
filtered. The filtrate was concentrated in vacuo to give methyl
6-[bis-(tert-butoxycarbonyl)amino]-3-(2H-pyrazol-3-yl)-2-vinylbenzoate
(2.38 g) as a white solid.
[0359] .sup.1H NMR (CDCl.sub.3) .delta.: 7.66 (2H, m), 7.19 (1H,
d), 6.91 (1H, dd), 6.54 (1H, s), 5.43 (2-H, m), 3.81 (3H, s), 1.42
(18H, s).
Intermediate 10
Methyl
6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-p-
yrazol-3-yl]-2-vinylbenzoate
##STR00025##
[0361] A mixture of methyl
6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-
-3-yl]-2-trifluoromethanesulfonyloxybenzoate (Intermediate 11, 4.35
g), vinylboronic acid pinacol ester (1.9 mL),
bis(triphenylphosphine)palladium (II) dichloride (0.255 g) and
cesium carbonate (7.1 g) in dioxane (300 mL) and water (47 mL) was
de-gassed and purged with nitrogen. The mixture was then heated to
80.degree. C. for 4 hours. After cooling, the mixture was diluted
with ether and the organic layer was separated, dried (MgSO.sub.4)
and filtered. The filtrate was concentrated in vacuo and the
residue was purified by chromatography on silica, eluting with a
mixture of ethyl acetate and cyclohexane with a gradient of 0-60%
to give methyl
6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-
-3-yl]-2-vinylbenzoate (2.84 g) as a gum.
[0362] .sup.1H NMR (CDCl.sub.3) .delta.: 7.62 (1H, s), 7.42 (1H,
d), 7.19 (1H, d), 6.53 (1H, dd), 6.24 (1H, s), 5.25 (2H, m), 4.85
(1H, d), 3.98 (1H, d), 3.81 (3H, s), 3.29 (1H, t), 2.46 (1H, m),
2.00 (1H, d), 1.78 (1H, d), 1.73-1.57 (1H, m), 1.46 (2H, m), 1.43
(18H, m).
Intermediate 11
Methyl
6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-p-
yrazol-3-yl]-2-trifluoromethanesulfonyloxybenzoate
##STR00026##
[0364] A mixture of methyl
6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxy-3-[2-(tetrahydropyran-2-yl)--
2H-pyrazol-3-yl]-benzoate (Intermediate 12, 4.84 g),
N,N-bis-(trifluoromethanesulfonyl)aniline (4.53 g), triethylamine
(2.5 mL) and DMAP (0.1 g) in DCM (200 mL) was stirred at room
temperature overnight. The resultant mixture was concentrated in
vacuo and the residue was purified by chromatography on silica,
eluting with a mixture of ethyl acetate and cyclohexane with a
gradient of 0-70%. The resultant gum was dissolved in the minimum
amount of ether and sonicated. It was then diluted with heptane and
the resultant solid was collected by filtration to give methyl
6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-
-3-yl]-2-trifluoromethanesulfonyloxybenzoate (4.35 g) as a white
solid.
[0365] .sup.1H NMR (CDCl.sub.3) .delta.: 7.76 (1H, d), 7.68 (1H,
s), 7.36 (1H, d), 6.50 (1H, d), 4.96 (1H, d), 4.09 (1H, d), 3.93
(3H, s), 3.45 (1H, t), 2.54 (1H, m), 2.08 (1H, d), 1.88 (1H, d),
1.74 (1H, m), 1.53 (2H, m), 1.43 (18H, s).
Intermediate 12
Methyl
6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxy-3-[2-(tetrahydropyran--
2-yl)-2H-pyrazol-3-yl]-benzoate
##STR00027##
[0367] A mixture of methyl
3-bromo-6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxy benzoate
(Intermediate 13, 5.0 g),
1-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
-1H-pyrazole (3.9 g), tris-(dibenzylideneacetone)dipalladium (0)
(0.51 g), tri-tert-butylphosphonium tetrafluoroborate (0.33 g) and
cesium carbonate (11.0 g) in dioxane (150 mL) and water (20 mL) was
degassed and purged with nitrogen. The resultant mixture was then
heated to 65.degree. C. for 1 hour. After cooling, the mixture was
filtered through Celite and washed with ethyl acetate. The filtrate
was concentrated in vacuo and the residue was purified by
chromatography on silica, eluting with a mixture of ethyl acetate
and cyclohexane with a gradient of 0-70% to give methyl
6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxy-3-[2-(tetrahydropyran-2-yl)--
2H-pyrazol-3-yl]-benzoate (4.84 g) as a gum.
[0368] .sup.1H NMR (CDCl.sub.3) .delta.: 11.64 (1H, s), 7.66 (1H,
s), 7.56 (1H, s), 6.81 (1H, d), 6.37 (1H, d), 5.07 (1H, d), 4.01
(1H, d), 3.96 (3H, s), 3.40 (1H, t), 2.50 (1H, m), 2.04 (1H, d),
1.97 (1H, d), 1.70 (2H, m), 1.51 (1H, m), 1.42 (18H, s).
Intermediate 13
Methyl 3-bromo-6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxy
benzoate
##STR00028##
[0370] Methyl
3-bromo-6-bis-(tert-butoxycarbonyl)amino-2-(4-methylbenzenesulfonyl-oxy)b-
enzoate (Intermediate 14, 6.2 g) was dissolved in methanol (200 mL)
and 1M aqueous sodium hydroxide solution (50 mL) was added. The
reaction mixture was stirred at room temperature for 30 minutes
then the methanol was removed in vacuo and the residue was diluted
with a mixture of ethyl acetate and water and then acidified with
acetic acid. The layers were separated and the organic phase was
dried (Na.sub.2SO.sub.4) and filtered. The filtrate was
concentrated in vacuo to give methyl
3-bromo-6-bis-(tert-butoxycarbonyl)amino-2-hydroxybenzoate (4.51 g)
as a sandy coloured solid.
[0371] .sup.1H NMR (CDCl.sub.3) .delta.: 11.88 (1H, s), 7.71 (1H,
d), 6.64 (1H, d), 3.96 (3H, s), 1.39 (18H, s).
Intermediate 14
Methyl
3-bromo-6-bis-(tert-butoxycarbonyl)amino-2-(4-methylbenzenesulfonyl-
oxy)benzoate
##STR00029##
[0373] Methyl 6-amino-3-bromo-2-hydroxybenzoate (prepared according
to Wang et al, Bioorg Med Chem Lett. 2007, 17, 2817; 19.88 g) was
dissolved in DCM (390 mL) and triethylamine (17.96 g), DMAP (9.86
g) and 4-methylbenzenesulfonyl chloride (15.43 g) were added. The
mixture was stirred at room temperature for 4 hours then washed
with water, dried (MgSO.sub.4) and filtered. The filtrate was
concentrated in vacuo to give a yellow gum. This was dissolved in
acetonitrile (390 mL) and DMAP (9.86 g) and di-tert-butyl
dicarbonate (37.2 g) were added and the resultant mixture was
stirred at room temperature overnight. Further di-tert-butyl
dicarbonate (14.5 g) was added and the mixture was stirred at room
temperature for an additional 1 hour. The mixture was concentrated
in vacuo and the residue was dissolved in ethyl acetate and washed
with aqueous citric acid (10%), aqueous sodium bicarbonate solution
and brine, dried (MgSO.sub.4) and filtered. The filtrate was
concentrated in vacuo and the residue was triturated with a mixture
of ether and cyclohexane (4:1, 100 mL) and the solid was removed by
filtration. The filtrate was concentrated in vacuo and the residue
was purified by chromatography on silica, eluting with a mixture of
ethyl acetate and cyclohexane with a gradient of 0-60% to give
methyl
3-bromo-6-bis-(tert-butoxycarbonyl)amino-2-(4-methylbenzenesulfonyloxy)be-
nzoate (43.37 g) as a pale yellow powder.
[0374] .sup.1H NMR (CDCl.sub.3) .delta.: 7.78 (2H, d), 7.62 (1H,
d), 7.33 (2H, d), 7.02 (1H, d), 3.81 (3H, s), 2.47 (3H, s), 1.39
(18H, s).
Intermediate 15
Methyl
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]--
4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate
##STR00030##
[0376] A mixture of methyl
7-(2-bromo-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]ox-
azine-6-carboxylate (Intermediate 16, 0.107 g) and
N,N-diethyl-N--((Z)-1-tributylstannanylprop-1-en-3-yl)-amine
(Intermediate 3, 0.179 g) in dioxane (3 mL) and DMSO (0.3 mL) was
degassed and purged with nitrogen.
Tris-(dibenzylideneacetone)dipalladium (0) (0.01 g) and
tri-tert-butylphosphonium tetrafluoroborate (0.006 g) were added
and the mixture was degassed and purged with nitrogen again, then
the mixture was heated to 95.degree. C. for 1 hour. After cooling,
the mixture was partitioned between ethyl acetate and water. The
aqueous layer was extracted with more ethyl acetate and the
combined organic layers were dried (MgSO.sub.4) and filtered. The
filtrate was concentrated in vacuo and the residue was purified by
chromatography on silica, eluting with a mixture of methanol and
DCM with a gradient of 0-5% to give methyl
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-ben-
zo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.074 g) as a sticky
yellow oil.
[0377] .sup.1H NMR (CDCl.sub.3) .delta.: 8.05 (1H, dd), 7.32 (1H,
d), 7.12-7.02 (4H, m), 6.97 (1H, d), 6.32 (1H, t), 6.09-6.03 (2H,
m), 5.13 (2H, s), 3.88 (3H, s), 3.19 (2H, br, d), 2.58 (4H, br, q),
0.97 (6H, t).
Intermediate 16
Methyl
7-(2-bromo-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][-
1,4]oxazine-6-carboxylate
##STR00031##
[0379] Methyl
7-amino-3a,4-dihydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate
(Intermediate 17, 0.370 g) was suspended in a mixture of DCM (6 mL)
and pyridine (2.43 mL) and 2-bromo-4-fluorobenzenesulfonyl chloride
(0.493 g) was added. The resultant deep red solution was stirred at
room temperature overnight then concentrated in vacuo. The residue
was diluted with DCM and water and passed through a phase
separator. The organic layer was concentrated in vacuo and the
residue was purified by chromatography on silica, eluting with a
mixture of ethyl acetate and cyclohexane with a gradient of 5-30%
to give methyl
7-(2-bromo-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]ox-
azine-6-carboxylate (0.107 g) as a white solid.
[0380] .sup.1H NMR (CDCl.sub.3) .delta.: 9.33 (1H, s), 8.15 (1H,
dd), 7.43 (1H, dd), 7.32 (1H, d), 7.24 (1H, d), 7.12 (1H, ddd),
7.04 (1H, dd), 6.32 (1H, t), 6.04 (1H, m), 5.14 (2H, d), 3.94 (3H,
s).
Intermediate 17
Methyl
7-amino-3a,4-dihydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carbox-
ylate
##STR00032##
[0382] A mixture of methyl
6-amino-3-bromo-2-(2,5-dihydro-1H-pyrrol-2-ylmethoxy)-benzoate
(Intermediate 18, 1.64 g), copper (I) iodide (0.095 g), L-proline
(0.115 g) and potassium phosphate tribasic (2.13 g) in anhydrous
DMSO (10 mL) was evacuated and purged with nitrogen then heated to
90.degree. C., under an atmosphere of nitrogen overnight. The
resultant mixture was cooled and partitioned between ethyl acetate
and water. The layers were separated and the aqueous layer was
extracted with more ethyl acetate. The combined organic layers were
dried (MgSO.sub.4) and filtered. The filtrate was concentrated in
vacuo and the residue was purified by chromatography on silica,
eluting with a mixture of ethyl acetate and cyclohexane with a
gradient of 10-30% to give methyl
7-amino-3a,4-dihydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate
(0.370 g) as a brown oil.
[0383] LCMS (Method A) r/t 2.19 (M+H) 247.
Intermediate 18
Methyl
6-amino-3-bromo-2-(2,5-dihydro-1H-pyrrol-2-ylmethoxy)-benzoate
##STR00033##
[0385] TFA (5 mL) was slowly added to a suspension of tert-butyl
2-(6-bromo-3-[bis-(tert-butoxycarbonyl)amino]-2-methoxycarbonylphenoxymet-
hyl)-2, 5-dihydropyrrole-1-carboxylate (Intermediate 19, 3.55 g) in
DCM (5 mL). The resultant dark solution was stirred at room
temperature for 3 hours. The volatiles were removed in vacuo and
the residue was partitioned between ethyl acetate and saturated
aqueous potassium carbonate solution. The layers were separated and
the aqueous layer was extracted with more ethyl acetate. The
combined organic layers were dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to give methyl
6-amino-3-bromo-2-(2,5-dihydro-1H-pyrrol-2-ylmethoxy)-benzoate
(0.64 g) as a dark oil.
[0386] LCMS (Method A) r/t 1.95 (M+H) 327 and 329
Intermediate 19
tert-Butyl
2-(6-bromo-3-[bis-(tert-butoxycarbonyl)amino]-2-methoxycarbonyl-
phenoxymethyl)-2,5-dihydropyrrole-1-carboxylate
##STR00034##
[0388] Diisopropylazodicarboxylate (1.4 g) was added to a
suspension of methyl
3-bromo-6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxybenzoate
(Intermediate 13, 2.58 g), tert-butyl
2-hydroxymethyl-2,5-dihydropyrrole-1-carboxylate (Prepared
according to Morriello et al, Bioorg. Med. Chem, 2008, 16(5), 2156;
1.27 g) and triphenylphosphine (1.82 g) in anhydrous THF (20 mL)
and the mixture was stirred at room temperature overnight. The
volatiles were removed in vacuo and the residue was purified by
chromatography on silica, eluting with a mixture of ethyl acetate
and cyclohexane with a gradient of 5-25% to give tert-butyl
2-(6-bromo-3-[bis-(tert-butoxycarbonyl)amino]-2-methoxycarbonylphenoxymet-
hyl)-2,5-dihydropyrrole-1-carboxylate (4.13 g) as a light brown
oil.
[0389] .sup.1H NMR (CDCl.sub.3) .delta.: 7.60 (1H, t), 6.85 (1H,
m), 5.91 (2H, m), 4.81 (1H, d), 4.38-4.21 (2H, m), 3.85 (3H, d),
3.76 (1H, m), 1.86 (1H, m), 1.49 (9H, s), 1.38 (18H, m).
Intermediate 20
Methyl
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]--
5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate
##STR00035##
[0391] A mixture of methyl
8-(2-bromo-4-fluorobenzenesulfonylamino)-5,6-dihydropyrazolo[5,1-a]isoqui-
noline-7-carboxylate (Intermediate 21, 0.088 g),
N,N-diethyl-N--((Z)-1-tributylstannanylprop-1-en-3-yl)-amine
(Intermediate 3, 0.222 g), tris-(dibenzylideneacetone)dipalladium
(0) (0.020 g) and tri-tert-butylphosphonium tetrafluoroborate (0.01
g) in dioxane (3 mL) was de-gassed and purged with nitrogen and
then heated to 80.degree. C., in a sealed vessel for 2 hours. The
resultant mixture was cooled, filtered through Celite and washed
with ethyl acetate. The filtrate was concentrated in vacuo and the
residue was purified by chromatography on silica, eluting with a
mixture of methanol and DCM with a gradient of 0-10% to give methyl
8-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-5,6-di-
hydropyrazolo[5,1-a]isoquinoline-7-carboxylate (0.057 g) as a
glass.
[0392] .sup.1H NMR (CDCl.sub.3) .delta.: 8.11 (1H, dd), 7.51 (2H,
m), 7.31 (1H, d), 7.13-7.07 (2H, m), 6.99 (1H, d), 6.47 (1H, d),
6.10 (1H, dt), 4.27 (21-1H, t), 3.96 (3H, s), 3.29 (2H, t), 3.10
(2H, d), 2.52 (41-1 q), 0.94 (6H, t).
Intermediate 21
Methyl
8-(2-bromo-4-fluorobenzenesulfonylamino)-5,6-dihydropyrazolo[5,1-a]-
isoquinoline-7-carboxylate
##STR00036##
[0394] A mixture of methyl
8-amino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate
(Intermediate 22, 0.060 g) and 2-bromo-4-fluorobenzenesulfonyl
chloride (0.081 g) in pyridine (2 mL) and DCM (4 mL) was stirred at
room temperature overnight. A further amount of
2-bromo-4-fluoro-benzenesulfonyl chloride (0.010 g) was added and
the reaction mixture was stirred at room temperature for 2 hours.
The resultant mixture was concentrated in vacuo and the residue was
dissolved in DCM and washed with 1M hydrochloric acid, dried
(MgSO.sub.4) and filtered. The filtrate was concentrated in vacuo
and the residue was purified by chromatography on silica, eluting
with a mixture of ethyl acetate and cyclohexane with a gradient of
0-100% to give methyl
8-(2-bromo-4-fluorobenzenesulfonylamino)-5,6-dihydropyrazolo[5,1-a]isoqui-
noline-7-carboxylate (0.088 g) as a glass.
[0395] .sup.1H NMR (CDCl.sub.3) .delta.: 9.31 (1H, br, s), 8.19
(1H, dd), 7.51 (3H, m), 7.43 (1H, dd), 7.14 (1H, ddd), 6.46 (1H,
d), 4.26 (2H, t), 3.99 (3H, s), 3.28 (2H, t).
Intermediate 22
Methyl
8-amino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate
##STR00037##
[0397] TFA (1 mL) was added to a mixture of methyl
8-[bis-(tert-butoxycarbonyl)amino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-
-7-carboxylate and methyl
8-tert-butoxycarbonylamino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carbo-
xylate (Intermediate 23, 0.114 g) in DCM (2 mL) and the resultant
mixture was stirred at room temperature for 1 hour. Saturated
aqueous sodium bicarbonate solution was added and the mixture was
stirred for 15 minutes, then extracted with DCM, dried (MgSO.sub.4)
and filtered. The filtrate was concentrated in vacuo to give methyl
8-amino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylate (0.060
g) as a gum.
[0398] .sup.1H NMR (CDCl.sub.3) .delta.: 7.48 (1H, d), 7.41 (1H,
d), 6.64 (1H, d), 6.37 (1H, d), 5.16 (2H, br, s), 4.24 (2H, t),
3.93 (3H, s), 3.34 (2H, t).
Intermediate 23
Mixture of methyl
8-[bis-(tert-butoxycarbonyl)amino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-
-7-carboxylate and methyl
8-tert-butoxycarbonylamino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carbo-
xylate
##STR00038##
[0400] A solution of methyl
8-[bis-(tert-butoxycarbonyl)amino]-pyrazolo[5,1-a]isoquinoline-7-carboxyl-
ate (Intermediate 7, 0.36 g) in dioxane was passed through the
H-Cube, using a 20% palladium hydroxide on carbon cartridge,
eluting at 0.5 mL/minute, at 100.degree. C. and 100 bar. Two
fractions were isolated. The first fraction was concentrated in
vacuo to give methyl
8-[bis-(tert-butoxycarbonyl)amino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-
-7-carboxylate (0.044 g). The second fraction, containing the
starting material was concentrated in vacuo then dissolved in a
mixture of acetic acid in dioxane solution (20%, 40 mL) and was
passed through the H-Cube.RTM., using a 20% palladium hydroxide on
carbon cartridge, eluting at 1 mL/minute, at 95.degree. C. and 100
bar. The eluent was concentrated in vacuo and the residue purified
by chromatography on silica, eluting with a mixture of ethyl
acetate and cyclohexane with a gradient of 0-80% to give a solid
which was combined with the earlier product to give a 3:7 mixture
of methyl
8-[bis-(tert-butoxycarbonyl)amino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-
-7-carboxylate and methyl
8-tert-butoxycarbonylamino-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carbo-
xylate (0.084 g).
[0401] .sup.1H NMR (CDCl.sub.3) .delta.: 7.63 (1H, d), 7.56 (1H,
d), 7.16 (1H, d), 6.59 (1H, d), 4.36 (2H, t), 3.90 (3H, s), 3.32
(2H, t), 1.41 (18H, s) (30%).
[0402] .delta.: 8.19 (1H, d), 7.62 (1H, d), 7.53 (1H, d), 6.51 (1H,
d), 4.30 (2H, t), 4.00 (3H, s), 3.32 (2H, t), 1.54 (9H, s)
(70%).
Intermediate 24
Methyl
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]--
4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate
##STR00039##
[0404] A mixture of methyl
7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-5-oxa-3,9b-diazacyclopenta[a]-
naphthalene-6-carboxylate (Intermediate 25, 0.598 g),
N,N-diethyl-N--((Z)-1-tributylstannanylprop-1-en-3-yl)-amine
(Intermediate 3, 0.997 g), tris-(dibenzylideneacetone)dipalladium
(0) (0.057 g) and tri-tert-butylphosphonium tetrafluoroborate
(0.036 g) in dioxane (15 mL) and DMSO (1.5 mL) was de-gassed and
purged with nitrogen then heated to 95.degree. C. under an
atmosphere of nitrogen for 2 hours. Further amounts of
tris-(dibenzylideneacetone)dipalladium (0) (0.057 g) and
tri-tert-butylphosphonium tetrafluoroborate (0.036 g) were added
and the mixture stirred and heated at 95.degree. C. for 2 hours.
Further amounts of
N,N-diethyl-N--((Z)-1-tributylstannanylprop-1-en-3-yl)-amine
(Intermediate 3, 0.997 g), tris-(dibenzylideneacetone)dipalladium
(0) (0.057 g) and tri-tert-butylphosphonium tetrafluoroborate
(0.036 g) were added and the mixture was stirred and heated at
95.degree. C. for 30 minutes. After cooling, the mixture was
diluted with ethyl acetate and washed with water, dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was concentrated in
vacuo and the residue was purified by chromatography on silica,
eluting with a mixture of methanol and DCM with a gradient of 0-30%
to give methyl
7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-5-o-
xa-3,9b-diaza-cyclopenta[a]naphthalene-6-carboxylate (0.158 g) as a
light brown foam.
[0405] .sup.1H NMR (CDCl.sub.3) .delta.: 8.10 (1H, dd), 7.27 (1H,
d), 7.25 (1H, d), 7.17 (1H, d), 7.16-7.06 (3H, m), 6.97 (1H, d),
6.06 (1H, dt), 5.28 (2H, s), 3.93 (3H, s), 3.04 (2H, d), 2.45 (4H,
q), 0.91 (6H, t).
Intermediate 25
Methyl
7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-5-oxa-3,9b-diazacyclope-
nta[a]naphthalene-6-carboxylate
##STR00040##
[0407] A mixture of methyl
7-amino-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate
(Intermediate 26, 0.379 g) and 2-bromo-4-fluorobenzenesulfonyl
chloride (0.466 g) in pyridine (10 mL) and DCM (10 mL) was stirred
at room temperature for 17 hours. A further amount of
2-bromo-4-fluorobenzenesulfonyl chloride (0.190 g) was added and
the mixture was stirred at room temperature for 5 hours. The
resultant mixture was concentrated in vacuo and the residue was
dissolved in DCM and water and passed through a phase separator.
The filtrate was concentrated in vacuo and the residue was purified
by chromatography on silica, eluting with ethyl acetate to give a
white solid which was triturated with ether to give methyl
7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-5-oxa-3,9b-diazacyclopenta[a]-
naphthalene-6-carboxylate (0.603 g) as an off-white solid.
[0408] .sup.1H NMR (CDCl.sub.3) .delta.: 9.57 (1H, br, s), 8.18
(1H, dd), 7.44 (1H, dd), 7.33-7.25 (3H, m), 7.18-7.11 (2H, m), 5.29
(2H, s), 3.97 (3H, s).
Intermediate 26
Methyl
7-amino-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate
##STR00041##
[0410] A solution of methyl
7-amino-3-(2,2-dimethoxyethylamino)-2H-benzo[1,4]oxazine-8-carboxylate
(Intermediate 27, 0.910 g) in concentrated aqueous hydrochloric
acid (8 mL) and methanol (10 mL) was heated to reflux for 3 hours.
After cooling, the mixture was concentrated in vacuo and the
residue was dissolved in a mixture of ethyl acetate and water and
basified with 2M aqueous sodium hydroxide solution. The layers were
separated and the aqueous layer was extracted several times with
ethyl acetate. The combined organic layers were dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was concentrated in
vacuo and the residue was purified by chromatography on silica,
eluting with a mixture of ethyl acetate and cyclohexane with a
gradient of 50-100% and then a mixture of methanol and ethyl
acetate (5%) to give methyl
7-amino-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate
(0.383 g) as a sandy coloured solid.
[0411] .sup.1H NMR (DMSO-d.sub.6) .delta.: 7.76 (1H, d), 7.52 (1H,
d), 7.06 (1H, d), 6.50 (1H, d), 5.94 (2H, br. s), 5.23 (2H, s),
3.81 (3H, s).
Intermediate 27
Methyl
7-amino-3-(2,2-dimethoxyethylamino)-2H-benzo[1,4]oxazine-8-carboxyl-
ate
##STR00042##
[0413] A solution of methyl
7-amino-3-methylsulfanyl-2H-benzo[1,4]oxazine-8-carboxylate
(Intermediate 28, 0.645 g) and aminoacetaldehyde dimethylacetal
(0.403 g) in ethanol (15 mL) was heated to reflux for 4 days. After
cooling, the mixture was concentrated in vacuo to give methyl
7-amino-3-(2,2-dimethoxyethylamino)-2H-benzo[1,4]oxazine-8-carboxylate
(0.910 g) as a brown oil.
[0414] LCMS (Method A) r/t 1.82 (M+H) 310
Intermediate 28
Methyl
7-amino-3-methylsulfanyl-2H-benzo[1,4]oxazine-8-carboxylate
##STR00043##
[0416] A mixture of methyl
7-amino-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylate
(Intermediate 29, 0.795 g), methyl iodide (0.710 g) and potassium
carbonate (1.38 g) in acetone (20 mL) was stirred at room
temperature for 2 hours. The resultant mixture was filtered and the
filtrate was concentrated in vacuo. The residue was purified by
chromatography on silica, eluting with a mixture of ethyl acetate
and cyclohexane with a gradient of 5-25% to give methyl
7-amino-3-methylsulfanyl-2H-benzo[1,4]oxazine-8-carboxylate (0.648
g) as a sandy coloured solid.
[0417] LCMS (Method A) r/t 3.26 (M+H) 253
Intermediate 29
Methyl
7-amino-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylate
##STR00044##
[0419] A mixture of methyl
7-amino-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylate
(Intermediate 30, 1.187 g) and Lawesson's reagent (1.08 g) in
anhydrous THF (20 mL) was heated to 60.degree. C., under an
atmosphere of nitrogen for 40 minutes. After cooling, the mixture
was diluted with cyclohexane and purified by chromatography on
silica, eluting with a mixture of ethyl acetate and cyclohexane
with a gradient of 10-50%. The resultant material was triturated
with ether to give a yellow solid (0.795 g). The filtrate from the
trituration was concentrated in vacuo and the residue was
re-purified by chromatography on silica, eluting with a mixture of
ethyl acetate and cyclohexane with a gradient of 10-50%. The
resultant material was triturated with ether to give a further
amount of a yellow solid (0.051 g). The two batches of yellow solid
were combined to give methyl
7-amino-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylate
(0.846 g).
[0420] .sup.1H NMR (DMSO-d.sub.6) .delta.: 12.52 (1H, br, s), 6.96
(1H, d), 6.39 (1H, d), 6.06 (2H, br, s), 4.72 (2H, s), 3.78 (3H,
s).
Intermediate 30
Methyl
7-amino-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylate
##STR00045##
[0422] A mixture of methyl
6-amino-3-bromo-2-carbamoylmethoxybenzoate (Intermediate 31, 5.64
g), N,N'-dimethylethylenediamine (1.64 g), copper (I) iodide (3.55
g) and potassium carbonate (5.13 g) in N-methylpyrrolidone (50 mL)
was heated to 140.degree. C., under an atmosphere of nitrogen for 1
hour. After cooling, the mixture was diluted with ethanol (400 mL)
and filtered through Celite. The filtrate was concentrated in vacuo
and the residue was dissolved in ethyl acetate and water and
filtered through Celite again. The layers were separated and the
aqueous layer was extracted with ethyl acetate (ten times). The
combined organic layers were washed with water, dried
(Na.sub.2SO.sub.4) and filtered. The filtrate was concentrated in
vacuo and the residue was triturated with ether to give an
orange/brown solid (1.10 g). The filtrate from the trituration was
concentrated in vacuo and the residue was purified by
chromatography on silica, eluting with a mixture of ethyl acetate
and cyclohexane with a gradient of 30-100%. The product obtained
was triturated with diethyl ether to give a pale yellow solid (0.28
g). The two batches of solid were combined to give methyl
7-amino-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylate (1.38
g).
[0423] .sup.1H NMR (DMSO-d.sub.6) .delta.: 10.36 (1H, br, s), 6.76
(1H, d), 6.36 (1H, d), 5.68 (2H, br. s), 4.47 (2H, s), 3.77 (3H,
s).
Intermediate 31
Methyl 6-amino-3-bromo-2-carbamoylmethoxybenzoate
##STR00046##
[0425] A mixture of methyl 6-amino-3-bromo-2-hydroxybenzoate
(prepared according to Wang et al, Bioorg Med Chem Lett. 2007, 17,
2817, 7.55 g), bromoacetamide (4.55 g) and potassium carbonate
(10.0 g) in DMF (70 mL) was heated to 60.degree. C. for 17 hours.
After cooling, the mixture was concentrated in vacuo and the
residue was dissolved in ethyl acetate and water and the layers
were separated. The aqueous layer was extracted with ethyl acetate
and the combined organic layers were dried (Na.sub.2SO.sub.4) and
filtered. The filtrate was concentrated in vacuo to give an orange
solid which was triturated with ether to give methyl
6-amino-3-bromo-2-carbamoylmethoxybenzoate (5.81 g) as a sandy
coloured solid.
[0426] .sup.1H NMR (CDCl.sub.3) .delta.: 7.36 (1H, d), 6.43 (1H,
d), 5.36 (2H, br, s), 4.49 (2H, s), 3.90 (3H, s).
Biological Example
[0427] Compounds are tested for their capacity to inhibit
recombinant human MetAP2 activity using the following assay.
[0428] Human recombinant MetAP2 expressed in Sf9 cells followed by
affinity purification and EDTA treatment to remove endogenous
active site cation was dialysed against MnCl.sub.2 to produce the
manganese enzyme used in the assay. The assay was carried out for
30 minutes at 25.degree. C., in 50 mM HEPES buffer containing 100
mM NaCl, pH 7.5 the presence of 0.75 mM Methionine-Alanine-Serine
(MAS) substrate and 50 .mu.g/ml amino acid oxidase using a dilution
of purified MetAP2 giving>3-fold signal:noise. Cleavage of the
substrate by MetAP2 and oxidation of free methionine by amino acid
oxidase was detected and quantified using fluorescence generated by
Amplex red (10-acetyl-3,7-dihydroxyphenoxazine) in combination with
horseradish peroxidase which detects H.sub.2O.sub.2 released during
the oxidation step. The fluorescent signal was detected using a
multiwell fluorimeter. Compounds were diluted in DMSO prior to
addition to assay buffer, the final DMSO concentration in the assay
being 1%.
[0429] The IC.sub.50 is defined as the concentration at which a
given compound achieves 50% inhibition of control. IC.sub.50 values
are calculated using the XLfit software package (version
2.0.5).
[0430] Compounds of the invention demonstrated activity in the
assay of this Example as indicated in the following table, wherein
A represents IC.sub.50<0.05 .mu.M, B represents IC.sub.50
between 0.05 .mu.M and 0.5 .mu.M, and C represents IC.sub.50>0.5
.mu.M.
TABLE-US-00001 Compound name Activity
8-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl- A
amino]-pyrazolo[5,1-a]isoquinoline-7-carboxylic acid
7-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl- A
amino]-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylic acid
8-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl- B
amino]-5,6-dihydropyrazolo[5,1-a]isoquinoline-7-carboxylic acid
7-[2-((Z)-3-Diethylaminoprop-1-enyl)-4-fluorobenzenesulfonyl- A
amino]-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6- carboxylic
acid
INCORPORATION BY REFERENCE
[0431] All publications and patents mentioned herein, including
those items listed below, are hereby incorporated by reference in
their entirety for all purposes as if each individual publication
or patent was specifically and individually incorporated by
reference. In case of conflict, the present application, including
any definitions herein, will control.
EQUIVALENTS
[0432] While specific embodiments of the subject invention have
been discussed, the above specification is illustrative and not
restrictive. Many variations of the invention will become apparent
to those skilled in the art upon review of this specification. The
full scope of the invention should be determined by reference to
the claims, along with their full scope of equivalents, and the
specification, along with such variations.
[0433] Unless otherwise indicated, all numbers expressing
quantities of ingredients, reaction conditions, and so forth used
in the specification and claims are to be understood as being
modified in all instances by the term "about." Accordingly, unless
indicated to the contrary, the numerical parameters set forth in
this specification and attached claims are approximations that may
vary depending upon the desired properties sought to be obtained by
the present invention.
* * * * *